A Phase 2 Study of Blinatumomab and POMP (Prednisone, Vincristine, Methotrexate, 6-Mercaptopurine) for Patients &gt;/= 65 Years of Age With Newly Diagnosed Philadelphia-Chromosome Negative (Ph-) Acute Lymphoblastic Leukemia (ALL) and of Dasatinib, Prednisone and Blinatumomab for Patients &gt;/= 65 Years of Age With Newly Diagnosed Philadelphia-Chromosome Positive (Ph+) ALL, Relapsed/Refractory Ph+ ALL, and Philadelphia-Chromosome-Like Signature (Ph-Like) ALL (Newly Diagnosed or Relapsed/Refractory) With Known or Presumed Activating Dasatinib-Sensitive Mutations or Kinase Fusions (DSMKF)
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, Recurrent Acute Lymphoblastic Leukemia, Refractory Acute Lymphoblastic Leukemia
Sponsor: National Cancer Institute (NCI)

 
 
Version Date:  
August 16, 2021 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS; CTSU 
 
FROM: 
SWOG Operations Office (Email: protocols@swog.org)  
 
RE: 
S1318, “A Phase II Study of Blinatumomab (NSC-765986) and POMP (Prednisone, Vincristine, 
Methotrexate 6-Mercaptopurine) for Patients ≥ 65yYears of Age with Newly Diagnosed 
Philadelphia-Chromosome Negative (Ph-) Acute Lymphoblastic Leukemia (ALL) and of 
Dasatinib (NSC-732517), Prednisone and Blinatumomab for Patients ≥ 65 Years of Age with 
Newly Diagnosed Philadelphia-Chromosome Positive (Ph+) ALL and Philadelphia-
Chromosome-Like Signature (Ph-like) ALL (Newly Diagnosed or Relapsed/Refractory) With 
Known or Presumed Activating Dasatinib-Sensitive Mutations or Kinase Fusions (DSMKF).” 
 
Study Chairs: Drs. Anjali Advani, Kristen O’Dwyer, and Brent Wood 
  
REVISION #15 
 
Study Chair:  Anjali S. Advani, M.D.  
Phone number:  216/445-9354 
E-mail: advania@ccf.org  
 
IRB Review Requirements 
(√ ) 
Expedited review allowed 
 
Protocol changes 
 (√ )   Other: Study Calendar Clarifications 
 
Sites using the CIRB as their IRB of record:  The protocol and/or informed consent form changes have 
been approved by the CIRB and must be activated within 30 days of the CIRB posting of this notice.  
 
Sites not using the NCI CIRB:  Per CTMB Guidelines, the protocol updates and/or informed consent 
changes must be approved by local IRBs within 90 days of distribution of this notice.  
 
 
REVISION #15 
 
The above referenced protocol has been revised as follows: 
 
1. 
The Version Date has been revised in the Protocol and the Model Consent Form. No additional 
changes were made to the Model Consent Form.  
 
2. 
Section 9.4: The timing of assessments/treatment on the calendar was updated from Days 8-15 to 
Days 8-14, from Days 16-21 to Days 15-21, and from Days 67-70 to Days 64-70.   
 
3. 
Section 9.6: On the calendar an ‘X’ was added to the Serum for Immunogenicity procedure during 
the Pre TX timepoint.  
 
4. 
Section 15.2a.3:  This specimen submission time point was updated to clarify that it is “within 30 
days after last dose of blinatumomab.” 
 
This study has been reviewed and approved by the NCI’s Central Institutional Review Board (CIRB).  
 
This memorandum serves to notify the NCI and the SWOG Statistics and Data Management Center. 
 
cc: 
PROTOCOL AND INFORMATION OFFICE 
Colin Burnett – ECOG-ACRIN 
Diane Feldman – Alliance 
 
 
Becky Fillingham – ECOG-ACRIN 
Sally Vanture – ECOG-ACRIN  
 
Chelsea Van Bastellar – LabConnect 

S1318 
Page 1 
Version Date 08/16/2021 
 
PRIVILEGED COMMUNICATION 
Activated January 12, 2015 
FOR INVESTIGATIONAL USE ONLY 
 
SWOG 
TITLE 
 
A PHASE II STUDY OF BLINATUMOMAB (NSC-765986) AND POMP (PREDNISONE, VINCRISTINE, 
METHOTREXATE, 6-MERCAPTOPURINE) FOR PATIENTS ≥ 65 YEARS OF AGE WITH NEWLY 
DIAGNOSED PHILADELPHIA-CHROMOSOME NEGATIVE (PH-) ACUTE LYMPHOBLASTIC 
LEUKEMIA (ALL) AND OF DASATINIB (NSC-732517), PREDNISONE AND BLINATUMOMAB FOR 
PATIENTS ≥ 65 YEARS OF AGE WITH NEWLY DIAGNOSED PHILADELPHIA-CHROMOSOME 
POSITIVE (PH+) ALL, RELAPSED/REFRACTORY PHILADELPHIA-CHROMOSOME POSITIVE (PH+) 
ALL, AND PHILADELPHIA-CHROMOSOME-LIKE SIGNATURE (PH-LIKE) ALL (NEWLY DIAGNOSED 
OR RELAPSED/REFRACTORY) WITH KNOWN OR PRESUMED ACTIVATING DASATINIB-SENSITIVE 
MUTATIONS OR KINASE FUSIONS (DSMKF) 
 
NCT #02143414 
 
STUDY CHAIRS: 
AGENTS: 
 
 
Anjali S. Advani, M.D. (Medical Oncology) 
IND-Exempt Agents: 
Cleveland Clinic/Taussig Cancer Center 
Department of Hem Oncology and Blood Disorders 
6-Mercaptopurine (NSC-755) 
Desk CA60 
Dexamethasone (Decadron)(NSC-34521)  
10201 Carnegie Avenue 
Methotrexate (NSC-740) 
Cleveland, OH 44195 
Prednisone (NSC-10023) 
Phone:  216/445-9354 
Vincristine (Oncovin) (NSC-67574) 
FAX:  216/444-9454 
 
E-mail:  advania@ccf.org  
NCI Supplied Investigational Agents  
 
 
Kristen M. O’Dwyer, M.D. (Medical Oncology) 
Blinatumomab (NSC-765986) 
University of Rochester Medical Center 
Dasatinib (BMS-354825) (NSC-732517)  
601 Elmwood Ave 
 
Box 704 
(NCI Sponsored Clinical Trial) 
Rochester, NY 14684 
 
Phone: 585/275-4099 
BIOSTATISTICIANS: 
FAX:  585/276-2596 
 
E-mail:  kristen_odwyer@urmc.rochester.edu  
Anna Moseley, M.S. (Biostatistics) 
 
Megan Othus, Ph.D. (Biostatistics) 
Brent Wood, M.D., Ph.D. (Translational Medicine) 
SWOG Statistics and Data Management Center 
University of Washington 
Fred Hutchinson Cancer Research Center 
1959 N.E. Pacific Street #357110 
1100 Fairview Avenue North, M3-C102 
Seattle, WA 98195 
P.O. Box 19024 
Phone:  206/598-6199 
Seattle, WA 981019-1024 
E-mail:  woodbl@u.washington.edu  
Phone:  206/667-4523 
 
FAX:  206/667-4408 
ALLIANCE STUDY CHAIR: 
FAX:  206/598-6189 
 
E-mail:  amoseley@fredhutch.org  
Matthew Wieduwilt, M.D. 
E-mail:  mothus@fredhutch.org  
University of California San Diego 
 
Moores Cancer Center 
ECOG-ACRIN STUDY CHAIR: 
 
3855 Health Sciences Drive, #0960 
 
La Jolla, CA 92093 
Jae Park, M.D. 
 
Phone: 858/822-6848 
Memorial Sloan Kettering Cancer Center 
E-mail:  mwieduwilt@ucsd.edu  
1275 York Avenue 
 
New York, NY 10065 
 
Phone: 212/639-4048 
 
E-mail:  parkj6@mskcc.org  
 

S1318 
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Version Date 08/16/2021 
 
PARTICIPANTS 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG / SWOG 
 
 
 
 
 
 
 

S1318 
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TABLE OF CONTENTS 
 
TITLE  ......................................................................................................................................................... 1 
PARTICIPANTS ............................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................... 3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 6 
SCHEMA ....................................................................................................................................................... 7 
1.0 
OBJECTIVES .................................................................................................................................. 9 
1.1 
Primary Objectives ........................................................................................................................... 9 
1.2 
Secondary Objectives ...................................................................................................................... 9 
1.3 
Additional Translational Medicine Objectives .................................................................................. 9 
2.0 
BACKGROUND ............................................................................................................................... 9 
3.0 
DRUG INFORMATION .................................................................................................................. 14 
3.1 
6-Mercaptopurine (NSC-755) ......................................................................................................... 15 
3.2 
Blinatumomab (AMG103, MT103) (NSC-765986) ......................................................................... 16 
3.3 
Dasatinib (BMS-354825) (NSC-732517) ....................................................................................... 31 
3.4 
Dexamethasone (Decadron) (NSC-34521).................................................................................... 39 
3.5 
Methotrexate (Methotrexate Sodium) (NSC-740) .......................................................................... 40 
3.6 
Prednisone (NSC-10023) ............................................................................................................... 43 
3.7 
Vincristine (Oncovin) (NSC-67574) ................................................................................................ 45 
4.0 
STAGING CRITERIA ..................................................................................................................... 46 
4.1 
Diagnostic Criteria .......................................................................................................................... 46 
4.2 
Staging Criteria .............................................................................................................................. 46 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 46 
5.1 
Registration Step 1 – Induction/Re-Induction ................................................................................ 47 
5.2 
Registration Step 2 – Post-Remission Therapy ............................................................................. 51 
5.3 
Registration Step 3 – Maintenance ................................................................................................ 52 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 53 
7.0 
TREATMENT PLAN ...................................................................................................................... 53 
7.1 
General Considerations, Prophylactic Therapy and Pre-Medication ............................................. 53 
7.2 
Cohort 1 – Philadelphia Chromosome Negative (Ph-) Patients (Permanently closed to accrual 
6/29/17) .......................................................................................................................................... 55 
7.3 
Cohort 2 – Philadelphia Chromosome Positive (Ph+) Patients and Ph-like DSMKF Patients ...... 58 
7.4 
Drug Compliance Documentation .................................................................................................. 61 
7.5 
Full CDUS Reporting Requirement ................................................................................................ 61 
7.6 
Criteria for Removal from Protocol Treatment ............................................................................... 61 
7.7 
Discontinuation of Treatment ......................................................................................................... 62 
7.8 
Follow-Up Period ............................................................................................................................ 62 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 62 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 62 
8.2 
General Considerations ................................................................................................................. 62 
8.3 
Dose Modifications ......................................................................................................................... 63 
8.4 
Supportive Care and Concomitant Medications ............................................................................ 74 
8.5 
Dose Modifications Contacts ......................................................................................................... 76 
8.6 
Adverse Event Reporting ............................................................................................................... 76 
9.0 
STUDY CALENDAR ...................................................................................................................... 77 
9.1 
Cohort 1 – Ph-Negative Patients – Induction/Re-Induction – Blinatumomab (Permanently closed 
to accrual 6/29/17) ......................................................................................................................... 77 
9.2 
Cohort 1 – Ph-Negative Patients – Post-Remission – Blinatumomab ........................................... 79 
9.3 
Cohort 1 – Ph-Negative Patients – Maintenance – POMP Chemotherapy ................................... 81 
9.4 
Cohort 2 – Newly-diagnosed Ph+ and Ph-like DSMKF Patients AND Relapsed/Refractory Ph+ 
and Ph-like DSMKF Patients who are naive to both dasatinib and other 2nd/3rd generation TKIs – 
Induction – Dasatinib/Prednisone λ ............................................................................................... 83 
9.5 
Cohort 2 – Re-Induction – Blinatumomab (Ph+ and Ph-like DSMKF Patients) λ .......................... 86 
9.6 
Cohort 2 – Ph+ and Ph-like DSMKF Patients–Post-Remission –Blinatumomab/Dasatinib .......... 88 
9.7 
Cohort 2 – Ph+ and Ph-like DSMKF Patients – Maintenance – Dasatinib/Prednisone ................. 90 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 92 

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10.1 
Extramedullary Disease ................................................................................................................. 92 
10.2 
Complete Remission (CR) ............................................................................................................. 92 
10.3 
Complete Remission with Incomplete Platelet Recovery (CRi) ..................................................... 92 
10.4 
Partial remission (PR) .................................................................................................................... 92 
10.5 
Treatment Failures ......................................................................................................................... 93 
10.6 
Relapse from CR or CRi ................................................................................................................ 93 
10.7 
Overall Survival (OS) ..................................................................................................................... 93 
10.8 
Disease-Free Survival (DFS) ......................................................................................................... 93 
10.9 
Toxicity Criteria .............................................................................................................................. 94 
10.10 
Performance Status ....................................................................................................................... 94 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 94 
11.1 
Ph-negative Cohort ........................................................................................................................ 94 
11.2 
Ph- positive and Ph-like DSMKF Cohort ........................................................................................ 95 
11.3 
Minimal Residual Disease .............................................................................................................. 96 
11.4 
Accrual ........................................................................................................................................... 96 
11.5 
Monitoring for Infection Rate of 72-Hour and 96-Hour Bag Changes in Blinatumomab 
Administration ................................................................................................................................ 96 
11.6 
Data and Safety Monitoring ........................................................................................................... 97 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 97 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 97 
13.1 
Registration Timing ........................................................................................................................ 97 
13.2 
Investigator/Site Registration ......................................................................................................... 97 
13.3 
OPEN Registration Requirements ............................................................................................... 100 
13.4 
Registration Procedures............................................................................................................... 101 
13.5 
Exceptions to SWOG registration policies will not be permitted. ................................................. 102 
14.0 
DATA SUBMISSION SCHEDULE .............................................................................................. 102 
14.1 
Data Submission Requirement .................................................................................................... 102 
14.2 
Master Forms ............................................................................................................................... 102 
14.3 
Data Submission Procedures ...................................................................................................... 102 
14.4 
Data Submission Overview and Timepoints ................................................................................ 103 
15.0 
SPECIAL INSTRUCTIONS.......................................................................................................... 106 
15.1  
Cytogenetics and FISH (Required) .............................................................................................. 108 
15.2 
Blinatumomab Immunogenicity Assessment (Required) ............................................................. 109 
15.3 
Translational Medicine (MRD) (optional for patient) (see Section 18.4) ...................................... 109 
15.4 
Collection of Bone Marrow Aspirate for Future Research (optional for Ph-Negative patients) ... 110 
15.5 
Banking for Future Correlatives (optional for patient) .................................................................. 111 
15.6 
General Specimen Submission Information ................................................................................. 112 
15.7 
Cohort 2, Run-in Phase Only - Mandatory Conference Calls ...................................................... 113 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................. 114 
16.1 
Adverse Event Reporting Requirements ...................................................................................... 116 
17.0 
BIBLIOGRAPHY .......................................................................................................................... 122 
18.0 
APPENDIX ................................................................................................................................... 126 
18.1 
Intake Calendars - Dasatinib ........................................................................................................ 127 
18.1 
Intake Calendars – 6-Mercaptopurine .......................................................................................... 131 
18.1 
Intake Calendars - Methotrexate .................................................................................................. 135 
18.1 
Intake Calendars – Prednisone .................................................................................................... 139 
18.2  
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4 .................................... 143 
18.3 
Writing Test .................................................................................................................................. 147 
18.4 
Translational Medicine (MRD) ..................................................................................................... 148 
18.5 
Categories of CNS and Steinherz/Bleyer Method of Evaluating Initial Traumatic Lumbar 
Punctures ..................................................................................................................................... 150 
18.6 
Specimen Submission Consent ................................................................................................... 151 
18.7 
Clinical Site Management of Out-Patient Treatment Using CTEP-Supplied Blinatumomab ....... 153 
18.8 
6-Mercaptopurine Dosing Guidelines ........................................................................................... 157 
18.9 
Blinatumomab Immunogenicity Assessment ............................................................................... 158 
18.10 
Summary of Treatment Outcomes in Patients ≥ 60 Years with Acute Lymphoblastic Leukemia 159 
18.11 
Dasatinib Handout and Wallet Card ............................................................................................. 164 
18.12 
Medication Guide Blinatumomab ................................................................................................. 166 

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18.13 
Shipment of Blinatumomab IV Bag from Site/Pharmacy to Patient's Home ................................ 170 
18.14 
Specimen Banking Instructions for the Specimen Repository – Leukemia Division (Lab #200) . 171 
18.15 
Translational Medicine:  Ph-Like Signatures ............................................................................... 172 
 

S1318 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory 
requirements: 
For patient 
enrollments: 
For study data submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the 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 866-
651-2878 to receive 
further information and 
support.   
 
Contact the CTSU 
Regulatory Help Desk at 
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_SYSTE
M/ 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  
 
Other Tools and Reports:  
Institutions participating through 
the CTSU continue to have 
access to other tools and reports 
available on the SWOG 
Workbench via the SWOG 
website (www.swog.org).   
The most current version of the study protocol and all related forms 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’ website is 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. Permission to view and download this 
protocol and its supporting documents is restricted and is based on person and site roster assignment 
housed in the CTSU RSS. Sites must use the current form version and adhere to the instructions and 
submission schedule outlined in the protocol. 
 
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 patient eligibility questions contact the SWOG Statistics and Data Management Center by 
phone or email: 
 
206/652-2267 
leukemiaquestion@crab.org 
 
For treatment or toxicity related questions contact the Study Chairs at S1318SC@swog.org. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU HelpDesk 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. 
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ 
website: 
 
https://www.ctsu.org  
The CTSU Web site is located at https://www.ctsu.org 
 

S1318 
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Version Date 08/16/2021 
 
SCHEMA 
 
 
Cohort 1 – Philadelphia Chromosome Negative (Ph-) Patients: 
 
 
Registration Step 1 
 
Induction 
 
(Blinatumomab x 1 cycle) 
 
 
 
CR or CRi? 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
Re-Induction 
 
    (Blinatumomab x 1 cycle) 
 
 
 
  
 
 
 
 
 
 
                CR or CRi? 
 
             Registration Step 2 
 
 
 
   
            Post-Remission Therapy                  
 
                                (Blinatumomab x 3 cycles) 
 
 
 
        Continued CR or CRi?                  
 
 
 
    
 
 
 
 
 
 
 
 
 
  
    
    Registration Step 3                   
 
 
Off Protocol Therapy 
 
 
 
         Maintenance 
 
  
    (POMP Chemotherapy x 18 cycles) 
 
 
 
 
                         Protocol Therapy Complete 
Yes 
Yes 
No 
Yes 
No 
No 

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Version Date 08/16/2021 
 
Cohort 2 – Philadelphia Chromosome Positive (Ph+) Patients, Relapsed/Refractory Ph+ Patients, 
and Ph-like DSMKF Patients: 
Registration Step 1 
 
(Newly-diagnosed patients and relapsed/refractory patients who are naive to both dasatinib 
and other 2nd/3rd generation TKIs) 
 
Induction 
(Dasatinib / Prednisone x 1 cycle) 
 
 
 
D28 CR or CRi? 
 
 
 
                             
                                                               
  Day 56 CR or CRi? 
 
 
 
 
 
 
 
              
 
 
        
    
 
 
 
 
 
 
 
Continue Prednisone to Day 32 (tapering) 
 
 
 
 
 
 
         Continue Dasatinib to Day 84 
   Continue Dasatinib to Day 84                Re-Induction 1 
(Blinatumomab x 1 cycle) 
 
OR 
 
Registration Step 1 
 
for relapsed/refractory 
 
patients with prior dasatinib 
 
exposure and/or exposure 
 
to other 2nd or 3rd generation 
 
TKIs: Follow Re-Induction 
 
Cycle 1, see Section 7.3b 
 
(Blinatumomab x 1 cycle) 
                
Continued CR or CRi? 
      CR or CRi? 
       
 
 
 
       
 
   
 
 
      Registration Step 2                               
 
 
 
 
 
 
 
 
 
 
   Re-Induction 2 
            
            Post-Remission Therapy 
 
   
       (Blinatumomab x 1 cycle) 
                             (Blinatumomab/Dasatinib x 3 cycles)  
                         
 
 
 
 
   
          
 
     
 
 
 
 
 
 
 
 
 
 
      CR or CRi? 
Continued CR or CRi? 
 
  
 
 
 
 
 
 
 
            
 
 
    
 
     Registration Step 3   
 
 
 
 
 
 
 
 
 
        Off Protocol Therapy 
                    
 
         Maintenance  
    
 
Dasatinib until intolerance or disease  
   
 
progression or for up to 10 years from registration.  
 
Prednisone pulses for up to 18 cycles. 
         
 
         Protocol Therapy Complete 
 
 
 
 
Yes 
No 
Yes 
No 
Yes 
No 
Yes 
Yes 
No 
Yes 
No 
No 

S1318 
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Version Date 08/16/2021 
 
1.0 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
a. 
To evaluate the 3-year overall survival rate in elderly patients with newly diagnosed 
Ph-negative ALL treated with blinatumomab followed by POMP maintenance. 
 
b. 
To evaluate in a preliminary manner (feasibility study) the safety of dasatinib-
steroid based induction followed by blinatumomab treatment in combination with 
dasatinib followed by dasatinib-based maintenance in patients with newly 
diagnosed, Ph-positive ALL, relapsed/refractory Ph-positive ALL, and Ph-like 
DSMKF ALL (newly-diagnosed relapsed or refractory). 
 
1.2 
Secondary Objectives 
 
a. 
To evaluate toxicities in these patient populations treated with these regimens. 
 
b. 
To estimate the rates of complete response (CR), complete remission with 
incomplete count recovery (CRi) and disease-free survival in Ph-negative patients. 
 
c. 
To estimate disease-free and overall survival in Ph-positive ALL and Ph-like 
DSMKF ALL. 
 
d. 
To estimate in each cohort the rate of minimal residual disease (MRD) negativity, 
and the time to achieve MRD negativity (exploratory analysis). 
 
To determine whether anti-idiotype antibodies directed against blinatumomab 
develop with blinatumomab treatment in this study. 
 
1.3 
Additional Translational Medicine Objectives 
 
a. 
To estimate the incidence of the Ph-like signature in elderly patients (≥ 65 years of 
age) with newly diagnosed Philadelphia-chromosome negative ALL (see Appendix 
18.15). 
 
b. 
To estimate the incidence of the various tyrosine-kinase fusions, making up the 
Ph-like signature in elderly patients with newly diagnosed Philadelphia-
chromosome negative ALL (see Appendix 18.15). 
 
c. 
To evaluate outcomes (EFS and OS) in patients with the Ph-like signature versus 
those without the Ph-like signature in Ph-negative ALL (see Appendix 18.15). 
 
 
2.0 
BACKGROUND 
 
Intensive combination chemotherapy remains the standard of care for adult patients with acute 
lymphoblastic leukemia (ALL).  Older adults with ALL (defined as patients aged > 60 years) have 
been difficult to treat with this conventional chemotherapy, however, and the five-year survival rate 
is estimated at 6-12%. (1) During the past decade, multiple clinical trials have attempted to improve 
upon the survival of adults with ALL with early dose intensification of myelosuppressive agents, but 
despite very intensive therapies, none have resulted in improvement in overall survival in the elderly 
cohort. (2,3,4,5,6,7,8)  Thus, the incorporation of new agents to ALL therapy for older patients is a 
priority.  The S1318 protocol proposes to improve the overall survival of older patients with de novo 
ALL by utilizing a novel chemo-immunotherapy regimen.   The hypothesis is that targeting the B-
cell surface antigen CD19 with blinatumomab will result in increased leukemia cytotoxicity with 
limited nonspecific toxicity, and thus will lead to improvement in overall survival in older adult 
patients with ALL. 
 

S1318 
Page 10 
Version Date 08/16/2021 
 
Rationale for Study Design 
 
An early trial of dose intensification for adult patients with ALL was the Cancer and Leukemia Group 
B’s CALGB-8811. (9) This study evaluated an intensive five-drug regimen for adults with newly 
diagnosed ALL, similar to the five-drug induction regimen used by the Children’s Cancer Group 
study for high-risk childhood ALL. (10) In this study, 197 patients were enrolled, of whom 18 were 
aged ≥ 60 years.  The induction treatment regimen was intensified by adding a single dose of 
cyclophosphamide (1,200 mg/m2) on Day 1 to three days of daunorubicin, weekly vincristine, bi-
weekly L-asparaginase and three weeks of prednisone.  Patients who entered remission proceeded 
to consolidation treatment, which was modified by increasing the dose of cyclophosphamide from 
600 to 1000 mg/m2 and adding 2 weeks of vincristine and L asparaginase.  Early intensification 
(Course II) included two months of treatment with cyclophosphamide, subcutaneous cytarabine, 
oral 6-mercaptopurine (6-MP), vincristine, L-asparaginase and intrathecal methotrexate (MTX). 
Course III included central nervous system prophylaxis with cranial irradiation, five weekly doses 
of intrathecal MTX, and daily 6-MP, followed by interim maintenance with daily oral 6-MP and 
weekly oral MTX.  Late intensification (Course IV) included 8 weeks of doxorubicin, vincristine, 
dexamethasone, cyclophosphamide, 6-thioguanine and subcutaneous cytarabine.  Prolonged 
maintenance (Course V) continued until 24 months from the time of diagnosis and included daily 
6-MP, weekly oral methotrexate, and monthly pulses of vincristine and prednisone (“POMP”). 
 
Initially, per the terms of the study, no dose reductions or treatment delays were permitted for 
myelosuppression alone, but after one year of accrual to the study, dose reductions (one-third dose 
reduction for cyclophosphamide and daunorubicin, and prednisone therapy was shortened to 1 
week) were implemented for patients older than 60 years due to treatment related mortality in 
induction of 50%, compared to a TRM of 8% for patients 30 to 59 years of age, and 1% for patients 
less than 30 years of age.  Remission induction was achieved in 39% of patients 60 years and 
older, 85% of patients between the ages of 30 and 59 years, and 94% of patients less than 30 
years old.  After a median follow-up of 43 months, the estimates of the proportion surviving at 3 
years were significantly associated with age, with 69% surviving for patients <30 years of age, 39% 
for patients 30-59 years of age, and only 17% for patients ≥ 60 years.  Overall, this intensive 
chemotherapy regimen produced a high-remission rate, and durable remissions in younger adults, 
but older adults continued to experience significant morbidity and mortality, mostly due to infection. 
 
The CALGB study CALGB-9111 investigated whether filgrastim (granulocyte colony stimulating 
factor [G-CSF]) could reduce the infectious complications of the intense induction chemotherapy 
developed in CALGB-8811. (11) This trial randomized 198 adults with ALL, of whom 41 were aged 
≥ 60 years, to receive G-CSF (5 mcg/kg/d) or placebo beginning on Day 4 of the induction regimen 
developed in CALGB-8811 and continuing until the absolute neutrophil count >1000/mcL for 2 
days. (12) The patients who received G-CSF in induction continued with G-CSF during the two 
monthly courses of consolidation chemotherapy.  The remission induction rate was 77% for patients 
≥ 60 years and 87% for patients < 60 years.  For the 21 patients ≥ 60 years assigned to G-CSF 
treatment, the remission rate was 81%, and the TRM was 10%.  For the 20 patients ≥ 60 years 
assigned to placebo, the remission rate was 55%, and the TRM was 25%.   For patients < 60 years 
of age, the remission rate was 89% with G-CSF and 83% with placebo, and the TRM was 4% and 
8% respectively.  The remission rate for the older adults is improved in CALGB-9111 as compared 
to CALGB-8811, and likely reflects fewer total induction deaths due to the introduction of dose 
reductions of cyclophosphamide, daunorubicin and prednisone in this age group.  The estimates 
of the proportion surviving at 3 years were still significantly associated with age when compared to 
CALGB-8811, with 57% surviving for patients < 30 years of age, 40% for patients 30-59 years of 
age, and only 17% for patients ≥ 60 years.  Overall, the use of G-CSF did not decrease overall 
toxicity and there was no significant difference in disease-free survival or overall survival for the 
patients assigned to G-CSF as compared to placebo.   
 
Data from the most recent CALGB Phase II study (CALGB-19802) evaluated whether dose 
intensification of daunorubicin during induction and cytarabine during consolidation could improve 
disease-free survival for adult patients with ALL. (13) This CALGB trial enrolled 161 patients, of 
whom 33 were aged ≥ 60 years.  The treatment consisted of 6 monthly courses of therapy that 
alternated vincristine, prednisone, cyclophosphamide, daunorubicin and L-asparaginase with high-

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doses of cytarabine and methotrexate, and intrathecal chemotherapy, followed by 18 months of 
“POMP” maintenance chemotherapy. (14) The dose intensification of daunorubicin for the patients 
aged > 60 years was 60 mg/m2 for 3 daily doses (prior daunorubicin doses for older patients 
enrolled in CALGB-8811 and CALGB-9111 was 30 mg/m2 for 3 daily doses), while 
cyclophosphamide was omitted.  Remission induction was achieved in 61% of patients, but 5-year 
disease free survival (DFS) was 10%, and the 5-year overall survival was 6% in the older cohort.  
Further, the reported treatment related mortality (TRM) for the entire cohort of CALGB-19802 was 
13%, but for patients older than 60 years, the treatment-related death was 21%. (15) This study 
concluded that adults older than 60 years of age showed no benefit to dose intensification of 
daunorubicin, and the overall survival remained very poor at 6%. 
 
The international MRC UKALL XII/ECOG-2993 study analyzed a cohort of 100 older adults (defined 
as age 55-65 years) and compared their outcomes to the 1,814 younger patients. (16)  All patients 
were treated with a two-stage 4-drug induction therapy and 3 cycles of intensification with high-
dose methotrexate and L-asparaginase. Patients were then randomized to post-remission 
consolidation consisting of 4 cycles combining cytarabine, etoposide, vincristine and 
dexamethasone, followed by POMP maintenance, or autologous transplantation.  Remission 
induction was achieved in 73% of older adults, as compared to 93% of adults <55 years. (17) 
Significantly more infections were reported in the older group during induction chemotherapy 81% 
versus 70%.  There were many more dose reductions in the older patients 14% versus younger 
patients 5%.   In addition, there were more dose omissions, with asparaginase being the drug that 
was most commonly omitted, and treatment delays in the older group. (18) The TRM was 18% in 
this older age group and 4% in the younger age group.  Overall outcomes were worse in the older 
group as well.  The 5-year overall survival was 21% in the older adults versus 41% in the younger 
adults. (19)  Five-year overall survival for those patients who achieved CR was also inferior in the 
older group versus the younger adults, 30% versus 44%, respectively.  It is worth noting that in this 
study, older patients were defined as those between 55 and 65 years, whereas in the CALGB series 
the older patients included patients up to age 82.   It is very likely that the treatment related toxicities 
and outcomes are more pronounced in a cohort > 65 years, and thus, in part, may explain the 
inferior outcome observed in the CALGB series.    
 
The University of Texas - MD Anderson Cancer Center (MDACC) reported the outcomes of 122 
patients aged ≥ 60 years with newly diagnosed ALL that received alternating Hyper-CVAD and high 
dose cytarabine and methotrexate. (20) This cohort was compared to 34 older patients who 
received less intense ALL regimens (prehyper-CVAD) and 409 younger patients (≤ 60 years) who 
received hyper-CVAD.  Remission induction was achieved in 84% of older patients receiving hyper-
CVAD, 59% in older patients receiving prehyper-CVAD, and 92% of younger patients receiving 
hyper-CVAD.  The treatment related mortality rates were 10%, 12%, and 2%, respectively.  Nearly 
all of the deaths that occurred during induction were related to infection. (21) The intensity of the 
therapy was effective, however, with the incidence of disease resistance during induction only 5% 
in the older group treated with hyper-CVAD as compared to 27% of the older patients who received 
prehyper-CVAD.  For all patients who achieved a CR, death in CR occurred in 34% of older patients 
treated with hyper-CVAD, 15% of patients treated with prehyper-CVAD, and 7% of younger patients 
treated with hyper-CVAD.   Among the deaths that occurred in the older patients treated with hyper-
CVAD, the majority (63%) were caused by infections. (22) The 5-year survival for older patients on 
hyper-CVAD improved to 20% compared to 9% for older patients treated with prehyper-CVAD.  The 
5-year survival for younger patients was 48%.  So although the outcome in the elderly cohort 
improved with the dose-intensification of Hyper-CVAD, the investigators observed that the 
incidence of death in CR from myelosuppression-associated infections increased, and thus 
concluded that the ultimate cause of treatment failure changed from disease recurrence to death 
in CR because of myelosuppression associated complications. 

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Figure 1:  Outcome for older and younger patients with ALL showing (A) Treatment outcome by 
age for 759 adults with ALL enrolled on CALGB studies between 1988 and 2002; (B) Survival by 
age and treatment for patients treated at MDACC; and (C) Overall survival of patients by age 
enrolled in MRC UKALL XII/ECOG2003 trial. (23,24,25) 
 
Taken together, these data from CALGB, MRC/ECOG and MDACC, as well as multiple 
retrospective analysis and population-based studies (see Section 18.10) underscore the limitation 
of intensive chemotherapy in older adults and the need to develop novel regimens with selective 
anti leukemia activity in older adults with de novo ALL.    
 
The development of antibody-based therapy that target B cell specific antigens, such as anti-CD20 
monoclonal antibody (Rituximab), and the anti-CD22 monoclonal antibody (Epratuzumab), have 
been incorporated into ALL therapy, both as initial therapy and in salvage regimens. (26,27,28) A 
novel antibody drug conjugate, Inotuzumab ozogamicin, which is an anti-CD22 monoclonal 
antibody bound to calicheamicin, has been used as a single agent in the relapsed/refractory 
disease settings, and a large international Phase III study in adults is ongoing (NCT01564784). 
(29)  
 
More recently, the CD19 antigen, which is expressed on the surface of virtually all B-ALL cells, has 
been emerging as a new therapeutic target.  Blinatumomab is a bi-specific antibody that engages 
the T cell and the malignant B cell by binding to both CD19 and CD3 (BiTE). The BiTE is 
hypothesized to cause interaction between the malignant B lymphoblasts and native T cells, 
resulting in cell-mediated cytotoxicity.  
 
Blinatumomab has demonstrated impressive clinical results in patients with minimal residual 
disease (MRD) positive ALL and in relapsed/refractory ALL. Topp et al. demonstrated an 80% rate 
of complete molecular remission in patients with relapsed or persistent MRD positive ALL. (30) A 
subsequent Phase II trial in adult patients demonstrated a 69% rate of complete remission or 
complete remission with partial hematologic recovery in patients with relapsed or refractory ALL. 
(17)  The most recent international multicenter Phase 2 study in adult patients with relapsed or 
refractory ALL demonstrated significant clinical activity with 43% of patients achieving a complete 
response (CR) or CR with partial hematologic recovery (CRh). (31)  Overall, blinatumomab has 
been well tolerated with the most significant treatment-related adverse events being neurologic 
toxicities in 50% of patients and the Cytokine Release Syndrome (CRS) in 11% of patients Grade 
3 or higher neurologic toxicities occurred in 15% of patients and included seizures, encephalopathy, 
and cerebellar toxicity (balance and coordination disorders).  Grade 3 or higher CRS occurred in 
1% of patients. The most frequent treatment-related adverse reactions (>20%) were pyrexia (62%), 
headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia 
(23%), rash (21%), and constipation (20%). The toxicity profile and response rate associated with 
blinatumomab in relapsed B-ALL patients suggest that this agent could improve outcomes in 
previously untreated B-ALL patients who are older than 65 years of age. 
 
This Phase II study will test the hypothesis that outcomes in older adults, defined as 65 years of 
age or older, with de novo Philadelphia chromosome negative ALL will be superior with the 
blinatumomab and low-dose POMP maintenance chemotherapy as compared to historical 
experience of standard multi-agent chemotherapy.  Given the dismal outcome and the significant 

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toxicity seen with standard chemotherapy regimens in the elderly population, the investigators 
believe that a single arm Phase II study is a reasonable approach to evaluate blinatumomab in 
combination with low-dose chemotherapy and will provide sufficient information as to whether 
blinatumomab should be further studied. 
 
The goals of our proposed study are to (1) improve the CR rate, disease-free survival, and overall 
survival of elderly patients with Philadelphia-chromosome negative B-ALL by using an induction 
treatment regimen of blinatumomab and intrathecal chemotherapy followed by low dose POMP 
maintenance chemotherapy (prednisone, vincristine, methotrexate, 6-mercaptopurine).  POMP 
maintenance chemotherapy for 2-3 years is a standard part of ALL therapeutic regimens, and 
omission of maintenance therapy has been associated with shorter disease-free survival rates. 
(32,33); And (2) to improve the disease-free survival and overall survival of older patients with 
Philadelphia-chromosome 
positive 
ALL 
by 
using 
a 
treatment 
induction 
regimen 
of 
dasatinib/prednisone, followed by post-remission therapy with blinatumomab/dasatinib, and 
maintenance therapy with dasatinib/prednisone.  CNS prophylaxis with intrathecal chemotherapy 
is included in each cycle of therapy. 
 
Accrual will be limited to patients 65 years of age or older, in order to avoid competing with patients 
being considered for E1910 (randomized Phase III ECOG study of Philadelphia chromosome 
negative ALL patients up to age 70 years). There is an industry-sponsored (Talon Pharmaceutical) 
Phase III study of standard ALL chemotherapy with either vincristine or liposomal vincristine 
(Marqibo) for previously untreated, older ALL patients. This proposed study would not compete with 
that Phase III study since the Phase III study of Marqibo will target patients eligible to receive 
intensive ALL chemotherapy regimens. 
 
Rationale for Cohort 2 (Ph+ Patients and Ph-like DSMKF Patients) 
 
Cohort 2 (the Ph+ / Ph-like DSMKF cohort) will have a maximum of 20 evaluable patients. 
Therefore, the rationale is best explained as a feasibility Phase II, rather than one of estimating 
outcome. This cohort will be studied as a Phase II feasibility to inform whether inclusion of this 
group would be advisable in late stage Phase II and III trials of Ph+ ALL using blinatumomab and 
the tyrosine kinase inhibitor, dasatinib. The study will be limited to a maximum of 6 patients with 
early stopping rules, and based on favorable safety evaluation, the study will allow for an additional 
expansion of the cohort to 14  more evaluable patients. The objective is to evaluate the safety of 
blinatumomab in combination with dasatinib and dexamethasone, and a study of 20 patients can 
provide that information for subsequent study design, but will not provide the kind of outcome data 
that will inform practice. 
 
Patients with Philadelphia chromosome positive ALL represent a distinct cohort of patients, with 
biological and clinical features that set it apart from other subtypes of ALL and require specific 
treatment. Historically, the diagnosis of Ph-positive ALL denoted an inferior prognosis than other 
forms of B-ALL. With the addition of tyrosine kinase inhibitors, several approaches have been 
studied, including a chemotherapy-free treatment based on TKI and steroids with complete 
response rates that are close to 100% and a 5-year overall survival approaching 40%. (34,35)  
Moreover, the most recent studies have shown improvement in survival rates > 60%. (36) However, 
due to the frequent occurrence of mutations bearing resistance to TKIs and a high incidence of 
relapse, allogeneic hematopoietic stem cell transplant remains the standard of care for these 
patients. Relapsed/refractory Ph-positive ALL also remains a significant clinical problem, and the 
outcomes are extremely poor with reported 5-year overall survival rate of 7%. (37)  These patients 
are difficult to salvage because most have chemotherapy-refractory disease.  For that reason, one 
benefit of CD19 directed therapy using blinatumomab is the potential to overcome chemotherapy 
resistance.  Therefore, inclusion of CD19 directed therapy in combination with TKIs for patients 
with relapsed disease may represent an effective salvage regimen.   
 
