Clinical trial NCT01256398
Conditions: Acute Lymphoblastic Leukemia Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1
Sponsor: National Cancer Institute (NCI)
Start date: 2010-12-14; Completion date: 2021-11-15
Enrollment: 66 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II clinical trial studies how well dasatinib followed by stem cell transplant works in treating older patients with newly diagnosed acute lymphoblastic leukemia. Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Monoclonal antibodies, such as alemtuzumab, may interfere with the ability of cancer cells to grow and spread. Giving more than one drug (combination chemotherapy) and giving dasatinib together with chemotherapy may kill more cancer cells.

Detailed description:
PRIMARY OBJECTIVES:

I. Estimate the disease-free survival (DFS) and overall survival (OS) profiles in newly diagnosed patients 18 years or older who have Philadelphia chromosome positive (Ph+) (BCR/(v-abl Abelson murine leukemia viral oncogene homolog \[ABL\]+) acute lymphoblastic leukemia (ALL) receiving sequential dasatinib followed by allogeneic or autologous hematopoietic cell transplant (HCT) or chemotherapy followed by dasatinib maintenance.

SECONDARY OBJECTIVES:

I. Compare the OS and DFS profiles for each of the three cohorts to those from similar populations from other studies.

II. Determine the ability of dasatinib to produce or maintain a BCR/ABL-negative status, as judged by quantitative-polymerase chain reaction (Q-PCR) following sequential dasatinib, chemotherapy, and HCT.

III. Determine the feasibility of collecting adequate peripheral blood stem cells for autologous HCT following dasatinib therapy and assess for residual Ph+ (BCR/ABL+) cells by Q-PCR.

IV. Study the safety and efficacy of autologous HCT following therapy with dasatinib.

V. Study the safety and efficacy of reduced-intensity preparatory regimen followed by an allogeneic HCT following induction therapy with dasatinib.

VI. Study the safety and efficacy of dasatinib maintenance administered after allogeneic or autologous HCT or chemotherapy.

VII. Correlate plasma and cerebrospinal fluid (CSF) levels of dasatinib when given orally during induction.

OUTLINE: As of 8/21/2014, no new patients may be enrolled on E3903.

REMISSION INDUCTION THERAPY (RIT): Patients receive dasatinib orally (PO) daily continuously and dexamethasone PO or intravenously (IV) on days 1-7.

EARLY INTENSIFICATION THERAPY: Patients with bone marrow =\< 20% blasts are assigned to cohort A and patients with bone marrow \> 20% blasts are assigned to cohort B.

COHORT A: Patients receive dasatinib and dexamethasone as in RIT.

COHORT B: Patients receive dasatinib and dexamethasone as in RIT, and vincristine sulfate IV and daunorubicin hydrochloride IV on days 1, 8, and 15. Patients who do NOT achieve a complete response (CR) or CR with incomplete hematologic recovery based on bone marrow continue on to second induction therapy; patients who achieve a hematologic and morphologic CR continue on to CNS prophylaxis therapy.

SECOND INDUCTION THERAPY: Patients receive dasatinib and dexamethasone as in RIT, cyclophosphamide IV on day 1, daunorubicin hydrochloride IV and vincristine sulfate IV on days 1 and 8, and filgrastim subcutaneously (SC) beginning on day 9 and continuing for \>= 7 days or one dose of pegfilgrastim on day 9.

CNS PROPHYLAXIS THERAPY: Patients receive dasatinib PO daily continuously during CNS prophylaxis therapy; methotrexate intrathecally (IT), vincristine sulfate IV, and methotrexate IV over 3 hours on days 1, 15, and 29; methotrexate PO every 6 hours for a total of 4 doses each on days 1-2, 15-16, and 29-30; leucovorin calcium IV on days 2, 16, and 30; and leucovorin PO calcium every 6 hours for a total of 8 doses each on days 3-4, 17-18, and 31-32.

TRANSPLANTATION OR ALTERNATIVE CHEMOTHERAPY AND MAINTENANCE THERAPY: Patients aged 50-70 years with an HLA-matched related or unrelated donor are assigned to allogeneic transplantation, patients aged 50-70 years without an HLA-matched related or unrelated donor are assigned to autologous transplantation, and patients aged \> 70 years or who are not transplantation candidates are assigned to alternative chemotherapy.

ALLOGENEIC TRANSPLANTATION: Patients receive fludarabine phosphate IV over 30 minutes and alemtuzumab IV over 30 minutes on days -7 through -3 and melphalan IV over 30 minutes on day -2. Patients undergo allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0. Patients then receive filgrastim SC beginning on day 1 and continuing until count recovery and tacrolimus IV or PO beginning on day -2 and beginning to taper on day 100 (for matched related donors) or day 180 (for mismatched related or unrelated donors). Beginning on day 30, patients receive dasatinib PO daily as maintenance therapy. Treatment continues for \>= 12 months in the absence of disease progression.

