A Phase III Randomized Trial of Blinatumomab for Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia in Adults
Phase: PHASE3
Conditions: Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative
Sponsor: National Cancer Institute (NCI)

E1910 
 
1 
This is an FDA Registration Trial 
A Phase III Randomized Trial of Blinatumomab for Newly 
Diagnosed BCR-ABL-negative B lineage Acute 
Lymphoblastic Leukemia in Adults 
STUDY CHAIR: Mark R. Litzow, MD 
STUDY CO-CHAIR: Ryan J. Mattison, MD 
STUDY STATISTICIAN: Zhuoxin Sun, PhD 
ALLIANCE CO-CHAIR: Matthew J. Wieduwilt, M.D., Ph.D. 
SWOG CO-CHAIR Michaela Liedtke, M.D. 
CCTG CO-CHAIR: Julie Bergeron, M.D. 
BMT CO-CHAIR: Hillard M. Lazarus, MD 
LABORATORY CO-CHAIRS: Elisabeth Paietta, Ph.D. 
Charles Mullighan, MD 
Cheryl Willman, MD 
LEUKEMIA COMMITTEE CHAIR: Martin S. Tallman, MD 
PATHOLOGY CO-CHAIR: Daniel Arber, M.D. 
CYTOGENETICS CO-CHAIR: Yanming Zhang, M.D. 
Version Date:  January 20, 2023 
NCI Update Date: August 14, 2014 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in Oncology  
December 17, 2013 
NRG / NRG Oncology Foundation, Inc 
 
Addendum #1 – 3/14 
Addendum #11 – 9/17 
SWOG / SWOG 
 
Addendum #2 – 7/14 
Addendum #12 – 2/18 
CCTG / Canadian Cancer Trials Group 
 
Update #1 – 8/14 
Addendum #13 
 
 
 
Addendum #3 – 3/15 
Addendum #14 
 
 
 
Addendum #4 – 4/15 
Addendum #15 
 
 
 
Addendum #5 – 6/15 
Addendum #16 
 
 
 
Addendum #6 – 6/16 
Addendum #17 
 
 
 
Addendum #7 – 1/17 
Addendum #18 
 
 
 
Addendum #8 – 1/17 
 
 
 
 
Addendum #9 – 8/17 
 
 
 
 
Addendum #10 - 8/17 
 
 
Agent 
IND 
NSC 
Supply 
Blinatumomab  
IND Sponsor DCTD, NCI IND#  
765986 
NCI 
IV Solution Stabilizer for 
blinatumomab 
 
773150 
NCI 
 
Rev. 7/14 
Rev. 7/14 
Rev. 3/15 
Rev. Add14 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
2 
Table of Contents 
Schema ...................................................................................................................... 7 
Schema ...................................................................................................................... 8 
 Schema ..................................................................................................................... 9 
 Schema ................................................................................................................... 10 
1. Introduction ...................................................................................................... 11 
1.1 
Background: ............................................................................................ 11 
1.2 
Minimal Residual Disease (MRD) Testing ............................................... 14 
1.3 
Monoclonal Antibody Therapy of Adult ALL ........................................... 15 
1.4 
Blinatumomab Dosing: Pharmacokinetic justification for fixed dosing 
versus dosing based on body surface area ............................................. 18 
1.5 
Summary ................................................................................................. 20 
2. Objectives ......................................................................................................... 22 
2.1 
Primary Objectives .................................................................................. 22 
2.2 
Secondary Objectives .............................................................................. 22 
2.3 
Laboratory Objectives ............................................................................. 22 
3. Selection of Patients ......................................................................................... 23 
3.1 
Pre-Registration ...................................................................................... 23 
3.2 
Induction Eligibility Criteria – Step 1 ....................................................... 24 
3.3 
Post-Induction Therapy Eligibility Criteria (prior to Intensification – Step 
2) ............................................................................................................. 26 
3.4 
Randomization or Assignment to Blinatumomab or No Blinatumomab – 
Step 3 ...................................................................................................... 27 
3.5 
Criteria for Allogeneic Transplantation ................................................... 27 
3.6 
Criteria for Maintenance Therapy – Step 4 ............................................. 28 
4. Registration Procedures .................................................................................... 29 
4.1 
Pre-Registration ...................................................................................... 32 
4.2 
Registration to Induction Arm A - Step 1 ................................................ 34 
4.3 
Register to Post-Induction Therapy - Intensification - Step 2- Arm B ..... 36 
4.4 
Randomization or Assignment to Blinatumomab or No Blinatumomab 
Step 3 (Arms C and D) ............................................................................. 37 
4.5 
Register to Maintenance Therapy – Step 4 ............................................. 38 
5. Treatment Plan ................................................................................................. 40 
5.1 
Overall Study Design ............................................................................... 40 
5.2 
Induction Therapy - Arm A ...................................................................... 41 
5.3 
Post-Induction Therapy - Intensification Arm B (28 days) ...................... 52 
5.4 
Allogeneic SCT ......................................................................................... 67 
5.5 
Consolidation Therapy ............................................................................ 68 
5.6 
Maintenance Chemotherapy – Arm E ..................................................... 72 
5.7 
Supportive Care Considerations .............................................................. 77 
5.8 
Adverse Event Reporting Requirements ................................................. 77 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
3 
5.9 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Blinatumomab (AMG103, NSC 765986) .................................................. 89 
5.10 Duration of Therapy ................................................................................ 96 
5.11 Duration of Follow-up ............................................................................. 96 
6. Measurement of Effect ..................................................................................... 97 
6.1 
Complete Remission (CR) ........................................................................ 97 
6.2 
Complete Remission incomplete (CRi) .................................................... 97 
6.3 
Partial Remission (PR) ............................................................................. 97 
6.4 
Relapse/Persistent Disease ..................................................................... 97 
7. Study Parameters .............................................................................................. 98 
7.1 
Therapeutic Parameters .......................................................................... 98 
7.2 
Biological Sample Submissions ............................................................. 101 
8. Drug Formulation and Procurement ............................................................... 104 
8.1 
Blinatumomab ....................................................................................... 105 
8.2 
Daunorubicin ......................................................................................... 110 
8.3 
Vincristine ............................................................................................. 112 
8.4 
Dexamethasone .................................................................................... 113 
8.5 
Erwinase ................................................................................................ 114 
8.6 
Pegaspargase ........................................................................................ 116 
8.7 
Methotrexate ........................................................................................ 118 
8.8 
Cyclophosphamide ................................................................................ 121 
8.9 
Cytarabine ............................................................................................. 125 
8.10 Mercaptopurine .................................................................................... 126 
8.11 Etoposide .............................................................................................. 128 
8.12 Leucovorin Calcium ............................................................................... 130 
8.13 Prednisone ............................................................................................ 132 
8.14 Rasburicase ........................................................................................... 133 
8.15 Rituximab .............................................................................................. 135 
9. Statistical Considerations ................................................................................ 139 
9.1 
Original Design Overview and Primary Endpoint .................................. 139 
9.2 
Summary of Design Changes and Rationale ......................................... 139 
9.3 
Sample Size and Primary Objective ....................................................... 139 
9.4 
Randomization Scheme......................................................................... 140 
9.5 
Interim Analyses of Primary Endpoint .................................................. 141 
9.6 
Secondary Objectives ............................................................................ 141 
9.7 
Accrual ................................................................................................... 143 
9.8 
Gender and Ethnicity ............................................................................ 143 
9.9 
Correlative Studies ................................................................................ 143 
9.10 Study Monitoring .................................................................................. 144 
9.11 Safety Monitoring ................................................................................. 144 
10. Research Sample Submissions ........................................................................ 146 
10.1 Sample Collection and Submission Schedule ........................................ 146 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
4 
10.2 Submissions to ECOG-ACRIN Leukemia Translational Research 
Laboratory (LTRL) .................................................................................. 148 
10.3 Submissions to ECOG-ACRIN Cytogenetic Laboratory .......................... 151 
10.4 Submissions to LabConnect .................................................................. 151 
10.5 ECOG-ACRIN Sample Tracking System .................................................. 151 
10.6 Use of Specimens in Research .............................................................. 152 
10.7 Sample Inventory Submission Guidelines ............................................. 152 
10.8 Banking .................................................................................................. 152 
11. Leukemia Correlative Studies ......................................................................... 154 
11.1 Immunophenotype and Molecular Genetics ........................................ 154 
11.2 Sample Collection and Banking ............................................................. 154 
11.3 Identification and Characterization of Patients with BCR/ABL1-like 
Phenotype ............................................................................................. 162 
11.4 Determination of CD20 Expression by leukemic B-lymphoblasts at the 
time of study entry ................................................................................ 165 
11.5 Blinatumomab Immunogenicity Assessment ....................................... 166 
11.6 Future Research Studies ....................................................................... 167 
11.7 Lab Data Transfer Guidelines ................................................................ 168 
12. Electronic Data Capture .................................................................................. 169 
12.1 Records Retention ................................................................................. 169 
13. Patient Consent and Peer Judgment .............................................................. 169 
14. References ...................................................................................................... 169 
 Appendix I  Patient Thank You Letter ................................................................... 176 
Appendix II  Patient Pill Calendar .......................................................................... 177 
 Appendix III  CRADA/CTA ...................................................................................... 184 
Appendix IV  ECOG Performance Status ............................................................... 186 
 Appendix V  Instructions for Reporting Pregnancies on a Clinical Trial ............... 187 
 Appendix VI  Writing Sample Page ....................................................................... 189 
 Appendix VII  Clinical Site Management of Out-patient Treatment Using CTEP-
supplied Blinatumomab .................................................................................. 190 
 Appendix VIII  Shipment of blinatumomab IV Bag from Site/Pharmacy to Patient’s 
Home ............................................................................................................... 194 
 Appendix IX  Mercaptopurine Dosing Guidelines ................................................. 195 
 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
5 
 
STUDY CHAIR 
STUDY CHAIR LIAISON (SCL) 
Mark R. Litzow, MD 
Division of Hematology 
Mayo Clinic 
200 First Street, S.W. 
Rochester, MN  55905-5905 
Phone: (507) 284-6921 
Fax: (507) 266-4972 
E-mail: litzow.mark@mayo.edu 
 
Jeffrey Hirvela 
Mayo Clinic - East 10, Room Ma 10-54W 
200 First Street, S.W. 
Rochester, MN 55905 
Phone: (507) 538-4212 
Fax: (507) 284-0658 
E-mail: hirvela.jeffrey@mayo.edu  
 
STUDY CO-CHAIR 
ALLIANCE CO-CHAIR 
Ryan Mattison, MD 
University of Wisconsin School of Medicine 
and Public Health 
Division of Hematology/Oncology 
4039 WIMR 
1111 Highland Avenue, MC2275 
Madison, WI 53705 
Phone: (608) 262-5697 
Fax: (608) 262-4598 
E-mail: rjmattison@medicine.wisc.edu 
Matthew J. Wieduwilt, M.D., Ph.D. 
Division of Bone Marrow Transplantation 
University of California, San Diego  
Moores Cancer Center 
3855 Health Sciences Drive, #0960 
La Jolla, CA 92093-0960 
Phone: (858) 822-6848 
Fax: (858) 822-6844 
E-mail: mwieduwilt@ucsd.edu 
SWOG CO-CHAIR 
CCTG CO-CHAIR 
Michaela Liedtke, M.D.   
Stanford Cancer Institute  
875 Blake Wilbur Dr, Rm 2327B  
Stanford, CA 94305  
Phone: (650) 498-6000  
Fax: (650) 724-5203  
E-mail: mliedtke@stanford.edu  
 
Julie Bergeron, M.D.   
Université de Montréal 
Hématologie et oncologie 
Hôpital Maisonneuve-Rosemont 
Phone: (514) 252-3404 
Fax: (514) 254-5094  
E-mail: juliebergeron.hmr@ssss.gouv.qc.ca  
 
 
Rev. 7/14 
Rev.6/16, 
2/18 
Rev. 2/18 
Rev. Add15 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
6 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory 
tab.)  
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org  
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave. 
Please see the data 
submission section of the 
protocol for further 
instructions. 
The most current version of the study protocol and supporting and documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ websiteis managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires user log on with CTEP-
IAM username and password. 
CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment, 
Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinicaldata submission) 
contact the CTSU Help Desk by phone or e-mail: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
Rev. 7/14, 
2/18 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
7 
Schema 
NO
CR
Total Accrual: 488
Off treatment
Intensification
See
Schema ii
R
E
G
I
S
T
E
R
Arm A, Cycle 1 (28 days)
Cytarabine 70 mg IT d1
Daunorubicin 25 mg/m2 IV Push d1, 8, 
15, 22
Vincristine 1.4 mg/m2 IV d1, 8, 15, 22 
(cap each dose at 2 mg total)
Dexamethasone 10 mg/m2 PO d1-7, 15-
21 (cap at 20 mg per day; days 1-7 only 
if age > 55)
Methotrexate 12.5 mg IT d14 +/- 1 only
Pegaspargase 2000 IU/m2 IV or IM d 18 
(OMIT if age > 55) (cap dose at 1 vial or 
3750 IU)
MRD* d 28
Rituximab 375 mg/m2 IV d8, 15 if CD20 
positive (optional)
Step 1 – Induction – Arm A
*time of Minimal Residual Disease (MRD) assessment
Arm A, Cycle 2 (42 days)
Cyclophosphamide 1000 mg/m2 IV d1, 
29 (Patients > 60 years give 800 mg/m2 
per dose)
Cytarabine 75 mg/m2 IV or SC d 1-4, 8-
11, 29-32, 36-39
6 Mercaptopurine 60 mg/m2 PO d1-14, 
29-42
Pegaspargase 2000 IU/m2 IV or IM d 15 
(omit if age > 55) (cap dose at 1 vial or 
3750 IU)
Methotrexate* 12.5 mg IT d1, 8, 15, 22 
+/- 1
MRD - Assess at the time of count 
recovery.
Rituximab 375 mg/m2 IV d8, 15 if CD20 
positive (optional)
CR
or
CRi
i
P
R
E
-
R
E
G
I
S
T
R
A
T
I
O
N
Centralized 
immunophenotyping 
performed to 
determine patient 
eligibility by ECOG-
ACRIN LSTL1
1.
Bone Marrow and peripheral blood specimens must be submitted for mandatory testing for participation in this study. 
*
During a shortage of preservative-free methotrexate, institutions without a sufficient supply of preservative-free methotrexate for intrathecal use can switch to using cytarabine intrathecally. The 
suggested dose of IT cytarabine is 100 mg (or per local institutional standard) and is to be administered following the IT methotrexate schedule for the given cycle. The cytarabine can optionally 
be combined with 50 mg of hydrocortisone if desired.
Step 0
 
Rev. 7/14, 6/16, 8/17 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
8 
Schema 
1. Stratification:
· < 55 yrs. vs > 55 years
· CD20 status positive vs. negative
· rituximab use yes or no
· Intent to receive allogeneic SCT or not
2. Patients may receive up to 2 cycles of consolidation chemotherapy prior to transplant.
NOTE: Only submit bone marrow aspirates from the FIRST PULL for MRD.
3. Patients may receive up to 3 cycles of consolidation chemotherapy prior to transplant.
NOTE: Only submit bone marrow aspirates from the FIRST PULL for MRD.
* During a shortage of preservative-free methotrexate, institutions without a sufficient supply of preservative-free methotrexate for intrathecal use can switch to using cytarabine 
intrathecally. The suggested dose of IT cytarabine is 100 mg (or per local institutional standard) and is to be administered following the IT methotrexate schedule for the given cycle. 
The cytarabine can optionally be combined with 50 mg of hydrocortisone if desired.
R
A
N
D
O
M
I
Z
 E1
Intensification
1 Cycle Only (28 days)
Methotrexate 3 g/m2 IV  d1, 8 
Pegaspargase 2000 IU/m2 IV or IM d9, 1000 
IU/m2 for patients >  55 years (cap dose at 1 
vial or 3750 IU)
Leucovorin rescue 10 mg/m2 IV q 6 hours x 4 
doses beginning 22-24 hours after completion 
of MTX; then 10 mg/m2 PO q 6 hours x 72 
hours
MRD - Assess at the time of count recovery.
Step 2 – Intensification – Arm B
Arm C Blinatumomab
Cycle 1 (28 days on, 14 days off)
Blinatumomab 28 mcg/day by 
continuous infusion for 28 days
2 weeks rest
Cycle 2 (28 days)
Blinatumomab 28 mcg/day by 
continuous infusion for 28 days
Assess for MRD 2 weeks after 
completion of cycle 2
If MRD 
negative
Arm D No Blinatumomab
Patients randomized to not receive 
blinatumomab may proceed directly to 
allogeneic BMT or to consolidation 
chemotherapy.
Allogeneic BMT2
For those with a suitable donor who elect 
to proceed to BMT
Allogeneic BMT3
For those with a suitable donor who elect 
to proceed to BMT
Consolidation Cycle 1 (28 days)
Cytarabine 75 mg/m2 IV or SC d1-5
Etoposide 100 mg/m2 IV d1-5
Methotrexate* 12.5 mg IT d1 +/- 1
Pegaspargase 2000 IU/m2  IV or IM, d5, 
1000 IU/m2 if age > 55 years  (cap dose at 
1 vial or 3750 IU)
Rituximab 375 mg/m2 IV d5 if CD20 
positive (optional)
ii
R
E
G
I
S
T
E
R
Step 3 – Randomization
Consolidation Cycle 1 (28 days)
Cytarabine 75 mg/m2 IV or SC d1-5
Etoposide 100 mg/m2 IV d1-5
Methotrexate* 12.5 mg IT d1 +/- 1
Pegaspargase 2000 IU/m2  IV or IM, d5, 
1000 IU/m2 if age > 55 years (cap dose at 
1 vial or 3750 IU)
Rituximab 375 mg/m2 IV d5 if CD20 
positive (optional)
R
E
G
I
S
T
E
R
If MRD 
positive
 
Rev.7/14,3/15, 6/16, 8/17 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
9 
 
Schema 
 
 
Consolidation Cycle 2 (28 days)
Cytarabine 75 mg/m2 IV or SC d1-5
Etoposide 100 mg/m2 IV d1-5
Methotrexate* 12.5 mg IT d1 +/- 1
Rituximab 375 mg/m2 IV d5 if CD20 
positive (optional)
Consolidation Cycle 3 (42 days)
Daunorubicin 25 mg/m2 IV Push d1, 8, 15, 22
Vincristine 1.4 mg/m2 IV d1, 8, 15, 22 (cap each dose at 2 
mg total)
Dexamethasone 10 mg/m2 PO d1-7, 15-21 (cap at 20 mg/
day; days 1-7 only if age > 55)
Methotrexate* 12.5 mg IT d2 +/- 1
Cyclophosphamide 650 mg/m2 IV d29
Cytarabine 75 mg/m2 IV or SC d30-33. 37-40
6-Mercaptopurine 60 mg/m2 orally 29-42
Rituximab 375 mg/m2 IV d8 if CD20 positive (optional)
Consolidation Cycle 4 (28 days)
(for those initially randomized to 
Blinatumomab)
Blinatumomab 28 mcg per day by 
continuous infusion for 28 days
Consolidation Cycle 4: (28 days)
Cytarabine 75 mg/m2 IV or SC d1-5
Etoposide 100 mg/m2 IV d1-5
Methotrexate* 12.5 mg IT d1 +/- 1
Rituximab 375 mg/m2 IV d5 if CD20 
positive (optional)
iii
Consolidation Cycle 2 (28 days)
Cytarabine 75 mg/m2 IV or SC d1-5
Etoposide 100 mg/m2 IV d1-5
Methotrexate* 12.5 mg IT d1 +/- 1
MRD – Assess at the time of count 
recovery 
(no blinatumomab arm only)
Rituximab 375 mg/m2 IV d5 if CD20 
positive (optional)
Consolidation Cycle 3 (42 Days)
Daunorubicin 25 mg/m2 IV Push d1, 8, 15, 22
Vincristine 1.4 mg/m2 IV d1, 8, 15, 22 (cap each dose at 2 
mg total)
Dexamethasone 10 mg/m2 PO d1-7, 15-21 (cap at 20 mg/
day; days 1-7 only if age > 55)
Methotrexate* 12.5 mg IT d2 +/- 1
Cyclophosphamide 650 mg/m2 IV d29
Cytarabine 75 mg/m2 IV or SC d30-33. 37-40
6-Mercaptopurine 60 mg/m2 orally 29-42
Rituximab 375 mg/m2 IV d8 if CD20 positive (optional)
Consolidation Cycle 5: (28 days)
Cytarabine 75 mg/m2 IV or SC d1-5
Etoposide 100 mg/m2 IV d1-5
Methotrexate* 12.5 mg IT d1 +/- 1
Rituximab 375 mg/m2 IV d5 if CD20 
positive (optional)
Arm C
Arm D
* During a shortage of preservative-free methotrexate, institutions without a sufficient supply of preservative-free methotrexate for intrathecal use can switch to using 
cytarabine intrathecally. The suggested dose of IT cytarabine is 100 mg (or per local institutional standard) and is to be administered following the IT methotrexate 
schedule for the given cycle. The cytarabine can optionally be combined with 50 mg of hydrocortisone if desired.
 
Rev.6/16, 8/17 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
10 
 
Schema 
 
Consolidation Cycle 6 (28 days)
(for those initially randomized to 
Blinatumomab):
Blinatumomab 28 mcg per day by 
continuous infusion for 28 days
Maintenance Therapy
To continue for 2 ½ years from start of Intensification (Arm B)
Vincristine
1.4 mg/m2 IV d1 (one dose) every 3 months 
(maximum 2mg/dose) with Prednisone
Prednisone
60 mg/m2 PO d1-5 every 3 months
Methotrexate* 
20 mg/m2 PO or IV once per week
6-mercaptopurine
75 mg/m2 PO/day continuous
Methotrexate
12.5 mg IT d1 (+/- 3 days) every 3 months
Step 4 – Maintenance – Arm E
iv
R
E
G
I
S
T
E
R
Arm C
Arm D
* During a shortage of preservative-free methotrexate, institutions without a sufficient supply of preservative-free methotrexate for intrathecal use can switch to using 
cytarabine intrathecally. The suggested dose of IT cytarabine is 100 mg (or per local institutional standard) and is to be administered following the IT methotrexate 
schedule for the given cycle. The cytarabine can optionally be combined with 50 mg of hydrocortisone if desired.
 
Rev.6/16, 1/17, 8/17 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
11 
1. 
Introduction 
1.1 
Background: 
The treatment of children with ALL is a shining example of the success of 
combination chemotherapy in curing malignancy.  Results of recent trials suggest 
that up to 90% of children may be cured of their disease1. Adult patients with ALL 
now have a 90% chance of entering first complete remission (CR) with modern 
chemotherapy2. However, most patients still relapse, and leukemia-free survival 
with three to seven years of follow-up is only 30-40% 2. The poor outcome of 
chemotherapy in adults with ALL as compared to children relates to multiple 
factors, some of which are known but others which remain unknown.  It is known 
that older adults with ALL do not tolerate intensive courses of chemotherapy as 
well as children and pediatric protocols tend to contain much higher doses of 
selected drugs. Also adults have a higher incidence of poor prognostic subtypes 
of ALL such as BCR-ABL ALL and a lower incidence of favorable subtypes such 
as the t(12;21)subtype3,4. 
The Medical Research Council, MRC, now known as the National Cancer 
Research Institute (NCRI), in Great Britain and the ECOG-ACRIN Cancer 
Research Group (ECOG-ACRIN) in the United States have conducted the largest 
trial in adult ALL ever reported, UKALLXII/E2993,  for patients 65 years of age or 
younger. All patients received two months of intensive induction chemotherapy 
followed by one month of intensification with high-dose methotrexate and L-
asparaginase. Patients under the age of 55 with an HLA-matched sibling were 
assigned to allogeneic SCT. All other patients were randomized between 
autologous SCT and consolidation/maintenance therapy for 2.5 years. Standard 
risk patients were defined as those patients who were either less than 35 years 
of age, achieved a remission after less than four weeks of therapy, had leukocyte 
count less than 30 x 109/L for B cell type and less than 100 x 109/L for T cell type 
or lacked a BCR-ABL gene rearrangement, 11q23 abnormality, t(4;11) or t(1;19). 
All other patients were considered high risk.  An analysis of 1,913 patients was 
reported. The CR rate for the BCR-ABL negative patients was excellent at 90%. 
For the comparison between autologous SCT and chemotherapy 456 patients 
were randomized, 229 to autologous transplant and 227 to chemotherapy.  The 
two groups were well balanced for age, gender, leukocyte count at diagnosis and 
immunophenotype. Event-free survival (EFS) at five years from the time of 
diagnosis or randomization was 41% for the chemotherapy group and 32% for 
the autologous group (p=0.02). Overall survival (OS) also favored chemotherapy 
(46%) compared to autologous SCT (37%) (p=0.03) 5. 
Important analyses from the study have compared the outcome of BCR-ABL-
negative patients assigned to HLA-matched sibling SCT compared to patients 
randomized to autologous SCT or chemotherapy (donor vs. no donor). In a 
comparison of 443 patients with a donor to 588 patients without a donor, the data 
indicate that BCR-ABL-negative patients have a superior OS at five years (53% 
versus 45%, p=0.01) with allogeneic SCT compared to the no donor patients who 
were randomized to autologous SCT or chemotherapy. Of interest, this benefit 
was primarily seen in the standard risk patients (OS 62% for donor versus 52% 
for no donor patients, p=0.02), but not in high risk patients (OS 41% versus 35%, 
p=0.2).  In both high risk and standard risk BCR-ABL-negative patients a clear 

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graft-versus-leukemia (GVL) effect was seen with significantly reduced relapse 
rates in donor patients (37% high risk and 24% standard risk for donor versus 
63% high risk and 49% standard risk for no donor patients for high risk and 
standard risk patients, respectively (p value for both comparisons < 0.0005).  The 
lack of difference in outcomes between donor and no donor patients in the high 
risk group were in part related to a high non-relapse mortality of 36% at two 
years (20% at two years for the standard risk patients)5. Patients who relapsed 
from first CR had an overall survival at 5 years of only 7%. Better outcomes were 
seen in younger patients and those whose first CR duration was > 2 years, but in 
these better risk groups the overall survival was still only 11-12%6. Factors 
predicting for a poorer overall and disease-free survival were older age, white 
blood cell count over 30 x 109/L for B lineage or over 100 x 109/L for T lineage, 
and B lineage patients had a poorer outcome than T lineage.  Of interest, the 
achievement of a CR within four weeks did not appear to be an independent 
prognostic factor7 . To build on our prior experience the chemotherapy backbone 
of the trial proposed here, E1910, will be based on the UKALLXII/E2993 
chemotherapy regimen.   
A study by Pulte et al. showed that outcomes in ALL worsen with increasing 
age8, and this may, in part, be related to the fact that pediatric regimens have 
more intensive doses and schedules of chemotherapy than adult regimens. 
Adolescents and young adults are sometimes treated by pediatric hematologists 
and sometimes by adult hematologists, so it was appropriate to ask whether 
outcomes of adolescents and young adults (AYA) on pediatric regimens were 
superior to AYA treated on adult regimens. Multiple retrospective studies in the 
United States and Europe have now demonstrated that, in the majority of these 
comparisons, survival outcomes are improved in AYA who are treated on 
pediatric as opposed to adult regimens. This was first demonstrated in a 
comparison of data from the Cancer and Leukemia Group B (CALGB) and the 
Children’s Cancer Group (CCG). A total of 321 AYA ages 16 to 20 were 
compared. Although the CR rates were identical at 90% between the two groups, 
the AYA in the CCG study had a 63% EFS and 67%OS at 7 years compared to 
the CALGB AYA where the 7-year EFS was only 34% and overall survival only 
46% (p < 0.001)9. A puzzling finding from this study was that the EFS for the 16- 
to 17-year-olds on the CALGB study was similar to the same age group on the 
CCG study (55% vs. 64%, respectively, p=0.49). The inferior outcome for the 
CALGB patients was confined to the 18- to 20-year-olds whose EFS was only 
29% as compared with 57% for the 18- to 20-year-old patients treated on the 
CCG studies (p=0.01). The CCG patients received intensive and earlier central 
nervous system prophylaxis, which resulted in a significantly lower incidence of 
isolated central nervous system relapses. Also the doses of non-
myelosuppressive drugs such as corticosteroids, vincristine (VCR), and L-
asparaginase were much higher in the CCG regimens compared with the CALGB 
regimens.  This increased intensity of non-myelosuppressive drugs was 
especially seen in post-remission therapy9. The other retrospective studies have 
shown largely similar outcomes with improved survivals in AYA treated on 
pediatric regimens compared to AYA treated on adult regimens and also 
confirmed that the pediatric regimens contain higher doses of non-
myelosuppressive drugs. The findings from these multiple studies are 
summarized in two recent publications10,11. Whether the improved outcomes seen 
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non-myelosuppressive drugs or whether they relate to other factors such as the 
greater experience of pediatric hematologists in caring for AYA with ALL 
compared with adult hematologists-oncologists or to stricter adherence to 
scheduled treatment regimens is unclear12.   
These studies have prompted the development of phase II trials utilizing 
pediatric-intense regimens in the young and middle-aged adults. The GRAALL-
2003 trial was a phase II study where patients between the ages of 15 and 60 
were eligible to receive a “pediatric-inspired therapy” that contained higher doses 
of L-asparaginase, VCR, and prednisone compared with the group’s previous 
adult protocols. The EFS and OS were 55 and 60% with a median follow-up of 42 
months, respectively.  Age was an important factor in outcome. The authors 
identified a best age cutoff of 45 years with patients over this age having a 
chemotherapy-induced death rate of 23% as compared with 5% in younger 
patients who had EFS of 58% compared with 46% in the older patients 
(p=0.03)13. The authors did not specify if there was any difference in outcome by 
age within the group of patients aged 15 to 45 years. A study from Canada by 
Storring et al. treated 85 adults with BCR-ABL-negative ALL between the ages of 
18 and 60 with a modified pediatric regimen that included weekly high doses of 
asparaginase for up to 30 weeks during intensification. At a median follow-up of 4 
years, the estimated 5-year OS and relapse-free survival were 63% and 71%, 
respectively. Patients at or less than the age of 35 years had a 3-year OS of 
83%, while patients over the age of 35 had an OS of 52%14. A trial reported by 
Ribera et al. in patients between the ages of 15 and 30 utilizing a pediatric-based 
protocol had an EFS and OS of 61% and 69% at 6 years with no difference in 
outcome noted between patients ages 15 to 18 and those 19 to 30 years of age. 
The hematologic toxicity was higher in the older group15.   
No randomized trials comparing pediatric-based protocols to standard adult 
protocols have been reported, but an innovative approach to attempt to 
prospectively compare these regimens is the CALGB 10403 protocol, which is 
treating adults with BCR-ABL-negative ALL up to the age of 40 years with a 
regimen that is taken from one arm of a CCG protocol. The CALGB 10403 study 
is a phase II study, but the results will be compared to the outcomes of patients 
treated on the designated arm of the CCG protocol. This will allow for a 
prospective comparison.  In addition to the usual outcomes and toxicity 
measurements, particular attention will also be placed on whether patients and 
physicians were able to adhere to the dosing and scheduling requirements of the 
protocol. An interim analysis of the results of the C10403 trial compared to similar 
aged patients treated on prior CALGB trials has suggested a significant 
improvement in outcome with the pediatric-based regimen (personal 
communication, Wendy Stock, MD). Given these encouraging results, 
components of the C10403 trial and other pediatric regimens will be incorporated 
into the design of E1910 in an attempt to improve the chemotherapy backbone 
without excessively increasing toxicity.     
However, these studies of pediatric-intensive regimens in adults indicate that 
while intensification of non-myelosuppressive chemotherapy improves outcomes, 
it is not well-tolerated by older adults and the ability to further intensify these 
regimens is limited. Furthermore, even with this incremental improvement, many 
patients will continue to relapse and die from their ALL. Alternative therapies are 
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antibody therapy represents a potentially promising approach. To place the use 
of monoclonal antibody therapy in ALL in context, the role of MRD testing will be 
discussed next. 
1.2 
Minimal Residual Disease (MRD) Testing  
The high rate of relapse seen in patients with adult ALL indicates that many 
patients have persistent residual disease despite achievement of a morphologic 
CR.  The introduction of sensitive molecular techniques utilizing clonal 
immunoglobulin or T-cell receptor gene rearrangements has been effectively 
utilized to detect MRD.  More than 10 years ago, it was demonstrated in pediatric 
ALL that the presence of residual disease at the end of induction chemotherapy 
or at later time points was a significant predictor of relapse that was independent 
of other risk factors16. The challenge of utilizing immunoglobulin or T-cell receptor 
gene rearrangement studies is that each patient’s gene rearrangement is unique 
and must be characterized for each patient. An alternative is to take advantage of 
the increasing sophistication of flow cytometry to identify the distinct 
immunophenotypes in patients that allow detection of one leukemia cell amongst 
10,000 normal cells17. In adult ALL, the German Multicenter Study Group for 
Adult ALL (GMALL) has demonstrated that patients who have a rapid decline in 
their MRD level within the first month of therapy had a 3-year relapse rate of 0%. 
Another subset of patients who had MRD detectable until week 16 of 
chemotherapy had a 3-year relapse rate of 94%. Patients in between these two 
groups had an intermediate risk of relapse of 47%18. Investigators in Italy, Poland 
and Spain have shown similar results with polymerase chain reaction (PCR) or 
flow cytometry techniques as indicated in the table below.19-21  
AUTHOR 
GROUP 
METHOD N 
PROGNOSTIC MODEL 
DFS 
Bruggeman18 
GMALL 
PCR 
105 
< 10-4 d11 + < 10-4 d24 
100% 
> 10-4 d11 + > 10-4 d24  
6% 
All others 
53% 
Holowiecki19 
PALG 
Flow 
115 
< 10-3 (4 weeks) 
61% 
> 10-3 (4 weeks) 
17% 
Bassan20 
NILG 
PCR 
142 
< 10-4 wk16, < 10-4 wk 22 
72% 
All others 
14% 
Ribera21 
PETHEMA Flow 
235 
< 10-3 (4 weeks), < 5x10-4 
(end consolidation) 
54% 
> 10-3 (4 weeks), > 5x10-4 
(end consolidation) 
31% 
A subset analysis of the MRC/ECOG trial patients who were MRD positive by 
immunoglobulin gene rearrangement studies after 2 months of induction 
chemotherapy had a relative risk of relapse that was 9-fold higher than the MRD-
negative patients, and the 5-year relapse-free survival was 15% for those who 
were MRD-positive compared to 71% in the MRD-negative patients22. Thus, 
incorporation of MRD assessment is an important component of the 
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in risk stratification. A recent review article has suggested that MRD should be 
“considered as a quantitative and objective extension of established endpoints of 
hematological remission and relapse” rather than a substitute for established risk 
factors23.  Further advances in this field incorporating next generation sequencing 
also promise to bring greater sensitivity to the detection of MRD24. The adult 
cooperative groups in the United States have not yet developed a standardized 
assay for MRD assessment in adults with ALL that utilizes molecular or 
immunophenotypic techniques. However, given the labor intensity required to 
develop primers for individual patients and the equivalence of PCR and flow 
cytometry25, flow cytometric approaches will be utilized for MRD assessment in 
this trial. The development and use of such an assay is an important component 
of this trial as discussed in the correlative science section of this concept 
proposal. Furthermore, the NCI has initiated a standardization effort for flow 
cytometric MRD assessment in ALL and the agreed upon antibody panel and 
procedures will be used by the ECOG-ACRIN laboratory in the MRD 
determination for this trial. 
1.3 
Monoclonal Antibody Therapy of Adult ALL 
The classification of ALL by immunophenotype plays a key role in diagnosis and 
is playing an emerging role in the identification of MRD. CD20 is a B-lineage 
antigen that is expressed on both normal and malignant lymphocytes during all 
except the earliest and latest stages of B cell differentiation. It is expressed on B-
lineage ALL in 40 to 50% of cases. CD20 antigen density (reflected by 
fluorescence intensity of antibody binding) and the percentage of CD20 
expressing blasts are lowest in immature subtypes, such as CD10 negative Pro-
B ALL, and in B-lineage ALL associated with the MLL/AF4 transcript. The 
prognostic importance of CD20 expression in newly diagnosed B-lineage ALL 
has been evaluated in both the pediatric and adult setting. In a Pediatric 
Oncology Group Study, CD20 expression and higher fluorescence intensity of 
CD20 antibody binding were associated with inferior EFS, independent of other 
known prognostic factors such as age and karyotype26. However, a study from 
St. Jude Children’s Hospital suggested that CD20 expression was associated 
with slightly better outcomes27. These differences were attributed to treatment 
effects. At the MD Anderson Cancer Center, the prognostic significance of CD20 
expression was analyzed in a group of 253 adult patients. Forty-seven percent of 
patients expressed CD20 on ≥ 20% of leukemic lymphoblasts. These patients 
had more thrombocytopenia, poorer performance status, and less 
lymphadenopathy than their CD20-negative counterparts. The CR rate was 
similar regardless of CD20 expression, but disease recurrence was higher in the 
CD20-positive group, which led to a significant decrease in remission duration 
and OS. In multivariate analysis, CD20 expression was an independent predictor 
of outcome. This detrimental effect of CD20 expression was particularly 
prominent in patients under the age of 6028.   
Rituximab, a chimeric IgG-1 anti-CD20 monoclonal antibody, induces antibody-
dependent cell-mediated cytotoxicity, apoptosis and complement-mediated 
cytolysis29. Combining rituximab with frontline chemotherapy regimens has 
significantly improved outcomes for patients with non-Hodgkin lymphoma and 
Burkitt-type leukemia/lymphoma30-32.   
A recently published study combining rituximab with the hyperCVAD regimen in 
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eighty-two adolescents and adults with de novo BCR-ABL negative B-lineage 
ALL were treated with hyperCVAD plus rituximab, and the results were compared 
to historical patients receiving hyperCVAD alone. The CR rate with rituximab plus 
hyperCVAD was 95% with 3-year rates of CR duration and OS of 60% and 50%.  
In patients under the age of 60, rates of CR duration and OS with the 
hyperCVAD and rituximab regimen compared with standard hyperCVAD alone 
were 70% vs. 38% (p < 0.001%) and 75% vs. 47% (p=0.003), respectively at 3 
years.  Patients over the age of 60 with CD20-positive ALL did not benefit from 
rituximab plus hyperCVAD with rates of CR duration of 45% vs. 50% (p=NS) and 
OS 28% vs. 32% (p=NS).  This was related in part to increased deaths in CR33.  
In a series of GMALL adult ALL patients between the ages of 15 and 55 years, 
41% expressed CD20 on >20% lymphoblasts and these patients received 
rituximab 275 mg/m2 day -1 before each induction course and before each of 6 
consolidations for a total of 8 doses34. One hundred and seventeen patients 
received rituximab in addition to chemotherapy compared to 70 patients who 
received chemotherapy alone.  In the standard-risk patients, CR and early death 
rates were similar between the two groups. However, the course of MRD differed 
significantly, in that there was a faster decrease in MRD in those who did versus 
those who did not receive rituximab, with molecular CR (MRD < 10-4) reached at 
day 21 in 60% vs. 19% of patients, respectively. The probability of continuous CR 
at 3 years was 64% vs. 48%, respectively (p=0.009) and for OS 75% with 
rituximab vs. 54% without at 3 years. For high-risk patients, the OS at 3 years 
was 54% with rituximab and 32% without.  Of the high-risk patients, 66% went on 
to BMT in first remission, and their OS was superior if they received rituximab 
pretransplant at 75% vs. 40% for those who were transplanted without receiving 
prior rituximab. This difference in outcome was attributable to fewer relapses in 
those who received rituximab34. The results of these studies, warrant further 
exploration of monoclonal-directed antibody therapy in ALL. Randomized trials of 
chemotherapy with rituximab compared to chemotherapy alone are awaited to 
determine if these retrospective results are confirmed.   
A novel approach to increase the efficacy of monoclonal antibody therapy is to 
utilize them to harness the tremendous cytotoxic potential of T-cells using a bi-
specific T-cell engaging (BiTE) antibody construct. In the case of blinatumomab, 
the variable regions of 2 parental murine antibodies are connected via a short 
linker sequence. Blinatumomab combines the variable regions of an anti-CD19 
antibody directed against B-cells and an anti-CD3 antibody directed against T-
cells. These BiTE antibodies physically link T-cells and in this case, malignant 
(and normal) B-cells and also trigger the signaling cascade of the T-cell receptor 
complex by binding to the CD3 portion of the receptor. This triggers polyclonal T-
cell recruitment with subsequent activation that occurs only if the second portion 
of the BiTE antibody is bound to its target antigen on the B- cell surface. Single 
binding of the BiTE antibody to T-cells does not cause T-cell activation35-36.   
Blinatumomab has been utilized in the treatment of patients with non-Hodgkin 
lymphoma in a phase I trial utilizing doses of 60 µg/m2 per day given by 
continuous intravenous infusion for 4 to 8 weeks (NCT00274742). A recent report 
on the results of 12 patients with indolent follicular or mantle cell lymphoma 
demonstrated objective responses in 11 of 12 patients with 7 partial responses 
(PR) and 4 CR. The median response duration was 12 months with 6 of 11 
responses still ongoing at the time of the report. A single non-responding patient 
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treatment early. Four patients had neurologic symptoms which were all 
reversible, and one patient had a port infection37. An update of the trial reported 
in abstract form of 14 patients with mainly follicular and mantle cell subtypes 
treated at 60 µ/m2/day demonstrated nine CR and four PR in 13 evaluable 
patients. As of February, 2010 response duration was up to 27+ months. Eight of 
13 responses were on-going after a median follow-up of 13 months. The single 
non-evaluable patient experienced a fully reversible, neurological adverse event 
leading to early discontinuation of therapy. Of the 13 responders, five had 
adverse events that were all fully reversible and consisted of one port infection 
and four neurologic events. These neurologic events were predicted by low 
peripheral blood B:T cell ratios. Implementation of a lower initial starting dose of 
5 and/or 15 µ/m2/day for 1-2 weeks followed by 60 µ/m2/day significantly lowered 
the risk of these adverse events38. An amendment to this study allowed the 
enrollment of patients with relapsed diffuse large B cell lymphoma. Two cohorts 
of six patients each were enrolled and they differed solely by the dose and 
schedule of corticosteroid pre-medication administered prior to blinatumomab to 
lessen adverse effects. Five of nine evaluable patients (56%) showed objective 
clinical responses (4 CR/CRu; 1PR).39  
Blinatumomab has also been tested in B-ALL patients but at a lower dose of 15 
µg/m2 per day by continuous infusion for 4 weeks (NCT00560794). The rationale 
for the lower dose is that in pilot studies, bone marrow clearance was seen at the 
15 µg/m2 per day dose. Patients in complete hematologic remission with either 
persistent or recurrent MRD at any time after initial consolidation of frontline 
therapy were eligible. Of 19 patients treated, 16 were evaluable for response; 13 
of 16 went into molecular CR after 1 cycle of blinatumomab. Three patients had 
stable MRD. Ten of the 13 responding patients had never achieved a molecular 
CR before blinatumomab treatment despite multiple treatment cycles including 
tyrosine kinase inhibitors in the case of BCR-ABL-positive ALL. Two patients with 
molecular CR had an extra-medullary relapse, one in the testis and one in the 
CSF.  The most common adverse events were lymphopenia, pyrexia, 
leukopenia, and hypogammaglobulinemia. Overall, the treatment was well 
tolerated40. A report of 21 patients enrolled in the trial (16 BCR-ABL-negative; 2 
patients with MLL-AF4; 5 pts with BCR-ABL-positive ALL) demonstrated that 16 
of 20 evaluable patients became MRD-negative. Of these, 13 had never before 
achieved MRD negativity on chemotherapy. All 16 patients (13/15 BCR-ABL-
negative and 3/5 BCR-ABL-positive) became MRD negative after the first cycle 
of blinatumomab. Nine patients were enrolled with an MRD load > 10-2 prior to 
study treatment and all reached a complete MRD response. Overall relapse-free 
survival was 78% at the time of the report with a median follow-up of 405 days. 
Eight patients underwent allogeneic transplant (6 responders and 2 non-
responders) and 8 are alive in hematologic remission with a median follow-up of 
434 days41. The most recent update of this trial shows that with a median follow-
up of 33 months, the hematological relapse-free survival of the entire evaluable 
cohort of 20 patients is 61% by Kaplan-Meier estimation. In a sub-group of six 
BCR-ABL-negative patients who received no further therapy after blinatumomab, 
four remain in hematologic and molecular remission42.   
Analysis of a phase II study in adult patients with ALL in hematologic relapse or 
refractory disease determined that the CR or CRh (CR with incomplete 
hematologic recovery) rate was 68% (17 of 25 patients) in patients treated at the 
optimal schedule of 5 μg/m2/day for the first week followed by 15 μg/m2/day for 

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the subsequent three weeks (NCT01209286). All responders achieved a 
negative MRD status (level < 10-4) within the first two cycles of therapy. Six 
patients proceeded to allogeneic transplant after blinatumomab therapy and one 
of them had a CD19 negative medullary relapse post-transplant. Of the 11 
patients not transplanted, five have relapsed-two were CD19 negative (one 
medullary and one extra-medullary) and three were CD19 positive (one 
medullary and two extra-medullary). Median response duration is 7.1 months 
with the median survival not yet reached and median follow-up time is 11.4 
months. The most significant toxicities in 25 evaluable patients were CNS events 
(seizures and disorientation) in five and DIC/cytokine release syndrome in two 
patients.43,44. Three pediatric patients in hematologic relapse after allogeneic 
BMT were treated with blinatumomab and all achieved a molecular CR after four 
to six weeks of therapy. No graft-versus-host disease developed45. 
Globally, 20 deaths have been reported in patients on blinatumomab trials. Five 
of the 20 (1 bacterial sepsis, 1 pneumocystis jiroveci pneumonia, 1 invasive 
fungal infection, 1 cardiac and respiratory failure, 1 respiratory failure) were 
considered by the investigator to be possibly related to blinatumomab 
(Investigator’s Brochure, edition 14.2). 
Blinatumomab represents a promising therapy in B-ALL and further trials are 
planned with larger patient numbers to better understand its benefit and efficacy, 
including an international trial for relapsed/refractory patients that is currently on-
going. 
1.4 
Blinatumomab Dosing: Pharmacokinetic justification for fixed dosing versus 
dosing based on body surface area  
The use of a fixed dose is expected to provide better compliance and less risk of 
medical errors in dose calculation. Therefore, Amgen analyzed the available 
exposure data from BSA-normalized doses from clinical trials to explore the 
effect of BSA and body weight (BWT) on clearance and to evaluate the variability 
in clearance under different dosing approaches i.e. fixed doses and BSA or BWT 
normalized-dosing. Available data as of May 20, 2011 (trials: MT103-104, 
MT103-202, and MT103-206) were pooled. The average Css through different 
cycles in each individual patient were considered. The clearance (CL =Ro/Css, 
where Ro is the dosing rate) was calculated and then normalized to BSA or 
BWT. The variability (CV%) in CL, CL/BSA, and CL/BWT was computed and 
compared. The CV% was also calculated for Css normalized to absolute dose, 
dose/kg or dose/m2 and compared. 
Figure 1 (a, b) shows no remarkable effect of either BWT or BSA on the 
clearance of blinatumomab. The results in Table 1, indicate that normalizing to 
BSA does not reduce inter-patient variability in systemic exposure which 
supports the feasibility of administering blinatumomab using a fixed dose 
regimen, as an alternative to the currently used BSA normalized dosing.  
Population PK analysis is foreseen to confirm these findings with more data 
becoming available. 
The average BSA in the trials population was 1.9 m2 (MT103-104, MT103-206 
and MT103-202 clinical trials).  Using this conversion factor a dose of 15 mcg /m2 
blinatumomab is equivalent to 28.5 mcg and a dose of 5 mcg /m2 is equivalent to 
9.5 mcg.  Therefore fixed doses of 9 mcg /day and 28 mcg /day (instead of 5 mcg 

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/m2/day and 15 mcg /m2/day, respectively) are proposed to be used in future 
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Figure 1(a) Relationship between CL and BWT, (b) Relationship between CL and 
BSA. 
Table 1: Mean clearance values and dose normalized Css values* 
 
 
* Data Source: 54 patients pooled from clinical studies MT103-104, MT 103-202 and MT 103-206 
with and without normalization to body size (BWT, BSA), together with variability parameters. 
In summary, dose normalization to BSA does not reduce inter-patient variability 
in systemic exposure which supports the feasibility of administering 
blinatumomab using a fixed dose regimen, as a potential alternative to the 
currently used BSA normalized dosing. Administration of blinatumomab as a 
fixed dose regimen is expected to lead to better compliance, and less risk of 
medical errors. 
In conclusion, the data from the clinical trials MT103-104, MT103-202, and   
MT103-206, serve as basis for the treatment plan selected for this trial. Step 
dosing was originally developed to prevent cytokine release syndrome in patients 
with high tumor burden.  Currently for patients in remission “flat” dosing without a 
step up (28mcg/day) is utilized.  Previous studies41,42 and an on-going clinical trial 
(MT103-203) have shown that step dosing is not necessary for patients in 
hematologic remission.  It is therefore recommended that “flat” dosing without a 
step up be used to be consistent with current ongoing studies.  Thus, the 
selected dose and regimen in this E1910 trial will consist of a dose of 28 mcg/day 
from the first day of the first cycle and for all the following cycles to achieve a 
high degree of efficacy. 
1.5 
Summary  
The poor prognosis of older adults with B ALL and their inability to tolerate 
intensive chemotherapy suitable for children and younger adults necessitates the 
incorporation of novel agents into the therapeutic regimens of these patients.  
The encouraging results of therapy with blinatumomab in converting patients who 
are MRD positive to MRD negative status and the acceptable toxicity profile seen 
with this bi-specific antibody suggest that it has the potential to improve survival 
and quality of life of older adults with B ALL. It will also be an important proof of 
biologic principle that BiTE therapy has the potential to improve outcomes in this 
challenging patient population. This trial will utilize the chemotherapy program 
from the UKALLXII/E2993 trial with dosing modifications based on the improved 
outcomes that are emerging from the completed C10403 AYA trial. Data from the 
GMALL group suggests that pegaspargase is less well-tolerated in older adults 
and therefore, will be omitted in patients 55 and older in induction (personal 
communication, N.Goekbuget)46. These patients also tolerate high-dose 
corticosteroid doses less well than younger adults and will, therefore, receive 
shorter courses of corticosteroids in the protocol. 
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A recently published trial of blinatumomab for adults with B-cell precursor ALL in 
hematologic complete remission with positive MRD results (>10-3) demonstrated 
that 82 of 103 patients (80%) achieved a complete MRD response after one 
cycle of blinatumomab with significantly improved survival compared to patients 
who did not achieve a complete MRD response.79 Based on this data on March 
29, 2018, the U.S. Food and Drug Administration granted accelerated approval to 
blinatumomab to treat adults and children with B-cell precursor ALL who are in 
remission but still MRD positive. On E1910 it had already been observed prior to 
this approval that patients who were MRD positive at the time of Step 3 
randomization were being taken off-study either prior to randomization or after 
randomization if they were not randomized to blinatuomomab. Therefore, the 
protocol is being amended to assign MRD positive patients at step 3 to Arm C to 
receive 2 cycles of blinatumomab and then continue on protocol to either go to 
allogeneic BMT or continue consolidation chemotherapy and subsequent 
blinatumomab and maintenance therapy. 
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2. 
Objectives 
2.1 
Primary Objectives 
2.1.1 
To compare the overall survival (OS) of blinatumomab in conjunction 
with chemotherapy to chemotherapy alone in patients with BCR-ABL-
negative B cell precursor ALL who are MRD negative after induction 
and intensification chemotherapy, based on multiparameter flow 
cytometric (MFC) assessment of residual blasts. 
2.2 
Secondary Objectives 
2.2.1 
To compare the relapse-free survival (RFS) of blinatumomab in 
conjunction with chemotherapy to chemotherapy alone in MRD 
negative patients after induction and intensification chemotherapy. 
2.2.2 
To compare the OS and RFS of those patients who are MRD+ at step 
3 randomization/ registration and then convert to MRD- after 2 cycles 
of blinatumomab to those patients who are MRD- at randomization 
and remain MRD- after 2 cycles of blinatumomab or consolidation 
chemotherapy. 
2.2.3 
To assess the toxicities of blinatumomab in this patient population 
2.2.4 
To assess the toxicities of the modified E2993 chemotherapy regimen 
in this patient population. 
2.2.5 
To describe the outcome of patients who proceed to allogeneic blood 
or marrow transplant after treatment with or without blinatumomab. 
2.3 
Laboratory Objectives 
2.3.1 
To determine differences in MRD kinetics among patients with the 
BCR/ABL1-like B-lineage ALL, and to compare the OS (and RFS) of 
patients with BCR-ABL-like phenotype with those without BCR-ABL-
like phenotype. 
2.3.2 
To evaluate the incidence of anti-blinatumomab antibody formation. 
 