There is limited data for the use of blinatumomab in Ph+ALL, however; only two patients with 
Ph+ALL were included in the first Phase II trial of blinatumomab, and no patients with Ph-positive 
ALL were enrolled in the larger Phase II study. (38,39)  The MD Anderson Cancer Center recently 
reported a retrospective analysis of 12 patients with relapsed/refractory Ph+ ALL who received 

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blinatumomab and dasatinib  and concluded that the combination was safe and generally well-
tolerated. (40)  Currently, in the United States, the only other open clinical trial evaluating the use 
of frontline treatment of blinatumomab with TKI in Ph-positive ALL is at MD Anderson Cancer 
Center. The relapsed/refractory Ph-positive ALL patient population has been included to provide 
additional data to inform whether blinatumomab and dasatinib combinatorial therapy should be 
further studied in this patient population. 
 
Likewise, since the incidence of ALL is rare, patients with Ph-like dasatinib-sensitive kinase 
mutations or kinase fusions have also been included to provide additional options and data to better 
inform future decisions regarding further study of this combinatorial therapy in this population. 
Moreover, the addition of both populations is anticipated to increase the overall accrual rate for this 
cohort. 
 
Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex categories 
is shown in the table below. 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
3 
4 
7 
Not Hispanic or Latino 
25 
26 
51 
Total Ethnic 
28 
30 
58 
Racial Category 
American Indian or Alaskan Native 
1 
2 
3 
Asian 
2 
1 
3 
Black or African American 
3 
4 
7 
Native Hawaiian or other Pacific Islander 
1 
1 
2 
White 
21 
22 
43 
Racial Category: Total of all Subjects 
28 
30 
58 
Note that gender accrual distribution is based on SWOG’s historical accrual data and may not be 
indicative of the current/actual accrual to this study, as there is no known data indicating that ALL 
is more common in males than in females. 
 
 
3.0 
DRUG INFORMATION 
 
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, 6-mercaptopurine, methotrexate, prednisone and vincristine are commercially 
available; therefore, Investigator Brochures are not applicable to these drugs.  Information about 
commercial drugs is publicly available in the Physician’s Desk Reference (PDR), prescribing 
information and other resources. 
 
For this study, blinatumomab and dasatinib are investigational and are being provided under INDs 
held by the National Cancer Institute.  The current versions of the Investigator Brochures for the 
agents will be accessible to site investigators and research staff through the PMB Online Agent 
Ordering 
Processing 
(OAOP) 
application 
(http://ctep.cancer.gov/branches/pmb/agent_order_processing.htm).  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 e-mail (ibcoordinator@mail.nih.gov). 

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3.1
6-Mercaptopurine (NSC-755)
a.
PHARMACOLOGY
Mechanism of Action
6-Mecaptopurine (6MP) is an antimetabolite chemically known as 1,7-dihydro-6H-
purine-6-thione monohydrate, an analogue of the purine bases, adenine and 
hypoxanthine.  6MP competes with hypoxanthine and guanine for the enzyme, 
hypoxanthine-guanine phosphoribosyltransferase (HGPRT). 6MP is 
converted to thioinosinic acid (TIMP) by HGPRT. The conversion to TIMP 
inhibits inosinic acid conversion to xanthylic acid and adenylic acid.  TIMP also 
inhibits glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first 
enzyme unique to the de novo pathway for purine ribonucleotide synthesis.
b.
PHARMACOKINETICS
Absorption: Variable and incomplete (~50%)
Distribution: CNS penetration is poor
Metabolism: Hepatic and in GI mucosa; hepatically via xanthine oxidase and 
methylation via TPMT to sulfate conjugates, 6-thiouric acid, and other inactive 
compounds
Elimination: Elimination half-life is 2 hours
c.
ADVERSE EFFECTS
Possible Side Effects of 6-Mercaptopurine:
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions.  The 
most frequently reported adverse reactions occurring in greater than 20% 
of patients are hepatotoxicity, rash, anorexia, and malaise. Adverse effects 
reported in 4 to 20 % of patients include pain, intestinal ulceration, drug 
fever, 
infection,
myelosuppression, 
leukopenia, 
anemia, 
thrombocytopenia, and oligospermia.  Rare but serious events occurring 
in less than or equal to 3% of patients include pancreatitis, hepatic 
encephalopathy, pulmonary fibrosis, and secondary malignancies.
Pregnancy and Lactation: 
Pregnancy Category D. It is not known whether 6-Mercaptopurine is 
excreted in human breast milk.
Drug Interactions: 
Due to potential drug interactions, a complete patient medication list, 
including 6-Mercaptopurine, should be screened prior to initiation of and 
during treatment with 6-Mercaptopurine. See Section 8.0 Toxicities to be 
Monitored and Dosage Modifications.
d.
DOSING & ADMINISTRATION
See Section 7.0 Treatment Plan

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e. 
HOW SUPPLIED  
 
6-Mercaptopurine is commercially available and will not be supplied. Refer to the 
current FDA-approved package insert for the most comprehensive and up to date 
information. 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
Refer to the current FDA-approved package insert. 
 
3.2 
Blinatumomab (AMG103, MT103) (NSC-765986)  
 
a. 
PHARMACOLOGY 
 
Blinatumomab is classified as a bispecific T-cell engaging antibody with a 
molecular weight of ~ 55 kDa. 
 
Mechanism 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 cytokine. 
 
Description: Blinatumomab is a fusion protein composed of two single-chain 
antibodies (scFv), murine anti-CD19 scFv and murine anti-CD3 scFv. 
 
b. 
ADVERSE EFFECTS  
 
1. 
Adverse Events: 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/
aeguidelines.pdf for further clarification. Frequency is provided based on 
996 patients. Below is the CAEPR for Blinatumomab (AMG 103). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
 
 
 
 
 
 
 
 
 

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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 
(lymphadenopat
hy) 
 
 
 
Blood and 
lymphatic 
system 
disorders - Other 
(pancytopenia) 
 
 
Disseminated 
intravascular 
coagulation2,3 
 
Disseminated 
intravascular 
coagulation2,3 (Gr 2) 
 
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 
(pneumoperiton
eum) 
 
 
Mucositis oral 
 
 

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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%) 
  
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 
 
INVESTIGATIONS 
 
 
 
Activated partial 
thromboplastin 
time prolonged2 
 
 
Alanine 
aminotransferase 
increased4 
 
Alanine 
aminotransferase 
increased4 (Gr 3) 

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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%) 
  
 
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 
 
 
Hypokalemia 
 
 
Hypokalemia (Gr 2) 
 
Hypomagnesemia  
 
 
Hypophosphatemi
a 
 
 
 
 
Tumor lysis 
syndrome9 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
 
 
Arthralgia 
 
 

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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%) 
  
 
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 
 
 
 
Leukoencephalo
pathy 
 
 
Memory 
impairment10 
 
 
 
Nervous system 
disorders - Other 
(apraxia) 
 
 
 
Nervous system 
disorders - Other 
(cerebellar 
syndrome)10 
 
 
 
 
Nervous system 
disorders - 
Other10  
 
 
Paresthesia10 
 
 
 
 
Reversible 
posterior 
leukoencephalo
pathy syndrome 
 
 
Seizure10 
 
 
 
Somnolence10 
 
 
 
 
Transient 
ischemic 
attacks10 
 
 
Tremor10 
 
Tremor10 (Gr 2) 
PSYCHIATRIC DISORDERS 
 
 
 
Agitation10 
 
 
Anxiety10 
 
 
 
Confusion10 
 
 

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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%) 
  
 
 
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) 
 
1This 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. 
 
2Blinatumomab (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. 

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3Symptoms 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. 
 
4Symptoms of hepatic dysfunction may include Alanine aminotransferase 
increased, Alkaline phosphatase increased, Aspartate aminotransferase 
increased, Blood bilirubin increased, and GGT increased under the 
INVESTIGATIONS SOC. 
 
5Immunodeficiency (immunoglobulin decreased) includes 
immunoglobulins decreased, blood immunoglobulin G decreased, blood 
immunoglobulin M decreased, and blood immunoglobulin A decreased. 
 
6Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC. 
 
7Overdoses 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. 
 
8Acute kidney injury (acute renal failure) is associated with increased 
creatinine levels. 
 
9Tumor lysis syndrome is defined as a massive overload of potassium, 
phosphate, uric acid, plus hypocalcemia, potentially causing lethal 
cardiac arrhythmias and/or renal failure. 
 
10Blinatumomab (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. 
 

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11Rash 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 
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) 

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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. 
 
2. 
Drug Interactions: Formal drug interaction studies have not been 
conducted with blinatumomab.  
 
3. 
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.  
 
 

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c. 
DOSING & ADMINISTRATION 
 
1. 
See Section 7.0 Treatment Plan 
 
2. 
Use a central line to administer the final blinatumomab prepared IV solution 
as a continuous infusion. Do not flush the IV line as it will create an IV bolus 
to be administered into the patient. 
 
3. 
All infusion interruptions must be recorded. 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 Section 3.2 of this 
protocol.  
 
d. 
HOW SUPPLIED 
 
1. 
Blinatumomab and IV solution stabilizer for blinatumomab will be supplied 
free of charge by Amgen and distributed by NCI/DCTD. 
 
2. 
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. 
 
3. 
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. 
 
e. 
STORAGE, PREPARATION & STABILITY 
 
1. 
Store intact vials of blinatumomab and IV solution stabilizer of 
blinatumomab refrigerated at 2-8°C (36°-46°F) and protect from light.  
 
2. 
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.   
 
IV Bags / IV Infusion Sets: 
• 
IV bags: Polyolefin/polyethylene, ethylene vinyl acetate (EVA) or PVC 
non-DEHP 
• 
IV Infusion sets:  PVC Non-DEHP with 0.2 µm inline filter  
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. 
 
Reconstitute blinatumomab lyophilized powder to a final concentration of 
12.5 mcg/mL.  

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To reconstitute blinatumomab lyophilized powder (38.5 mcg/vial):  
 
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°-27°C) or 24 hours refrigerated at 2° to 8°C.  
 
Following the reconstitution of the vial, blinatumomab needs to be further 
diluted prior to administration. The final IV solution must be prepared in 
the following order:  
 
(1) First, add 0.9% NaCl to the IV bag; 
 
(2) next, add the IV solution stabilizer for blinatumomab;  
 
(3) last, add the calculated dose (mL) of blinatumomab to the solution.  
 
The total volume of blinatumomab IV solution will account for the volume 
of the IV infusion set for the inpatient or outpatient setting. 
 
 
INPATIENT: (24-hour IV bag): Infusion rate = 10 mL/hr over 24 
hrs 
 
Volume to be prepared 
Volume to be 
infused 
 
 
 
24-hour IV 
bag 
1. Add calculated volume of 0.9% 
NaCl(mL)1 into approved IV bag  
 
2. Add 5.4 mL IV solution 
stabilizer for blinatumomab 2  
 
3. Add blinatumomab calculated 
dose volume per 270 mL bag(mL)3  
 
270 mL total volume4 
 
 
 
240 mL 
1 0.9% NaCl (mL) = total volume to be prepared (270 mL) – stabilizer 
solution volume (5.4 mL) – blinatumomab calculated dose volume 
(mL) per 270 mL bag 
 
2 stabilizer solution (5.4 mL) = 0.02 x total volume to be prepared 
(270 mL)  
 
3 blinatumomab calculated dose volume per 270 mL bag (mL) = daily 
dose (mcg) ÷ volume (240 mL) to be infused x total volume to be 
prepared (270 mL) ÷ 12.5 mcg/mL of blinatumomab vial 
concentration  
 
4 total volume (270 mL) = Volume to be infused (240 mL) + 30 mL f 
for inpatient IV infusion volume  
 
 
 
 

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OUTPATIENT (24-hour infusion): Infusion rate = 10 mL/hr over 24 
hours 
 
Volume to be prepared 
Volume to be 
infused 
 
 
24-hour IV 
bag  
 
1. Add calculated volume of 0.9% 
NaCl(mL)1 into approved IV bag  
 
2. Add 5.4 mL IV solution stabilizer 
for blinatumomab2  
 
3. Add blinatumomab calculated 
dose volume per 270 mL bag(mL)3  
 
270 mL total volume 4  
 
 
 
240 mL 
1 0.9% NaCl (mL) = total volume to be prepared (270 mL) – stabilizer 
solution volume (5.4 mL) – blinatumomab calculated dose volume 
(mL) per 270 mL bag 
 
2 stabilizer solution (5.4 mL) = 0.02 x total volume to be prepared (270 
mL)  
 
3 blinatumomab calculated dose volume per 270 mL bag (mL) = 24 
hour dose (mcg) ÷ volume to be infused (240 mL) x total volume to be 
prepared (270 mL) ÷ 12.5 mcg/mL of blinatumomab vial concentration  
 
4 total volume (270 mL) = Volume to be infused (240 mL) + 30 mL for 
outpatient IV infusion volume  
 

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OUTPATIENT (48-hour infusion): Infusion rate = 5 mL/hr over 48 
hours 
 
Volume to be prepared 
Volume to be 
infused 
 
 
48-hour IV 
bag  
 
1. Add calculated volume of 0.9% 
NaCl(mL)1 into approved IV bag  
 
2. Add 5 mL IV solution stabilizer 
for blinatumomab2  
 
3. Add blinatumomab calculated 
dose volume per 250 mL bag(mL)3  
 
250 mL total volume4  
 
 
 
 
240 mL 
1 0.9% NaCl (mL) = total volume to be prepared (250 mL) – stabilizer 
solution volume (5 mL) – blinatumomab calculated dose volume (mL) 
per 250 mL bag 
2 stabilizer solution (5 mL) = 0.02 x total volume to be prepared (250 
mL)  
3 blinatumomab calculated dose volume per 250 mL bag (mL) = 48 
hour dose (mcg) ÷ volume to be infused (240 mL) x total volume to be 
prepared (250 mL) ÷ 12.5 mcg/mL of blinatumomab vial concentration  
4 total volume (250 mL) = Volume to be infused (240 mL) + 10 mL for 
outpatient IV infusion volume  
OUTPATIENT (72-hour infusion): Infusion rate = 3.3 mL/hr over 
72 hrs 
 
Volume to be prepared 
Volume to be 
infused 
 
 
72-hour IV 
bag  
 
1. Add calculated volume of 0.9% 
NaCl(mL)1 into approved IV bag  
 
2. Add 5 mL IV solution stabilizer 
for blinatumomab2  
 
3. Add blinatumomab calculated 
dose volume per 250 mL bag(mL)3  
 
250 mL total volume4  
 
 
 
237.6 mL 
1 0.9% NaCl (mL) = total volume to be prepared (250 mL) – stabilizer 
solution volume (5 mL) – blinatumomab calculated dose volume (mL) 
per 250 mL bag 
2 stabilizer solution (5 mL) = 0.02 x total volume to be prepared (250 
mL)  
3 blinatumomab calculated dose volume per 250 mL bag (mL) = 72 
hour dose (mcg) ÷ volume to be infused (238 mL) x total volume to be 
prepared (250 mL) ÷ 12.5 mcg/mL of blinatumomab vial concentration  
4 total volume to be made is 250 mL of which patient will receive 
237.6 mL at 3.3 mL/hour and 12.4 mL will remain in the IV-line set.  

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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 
 
Rotate IV bag to thoroughly mix the solution. Do not shake. Avoid 
foaming the IV bag.  
 
Visually inspect for floating particles or discoloration of the IV solution. If 
present, do not use the prepared solution. 
 
Prime the IV line with the prepared IV solution prior to administering it to 
the patient. 
 
Infusion bags should be changed in accordance with local pharmacy 
standards for infusion of compounded sterile products. All infusion bags 
may be changed at least every 4th day (not to exceed 96 hours) in the 
US and in the foreign sites. Shorter time intervals of 24, 48 or 72 hours 
may also be utilized for convenience of patient scheduling as needed. 
 
Label the final product with the following information: 
• 
Patient name and number 
• 
Name of the drug 
• 
Dose (mcg/day and volume/day) 
• 
Infusion rate 
OUTPATIENT (96-hour infusion): Infusion rate 2.5 mL/hr over 96 
hrs 
 
Volume to be prepared 
Volume to be 
infused 
 
 
96-hour IV bag  
 
1. Add calculated volume of 
0.9% NaCl(mL)1 into approved 
IV bag  
 
2. Add 5 mL IV solution 
stabilizer for blinatumomab2  
into the normal saline IV bag 
 
3. Add blinatumomab 
calculated dose volume per 
250 mL bag (mL)3  
 
250 mL total volume4  
 
 
 
240 mL 
1 0.9% NaCl (mL) = total volume to be prepared (250 mL) – stabilizer 
solution volume (5 mL) – blinatumomab calculated dose volume (mL) 
per 250 mL bag 
 
2 stabilizer solution (5 mL) = 0.02 x total volume to be prepared (250 
mL)  
 
3 blinatumomab calculated dose volume per 250 mL bag (mL) = 96 
hour dose (mcg) ÷ volume to be infused (240 mL) x total volume to be 
prepared (250 mL) ÷ 12.5 mcg/mL of blinatumomab vial 
concentration  
 
4 total volume (250 mL) = Volume to be infused (240 mL) + 10 
mL*(will remain in the IV line set) for outpatient IV infusion volume 
over 96 hours at 2.5mL/hour infusion rate. 

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• 
Expiration date and time 
• 
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. 
 
3. 
Stability: Shelf life stability studies of the intact vials of blinatumomab and 
stabilizer solution are on-going. The stability of the prepared IV solution is 
8 days when stored refrigerated at 2° - 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. 
See Section 18.7 “Clinical Site Management of Out-Patient Treatment 
Using CTEP-Supplied Blinatumomab” for additional administration 
information. 
 
f. 
DRUG ORDERING & ACCOUNTABILITY 
 
1. 
Drug ordering: NCI-supplied agents may be requested by eligible 
participating Investigators (or their authorized designee) at each 
participating institution.  The CTEP assigned protocol number (S1318) 
must be used for ordering all CTEP supplied investigational agents.  The 
eligible participating investigators at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 
1572 (Statement of Investigator),  NCI Biosketch, Agent Shipment Form  
and a Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for 
the study should be ordered under the name of one lead participating 
investigator at that institution.  
 
2. 
Sites may order initial agent supplies after a subject has been assigned to 
an arm on the study. 
 
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, a “current” password, 
and active person registration status.  For questions about drug orders, 
transfers, returns, or accountability, call or email PMB any time.  Refer to 
the PMB’s website for specific policies and guidelines related to agent 
management. 
 
3. 
Agent Inventory Records – The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of the 
receipt, dispensing and final disposition of all agents received from PMB 
using the appropriate NCI Investigational Agent (Drug) Accountability 
Record (DARF) available on the CTEP forms page.  Store and maintain 
separate NCI Investigational Agent Accountability Records for each agent, 
strength, formulation and ordering investigator in this protocol. 
 
Useful Links and Contacts 
• 
CTEP 
Forms, 
Templates, 
Documents:  
http://ctep.cancer.gov/forms/  
• 
NCI CTEP Investigator Registration (RCR) Help Desk:  
RCRHelpDesk@nih.gov  
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  

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• 
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/index.jsp  
• 
CTEP IAM account help:   
ctepreghelp@ctep.nci.nih.gov  
• 
PMB IB Coordinator:  IBCoordinator@mail.nih.gov  
• 
PMB e-mail:  PMBAfterHours@mail.nih.gov  
 
PMB phone and hours of service:  240/276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) and hours of service:  240/276-6575 
Monday through Friday between 8:30 am and 4:30 pm (ET) 
 
3.3 
Dasatinib (BMS-354825) (NSC-732517)  
 
a. 
PHARMACOLOGY  
 
Mechanism of Action:  BMS-354825 is a potent, broad spectrum ATP-competitive 
inhibitor of 5 critical oncogenic tyrosine kinase families:  BCR-ABL, SRC family 
kinases, c-KIT, ephrin (EP) receptor kinases, and PDGFβ receptor.  Each of these 
protein kinases has been strongly linked to multiple forms of human malignancies. 
 
b. 
PHARMACOKINETICS 
 
Approximate Solubility:  BMS-354825 is slightly soluble in ethanol (USP), methanol, 
polyethylene glycol 400, and propylene glycol.  It is very slightly soluble in acetone 
and acetonitrile, practically insoluble in corn oil, and insoluble in water.  
 
c. 
ADVERSE EFFECTS 
 
1. 
Adverse Effects 
 
The following is a description of major adverse events associated with 
BMS-354825 therapy.  A list of Comprehensive Adverse Events and 
Potential Risks (CAEPR) in NCI-CTCAE Version 5.0 terms is listed below.  
For additional information, see the Investigator Brochure and the package 
insert. 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) For 
Dasatinib (BMS-354825, Sprycel, NSC 732517) 
 
The Comprehensive Adverse Event 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 via CTEP-AERS (except as noted below).  
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification.  Frequency is provided based on 
2937 patients. Below is the CAEPR for dasatinib (BMS-354825). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 

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listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.7, September 10, 2018 
 
 Adverse Events with Possible  
 Relationship to Dasatinib (BMS-354825, 
Sprycel) 
 (CTCAE 5.0 Term) 
[n= 2937] 
 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
(formerly known as 
ASAEL) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
Anemia (Gr 3) 
 
Febrile 
neutropenia 
 
CARDIAC DISORDERS 
 
 
 
Heart failure 
 
 
 
Left ventricular 
systolic 
dysfunction 
 
 
 
Myocardial 
infarction 
 
 
Pericardial 
effusion 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal 
distension 
 
 
 
 
Abdominal pain (Gr 3) 
 
Abdominal 
pain 
 
 
Anal mucositis  
 
Constipation 
 
Diarrhea 
 
 
Diarrhea (Gr 3) 
 
Dyspepsia 
 
 
 
Gastrointestinal 
hemorrhage2 
 
 
 
Mucositis oral  
 
Nausea 
 
 
Nausea (Gr 3) 
 
Rectal 
mucositis 
 
 
Small 
intestinal 
mucositis 
 
 
 
Vomiting 
 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
 
Edema limbs  
 
Fatigue 
 
 
Fatigue (Gr 3) 
 
Fever 
 
 
Fever (Gr 2) 
 
General 
disorders and 
administration 
 
General disorders and 
administration site 
conditions - Other 

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 Adverse Events with Possible  
 Relationship to Dasatinib (BMS-354825, 
Sprycel) 
 (CTCAE 5.0 Term) 
[n= 2937] 
 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
(formerly known as 
ASAEL) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
site conditions 
- Other 
(superficial 
edema) 
(superficial edema) 
(Gr 2) 
 
Generalized 
edema 
 
 
 
Non-cardiac 
chest pain 
 
 
Pain 
 
INFECTIONS AND INFESTATIONS 
 
 
Infection3 
 
Infection3 (Gr 3) 
INVESTIGATIONS 
 
 
Alanine 
aminotransfer-
ase increased 
 
 
 
Aspartate 
aminotransfer-
ase increased 
 
 
 
Electrocardiogra
m QT corrected 
interval prolonged 
Neutrophil count 
decreased 
 
 
Neutrophil count 
decreased (Gr 4) 
Platelet count 
decreased (Gr 4) 
Platelet count 
decreased 
 
 
 
Weight gain 
 
 
Weight loss 
 
 
White blood 
cell decreased 
 
White blood cell 
decreased Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
Anorexia (Gr 3) 
 
Hypocalcemia  
 
 
Hypokalemia  
Hypophosphatemia 
(Gr 3) 
 
Hypophos-
phatemia 
 
 
 
Tumor lysis 
syndrome 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
 
 
Arthralgia 
 
 
 
 
Growth 
suppression4 
 
 
 
Musculoskeletal 
and connective 
 
 

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 Adverse Events with Possible  
 Relationship to Dasatinib (BMS-354825, 
Sprycel) 
 (CTCAE 5.0 Term) 
[n= 2937] 
 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
(formerly known as 
ASAEL) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
tissue disorder – 
Other (epiphyses 
delayed fusion)4 
 
 
 
 
 
 
 
 
Myalgia (Gr 2) 
 
 
Musculoskeletal 
and connective 
tissue disorder – 
Other 
(osteopenia)4 
Myalgia 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
 
Headache 
 
 
Headache (Gr 3) 
 
 
Intracranial 
hemorrhage 
 
 
Leuko-
encephalopathy 
 
 
Reversible 
posterior 
leukoencephalop
athy syndrome 
REPRODUCTIVE SYSTEM AND BREAST 
DISORDERS 
 
 
 
Gynecomastia4 
 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
 
 
Cough 
 
 
Dyspnea (Gr 3) 
 
 
 
 
 
Pleural effusion (Gr 3) 
Dyspnea 
 
 
 
Laryngeal 
mucositis 
 
 
Pharyngeal 
mucositis 
 
Pleural effusion 
 
 
 
Pneumonitis 
 
 
 
 Pulmonary 
hypertension 
 
 
Tracheal 
mucositis 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Alopecia 
 
 
 
 
Erythema 
multiforme 
 
 
Pruritus 
 
 
 
Rash 
acneiform 
 
 
 

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 Adverse Events with Possible  
 Relationship to Dasatinib (BMS-354825, 
Sprycel) 
 (CTCAE 5.0 Term) 
[n= 2937] 
 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
(formerly known as 
ASAEL) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
Rash  
maculo-papular 
 
 
Rash maculo-papular 
(Gr 2) 
 
 
Stevens-Johnson 
syndrome 
 
 
Toxic Epidermal 
necrolysis 
VASCULAR DISORDERS 
 
 
Flushing 
 
 
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 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal 
hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal 
hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal 
hemorrhage, 
Ileal 
hemorrhage, 
Intra-abdominal 
hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, 
Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage 
under the GASTROINTESTINAL DISORDERS SOC. 
3 Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC. 
4 Effects on growth and development have been observed in pediatric 
patients and may include epiphyses delayed fusion, osteopenia, growth 
retardation, and gynecomastia 
5 Gastrointestinal ulcer includes Anal ulcer, Colonic ulcer, Duodenal ulcer, 
Esophageal ulcer, Gastric ulcer, Ileal ulcer, Jejunal ulcer, Rectal ulcer, 
and Small intestine ulcer under the GASTROINTESTINAL DISORDERS 
SOC. 
 
Adverse events reported on Dasatinib (BMS-354825, Sprycel) trials, 
but for which there is insufficient evidence to suggest that there was 
a reasonable possibility that Dasatinib (BMS-354825, Sprycel) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic 
system disorders - Other (pancytopenia)  
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other 
(cardiomegaly); Cardiac disorders - Other (heart rate increased); Chest 
pain - cardiac; Myocarditis; Palpitations; Pericarditis; Sinus tachycardia; 
Ventricular tachycardia 
CONGENITAL, FAMILIAL AND GENETIC DISORDERS - Congenital, 
familial and genetic disorders - Other (Keratosis follicular) 
EAR AND LABYRINTH DISORDERS - Ear pain; Middle ear inflammation; 
Tinnitus; Vertigo 

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EYE DISORDERS - Blurred vision; Dry eye; Eye disorders - Other (optic 
nerve neuritis); Periorbital edema 
GASTROINTESTINAL DISORDERS - Anal fissure; Ascites; Colitis; Dry 
mouth; Dysphagia; Esophagitis; Flatulence; Gastritis; Gastrointestinal 
disorders - Other (enteritis); Gastrointestinal disorders - Other (oral soft 
tissue disorder); Gastrointestinal disorders - Other (tongue eruption); 
Gastrointestinal ulcer5; Ileus; Oral pain; Pancreatitis; Periodontal disease; 
Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Chills; Edema face; Edema trunk; Flu like symptoms; Gait disturbance; 
General disorders and administration site conditions - Other (temperature 
intolerance); Localized edema; Malaise 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatobiliary disorders - 
Other (cholestasis) 
IMMUNE SYSTEM DISORDERS - Anaphylaxis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - 
Bruising 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin 
increased; Cardiac troponin T increased; CD4 lymphocytes decreased; 
CPK increased; Creatinine increased; Electrocardiogram T wave 
abnormal; GGT increased; Investigations - Other (bone densitometry); 
Investigations - Other (thermometry abnormal); Lymphocyte count 
decreased; Lymphocyte count increased 
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Dehydration; 
Hyperkalemia; Hyperuricemia; Hypoalbuminemia; Hypomagnesemia; 
Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Arthritis; Back pain; Bone pain; Chest wall pain; Generalized muscle 
weakness; Muscle cramp; Musculoskeletal and connective tissue disorder 
- Other (muscle stiffness); Musculoskeletal and connective tissue disorder 
- Other (nuchal rigidity); Musculoskeletal and connective tissue disorder - 
Other 
(tendonitis); 
Myositis; 
Osteoporosis; 
Pain 
in 
extremity; 
Rhabdomyolysis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified 
(incl cysts and polyps) - Other (hemangiomatosis) 
NERVOUS SYSTEM DISORDERS - Acoustic nerve disorder NOS; 
Amnesia; Cognitive disturbance; Concentration impairment; Dysarthria; 
Dysgeusia; Ischemia cerebrovascular; Lethargy; Peripheral motor 
neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; 
Syncope; Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia; 
Libido decreased; Suicidal ideation 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria; 
Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS -Irregular 
menstruation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult 
respiratory distress syndrome; Bronchospasm; Epistaxis; Hypoxia; 
Oropharyngeal pain; Pulmonary edema; Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; 
Dry skin; Hair color changes; Hyperhidrosis; Nail loss; Pain of skin; 
Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Purpura; 
Skin and subcutaneous tissue disorders - Other (acute febrile neutrophilic 
dermatosis); Skin and subcutaneous tissue disorders - Other 
(panniculitis); Skin ulceration; Urticaria 

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VASCULAR DISORDERS - Hematoma; Hot flashes; Hypertension; 
Hypotension; Phlebitis; Superficial thrombophlebitis; Thromboembolic 
event; Vasculitis 
 
Note: Dasatinib (BMS-354825, Sprycel) 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. 
 
2. 
Drug Interactions:  BMS-354825 is primarily metabolized by the human 
CYP3A4 enzyme, is a significant inhibitor of CYP3A4, and is a weak inhibitor 
of CYP1A2, CYP2D6, CYP2C9, and CYP2C19.  It may decrease the 
metabolic clearance of drugs that are significantly metabolized by the 
CYP3A4 enzyme.  Due to the potential of BMS-354825 to prolong the 
QT/QTc, use caution when administering BMS-354825 with other potential 
QTc-prolonging medications.  Due to the possibility of gastrointestinal, 
cardiac, and cutaneous hemorrhage, avoid using medications that inhibit 
platelet function or anticoagulants with BMS-354825.  
 
BMS-354825 is not a P-glycoprotein inhibitor. 
 
d. 
DOSING AND ADMINISTRATION  
 
1. 
See Section 7.0 Treatment Plan. 
 
Administration:  Administer orally, with or without food.  Tablets should 
be swallowed whole and cannot be crushed or broken.  Grapefruit juice 
should not be consumed during study drug therapy, as P450 enzyme 
inhibition may increase drug exposure. In vitro solubility data indicate that 
dasatinib may have decreased solubility and absorption at pH > 4.  
Patients should not take antacids, proton pump inhibitors or H2 
antagonists. If antacids are absolutely necessary, they must be taken at 
least 2 hours before or 2 hours after dosing of dasatinib. 
 
e. 
HOW SUPPLIED 
 
1. 
Dasatinib will be supplied free of charge by Bristol-Myers Squibb and 
distributed by NCI/DCTD. 
 
2. 
How Supplied:  BMS-354825 is available in the following tablet/bottle sizes: 
 
• 
20 mg biconvex round, white to off-white film-coated tablets containing 
30 tablets per bottle.  The tablet is debossed with “20” on one side and 
“527” on the other side (or BMS on one side and 527 on the other side)  
• 
50 mg biconvex oval, white to off-white film-coated tablets containing 
30 tablets per bottle.  The tablet is debossed with “50” on one side and 
“528” on the other side (or BMS on one side and 528 on the other side).  
 
Inactive 
ingredients 
include 
lactose, 
microcrystalline 
cellulose, 
croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. 
The 
film-coating 
contains 
hypromellulose, 
titanium 
trioxide, 
and 
polyethylene glycol (in the 20 mg tablets and 50 mg tablets). 
 
 

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f. 
STORAGE, PREPARATION & STABILITY 
 
1. 
The intact bottles should be stored at controlled room temperature (15°C-
25°C) and protected from light.  Excursions are permitted up to 30° C.  
Stability studies are ongoing. 
 
2. 
Special handling:  BMS-354825 tablets consist of a core tablet 
(containing the active drug) surrounded by a film coating to prevent 
exposure to the active drug substance.  If tablets are accidentally 
crushed or broken, caregivers should wear disposable chemotherapy 
gloves.  Pregnant women should avoid exposure to crushed and/or 
broken tablets. 
 
g. 
DRUG ORDERING & ACCOUNTABILITY 
 
1. 
NCI-supplied agents may be requested by the eligible participating  
Investigators (or their authorized designee) at each participating 
institution. The CTEP assigned protocol number (S1318) must be used for 
ordering all CTEP supplied investigational agents. The eligible 
participating investigators at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 
1572 (Statement of Investigator), NCI Biosketch, Agent Shipment Form, 
and a Financial Disclosure Form (FDF). If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for 
the study should be ordered under the name of one lead investigator at 
that institution.   
 
Sites may order initial agent supplies after a subject has been assigned to 
an arm on the study. 
 
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, a “current” password, 
and active person registration status.  For questions about drug orders, 
transfers, returns, or accountability, call or email PMB any time.  Refer to 
the PMB’s website for specific policies and guidelines related to agent 
management. 
 
Agent Inventory Records – The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of the 
receipt, dispensing and final disposition of all agents received from PMB 
using the appropriate NCI Investigational Agent (Drug) Accountability 
Record (DARF) available on the CTEP forms page.  Store and maintain 
separate NCI Investigational Agent Accountability Records for each agent, 
strength, formulation and ordering investigator in this protocol. 
 
Useful Links and Contacts 
• 
CTEP 
Forms, 
Templates, 
Documents:  
http://ctep.cancer.gov/forms/  
• 
NCI CTEP Investigator Registration (RCR) Help Desk:  
RCRHelpDesk@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:   

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https://ctepcore.nci.nih.gov/iam/index.jsp
•
CTEP IAM account help:  
ctepreghelp@ctep.nci.nih.gov
•
PMB IB Coordinator:  IBCoordinator@mail.nih.gov
•
PMB e-mail:  PMBAfterHours@mail.nih.gov
PMB phone and hours of service:  240/276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET).
3.4
Dexamethasone (Decadron) (NSC-34521)
a.
PHARMACOLOGY
Mechanism of Action: Dexamethasone is a synthetic adrenocortical steroid with 
potent anti-inflammatory effects in disorders of many organ systems, however, it 
lacks the sodium-retaining property of hydrocortisone. 
b.
PHARMACOKINETICS
1.
Absorptions: 
Bioavailability: 61-86% after oral administration
Tmax: 10-60 minutes (oral elixir), 1-2 hours (oral tablet), 5-10 
minutes (IV), 30-120 minutes (IM)
2.
Distribution: VD 2 L/kg 
3.
Elimination: 
Half-life: 4 hours (oral) and 1-5 hours (IV).  
Approximately 10 % of drug is excreted in urine.
c.
ADVERSE EFFECTS
1.
Possible Side Effects of Dexamethasone
The most common adverse effects occurring in >20% people receiving 
dexamethasone include: fluid and electrolyte disturbances, congestive 
heart failure in susceptible persons, hypertension, euphoria, personality 
changes, insomnia, exacerbation of infection (e.g., tuberculosis), 
hyperglycemia, psychosis, muscle weakness, osteoporosis, , pancreatitis, 
esophagitis, , dermatologic disturbances (e.g. acne, rash and skin 
atrophy), convulsions, vertigo and headache, endocrine abnormalities, 
glaucoma, conjunctival hemorrhage, metabolic changes (e.g. decreased 
body growth, Cushing’s syndrome), peripheral edema, fatigue, bruising, 
abdominal pain, increase appetite and weight gain.
Adverse effects occurring in 4–20% patients: cataract, non-healing wound, 
heartburn, kidney stones
Rare and Serious (< 3%): blurred vision, peptic ulcer, vertebral 
compression fractures
Some patients have experienced itching and other allergic, anaphylactic 
or other hypersensitivity reactions.  Withdrawal from prolonged therapy 

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may result in symptoms including fever, myalgia and arthralgia.  Phenytoin 
phenobarbital 
and 
ephedrine 
enhance 
metabolic 
clearance 
of 
corticosteroids.   
 
Corticosteroids should be used cautiously in patients with hypothyroidism, 
cirrhosis, ocular herpes simplex, existing emotional instability or psychotic 
tendencies, nonspecific ulcerative colitis, diverticulitis, fresh intestinal 
anastomoses, peptic ulcer, renal insufficiency, hypertension, osteoporosis 
and myasthenia gravis.  Immunization procedures (especially smallpox 
vaccination) should not be undertaken in patients on corticosteroids. 
 
Refer to the FDA-approved package insert for the most comprehensive 
and up to date information on adverse reactions. 
 
2. 
Pregnancy and Lactation: Pregnancy Category C. When systemic 
corticosteroids are needed in pregnancy, it is generally recommended to 
use the lowest effective dose for the shortest duration of time, avoiding 
high doses during the first trimester. Corticosteroids are excreted in human 
milk; information specific to dexamethasone is unknown.  
 
3. 
Drug Interactions: Dexamethasone is a substrate of CYP3A4 (major) and 
P-glycoprotein. It is an inducer of several cytochrome P450 isoenzymes 
including 
CYP3A4 
(strong), 
CYP2A6 
(weak/moderate), 
CYP2B6 
(weak/moderate), CYP2C9 (weak/moderate).  Dexamethasone is an 
inducer and inhibitor and P-glycoprotein.  
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED 
 
Dexamethasone is commercially available and will not be supplied. Refer to the 
current FDA-approved package insert for the most comprehensive and up to date 
information.  
 
3.5 
Methotrexate (Methotrexate Sodium) (NSC-740) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Methotrexate, an antimetabolite, inhibits dihydrofolic acid 
reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme 
before they can be utilized as carriers of 1-carbon groups in the synthesis of purine 
nucleotides and thymidylate. Therefore, methotrexate interferes with DNA 
synthesis, repair, and cellular replication. Actively proliferating tissues such as 
malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells 
of the urinary bladder are in general more sensitive to this effect of methotrexate. 
When cellular proliferation in malignant tissues is greater than in most normal 
tissues, methotrexate may impair malignant growth without irreversible damage to 
healthy tissues. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Methotrexate is generally completely absorbed from 
parenteral routes of injection. After intramuscular injection, peak serum 
concentrations occur in 30 to 60 minutes. 
 