AUTOLOGOUS TRANSPLANTATION:

MOBILIZATION: Patients receive etoposide phosphate IV continuously on days 1-4, high-dose cytarabine IV over 2 hours every 12 hours for a total of 8 doses on days 1-4, and filgrastim SC once or twice daily beginning on day 14 and continuing until peripheral blood stem cell collection is complete or WBC \> 50,000/μL.

LEUKAPHERESIS: Patients undergo leukapheresis beginning when WBC \> 10,000/μL for a target collection of \>= 5 x 10\^6 CD34+ cells/kg. After completion of stem cell collection, patients receive dasatinib PO twice daily until 3 days before transplantation.

TRANSPLANTATION: Beginning \>= 4 weeks after recovery from toxicity related to previous treatment, patients receive melphalan IV over 30 minutes on days -2 and -1. Patients undergo autologous PBSCT on day 0. Patients then receive filgrastim SC beginning on day 0 and continuing until count recovery.

MAINTENANCE THERAPY: Beginning on day 30, patients receive dasatinib PO once daily. Treatment continues for \>= 12 months in the absence of disease progression.

ALTERNATIVE CHEMOTHERAPY: Beginning 3-10 days after completion of CNS prophylaxis therapy, patients receive etoposide phosphate IV continuously on days 1-4, high-dose cytarabine IV over 2 hours every 12 hours for a total of 8 doses on days 1-4, and filgrastim SC once or twice daily beginning on day 14 and continuing until count recovery.

MAINTENANCE THERAPY: Patients receive dasatinib PO once daily beginning on day 30. Patients also receive vincristine sulfate IV every 4 weeks, dexamethasone for 5 days every 4 weeks, mercaptopurine PO once daily, and methotrexate PO once weekly. Treatment continues for \>= 12 months in the absence of disease progression.

NOTE: Patients with CNS leukemia or testicular disease may receive additional treatment.

After completion of study treatment, patients are followed up every month for 1 year, every 3 months for 2 years, every 6 months for 2 years, and every year for 5 years.

Arms: arm 1: See Detailed Description
Interventions: intervention 1: Alemtuzumab intervention 2: Allogeneic Hematopoietic Stem Cell Transplantation intervention 3: Autologous Hematopoietic Stem Cell Transplantation intervention 4: Cyclophosphamide intervention 5: Cytarabine intervention 6: Dasatinib intervention 7: Daunorubicin Hydrochloride intervention 8: Dexamethasone intervention 9: Etoposide Phosphate intervention 10: Filgrastim intervention 11: Fludarabine Phosphate intervention 12: In Vitro-Treated Peripheral Blood Stem Cell Transplantation intervention 13: Laboratory Biomarker Analysis intervention 14: Leucovorin Calcium intervention 15: Melphalan intervention 16: Mercaptopurine intervention 17: Methotrexate intervention 18: Pegfilgrastim intervention 19: Pharmacological Study intervention 20: Tacrolimus intervention 21: Vincristine Sulfate
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo peripheral blood allogeneic HCT intervention 3: Undergo peripheral blood autologous HCT intervention 4: Given IV intervention 5: Given IV intervention 6: Given PO intervention 7: Given IV intervention 8: Given PO or IV intervention 9: Given IV intervention 10: Given SC intervention 11: Given IV intervention 12: Undergo peripheral blood autologous or allogeneic HCT intervention 13: Correlative studies intervention 14: Given IV or PO intervention 15: Given IV intervention 16: Given PO intervention 17: Given IT, IV, or PO intervention 18: Given SC intervention 19: Correlative studies intervention 20: Given IV or PO intervention 21: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
1
Protocol Update #11 
XX/XX/17 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
PROTOCOL UPDATE TO CALGB 10701/CTSU 10701 
_________________________________________ 
 
A PHASE II STUDY OF DASATINIB (SPRYCEL®) (IND #73969, NSC #732517) AS PRIMARY THERAPY 
FOLLOWED BY TRANSPLANTATION FOR ADULTS ≥ 18 YEARS WITH NEWLY DIAGNOSED PH+ ACUTE 
LYMPHOBLASTIC LEUKEMIA BY CALGB, ECOG AND SWOG  
Investigational Agent: Dasatinib (IND #73969, NSC # 732517 will be supplied by NCI DCTD 
Companion Studies for Alliance Institutions: CALG 8461 (required), 9665 (optional) 
Companion Study for ECOG-ACRIN Institutions: E3903 (required) 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
 
Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
X Data Submission / Forms changes 
 
 
 
 
 
 
 
 
 
Editorial / Administrative changes 
 
 
 
 
 
 
 
 
 
Other :  
 
 
 
 
Expedited review is allowed. IRB approval (or disapproval) is required within 90 days. Please follow 
your IRB of record guidelines.  
 