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NCI Update Date: August 14, 2014 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date _________________________________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician.  
NOTE: 
This study involves pre-registration (see Section 4). Bone marrow and 
peripheral blood specimens must be submitted for centralized 
immunophenotyping. 
3.1 
Pre-Registration 
Diagnostic bone marrow and/or peripheral blood specimens must be submitted 
for immunophenotyping and selected molecular testing, and the establishment of 
BCR/ABL status.  Testing will be performed by the ECOG-ACRIN Leukemia 
Translational Research Laboratory (LTRL) and reported to the institution. 
NOTE: 
IT IS ESSENTIAL THAT A SAMPLE CONTAINING SUFFICIENT 
BLAST CELLS BE SUBMITTED TO THE ECOG-ACRIN LTRL AT 
BASELINE SO THAT SUBSEQUENT BONE MARROW 
ASSESSMENTS OF MRD CAN BE DONE. IN ADDITION TO 
ALLOWING THE LTRL TO CONFIRM ELIGIBILITY BASED ON 
BLAST CELL IMMUNOPHENOTYPE AND BCR/ABL STATUS, IT IS 
ALSO IMPERATIVE THAT AN ADEQUATE NUMBER OF BLASTS 
BE BANKED FOR ANALYSIS BY DRS MULLIGHAN/WILLMAN. 
WITHOUT ADEQUATE BASELINE SAMPLES, PATIENTS WILL 
NOT BE ABLE TO BE TREATED AND RANDOMIZED ON THIS 
PROTOCOL. IF A BONE MARROW ASPIRATE IS NOT 
AVAILABLE FOR LTRL SUBMISSION AT BASELINE, IT IS 
IMPERATIVE THAT DR PAIETTA FROM THE LTRL IS CALLED TO 
DISCUSS THE PERIPHERAL BLOOD WBC AND BLAST COUNT 
BEFORE BLOOD ONLY IS SUBMITTED. 
NOTE: 
Hydroxyurea can be given for up to 5 days prior to initiation of protocol 
therapy for control of leukocyte count and/or other symptoms or 
signs.  Corticosteroids can be given after pre-registration to the 
protocol and submission of baseline marrow and blood samples for 
control of leukocyte count and/or other symptoms or signs prior to 
Rev. 7/14 
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initiation of protocol therapy if needed. If corticosteroids are given 
prior to pre-registration, contact the study chair as the patient may still 
be eligible to participate. 
3.2 
Induction Eligibility Criteria – Step 1 
3.2.1 
Age ≥ 30 years and ≤ 70 years. 
New diagnosis of B lineage ALL must be made upon bone marrow or 
peripheral blood immunophenotyping. Cases with myeloid antigen 
expression, but unequivocal lymphoid immunophenotype, are eligible. 
3.2.2 
Mature B ALL (Burkitt’s-like leukemia) is excluded from enrollment in 
this trial. 
Pre-study bone marrow biopsy and aspirate must be completed ≤ 1 
week prior to registration. 
3.2.3 
Negativity for the Philadelphia chromosome must be established by 
conventional cytogenetics, FISH and/or PCR.  Patients who are 
negative for the Philadelphia chromosome by conventional 
cytogenetics must have FISH or PCR performed for BCR/ABL to 
exclude occult translocations. 
3.2.4 
Cytogenetic analysis must be performed from diagnostic bone marrow 
(preferred) or if adequate number of circulating blasts from peripheral 
blood. FISH testing for common B-lineage ALL abnormalities including 
t(9;22) (BCR/ABL1), t(12;21) (ETV6/RUNX1), t(1;19) (PBX1/TCF3), 
+4,+10,+17, (Cen4/Cen10/Cen17), t(11q23;var), (MLL), del(9p) 
(CDKN2A/Cen9), and t(14;var) (IGH is encouraged. If there are few or 
no circulating blasts and an adequate marrow sample cannot be 
obtained for cytogenetic analysis, the patient may still enroll on the 
trial. 
3.2.5 
Patient must not have a concurrent active malignancy for which they 
are receiving treatment. 
3.2.6 
Have lab values obtained ≤ 48 hours prior to registration. Serum direct 
bilirubin < 2 mg/dl or serum total bilirubin ≤ 3, and serum creatinine < 
2 mg/dl. 
Serum direct bilirubin: _________ Serum creatinine: _________  
Serum total bilirubin: __________ 
Date of tests: _______ 
NOTE: 
The above stipulation for normal hepatic function does not 
apply if liver dysfunction is due to leukemia infiltration. 
3.2.7 
Patient should be HLA typed (A, B, C, DR and DQ) during induction 
therapy phase or a written explanation for not undergoing HLA typing 
on the flow sheet. 
3.2.8 
Patient must not have intercurrent organ damage or medical problems 
that will jeopardize the outcome of therapy (i.e., psychiatric disorder, 
drug abuse, pregnancy). 
______
______
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3.2.9 
Patients with known HIV infection are eligible If they meet all of the 
following criteria: 
3.2.9.1 
No history of AIDS-related complications other than a 
history of low CD4+ T-cell count (< 200/mm3) prior to 
initiation of combination antiretroviral therapy.  On study 
CD4+ T-cell count may not be informative due to leukemia 
and should not be used as an exclusion criterion if low. 
3.2.9.2 
Patient must be healthy on the basis of HIV disease with 
high likelihood of near normal life span were it not for the 
leukemia. 
3.2.9.3 
Patient must have serum HIV viral load of < 200 
copies/mm3. 
3.2.9.4 
Patient must be on combination antiretroviral therapy with 
minimal pharmacokinetic interactions with study therapy 
and minimal overlapping clinical toxicity with protocol 
therapy. 
3.2.9.5 
Patient must not be receiving protease inhibitors or once 
daily formulations containing cobicistat, stavudine, or on 
regimens containing stauvidine or zidovudine. 
3.2.9.6 
It is recommended to utilize a regimen of the integrase 
inhibitor, dolutegravir, combined with either disoproxil 
fumarate/emtricitabine or dolutegravir combined with 
tenofovir alafenamide/emtricitabine. 
3.2.10 
Patient must not have an antecedent hematologic disorder. 
3.2.11 
Patient must have no history of recent myocardial infarction (within 
three months), uncontrolled congestive heart failure, or uncontrolled 
cardiac arrhythmia.  
3.2.12 
Patient must not have a history or presence of clinically relevant CNS 
pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe 
brain injuries, dementia, Parkinson’s disease, cerebellar disease, 
organic brain syndrome, psychosis, or other significant CNS 
abnormalities. 
3.2.13 
Patient must have a normal cardiac ejection fraction by pretreatment 
MUGA or echocardiogram within 4 weeks prior to registration (resting 
ejection fraction ≥ 40% or ≥ 5% increase with exercise), shortening 
fraction by echocardiogram ≥ 24%, or to within the normal range of 
values for the institution. 
3.2.14 
Patient must not have an active uncontrolled infection.   
3.2.15 
Women must not be pregnant or breast-feeding due to administration 
of teratogenic chemotherapy and must not become pregnant or 
breastfeed during protocol therapy and for at least 3 months after 
protocol therapy. Woman of childbrearing potential must abstain from 
sexual activity or be willing to use 2 highly effective forms of 
contraception throughout protocol therapy and for at least an 
additional 3 months after the last dose of protocol-specified therapy. 
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NCI Update Date: August 14, 2014 
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All females of childbearing potential must have a blood test or urine 
study within 2 weeks prior to registration to rule out pregnancy. A 
female of childbearing potential is any woman, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets 
the following criteria: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
Female? ______ (Yes or No) 
Date of blood test or urine study: ______________ 
3.2.16 
Men who have a female partner of childbearing potential must be 
willing to use 2 highly effective forms of contraception throughout 
protocol therapy and for at least an additional 3 months after the last 
dose of protocol-specified therapy. 
Men who have a pregnant partner must be willing to use a condom 
during sexual activity throughout protocol therapy and for 3 months 
after the last dose of protocol-specified therapy. 
3.2.17 
ECOG performance score 0-3. 
3.2.18 
Patient must have given written informed consent. 
3.3 
Post-Induction Therapy Eligibility Criteria (prior to Intensification – Step 2) 
3.3.1 
ECOG performance status 0-2.  
3.3.2 
Patients must have achieved a CR or CRi as defined in Section 6.  
3.3.3 
Patients who have achieved a CR or CRi must have maintained 
peripheral blood evidence of a CR or CRi as defined in Section 6.  
3.3.4 
Patient must be CNS (CSF) negative for leukemia. 
3.3.5 
Patients must have resolved any serious infectious complications 
related to induction.  
3.3.6 
Any significant medical complications related to induction must have 
resolved.  
3.3.7 
Have lab values obtained ≤ 48 hours prior to registration. Patients 
must have serum creatinine ≤ 2.0 mg/dl. 
Serum creatinine: __________ 
Date of tests: _________________ 
Serum direct bilirubin < 2 mg/dL or serum total bilirubin ≤ 3, and AST 
and ALT < 3x upper limit of normal (ULN). 
Serum direct or total bilirubin:_____________ 
AST: ___________ 
ALT: _______________ 
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3.4 
Randomization or Assignment to Blinatumomab or No Blinatumomab – Step 3 
3.4.1 
Patients must have an ECOG performance status of 0-2.  
3.4.2 
Patients must have maintained peripheral blood evidence of a 
remission as defined in Section 6 and must have a CR or CRi, 
confirmed on restaging BM aspirate and biopsy.  
3.4.3 
Patients must have resolved any serious infectious complications 
related to therapy.  
3.4.4 
Any significant medical complications related to therapy must have 
resolved. 
3.4.5 
Patients must have a direct or total bilirubin < 1.5xULN (unless related 
to Gilbert’s or Meulengracht’s syndrome, and a serum creatinine < 1.5 
x ULN. The values must be obtained within 48 hours prior to 
randomization. 
3.4.6 
Bone marrow aspirates must be submitted as outlined in Section 
10 for centralized minimal residual disease (MRD) assessment 
performed by the ECOG-ACRIN Leukemia Translational Research 
Laboratory. 
3.4.7 
MRD results will be reported to the submitting institution. 
NOTE: 
FOR MRD ASSESSMENTS, AN ASPIRATE FROM A 
SEPARATE BONE MARROW ASPIRATION SITE MUST 
BE SUBMITTED (THE NEEDLE CAN BE RE-DIRECTED 
THROUGH THE SAME SKIN PUNCTURE SITE).  ONLY 
SUBMIT ASPIRATES FROM THE FIRST PULL OF AN 
ASPIRATION SITE FOR MRD TESTING. DO NOT 
SUBMIT SAMPLES FROM THE SECOND OR THIRD 
PULL OF THE SAME ASPIRATION SITE. 
In B-lineage ALL, MRD levels in peripheral blood or 
from a dilute marrow aspiration can be 300% lower, on 
average, than those in bone marrow at a given time 
point. Submitting a first pull from a separate aspiration 
site will ensure that MRD determinations used in 
randomization and trial interpretation are accurate. 
NOTE: 
Failure to submit bone marrow aspirates will 
result in a major violation at the time of an 
audit. 
3.5 
Criteria for Allogeneic Transplantation 
3.5.1 
A suitable donor must be identified. There are no restrictions on donor 
type and can include a matched sibling, a matched or mismatched 
unrelated donor, a family haplotype matched donor or a cord blood 
donor (single or double). 
3.5.2 
Patients should meet the eligibility criteria in Section 3.4. 
3.5.3 
Patients must be considered reliable enough to comply with the 
medication regimen and follow-up, and have social support necessary 
to allow this compliance. 
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3.6 
Criteria for Maintenance Therapy – Step 4 
3.6.1 
Patients must have an ECOG performance status of 0 -3.  
3.6.2 
Patients must have maintained peripheral blood evidence of a 
remission as defined in Section 6 and must have a CR or CRi, 
confirmed on restaging BM aspirate and biopsy.  
3.6.3 
Patients must have resolved any serious infectious complications 
related to therapy.  
3.6.4 
Any significant medical complications related to therapy must have 
resolved. 
 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions 
wishing to use the eligibility checklist as source 
documentation. 
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NCI Update Date: August 14, 2014 
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4. 
Registration Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  
Documentation requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
· 
Added to a site roster 
· 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
· 
Act as the site-protocol PI on the IRB approval 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact 
the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
This study commences with a single induction arm. 
At the time of registration, investigators should declare whether, to the best of 
their knowledge, the patient is a potential candidate for allogeneic hematopoietic 
cell transplantation (HCT) or not.   
All patients who meet CR or CRi criteria in Section 6 at the end of induction 
therapy receive a single cycle of intensification therapy and are either randomized 
to: 
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NCI Update Date: August 14, 2014 
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2 cycles of blinatumomab followed by allogeneic HCT or 
consolidation/maintenance chemotherapy or proceed directly to allogeneic HCT 
or consolidation/maintenance chemotherapy. 
Patients who do not meet CR or CRi criteria in Section 6 at the end of induction 
therapy will go off-study.   
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data 
to make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to the following: 
· 
An active Federal Wide Assurance (FWA) number 
· 
An active roster affiliation with the Lead Network or a participating organization 
· 
A valid IRB approval 
· 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
· 
Active registration status 
· 
The IRB number of the site IRB of record listed on their Form FDA 1572 
· 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study 
are not required to submit IRB approval documentation to the CTSU Regulatory Office. 
For sites using the CIRB, IRB approval information is received from the CIRB and 
applied to the RSS in an automated process. Signatory Institutions must submit a Study 
Specific Worksheet for Local Context (SSW) to the CIRB via IRB Manager to indicate 
their intent to open the study locally.  The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office.  In order for the SSW approval to be 
processed, the Signatory Institution must inform the CTSU which CIRB-approved 
institutions aligned with the Signatory Institution are participating in the study. 
Downloading Site Registration Documents: 
Site registration forms may be downloaded from the E1910 protocol page located on the 
CTSU members’ website.   
· 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
· 
Click on the Protocols tab in the upper left of your screen 
· 
Either enter the protocol # in the search field at the top of the protocol tree, or 
· 
Click on the By Lead Organization folder to expand 
· 
Click on the ECOG-ACRIN link to expand, then select trial protocol E1910 
· 
Click on the LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided 
Requirements for E1910 site registration: 
· 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
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Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted ) 
Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
Required Protocol Specific Regulatory Documents 
Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information 
concerning risks or alternative procedures contained in the 
sample informed consent document must be justified in writing 
by the investigator and approved by the IRB. 
A.  
CTSU IRB Certification Form. 
 
Or 
B.  
Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  
IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
· 
Indicate all sites approved for the protocol under an 
assurance number. 
· 
OHRP assurance number of reviewing IRB 
· 
Full protocol title and number 
· 
Version Date 
· 
Type of review (full board vs. expedited) 
· 
Date of review. 
· 
Signature of IRB official 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU 
website. 
· 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
· 
Click on the Regulatory tab 
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· 
Click on the Site Registration tab 
· 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements outlined by the 
Lead Network. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status 
with the NCI or their affiliated networks. 
Patient Enrollment 
Patients must not start protocol treatment prior to registration. 
Treatment should start within three working days after registration. 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.  
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at https://ctepcore.nci.nih.gov/iam ) and a 'Registrar' role on either the LPO 
or participating organization roster. Registrars must hold a minimum of an AP 
registration type. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database. OPEN can be accessed at https://open.ctsu.org or from 
the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org. To 
assign an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), 
or investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form 
FDA 1572 in RCR the IRB number used on the site’s IRB approval. 
Prior to accessing OPEN site staff should verify the following:  
· 
All eligibility criteria have been met within the protocol stated timeframes. 
· 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
The following information will be requested  
4.1 
Pre-Registration 
NOTE: 
Patients who are only pre-registered must not begin treatment.  
Treatment should start within three working days after registration. 
To proceed to registration, patients must have centralized immunophenotyping 
performed by the ECOG-ACRIN Leukemia Translational Research Laboratory. 
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4.1.1 
Protocol Number  
4.1.2 
Investigator Identification 
4.1.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.1.2.2 
Investigator’s name (NCI number) 
4.1.2.3 
Cooperative Group Credit 
4.1.2.4 
Credit Investigator 
4.1.2.5 
Protocol specific contact information 
4.1.3 
Patient Identification  
4.1.3.1 
Patient’s initials (first and last) 
4.1.3.2 
Patient’s Hospital ID and/or Social Security number 
4.1.3.3 
Patient demographics 
4.1.3.3.1 
Gender 
4.1.3.3.2 
Birth date 
4.1.3.3.3 
Race 
4.1.3.3.4 
Ethnicity 
4.1.3.3.5 
Nine-digit ZIP code 
4.1.3.3.6 
Method of payment 
4.1.3.3.7 
Country of residence 
4.1.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1. 
4.1.5 
Additional Requirements  
4.1.5.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: 
During a shortage of preservative-free 
methotrexate, institutions without a sufficient 
supply of preservative-free methotrexate, 
defined as 2 induction cycles worth of 
methotrexate, may not consent patients to the 
study. 
NOTE: 
During a shortage of sodium bicarbonate, 
institutions without a sufficient supply of sodium 
bicarbonate, defined as a one month supply, 
may not consent patients to the study. 
4.1.6 
Bone marrow and/or peripheral blood specimens must be submitted 
at pre-registration for centralized immunophenotyping. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office - Boston. However the ECOG-
ACRIN Leukemia Translational Research Laboratory 
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(LTRL) requires institutions to submit a copy of the E1910 
consent and a copy of the HIPAA Authorization form. 
NOTE: 
FACT (Foundation for the Accreditation of Cellular 
Therapy) credentialing certificate must be submitted to the 
CTSU Patient Registrar at 1-888-691-8039 at the time the 
patient elects to proceed to BMT. 
4.2 
Registration to Induction Arm A - Step 1 
4.2.1 
Protocol Number  
4.2.2 
Investigator Identification  
4.2.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.2.2.2 
Investigator’s name (NCI number) 
4.2.2.3 
Cooperative Group Credit 
4.2.2.4 
Credit Investigator 
4.2.2.5 
Protocol specific contact information 
4.2.3 
Patient Identification  
4.2.3.1 
Patient’s initials (first and last) 
4.2.3.2 
Patient’s Hospital ID and/or Social Security number 
4.2.3.3 
Patient demographics 
4.2.3.3.1 
Gender 
4.2.3.3.2 
Birth date 
4.2.3.3.3 
Race 
4.2.3.3.4 
Ethnicity 
4.2.3.3.5 
Nine-digit ZIP code 
4.2.3.3.6 
Method of payment 
4.2.3.3.7 
Country of residence 
4.2.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1. 
4.2.5 
Classification 
4.2.5.1 
Intent to receive an allogeneic SCT or not 
4.2.6 
Additional Requirements  
4.2.6.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office – Boston. 
NOTE: 
During a shortage of preservative-free 
methotrexate, institutions without a sufficient 
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supply of preservative-free methotrexate, 
defined as 2 induction cycles worth of 
methotrexate, may not consent patients to the 
study. 
NOTE: 
During a shortage of sodium bicarbonate, 
institutions without a sufficient supply of sodium 
bicarbonate, defined as a one month supply, 
may not consent patients to the study. 
4.2.6.2 
Biological samples are to be submitted for defined 
laboratory research studies and/or future undefined 
research as outlined in Section 10. 
4.2.6.3 
Data collection for this study will be done exclusively 
through Medidata Rave clinical data management system. 
Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles 
assigned in Regulatory Support System (RSS). To access 
Rave via Medidata, the site user must have an active 
CTEP IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave 
role (Rave CRA, Rave Read-Only, Rave CRA (Lab 
Admin), Rave SLA, or Rave ) on either the LPO or 
participating organization roster at the enrolling site. To the 
hold Rave CRA role or Rave CRA (Lab Admin) role, the 
user must hold a minimum of an AP registration type. To 
hold the Rave Investigator role, the individual must be 
registered as an NPIVR or IVR. Associates can hold read-
only roles in Rave. 
Upon initial site registration approval for the study in RSS, 
all persons with Rave roles assigned on the appropriate 
roster will be sent study invitation e-mail from iMedidata. 
To accept the invitation, site users must log into the Select 
Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by 
clicking on the link in the upper right pane of the iMedidata 
screen. 
Users that have not previously activated their 
iMedidata/Rave accounts will also receive a separate 
invitation from iMedidata to activate their account. Account 
activation instructions are located on the CTSU website, 
Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). 
Additional information on iMedidata/Rave is available on 
the CTSU website under the Rave tab at 
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www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk 
at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.2.6.4 
Instructions for Patients who Do Not Start Assigned 
Protocol Treatment  
If a patient does not receive any assigned protocol 
treatment, baseline and follow-up data will still be collected 
and must be submitted through Medidata Rave according 
to the schedule in the E1910 Forms Completion 
Guidelines. 
4.3 
Register to Post-Induction Therapy - Intensification - Step 2- Arm B 
All patients meeting CR or CRi criteria in Sections 6.1 and 6.2 will register for 
post-induction therapy. 
4.3.1 
Protocol Number  
4.3.2 
Investigator Identification  
4.3.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.3.2.2 
Investigator’s name (NCI number) 
4.3.2.3 
Cooperative Group Credit 
4.3.2.4 
Credit Investigator 
4.3.2.5 
Protocol specific contact information 
4.3.3 
Patient Identification  
4.3.3.1 
Patient’s initials (first and last) 
4.3.3.2 
Patient’s Hospital ID and/or Social Security number 
4.3.3.3 
Patient demographics 
4.3.3.3.1 
Gender 
4.3.3.3.2 
Birth date 
4.3.3.3.3 
Race 
4.3.3.3.4 
Ethnicity 
4.3.3.3.5 
Nine-digit ZIP code 
4.3.3.3.6 
Method of payment 
4.3.3.3.7 
Country of residence 
4.3.4 
Additional Requirements 
4.3.4.1 
Biological samples are to be submitted for defined 
laboratory research studies and/or future undefined 
research as outlined in Section 10. 

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4.3.5 
Instructions for Patients who Do Not Start Assigned Protocol 
Treatment  
If a patient does not receive any assigned protocol treatment, baseline 
and follow-up data will still be collected and must be submitted 
through Medidata Rave according to the schedule in the E1910 Forms 
Completion Guidelines. 
4.4 
Randomization or Assignment to Blinatumomab or No Blinatumomab Step 3 
(Arms C and D) 
4.4.1 
Protocol Number  
4.4.2 
Investigator Identification  
4.4.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.4.2.2 
Investigator’s name (NCI number) 
4.4.2.3 
Cooperative Group Credit 
4.4.2.4 
Credit Investigator 
4.4.2.5 
Protocol specific contact information 
4.4.3 
Patient Identification  
4.4.3.1 
Patient’s initials (first and last) 
4.4.3.2 
Patient’s Hospital ID and/or Social Security number 
4.4.3.3 
Patient demographics 
4.4.3.3.1 
Gender 
4.4.3.3.2 
Birth date 
4.4.3.3.3 
Race 
4.4.3.3.4 
Ethnicity 
4.4.3.3.5 
Nine-digit ZIP code 
4.4.3.3.6 
Method of payment 
4.4.3.3.7 
Country of residence 
4.4.4 
Stratification 
4.4.4.1 
Age: < 55 years vs. age ≥ 55 years. 
4.4.4.2 
MRD status post intensification: Positive vs. Negative 
4.4.4.3 
CD20 status at study entry: Presence of distinct blast cell 
population of CD20 staining cells vs. absence of distinct 
blast cell population of CD20 staining cells 
4.4.4.4 
Rituximab use: Whether patient received or plans to 
receive rituximab 
4.4.4.5 
Whether patient intends to receive HSCT or not. 
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4.4.5 
Instructions for Patients who Do Not Start Assigned Protocol 
Treatment  
If a patient does not receive any assigned protocol treatment, baseline 
and follow-up data will still be collected and must be submitted 
through Medidata Rave according to the schedule in the E1910 Forms 
Completion Guidelines. 
4.4.6 
Additional Requirements 
4.4.6.1 
Bone marrow samples are required to be submitted for 
defined laboratory research studies as indicated in Section 
10.  
NOTE: 
FOR MRD ASSESSMENTS, AN ASPIRATE 
FROM A SEPARATE BONE MARROW 
ASPIRATION SITE MUST BE SUBMITTED 
(THE NEEDLE CAN BE RE-DIRECTED 
THROUGH THE SAME SKIN PUNCTURE 
SITE). ONLY SUBMIT ASPIRATES FROM 
THE FIRST PULL OF AN ASPIRATION SITE 
FOR MRD TESTING. DO NOT SUBMIT 
SAMPLES FROM THE SECOND OR THIRD 
PULL OF THE SAME ASPIRATION SITE. 
In B-lineage ALL, MRD levels in peripheral 
blood or from a dilute marrow aspiration can 
be 300% lower, on average, than those in 
bone marrow at a given time point. 
Submitting a first pull from a separate 
aspiration site will ensure that MRD 
determinations used in randomization and 
trial interpretation are accurate.  
MRD results will be reported to the 
submitting institution. 
4.4.6.2 
Biological samples are to be submitted for defined 
laboratory research studies and/or future undefined 
research as outlined in Section 10. 
4.5 
Register to Maintenance Therapy – Step 4 
4.5.1 
Protocol Number  
4.5.2 
Investigator Identification  
4.5.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.5.2.2 
Investigator’s name (NCI number) 
4.5.2.3 
Cooperative Group Credit 
4.5.2.4 
Credit Investigator 
4.5.2.5 
Protocol specific contact information 
4.5.3 
Patient Identification  
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4.5.3.1 
Patient’s initials (first and last) 
4.5.3.2 
Patient’s Hospital ID and/or Social Security number 
4.5.3.3 
Patient demographics 
4.5.3.3.1 
Gender 
4.5.3.3.2 
Birth date 
4.5.3.3.3 
Race 
4.5.3.3.4 
Ethnicity 
4.5.3.3.5 
Nine-digit ZIP code 
4.5.3.3.6 
Method of payment 
4.5.3.3.7 
Country of residence 
4.5.4 
Additional Requirements 
4.5.4.1 
Biological samples are to be submitted for defined 
laboratory research studies and/or future undefined 
research as outlined in Section 10. 
4.5.5 
Instructions for Patients who Do Not Start Assigned Protocol 
Treatment  
If a patient does not receive any assigned protocol treatment, baseline 
and follow-up data will still be collected and must be submitted 
through Medidata Rave according to the schedule in the E1910 Forms 
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5. 
Treatment Plan 
5.1 
Overall Study Design 
NOTE: 
Chemotherapy may be given +/- 1 day from the scheduled day as 
outlined throughout Section 5 
The study commences with a single induction arm that is administered in 2 
cycles. Patients who achieve CR or CRi after induction will undergo 
intensification with high-dose methotrexate and then be randomized to receive or 
not receive two cycles of blinatumomab followed by allogeneic SCT or 
consolidation/maintenance therapy. Patients initially randomized to 
blinatumomab will receive 2 additional cycles of blinatumomab in consolidation 
for a total of 4 cycles of blinatumomab.  
Hydroxyurea can be given for up to 5 days prior to initiation of protocol therapy 
for control of leukocyte count and/or other symptoms or signs. Corticosteroids 
can be given after pre-registration to the protocol and submission of baseline 
marrow and blood samples for control of leukocyte count and/or other symptoms 
or signs prior to initiation of protocol therapy if needed. If corticosteroids are 
given prior to pre-registration, contact the study chair as the patient may still be 
eligible to participate. 
Patients may receive the Day 1 dose of intrathecal cytarabine prior to study 
registration (see Sections 5.2.1.4 and 5.2.2.1). If administered prior to study 
registration, systemic chemotherapy must begin within 72 hours of this 
intrathecal therapy. 
Investigators must now declare their intention regarding allogeneic 
transplant for their patient as part of registration to step 3 as per Section 
4.2.5.1. The intent is for patient to receive/not receive transplant regardless 
of blinatumomab randomization. All patients who are considered to be 
possible allogeneic SCT candidates must be HLA typed as soon as 
possible, preferably in Cycle 1 of induction, to prevent delays in 
proceeding to transplant. 
The following options for donors should be explored: 
1. The availability of a matched sibling donor. 
2. The availability of a matched or mismatched unrelated donor (MUD or 
MMUD). 
3. The availability of single or double cord blood unit(s). 
4. The availability of a related haplotype match.  
NOTE: 
MRD assessments will be performed periodically during the 
course of treatment on this protocol as noted in Section 7 of the 
protocol. 
FOR MRD ASSESSMENTS, AN ASPIRATE FROM A SEPARATE 
BONE MARROW ASPIRATION SITE MUST BE SUBMITTED (THE 
NEEDLE CAN BE RE-DIRECTED THROUGH THE SAME SKIN 
PUNCTURE SITE).  ONLY SUBMIT ASPIRATES FROM THE FIRST 
PULL OF AN ASPIRATION SITE FOR MRD TESTING. DO NOT 
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SUBMIT SAMPLES FROM THE SECOND OR THIRD PULL OF THE 
SAME ASPIRATION SITE. 
In B-lineage ALL, MRD levels in peripheral blood or from a dilute 
marrow aspiration can be 300% lower, on average, than those in 
bone marrow at a given time point. Submitting a first pull from a 
separate aspiration site will ensure that MRD determinations 
used in randomization and trial interpretation are accurate. 
5.2 
Induction Therapy - Arm A 
5.2.1 
Initial Considerations 
5.2.1.1 
All patients are begun on Allopurinol at least 300 mg/day 
orally between days 1 and 22, inclusive. Reversible 
abnormalities of renal or metabolic function should be 
treated aggressively and corrected prior to induction. 
Provide appropriate and aggressive hydration as the 
situation warrants maintaining good urine output. Patients 
at high risk for tumor lysis syndrome can be considered for 
rasburicase therapy, 0.1 to 0.2 mg/kg/day IV over 30 
minutes for 1-3 days or up to five days (or a flat dose of 3 
or 6 mg daily) in addition to oral allopurinol depending on 
uric acid levels and the clinical status of the patient. 
NOTE: Rasburicase is contraindicated in patient with 
G6PD deficiency with or without chronic non-
spherocytic hemolytic anemia (CNSHA). Patients 
of Asian, African and Mediterranean ancestry 
should be tested for G6PD deficiency prior to 
starting rasburicase.   
5.2.1.2 
Immediate measures to diagnose and begin treatment of 
infections should be instituted prior to induction therapy. 
5.2.1.3 
Pre-medications including corticosteroids to prevent 
chemotherapy toxicities are permitted as per institutional 
standards. 
5.2.1.4 
Spinal Fluid Examination 
· 
Regardless of spinal fluid sugar or protein 
concentrations or cell count, a concentrated properly 
stained sediment should be examined (preferably by 
cytospin technique) for the presence of blast forms. 
This spinal fluid exam can be done prior to study 
registration or on day 1 of therapy with administration 
of intrathecal cytarabine (see Section 5.2.2.1). 
5.2.1.5 
Categories of CNS Involvement at Diagnosis 
· 
CNS 1: CSF has < 5 WBC/µL with cytospin negative 
for blasts; or > 10 RBC/µL with cytospin negative for 
blasts. 
· 
CNS 2: CSF has < 5 WBC/µL with cytospin positive for 
blasts; or > 10 RBC/µL with cytospin positive for blasts; 
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or ≥ 10 RBC/µL, WBC/µL ≥ 5, but less than 
Steinharz/Bleyer algorithm with cytospin positive for 
blasts (see below). 
· 
CNS 3: CSF has ≥ 5WBC/µL with cytospin positive for 
blasts; or ≥ 10 RBC/µL, ≥ 5 WBC/µL and positive by 
Steinharz/Bleyeer algorithm (see below); or clinical 
signs of CNS leukemia (such as facial nerve palsy, 
brain/eye involvement or hypothalamic syndrome). 
CNS2 and CNS3 patients who achieve a CR or CRi 
will receive 1800 cGy cranial radiation in 10 
fractions of 180 cGy per fraction during the first 
cycle of maintenance therapy. See Section 5.6. 
Steinharz/Bleyer Method of Evaluating Initial 
Traumatic Lumbar Punctures: 
If the patient has leukemia cells in the peripheral blood 
and the lumbar puncture is traumatic and contains ≥ 
5WBC/µL with blasts, the following algorithm should be 
used to define CNS disease: 
CSF WBC       >2X     Blood WBC 
 
CSF RBC                    Blood RBC 
Example: 
A patient with CSF WBC ≥ 5/µL with blasts whose CSF 
WBC/RBC is greater than twice the blood WBC/RBC 
ratio has CNS disease at diagnosis. If the CSF 
WBC=60/µL; CSF RBC=1500/µL; blood 
WBC=46,000/µL; blood RBC=3 x 106/µL: 
60/µL   = 0.04, and is >2X   46,000/µL = 0.015 
1500/µL                                 3x106/µL 
If CNS leukemia (CNS 2 or CNS 3 categories) is 
present at diagnosis, methotrexate 12.5 mg 
intrathecally or via an Ommaya Reservoir should be 
given twice weekly until blasts are not present in the 
spinal fluid. If the patient subsequently achieves a 
complete remission, a total dose of 1800 cGy of cranial 
irradiation in 10 daily fractions of 180 cGy per fraction 
will be administered during the first cycle of 
maintenance therapy (Section 5.6). 
5.2.1.6 
Radiation Therapy and Quality Assurance 
5.2.1.6.1 
Cranial Irradiation for CNS2 and CNS3 
Patients 
All patients who present with CNS2 and 
CNS3 leukemia at diagnosis and who 
achieve a CR will receive cranial radiation 
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during the first cycle of Maintenance 
Therapy. 
5.2.1.6.2 
Equipment and Calibration 
· 
Modality: X-ray beams with a nominal 
energy between 4 and 6 MV. 
· 
Calibration: Calibration of therapy units 
used in this protocol will be verified by 
the Radiological Physics Center (RPC). 
5.2.1.6.3 
Target Volume 
Target volume consists of entire brain and 
meninges, including frontal lobe as well as 
posterior halves of globes of eyes, with optic 
disk and nerve superior to vertex and 
posterior to occiput. Caudal border will be 
below skull base at C2 vertebral level. 
5.2.1.6.4 
Target Dose 
· 
Prescription Point: The prescription 
point in the cranial volume is at or near 
the center. For multi-convergent beams, 
the prescription point is usually at 
intersection of beam axes.  
NOTE: 
Regardless of the location of 
central axis, dose should be 
prescribed at the center of 
the cranial volume (midway 
between the maximum 
separation). 
· 
Dose Definition: Absorbed dose is 
specified in centigrays (cGy)-tomuscle. 
· 
Tissue Heterogeneity: No corrections for 
bone attenuation will be made. 
· 
Prescribed Dose and Fractionation: A 
total dose of 1800 cGy will be given in 
10 daily fractions of 180 cGy per 
fraction, administered Monday through 
Friday. 
5.2.1.6.5 
Dose Uniformity  
Dose variations in target volume will be 
within +7%, -5% of prescription point dose 
(From ICRU Report 50: small high-dose 
volumes can be excluded from evaluation of 
dose uniformity but not small low-dose 
volumes). 
5.2.1.6.6 
Treatment Interruptions 