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2. 
Distribution: After intravenous administration, the initial volume of 
distribution is approximately 0.18 L/kg (18% of body weight) and steady-
state volume of distribution is approximately 0.4 to 0.8 L/kg (40% to 80% 
of body weight). Methotrexate competes with reduced folates for active 
transport across cell membranes by means of a single carrier-mediated 
active transport process. At serum concentrations greater than 100 
micromolar, passive diffusion becomes a major pathway by which effective 
intracellular concentrations can be achieved. Methotrexate in serum is 
approximately 50% protein bound. Laboratory studies demonstrate that it 
may be displaced from plasma albumin by various compounds including 
sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. 
 
Methotrexate does not penetrate the blood-cerebrospinal fluid (CSF) 
barrier in therapeutic amounts when given orally or parenterally. High CSF 
concentrations of the drug may be attained by intrathecal administration. 
 
3. 
Metabolism: Methotrexate undergoes hepatic and intracellular metabolism 
to polyglutamated forms which can be converted back to methotrexate by 
hydrolase enzymes. These polyglutamates act as inhibitors of 
dihydrofolate reductase and thymidylate synthetase. Small amounts of 
methotrexate polyglutamates may remain in tissues for extended periods. 
The retention and prolonged drug action of these active metabolites vary 
among different cells, tissues and tumors. A small amount of metabolism 
to 7-hydroxymethotrexate may occur at doses commonly prescribed. 
Accumulation of this metabolite may become significant at the high doses 
used 
in 
osteogenic 
sarcoma. 
The 
aqueous 
solubility 
of 
7-
hydroxymethotrexate is 3- to 5-fold lower than the parent compound. 
 
4. 
Elimination:  Renal excretion is the primary route of elimination and is 
dependent upon dosage and route of administration. With IV 
administration, 80% to 90% of the administered dose is excreted 
unchanged in the urine within 24 hours. There is limited biliary excretion 
amounting to 10% or less of the administered dose. Enterohepatic 
recirculation of methotrexate has been proposed. 
 
Renal excretion occurs by glomerular filtration and active tubular 
secretion. Nonlinear elimination due to saturation of renal tubular 
reabsorption has been observed in psoriatic patients at doses between 7.5 
and 30 mg. Impaired renal function, as well as concurrent use of drugs 
such as weak organic acids that also undergo tubular secretion, can 
markedly increase methotrexate serum levels. Excellent correlation has 
been reported between methotrexate clearance and endogenous 
creatinine clearance. 
Methotrexate clearance rates vary widely and are generally decreased at 
higher doses. Delayed drug clearance has been identified as one of the 
major factors responsible for methotrexate toxicity. It has been postulated 
that the toxicity of methotrexate for normal tissues is more dependent upon 
the duration of exposure to the drug rather than the peak level achieved. 
When a patient has delayed drug elimination due to compromised renal 
function, a third-space effusion, or other causes, methotrexate serum 
concentrations may remain elevated for prolonged periods.  
 
The terminal half-life reported for methotrexate is approximately 3 to 10 
hours for patients receiving treatment for psoriasis, or rheumatoid arthritis 
or low-dose antineoplastic therapy (less than 30 mg/m2). For patients 
receiving high doses of methotrexate, the terminal half-life is 8 to 15 hours. 
 
 

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c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Methotrexate: Refer to the current FDA-approved 
package insert for the most comprehensive and up to date information on 
adverse reactions. In general, the incidence and severity of acute side 
effects are related to dose and frequency of administration. The most 
frequently reported adverse reactions occurring in  greater than 20% of 
patients are photosensitivity and rash,  Adverse effects reported in 4 to 20 
% of patients include pneumonitis, pericarditis, pericardial effusion, 
internal hemorrhage, nausea, vomiting, diarrhea, ulcerative stomatitis, 
mucositis, gingivitis, cirrhosis, hepatic fibrosis, hepatitis, elevated 
transaminases, alopecia, thrombocytopenia, bone marrow depression 
(nadir: 7-10 days), leukopenia, infection, anemia, secondary cancer, 
confusion, seizure, renal failure, dermatologic reactions including toxic 
epidermal necrolysis, Stevens-Johnson Syndrome, exfoliative dermatitis, 
skin necrosis, and erythema multiforme, thromboembolic events.  Rare but 
serious events occurring in less than or equal to 3% or patients include 
neurotoxicity, encephalopathy and leukoencephalopathy. 
 
2. 
Pregnancy 
and 
Lactation: 
Category 
X. 
Methotrexate 
causes 
embryotoxicity, abortion, and fetal defects in humans. Pregnancy should 
be avoided if either partner is receiving methotrexate; during and for a 
minimum of 3 months after therapy for male patients, and during and for 
at least 1 ovulatory cycle after therapy for female patients. 
 
Because of the potential for serious adverse reactions from methotrexate 
in breastfed infants, it is contraindicated in nursing mothers. 
 
3. 
Drug Interactions: Nonsteroidal anti-inflammatory drugs (NSAIDs) should 
not be administered prior to or concomitantly with the high doses of 
methotrexate, such as used in the treatment of osteosarcoma. 
Concomitant administration of some NSAIDs with high dose methotrexate 
therapy has been reported to elevate and prolong serum methotrexate 
levels, resulting in deaths from severe hematologic and gastrointestinal 
toxicity. 
 
Caution should be used when NSAIDs and salicylates are administered 
concomitantly with lower doses of methotrexate. These drugs have been 
reported to reduce the tubular secretion of methotrexate in an animal 
model and may enhance its toxicity. 
 
Methotrexate is partially bound to serum albumin, and toxicity may be 
increased because of displacement by certain drugs, such as salicylates, 
phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is 
also diminished by probenecid; use of methotrexate with this drug should 
be carefully monitored. 
 
In the treatment of patients with osteosarcoma, caution must be exercised 
if high-dose methotrexate is administered in combination with a potentially 
nephrotoxic chemotherapeutic agent (e.g., cisplatin). 
 
Methotrexate increases the plasma levels of mercaptopurine. The 
combination of methotrexate and mercaptopurine may therefore require 
dose adjustment.  
 
Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable 
broad spectrum antibiotics, may decrease intestinal absorption of 

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methotrexate or interfere with the enterohepatic circulation by inhibiting 
bowel flora and suppressing metabolism of the drug by bacteria.  
 
Penicillins may reduce the renal clearance of methotrexate; increased 
serum concentrations of methotrexate with concomitant hematologic and 
gastrointestinal toxicity have been observed with high and low dose 
methotrexate. Use of methotrexate with penicillins should be carefully 
monitored. 
 
The potential for increased hepatotoxicity when methotrexate is 
administered with other hepatotoxic agents has not been evaluated. 
However, hepatotoxicity has been reported in such cases. Therefore, 
patients receiving concomitant therapy with methotrexate and other 
potential hepatotoxins (e.g., azathioprine, retinoids, sulfasalazine) should 
be closely monitored for possible increased risk of hepatotoxicity. 
 
Methotrexate may decrease the clearance of theophylline; theophylline 
levels should be monitored when used concurrently with methotrexate.  
 
Vitamin preparations containing folic acid or its derivatives may decrease 
responses to systemically administered methotrexate. Preliminary animal 
and human studies have shown that small quantities of intravenously 
administered 
leucovorin 
enter 
the 
CSF 
primarily 
as 
5methyltetrahydrofolate and, in humans, remain 1 to 3 orders of 
magnitude lower than the usual methotrexate concentrations following 
intrathecal administration. However, high doses of leucovorin may reduce 
the efficacy of intrathecally administered methotrexate.  
 
Folate 
deficiency 
states 
may 
increase 
methotrexate 
toxicity. 
Trimethoprim/sulfamethoxazole has been reported rarely to increase bone 
marrow suppression in patients receiving methotrexate, probably by 
decreased tubular secretion and/or an additive antifolate effect. 
 
d. 
DOSING & ADMINISTRATION 
 
Dosing – See Section 7.0 Treatment Plan. 
 
e. 
HOW SUPPLIED  
 
Methotrexate is commercially available and will not be supplied. Refer to the 
current FDA-approved package insert for the most comprehensive and up to date 
information. 
 
3.6 
Prednisone (NSC-10023) 
 
a. 
PHARMACOLOGY 
 
Prednisone 
decreases 
inflammation 
by 
inhibiting 
the 
migration 
of 
polymorphonuclear leukocytes; at high doses it suppresses adrenal function. The 
antitumor effects may be due to inhibition of glucose transport, phosphorylation, or 
induction of cell death of immature lymphocytes. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: 50-90% after oral administration. Tmax: 2 hours (oral regular-
release), 6-6.5 hours (oral delayed-release) 
 

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2. 
Distribution: 70% protein binding, VD: 0.4 to 1 L/kg 
 
3. 
Metabolism: Converted from prednisone to prednisolone (active drug)  
hepatically. 
 
4. 
Elimination: Half-life (normal renal function): 3.5 hours 
 
c. 
ADVERSE EFFECTS  
 
Possible Side Effects of Prednisone:  The most common adverse effects occurring 
in > 20% of people receiving prednisone include: increase in absolute granulocyte 
count, decrease in lymphocyte and monocyte count, hypertension, GI disorder, 
infection, oropharyngeal candidiasis, hypernatremia, fluid retention, growth 
retardation, osteoporosis, depression, euphoria, skin atrophy, acne, impaired skin 
healing. 
 
Adverse effects occurring in ≤ 20% of people receiving prednisone include: 
hypokalemia, hyperuricemia, hyperglycemia, myopathy, petechiae, ecchymosis, 
dermatitis, facial erythema, hirsutism, increased sweating, healing wound, kidney 
stones, and heartburn. 
 
Rare (< 3%) but potentially serious adverse effects include: leukemoid reaction, 
cataracts, glaucoma, gastrointestinal perforation and ulceration, pancreatitis, 
pulmonary tuberculosis, Cushing’s syndrome, primary adrenocortical insufficiency, 
diabetes mellitus, aseptic necrosis of bone, pseudotumor cerebri, mental status 
changes, personality changes, mania, hallucinations, Kaposi’s sarcoma. 
 
Adverse events occurring in < 1%, postmarketing, and/or case reports: 
staphylococcal scalded skin syndrome, disseminated varicella-zoster virus, 
hyperthyroidism, porphyria, abnormal lipids, extrapyramidal sign, lung abscess, 
aspergillosis, interstitial pneumonia, pulmonary nocardiosis, decreases in cardiac 
function. 
 
Refer to package insert or manufacturer website for the most complete and up to 
date information on contraindications, warnings and precautions, and adverse 
reactions. 
 
Pregnancy and Lactation: Pregnancy Category C.  Adverse events have been 
observed with corticosteroids in animal reproduction studies. Prednisone and 
prednisolone cross the human placenta. Prednisone enters breast milk.  American 
Academy of Pediatrics rates it as compatible. 
 
Drug Interactions:  Prednisone is a minor substrate of CYP3A4 and induces both 
CYP2C19 and CYP3A4 weakly/moderately.  Refer to the current FDA-approved 
package insert for additional information.  Due to potential drug interactions, a 
complete patient medication list, including prednisone, should be screened prior to 
initiation of prednisone.  
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan  
 
e. 
HOW SUPPLIED  
 
Prednisone is commercially available and will not be supplied. Please refer to the 
current FDA-approved package insert for most comprehensive and up to date 
information. 
 

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3.7 
Vincristine (Oncovin) (NSC-67574) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Vincristine is a vinca alkaloid. The mechanism of action of 
vincristine is thought to be due to inhibition of microtubule formation in the mitotic 
spindle. This leads to arrest of dividing cells during the metaphase stage. 
 
b. 
PHARMACOKINETICS 
 
1. 
Distribution: Within 15-30 minutes of injection, 90% of the drug is 
distributed from the blood into tissues where it is tightly bound. 
 
2. 
Metabolism: Extensively metabolized by the liver via cytochrome P450 
isoenzymes in the 3A subfamily (CYP3A).  
 
3. 
Elimination: Terminal half-life: 85 hours (range, 19-155 hours); 80% 
excreted in feces, 10-20% excreted in urine. 
 
c. 
ADVERSE EFFECTS  
 
Possible Side Effects of Vincristine: Refer to the current FDA-approved package 
insert for the most comprehensive and up to date information on adverse reactions. 
Adverse effects reported in more than 20% of patients include constipation, 
alopecia, injection site reaction, peripheral neuropathy, headache, jaw pain and/or 
myalgia, weakness, gait instability and difficulty walking, and edema.  Anemia, 
ptosis, and hoarseness is reported in 4 to 20% of patients and seizures are 
reported in 3% or less patients. 
 
1. 
Pregnancy and Lactation: Pregnancy Category D. It is not known whether 
vincristine is excreted in human breast milk. 
 
Drug Interactions: Due to potential drug interactions, a complete patient 
medication list, including vincristine, should be screened prior to initiation 
of vincristine and during treatment with vincristine. See Section 8.0 
Toxicities to be Monitored and Dosage Modifications. Of note, vincristine 
is a CYP3A subfamily and P-glycoprotein (P-gp) substrate. Caution should 
be used in patients concurrently taking drugs known to inhibit drug 
metabolism by the CYP3A subfamily or in patients taking potent P-gp 
inhibitors.  
 
d. 
DOSING & ADMINISTRATION 
 
1. 
Dosing – See Section 7.0 Treatment Plan. 
 
2. 
To reduce the potential for fatal medication errors due to incorrect route of 
administration, vincristine injection should be diluted in a flexible plastic 
container and prominently labeled to indicate that it is for intravenous use 
only. Syringes containing vincristine must be labeled with an auxiliary label 
stating “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER 
ROUTES.” 
 
3. 
Vincristine must be administered via an intact, free-flowing intravenous 
needle or catheter. The needle or catheter must be secured within the vein 
to avoid extravasation during administration. The solution may be injected 
either directly into a vein or into the tubing of a running intravenous 
infusion. 
 

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e. 
HOW SUPPLIED  
 
Vincristine is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for the most comprehensive and up to date 
information. 
 
 
4.0 
STAGING CRITERIA 
 
4.1 
Diagnostic Criteria 
 
a. 
Definitions: 
 
 
1. 
Bone marrow cellularity: The volume of hematopoietic nucleated cells, 
expressed as a percentage of marrow volume minus the volume of 
fibrosis. 
 
2. 
Blasts: Blasts characteristic of L1, L2, or L3 are included in the calculation 
of blast percentages. (41,42) 
 
3. 
Marrow Blast Percentage: Bone marrow blast percentage is calculated as 
the percentage of blasts among all nucleated marrow cells except mature 
lymphocytes and plasma cells. 
 
b. 
WHO Classification of ALL, with the following additions and classifications 
(43,44,45) 
 
 
ICD-O Code 
FAB 
 
Equivalent 
Precursor B-cell neoplasm 
Precursor B lymphoblastic  
9836/3 
L1, L2 
Leukemia 
 
Precursor T-cell neoplasms 
Precursor T lymphoblastic leukemia 
9837/3 
L1, L2 
 
 
4.2 
Staging Criteria 
 
Staging criteria are not applicable to this protocol. 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration in OPEN.  Use the spaces provided to confirm a patient's eligibility. Section 5.0 may be printed 
and used by the site but is not to be uploaded in RAVE (unless specially stated). For each criterion requiring 
test results and dates, please record this information on the Onstudy Form and submit via Medidata Rave® 
(see Section 14.0).  Any potential eligibility issues should be addressed to the SWOG Statistics and Data 
Management (SDMC) in Seattle at 206/652-2267 prior to registration. NCI policy does not allow for waiver 
of any eligibility criterion (http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
  
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 4 weeks later would be considered Day 28.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 14 or 28 falls on a weekend 
or holiday, the limit may be extended to the next working day. 

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5.1 
Registration Step 1 – Induction/Re-Induction 
 
Disease Related Criteria 
 
a. 
Patients must have a new morphologic diagnosis of precursor B cell acute 
lymphoblastic leukemia (ALL) (non T cell) based on WHO criteria as defined in 
Section 4.1b.  Patients with Burkitts (L3) are excluded. Patients with Ph-positive or 
Ph-like ALL with dasatinib-sensitive mutations or kinase fusions may have 
relapsed or refractory diagnoses. 
 
NOTE: Relapsed/Refractory Ph-positive patients or Ph-like patients with dasatinib-
sensitive mutations or kinase fusions who have previous exposure to either 
dasatinib or another 2nd or 3rd generation TKI will begin protocol therapy with 
Cohort 2: Re-Induction Cycle 1 (see Section 7.3b). 
 
b. 
Patients must have a diagnosis of Philadelphia chromosome negative ALL or Ph 
chromosome positive ALL by cytogenetics, FISH or polymerase chain reaction 
(PCR). Patients will be registered to receive treatment in either Cohort 1 (Ph-) or 
Cohort 2 (Ph+ or Ph-like DSMKF) based on these results.  Diagnostic specimens 
must be submitted to the site’s local CLIA-approved cytogenetics laboratory and 
results of tests (cytogenetics, FISH or PCR) must confirm Ph status prior to 
registration.  If not already known, BCR-ABL status (p190 or p210) must be 
evaluated in Ph-positive patients by PCR.   
 
For Cohort 2, Ph-like testing is not required specifically for this study. However, to 
be registered to Cohort 2 under the Ph-like DSMKF criterion, the patient must have 
a known or presumed activating Ph-like signature and dasatinib-sensitive mutation 
or kinase fusion, such as: ABL1, ABL2, CSF1R, PDGFRB, PDGFRA, or FGFRs 
that was otherwise identified as part of normal standard of care.  Prior to registering 
any patients with a known or presumed activating Ph-like signature and dasatinib-
sensitive mutations or kinase fusions (DSMKF) treating physicians must confirm 
eligibility with the study chairs via email to S1318SC@swog.org. The study chairs 
must respond via email with confirmation of patient eligibility prior to patient 
registration. 
 
c. 
All newly diagnosed patients must have evidence of ALL in their marrow or 
peripheral blood with at least 20% lymphoblasts present in blood or bone marrow 
collected within 28 days prior to registration. All relapsed/refractory patients 
(Cohort 2) must have at least 5% lymphoblasts present in blood or bone marrow 
collected within 28 days prior to registration. For relapsed/refractory patients, 
pathology and cytogenetics reports (both from time of original diagnosis) must be 
submitted at time of registration. See Section 14.4a. 
 
If a bone marrow aspirate cannot be obtained despite an attempt (dry tap), 
appropriate IHC testing, including CD19, must be performed on the bone marrow 
biopsy to determine lineage. 
 
For ALL in marrow or peripheral blood, immunophenotyping of the blood or marrow 
lymphoblasts must be performed to determine lineage (B cell, T cell or mixed B/T 
cell).  Appropriate marker studies including C D19 (B cell), must be performed.  Co-
expression of myeloid antigens (CD13 and CD33) will not exclude patients.  If 
possible, the lineage specific markers (myeloid cells) should be determined.  The 
blood/bone marrow sample for these assays must be obtained within 28 days prior 
to registration. 
 
Patients with only extramedullary disease in the absence of bone marrow or blood 
involvement are not eligible. 

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Clinical/Laboratory Criteria
d.
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, active ALL in the CNS confirmed by CSF analysis, or other significant 
CNS abnormalities.
e.
Patients must have a lumbar puncture to determine CNS involvement of ALL within 
14 days prior to registration.  Categories of CNS involvement are outlined in 
Section 18.5.  Patients with CNS3 are excluded from the trial; patients with CNS1 
or CNS2 will be eligible, but will be monitored for CNS involvement. Note that 
intrathecal methotrexate administered during the pre-study lumbar puncture may 
count as the first dose of intrathecal therapy required as part of the study (see 
Section 7.1a).
f.
Cohort 1, Ph- Patients Only:
Patients must not have received any prior chemotherapy, radiation therapy, or 
other therapy for the treatment of ALL (other than those noted below) and must not 
be receiving any immunosuppressive therapy. Patients may not have received any 
prior investigational therapy within 28 days prior to registration. Patients must not 
have received any monoclonal antibody therapy within 42 days of registration.
1.
Patients may have received the following within any time prior to 
registration: low dose chemotherapy-including: cyclophosphamide 1 g/m2, 
oral 
6-mercaptopurine, 
or 
oral 
methotrexate 
(Other 
low 
dose 
chemotherapy may be allowable, however any other options not listed 
here should be confirmed with the study chairs), TKI therapy, steroids, 
hydroxyurea, leukapheresis, intrathecal chemotherapy or vincristine.
2.
In the event that the patient’s bone marrow blast count is ≥ 50% blasts, 
patients may be registered but should receive steroids for 3-5 days in order 
to reduce tumor burden prior to blinatumomab administration, as follows.
Prephase treatment with dexamethasone (10-20 mg/m2) for 3-5 
days is required for patients with bone marrow blasts ≥ 50%, 
peripheral blood blasts 15,000/uL or higher, or elevated LDH 
suggesting rapidly progressive disease per investigator opinion.
1.
Pre-treatment should conclude at least 24 hours prior to
the first dose of blinatumomab (although additional 
dexamethasone is automatically given as a pre-med prior 
to the first dose). At the time of first infusion of 
blinatumomab, the absolute peripheral blast count should 
be < 25,000/uL.
2.
Note: For the purposes of the study, Day 1 of the cycle 
will be the first day of blinatumomab administration.
3.
It is preferred, but not required, that corticosteroids and hydroxyurea 
should start only after all diagnostic samples have been obtained. 
However, if the patient was previously on corticosteroids and/or 
hydroxyurea, this is allowable provided that the patient still has 
measurable disease at time of the bone marrow aspirate.

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Corticosteroids and/or hydroxyurea, as well as any of the other 
therapies mentioned (with the exception of IV cyclophosphamide), 
may continue to be administered, at physician discretion, until 1 
day prior to blinatumomab administration.
IV cyclophosphamide must be discontinued at least 7 days prior 
to blinatumomab administration.
g.
Cohort 2, Ph+ and Ph-like DSMKF Patients Only:
Patients must NOT have received a prior autologous or allogeneic hematopoietic 
stem cell transplant at any time. Patients must NOT have received any 
chemotherapy, investigational agents, or undergone major surgery within 14 days 
prior to registration, with the following exceptions:
1.
Monoclonal antibodies must not have been received for 1 week prior to 
registration.
2.
Chimeric antigen receptor (CAR) T-cells must not have been received for 
28 days prior to registration.
3.
Steroids, hydroxyurea, vincristine, 6-mercaptopurine, methotrexate, 
thioguanine and intrathecal chemotherapy are permitted within any 
timeframe prior to registration. FDA-approved TKIs may also be 
administered until 1 day prior to start of study therapy (C1, D1). IV 
cyclophosphamide may be administered at doses of 1 g/m2 or less until up 
to 7 days prior to registration.
h.
Patients must be ≥ 65 years of age.  For patients 65-69 years of age, patient must 
be deemed not suitable for standard intensive Induction chemotherapy at the 
discretion of the local investigator, or must have refused standard intensive 
chemotherapy.
i.
Cohort 1, Ph- Patients Only:
Patients must not be candidates for allogeneic hematopoietic stem cell transplant. 
NOTE: Subjects up to age 70 years who are considered fit for allogeneic 
hematopoietic stem cell transplant, should be considered for enrollment on E1910, 
in order to avoid competing with that study. If a patient is considered unfit for 
intensive chemotherapy at the time of initial diagnosis, but subsequently achieves 
a CR, then it will be left to the treating physician’s discretion to consider HSCT.
j.
Patients must have complete history and physical examination within 28 days prior 
to registration.
k.
Patients must have a Zubrod Performance Status of 0-2 (see Section 10.10).
l.
Patients must have serum creatinine ≤ 1.5 mg/dl within 14 days prior to registration.
m.
Patients must have AST and ALT ≤ 3.0 x Institutional Upper Limit of Normal (IULN) 
within 14 days prior to registration.
n.
Patients must have total bilirubin ≤ 2.0 x IULN within 14 days prior to registration.
o.
Patients must have alkaline phosphatase ≤ 2.5 x IULN within 14 days prior to 
registration.

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p. 
Patients must not have systemic fungal, bacterial, viral or other infection that is not 
controlled (defined as exhibiting ongoing signs/symptoms related to the infection 
and without improvement, despite appropriate antibiotics or other treatment). 
 
q. 
Patients must not have CTCAE ≥ Grade 2 neuropathy (cranial, motor or sensory) 
within 14 days prior to registration. 
 
r. 
Patients known to be positive for HIV (the human immunodeficiency virus) may be 
eligible, providing they meet the following additional criteria within 28 days prior to 
registration:   
 
• 
No history of AIDS-defining conditions 
• 
CD4 cells > 350 cells/mm3 
• 
If on antiretroviral agents, must not include zidovudine or stavudine 
• 
Viral load ≤ 50 copies HIV mRNA/mm3 if on cART or ≤ 25,000 copies HIV 
mRNA/mm3 if not on cART. 
• 
HAART regimens are acceptable providing they have only weak P450A4 
interactions.   
 
s. 
Patients must not have any known autoimmune disease. 
 
t. 
Patients must not have testicular involvement.  If clinical or ultrasound findings are 
equivocal, biopsy must be performed.  All tests for establishing testicular 
involvement must be completed within 14 days prior to registration. 
 
 
u. 
Patients with evidence of extramedullary disease at diagnosis will have CT scan 
or MRI of the chest, abdomen and pelvis to obtain baseline values within 28 days 
prior to registration.  See Section 7.1b for additional CT/MRI time points during 
treatment. 
 
v. 
No other prior malignancy is allowed except for the following:  adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated 
Stage I or II cancer from which the patient is currently in complete remission, or 
any other cancer from which the patient has been disease free for five years. 
 
w. 
Patients must have the following tests within 28 days prior to registration to obtain 
baseline measurements: 
 
• 
PT/PTT/INR/fibrinogen (all patients) 
 
Cohort 1, Ph- Patients Only 
• 
Neurologic assessment (see Section 7.1c.2) 
 
x. 
Cohort 2, Ph+ and Ph-like DSMKF Patients Only: 
 
Patients must not have active pericardial effusion, ascites or pleural effusion of any 
grade based on chest x-ray and echocardiogram within 28 days prior to 
registration.  Exception:  If the effusion is suspected to be related to the leukemia, 
the patient may have pericardial effusion ≤ Grade 2 or pleural effusion ≤ Grade 1. 
 
y. 
Cohort 2, Ph+ and Ph-like DSMKF Patients Only: 
 
Patients must have ejection fraction ≥ 45% based on echocardiogram performed 
within 28 days prior to registration.   
 
 

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z. 
Cohort 2, Ph+ and Ph-like DSMKF Patients Only: 
 
Patients must have QTcF (by Fridericia calculation) < 480/msec based on EKG 
performed within 28 days prior to registration. 
 
QTcF = QT/(RR)0.33   
 
(QTcF = QT interval divided by the cube root of the RR [heart rate] in seconds) 
 
aa. 
Cohort 2, Ph+ and Ph-like DSMKF Patients Only: 
 
Patients must not be receiving any proton pump inhibitors at the time of 
registration. 
 
Specimen Submission Criteria 
 
bb. 
Pretreatment cytogenetics must be performed on all patients.  Collection of 
pretreatment specimens must be completed up to 28 days prior to registration to 
S1318.  Specimens must be submitted to the site’s preferred CLIA-approved 
cytogenetics laboratory.  BCR-ABL status must be verified in Ph-positive patients 
by FISH, cytogenetics, and/or PCR prior to enrollment.  If a patient is Ph-positive, 
PCR for both p190 and p210 must be sent. If PH status cannot be determined, see 
Section 15.4d for instructions on obtaining a SWOG patient ID for specimen 
submission prior to registration. 
 
cc. 
Patients must be offered participation in specimen submission for future research.  
With patient’s consent, specimens must be submitted as outlined in Section 15.3 
and Section 15.4. 
 
dd. 
Cohort 1, Ph-negative patients only: Patients must have specimens submitted 
for blinatumomab immunogenicity assessment.  Collection of pretreatment 
specimens must be completed up to 28 days prior to registration to S1318.  
Specimens must be submitted to LabConnect as outlined in Section 15.2. 
 
Cohort 2, Ph-positive and Ph-like DSMKF patients only:  Patients must agree 
to have specimens submitted for blinatumomab immunogenicity testing if 
subsequently moved to a blinatumomab containing treatment regimen on protocol. 
 
Regulatory Criteria 
 
 
ee. 
Patients or their legally authorized representative must be informed of the 
investigational nature of this study and must sign and give written informed consent 
in accordance with institutional and federal guidelines. 
 
ff. 
As a part of the OPEN registration process (see Section 13.5 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system. 
 
5.2 
Registration Step 2 – Post-Remission Therapy 
 
a. 
Cohort 1, Ph-negative Patients Only:  Patients must have achieved CR or CRi 
within 2 cycles of Induction/Re-Induction with blinatumomab. 
 
NOTE: For Cohort 1: Day 1 of Post-Remission = Day 43 of the preceding cycle (+/- 
3 days) 
 

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Cohort 2, Ph-positive and Ph-like DSMKF Patients Only:  Newly diagnosed 
Ph+, Newly-diagnosed Ph-like DSMKF, and relapsed/refractory Ph+ patients 
without prior dasatinib or other 2nd or 3rd generation TKI therapy, must have 
achieved CR or CRi within 1 cycle of Induction with dasatinib/prednisone, or within 
2 cycles of Re-Induction with blinatumomab. Relapsed/refractory Ph+ or Ph-like 
DSMKF patients with prior dasatinib or other 2nd or 3rd generation TKI therapy must 
have achieved CR or CRi within 2 cycles of Re-Induction therapy with 
blinatumomab. 
 
NOTE: For Cohort 2: Day 1 of Post-Remission = Day 85 of the preceding Induction 
cycle (+/- 3 days), or Day 43 of the preceding Re-Induction cycle (+/- 3 days) as 
applicable. 
 
See Section 7.3 for additional information regarding timing of Post-Remission Day 
1. 
 
b. 
Patients must have serum creatinine ≤ 1.5 mg/dl within 14 days prior to registration. 
 
c. 
Patients must have AST and ALT ≤ 3.0 x Institutional Upper Limit of Normal (IULN) 
within 14 days prior to registration. 
 
d. 
Patients must have total bilirubin ≤ 2.0 x IULN within 14 days prior to registration. 
 
e. 
Patients must have adequate marrow function as evidenced by ANC ≥ 750/mcL 
and platelets ≥ 50,000/mcL within 28 days prior to registration. 
 
f. 
Patients must be registered to Step 2 within 28 days after count recovery.  (Note: 
there is no maximum allotted time period for count recovery, providing patient 
remains in CR or CRi.) 
 
g. 
All non-hematologic treatment related toxicities that are deemed clinically 
significant by the treating investigator must have resolved to ≤ Grade 2. 
 
5.3 
Registration Step 3 – Maintenance 
 
a. 
Patients must have documented CR or CRi within 28 days prior to registration.  
Note that bone marrow examination is only required if there are clinical 
signs/symptoms of progression.  If progression is a concern due to the length of 
the time for count recovery, a bone marrow examination is recommended. 
 
b. 
Patients must have serum creatinine ≤ 1.5 mg/dl within 14 days prior to registration. 
 
c. 
Patients must have AST and ALT ≤ 3.0 x Institutional Upper Limit of Normal (IULN) 
within 14 days prior to registration. 
 
d. 
Patients must have total bilirubin < 2.0 x Institutional Upper Limit of Normal (IULN) 
within 14 days prior to registration. 
 
e. 
Patients must have adequate marrow function as evidenced by ANC ≥ 750/mcL 
and platelets ≥ 75,000/mcL within 28 days prior to registration. 
 
f. 
All non-hematologic treatment related toxicities that are deemed clinically 
significant by the treating investigator must have resolved to ≤ Grade 2. 
 
 
 

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6.0 
STRATIFICATION FACTORS 
 
Patients will be stratified by Registration Cohort (1 and 2). 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Anjali Advani 216/445-9354 or Dr. 
Kristen O’Dwyer at 585/275-4099.  For dosing principles or questions, please consult the SWOG 
Policy #38 "Dosing Principles for Patients on Clinical Trials" at  
https://www.swog.org/sites/default/files/docs/2017-11/Policy38.pdf. 
 
7.1 
General Considerations, Prophylactic Therapy and Pre-Medication 
 
a. 
IT Methotrexate and Lumbar Punctures 
 
1. 
IT Methotrexate Administration 
 
All patients, regardless of Ph-status, will receive prophylactic intrathecal 
(IT) chemotherapy with methotrexate (12 mg) every 4-6 weeks for at least 
8 doses.  Subsequent doses may be administered at physician discretion. 
 
IT methotrexate must not be given on the same days as blinatumomab, 
but should be given 2 days apart from blinatumomab administration (Day 
-2 or Day +31).  Note: The first dose of IT methotrexate must be given 
within 5 weeks of initiation of blinatumomab therapy. During Maintenance, 
IT methotrexate may be delayed by up to 2 weeks if toxicities are thought 
to be attributable to IT methotrexate administration. 
 
2. 
Substitutions/Alternative IT Methotrexate Administration 
 
If a patient is intolerant to IT methotrexate, it may be substituted with 70 
mg intrathecal cytarabine. 
 
Alternatively, IT chemotherapy may be administered by Ommaya 
reservoir.   
 
3. 
Additional Instructions 
 
Patients should remain in a horizontal position for at least 30 minutes 
following the administration of IT chemotherapy to enhance drug delivery 
to the head. 
 
Concomitant medication of hydrocortisone (50 mg) with either IT 
methotrexate or cytarabine is allowable at treating physician discretion. 
Hydrocortisone should not be administered through an Ommaya reservoir. 
 
4. 
Lumbar Puncture for CNS Involvement Monitoring 
 
A lumbar puncture to monitor for CNS involvement is performed every 4-
6 weeks with IT methotrexate administration during administration of IT 
chemotherapy.  If IT methotrexate is delayed per the allowance in Section 
7.1a.1, LP may also be delayed up to 2 weeks to correspond. 
 
b. 
Patients with evidence of extramedullary disease at diagnosis will have CT scan 
or MRI of the chest, abdomen and pelvis within 28 days prior to registration, then 

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every 3 months for 2 years, then every 6 months until 5 years after initial 
registration. 
 
c. 
For the prevention of acute reaction, patients must receive dexamethasone 20 mg 
IV within 1 hour prior to the start of treatment (or re-start of treatment) in each cycle 
of blinatumomab. For patients with ≥ 5% blasts, dexamethasone 20 mg IV must 
be given within 1 hour prior to start of  blinatumomab infusion at 9 mcg/day on Day 
1 and repeat at same dose (dexamethasone 20 mg IV) within 1 hour prior to start 
of blinatumomab infusion at 28 mcg/day on Day 8. 
 
During treatment with blinatumomab patients must: 
  
1. 
Receive adequate hydration according to institutional guidelines. 
 
2. 
Perform a writing test (see Section 18.3) at the time of visits for 
blinatumomab infusion bag changes or weekly clinical visits (or weekly for 
patients receiving inpatient therapy or home-health infusions). The test will 
be evaluated immediately by medical staff for evidence of early signs of 
neurologic toxicity.  If changes are noted, patients should be monitored 
and graded for signs of neurologic toxicity. See Section 8.3a for timing of 
writing test for patients experiencing neurologic toxicities. The writing test 
samples should be kept in the patient chart; they are not submitted 
centrally. 
 
3. 
Avoid non-steroidal anti-inflammatory drugs (NSAIDs) if possible because 
they are a potential cause of endothelial stress. 
 
4. 
Be hospitalized per FDA recommendation. If patients have not achieved 
CR, Cohort 1 (Ph-negative) patients should be hospitalized for the first 9 
days of Induction Cycle 1.  Similarly, Cohort 2 (Ph-positive) patients with 
≥ 5% blasts should be hospitalized for the first 9 days of re-induction Cycle 
1. If patients have achieved CR, it is recommended that patients be 
hospitalized for at least the first 3 days (72 hours) of the first cycle of 
blinatumomab, and the first 2 days (48 hours) of subsequent cycles.  
 
5. 
Have blinatumomab bag changed every 24-96 hours. 
 
Note:  Home health care for blinatumomab administration and bag changes is 
acceptable, providing it is in accordance with local policies and procedures and the 
patient continues to make minimum weekly clinic visits.  The Study Chair must be 
contacted to discuss prior to allowing the patient to receive home health care for 
blinatumomab.  
 
IMPORTANT NOTE: Please see Section 18.7: Clinical Site Management of Out-
Patient Treatment Using CTEP-Supplied Blinatumomab, Section 18.13: Shipment 
of Blinatumomab IV Bag from Site/Pharmacy to Patient’s Home, and the "Manual 
for Blinatumomab Outpatient Administration".  All participating investigators must 
also complete the Outpatient Administration Investigator Statement of Verification, 
accessible from the SWOG protocol abstract page (www.swog.org), certifying that 
these materials have been reviewed, that the "Manual for Blinatumomab 
Outpatient Administration" has been provided to any/all applicable Outpatient 
Administration Facilities or Organizations that are being utilized at the 
Investigator’s site, and that a communication plan has been established with these 
same Outpatient Administration Facilities or Organizations. 
 
d. 
Note that specimens must be submitted to the local CLIA-approved laboratory for 
cytogenetics every time a marrow/blood is collected for response assessment. 
 

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e. 
Cardiopulmonary Considerations (Cohort 2, Ph+ and Ph-like DSMKF Patients 
Only) 
 
Patients should be evaluated for signs and symptoms of underlying 
cardiopulmonary disease prior to initiating dasatinib and during dasatinib 
treatment. 
 
Symptoms of pulmonary arterial hypertension (PAH) include dyspnea, fatigue, 
hypoxia, and edema. Since other medical conditions may also cause these 
symptoms, non-invasive procedures (including echocardiogram) should be done 
first to rule out more the common etiologies of these symptoms, such as pleural 
effusion, pulmonary edema, anemia, and lung infiltration. 
 
Right heart catheterization can confirm the diagnosis of PAH. Hypertension is “pre-
capillary” and not a consequence of left heart failure or chronic lung disease if there 
is normal pulmonary capillary wedge pressure (< 15 mm Hg) but elevated 
pulmonary artery pressure (mean pulmonary artery pressure > 25 mm Hg). Since 
PAH may be reversible upon discontinuation of dasatinib, a diagnostic approach 
of interruption of dasatinib treatment may be considered at the discretion of the 
treating physician; however, if PAH is confirmed, dasatinib should be permanently 
discontinued. 
 
f. 
Cohort 1, Ph- Patients:  Patients should have baseline PT, PTT, INR and 
fibrinogen testing performed at baseline (during screening or prior to beginning 
treatment) to establish baseline measurements.  These tests will then be repeated 
weekly during Days 1-28 of Induction and Re-Induction.   
 
g. 
Considerations for Ph-like DSMKF patients: In the event that a patient is 
registered to Cohort 1 for Ph-negative patients, and the investigator subsequently 
receives result indication that the patient is not Ph-negative (that is, the patient is 
determined to be Ph-like DSMKF), the participating investigator must notify the 
study 
chair 
and 
SWOG 
Statistics 
and 
Data 
Management 
Center 
(leukemia@crab.org).  NOTE: Due to differences in schema, transfer between 
cohorts will not be allowed. 
 
7.2 
Cohort 1 – Philadelphia Chromosome Negative (Ph-) Patients (Permanently closed to 
accrual 6/29/17) 
 
a. 
Registration Step 1 – Induction/Re-Induction – Blinatumomab 
 
Induction 
 
Agent 
Dose 
Route 
Day 
Schedule a 
 
 
Blinatumomab b, c 9 mcg/day 
continuous IV 
1-7 
One Induction cycle 
 
 
28 mcg/day 
continuous IV 
8-28 
One Induction cycle 
 
IT Methotrexate 
12 mg 
Intrathecal 
See Section 7.1a 
Dexamethasone 20 mg 
IV 
See Section 7.1c 
 
a 
Note:  One cycle = 42 days 
b 
See Section 7.1c for blinatumomab premedication and administration 
requirements.   
c 
Patients should be given a blinatumomab medication guide prior to beginning 
blinatumomab therapy (see Section 18.12). 
 