UPDATES TO THE PROTOCOL: 
 
Section 6.1 Data Submission 
- 
In the data submission table, the form “C10701 ABL1 Mutational Analysis Form” has been added prior 
to “During Treatment (Course I).” This form must be completed for all patients and mailed to the 
Alliance Statistics and Data Center. 
- 
In the data submission table, under “During Treatment (Course VI) and Post-Treatment Follow-Up,” 
the form “C10701 ABL1 Mutational Analysis Form” has been added. This form must be completed for 
all patients and mailed to the Alliance Statistics and Data Center. 


 
2
 
Section 10.13 Filgrastim (G-CSF: Granulocyte Colony-Stimulating Factor; Neupogen; recombinant-
methionyl human granulocyte-colony stimulating factor; r-methHuG-CSF; filgrastim-sndz, Zarxio(R)) 
Zarxio can be used in place of neupogen, therefore, the text “filgrastim-sndz, Zarxio(R)” has been added to the end of 
the section title.  
 
_____________________________________________________________________________ 
 
UPDATES TO THE DONOR CONSENT: 
No changes have been made to the Donor Consent. 
 
UPDATES TO THE RECIPIENT CONSENT: 
No changes have been made to the Recipient Consent. 
 
 
 
A replacement protocol document and model consent have been issued. 
 
This study remains closed to new patient accrual. 
____________________________________________________________ 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
____________________________________________________________ 
 
 
 
CC: CTSU 
 


 
Version Date: 02/21/2017 
1 
Update #11 
Activation Date: 12/15/10 
 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
CALGB 10701/CTSU C10701 
 
A PHASE II STUDY OF DASATINIB (SPRYCEL®) (IND #73969, NSC #732517) AS PRIMARY THERAPY FOLLOWED 
BY TRANSPLANTATION FOR ADULTS ≥ 18 YEARS WITH NEWLY DIAGNOSED PH+ ACUTE LYMPHOBLASTIC 
LEUKEMIA BY CALGB, ECOG AND SWOG  
 
Investigational Agent: Dasatinib (IND # 73969, NSC # 732517) will be supplied by NCI DCTD 
Companion Studies for Alliance Institutions: CALGB 8461 (required), 9665 (optional) 
Companion Study for ECOG-ACRIN Institutions: E3903 (required) 
 
Alliance Study Chair 
Matthew Wieduwilt, MD PhD 
University of California San Diego 
Moores Cancer Center 
La Jolla, CA 92093-0960 
Tel: 858-822-6848 Fax: 858-822-6844 
mwieduwilt@ucsd.edu 
 
Radiation Oncology Co-Chair 
Jeffery Bogart, MD 
Dept of Radiology 
State University of New York Upstate Medical University 
70 E Adams St 
Syracuse, NY 13210 
Tel: 315-464-5276 Fax: 315-464-5943 
bogartj@upstate.edu  
 
Alliance Leukemia Committee Chair 
Alliance Transplant Committee Chair 
Richard M. Stone, MD 
Steven Devine, MD 
Tel: 617-632-2214 Fax: 617-632-2933 
Tel: 614-293-5655 Fax: 614-293-6690  
rstone@partners.org 
steven.devine@osumc.edu 
 
Alliance Radiation Oncology Committee Chair 
PPP Co Chair 
Jeffrey A. Bogart, MD 
Jan H Beumer, PharmD., PhD 
Tel: 315-464-5276  Fax:315-464-5943 
Tel: 412-623-3216  Fax: 412-623-1212  
bogartj@upstate.edu 
jhb11@pitt.edu 
 
Faculty Statistician 
Staff Statistician 
Jun Yin, PhD 
Lydia Hodgson, MS 
Tel: 507-538-6252  Fax: 507-266-2477 
Tel: 919-681-1632 Fax: 919-681-8028 
yin.jun@mayo.edu 
lydia.hodgson@duke.edu 
 
Data Coordinator 
Protocol Coordinator 
Natalie Kyek 
Samantha Sublett 
Tel: 507-284-8666 Fax: 507-284-1902 
Tel: 773-834-4091 Fax: 312-345-0117 
kyek.natalie@mayo.edu 
ssublett@uchicago.edu 
 
Participating Organizations: ALLIANCE/ Alliance for Clinical Trials in Oncology, ECOG-ACRIN/ ECOG-
ACRIN Cancer Research Group, SWOG/ SWOG 