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No corrections will be made for treatment 
interruptions less than 7 days. For treatment 
interruptions greater than 7 days, notify the 
Study Radiation Oncology Co-Chair. 
5.2.1.6.7 
Treatment Technique 
· 
Patient Position: It is recommended that 
the patient be treated in supine position. 
· 
Beam Configuration: Cranial volume is 
treated with two lateral, equally 
weighted photon beams. Fields will 
extend at least 1 cm beyond periphery 
of scalp. 
· 
Field Shaping: Field-shaping will be 
done with blocks which are at least 5 
HVL thick. Multi-leaf collimators are 
acceptable. 
· 
Eye Protection: A simple method to 
minimize lens XRT, while radiating 
posterior halves of eyes: let central axes 
of horizontal cranial beams go through 
both orbits. Anterior edges of beams are 
defined by external block or by 
independently controlled collimator and 
meet at a point 1 cm anterior to frontal 
lobe meninges. Shielding blocks cover 
anterior halves of eyes and protect nose 
and mouth. Essentially the same 
geometry can be achieved with central 
axes through center of head by angling 
lateral fields so rays through the eyes lie 
in the same horizontal plane. It is 
acceptable to use parallel-opposed 
beam pair, without such angling, with 
shielding blocks that cover anterior half 
of proximal eye. (Dose to contralateral 
lens will then increase). 
5.2.1.7 
Quality Assurance Documentation for Cranial RT 
5.2.1.7.1 
QARC Post Treatment Review 
Patients receiving cranial radiation therapy 
on this study will have a simple review of 
the treatment delivered.  
There will be no on-treatment review in this 
study. There is no volume review required. 
Within one week of the completion of 
radiotherapy, the following data shall be 
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· 
RT-2 Radiotherapy Total Dose Record 
· 
A copy of the patient’s radiotherapy 
record including the prescription, and 
daily and cumulative doses 
These data should be sent to: 
Quality Assurance Review Center 
640 George Washington Highway,  
Building A, Suite 201 
Lincoln, RI 02865 
Telephone: (401) 753-7600 
Fax: (401) 753-7601 
ECOG@QARC.org  
Questions regarding the dose calculations 
or documentation should be directed to: 
ECOG-ACRIN Protocol Dosimetrist 
Quality Assurance Review Center   
Contact information same as above 
5.2.1.7.2 
Definitions of Deviation in Protocol 
Performance 
· 
Prescription Dose Minor Deviation: 
The dose to the prescription point differs 
from that in the protocol by between 6% 
and 10%. 
· 
Prescription Dose Major Deviation: 
The dose to the prescription point differs 
from that in the protocol by more than 
10%. 
5.2.1.8 
All drug doses throughout the protocol are based on the 
patient’s actual weight. 
5.2.2 
Induction Drug Administration Schedule 
NOTE: 
Please see Section 5.3 for information regarding the 
substitution of IT cytarabine for IT methotrexate in the case 
of a methotrexate shortage. 
Two Cycles (1 and 2) of induction therapy are used. Doses are based 
on actual weight. 
5.2.2.1 
Cycle 1 Induction - Arm A (28 days) 
Cytarabine 70 mg IT Day 1 
Daunorubicin 25 mg/m2 IV push Day 1, 8, 15 and 22 
Vincristine 1.4 mg/m2 IV push Day 1, 8, 15 and 22 
(maximum amount 2 mg per dose) 
Dexamethasone 10 mg/m2 PO daily Day 1-7, 15-21 (cap at 
20 mg per day; Days 1-7 only if age ≥ 55 years) 
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Methotrexate 12.5 mg intrathecally day 14 +/- 1 (omit if 
patient received intrathecal treatment for CNS leukemia as 
per Section 5.2.1.5).Hydrocortisone 50 mg intrathecally 
can optionally combined with methotrexate if desired to 
lessen the risk of arachnoiditis. 
Pegaspargase 2,000 international units/m2 (IU) IM or IV 
(recommended) Day 18 (OMIT if age ≥ 55 years) (Cap 
dose at one vial total, 3750 IU). Premedicate with 
acetaminophen 650 mg PO, diphenhydramine 25-50 mg 
PO or IV and hydrocortisone 100 mg IV (hydrocortisone is 
optional if receiving dexamethasone on the same day). 
Rituximab 375mg/m2 IV infusion Day 8 and 15 if CD20 
positive (do not administer if patient is CD20 negative); 
optional and not required to give if not available or desired. 
NOTE: 
If patient is CD20 positive and positive for 
hepatitis B, and rituximab treatment is planned, 
prophylaxe the patient with lamivudine, 
entecavir, or tenofovir as per figure 1 of recently 
published guidelines78. 
· 
HLA Typing and Donor Search 
This should be done as soon as possible before or during 
Cycle 1 of induction chemotherapy if the patient is 
considered to be a candidate for allogeneic SCT. 
· 
Bone Marrow Aspiration and Biopsy 
A bone marrow aspiration and biopsy is performed on Day 
28 of induction (or as close to this date as possible) to 
assess remission status. See Section 5.1 above regarding 
MRD sample from this marrow. Regardless of the results, 
Cycle 2 should then be initiated. 
FOR MRD ASSESSMENTS, AN ASPIRATE FROM A 
SEPARATE BONE MARROW ASPIRATION SITE MUST 
BE SUBMITTED (THE NEEDLE CAN BE RE-DIRECTED 
THROUGH THE SAME SKIN PUNCTURE SITE).  ONLY 
SUBMIT ASPIRATES FROM THE FIRST PULL OF AN 
ASPIRATION SITE FOR MRD TESTING. DO NOT 
SUBMIT SAMPLES FROM THE SECOND OR THIRD 
PULL OF THE SAME ASPIRATION SITE. 
In B-lineage ALL, MRD levels in peripheral blood or 
from a dilute marrow aspiration can be 300% lower, on 
average, than those in bone marrow at a given time 
point. Submitting a first pull from a separate aspiration 
site will ensure that MRD determinations used in 
randomization and trial interpretation are accurate. 
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5.2.2.2 
Cycle 2 Induction - Arm A (42 Days) 
· 
Cycle 2 of the induction regimen begins on day 29 from 
start of Cycle 1 induction. It should be postponed until 
ANC ≥ 0.75 x 109/L and platelets > 75 x 109/L, 
whichever is later, in patients with delayed hematologic 
recovery. If patient has residual disease that is 
delaying count recovery, cycle 2 can begin 
immediately. 
· 
If the ANC and/or platelets fail to recover within 2 
weeks of day 28 (i.e., by day 42), contact the study 
chair or co-chair.  
· 
Therapy should be interrupted for patients who are 
febrile, neutropenic, and proven infected and resumed 
at the same point when the signs of infection have 
abated. Otherwise, therapy during this course should 
not be interrupted for myelosuppression alone except 
on day 29. Hold all of the day 29 chemotherapy of 
cycle 2 Induction until ANC ≥ 0. 75x109 /L and 
platelets > 75x109 /L, then continue chemotherapy 
to complete the full course of cycle 2 of Induction 
(no doses of any drugs should be omitted). 
· 
Cycle 2 consists of the following: 
Cyclophosphamide 1000 mg/m2   IV in 250 cc normal 
saline over 30 min Days 1 and 29. (Patients > 60 years 
give Cyclophosphamide 800 mg/m2 per dose) 
Cytarabine 75 mg/m2/day IV or Sub-Q on Day 1-4, 8-
11, 29-32, and 36-39. Intravenous cytarabine can be 
prepared in 100 cc D5W and given over 30 minutes. 
6-mercaptopurine (6-MP) 60 mg/m2 orally Days 1-14, 
29-42 (take at bedtime on an empty stomach 1 hour 
before or 2 hours after food and/or milk products). 
Adjust dose using 50 mg tablets and different doses on 
alternating days in order to attain a weekly cumulative 
dose as close to 420 mg/m2/week. See Appendix IX 
for details. 
Pegaspargase 2,000 international units/m2 (IU) IM or IV 
(recommended) Day 15 (OMIT if age ≥ 55 years) (cap 
dose at 1 vial total, 3750 IU). Premedicate with 
acetaminophen 650 mg PO, diphenhydramine 25-50 
mg PO or IV and hydrocortisone 100 mg IV. 
Methotrexate 12.5 mg intrathecally days 1, 8, 15 and 
22 +/- 1 day. These 4 doses should be given even if 
the patient was treated for CNS 2 or 3 leukemia in 
cycle 1. Hydrocortisone 50 mg intrathecally can 
optionally combined with methotrexate if desired to 
lessen the risk of arachnoiditis. 
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Rituximab 375mg/m2 IV infusion Day 8 and 15 if CD20 
positive (do not administer if patient is CD20 negative); 
optional and not required to give if not available or 
desired. 
NOTE: 
If patient is CD20 positive and positive for 
hepatitis B, and rituximab treatment is 
planned, prophylaxe the patient with 
lamivudine, entecavir, or tenofovir as per 
figure 1 of recently published guidelines78. 
A bone marrow biopsy with cytogenetics should be 
performed upon blood count recovery to confirm the 
patient has achieved a CR or CRi. If blood counts are 
not recovering, a bone marrow biopsy should be done 
to look for residual disease. If no residual disease 
noted and counts have not recovered by 4 weeks after 
day 42 (day 70), contact the study chair or co-chair. 
5.2.2.2.1 
Dose Modifications for Initial Induction 
· 
Pegaspargase Related Toxicities 
NOTE: 
If the patient is allergic to 
pegaspargase or if 
pegaspargase is not 
available, Erwinia-
Asparaginase may be 
substituted. 
Erwinia asparaginase 25,000 
international units/m2 (IU/m2) IM or IV 3 
times per week for 6 doses for each 
planned dose of pegaspargase. 
Modifications of pegaspargase dosage 
in the initial Cycle 1 induction treatment 
should be made as follows: 
For each dose of pegaspargase or 
Erwinia asparaginase, an anaphylaxis 
kit should be available at the bedside 
and the patient should be observed for 1 
h after IM or IV administration. Steroids, 
antihistamines, oxygen, and epinephrine 
should be administered as clinically 
indicated. 
Read More: 
http://informahealthcare.com/doi/full/10.
3109/10428194.2011.596963 
Despite hyperglycemia, the drug should 
be continued in full doses with insulin 
administration as indicated. Patients 
being retreated (8 week gap between 
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induction, Cycle 1 and intensification) 
and those receiving infrequent dosing 
are at increased risk of experiencing 
anaphylaxis. 
Dose modifications of asparaginase for 
the following toxicities: 
a. Pancreatitis – for clinical > grade 2 
pancreatitis with elevated serum 
amylase or lipase and/or 
radiographic abnormalities, 
discontinue asparaginase. No further 
asparaginase should be given. 
b. Hyperbilirubinemia – for grade 3 or 4 
hyperbilirubinemia withhold 
asparaginase and administer next 
scheduled dose if toxicity has 
resolved. Do not make up missed 
doses. 
c. Deep venous thrombosis or 
pulmonary embolism – for > grade 3 
thrombosis, withhold asparaginase 
until acute toxicity and clinical signs 
resolve and consider treatment with 
fresh frozen plasma or antithrombin 
III (AT3). Do not withhold dose for 
abnormal laboratory findings without 
clinical correlate. Discuss 
anticoagulant therapy with the study 
chair if needed. Contact the study 
chair if considering discontinuation 
of further asparaginase. 
d. Hemorrhage – for > grade 2 
hemorrhage in conjunction with 
hypofibrinogenemia, withhold 
asparaginase until toxicity is < grade 
1. Consider treatment with 
cryoprecipitate or fresh frozen 
plasma. 
e. Hypertriglyceridemia - For grade 4 
hypertriglyceridemia, hold further 
doses of asparaginase until 
triglyceride level is < grade 3. 
Strongly consider therapy with 
omega-3 fatty acids and a lipid-
lowering agent such as gemfibrozil 
or fenofibrate. Can resume 
asparaginase if triglyceride level  
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Contact study chair if additional 
clarification needed. 
Prevention of thrombo-hemorrhagic 
complications 
Practices vary widely in prevention of these 
complications and range from no screening 
and prophylaxis to screening and 
administration of antithrombin III (ATIII) and 
clotting factors. One suggested approach is 
to obtain aPTT, PT, ATIII and fibrinogen 
levels at baseline and to monitor these 
parameters daily to every few days and to 
administer cryoprecipitate, 10 units, for 
fibrinogen levels < 50-100 mg/dL and to 
administer ATIII for levels < 60-70% of 
normal.  Dosage of AT (THROMBATE III) 
can be calculated from the following formula 
(refer to the package insert):  
units required (IU)= 
[desired - baseline AT level ] × weight (kg) 
1.4 
· 
Hepatic Toxicity 
Daunorubicin and Vincristine doses 
should be modified on a weekly basis. 
Direct Bilirubin 
Dose of Vincristine to Give 
Dose of Daunorubicin to Give 
2 - 3 (mg/dL) 
100% calculated 
50% calculated 
> 3 
50% calculated 
25% calculated 
· 
Neurotoxicity 
The vincristine dose should be modified 
to 50% for paresthesia proximal to the 
DIP joints and stopped entirely for major 
muscle weakness, cranial nerve palsy or 
severe ileus. 
· 
Hematologic Toxicity 
Patients developing anemia may be 
transfused at the discretion of the 
investigator. No dose reductions are 
needed for any degree of anemia or for 
grade 1-4 neutropenia. 
Similarly, if platelet counts can be 
maintained by the periodic 
administration of platelet transfusions, 
no dose reductions are foreseen for 
grade 4 thrombocytopenia. 
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There will be no routine 6-MP dose 
modifications based on ANC or platelets 
during induction therapy.  It is 
recommended that patients have their 
thiopurine methyltransferase (TPMT) 
status and/or their thiopurine metabolite 
concentrations evaluated, so that the 
dose of 6-MP can be reduced in patients 
with a TPMT defect.  Patients with the 
rare homozygous deficient TPMT 
phenotype may tolerate only 1/10th to 
1/20th the average 6-MP dose. 
Heterozygotes may need a 30-50% 
dose reduction of 6-MP. TPMT testing 
and thiopurine metabolite 
measurements are commercially 
available. 
NOTE: 
When administered with 
allopurinol, the dose of 
mercaptopurine is reduced to 
25%-30% of the usual dose. 
Allopurinol inhibits xanthine 
oxidase, which metabolizes 
mercaptopurine. 
5.2.2.3 
Supportive Care 
Throughout both cycles of induction therapy, 
hematopoietic growth factor (HGF) therapy – either G-CSF 
or GM-CSF - may be used at the investigators discretion. 
Use of HGF during such therapy should be noted on the 
data forms. 
However, HGF therapy should not be used concurrently 
with alkylating agents, anthracyclines or antimetabolite 
chemotherapy drugs. 
· 
Beginning with induction start 
trimethoprim/sulfamethoxazole prophylaxis. Dose and 
schedule can be as per local institutional standards. 
For patients allergic to or experiencing excessive 
myelosuppression with trimethoprim/sulfamethoxazole, 
alternative prophylactic regimens including dapsone, 
atovaquone, or aerolized pentamidine (300 mg monthly 
via nebulizer).   
· 
Additional antibiotic therapy can be given based on 
institutional guidelines.  Avoid use of voriconazole or 
posaconazole with vincristine therapy. 
5.2.3 
Preservative-Free Methotrexate Shortage Guidelines 
The following are guidelines for managing the treatment of enrolled 
participants on E1910, as well as those individuals who have been 
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screened, and future participants, when the methotrexate supply is 
not adequate: 
5.2.3.1 
For enrolled patients (including those who are consented, 
but not yet registered/treated) 
During a shortage of preservative-free methotrexate, 
institutions without a sufficient supply of preservative-free 
methotrexate for intrathecal use can switch to using 
cytarabine intrathecally. The suggested dose of IT 
cytarabine is 100 mg (or per local institutional standard) 
and is to be administered following the IT methotrexate 
schedule for the given cycle. The cytarabine can optionally 
be combined with 50 mg of hydrocortisone if desired. 
Once an adequate supply of IT methotrexate has been 
obtained, the patient should be switched back to IT 
methotrexate in the following cycle. 
All other aspects of therapy and monitoring should be 
followed. 
NOTE: 
This substitution constitutes an unanticipated 
event that must be reported to the IRB of 
record. It is very important to document in the 
research record that the substitution was due to 
the preservative-free methotrexate shortage. 
5.2.3.2 
For screened patients (not yet consented) and future 
patients: 
An adequate supply of preservative-free methotrexate, 
defined as 2 induction cycles worth of methotrexate, must 
be available for a potential participant prior to consenting 
and registering the patient to E1910. Institutions whose 
methotrexate supply is not adequate to cover at least 2 
induction cycles worth of therapy for a potential participant 
must not consent or register new patients into the study 
until the methotrexate supply issue is resolved. 
5.3 
Post-Induction Therapy - Intensification Arm B (28 days) 
Patients must have achieved CR or CRi in order to begin intensification 
therapy. See Section 6 for definitions. 
NOTE: 
Please see Section 5.3.1.1 for information regarding the substitution 
of cytarabine, followed the next day by pegaspargase for high dose 
methotrexate in the case of a methotrexate shortage. 
NOTE: 
If dosing modifications or delays are required during intensification 
therapy, contact the study chair to discuss. 
5.3.1 
Intensification Therapy with High Dose Methotrexate 
Intensification commences upon achievement of a CR or CRi after the 
completion of the second cycle of induction (Arm A, Cycle 2). If CR or 
CRi not achieved and there is no evidence of refractory or relapsed 
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disease by 4 weeks after end of cycle 2 of induction, contact the study 
chair or co-chair. 
NOTE: 
A BONE MARROW ASPIRATE AND BIOPSY WILL BE 
PERFORMED AT THE TIME OF BLOOD COUNT 
RECOVERY WHEN PLATELETS > 75 x 10^9/L (> 
75,000/mm^3) AND NEUTROPHILS ≥ 0.75x10^9/L (≥ 
750/mm^3). IF COUNTS FAIL TO RECOVER WITHIN 6 
WEEKS AFTER THE END OF INTENSIFICATION, 
CONTACT THE STUDY CHAIR. A SAMPLE FOR MRD 
MUST BE OBTAINED. WITHOUT THIS MRD SAMPLE 
PATIENTS WILL NOT BE ABLE TO BE RANDOMIZED 
AND WILL HAVE TO BE TREATED OFF-STUDY. 
Methotrexate 3 g/m2-in 500 ml NS IV over 2 hrs Day 1 and 8 
NOTE: 
With high doses of methotrexate recommend pre-hydration 
and other supportive care according to the institutional 
guidelines. In addition, there are potential drug-interactions 
with methotrexate. Avoid using NSAIDs, 
trimethoprim/sulfamethoxazole, penicillin, probenecid, IV 
contrast media, proton pump inhibitors, phenytoin and 
fosphenytoin on the same day of MTX.  
NOTE: 
Order leucovorin as per guidelines below (or may use 
institutional guidelines for measurement of methotrexate 
levels and leucovorin dosing). Check methotrexate level at 
24 and 48 hours post infusion, and repeat every 24 hours 
until methotrexate level < 0.1 µmol/L.  Order leucovorin as 
per guidelines below: 
Guidelines at 24 hours: If methotrexate level is less than 10 umol/L 
continue leucovorin at current dosing.  If methotrexate level is greater 
than 10 µmol/L at 24 hours or if creatinine increases greater than 50% 
of the pre- methotrexate level increase leucovorin to 100 mg/m2 IV in 
100 ml D5W every three hours until methotrexate level is less than 0.1 
µmol/L. 
Guidelines at 48 hours: If methotrexate level is greater than 1 µmol/L 
at 48 hours or if creatinine increases greater than 50% of the pre- 
methotrexate level increase leucovorin to 100 mg/m2 IV in 100 ml 
D5W every three hours until methotrexate level is less than 0.1 
µmol/L. 
Pegaspargase 2,000 IU/m2 IM (1,000 IU/m2 age ≥ 55) or IV 
(recommended) day 9 (Cap dose at one vial total, 3750 IU). 
Premedicate with acetaminophen 650 mg PO, diphenhydramine 25-
50 mg PO or IV and hydrocortisone 100 mg IV. Refer to Section 
5.2.2.2.1 for pegaspargase related toxicities and dose modifications. 
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Leucovorin Rescue 10 mg/m2 IV in 50 ml D5W 22-24 hrs after 
completion of each methotrexate infusion every 6 hrs for 4 doses 
followed 6 hours later by 10 mg/m2 orally every 6 hours for 72 hrs. 
NOTE: 
A BONE MARROW ASPIRATE AND BIOPSY WILL BE 
PERFORMED AT THE TIME OF BLOOD COUNT 
RECOVERY.  A SAMPLE FOR MRD MUST BE 
OBTAINED.  WITHOUT THIS MRD SAMPLE PATIENTS 
WILL NOT BE ABLE TO BE RANDOMIZED AND WILL 
HAVE TO BE TREATED OFF-STUDY. PLEASE ALLOW 
UP TO 7-10 DAYS IN TREATMENT PLANNING FOR 
THE PATIENT FOR THE MRD ANALYSIS TO BE 
COMPLETED AND RESULTS POSTED IN RAVE. 
FOR MRD ASSESSMENTS, AN ASPIRATE FROM A 
SEPARATE BONE MARROW ASPIRATION SITE MUST 
BE SUBMITTED (THE NEEDLE CAN BE RE-DIRECTED 
THROUGH THE SAME SKIN PUNCTURE SITE).  ONLY 
SUBMIT ASPIRATES FROM THE FIRST PULL OF AN 
ASPIRATION SITE FOR MRD TESTING. DO NOT 
SUBMIT SAMPLES FROM THE SECOND OR THIRD 
PULL OF THE SAME ASPIRATION SITE. 
In B-lineage ALL, MRD levels in peripheral blood or 
from a dilute marrow aspiration can be 300% lower, on 
average, than those in bone marrow at a given time 
point. Submitting a first pull from a separate aspiration 
site will ensure that MRD determinations used in 
randomization and trial interpretation are accurate. 
NOTE: 
Only patients who are MRD negative as determined by 
central assessment in the E-A Leukemia Translational 
Research Laboratory (LTRL) will be randomized. 
Patients who are MRD positive as determined by 
central assessment in the LTRL will be assigned to 
Arm C of the protocol and receive blinatumomab.   
Patients randomized to receive blinatumomab will proceed to 
blinatumomab therapy as per Section 5.3.1.1. 
Patients randomized to NOT receive blinatumomab will proceed 
directly to consolidation chemotherapy as per Section 5.5. 
5.3.1.1 
Preservative-Free Methotrexate Shortage Guidelines 
The following are guidelines for managing the treatment of 
enrolled participants on E1910, as well as those individuals 
who have been screened, and future participants, when 
the methotrexate supply is not adequate: 
5.3.1.1.1 
For enrolled patients (including those who 
are consented, but not yet 
registered/treated) 
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This substitution is for Intensification-Arm B. 
During a shortage of preservative-free 
methotrexate, institutions can substitute 
high dose methotrexate with cytarabine. 
The dose of cytarabine is 2 g/m2 IV Q12H 
over 2 hours on day 1 and 8 (or 1 g/m2 if the 
patient age > 60). This is followed by 
pegaspargase 1,000 IU/m2 IM or IV on day 
9 (500 IU/m2 if patient age ≥ 55) (cap dose 
at one vial total or 3750 IU). 
All other aspects of therapy and monitoring 
should be followed. 
NOTE: 
This substitution constitutes an 
unanticipated event that must be 
reported to the IRB of record. It 
is very important to document in 
the research record that the 
substitution was due to the 
preservative-free methotrexate 
shortage. 
5.3.1.1.2 
For screened patients (not yet consented) 
and future patients: 
An adequate supply of preservative-free 
methotrexate, defined as 2 induction cycles 
worth of methotrexate, must be available for 
a potential participant prior to consenting 
and registering the patient to E1910. 
Institutions whose methotrexate supply is 
not adequate to cover at least 2 induction 
cycles worth of therapy for a potential 
participant must not consent or register new 
patients into the study until the methotrexate 
supply issue is resolved. 
5.3.2 
Blinatumomab Therapy - Arm C: Cycle 1 and 2 (28 days each, with a 
14 day break between cycles) 
NOTE: 
Patients who are MRD positive as determined by 
central assessment in the LTRL will be assigned to 
Arm C of the protocol and receive blinatumomab. 
Blinatumomab therapy commences after recovery from intensification 
when ANC ≥ 0.75 x 109/L and platelets > 75 x 109/L. 
Patients randomized to blinatumomab will receive two treatment 
cycles of blinatumomab at a dose of 28 mcg/day by continuous 
infusion. For dose modifications in case of AEs see Section 5.3.2.2. 
NOTE: 
See Section 5.3.2.2.1 regarding inpatient and outpatient 
treatment with blinatumomab. It is recommended that 
patients are hospitalized at least during the first three days 
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of the first cycle and the first two days of the subsequent 
cycle. 
NOTE: 
HGF therapy should not be administered during any cycles 
of blinatumomab therapy.   
NOTE: 
A bone marrow aspirate and biopsy will be performed at 
the time of blood count recovery after the second cycle of 
blinatumomab. A sample for MRD assessment must be 
obtained. For MRD assessments, an aspirate from a 
separate bone marrow aspiration site must be submitted 
(the needle can be re-directed through the same skin 
puncture site). Only submit aspirates from the first pull of 
an aspiration site for MRD testing. Do not submit samples 
from the second or third pull of the same aspiration site. 
NOTE: 
MRD positive patients who are assigned to receive 
blinatumomab should also have a bone marrow biopsy 
performed at the end of the first cycle of blinatumomab to 
assess MRD status. 
A cycle consists of a continuous IV infusion over four weeks. Cycle 1 
of blinatumomab should be followed by a treatment free interval of two 
weeks before beginning cycle 2 of treatment. 
Blinatumomab should be administered through a central venous 
access. In the event that administration through a central venous 
access is not possible, blinatumomab may be administered 
temporarily through a peripheral venous line if the patient is 
hospitalized. The final solution for infusion should be administered 
through a sterile 0.2 μm in-line filter. 
The drug administration should not be interrupted, if possible. In case 
of infusion interruption due to any technical or logistic reason the 
interruption should be as short as possible and the infusion continued 
at the earliest time possible. Every interruption longer than one hour 
should be documented. If the interruption is longer than four hours, re-
start of the infusion should be performed in the hospital, under 
supervision of the investigator. The patient should be observed 
overnight for possible side effects after the re-start in the hospital and 
can be dismissed the following day if no difficulties arise. 
Administration of the premedication described in Section 5.3.2.1, 
Premedication and Concomitant Medication, is recommended. If 
possible, the infusion time before and after a break should sum up to 
28 days treatment per cycle. 
NOTE: 
It should be emphasized to the medical staff and the 
patient and family regarding the importance of not having 
any treatment interruption during the blinatumomab 
therapy to the extent possible 
Infusion bags should be changed in accordance with local pharmacy 
standards for infusion of compounded sterile products. All infusion 
bags may be changed every 4th day (not to exceed 96 hours) if 
preservative-free 0.9% sodium chloride is used in the US and in the 
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foreign sites. Shorter time intervals of 24, 48 or 72 hours may also be 
utilized for convenience of patient scheduling as needed. If 
bacteriostatic sodium chloride is used, a longer time interval of 7 days 
(168 hours) for bag changes may be used. See Section 8.1.7 for 
details. 
5.3.2.1 
Pre-Medication and Concomitant Medications 
Within one hour prior to start of treatment in each 
treatment cycle for the prevention of acute reactions to 
blinatumomab: 
· 
Mandatory administration of dexamethasone (20 mg 
IV) 
During treatment period: 
· 
Patients should receive adequate hydration according 
to institutional guidelines. 
· 
Patients will perform a writing test (Appendix VI) which 
will be evaluated by medical staff and performed at the 
time of visits for blinatumomab bag changes or weekly 
clinical visits for evidence of early signs of neurologic 
toxicity.  If changes noted, patients should be 
monitored and graded for other signs of neurologic 
toxicity according to CTCAE.  The writing test samples 
can be filed at the center and need not be submitted to 
ECOG-ACRIN 
· 
Non-steroidal anti-inflammatory drugs (NSAIDs) should 
be avoided if possible because they are a potential 
cause of endothelial stress.  
· 
Recommended first choice medications for fever 
management are paracetamol/acetaminophen and/or 
dexamethasone. The dexamethasone dose should be 
reduced step-wise as soon as the fever resolves. If 
these medications are not sufficiently effective, 
pethidine/meperidine is recommended. For 
pethidine/meperidine, adequate anti-emetic prophylaxis 
should be administered. 
Fluid Intake/Output Monitoring 
Close monitoring of fluid status by intake and output 
should be undertaken for the first week of blinatumomab 
infusion. Efforts to keep patients balanced between intake 
and output should be maintained, even if diuretic therapy 
(furosemide or similar) is needed to do this. Careful 
attention to fluid status may prevent deterioration from 
capillary leak, however even with meticulous attention, 
some patients will experience pulmonary edema and 
require more aggressive respiratory support. Treating 
physicians should use their clinical judgment and 
institutional standards for whatever supportive care 
measures are needed during this period of time. 
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Monitoring of Disseminated Intravascular Coagulation 
(DIC) 
In the first days of treatment, transient disseminated 
intravascular coagulation (DIC)-like pictures may develop. 
Because patients are at risk for capillary leak syndrome 
and cytokine release syndrome, appropriate supportive 
care with dexamethasone (see Table 5.2 under the 
“Action” heading), blood products and factors (packed red 
cells, platelets, cryoprecipitate, fresh frozen plasma), 
vitamin K, and/or albumin should be considered according 
to institutional standards of care. Particularly in the first 
week of infusion, when the risk of capillary leak and 
cytokine release is more prominent, appropriate use of 
blood products and factors is preferred if laboratory 
indications suggest the need for replacement, as large 
volumes of crystalloid fluids tend to exacerbate the 
capillary leak. See the “Dose Modifications/Infusion 
Interruptions for Blinatumomab” section for guidelines 
regarding blinatumomab dose modifications and AE 
management. 
Hematological Monitoring 
In the first days of treatment, a rapid transient drop in 
platelets, neutrophils and/or hemoglobin may be observed. 
These effects are not necessarily cytokine-mediated. 
Counts typically recover to baseline during treatment, and 
usually within two weeks of starting blinatumomab. 
Transfusion of blood and platelets should be performed 
according to appropriate institutional standards. 
Blinatumomab dose modification and AE management 
guidelines for decreases in neutrophils, lymphocytes, and 
platelets can be found in the “Dose Modifications/Infusion 
Interruptions for Blinatumomab” section. 
Monitoring of Blood ALT/AST levels 
In the first days of treatment, transient increases in 
transaminases (alanine aminotransferase [ALT] and 
aspartate aminotransferase [AST]) up to over 1000 U/L 
may develop.  These have generally returned to baseline 
in the first week of treatment.  Blinatumomab dose 
modification and AE management guidelines for Grade 3 
and 4 increases in ALT or AST can be found in the “Dose 
Modifications/Infusion Interruptions for Blinatumomab” 
section. 
5.3.2.2 
Dose Modifications/Infusion Interruptions for Blinatumomab 
Before any re-start, for an interruption of 4 hours or longer, 
the pre-treatment has to be administered as described in 
Section 5.3.2.1. 
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Re-start of the infusion should be performed in the 
hospital, under supervision of the investigator.   
Treatment interruptions of up to 28 days for reasons other 
than adverse events (including but not limited to issues 
with access to care) are permitted. The reason for the 
delay must be documented in the patient’s record. 
Please see table below for determination of treatment 
cycle duration following treatment interruption for all 
adverse events. 
Table 5.1 Determination of Cycle Length Following 
Treatment Interruption for Adverse Events 
Length of Dose 
Interruption Due to 
AE 
Length of Treatment 
Prior to AE Onset 
Investigator Action Once Blinatumomab 
is Restarted 
≤ 7 days 
- 
Continue same cycle of blinatumomab for a 
total treatment duration of 28 days on 
blinatumomab 
8 to 28 days 
≤ 14 days 
Cycle of treatment will be re-started as if a 
new cycle and continue for an additional 28 
days total 
8 to 28 days 
> 14 days 
This cycle of treatment will terminated and 
not be repeated 
> 28 days 
- 
Permanent discontinuation of treatment 
NOTE: 
If the above adverse events resolve to a level allowing resumption of 
blinatumomab in less than 28 days, but logistical difficulties arise, restart of 
treatment can be postponed for up to five additional days without resulting 
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Table 5.2 Table of Dose Modifications for Adverse Events Possibly, Probably, or 
Definitely Related to Blinatumomab 
Adverse Event 
(CTCAE v4.0 term) 
AE Grade 
Action 
Events within the 
“Nervous system 
disorders” or 
“Psychiatric 
disorders” System 
Organ Class 
(SOC)* 
Grade 1 
Continue at same dose level. 
 
Grade 2 
Dexamethasone should be administered at a dose of at least 24 mg 
per day (8 mg every 8 hours orally or IV) for up to three days.  The 
dexamethasone dose will then be reduced step-wise over up to four 
days.  
 
Grade 3 
Infusion of the blinatumomab must be stopped immediately. 
Dexamethasone should be administered at a dose of at least 24 mg 
per day (8 mg every 8 hours orally or IV) for up to three days.  The 
dexamethasone dose will then be reduced step-wise over up to four 
days.  
Hold blinatumomab until AE resolves to Grade ≤ 1, then resume 
drug at 9 mcg/day. Subsequent cycles of blinatumomab will be 
administered at 9mcg/day. 
Infusion should be re-started in the hospital, under supervision of 
the investigator and the patient should remain hospitalized for at 
least two days.  
Within one hour prior to re-start of treatment and within one hour 
prior to any dose increases, patients must receive 20 mg of 
dexamethasone intravenously. 
At first three days after re-start, vital sign measurements and writing 
tests should be performed on study days 1- 3.  
If patient has already been dose reduced to 9 mcg/day dose for any 
reason and Grade 3 event occurs, blinatumomab should be 
discontinued permanently.  
 
Grade 4 
Infusion of the blinatumomab must be stopped immediately. 
Dexamethasone should be administered at a dose of at least 24 mg 
per day (8 mg every 8 hours orally or IV) for up to three days. The 
dexamethasone dose will then be reduced step-wise over up to four 
days.  
Blinatumomab should be discontinued permanently. 
Seizure 
Grade 1-3 
As per Grade 3 Nervous System/Psychiatric Disorders (above). 
Appropriate prophylactic therapeutic doses of anticonvulsant 
treatment (e.g. phenytoin or levetiracetam) will be administered 
during subsequent infusions of blinatumomab. 
 
Grade 4 
As per Grade 4 Nervous System/Psychiatric Disorders (above). 
Appropriate prophylactic therapeutic doses of anticonvulsant 
treatment (e.g. phenytoin or levetiracetam) will be administered 
during subsequent infusions of blinatumomab. 

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Adverse Event 
(CTCAE v4.0 term) 
AE Grade 
Action 
All other events 
under “Nervous 
system disorders” 
or “Psychiatric 
disorders” SOC** 
Grade 1-4 
Continue therapy with supportive care as per institutional guidelines. 
Cytokine release 
syndrome (CRS), 
Allergic reaction, 
Anaphylaxis, or 
Infusion related 
reaction 
Grade 1 
Continue therapy with supportive care, as per local institutional 
guidelines. 
 
Grade 2 
The infusion of the blinatumomab must be stopped immediately. 
Supportive care, as per institutional guidelines. 
If the interruption is longer than four hours, re-start of the infusion 
should be performed in the hospital, under supervision of the 
investigator.  
Within one hour prior to re-start of treatment and within one hour 
prior to any dose increases, patients must receive 20 mg of 
dexamethasone intravenously. 
 
Grade 3 
The infusion of the blinatumomab must be stopped immediately. 
Dexamethasone should be administered at a dose of at least 24 mg 
per day (8 mg every 8 hours orally or IV) for up to three days.  
The dexamethasone dose will then be reduced step-wise over up to 
four days.  
Hold blinatumomab until resolves to Grade ≤ 1, then resume drug at 
9 mcg/day for one week. If toxicity remains Grade ≤ 1, increase 
dose to 28 mcg/day to complete 28 day cycle of therapy.  
Within one hour prior to re-start of treatment and within one hour 
prior to any dose increases, patients must receive 20 mg of 
dexamethasone intravenously. 
If Grade 3 recurs after blinatumomab is resumed, stop drug 
permanently.   
If the initial adverse event lasts for ≥ 2 weeks without improvement, 
then blinatumomab will be permanently discontinued.   
 
Grade 4 
Blinatumomab should be discontinued permanently. 

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Adverse Event 
(CTCAE v4.0 term) 
AE Grade 
Action 
Aspartate 
aminotransferase 
increased, Alanine 
aminotransferase 
increased (AST, 
ALT) 
Grade 1-2 
Continue at same dose level. 
 
Grade 3-4 
Hold blinatumomab until AE resolves to Grade ≤ 1, then resume 
drug at 9 mcg/day for one week.  If toxicity remains Grade ≤ 1, 
increase dose to 28 mcg/day to complete 28 day cycle of therapy. If 
Grade 3-4 toxicity recurs, stop drug permanently. 
Within one hour prior to re-start of treatment and within one hour 
prior to any dose increases, patients must receive 20 mg of 
dexamethasone intravenously.   
Blood bilirubin 
increased 
Grade 1-2 
Continue at same dose level. 
 
Grade 3-4 
Hold blinatumomab until AE resolves to Grade ≤ 1, then resume 
drug at 9 mcg/day for one week.  If toxicity remains Grade ≤ 1, 
increase dose to 28 mcg/day to complete 28 day cycle of therapy. If 
Grade 3-4 toxicity recurs, stop drug permanently. 
Within one hour prior to re-start of treatment and within one hour 
prior to any dose increases, patients must receive 20 mg of 
dexamethasone intravenously. 
Disseminated 
intravascular 
coagulation 
Grade 2 
Continue at same dose level. 
 
Grade 3-4 
Hold blinatumomab until AE resolves to Grade ≤ 2, then resume 
drug at 9 mcg/day for one week. If toxicity remains Grade ≤ 1, 
increase dose to 28 mcg/day to complete 28 day cycle of therapy. If 
Grade 3-4 toxicity recurs, stop drug permanently.  If the initial 
adverse event lasts for ≥ 2 weeks without improvement, then 
blinatumomab will be permanently discontinued.   
Within one hour prior to re-start of treatment and within one hour 
prior to any dose increases, patients must receive 20 mg of 
dexamethasone intravenously. 
Thromboembolic 
event 
Grade 1 
Continue at same dose level. 
 
Grade 2-4 
Hold blinatumomab until clot and clinical situation stabilized, then 
resume drug at 9 mcg/day for one week. If no progression of 
thrombus, increase dose to 28 mcg/day to complete 28 day cycle of 
therapy. If progression of existing thrombosis or new thrombosis or 
Grade 4 initially, stop drug permanently. 
Within one hour prior to re-start of treatment and within one hour 
prior to any dose increases, patients must receive 20 mg of 
dexamethasone intravenously. 
Lymphocyte count 
decreased 
Grade 1-4 
Continue at same dose level. 

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Adverse Event 
(CTCAE v4.0 term) 
AE Grade 
Action 
Neutrophil count 
decreased 
Grade 1-2 
Continue at same dose level. 
 
Grade 3-4 
Hold blinatumomab until AE resolves to Grade ≤ 1, then resume 
drug at 9 mcg/day for one week. If toxicity remains Grade ≤ 1, 
increase dose to 28 mcg/day to complete 28 day cycle of therapy. If 
Grade 3 recurs, reduce dose to 9 mcg/day and if after one week 
toxicity is Grade ≤ 2, continue at 9 mcg/day. If Grade 4 toxicity 
recurs, stop drug permanently. 
Within one hour prior to re-start of treatment and within one hour 
prior to any dose increases, patients must receive 20 mg of 
dexamethasone intravenously. 
Platelet count 
decreased 
Grade 1-3 
Continue at same dose level. 
 
Grade 4 
Hold blinatumomab until AE resolves to Grade ≤ 2, then resume 
drug at 9 mcg/day for one week. If toxicity remains Grade ≤ 3, 
increase dose to 28 mcg/day to complete 28 day cycle of therapy. If 
Grade 4 toxicity recurs, reduce dose to 9 mcg/day and if after one 
week toxicity is Grade ≤ 2, continue at 9 mcg/day. If Grade 4 toxicity 
recurs, stop drug permanently. 
Within one hour prior to re-start of treatment and within one hour 
prior to any dose increases, patients must receive 20 mg of 
dexamethasone intravenously. 
All other AEs within 
the “Investigations” 
SOC and 
“Metabolism and 
nutrition disorders” 
SOC 
Grade 1-4 
Continue at same dose level, provided AE is not medically 
consequential and has been readily corrected. 
If abnormality is medically consequential, refer to guidelines for 
other non-hematologic AEs. 
Patients who develop Grade 3 or 4 electrolyte laboratory 
abnormalities may continue study treatment without interruption but 
should receive appropriate medical therapy. 
Other non-
hematologic AEs 
Grade 1-2 
Continue at same dose level. 
 
Grade 3-4 
Hold blinatumomab until AE resolves to Grade ≤ 1, then resume 
drug at 9 mcg/day for one week. If toxicity remains Grade ≤ 1, 
increase dose to 28 mcg/day to complete 28 day cycle of therapy. If 
Grade 3 recurs, reduce dose to 9 mcg/day and if after one week 
toxicity is Grade ≤ 2, continue at 9 mcg/day. If Grade 4 toxicity 
recurs, stop drug permanently. 
Within one hour prior to re-start of treatment and within one hour 
prior to any dose increases, patients must receive 20 mg of 
dexamethasone intravenously. 
* Please see Table 5.3 below to assist in determining which adverse events are likely to have a plausible 
relationship to blinatumomab and require blinatumomab-Specific Dose Modification and Management 
Guidelines. 
** Please see Table 5.4 below to assist in determining which adverse events are not likely to have a 
plausible relationship to blinatumomab and require local institutional guidelines. 

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If a patient experiences one or more of the AEs listed in Table 5.3 below, and the AE(s) 
is/are determined by the investigator to be possibly, probably, or definitely related to 
blinatumomab, follow the dose management guidelines for nervous system or 
psychiatric disorders specified at the top of Table 5.2, above.  Note that Seizure (an AE 
under the “Nervous system disorders” SOC) also has a possible, probable, or definite 
link to blinatumomab but has a separate set of management guidelines in Table 5.2. 
Table 5.3 Adverse Events Under “Nervous system disorders” or “Psychiatric disorders” 
SOC Requiring Blinatumomab-Specific Dose Modification and Management Guidelines 
Nervous system disorders 
Aphoria 
Amnesia 
Cognitive disturbances 
Concentration impairment 
Depressed level of consciousness 
Dysarthria 
Dysphasia 
Encephalopathy 
Memory impairment 
Tremor 
Psychiatric disorders 
Confusion 
Delirium 
Hallucinations 
Psychosis 
The events listed in Table 5.4 below, have been determined by the pharmaceutical collaborator 
not to have a causal link to blinatumomab.  If a patient experiences any of the AEs listed in 
Table 5.4 below, they should be treated according to institutional guidelines (i.e., administer 
antidepressants for depression), and blinatumomab may be held or discontinued as needed for 
supportive care (such as for Ischemia cerebrovascular). 
Table 5.4 Adverse Events Under “Nervous system disorders” or “Psychiatric disorders” 
SOC Requiring Management According to Normal Institutional Guidelines 
Infections and infestations 
Cranial nerve infection 
Encephalitis infection 
Encephalomyelitis infection 
Meningitis 
Nervous system disorders 
Edema cerebral 
Headache 
Hydrocephalus 
Hypersomnia 
Ischemia cerebrovascular 
Intracranial hemorrhage 

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Lethargy 
Movements involuntary 
Neuralgia 
Nystagmus 
Oculomotor nerve disorder 
Paresthesia 
Peripheral motor neuropathy 
Peripheral sensory neuropathy 
Radiculitis 
Sinus pain 
Somnolence 
Transient ischemic attacks 
Psychiatric disorders 
Agitation 
Anxiety 
Depression 
Euphoria 
Insomnia 
Mania 
Personality change 
Psychiatric disorders - Other 
Restlessness 
any sexual dysfunctions, disturbances, or gender identity disorders 
5.3.2.2.1 
Inpatient/Outpatient Treatment 
Inpatient 
Blinatumomab will be administered as a 
continuous IV infusion over four weeks 
followed by a two-week treatment free 
interval. It is recommended that patients are 
hospitalized at least during the first three 
days of the first cycle and the first two days 
of each of the subsequent three cycles. The 
hospitalization time depends on 
investigator´s judgment, as well as safety 
and tolerability of blinatumomab. 
The infusion bags will be changed by site 
nursing personnel. Close monitoring during 
the first 48 - 72 hours of treatment in the 
first two cycles will be indicated because of 
the potential AEs associated with T cell 
redistribution and potential cytokine release 
effects triggered by the administration of 
blinatumomab. Nurses/physicians trained in 
critical care medicine should be available for 

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immediate intervention in case of 
complications. Afterwards the treatment 
may be continued on an outpatient basis, if 
it is judged to be safe and feasible by the 
investigator. 
Outpatient 
In the outpatient setting, several options are 
available for blinatumomab administration: 
1. The patient will return to the study site 
for all changes of infusion bags.  
2. If allowable by the treating physician's 
institution, infusion bag changes may be 
performed in the patient’s home by an 
ambulatory/home care service provider.  
In this case, the ambulatory/home care 
service provider will be given the 
remaining bags for the week of 
treatment that have been prepared by 
the site investigational pharmacy in a 
validated shipper for transport. The 
validated shipper will maintain proper 
storage conditions during transport for 
the prepared infusion bags.  The 
infusion bags are to kept/stored at the 
ambulatory/home care service provider 
in a controlled temperature monitored 
refrigerator used at the 
ambulatory/home care service provider. 
Patients will be visited by an 
ambulatory/home care service provider 
at specific intervals to change the 
infusion bag. The ambulatory/home care 
service will be trained and will receive 
written instruction for transport of drug 
from the site investigational pharmacy 
and from the ambulatory/home care 
service provider to the patient’s home 
for infusion. If necessary shipment of the 
infusion bags from the site 
investigational pharmacy to the 
ambulatory/home care service provider 
for subsequent transport to the patient’s 
home for infusion will be allowed via use 
of a validated shipper and a traceable 
method of shipment via an express 
courier.  
3. If all options above are not feasible, 
shipping the prepared infusion bags in a 
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pre-qualified insulated shipper directly to 
patient’s home via overnight courier 
delivery service for administration by 
home healthcare agency staff is 
acceptable. Patients are not to open 
the box upon the receipt of the drug. 
Sites interested in utilizing home 
infusion must contact the E1910 Home 
Infusion Team at The ECOG-ACRIN 
Headquarters 
E1910.homeinfusion@ecogchair.org to 
initiate set-up for home infusion.  See 
Appendix VIII for additional guidelines of 
the blinatumomab administration in the 
outpatient setting. 
NOTE: The NCI Drug Accountability 
Record Form (DARF) must reflect 
all transaction for preparing and 
providing the infusion bags to an 
ambulatory/home care service 
provider.  The ambulatory/home 
care service provider must also 
keep DARFs to log in/out date 
when receiving the infusion bags 
from the sites and when 
dispensing the infusion bags to 
patients as well as the times of all 
infusion bag changes.  
NOTE: The pre-qualified shipper box will 
include a form of shipment of 
blinatumomab IV bag(s) to 
patient’s home (See Appendix 
VIII). That form will be completed 
by site/pharmacy prior to shipping 
the IV blinatumomab bags.  The 
home healthcare service will open 
the box at the time that the IV drug 
is to be administered to patient.  
The home healthcare service staff 
will complete the second portion of 
the form and any discrepancy 
must be reported immediately to 
the site pharmacy.  ECOG–ACRIN 
will submit the completed forms to 
CTEP. 
5.4 
Allogeneic SCT 
Patients may be taken to allogeneic SCT following completion of blinatumomab 
therapy or if randomized to the “No Blinatumomab” arm directly following 