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Blinatumomab Induction/Re-Induction consists of 28 day continuous IV infusion, 
followed by 14 days of no treatment, for a total of a 42 day cycle. 
 
Response will be assessed at Day 35 (± 2 days) of the Induction cycle.  Patients 
achieving CR or CRi will be registered to Step 2 and receive up to 3 Post-
Remission cycles of blinatumomab therapy as outlined in Section 7.2b, after 
completion of the first Induction cycle.  Patients may proceed to Step 2 Registration 
as soon as CR or CRi is documented and the 14 day treatment free period is 
completed. Cycle 1, Day 1 of Post-Remission = Day 43 of the preceding Induction 
Cycle (+/- 3 days).  
 
Patients not achieving CR or CRi will receive a second cycle of blinatumomab 
Induction (Re-Induction) as outlined below, after completion of the first Induction 
cycle.  
 
IMPORTANT NOTE: Please see Section 18.7: Clinical Site Management of Out-
Patient Treatment Using CTEP-Supplied Blinatumomab, Section 18.13: Shipment 
of Blinatumomab IV Bag from Site/Pharmacy to Patient’s Home, and the "Manual 
for Blinatumomab Outpatient Administration".  All participating investigators must 
also complete the Outpatient Administration Investigator Statement of Verification, 
accessible from the SWOG protocol abstract page (www.swog.org), certifying that 
these materials have been reviewed, that the "Manual for Blinatumomab 
Outpatient Administration" has been provided to any/all applicable Outpatient 
Administration Facilities or Organizations that are being utilized at the 
Investigator’s site, and that a communication plan has been established with these 
same Outpatient Administration Facilities or Organizations. 
 
Re-Induction 
 
Agent 
Dose 
Route 
Day Schedule a 
 
 
Blinatumomab b 28 mcg/day 
continuous IV 1-28 One Re-Induction cycle 
 
IT Methotrexate 
12 mg 
Intrathecal 
See Section 7.1a 
 
Dexamethasone 20 mg 
IV 
See Section 7.1c 
 
a 
Note:  One cycle = 42 days 
b 
Patients should be given a blinatumomab medication guide prior to beginning 
blinatumomab therapy (see Section 18.12). 
 
Response will then be assessed again on Day 35 (± 2 days) of the Re-Induction 
Cycle.  Patients achieving CR or CRi will be registered to Step 2 and receive up to 
3 Post-Remission cycles of blinatumomab therapy as outlined in Section 7.2b.  
Patients may proceed to Step 2 Registration as soon as CR or CRi is documented 
and the 14 day treatment free period is completed.  Cycle 1, Day 1 of Post-
Remission = Day 43 of the preceding Re-Induction Cycle (+/- 3 days). 
 
Patients not achieving CR or CRi after a second Induction cycle will be removed 
from protocol therapy. 
 
 

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b. 
Registration Step 2 – Post-Remission – Blinatumomabc 
 
Patients must be registered to Step 2 prior to beginning Post-Remission therapy. 
 
Agent 
Dose 
Route 
Day Schedulea 
 
 
Blinatumomabb 
28 mcg/day 
continuous IV 1-28 every Post-Remission 
  
 
 
 
cycle 
 
IT Methotrexate 
12 mg 
Intrathecal 
See Section 7.1a 
 
Dexamethasone 20 mg 
IV 
See Section 7.1c 
 
  
 
 
 
  
 
a 
Note:  One cycle = 42 days 
b 
Patients should be given a blinatumomab medication guide prior to beginning 
blinatumomab therapy (see Section 18.12). 
c 
Note: Cycle 1, Day 1 of Post-Remission should begin on Day 43 of the 
preceding Induction or Re-Induction cycle, as applicable (+/- 3 days) 
 
Patients will receive 3 cycles of Post-Remission therapy with blinatumomab.  
Patients remaining in CR or CRi will proceed to Maintenance as outlined in Section 
7.2c.  Patients not remaining in CR or CRi will be removed from protocol therapy. 
 
c. 
Registration Step 3 – Maintenance – POMP Chemotherapye 
 
Patients must be registered to Step 3 prior to beginning Maintenance therapy. 
 
Agent 
Dose 
Route Day 
Schedulea 
 
 
Prednisone 
60 mg/m2/day PO 
1-5 
every Maintenance cycle 
 
(max 120 mg/day) 
for up to 18 cycles 
 
Vincristineb 
1.4 mg/m2 
IV 
1 
every Maintenance cycle 
 
(max 2 mg) 
 
 
 
6-mercaptopurined 60 mg/m2/day PO 
1-28 
every Maintenance cycle 
 
Methotrexatec 
20 mg/m2/day PO 
1, 8, 15, 22 
every Maintenance cycle 
 
IT Methotrexate 
12 mg 
Intrathecal 
See Section 7.1a 
 
 
 
 
 
 
a 
Note:  One cycle = 28 days 
b 
Patients should not receive azoles (except for fluconazole) within ± 2 days of 
vincristine administration. 
c 
Patients should not receive NSAIDS, penicillins, proton pump inhibitors or 
Bactrim (sulfamethoxazole and trimethoprim) on the same day as 
methotrexate (see Section 3.5 for potential drug interactions). 
d 
Doses should be taken without milk or citrus products, and at least one hour 
after the evening meal.  Adjust dose using 50 mg tablets and different doses 
on alternating days to achieve cumulative weekly dose as close to 420 mg/m2 
as possible (see Section 18.8). 
e  
Note: Cycle 1, Day 1 of Maintenance should begin on Day 43 of the preceding 
Post-remission cycle (+/- 7 days). 
 
Patients will receive POMP chemotherapy for 18 cycles, or until one of the criteria 
in Section 7.6 has been met.   

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7.3 
Cohort 2 – Philadelphia Chromosome Positive (Ph+) Patients and Ph-like DSMKF Patients 
 
a. 
Registration Step 1 – Induction – Dasatinib/Prednisone 
 
1. 
Newly-diagnosed Ph-positive Patients, Newly-diagnosed Ph-like DSMKF 
Patients,   and Relapsed/Refractory Ph-positive Patients who are both 
dasatinib and other 2nd/3rd generation TKI-naive. 
 
Induction – Dasatinib/Prednisonea 
 
Agent 
Dose 
Route 
Day 
Scheduleb 
 
 
Dasatinibe 
140 mg/day 
PO 
1-84d 
one Induction cycle 
 
Prednisonec 
60 mg/m2/day 
PO 
1-24 
one Induction cycle 
 
(max 120 mg/day) 
 
Prednisonec 
tapering 
PO 
25-32 
one Induction cycle 
 
IT 
12 mg 
Intrathecal 
See Section 7.1a 
Methotrexate 
 
a 
Ph+ and Ph-like DSMKF patients who received dasatinib or another 2nd or 3rd 
generation TKI prior to Registration will begin protocol therapy with Re-
Induction Cycle 1 (see Section 7.3b). 
b 
Note:  One cycle = 84 days  
c 
Prednisone dose will taper starting on Day 25 and stop at Day 32, with the last 
tapered dose administered on Day 32.  It is recommended that dose be 
tapered by 15%/day for 7 days, but local institutional standards for dose 
tapering may be used instead.  
d 
Patients not achieving CR or CRi by Day 56 will not receive dasatinib on Days 
57-84, but will proceed directly to Re-Induction as outlined in Section 7.3b. 
e 
Patients should be given a dasatinib handout/wallet card prior to beginning 
dasatinib therapy (see Section 18.11). 
 
Response will be assessed on Day 28 (± 2 days).  Patients not achieving 
Day 28 response (CR or CRi) will be re-evaluated at Day 56 (± 2 days).  
Patients achieving CR or CRi (Day 28 or Day 56) and with continued 
hematologic remission after Day 84 will then receive up to 3 cycles of post-
remission blinatumomab/dasatinib as outlined in Section 7.3c. Patients not 
achieving CR or CRi by Day 56 will not receive dasatinib on Days 57-84, 
but will proceed directly to Re-Induction as outlined in Section 7.3b.  
Patients who do not have continued hematologic remission after Day 84 
will proceed to Re-Induction as outlined in Section 7.3b.  
 
Dasatinib may be taken with or without meals. The dosing time may be 
adjusted as required (for once daily dosing, recommend skipping doses 
that are missed by more than 12 hours). If doses are missed for toxicity, 
they should not be replaced. If vomiting occurs within 30 minutes of intake, 
that dose may be repeated. Crushing or cutting dasatinib tablets is 
prohibited. 
 
 

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2. 
Relapsed/Refractory Ph-positive and Ph-like DSMKF Patients who have 
received prior therapy with either dasatinib or another 2nd/3rd generation 
TKI.  
 
Ph+ and Ph-like DSMKF patients who received dasatinib or another 2nd or 
3rd generation TKI prior to Registration will begin protocol therapy with Re-
Induction Cycle 1 (see Section 7.3b below). 
 
b. 
Re-Induction – Blinatumomab  
 
Agent 
Dose 
Route 
Day 
Schedule a 
 
 
Blinatumomab b 
9 mcg/day 
continuous IV 
1-7 
Re-Induction Cycle 1  
 
28 mcg/day 
continuous IV 
8-28 
Re-Induction Cycle 1 
 
Blinatumomab 
28 mcg/day 
continuous IV 
1-28 c Re-Induction Cycle 2 
 
IT Methotrexate 
12 mg 
Intrathecal 
See Section 7.1a 
 
Dexamethasone 
20 mg 
IV 
See Section 7.1c 
 
a 
Note:  One cycle = 42 days 
b 
Patients should be given a blinatumomab medication guide prior to beginning 
blinatumomab therapy (see Section 18.12). 
c 
Blinatumomab Re-Induction consists of a 28-day continuous IV infusion, 
followed by 14 days of no treatment, for a total of a 42 day cycle. 
 
Response will be assessed at Day 35 (± 2 days) of Cycle 1.  Patients achieving 
CR or CRi will proceed to blinatumomab/dasatinib therapy as outlined in Section 
7.3c.  Patients not achieving CR or CRi will receive a second cycle of 
blinatumomab re-Induction.  Response will then be assessed again on Day 35 (± 
2 days) of Cycle 2.  Patients achieving CR or CRi will proceed to 
blinatumomab/dasatinib therapy as outlined in Section 7.3c.  Patients not 
achieving CR or CRi will be removed from protocol therapy.  Patients may proceed 
to Step 2 Registration as soon as CR or CRi is documented and the 14 day 
treatment free period is completed. 
 
c. 
Registration Step 2 – Post-Remission – Blinatumomab/Dasatinib (see Section 
7.3e) d 
 
Patients must be registered to Step 2 prior to beginning Post-Remission therapy. 
 
Agent 
Dose 
Route 
Day 
Schedule a 
 
 
 
Blinatumomab b c 
28 mcg/day 
continuous IV 
1-28 
Post-Remission 
Cycles 1-3 
 
Dasatinib c 
70 mg/day 
PO  
1-42 
Post-Remission  
 
 
 
 
Cycles 1-3 
 
IT Methotrexate 
12 mg 
Intrathecal 
See Section 7.1a 
 
Dexamethasone 
20 mg 
IV 
See Section 7.1c 
 
a 
Note:  One cycle = 42 days 

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b 
Blinatumomab dosing frequency is 28 days on-treatment and 14 days off- 
treatment in a 42-day cycle. 
c  
Patients should be given a blinatumomab medication guide prior to beginning 
blinatumomab therapy (see Section 18.12).  
d  
Patients should be given a dasatinib handout/wallet card prior to beginning 
dasatinib therapy (see Section 18.11). 
e 
Note: Day 1, Cycle 1 of Post-Remission should begin on Day 43 of the 
preceding Induction cycle (+/- 3 days) or Day 85 of the preceding Re-Induction 
cycle (+/- 3 days), as applicable. 
 
Patients will receive 3 post-remission cycles of blinatumomab/dasatinib therapy.  
Patients remaining in CR or CRi will proceed to Maintenance as outlined in Section 
7.3d.  Patients not remaining in CR or CRi will be removed from protocol therapy. 
 
Dasatinib may be taken with or without meals. The dosing time may be adjusted 
as required (for once daily dosing, recommend skipping doses that are missed by 
more than 12 hours). If doses are missed for toxicity, they should not be replaced. 
If vomiting occurs within 30 minutes of intake, that dose may be repeated. Crushing 
or cutting dasatinib tablets is prohibited. 
 
d. 
Registration Step 3 – Maintenance – Dasatinib/Prednisonec  
 
Patients must be registered to Step 3 prior to beginning Maintenance therapy. 
 
Agent 
Dose 
Route Day Schedulea 
 
 
Dasatinibb 
140 mg/day 
PO  
1-28 each Maintenance cycle 
 
Prednisone 
60 mg/m2/day PO 
1-5 
each Maintenance cycle for  
 
(max 120 mg/day) 
up to 18 cycles 
 
IT Methotrexate 
12 mg 
Intrathecal 
See Section 7.1a 
 
a 
Note:  One cycle = 28 days 
b 
Patients should be given a dasatinib handout/wallet card prior to beginning 
dasatinib therapy (see Section 18.11). 
c  
Note: Cycle 1, Day 1 of Maintenance should begin on Day 43 of the preceding 
Post-remission cycle (+/- 7 days). 
 
Dasatinib may be taken with or without meals. The dosing time may be adjusted 
as required (for once daily dosing, recommend skipping doses that are missed by 
more than 12 hours). If doses are missed for toxicity, they should not be replaced. 
If vomiting occurs within 30 minutes of intake, that dose may be repeated.  
 
Patients will receive Maintenance until one of the criteria in Section 7.6 has been 
met. 
 
e. 
Dose Limiting Toxicities and Feasibility 
 
For 
Cohort 
2 
only, 
a 
feasibility 
study 
will 
be 
conducted 
for 
the 
dasatinib/blinatumomab portion of the trial. After the first 9 patients who receive 
post-remission therapy are accrued, the trial will be evaluated in a run-in phase.  
Although there will not be a dose escalation, the regimen will not be considered 
feasible if 3 or more of the first 9 patients have dose limiting toxicities (DLT).  Dose-
limiting toxicity (DLT) will be defined as any of the following events occurring during 
the first cycle of post-remission treatment that are possibly, probably, or definitely 
attributable to blinatumomab or dasatinib: (1) Grade 3 or higher non-hematologic 

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toxicities, with the exception of nausea, vomiting, or diarrhea (if manageable with 
supportive care measures and does not require hospitalization, TPN, or tube 
feeding); and (2) Grade 4 neutropenia that lasts > 42 days.  Section 11.2 contains 
further details of this design. 
 
Adverse events and accrual monitoring are done routinely by the Study Chairs and 
Study Statisticians. A mandatory conference call for study teams with active 
patients will take place twice a month (see Section 15.6). 
 
7.4 
Drug Compliance Documentation 
 
Drug compliance of oral drugs will be recorded by patients in the Intake Calendar (see 
Section 18.1). Institutional CRAs will review and ascertain patient adherence with oral 
protocol therapy at the end of treatment for each applicable cycle.  The calendar should be 
kept in the patient's clinic chart. Sites utilizing the CIRB must use the Intake Calendar 
provided. Sites not utilizing the CIRB may utilize institutional pill diaries or other source 
documentation in place of the Intake Calendar at the discretion of the treating physician. 
 
7.5 
Full CDUS Reporting Requirement 
 
Because this study contains an investigational drug for which CTEP holds the IND, it falls 
under CTEP requirements for full reporting.  This involves required submission of cycle-
specific toxicity and dose information (see Section 14.4d, the S1318 Treatment Form, and 
the S1318 Adverse Event Form).  Cycle definitions are as follows: 
 
a. 
Cohort 1 – Ph-Negative Patients 
 
1. 
Induction/Re-Induction – Blinatumomab:  35-42 days 
 
2. 
Post-Remission – Blinatumomab:  35-42 days 
 
3. 
Maintenance – POMP Chemotherapy:  28 days 
 
 
b. 
Cohort 2 – Ph-Positive and Ph-like DSMKF Patients 
 
1. 
Induction – Dasatinib/Prednisone:  56-84 days (for newly diagnosed 
patients and relapsed/refractory patients without prior dasatinib or another 
2nd or 3rd generation TKI) 
 
2. 
Re-Induction – Blinatumomab:  35-42 days 
 
3. 
Post-Remission – Blinatumomab/Dasatinib:  42 days 
 
4. 
Maintenance – Dasatinib/Prednisone:  28 days 
 
7.6 
Criteria for Removal from Protocol Treatment 
 
a. 
Relapse (as defined in Section 10.5). 
 
b. 
Failure to achieve remission (CR or CRi) after completion of Induction/Re-
Induction therapy. 
 
c. 
Failure to remain in remission (CR or CRi) following Post-Remission Therapy. 
 
d. 
Ph- patients:  Completion of 18 cycles of POMP chemotherapy. 
 

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e. 
Ph+ and Ph-like DSMKF patients:  Completion of 10 years of protocol therapy 
(from time of initial registration). 
 
f. 
Unacceptable toxicity. See Section 8.3 for allowable treatment interruption 
timeframes due to toxicity. 
 
g. 
The patient may withdraw from the study at any time for any reason. 
 
h. 
Treatment delay for any reason > 42 days. 
 
7.7 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice.  
 
7.8 
Follow-Up Period 
 
All patients will be followed until death or 10 years after initial registration, whichever occurs 
first. 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
Two different versions of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be used on this study. 
 
a. 
Serious Adverse Event (SAE) reporting 
 
The CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 
will be utilized for SAE reporting only. The CTCAE Version 5.0 can be 
downloaded from the CTEP home page (https://ctep.cancer.gov).  All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0. 
 
b. 
Routine toxicity reporting 
 
This study will utilize the CTCAE Version 4.0 for routine toxicity reporting.  A copy 
of the CTCAE Version 4.0 can be downloaded from the CTEP home page 
(https://ctep.cancer.gov).  All appropriate treatment areas should have access to a 
copy of the CTCAE Version 4.0. 
 
8.2 
General Considerations 
 
a. 
Dose modifications will be made only as outlined below. 
 
b. 
Missed doses should be made up as soon as possible, unless otherwise noted 
below. 
 
c. 
If multiple toxicities are experienced, dose modifications will be based on the 
toxicity requiring the largest dose reduction.  Doses will not be reduced for 
alopecia. 
 
d. 
Reductions are based on the dose given in the preceding cycle and are based on 
toxicities observed since the prior toxicity evaluation. 
 

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e. 
If a drug must be permanently discontinued, the patient may continue on protocol 
treatment with the remaining drug(s).  Exceptions:  If blinatumomab is permanently 
discontinued in either cohort or dasatinib is permanently discontinued in Cohort 2 
(Ph+/Ph-like DSMKF), patients must be removed from protocol therapy. 
 
f. 
For dose reductions of oral medications, dose should be reduced to the nearest 
available pill/tablet/capsule strength to the calculated reduction. 
 
8.3 
Dose Modifications 
 
 
a. 
Blinatumomab 
 
Pretreatment as outlined in Section 7.1 is required prior to re-starting 
blinatumomab infusion.  Re-start of the infusion should be performed in the hospital 
under supervision of the principal investigator.  The table below outlines treatment 
cycle duration following treatment interruption for adverse events: 
 
Length of 
Interruption 
Length of 
Treatment Prior 
to Interruption 
Re-Starting Infusion 
≤ 7 days 
Any 
Continue same cycle of blinatumomab 
for total treatment duration 28 days on 
blinatumomab. 
8-14 days 
≤ 14 days 
Same Cycle of treatment will be re-
started as if a new cycle and continue 
for an additional 28 days total. 
8-14 days 
> 14 days 
The cycle of treatment will be 
terminated and will not be repeated.  
The next cycle will begin as 
scheduled. 
> 14 days  
(+5 days for 
logistical issues 
– see below) 
Any 
Blinatumomab is permanently 
discontinued; patient is removed from 
protocol therapy. 
 
Note that if the adverse events resolve to a level allowing resumption of 
blinatumomab in < 14 days, but logistical difficulties arise, re-start of treatment can 
be postponed for up to 5 additional days without resulting in permanent treatment 
discontinuation. 
 
 

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Dose modifications for adverse events thought to be related to blinatumomab are 
listed in the table below:   
 
Adverse Event 
Toxicity Grade 
Action 
Events within the 
“Nervous System 
Disorders” or 
“Psychiatric 
Disorders” “System 
Organ Class (SOC) 
(other than 
seizures)” 1 
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 toxicity 
resolves to Grade ≤ 1, and for at least 3 
days, then resume blinatumomab at 9 
mcg/day. Escalate to 28 mcg/day after  
 
 
 
 

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Adverse Event 
Toxicity Grade 
Action 
Events within the 
“Nervous System 
Disorders” or 
“Psychiatric 
Disorders” “System 
Organ Class (SOC) 
(other than 
seizures)” 1  
(contd.) 
Grade 3 
(contd.) 
 
 
7 days if the toxicity does not recur. If 
the toxicity occurred at 9 mcg/day or if 
the toxicity takes more than 7 days to 
resolve, discontinue blinatumomab 
permanently.  Subsequent cycles of 
blinatumomab will be started at 9 
mcg/day and then escalated to 28 
mcg/day after 7 days if the toxicity does 
not recur. 
 
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 is discontinued 
permanently and the patient is removed 
from protocol therapy. 
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 is discontinued 
permanently and the patient is removed 
from protocol therapy. 
Seizure 
 
Grade 1-2 
Discontinue blinatumomab permanently 
if more than 1 seizure occurs. 
 
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. 

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Adverse Event 
Toxicity Grade 
Action 
Seizure 
(contd.) 
Grade 3 
Discontinue blinatumomab permanently 
if more than 1 seizure occurs. 
 
Withhold blinatumomab until no more 
than Grade 1 (mild) and for at least 3 
days, then restart blinatumomab at 9 
mcg/day. Escalate to 28 mcg/day after 
7 days if the toxicity does not recur. If 
the toxicity occurred at 9 mcg/day, or if 
the toxicity takes more than 7 days to 
resolve, discontinue blinatumomab 
permanently. 
Grade 4 
Discontinue blinatumomab 
permanently. 
All other events 
under “Nervous 
System Disorders” 
or “Psychiatric 
Disorders” “System 
Organ Class 
(SOC)” 
Grade 1-4 
Continue therapy with supportive care 
as per local institutional guidelines 
Cytokine Release 
Syndrome (CRS), 
Allergic Reactions, 
Anaphylaxis, or 
Infusion Related 
Reaction 
Grade 1 
Continue therapy with supportive care, 
as per 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 toxicity 
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. 

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Adverse Event 
Toxicity Grade 
Action 
Cytokine Release 
Syndrome (CRS), 
Allergic Reactions, 
Anaphylaxis, or 
Infusion Related 
Reaction 
(contd.) 
Grade 3 
(contd.) 
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; 
patient is removed from protocol 
therapy. 
 
If the initial adverse event lasts for ≥ 2 
weeks without improvement, then 
blinatumomab is discontinued 
permanently and the patient is removed 
from protocol therapy. 
Grade 4 
Blinatumomab is discontinued 
permanently; patient is removed from 
protocol therapy. 
Sepsis, bacteremia, 
device or catheter-
related infection 
Grade 1-2 
Continue therapy with supportive care 
as per local institutional guidelines 
Grade 3-4 
Monitor for recurrence.  Per Section 
11.5, SWOG will evaluate overall 
infection rate for all patients receiving 
72-96 hour IV bags. 
Aspartate 
Aminotransferase 
(AST) Increased, 
Alanine 
Aminotransferase 
(ALT) Increased  
Grade 1-2 
Continue at same dose level. 
Grade 3-4 
Hold blinatumomab until toxicity 
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; patient 
is removed from protocol 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.   
Blood Bilirubin 
Increased 
Grade 1-2 
Continue at same dose level. 
Grade 3-4 
Hold blinatumomab until toxicity 
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; patient 
is removed from protocol therapy. 
 

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Adverse Event 
Toxicity Grade 
Action 
Blood Bilirubin 
Increased  
(contd.) 
Grade 3-4 
(Contd.) 
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 1-2 
Continue at same dose level. 
Grade 3-4 
Hold blinatumomab until 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; patient is removed from 
protocol 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. 
Thromboembolic 
Events 
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; 
patient is removed from protocol 
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. 
Lymphocyte Count 
Decreased 
Grade 1-4 
Continue at same dose level. 
Neutrophil Count 
Decreased 
Grade 1-2 
Continue at same dose level. 
Grade 3-4 
 
Hold blinatumomab until toxicity 
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  
 
 

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Adverse Event 
Toxicity Grade 
Action 
Neutrophil Count 
Decreased 
(contd.) 
Grade 3-4 
(contd.) 
toxicity recurs, stop drug permanently; 
patient is removed from protocol 
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. 
Platelet Count 
Decreased 
Grade 1-3 
Continue at same dose level. 
Grade 4 
Hold blinatumomab until 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; 
patient is removed from protocol 
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. 
All Other AEs 
within the 
“Investigation” SOC 
and “Metabolism 
and Nutrition 
Disorders” SOC 
Grade 1-4 
Continue at same dose level, provided 
toxicity is not medically consequential 
and has been readily corrected. 
 
If abnormality is medically 
consequential, refer to guidelines for 
other non-hematologic events. 
 
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 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; patient is removed 
from protocol therapy. 
 
 

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Adverse Event
Toxicity Grade
Action
Other Non-
Hematologic AEs
(contd.)
Grade 3-4
(contd.)
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.
1 For the purposes of blinatumomab dose modification, neurological toxicity does 
not include:  CNS infections, CNS bleeding events, or CNS events due to 
leukemic involvement.
If a patient experiences one or more of the AEs listed in the table above, 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 the table 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 as outlined in the table.
b.
Dasatinib
1.
Induction:
For Grade 3-4 non-hematologic toxicity, hold dasatinib until toxicity 
resolves to ≤ Grade 1.  Dose may be reduced to 70 mg once daily for 
Grade 3 or 4 non-hematologic toxicity.  Consider discontinuing if Grade 3 
or Grade 4 non-hematologic toxicity recurs.  Further dose reductions 
should be discussed with the Study Chair.
2.
Post-Remission:
For Grade 3-4 non-hematologic toxicity, hold dasatinib until 
toxicity resolves to ≤ Grade 1.
Upon resumption of protocol 
therapy, the dose may be reduced to 40 mg once daily.
For ANC < 500/ mcL or platelets < 30,000/ mcL, hold dasatinib 
until ANC ≥ 1000/mcL and platelets ≥ 50,000/mcL. If recovery 
occurs in ≤ 2 weeks, resume at previous dose. If recovery occurs 
in > 2 weeks, resume at 40 mg/day.
Further dose reductions should be discussed with the Study Chair.
3.
Maintenance
For Grade 3-4 non-hematologic toxicity, hold dasatinib until 
toxicity resolves to ≤ Grade 1.  Upon resumption of protocol 
therapy, the dose may be reduced to 70 mg once daily.
For ANC < 500/mcL or platelets < 30,000/mcL, hold until ANC > 
1,000/mcL and platelets > 50,000/mcL.  If recovery occurs in ≤ 2 
weeks, resume at same dose.  If recovery occurs in > 2 weeks, 
resume at 70 mg once daily.
Further dose reductions should be discussed with the Study Chair.

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c.
Prednisone
Any dose reductions or omissions of prednisone while on any portion of the trial 
must be discussed with the Study Chair and documentation of this discussion must 
be kept in the patient’s clinical chart.
d.
POMP Chemotherapy
1.
Recommendations for Thiopurine Monitoring and Dosage Adjustments for 
Myelosuppression (6-Mercaptopurine as part of POMP Chemotherapy)
It is recommended that patients have their Thiopurine 
Methyltransferase 
(TPMT) 
status 
and/or 
their 
thiopurine 
metabolite concentrations evaluated, so that the dose of 6-
mercaptopurine 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- mercaptopurine 
dose. Heterozygotes may need a 30-50% dose reduction of 6-
mercaptopurine. TPMT testing and thiopurine metabolite 
measurements are commercially available.
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. 
For patients with TPMT mutation, 6-mercaptopurine dose will not 
be re-escalated if reduced.
NOTE: Genotyping can be done despite recent transfusions.
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. 
•
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. 

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•
If the patient is homozygous wild-type (high activity) for 
TPMT, then discontinue cotrimoxazole (if used) and use 
pentamidine or dapsone. Should ANC fall again below 
500/mcL on two or more occasions, decrease dose of 6-MP 
or MTX by 25% on an alternating basis upon resumption of 
therapy.
2.
Oral Methotrexate and 6-Mercaptopurine
Cytopenias
ANC < 
500/mcL
1st Instance:  Hold 6-MP and PO MTX until 
ANC ≥ 750/mcl then resume at full dose. 
2nd Instance: Discontinue 6-MP and PO MTX 
until ANC ≥ 750/mcL. 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/mcL. Consider 
discontinuing cotrimoxazole and switching 
patient to dapsone or pentamidine. 
Subsequent Instances:  If ANC < 500/mcL on 
≥ 
2 
occasions, 
perform 
thiopurine 
pharmacology testing (see Section 8.3d.1). 
Should 
therapy 
be 
withheld 
for 
myelosuppression, do not “make up” that 
week. Resume therapy at the correct point 
chronologically. 
Platelets < 
75,000/mcL
1st Instance:  Hold 6-MP and PO MTX. 
Resume at full dose once platelets ≥ 
75,000/mcL. 
2nd Instance:  Discontinue 6-MP until platelets 
≥ 75,000/mcL. 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/mcL. Consider 
discontinuing cotrimoxazole and switching 
patient to dapsone or pentamidine. 
Subsequent 
Instances: 
 
If 
platelets 
< 
75,000/mcL on ≥ 2 occasions, perform 
thiopurine pharmacology testing (see Section 
8.3d.1). Should therapy be withheld for 
myelosuppression, do not “make up” that 
week. Resume therapy at the current point 
chronologically. 
Oral MTX and 6-MP Dose Escalation During Maintenance 
Therapy
For ANC ≥ 1500/mcL, on 3 CBCs done over 6 weeks or 2 
successive monthly CBCs, first increase the dose of either PO 

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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.
Oral MTX Dose Modifications for Maintenance Therapy for 
Elevated Transaminases 
ALT or AST > 5 x 
ULNa
Obtain total bilirubin. Monitor ALT or 
AST and total bilirubin every week 
during Maintenance Therapy as long 
as transaminases remain > 5 x ULN.
ALT or AST > 8 x 
ULN on two 
determinations at 
least one week apart 
or total 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.
a The investigator may reduce the dose of methotrexate for AST 
or ALT >8x ULN at their discretion in elderly patients.
Exclude infectious hepatitis (A, B, C) for persistent (> 1 month) 
elevations in ALT or AST.
Oral MTX Dose Modifications for Mucositis During Maintenance 
Therapy 
Grade 3 
PO MTX should be given at 50% of the previous 
dose.
Grade 4 
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.
Oral MTX Dose Modifications for Diarrhea and Vomiting During 
Maintenance Therapy 
If either severe diarrhea or vomiting (≥ Grade 3) 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. 
Oral MTX for Bilirubin
If direct bilirubin > 2.0 mg/dl, then hold methotrexate.  Monitor labs 
weekly until bilirubin ≤ 2.0 mg/dl, then resume at previous dose.  

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Dose Modifications for Renal/Genitourinary Toxicity During 
Maintenance Therapy 
•
For ≥ Grade 2 creatinine, hold PO MTX until toxicity resolves 
to ≤ Grade 2. Once toxicity has resolved to this level, then PO 
MTX may be resumed at the previous dose. 
•
For ≥ Grade 2 creatinine, 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.
3.
Vincristine
Obtain bilirubin within ± 2 days of vincristine administration.  Hold 
vincristine for direct bilirubin ≥ 2.  
Hold vincristine for neuropathy ≥ Grade 2.
If toxicity (bilirubin or neuropathy) resolves to ≤ Grade 1 within 1 week 
dose may be made up; otherwise dose is skipped.
8.4
Supportive Care and Concomitant Medications
a.
General Instructions for Blinatumomab
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.
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 dose modification table in Section 8.3a), 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 Section 
8.3a
for guidelines regarding blinatumomab dose modifications and AE 
management.
Cytokine Release Syndrome (CNS) Risk Mitigation Plan
Manifestations of cytokine release syndrome include fever, headache, nausea, 
asthenia, hypotension, increased alanine aminotransferase, increased aspartate 
aminotransferase, increased total bilirubin, and disseminated intravascular 
coagulation (DIC).

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Monitor patients for signs or symptoms of these symptoms: 
• 
In patients treated for MRD-positive B-cell precursor ALL, hospitalization is 
recommended for the first 3 days of the first cycle and the first 2 days of the 
second cycle. 
• 
In patients treated for relapsed or refractory B-cell precursor ALL, 
hospitalization is recommended for the first 9 days of the first cycle and the 
first 2 days of the second cycle. 
 
Administer corticosteroids for severe or life-threatening cytokine release syndrome. 
 
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 Section 8.3a. 
 
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 Section 8.3a. 
 
b. 
Supportive care regarding adequate hydration and use of antiemetics for nausea 
and vomiting should be administered according to institutional guidelines. 
 
c. 
G-CSF/GM-CSF Guidelines   
 
G-CSF/GM-CSF may be used at the discretion of the treating investigator and in 
accordance with ASCO guidelines.   
 
Growth factors should not be administered on the same day as methotrexate or 6-
mercaptopurine, or during any cycles of blinatumomab treatment. 
 
The use of G-CSF/GM-CSF must be documented on the S1318 Treatment Form.  
Any toxicities associated with G-CSF must also be documented on the S1318 
Adverse Event Form.    
 
d. 
Patients should not take antacids, but if they are absolutely necessary they must 
be taken at least 2 hours before or 2 hours after dosing of dasatinib. 
 
e. 
For Cohort 2 (Ph+/Ph-like DSMKF cohort) during dasatinib treatment:  Patients 
currently taking drugs that are generally accepted to have a risk of causing 
Torsades de Pointes (including: quinidine, procainamide, disopyramide, 
amiodarone, 
sotalol, 
ibutilide, 
dofetilide, 
erythromycins, 
clarithromycin, 
chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, cisapride, 
bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, 
levomethadyl, pentamidine, sparfloxacin, lidofazine) should change these to 
acceptable alternatives. 
 

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f. 
For Cohort 2 (Ph+/Ph-like DSMKF cohort) during dasatinib treatment:  Medications 
that inhibit platelet function (i.e., aspirin, dipyridamole, epoprostenol, eptifibatide, 
clopidogrel, cilostazol, abciximab, ticlopidine, and any non-steroidal anti-
inflammatory drug) or anticoagulants (warfarin, heparin/low molecular weight 
heparin [e.g., danaparoid, dalteparin, tinzaparin, enoxaparin]) should be avoided 
as much as possible. 
 
Exceptions include low-dose warfarin for prophylaxis to prevent catheter 
thrombosis, and for heparin-flushes for IV lines.  If patients develop deep vein 
thrombosis during the course of therapy or are receiving anticoagulation for 
indications such as recent thrombosis or artificial heart valves these drugs may be 
continued with close monitoring of the patients. 
 
g. 
Dasatinib should not be used concomitantly with strong CYP3A4 inhibitors, such 
as ketoconazole, itraconazole, voriconazole, and posaconazole. Dasatinib may be 
used with moderate CYP3A4 inhibitors such as isavuconzole or fluconazole when 
necessary for oral antifungal prophylaxis. (A list of CYP3A4 inhibitors can be found 
in Section 18.3). Dose reduction while administering oral antifungal agents is not 
necessary. 
 
h. 
Recommended 
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. 
 
i. 
During POMP Chemotherapy, it is recommended that patients receive prophylaxis 
with Sulfamethoxazole/trimethoprim 800/160 mg (Bactrim DS), one tablet oral 
daily on Monday, Wednesday, and Friday continuing throughout and for 6 months 
after the completion of POMP chemotherapy. For patients allergic to or 
experiencing excessive myelosuppression with cotrimoxazole, alternative 
prophylactic regimens include dapsone or aerosolized pentamide (300 mg once 
every 4 weeks via nebulizer).  In some settings IV pentamidine may be considered.  
 
Allopurinol must be stopped during administration of 6-Mercaptopurine. 
Concurrent use can result in excess toxicity.  Allopurinol inhibits xanthine oxidase, 
which metabolizes mercaptopurine. When administered with allopurinol, the dose 
of 6-Mercaptopurine must be reduced to 25-30% of the usual dose.   
 
Avoid use of itraconazole, voriconazole or posaconazole with vincristine therapy 
(Echinocandin or amphotericin may be considered, in accordance with local 
institutional guidelines). 
 
j. 
Other supportive measures and prophylactic antibiotics, antivirals and/or 
antifungals may be used at the discretion of the treating physician. 
 
8.5 
Dose Modifications Contacts 
 
For treatment or dose modification questions, please contact the Study Chairs at 
S1318SC@swog.org (email preferred) or via phone Dr. Anjali Advani at 216/445-9354 or 
Dr. Kristen O’Dwyer at 585/275-4099. 
 
8.6 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 

 
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9.0 
STUDY CALENDAR 
 
9.1 
Cohort 1 – Ph-Negative Patients – Induction/Re-Induction – Blinatumomab (Permanently closed to accrual 6/29/17) 
 
 
Pre-
Treatment 
Days 
1-7 
Days 
8-14 
Days 
15-21 
Days 
22-28 
Days 
29-35 
Days 
36-42 
Off 
Protocol 
Therapy 
Follow 
Up Ω 
# 
REQUIRED STUDIES 
 
 
 
 
 
 
 
 
 
PHYSICAL 
 
 
 
 
 
 
 
 
 
History and Physical Exam £ 
X 
X 
X 
X 
X 
X 
X 
 
X 
Weight and Performance Status 
X 
 
 
 
 
 
 
 
 
Toxicity Notation £ 
X 
X 
X 
X 
X 
X 
X 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
CBC, Differential, Platelets  £ 
X 
X 
X 
X 
X 
X 
X 
 
X 
Comprehensive Metabolic Panel £ β 
X 
X 
X 
X 
X 
X 
X 
 
X 
PT/PTT/INR/Fibrinogen ^ 
X 
X 
X 
X 
X 
 
 
 
 
Bone Marrow Aspirate and Biopsy # 
X 
 
 
 
 
X % 
 
X 
 
Biopsy for Testicular Involvement € 
X 
 
 
 
 
 
 
 
 
Lumbar Puncture ∑ 
X 
X ∑ 
 
 
FISH and/or PCR µ 
X 
 
 
 
 
 
 
 
 
Neurologic Assessment &  
X 
X 
X 
X 
X 
X 
X 
 
 
CD4/Viral Load   
X 
 
 
 
 
 
 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
 
 
Chest X-Ray ¥ 
X 
 
 
 
 
 
 
 
 
CT or MRI $  
X 
X 
X 
X 
ECHO  ¥ 
X 
 
 
 
 
 
 
 
 
EKG  
X 
 
 
 
 
 
 
 
 
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
 
 
BM Aspirate/Biopsy - TM (MRD) ƒ 
X 
 
 
 
 
X% 
 
 
 
BM/PB for Cytogenetics ® 
X 
 
 
 
 
X% 
 
X 
 
Serum for Immunogenicity  
X 
 
 
 
 
 
X 
X 
 
BMA Banking & Future Research π 
X 
 
 
 
 
X 
 
 
 
TREATMENT Φ 
 
 
 
 
 
 
 
 
 
Blinatumomab 
 
X 
X 
X 
X 
 
 
 
 
IT Methotrexate  
 
X ∑ 
 
 
Note: Forms accessible from protocol page at www.swog.org.  Form submission schedule is listed in Section 14.0. 
Click here for footnotes. 
 