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intensification therapy utilizing any suitable donor and any suitable conditioning 
regimen (myeloablative, reduced intensity or non-myeloablative) per investigator 
discretion. 
NOTE: It is strongly encouraged that patients randomized to blinatumomab 
receive both cycles of blinatumomab therapy before proceeding to 
allogeneic SCT. If only one cycle of blinatumomab is given, then an 
MRD assessment should be done prior to proceeding to allogeneic 
SCT. 
NOTE: For Arm C patients, up to 2 cycles of consolidation therapy may be 
given if there are delays in going to SCT. For Arm D patients, up to 3 
cycles of consolidation therapy may be given if there are delays in going 
to SCT. 
5.5 
Consolidation Therapy 
NOTE: 
Please see Section 5.5.8 for information regarding the substitution of 
IT cytarabine for IT methotrexate in the case of a methotrexate 
shortage. 
Four-to six courses depending on whether the patient was randomized to 
blinatumomab (six courses) or no blinatumomab (four courses) of conventional 
consolidation therapy (after blinatumomab if randomized to it or 4 weeks after 
intensification if not randomized to blinatumomab) will be administered following 
intensification therapy for patients who will not receive an allogeneic transplant. 
5.5.1 
Cycle 1 Consolidation- Arms C & D (28 Days) 
Begins after second cycle of blinatumomab (for those randomized to 
this arm) or after intensification (for those not randomized to 
blinatumomab) when ANC ≥ 0.75 x 109/L and platelets > 75 x 109/L, 
whichever is later. 
If the ANC and/or platelets fail to recover within 2 weeks of the end of 
blinatumomab therapy or within 6 weeks of the end of intensification, 
contact the study chair or co-chair. 
Cytarabine 75 mg/m2/day IV or Sub-Q on Day 1-5.  Intravenous 
cytarabine can be prepared in 100 cc D5W and given over 30 
minutes. 
Etoposide 100 mg/m2 in 500 ml NS IV over 1 hr Day 1-5 
Methotrexate 12.5 mg intrathecally day 1 +/- 1. Hydrocortisone 50 mg 
intrathecally can optionally combined with methotrexate if desired to 
lessen the risk of arachnoiditis. 
Pegaspargase 2,000 IU/m2 IM (1,000 IU/m2 if age ≥ 55 years) or IV 
Day 5 
Cap dose at one vial total, 3750 IU 
Rituximab 375mg/m2 IV infusion Day 5 if CD20 positive (do not 
administer if patient is CD20 negative); optional and not required to 
give if not available or desired. 
Rev. 7/14 
Rev. 7/14 
Rev. 3/15, 6/15 
Rev. 3/15 
Rev. 3/15, 8/17 
Rev. 6/16 
Rev. 8/17 
Rev. 2/18 
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NOTE: 
If patient is CD20 positive and positive for hepatitis B, and 
rituximab treatment is planned, prophylaxe the patient with 
lamivudine, entecavir, or tenofovir as per figure 1 of 
recently published guidelines78. 
Premedicate with acetaminophen 650 mg PO, diphenhydramine 25 - 
50 mg PO or IV and hydrocortisone 100 mg IV. Refer to Section 
5.2.2.2.1 for pegaspargase related toxicities and dose modifications. 
5.5.2 
Cycle 2 Consolidation- Arms C & D (28 Days) 
Begins 4 weeks from day 1 of first cycle of consolidation or when ANC 
≥ 0.75 x 109 /L and platelets > 75 x 109/L, whichever is later. 
NOTE: If counts fail to recover within 6 weeks from day 1 of the first 
cycle of consolidation, contact the study chair or co-chair. 
NOTE: FOR ARM D PATIENTS: Bone marrow aspirate and biopsy 
will be performed after recovery of blood counts from cycle 2 
of consolidation for patients on Arm D. A sample for MRD 
assessment must be obtained. For MRD assessments, an 
aspirate from a separate bone marrow aspiration site must 
be submitted (the needle can be re-directed through the 
same skin puncture site). Only submit aspirates from the first 
pull of an aspiration site for MRD testing. Do not submit 
samples from the second or third pull of the same aspiration 
site. 
Cytarabine 75 mg/m2/day IV or Sub-Q on Day 1-5. Intravenous 
cytarabine can be prepared in 100 cc D5W and given over 30 
minutes. 
Etoposide 100 mg/m2 in 500 ml NS IV over 1 hr Day 1-5 
Methotrexate 12.5 mg intrathecally day 1+/- 1. Hydrocortisone 50 mg 
intrathecally can optionally combined with methotrexate if desired to 
lessen the risk of arachnoiditis. 
Rituximab 375mg/m2 IV infusion Day 5 if CD20 positive (do not 
administer if patient is CD20 negative); optional and not required to 
give if not available or desired. 
NOTE: 
If patient is CD20 positive and positive for hepatitis B, and 
rituximab treatment is planned, prophylaxe the patient with 
lamivudine, entecavir, or tenofovir as per figure 1 of 
recently published guidelines78. 
5.5.3 
Cycle 3 Consolidation- Arms C & D (42 Days) 
Begins 4 weeks from day 1 of second cycle of consolidation or when 
ANC ≥ 0.75 x 109/L and platelets > 75 x 109/L or whichever is later. 
NOTE: If counts fail to recover within 6 weeks from day 1 of the 
second cycle of consolidation, contact the study chair or co-
chair. 
Daunorubicin 25 mg/m2 IV push Days 1, 8, 15 and 22 
Rev. 3/15 
Rev. 3/15 
Rev. 6/16 
Rev. 8/17 
Rev. 8/17 
Rev. 8/17 
Rev. 2/18 
Rev. 2/18 
Rev. 2/18 
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Vincristine 1.4 mg/m2 IV Days 1, 8, 15, 22 (maximum amount per 
dose 2 mg) 
Cyclophosphamide 650 mg/m2 in 250 ml NS IV over 30 min, Day 29 
only 
Cytarabine 75 mg/m2/day IV or Sub-Q on Days 30-33 and 37-40.  
Intravenous cytarabine can be prepared in 100 cc D5W and given 
over 30 minutes. 
6-Mercaptopurine (6-MP) 60 mg/m2 orally Days 29-42 (take at 
bedtime on an empty stomach 1 hour before or 2 hours after food 
and/or milk products).  Adjust dose using 50 mg tablets and different 
doses on alternating days in order to attain a weekly cumulative dose 
as close to 420 mg/m2/week. See Appendix IX for details. 
Methotrexate 12.5 mg intrathecally Day 2 +/- 1. Hydrocortisone 50 mg 
intrathecally can optionally combined with methotrexate if desired to 
lessen the risk of arachnoiditis. 
Dexamethasone 10 mg/m2  Days 1-7, 15-21 (cap at 20 mg/day; days 
1-7 only if age ≥ 55) 
Rituximab 375mg/m2 IV infusion Day 8 if CD20 positive (do not 
administer if patient is CD20 negative); optional and not required to 
give if not available or desired. 
NOTE: 
If patient is CD20 positive and positive for hepatitis B, and 
rituximab treatment is planned, prophylaxe the patient with 
lamivudine, entecavir, or tenofovir as per figure 1 of 
recently published guidelines78. 
5.5.4 
Cycle 4 Consolidation - Arm C patients randomized or assigned to 
blinatumomab (28 days) 
Blinatumomab 28 mcg/day, Days 1-28 as per guidelines in Section 
5.3.1 and 5.3.1.1. It is recommended that patients be hospitalized for 
the first two days of this cycle. 
Begins 8 weeks following start of consolidation cycle 3 or when ANC  
≥ 0.75 x 109 /L. and platelets > 75 x 109/L, whichever is later. 
NOTE: If counts fail to recover within 10 weeks from day 1 of the 
third cycle of consolidation, contact the study chair or co-
chair. 
5.5.5 
Cycle 4 Consolidation - Arm D patients randomized to No 
blinatumomab (28 days)  
Begins 8 weeks following start of consolidation cycle 3 or when  
ANC ≥ 0.75 x 109 /L. and platelets > 75 x 109/L, or whichever is later.  
NOTE: If counts fail to recover within 10 weeks from day 1 of the 
third cycle of consolidation, contact the study chair or co-
chair. 
Rev. 3/15 
Rev. 3/15, 8/17 
Rev. 3/15 
Rev. 7/14 
Rev. 6/16 
Rev. 8/17 
Rev. 8/17 
Rev. 8/17, 9/17 
Rev. 2/18 
Rev. 2/18 
Rev. 2/18 
Rev. Add14 

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Cytarabine 75 mg/m2/day IV or Sub-Q on Day 1-5. Intravenous 
cytarabine can be prepared in 100 cc D5W and given over 30 
minutes. 
Etoposide 100 mg/m2 in 500 ml NS IV over 1 hr Day 1-5 
Methotrexate 12.5 mg intrathecally day 1 +/- 1. Hydrocortisone 50 mg 
intrathecally can optionally combined with methotrexate if desired to 
lessen the risk of arachnoiditis. 
Rituximab 375mg/m2 IV infusion Day 5 if CD20 positive (do not 
administer if patient is CD20 negative); optional and not required to 
give if not available or desired. 
NOTE: 
If patient is CD20 positive and positive for hepatitis B, and 
rituximab treatment is planned, prophylaxe the patient with 
lamivudine, entecavir, or tenofovir as per figure 1 of 
recently published guidelines78. 
5.5.6 
Cycle 5 Consolidation - Arm C patients randomized or assigned to 
blinatumomab (28 days). 
Begins when ANC ≥ 0.75 x 109/L and platelets > 75 x 109/L, 
whichever is later. 
NOTE: If counts fail to recover within 6 weeks from day 1 of the 
fourth cycle of consolidation, contact the study chair or co-
chair. 
Cytarabine 75 mg/m2/day IV or Sub-Q on Day 1-5. Intravenous 
cytarabine can be prepared in 100 cc D5W and given over 30 
minutes. 
Etoposide 100 mg/m2 in 500 ml NS IV over 1 hr Day 1-5 
Methotrexate 12.5 mg intrathecally day 1 +/- 1. Hydrocortisone 50 mg 
intrathecally can optionally combined with methotrexate if desired to 
lessen the risk of arachnoiditis. 
Rituximab 375mg/m2 IV infusion Day 5 if CD20 positive (do not 
administer if patient is CD20 negative); optional and not required to 
give if not available or desired. 
NOTE: 
If patient is CD20 positive and positive for hepatitis B, and 
rituximab treatment is planned, prophylaxe the patient with 
lamivudine, entecavir, or tenofovir as per figure 1 of 
recently published guidelines78. 
5.5.7 
Cycle 6 Consolidation - Arm C patients randomized or assigned to 
blinatumomab (28 days). 
Begins 4 weeks following start of consolidation cycle 5 or when ANC  
≥ 0.75 x 109/L and platelets > 75 x 109/L, whichever is later. 
NOTE: If counts fail to recover within 6 weeks from day 1 of the fifth 
cycle of consolidation, contact the study chair or co-chair. 
Rev. 3/15 
Rev. 3/15, 8/17 
Rev. 6/16 
Rev. 6/16 
Rev. 8/17 
Rev. 8/17 
Rev. 8/17 
Rev. 8/17 
Rev. 2/18 
Rev. 2/18 
Rev. 2/18 
Rev. 2/18 
Rev. 2/18 
Rev. Add14 
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Blinatumomab 28 mcg/day, Days 1-28 as per guidelines in Section 
5.3.1 and 5.3.1.1. It is recommended that patients be hospitalized for 
the first two days of this cycle. 
5.5.8 
Preservative-Free Methotrexate Shortage Guidelines 
The following are guidelines for managing the treatment of enrolled 
participants on E1910, as well as those individuals who have been 
screened, and future participants, when the methotrexate supply is 
not adequate: 
5.5.8.1 
For enrolled patients (including those who are consented, 
but not yet registered/treated) 
During a shortage of preservative-free methotrexate, 
institutions without a sufficient supply of preservative-free 
methotrexate for intrathecal use can switch to using 
cytarabine intrathecally. The suggested dose of IT 
cytarabine is 100 mg (or per local institutional standard) 
and is to be administered following the IT methotrexate 
schedule for the given cycle. The cytarabine can optionally 
be combined with 50 mg of hydrocortisone if desired. 
Once an adequate supply of IT methotrexate has been 
obtained, the patient should be switched back to IT 
methotrexate in the following cycle. 
All other aspects of therapy and monitoring should be 
followed. 
NOTE: 
This substitution constitutes an unanticipated 
event that must be reported to the IRB of 
record. It is very important to document in the 
research record that the substitution was due to 
the preservative-free methotrexate shortage. 
5.5.8.2 
For screened patients (not yet consented) and future 
patients: 
An adequate supply of preservative-free methotrexate, 
defined as 2 induction cycles worth of methotrexate, must 
be available for a potential participant prior to consenting 
and registering the patient to E1910. Institutions whose 
methotrexate supply is not adequate to cover at least 2 
induction cycles worth of therapy for a potential participant 
must not consent or register new patients into the study 
until the methotrexate supply issue is resolved. 
5.6 
Maintenance Chemotherapy – Arm E 
NOTE: 
Patients who had evidence of CNS leukemia at diagnosis and 
subsequently achieved a CR should receive a total dose of 1800 cGy 
of cranial irradiation in 10 daily fractions of 180 cGy per fraction during 
the first cycle of maintenance therapy (Section 5.2.1.4). 
Rev. 3/15, 
8/17 
Rev. 8/17 
Rev. 8/17 
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NOTE: 
Please see Section 5.6.11 for information regarding the substitution of 
IT cytarabine for IT methotrexate in the case of a methotrexate 
shortage. 
Patients completing consolidation will continue on maintenance chemotherapy 
consisting of: 
6-mercaptopurine (6-MP) 75 mg/m2 orally PO/day continuously (take at bedtime 
on an empty stomach 1 hour before or 2 hours after food and/or milk products). 
Adjust dose using 50 mg tablets and different doses on alternating days in order 
to attain a weekly cumulative dose as close to 525 mg/m2/week. See Appendix IX 
for details. 
Methotrexate 20 mg/m2 PO or IV once a week 
Vincristine 1.4 mg/m2 IV day 1 (one dose) every 3 months with prednisone 
(maximum 2mg/dose) 
Prednisone 60 mg/m2 for days 1-5 PO taken with meals every 3 months 
Methotrexate 12.5 mg intrathecally day 1 +/- 3 days every 3 months.  
Hydrocortisone 50 mg intrathecally can optionally combined with methotrexate if 
desired to lessen the risk of arachnoiditis. 
Maintenance chemotherapy will begin 4-6 weeks after day 1 of the fourth cycle 
(Arm D) or sixth cycle (Arm C) of consolidation or when ANC ≥ 0.75 x 109/L and 
platelets >75 x 109/L, whichever is later. If counts fail to recover within 6 weeks, 
contact the study chair or co-chair. 
NOTE: Maintenance should continue for 2½ years from the start of 
Intensification therapy (Arm B). 
5.6.1 
Recommendations for Thiopurine Monitoring and Dosage 
Adjustments for Myelosuppression 
When myelosuppression has led to significant delays in therapy (> 2 
weeks) or is disproportionate to the therapy, thiopurine testing should 
be performed (If not already done). 
· 
For patients who have received full dose thiopurine during the 2 
weeks immediately preceding the test, RBC thiopurine metabolites 
will likely predict the TPMT status and actual thiopurine exposure. 
· 
In the absence of RBC transfusions for 3 months prior, TPMT 
activity will accurately reflect TPMT status. 
· 
TPMT genotyping will be informative in all patients, if at least one 
mutant allele is identified.  If not, and myelosuppression continues, 
send samples for TPMT activity and/or metabolites since TPMT 
genotyping will miss 5-10% of mutants.   
NOTE: Genotyping can be done despite recent transfusions. 
5.6.2 
Dose Adjustments for Patients with Unacceptable 
Myelosuppression 
· 
If the patient is homozygous deficient for TPMT, the thiopurine 
dose should be reduced to 10-20 mg/m2/day given 3 days per 
week. 
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· 
If the patient is heterozygous for TPMT and has experienced 
significant myelosuppression, the thiopurine dose should be 
reduced by 30-50%.  Do not increase the dose in response to a 
high ANC for four weeks to allow for achievement of steady state.  
All other myelosuppressive medications should be delivered at full 
dose, and the thiopurine dose should be titrated based on blood 
counts.  Further thiopurine pharmacologic measures are often not 
necessary. 
· 
If the patient is homozygous wild-type (high activity) for 
TPMT and should the ANC fall again below 500/µL on two or 
more occasions, follow guidelines in Section 5.6.3 below. 
5.6.3 
Oral MTX and 6-MP Dose Modifications During Maintenance 
Therapy for Cytopenias  
· 
If ANC is < 500/µL, then hold 6-MP and PO MTX until recovery 
above this level and then resume at full dose once ANC ≥ 750/µL. 
If ANC is < 500/µL a second time, discontinue 6-MP and PO MTX 
until ANC ≥ 750/µL. Restart 6-MP and/or MTX at 50% of the 
original dose on the same day the counts recover. Increase to 
75% and then 100% of the original dose in 2-4 week intervals 
provided ANC ≥ 750/µL. Consider discontinuing cotrimoxazole 
and switching patient to dapsone or pentamidine. If ANC < 500/μL 
on ≥ 2 occasions during Arm E, perform thiopurine pharmacology 
testing (see Section 8.4.2). Investigators may proceed at their own 
discretion or contact the study chair or co-chair to discuss how to 
proceed. Should therapy be withheld for myelosuppression, do not 
“make up” that week. Resume therapy at the correct point 
chronologically. 
· 
If platelet count is < 75,000/μL, then hold 6-MP and PO MTX until 
recovery above this level and then resume at full dose once 
platelets ≥ 75,000/μL. If platelet count is < 75,000/μL a second 
time, discontinue 6-MP and PO MTX until platelets ≥ 75,000 μL. 
Restart 6-MP and/or MTX at 50% of the original dose on the same 
day the counts recover. Increase to 75% and then 100% of the 
original dose at 2-4 week intervals provided platelets ≥ 75,000/μL. 
Consider discontinuing cotrimoxazole and switching patient to 
dapsone or pentamidine. If platelets < 75,000/μL on ≥ 2 occasions 
during Arm E, perform thiopurine pharmacology testing (see 
Section 8.4.2). Investigators may proceed at their own discretion 
or contact the study chair or co-chair to discuss how to proceed.  
Should therapy be withheld for myelosuppression, do not “make 
up” that week. Resume therapy at the correct point 
chronologically. 
· 
Patients experiencing myelosuppression should have their TPMT 
status and/or their thiopurine metabolite concentrations evaluated, 
so that the dose of 6-MP can be reduced in patients with TPMT 
defect. 
5.6.4 
Oral MTX and 6-MP Dose Escalation During Maintenance 
Therapy 
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For ANC ≥ 1500/µL, on 3 CBC(s) done over 6 weeks or 2 successive 
monthly CBC(s), first increase the dose of either PO MTX or 6-MP by 
25%. Then increase the dose of the other drug by 25%. If there is no 
fall in ANC after both PO MTX and 6-MP have been increased once, 
consider noncompliance is a possibility. Consider observing the 
administration of an oral dose of MTX and checking plasma MTX 
concentration 2-4 hours later. This will document whether or not poor 
absorption contributes to lack of response and may facilitate 
discussions about noncompliance. If oral MTX dose is escalated to 
40 mg/m2, contact the Study Chair before further escalation. 
5.6.5 
Oral or IV MTX Dose Reductions During Maintenance Therapy for 
Elevated Bilirubin 
If direct bilirubin > 2.0 mg/dL, then hold IV or oral MTX.  When direct 
bilirubin ≤ 2 mg/dL, then resume MTX at the previous dose.  
5.6.6 
Oral MTX Dose Modifications for Maintenance Therapy for 
Elevated Transaminases 
· 
For increase in ALT or AST > 5 x ULN, obtain direct bilirubin.  
Monitor ALT or AST and direct bilirubin every 4 weeks during 
Maintenance Therapy (Arm E) as long as transaminases remain > 
5 x ULN. 
· 
If ALT or AST > 20 x ULN on two determinations at least one 
week apart or direct bilirubin > 2 mg/dL, hold MTX and monitor 
labs weekly.  When ALT or AST is < 5 x ULN and direct bilirubin is 
within normal, then resume at the previous dose. 
Exclude infectious hepatitis (A, B, C) for persistent (> 1 month) 
elevations in ALT or AST. 
5.6.7 
Oral MTX Dose Modifications for Mucositis During Maintenance 
Therapy 
· 
For grade 3 mucositis, PO MTX should be given at 50% of the 
previous dose. 
· 
For grade 4 toxicity, PO MTX should be temporarily held. Once 
toxicity resolves, then resume PO MTX at 50% of the previous 
dose. PO MTX should then be escalated as tolerated. Consider 
culturing lesions for herpes simplex if mucositis persists or recurs. 
5.6.8 
Oral MTX Dose Modifications for Diarrhea and Vomiting During 
Maintenance Therapy 
If either severe diarrhea or vomiting develops after PO MTX 
administration, PO MTX should be temporarily held. After resolution of 
symptoms (i.e., < grade 2) for a period of one week, resume PO MTX 
at 50% of the previous dose. PO MTX should then be escalated as 
tolerated. If symptoms recur, adjust the dose to the maximum 
tolerated to prevent recurrent symptoms. The patient should be 
evaluated for infectious as well as other causes of diarrhea and 
vomiting. 
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5.6.9 
Dose Modifications for Renal/Genitourinary Toxicity During 
Maintenance Therapy  
· 
 For ≥ grade 2 creatinine level increase, hold PO MTX until toxicity 
resolves to ≤ grade 1. Once toxicity has resolved to this level, then 
PO MTX may be resumed at the previous dose. 
· 
For ≥ grade 2 creatinine level increase, hold 6-MP until toxicity 
resolves to ≤ grade 1. Once toxicity has resolved to this level, then 
6-MP may be resumed at the previous dose. 
5.6.10 
Dose Modifications for Other Toxicity During Maintenance 
Therapy (at investigator discretion) 
For ≥ grade 2 symptoms believed due to PO MTX or requiring 
cessation of PO MTX despite optimal supportive care, hold PO MTX 
until toxicity resolves to ≤ grade 1. Once toxicity has resolved to this 
level, then PO MTX may be resumed at the starting dose. 
For ≥ grade 2 symptoms believed due to 6-MP or requiring cessation 
of 6-MP despite optimal supportive care, hold 6-MP until toxicity 
resolves to ≤ grade 1. Once toxicity has resolved to this level, then 6-
MP may be resumed at the starting dose. 
If the same toxicity recurs at ≥ grade 2 with resumption of previous 
dose, then hold PO MTX and/or 6-MP until toxicity resolves to <grade 
1 then restart PO MTX and/or 6-MP at a 25% dose reduction from the 
previous dose. 
If the same toxicity does not recur at grade 2 or higher within 28 days 
of resumption of PO MTX and/or 6-MP, then dose may be increased 
to the previous dose level at the investigator’s discretion. This may be 
repeated every 28 days up to the starting dose. 
If omission or dose reduction of a drug is desired, contact study 
chair for guidance. 
5.6.11 
Preservative-Free Methotrexate Shortage Guidelines 
The following are guidelines for managing the treatment of enrolled 
participants on E1910, as well as those individuals who have been 
screened, and future participants, when the methotrexate supply is 
not adequate: 
5.6.11.1 
For Enrolled patients (including those who are consented, 
but not yet registered/treated) 
During a shortage of preservative-free methotrexate, 
institutions without a sufficient supply of preservative-free 
methotrexate for intrathecal use can switch to using 
cytarabine intrathecally. The suggested dose of IT 
cytarabine is 100 mg (or per local institutional standard) 
and is to be administered following the IT methotrexate 
schedule for the given cycle. The cytarabine can optionally 
be combined with 50 mg of hydrocortisone if desired. 
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Once an adequate supply of IT methotrexate has been 
obtained, the patient should be switched back to IT 
methotrexate in the following cycle. 
All other aspects of therapy and monitoring should be 
followed. 
NOTE: 
This substitution constitutes an unanticipated 
event that must be reported to the IRB of 
record. It is very important to document in the 
research record that the substitution was due to 
the preservative-free methotrexate shortage. 
5.6.11.2 
For screened patients (not yet consented) and future 
patients: 
An adequate supply of preservative-free methotrexate, 
defined as 2 induction cycles worth of methotrexate, must 
be available for a potential participant prior to consenting 
and registering the patient to E1910. Institutions whose 
methotrexate supply is not adequate to cover at least 2 
induction cycles worth of therapy for a potential participant 
must not consent or register new patients into the study 
until the methotrexate supply issue is resolved. 
5.7 
Supportive Care Considerations 
Supportive care regarding adequate hydration and use of antiemetics for nausea 
and vomiting should be supplied according to institutional guidelines. 
5.7.1 
Hematopoietic Growth Factor (HGF) Therapy 
Throughout both cycles of induction chemotherapy, consolidation 
chemotherapy and maintenance chemotherapy, HGF therapy - either 
G-CSF or GM-CSF - may be used at the investigators discretion. Use 
of CSF during such therapy should be noted on the data forms. 
NOTE: However, HGF therapy should not be used concurrently with 
alkylating agents, anthracyclines or antimetabolite 
chemotherapy drugs. 
HGF therapy should also not be administered during any 
cycles of blinatumomab therapy. 
5.8 
Adverse Event Reporting Requirements  
NOTE: Effective April 1, 2018, expedited adverse event reporting done via 
CTEP-AERS will use CTCAE version 5.0 terminology and grading.  
Routine adverse event reporting and dose modifications 
guidelines in this protocol will continue to be based on CTCAE 
version 4.0 terminology and grading. 
NOTE: CTCAE term (AE description) and grade: The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
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downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.
htm  
5.8.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
· 
Routine reporting: Adverse events are reported in a routine 
manner at scheduled times during a trial using Medidata Rave. 
· 
Expedited reporting: In addition to routine reporting, certain 
adverse events must be reported in an expedited manner via 
CTEP-AERS for timelier monitoring of patient safety and care. The 
following sections provide information and instructions regarding 
expedited adverse event reporting. 
5.8.2 
Terminology 
· 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
· 
Attribution:  An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
· 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List): An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND. Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports.   
· 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting. A grade (severity) is provided for each AE term.  
· 
Hospitalization (or prolongation of hospitalization):  For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.   

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· 
Life Threatening Adverse Event: Any AE that places the subject 
at immediate risk of death from the AE as it occurred.   
· 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
· 
Death  
· 
A life-threatening adverse event  
· 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
· 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
· 
A congenital anomaly/birth defect.  
· 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered a serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
· 
SPEER (Specific Protocol Exceptions to Expedited 
Reporting):  A subset of AEs within the CAEPR that contains list 
of events that are protocol specific exceptions to expedited 
reporting. If an AE meets the reporting requirements of the 
protocol, and it is listed on the SPEER, it should ONLY be 
reported via CTEP-AERS if the grade being reported exceeds the 
grade listed in the parentheses next to the event. 
5.8.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use the 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
· 
the AE Team at ECOG-ACRIN (857-504-2900) for all treatment 
Arms 
· 
the NCI (301-897-7497) for all treatment Arms  
· 
the FDA (1-800-FDA-1088) for Arms A, B, D and E (only if 
previously NOT on Blinatumomab) 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow-up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours.  In addition, supporting or follow 
up documentation must be faxed to the NCI (301-897-7404) for all 
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treatment Arms and FDA (800-332-0178) for Arms A, B, D and E (only 
if previously NOT on Blinatumomab) in the same timeframe. 
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.8.4 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
· 
the phase (0, 1, 2, or 3) of the trial  
· 
whether the patient has received an investigational or commercial 
agent or both 
· 
the seriousness of the event 
· 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
· 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
· 
when the adverse event occurred (within 30 days of the last 
administration of investigational agent vs. ≥ 30 days after the last 
administration of investigational agent)  
· 
the relationship to the study treatment (attribution) 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol E1910 and outline the 
specific expedited adverse event reporting requirements for study 
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5.8.5 
Steps to determine if an adverse event is to be reported in an 
expedited manner – Arm C and E (for those previously on 
Blinatumomab) 
5.8.5.1 
Guidelines for adverse events OCCURRING WHILE ON 
PROTOCOL TREATMENT AND WITHIN 30 DAYS of the 
last administration of the investigational agent(s). 
Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the six 
criteria in the top portion of the 
table below in Section 5.8.6. 
Yes 
No 
Identify the type and 
grade of the event 
using CTCAE v5.0. 
With this information, 
review the chart in Section 
5.8.6 to determine if event 
is reportable via CTEP-
AERS. 
Refer to Section 5.8.7 to 
determine if the event 
meets the protocol specific 
reporting requirements for 
this study. If so, report the 
event via CTEP-AERS. 
Refer to Section 5.8.7 to determine 
if the event meets the protocol 
specific reporting requirements for 
this study.  If so, report the event 
via CTEP-AERS. 
Is the event 
reportable? 
No 
Yes 
Refer to Section 5.8.7 to determine if 
the event meets the criteria as an 
exception to reporting on this protocol. 
If it does not, report the event via 
CTEP-AERS. 
Determine if the patient was 
hospitalized for ≥ 24 hours 
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5.8.5.2 
Guidelines for adverse events OCCURRING GREATER 
THAN 30 DAYS after the last administration of the 
investigational agent(s). 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.8.6, AND has an 
attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
· 
All Grade 4 and Grade 5 AEs  
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational agent with an 
attribution of possible, probable or definite must 
be reported via CTEP-AERS even if the patient 
is off study. 
Expedited 10 calendar day reports for: 
· 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
· 
Grade 3 adverse events   
5.8.6 
Expedited Reporting Requirements for Arm C and E (for those 
previously on Blinatumomab) on protocol E1910 
Investigational Agents: Blinatumomab 
Commercial Agents: Vincristine, Prednisone, 6 Mercaptopurine, 
Methotrexate, PEG-Asparaginase, Cytarabine, Etoposide, 
Daunorubicin, Dexamethasone, Cyclophosphamide, Rituximab 
Late Phase 2 and Phase 3 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention.1 
NOTE: Footnote 1 instructs how to report serious adverse events 
that occur more than 30 days after the last administration of 
investigational agent/intervention. 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: 
Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE: 
Protocol-specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
· 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
· 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
· 
Grade 3 adverse events 
Effective Date:  May 5, 2011 
 
 

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5.8.7 
Additional instructions, requirements and exceptions for protocol 
E1910 
Additional Instructions: 
· 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events via CTEP-AERS, please contact the AEMD 
Help Desk at aemd@tech-res.com or 301-897-7497. This will 
need to be discussed on a case-by-case basis. 
· 
Reporting a death on study: A death occurring while on study 
or within 30 days of the last dose of treatment requires both 
routine and expedited reporting, regardless of causalty. 
Attribution to treatment or other cause must be provided. 
NOTE: 
A death due to progressive disease should be 
reported as a Grade 5 “Disease progression” under 
the System Organ Class (SOC) “General disorder and 
administration site conditions”.  Evidence that the 
death was a manifestation of underlying disease (e.g. 
radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
E1910 specific expedited reporting requirements: 
· 
Pregnancy  
Pregnancies and suspected pregnancies (including a 
positive/inconclusive pregnancy test regardless of age or disease 
state) occurring while the subject is on Blinatumomab, or within 
28 days of the subject’s last dose of Blinatumomab, are 
considered immediately reportable events. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be 
reported via CTEP-AERS within 24 hours of the 
Investigator’s knowledge.  Please refer to Appendix V for 
detailed instructions on how to report the occurrence of a 
pregnancy as well as the outcome of all pregnancies.  
· 
Infection 
Any grade 3 or higher infection (defined as sepsis, bacteremia, 
device or catheter-related infection) that occurs while the patient 
is on protocol treatment or within 30 days of the last 
administration of the investigational agent, regardless of 
attribution, must be reported via CTEP-AERS according to the 
timeframes outline in the AE table in Section 5.8.6.  Any grade 3 
or higher infection (defined as sepsis, bacteremia, device or 
catheter-related infection) that occurs more than 30 days after 
the last administration of the investigational agent and has an 
attribution of possible, probable, or definite must also be reported 
via CTEP-AERS.  
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E1910 specific expedited reporting exceptions: 
For study arms C and E (for those previously on Blinatumomab), the 
adverse events listed below do not require expedited reporting via 
CTEP-AERS: 
· 
If an AE meets the reporting requirements of the protocol, and it 
is listed on the SPEER, it should ONLY be reported via CTEP-
AERS if the grade being reported exceeds the grade listed in the 
parentheses next to the event. 
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5.8.8 
Steps to determine if an event is to be reported in an expedited 
manner - Arms A, B, D and E (for those previously NOT on 
Blinatumomab) 
 
Identify the type and grade of the event 
using CTCAE v5.0. 
Determine if the event is related to the 
protocol treatment (attribution). 
With this information, review the chart in 
Section 5.8.9 to determine if event is 
reportable via CTEP-AERS. 
Refer to footnote b in 
Section 5.8.9 to determine 
if the event meets the 
protocol specific reporting 
requirements for this 
study. If so, report the 
event via CTEP-AERS. 
Is the event 
reportable?
No 
Yes 
Determine the expectedness of the 
event. An unexpected event is defined as 
one where the type of severity of the 
event is not listed in the investigator’s 
brochure, package insert or protocol. 
Report the event 
via CTEP-AERS. 

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5.8.9 
Expedited Reporting Requirements for Arms A, B, D and E (for those 
NOT previously on Blinatumomab) on protocol E1910 
Commercial Agents: Vincristine, Prednisone, 6 Mercaptopurine, and 
Methotrexate, PEG-Asparaginase, Cytarabine, Etoposide, 
Daunorubicin, Dexamethasone, Cyclophosphamide, Leucovorin, 
Rituximab 
Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial agents only  
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
Unrelated or Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the 
event. 
a 
A death occurring while on study or within 30 days of the last dose of treatment requires both routine and 
expedited reporting, regardless of causality.  Attribution to treatment or other cause must be provided. NOTE: A 
death due to progressive disease should be reported as a Grade 5 “Disease progression” under the 
System Organ Class (SOC) “General disorder and administration site conditions”.  Evidence that the 
death was a manifestation of underlying disease (e.g. radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be submitted. NOTE: Any 
death that occurs > 30 days after the last dose of treatment and is attributed possibly, probably, or 
definitely to the treatment must be reported within 7 calendar days of learning of the event.   
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS within 7 calendar 
days of learning of the event.  For instructions on how to specifically report these events via 
CTEP-AERS, please contact the AEMD Help Desk at aemd@tech-res.com  or 301-897-7497.  
This will need to be discussed on a case-by-case basis. 
5.8.10 
Other recipients of adverse event reports and supplemental data 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to the FDA. Any additional written AE information 
requested by ECOG-ACRIN MUST be submitted to BOTH the NCI 
and ECOG-ACRIN. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.8.11 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
Rev. 8/17 
Rev. Add14 

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NCI Update Date: August 14, 2014 
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· 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
· 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
· 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even if 
ECOG-ACRIN was not the patient's most recent trial. 
NOTE: Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should be 
submitted via CTEP-AERS or by the Second Primary Form. 

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NCI Update Date: August 14, 2014 
89 
5.9 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Blinatumomab (AMG103, NSC 765986) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 1276 patients. 
Below is the CAEPR for Blinatumomab (AMG 103). 
NOTE: If an AE meets the reporting requirements of the protocol, and it is listed 
on the SPEER, it should ONLY be reported via CTEP-AERS if the 
grade being reported exceeds the grade listed in the parentheses next 
to the event in the SPEER 
NOTE: Although grade 4 infections are listed as an exception to expedited 
reporting in the SPEER column below, all grade 3 and high infections 
(defined as sepsis, bacteremia, device or catheter-related infection) 
must still be reported per section 5.8.7 
Version 2.5, September 4, 20191 
 
Adverse Events with Possible 
Relationship to Blinatumomab (AMG 103) 
(CTCAE 5.0 Term) 
[n= 1276] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting 
(SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 2) 
 
Blood and lymphatic 
system disorders - Other 
(coagulopathy)2 
 
 
Blood and lymphatic 
system disorders - Other 
(coagulopathy)2 (Gr 2) 
 
 
Blood and lymphatic 
system disorders - Other 
(hematophagic 
histiocytosis) 
  
 
 
Blood and lymphatic 
system disorders - Other 
(lymphadenitis) 
  
 
 
Blood and lymphatic 
system disorders - Other 
(lymphadenopathy) 
  
 
 
Blood and lymphatic 
system disorders - Other 
(pancytopenia) 
  
 
Disseminated 
intravascular 
coagulation2,3 
 
 Disseminated intravascular 
coagulation2,3 (Gr 2) 
Rev. 3/14, 
4/15, 1/17 
Rev. 3/15 
Rev. Add15 
Rev. Add17 

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NCI Update Date: August 14, 2014 
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Adverse Events with Possible 
Relationship to Blinatumomab (AMG 103) 
(CTCAE 5.0 Term) 
[n= 1276] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting 
(SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
CARDIAC DISORDERS 
  
 
Sinus tachycardia 
 
 Sinus tachycardia (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
 
Gastric hemorrhage 
  
 
 
Gastrointestinal disorders 
- Other 
(pneumoperitoneum) 
  
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
 
Oral hemorrhage 
  
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills3 
 
 Chills3 (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue3 
 
 
 Fatigue3 (Gr 2) 
Fever3 
 
 
 Fever3 (Gr 2) 
 
Generalized edema 
 
  
 
Non-cardiac chest pain 
 
  
 
Pain 
 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - 
Other (hepatic function 
abnormal)4 
 
 
Hepatobiliary disorders - 
Other (hepatic function 
abnormal)4 (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
 
Cytokine release 
syndrome3 
 
 Cytokine release 
syndrome3 (Gr 3) 
 
Immune system 
disorders - Other 
(immunodeficiency 
[immunoglobulin 
decreased])5 
 
 
Immune system disorders - 
Other (immunodeficiency 
[immunoglobulin 
decreased])5 (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
Infection6 
 
 
 Infection6 (Gr 4) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction  
  
 
 
Injury, poisoning and 
procedural complications - 
Other (overdose)7 
  

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NCI Update Date: August 14, 2014 
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Adverse Events with Possible 
Relationship to Blinatumomab (AMG 103) 
(CTCAE 5.0 Term) 
[n= 1276] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting 
(SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
INVESTIGATIONS 
  
 
 
Activated partial 
thromboplastin time 
prolonged2 
  
 
Alanine 
aminotransferase 
increased4 
 
 Alanine aminotransferase 
increased4 (Gr 3) 
 
Alkaline phosphatase 
increased4 
 
 
Alkaline phosphatase 
increased4  
(Gr 2) 
 
Aspartate 
aminotransferase 
increased4 
 
 
Aspartate 
aminotransferase 
increased4 (Gr 4) 
 
Blood bilirubin increased4  
 Blood bilirubin increased4 
(Gr 2) 
 
Blood lactate 
dehydrogenase 
increased 
 
  
 
 
Creatinine increased8 
  
 
GGT increased4 
 
 GGT increased4 (Gr 2) 
 
 
Investigations - Other 
(blood fibrinogen 
increased)2 
  
 
Investigations - Other (C-
reactive protein 
increased) 
 
 
Investigations - Other (C-
reactive protein increased) 
(Gr 2) 
 
Investigations - Other 
(fibrin D dimer 
increased)2 
 
  
Lymphocyte count 
decreased 
 
 
 Lymphocyte count 
decreased (Gr 4) 
Neutrophil count 
decreased 
 
 
 Neutrophil count 
decreased (Gr 4) 
Platelet count 
decreased2 
 
 
 Platelet count decreased2 
(Gr 2) 
 
Weight gain 
 
 Weight gain (Gr 2) 
 
Weight loss 
 
  
 
White blood cell 
decreased 
 
 White blood cell decreased 
(Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Hyperglycemia 
 
 Hyperglycemia (Gr 2) 
 
Hyperuricemia 
 
  
 
Hypoalbuminemia 
 
  
 
Hypocalcemia 
 
  

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Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
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Adverse Events with Possible 
Relationship to Blinatumomab (AMG 103) 
(CTCAE 5.0 Term) 
[n= 1276] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting 
(SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Hypokalemia 
 
 
 Hypokalemia (Gr 2) 
 
Hypomagnesemia 
 
  
 
Hypophosphatemia 
 
  
 
 
Tumor lysis syndrome9 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Bone pain 
 
  
 
Generalized muscle 
weakness 
 
  
 
Myalgia 
 
  
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Ataxia10 
 
  
 
Cognitive disturbance10  
  
 
Dizziness10 
 
 Dizziness10 (Gr 2) 
 
 
Dysarthria10 
  
 
Dysphasia10 
 
  
 
Encephalopathy10 
 
  
 
 
Facial nerve disorder10 
  
Headache10 
 
 
 Headache10 (Gr 2) 
 
 
Intracranial hemorrhage 
  
 
 
Leukoencephalopathy 
  
 
Memory impairment10 
 
  
 
Nervous system 
disorders - Other 
(apraxia) 
 
  
 
Nervous system 
disorders - Other 
(cerebellar syndrome)10 
 
  
 
 
Nervous system disorders 
- Other10  
  
 
Paresthesia10 
 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
 
Seizure10 
 
  
 
Somnolence10 
 
  
 
 
Transient ischemic 
attacks10 
  
 
Tremor10 
 
 Tremor10 (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
 
Agitation10 
  
 
Anxiety10 
 
  

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Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
93 
 
Adverse Events with Possible 
Relationship to Blinatumomab (AMG 103) 
(CTCAE 5.0 Term) 
[n= 1276] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting 
(SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Confusion10 
 
  
 
 
Hallucinations10 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
 
 
Personality change10 
  
 
 
Psychosis10 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
  
 
Epistaxis 
 
  
 
 
Hypoxia 
  
 
Oropharyngeal pain 
 
  
 
 
Pneumonitis 
  
 
Voice alteration10 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Hyperhidrosis 
 
  
 
Pruritus 
 
  
 
Skin and subcutaneous 
tissue disorders - Other 
(rash)11 
 
 
Skin and subcutaneous 
tissue disorders - Other 
(rash)11 (Gr 2) 
VASCULAR DISORDERS 
  
 
 
Capillary leak syndrome3   
 
Flushing3 
 
  
 
Hypertension3 
 
 Hypertension3 (Gr 2) 
 
Hypotension3 
 
 Hypotension3 (Gr 2) 
 
Thromboembolic event2  
 Thromboembolic event2 (Gr 
2) 
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV .   Your name, the name of the investigator, the protocol and the agent 
should be included in the e-mail. 
2 Blinatumomab (AMG 103) is known to cause a variety of adverse events associated with coagulopathy 
which may include: Activated partial thromboplastin time prolonged, Disseminated intravascular 
coagulation, Fibrinogen decreased, INR increased, Investigations - Other (blood fibrinogen increased), 
Investigations - Other (fibrin D dimer increased), Investigations - Other (activated partial thromboplastin 
time shortened), Investigations - Other (antithrombin III decreased), Investigations - Other (coagulation 
factor XII level decreased), Investigations - Other (coagulation factor XIII level increased), 
Investigations - Other (haptoglobin decreased), Investigations - Other (protein S decreased), Platelet 
count decreased, and Thromboembolic events. 
3 Symptoms of cytokine release syndrome (CRS) and/or allergic reaction may include chills, fever, 
fatigue, flushing, bronchospasm, and hypotension.  In some cases, disseminated intravascular 
coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic 
lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) have been reported in the setting of 
CRS. 
Rev. Add15 

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NCI Update Date: August 14, 2014 
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4 Symptoms of hepatic dysfunction may include Alanine aminotransferase increased, Alkaline 
phosphatase increased, Aspartate aminotransferase increased, Blood bilirubin increased, and GGT 
increased under the INVESTIGATIONS SOC. 
5 Immunodeficiency (immunoglobulin decreased) includes immunoglobulins decreased, blood 
immunoglobulin G decreased, blood immunoglobulin M decreased, and blood immunoglobulin A 
decreased. 
6 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
7 Overdoses have been observed. Overdoses resulted in adverse reactions, which were consistent with 
the reactions observed at the recommended therapeutic dose and included fever, tremors, and 
headache. In the event of overdose, interrupt the infusion, monitor the patient for signs of toxicity, and 
provide supportive care. Consider re-initiation of blinatumomab at the correct therapeutic dose when all 
toxicities have resolved and no earlier than 12 hours after interruption of the infusion 
8 Acute kidney injury (acute renal failure) is associated with increased creatinine levels. 
9 Tumor lysis syndrome is defined as a massive overload of potassium, phosphate, uric acid, plus 
hypocalcemia, potentially causing lethal cardiac arrhythmias and/or renal failure. 
10 Blinatumomab (AMG103) is known to cause a variety of nervous system disorders which may include: 
Ataxia, Cognitive disturbance, Concentration impairment, Depressed level of consciousness, Dizziness, 
Dysphagia, Dysarthria, Dysesthesia, Dysphasia, Encephalopathy, Facial nerve disorder, Headache, 
Lethargy, Memory impairment, Paresthesia, Peripheral sensory neuropathy, Seizure, Somnolence, 
Syncope, Transient ischemic attacks, Tremor, Voice alteration, Nervous system disorders - Other 
(allodynia), Nervous Systems disorders - Other (cerebellar syndrome), Nervous system disorders - 
Other (dysgraphia), Nervous system disorders - Other (epilepsy), Nervous system disorders - Other 
(facial palsy), Nervous system disorders - Other (hemiparesis), Nervous system disorders - Other 
(hypertonia), Nervous system disorders - Other (hypotonia), Nervous system disorders - Other 
(pleocytosis), and Nervous system disorders - Other (polyneuropathy).  Additionally, symptoms of some 
nervous system disorders are adverse events under the PSYCHIATRIC DISORDERS SOC and may 
include: Agitation, Anxiety, Confusion, Hallucinations, Personality change, and Psychosis. 
11 Rash includes rash, rash maculo-papular, erythema, local erythema, erythematous rash, generalized 
rash, exanthema, allergic dermatitis, and palmar-plantar erythrodysesthesia syndrome. 
Adverse events reported on blinatumomab (AMG 103) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that 
blinatumomab (AMG 103) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Heart failure; Left ventricular systolic 
dysfunction; Myocardial infarction; Pericardial effusion; Sinus bradycardia; Supraventricular 
tachycardia 
CONGENITAL, FAMILIAL AND GENETIC DISORDERS - Congenital, familial and genetic 
disorders - Other (aplasia) 
EAR AND LABYRINTH DISORDERS - Vertigo 
EYE DISORDERS - Blurred vision; Optic nerve disorder; Papilledema; Periorbital edema; 
Photophobia 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal mucositis; Dyspepsia; 
Dysphagia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Gait 
disturbance; General disorders and administration site conditions - Other (thrombosis in device); 
Hypothermia; Malaise; Multi-organ failure 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Vascular access 
complication 

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INVESTIGATIONS - Cardiac troponin I increased; Electrocardiogram QT corrected interval 
prolonged; INR increased; Investigations - Other (hypoproteinemia); Investigations - Other 
(lipase decreased); Lipase increased; Lymphocyte count increased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hypercalcemia; 
Hyperkalemia; Hyperphosphatemia; Hyponatremia; Metabolism and nutrition disorders - Other 
(fluid overload) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Muscle cramp; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Leukemia secondary to oncology chemotherapy; Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Amnesia; Facial muscle weakness; Muscle weakness left-
sided; Nervous system disorders - Other (difficulty following commands); Neuralgia 
PSYCHIATRIC DISORDERS - Delirium; Depression; Psychiatric disorders - Other (altered 
mental status); Psychiatric disorders - Other (sleep disorder); Restlessness 
RENAL AND URINARY DISORDERS - Acute kidney injury7; Hematuria; Proteinuria; Urinary 
incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital edema 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Bronchospasm3; Pleural effusion; Productive cough; Pulmonary edema; Respiratory 
failure; Respiratory, thoracic and mediastinal disorders - Other (chronic obstructive pulmonary 
disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Purpura; Skin and 
subcutaneous tissue disorders - Other (skin irritation) 
VASCULAR DISORDERS - Hematoma 
NOTE: 
Blinatumomab (AMG 103) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
agent. 
 

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5.10 
Duration of Therapy  
Patients will receive protocol therapy unless: 
5.10.1 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event submit forms according to the 
instructions in the E1910 Forms Packet. 
5.10.2 
Patient withdraws consent. 
5.10.3 
Patient experiences unacceptable toxicity. 
5.10.4 
Non-protocol therapies are administered.  
5.10.5 
Failure to achieve CR or CRi (Sections 6.1 and 6.2) after completion 
of Cycles 1 and 2 Induction-Arm A. 
5.10.6 
Relapse of leukemia at any time after achieving a CR or CRi. 
5.11 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for 10 years from the start of treatment, even if non-
protocol therapy is initiated, and for survival. 
 
Rev. 3/15 
Rev. 8/17 

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6. 
Measurement of Effect 
6.1 
Complete Remission (CR)  
Requires that all of the following be present 
6.1.1 
Peripheral Blood Counts  
6.1.1.1 
Neutrophil count ≥ 1.0 x 109/L (≥ 1000/mm^3) 
6.1.1.2 
Platelet count ≥ 100 x 109/L (≥ 100,000/mm^3) 
6.1.1.3 
Reduced hemoglobin concentration or hematocrit has no 
bearing on remission status. 
6.1.1.4 
Leukemic blasts must not be present in the peripheral 
blood. 
6.1.2 
Bone Marrow Aspirate and Biopsy  
6.1.2.1 
Adequate bone marrow cellularity with trilineage 
hematopoiesis. 
6.1.2.2 
≤ 5% blasts. 
6.1.3 
Extramedullary leukemia, such as CNS or soft tissue involvement, 
must not be present. 
6.2 
Complete Remission incomplete (CRi)  
All the same response criteria in peripheral blood and bone marrow as CR with 
the exception that there is incomplete platelet recovery (platelets > 75 but <100 x 
10^9/L (> 75,000 but < 100,000/mm^3) independent of platelet transfusions) or 
incomplete neutrophil count recovery > .75 but < 1 x 10^9/L (> 750 but  
< 1000/mm^3). 
6.3 
Partial Remission (PR)  
6.3.1 
Requires that all of the criteria for complete remission be satisfied 
except that the bone marrow may contain > 5% blasts but < 25% 
blasts. 
6.4 
Relapse/Persistent Disease  
Persistent disease/Relapse following complete remission (CR)/complete 
remission incomplete (CRi) is defined as: 
6.4.1 
Peripheral Blood Counts  
6.4.1.1 
Reappearance or persistence of blasts in the blood. 
6.4.2 
Bone Marrow Aspirate and Biopsy  
6.4.2.1 
Presence of > 5% blasts, not attributable to another cause 
(e.g., bone marrow regeneration). 
6.4.3 
In the case of isolated CNS relapse such as a positive cytospin 
examination of CSF, please consult with Study Chair. Perform bone 
marrow biopsy (if not already done) to confirm presence or lack of 
medullary relapse. 
Rev. 3/15, 8/17 
Rev. 3/15 
Rev. 6/16 
Rev. 8/17 

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Version Date: January 20, 2023 
 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters  
All prestudy scans and x-rays should be done ≤ 4 weeks before registration. 
1. Prestudy scans or x-rays used to document measurable or evaluable disease should be done within 2 weeks of 
registration. 
2. Prestudy CBC with differential, LFTs should be done ≤ 48 hours before registration. 
3. All required prestudy chemistries should be done ≤ 1 week before registration - unless specifically required on Day 
1 as per protocol. If abnormal, they must be repeated within 48 hours prior to registration. Serum creatinine and 
total/direct bilirubin must be completed ≤ 48 hours before registration. 
4. Pre-study bone marrow biopsy and aspirate and/or blood samples must be completed ≤ 1 week prior to registration. 
Table 1. Study Parameters 
 
Cycle 1 Induction 
Prior to 
Cycle 2 
Intensification 
Post Inten-
sification 
During Cycles 
1 and 2 
Blinatumomab  
Post 
Blinatumomab 
 
Prior 
Daily Weekly 
 
Prior 
Daily 
Weekly 
 
Weekly 
 
History and Physical 
X 
 X1 
 
X 
X 
 
 
 
X 
 
Weight and Height 
X 
 
 
X 
X 
 
 
 
X 
 
CBC with Differential 2 
X 
 X1 
 
X 
X 
X1 
 
X 
X 
X 
HLA typing3 
X 
 
 
 
 
 
 
 
 
 
Serum Sodium, Potassium, Calcium, Serum 
Creatinine, Phosphate, Magnesium, Urates 
X 
 X5 
X 
X 
X 
 
X 
 
X 
 
Serum Direct or Total Bilirubin, SGPT (AST), SGPT 
(ALT), Alkaline Phosphatase, LDH 
X 
 X9 
 X9 
X 
X 
 
X 
 
X 
 
PT, aPTT, Fibrinogen, D-dimer 
X 
 
 X6 
X 
 
 
 X6 
 
 
 
Antithrombin III 
 
 
 X6 
 
 
 
 X6 
 
 
 
Triglycerides 
 
 
X6 
 
 
 
 X6 
 
 
 
Amylase, Lipase 
 
 
X6 
 
 
 
 X6 
 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
Lumbar puncture 
  X10 
 
 
  X10 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
Cardiac Ejection Fraction (MUGA/Echocardiogram)4 
X 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspirate, Biopsy and Cytogenetics 
X 
 
 
X 
  X18 
 
 
  X19 
 
X21 
Serum or Urine Pregnancy Test 7 
X 
 
 
 
 
 
 
 
 
 
Writing Test 12 
 
 
 
 
 
 
 
 
X 
 
HBsAG, anti-HBc 
X 
 
 
 
 
 
 
 
 
 
Biological Sample Submissions 
See Sections 7.2 and 10 
Rev. 7/14 
Rev. 7/14 
Rev. 3/15 
Rev. 3/15 
Rev. 6/15 
Rev. 6/16 
Rev. 8/17 
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ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
99 
 
 
Allogeneic SCT 
Post – 
Allogeneic 
SCT 
With each Consolidation 
Cycle 
During Cycles 
4 and 6 
Blinatumomab 
Prior to and 
during 
Maintenance 
Follow-
Up16 
 
Prior 
Daily 
Weekly 
 
Prior 
Daily 
Weekly 
Weekly 
 
 
History and Physical 
X 
 
 
 
X 
 
 
X 
 
 
Weight and Height (height baseline only) 
X 
 
 
 
X 
 
 
X 
 
 
CBC with Differential 2 
X 
 X1 
 
  X16 
X 
 X1 
 
X 
  X13 
X 
HLA typing3 
 
 
 
 
 
 
 
 
 
 
Serum Sodium, Potassium, Calcium, Creatinine, 
Phosphate, Magnesium, Urates 
X 
 X8 
 
 
X 
 
X 
X 
  X14 
 
Serum Direct or Total Bilirubin, SGPT (AST), SGPT 
(ALT), Alkaline Phosphatase, LDH 
X 
 X8 
 
 
X 
 
X 
X 
  X14 
 
PT, aPTT, Fibrinogen, D-dimer 
 
 
 
 
 
 
 X6 
 
 
 
Antithrombin III 
 
 
 
 
 
 
 X6 
 
 
 
Triglycerides  
 
 
 
 
 
 
X6 
 
 
 
Amylase, Lipase 
 
 
 
 
 
 
X6 
 
 
 
Chest X-ray 
 
 
 
 
 
 
 
 
 
 
Lumbar puncture 
 
 
 
 
 
 
 
 
 
 
ECG 
 
 
 
 
 
 
 
 
 
 
Cardiac Ejection Fraction (MUGA/Echocardiogram)4 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspirate, Biopsy and Cytogenetics 
X 
 
 
  X17 
  X20 
 
 
 
  X15 
  X17 
Serum or Urine Pregnancy Test 7 
 
 
 
 
 
 
 
 
 
 
Writing Test 12 
 
 
 
 
 
 
 
X 
 
 
HBsAg. anti-HBc 
 
 
 
 
 
 
 
 
 
 
Biological Sample Submissions 
See Sections 7.2 and 10 
1. 
The daily evaluations should be performed until discharge from the hospital. If the patient is discharged prior to recovery of ANC or platelet 
count the values should be obtained no less than twice weekly until the outcome BM is performed 
2. 
CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct required for protocol therapy must be done < 24 
hours prior to the treatment cycle. 
3. 
For patients who are considered to be SCT candidates. High resolution class I and class II typing should be performed.    
4. 
If a cardiac ejection fraction cannot be obtained due to weekend or holiday then patients may be enrolled provided there are no clinical signs 
or there is no history of significant cardiovascular disease and a measurement of cardiac ejection fraction will be performed within 5 days of 
study enrollment. 
5. 
Monitoring for tumor lysis syndrome at the initiation of induction therapy is strongly suggested at least every 8-12 hours for at least the first 3-5 
days of treatment, and at further intervals at the discretion of the investigator. 
Rev. 8/17 
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Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
100 
6. 
Suggested but not required to monitor for coagulopathy related to pegaspargase use. 
7. 
For women of childbearing potential. 
8. 
Twice weekly and as indicated. 
9. 
At least 2x a week during induction chemotherapy, more often as needed. 
10. As per schedule outlined in Section 5.  Initial lumbar puncture is done on Day 1 of Induction Arm A (see Section 5.2.2) and does not need to 
be done prior to registration. If the patient received IT chemotherapy within 5 days of enrollment and received lumbar puncture with cytology 
and cell count, the lumbar puncture does not need to be performed on Day 1 of Induction. 
12. To be done and checked by medical staff seeing patient at each time of assessment See Appendix VI for writing test form. 
13. Monthly and as clinically indicated. 
14. Every 3 months and as clinically indicated. 
15. Prior to maintenance and every 6 months for 2 years or until the end of maintenance Karyotype analysis is optional. 
16. Patients will be followed at the following time points: every 3 months (90 days) if patient is < 2 years from study entry, every 6 months (180 
days) if patient is 2-5 years from study entry, every 12 months (365 days) if patient is 6-10 years from study entry. Patients will be followed for 
both survival and relapse. 
17. 2-3 months after the end of all therapy, at relapse, and as clinically indicated. 
18. Blood count recovery to confirm CR or CRi. If blood counts are not recovering, bone marrow should be done to look for residual disease. 
19. Perform marrow upon blood count recovery when platelets >75x10^9/L (> 75,000/mm^3) and neutrophils >0.75x10^9/L (>750/mm^3).  If 
counts fail to recover within 6 weeks after the end of intensification, contact the study chair. 
20. Bone Marrow Aspirate, Biopsy, Cytogenetics to be done post cycle 2, prior to cycle 3 for patients on Arm D. 
21. Bone Marrow Aspirate and Biopsy should be done for MRD positive patients assigned to Arm C after both cycles 1 and 2 of blinatumomab.   
 
Rev. 7/14 
Rev. 3/15, 
8/17 
Rev. 3/15 
Rev. 3/15 
Rev. 8/17 
Rev. 3/15 
Rev. 6/15, 
8/17 
Rev. Add14 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
101 
7.2 
Biological Sample Submissions  
All specimens submitted must be entered and tracked via the online ECOG-ACRIN Sample Tracking System (STS). 
 
Pre-Reg-
istration2 
Prior to 
Start of 
Treatment 
(Step 1) 
Post 
Cycle 1 of 
Induction 
Chemoth-
erapy 
(day 28) 
Post Cycle 
2 of 
Induction 
Chemoth-
erapy (at 
time of 
count 
revcovery) 
Prior to 
Randomi-
zation / 
Post 
Intensifi-
cation 
Post Cycle 
1 of Blinat-
umomab 
Post Initial 2 
Cycles of Blinat-
umomab (Prior to 
Cycle 3 / Post 
Cycle 2 of 
Consolidation for 
those on Arm D) 
Prior to Cycle 4 
of Consolid-
ation with 
Blinatumomab 
(Cycle 3 of 
Blinatum-
omab) 
Post 
Consolid-
ation / 
Prior to 
Start of 
Mainten-
ance 
Relapse15 Submit to: 
 
MANDATORY for Central Diagnostic Review and Defined Laboratory Research Studies 
Bone Marrow 
Aspirate for 
MRD (heparin, 
FIRST PULL)3 
X 
 
X 
  X16 
  X11 
X5 
(MRD 
Positive Pts 
at Step 3 
Registration 
& HSCT 
patients 
only) 
  X12 
 
 
X 
LTRL1 
Peripheral 
Blood 
(heparin, 
green or 
purple (EDTA) 
top tubes, 30-
40mL) 
X 
 
 
 
 
 
 
 
 
 
Bone Marrow/ 
Peripheral 
Blood Smears 
(Wright-
Giemsa 
Stained) 
X 
 
X 
X 
X 
 
X 
 
 
X 
Karyotypes 
 
X 
  X14 
  X14 
 
 
 
 
 
X 
Cytogenetic 
Laboratory 
Peripheral 
blood (SST, 
serum, 5mL 
tube) 6,8 
 
 
 
 
  X13 
 
  X10s 
  X10 
 X7 
 
LabConnect 
Rev. 7/14 
Rev. 3/15 
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ECOG-ACRIN 
E1910 
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Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
102 
 
Pre-Reg-
istration2 
Prior to 
Start of 
Treatment 
(Step 1) 
Post 
Cycle 1 of 
Induction 
Chemoth-
erapy 
(day 28) 
Post Cycle 
2 of 
Induction 
Chemoth-
erapy (at 
time of 
count 
revcovery) 
Prior to 
Randomi-
zation / 
Post 
Intensifi-
cation 
Post Cycle 
1 of Blinat-
umomab 
Post Initial 2 
Cycles of Blinat-
umomab (Prior to 
Cycle 3 / Post 
Cycle 2 of 
Consolidation for 
those on Arm D) 
Prior to Cycle 4 
of Consolid-
ation with 
Blinatumomab 
(Cycle 3 of 
Blinatum-
omab) 
Post 
Consolid-
ation / 
Prior to 
Start of 
Mainten-
ance 
Relapse15 Submit to: 
 
From patients who answer “Yes” to “I agree to participate in the laboratory research studies that are being done as part of this clinical trial.” 
Peripheral 
Blood 
(heparin, 
green or 
purple EDTA 
top tubes, 30-
40mL) 
 
 
X 
X 
X 
 
X 
 
 
X 
LTRL 
 
From patients who answer “Yes” to “I agree to provide additional specimens for research.” 
Peripheral 
Blood (red top 
tubes, 15-
20mL) 
X 
 
X 
X 
X 
 
X 
 
 
X 
LTRL 
Buccal Rinse 
(preferred) or 
Swab4 
X 
 
 
 
 
 
 
 
 
 
1. 
Signed E1910 patient consents and HIPAA authorizations must be submitted to the ECOG-ACRIN Leukemia Translational Research 
Laboratory (LTRL) prior to or at the time of submission of the pre-registration specimens to the LTRL. 
2. 
Pre-study (prior to cycle 1 induction) bone marrow and/or peripheral blood specimens must be submitted for centralized immunophenotyping. 
3. 
Bone marrow aspirates must be submitted at the designated time points for Minimal Residual Disease (MRD) assessments.  Bone marrow 
will also be used as part of the optional defined laboratory research studies, per patient consent. The laboratory will accept any amount as 
long as it represents a first pull. 
For the MRD assessments, aspirate from a separate bone marrow aspiration site must be submitted. ONLY SUBMIT ASPIRATES FROM 
THE FIRST PULL OF AN ASPIRATION SITE FOR MRD TESTING. DO NOT SUBMIT ASPIRATES FROM THE SECOND OR THIRD PULL 
OF THE SAME ASPIRATION SITE. 
MRD results will be reported to the submitting institution. 
4. 
Buccal rinse (preferred) or swabs are strongly encouraged to be collected prior to the start of treatment, but can be collected at any other time 
during the study, if necessary. 
5. 
For patients who were MRD positive at registration to Step 3 and patients who go to HSCT after only 1 cycle of blinatumomab, collect prior to 
HSCT. 
6. 
For patients receiving blinatumomab (Arm C). 
Rev. 7/14 
Rev. 7/14 
Rev. 7/14 
Rev. 7/14 
Rev. 3/15 
Rev. 3/15 
Rev. 8/17 
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Rev. Add14 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
103 
7. 
Patients who test positive for neutralizing antibodies to blinatumomab at the final scheduled study visit will be asked to return for additional 
follow-up testing. This testing is to occur approximately every 3 months starting from when the site has been notified of the positive result, 
until: (1) neutralizing antibodies are no longer detectable or (2) the subject has been followed for a period of at least 1 year (± 4 weeks) post 
administration of blinatumomab. More frequent testing (e.g. every month) or testing for a longer period of time may be requested in the event 
of safety-related concerns. Patients who test positive for binding, non-neutralizing antibodies and have clinical sequelae that are considered 
potentially related to an anti-blinatumomab antibody response may also be asked to return for additional follow-up testing. 
8. 
Kits are available for collection and shipment of the blood samples. See Section 10.4 for instructions.  
9. 
[Deleted in Addendum #2] 
10. Collect immediately prior to the next dose of treatment. 
11. Collect at time of count recovery. 
12. Collect 2 weeks after completion of cycle 2 of blinatumomab and at the time of count recovery for non-blinatumomab. 
13. Collect post randomization, prior to start of treatment, for patients randomized to Arm C. 
14. Cytogenetic submission not necessary if prior study demonstrated normal karyotype (with at least 20 bone marrow metaphases analyzed). 
They should be repeated at each time point if abnormal at baseline or less than 20 bone marrow metaphases are analyzed. 
15. First relapse sample in patients who achieve CR post induction (1 or 2) is mandatory. Subsequent relapse samples are also requested but not 
required. 
16. Bone marrow biopsy must be done at time of blood count recovery and not before. 
 
Rev. 7/14 
Rev. 3/15 
Rev. 8/17 
Rev. 8/17 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
104 
8. 
Drug Formulation and Procurement 
Availability 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application <https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx>. 
Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account <https://ctepcore.nci.nih.gov/iam/> and the maintenance of 
an “active” account status and a “current” password. For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
Drug Returns: All unused drug supplies must be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed vials remaining when a patient permanently 
discontinues protocol treatment, expired vials recalled by the PMB), investigators must 
return the study drug to the PMB using the NCI Return Agent Form available on the NCI 
home page (http://ctep.cancer.gov) or by calling the PMB at 240-276-6575.  
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of all 
drugs received from the PMB using the NCI Investigational Agent Accountability Record 
available on the NCI home page (http://ctep.cancer.gov) or by calling the PMB at 240-
276-6575.  These forms will be reviewed for accuracy and completeness during NCI 
cooperative group quality assurance audits.   
NOTE:  
For commercial drugs, sites can prepare and administer the drugs according 
to their institutional SOP, if preferred. 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status and a 
“current” password.  Questions about IB access may be directed to the PMB IB 
coordinator via email. 
Useful Links and Contacts 
· 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
· 
NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
· 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm   
· 
PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx   
· 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
· 
CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov   
· 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
· 
PMB email:  PMBAfterHours@mail.nih.gov 
Rev.6/16 
Rev. 2/18 
Rev. Add14 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
105 
· 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
· 
IB Coordinator: IBCoordinator@mail.nih.gov 
8.1 
Blinatumomab 
8.1.1 
Other Names  
AMG103, MT103, Blincyto® 
8.1.2 
Classification  
Bispecific T cell engaging antibody 
8.1.3 
Mode of Action  
Through CD3 binding, blinatumomab recruits and engages T cells for 
redirected lysis of CD19-positive B cells, including those expressed 
with B-cell malignancies.  T cells are bound by its anti-CD3 moiety, 
whereas B cells are bound by the anti-CD19 moiety.  The subsequent 
serial lysis of multiple malignant cells by a single blinatumomab-
activated T cell closely resembles a natural cytotoxic T cell reaction.  
Treatment with blinatumomab is associated with a rapid depletion of 
peripheral B cells, accompanied by T cell activation and a transient 
increase in cytokines. 
8.1.4 
Storage and Stability  
Storage: Store intact vials of blinatumomab and IV solution stabilizer 
of blinatumomab refrigerated at 2° – 8°C (36°- 46°F), protect from 
light. 
Stability: Shelf life stability studies of the intact vials of blinatumomab 
and stabilizer solution are on-going. The stability of the prepared IV 
solution in preservative-free 0.9% NaCl is 8 days when stored 
refrigerated at 2° to 8° C.  The total storage and administration time 
must not exceed 8 days.  Once at room temperature, discard the IV 
bag after 96 hours (4 days). The stability of the prepared IV solution in 
Bacteriostatic 0.9% NaCl is 14 days when stored refrigerated at 2° to 
8° C. The total storage and administration time must not exceed 14 
days.  Once at room temperature, discard the IV bag after 168 hours 
(7 days). 
8.1.5 
Dose Specifics  
Step 3 (Cycles 1 and 2): 
28 mcg/day by continuous infusion for 28 days. 
Consolidation (Cycles 4 and 6): 
28 mcg/day by continuous infusion for 28 days. 
8.1.6 
How Supplied and Description 
Description: Blinatumomab is a fusion protein composed of two 
single-chain antibodies (scFv), murine anti-CD19 scFv and murine 
anti-CD3 scFv. 
Rev. 7/14 
Rev. 3/15 
Rev. 3/15 
Rev. 6/15 
Rev. 2/18 
Rev. Add16 
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ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
106 
Amgen provides and NCI/DCTD distributes blinatumomab and IV 
solution stabilizer for blinatumomab. 
1. Blinatumomab is available as a 38.5 mcg preservative-free, white 
to off-white lyophilized powder for injection in 4 mL single-use vial.  
The agent is formulated with 3.68 mg citric acid monohydrate, 105 
mg trehalose dihydrate, and 25.55 mg lysine hydrochloride, and 
0.70 mg polysorbate 80, pH 7. The stopper of the vial is latex free. 
2. IV solution stabilizer for blinatumomab (NSC 773150) is not 
for reconstitution of blinatumomab. The solution is available as 
a 10 mL single-use vial, preservative-free, clear, colorless-to-
slightly yellow liquid solution. Each solution consists of 25 mM 
citric acid monohydrate, 1.25 M L-lysine hydrochloride, and 0.1% 
(w/v) polysorbate 80, pH 7. The stopper of the vial is latex free. 
8.1.7 
Preparation 
NOTE: 
Only trained staff may prepare blinatumomab IV solution. 
Sites’ standard procedure for compounding blinatumomab 
must be in compliance with the USP <797> guidelines 
(ISO Class 5 or better). Use aseptic technique and prepare 
blinatumomab IV solution under a qualified laminar flow 
hood.   
a. You need an empty IV bag that is made of 
Polyolefin/polyethylene, ethylene vinyl acetate (EVA) or PVC non-
DEHP.  The IV Infusion sets must be a PVC Non-DEHP with a 
low protein binding 0.2 µm inline filter.  
NOTE: 
168-hour (7-day) IV bag does NOT require an in-line 
filter. 
b. Next, reconstitute blinatumomab lyophilized powder: 
a) Add 3 mL of Sterile Water for Injection (SWI) to the vial to yield 
3.08 mL of blinatumomab at a final concentration of 12.5 
mcg/mL. 
b) Rotate the vial to dissolve all powder. Do not shake. 
c) The stability of the reconstituted vial is 4 hours at room 
temperature (22° C to 27° C) or 24 hours refrigerated at 2° to 
8° C. 
c. Then, further dilute blinatumomab prior to administration: Steps to 
prepare solution are in sequential order.  The IV solution stabilizer 
for blinatumomab must be added into the 0.9% NaCl bag before 
adding blinatumomab. 
Rev. 7/14 
Rev. 3/15 
Rev. 2/18 
Rev. Add14 
Rev. Add16 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
107 
24-hour (1-day) IV bag (Inpatient): Infusion rate 10 mL/Hour 
Preparation: Final volume is 270 mL 
(steps are and must be in sequential order) 
Volume to 
be infused 
Step 1: Add the calculated preservative-free 0.9% NaCl volume into the approved empty 
IV bag 
Calculated 0.9% NaCl (mL):  
[total volume to be prepared (270 mL)] -  [stabilizer solution volume (5.4 mL) ] – 
[blinatumomab calculated dose volume (mL)]  
Step 2: Add 5.4 mL IV solution stabilizer into the preservative-free normal saline IV bag 
IV Stabilizer solution (5.4 mL): 
0.02 x total volume to be prepared (270 mL) 
Step 3: Add the calculated blinatumomab dose volume  into solution  
Blinatumomab calculated dose volume ( per 270 mL bag ): 
24 hour dose (mcg) ÷ Volume to be infused (240 mL) x total volume to be prepared 
(270 mL) ÷ 12.5 mcg/mL of blinatumomab 
240 mL 
In summary, the total volume to be made is 270 mL of which patient will receive a total volume of 240 
mL over 24 hours at 10 mL/hour rate and 30 mL* will remain in the IV-line set. You may also prepare a 
24-hour IV bag for outpatient use but the overfill volume for the IV line infusion may be different and 
must be changed accordingly in the calculation. 
 
48-Hour (2-day) IV Bag (Outpatient): Infusion rate 5 mL/Hour 
Preparation:  Final volume is 250 mL 
(steps are and must be in sequential order) 
Volume to 
be infused 
Step 1: Add the calculated volume of preservative-free 0.9% NaCl into approved empty 
IV bag 
0.9% NaCl volume : 
[Total volume to be prepared (250 mL)]  –  [IV Stabilizer Solution volume (5 mL) ] – [ 
blinatumomab calculated dose volume (mL)]  
Step 2: Add 5 mL IV stabilizer solution into the preservative-free normal saline IV bag 
IV Stabilizer solution (5 mL): 
0.02 x total volume to be prepared (250 mL) 
Step 3: Add the calculated dose volume of blinatumomab into solution  
Blinatumomab dose volume (per 250 mL bag): 
48 hour dose (mcg) ÷ volume to be infused (240 mL) x total volume to be prepared (250 
mL) ÷ 12.5 mcg/mL of blinatumomab. 
240 mL 
In summary, the total volume to be made is 250 mL of which patient will receive 240 mL over 48 hours 
at 5 mL/hour rate and 10 mL* will remain in the IV line set. 
 
Rev. Add16 
Rev. Add16 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
108 
72-Hour (3-day) IV Bag (Outpatient): Infusion rate 3.3 mL/Hour 
Preparation:  Final volume is 250 mL 
(steps are and must be in sequential order) 
Volume to be 
infused 
Step 1. Add the calculated volume of preservative-free 0.9% NaCl into approved 
empty IV bag 
0.9% NaCl volume : 
[Total volume to be prepared (250 mL)]  –  [IV Stabilizer Solution volume (5 mL) ] – [ 
blinatumomab calculated dose volume (mL)]  
Step 2: Add 5 mL IV stabilizer solution into the preservative-free normal saline IV bag 
IV Stabilizer solution (5 mL): 
0.02 x total volume to be prepared (250 mL) 
Step 3: Add the calculated dose volume of blinatumomab into solution  
Blinatumomab dose volume (per 250 mL bag): 
72 hour dose (mcg) ÷ volume to be infused (237.6 mL) x total volume to be prepared 
(250 mL) ÷ 12.5 mcg/mL of blinatumomab. 
237.6 mL 
In summary, the total volume to be made is 250 mL of which patient will receive 237.6 mL over 72 
hours at 3.3 mL/hour rate and 12.4 mL* will remain in the IV-line set. 
 
96-Hour (4-day) IV Bag (Outpatient): Infusion rate 2.5 mL/Hour 
Preparation:  Final volume is 250 mL 
(steps are and must be  in sequential order) 
Volume to be 
infused 
Step 1: Add the calculated volume of preservative-free 0.9% NaCl into approved 
empty IV bag 
0.9% NaCl volume: 
[Total volume to be prepared (250 mL)]  – [ IV stabilizer solution volume (5 mL)] –  
[blinatumomab calculated dose volume (mL)]  
Step 2: Add 5 mL IV stabilizer solution into the preservative-free normal saline IV bag 
IV Stabilizer solution (5 mL): 
0.02 x total volume to be prepared (250 mL) 
Step 3: Add the calculated dose volume of blinatumomab into solution 
Blinatumomab dose volume (per 250 mL bag): 
96 hour dose (mcg) ÷ volume to be infused (240 mL) x total volume to be prepared 
(250 mL) ÷ 12.5 mcg/mL of blinatumomab. 
240 mL 
In summary, the total volume to be made is 250 mL of which patient will receive 240 mL over 96 hours 
at 2.5 mL/hour infusion rate and 10 mL* will remain in the IV line set. 
 
Rev. 6/16 
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ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
109 
168-hour (7-day) IV Bag (Outpatient) (Only for patients weighing > 22 kg): Infusion rate 
0.6mL/hour 
Preparation:  Final volume is 110 mL 
(steps must be in sequential order) (NOTE: 168-hour (7-day) IV bag does not 
require an in-line filter) 
Volume to be 
infused 
Step 1. Add 90 mL Bacteriostatic 0.9% Sodium Chloride Injection, USP, 
preserved with 0.9% benzyl alcohol into compatible empty IV bag. 
Step 2: Add 2.2 mL IV Solution Stabilizer (IVSS) into 90mL Bacteriostatic Sodium 
Chloride IV Solution bag. 
IV Stabilizer solution (2.2 mL): 
0.02 x total volume to be prepared (110 mL) 
Step 3: Add the calculated dose volume of blinatumomab into solution  
Blinatumomab dose volume (per 110 mL bag): 
168-hour dose (mcg) ÷ volume to be infused (100.8 mL) x total volume to be prepared 
(110 mL) ÷ 12.5 mcg/mL of blinatumomab. 
Step 4: q.s. with preservative-free 0.9% NaCl to final volume of 110 mL. 
Calculated volume of preservative-free 0.9% NaCl (mL): [Total volume to be prepared 
(110 mL)] – [Bacteriostatic Sodium Chloride volume (90 mL)] + [IV stabilizer solution 
volume (2.2 mL)] + [blinatumomab calculated dose volume (mL)]  
100.8 mL 
In summary, the total volume to be made is 110 mL of which patient will receive 100.8 mL over 168 
hours at 0.6 mL/hour infusion rate and 9.2 mL will remain in the IV-line set. 
* Volume for the dead space of the IV line may be adjusted according to the size of the infusion IV line being 
used at each institution 
a) Rotate IV bag to mix thoroughly the solution.  Do not shake. Avoid 
foaming the IV bag. 
b) Visually inspect for floating particles or discoloration of the IV 
solution. If that occurs, do not use the prepared solution. 
c) Prime the IV line with the prepared IV solution before 
administering it to patient. 
Infusion Pump: 
· 
Use programmable pump that is approved by the appropriate 
regulatory authority for the country in which the subject is 
undergoing treatment.    
· 
Pump alarm must be visual and auditory 
· 
Pump must be lockable  
· 
Elastomeric pumps are NOT allowed 
· 
CADD Infusion pumps are allowed 
IV bag label: Suggestion for the IV bag label 
· 
Patient name and number 
· 
Name of the drug 
· 
Dose (mcg/day and volume/day) 
· 
Infusion rate 
· 
Expiration date and time  
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· 
CAUTION: NEW DRUG – Limited by United States law to 
investigational use. 
· 
Bag number 
· 
[Additional information may be provided on the label in 
accordance with state, local, and country pharmacy regulations.] 
8.1.8 
Route and Method of Administration: IV infusion 
Method of Administration: Use a central line to administer the IV 
solution.  Do not flush the IV line as it will create an IV bolus to be 
administered into the patient.   
NOTE: 
Infusion interruption: Record all interruption.  Technical or 
logistical interruption must be as minimal as possible and 
re-start the infusion as soon as possible.  If an interruption 
is longer than four hours, the re-start of the infusion must 
take place in the hospital under supervision of the 
investigator. Monitor patients for potential adverse events 
as described in the protocol and the Investigator Brochure. 
8.1.9 
Nursing/Patient Implications 
Patient Care Implications: The effect of blinatumomab on fertility 
has not been evaluated. Blinatumomab is not recommended in 
pregnant women and in women of childbearing potential not using 
contraception. It is not known whether blinatumomab or its 
metabolites are excreted in human milk. Women are not allowed to 
breastfeed while receiving blinatumomab. Monitor patients for 
cytokine release syndrome, tumor lysis syndrome, and infusion 
reaction. Refer to protocol for specific recommendation. Monitor 
patients for psychiatric events such as confusion, disorientation, and 
cognitive attention disturbances. Patients should not drive or operate 
dangerous machinery while receiving blinatumomab. 
The 7-day infusion with Bacteriostatic 0.9% NaCl preserved with 
benzyl alcohol is not allowed in patients weighing less than 22 Kg. 
8.2 
Daunorubicin 
8.2.1 
Other Names 
Daunomycin, Rubidomycin, Cerubidine. 
8.2.2 
Classification 
Anthracycline antibiotic. 
8.2.3 
Mode of Action 
Anthracycline mechanism of action results in a very tight binding of 
the drug to the DNA molecule.  The ultimate effect is interference with 
nucleic acid synthesis, both RNA and DNA. 
8.2.4 
Storage and Stability 
Intact vials are stored at room temperature and protected from direct 
sunlight. Reconstituted solutions are stable for 48 hours when 
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refrigerated and 24 hours at room temperature, when protected from 
sunlight. 
8.2.5 
Dose Specifics:  
Induction (Cycle 1) and Consolidation (Cycle 3): 
25 mg/m2 IV push, days 1, 8, 15, and 22 
8.2.6 
Preparation 
Each 20 mg vial is reconstituted with 4 mL of sterile water to give a 
final concentration of 5 mg/mL. The desired dose is drawn into a 
syringe containing 10-15 mL of normal saline. Protect from sunlight. 
8.2.7 
Administration 
10-15 minute intravenous infusion. Injection will be injected into the 
tubing of a rapidly flowing NS or D5W IV infusion. Do not give IM or 
SubQ. 
8.2.8 
Incompatibilities 
Sodium heparin. 
8.2.9 
Availability 
Commercially available in 20 mg glass vials of red colored lyophilized 
drug. Also available in 50 mg vials. 
8.2.10 
Side Effects 
1.  Hematologic: Myelosuppression (leukopenia with a nadir between 
1-2 weeks). 
2.  Dermatologic: Rash; alopecia; chemical thrombophlebitis or local 
necrosis if extravasation occurs. 
3.  Gastrointestinal: Nausea, vomiting, commonly occurring one hour 
after a dose and lasting for several hours; diarrhea, stomatitis. 
4.  Cardiovascular: Arrhythmias, usually transient; congestive 
cardiomyopathy; maximum total (lifetime) dose of 500-600 mg/m² 
is recommended because of cumulative cardiotoxicity. 
5. Renal: Red urine; not hematuria. 
6.  Other: Fever; transient elevations in serum bilirubin, AST, alkaline 
phosphatase. 
8.2.11 
Nursing Implications 
1. Vesicant - avoid extravasation.  Refer to extravasation protocol if 
inadvertent infiltration occurs. 
2. Monitor CBC, platelet counts. 
3. Advise patient of red coloration of urine. 
4. Administer antiemetics as needed. 
8.2.12 
References 
Von Hoff DD, Rozencweig M, Layard M, et al. Daunomycin-induced 
cardiotoxicity in children and adults: A review of 110 cases.  Am J 
Med 1977; 62:200-208. 
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Yates J, Glidewell O, Wiernik P, et al. Cytosine arabinoside with 
daunorubicin or Adriamycin for therapy of acute myelocytic leukemia:  
A CALGB study.  Blood 1982; 60:454-462. 
8.3 
Vincristine 
NOTE: 
Refer to drug package insert for additional information. 
NOTE: 
Potential drug interaction; i.e., Itraconazole should not be 
concomitantly administered with vincristine because it leads to severe 
neurotoxicity. Caution should be used with drug known to be 
CYP3A4/5 inhibitors or inducers. 
8.3.1 
Other Names 
Oncovin®, Vincasar PFS®, VCR, leucocristine, LCR 
8.3.2 
Classification 
Vinca alkaloid (tubulin inhibitor). 
8.3.3 
Mode of Action 
Binds to tubulin, a protein that forms microtubules, thus interfering 
with spindle formation during metaphase and interrupting mitosis. 
8.3.4 
Storage and Stability 
Must be refrigerated. 
8.3.5 
Dose Specifics 
Induction (Cycle 1):  
1.4 mg/m2 IV, d1, 8, 15, 22 (cap each dose at 2mg total) 
Consolidation (Cycle 3):  
1.4 mg/m2 IV, d1, 8, 15, 22 (cap each dose at 2mg total) 
Maintenance therapy:  
1.4 mg/m2 IV every 3 months with prednisone (cap each dose at 2mg 
total) 
8.3.6 
Preparation 
Doses for bolus injection are withdrawn from refrigerated vials without 
further dilution. 
8.3.7 
Administration 
Intravenous bolus injection using extravasation precautions. 
8.3.8 
Incompatibilities 
Furosemide, some in-line filters, polysiloxan containers used in 
portable delivery devices. 
8.3.9 
Compatibilities 
Chemically stable in normal saline or 5% dextrose for at least four 
days, alone or mixed with doxorubicin (not used in this study) at room 
temperature in either glass or PVC containers. Also compatible with 
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bleomycin, cytarabine, fluorouracil, (not used in this study), 
methotrexate and metoclopramide.  
8.3.10 
Availability 
Commercially available in a concentration of 1 mg/mL in 1, 2, and 5 
mg vials; and 1 mg and 2 mg syringes (hyporets). 
8.3.11 
Side Effects 
1. 
Hematologic: Leukopenia (mild and rare), thrombocytopenia 
(rare), anemia. Dysplastic marrow red cell precursors. 
2. 
Dermatologic: Alopecia, skin and soft tissue damage if 
extravasated (subcutaneous injection of hyaluronidase and 
application of heat recommended by manufacturer to help 
disperse extravasated drug, rash). 
3. 
Gastrointestinal: Nausea, vomiting (rare); constipation; 
abdominal pain and/or cramps; anorexia, diarrhea 
4. 
Hepatic: Elevations of SGOT (AST), SGPT (ALT) which are 
usually mild and transient. 
5. 
Neurologic: Peripheral neuropathy (loss of deep tendon reflexes, 
paresthesias, paralysis); autonomic neuropathy (constipation, 
paralytic ileus, urinary retention, orthostasis); ataxia; myalgias; 
cortical blindness; headache; seizures. Fatal ascending 
paralysis follows intrathecal administration. 
6. 
Pulmonary: Bronchospasm (more common when administered 
with mitomycin which is not used in this study). 
8.4 
Dexamethasone 
NOTE: 
Refer to drug package insert for additional information. 
8.4.1 
Other Names 
Decadron®, Hexadron®, Dexone® 
8.4.2 
Classification 
Adrenal corticosteroid 
8.4.3 
Mode of Action 
A potent synthetic glucocorticoid with anti-inflammatory, 
immunodepressant, antiemetic and antineoplastic activity. May form 
steroid-receptor complexes and alter mRNA and protein synthesis. 
Increases ribonuclease activity and decreases RNA concentration in 
lymphoid tissue. 
8.4.4 
Storage and Stability 
Tablets are stored at room temperature. 
8.4.5 
Dose Specifics 
Induction (Cycle 1) and, Consolidation (Cycle 3): 
10 mg/m2 days 1-7, and 15-21. Cap at 20 mg/day, days 1-7 only if 
age is greater than or equal to 55. 
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8.4.6 
Preparation 
Dexamethasone should always be taken after eating and never on an 
empty stomach. 
8.4.7 
Administration 
Oral. 
A pill calendar will be provided to patients. See Appendix II 
8.4.8 
Availability 
Commercially available as 0.25, 0.5, 0.75, 1.0, 1.5, 2, 4 and 6 mg 
tablets and 0.1 mg/mL oral solution or syrup. 
8.4.9 
Side Effects 
1. Gastrointestinal: Nausea, vomiting, anorexia, increased appetite, 
weight gain, aggravation of peptic ulcer. 
2. Dermatologic: Rash, skin atrophy, facial hair growth, acne, facial 
erythema, ecchymoses. 
3. Genitourinary: Menstrual dysfunction. 
4. Neurologic: Insomnia, euphoria, headache, vertigo, psychosis, 
depression, seizures, muscle weakness. 
5. Cardiovascular: Fluid retention and edema, hypertension, 
thrombophlebitis (rare). 
6. Ocular: Cataracts, increased intraocular pressure, exophthalmos. 
7. Metabolic: Hyperglycemia, decreased glucose tolerance, 
aggrevation or precipitation of diabetes mellitus, adrenal 
suppression, Cushing syndrome, hypokalemia. 
8. Hematologic: Leukocytosis. 
9. Other: Osteoporosis with or without back pain; avascular necrosis 
of bone; serious infections including Herpes zoster, Varicella 
zoster, fungal infections, Pneumocystis carinii, tuberculosis; 
muscle wasting; delayed wound healing; suppression of skin test 
reactions. 
8.4.10 
Nursing/Patient Implications 
1. 
Always give oral dexamethasone with milk or food. 
2. 
Observe for signs of hyperglycemia. 
3. 
Observe for subtle signs of infection, such as lethargy, coldness 
to the touch, pain, etc. 
8.5 
Erwinase 
NOTE: 
Refer to drug package insert for additional information.  
NOTE: 
Erwinase will be substituted for patients who cannot take 
pegaspargase. 
8.5.1 
Other Names  
Erwinase® (Erwinia derived) 
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8.5.2 
Classification  
Enzyme 
8.5.3 
Indication 
Treatment of acute lymphocytic leukemia in pediatrics and adults 
8.5.4 
Mode of Action 
Inhibits protein synthesis, including that of dihydrofolate reductase. 
Kills leukemic cells by depriving them of asparagines, which inhibits 
intracellular protein synthesis. 
8.5.5 
Storage and Stability 
Intact vials are stored in refrigerator protected from light. The 
reconstituted solution drawn into syringe should be used within 6 
hours 
8.5.6 
Dose Specifics 
Erwinia asparaginase 25,000 international units/m2 (IU) IM or IV 3 
times per week for 6 doses for each planned dose of pegaspargase. 
8.5.7 
Preparation 
Reconstitute Erwinia formulation with 1 ml sodium chloride injection 
without preservative resulting in 10,000 IU/ml. 
8.5.8 
Incompatibilities 
None known. 
8.5.9 
Compatibility 
Erwinia derived stable with NSS 
8.5.10 
Availability 
Erwinase® 10,000 IU vials 
8.5.11 
Side Effects 
1. Hematologic: Prolonged thrombin and prothrombin times. 
Decreased fibrinogen and clotting factor concentration, 
particularly antithrombin III, resulting in thrombosis and/or 
pulmonary embolism. 
2. Gastrointestinal: Nausea and vomiting uncommonly occur with IM 
use and can be readily controlled with standard antiemetics. 
Anorexia, abdominal cramps, weight loss, diarrhea, mucositis and 
malabsorption can each occur, but are rare with IM injection. 
3. Hepatic: Liver enzyme elevations; depression of serum albumin, 
cholesterol and/or plasma fibrinogen. 
4. Neurologic: EEG changes, depression, somnolence, lethargy, 
fatigue, convulsions and seizures (rare), coma (rare), headache, 
confusion, irritability, agitation, dizziness, hallucinations. All are 
uncommon or rare with IM use of doses prescribed in this 
protocol. 
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5. Hypersensitivity reactions: Urticarial eruptions, anaphylactoid 
reactions including laryngeal constriction, hypotension, 
diaphoresis, edema, asthma, and/or loss of consciousness. The 
most serious reactions are more likely to occur after several 
intravenous injections, but they may occur with the first injection 
and may occur with intramuscular injection.  Leucovorin calcium is 
used if a hypersensitivity reaction to E. coli asparaginase occurs.  
6. Renal: Azotemia, usually prerenal; rarely, severe renal failure.   
7. Other: Pancreatitis, sometimes fulminant; hyperglycemia requiring 
insulin, chills, fever, hyperthermia (rare). 
8. Adverse effects: Anaphylaxis and serious allergic reactions, 
serious thrombosis, pancreatitis, glucose intolerance, 
coagulopathy. 
8.5.12 
Nursing/Patient Implications  
1. Use IM or IV route. 
2. Limit IM volume at a single injection site to 2 mL. 
3. Obtain baseline vital signs. 
4. Have emergency medications such as parenteral 
diphenhydramine, epinephrine 1:1000, and parenteral 
hydrocortisone on hand. 
5. Monitor liver and renal function, and blood glucose. 
6. Assess for bleeding. 
7. Assess for pancreatitis 
8. Administer acetaminophen 30 – 60 minutes before injection. 
9. Intradermal skin test if indicated. 
10. Assess for anaphylaxis 
8.6 
Pegaspargase 
NOTE: 
Refer to drug package insert for additional information. 
8.6.1 
Other Names  
Pegaspargase (Oncaspar®) 
8.6.2 
Classification  
Enzyme 
8.6.3 
Indication 
Treatment of acute lymphocytic leukemia in pediatrics and adults 
8.6.4 
Mode of Action 
Inhibits protein synthesis, including that of dihydrofolate reductase. 
Kills leukemic cells by depriving them of asparagines, which inhibits 
intracellular protein synthesis. 
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8.6.5 
Storage and Stability 
Intact vials are stored in refrigerator protected from light. The 
reconstituted solution drawn into syringe should be used within 6 
hours 
8.6.6 
Dose Specifics 
NOTE: 
Cap dose at 1 vial total (3750 IU). 
Induction (Cycle1): 
pegaspargase 2,000 IU/m2, IV or IM, d18, (omit if age ≥ 55 years) 
Induction (Cycle 2): 
pegaspargase 2,000 IU/m2, IV or IM, d15 (omit if age ≥ 55 years) 
Intensification: 
pegaspargase 2,000 IU/m2, IV or IM, d9 (1000 IU/m2 if age ≥ 55 
years) 
Consolidation (Cycle 1): 
pegaspargase 2,000 IU/m2, IV or IM d5 (1000 IU/m2 if age ≥ 55 years) 
8.6.7 
Preparation 
Pegaspargase is available as liquid preparation  
For IM administration, the injection solution drawn into a syringe 
should be used within 6 hours. 
For IV administration, the manufacturer recommends diluting the dose 
of pegaspargase in 100 mL of dextrose 5% or sodium chloride 0.9% 
over one to two hours and giving in an already running line. 
8.6.8 
Incompatibilities 
None known. 
8.6.9 
Availability 
Oncaspar® 3750 IU/5 ml vial 
NOTE: 
For participating CCTG sites only, pegaspargase will be 
supplied by Baxalta/Shire and distributed by Bay Area 
Research Logistics (BARL). Please refer to 
http://www.ecog.org for the drug distribution request form. 
8.6.10 
Side Effects 
1. Hematologic: Prolonged thrombin and prothrombin times. 
Decreased fibrinogen and clotting factor concentration, particularly 
antithrombin III, resulting in thrombosis and/or pulmonary 
embolism. 
2. Gastrointestinal: Nausea and vomiting uncommonly occur with IM 
use and can be readily controlled with standard antiemetics. 
Anorexia, abdominal cramps, weight loss, diarrhea, mucositis and 
malabsorption can each occur, but are rare with IM injection. 
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3. Hepatic: Liver enzyme elevations; depression of serum albumin, 
cholesterol and/or plasma fibrinogen. 
4. Neurologic: EEG changes, depression, somnolence, lethargy, 
fatigue, convulsions and seizures (rare), coma (rare), headache, 
confusion, irritability, agitation, dizziness, hallucinations. All are 
uncommon or rare with IM use of doses prescribed in this 
protocol. 
5. Hypersensitivity reactions: Urticarial eruptions, anaphylactoid 
reactions including laryngeal constriction, hypotension, 
diaphoresis, edema, asthma, and/or loss of consciousness. The 
most serious reactions are more likely to occur after several 
intravenous injections, but they may occur with the first injection 
and may occur with intramuscular injection.  Leucovorin calcium is 
used if a hypersensitivity reaction to E. coli asparaginase occurs.  
6. Renal: Azotemia, usually prerenal; rarely, severe renal failure.   
7. Hyperlipidemia: elevated cholesterol and triglycerides. 
8. Other: Pancreatitis, sometimes fulminant; hyperglycemia requiring 
insulin, chills, fever, hyperthermia (rare). 
9. Adverse effects: Anaphylaxis and serious allergic reactions, 
serious thrombosis, pancreatitis, glucose intolerance, 
coagulopathy. 
8.6.11 
Nursing/Patient Implications  
1. Use IV or IM route (refer to Section 8.6.7 for administration 
instructions). 
2. Limit IM volume at a single injection site to 2 mL. 
3. Obtain baseline vital signs. 
4. Have emergency medications such as parenteral 
diphenhydramine, epinephrine 1:1000, and parenteral 
hydrocortisone on hand. 
5. Monitor liver and renal function, and blood glucose. 
6. Assess for bleeding. 
7. Assess for pancreatitis 
8. Administer acetaminophen 30 – 60 minutes before injection. 
9. Intradermal skin test if indicated. 
10. Assess for anaphylaxis 
8.7 
Methotrexate 
NOTE: 
Refer to drug package insert for additional information. 
8.7.1 
Other Names 
Mexate®, Mexate-AQ®, Folex®, Folex PFS®, Abitrexate®, 
Rheumatrex®, Amethopterin, MTX 
8.7.2 
Classification 
Antimetabolite 
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8.7.3 
Mode of Action 
Methotrexate inhibits the enzyme dihydrofolate reductase thereby 
blocking the conversion of folic acid to its active form, tetrahydrofolic 
acid. Inhibition of this enzyme reduces purine synthesis and the 
conversion of deoxyuridylate to thymidylate, which inhibits the 
synthesis of DNA, RNA and proteins. 
8.7.4 
Storage and Stability 
Store at room temperature protected from light. Reconstituted 
solutions are stable at room temperature for at least one week. 
Solutions (50mg/100mL) in PVC bags of 5% dextrose may be frozen 
at -20ºC for at least 30 days and thawed in two minutes by microwave 
radiation. There is no loss of potency after five freeze-thaw cycles. 
8.7.5 
Dose Specifics 
Induction cycles: (Cycle 1) 12.5 mg IT day 14 +/- 1 only 
 