 

 
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Footnotes for Calendar 9.1. 
 
£ Pre-study, then weekly during Induction and Re-Induction. All Grade 3 or higher relevant infections will be evaluated every 6 months (see 
Section 11.5). 
β  Institutional standard metabolic panel is sufficient, providing it includes total bilirubin, AST and ALT, serum creatinine & alkaline 
phosphatase. 
& See Section 7.1c.2. 
$ Only if there is evidence of extramedullary disease at diagnosis, CT scan or MRI of the chest, abdomen & pelvis will be performed pre-
study, then every 3 months until CT/MRI is negative for extramedullary disease.  Once negative, CT/MRI will be performed every 3 months 
for 2 years, then every 6 months until 5 years after initial registration. CT/MRI is also required at the time the patient is removed from 
protocol therapy for any reason. 
^ Performed at pre-study, then weekly during Days 1-28. 
¥ Results do not determine eligibility.   
® See Section 15.1. Note: Bone marrow aspirate or (if dry tap) peripheral blood should be submitted for cytogenetic (and FISH, if possible) 
any time a bone marrow biopsy is performed for disease assessment. 
 See Sections 15.2 and 18.9. 
ƒ See Sections 15.3 and 18.4. 
π See Section 15.4 and 15.5. Note: The banked samples will be used for the translational medicine portion detailed in Section 18.15. 
% Day 35 (± 2 days) of Induction and Day 35 (± 2 days) of Re-Induction (if needed). 
€ Required only if clinical or ultrasound findings are equivocal. 
µ Cytogenetics (& FISH, if possible) analyses must be done up to 28 days prior to registration, then subsequently at any time a bone marrow 
biopsy is performed for disease assessment (see Sections 5.1b & 15.1). 
∑ See Section 7.1a. 
Ω F/U visits/labs will be performed every 3 months for the first 2 years, then every 6 months for the next 2 years, then annually until 10 years 
from initial registration. 
Φ See Section 7.2a for treatment days and details. 
 Required for patients known to be HIV+ only (see Section 5.1r).  
# After CR or CRi, marrows will be obtained at the discretion of the treating physician. 
 
NOTE:  Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment 
for continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines 
as outlined in https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 

 
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9.2 
Cohort 1 – Ph-Negative Patients – Post-Remission – Blinatumomab 
 
 
Pre-
Treatment 
Days 
1-7 
Days 
8-14 
Days 
15-21 
Days 
22-28 
Days 
29-35 
Days 
36-42 
Removal from 
Protocol Therapy 
Follow 
Up Ω # 
REQUIRED STUDIES 
 
 
 
 
 
 
 
 
 
PHYSICAL 
 
 
 
 
 
 
 
 
 
History and Physical Exam £ 
X 
X 
X 
X 
X 
X 
X 
 
X 
Weight and Performance Status 
X 
 
 
 
 
 
 
 
 
Toxicity Notation £ 
X 
X 
X 
X 
X 
X 
X 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
CBC, Differential, Platelets  £ 
X 
X 
X 
X 
X 
X 
X 
 
X 
Comprehensive Metabolic Panel  £ β 
X 
X 
X 
X 
X 
X 
X 
 
X 
Bone Marrow Aspirate and Biopsy # 
X 
 
 
 
 
 
 
X 
 
Lumbar Puncture ∑ 
 
X ∑ 
 
 
FISH and/or PCR µ 
X 
 
 
 
 
 
 
 
 
Neurologic Assessment &  
X 
X 
X 
X 
X 
X 
X 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
 
 
CT or MRI $  
 
X 
X 
X 
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
 
 
BM and PB for Cytogenetics ® 
 
X 
X 
 
Serum for Immunogenicity   
 
 
 
 
 
 
 
X 
 
TREATMENT Φ 
 
 
 
 
 
 
 
 
 
Blinatumomab 
 
X 
X 
X 
X 
 
 
 
 
IT Methotrexate  
 
X ∑ 
 
 
Note:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  The schedule for submission of these forms is listed 
in Section 14.0. 
 
Click here for footnotes: 
 

 
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Footnotes for 9.2 
 
£ Pre-txt, then weekly. All Gr. 3 or higher relevant infections will be evaluated every 6 months (see Section 11.5). 
β  Institutional standard metabolic panel is sufficient, providing it includes total bilirubin, AST and ALT, serum creatinine and alkaline phosphatase.   
µ Cytogenetics (and FISH, if possible) analyses must be done up to 28 days prior to registration, then subsequently at any time a bone marrow 
biopsy is performed for disease assessment (see Sections 5.2a and 15.1). 
& See Section 7.1c.2. 
$ Only if there is evidence of extramedullary disease at diagnosis, CT scan or MRI of the chest, abdomen and pelvis will be performed pre-study, 
then every 3 months until CT/MRI is negative for extramedullary disease.  Once negative, CT/MRI will be performed every 3 months for 2 years, 
then every 6 months until 5 years after initial registration.  CT/MRI is also required at the time the patient is removed from protocol therapy for any 
reason. 
® See Section 15.1. Note: Bone marrow aspirate or (if dry tap) peripheral blood should be submitted for cytogenetic (and FISH, if possible) any time 
a bone marrow biopsy is performed for disease assessment. 
 See Sections 15.2 and 18.9. 
∑ See Section 7.1a. 
Ω Follow up visits/labs will be performed every 3 months for the first 2 years, then every 6 months for the next 2 years, then annually until 10 years 
from initial registration. 
Φ See Section 7.2b for treatment days and details. 
# After CR or CRi, marrows will be obtained at the discretion of the treating physician. 
 
NOTE:  Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
 

 
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9.3 
Cohort 1 – Ph-Negative Patients – Maintenance – POMP Chemotherapy 
 
 
Pre-
Treatment 
Days 1-
7 
Days 8-
14 
Days 15-21 
Days 22-
28 
Removal from 
Protocol Therapy 
Follow Up Ω # 
REQUIRED STUDIES 
 
 
 
 
 
 
 
PHYSICAL 
 
 
 
 
 
 
 
History and Physical Exam % 
 
X 
 
 
 
 
X 
Weight and Performance Status % 
 
X 
 
 
 
 
 
Toxicity Notation % 
X 
 
 
 
 
 
 
Intake Calendar ≠ 
 
 
 
 
X 
 
 
LABORATORY 
 
 
 
 
 
 
 
CBC, Differential, Platelets  £ 
X 
X 
X 
 
X 
Comprehensive Metabolic Panel  £ β 
X 
X 
X 
 
X 
Bone Marrow Aspirate and Biopsy # 
X 
 
 
 
 
X 
 
Lumbar Puncture ∑ 
 
X ∑ 
 
 
FISH and/or PCR µ 
X 
 
 
 
 
 
 
Peripheral Neuropathy Assessment % 
X 
 
 
 
 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
CT or MRI $  
 
X 
X 
X 
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
BM and PB for Cytogenetics ® 
 
X 
X 
 
TREATMENT Φ 
 
 
 
 
 
 
 
Prednisone + 
 
X 
 
 
 
 
 
Vincristine 
 
X 
 
 
 
 
 
6-Mercaptopurine 
 
X 
X 
X 
X 
 
 
Methotrexate 
 
X 
X 
X 
X 
 
 
IT Methotrexate 
 
X ∑ 
 
 
Note:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  The schedule for submission of these forms is listed 
in Section 14.0. 
 
Click here for footnotes. 
 
 

 
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Footnotes for Calendar 9.3: 
 
£ 
Weekly for the first cycle, then every other week for subsequent cycles. 
% Prior to Day 1 treatment each cycle.   
β  Institutional standard metabolic panel is sufficient, providing it includes total bilirubin, AST and/or ALT, serum creatinine and alkaline 
phosphatase. CMP should be checked weekly if Grade 3 ALT or AST elevations develop during maintenance therapy. 
$ 
Only if there is evidence of extramedullary disease at diagnosis, CT scan or MRI of the chest, abdomen and pelvis will be performed pre-study, 
then every 3 months until CT/MRI is negative for extramedullary disease.  Once negative, CT/MRI will be performed every 3 months for 2 years, 
then every 6 months until 5 years after initial registration.  CT/MRI is also required at the time the patient is removed from protocol therapy for 
any reason. 
® See Section 15.1. Note: Bone marrow aspirate or (if dry tap) peripheral blood should be submitted for cytogenetic (and FISH, if possible) any 
time a bone marrow biopsy is performed for disease assessment. 
∑ 
See Section 7.1a. 
µ 
Cytogenetics (and FISH, if possible) analyses must be done up to 28 days prior to registration, then subsequently at any time a bone marrow 
biopsy is performed for disease assessment (see Sections 5.3a and 15.1). 
Ω Follow up visits/labs will be performed every 3 months for the first 2 years, then every 6 months for the next 2 years, then annually until 10 years 
from initial registration. 
≠ 
CRA will review Intake Calendar at the end of each cycle (see Section 18.1). 
Φ See Section 7.2c for treatment days and details. 
# 
After CR or CRi, marrows will be obtained at the discretion of the treating physician. 
+ 
Prednisone dosing during the maintenance phase is limited to a maximum of 18 cycles. 
 
NOTE:  Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
 

 
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9.4 
Cohort 2 – Newly-diagnosed Ph+ and Ph-like DSMKF Patients AND Relapsed/Refractory Ph+ and Ph-like DSMKF Patients who 
are naive to both dasatinib and other 2nd/3rd generation TKIs – Induction – Dasatinib/Prednisone λ 
 
 
Pre 
Tx 
Days 
1-7 
Days 
8-14 
Days 
15-21 
Days 
22-28 
Days 
29-35 
Days 
36-42 
Days 
43-49 
Days 
50-56 
Days 
57-63 
Days 
64-70 
Days 
71-77 
Days 
78-84 
Removal 
from 
Protocol 
Therapy 
Follow 
Up Ω # 
REQUIRED 
STUDIES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and 
Physical Exam £ 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Weight and 
Performance 
Status £ 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Toxicity Notation £ 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Intake Calendar ≠ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC, Differential, 
Platelets £ 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Comprehensive 
Metabolic Panel £ 
β 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Bone Marrow 
Aspirate and 
Biopsy # 
X 
 
 
 
X 
 
 
 
X√ 
 
 
 
 
X 
 
Biopsy for 
Testicular 
Involvement € 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lumbar Puncture ∑ 
X 
X ∑ 
 
 
FISH and/or PCR µ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4/Viral Load   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS AND 
SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-Ray  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI $  
X 
X 
X 
X 
ECHO  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Calendar continued on next page.  Click here for footnotes. 
 
 

 
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Pre 
Tx 
Days 
1-7 
Days 
8-14 
Days 
15-21 
Days 
22-28 
Days 
29-35 
Days 
36-42 
Days 
43-49 
Days 
50-56 
Days 
57-63 
Days 
64-70 
Days 
71-77 
Days 
78-84 
Removal from 
Protocol 
Therapy 
Follow 
Up Ω # 
SPECIMEN 
SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM Aspirate/Biopsy -
TM (MRD) ƒ 
X 
 
 
 
D28 α 
 
 
 
D56 
α√ 
 
 
 
 
 
 
BMA Banking & 
Future Research Ѧ 
X 
 
 
 
D28 α 
 
 
 
D56 
α√ 
 
 
 
 
 
 
BM and PB for 
Cytogenetics ® 
X 
 
 
 
D28 α 
 
 
 
D56 
α√ 
 
 
 
 
X 
 
TREATMENT Φ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prednisone 
 
X 
X 
X 
Xπ 
Xπ 
 
 
 
 
 
 
 
 
 
Dasatinib 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
IT Methotrexate 
 
X ∑ 
 
 
Note:  Forms are found on the SWOG website (www.swog.org).  The schedule for submission of these forms is listed in Section 14.0. 
 
Click here for footnotes: 
 
 

 
S1318 
 
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Footnotes for Calendar 9.4. 
 
λ  NOTE: Relapsed/Refractory Ph+ and Ph-like DSMKF patients who received dasatinib or another 2nd or 3rd generation TKI prior to Registration 
will begin protocol therapy with Re-Induction Cycle 1 (see Section 7.3b). 
£ 
Pre-study, then weekly Days 1-28, then every other week Days 29-84. 
β  Institutional standard metabolic panel is sufficient, providing it includes total bilirubin, AST and/or ALT, serum creatinine and alkaline 
phosphatase.   
$ 
Only if there is evidence of extramedullary disease at diagnosis, CT scan or MRI of the chest, abdomen and pelvis will be performed pre-study, 
then every 3 months until CT/MRI is negative for extramedullary disease.  Once negative, CT/MRI will be performed every 3 months for 2 years, 
then every 6 months until 5 years after initial registration.  CT/MRI is also required at the time the patient is removed from protocol therapy for 
any reason 
π 
Tapering Days 25-32 (see Section 7.3a). 
α 
± 2 days. 
® See Section 15.1. Note: Bone marrow aspirate or (if dry tap) peripheral blood should be submitted for cytogenetic (and FISH, if possible) any 
time a bone marrow biopsy is performed for disease assessment. 
ƒ 
See Sections 15.3 and 18.4. 
√ 
If necessary; see Section 7.3a. 
€ 
Required only if clinical or ultrasound findings are equivocal. 
µ 
Cytogenetics (and FISH, if possible) analyses must be done up to 28 days prior to registration, then subsequently at any time a bone marrow 
biopsy is performed for disease assessment (see Sections 5.1b and 15.1). For Ph+ patients, PCR for BCR/ABL should be obtained each time 
cytogenetics is performed. BCR/ABL is not required for Ph-like DSMKF patients (at baseline or subsequently). If not already known, baseline 
(up to 28 days prior to registration) PCR should include BCR-ABL status (both p190 and p210 analyses) for Ph+ patients. Subsequently, only 
the baseline positive (p190 or p210) result needs to be repeated. 
∑ 
See Section 7.1a. 
Ω Follow up visits/labs will be performed every 3 months for the first 2 years, then every 6 months for the next 2 years, then annually until 10 years 
after initial registration. 
≠ 
CRA will review Intake Calendar at the end of each cycle (see Section 18.1). 
Φ See Section 7.3a for treatment days and details.  
 
Required for patients known to be HIV+ only (see Section 5.1r) 
Ѧ 
See Section 15.5. Note: The banked samples will NOT be used for the translational medicine portion detailed in Section 18.15. 
# 
After CR or CRi, marrows will be obtained at the discretion of the treating physician. 
 
NOTE:  Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
 

 
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9.5 
Cohort 2 – Re-Induction – Blinatumomab (Ph+ and Ph-like DSMKF Patients) λ 
 
 
Pre 
Tx 
Days 1-
7 
Days 
8-14 
Days 15-
21 
Days 
22-28 
Days 29-
35 
Days 
36-42 
Removal from 
Prot Therapy 
FU Ω # 
REQUIRED STUDIES 
 
 
 
 
 
 
 
 
 
PHYSICAL 
 
 
 
 
 
 
 
 
 
H&P Exam £ 
X 
X 
X 
X 
X 
X 
X 
 
X 
WT & Perf Status £ 
X 
X 
X 
X 
X 
X 
X 
 
 
Toxicity Notation £ 
X 
X 
X 
X 
X 
X 
X 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
CBC, Differential, Platelets  £ 
X 
X 
X 
X 
X 
X 
X 
 
X 
Comprehensive Metabolic Panel  £ β 
X 
X 
X 
X 
X 
X 
X 
 
X 
PT/PTT/INR/ 
Fibrinogen ^ 
X 
X 
X 
X 
X 
 
 
 
 
BMA and Biopsy # 
 
 
 
 
 
D35 % 
 
X 
 
Lumbar Puncture ∑ 
 
X ∑ 
 
 
FISH and/or PCR µ 
X 
 
 
 
 
 
 
 
 
Neurologic Assessment & 
X 
X 
X 
X 
X 
X 
X 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
 
 
CT or MRI $  
 
X 
X 
X 
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
 
 
BM and PB for Cytogenetics ® 
 
X 
X 
 
Serum for Immunogenicity   
X 
 
 
 
 
 
X 
X 
 
BM Aspirate/Biopsy -TM (MRD) ƒ 
X 
 
 
 
 
D35 % 
 
 
 
BMA Banking & Future Research Ѧ 
X 
 
 
 
 
D35 % 
 
 
 
TREATMENT Φ 
 
 
 
 
 
 
 
 
 
Blinatumomab 
 
X 
X 
X 
X 
 
 
 
 
IT Methotrexate 
 
X ∑ 
 
 
Note:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  The schedule for submission of these forms is listed in Section 14.0. 
 
Click here for Footnotes. 

 
S1318 
 
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Version Date 08/16/2021 
 
Footnotes for Calendar 9.5: 
 
λ NOTE: Relapsed/Refractory Ph+ and Ph-like DSMKF patients who received dasatinib or another 2nd or 3rd generation TKI prior to Registration will 
begin protocol therapy with Re-Induction Cycle 1 (see Section 7.3b). 
£ Pre-treatment and then weekly. All Grade 3 or higher relevant infections will be evaluated every 6 months (see Section 11.5). 
β  Institutional standard metabolic panel is sufficient, providing it includes total bilirubin, AST and/or ALT, serum creatinine and alkaline phosphatase.   
& See Section 7.1c.2. 
µ Cytogenetics (and FISH, if possible) analyses must be done up to 28 days prior to registration, then subsequently at any time a bone marrow 
biopsy is performed for disease assessment (see Sections 5.1b and 15.1). For Ph+ patients, PCR for BCR/ABL should be obtained each time 
cytogenetics is performed. BCR/ABL is not required for Ph-like DSMKF patients (at baseline or subsequently). If not already known, baseline (up 
to 28 days prior to registration) PCR should include BCR-ABL status (both p190 and p210 analyses) for Ph+ patients. Subsequently, only the 
baseline positive (p190 or p210) result needs to be repeated. 
$ Only if there is evidence of extramedullary disease at diagnosis, CT scan or MRI of the chest, abdomen and pelvis will be performed pre-study, 
then every 3 months until CT/MRI is negative for extramedullary disease.  Once negative, CT/MRI will be performed every 3 months for 2 years, 
then every 6 months until 5 years after initial registration.  CT/MRI is also required at the time the patient is removed from protocol therapy for any 
reason. 
® See Section 15.1. Note: Bone marrow aspirate or (if dry tap) peripheral blood should be submitted for cytogenetic (and FISH, if possible) any time 
a bone marrow biopsy is performed for disease assessment. 
 See Sections 15.2 and 18.9. Note: Pretreatment and Day 36-42 specimens are needed for patient’s first cycle of blinatumomab administration 
only.  The follow-up specimen must be submitted within 30 days of the last dose of blinatumomab. 
% ± 2 days.  
^ Performed weekly during Days 1-28 
∑ See Section 7.1a. 
Ω Follow up visits/labs will be performed every 3 months for the first 2 years then every 6 months for the next 2 years, then annually  until 10 years 
after initial registration. 
ƒ To be obtained during Re-induction Cycle 1 for relapsed/refractory patients only. See Sections 15.3 and 18.4.  
Ѧ 
To be obtained during Re-induction Cycle 1 for relapsed/refractory patients only. See Section 15.5. Note: The banked samples will NOT be used 
for the translational medicine portion detailed in Section 18.15. 
Φ See Section 7.3b for treatment days and details. 
# After CR or CRi, marrows will be obtained at the discretion of the treating physician. 
 
NOTE:  Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
 

 
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9.6 
Cohort 2 – Ph+ and Ph-like DSMKF Patients–Post-Remission –Blinatumomab/Dasatinib 
 
 
Pre 
Tx 
Days 
1-7 
Days 
8-14 
Days 
15-21 
Days 
22-28 
Days 
29-35 
Days 
36-42 
Removal 
from Protocol 
Therapy 
Follow 
Up Ω # 
REQUIRED STUDIES 
 
 
 
 
 
 
 
 
 
PHYSICAL 
 
 
 
 
 
 
 
 
 
History and Physical Exam % 
X 
X 
X 
X 
X 
X 
X 
 
X 
Weight and Performance Status % 
X 
X 
X 
X 
X 
X 
X 
 
 
Toxicity Notation % 
X 
X 
X 
X 
X 
X 
X 
 
 
Intake Calendar  ≠ 
 
 
 
 
 
 
X 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
CBC, Differential, Platelets  £ 
X 
X 
X 
X 
X 
X 
X 
 
X 
Comprehensive Metabolic Panel  £ β 
X 
X 
X 
X 
X 
X 
X 
 
X 
Bone Marrow Aspirate and Biopsy # 
 
 
 
 
 
 
 
X 
 
Lumbar Puncture ∑ 
 
X ∑ 
 
 
FISH and/or PCR µ 
X 
 
 
 
 
 
 
 
 
Neurologic Assessment & 
X 
X 
X 
X 
X 
X 
X 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
 
 
CT or MRI $  
 
X 
X 
X 
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
 
 
BM and PB for Cytogenetics ® 
 
X 
X 
 
Serum for Immunogenicity   
X 
 
 
 
 
 
X∆ 
X 
 
TREATMENT Φ 
 
 
 
 
 
 
 
 
 
Blinatumomab 
 
X 
X 
X 
X 
 
 
 
 
Dasatinib 
 
X 
X 
X 
X 
X 
X 
 
 
IT Methotrexate 
 
X ∑ 
 
 
Note:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  The schedule for submission of these forms is listed in 
Section 14.0. 
 
Click her for footnotes. 
 
 

 
S1318 
 
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Footnotes for Calendar 9.6 
 
£ 
Performed twice weekly. 
% Pre-treatment and then weekly. All Grade 3 or higher relevant infections will be evaluated every 6 months (see Section 11.5). 
β  Institutional standard metabolic panel is sufficient, providing it includes total bilirubin, AST and/or ALT, serum creatinine and alkaline 
phosphatase.   
& 
See Section 7.1c.2. 
µ 
Cytogenetics (and FISH, if possible) analyses must be done up to 28 days prior to registration, then subsequently at any time a bone marrow 
biopsy is performed for disease assessment (see Sections 5.2a and 15.1). For Ph+ patients, PCR for BCR/ABL should be obtained each time 
cytogenetics is performed. BCR/ABL is not required for Ph-like DSMKF patients (at baseline or subsequently). If not already known, baseline 
(up to 28 days prior to registration) PCR should include BCR-ABL status (both p190 and p210 analyses) for Ph+ patients. Subsequently, only 
the baseline positive (p190 or p210) result needs to be repeated. 
$ 
Only if there is evidence of extramedullary disease at diagnosis, CT scan or MRI of the chest, abdomen and pelvis will be performed pre-study, 
then every 3 months until CT/MRI is negative for extramedullary disease.  Once negative, CT/MRI will be performed every 3 months for 2 years, 
then every 6 months until 5 years after initial registration.  CT/MRI is also required at the time the patient is removed from protocol therapy for 
any reason. 
≠ 
CRA will review Intake Calendar at the end of each cycle (see Section 18.1). 
® See Section 15.1. Note: Bone marrow aspirate or (if dry tap) peripheral blood should be submitted for cytogenetic (and FISH, if possible) any 
time a bone marrow biopsy is performed for disease assessment. 
 
See Sections 15.2 and 18.9. 
∑ 
See Section 7.1a. 
Ω Follow up visits/labs will be performed every 3 months for the first 2 years then every 6 months for the next 2 years, then annually until 10 years 
after initial registration. 
Φ See Section 7.3c for treatment days and details. 
# 
After CR or CRi, marrows will be obtained at the discretion of the treating physician. 
∆ 
For patients receiving their first cycle on blinatumomab. 
 
NOTE:  Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
. 
 

 
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9.7 
Cohort 2 – Ph+ and Ph-like DSMKF Patients – Maintenance – Dasatinib/Prednisone 
 
 
Pre 
Treatment 
Days 
1-7 
Days 
8-14 
Days 
15-21 
Days 
22-28 
Removal from 
Protocol Therapy 
Follow Up 
Ω # 
REQUIRED STUDIES 
 
 
 
 
 
 
 
PHYSICAL 
 
 
 
 
 
 
 
History and Physical Exam £ 
X 
X 
 
 
 
 
X 
Weight and Performance Status 
X 
X 
 
 
 
 
 
Toxicity Notation £ 
X 
X 
 
 
 
 
 
Intake Calendar  ≠ 
 
 
 
 
X 
 
 
LABORATORY 
 
 
 
 
 
 
 
CBC, Differential, Platelets  £ 
X 
X 
 
 
 
 
X 
Comprehensive Metabolic Panel  £ β 
X 
X 
 
 
 
 
X 
Bone Marrow Aspirate and Biopsy # 
X 
 
 
 
 
X 
 
Lumbar Puncture ∑ 
 
X ∑ 
 
 
FISH and/or PCR µ 
X 
 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
CT or MRI $  
 
X 
 
 
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
BM and PB for Cytogenetics ® 
 
X 
X 
 
TREATMENT Φ 
 
 
 
 
 
 
 
Prednisone + 
 
X 
 
 
 
 
 
Dasatinib 
 
X 
X 
X 
X 
 
 
IT Methotrexate 
 
X ∑ 
 
 
Note:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  The schedule for submission of these forms is listed in Section 
14.0. 
 
Click here for footnotes. 

 
S1318 
 
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Version Date 08/16/2021 
 
Footnote for Calendar 9.7 
 
£ 
Performed ON Day 1 of each cycle. 
β  
Institutional standard metabolic panel is sufficient, providing it includes total bilirubin, AST and/or ALT, serum creatinine and alkaline phosphatase. 
µ 
Cytogenetics (and FISH, if possible) analyses must be done up to 28 days prior to registration, then subsequently at any time a bone marrow biopsy is performed 
for disease assessment (see Sections 5.3a and 15.1). PCR for BCR/ABL should be obtained each time cytogenetics is performed. Baseline (up to 28 days prior 
to registration) PCR should include both p190 and p210 analyses. Subsequently, only the baseline positive (p190 or p210) result needs to be repeated. 
$ 
Only if there is evidence of extramedullary disease at diagnosis, CT scan or MRI of the chest, abdomen and pelvis will be performed pre-study, then every 3 
months for 2 years, then every 6 months until from years after initial registration. Once negative, CT/MRI will be performed every 3 months for 2 years, then 
every 6 months until 5 years after initial registration.  CT/MRI is also required at the time the patient is removed from protocol therapy for any reason. 
≠ 
CRA will review Intake Calendar at the end of each cycle (see Section 18.1). 
® 
See Section 15.1. Note: Bone marrow aspirate or (if dry tap) peripheral blood should be submitted for cytogenetic (and FISH, if possible) any time a bone 
marrow biopsy is performed for disease assessment. 
∑ 
See Section 7.1a. 
Ω 
Follow up visits/labs will be performed every 3 months for the first 2 years then every 6 months for the next 2 years, then annually until 10 years after initial 
registration. 
Φ 
See Section 7.3c for treatment days and details. 
# 
After CR or CRi, marrows will be obtained at the discretion of the treating physician. 
+ 
Prednisone dosing during the maintenance phase is limited to a maximum of 18 cycles. 
 
NOTE:  Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for continuous treatment, 
disease 
assessment, 
specimen 
collection 
and 
follow-up 
activities) 
must 
follow 
the 
established 
SWOG 
guidelines 
as 
outlined 
in 
https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
. 
 
 
 

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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
Note: For all sites of extramedullary disease present prior to treatment, subsequent disease 
measurements must be made using the same techniques as at baseline. 
 
10.1 
Extramedullary Disease 
 
a. 
Measurable Extramedullary Disease: Lesions that can be accurately measured in 
two dimensions by CT, MRI, medical photograph (skin or oral lesion), plain x-ray, 
or other conventional technique and a greatest transverse diameter of 1 cm or 
greater; or palpable lesions with both diameters ≥ 2 cm. Note: CT scans remain 
the standard for evaluation of nodal disease. 
 
b. 
Non-measurable 
Extramedullary 
Disease: 
All 
other 
lesions 
including 
unidimensional lesions, lesions too small to be considered measurable, pleural or 
pericardial effusion, ascites, bone disease, leptomeningeal disease, lymphangitis, 
pulmonitis, abdominal masses not confirmed or followed by imaging techniques or 
disease documented by indirect evidence only (e.g., lab values). 
 
c. 
Extramedullary Disease Status: 
 
C1.  
Complete disappearance of all measurable and non-measurable 
extramedullary disease with the exception of lesions for which the 
following must be true: for patients with at least one measurable lesion, all 
nodal masses > 1.5 cm in greatest transverse diameter (GTD) at baseline 
must have regressed to ≤ 1.5 cm in GTD and all nodal masses ≥ 1 cm and 
≤ 1.5 cm in GTD at baseline must have regressed to < 1 cm GTD or they 
must have reduced by 75% in sum of products of greatest diameters 
(SPD). No new lesions. Spleen and other previously enlarged organs must 
have regressed in size and must not be palpable. All disease must be 
assessed using the same technique as at baseline. 
 
C2.  
Patient does not qualify for C1 status. 
 
10.2 
Complete Remission (CR) 
 
a. 
< 5% marrow aspirate blasts. Blasts can be ≥ 5% if the blasts are found to be 
myeloid and there is no evidence of lymphoblasts by flow cytometry or 
immunostaining. 
 
b. 
Neutrophils (ANC) > 1,000/mcL; platelets > 100,000/mcL; and no blasts in the 
peripheral blood. 
 
c. 
C1 Extramedullary disease status (see Section 10.1c). 
 
10.3 
Complete Remission with Incomplete Platelet Recovery (CRi) 
 
Same as CR but platelet count may be ≤ 100,000/mcL and/or ANC ≤ 1,000/mcL. 
 
 
10.4 
Partial remission (PR)  
 
Improvement or no worsening of ALL, as indicated by all of the following: 
 
a. 
No blasts in the peripheral blood 
 
b. 
Neutrophils (ANC) ≥ 1,000/mcL; platelets > 100,000/mcL 

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c. 
Either or both of the following: 
 
1. 
At least a 50% decrease in the marrow blast percentage, compared to the 
pretreatment value, and marrow blast percentage ≥ 5% and ≤ 25%. 
 
2. 
C2 extramedullary disease status (see Section 10.1c). 
 
10.5 
Treatment Failures 
 
Patients who fail to achieve CR, CRi, or PR following induction will be classified according 
to the type of failure: 
 
a. 
Resistant Disease: patient survives ≥ 7 days following completion of initial 
treatment course and has persistent leukemia in the most recent peripheral blood 
smear or bone marrow and/or persistent disease involvement at any 
extramedullary site after completion of therapy. 
 
b. 
Death during Aplasia: patient survives ≥ 7 days following completion of initial 
treatment course then dies while cytopenic, with the last post-induction bone 
marrow without leukemic blasts. 
 
c. 
Indeterminate: 
 
1. 
Patient survives < 7 days after completion of initial treatment course. 
 
2. 
Patient survives ≥ 7 days following completion of initial treatment course 
then dies with no persistent leukemia in the peripheral smear but no post 
induction 
bone 
marrow 
examination 
or 
extramedullary 
disease 
examination. 
 
10.6 
Relapse from CR or CRi 
 
a. 
Appearance of leukemic blasts in the peripheral blood. 
 
b. 
Appearance of extramedullary disease. 
 
c. 
≥ 5% blasts in the bone marrow not attributable to another cause (e.g. recovery of 
normal cells following chemotherapy-induced aplasia). If there are no circulating 
blasts and no extramedullary disease and the bone marrow blast percentage is ≥ 
5% but < 20%, then a repeat bone marrow performed at least 7 days after the first 
marrow examination and documenting bone marrow blast percentage is ≥ 5% is 
necessary to establish relapse. 
 
10.7 
Overall Survival (OS) 
 
Overall survival will be measured from the day of registration on study until death from any 
cause with observations censored on the day of last contact for patients not known to have 
died. 
 
 
10.8 
Disease-Free Survival (DFS)  
 
DFS will be defined only for patients who achieve CR or CRi and will be measured from 
the date the patient first achieves CR or CRi until relapse from CR/CRi or death from any 
cause. Observations will be censored on the day of last contact for patients not known to 
have relapsed from CR/CRi or to have died. 

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10.9 
Toxicity Criteria 
 
The NCI Common Terminology Criteria for Adverse Events will be used to determine 
severity of toxicity. 
 
10.10 
Performance Status 
 
Patients will be graded according to the Zubrod performance status scale. 
 
POINT  
DESCRIPTION 
 
0  
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1  
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light 
housework, office work. 
 
2  
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours. 
 
3  
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours. 
 
4  
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Ph-negative Cohort 
 
a. 
Primary Objective 
 
The primary objective of this study is to test whether overall survival (OS) at 3 
years among elderly patients with newly diagnosed Ph-negative ALL is sufficiently 
high to warrant further investigation.  
 
Historical estimates of OS in this patient population provide 3-year OS estimates 
ranging from 6-12%. (2,9) Based on this historical data, the current regimen would 
be of no further interest in the Ph-negative cohort if it yields a true 3-year OS rate 
of 10% or less (null), and would be of further interest if it yields a true 3-year OS 
rate of 33% or higher (alternative).  
 
b. 
Analyses and Power Justification 
 
Up to 26 eligible patients with Ph- ALL will be accrued. All eligible patients enrolled 
will be used in the analysis. Although a one-stage design will be used for patient 
accrual, an interim analysis of futility will be performed to allow for early 
termination. If among the first 11 eligible patients, at least 5 complete remissions 
(CR or CRi) are observed, then the study will continue to full accrual. If fewer than 
5 complete remissions (CR or CRi) are observed, that will be considered evidence 
that this regimen does not warrant further testing, and the cohort will be closed. 
Accrual will continue while the CR data is being reviewed.   
 

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The final analysis will test whether the observed 3-year OS is improved over an 
historical rate of 10% with a one-sided binomial test at the 0.04 level. If 6 or more 
of the 26 patients are alive at three years after entering the study then the regimen 
will be considered sufficiently effective to warrant further investigation. Accounting 
for the interim analysis, this design has critical level (probability of erroneously 
concluding the regimen warrants further study) of 0.03 if the true response rate is 
50% and the true probability of 3-year OS is 10%, and power (probability of 
correctly concluding the regimen warrants further study) of 0.89 if the true 
response rate is 70% and the true 3-year OS is 33%. In the event of censoring, the 
3-year OS rate will be estimated using the method of Kaplan-Meier and a one-
sided 90% confidence interval will be constructed with the standard error 
calculated using the log-log transformation.  
 
With 26 patients in the study cohort, complete response (CR + CRi) rate can be 
estimated to within at most ± 20% (95% confidence interval). Distributions of 
disease-free survival and overall survival will be estimated using the method of 
Kaplan-Meier. 
 
The probability of any particular toxicity of the blinatumomab and POMP regimen 
can be estimated to within at most ± 20% (95% confidence interval). Any toxicity 
having a true occurrence rate of 9% or more is very likely to be observed in at least 
one patient (probability ≥ 91%). 
 
11.2 
Ph- positive and Ph-like DSMKF Cohort 
 
a. 
Primary Objective 
 
The primary objective of this study is feasibility: to assess the safety of 
dasatinib/steroid based-induction followed by blinatumomab/dasatinib treatment 
followed by dasatinib-based maintenance in patients with newly diagnosed Ph-
positive ALL, relapsed/refractory Ph-positive ALL, and either newly diagnosed or 
relapsed/refractory Ph-like ALL with dasatinib-sensitive mutations or kinase 
fusions.   
 
b. 
Analyses 
 
This study will initially accrue 9  eligible and evaluable patients to post-remission 
therapy. To be evaluable for DLT, patients must have experienced a DLT during 
Cycle 1 of blinatumomab post-remission therapy or must have received at least 
75% of the prescribed dose of Cycle 1 blinatumomab of Post-Remission therapy. 
Accrual to Step 1 will be closed once 9 patients are enrolled to post-remission 
therapy.  In the event that one or more of these 9 patients is not eligible and 
evaluable in Step 2, the study will re-open to enroll additional patients as needed. 
 
The trial will employ careful adverse event monitoring on these 9 patients. The 
Study Chairs and Leukemia Committee chair will be responsible for evaluating 
safety. Dose-limiting toxicity (DLT) will be defined as any of the following events 
occurring during the first cycle of post-remission treatment that are possibly, 
probably, or definitely attributable to blinatumomab or dasatinib: (1) any Grade 3 
or higher non-hematologic toxicity, with the exception of nausea, vomiting, or 
diarrhea (if manageable with supportive care measures and does not require 
hospitalization, TPN, or tube feeding); (2) any Grade 4 neutropenia that lasts > 42 
days. If 3 or more patients experience a DLT, the study will be temporarily closed 
to accrual pending a decision as to whether to continue accrual.  If, due to 
unexpected accrual patterns there are ultimately 12 patients evaluable for DLT, 
the following modified DLT rule will be evaluated: if 4 or more of the 12 patients 
experience a DLT, the study will be temporarily closed to accrual pending a 

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decision as to whether to continue accrual.  If accrual is re-opened, a protocol 
revision will include justification for continued accrual and for any treatment 
regimen modification.  Upon reopening of accrual, 8 additional eligible and 
evaluable patients will be enrolled for a total of 20 eligible and evaluable patients.  
Accounting for ineligibility and non-evaluability, this will require approximately 11 
additional patients. 
 
Statistical Considerations for 20 Evaluable Patients 
 
The activity (response rate, disease-free survival and overall survival) of this 
combination will be estimated in a preliminary manner given the small number of 
patients. With 20 patients receiving post-remission therapy, the response rate and 
DFS and OS at a particular time point can be estimated to within at most 23% (95% 
confidence interval). Distributions of disease-free survival and overall survival will 
be estimated using the method of Kaplan-Meier. 
 
With 20 patients, the probability of any particular toxicity can be estimated to within 
at most 23% (95% confidence interval). Any toxicity having a true occurrence rate 
of 15% or more is likely to be observed in at least one patient (probability ≥ 96%).   
 
11.3 
Minimal Residual Disease 
 
Minimal residual disease (MRD) negativity and time to achieve MRD negativity will be 
examined separately in descriptive analyses within each cohort (Cohort 1: Ph-negative and 
Cohort 2: Ph-positive or Ph-like DSMKF).  
 
11.4 
Accrual 
 
Based on S0333, and after consideration of the difference in eligible age, the expected 
accrual rate is 15 Ph-negative patients per year and 10 Ph-positive/Ph-like DSMKF patients 
per year. Accounting for the possibility of a 5% ineligibility rate, the study will accrue 
approximately 31 Ph-negative patients and 27 Ph-positive/Ph-like DSMKF patients (to 
have 20 Ph-positive/Ph-like DSMKF patients who receive post-remission therapy and are 
evaluable for DLTs). Accrual to the Ph-negative cohort is estimated to complete in 
approximately 23 months. Accrual to the Ph-positive and Ph-like DSMKF cohort is 
estimated to take 38 months, not accounting for temporary closures.  
 