 
 
(Cycle 2) 12.5 mg IT days 1, 8, 15, and 22 +/- 1 
Intensification: 
3 g/m2 IV days 1 and 8 
Consolidation: 
(Cycle 1, 2, 4) 12.5 mg IT day 1 +/- 1 
 
 
 
(Cycle 3) 12.5 mg IT day 2 +/- 1 
Maintenance: 
20 mg/m2 PO or IV once per week. 
12.5 mg IT day 1 +/- 3 every 3 months. 
NOTE: 
During a shortage of preservative-free methotrexate, 
institutions without a sufficient supply of preservative-free 
methotrexate for intrathecal use can switch to using 
cytarabine intrathecally. The suggested dose of IT 
cytarabine is 100 mg (or per local institutional standard) 
and is to be administered following the methotrexate 
schedule for the given cycle. The cytarabine can optionally 
be combined with 50 mg of hydrocortisone if desired. Once 
an adequate supply of preservative-free methotrexate has 
been obtained, the patient should be switched back to IT 
methotrexate in the following cycle. 
Institutions without a sufficient supply of preservative-free 
methotrexate for high dose use can switch to using 
cytarabine, followed the next day by pegaspargase. The 
dose of cytarabine is 2 g/m2 (or 1 g/m2 if the patient age > 
60) over 2 hours every 12 hours x four doses followed the 
next day by pegaspargase 1,000 IU/m2 (500 IU/m2 if 
patient age ≥ 55) IM or IV (recommended) (Maximum dose 
at one vial total; 3750 IU). This regimen is to be 
administered following the methotrexate schedule for 
Intensification – Arm B. 
All other aspects of therapy and monitoring should be 
followed when using substitutions for methotrexate. 
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Rev. 3/15 
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8.7.6 
Preparation 
Lyophilized sterile vials of 20, 50, 100 or 250 mg are reconstituted 
with sterile water, normal saline or 5% dextrose to a concentration no 
greater than 25 mg/mL. 1000 mg vials are reconstituted with 19.4 mL 
to provide a concentration of 50 mg/mL. Higher doses (> 100 mg) are 
usually further diluted with 100 mL or more of 0.45%-0.9% sodium 
chloride or 5% dextrose. 
8.7.7 
Administration 
In induction and consolidation, methotrexate is given by intrathecal 
injection. In intensification it is given as a 2-hr intravenous infusion. In 
maintenance methotrexate is given orally or intravenously and 
intrathecally. 
8.7.8 
Compatibilities 
Methotrexate is compatible with sodium bicarbonate, cytarabine, 
cephalothin, mercaptopurine, vincristine sulfate, hydrocortisone, 
leucovorin, furosemide, and amino acids. 
8.7.9 
Incompatibilities 
Incompatible in solution with bleomycin, fluorouracil, prednisolone 
sodium phosphate, droperidol, metoclopramide and ranitidine. Aspirin, 
probenecid, and nonsteroidal anti-inflammatory drugs may prolong 
methotrexate clearance and increase toxicity. They should not be 
given to patients receiving larger methotrexate doses during 
methotrexate infusion and for 48 hours afterward. 
8.7.10 
Availability 
Commercially available as a lyophilized powder for injection (20, 50, 
100, 250, and 1000 mg/vial), as a 25 mg/mL preservative-free isotonic 
solution for injection (50, 100, 200 and 250 mg vials), as a 2.5 mg/mL 
(5 mg vial) and 25 mg/mL (50 and 250 mg vials) preservative 
protected isotonic solution for injection, and as a 2.5, 7.5, 10, and 15 
mg tablet. 
8.7.11 
Side Effects 
1. Hematologic: Leukopenia, thrombocytopenia (dose-related and 
more likely with prolonged drug exposure), anemia. 
2. Dermatologic: Skin erythema and/or rash, sometimes pruritic; 
alopecia, photosensitivity, furunculosis, depigmentation or 
hyperpigmentation, acne, telangiectasia, skin desquamation and 
bullae formation, exfoliative dermatitis, folliculitis. 
3. Gastrointestinal: Nausea and vomiting (uncommon with 
conventional doses; usually mild), stomatitis (dose and infusion-
related, common), diarrhea, anorexia, hematemesis, melena. 
4. Genitourinary:  Renal dysfunction manifested by increased serum 
creatinine and/or hematuria), which is dose-related and more 
likely to occur in patients with already compromised renal function, 
dehydration, or on other nephrotoxic drugs. 
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5. Hepatic: Increased SGOT (AST), mild and transient; hepatic 
fibrosis and cirrhosis, more likely to occur in patients receiving 
long-term continuous or daily methotrexate treatment. 
6. Neurologic: Encephalopathy, more commonly with multiple 
intrathecal doses and in patients who have received cranial 
irradiation; tiredness, weakness, confusion, ataxia, tremors, 
irritability, seizures, coma. Acute side effects of intrathecal 
methotrexate (not used in this protocol) may include dizziness, 
blurred vision, headache, back pain, nuchal rigidity, seizures, 
paralysis, and hemiparesis. 
7. Allergic: Fever and chills; rash; urticaria; anaphylaxis. 
8. Ocular: Conjunctivitis, excessive lacrimation, cortical blindness 
(rare, with high doses). 
9. Pulmonary: Pneumonitis, pulmonary fibrosis, cough, dyspnea. 
10. Other: Malaise, osteoporosis, avascular necrosis of bone 
(especially femoral head), hyperuricemia, reversible oligospermia, 
teratogenesis. 
8.7.12 
Nursing/Patient Implications 
1. Administer antiemetics as indicated. 
2. Monitor for hematologic toxicity. 
3. Observe for stomatitis and diarrhea, offer symptomatic care if 
indicated. 
4. Prior to the cytoreduction phase of this study proper functioning of 
the kidneys must be documented. During the cytoreduction phase 
proper hydration and alkalinization of the urine must be 
maintained. 
5. Patient must use topical sunscreen when exposed to the sun. 
6. The time of administration of methotrexate infusions and the 
duration of those infusions is critical in this study, especially during 
the cytoreduction phase. Methotrexate infusions must be carefully 
monitored, and should be controlled with an electronic pump. 
7. Methotrexate infusions during the cytoreduction phase must be 
followed as indicated by leucovorin administration. The schedule 
and dose of both should be strictly adhered. 
8.8 
Cyclophosphamide 
NOTE: 
Refer to drug package insert for additional information. 
8.8.1 
Other Names 
Cytoxan®, Neosar®, CTX, CPM 
8.8.2 
Classification 
Cyclophosphamide is a prodrug biotransformed to active alkylating 
metabolites by a mixed function microsomal oxidase system. 

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8.8.3 
Mode of Action 
Cyclophosphamide metabolites are thought to disrupt cell division 
primarily by crosslinking DNA strands. Cyclophosphamide is 
considered cell cycle phase non-specific. 
8.8.4 
Storage and Stability 
Tablets and injectable powder are stored at room temperature 25°C 
(77°F). The temperature is not to exceed 30°C (90 F°). Reconstituted 
parenteral solutions are stable for 24 hours at room temperature for 6-
14 days if refrigerated.1-4 
8.8.5 
Dose Specifics 
Induction (Cycle 2): 
1,000 mg/m2 IV days 1 and 29 (Patients > 60 years give 800 mg/m2 
per dose) 
Consolidation (Cycle 3):  
650 mg/m2 IV day 29 
8.8.6 
Preparation 
Dissolve the 100 mg, 200 mg, 500 mg, 1 gm, and 2 gm vials in 5, 10, 
25, 50, and 100 ml of sterile water, respectively, resulting in a solution 
of 20 mg/ml. Shake vials vigorously and warm slightly in lukewarm 
water to facilitate dissolution. The lyophilized form is more easily 
solubilized. 
Reconstituted solutions may be further diluted in D5W, D5W/NS, 
D5W/Ringer’s Injection, Lactated Ringer’s Injection, ½ NS or NS. 
8.8.7 
Administration 
May be given orally, IV push, or by IV infusion. A pill calendar will be 
provided to patients. See Appendix II 
8.8.8 
Compatibilities 
Numerous compatibility studies have been published. For specific 
details refer to Handbook on Injectable Drugs by Lawrence A. 
Trissel5.  
8.8.9 
Availability 
Cyclophosphamide is commercially available as 25 mg and 50 mg 
tablets and for parenteral injection as 100 mg, 200 mg, 500 mg, 1 g, 
and 2 g vials. 
8.8.10 
Side Effects 
Side effects vary significantly based on the specific dose and duration 
of cyclophosphamide. 
Incidence more frequent (> 5%): 
Anemia, leukopenia (usually asymptomatic; less frequently fever 
and/or chills); Thrombocytopenia (usually asymptomatic; less 
frequently unusual bleeding or bruising; black tarry stools; blood in 
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urine or stools; pinpoint red spots on skin). Nadir counts usually occur 
7 to 12 days after administration and recovery usually compete by day 
17 to 21. 
Alopecia 
Anorexia, nausea and vomiting 
Gonadal suppression (azoospermia, missed menstrual periods) 
resulting in infertility. 
Return of normal gonadal function and fertility occurs with time in 
many younger men and women.3 
Hemorrhagic cystitis3,8 
Incidence less frequent (1-5%): 
Stomatitis 
Incidence rare (1%): 
Anaphylaxis (tachycardia, shortness of breath, wheezing, tightness in 
throat), flushing or redness of face, diarrhea , skin rash, pneumonitis 
or interstitial pulmonary fibrosis, syndrome of inappropriate antidiuretic 
hormone (SIADH), chemical phlebitis (redness, swelling or pain at site 
of injection), secondary malignancies, blurred vision, cardiac toxicity 
presenting as congestive heart failure, hemorrhagic myocarditis, 
myocardial necrosis, and pericarditis (seen with high dose regimens 
used with bone marrow transplantation). 
8.8.11 
Drug Interactions 
Digoxin: Several studies conducted in lymphoma patients receiving 
combination chemotherapy including cyclophosphamide revealed a 
20–50% reduction in digoxin absorption when digoxin tablets were 
administered. When digoxin capsules were administered no 
significant decrease in digoxin absorption occurred. To avoid 
decreased serum digoxin levels the use of digoxin in liquid form (liquid 
or capsules containing liquid digoxin) instead of tablets is 
recommended. 3,10-11 
Pentostatin: Two case reports describe fatal cardiac toxicity in 
patients receiving CTX 6.4 g/m2 over 4 days and pentostatin 4 mg/m2 
over 4 hours on day 3. Until additional data from clinical trials 
demonstrate the safety of concurrent use of these drugs concurrent 
administration is not recommended. 3,7 
Succinylcholine: Cyclophosphamide may prolong the effects of 
succinylcholine by irreversibly inhibiting the enzyme 
pseudocholinesterase. Limited clinical observations and in vitro 
studies suggest that prolonged apnea might result when 
succinlycholine is administered to some patients also receiving 
cyclophosphamide. Management options include avoiding concurrent 
therapy or if concurrent therapy cannot be avoided, to monitor for 
prolonged succinlycholine effect in patients receiving both drugs. If 
cyclophosphamide has been administered within 10 days of 
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administration. The anesthesiologist should be informed of the 
potential for succinylchoine-induced apnea and appropriate 
precautions and monitoring should be implemented. 3,10,11 
Trastuzumab: In early clinical trials the concurrent administration of 
cyclophosphamide and trastuzumab increased the incidence and 
severity of cardiac dysfunction. Until additional data from clinical trials 
demonstrate the safety of concurrent use of these drugs concurrent 
administration is not recommended. 3,12 
8.8.12 
Nursing Implications 
1. Monitor CBC, platelet count. Advise patients of increased risk of 
infection with an absolute neutrophil count less than 500 
cells/mm3 and increased risk of bleeding with platelet counts less 
than 20,000 cells/ mm3. Advise patients to call the clinic if they 
develop a fever above 101°F or notice any easy bruising, 
petechiae (pinpoint red spots on skin), or prolonged bleeding. 
2. Advise patient of possible alopecia. Instruct how to obtain wig, 
hairpiece, etc. 
3. Assess hydration and fluid balance. Patients receiving larger 
doses should force fluids up to 2 liters above normal intake for 72 
hours after administration. Instruct patients to void more frequently 
to minimize occurrence of hemorrhagic cystitis. For high-dose 
therapy MESNA may be used. 
4. Premedicate with antiemetics. 
5. Observe for possible phlebitis at injection site. 
6. Administer antiemetics as indicated. 
8.8.13 
References 
1. American Hospital Formulary Service 99 – Drug Information;832-
837. 
2. Cytoxan package insert, Princeton, NJ: Mead Johnson Oncology 
Products 1998; July 
3. Micromedex Inc. Vol. 101; 1999. 
4. USPDI Volume1 1999:1128-1134. 
5. Trissel, L.A., Handbook on Injectable Drugs (8th ed), Bethesda, 
MD: American Society of Hospital Pharmacists, 1994, pp. 287-
295. 
6. Cazin B., Gorin NC, LaPorte JP. Cardiac complications after bone 
marrow transplantation: A Report of a series of 63 consecutive 
transplants. Cancer 1986;57:2061-2069. 
7. Gryn et.al., Pentostatin increases the acute toxicity of high dose 
cyclophosphamide. Bone Marrow Transplantation 1993;12:217-
220. 
8. Pedersen-Bjergaard J, Ersboll J, Sorenson HM. Risk of acute 
nonlymphocytic leukemia and preleukemia in patients treated with 
cyclophosphamide for non- Hodgkin’s lymphoma. Ann Intern Med 
1985;103:195-200. 

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9. Stillwell TJ, Benson RJ. Cyclophosphamide-induced hemorrhagic 
cyctitis: A review of 100 patients. Cancer 1988;61:451-457. 
10. Zucchero FJ, ed. Evaluation of drug interactions. St. 
Louis:Professional Drug Systems, 1997:2/35, 12/21. 
11. Hansten PD, ed. Drug interactions analysis and management. 
Applied Therapeutics, Inc., Vancouver, WA: 1998:185-186. 
12. Trastuzumab package insert, South San Francisco, CA: 
Genentech, Inc. 1998;September Date/Reviewer: July 
1999/Robert K. Sylvester, Pharm.D. (701) 234-5154 
8.9 
Cytarabine 
NOTE: 
Refer to drug package insert for additional information. 
8.9.1 
Other Names 
Cytosar-U‚, Ara-C, Arabinosyl, cytosine arabinoside. 
8.9.2 
Classification 
Antimetabolite. 
8.9.3 
Mode of Action 
Converted to cytarabine triphosphate (Ara-CTP), a competitive 
inhibitor of DNA polymerase.  The drug is also incorporated into 
cellular DNA and RNA.  It is active against cells in S-phase and is 
considered to be phase specific. 
8.9.4 
Storage and Stability 
The dry powder is stored at room temperature.  Solutions 
reconstituted with sterile water without preservative should be used 
immediately; solutions reconstituted with Bacteriostatic of Water are 
stable up to 48 hours at controlled room temperature (15o to 30oC).  
Solutions with a slight haze should be discarded. 
8.9.5 
Dose Specifics 
Induction 
(Cycle 1): 70 mg IT day 1 
(Cycle 2): 75 mg/m2 IV days 1-4, 8-11, 29-32, 36-39 
Consolidation (Cycle 1, 2, 4, 5): 75 mg/m2 IV days 1-5 
(Cycle 3): 75 mg/m2 IV days 30-33, 37-40 
8.9.6 
Preparation 
For IV use, reconstitute the 100 mg vial with 5 mL bacteriostatic water 
for injection to achieve a concentration of 20 mg/mL.  Add 10 mL of 
bacteriostatic water to the 500 mg vial to achieve a final concentration 
of 50 mg/mL.  Add 10 and 20 mL of bacteriostatic water to the 1 and 2 
gm vials respectively to achieve a final concentration of 100 mg/mL.  
For subcutaneous use, reconstitute the powder with sterile water or 
saline to a concentration of 50-100 mg/mL.  For IT use, mix with 
lactated Ringer's solution or normal saline without preservatives. 
8.9.7 
Administration 
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IV push, IV continuous infusion, subcutaneous, or IT.  Cytarabine is 
not absorbed when given orally. 
8.9.8 
Incompatibilities 
Possible interaction with fluorouracil. 
8.9.9 
Compatibilities 
Cytarabine (0.25 mg/mL), daunorubicin (0.03 mg/mL) and etoposide 
(0.4 mg/mL) are stable in D5/0.45% NaCl for 72 hours at room 
temperature.  Cytarabine is also compatible with sodium chloride, 
potassium chloride, calcium, and magnesium sulfate.  
8.9.10 
Availability 
Commercially available in 100 mg, 500 mg, 1 gm, and 2 gm vials. 
8.9.11 
Side Effects 
1. Hematologic:  Leukopenia, thrombocytopenia, anemia, and 
phlebitis.  Nadir occurs in 5-7 days with recovery in 2-3 weeks. 
2. Dermatologic:  Rash, alopecia. 
3. Gastrointestinal:  Nausea, vomiting, diarrhea, dysphagia, mucositis, 
anorexia. 
4. Hepatic:  Transient increase in liver enzymes. 
5. Renal:  Urinary retention. 
6. Other:  Flu-like syndrome, fever.  Profound hyperuricemia may 
occur in leukemia patients with high white blood counts. 
Conjunctivitis, dizziness, shortness of breath, headache, urticaria, 
pruritis, abdominal pain, pericarditis. 
7. After intrathecal administration, the most common side effects are 
nausea, vomiting, fever, and headache, usually mild and self-
limiting.  Meningism, paresthesia, paraplegia, seizures, blindness, 
necrotizing encephalopathy have occurred. 
8.10 
Mercaptopurine 
NOTE: 
Refer to drug package insert for additional information. 
8.10.1 
Other Names 
Purinethol®, 6-MP 
8.10.2 
Classification 
Antimetabolite 
8.10.3 
Mode of Action 
Mercaptopurine is converted intracellularly to the ribonucleotide 
derivative 6-MP ribose phosphate (6-thioinosinic acid), which may be 
incorporated into RNA, thus inhibiting its effects. It also blocks several 
steps in the synthesis of purines. 
8.10.4 
Storage and Stability 
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8.10.5 
Dose Specifics 
Take at bedtime on an empty stomach 1 hour before or 2 hours after 
food and/or milk products. Round the dose to the nearest 25 mg half-
tablet.  
NOTE: 
If tablets may not be split into 25 mg increments, calculate 
the daily dose, round to the nearest 50 mg tablet size, and 
determine the number of tablets needed per week and 
administer tablets accordingly. 
Induction (Cycle 2): 60 mg/m2 orally days 1-14, 29-42 
Consolidation (Cycle 3): 60 mg/m2 PO days 29-42 
Maintenance 
75 mg/m2 PO/day continuously. 
8.10.6 
Preparation and Administration 
Tablets are given orally. The investigational parenteral form of this 
agent is not used in this study. A pill calendar will be provided to 
patients. See Appendix II 
8.10.7 
Incompatibilities 
When administered with allopurinol, the dose of mercaptopurine is 
reduced to 25%-30% of the usual dose. Allopurinol inhibits xanthine 
oxidase, which metabolizes mercaptopurine. 
8.10.8 
Availability 
Commercially available as 50 mg tablets. 
8.10.9 
Side Effects 
Hematologic: Leukopenia, thrombocytopenia, anemia 
Dermatologic: Hyperpigmentation (rare), rash (rare) 
Gastrointestinal: Nausea, vomiting, anorexia, abdominal pain, 
mucositis (all uncommon) 
Hepatic: Jaundice, elevated hepatic enzymes, cholestasis, ascites, 
hepatic encephalopathy associated with hepatic necrosis and fibrosis. 
Variable onset, usually in 1-2 months. Deaths have occurred. All more 
frequently associated with doses over 2.5 mg/kg/day. 
Other: Fever, headache 
8.10.10 
Nursing/Patient Implications 
1. Monitor CBC, platelet count, liver function tests. 
2. Monitor for GI toxicities and drug fever, and treat symptomatically. 
3. The parenteral preparation is a vesicant (not used in this study). 
4. Administer in evening on empty stomach (at least 1 hour before or 
2 hours after food or drink except water). 
5. Maintain adequate hydration to prevent hyperuricemia 
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8.11 
Etoposide 
NOTE: 
Refer to drug package insert for additional information. 
8.11.1 
Other Names 
VP-16, VePesidÒ, VP-16-213, EPEG, epipodophyllotoxin, NSC 
#141540 
8.11.2 
Classification 
Podophyllotoxin derivative. 
8.11.3 
Mode of Action 
The exact mechanism(s) of action of etoposide is not fully understood; 
it is thought to produce its antineoplastic effects by inhibiting or 
altering DNA synthesis. Single-stranded and double-stranded DNA 
breaks may result from etoposide’s inhibition of the intranuclear 
enzyme topoisomerase II, endonuclease activation or formation of a 
free-radical metabolite. In vitro data suggest that it has phase-specific 
activity inducing G2 arrest resulting in cell death in the G2 and late S 
phases.1,2 
8.11.4 
Storage and Stability 
Parenteral: Unopened vials of etoposide injection are stable for 18 
months at room temperature (59-86º F). Vials diluted as 
recommended to a concentration of 0.2 or 0.4 mg/ml are stable for 96 
and 242 to 483 hours respectively, at room temperature (25º C) under 
normal room fluorescent light in both glass and plastic containers.2 
Bristol-Myers in-house data indicate that etoposide may be stable in 
5% dextrose or normal saline at the following more concentrated 
solutions for decreasingly shorter times (0.6 mg/mL for 8 hours, 1 
mg/mL for 2 hours, 2 mg/ml for 30 minutes). 10 Capsules: Capsules 
must be stored under refrigeration 2º to 4º C (36º to 46º F). The 
capsules are stable for 24 months when stored according to these 
recommendations.3 
8.11.5 
Dose Specifics 
Consolidation (Cycle 1, 2, 4, 5): 100 mg/m2 IV days 1-5 
8.11.6 
Preparation 
The desired dose is usually diluted to a concentration of < 0.4 mg/ml 
in normal saline or 5% dextrose. More concentrated solutions may be 
used but have shorter stability (and may precipitate). 
8.11.7 
Administration 
Slow IV infusion over at least 30-60 minutes to prevent hypotension. 
8.11.8 
Compatibilities 
At concentrations of 400 mcg/mL etoposide is compatible with 
cisplatin 200 mcg/ml in NS, at room temperature for 5 days. 
At concentrations of 200 mcg/mL or 400 mcg/mL etoposide is 
compatible with cisplatin 200, mannitol 18.75 g/L, and potassium 
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chloride 20 mEq/L in NS, should be protected from light and used 
within 8 hours. 
At concentrations of 200 mcg/mL or 400 mcg/mL etoposide is 
compatible with cisplatin 200, mannitol 18.75 g/L, and potassium 
chloride 20 mEq/L in 5% Dextrose and 0.45% NS for 24 hours. 
Potential drug-device interaction during use of undiluted etoposide: 
There is a potential drug-device interaction regarding undiluted 
etoposide and some plastics. Cracking of venting pins and line 
connectors containing a hard plastic called ABS (a polymer produced 
from acrylonitrile, butadiene and styrene) has been reported.12  When 
administering undiluted etoposide in an investigational setting you are 
recommended to contact the manufacturer of the plastic device 
coming in contact with undiluted etoposide, in order to determine (a) 
the type of plastic used in the device and (b) compatibility with the 
various solvents found in etoposide injection [PEG 300; alcohol 
(30.5% by volume); benzyl alcohol; Tween 80; polysorbate 80].13 
8.11.9 
Availability 
Commercially available for injection in the concentration of 20 mg/mL 
in 5, 7.5, 25, and 50 Ml multiple dose vials.  
8.11.10 
Side Effects 
Incidence more frequent (>5%): 
Alopecia, anorexia, nausea and vomiting, anemia, leukopenia (usually 
asymptomatic; less frequently fever and/or chills), thrombocytopenia 
(usually asymptomatic; less frequently unusual bleeding or bruising, 
black tarry stools, blood in urine or stools, pinpoint red spots on skin). 
Nadir counts usually occur 7 to 16 days after administration and 
recovery usually complete by day 20. 
Incidence less frequent (1-5%): 
Anaphylaxis (tachycardia, shortness of breath, wheezing, tightness in 
throat); stomatitis; diarrhea, secondary leukemia (acute myeloid 
leukemia) 15,16 
Incidence rare (< 1%): 
Chemical phlebitis, neurotoxicity, skin rash or itching 
8.11.11 
Nursing Implications 
1. Monitor CBC, platelet count 
2. Advise patient of possible alopecia. Instruct how to obtain wig, 
hairpiece, etc. 
3. Infuse drug over at least 30 minutes. A more rapid infusion may 
cause hypotension. 
4. Observe for possible phlebitis at injection site or burning pain with 
infusion. 
5. Administer antiemetics as indicated. 
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8.11.12 
References 
1. American Hospital Formulary Service 98 – Drug Information;810-
817. 
2. Etoposide package insert, North Chicago, IL: Abbott Laboratories 
1993; Sept. 
3. Etoposide package insert, Princeton, NJ; Bristol Laboratories 
Oncology Products 1997; March. 
4. Copelan EA, et al. Mobilization of peripheral-blood progenitor cells 
with high-dose etoposide and g-csf in patients with breast cancer, 
non-Hodgkin’s lymphomas and Hodgkin’s disease. J Clin Oncol 
1997;15:759-65. 
5. Creger RJ, et al. Infusion of high doses of undiluted etoposide 
through central venous catheters during preparation for bone 
marrow transplantation. Cancer Treat Rep. 1986;70,819-820. 
6. Rosenfeld CS, et al. Autologous bone marrow transplantation 
following high-dose busulfan and VP-16 for advanced non-
Hodgkin’s lymphoma and Hodgkin’s disease. Exp Hematol. 
1991;28:317-21. 
7. Ehninger G, et al. Unaltered pharmacokinetics after the 
administration of high-dose etoposide without prior dilution. 
Cancer Chemotherap Pharmacol. 1991;28:214-6. 
8. Hainsworth JD et al. Chronic daily administration of oral etoposide 
– a phase I trial. J Clin Oncol 19897:396-401. 
9. Jeremic B et al. Prolonged administration of oral etoposide alone 
or with intravenous carboplatin in stage IV nonsmall cell lung 
cancer: a randomized trial Lung Cancer 1997;18:179-88. 
10. Perry MC. Chemotherapeutic agents and hepatotoxicity. Seminars 
Oncol 1992;19;551-65. 
11. Micromedex Inc. Vol 89 1974-1996. 
12. Schwinghammer TL, et al. Safety, Pharmacokinetics, and 
Pharmacodynamics of High-Dose Etoposide. Am J Hosp Pharm 
1988;45:1277. 
13. Personal communication. Bristol-Myers Squibb Oncology; May 13, 
1998. 
14. USPDI Volume1 1998:1401. 
15. Whitlock JA et al. Epipodophyllotoxin-related leukemia: 
Identification of a new subset of secondary leukemia. Cancer 
1991;68:600-4. 
16. Sandler ES et al. Treatment of children with epipodophyllotoxin-
induced secondary acute myeloid leukemia. Cancer 
1997:79:1049-54. 
8.12 
Leucovorin Calcium 
8.12.1 
Other Names 
Leucovorin®, Wellcovorin®, folinic acid, 5-formyltetrahydrofolate, 
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8.12.2 
Classification 
Tetrahydrofolic acid derivative 
8.12.3 
Mode of Action 
Leucovorin calcium acts as a cofactor for 1-carbon transfer reactions 
in the synthesis of purines and pyrimidines.  Leucovorin calcium does 
not require dihydrofolate reductase (DHFR) for conversion to 
tetrahydrofolic acid. The effects of methotrexate and other DHFR-
antagonists are inhibited by leucovorin calcium. 
8.12.4 
Storage and Stability 
All dosage forms are stored at room temperature. The reconstituted 
parenteral solution (10 mg/mL) is stable for at least seven days at 
room temperature. Concentrations of 0.5-0.9 mg/mL are only stable 
for approximately 24 hours at room temperature. The oral solution (1 
mg/mL) is stable for 14 days refrigerated and seven days at room 
temperature. 
8.12.5 
Dose specifics 
Intensification 10 mg/m2 IV every 6 hours x 4 doses beginning 22-24 
hours after completion of MTX, then 10 mg/m2 PO every 6 hours x 72 
hours. 
8.12.6 
Preparation 
The 50 and 100 mg vials for injection are reconstituted with 5 and 10 
mL of sterile water or bacteriostatic water, respectively, resulting in a 
10 mg/mL solution. The 350 mg vial is reconstituted with 17 mL of 
sterile water resulting in a 20 mg/mL solution. The 60 mg bottle for 
oral solution is reconstituted with 60 mL of aromatic elixir provided, 
resulting in a 1 mg/mL oral solution. 
8.12.7 
Administration 
Leucovorin calcium is given intravenously or orally. The former is 
preferred after high-dose methotrexate. A pill calendar will be 
provided to patients. See Appendix II 
8.12.8 
Compatibilities 
Leucovorin calcium can be reconstituted in normal saline, 5% 
dextrose, 10% dextrose, Ringer’s or lactated Ringer’s solutions. It 
may be admixed with certain fluoropyrimidines for other protocols. 
8.12.9 
Availability 
Commercially available as tablets (5, 10, 15, 25 mg), cryodessicated 
powder for oral solution, and in parenteral formulations (ampoules of 3 
and 5 mg; vials of 50, 100, and 350 mg). 
8.12.10 
Side Effects 
1. Hematologic: Thrombocytosis 
2. Dermatologic: Skin rash 
3. Gastrointestinal: Nausea, stomach discomfort, diarrhea 
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4. Allergic: Hives, pruritis, skin rash 
5. Pulmonary: Wheezing 
6. Other: Headache. May potentiate side effects of fluoropyrimidines 
8.12.11 
Nursing/Patient Implications 
1. Observe for sensitization reactions. 
2. Dose timing is critical. The schedule must be understood 
thoroughly. 
8.13 
Prednisone 
8.13.1 
Other Names 
Deltasone, Orasone, Medicorten, Panasol-S, Liquid-Pred, others  
8.13.2 
Classification 
Adrenal corticosteroid. 
8.13.3 
Mode of Action 
Prednisone is a potent synthetic glucocorticoid that affects almost 
every body system. It has anti-inflammatory, immunosuppressant, and 
minimal mineralocorticoid activity, and antineoplastic properties. As an 
antineoplastic agent, prednisone may bind to specific proteins 
(receptors) within the cell forming a steroid-receptor complex. Binding 
of the receptor-steroid complex with nuclear chromatin alters mRNA 
and protein synthesis within the cell. 
8.13.4 
Storage and Stability 
The drug is stored at room temperature in a dry place. Refer to the 
package insert from the manufacturer for storage specifics. 
8.13.5 
Dose Specifics 
Maintenance therapy: 60 mg/m2 for 5 days by mouth taken with meals 
every 3 months with vincristine 
8.13.6 
Administration 
Prednisone is taken orally (with food or a meal). A pill calendar will be 
provided to patients. See Appendix II. 
8.13.7 
Availability 
Commercially available in 1, 2.5, 5, 10, 20, 25 and 50 mg tablets. Also 
available as a 1 mg/ml oral solution or syrup and as a 5 mg/mL oral 
solution. 
8.13.8 
Side Effects 
1. 
Gastrointestinal: Nausea, vomiting, anorexia; increased appetite 
and weight gain; peptic ulceration. 
2. 
Dermatologic: Rash; skin atrophy; facial hair growth, acne, facial 
erythema; ecchymoses. 
3. 
Genitourinary: Menstrual changes (amenorrhea, menstrual 
irregularities), urinary frequency. 
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4. 
Neurologic: Insomnia; muscle weakness; euphoria, psychosis, 
depression; headache, vertigo, seizures. 
5. 
Cardiovascular: Fluid retention and edema; hypertension. 
6. 
Ocular: Cataracts; increased intraocular pressure; exophthalmos. 
7. 
Metabolic: Hyperglycemia; decreased glucose tolerance; 
aggravation or precipitation of diabetes mellitus; adrenal 
suppression; Cushingoid features; hypokalemia. 
8. 
Hematologic: Leukocytosis. 
9. 
Other: Osteoporosis (and resulting back pain); serious infections 
including herpes zoster, varicella zoster, fungal infections, 
pneumocystis carinii, tuberculosis; muscle wasting; delayed 
wound healing; suppression of reactions to skin tests. 
8.13.9 
Nursing Implications 
1. 
Instruct patients to take prednisone after meals. Should not be 
taken too close to bedtime to avoid insomnia. A mild sedative 
may be required. 
2. 
GI symptoms should be treated symptomatically. 
3. 
Monitor blood glucose levels. 
4. 
Educate patient concerning potential mood swings. 
NOTE: 
Please refer to the commercially-available package 
labeling for more information. 
8.13.10 
References 
Pickup ME: Clinical pharmacokinetics of prednisone and 
prednisolone. Clin Pharmacokinet 4:111-128, 1979. 
The Boston Collaborative Drug Surveillance Program: Acute reactions 
to prednisone in relation to dosage. J Clin Pharmacol 13:694-698, 
1972. 
Ling MHM, Perry PJ, Tsuang MT: Side effects of corticosteroid 
therapy: Psychiatric aspects. Arch Gen Psychiatry 38:471-477, 1981. 
8.14 
Rasburicase 
NOTE: 
Refer to drug package insert for additional information. 
8.14.1 
Other Names 
Elitek® 
8.14.2 
Classification 
Recombinant enzyme, urate-oxidase 
8.14.3 
Mode of Action 
Rasburicase is a recombinant urate-oxidase enzyme, which converts 
uric acid to allantoin.  Allantoin is an inactive and highly soluble 
metabolite of uric acid. 
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8.14.4 
Storage and Stability 
Prior to reconstitution, store with diluent at 2°C to 8°C (36°F to 46°F); 
do not freeze. Protect from light. Reconstituted solution may be stored 
up to 24 hours at 2°C to 8°C (36°F to 46°F). 
8.14.5 
Dose Specifics 
Rasburicase 0.1 to 0.2 mg/kg/day IV over 30 minutes for 1-3 days or 
up to five days (or a flat dose of 3 or 6 mg daily) 
8.14.6 
Preparation 
Reconsitute with the provided diluent.  Use 1ml of diluent for the 
1.5mg vial and 5ml diluent for the 7.5mg vial.  Mix by gently swirling; 
do not shake. Total dose should be further diluted in NS to a final 
volume of 50ml. 
8.14.7 
Administration 
IV infusion over 30 minutes 
8.14.8 
Compatibilities 
NS. No known drug compatibilities. 
8.14.9 
Availability 
Rasburicase is commercially available as a 1.5 and 7.5mg vial. 
8.14.10 
Side Effects 
Incidence >10%: 
Cardiovascular: Peripheral edema (≤50%), fluid overload (≤12%) 
Central nervous system: Fever (46%; serious: 5%), headache (26%), 
anxiety (≤24%) 
Dermatologic: Rash (13%; serious: 1%) 
Endocrine & metabolic: Hypophosphatemia (≤17%) 
Gastrointestinal: Vomiting (50%), nausea (27%), abdominal pain 
(20%), constipation (20%), diarrhea (20%), mucositis (15%; serious: 
2%) 
Hepatic: Hyperbilirubinemia (≤16%), ALT increased (≤11%) 
Respiratory: Pharyngolaryngeal pain (≤14%) 
Miscellaneous: Antibody formation (healthy volunteers: 61% to 64%; 
patients with malignancies: 11%), sepsis (≤12%; serious: 3% to 5%) 
1% to 10%: 
Cardiovascular: Ischemic coronary disorder, supraventricular 
arrhythmia  
Endocrine & metabolic: Hyperphosphatemia (≤ 10%) 
Gastrointestinal: Abdominal/gastrointestinal infection 
Hematologic: Neutropenic fever (serious: 4%), neutropenia (serious: 
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Respiratory: Respiratory distress (serious: 3%), pulmonary 
hemorrhage, respiratory failure 
Miscellaneous: Hypersensitivity (≤ 4%) 
< 1% (Limited to important or life-threatening): Acute renal failure, 
anaphylaxis, arrhythmia, cardiac arrest, cardiac failure, cellulitis, 
cerebrovascular disorder, chest pain, cyanosis, dehydration, 
hemolysis, hemorrhage, hot flashes, ileus, infection, intestinal 
obstruction, liver enzymes increased, methemoglobinemia, MI, 
pancytopenia, paresthesia, pneumonia, pulmonary edema, pulmonary 
hypertension, retinal hemorrhage, rigors, seizure, thrombosis, 
thrombophlebitis 
8.14.11 
Drug Interactions 
No known significant drug interactions 
8.15 
Rituximab 
8.15.1 
Other Names 
IDEC-C2B8, Rituxan® 
8.15.2 
Classification 
Antibody. 
8.15.3 
Mode of Action 
Rituximab is a chimeric murine/human gamma 1 kappa monoclonal 
antibody (Chinese hamster ovary [CHO] transfectoma). It recognizes 
the CD20 antigen expressed on normal B cells. It binds with high 
affinity to CD20-positive cells, performs human effector functions in 
vitro, and depletes B cells in vivo. The Fab domain of rituximab binds 
to the CD20 antigen on B-lymphocytes and the Fc domain recruits 
immune effector functions to mediate B-cell lysis in vitro. The 
biological effect is manifested by B-cell depletion in peripheral blood, 
lymph nodes, and bone marrow. 
8.15.4 
Storage and Stability 
Intact vials should be stored under refrigeration (2°-8°C). Dilute 
solutions for infusion (1-4 mg/mL) are stable for 24 hours under 
refrigeration, and for an additional 24 hours at room temperature. 
8.15.5 
Dose Specifics 
Administer if CD20 positive (do not administer if patient is CD20 
negative); optional and not required to give if not available or desired. 
If patient is CD20 positive and positive for hepatitis B, and rituximab 
treatment is planned, prophylaxe the patient with lamivudine, 
entecavir, or tenofovir as per figure 1 of recently published 
guidelines78. 
Induction (Cycles 1, 2): 375mg/m2 IV on Day 8 and 15 
Consolidation (Cycles 1, 2, 4 (Arm D only), and 5 (Arm C Only)): 
375mg/m2 IV on Day 5 
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Consolidation (Cycle 3): 375mg/m2 IV on Day 8 
8.15.6 
Preparation 
Withdraw the necessary amount of rituximab and dilute to a final 
concentration of 1 to 4 mg/mL into an infusion bag containing either 
0.9% Sodium Chloride or 5% Dextrose in Water. Gently invert the bag 
to mix the solution. Caution should be taken during the preparation of 
the drug, as shaking can cause aggregation and precipitation of the 
antibody. 
8.15.7 
Administration 
Rituximab is administered intravenously. An in-line filter is not 
required. The initial rate is 50 mg/hr for the first hour. If no toxicity is 
seen, the rate may be escalated gradually in 50 mg/hour increments 
at 30-minute intervals to a maximum of 400mg/hr. If the first dose is 
well tolerated, the initial rate for subsequent dose is 100mg/hr, 
increased gradually in 100 mg/hr increments at 30-minute intervals, 
not to exceed 400 mg/hr. If the patient experiences fever and rigors, 
the antibody infusion is discontinued. The severity of the side effects 
should be evaluated. If the symptoms improve, the infusion is 
continued initially at one-half the previous rate. Following the antibody 
infusion, the intravenous line should be maintained for medications as 
needed. If there are no complications after one hour of observation, 
the intravenous line may be discontinued. Oral pre-medication (2 
tablets, 650 to 1000 mg, of acetaminophen and 25 to 50 mg 
diphenhydramine) will be administered 30 to 60 minutes prior to 
starting each infusion of rituximab. The patient should be treated 
according to the best available local practices and procedures. 
NOTE:  
In addition, alternative rituximab infusion rates (i.e., “rapid 
rituximab infusion”) can be used per institutional guidelines 
as long as the total number of milligrams of rituximab is the 
same and that “rapid infusion” is not administered with the 
patients first rituximab cycle. Further, a rituximab infusion 
time should never be given over less than 90 minutes 
(common infusion time for “rapid infusion” is 20% of the 
bag volume over 30 minutes, and then 80% of the 
remaining bag volume over 60 mintues). 
8.15.8 
Availability 
Rituximab is commercially available in 10 mL and 50 mL single-use 
vials containing 100 mg or 500 mg rituximab solution, respectively, at 
a concentration of 10 mg/mL. Please refer to the agent’s package 
insert for additional information. 
8.15.9 
Side Effects 
Likely side effects:  
Chills, fever; Reaction that can occur during or following infusion of 
the drug. The reaction may include fever, chills, rash, low blood 
pressure, and difficulty breathing. Lowered white blood cell count. 
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Less likely side effects: 
Lowered red blood cell count (may cause anemia, weakness, fatigue), 
Fever associated with dangerously low levels of a type of white blood 
cell (neutrophils), Heart attack caused by a blockage of a blood vessel 
supplying part of the heart, Fast heartbeat, Belly pain, Diarrhea, 
Nausea or the urge to vomit, Vomiting, Swelling of the arms and/or 
legs, Fatigue or tiredness, Pain, Allergic reaction by your body to the 
drug product that can occur immediately or may be delayed. The 
reaction may include hives, low blood pressure, wheezing, swelling of 
the throat, and difficulty breathing; Allergic reaction to other 
medications, injected proteins, or antisera (blood product) used to 
treat certain medical conditions (such as an infectious or poisonous 
substance), Infection, Awakening of viruses which have been 
latent/dormant, Infection in HIV positive patients, Lowered platelet 
count that might interfere with clotting (may make you more likely to 
bruise or bleed), Decrease in the total number of white blood cells 
(leukocytes), Increased blood sugar level, Decreased blood level of 
calcium, Decreased blood level of potassium, Joint pain, Back pain, 
Muscle pain, Dizziness (or sensation of lightheadedness, 
unsteadiness, or giddiness), Headache or head pain, Abnormal 
drowsiness or sluggishness, an unusual lack of energy, Convulsion or 
seizure, Sudden or traumatic injury to the kidney, Stuffy or runny 
nose, sneezing, Sudden constriction of the small airways of the lung 
that can cause wheezing and shortness of breath, Cough, Shortness 
of breath, Decrease in the oxygen supply to a tissue, Inflammation of 
the lungs that may cause difficulty breathing and can be life-
threatening, Sore throat, Excess sweating, Itching, Skin rash, Swelling 
of body tissue underneath the skin, Hives, Sudden reddening of the 
face and/or neck, High blood pressure, Low blood pressure. Rare but 
serious side effects include: Serious, life-threatening allergic reaction 
requiring immediate medical treatment by your doctor. The reaction 
may include extremely low blood pressure, swelling of the throat, 
difficulty breathing, and loss of consciousness. Group of signs and 
symptoms due to rapid breakdown of tumor that can occur after 
treatment of cancer has started that causes increased levels of blood 
potassium, uric acid, and phosphate, decreased levels of blood 
calcium, and kidney failure. Disease affecting brain tissue, caused by 
the JC virus. Severe potentially life-threatening damage to the lungs 
which can lead to fluid in the lungs. Severe reaction of the skin and 
gut lining that may include rash and shedding or death of tissue. 
Potentially life-threatening condition affecting less than 10% of the 
skin in which cell death causes the epidermis (outer layer) to separate 
from the dermis (middle layer). Life-threatening condition affecting 
greater than 30% of the skin in which cell death causes the epidermis 
(outer layer) to separate from the dermis (middle layer). 
8.15.10 
Nursing Implications 
1.  Monitor blood pressure, pulse, respiration, and temperature every 
15 minutes x 4 or until stable and then hourly until the infusion is 
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2.  Have epinephrine for subcutaneous injections, diphenhydramine 
for intravenous injection, and resuscitation equipment for 
emergency management of anaphylactoid reactions available. 
3.  Monitor and alter infusion rates in the presence of toxicities. 
4. Carriers of hepatitis B virus should be closely monitored for clinical 
and laboratory signs of active HBV infection and for signs of 
hepatitis throughout study participation. 
5. Due to the risks of bowel obstruction and bowel perforation, 
patients should be monitored for complaints of abdominal pain, 
especially early in the course of treatment. 
6. Patients with concurrent RA should be monitored throughout the 
infusion and rituximab ahould be discontinued in the event of a 
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9. 
Statistical Considerations 
9.1 
Original Design Overview and Primary Endpoint 
In the original design, patients with BCR/ABL-negative B cell precursor ALL aged 
30-70 will be randomized to receive either blinatumomab or no blinatumomab 
after achieving CR/CRi and receiving intensification treatment, stratified by MRD 
status (positive vs. negative), age (30-54 vs. ≥ 55 years), CD20+ status (positive 
vs. negative), rituximab use (yes vs. no), and whether patients intend to receive 
HSCT or not. Patients will not be randomized until they have completed 
intensification and the bone marrow MRD sample has been analyzed. If there is 
no bone marrow sample available, peripheral blood (PB) will be analyzed for 
MRD. Patient with MRD positive status based on the PB sample will also be 
randomized. After randomization, suitable patients may then proceed to 
myeloablative or reduced intensity HSCT at investigator discretion. The primary 
objectives of this phase III study are to compare the OS in patients who received 
blinatumomab in conjunction with chemotherapy to that of patients who received 
chemotherapy alone in MRD+ subset, MRD- subset, and the overall population. 
OS is defined as the time between randomization and death from any cause. 
Patients last known to be alive at the time of an analysis will be censored. To 
control the overall one-sided type I error at 0.025, the OS comparison in the 
MRD+ subset will be tested first at one-sided type I error of 0.02. If it is 
significant, the OS comparison in MRD- subset will be tested at one-sided type I 
error of 0.025. Otherwise, the OS comparison in overall population will be tested 
at one-sided type I error of 0.005. (See Freidlin et al.47) 
9.2 
Summary of Design Changes and Rationale 
On March 29, 2018, the U.S. Food and Drug Administration granted accelerated 
approval to blinatumomab to treat adults and children with B-cell precursor ALL 
who are in remission but still MRD+. Considering the current high non-
compliance rate of the MRD+ patients in the no blinatumomab arm and 
anticipating that the rate will go higher after the FDA approval, to answer the 
blinatumomab question in MRD+ patients as originally designed will be 
infeasible. The study team decided to discontinue randomizing MRD+ patients. 
From this amendment, all MRD+ patients will be registered at Step 3 to receive 
blinatumomab directly. Patients who are MRD- after achieving CR/CRi and 
receiving intensification treatment will continue to be randomized to receive either 
blinatumomab or no blinatumomab. 
9.3 
Sample Size and Primary Objective 
In the revised design, the primary objective of the study will be to compare the 
OS in patients who received blinatumomab in conjunction with chemotherapy to 
that of patients who received chemotherapy alone in MRD- patients. As a 
secondary objective, the OS of those patients who are MRD+ at step 3 
randomization/registration and then convert to MRD- after 2 cycles of 
blinatumomab will be compared to those patients who are MRD- at 
randomization and remain MRD- after 2 cycles of blinatumomab or consolidation 
chemotherapy. 
We plan to enter a total of 488 BCR/ABL-negative B cell precursor ALL patients 
aged 30-70 in this study. Based on current data, we assume that a total of 190 
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(39% of the 488) patients will be MRD- and be randomized to receive either 
blinatumomab or no blinatumomab.  Based on E2993, we assume the survival 
function of this ALL patient population can be described by a cure rate model. 
For MRD- patients, we assume a 35% long-term cure rate and 13-month median 
OS in the non-cured group in the control arm. Adjusted for sequential monitoring, 
with 190 MRD- patients, the study will have 80% power to detect 45% reduction 
in hazard rate in the blinatumomab arm relative to the no blinatumomab arm, 
using one-sided log rank test at the significance level of 0.025 and assuming 2 
years of follow-up, which is equivalent to detecting an improvement in the 3-year 
OS rate from 45% to 64%. The number of events needed is 94. 
The final analyses will be done when the full information for MRD- patients (94 
events) is reached. Estimates of OS, including medians and confidence intervals, 
will be calculated using the Kaplan-Meier method. Comparison of OS between 
treatment arms will be conducted using the one-sided stratified log-rank test with, 
age, CD20 status, rituximab use, and whether patients intend to receive HSCT or 
not as stratification factors at overall one-sided type I error of 0.025. The primary 
comparisons of OS will be based on the intention-to-treat (ITT) principle, 
including all patients as randomized. The critical values at the final analyses for 
each comparison conducted will be determined using a truncated version of the 
Lan-DeMets error spending rate function corresponding to the O-F boundary, 
taking into account the errors spent at the interim efficacy analyses for that 
comparison. Cox proportional hazards models, stratified on age, CD20 status, 
rituximab use, and whether patients intend to receive HSCT or not, will also be 
used to assess the treatment effect by adjusting other possible clinical and 
biological risk factors, including cytogenetic abnormalities. 
The rate of HSCT in each treatment arm will be monitored by the ECOG-ACRIN 
Data Safety Monitoring Committee (DSMC). To assess the potential impact of 
transplant on the primary comparison, at the time of final analysis, a sensitivity 
analysis will be performed. A Cox proportional hazards model of OS, stratified on 
MRD status, age, CD20 status, and rituximab use, will be used to assess the 
effect of treatment and will include receipt of transplant as a time-varying 
covariate. 
9.4 
Randomization Scheme 
Randomized treatment codes will be assigned using a permuted blocks within 
strata algorithm with dynamic balancing on institution (with main institutions 
combined with their affiliate networks for balancing).  Treatment codes are 
generated by the ECOG-ACRIN Patient Registration System (PRS) using a 
computerized random number generator to produce permuted blocks of 
treatment codes for each stratum. The block size is the blocking factor multiplied 
by the number of treatments. The number of possible permutations depends on 
the block size and resulting number of individual treatments. Treatment 
assignments are consumed sequentially and within each stratum. The 
stratification factors for this study are: MRD status (positive vs. negative), age 
(30-54 vs. ≥ 55 years), CD20 status (positive vs. negative), rituximab use (yes vs. 
no) and whether patients intend to receive HSCT (yes vs. no). Dynamic 
balancing is used to maintain treatment balance within main institution and their 
affiliate networks. As with all NCTN studies, the sites enroll patients through the 
Oncology Patients Enrollment Network (OPEN) web system, which transmits 
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information to the PRS system.  The PRS system then determines the treatment 
assignment and transmits the assignment back to OPEN. 
9.5 
Interim Analyses of Primary Endpoint 
This study will be monitored by the ECOG-ACRIN DSMC. Interim analyses will 
be performed annually. The first efficacy interim analysis and the first futility 
interim analysis in the MRD- patients will be performed, when at least 24 events, 
that is approximately 25% of the planned full information, have occurred in the 
MRD- patients, and will continue until either criteria for early stopping are met or 
the full information is reached, except that a scheduled interim analysis will not 
be performed if small increments of information (< 10%) are gained during twelve 
months in the MRD- patients. To preserve the overall type I error rate, critical 
values at the interim efficacy analyses will be determined using a truncated 
version of the Lan-DeMets error spending rate function corresponding to the 
O’Brien-Fleming (O-F) boundary. If at one of the scheduled interim analyses, the 
upper O-F efficacy boundary has been crossed, the study may be stopped in 
favor of effectiveness in the MRD- patients by the DSMC. Table 1 gives the 
boundary at the expected analysis times under the assumptions detailed above. 
Table 1: The Interim Efficacy Analyses for the OS Comparison in MRD patients 
Time from Study Start 
(Years) 
Information 
Time 
Events 
Under H1 
Truncated O-F 
Boundary 
3.0 
0.25 
24 
3.29 
4.0 
0.40 
38 
3.29 
5.0 
0.55 
52 
2.87 
6.0 
0.71 
67 
2.46 
7.0 
0.86 
81 
2.22 
8.4 
1.00 
94 
2.06 
This study will be monitored for early stopping for harm and futility for the OS 
comparisons in the MRD- patients. At the first interim analysis (about 25% 
information of MRD- patients), we may consider blinatumomab to be harmful in 
that population if the lower bound of a 95% confidence interval in the hazard ratio 
(blinatumomab/no blinatumomab) is above 1. Inefficacy monitoring is scheduled 
to start approximately after 49% of the full information (46 events) become 
available in the MRD- patients, with repeated analyses annually at DSMC 
meeting. Linear 20% Inefficacy Boundaries (LIB20) proposed by Freidlin et al.48 
will be used. At each interim analysis, if the estimated hazard ratio is larger than 
the cut-off value given in the LIB20 boundary, the DSMC may recommend that 
that blinatumomab is futile in MRD- patients. 
9.6 
Secondary Objectives 
As one of the secondary objectives, the relapse-free survival (RFS) of 
blinatumomab in conjunction with chemotherapy will be compared to 
chemotherapy alone in MRD- patients after induction and intensification 
chemotherapy. RFS is defined as time from Step 3 randomization to relapse 
(defined as in Section 6.4) or to death without documentation of relapse. Patients 
last known to be alive will be censored at the date of last contact. 
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For MRD- patients, we assume a 30% long-term cure rate of RFS and 11-month 
median RFS in the non-cured group in the control arm. With 190 MRD- patients, 
the study will have 80% power to detect 43% reduction in hazard rate in the 
blinatumomab arm relative to the no blinatumomab arm, using one-sided log rank 
test at the significance level of 0.025 and assuming 2 years of follow-up, which is 
equivalent to detecting an improvement in the 3-year RFS rate from 37% to 57%. 
The number of events needed is 106. 
At the final analysis, estimates of RFS, including medians and confidence 
intervals, will be calculated using the Kaplan-Meier method. Comparison of RFS 
between treatment arms will be conducted using the one-sided stratified log-rank 
test with age, CD20 status, rituximab use, and whether patients intend to receive 
HSCT or not as stratification factors. Stratified on those factors, Cox proportional 
hazards models, will also be used to assess the treatment effect by adjusting 
other possible clinical and biological risk factors, including cytogenetic 
abnormalities and the receipt of transplant (included as a time-varying covariate). 
From this amendment, after achieving CR/CRi and receiving intensification 
treatment, patients who are MRD+ will be registered to Step 3 and receive 
blinatumomab directly on Arm C. Combining with those MRD+ patients 
randomized to Step 3 blinatumomab arm prior to this amendment, we assume a 
total of 62 MRD+ will receive blinatumomab on study. As a secondary objective, 
the OS and RFS of those patients who are MRD+ at step 3 randomization/ 
registration and then convert to MRD- after 2 cycles of blinatumomab will be 
compared to those patients who are MRD- at randomization and remain MRD- 
after 2 cycles of blinatumomab or consolidation chemotherapy. Assume 50 (80% 
of 62) of those MRD+ patients will convert to MRD– after two cycles of 
blinatumomab and 90 patients (95% of 95 randomized to each arm) who are 
MRD- at randomization will remain MRD- after 2 cycles of blinatumomab (or 
consolidation chemotherapy). For MRD+ converting to MRD- patients, we 
assume a 45% long-term cure rate and 14-month median OS in the non-cured 
group. The study will have 80% power to detect 56% reduction in hazard rate in 
the MRD- remain as MRD- patients (after blinatumomab/consolidation 
chemotherapy), using one-sided log rank test at the significance level of 0.025 
and assuming 2 years of follow-up, which is equivalent to detecting an 
improvement in the 3-year OS rate from 54% to 76%. The number of events 
needed is 49. At the final analysis, landmark analysis will be performed and only 
patients with MRD data available after 2 cycles of blinatumomab or consolidation 
chemotherapy will be included. Comparison of OS and RFS between the groups 
will be conducted using the one-sided log-rank test. Cox proportional hazards 
models, will also be used to assess the group effect by adjusting age, CD20 
status, rituximab use and other possible clinical and biological risk factors, 
including cytogenetic abnormalities and the receipt of transplant (included as a 
time-varying covariate). 
In this study, we will also examine the effect of rituximab on CD20+ patients. 
Among those CD20+ patients entering step 3, OS and RFS of those receiving 
rituximab will be compared to those not receiving rituximab. Cox regression 
analysis will be used to examine the rituximab effect, adjusted by blinatumomab 
treatment effect, MRD status, age, cytogenetic abnormalities, and the receipt of 
transplant (included as a time-varying covariate). 
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As per NCI CTCAE, the term toxicity is defined as adverse events that are 
classified as either possibly, probably, or definitely related to study treatment.  
The maximum grade for each type of toxicity will be recorded for each patient, 
and frequency tables will be reviewed to determine toxicity patterns.  In addition, 
we will review all adverse event data that is graded as 3, 4, or 5 and classified as 
either “unrelated or unlikely to be related” to study treatment in the event of an 
actual relationship developing. 
9.7 
Accrual 
Based on the accrual rate of E2993 and also considering the participation of 
other collaborative groups, we originally estimated the accrual rate per year of 
this study to be roughly 72 patients. The accrual rate as of May, 2018 is about 
116 patients per year. With this accrual rate, we anticipate the enrollment of 488 
patients with BCR/ABL-negative B cell precursor ALL could be completed around 
November 2019. 
9.8 
Gender and Ethnicity  
Based on previous data from E2993 the anticipated accrual in subgroups defined 
by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
14 
21 
35 
Not Hispanic or Latino 
177 
276 
453 
Ethnic Category: Total of all subjects 
191 
297 
488 
Racial Category 
American Indian or Alaskan Native 
1 
2 
3 
Asian 
8 
4 
12 
Black or African American 
14 
23 
37 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
168 
268 
436 
Racial Category: Total of all subjects 
191 
297 
488 
The accrual targets in individual cells are not large enough for definitive 
treatment comparisons to be made within these subgroups. Therefore, overall 
accrual to the study will not be extended to meet individual subgroup accrual 
targets. 
9.9 
Correlative Studies  
9.9.1 
Identification and Characterization of the BCR/ABL1-like Phenotype49 
The OS (and RFS) of patients with BCR-ABL-like phenotype will be 
compared to those without BCR-ABL-like phenotype. It is expected 
that patients with BCR-ABL-like phenotype will have poor outcome. 
Assume 40% of patients will have BCR-ABL-like phenotype. We 
assume a 30% long-term cure rate and 11-month median OS in the 
non-cured group in patients with BCR-ABL-like phenotype. With 
approximately 275 patients entering Step 3, the study will have 80% 
power to detect 37% reduction in hazard rate in patients without BCR-
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ABL-like phenotype, using one-sided log rank test at the significance 
level of 0.025 and assuming 2 years of follow-up. The number of 
events needed is 156. 
Cox regression analysis will be used to assess whether BCR-ABL-like 
phenotype is an independent predictor for OS (and RFS), adjusted by 
treatment effect, MRD status, age, cytogenetic abnormalities,  CD20 
status, rituximab use, and whether patients intend to receive HSCT or 
not. The interaction of treatment and BCR-ABL-like phenotype will be 
tested in the model. If a strong interaction effect is detected, Cox 
regression analysis will be used to look at the treatment difference 
separately within each of the BCR-ABL-like phenotype categories 
(negative/positive) to see if the magnitude and direction of the 
treatment effect differs by phenotype. 
9.10 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Operations Center. 
9.11 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. The DSMC reviews comprehensive toxicity reports twice each year. 
Reports of these analyses are sent to the ECOG-ACRIN Principal Investigator or 
Senior Investigator at the participating institutions. Expedited reporting of certain 
adverse events is required, as described in Section 5. 
9.11.1 
Early Stopping for Excessive Toxicity 
Since little is known about the toxicity of blinatumomab in this 
treatment paradigm, the tolerability of this regimen will be tested in the 
first 50 patients treated in the blinatumomab arm. All grade 5 events 
occur during the first 2 cycles of blinatumomab will be evaluated. We 
will consider blinatumomab tolerable if the grade 5 events is 5% or 
less, and intolerable if the rate is 20% or higher. If, in the first 50 
patients treated in blinatumomab arm, we observe 6 or more patients 
with grade 5 events, the DSMC will be consulted regarding a 
recommendation on the termination of the trial. With this design, the 
probability of concluding the regimen intolerable is 0.04 if the true but 
unknown rate of grade 5 events is 5%; the probability of concluding 
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the regimen intolerable is at least 0.95 if the true but unknown rate of 
grade 5 events is 20%. 
9.11.2 
Monitoring for Infection Rate of 72 or 96 Hour Bag Changes in 
Blinatumomab Administration 
The rate of grade 3 or higher relevant infections (defined as sepsis, 
bacteremia, device or catheter-related infection) will be monitored 
among patients who received blinatumomab with the infusion bag 
changed up to 72 or 96 hours. We will consider 72 or 96 hour bag 
change is acceptable if the infection rate is 5% or less. All grade 3 or 
higher relevant infections will be evaluated every six months and the 
infection rate will be tested to determine whether the true rate is 5% 
using exact one-sided one-sample binomial test, and the results will 
be presented to DSMC. If at one of scheduled analyses, the one-
sided p-value of the test is less than 0.05, the 72 or 96 hour bag 
change would be considered unacceptable and the DSMC will be 
consulted regarding whether the bag change frequency should be 
changed back to 48 hours. The two-sided 90% confidence interval for 
the infection rate will also be provided. For example, if at one of 
scheduled analyses, 35 patients were treated in blinatumomab arm 
with the 72 or 96 hour bag change, with the monitoring rule as 
described above, the 72 or 96 hour bag change would be considered 
unacceptable if we observe 5 or more patients with grade 3 or higher 
relevant infection. At this time point (with 35 patients), the probability 
of concluding 72 or 96 hour bag change is unacceptable is 0.03 if the 
true but unknown rate of grade 3 or higher relevant infections is 5%; 
the probability of concluding 72 or 96 hour bag change is 
unacceptable is 0.27 if the true but unknown rate of grade 3 or higher 
relevant infections is 10%; and the probability of concluding 72 or 96 
hour bag change is unacceptable is 0.86 if the true but unknown rate 
of grade 3 or higher relevant infections is 20%. The overall probability 
of concluding that the 72 or 96 hour bag change is unacceptable 
depends on the number of analyses and the number of patients 
treated at the times of those analyses. 
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10. 
Research Sample Submissions 
NOTE: 
For institutions outside of the United States, special arrangements have been 
made between the LTRL and submitting institutions. Laboratories in Israel 
have been harmonized with the LTRL both for BCR-ABL PCR and flow 
cytometric assessments of baseline eligibility and MRD levels. Residual 
material for laboratory research studies will be banked in these laboratories, 
as instructed by Dr. Elisabeth Paietta, and mailed frozen to the LTRL in 
batches. Institutions in Canada will send fresh bone marrow and blood 
samples to the LTRL for eligibility and correlative studies as well as banking. 
Bone marrow and/or peripheral blood, and karyotypes must be submitted for central 
diagnostic review. Bone marrow must be submitted at all other time points for the 
mandatory laboratory research studies being performed at the ECOG-ACRIN LTRL. 
Additional peripheral blood and buccal swabs/rinse are to be submitted from consenting 
patients for defined laboratory research studies and/or future undefined research 
studies. These laboratory research studies are defined in Section 11. 
The IRB approved consent must allow patients the option to provide specimens for use 
in the optional defined laboratory research studies and/or for undefined future research 
studies. Failure to allow this option will result in a major violation at the time of an audit. 
It is required that all samples submitted on this trial be entered and tracked using the 
ECOG-ACRIN Sample Tracking System (STS) (see Section 10.6). An STS shipping 
manifest form is to be included with every submission. 
All samples must be labeled clearly with the ECOG-ACRIN protocol number (E1910), 
ECOG-ACRIN patient sequence number, patient’s initials, date of collection and sample 
type. 
10.1 
Sample Collection and Submission Schedule 
Samples are to be submitted as follows: 
10.1.1 
Bone marrow (first pull), peripheral blood, smears, and buccal 
swabs/rinse are to be submitted to the ECOG-ACRIN LTRL as 
outlined in Section 10.2 on the day of collection. Samples are to be 
collected at the following time points (refer to the table in Section 7.2 
for the specific time points and consent levels for each sample type): 
· 
Pre-Registration: 
The ECOG-ACRIN Leukemia Translational Research Laboratory will 
inform institutions of patient eligibility the day of sample receipt, 
provided they arrive before noon. Samples received after noon will be 
reported out the following day. Eligibility confirmation includes both 
the diagnosis of B-lineage ALL and BCR/ABL-negativity. 
Samples must be submitted to the ECOG-ACRIN Leukemia 
Translational Research Laboratory at the following time-points: 
· 
Prior to Start of Treatment 
· 
Post Cycle One (1) of Induction Chemotherapy (day 28) 
· 
Post Cycle Two (2) of Induction Chemotherapy (at time of count 
recovery) 
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· 
Prior to Randomization / Post Intensification 
· 
Post Cycle One (1) of Blinatumomab (MRD Positive Pts at Step 3 
Registration and HSCT patients only) 
· 
Post Initial Two (2) Cycles of Blinatumomab / Post Cycle Two (2) 
of Consolidation 
· 
Suspected/Confirmed Relapse 
NOTE: 
FOR MRD ASSESSMENTS, AN ASPIRATE FROM A 
SEPARATE BONE MARROW ASPIRATION SITE 
MUST BE SUBMITTED (THE NEEDLE CAN BE RE-
DIRECTED THROUGH THE SAME SKIN PUNCTURE 
SITE). ONLY SUBMIT ASPIRATES FROM THE 
FIRST PULL OF AN ASPIRATION SITE FOR MRD 
TESTING. DO NOT SUBMIT SAMPLES FROM THE 
SECOND OR THIRD PULL OF THE SAME 
ASPIRATION SITE. 
In B-lineage ALL, MRD levels in peripheral blood or 
from a dilute marrow aspiration can be 300% lower, 
on average, than those in bone marrow at a given 
time point. Submitting a first pull from a separate 
aspiration site will ensure that MRD determinations 
used in randomization and trial interpretation are 
accurate.  
MRD results are reported when available except for 
Pre-Randomization which is reported within 7-10 
days after sample receipt. 
The results for samples from suspected relapse 
will be provided the day of sample receipt. 
10.1.2 
Karyotype images are to be submitted via Medidata Rave as outlined 
in Section 10.3 within one (1) month of collection at the following time 
points: 
· 
Prior to Start of Treatment 
· 
Post Cycle 1 of Induction Chemotherapy (day 28)* 
· 
Post Cycle 2 of Induction Chemotherapy (at time of count 
recovery)* 
· 
Relapse 
· 
*NOTE: 
Cytogenetic submission not necessary prior study 
demonstrated normal karyotype (with at least 20 bone 
marrow metaphases analyzed). They should be 
repeated at each time point if abnormal at baseline or 
less than 20 bone marrow metaphases are analyzed. 
10.1.3 
Peripheral blood (serum) must be submitted to LabConnect as 
outlined in Section 10.4 on the day of collection. Samples are to be 
collected at the following time points from Arm C patients: 
· 
Post Randomization. Prior to Start of Treatment 
· 
Prior to Cycle Three (3) of Treatment 
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· 
Prior to Cycle Four (4) of Consolidation with Blinatumomab (Cycle 
3 of Blinatumomab) 
· 
Post Consolidation / Prior to Start of Maintenance 
10.2 
Submissions to ECOG-ACRIN Leukemia Translational Research Laboratory 
(LTRL) 
NOTE: 
All cooperative groups should send specimens to the ECOG-ACRIN 
Leukemia Translational Research Laboratory. 
Dr. Paietta’s institutional regulations require that she receive a copy of the 
patient’s consent and a copy of the HIPAA authorization at the time of or prior to 
the submission of the baseline samples. 
10.2.1 
Sample Preparation Guidelines 
NOTE: 
FOR MRD ASSESSMENTS, AN ASPIRATE FROM A 
SEPARATE BONE MARROW ASPIRATION SITE MUST 
BE SUBMITTED (THE NEEDLE CAN BE RE-DIRECTED 
THROUGH THE SAME SKIN PUNCTURE SITE). ONLY 
SUBMIT ASPIRATES FROM THE FIRST PULL OF AN 
ASPIRATION SITE FOR MRD TESTING. DO NOT 
SUBMIT SAMPLES FROM THE SECOND OR THIRD 
PULL OF THE SAME ASPIRATION SITE.   
In B-lineage ALL, MRD levels in peripheral blood or 
from a dilute marrow aspiration can be 300% lower, on 
average, than those in bone marrow at a given time 
point. Submitting a first pull from a separate aspiration 
site will ensure that MRD determinations used in 
randomization and trial interpretation are accurate.  
MRD and CD20 status results will be reported to the 
submitting institution. 
The following are to be submitted: 
1. MANDATORY AT ALL TIME POINTS:  Heparinized  bone marrow 
aspirate (the laboratory will accept any amount as long as it 
represents a first pull) 
2. Heparinized or EDTA peripheral blood (four (4) green or purple 
top tubes, 30-40mL). 
· 
BASELINE MANDATORY 
· 
Additional time points from patients who answer “Yes” to “I 
agree to participate in the laboratory research studies that are 
being done as part of this clinical trial.” 
3. Two (2) red top serum tubes of peripheral blood (15-20mL). 
· 
From patients who answer “Yes” to “I agree to provide 
additional specimens for research.” 
4. MANDATORY AT ALL TIME POINTS:  At least two (2) Wright-
Giemsa stained bone marrow smears and one (1) Wright-Giemsa 
stained peripheral blood smear. 
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NOTE: 
These smears will be forwarded to Dr. Daniel Arber at 
Stanford University for morphologic review, if 
necessary. 
5. MANDATORY AT ALL TIME POINTS:  A copy of the institutional 
pathology report on the bone marrow must be submitted via 
Medidata Rave. The pathology report must include cytogenetic 
results and any results from fluorescence-in-situ (FISH) 
hybridization and/or molecular studies done at the submitting 
institution. 
These documents are to be submitted via Medidata Rave 
If Rave is unavailable, please fax to the LTRL at (718) 920-1161 
6. Buccal Cell Samples 
· 
Preferably, Scope, a commercial brand mouthwash, or normal 
saline in a small sealed bottle can be given to the patient for a 
mouthwash. Brushes or buccal swabs are acceptable though 
commonly do not yield sufficient germline DNA. 
· 
Aseptic techniques must be used to collect buccal cells from 
patients on-site and buccal cells must not be contaminated 
with cells from any other source. Patients should not brush 
their teeth or consume food prior to buccal cell collection.   
· 
If a cytobrush is used, the collection end should not be 
touched and the patient should not scrape his/her cheek too 
vigorously. The inside of the cheek should be scraped 6 times. 
Several models of cytobrushes are available, such as the 
Omni swab or Bio-Swab from Arrowhead Forensics or the 
Cyto-Pak CytoSoft Brush from Medical Packaging Corp. 
· 
If mouthwash (e.g., Scope) or normal saline is used, the 
patient should pour approximately 10cc of mouthwash or 
saline into his/her mouth and vigorously swish it against the 
cheeks for 10 seconds and deliver the solution into a labeled 
50mL sterile polypropylene test tube or a sterile urine cup. 
Among mouthwashes, the Scope brand fares best in collecting 
buccal cells for the preparation of high-quality DNA in high 
yield.  
· 
It is important that buccal cells do not dry out during shipping. 
Institutions are advised to seal the container containing the 
buccal cells tightly. Ship containers on ice-packs, together with 
the patient’s peripheral blood and bone marrow specimens. 
· 
Submit from patients who answer “Yes” to “I agree to provide 
additional specimens for research.” 
NOTE: 
Buccal rinse (preferred) or swabs are strongly 
encouraged to be collected prior to the start of 
treatment, but can be collected at any other time 
during the study, if necessary. 
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10.2.2 
Shipping Procedures  
The LTRL must be notified by telephone or email the day of 
shipment for ALL shipments, including follow-up submissions. 
The laboratory must be aware that specimens are forthcoming as 
immediate processing is essential to the integrity of the specimens. 
Telephone: (718) 920-4100 
During off hours, all information regarding the shipment should be left 
on the answering machine in the LTRL including: 
E1910 sequence number 
Patient Initials 
Type of specimens shipped 
Name, telephone number, and institution  
For questions regarding the shipment, Dr. Paietta and her staff can be 
reached at the phone numbers provided on the recorded message, 
please always try Dr. Paietta first.  Questions can also be addressed 
to Dr. Paietta via e-mail (epaietta@earthlink.net or 
epaietta@montefiore.org) or by calling her cell phone (914-806-0345). 
Heparinized bone marrow and peripheral blood or EDTA samples, 
coagulated blood in red top tubes and buccal cells must be sent fresh 
(on the day of collection) on cool packs (do not freeze and do not use 
ice cubes) by overnight courier (preferably Federal Express) to arrive 
within 24 hours to: 
Elisabeth Paietta, Ph.D.Department of Oncology 
Hofheimer 3rd Floor 
Leukemia Oncology Laboratory 
111 East 210th Street 
Bronx, NY 10467 
Tel: (718) 920-4100 
FAX: (718) 920-1161 
Email: epaietta@earthlink.net 
It is imperative that all E1910 specimens be shipped by Fedex FIRST 
OVERNIGHT DELIVERY (FO), as this will allow the LTRL to run PCR 
on baseline specimens the day of specimen receipt and will allow for 
the long acquisitioin of follow-up specimens. 
The LTRL is open to receive shipments Monday through Saturday. 
Shipments on Fridays for Saturday delivery must have “Saturday 
Delivery” marked on the overnight courier slip. Also, please label the 
package with a hand-written note that says: “Deliver to Hospital Main 
Lobby/Security”. 
In general, always ship specimens the day before a holiday for 
delivery the day after the holiday. 
An STS shipping manifest form must be generated and shipped with 
all sample submissions.   
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Please enter all information into the STS, including time and date of 
specimen collection and peripheral blood WBC count and blast count. 
If samples need to be drawn late at night, on Sunday, or on a holiday 
when Federal Express does not operate, keep the samples in a 
refrigerator between 10 and 15 degrees Celsius until the next day 
when it can be shipped. 
10.3 
Submissions to ECOG-ACRIN Cytogenetic Laboratory 
Direct questions to Gary Hicks at Tel: (507) 284-2950 or Fax: (507) 284-0043. 
10.3.1 
Sample Preparation Guidelines 
Karyotypes (MANDATORY AT ALL TIME POINTS) 
Within 30 days of specimen collection at each time point, investigators 
must submit two (2) original karyotypes per clone, FISH results, 
institution’s cytogenetic laboratory report, and the Leukemia 
Cytogenetic Form (#365R) via Medidata Rave. 
NOTE: If cytogenetic studies are not successful, submit the 
laboratory report and #365R form 
NOTE: Karyotypes are not to be logged and tracked via the ECOG-
ACRIN Sample Tracking System. 
10.4 
Submissions to LabConnect 
Peripheral blood for serum must be submitted at all time points outlined in 
Section 10.1.3 to LabConnect.  Collection and shipping kits are available.  To 
obtain starter kits please enter the kit shipping address in OPEN during step 2 
registration. Initial kit orders take about one-two weeks for delivery. 
If you have any questions, please contact LabConnect Investigator Support 
Services at (800) 501-7947. 
 Please refer to the Laboratory Manual provided in the initial kit for details on 
Specimen Collection and Shipment Preparation Guidelines. If you require the 
Laboratory Manual for IRB review please contact Chelsea Van Bastelaar (805-
630-0357 or cvanbastelaar@labconnectllc.com). Please use the resupply order 
form found in the lab manual for future kit orders. 
LabConnect will forward blood samples to Amgen quarterly for analysis. 
An STS shipping manifest form must be generated and shipped with all sample 
submissions 
10.5 
ECOG-ACRIN Sample Tracking System 
It is required that all specimens submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the specimens 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst.  
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Important: 
Please note that the STS software creates pop-up windows, so 
you will need to enable pop-ups within your web browser while 
using the software. A user manual and interactive demo are 
available by clicking this link: 
http://www.ecog.org/general/stsinfo.html 
Please take a moment to familiarize yourself with the software prior to using the 
system. 
An STS generated shipping manifest form should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu.  
10.5.1 
Study Specific Notes 
Generic Specimen Submission Form (#2981v2) will be required only if 
STS is unavailable at time of sample submission. Notify the laboratory 
of the shipment by faxing a copy of the completed form to the 
laboratory. Indicate the appropriate Lab ID# on the submission form: 
· 
0002 = ECOG-ACRIN Leukemia Translational Research 
Laboratory 
· 
0174 = LabConnect 
Retroactively, enter all specimen collection and shipping information 
when STS is available. 
NOTE: 
LabConnect will not be utilizing the STS to confirm receipt. 
10.6 
Use of Specimens in Research 
Specimens will be distributed to investigators for the defined laboratory research 
studies outlined in Section 11. 
Specimens from patients who consented to allow their specimens to be used for 
future ECOG-ACRIN approved research studies will be retained in the ECOG-
ACRIN Leukemia Tissue Bank (LTB). 
Specimens submitted will be processed to maximize their utility for current and 
future research projects.  
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future research study.   
10.7 
Sample Inventory Submission Guidelines 
Inventories of all samples submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory. 
Inventories of samples forwarded by the LTRL/LTB and utilized for approved 
laboratory research studies will be submitted by the LTRL/LTB to the ECOG-
ACRIN Operations Office – Boston on a monthly basis in an electronic format.  
10.8 
Banking  
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11. 
Leukemia Correlative Studies 
11.1 
Immunophenotype and Molecular Genetics   
Immunophenotyping has become an essential part of the diagnostic work-up of 
all leukemia patients. In fact, the diagnosis of leukemia without 
immunophenotypic characterization is no longer acceptable. ECOG-ACRIN has, 
therefore, developed a model system for antigenic data collection that requests 
specimens from all patients entered on ECOG-ACRIN leukemia treatment trials 
be studied by the ECOG-ACRIN LTRL. In addition to establishing the leukemia 
subtype, this centralized testing and data collection has allowed that research 
questions of clinical relevance to be applied to a growing database (e.g., 
definition of prognostically significant antigen expression levels to eventually yield 
specific treatment subcategories). Depending on the study protocol and tissue 
availability, anti-coagulated (heparin, EDTA, ACD) peripheral blood or bone 
marrow or both are to be submitted to the LTRL. In E1910, an additional 
significance for central immunophenotyping is provided by the flow cytometric 
assessment of minimal residual disease (MRD). Sample submissions for MRD 
determination in bone marrow aspirates will coincide with clinically required bone 
marrow examinations. 
In addition to the study of abnormal hematopoietic cells, the focus of research on 
circulating serum factors in patients with leukemia or myelodysplasia has 
increased. Two tubes of coagulated peripheral blood (red top tubes) are 
requested for future research studies that may aim at identifying pathogenetic, 
diagnostic, or prognostic factors associated with leukemia or myelodysplasia.  
Serum and cells from peripheral blood or bone marrow from patients entered on 
studies of hematologic malignancies are stored in ECOG-ACRIN's LTB for E1910 
embedded and future laboratory studies. The bank provides the scientific 
community with a source of leukemia specimens that are collected, processed, 
and maintained following quality control and quality assurance guidelines. The 
bank will accommodate requests from investigators within and outside ECOG-
ACRIN in a timely and efficient manner, with respect to tissue type, tissue 
preparation, and most importantly, biologic characteristics of specimens.  
11.2 
Sample Collection and Banking 
Establishment of Immunophenotype and BCR/ABL Status to Determine 
Eligibility, Minimal Residual Disease (MRD) Monitoring, - Integrated Genomic, 
Epigenomic, and Metabolic Profiling. 
11.2.1 
ECOG-ACRIN’s Centralized Collection, Characterization and 
Distribution of Leukemia Specimens: 
Specimens from ECOG-ACRIN and non-ECOG-ACRIN patients 
MUST be submitted to the ECOG-ACRIN LTRL at all time-points of 
the study. All patients will be required to submit bone marrow and 
peripheral blood specimens to the LTRL for eligibility testing. The 
ECOG-ACRIN LTRL will assess the BCR/ABL status of patients, 
perform central flow cytometric cytometry for eligibility testing and 
MRD testing as well as banking for all E1910 patients. The LTRL will 
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also prepare and distribute viably frozen mononuclear cells from 
baseline samples for the studies on BCR-ABL-like phenotype. 
Our track record indicates that the LTRL receives diagnostic 
specimens on at least 95% of phase III patients and is successful in 
obtaining an informative immunophenotype on about 99% of these 
patients. Initial flow cytometric evaluation will characterize B- lineage 
ALL based on established criteria,50, 51 as well as establish the 
BCR/ABL status by multiplex qualitative (PCR).52 The initial antibody 
panel will contain at a minimum all antibodies planned for MRD 
testing. Antibodies suitable for monitoring of MRD a) distinguish 
leukemic blasts from normal B-cell precursors (hematogones) in bone 
marrow; b) detect expression of lineage-foreign markers, e.g., myeloid 
antigens (e.g., CD33, CD65), c) detect altered density of B-lineage 
and lineage-uncommitted antigens, (e.g.,  CD20, CD58) or d) detect 
asynchronous expression of antigens, (e.g., CD44. CD123). 
Given the novelty of blinatumomab, potential changes in the 
leukemia-specific signatures due to treatment cannot be predicted, 
e.g., similar to those seen with glucocorticoids.53 However, relapses 
with CD19NEG B-lymphoblasts have been reported following 
blinatumomab.42 
Specimens will be sent by overnight mail to the LTRL which also 
houses LTB, which are both managed by Dr. Elisabeth Paietta at 
Montefiore Medical Center-North Division in Bronx, NY.  Results of 
testing diagnostic specimens and patient eligibility will be reported to 
referring institutions within 4-6 hours of sample receipt. PCR for 
BCR/ABL will be performed within 24 hours of sample receipt. Bone 
marrow smears will be stored for potential morphology review, if 
deemed necessary. Bone marrow smears can also serve as a source 
for DNA if no other material can be banked. Preparation of RNA and 
DNA will be a priority after establishing the basic diagnosis for the 
performance of PCR for other leukemia-specific transcripts, including 
TEL/AML1, E2A/PBX1, and MLL/AF4, mutation analyses, and 
epigenetic studies. Viable cells will be frozen to allow investigators to 
sort leukemic lymphoblasts and normal cells, if required. Central 
immunophenotyping and molecular studies, as done by ECOG-
ACRIN, are a vital advantage in a study like this, since they allow for  
the use of identical antibody panels and interpretation by a single 
investigator (E. Paietta) for all patients both at the time of presentation 
and during MRD monitoring (see below for MRD standardization). 
Residual cells will be banked for embedded and for future research. 
The only ECOG-ACRIN institutions exempted from the submission of 
fresh material for eligibility studies will be Rambam Medical Center in 
Haifa, Israel and Shaare Zedek Hospital in Jerusalem, Israel.  Based 
on our current experience on E2906, flow cytometric studies and 
BCR/ABL evaluation by PCR will be done by laboratories in 
Jerusalem and flow cytometric files and BCR/ABL reports will be sent 
to the ECOG-ACRIN LTRL via e-mail.  Dr. Paietta has communicated 
with the flow cytometry laboratory at Shaare Zedek and ensured that 
the standard MRD panel is set up. Flow cytometry files of MRD data 
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will be sent electronically to Dr. Paietta for immediate MRD evaluation 
at the time of patient randomization. Other MRD time-points will be 
assessed by the LTRL retrospectively based on submitted flow 
cytometry files. Initial testing for BCR/ABL on Israel patients will be 
done by Dr. Dvora Sahar, in the Hematology Laboratory of the 
Rambam Hhealth Care Campus in Haifa. Dr. Paietta has harmonized 
the BCR/ABCL PCR assay done in the LTRL with that performed by 
Dr. Sahar. 
Institutions will submit anti-coagulated bone marrow and peripheral 
blood as well as 2 tubes with coagulated blood (for serum) to the 
LTRL. The laboratory will perform eligibility testing on bone marrow 
preferentially, while peripheral blood mononuclear cells (MNC) are 
banked, if targeted flow cytometry (to establish the blast count only) 
has demonstrated the presence of circulating lymphoblasts. Plasma 
will be separated and frozen for future studies from the anti-
coagulated blood, while serum will be separated and frozen for future 
studies from coagulated blood, as routinely performed on ECOG-
ACRIN leukemia trials. Buccal cells are requested at baseline or at 
any of the follow-up time-points (if patients’ mucositis or other logistics 
prevent collection of buccal cells at study entry) for isolation of 
germline DNA and banked at the LTB. 
At all MRD time-points, aliquots of unseparated heparinized bone 
marrow aspirate and peripheral blood, containing between 2x106 and 
10x106 white blood cells (dependent on availability), will be subjected 
to red cell lysis (e.g., with ammonium chloride Lysing Buffer). Cell 
pellets will be resuspended in Gentra Lysis buffer (Qiagen) and 
banked at 4ºC for future DNA isolation, as done routinely in the LTRL 
for molecular MRD determination. During the course of this protocol, 
DNA will be isolated from these lysates by the LTRL and DNA will be 
stored at -80ºC until distribution (stable indefinitely). These 
specimens, which will serve the development of a companion 
diagnostic, will be retained for Amgen and/or their designated third 
party vendor until such time it is clear that a companion diagnostic is 
needed and the specific platform for molecular MRD assessment and 
vendor are identified.  Once this determination is made, Amgen will 
notify ECOG-ACRIN and CTEP of specific plans (along with any FDA 
regulatory information to assure the companion diagnostic will be 
accepted by the Agency). This information will be reviewed in order to 
release the specimens for the appropriate companion diagnostic. 
ECOG-ACRIN will retain a minimum DNA quantity on every patient 
with adequate specimen collection for future correlative studies, 
provided that the request by Amgen or their designated third party 
vendor has been satisfied. The specimens for Amgen will not 
otherwise be released unless it is determined that a companion 
diagnostic is not needed for drug labeling. 
For molecular studies, other than molecular MRD assessment, DNA 
(from 2-5 million cells) and RNA (usually from 5-10 million cells) will 
be isolated from mononuclear cells (MNC), obtained by density 
gradient centrifugation, to ensure blast enrichment. MNC cells that are 
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left over after preparation of cell lysates for nucleic acid isolation will 
be banked in 90% fetal bovine serum and 10% dimethylsulfoxide 
(DMSO) at 20-50 million cells per 1.8ml aliquot. Cells frozen under 
these conditions at ultralow temperature (-120ºC) remain viable after 
thawing even when stored for 10-20 years (experience by LTB).  At 
the time of presentation, the percentage of lymphoblasts in the MNC 
fraction – compared to that in whole, unseparated tissues – will be 
established by flow cytometry and provided to the investigators who 
request banked specimens.  
Mononuclear cells from baseline marrow or blood will be frozen in a 
viable state and aliquots of 20-40 million MNC will be shipped to Drs. 
C. Mullighan/C. Willman for the assessment of the BCR-ABL-like 
phenotype. Any left-over material will be banked for future research, 
provided that patients have consented to that in the E1910 consent. 
To be absolutely certain that a patient’s wishes are respected, ECOG-
ACRIN’s  LTRL routinely collects and keeps on file a paper copy of 
the patient’s consent to the use and storage of biologic material. Since 
the laboratory collects personal information, it also keeps a copy of 
the patient’s HIPAA Authorization form. Any material that is received 
by ECOG-ACRIN’s LTRL is immediately stripped of personal 
identifiers and coded by a unique laboratory identifier, a specimen 
accession number. Bone marrow and peripheral blood samples from 
one patient taken at the same time-point (e.g., at diagnosis), even if 
received on different dates (e.g., BM on 10/3/09 and PB on 10/4/09 
but both are from diagnosis, prior to initiation of therapy) receive the 
identical accession number. Multiple specimen submissions from the 
same patient on different dates are coded with distinct accession 
numbers, while the E1910 sequence numbers link all submissions to 
the same patient. Vials containing frozen cells serum/plasma, or 
nucleic acids are labeled with the accession number, the specimen 
date, and the specimen type but NOT the parent protocol sequence 
number; therefore, any investigator receiving those materials will be 
unable to link the cells received to a particular patient. 
Specimens from E1910 patients from participating, non-ECOG-ACRIN 
groups will likewise be received by the ECOG-ACRIN LTRL and 
treated the same way as ECOG-ACRIN patients. Any patient 
considered a candidate for E1910 will sign the E1910 consent, 
including consent for central laboratory testing, prior to specimens 
being sent to the ECOG-ACRIN LTRL. 
The results from cytogenetic analysis, FISH and any molecular tests 
performed at the submitting institutions will also be submitted to 
ECOG-ACRIN’s LTRL, as part of the pathology report. Dr. Paietta will 
enter those results in her comprehensive leukemia database.  ECOG-
ACRIN institutions submit bone marrow (or rarely peripheral blood) for 
cytogenetic studies to the cytogenetic laboratory preferred by each 
institution. Results from that analysis plus two representative 
karyotypes are subsequently submitted to the ECOG-ACRIN 
Cytogenetics Committee for review. Once accepted, the chair of the 
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Northwestern University, Chicago, IL, or his representative, Gary 
Hicks at Mayo, Rochester, MN, will mail those results via secured 
electronic submission to the ECOG-ACRIN Operations Office – 
Boston and to Dr. Paietta, who will enter those results in her 
comprehensive leukemia database. 
11.2.2 
Monitoring of Minimal Residual Disease (MRD) 
11.2.2.1 
Hypotheses:  
a) MRD levels at various time-points and particularly 
before and after blinatumomab therapy are associated 
with outcome 
b) Blinatumomab therapy successfully eradicates MRD. 
11.2.2.2 
Correlative Study Design 
There is solid evidence indicating that MRD testing is 
clinically useful in pediatric and adult ALL54,55, including the 
recent ECOG phase III trial, E299322. Comparative studies 
of MRD assessment by PCR and flow cytometry have 
proven the two methodologies to be equally reliable in 
terms of sensitivity, specificity, and reproducibility 54, 56-58. 
However, flow cytometry delivers results much more 
rapidly and at considerably lower costs. Therefore, in 
E1910, MRD levels will be assessed by flow cytometry as 
integrated markers 4 times during the trial and as an 
integral marker prior to randomization. MRD positive 
patients will be assigned to blinatumomab while MRD 
negative patients will be randomized between 
blinatumomab and consolidation chemotherapy. Patients 
will not be randomized until they have completed 
intensification and the E1910 ECOG-ACRIN statistician 
has been informed of the bone marrow MRD result by the 
LTRL. 
All NCTN flow cytometry reference laboratories are 
currently involved in an NCI-led standardization effort for 
flow cytometric MRD evaluation in ALL. We will utilize 
antibody combinations selected by the NCI-led MRD 
standardization group (ECOG-ACRIN, SWOG and 
CALGB/ALLIANCE). Auxiliary antibodies can be added if 
needed. The first 2 tubes are modeled after the MRD panel 
developed and used by the Children’s Oncology Group 
(COG), given the unrivaled experience of COG in ALL 
MRD. 
The 3rd tube includes CD22 as well as the myeloid 
antibodies [CD15 and CD65] which are frequently 
expressed by leukemic blasts with KMT2A gene 
rearrangement. 
The 4th tube measures the fraction of nucleated cells that 
are B cells with the Syto16 dye. Eventually, MRD is 
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expressed as a fraction of all nucleated cells, as routinely 
done in the LTRL. CD71 in the 4th tube detects nucleated 
erythroid cells which are excluded from the calculation. 
1. Standardized MRD Antibody Panel 
TUBE 
FLUOROCHROMES (Excitation-Max/Emission-Max in nm) 
 
FITC  
(494/520) 
PE 
(496/578) 
PC5.5/ 
PerCPCy5.5 
(488/692) 
PECy7 
496/785) 
APC 
(650/660) 
APC-H7 
(650/785) 
 
1 
CD20 
CD10 
CD38 
CD19 
CD58 
CD45 
2 
CD9 
CD13+CD33 
CD34 
CD19 
CD10 
CD45 
3 
CD65+CD15 
CD58 
CD22 
CD19 
CD10 
CD45 
4 
Syto16 
 