11.5 
Monitoring for Infection Rate of 72-Hour and 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 96 hours. We will consider the 72 hour and 96 hour 
bag changes acceptable if the infection rate is 5% or less for each bag change time. 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 for either the 72 hour or the 
96 hour bag change, then that respective 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 or 72 hours, respectively. 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 96 hour bag change, with the 
monitoring rule as described above, the 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 96 hour bag change is 
unacceptable is 0.03 if the true but unknown rate of grade 3 or higher relevant infections is 

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5%; the probability of concluding 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 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 
96 hour bag change is unacceptable depends on the number of analyses and the number 
of patients treated at the times of those analyses. 
 
11.6 
Data and Safety Monitoring 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study. The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting). The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistics and Data Management Center, and will meet at 
the Group's bi-annual meetings as necessary. The Committee will be responsible for 
decisions regarding possible changes to blinatumomab administration. 
 
In addition to the above DSMC review, toxicity and accrual monitoring are done routinely 
by the Study Chair, study Statistician, and the Disease Committee Chair. Endpoint 
monitoring is done by the study Statistician and Study Chair. Accrual reports are generated 
weekly, and formal toxicity reports are generated every 6 months. In addition, the SWOG 
Statistics and Data Management Center, Adverse Event Coordinator at the Operations 
Office, SAE Physician Reviewer, and Study Chair monitor toxicities on an ongoing basis. 
 
 
12.0 
DISCIPLINE REVIEW 
 
This study will not utilize discipline review. 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than five calendar days 
prior to planned start of treatment). 
 
NOTE: If a patient was assigned a SWOG patient ID prior to registration, that patient ID 
must be used at the time of study registration. For questions about entering a previously 
assigned patient ID please contact the SWOG Statistics and Data Management Center at 
206/652-2267. 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet to CTEP. 
 
a. 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all individuals contributing to NCI-sponsored clinical 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 

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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 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log 
(DTL).     
 
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 >. 
 
b. 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
1. 
IRB Approval:   
 
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 

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• 
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. 
 
 
 
 
2. 
Downloading Site Registration Documents: 
 
 
Site registration forms may be downloaded from the S1318 protocol 
page located on the CTSU members’ website.  Permission to view and 
download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU RSS. 
▪ 
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 SWOG link to expand, then select S1318.  
▪ 
Click on LPO Documents, select the Site Registration documents 
link, and download and complete the forms provided. 
 
3. 
Requirements for S1318 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 Identification/IRB Certification/Declaration of 
Exemption Form, or combination is accepted) 
 
4. 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU 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 1100 
Philadelphia, PA 19103 
 
5. 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the 
CTSU website. 

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▪ 
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 at the top of your screen 
▪ 
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 as 
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. 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
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.  If a DTL 
is required for the study, the registrar(s) must also be assigned the OPEN Registrar task 
on the DTL.  
 
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.  If a DTL is required for the 
study, the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 

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j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN 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, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on the 
SWOG CRA Workbench. 
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes and 
the affirmation of eligibility on the Registration Worksheet has been signed by 
the registering investigator or another investigator designate. Site staff should 
refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
c. 
The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.  Please print this confirmation for your records. 
 

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d. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the 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. 
 
13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3a for details. 
 
14.3 
Data Submission Procedures 
 
a. 
Data collection for this study will be done exclusively through the 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 iMedidata, you must have 
an 
active 
CTEP-IAM 
account 
(check 
at 
https://eapps-
ctep.nci.nih.gov/iam/index.jsp) and the appropriate Rave role (Rave CRA, Read-
Only, Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent a 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 account at the time 
of initial registration approval for the study in RSS 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 

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information on iMedidata/Rave is available on the CTSU members’ website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com 
 
b. 
You may also access Rave® via the SWOG CRA Workbench via the SWOG web 
site (https://swog.org). 
 
 
For 
difficulties 
with 
the 
CRA 
Workbench, 
please 
e-mail 
technicalquestion@crab.org. 
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU) please 
refer to the CTSU Participation Table. 
 
14.4 
Data Submission Overview and Timepoints  
 
a. 
WITHIN 7 DAYS OF INITIAL REGISTRATION (STEP 1): 
 
Submit the following: 
 
S1318 Onstudy Form 
 
S1318 Baseline Abnormalities Form 
 
S1318 Baseline Disease Assessment Form 
 
Pathology Report 
If the patient is a relapsed/refractory patient with prior dasatinib exposure 
and/or exposure to other 2nd or 3rd generation TKIs, two pathology reports must 
be submitted within 7 days of initial registration:  
1.  Confirming diagnosis within 28 days prior to registration to step 1 
2.  Confirming diagnosis within 28 days prior to start of first induction of 
previous therapy 
 
For relapsed/refractory patients in Cohort 2: Cytogenetics report (from time of 
original diagnosis). 
 
b. 
WITHIN 14 DAYS AFTER INITIAL REGISTRATION (STEP 1): 
 
Submit the following: 
 
Specimens as outlined in Section 15.0 
 
c. 
WITHIN 28 DAYS AFTER INITIAL REGISTRATION (STEP 1): 
 
Submit the following: 
 
Cytogenetics and/or FISH Reports from lab (see Section 15.1a.1) 
 
S1318 Cytogenetics and FISH Analysis Form 
 
d. 
WITHIN 14 DAYS AFTER EACH CYCLE OF PROTOCOL TREATMENT: 
 
Submit the following: 
 
Appropriate S1318 Treatment Form 
 

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S1318 Adverse Event Form 
 
If applicable, S1318 Blinatumomab Related Infection Monitoring Form 
 
Specimens as outlined in Section 15.0 
 
e. 
COHORT 2 (Ph+ or Ph-like DSMKF): AT THE END OF EACH WEEK OF POST-
REMISSION THERAPY DURING CYCLE 1: 
 
Submit the following: 
 
S1318 Adverse Event Form 
 
(Note: It is important that the Adverse Event Form is updated / amended 
WEEKLY in RAVE). 
 
f. 
WITHIN 14 DAYS AFTER EACH DISEASE ASSESSMENT: 
 
Submit the following: 
 
ALL Disease Assessment Form documenting results of assessment 
 
Pathology Report 
 
g. 
WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT AT EACH 
REGISTRATION STEP: 
 
Submit the following: 
 
Off Treatment Notice  
 
Appropriate S1318 Treatment Form 
 
S1318 Adverse Event Form 
 
If applicable, S1318 Blinatumomab Related Infection Monitoring Form 
 
h. 
WITHIN 14 DAYS AFTER POST-REMISSION REGISTRATION (STEP 2): 
 
Submit the following: 
 
S1318 Post-Remission Eligibility Form 
 
i. 
WITHIN 14 DAYS AFTER MAINTENANCE REGISTRATION (STEP 3): 
 
Submit the following: 
 
S1318 Maintenance Eligibility Form 
 
j. 
WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 
 
Submit final appropriate S1318 Treatment Form and appropriate S1318 Adverse 
Event Form (if the patient was still on protocol treatment) or Leukemia Follow-Up 
Form (if the patient was off protocol treatment) documenting date, site and method 
for determining progression/relapse. 
 

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k. 
EVERY 3 MONTHS FOR THE FIRST YEAR, EVERY 6 MONTHS FOR THE 
SECOND AND THIRD YEARS, THEN ANNUALLY UNTIL 10 YEARS FROM 
INITIAL REGISTRATION: 
 
Submit the following: 
 
Leukemia Follow Up Form 
 
S1318 Transplant Form (if patient received HCT) 
 
Late Effects Form (if prior to treatment for progression or relapse or a second 
primary, and prior to non-protocol treatment, the patient experiences any severe 
[Grade ≥ 3] long term toxicity that has not been previously reported) 
 
l. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH:  
 
Submit the following: 
 
Notice of Death 
 
Final appropriate S1318 Treatment Form  
 
S1318 Adverse Event Form if the patient was still on protocol treatment) or 
Leukemia Follow-Up Form (if the patient was off protocol treatment) documenting 
death information. 
 
 

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15.0 
SPECIAL INSTRUCTIONS 
 
Purpose  
Specimens  
Timepoint  
Patients  
Additional 
required 
information 
Cytogenetics and 
FISH (if possible) 
(see Section 15.1)  
 
 
Bone Marrow Aspirate 
(or peripheral blood if 
dry tap) 
 
 
(1) 
Pre-Treatment (up 
to 28 days prior to 
registration). See 
Section 15.1a.1. 
 
(2) 
At any time point 
that a bone 
marrow biopsy is 
performed for 
disease 
assessment. 
(1) 
REQUIRED 
FOR ALL 
PATIENTS  
 
(2) 
For Ph-
positive 
patients, 
PCR for 
BCR/ABL 
should be 
obtained 
each time 
cytogenetic
s are 
performed. 
The S1318 
Cytogenetics Lab 
Report Form must 
be submitted to the 
laboratory with the 
specimen. 
 
The lab will return 
the completed form 
with results to the 
email address for 
the Data Manager, 
as provided on the 
form. 
 
The S1318 
Cytogenetics and 
FISH Analysis Form 
must be completed 
in Medidata Rave® 
using the 
information 
provided by the lab. 
Blinatumomab 
Immunogenicity 
Testing  
(see Section 15.2)  
 
5 mL Serum 
 
  
(1) a) For Ph-
negative 
Patients: Pre-
Treatment (up to 
28 days prior to 
registration).  
 
b) For Ph-
positive and Ph-
like DSMKF 
Patients: Up to 28 
days prior to 
receiving the first 
dose of 
blinatumomab. 
 
(2) Between Days 36-
42 AFTER initial 
blinatumomab 
administration. 
 
(3) Within 30 days of 
last dose of 
blinatumomab. 
 
REQUIRED FOR 
ALL PATIENTS 
At each timepoint 
serum must be 
centrifuged 
aliquoted, pipetted, 
and then frozen per 
instructions in 
Section 15.2b. 
 
A lab manual with 
complete specimen 
processing and 
shipment 
information is 
posted on the 
SWOG protocol 
abstract page at 
www.swog.org. 
 
 
 

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MRD – Correlative 
studies  
(see Section 15.3)  
 
 
With patient’s consent, 
1-2 mL anticoagulated 
bone marrow aspirate 
from first draw OR in 
event of dry tap, submit 
bone marrow biopsy 
(core, plug).  
 
 
Ph-negative patients: 
(1) Pre-Treatment (up 
to 28 days prior to 
registration). 
(2) Day 35 of 
Induction Cycle 1 
(± 2 days). 
(3) Day 35 of Re-
Induction Cycle 1 
(± 2 days, if 
applicable). 
Ph-positive and Ph-like 
DSMKF patients 
(newly diagnosed): 
1) Pre-Treatment (up to 
28 days prior to 
registration). 
(2) Day 28 of Induction 
Cycle 1 (± 2 days). 
(3) Day 56 of Induction 
Cycle 1 (± 2 days, if 
applicable). 
 
Ph-positive and Ph-like 
DSMKF patients 
(relapsed/refractory): 
(1) Pre-Treatment (up 
to 28 days prior to 
registration). 
(2) Day 35 of Re-
Induction Cycle 1 (± 2 
days). 
(3) Day 35 of Re-
Induction Cycle 1 (± 2 
days, if applicable). 
(3) Day 35 of Re-
Induction Cycle 2 (± 2 
days; if applicable 
 
OPTIONAL for 
ALL PATIENTS 
Ship to Lab #103: 
Wood Lab 
Phone 206/288-
7060 
Bone Marrow 
Aspirate (banking) 
for Future Research 
(see Section 15.4)  
With patient’s consent, 
3-4 mL bone marrow 
aspirate OR 3mL 
peripheral blood in 
event of dry tap, if the 
patient’s bone marrow 
blast count is ≥30%, or 
if bone marrow aspirate 
is not done (at 
physician discretion).  
Drawn at time of 
diagnosis and 
submitted at time 
of registration of 
Ph-Negative 
patients 
  
 
OPTIONAL for 
Ph-Negative 
Patients  
Ship to Lab #200 
SWOG Specimen 
Repository – 
Leukemia Division, 
Lab #200 
Banking – Future 
Correlative Studies 
(see Section 15.5)  
 
With patient’s consent, 
7-8 mL bone marrow 
aspirate AND 22-24 mL 
peripheral blood in 
EDTA tube. (In event of 
dry tap, submit only the 
peripheral blood.) 
Ph-negative patients: 
(1) Pre-Treatment 
(up to 28 days 
prior to 
registration). 
(2) Day 35 of 
Induction Cycle 1 
(± 2 days). 
OPTIONAL for 
ALL PATIENTS 
Ship to Lab #200 
SWOG Specimen 
Repository – 
Leukemia Division, 
Lab #200 
 
 

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Banking – Future 
Correlative Studies 
(see Section 15.5)  
 (contd.) 
 
 
 
(3) Day 35 of Re-
Induction Cycle 1 
(± 2 days, if 
applicable). 
 
Ph-positive and Ph-like 
DSMKF patients: 
(1) 
Pre-Treatment 
(up to 28 days 
prior to 
registration). 
(2) 
Day 28 of 
Induction Cycle 1 
(± 2 days). 
(3) 
Day 56 of 
Induction Cycle 1 
(± 2 days, if 
applicable). 
 
 
 
15.1  
Cytogenetics and FISH (Required) 
 
Specimens for cytogenetic (and FISH if possible) analysis must be submitted to the site’s 
preferred local CLIA-approved laboratory.  
 
a. 
Specimens (bone marrow aspirate, or peripheral blood if dry tap) must be 
submitted for cytogenetic (and FISH if possible) analysis at the following time 
points: 
 
1. 
Pre-treatment (up to 28 days prior to registration) 
 
If the patient is a relapsed/refractory patient with prior dasatinib exposure 
and/or exposure to other 2nd or 3rd generation TKIs, pre-treatment 
cytogenetic and/or FISH analysis must be performed up to 28 days prior 
to the start of the first induction of the previous therapy.  For these patients 
only, cytogenetic and/or FISH analysis is not required up to 28 days prior 
to registration to S1318. 
 
2. 
Any time a bone marrow biopsy is performed for disease assessment. 
 
For Ph+ patients, PCR for BCR/ABL (for both p190 and p210 transcripts) 
should be obtained each time cytogenetics are performed. 
 
b. 
Cytogenetics lab report forms must be submitted as outlined in Section 14.0. 
 
c. 
The S1318 Cytogenetics Lab Report Form must be submitted to the laboratory 
along with the specimen.  The laboratory will then return the completed form with 
the results.  E-mail contact information for the Data Manager at the site must be 
provided to the lab performing cytogenetic studies.  The institution will complete 
the S1318 Cytogenetics and FISH Analysis Form in Medidata Rave® using the 
information provided by the lab. 
 
 

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15.2 
Blinatumomab Immunogenicity Assessment (Required) 
 
Also see Section 18.9. 
 
a. 
Specimens (serum) must be submitted for blinatumomab immunogenicity 
assessment at the following timepoints:  
 
1. 
Pre-treatment (Cohort 1: up to 28 days prior to registration for Ph-negative 
patients; Cohort 2: up to 28 days prior to receiving first dose of 
blinatumomab for Ph-positive or Ph-like DSMKF patients).  
 
2. 
Between Days 36-42 after initial blinatumomab administration  
 
3. 
Within 30 days after last dose of blinatumomab 
 
b. 
At each timepoint, 5 mL of blood will be drawn into the provided Vacutainer.  
Vacutainer will be inverted 5 times after specimen collection (one complete turn of 
the wrist, 180 degrees and back), then will be left to stand upright for 30 minutes.  
Tubes will then be centrifuged for 10 minutes at 3500-4500 rpm (preferably with 
swing bucket rotor).  Specimen is properly centrifuged when solid black 
components and liquid are approximately equally separated.  Serum will then be 
aliquoted with pipette into two red capped cryovials (1 mL per vial).  Specimen will 
be immediately frozen at ≤ 20°C.  Specimen must be shipped on dry ice via courier 
service. 
 
A lab manual containing complete specimen collection, processing and shipment 
instructions can be found on the protocol abstract page of the SWOG website 
(www.swog.org). 
 
c. 
Specimen collection kits may be ordered by submitting the LabConnect Kit Order 
Form via the instructions on the form. 
 
d. 
In the online specimen tracking system, the appropriate SWOG laboratory for 
submission of serum specimens for blinatumomab immunogenicity testing is 
identified as follows: 
 
Lab #215:  
LabConnect 
Phone: 800/501-7947 
Contact:  Ben Booher 
 
15.3 
Translational Medicine (MRD) (optional for patient) (see Section 18.4) 
 
a. 
With patient’s consent to MRD, specimens (1-2 mL anticoagulated bone marrow 
aspirate from the first draw) must be submitted at the timepoints listed below. In 
the event of dry tap, submit bone marrow biopsy (core, plug).  A minimum of 2 cm 
of marrow space, excluding the cortical bone must be submitted in RPMI as 
indicated in Section 15.3c. (Purple/Lavender top tubes not accepted for biopsy.) 
 
Cohort 1 Ph-negative patients:   
 
1. 
Pretreatment (up to 28 days prior to registration). 
 
2. 
Day 35 of Induction Cycle 1 (± 2 days). 
 
3. 
Day 35 of Re-Induction Cycle 1 (± 2 days, if applicable). 
 

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Cohort 2 Ph-positive and Ph-like DSMKF patients (newly diagnosed 
patients):   
 
 
1. 
Pretreatment (up to 28 days prior to registration). 
 
2. 
Day 28 of Induction Cycle 1 (± 2 days). 
 
3. 
Day 56 of Induction Cycle 1 (± 2 days; if applicable). 
 
Cohort 2 Ph-positive and Ph-like DSMKF patients (relapsed/refractory 
patients previously treated with dasatinib or other TKI):   
 
 
1. 
Pretreatment (up to 28 days prior to registration). 
 
2. 
Day 35 of Re-Induction Cycle 1 (± 2 days). 
 
3. 
Day 35 of Re-Induction Cycle 2 (± 2 days; if applicable). 
 
b. 
Batch shipping is not allowed. Specimens must be transported the same day as 
collected via overnight express courier (at room temperature) to arrive on Monday 
through Saturday.  A cool pack in the container during the summer season is 
strongly encouraged.  
 
c. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. Bone marrow aspirates are to be submitted in either a) RPMI 
1640 containing 10% fetal calf serum and EDTA (20 mg/mL) added as an 
anticoagulant or b) purple/lavender top tubes.   Bone marrow biopsies are to be 
submitted in RPMI 1640 containing 10% fetal calf serum (purple top tubes are not 
acceptable for biopsies). 
 
d. 
In the online specimen tracking system, the appropriate SWOG laboratory for 
submission of bone marrow, serum, and peripheral blood samples for SWOG MRD 
testing is identified as follows: 
 
Lab #103:  
Wood Lab 
Phone: 206/288-7060 
Contact:  Brent Wood, M.D., Ph.D. 
 
 
15.4 
Collection of Bone Marrow Aspirate for Future Research (optional for Ph-Negative patients) 
 
 
 
a. 
With patient’s consent, 3-4 mL of bone marrow aspirate (from specimen drawn 
prior to receiving treatment) must be submitted at time of registration of all Ph-
Negative (Ph-) patients. In the event of the following, 3 mL (purple top) of peripheral 
blood should be submitted instead of a bone marrow aspirate: i) the patient’s bone 
marrow blast count is ≥ 30%, ii) a bone marrow aspirate is not done (at physician 
discretion), or iii) if in case of a dry tap. 
 
b. 
Specimen Collection and Submission Instructions  
 
1. 
Specimens must be collected into a heparinized syringe and transferred 
to an EDTA (purple) vacutainer for transport to the SWOG Specimen 
Repository – Leukemia Division, Lab #200.  
 
2. 
EDTA (purple top) vacutainer must be transported with a cold pack.  The 
vacutainer should be wrapped in absorbent material to prevent direct 

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contact with the cold packs (which could result in freezing and lysis of the 
sample). 
 
3. 
Batch shipping is not allowed. Specimens must be transported the same 
day as specimen collection via overnight courier. 
 
4. 
Specimen collection and submission instructions can be accessed on the 
SWOG Specimen Submission webpage. (). https://www.swog.org/clinical-
trials/biospecimen-resources/biospecimen-processing-and-submission-
procedures). 
 
c. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
d. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. If Ph status cannot be determined prior to registration, use 
the SWOG specimen tracking system  
https://crawb.crab.org/TXWB/ctsulogon.aspx Select “Specimen Tracking” and use 
the “Log a Specimen” link from the Specimen Tracking Home page. Use the “No 
Patient ID yet?” link and enter demographic information for the patient on the next 
page. This will assign a SWOG patient ID number and will remain the patient’s ID 
number.  If the patient does register to the study, it is important to remember to 
use this patient ID number on the OPEN system so the specimens will match with 
the correct patient. Specimens will be destroyed if the patient is not subsequently 
registered to the study. 
 
15.5 
Banking for Future Correlatives (optional for patient) 
 
a. 
With patient’s consent to banking, an additional 7-8 mL of bone marrow aspirate, 
and 22-24 mL peripheral blood must be submitted in separate EDTA tubes 
(additional details below) at the same timepoints (as for MRD- Section 15.3).  
 
 
 
Note: If bone marrow aspirate is “dry tap” or if there is no diagnostic bone marrow 
specimen available, submit only the 22-24 mL peripheral blood. Questions 
regarding banked specimens should be directed to leukemia@swog.org. 
 
Cohort 1 Ph-negative patients:   
 
1. 
Pretreatment (up to 28 days prior to registration). 
 
2. 
Day 35 of Induction Cycle 1 (± 2 days). 
 
3. 
Day 35 of Re-Induction Cycle 1 (± 2 days, if applicable). 
 
Cohort 2 Ph-positive and Ph-like DSMKF patients (newly diagnosed patients):   
 
 
1. 
Pretreatment (up to 28 days prior to registration). 
 
2. 
Day 28 of Induction Cycle 1 (± 2 days). 
 
3. 
Day 56 of Induction Cycle 1 (± 2 days; if applicable). 
 
Cohort 2 Ph-positive and Ph-like DSMKF patients (relapsed/refractory patients 
previously treated with dasatinib or other TKI):    
 

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1. 
Pretreatment (up to 28 days prior to registration). 
 
2. 
Day 35 of Re-Induction Cycle 1 (± 2 days). 
 
3. 
Day 35 of Re-Induction Cycle 2 (± 2 days; if applicable). 
 
b. 
The EDTA (purple top) vacutainer must be transported with a cold pack.  The 
vacutainer should be wrapped with absorbent material to prevent direct contact 
with the cold packs (which could result in freezing and lysis of the sample). 
 
1. 
Batch shipping is not allowed. Specimens must be transported the same 
day as specimen collection via overnight courier to  
 
Lab #200:  SWOG Specimen Repository – Leukemia Division 
Nationwide Children’s Hospital  
700 Children’s Drive, Room C1961 
Columbus, OH 43205 
Contact: Denise Ell 
Phone: 614/722-2866 
Email: mglab@nationwidechildrens.org 
 
 
c. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies.  
 
d. 
Batch shipping is not allowed. Specimens must be transported the same day as 
specimen collection via overnight courier. 
 
e. 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage.  
(https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures ) 
 
 
15.6 
General Specimen Submission Information 
 
a. 
In instances when a pre-treatment specimen must be submitted before the patient 
is consented to S1318, sites may consent patients to specimen submission only 
using local IRB approved specimen submission consent forms. For sites that do 
not have local specimen submission consents, a template has been included in 
Section 18.6. Please note that sites must obtain a SWOG patient ID from the 
SWOG Specimen Tracking System (STS) to be used on the specimen label. This 
patient ID will be used at the time of patient registration (see Section 13.1). 
 
b. 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked using the 
SWOG online Specimen Tracking system. SWOG members may log on the online 
system via the CRA Workbench. To access the CRA Workbench, go to the SWOG 
Web site (http://swog.org) and logon to the Members Area. After you have logged 
on using your SWOG roster ID number and password, click on the CRA 
Workbench link to access the home page for CRA Workbench website. First time 
non- 
SWOG 
users 
must 
refer 
to 
start-up 
instructions 
located 
at 
https://gill:crab.org/SpecTrack/. 
 
 

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A copy of the Shipment Packing List produced by the online Specimen Tracking 
system should be printed and placed in the pocket of the specimen bag if it has 
one, or in a separate resealable bag.  
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database errors or 
connectivity issues, please send an email to technicalquestion@crab.org. For 
procedural help with logging and shipping specimens, there is an introduction to 
the system on the Specimen Tracking main page 
(http://dnet.crab.org/SpecTrack/Documents/Instructions.pdf); 
or 
contact 
the 
SWOG Statistics and Data Management Center at 206/652-2267 to be routed to 
the Data Coordinator for further assistance. 
 
c. 
Federal guidelines for the shipment of blood products: 
 
1. 
The tube must be wrapped in an absorbent material. 
 
2. 
The tube must then be placed in an AIRTIGHT container (like a resealable 
bag). 
 
3. 
Pack the resealable bag and tube in a Styrofoam shipping container. 
 
4. 
Pack the Styrofoam shipping container in a cardboard box. 
 
5. 
Mark the box "Biohazard". 
 
15.7 
Cohort 2, Run-in Phase Only - Mandatory Conference Calls 
 
A mandatory conference call for study teams with active patients in Cycle 1 of post-
remission therapy will take place twice a month. The call will update participants on the 
current status of the Cohort 2 Run-In Phase portion of the trial and will include 
representatives from the study team, investigators from all participating institutions and 
representatives from Amgen. At this time any serious toxicities encountered will be 
discussed and appropriate action taken. In between these regularly scheduled conference 
calls, investigators will be informed of important study decisions via e-mail.  
 
Institutional participation on these calls requires the identification of an investigator contact 
and a CRA contact. Prior to registration of the first patient, each institution must 
provide the contact names, e-mail addresses, and phone numbers to the SWOG 
Operations Office. Institutions will be responsible for keeping this information up-
to-date and must notify the study Leukemia Protocol Coordinator (Cynthia 
Smithcsmith@swog.org) of any changes. The investigator and the contact CRA will 
receive e-mail reminders with the conference call information. 
 
The conference call schedule is as follows: 
 
• 
Second and Fourth Friday of each month at 1:00 p.m. ET (10:00 a.m. PT) 
 
PRIOR TO EACH SCHEDULED CONFERENCE CALL:  Study teams with active patients 
in Cycle 1 of post-remission therapy MUST provide an e-mail to the Protocol Coordinator 
in advance of the call providing the information below.  The compiled information will be 
distributed for use on the conference calls. 
 
• 
Patient’s SWOG ID 
• 
Patient’s current treatment status 

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• 
Toxicity information 
• 
Any other information the study team feels is relevant 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312. 
 
Publication and Industry Contact 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) 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 in this study: 
 
1. 
Agent(s) may not be used 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 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 written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 

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proposed combination protocol, and the existence of any obligations which 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 Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order as described in the IP 
Option to Collaborator 
(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. 
 
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 the Collaborator(s) for Phase III 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(s) will have 30 days from 
the date of receipt for review.  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 the 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: 
 
E-mail:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to the Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information. 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are due January 31, 
April 30, July 31 and October 31. 
Confidentiality 

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Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
16.1 
Adverse Event Reporting Requirements  
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well 
as those who will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial. (Directions for 
routine reporting are provided in Section 14.0.) Additionally, certain adverse events 
must be reported in an expedited manner to allow for more timely monitoring of 
patient safety and care. The following guidelines prescribe expedited adverse 
event reporting for this protocol. 
 
b. 
Reporting method 
 
This study requires that expedited adverse event reporting use the Cancer 
Therapy Evaluation Program Adverse Events 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 to the SWOG Operations Office 
electronically via the CTEP-AERS web-based application located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm. 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS.  
 
When the adverse event requires expedited reporting, submit the report within the 
number of calendar days of learning of the event, as specified in Table 16.1. 
 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to NCI by telephone at 301-897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection.   
 
Any supporting documentation should be submitted to CTEP per NCI guidelines 
for AE reporting located at:   
http://ctep.cancer.gov/protocolDvelopment/electronic_applications/docs/aeguideli
nes.pdf.  
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures. 
 
 

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e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent(s) as part of the trial. Reporting requirements are provided in 
Table 16.1. The investigational agents used in this study are blinatumomab and 
dasatinib.  If there is any question about the reportability of an adverse event or if 
on-line CTEP-AERS cannot be used, please telephone or email the SAE Specialist 
at the Operations Office, 210/614-8808 or adr@swog.org, before preparing the 
report. 
 
 

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Table 16.1: 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under a CTEP IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1 Blinatumomab or Dasatinib. 
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 or [Section 
16.1f.]   
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. 
1Serious 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 
 
May 5, 2011 
 
 
 

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f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Late Phase 2 and Phase 3 Studies Utilizing an Agent under 
a CTEP IND: 
 
1. 
Group-specific instructions 
 
Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements.  In 
addition, you may be asked to submit supporting clinical data to the 
Operations Offices in order to complete the evaluation of the event.  If 
requested, the supporting data should be sent within 5 calendar days 
by fax to 210-614-0006.  Supporting clinical data submitted should 
include: 
• 
Printed copy of the first page of the CTEP-AERS Report. 
• 
Copies of clinical sourced documentation of the event. 
• 
If applicable, and they have not yet been submitted to the 
SWOG Statistics and Data Management Center, copies of Off 
Treatment Notice and/or Notice of Death. 
 
2. 
The adverse events listed below also require expedited monitoring for this 
trial: 
• 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization, regardless of any exception 
indicated in the SPEER(s) for assigned agent(s). 
• 
Grade 3 adverse events, regardless of any exception indicated 
in the SPEER(s) for assigned agent(s). 
• 
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 outlined in Table 16.1. 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. 
 
g. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
 
CTEP requires all secondary malignancies that occur following treatment 
with an agent under an NCI IND to be reported via CTEP-AERS.  Three 
options are available to describe the event. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
 

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Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in 
each protocol.
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the initial 
malignancy). Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified.
For more information see:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf. 
2.
Any supporting documentation should be submitted to CTEP per NCI 
guidelines for AE reporting located at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf with instructions provided by the CTEP-AERS system.  
A copy of the report and the following supporting documentation must also 
be submitted to SWOG Operations Office within 30 days by fax to 
210/614-0006 or mail to the address below:
•
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis
•
(if available) a copy of the cytogenetics report  
SWOG
ATTN: SAE Program
4201 Medical Drive, Suite 250
San Antonio, Texas 78229
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial.
h.
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal
1.
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)”
under the Pregnancy, puerperium and perinatal 
conditions SOC.  
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report.
Pregnancy Loss Pregnancy loss is defined in CTCAE as “Death in utero.”
Pregnancy loss should be reported expeditiously as Grade 4 “Fetal
Loss at any gestational age” under the Pregnancy, puerperium and 
perinatal conditions SOC.  
A Pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-
AERS recognizes this event as a patient death.
3.
Death Neonatal Death neonatal is defined in CTCAE as “Newborn death 
occurring during the first 28 days after birth.” A neonatal death should be 

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reported expeditiously as Grade 4 “Neonatal loss of life” under the 
General disorders and administration SOC. 
 
Neonatal death should not be reported as a Grade 5 event under the 
General disorders and administration SOC as currently CTEP-AERS 
recognizes this event as a patient death. 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Death Neonatal”, the Pregnancy Information Form should also be completed 
and faxed with any additional medical information to 301-230-0159.  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. 
 
The Pregnancy Information Form is available at:  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm 
 
 
 
 

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17.0 
BIBLIOGRAPHY 
 
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Thomas DA, O’Brien S, Faderl S, et al. Anthracycline dose intensification in adult acute 
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Steinherz PG, Gaynon P, Miller DR et al.  Improved disease-free survival of children with acute 
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Larson RA, Dodge RK, Linker CA et al.  A Randomized Control Trial of Filgrastim During 
Remission Induction and Consolidation Chemotherapy for Adults with acute lymphoblastic 
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12  
Larson RA, Dodge RK, Linker CA et al.  A Randomized Control Trial of Filgrastim During 
Remission Induction and Consolidation Chemotherapy for Adults with acute lymphoblastic 
leukemia: CALGB study 9111.  Blood 92:1556-1564, 1998. 
 
13  
Stock W, Johnson JL, Stone RM et al.  Dose Intensification of Daunorubicin and Cytarabine During 
Treatment of Adult Acute Lymphoblastic Leukemia: results of Cancer and Leukemia Group B 
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Stock W, Johnson JL, Stone RM et al.  Dose Intensification of Daunorubicin and Cytarabine During 
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15  
Stock W, Johnson JL, Stone RM et al.  Dose Intensification of Daunorubicin and Cytarabine During 
Treatment of Adult Acute Lymphoblastic Leukemia: results of Cancer and Leukemia Group B 
Study 19802.  Cancer 119:90-8, 2013. 
 
16  
Sive, JI, Buck G, Fielding A et al.  Outcomes in older adults with lymphoblastic leukaemia (ALL): 
results from the international MRC UKALL XII/ECOG2993 trial.  Br J Haemat 157:463-71, 2012. 
 
17  
Sive, JI, Buck G, Fielding A et al.  Outcomes in older adults with lymphoblastic leukaemia (ALL): 
results from the international MRC UKALL XII/ECOG2993 trial.  Br J Haemat 157:463-71, 2012. 
 
18  
Sive, JI, Buck G, Fielding A et al.  Outcomes in older adults with lymphoblastic leukaemia (ALL): 
results from the international MRC UKALL XII/ECOG2993 trial.  Br J Haemat 157:463-71, 2012. 
 
19  
Sive, JI, Buck G, Fielding A et al.  Outcomes in older adults with lymphoblastic leukaemia (ALL): 
results from the international MRC UKALL XII/ECOG2993 trial.  Br J Haemat 157:463-71, 2012. 
 
20  
O’Brien, S, Thomas DA, Ravandi F et al.  Results of the Hyperfractionated Cyclophosphamide, 
Vincristine, Doxrubicin, and Dexamethasone Regimen in Elderly Patients with Acute Lymphocytic 
Leukemia.  Cancer 113:2097-2101, 2008. 
 
21  
O’Brien, S, Thomas DA, Ravandi F et al.  Results of the Hyperfractionated Cyclophosphamide, 
Vincristine, Doxrubicin, and Dexamethasone Regimen in Elderly Patients with Acute Lymphocytic 
Leukemia.  Cancer 113:2097-2101, 2008. 
 
22  
O’Brien, S, Thomas DA, Ravandi F et al.  Results of the Hyperfractionated Cyclophosphamide, 
Vincristine, Doxrubicin, and Dexamethasone Regimen in Elderly Patients with Acute Lymphocytic 
Leukemia.  Cancer 113:2097-2101, 2008. 
 
23  
Larsen RA, Stone, RM, Mayer RJ, et al.  Clin Cancer Res 12(11 Suppl), June 1, 2006. 
 
24  
O’Brien, S, Thomas DA, Ravandi F et al.  Results of the Hyperfractionated Cyclophosphamide, 
Vincristine, Doxrubicin, and Dexamethasone Regimen in Elderly Patients with Acute Lymphocytic 
Leukemia.  Cancer 113:2097-2101, 2008. 
 
25  
Sive, JI, Buck G, Fielding A et al.  Outcomes in older adults with lymphoblastic leukaemia (ALL): 
results from the international MRC UKALL XII/ECOG2993 trial.  Br J Haemat 157:463-71, 2012. 
 
26  
Thomas DA, Faderl S, O’Brien S, et al.  Chemoimmunotherapy with hyper-CVAD plus Rituximab 
for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia.  
Cancer 106:1569-1580, 2006. 
 
27  
Thomas DA, O’Brien S, Faderl S, et al.  Chemoimmunotherapy with a modified hyper-CVAD and 
Rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor 
B-lineage acute lymphoblastic leukemia. J Clin Oncol 28:3880-3889, 2010. 
 
28  
Advani AS, McDonough S, Coutre S, et al.  SWOG S0910: a phase 2 trial of 
clofarabine/cytarabine/epratuzumab for relapsed/refractory acute lymphocytic leukemia.  Br J 
Haematol 165(4):504-9. 2014. 
 
29  
Kantarjian H, Thomas D, Jorgensen J. et al.  Results of inotuzumab ozogamicin, a CD22 
monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia.  Cancer 119:2728-
36, 2013. 
 
30  
Topp MS, Kufer P, and Goekbuget N.  Targeted therapy with the T-cell-engaging antibody 
blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute 
 

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lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free 
survival.  J Clin Oncol 29:2493-2498, 2011. 
 
31  
Topp MS, Goekbuget N, Stein AS, et al.  Safety and activity of blinatumomab for adult patients 
with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicenter, single-arm, 
phase 2 study.  Lancet Oncol 16:57-66, 2015. 
 
32  
Faderl S, Jeha S. Kantarjian HM.  The biology and therapy of acute lymphoblastic leukemia.  
Cancer 98:1337-54, 2003. 
 
 
33  
Childhood ALL Collaborative Group.  Duration and intensity of maintenance chemotherapy in 
acute lymphoblastic leukemia: overview of 42 trials involving 12,000 randomized children.  Lancet 
347:1783-88, 1996 
 
34  
Vignetti M. et al.  Imatinib plus steroids induces complete remissions and prolonged survival in 
elderly Philadelphia Chromosome-positive patients with acute lymphoblastic leukemia without 
additional chemotherapy; results of the Gruppo Italiano Malattie Ematologiche dell Adulto 
(GIMEMA) LAL0201-B protocol.  Blood 109:3676-3678, 2007. 
 
35  
Foa R, Vitale A, Vignett M et al.  Dasatinib as first-line treatment for adult patients with Philadelphia 
chromosome-positive acute lymphoblastic leukemia.  Blood 118:6521-6528, 2011. 
 
36  
Steinherz PG, Gaynon P, Miller DR et al.  Improved disease-free survival of children with acute 
lymphoblastic leukemia at high-risk for early relapse with the New York regimen – A new intensive 
therapy protocol: A report from the Children’s Cancer Study Group. J Clin Oncol 4:744, 1986. 
 
37  
Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute 
lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG2993 study.  Blood 109(3):944-50, 2007. 
[PMID: 17032921]. 
 
38  
Topp MS, Goekbuget N., Zugmaier G et al.  Phase II trial of anti-CD19 bispecific Tcell-engager 
blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory 
B-precursor acute lymphoblastic leukemia.  J Clin Oncol 20 32(36):4134-40, 2014. 
 
39  
Topp MS, Goekbuget N, Stein AS, et al.  Safety and activity of blinatumomab for adult patients 
with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicenter, single-arm, 
phase 2 study.  Lancet Oncol 16:57-66, 2015. 
 
40  
 Assi R, Kantarjian H, Short N, et al. Safety and Efficacy of Blinatumomab in Combination with a  
Tyrosine Kinase Inhibitor for the Treatment of Relapsed Philadelphia Chromosome-positive 
Leukemia. Clinical Lymphoma, Myeloma & Leukemia 17: 897-901, 2017. 
 
41  
Reichelova V, Liliemark J, Albertioni F. Structure activity relationships of 2-chloro-2’-rabinofluoro-
2’deoxyadenosine and related analogues: protein binding, liphophilicity, and  retention in 
reversed-phase LC. J Liq Chromatograph 18(6):1123-35, 1995. 
 
42  
Cave H, et al. Clinical significance of minimal residual disease in childhood acute 
lymphoblasticleukemia. NEJM 339:591-598, 1998. 
 