CD3 
CD19 
CD71 
CD45 
FITC, fluorescein isothiocyanate; PE, R-phycoerythrin; 
PC5.5, R-phycoerythrin-cyanine 5.5; PerCP Cy5.5, 
Peridinin–chlorophyll cyanine 5.5; PC7, phycoerythrin-
cyanine 7; APC, allophycocyanin; APC-H7, 
allophycocyanin-cyanine tandem dye.7 
The above panel is still a work in progress and may 
change as the result of upcoming NCI-meetings. 
Given the impact of MRD levels on randomization and trial 
analysis, flow cytometric MRD assessment will have 
highest priority for sample usage. While at presentation, 
small sample aliquots are usually sufficient to establish the 
diagnosis, given the elevated blast count, larger sample 
amounts will be required following treatment. 
At baseline, WBC counts will be adjusted to 107 WBC/ml. If 
the cell count is at least 3 times higher than that, samples 
will be diluted with HEPES-buffer containing human AB 
and fetal bovine serum (IFA buffer) to the desired 
concentration; for slightly higher cell counts, sample 
volume can be reduced from 20μl per antibody tube for a 
1x107/ml cell suspension to a proportionate volume. For 
baseline samples with low WBC counts, a larger sample 
volume up to 200μl per antibody combination can be used. 
At MRD time-points, cell counts can be extremely low, 
making it necessary to concentrate samples using an 
ammonium chloride red cell lysing buffer, as recommended 
by the NCI MRD Working Group. It is important that 
sufficient white cells be stained with antibodies to allow  
> 500,000 (optimally 1 million) cells to be acquired for 
adequate sensitivity. Staining with antibodies will be done 
for 30 minutes at RT in the dark; excessive antibody will be 
washed away with IFA buffer before red cell lysis (unless 
red cell lysis was done prior to staining) and cell fixation 
with formaldehyde- containing red cell lysis buffer. Prior to 
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acquisition, fixed cells will be washed and resuspended in 
PBS. An aliquot of cells will be incubated with the Syto16 
dye for 10 minutes at RT in the dark prior to acquisition. 
Stained cells will be acquired on a FACSCanto II (Beckton-
Dickinson, BD) flow cytometer. 
All MRD results in E1910 will be derived from bone marrow 
aspirates based on data showing that in pediatric B-
lineage ALL MRD levels are much lower in peripheral 
blood than bone marrow both by molecular60 and flow 
cytometric evaluation61. ECOG-ACRIN has seen identical 
results in adult trials E2993 with PCR and in C10403 with 
flow cytometric MRD determination (Paietta E, 
unpublished). 
The ECOG-ACRIN LTRL will perform all MRD testing.  All 
samples will be sent to this laboratory for initial 
characterization and subsequently for MRD testing. The 
randomization stratification will be based on the LTRL 
result, following the NCI’s suggestion to assess the integral 
marker only in one laboratory. This routing of specimens is 
preferred over the use of individual group laboratories for 
non-ECOG-ACRIN specimens to ensure optimal sample 
collection and does not reflect reservations regarding the 
standards of MRD testing in non-ECOG-ACRIN flow 
cytometry cores. The LTRL has ample experience in 
assessing immunologic MRD in both AML (E1900, E2906) 
and ALL trials (E2993, C10403, S0805). Concerns 
regarding standardization of flow cytometric MRD assays 
among group laboratories have largely diminished with the 
NCI-led standardization effort which demonstrated that the 
LTRL produced data comparable to those provided by the 
COG laboratories, the laboratories with more experience in 
flow cytometric MRD analysis than any other laboratory in 
the country. Adult leukemia trials present with their own 
specific challenges, in particular, the timely sample 
collection for MRD assessment and the quality of samples 
for MRD testing. For instance, in pediatric trials, the 
submission of a separate or first bone marrow aspirate for 
MRD studies has become routine, while in adult trials, the 
aspirates submitted are largely contaminated with 
peripheral blood, indicating that the second or even third 
pull was submitted. The LTRL has, therefore, engaged in 
close interactions with participating institutions to 
emphasize the need for sample quality. Over the last few 
years, as a result of these efforts, the submission of follow-
up specimens has markedly improved-however, to 
optimize sample collection on E1910, ECOG-ACRIN will 
utilize automated email reminders to be incorporated into 
the new Rave clinical management system. Given that all 
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this system will allow us to monitor all E1910 patients, 
irrespective of group affiliation. 
Regarding the quality of bone marrow aspirates, the 
technique of bone marrow aspiration has been shown to 
impact the MRD level measured in the aspirate62.  In 
particular, the common procedure to aspirate a small 
sample of marrow (2ml) for morphologic examination and 
thereafter, without changing the position of the needle, to 
aspirate 5-10cc of marrow for flow cytometry results in an 
underestimation of MRD levels.  Therefore, the amount of 
MRD should be measured by flow cytometry (or molecular 
techniques) in the first 2.5cc of bone marrow aspirated 
from one puncture site. In fact, MRD-guided COG 
protocols include such directive (Brent Wood, personal 
communication).  Dr. Paietta will continue to hold repeated 
presentations in the general Education Session for Clinical 
Trial Professionals during the semiannual ECOG-ACRIN 
meetings (the first one occurred in November, 2012), to 
convey this information to CRAs, nurses and fellows. In 
addition, a memorandum will be distributed by ECOG-
ACRIN to all participating institutions carrying the same 
message. Drs Paietta and Litzow will communicate with 
the Leukemia Committee chairs from other cooperative 
groups to ensure proper bone marrow sampling. 
Although MRD is quantified as a continuous variable, 
reflected by the percentage of blasts among all nucleated 
cells, the data will be used for randomization qualitatively, 
non-ordered categorical (MRD+ versus MRD-). The value 
that will be used to dichotomize into MRD+ and MRD- will 
be 10-4 or 0.01% of leukemic cells among all normal 
nucleated cells. In each antibody tube, MRD, if present, will 
be detected independently by setting a series of sequential 
gates that exclude normal cells at each step, until a distinct 
population of abnormal cells remains. 
This commonly used cut-off level for the definition of flow 
cytometric MRD positivity,1 target cell in 104 normal cells, 
is a realistic sensitivity for clinical samples and found to be 
predictive of outcome in pediatric and adult ALL. The 
backbone of the common MRD antibody panel in E1910 
consists of CD45, CD19, and CD10 to detect B-cell 
precursors (leukemic and normal). The first gate identifies 
lymphocytes by CD45 versus cellular granularity (side 
scatter). CD45 is typically expressed by leukemic blasts at 
a density lower than that of normal lymphocytes. Next, 
CD19POS cells are spotted in the CD45LOW population, 
followed by detection of CD10 in the CD45LOWCD19POS 
gate. In the CD45LOWCD19POSCD10POS or CD10NEG gate (if 
initial blasts were CD10NEG) We will use the COG Different-
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lymphoblasts from hematogones (normal B-lymphoid bone 
marrow precursors). The incidence of hematogones 
decreases as a function of age, but is particularly elevated 
after chemotherapy. Leukemic antigen features must be 
identified on a certain number of cells (‘cluster’). 
Dependent on the number of cells in the abnormal cluster 
and the total number of normal cells present, abnormal 
cells can be recognized at a level of sensitivity of ≤ 10-4. 
Because leukemic cells are directly quantified in relation to 
other cells in the specimen, there is no need for external 
calibrators. In the ECOG-ACRIN LTRL, clusters that are 
considered to represent MRD may constitute as few as 15-
20 cells (sensitivity reaching < 10-4). The analysis software 
used on the FACSCanto II flow cytometer is FACS DIVA 
version 6. 
11.3 
Identification and Characterization of Patients with BCR/ABL1-like Phenotype 
11.3.1 
Hypotheses: 
11.3.1.1 
The incidence of the BCR/ABL1-like phenotype is 
considerably higher in older adults than in children or 
adolescents with B-lineage ALL. 
11.3.1.2 
As previously seen in children, the outcome of patients 
with BCR/ABL1-like phenotype is also poor in adults, 
independent of MRD. 
11.3.1.3 
As in children, the BCR/ABL1-like phenotype in adults is 
associated with a spectrum of tyrosine kinase 
mutations/translocations resulting in tyrosine kinase 
activation. 
11.3.1.4 
Blinatumomab can efficiently eradicate MRD also in B-
lineage ALL with the BCR/ABL1-like phenotype. 
ALL remains an important cause of morbidity and mortality 
in adults, with event-free and OS substantially inferior to 
those observed in children. The biologic basis of this poor 
outcome is incompletely understood. Recent genome wide 
profiling studies identified recurrent alterations in pediatric 
ALL, including alterations in early B lineage transcription 
factor genes (PAX5, IKZF1, EBF1). Deletion or, less 
commonly, alteration of IKZF1 (encoding the early 
lymphoid transcription factor IKAROS), is associated with 
risk of treatment failure, and is a hallmark of two subtypes 
of leukemia: BCR-ABL1POS ALL and BCR/ABL1-like 
phenotype ALL.49,63,64 
BCR/ABL1-like ALL comprises 15% of childhood B-
progenitor ALL65-69. These cases exhibit a gene expression 
profile similar to that of BCR-ABL1POS ALL, harbor IKZF1 
alterations, and respond poorly to contemporary ALL 
therapy. Up to 50% of these cases harbor a rearrangement 
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IGH@-CRLF2 rearrangement, or a focal deletion proximal 
of CRLF2, that results in expression of the P2RY8-CRLF2 
fusion. Less commonly, a CRLF2 F232C mutation is 
present. Half of CRLF2 rearranged cases harbor 
concomitant activating JAK mutations, and all CRLF2 
rearranged cases exhibit constitutively active JAK-STAT 
signaling that is attenuated by JAK inhibitors. ALL cells 
harboring CRLF2/JAK alterations are inhibited by JAK 
inhibitor monotherapy in vivo. Exome and RNA-sequencing 
of childhood BCR/ABL1-like B-ALL cases identified 
additional kinase activating lesions in the majority of non-
CRLF2 rearranged cases. These include chimeric fusions, 
focal deletions and sequence mutations which activate 
kinases and signaling effectors including JAK2, ABL1, 
PDGFRB, CSF1R, EPOR, the interleukin 7 receptor gene 
IL7R, and the JAK2 negative regulator SH2B3 (LNK). 
Despite the diversity of alterations, these lesions largely 
converge on a limited number of kinase signaling 
pathways, most notably ABL1, PDGFRB, and JAK2.  Of 
note, these alterations comprise approximately 80% of Ph-
like ALL (unpublished data). 
In contrast to pediatric ALL, the genetic basis of adult ALL 
is poorly understood. Although BCR-ABL1POS and MLL-
rearranged ALLs are more common in adults, these fail to 
explain the poor outcome of adult ALL. We have 
performed genetic studies in about 800 pre-treatment 
leukemia samples from adolescent and young adults (17-
39 years) with ALL (AYA), including 100 patients from 
ECOG-ACRIN and samples from St. Jude, COG, 
CALGB/ALLIANCE and MD Anderson Cancer Center. The 
frequency of BCR/ABL1-like ALL increased with patient 
age, rising from 25% in adolescents to 35% in young 
adults. Notably, in the cohort of ECOG-ACRIN cases, 
BCR/ABL1-like ALL occurred in 23.6%, a frequency 
approaching that of BCR/ABL1POS ALL (28.9%). Consistent 
with our previous data, 89% of ECOG-ACRIN BCR/ABL1-
like cases had IKZF1 alterations by SNP array profiling, 
and all had alterations of genes regulating lymphoid 
development (e.g., PAX5 or EBF1). 
Importantly, our studies have shown that many of these 
alterations are sensitive to TKI therapy. Cell lines 
expressing ABL1/PDGFRB fusions found in BCR/ABL1-
like ALL are sensitive to ABL1/PDGFRB inhibitors 
including imatinib and dasatinib. Primary patient cells 
harboring JAK kinase or IL7R/SH2B3 alterations are 
sensitive to JAK2 inhibitors. Moreover, we have recently 
seen a childhood case of primary refractory ALL with an 
underlying cryptic EBF1-PDGFRB translocation which 
achieved a CR upon addition of imatinib to conventional 
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data indicate that identification of BCR-ABL1-like ALL is 
warranted to identify those patients who may benefit from 
TKI therapy or novel therapeutic interventions.   
11.3.2 
Correlative Study Design:  
Sample Distribution and Workflow. As part of the flow cytometric 
evaluation of baseline specimens, the LTRL will determine the 
expression of CRLF2 on the surface of leukemic lymphoblasts and 
report the result to the Willman/Mullighan laboratories. Subsequently. 
the LTRL will prepare one aliquot of bone marrow or peripheral blood 
mononuclear cells (with known lymphoblast count) frozen in a viable 
state in the presence of 90% fetal bovine serum and 10% DMSO for 
each registered E1910 patient with sufficient cell material. An aliquot 
of 20-40 million frozen bone marrow or blood MNC will be shipped to 
Dr. Charles Mullighan, whose laboratory will isolate nucleic acids for 
RT-PCR analyses and forward the required material (RNA or cDNA) 
for TLDA analysis to Dr. Cheryl Willman. BCR-ABL-like patients that 
were found to be CRLF2 negative will be subjected to fusion 
detection, which is currently done by RT-PCR, though this might be 
switched to Next Generation Sequencing (NGS) in the lifetime of this 
protocol. NGS will be performed on all specimens that are negative for 
known BCR-ABL-like kinase alterations in the Mullighan laboratory. 
While a minimum of 20 million cells is required, for samples with 
<70% leukemic cells, fluorescence-activated cell sorting will be 
performed by the Mullighan laboratory to purify blast populations, thus 
requiring a higher starting cell count of 40 million cells. Baseline 
samples will be sent to the Mullighan laboratory batchwise; samples 
from 10 patients in each batch. If available, left-over DNA will be 
provided by Dr. Mullighan to Dr. Ross Levine (MSKCC, New York) for 
the assessment of the JAK mutation status. Alternatively, the required 
amount of DNA will be prepared by the ECOG-ACRIN LTRL and sent 
to the Levine laboratory. The intent is to subject all E1910 patients to 
these analyses, irrespective of chromosomal alterations. Aside from 
baseline specimens, no further specimens will be needed for these 
primary analyses. However, genomic DNA from remission samples or 
buccal cells will be required for subsequent genomic assays 
distinguishing somatic from inherited variants. Genomic control DNA 
will be provided by the LTRL. 
Targeted Low Density Array (TLDA) Analysis. The gene expression 
profile of BCR-ABL1-like ALL cases is highly similar to those ALL 
cases with a BCR-ABL translocation. We will use microarray gene 
expression profiling to identify cases with BCR-ABL1-like ALL. We 
have used statistic approaches to identify 12-15 genes that robustly 
identify BCR-ABL1-like ALL using TLDA cards (IGJ, SPATS2L, 
MUC4, CRLF2, CA6, NRXN3, BMPR1B, GPR110, SEMA6A, PON2, 
CHN2, S100Z, SLCA5, TP53INP1, IFITM1.  We will perform analysis 
of E1910 cases using TLDA cards to identify BCR-ABL1-like cases.  
Flow Cytometric Phosphoflow Analysis. It is the plan to screen BCR-
ABL1-like samples based on TLDA analysis for activation of specific 
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Since this part of the BCR-ABL-like phenotype analysis would require 
an additional aliquot of cells to be obtained from the ECOG-ACRIN 
LTB, a separate proposal for phosphoflow analysis will be submitted 
at a later time-point. 
Expected Outcomes: We will use the complementary genomic and 
proteomic approaches to identify and validate the frequency of BCR-
ABL1-like ALL in adult ALL. 
CRLF2 Rearrangement Testing. We will screen for CRLF2 alterations 
by flow cytometry of leukemic cells (ECOG-ACRIN – E. Paietta), RT-
PCR for P2RY8-CRLF2 (St. Jude – C. Mullighan) and CRLF2 FISH 
(UNM – C. Willman). The ECOG-ACRIN LTRL at MSKCC, NY (R. 
Levine) will perform JAK mutational testing. 
RT-PCR for Candidate Fusions. Our current studies in childhood ALL 
have identified 11 fusions in BCR-ABL1 like ALL. We will perform RT-
PCR for these fusions in E1910 BCR-ABL1-like ALL cases. 
Next Generation Sequencing Analysis to Identify Novel Alterations. 
We will subject E1910 cases lacking known alterations to mRNA-
sequencing and exome sequencing. Our studies in progress indicate 
we can identify pathogenic, therapeutically tractable fusions in 
approximately two thirds of cases. In the remainder, exome 
sequencing, SNP array analysis and/or whole genome sequencing 
will be required to identify causative lesions. 
Expected Results: We will determine the incidence of BCR-ABL1-like 
genotype in adults, and the spectrum and nature of the underlying 
mutations in tyrosine kinases signaling pathways in adult ALL. We will 
also assess whether Blinatumomab has efficacy in eradicating MRD 
in BCR-ABL1-like ALL. 
This analysis will be performed by Dr. Charles Mullighan at St. Jude 
Children’s Research Hospital and Dr. Cheryl Willman at the University 
of New Mexico Cancer Research Center. 
11.4 
Determination of CD20 Expression by leukemic B-lymphoblasts at the time of 
study entry 
CD20 expression is routinely determined by flow cytometry, using a FITC-
conjugated antibody, as part of the eligibility testing for E1910 patients. We have 
noticed 3 distinct patterns of CD20 expression in B-lineage ALL, 1) blasts are 
completely negative for CD20, 2) blasts are predominantly positive for CD20, and 
3) a small fraction of lymphoblasts expresses CD20, consistently between 20 and 
30% of the entire leukemia population. This CD20+ subpopulation is not an 
artifact, it is seen when leukemic blasts are thawed, when different CD20 
antibody lot numbers are tested and even with the use of different fluorochromes 
conjugated to the CD20 antibody. 
Rather than using an a priori set cut-off point of antigen expression to call a 
patient’s leukemia population positive or negative, we will recommend rituximab 
treatment for any patient whose blast cell population shows a distinct population 
of CD20 staining cells, irrespective of the percentage of CD20+ blasts.  The 
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CD20 result will be entered on RAVE at the time the baseline report will be sent 
to the referring institution. 
11.5 
Blinatumomab Immunogenicity Assessment 
Blinatumomab is a novel protein therapeutic under clinical development.  As 
outlined in the Draft Guidance: Immunogenicity Assessment for Therapeutic 
Protein Products (Feb 2013) pre-specified immunogenicity sampling will be 
performed to evaluate and mitigate risk 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/UCM338856.pdf).  
Blood samples for the assessment of blinatumomab immunogenicity will be 
collected to determine whether anti-idiotype antibodies directed against 
blinatumomab have been developed. Screening for these antibodies will be done 
by ELISA assay on ECL Basis (electrochemiluminescence), and binding will be 
confirmed with a Biacore assay to measure protein-protein interaction and 
binding affinity. 
In a tiered approach patient samples are initially tested in a screening assay. 
Samples that produce signals above a certain screening cut point (classified as 
“positive”) may be subjected to a confirmatory assay. The screening assay is 
designed to minimize false negatives, so positive screening assays need to be 
confirmed as positive. These are performed using the same format as the 
screening assay. A comparison of patient serum in the presence and absence of 
excess blinatumomab is used to confirm or deny the existence of anti 
blinatumomab antibodies. The screening and confirmation assay in the context of 
blinatumomab clinical studies will be performed according to an internal 
standardized protocol using a validated assay.  
Immunoassay-positive samples will be analyzed in a third step using a cell based 
blinatumomab-mediated cytotoxicity assay to determine if the detected 
antibodies have neutralizing properties. Detection of neutralizing anti-
blinatumomab antibodies relies on a validated bioassay measuring changes in 
the biologic activity of blinatumomab triggered by the presence of the antibody. 
Serum samples for antibody testing are being collected on all patients 
randomized to receiving blinatumomab for the measurement screening of anti-
blinatumomab binding antibodies. Samples testing positive for binding antibodies 
will also be tested for neutralizing antibodies and may be further characterized for 
quantity/titer, isotype, affinity and presence of immune complexes. The ‘cell-
based assay’ for neutralizing antibody detection tests patient sera in a model cell 
based system. This does not require patient cells or additional serum to be 
collected. Both the screening and the neutralizing assays are well-established at 
the Amgen Research Munich laboratory. 
ECOG-ACRIN will be notified of any positive neutralizing antibody results to 
blinatumomab. If results are not provided, no neutralizing antibodies to 
blinatumomab have been detected. 
Patients who test positive for neutralizing antibodies to blinatumomab at the final 
scheduled study visit will be asked to return for additional follow-up testing. This 
testing is to occur approximately every three months starting from when the site 
has been notified of the positive result, until: (1) neutralizing antibodies are no 
longer detectable or (2) the subject has been followed for a period of at least one 
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year (± 4 weeks) post administration of blinatumomab. All follow-up results, both 
positive and negative will be communicated to ECOG-ACRIN. More frequent 
testing (e.g. every month) or testing for a longer period of time may be requested 
in the event of safety-related concerns. Follow-up testing is not required where it 
is established that the subject did not receive blinatumomab. Patients who test 
positive for binding, non-neutralizing antibodies and have clinical sequelae that 
are considered potentially related to an anti-blinatumomab antibody response 
may also be asked to return for additional follow-up testing.  
11.6 
Future Research Studies  
The following correlative studies are proposed as outlined below.  Final analysis 
of the proposed studies requires the results of the parent study.  When sufficient 
information is available from the parent study a full correlative science proposal 
or amended protocol document detailing the scientific hypotheses, research 
plans, assay methods for use of the biospecimens, and a formal statistical 
analysis plan with adequate power justification will be submitted to and reviewed 
by CTEP.  
Correlative Genomic Studies of B-Lineage ALL. 
11.6.1 
Hypotheses: 
11.6.1.1 
a) Develop an improved, clinically useful molecular 
classification of B-ALL, identify more accurate biomarkers 
that could be used to further personalize therapy in future 
clinical trials, and identify the molecular features 
associated with disease relapse. b) Correlate novel 
findings with established prognostic parameters, such as 
karyotypes and MRD levels and c) Compare findings in 
E1910 with those published from E2993. 
11.6.1.2 
Two of the major challenges in improving the therapeutic 
outcome for patients with ALL are i) lack of diagnostic 
markers able to predict risk of relapse to specific 
therapeutic regimens, and ii) lack of understanding of 
disease biology, impeding the development of specific 
targeted therapy agents.   It is currently accepted by 
leaders in the leukemia field that the best way to capture 
the molecular pathophysiology of leukemias and address 
these two issues is through using advanced microarray 
profiling methods (see report of the NCI think tank on 
molecular targets in lymphoid malignancies = 
http://cancermeetings.org/ThinkTank/Think_Tank_Summar
y_Online.pdf). The NCI think tank recommended that all 
patients enrolled in cooperative group studies be studied in 
this way.  The reason for this recommendation is that 
leukemia cells are profoundly altered from the genetic and 
epigenetic standpoints. These alterations collectively 
determine the biological phenotype of the cell, which can 
best be captured through these kinds of analysis. 
11.6.2 
Correlative Study Design: 

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Integrated genomic and epigenomic profiling of patients enrolled in 
E1910 will be performed, both at diagnosis and relapse. Specifically, 
leukemia blast cells will be subjected to exome capture and 
sequencing, RNA-seq and DNA methyl-seq. These three 
methodologies are performed high throughput and inexpensively 
using bar-coding and Illumina HiSeq2000 technology. Diagnostic 
samples will also be assessed by ChIP-seq to determine the impact of 
histone modifications on leukemia cell transcriptional profiling. This is 
important since a number of ALL oncoproteins contain or associate 
with histone modifying enzymes (e.g. MLL, TEL-AML, etc). The 
technology is available and implemented in the laboratories of two of 
the members of the ECOG-ACRIN Leukemia Laboratory Committee 
(A. Melnick and R. Levine). These methods require very little in the 
way of starting material and can be readily performed in as little as ten 
million cells. T cells will be selected from the bone marrow or 
peripheral blood specimens as a source of control DNA or 
alternatively, buccal cell DNA will be used. Drs. Melnick and Levine 
have previously performed more limited integrative genomics studies 
using microarrays in over 400 ALL and 800 AML patients (in the 
ECOG E1900, E1905, and E2993 clinical trials, as well as from 
patients enrolled in COG, St Jude’s and HOVON clinical trials).  
These previous studies, which also included multiplatform analysis 
demonstrated that such approaches are feasible in ECOG-ACRIN and 
other clinical trial specimens, as published 70-77. Although highly 
informative these previous studies could not capture the depth of 
information that is uncovered through deep sequencing strategies. 
The results of the current correlative study will be crucial to the design 
of subsequent studies and for the development of targeted therapy 
approaches that could subsequently be translated to the clinic. Once 
analyzed, the data will be placed on the Melnick lab sequencing and 
genomics visualization server as a public service to ECOG-ACRIN 
and non-ECOG-ACRIN investigators. The data will provide critical 
explanations as to why certain patients respond and others do not on 
this clinical trial, by providing indepth molecular mapping of the 
genomic and epigenomic circuitry of these tumors. Upon publication, 
all genomic and epigenomic data will be posted on publically 
accessible sites, such as the GO database, as routinely done by 
ECOG-ACRIN Leukemia Laboratory investigators. 
This analysis will be performed by Dr. Ari Melnick of Weill Cornell 
Medical College and Dr. Ross Levine of Memorial Sloan Kettering 
Cancer Center. 
11.7 
Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secure data transfer to the ECOG-ACRIN 
Operations Office – Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. 
 

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12. 
Electronic Data Capture 
Please refer to the E1910 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
12.1 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study will be used in support of a US marketing application (New Drug 
Application), all records pertaining to the trial (including source documents) must 
be maintained for: 
· 
two years after the FDA approves the marketing application, or 
· 
two years after the FDA disapproves the application for the indication being 
studied, or 
· 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted.  
Please contact the ECOG-ACRIN Operations Office – Boston prior to destroying 
any source documents. 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
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lineage Acute Lymphoblastic Leukemia in Adults 
 
Appendix I 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG web site at http://www.ecog.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we will improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you.  This will allow me to provide you with the best 
care while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 
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lineage Acute Lymphoblastic Leukemia in Adults 
 
Appendix II 
 
Patient Pill Calendar 
 
 
Pill Calendar Directions 
1. Take your scheduled dose of each pill. 
If you forget, the missed pills will not be taken later. 
Please bring the empty bottle or any leftover tablets and your  
pill calendar to your next clinic visit. 
 
 

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Patient Pill Calendar 
This is a calendar on which you are to record the time and number of tablets you take each day.  
You should take your scheduled dose of each pill. Note the times and the number of tablets 
that you take each day.  If you develop any side effects, please record them and anything you 
would like to tell the doctor in the space provided. Bring any unused tablets and your completed 
pill calendar to your doctor’s visits. 
CYCLOPHOSPHAMIDE 
DAY 
Date 
 
 
Month   Day   
Year 
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you 
think would be of interest.) 
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DEXAMETHASONE 
DAY 
Date 
 
 
Month   Day   
Year 
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you 
think would be of interest.) 
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6-MERCAPTOPURINE (take at bedtime on an empty stomach 1 hour before or 2 hours after 
food and/or milk products) 
DAY 
Date 
 
 
Month   Day   
Year 
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you 
think would be of interest.) 
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LEUCOVORIN 
DAY 
Date 
 
 
Month   Day   
Year 
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you 
think would be of interest.) 
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METHOTREXATE 
DAY 
Date 
 
 
Month   Day   
Year 
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you 
think would be of interest.) 
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PREDNISONE 
DAY 
Date 
 
 
Month   Day   
Year 
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you 
think would be of interest.) 
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A Phase III Randomized Trial of Blinatumomab for Newly Diagnosed BCR-ABL negative B 
lineage Acute Lymphoblastic Leukemia in Adults 
 
Appendix III 
 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing investigational Agents contain confidential information and should not be shared 
or distributed without the permission of the NCI.  If a copy of this protocol is requested by a 
patient or patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data.”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available as described in the IP Option to Collaborator to Collaborator(s), the 
NCI, and the FDA, as appropriate and unless additional disclosure is required by law or 
court order (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected , used and 
disclosed consistent with all applicable federal statutes and regulations for the protection 
of human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
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4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication. Collaborator shall have the right to 
request that publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s intellectual 
property rights, are protected.  Copies of abstracts must be provided to CTEP for 
forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at 
least three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings. Press releases and other media presentations 
must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract 
and/or press release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 

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Appendix IV 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled.  Cannot carry on any self-care. Totally confined to bed or 
chair. 
 

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lineage Acute Lymphoblastic Leukemia in Adults 
 
Appendix V 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy test 
regardless of age or disease state) of a female patient while she is on Blinatumomab, or within 
28 days of the female patient’s last dose of Blinatumomab must be reported in an expeditious 
manner.  The outcome of the pregnancy and neonatal status must also be reported. 
How should the pregnancy be reported? 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be reported 
via CTEP’s Adverse Event Reporting System (CTEP-AERS)   
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy test 
need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, followed 
by a complete expedited CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
What other information do I need in order to complete the CTEP-AERS report for a 
pregnancy? 
· 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium and 
perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions” 
· 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
· 
The start date of the pregnancy should be reported as the calculated date of conception.   
· 
The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section of the CTEP-AERS 
report.  
What else do I need to know when a pregnancy occurs to a patient? 
· 
The Investigator must follow the female patient until completion of the pregnancy and must 
report the outcome of the pregnancy and neonatal status via CTEP-AERS.  
· 
The decision on whether an individual female patient can continue protocol treatment will be 
made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Operations Office – Boston.   Please contact the ECOG-ACRIN Operations Office – Boston 
to ask for a conference call to be set up with the appropriate individuals.   
· 
It is recommended the female subject be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling.  
How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERS 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself.  However, if 
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the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-AERS report 
should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions (formerly referred to as disabilities), congenital anomalies, or birth defects.  For 
assistance in recording the grade or category of these events, please contact the CTEP AEMD 
Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed on a case 
by case basis.   
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.” 
It must be reported via CTEP-AERS as Grade 4 “Pregnancy loss” under the System Organ 
Class (SOC) “Pregnancy, puerperium and perinatal conditions”.   
A fetal death should NOT be reported as a Grade 5 event as currently CTEP-AERS recognizes 
this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A death occurring during the first 28 days after birth” 
that is felt by the investigator to be at least possibly due to the investigational agent/intervention. 
However, for this protocol, any neonatal death that occurs within 28 days of birth, without regard 
to causality, must be reported via CTEP-AERS AND any infant death after 28 days that is 
suspected of being related to the in utero exposure to Blinatumomab must also be reported via 
CTEP-AERS. 
It must be reported via CTEP-AERS as Grade 4 “Death Neonatal” under the System Organ 
Class (SOC) “General disorder and administration site conditions”. 
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERS reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any additional 
medical information to CTEP (301-897-7404).  This form is available on CTEP's website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReportFor
m.pdf)  
 
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Appendix VI 
 
Writing Sample Page 
 
 
Subject ID  
 
Instructions for the Subject:  Enter the date and time of day. Rewrite the phrase listed. 
Study 
Day 
Date 
Time 
Sweet as apple pie 
Study Staff  
or ACS-  
Initial & Date 
 
 
 
 
 
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Appendix VII 
 
Clinical Site Management of Out-patient Treatment Using CTEP-supplied Blinatumomab 
· 
PREPARED IV INFUSION BAGS MAY NOT BE CHANGED BY THE STUDY SUBJECT 
· 
PREPARED INFUSION BAGS OR INTACT VIALS MUST NOT BE TRANSPORTED TO 
ANOTHER LOCATION BY THE STUDY SUBJECT 
AGENT PREPARATION AND ADMINISTRATION OPTIONS 
1. Prepare all out-patient infusion bags at the registering/treating NCTN Network institution. 
Study subjects should return to the registering/treating institution for all infusion bag 
changes. 
2. For study subjects that cannot return to the registering/treating institution every 48-hours for 
infusion bag exchanges, the next preference would be for another NCTN Network 
institution that is participating on the trial and is closer to the subject’s home take 
over responsibility for the study subject’s protocol participation. In such cases, transfer of 
the subject’s protocol registration to another participating investigator and institution should 
be considered. 
3. If transferring the subject’s protocol registration to another participating investigator and trial 
site within the NCTN Network is not feasible, use of a local outpatient infusion center 
could be considered. 
a. First preference would be for all infusion bags to be prepared by the registering/treating 
institution and shipped via overnight courier delivery service in a 2° to 8°C pre-qualified 
shipping container to the local out-patient infusion center.  
b. The prepared infusion bags are stored at the local outpatient infusion center. The 
infusion center would perform each infusion bag change.   
c. If the local outpatient infusion center will not administer prepared infusion bags admixed 
by the registering/treating institution, the registering/treating institution may provide intact 
vials of blinatumomab to the local outpatient infusion center, with infusion bags prepared 
and administered by the local outpatient infusion center staff.  
d. In either case, the local outpatient infusion center would be managed as a satellite 
pharmacy of the registering/treating institution (see evaluation criteria below).  
e. If physical transport of intact vials of blinatumomab from the registering/treating 
institution to the local infusion center by registering/treating institution or local infusion 
center staff is not possible, CTEP will allow shipment of the vials from the 
registering/treating institution to the local infusion center via overnight courier delivery 
service in a 2° to 8°C pre-qualified shipping container.  
4. If an outpatient infusion center is not an option, use of a home health care service provider 
can be considered.  
a. The first preference would be for all outpatient infusion bags to be prepared by the 
registering/treating institution and shipped via overnight courier delivery service in a 2° to 
8°C pre-qualified shipping container to the servicing home health care agency. 
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b. The prepared infusion bags are stored by the home health care agency and each 
individual infusion bag transported to the subject’s home by the home health care 
service nursing staff under refrigerated storage conditions for each infusion bag change. 
c. If home health care agency will not administer prepared infusion bags admixed by the 
registering/treating institution, the registering/treating institution may provide intact vials 
of blinatumomab to the home health care agency, with infusion bags prepared and 
administered by the home health care agency staff.  
d. In either case, the home health care agency would be managed as a satellite pharmacy 
of the registering/treating institution (see evaluation criteria below).  
e. If physical transport of intact vials of blinatumomab from the registering/treating 
institution to the home health care agency by registering/treating institution or home 
health care agency staff is not possible, CTEP will allow shipment of the vials from the 
registering/treating institution to the home health care agency via overnight courier 
delivery service in a 2° to 8°C pre-qualified shipping container 
5. If all options above are not feasible, shipping the prepared infusion bags directly to patient’s 
home via overnight courier delivery service for administration by home healthcare agency 
staff is acceptable. 
a. The prepared infusion bags are to be shipped in a 2° to 8°C pre-qualified shipping 
container containing one infusion bag per box. Example, if you are making 2 x 48 hour 
infusion bags, each infusion bag will be shipped in a separate 2° to 8°C pre-qualified 
shipping container. The number of infusion bags that may be prepared and shipped is 
dependent on the duration the shipping container used is qualified to maintain 2° to 8°C 
temperature. 
b. Patients should NOT open the shipping container upon arrival. Shipping containers are 
to be stored in a secured area away from reach of children or pets. 
c. Shipping containers must only be opened by the home health care service staff at the 
time of the infusion bag change. Only one shipping container should be opened at a 
time. If cold-chain management of the prepared infusion bag has been interrupted by 
opening of the shipping container or storage of the prepared infusion bag in the shipping 
container exceeds the duration of the qualified time the container will maintain 2° to 8°C 
temperature, the infusion bag should not be used. 
 
The home health care service staff should immediately contact the registering/treating 
institution site pharmacy as indicated on the shipment form. Within 1 business day, the 
registering/treating institution site should inform the ECOG-ACRIN Operations office at 
(617) 632-3610 to report such occurrences. ECOG-ACRIN should notify PMB/CTEP at 
PMBafterhours@mail.nih.gov of all such occurrences of prepared, unusable infusion 
bags shipped to a patient’s home within 1 business day of receiving notification from the 
registering/treating institution. 
 
d. Form documenting the time of packaging in the shipping container, duration of time the 
container will maintain 2° to 8°C temperature and verification that cold-chain 
management was maintained prior to administration must be included in each shipping 
container and returned to registering/treating institution for documentation purposes. 
e. Home health care service staff is to use GCP guidelines. 

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EVALUATION OF POTENTIAL SATELLITE PHARMACY SITES 
When the registering/treating institution is considering use of a local infusion center or home 
health care agency as a satellite pharmacy, the following must be assessed by the 
registering/treating institution in relation to the suitability of the local infusion center or home 
health care agency: 
· 
Ability to appropriately store(temperature and security) the intact agent vials and prepared 
infusion bags 
· 
Ability to provide documentation of controlled and monitored temperature storage conditions 
while the IND agent is in the local infusion center or home health care agency possession 
· 
Availability of appropriately trained staff to prepare doses in compliance with USP <797> 
guidelines and the protocol, to label infusion bags according to the protocol instructions and 
to store agent doses under appropriate controlled temperature conditions. 
· 
Availability of appropriately trained staff to administer the prepared doses and perform the 
infusion bag changes according to the protocol 
· 
Methods for proper disposal of the waste, empty vials, IV bags, etc. are inplace 
· 
Plan for return of unused intact vials to the registering/treating institution is inplace 
· 
Source documentation to confirm agent administration must be maintained by the local 
infusion center or home health care agency and must be provided to the registering/treating 
institution for incorporation into the patient’s medical/research records and for audit 
purposes 
· 
Plan for handling missed doses is in place 
· 
Agent accountability must be maintained via use of the NCI Drug Accountability Record 
Form (DARF).  The originating site must keep a Control DARF and the local infusion center 
or home health care agency would be required to maintain a Satellite DARF if receiving and 
storing supplies of intact vials or receiving and storing infusion bags prepared by the 
registering/treating institution. Maintenance of a Satellite DARF is not required by home 
health care agency staff for prepared infusions bags shipped to the subject’s home. 
· 
The DARF must be provided to the registering/treating institution for record keeping 
purposes and audits 
· 
Documentation of IRB coverage for the protocol must be maintained. The IRB of record for 
the site must be informed that the study subject may receive therapy administered by a non-
research site (i.e., the local infusion center or home health care agency). 
TRAINING FOR ALL PARTICIPATING SITES 
The Lead Network Group for the trial must work with participating sites to: 
a. Implement a training process for participating NCTN Network sites regarding blinatumomab 
preparation and administration. Documentation of participating site training must be 
submitted via RSS as a protocol specific requirement at the time of site activation for 
participation on the trial.  
b. Develop a plan for participating NCTN Network sites to assess local outpatient infusion 
centers or home health care agency for patient treatment if required and document training 
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c. Have a training manual available for local outpatient infusion centers or home health care 
agencies on the clinical trial, appropriate agent preparation, handling and administration 
requirements and appropriate record keeping requirements 
d. Create a definitive written communication plan for use between registering/treating 
institution and the local outpatient infusion centers or home health care agency on an 
ongoing basis during subject’s treatment regimen, including emergency contact information 
for the registering/treating institution and investigator 

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A Phase III Randomized Trial of Blinatumomab for Newly Diagnosed BCR-ABL negative B 
lineage Acute Lymphoblastic Leukemia in Adults 
 
Appendix VIII 
 
Shipment of blinatumomab IV Bag from Site/Pharmacy to Patient’s Home 
To be completed by Site/Pharmacy: 
From: (Investigator Name, Address) 
To Patient: (Patient Initials, Study ID No) 
_________________ ;  
____________________ 
Protocol No.: 
Site Pharmacy contact 
Prepare shipment of IV bag at 2°C to 8°C in validated/pre-qualified insulated shipper as 
per manufacturer instructions (see shipping container instructions). Please take care to 
use the applicable instructions for summer or winter package preparation, respectively. 
IV Bag number 
Date of packaging 
[DD/MMM/YYYY] 
Time of packaging 
[hh:mm] 
pa
ck
Please tick the boxes and fill in the information below when preparing the IV bag shipment! 
□ 
Validated/pre-qualified shipping container duration of time 2°C to 8°C  temperature is 
maintained: ___________________________ hours 
□ 
Cooling elements for provided box used according to manufacturer’s instruction 
Confirmed by: 
 
 
 
(print name, signature) 
(date) 
 
To be completed by Ambulant/Home Care Service Provider: 
Shipment box unopened and content intact? 
YES 
 
NO 
 
IF NO, please comment  
 
Date and time shipment box opened: _________________  _________________ 
 
(date) 
(time) 
Confirmed by: 
  
    
 
(print name, signature) Amb. Care Service 
(date) 
NOTE: 
If content is not intact, please do not use IV bag and inform site pharmacy 
immediately! If time box opened minus time of packaging exceeds the time 
duration the shipping container maintains 2°C to 8°C, please do not use IV 
bag and inform site pharmacy immediately! 
Rev. 3/15 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
195 
A Phase III Randomized Trial of Blinatumomab for Newly Diagnosed BCR-ABL negative B 
lineage Acute Lymphoblastic Leukemia in Adults 
 
Appendix IX 
 
Mercaptopurine Dosing Guidelines 
 
60 mg/m2 DOSES OF MERCAPTOPURINE 
Body Surface Area (m²) Daily Dose for 7 days*  (1 tablet = 50 mg) 
1.26 - 1.30 
1 ½ tab / d x 6; 2 tab / d x 1 
(550 mg/wk) 
1.31 - 1.36 
2 tab / d x 2; 1½ tab / d x 5 
(575 mg/wk) 
1.37 - 1.43 
2 tab / d x 3; 1½ tab / d x 4 
(600 mg/wk) 
1.44 - 1.49 
2 tab / d x 4; 1½ tab / d x 3 
(625 mg/wk) 
1.50 - 1.55 
2 tab / d x 5; 1½ tab / d x 2 
(650 mg/wk) 
1.56 - 1.61 
2 tab / d x 6; 1½ tab / d x 1 
(675 mg/wk) 
1.62 - 1.67 
2 tab / d x 7 
(700 mg/wk) 
1.68 - 1.73 
2 tab / d x 6; 2½ tab / d x 1 
(725 mg/wk) 
1.74 - 1.79 
2½ tab / d x 2; 2 tab / d x 5 
(750 mg/wk) 
1.80 - 1.85 
2½ tab / d x 3; 2 tab / d x 4 
(775 mg/wk) 
1.86 - 1.91 
2½ tab / d x 4; 2 tab / d x 3 
(800 mg/wk) 
1.92 - 1.97 
2½ tab / d x 5; 2 tab / d x 2 
(825 mg/wk) 
1.98 - 2.03 
2½ tab / d x 6; 2 tab / d x 1 
(850 mg/wk) 
2.04 – 2.09 
2 ½ tab / d x 7 
(875 mg/wk)           
2.10 – 2.15 
2 ½ tab / d x 6; 3 tab / d x 1 
(900 mg/wk) 
2.16 – 2.21 
3 tab / d x 2;  2 ½ tab x 5 
(925 mg/wk) 
2.22 – 2.27  
3 tab / d x 3; 2 ½ tab / d x 4 
(950 mg /wk) 
2.28 – 2.33  
3 tab / d x 4; 2 ½ tab / d x 3 
(975 mg/wk) 
2.34 – 2.39 
3 tab / d x 5; 2 ½ tab / d x 2 
(1,000 mg/wk) 
2.40 – 2.45  
3 tab / d x 6; 2 ½ tab / d x 1 
(1,025 mg/wk) 
2.46 – 2.51 
3 tab / d x 7                             
(1,050 mg/wk) 
* The 7-day daily dose refers to 7-day cycles within continued daily administration (e.g., during induction, 
consolidation, and throughout maintenance). The doses should be taken in the evening, at least one hour 
after eating. 
75 mg/m2 DOSES OF MERCAPTOPURINE 
Body Surface Area (m²) Daily Dose for 7 days*  (1 tablet = 50 mg) 
1.25 - 1.29 
2 tab / d x 5; 1½ tab / d x 2  
(650 mg/wk) 
1.30 - 1.34 
2 tab / d x 6; 1½ tab / d x 1  
(675 mg/wk) 
1.35 - 1.39 
2 tab / day                   
(700 mg/wk) 
1.40 - 1.44 
2 tab / d x 6; 2½ tab / d x 1  
(725 mg/wk) 
1.45 - 1.49 
2 tab / d x 5; 2½ tab / d x 2  
(750 mg/wk) 
1.50 - 1.54 
2 tab / d x 4; 2½ tab / d x 3  
(775 mg/wk) 
1.55 - 1.59 
2½ tab/ d x 4; 2 tab / d x 3  
(800 mg/wk) 
1.60 - 1.64 
2½ tab/ d x 5; 2 tab / d x 2  
(825 mg/wk) 
1.65 - 1.69 
2½ tab/ d x 6; 2 tab / d x 1  
(850 mg/wk) 
1.70 - 1.74 
2½ tab/ d x 7 
(875 mg/wk) 
1.75 - 1.79 
2½ tab/ d x 6; 3 tab / d x 1 
(900 mg/wk) 
Rev. 8/17 
Rev. 2/18 
Rev. 2/18 

ECOG-ACRIN 
E1910 
Cancer Research Group 
Version Date: January 20, 2023 
 
NCI Update Date: August 14, 2014 
196 
1.80 - 1.84 
2½ tab/ d x 5; 3 tab / d x 2 
(925 mg/wk) 
1.85 – 1.89 
2½ tab/ d x 4; 3 tab / d x 3 
(950 mg/wk) 
1.90 – 1.94 
3 tab/ d x 4; 2½ tab / d x 3 
(975 mg/wk) 
1.95 – 1.99  
3 tab/ d x 5; 2½ tab / d x 2 
(1000 mg/wk) 
2.00 – 2.04  
3 tab/ d x 6; 2½ tab / d x 1 
(1,025 mg/wk) 
2.05 – 2.09 
3 tab/ d x 7 
(1,050 mg/wk) 
2.10 – 2.14 
3 tab/ d x 6; 3½ tab / d x 1 
(1,075 mg/wk) 
2.15 – 2.19 
3 tab/ d x 5; 3½ tab / d x 2 
(1,100 mg/wk) 
2.20 – 2.24 
3 tab/ d x 4; 3½ tab / d x 3 
(1,125 mg/wk) 
2.25 – 2.29 
3 ½ tab/ d x 4; 3 tab / d x 3 
(1,150 mg/wk) 
2.30 – 2.34 
3 ½ tab/ d x 5; 3 tab / d x 2 
(1,175 mg/wk) 
2.35 – 2.39 
3 ½ tab/ d x 6; 3 tab / d x 1 
(1,200 mg/wk) 
2.40 – 2.44 
3 ½ tab/ d x 7 
(1,225 mg/wk) 
2.45 – 2.49 
3 ½ tab/ d x 6; 4 tab / d x 1 
(1,250 mg/wk) 
2.50 – 2.54 
3 ½ tab/ d x 5; 4 tab / d x 2 
(1,275 mg/wk) 
* The 7-day daily dose refers to 7-day cycles within continued daily administration (e.g., during induction, 
consolidation, and throughout maintenance). The doses should be taken in the evening, at least one hour 
after eating. 
(Taken and adapted from CALGB 10403) 
Rev. Add16