43  
Brunning RD, Matutes E, Borowitz M, Flandrin G, Vardiman JW, Bennett J, Head D. Acute 
leukemias of ambiguous lineage. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health 
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44  
Brunning RD, Borowitz M, Matutes E, Head D, Flandrin G, Swerdlow SH, Bennett JM. Precursor 
B lymphoblastic leukaemia/lymphoblastic lymphoma. In: Jaffe ES, Harris NL, Stein H, Vardiman 
JW, eds. World Health Organization classification of tumours: pathology and genetics of tumours 
of the hematopoietic and lymphoid tissues. Lyon: IARC Press 111-114, 2001. 
 
45  
Brunning RD, Borowitz M, Matutes E, Head D, Flandrin G, Swerdlow SH, Bennett JM. Precursor 
T lymphoblastic leukaemia/lymphoblastic lymphoma. In: Jaffe ES, Harris NL, Stein H, Vardiman 
JW, eds. World Health Organization classification of tumours: pathology and genetics of tumours 
of the hematopoietic and lymphoid tissues. Lyon: IARC Press 115-117, 2001. 
 
 
 

 
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18.0 
APPENDIX 
 
18.1 
Intake Calendars 
 
18.2 
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4  
 
18.3 
Writing Test 
 
18.4 
Translational Medicine (MRD) 
 
18.5 
Categories of CNS and Steinherz/Bleyer Method of Evaluating Initial Traumatic Lumbar 
Punctures 
 
18.6 
Specimen Submission Consent  
 
18.7 
Clinical Site Management of Out-Patient Treatment Using CTEP-Supplied Blinatumomab 
 
18.8 
6-Mercaptopurine Dosing Guidelines 
 
18.9 
Blinatumomab Immunogenicity Assessment  
 
18.10 
Summary of Treatment Outcomes in Patients ≥ 60 Years with Acute Lymphoblastic 
Leukemia 
 
18.11 
Dasatinib Handout and Wallet Card 
 
18.12 
Medication Guide Blinatumomab 
 
18.13 
Shipment of Blinatumomab IV Bag from Site/Pharmacy to Patient's Home 
 
18.14 
Specimen Banking Instructions for the Specimen Repository – Leukemia Division (Lab 
#200) 
 
18.15 
Translational Medicine:  Ph-Like Signatures 
 
 

 
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18.1 
Intake Calendars - Dasatinib 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinician review at each visit – date and initials_____     _____     _____     _____     _____ 
 
SWOG Patient ID________  Patient Initials (L, F, M) ________ SWOG Study #__________ 
 
Institution/Affiliate _______________________  Physician _____________________________ 
Instructions for the participant: 
The chart below is a monthly intake calendar for dasatinib on which you are to record the 
number of dasatinib tablets you take each day.  Be sure you have enough calendars to 
last until your next appointment.  If you develop any side effects from the tablets, mark 
this on the calendar on the day you note the effect.  Bring your calendars with you each 
time you have an appointment. 
 
If you have questions contact: __________________ Telephone: __________________ 
Your next appointment is: ___________________ Date Dispensed:  _______________ 
• 
Dasatinib should be taken once daily 
• 
Your nurse or doctor will review your prescribed dose with you.   
• 
Record all doses or missed doses in this pill diary. 
• 
Tablets may be taken with or without food, but should be taken with a glass of water.  
They should be swallowed whole and not crushed or broken. 
• 
Tablets can be taken in the morning or evening but should be taken at approximately the 
same time each day. 
• 
If you miss a dose mark down as “0” and write the reason for missing your dose under the 
“comments” below. 
• 
If doses are missed because of side effects, they should not be made up.  If vomiting 
occurs within 30 minutes of taking a dose, that dose may be repeated. 
• 
You should skip doses that are missed by more than 12 hours. 
• 
Do not take any other medications 2 hours before or 2 hours after taking dasatinib. 
• 
Open only one bottle at a time when taking out your dose.  Do not transfer pills from one 
bottle to another. 
• 
Store bottles at room temperature and protect from light. 
• 
Bring your study pills and this diary to every clinic visit.  You will take dasatinib with a 
nurse (not at home) on the days you come in for appointments. 
• 
Do not throw away any study pill bottles.  Your doctor or nurse will collect them. 
• 
If you think you are having any side effects, feel sick, or have any other questions about 
your pills, please call your doctor/nurse at the number above. 
• 
Take your doses this cycle as your doctor has written them in the special instructions 
below. 
• 
Several drugs and supplements interact with dasatinib and need to be avoided while you 
are taking it.  Your doctor/nurse will give you a handout with complete information about 
what drugs and supplements to avoid that you should refer to while taking dasatinib. 
Special instructions: [Note to Investigators:  Please include instructions for when to take 
dose, as appropriate to each patient at each visit.] 

 
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DASATINIB INTAKE CALENDAR  
Date  
Was Dose 
Taken? 
At What Time? 
Total # of Pills Taken? 
 
__/ __/ __ 
Day 1 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 mg 
 
__/ __/ __ 
Day 2 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 mg 
 
__/ __/ __ 
Day 3 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 mg 
 
__/ __/ __ 
Day 4 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 mg 
 
__/ __/ __ 
Day 5 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 mg 
 
__/ __/ __ 
Day 6 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 mg 
 
__/ __/ __ 
Day 7 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 mg 
 
__/ __/ __ 
Day 8 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 mg 
 
__/ __/ __ 
Day 9 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 mg 
 
__/ __/ __ 
Day 10 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 mg 
 
__/ __/ __ 
Day 11 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 mg 
Comments: 
 
 
 
Clinician review at each visit – date and initials _____     _____     _____     _____     _____     _____     
 

 
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__/ __/ __ 
Day 12 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 13 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 14 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 15 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 16 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 17 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 18 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 19 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 20 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 21 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 22 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 23 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
Comments: 
 
 
 

 
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Clinician review at each visit – date and initials_____     _____     _____     _____     _____     _____      
 
__/ __/ __ 
Day 24 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 25 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 26 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 27 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
 
__/ __/ __ 
Day 28 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____50 mg   ____20 
mg 
Comments: 
 
 
 
 
 
Clinician review at each visit – date and initials 
_____     _____     _____     _____     _____     _____     _____     _____     _____     _____      
 
Pill bottle(s) returned?  Yes / No (circle one) 
 
# of pills returned (to be completed by RN or MD)   50mg _____     20mg_____ 
 
FINAL REVIEW AND COLLECTION 
 
 
Patient Signature:  ____________________________________  Date:  __/ __/ __ 
 
MD/RN Signature:  ____________________________________  Date:  __/ __/ __ 
 
 
[Note to investigators:  For cycles of dasatinib that are longer than 28 days, please distribute 
additional calendar pages with adjusted calendar days to be as patient-friendly as possible.  
Please ensure that patients understand the length of the cycle that they are to take.] 

 
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18.1 
Intake Calendars – 6-Mercaptopurine 
 
 
 
 
 
 
PREDNISONE INTAKE CALENDAR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinician review at each visit – date and initials 
_____     _____     _____     _____     _____     _____     _____     _____     _____     _____ 
 
 
 
 
 
 
 
 
Clinician review at each visit – date and initials_____     _____     _____     _____     _____    
Instructions for the participant: 
The chart below is a monthly intake calendar for 6-mercaptopurine on which you are to record the 
number of 6-mercaptopurine tablets you take each day.  Be sure you have enough calendars to 
last until your next appointment.  If you develop any side effects from the tablets, mark this on the 
calendar on the day you note the effect.  Bring your calendars with you each time you have an 
appointment. 
 
If you have questions contact: ____________________ Telephone: _____________________ 
Your next appointment is: _______________________  Date Dispensed:  ________________ 
• 
Doses should be taken without milk or citrus products. 
• 
Doses should be taken at least one hour after the evening meal. 
• 
Missed doses should be made up as soon as possible, unless your doctor advises you 
not to make up the dose. 
• 
Your nurse or doctor will review your prescribed dose with you.   
• 
Record all doses or missed doses in this pill diary. 
• 
Tablets can be taken in the morning or evening but should be taken at approximately the 
same time each day. 
• 
If you miss a dose mark down as “0” and write the reason for missing your dose under the 
“comments” below. 
• 
Open only one bottle at a time when taking out your dose.  Do not transfer pills from one 
bottle to another. 
• 
Store bottles at room temperature and protect from light. 
• 
Bring your study pills and this diary to every clinic visit.  If you have stopped therapy, bring 
all pill bottles and extra pills to your next clinic visit to be counted and then the study nurse 
or doctor will tell you when you can throw them away. 
• 
If you think you are having any side effects, feel sick, or have any other questions about 
your pills, please call your doctor/nurse at the number above. 
• 
Take your doses this cycle as your doctor has written them in the special instructions 
below. 
SWOG Patient ID________  Patient Initials (L, F, M) ________ SWOG Study #__________ 
Institution/Affiliate _______________________  Physician _____________________________ 
 
Special instructions: [Note to Investigators:  Please include instructions for when to take 
dose, as appropriate to each patient at each visit.] 

 
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6-MERCAPTOPURINE INTAKE CALENDAR  
 
Date  
Was Dose Taken? 
At What Time? 
Total # of Pills Taken? 
 
__/ __/ __ 
Day 1 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 2 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 3 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 4 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 5 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 6 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 7 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 8 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 9 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 10 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 11 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
Comments: 
 
 
 
 
Clinician review at each visit – date and initials_____     _____     _____     _____     _____     _____ 

 
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__/ __/ __ 
Day 12 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 13 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 14 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 15 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 16 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 17 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 18 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 19 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 20 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 21 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 22 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 23 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
Comments: 
 

 
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Clinician review at each visit – date and initials_____     _____     _____     _____     _____     _____      
 
 
__/ __/ __ 
Day 24 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 25 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 26 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 27 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
 
__/ __/ __ 
Day 28 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
____ whole pills   
____ half pills 
Comments: 
 
 
 
 
 
Clinician review at each visit – date and initials 
_____     _____     _____     _____     _____     _____     _____     _____     _____     _____      
 
Pill bottle(s) returned?  Yes / No (circle one) 
 
# of unused pills  to be discarded pills (to be completed by RN or MD)      50mg _____      
 
FINAL REVIEW AND COLLECTION 
 
 
Patient Signature:  ____________________________________  Date:  __/ __/ __ 
 
MD/RN Signature:  ____________________________________  Date:  __/ __/ __ 
 

 
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18.1 
Intake Calendars - Methotrexate 
 
 
 
 
 
PREDNISONE INTAKE CALENDAR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinician review at each visit – date and initials_____     _____     _____     _____     _____ 
Instructions for the participant: 
The chart below is a monthly intake calendar for methotrexate on which you are to record the 
number of methotrexate tablets you take each day.  Be sure you have enough calendars to last 
until your next appointment.  If you develop any side effects from the tablets, mark this on the 
calendar on the day you note the effect.  Bring your calendars with you each time you have an 
appointment. 
 
If you have questions contact: ____________________ Telephone: _____________________ 
Your next appointment is: _______________________  Date Dispensed:  ________________ 
• 
Your nurse or doctor will review your prescribed dose with you.   
• 
Record all doses or missed doses in this pill diary. 
• 
Tablets can be taken in the morning or evening but should be taken at approximately 
the same time each day. 
• 
If you miss a dose mark down as “0” and write the reason for missing your dose under 
the “comments” below. 
• 
Open only one bottle at a time when taking out your dose.  Do not transfer pills from one 
bottle to another. 
• 
Store bottles at room temperature and protect from light. 
• 
Bring your study pills and this diary to every clinic visit. If you have stopped therapy, 
bring all pill bottles and extra pills to your next clinic visit to be counted and then the 
study nurse or doctor will tell you when you can throw them away. 
• 
If you think you are having any side effects, feel sick, or have any other questions about 
your pills, please call your doctor/nurse at the number above. 
• 
Do not take NSAIDS, penicillins, proton pump inhibitors, or Bactrim on the same day as 
methotrexate.   
• 
Missed doses should be made up as soon as possible, unless your doctor advises you 
not to make up the dose. 
• 
Take your doses this cycle as your doctor has written them in the special instructions 
below. 
• 
Only take methotrexate on Days 1, 8, 15 and 22 of each cycle. 
• 
Even though you don’t take methotrexate every day of the cycle, please write down that 
you did not take drug on days methotrexate is not taken.  If you accidentally take 
methotrexate on a day it should not be taken, please write that down as well. 
Special instructions: [Note to Investigators:  Please include instructions for when to take 
dose, as appropriate to each patient at each visit.] 
SWOG Patient ID________  Patient Initials (L, F, M) ________ SWOG Study #__________ 
Institution/Affiliate _______________________  Physician _____________________________ 
 

 
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METHOTREXATE INTAKE CALENDAR – ORAL WEEKLY EVERY 28 DAYS 
Date  
Was Dose Taken? 
At What Time? 
Total # of Pills Taken? 
 
__/ __/ __ 
Day 1 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 2 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 3 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 4 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 5 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 6 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 7 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 8 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 9 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 10 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 11 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
Comments: 
 
 
 
 
Clinician review at each visit – date and initials_____     _____     _____     _____     _____     _____ 
 

 
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__/ __/ __ 
Day 12 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 13 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 14 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 15 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 16 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 17 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 18 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 19 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 20 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 21 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 22 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 23 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
Comments: 
 
 
Clinician review at each visit – date and initials_____     _____     _____     _____     _____     _____      
 
 

 
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__/ __/ __ 
Day 24 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 25 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 26 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 27 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 28 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
Comments: 
 
 
 
 
 
Clinician review at each visit – date and initials 
_____     _____     _____     _____     _____     _____     _____     _____     _____     _____      
 
Pill bottle(s) returned?  Yes / No (circle one) 
 
# of unused pills to be discarded  (to be completed by RN or MD)    2.5mg _____ 
 
FINAL REVIEW AND COLLECTION 
 
 
Patient Signature:  ____________________________________  Date:  __/ __/ __ 
 
MD/RN Signature:  ____________________________________  Date:  __/ __/ __ 
 

 
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18.1 
Intake Calendars – Prednisone 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinician review at each visit – date and initials_____     _____     _____     _____     _____ 
Special instructions: [Note to Investigators:  Please include instructions for when to take 
dose, as appropriate to each patient at each visit.} 
SWOG Patient ID________  Patient Initials (L, F, M) ________ SWOG Study #__________ 
Institution/Affiliate _______________________  Physician 
_____________________________ 
Instructions for the participant: 
The chart below is a monthly intake calendar for prednisone on which you are to record the 
number of prednisone tablets you take each day.  Be sure you have enough calendars to last 
until your next appointment.  If you develop any side effects from the tablets, mark this on the 
calendar on the day you note the effect.  Bring your calendars with you each time you have an 
appointment. 
 
If you have questions contact: ____________________ Telephone: _____________________ 
Your next appointment is: _______________________  Date Dispensed:  ________________ 
• 
Your nurse or doctor will review your prescribed dose with you.   
• 
Record all doses or missed doses in this pill diary. 
• 
Tablets can be taken in the morning or evening but should be taken at approximately 
the same time each day. 
• 
If you miss a dose mark down as “0” and write the reason for missing your dose under 
the “comments” below. 
• 
Open only one bottle at a time when taking out your dose.  Do not transfer pills from 
one bottle to another. 
• 
Store bottles at room temperature and protect from light. 
• 
Bring your study pills and this diary to every clinic visit. If you have stopped therapy, 
bring all pill bottles and extra pills to your next clinic visit to be counted and then the 
study nurse or doctor will tell you when you can throw them away. 
• 
If you think you are having any side effects, feel sick, or have any other questions 
about your pills, please call your doctor/nurse at the number above. 
• 
Missed doses should be made up as soon as possible, unless your doctor advises you 
not to make up the dose. 
• 
Even though you don’t take prednisone every day of the cycle, please write down that 
you did not take prednisone on days it is not taken.  If you accidentally take prednisone 
on a day it should not be taken, please write that down as well. 
• 
Take your doses this cycle as your doctor has written them in the special instructions 
below. 

 
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PREDNISONE INTAKE CALENDAR - ORAL 
Date  
Was Dose Taken? 
At What Time? 
Total # of Pills Taken? 
 
__/ __/ __ 
Day 1 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 2 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 3 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 4 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 5 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 6 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 7 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 8 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 9 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 10 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 11 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
Comments: 
 
 
 
 
Clinician review at each visit – date and initials_____     _____     _____     _____     _____     _____ 
 

 
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__/ __/ __ 
Day 12 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 13 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 14 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 15 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 16 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 17 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 18 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 19 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 20 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 21 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 22 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 23 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
Comments: 
 
 

 
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Clinician review at each visit – date and initials____ 
_     _____     _____     _____     _____     _____      
 
__/ __/ __ 
Day 24 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 25 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 26 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 27 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
 
__/ __/ __ 
Day 28 
 
□  Yes 
□  No 
 
____:____ AM / PM 
 
__________ 
Comments: 
 
 
 
 
 
Clinician review at each visit – date and initials 
_____     _____     _____     _____     _____     _____     _____     _____     _____     _____      
 
Pill bottle(s) returned?  Yes / No (circle one) 
 
# of unused pills to be discarded (to be completed by RN or MD)   
 
 50mg _____     20mg_____  10mg _____     5mg____   2.5mg _____     1mg____ 
 
FINAL REVIEW AND COLLECTION 
 
 
Patient Signature:  ____________________________________  Date:  __/ __/ __ 
 
MD/RN Signature:  ____________________________________  Date:  __/ __/ __ 
 
[Note to investigators:  For cycles of prednisone that are longer than 28 days, please distribute 
additional calendar pages with adjusted calendar days to be as patient-friendly as possible.  
Please ensure that patients understand the length of the cycle that they are to take.] 
 
 

 
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18.2  
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4  
 
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; medical 
reference texts such as the Physicians’ Desk Reference may also provide this information. 
 
CYP2D6 
Substrates 
Amitriptyline (hydroxylation) 
Amphetamine 
Betaxolol 
Bisoprolol 
Brofaromine 
Buturolol 
Bupropion 
Captopril 
Carvedilol 
Cevimeline 
Chlorpheniramine 
Chlorpromazine 
Cinnarizine 
 
Clomipramine (hydroxylation) 
Clozapine (minor pathway) 
Codeine (hydroxylation, O-demethylation) 
Cyclobenzaprine (hydroxylation) 
Cyclophosphamide 
Debrisoquin 
Delavirdine 
Desipramine 
Dexfenfluramine 
Dextromethorphan (O-demethylation) 
Dihydrocodeine 
Diphenhydramine 
Dolasetron 
Donepezil 
Doxepin 
Encainide 
Fenlluramine 
Flecainide 
Fluosetine (minor pathway) 
Fluphenazine 
Haiofantrine 
Haioperidol (minor pathway) 
Hydrocodone 
Hydrocortisone 
Hydroxyamphetamine 
lmipramine (hydroxylation) 
Labetalol 
Loratadine 
Maprotiline 
m-Chlorophenylpiperazine (m-CPP) 
Meperidine 
Methadone 
 
Methamphetamine 
Metoclopramide 
Metoprolol 
Mexitetine 
Mianserin 
Mirtazapine (hydroxylation) 
Molindone 
Morphine 
Nortriptyline (hydroxylation) 
Olanzapine (minor, hydroxymethylation) 
Ondansetron 
Orphenadrine 
Oxycodone 
Papaverine 
Paroxetine (minor pathway) 
Penbutolol 
Pentazocine 
Perhexiline 
Perphenazine 
Phenformin 
Pindolol 
Promethazine 
Propafenone 
Propranolol 
Quetiapine 
Remoxipride 
Risperidone 
Ritonavir (minor) 
Ropivacaine 
Selegiline 
Sertindole 
Sertratine (minor pathway) 
Sparteine 
Tamoxifen 
Thioridazine 
Tiagabine 
Timolol 
Tolterodine 
Tramadol 
Trazodone 
Trimipramine 
Tropisetron 
Venlafaxine (O-demethylation) 
Yohimbine 
 
 

 
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INHIBITORS 
Amiodarone 
Celecoxib 
Chloroquine 
Chlorpromazine 
Cimelidine 
Citalopram 
Clomipramine 
Codeine 
Deiavirdine 
Desipramine 
Dextropropoxyphene 
Diitiazem 
Doxorubicin 
Entacapone (high dose) 
Fluoxetine 
Fluphenazine 
Fluvoxamine 
Haloperidol 
Labetalol 
Lobeline 
Lomustine 
 
Methadone 
Mibefradil 
Moclobemide 
Nortluoxeline 
Paroxetine 
Perphenazine 
Propafenone 
Quinacrine 
Quinidine 
Ranitidine 
Risperidone (weak) 
Ritonavir 
Sertindole 
Sertraline (weak) 
Thioridazine 
Vaiprolc acid 
Venlafaxine (weak) 
Vinblastine 
Vincristine 
Vinorelbine 
Yohimbine 
 
CYP3A3/4 
SUBSTRATES 
Acetaminophen 
Aifentanil 
Alosetron 
Alprazolam 
Amiodarone 
Amitriptyline (minor) 
Amlodipine 
Anastrozole 
Androsterone 
Antipyrine 
Astemizole 
Atorvastatin 
Benzphetamine 
Bepridil 
Bexarotene 
Bromazepam 
Bromocriptine 
Budesonide 
Bupropion (minor) 
Buspirone 
Busutfan 
Caffeine 
Cannabinoids 
Carbamazepine 
Cevimeline 
Cerivastatin 
Digitoxin 
Diltiazem 
 
Chlorpromazine 
Cimetidine 
Cisapride 
Citałopram 
Clarithromycin 
Clindamycin 
Clomipramine 
Clonazepam 
Clozapine 
Cocaine 
Codeine (demethylation) 
Cortisol 
Cortisone 
Cyclobenzaprine (demethylation) 
Cyclophosphamide 
Cyclosporine 
Dapsone 
Dehydroepiandrostendione 
Delavirdine 
Desmethyldiazepam 
Dexamethasone 
Dextromethorphan (minor, N-
demethylation)  
Diazepam (minor; hydroxylation, N-
demethylation) 
Nefazodone 
Nelfinavir 
Nevirapine 
 

 
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CYP3A3/4 (contd.) 
Substrates 
Disopyramide 
Docetaxel 
Dolasetron 
Donepezil 
Doxorubicin 
Doxycycline 
Dronabinol 
Enalapril 
Erylhromycin 
Estradiol 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestene 
Dofetilide (minor) 
Felodipine 
Fentanyl 
Fexotenadine 
Finaxteride 
Fluoxetine 
Nicardipine 
Nifedipine 
Niludipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Omeprazole (sulfonation) 
Ondansetron 
Oral contraceptives 
Orphenadrine 
Paclitaxel 
Pantoprazole 
Pimozide 
Pioglitazone 
Pravastatin 
Prednisone 
Progesterone 
Proguanil 
Propafenone 
 
FLUTAMIDE 
Substrates 
Glyburide 
Granisetron 
Halofantrine 
Hydrocortixone 
Hydroxyarginine 
lfosfamide 
lmipramine 
lndinavir 
lsradipine 
ltraconazole 
Ketoconazole 
Lansoprazole (minor) 
Letrozole 
Levobupivicaine 
Lidocaine 
Loratadine 
Losartan 
Lovastatin 
Methadone 
Mibefradil 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine (N-demethylation) 
Montelukast 
Navelbine 
Toremifene 
Trazodone 
Tretinoin 
 
Quercetin 
Quetiapine 
Quinidine 
Quinine 
Repaglinide 
Retinoic acid 
Rifampin 
Risperidone 
Ritonavir 
Salmeterol 
Saquinavir 
Sertindole 
Sertraline 
Sibutramine 
Sildenafil citrate 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Temazepam 
Teniposide 
Terfenadine 
Testosterone 
Tetrahydrocannabinol 
Theophylline 
Tiagabine 
Tolterodine 
Vincristine 
 

 
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FLUTAMIDE  (contd.) 
Substrates 
Triazolam 
Troglitazone 
Troleandomycin 
Venlafaxine (N-demethylation) 
Verapamil 
Vinblastine 
 
Warfarin (R-warfarin) 
Yohimbine 
Zaleplon (minor pathway) 
Zatoestron 
Zileuton 
Ziprasidone 
Zolpidem 
Zonisamide 
INDUCERS 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampin 
Rofecoxib (mild) 
St John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
INHIBITORS 
Amiodarone 
Anastrozole 
Azithromycin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
lndinavir 
lsoniazid 
ltraconazole  
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Posaconozole 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Voriconazole 
Zafirlukast 
Zileuton 
 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In : Lacy CF, Armstrong LL, 
Goldman MP, Lance LL eds. Drug Information Handbook 8th ed. Hudson, OH; LexiComp Inc. 2000: 
1364-1371) 

 
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18.3 
Writing Test 
 
Patient ID_____________________________ 
 
Instructions for the Patient: 
 
Enter the date and time of test.  Rewrite the phrase listed. 
 
Study 
Day 
Date 
Time 
Sweet as apple pie 
Study Staff 
Initial and Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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18.4 
Translational Medicine (MRD) 
 
a. 
Objective:  To estimate the rate of minimal residual disease (MRD) negativity and 
the time to achieve MRD negativity. 
 
b. 
Background:  
 
Older patients with acute lymphoblastic leukemia (ALL) have a significantly worse 
outcome than their younger adult peers. Disease fundamental biological 
differences (mainly increased incidence of poor risk cytogenetics), together with 
coexisting medical disorders leading to decreased tolerance to chemotherapy are 
the main causes for low rates of disease free survival.  Complete remission rates 
in older adults with ALL are typically greater than 50%, but overall survival at 3 
years remains around 10%. (1) Additionally, despite being the adult sub-group with 
highest incidence of leukemia, older patients have been underrepresented in 
prospective clinical trials, and very few clinical trials have focused on therapies 
designed specifically for older patients. 
 
The prevalence of Philadelphia chromosome, a cytogenetic abnormality that 
strongly correlates with worse outcome, clearly increases with age, and its 
incidence peaks at over 50% in patients 55 or older. (2) Since the incorporation of 
tyrosine kinase inhibitors (TKIs) to frontline therapies CR rates achieved with 
chemotherapy alone have increased significantly in patients with Ph+ ALL, 
although improvements in long-term survival are still needed. However, no new 
drugs have made an improvement in the outcome of Ph-negative patients. 
 
Blinatumomab is a constructed monoclonal antibody that belongs to the family of 
T cell engaging bispecific antibodies (BiTE). It binds to CD19 and to the CD3 site 
of T cells activating the T cells to exert cytotoxic activity on the target cell. CD19 is 
an antigen expressed on the surface of essentially all B cells, in all stages of 
differentiation, so virtually all lymphoblasts in B-ALL will express CD19. Studies 
with Blinatumomab in minimal residual disease setting and relapsed/resistant ALL 
have demonstrated impressive results. (3,4) 
 
The mechanism of resistance in ALL is unknown. Recently, mutations in Ikaros, 
CRLF2, JAK1, JAK 2, Ras, and PAX5, and P2RY8-CRLF2 rearrangements, have 
been found in high-risk pediatric ALL. The gene expression profile in these high-
risk cases exhibit a “Ph-like” pattern. In addition, poor risk is associated with 
“cryptic” 
translocations 
involving 
kinases 
with 
immunoglobulin 
gene 
rearrangements. (5) 
 
 
c. 
Experimental Approach and Assays 
 
Flow cytometry detection of MRD.  This will be done in the SWOG CAP/ CLIA 
referral lab of Dr. Brent Wood at the University of Washington.  MRD will be 
assessed by standard methods employed in other COG and SWOG trials.  On the 
pre-treatment sample, the reference laboratory receives a specimen that is used 
to identify immunophenotypic abnormalities characteristic of the patient’s leukemia 
and 
confirms 
that 
the 
antibody 
combination is informative 
for 
MRD 
detection.  Two separate aliquots of the diagnostic sample are stained for 6-color 
flow cytometry using the following antibody combinations selected and optimized 
for their ability to detect MRD in B lineage ALL: CD20 FITC/ CD10 PE/ CD38 
PerCP-Cy5.5/ CD19 PE-Cy7/ CD58 APC/ CD45 APC-H7 and CD9 FITC/ 
CD13+CD33 PE/ CD34 PerCP-Cy5.5/ CD19 PE-Cy7/ CD10 APC/ CD45 APC- 
H7.  Given the use of an anti-CD19 directed therapy on this trial, one additional 

 
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aliquot of sample will be stained with a combination containing additional B cell 
antigens as follows:  CD10 BV421/ CD20 FITC/ CD22 PE/ CD34 PerCP-Cy5.5/ 
CD13/33 PE-Cy7/ CD38 A594/ CD24 APC/ CD45 APC-H7.  In cases in which 
the combination outlined above is not informative, additional markers may be 
employed in the panel.  
 
For the follow-up MRD analysis (see Section 15.3), aliquots of the marrow 
specimen are prepared using the same antibody panel and a minimum of 750,000 
cells acquired through the flow cytometer.  Clusters of events that are distinct 
from positions 
occupied 
by 
normal 
B 
cells 
are 
identified 
are 
dual-
parameter displays of antigenic intensity, using the diagnostic displays as a 
guide.  Clusters of events will allow the recognition of abnormal populations at 
a level of sensitivity of 0.01%; in practice, well-defined clusters can be recognized 
when they constitute as few as 15-20 cells, so that in many cases sensitivity is 
better than 0.01%.  In a separate tube, the fraction of nucleated cells that are B 
cells is determined by using the SYTO16 dye as a marker for nucleated cells, and 
results from the two tubes combined to define the percentage of MRD as a fraction 
of all nucleated cells. 
 
References:
 
1  
Stock W, Johnson J, Stone R, et al. Dose intensification of daunorubicin 
and cytarabine during treatment of acute lymphoblastic leukemia: results 
of Cancer and Leukemia Group B CALGB 19802. Cancer 2013; 119: 90-
8. 
 
2  
Topp M, Kufer P, Goekbuget N, et al. Targeted therapy with the T-cell 
engaging antibody Blinatumomab of chemotherapy-refractory minimal 
residual disease in B-lineage acute lymphoblastic leukemia patients 
results in high response rates and prolonged leukemia-free survival. 
Journal of Clinical Oncology 2011; 29:2043-8. 
 
3  
Topp M, Kufer P, Goekbuget N, et al. Targeted therapy with the T-cell 
engaging antibody Blinatumomab of chemotherapy-refractory minimal 
residual disease in B-lineage acute lymphoblastic leukemia patients 
results in high response rates and prolonged leukemia-free survival. 
Journal of Clinical Oncology 2011; 29:2043-8. 
 
4  
Topp M, Goekbuget N, Zugmaier G, et al. Effect of anti-CD19 BiTE 
blinatumomab on complete remission rate and overall survival in adult 
patients with relapsed/refractory B precursor ALL. Journal of Clinical 
Oncology 2012, Abstract 6500. 
 
5  
Roberts KG, Morin RD, Zhang J,  et al. Genetic alterations activating 
kinase and cytokine receptor signaling in high risk acute lymphoblastic 
leukemia. Cancer Cell 2012; 22(2) 153-66. 
 
 

 
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18.5 
Categories of CNS and Steinherz/Bleyer Method of Evaluating Initial Traumatic Lumbar 
Punctures 
 
Categories of CNS 
 
• 
CNS 1: CSF has < 5 WBC/mcL with cytospin negative for blasts; or > 10 RBC/mcL 
with cytospin negative for blasts.  
• 
CNS 2: CSF has < 5 WBC/mcL with cytospin positive for blasts; or > 10 RBC/mcL with 
cytospin positive for blasts; or ≥ 10 RBC/mcL, WBC/mcL ≥ 5, but less than 
Steinherz/Bleyer algorithm with cytospin positive for blasts (see below).  
• 
CNS 3: CSF has ≥ 5 WBC/mcL with cytospin positive for blasts; or ≥ 10 RBC/mcL, ≥ 5 
WBC/mcL and positive by Steinherz/Bleyeer algorithm (see below); or clinical signs of 
CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic 
syndrome).  
 
Steinherz/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/mcL 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/mcL 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/mcL; CSF 
RBC=1500/mcL; blood WBC=46,000/mcL; blood RBC=3 x 106/mcL:  
 
  60/mcL   = 0.04, and is >2x    46,000/mcL = 0.015  
1500/mcL  
 
           3x106/mcL 
 
 

 
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18.6 
Specimen Submission Consent 
 
*  
NOTES FOR LOCAL INVESTIGATORS: 
 
• 
This template specimen submission consent is provided as a tool to be used 
when specimens must be submitted prior to the patient being consented to the 
clinical trial if a local specimen submission consent is not available. This 
consent is not mandatory. Sites may use local specimen consent forms, modify 
specimen collection consents to include specimen submission information, or 
consent the patient to the clinical trial for the purpose of specimen submission, 
so long as specimen submission consent is obtained in some written and IRB 
approved form prior to specimen shipment. 
• 
This template has been reviewed by the DCTD/NCI. Local IRB changes to this 
document are allowed without prior approval from the SWOG Operations 
Office. It is suggested that sections of this document that are in bold type be 
used in their entirety. 
 
*  
These notes for investigators are instructional and should not be included in the 
informed consent form given to the prospective research participant. 

 
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Specimen Submission Consent 
 
What is the purpose of this consent form? 
 
You are going to have a bone marrow exam and blood tests to see if you have cancer. Your doctor will 
remove some body tissue to do some tests. The results of these tests will be given to you by your doctor 
and will be used to plan your care. 
 
If you do have cancer, one of your treatment options might be a clinical trial. A clinical trial is a type of 
research study. If your doctor thinks a clinical trial would be a good option for you, he or she will discuss 
everything that would be involved in taking part in the study, like what type of treatment you would get and 
what tests you will need to take part. 
 
Many clinical trials require that samples (specimens) of your bone marrow and blood be submitted before 
you start treatment. The specimens are used for testing that is needed as part of the clinical trial. 
 
The purpose of this consent form is to ask your permission to draw extra blood and bone marrow at the 
same time they are being taken for your diagnosis to send to a central laboratory, so that if you decide to 
take part in a clinical trial you will not have to have another bone marrow and blood draw. If you agree, you 
will have an extra 2 teaspoons of bone marrow and 1-2 tablespoons of blood taken. The extra marrow and 
blood can usually be taken through the same needle stick and do not require extra procedures. By taking 
the extra marrow and blood at the time of diagnosis, we hope to prevent the need for an extra marrow/blood 
draw if the clinical trial requires them.  
 
No tests will be done on any of your specimens without your permission. If you and your doctor do not feel 
that a clinical trial is your best option after getting your diagnosis, or if you decide not to take part in the 
clinical trial for any reason, your specimens will not be used for testing. 
If you and your doctor decide a clinical trial is your best option, and the trial requires specimens before you 
start treatment, you will be told about any tests that will be done with your specimens as part of the clinical 
trial consent. Your specimens will not be used unless you agree to take part in the clinical trial. 
 
By signing this consent form you are agreeing to allow extra bone marrow and blood to be drawn 
at the time specimens are being taken to get your diagnosis, and to allow these specimens to be 
sent to the central laboratory to be used as part of a clinical trial if you take part in one. You are not 
consenting to take part in a clinical trial or to have your specimens used for any other research. 
 
What are the risks? 
 
The bone marrow and blood draws are part of your regular cancer screening and care, so your 
doctor will discuss their risks with you. The risks that are part of collecting extra specimens are 
unlikely, but are: 
 
• 
Extra pain during the bone marrow draw 
• 
A second needle stick might be needed to get enough bone marrow or blood 
 
Your name and identifying information will not be sent with your specimens, so there is little risk of 
anyone getting your identifying information. Instead, your specimens will be labeled with a number 
that is assigned by the clinical trials registration system. Your identifying information will be linked 
to the number in a secure database to help make sure it cannot be accessed. 
 
Signature 
I have been given a copy of all 2 pages of this form. I have read it or it has been read to me. I understand 
the information and have had my questions answered. I agree to take part in this study. 
 
Participant _______________________________ 
 
Date _____________________________________ 

 
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18.7 
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 
 
• 
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. 
 
• 
For study subjects that cannot return to the registering/treating institution every 96-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. 
 
• 
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 2o to 8oC 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 2o to 8oC pre-qualified shipping container.  
 
• 
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 2o to 8oC pre-qualified shipping container to the servicing home health care 
agency. 
 
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. 
 

 
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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 2o to 8oC pre-qualified shipping container. 
 
• 
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 2o to 8oC 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 2o to 8oC 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 2o to 8oC 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 2o to 8oC 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 SWOG Operations office at (210/614-8808) to report such 
occurrences. 
SWOG 
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 2o to 8oC 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. 
 
 

 
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e. 
Home health care service staff is to use GCP guidelines. 
 
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/or 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.  
 
• 
For home health care agency services, the ability to transport each prepared dose individually 
to the subject’s home under appropriate controlled storage conditions or the ability to assess 
and confirm that cold-chain management of prepared infusion bags shipped to the subject’s 
home is maintained prior to administration. 
 
• 
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 in place. 
 
• 
Plan for return of unused intact vials to the registering/treating institution is in place. 
 
• 
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). 
 
 

 
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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 and train local outpatient 
infusion centers or home health care agency for patient treatment if required and document 
training of such sites 
 
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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18.8 
6-Mercaptopurine Dosing Guidelines 
 
6-mercaptopurine 60 mg/m2/day continuously for 28 days (cumulative weekly dose 
approximately 420 mg/m2) (1 tablet = 50 mg) 
 
Body 
Surface Area 
(m2) 
Cumulative  
Weekly Dose 
Daily Dose for per Week* 
1.26 - 1.30 
550 mg 
1 ½ tablets/day for 6 days; 2 tablets for 1 day 
1.31 - 1.36 
575 mg 
2 tablets/day for 2 days; 1½  tablets/day for 5 
days 
1.37 - 1.43 
600 mg 
2 tablets/day for 3 days; 1 ½  tablets/day for 4 
days 
1.44 - 1.49 
625 mg 
2 tablets/day for 4 days; 1 ½  tablets/day for 3 
days  
1.50 - 1.55 
650 mg 
2 tablets/day for 5 days; 1 ½ tablets/day for 2 
days 
1.56 - 1.61 
675 mg 
2 tablets/day for 6 days; 1 ½  tablets/day for 1 day  
1.62 - 1.67 
700 mg 
2 tablets/day for 7 days 
1.68 - 1.73 
725 mg 
2 tablets/day for 6 days; 2 ½  tablets/day for 1 day 
1.74 - 1.79 
750 mg 
2 ½  tablets/day for 2 days; 2 tablets/day for 5 
days  
1.80 - 1.85 
775 mg 
2 ½  tablets/day for 3 days; 2 tablets/day for 4 
days 
1.86 - 1.91 
800 mg 
2 ½  tablets/day for 4 days; 2 tablets/day for 3 
days 
1.92 - 1.97 
825 mg 
2 ½  tablets/day for 5 days; 2 tablets/day for 2 
days 
1.98 - 2.03 
850 mg 
2 ½  tablets/day for 6 days; 2 tablets/day for 1 day  
 
*  The daily dose per week refers to 7-day cycles within the continued 28 day daily 
administration cycle (see Section 7.2c).  Doses should be taken in the evening, at least 
one hour after the evening meal. 
 

 
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18.9 
Blinatumomab Immunogenicity Assessment  
 
Blinatumomab is a novel protein therapeutic under clinical development by Amgen, Inc. As 
outlined in the Draft Guidance: Immunogenicity Assessment for Therapeutic Protein 
Products (Feb 2013) pre-specified immunogenicity sampling will be performed as part of 
Amgen’s initiative to evaluate and mitigate risk 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/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 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. 
 
SWOG 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 year (± 4 weeks) post administration of 
blinatumomab. All follow-up results, both positive and negative will be communicated to 
SWOG. 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. 

 
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18.10 
Summary of Treatment Outcomes in Patients ≥ 60 Years with Acute Lymphoblastic 
Leukemia 
 
Reference 
 
N 
N ≥ 60 
years of 
age 
 
CR  
 
 
TRM 
 
 
OS  
 
Larson (CALGB 8811)4,b 
197 
18 
39% 
50% 
17% (3 yr estimated) 
 
Larson (CALGB 9111)5,b 
198 
41 
77% 
25% 
17% (3 yr estimated) 
 
Stock (CALGB 19802)9,b 
163 
33 
61% 
21% 
6% (5 yr estimated) 
 
Sive (MRC UKALL 
XII/ECOG 2993)10,a,b 
1914 
100 
73% 
18% 
21% (5 yr estimated) 
 
O’Brien (MDACC)11,c,d 
531 
122 
84% 
10% 
20% (5 yr estimated) 
 
Thomas (Edouard Herriot 
Hospital)23,d 
378 
69 
62% 
24% 
10% (3 yr estimated) 
 
Martell (Princess Margaret 
Hospital)24,c,d 
51 
51 
75% 
20% 
40% (5 yr estimated) 
 
Taylor (Royal Victoria 
Infirmary)25, a,e 
157 
49  
67% 
16% 
4% (5 yr actuarial) 
 
Gokbuget (GMALL)26,b 
268 
268 
76% 
14% 
23% (5 yr estimated) 
Delannoy  (Hopital de 
Jolimont, Belgium)27,a,d 
18 
18 
44% 
28% 
3 months (median 
OS)  
 
Ferrari (University La 
Sapienza)28,d 
49 
N/A 
59% 
23% 
9 months (median 
OS) 
Bassan (Ospedali Riuniti, 
Bergamo Italy)29,b 
22 
22 
59% 
18% 
23% (estimated at 2.6 
years) 
 
Offidani (GIMEMA 0288)30,b 
 
 
17 
 
17 
 
41% 
 
35% 
 
12% (3 yr estimated) 
 
 
 

 
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Reference 
 
N 
N ≥ 60 years 
of age 
 
CR  
 
 
TRM 
 
 
OS  
 
Offidani (GIMEMA VDXD)30,b 
 
17 
 
17 
 
76.5
% 
 
17.5% 
 
23% (3 yr estimated) 
LeGrand (Hopital Hotel-
Dieu, Paris France)31,c 
 
148 
 
46 
 
43% 
 
18% 
 
7.6% (5 yr estimated) 
Pagano (Universita Cattolica 
del Sacro Cuore, Rome, 
Italy)32,c,d 
 
119 
 
37 
 
67% 
 
24% 
 
8% (7 yr estimated) 
Nagura (Chubu National 
Hospital, Nagoya Japan)33,c 
 
20 
 
20 
 
55% 
 
Unknow
n 
 
10% (2 yr estimated) 
 
Robak (PALG)34,c 
 
87 
 
87 
 
45% 
 
15% 
 
2.4 months (median 
OS) 
Spath-Schwalbe (University 
of Ulm, Germany)35c,d 
 
29 
 
29 
 
43% 
 
37.5% 
 
3% (actuarial) 
 
Delannoy (LALAG97)36,b 
 
58 
 
58 
 
58% 
 
12% 
 
<10% (3 yr 
estimated) 
 
Hunault-Berger (GRAALL-
SA1)37, a,b 
 
60 
 
60 
 
82% 
 
8% 
 
29% (2 yr estimated) 
Moorman (Northern England 
United Kingdom)38,e 
 
349 
 
124 
 
N/A 
 
N/A 
 
12% (5 yr estimated) 
Juliusson (Swedish Acute 
Leukemia Registry)39,e 
 
464 
 
217 
 
N/A 
 
N/A 
5 yr OS by decade: 
5% for 75-84 yrs 
15% for 65-74 yrs 
30% for 55-64 yrs 
 
Toft (Danish Cancer 
Registry)40,e 
 
277 
 
65 (>65 
years) 
 
40% 
 
N/A 
 
6.5% (4 yr estimated) 
N = number of patients; CR = complete remission; TRM = treatment related mortality; OS 
= overall survival 
a reference 10, 25, 27, and 37 included patients aged 55 and older 
bprospective studies for older patients with ALL treated with intensive chemotherapy 
c retrospective analysis of older patients with ALL treated with intensive chemotherapy 
dsingle institution data 
e population-based studies  
 
References 
 
1.  
National Cancer Institute.  SEER Stat Fact Sheet: Acute Lymphocytic Leukemia, Bethesda: 2012.  
Available at http://seer.cancer.gov/statfacts/html/alyl.html. 

 
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2.  
Stock W, personal communication. Data from 5 CALGB trials 1988-2001. 
 
3.  
Larson RA.  The US trials in adult acute lymphoblastic leukemia. Ann Hematol. 2004;83 (suppl 
I):S127-S128. 
 
4.  
Larson RA, Dodge RK, Burns CP et al.  A Five-Drug Remission Induction Regimen with Intensive 
Consolidation for adults with acute lymphoblastic leukemia:  Cancer and Leukemia Group B Study 
8811.  Blood 1995:85:2025-2037.  
 
5.  
Larson RA, Dodge RK, Linker CA et al.  A Randomized Control Trial of Filgrastim During Remission 
Induction and Consolidation Chemotherapy for Adults with acute lymphoblastic leukemia: CALGB 
study 9111.  Blood 1998;92:1556-1564. 
 
6.  
Bassan R, Pogliani E, Casula P et al.  Risk-oriented postremission strategies in adult acute 
lymphoblastic leukemia: prospective confirmation of anthracycline activity in standard-risk groups.  
Hematol J. 2001 2:117-126. 
 
7.  
Todeschini G, Tecchio C, Meneghini V et al.  Estimated 6-year event-free survival of 55% in 60 
consecutive adult acute lymphoblastic leukemia patients treated with an intensive phase II protocol 
based on high induction dose of daunorubicin.  Leukemia 1998 12:144-49. 
 
8.  
Thomas DA, O’Brien S, Faderl S, et al. Anthracycline dose intensification in adult acute 
lymphoblastic leukemia: lack of benefit in the context of the fractionated cyclophosphamide, 
vincristine, doxorubicin, and dexamethasone regimen.  Cancer. 2010 116:4580-4589. 
 
9.  
Stock W, Johnson JL, Stone RM et al.  Dose Intensification of Daunorubicin and Cytarabine During 
Treatment of Adult Acute Lymphoblastic Leukemia: results of Cancer and Leukemia Group B Study 
19802.  Cancer 2013;119:90-8. 
 
10.  
Sive, JI, Buck G, Fielding A et al.  Outcomes in older adults with lymphoblastic leukaemia (ALL): 
results from the international MRC UKALL XII/ECOG2993 trial.  Br J Haemat 2012;157:463-71. 
 
11.  
O’Brien, S, Thomas DA, Ravandi F et al.  Results of the Hyperfractionated Cyclophosphamide, 
Vincristine, Doxrubicin, and Dexamethasone Regimen in Elderly Patients with Acute Lymphocytic 
Leukemia.  Cancer 2008;113:2097-2101. 
 
12.  
Thomas DA, Faderl S, O’Brien S, et al.  Chemoimmunotherapy with hyper-CVAD plus Rituximab 
for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia.  
Cancer 2006;106:1569-1580 
 
13.  
Thomas DA, O’Brien S, Faderl S, et al.  Chemoimmunotherapy with a modified hyper-CVAD and 
Rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-
lineage acute lymphoblastic leukemia. J Clin Oncol 2010;28:3880-3889. 
 
14.  
Advani AS, McDonough S, Coutre S, et al.  SWOG S0910: a phase 2 trial of 
clofarabine/cytarabine/epratuzumab for relapsed/refractory acute lymphocytic leukemia.  Br J 
Haematol. 2014 May;165(4):504-9. 
 
15.  
Kantarjian H, Thomas D, Jorgensen J. et al.  Results of inotuzumab ozogamicin, a CD22 
monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia.  Cancer 
2013;119:2728-36. 
 
16.  
Topp MS, Kufer P, and Goekbuget N.  Targeted therapy with the T-cell-engaging antibody 
blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute 

 
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lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival.  
J Clin Oncol 2011; 29:2493-2498. 
. 
17.  
Topp MS, Goekbuget N., Zugmaier G et al.  Effect of anti-CD19 BITE blinatumomab on complete 
remission rate and overall survival in adult patients with relapsed/refractory B precursor ALL.  J 
Clin Oncol 2012; Abstract 6500. 
 
18.  
Faderl S, Jeha S. Kantarjian HM.  The biology and therapy of acute lymphoblastic leukemia.  
Cancer 2003; 98:1337-54. 
 
19.   
Childhood ALL Collaborative Group.  Duration and intensity of maintenance chemotherapy in acute 
lymphoblastic leukemia: overview of 42 trials involving 12,000 randomized children.  Lancet 
1996;347:1783-88.  
 
20. 
Vignetti M. et al.  Imatinib plus steroids induces complete remissions and prolonged survival in 
elderly Philadelphia Chromosome-positive patients with acute lymphoblastic leukemia without 
additional chemotherapy; results of the Gruppo Italiano Malattie Ematologiche dell Adulto 
(GIMEMA) LAL0201-B protocol.  Blood 2007; 109:3676-3678. 
 
21.  
Foa R, Vitale A, Vignett M et al.  Dasatinib as first-line treatment for adult patients with Philadelphia 
chromosome-positive acute lymphoblastic leukemia.  Blood 2011; 118:6521-6528. 
 
22.  
Steinherz PG, Gaynon P, Miller DR et al.  Improved disease-free survival of children with acute 
lymphoblastic leukemia at high-risk for early relapse with the New York regimen – A new intensive 
therapy protocol: A report from the Children’s Cancer Study Group. J Clin Oncol 1986;4:744. 
 
23.  
Thomas X, Olteanu N, Charrin C et al.  Acute Lymphoblastic Leukemia in the Elderly: The Edouard 
Herriot Hospital Experience.  Am J Hematol 2001;67:73-83. 
 
24.  
Martell MP, Atenafu EG, Minden MD et al.  Treatment of elderly patients with acute lymphoblastic 
leukemia using a paediatric-based protocol.  Br J Haematol 2013;163:458-464. 
 
25.  
Taylor PRA, Reid MM, Bown TJ et al.  Acute lymphoblastic leukemia in patients aged 60 years and 
over:  A population-based study of incidence and outcome.  Blood 1992;80:1813-1817. 
 
26.  
Goekbuget N, Beck J, Brueggemann M et al.  Moderate intensive chemotherapy including CNS-
prophylaxis with liposomal cytarabine is feasible and effective in older patients with Ph-negative 
acute lymphoblastic leukemia (ALL): Results of a prospective trial from the German multicenter 
study group for adult ALL (GMALL) [abstract].  Blood 2012;120:Abstract 1493.  
 
27.  
Delannoy A, Ferrant A, Bosly A et al.  Acute lymphoblastic leukemia in the elderly.  Eur J Haematol 
1990;45:90-93. 
 
28.  
Ferrari A, Annino L, Crescenzi S et al.  Acute lymphoblastic leukemia in the elderly: results of two 
different treatment approaches in 49 patients during a 25-year period.  Leukemia 1995;9:1643-
1647. 
 
29.   
Bassan R, Bona ED, Lerede T et al.  Age-adapted moderate-dose induction and flexible outpatient 
postremission therapy for elderly patients with acute lymphoblastic leukemia.  Leuk Lymphoma 
1996;22:295-301.  
 
30.  
Offidani M, Corvatta L, Malerba L et al.  Comparison of two regimens for the treatment of elderly 
patients with acute lymphoblastic leukaemia (ALL).  Leuk Lymphoma 2005;46:233-238. 
 
31.  
Legrand O, Marie JP, Marjanovic Z et al.  Prognostic factors in elderly acute lymphoblastic 
leukaemia.  British Journal of Haematology 1997;97:596-602. 

 
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32.  
Pagano L, Mele L, Casorelli I et al.  Acute lymphoblastic leukemia in the elderly.  A twelve-year 
retrospective, single center study.  Haematologica 2000;85:1327-1328. 
 
33.  
Nagura E, Minami S, Nagata K et al.  Analysis of elderly patients, aged 60 years old or over, with 
acute lymphoblastic leukemia.  Nihon Ronen Iqakkai Zasshi 1999;36:52-58. 
 
34.  
Robak T, Szmigielska-Kaplan A, Wrzesien-Kus A et al.  Acute lymphoblastic leukemia in elderly: 
the Polish Adult Leukemia Group (PALG) experience. Ann Hematol 2004;83:225-231. 
 
35.  
Spath-Schwalbe E, Heil G, Heimpel H.  Acute lymphoblastic leukemia in patients over 59 years of 
age.  Experience in a single center over a 10-year period.  Ann Hematol 1994;69:291-296. 
 
36.  
Delannoy A, Cazin B, Thomas X et al.  Treatment of acute lymphoblastic leukemia in the elderly: 
an evaluation of interferon alpha given as a single agent after complete remission. Leuk Lymphoma 
2002;43:75-81. 
 
37.  
Hunault-Berger M, Leguay T, Thomas X et al.  A randomized study of pegylated liposomal 
doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic 
leukemia: the GRAALL-SA1 study. Haematologica 2011;96:245-252. 
 
38.   
Moorman AV, Chilton L, Wilkinson J et al.  A population-based cytogenetic study of adults with 
acute lymphoblastic leukemia.  Blood 2010;115:206-214. 
 
39.  
Juliusson G, Karlsson K, Hallbook H.  Population-based analysis in adult acute lymphoblastic 
leukemia.  Blood 2010;116:1011. 
 
40.   
Toft N, Schmiegelow K, Klausen TW et al.  Adult acute lymphoblastic leukaemia in Denmark.  A 
national population-based retrospective study of acute lymphoblastic leukaemia in Denmark 1998-
2008.  Br J Haematol 2012;157:97-104. 
 

 
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18.11 
Dasatinib Handout and Wallet Card 
 
SWOG Protocol#: S1318  
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team  
 
[Note to investigators: This appendix consists of an “information sheet” to be handed to the patient 
at the time of enrollment. Use or modify the text as appropriate for the study agent, so that the 
patient is aware of the risks and can communicate with their regular prescriber(s) and pharmacist. 
A convenient wallet-sized information card is also included for the patient to clip out and retain at 
all times.]  
 
The patient ____________________________ is enrolled on a clinical trial S1318 using the 
experimental agent Dasatinib. This clinical trial S1318 is sponsored by SWOG. This form is 
addressed to the patient, but includes important information for others who care for this patient.  
 
Dasatinib interacts with many drugs that are processed by your liver. Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study. It is also 
very important to tell them if you stop taking any regular medicine, or if you start taking a new 
medicine while you take part in this study. When you talk about your medicine with your study 
doctor, include medicine you buy without a prescription at the drug store (over-the-counter remedy), 
or herbal supplements.  
 
Many health care prescribers can write prescriptions. You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet. These are 
the things that you and they need to know:  
 
Dasatinib interacts with a certain specific enzyme in your liver.  
• 
The enzyme in question is CYP3A4. Dasatinib is broken down by this enzyme in order to be 
cleared from your system. The dose of this drug that you are taking assumes that these 
enzymes are working normally.  
• 
Certain drugs may reduce the activity of CYP3A4, which can increase the amount of active 
drug in your system. This increases your chances of experiencing harmful side effects. Other 
drugs might increase the activity of CYP3A4, reducing the level of active drug in your system 
and making it less effective.  
• 
Dasatinib must be used very carefully with such drugs; it is therefore vitally important that you 
provide your study doctor with a complete list of your medications. Before you begin the study, 
your study doctor will work with your regular prescriber to switch any medicines that are 
considered inducers or strong inhibitors of CYP3A4, drugs that are generally accepted to have 
a risk of causing Torsades de Pointes, medications that inhibit platelet function, and  antacids, 
proton pump inhibitors or H2 antagonists. Once the study begins, you and your healthcare 
providers must be very careful about adding or removing any drugs in this category. Your 
prescribers 
should 
look 
at 
the 
following 
web 
sites 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
or your study doctor to see if any medicine they want to prescribe is on a list of drugs to avoid. 
Please be very careful! Over-the-counter drugs have a brand name on the label—it’s usually 
big and catches your eye. They also have a generic name—it’s usually small and located above 
or below the brand name, and printed in the ingredient list. Find the generic name and 
determine, with the pharmacist’s help, whether there could be an adverse interaction. 

 
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Be careful:  
• 
If you take acetaminophen regularly: You should not take more than 12 regular strength (or 8 
extra-strength) tablets a day if you are an adult or 7 regular strength (or 4 extra-strength) tablets 
a day if you are older than 65 years of age.  If you have questions about the correct dose please 
ask your study doctor. Read labels carefully! Acetaminophen is an ingredient in many 
medicines for pain, flu, and cold.  
• 
If you drink grapefruit juice or eat grapefruit: Avoid these until the study is over.  
• 
If you take herbal medicine regularly: You should not take St. John’s wort while you are taking 
Dasatinib. 
Be careful:  
Other medicines can be a problem with your study drug.  
• 
You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement.  
 
• 
Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you. Your study doctor’s name is  
 
_____________________________________  
 
and he or she can be contacted at ________________________________ 
 
INFORMATION ON POSSIBLE DRUG 
INTERACTIONS  
You are enrolled on a clinical trial S1318 using 
the experimental agent Dasatinib. This clinical 
trial is sponsored by SWOG.  
Dasatinib interacts with drugs that are processed 
by your liver. Because of this, it is very important 
to:  
Tell your doctors if you stop taking regular 
medicine or if you start taking a new medicine.  
Tell all of your prescribers (doctor, physicians’ 
assistant, nurse practitioner, pharmacist) that you 
are taking part in a clinical trial.  
Check with your doctor or pharmacist 
whenever you need to use an over-the-counter 
medicine or herbal supplement.  
 
Dasatinib interacts with a specific liver enzyme 
called CYP3A4, and must be used very carefully 
with other medicines that interact with this enzyme.  
Before you start the study, your study doctor will 
work with your regular prescriber to switch any 
medicines that are considered “potent or moderate 
inhibitors or inducers of CYP3A4, sensitive 
CYP3A4 substrates, and CYP3A4 substrates with 
a narrow therapeutic window”.  
Before prescribing new medicines, your regular 
prescribers should go to 
http://medicine.iupui.edu/clinpharm/ddis/main-
table/ for a list of drugs to avoid, or contact your 
study doctor.  
 
Your study doctor’s name is 
_____________________________ and  
 
can be contacted at 
_________________________________.  
 
 

 
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18.12 
Medication Guide Blinatumomab  
 
MEDICATION GUIDE BLINATUMOMAB FOR INJECTION 
 
Read this Medication Guide before you receive BLINATUMOMAB and before each BLINATUMOMAB 
infusion. There may be new information. This information does not take the place of talking with your 
study doctor about your medical condition or treatment. 
 
WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT BLINATUMOMAB? 
 
Call your study doctor or get emergency medical help right away if you get any of the symptoms 
listed below. 
 
BLINATUMOMAB may cause serious side effects that can be severe, life- threatening, or lead to 
death, including: 
 
• 
Cytokine Release Syndrome (CRS) and Infusion Reactions. Symptoms of CRS and infusion 
reactions may include: 
 
• 
fever 
• 
tiredness or weakness 
• 
dizziness 
• 
headache 
• 
low blood pressure 
• 
nausea 
• 
vomiting 
• 
chills 
• 
face swelling 
• 
wheezing or trouble breathing 
• 
skin rash 
• 
Neurologic problems. Symptoms of neurologic problems may include: 
• 
seizures 
• 
difficulty in speaking or slurred speech 
• 
loss of consciousness 
• 
confusion and disorientation 
• 
loss of balance 
 
Your study doctor will check you for these problems during treatment with BLINATUMOMAB. Your study 
doctor may temporarily stop or completely stop your treatment with BLINATUMOMAB, if you have severe 
side effects. 
 
See “What are the possible side effects of BLINATUMOMAB?” below for other side effects of 
BLINATUMOMAB. 
 
WHAT IS BLINATUMOMAB? 
 
BLINATUMOMAB is a prescription medicine used to treat a certain type of acute lymphoblastic leukemia 
(ALL). Acute lymphoblastic leukemia is a cancer of the blood in which a particular kind of white blood cell 
is growing out of control. 
 
WHO SHOULD NOT RECEIVE BLINATUMOMAB? 
 
Do not receive BLINATUMOMAB if you are allergic to blinatumomab or to any of the ingredients of 
BLINATUMOMAB. 
See the end of this Medication Guide for a complete list of ingredients in 
BLINATUMOMAB. 
 
WHAT SHOULD I TELL MY STUDY DOCTOR BEFORE RECEIVING BLINATUMOMAB? 
 
Before you receive BLINATUMOMAB, tell your study doctor about all of your medical conditions, 
including if you: 

 
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• 
have a history of neurological problems, such as seizures, confusion, trouble speaking or loss of 
balance. 
• 
have an infection. 
• 
have ever had an infusion reaction after receiving BLINATUMOMAB or other medications. 
 
Tell your study doctor about all the medicines you take, including prescription and over-the-counter 
medicines, vitamins, and herbal supplements. 
 
Know the medicines you take. Keep a list of your medicines with you and show it to your study doctor 
when you get a new medicine. 
 
HOW WILL I RECEIVE BLINATUMOMAB? 
 
• 
BLINATUMOMAB will be given to you by intravenous (IV) infusion into your vein by an infusion pump. 
 
• 
If you are in the Ph-negative (Ph-) study group, then: 
▪ 
Induction: You will receive BLINATUMOMAB by continuous IV infusion for 4 weeks (28 days), 
followed by a 2-week break during which you will not be given BLINATUMOMAB. This is one 
treatment cycle, and this first cycle is considered the “Induction” cycle.  
▪ 
Re-Induction: After the 2-week break, your study doctor will conduct a bone marrow exam to 
see if your leukemia is gone. If it is not gone, you will receive another “Re-Induction” cycle 
(continuous IV infusion for 4 weeks, followed by a 2-week break), and then you will have 
another bone marrow exam.   
▪ 
Post-Remission: If the leukemia goes away after either the Induction cycle or the Re-Induction 
cycle, then you will receive 3 more cycles of blinatumomab as “Post-Remission” treatment.  
 
• 
If you are in the Ph-positive (Ph+) or Ph-like  mutation study group, then: 
▪ 
If you have newly diagnosed ALL or if you have relapsed/refractory ALL and have not 
previously received dasatinib or another tyrosine kinase inhibitor (medication similar to 
blinatumomab), then you will start protocol treatment with Induction therapy (below) and then 
(if your leukemia is not gone) receive Re-Induction therapy (below), and (if your leukemia is 
gone) receive Post-Remission therapy (below). 
▪ 
If you have relapsed/refractory ALL and have previously received dasatinib or another 
tyrosine kinase inhibitor (medication similar to blinatumomab), then you will start protocol 
treatment with Re-Induction therapy (below), and then (if your leukemia is gone) receive Post-
Remission therapy (below). 
• 
Induction: You will receive different study drugs (dasatinib by mouth on days 1-84 and 
prednisone by mouth on days 1-32) for your first treatment (“Induction”) cycle (as 
described in the informed consent document). You will be given a bone marrow exam 
at 4 weeks and 8 weeks after you start study treatment. If your leukemia is gone after 
either bone marrow exam you will go on to receive “Post-Remission” therapy.   
• 
Re-Induction: If your leukemia is not gone, you will receive one cycle of “Re-Induction” 
therapy, where you will receive BLINATUMOMAB by continuous IV infusion for 4 
weeks (28 days), followed by a 2-week break during which you will not be given 
BLINATUMOMAB. About 1 week after you stop taking, blinatumomab, you will receive 
a bone marrow exam to see if your leukemia is gone. If your leukemia is not gone then 
you will receive one more “Re-Induction” cycle (continuous IV infusion of 
blinatumomab for 4 weeks, followed by a 2-week break), and then you will have 
another bone marrow exam. If your leukemia is still not gone, then you will not 
receive any further treatment on this study.  If your leukemia is gone after either 
“Re-Induction” cycle, then you will receive “Post-Remission” treatment.   
• 
Post-Remission: One “Post-Remission” cycle is 6 weeks, during which you will 
receive dasatinib by mouth every day. You will also receive BLINATUMOMAB by 
continuous IV infusion for the first 4 weeks (28 days) of each Post-Remission cycle, 
followed by a 2-week break during which you will not be given BLINATUMOMAB. 
You will receive 3 cycles of Post-Remission treatment. 
 
 

 
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• 
Most patients will receive BLINATUMOMAB in the hospital for about the first 9 days of the first 
treatment cycle (that includes blinatumomab treatment) and for  the first 2 days of every additional 
cycle (that includes blinatumomab treatment) to check you for side effects. If you achieve a remission, 
then you may only be hospitalized for 3 days of the first treatment cycle that includes blinatumomab 
and then for the first 2 days of every additional cycle that includes blinatumomab. If you experience 
side effects, you may also be admitted to the hospital. 
 
• 
Your study doctor may change your dose of BLINATUMOMAB, delay, or completely stop treatment 
with BLINATUMOMAB if you have certain side effects. 
 
• 
Your study doctor will do blood tests during treatment with BLINATUMOMAB to check you for side 
effects. 
 
• 
Before you receive BLINATUMOMAB, you will be given a corticosteroid medicine to help reduce 
infusion reactions. 
 
• 
It is very important to keep the area around the IV catheter clean to reduce the risk of getting an 
infection. Your study doctor will show you how to care for your catheter site. 
 
• 
Do not change the settings on your infusion pump, even if there is a problem with your pump or 
your pump alarm sounds. Any changes to your infusion pump settings may cause a dose that is too 
high or too low to be given. 
 
CALL YOUR STUDY DOCTOR OR NURSE RIGHT AWAY IF YOU HAVE ANY PROBLEMS WITH 
YOUR PUMP OR YOUR PUMP ALARM SOUNDS. 
 
WHAT SHOULD I AVOID WHILE RECEIVING BLINATUMOMAB? 
 
Do not drive, operate heavy machinery, or do other dangerous activities while you are receiving 
BLINATUMOMAB because BLINATUMOMAB can cause neurological symptoms such as dizziness, 
seizures, and confusion. 
 
WHAT ARE THE POSSIBLE SIDE EFFECTS OF BLINATUMOMAB? 
 
See “What is the most important information I should know?” BLINATUMOMAB may cause serious 
side effects, including: 
 
• 
Infections. BLINATUMOMAB may cause life-threatening infections that may lead to death. Tell your 
study doctor right away if you develop an infection. 
 
• 
Low white blood cell counts (neutropenia). Neutropenia is common with BLINATUMOMAB 
treatment and may sometimes be life-threatening. Low white blood cell counts can increase your risk 
of infection. Tell your study doctor right away if you get a fever. 
 
• 
Abnormal liver blood test. Your study doctor will do blood tests before you start BLINATUMOMAB 
and during treatment with BLINATUMOMAB to check your liver. 
 
The most common side effects of BLINATUMOMAB include: 
• fever 
• headache 
• swelling of hands, ankles or feet 
• nausea 
• constipation 
• shaking (tremor) 
• rash 
 
 

 
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Tell your study doctor if you have any side effect that bothers you or that does not go away. 
These are not all the possible side of effects of BLINATUMOMAB. 
 
HOW SHOULD I STORE BLINATUMOMAB? 
 
Intravenous bags containing BLINATUMOMAB for infusion will arrive in a special package. 
• 
Do not open the package. 
• 
Do not freeze the package. 
• 
The package containing BLINATUMOMAB will be opened by the home healthcare infusion nurse at 
the time of administration of the drug. Only one shipping container should be opened at a time. 
• 
Do not throw away (dispose of) any BLINATUMOMAB in your household trash. Talk with your study 
doctor about disposal of BLINATUMOMAB and used supplies. 
 
KEEP BLINATUMOMAB AND ALL MEDICINES OUT OF REACH OF CHILDREN. 
 
General information about BLINATUMOMAB 
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not 
use BLINATUMOMAB for a condition for which it was not prescribed. Do not give BLINATUMOMAB to 
other people even if they have the same symptoms that you have. It may harm them. 
If you would like more information about BLINATUMOMAB, talk with your study doctor. You can ask your 
pharmacist or study doctor for information about BLINATUMOMAB that is written for health professionals. 
For more information, go to www.blinatumomab.com. 
 
WHAT ARE THE INGREDIENTS IN BLINATUMOMAB? 
 
Active ingredient: blinatumomab 
Inactive ingredients: citric acid monohydrate, lysine hydrochloride, polysorbate 
80, trehalose dehydrate, sodium hydroxide and water for injection. 

 
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18.13 
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) 
_________________ ;  ____________________ 
Patient Initials             Study ID Number 
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! 

 
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18.14 
Specimen Banking Instructions for the Specimen Repository – Leukemia Division (Lab 
#200) 
 
Future Research 
One 3-4 mL bone marrow aspirate purple top (EDTA) tube will be submitted at diagnosis 
and at time of registration for Ph-Negative patients *.  
 
*If dry tap and bone marrow blast count is ≥30%, 3mL peripheral blood purple top (EDTA) 
tube will be submitted. 
 
Upon receipt, the SWOG Biospecimen Bank will isolate white blood cells from the bone 
marrow EDTA sample using a Ficoll gradient procedure at diagnosis and red blood cell 
lysing procedure at time of registration for Ph-Negative patients. If peripheral blood is 
received in leu of bone marrow, the Bank will isolate white blood cells from the EDTA 
sample using a red blood cell lysing procedure. Specimens will be stored in aliquots in a 
liquid nitrogen (vapor phase) freezer for protocol designated future research. 
 
Future Correlative Studies 
For Cohort 1 - Ph-negative patients, one 7-8 mL bone marrow aspirate purple top (EDTA) 
tube will be submitted at Pre-Treatment, Day 35 of Induction Cycle 1, and Day 35 of Re-
Induction Cycle 1. 
 
For Cohort 2 - Ph-positive and Ph-like DSMKF patients, one 7-8 mL bone marrow aspirate 
purple top (EDTA) tube and 22-24 mL peripheral blood in purple top (EDTA) tubes will be 
submitted at Pre-Treatment, Day 28 of Induction Cycle 1, and Day 56 of Induction Cycle 1. 
  
**If dry tap, only 22-24 mL peripheral blood in purple top (EDTA) tubes will be submitted. 
 
Upon receipt, the SWOG Biospecimen Bank will isolate white blood cells from the bone 
marrow EDTA sample using a Ficoll gradient procedure for Cohort 1 and 2 at pretreatment 
and the Bank will isolate white blood cells from the bone marrow and peripheral blood 
EDTA samples using a red blood cell lysing procedure for Cohort 1 and 2 patients at Day 
28 of Induction Cycle 1 and Day 56 of Induction Cycle 1. Specimens will be stored in 
aliquots in a liquid nitrogen (vapor phase) freezer for future correlative studies (to be 
determined). 
 
 

 
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18.15 
Translational Medicine:  Ph-Like Signatures 
 
a. 
Objectives 
 
1. 
To estimate the incidence of the Ph-like signature in elderly patients (≥ 65 
years of age) with newly diagnosed Philadelphia-chromosome negative 
ALL. 
 
2. 
To estimate the incidence of the various tyrosine-kinase fusions, making 
up the Ph-like signature in elderly patients with newly diagnosed 
Philadelphia-chromosome negative ALL. 
 
3. 
To evaluate outcomes (EFS and OS) in patients with the Ph-like signature 
versus those without the Ph-like signature in Ph-negative ALL. 
 
b. 
Background and Rationale 
 
Acute lymphoblastic leukemia (ALL) in adults remains a difficult disease to treat 
and only approximately 40% of adults are cured with standard therapy.  The 
prognosis of elderly adults (defined as ≥ 65 years of age) remains particularly poor, 
with only 10% of patients alive at 5 years.  The poor prognosis of this group has 
been attributed to an increased incidence of poor risk cytogenetics (more than half 
have the Ph chromosome) in addition to poor tolerance of intensive chemotherapy.  
This study evaluates the new BiTE specific antibody (Blinatumomab) in 
combination with low dose chemotherapy (prednisone, vincristine, methotrexate, 
6-mercaptopurine) to see if such a strategy might improve outcomes in this elderly 
population.  This trial is an intergroup collaboration, and includes both Ph-positive 
and Ph-negative ALL.  
 
Another possible explanation for the poor prognosis of Ph-negative elderly ALL 
could be the presence of the “Ph-like” signature.  This signature has been recently 
identified in children and young adults with ALL and has been associated with a 
poor prognosis with respect to both event-free and overall survival. (1) However, 
such work has not been conducted in the elderly population.  Such data could be 
very important since the presence of such a signature (Ph-like) would have 
therapeutic implications and may inform future clinical trials.  Previous data has 
demonstrated the presence of fusions carrying FLT3, Ras mutations, the IL7 
receptor, JAK2, PDGFRB, and ABL1/ ABL2 in children and young adults with the 
Ph-like signature. (2) Current therapeutics are already available to target these 
including ruxolitinib (JAK inhibitors), imatinib (PDGFR inhibitor).  This clinical trial 
represents the best opportunity to study elderly Ph-negative ALL samples since it 
is an intergroup collaboration, and this is a rare disease.   
 
c. 
Laboratory Assay Methods 
 
1. 
Laboratory Information: 
 
The analyses will be done in the laboratory of Dr. Cheryl Willman, who 
has pioneered the work in this particular arena. 
 
Center for Molecular and Cellular Diagnostics (CLIA #32D1045443) 
2325 Camino de Salud NE, MSC 07-4025 
Albuquerque, NM  87131 
Phone:  505-272-6793 Email:  CMCD@salud.unm.edu 

 
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2. 
Assay Information 
 
The Ph-like gene expression signature was originally defined in childhood 
B-ALL using more than 100 probe sets on the Affymetrix U133_Plus_2.0 
chip, but has since been distilled by Dr. Willman’s group to just eight genes 
with quantitative PCR assays on a low-density array (LDA) card.  The 
performance of the LDA card has been validated using more than 5,000 
childhood ALL samples as well as more than 1,000 adolescent and young 
adult cases.  In addition to having significantly worse outcomes, patients 
with the signature have an extremely high frequency of CRLF2 fusions, 
gene fusions involving tyrosine kinase genes and mutations of JAK1 and 
JAK2.  Dr. Willman’s group designed and developed the LDA assay and 
currently has one issued US patent and another one pending.  
Additionally, the Ph-like Gene Expression Signature Assay has been 
approved by the Cancer Therapy Evaluation Program (CTEP) Biomarker 
Review Committee (BRC).  The Center for Devices and Radiological 
Health at the FDA (CDRH) has determined that this assay, together with 
confirmatory gene fusion tests, is considered a nonsignificant risk device 
for screening patients in the COG clinical trial AA1131.  Based on the FDA 
review of the assay, it is considered to be analytically and clinically 
validated and was deemed a nonsignificant risk device with abbreviated 
IDE status. Samples will be obtained from banked samples previously 
collected from the Cohort 1 group. Samples will be shipped to the Center 
for Molecular and Cellular Diagnostics laboratory. The assay is being run 
in Dr. Willman’s CLIA laboratory at the University of New Mexico.  
 
The experimental approach is to test the RNA of diagnostic samples using 
the LDA assay to determine whether they have the Ph-like expression 
signature.  Those patients with the signature will then be subsequently 
tested for CRLF2 fusions (by PCR and FISH) as well as for fusions 
involving tyrosine kinase genes (PCR and/or RNA-seq).  Patients will be 
run in batches of eight samples on the LDA cards and the results will be 
available the same day.  Samples with the signature will be tested for the 
other fusions will be batched and tested for the other fusions within two 
weeks. 
 
The assays will require 3-4 mL of bone marrow aspirate from the 
diagnostic (pre-treatment) specimen collected in EDTA (purple top) 
vacutainer tubes.   
 
Total RNA is isolated from the Ficolled sample and 1 mcg is converted into 
cDNA for the LDA card.  The custom cards are run on an Applied 
Biosystems QuantStudio 12K Flex instrument (~2 hours/run).  The raw 
data are analyzed using proprietary software and the results are reported 
as either Ph-like or not.  Additional information provided by the card 
indicates whether the sample is P2RY8-CRLF2 or is likely to have an IGH-
CRLF2 fusion. 
 
Figure 2 shows the pipeline for the analysis.  The predictor score is 
calculated from the gene expression on the LDA card.  If the score is less 
than 0.5 the sample is not Ph-like.  If the score is ≥ 0.5, then the sample is 
Ph-like unless either the BCR-ABL1 or ETV6-RUNX1 fusions are present.  

 
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Several isoforms of these fusions are included on the LDA card and used 
to exclude those cases that have other fusions.  The LDA card also 
includes an assay for the P2RY8-CRLF2 fusion, which is relatively 
common among Ph-like cases.  Similarly, high expression of the CRLF2 
gene is predictive of CRLF2 rearrangements (CRLF2-R), both P2RY8 and 
other types.  It may be used to identify Ph-like patients who may be 
screened by FISH to identify CRLF2-R.  The remaining patients who are 
not CRLF2-R are candidates for additional fusion analysis, either by 
sequencing or other methods. 
 
 
 

 
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Figure 2: Steps in the LDA Testing Pipeline 
 
 
 
3. 
Result Reporting 
 
Results of the assays will not be reported to the patient or treating 
institution. 
 
d. 
Statistical Considerations 
 
Based on SWOG ALL study S0530, it is expected that 95% of eligible patients 
(n=26) will provide pre-treatment specimens or specimens from later time points 
so it is anticipated that about 25 patients may be used in these integrated 
translational medicine analyses. Note that Ph-like patients enrolled in Cohort 2 will 
not be included in this translational medicine study. 
 
The number and proportion of patients with a Ph-like signature will be tallied and 
an exact binomial confidence interval for the proportion will be calculated. With 25 
patients, the incidence rate can be estimated to within at most 20% (95% 
confidence interval). Among those with the Ph-like signature, the number and 
proportion of the various tyrosine-kinase fusions making up the Ph-like signatures 
will be tallied and an exact binomial confidence interval for the proportion will be 
calculated. Assuming 50% of patients (n=12) have the Ph-like signature, the 
incidence rate of any particular tyrosine-kinase fusion can be estimated to within 
at most 29% (95% confidence interval).  
 
Distributions of EFS and OS, stratified by Ph-like signature (Ph-like or not), will be 
estimated using the method of Kaplan-Meier. There will be low power to test EFS 
or OS between the two groups. Assuming 2 years of accrual, 10 years of follow-
up, overall 3-year OS rate of 33% (alternative as stated in Section 11.0) and that 
50% have the Ph-like signature, the study will have 77% power to detect a hazard 
ratio of 2.65 for a one-sided test at the 5% level. This corresponds to a 3-year OS 
rate of 50% among those without the Ph-like signature and 16% otherwise. 
 
 
References 
 
1  
Loh M, Chang Jinghui, Harvey RC, et   Harvey RC, Mulligan CG, Wang X, et al.  Identification of 
novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene 
express.  
 
2  
Harvey RC, Mulligan CG, Wang X, et al.  Identification of novel cluster groups in pediatric high-
risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with 
genome-side DNA copy number alterations, clinical characteristics, and outcome.  Blood 116(23): 
4874-84, 2010.