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
2 
Update #11 
 
Alliance Protocol Operations Program Office 
125 South Wacker Street, Suite 1600 
 
 
Chicago, IL 60606-4703 
Tel: 773-702-9171 Fax: 312-345-0117 
www.allianceforclinicaltrialsinoncology.org 
Alliance Statistics and Data Center 
RO FF-3-24-CC/NW Clinic 
200 First Street Southwest 
Rochester, MN 55905 
Adverse Event Reporting 
https://eapps-ctep.nci.nih.gov/ctepaers/ 
CTSU Helpdesk 
1-888-823-5923 
Alliance Biorepository at Ohio State University 
(OSU) 
Department of Pathology 
Polaris Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073 Fax: 614-293-7967 
path.calgb@osumc.edu 
Alliance Hematologic Malignancy 
Biorepository 
Michael Caligiuri, MD 
The Arthur G. James Cancer Hospital and 
Research Institute 
300 West Tenth Avenue, Lobby 
Columbus, OH 43210 
Tel: 614-688-4754 Fax: 614-688-4755  
Alliance Pharmacy Contact 
LeAnne Kennedy, PharmD, BCOP 
Wake Forrest University School of Medicine 
Tel: 336-713-3416 Fax: 336-713-3401 
lakenned@wfubmc.edu 
Alliance Nursing Contact 
Ilene Galinsky, MSN, ANP-C 
Dana Farber Cancer Institute 
Tel: 617-632-3902  
igalinsky@partners.org  
 
 
 


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
3 
Update #11 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data  directly to the 
Lead Cooperative Group unless 
otherwise specified in the protocol:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.coccg.
org (for submitting regulatory 
documents only) 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network 
(OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN
_SYSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help 
Desk with any OPEN-
related questions at 
ctsucontact@westat.com. 
Alliance Statistics and Data Center 
RO FF-3-24-CC/NW Clinic 
200 First Street Southwest 
Rochester, MN 55905  
 
Data Operations  
Sites should submit Teleforms 
electronically using the “Submit to 
CALGB” button or by Mail. 
 
See Section 6.1 Data Submission 
Section for details on forms 
submission. 
 
Do not submit study data or forms to 
CTSU Data Operations. Do not copy 
the CTSU on data submissions. 
The study protocol and all related forms and documents must be downloaded from the protocol-specific 
page of the CTSU Member website 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.   
For patient eligibility or treatment-related questions contact the Study PI of the Coordinating 
Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU Web site is located at   https://www.ctsu.org 
 
 
Participating organizations: 
ECOG-ACRIN 
SWOG 
Ryan James Mattison, MD 
Michaela Liedtke, MD 
Tel: 608-262-5697 
Tel: 650-498-6000 
rjmattison@medicine.wisc.edu 
miledtke@stanford.edu 
 
 


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
4 
Update #11 
A PHASE II STUDY OF DASATINIB (SPRYCEL®) (IND #73969, NSC #732517) AS PRIMARY THERAPY FOLLOWED BY 
TRANSPLANTATION FOR ADULTS ≥ 18 YEARS WITH NEWLY DIAGNOSED PH+ ACUTE LYMPHOBLASTIC LEUKEMIA BY CALGB, 
ECOG AND SWOG 
Schema Page 1 of 7 
ELIGIBILITY CRITERIA: 
• Unequivocal histologic diagnosis of acute lymphoblastic leukemia (ALL). 
• Detection of the t(9;22)(q34;q11) or 3-way variant by metaphase cytogenetics or BCR-ABL positive by molecular analysis (Q-
PCR or FISH) in a CLIA-approved laboratory. 
• Prior therapy excluded except for up to one week of corticosteroids and/or hydroxyurea to enable time for the detection of 
t(9;22)(q34;q11) or BCR-ABL. 
• Age ≥ 18 years. 
• Non-pregnant and non-nursing (see Section 4.5). 
• Left ventricular ejection fraction ≥ lower limit of institutional normal. 
• No myocardial infarction within 6 months. 
• No ventricular tashyarrhythmia within 6 months. 
• No major conduction abnormality (unless a cardiac pacemaker is present). 
STUDY MONITORING:  
A representative from each institution with one of the first 24* patients enrolled on the trial ARE REQUIRED to participate in a 
teleconference with members of the Alliance Statistics and Data Center and Alliance Protocol Operations Program Office staff.  
* Based on the results of the first interim analysis for feasibility and safety, it was decided that the monitoring teleconferences 
would be extended from 12 patients to 24 patients.  
Institutions that do not participate in the teleconferences may be denied future registrations to this trial. See Section 5.1.2 for 
details. 
SCHEMA OVERVIEW: 
Treatment courses are specified using a roman numeral followed by a cardinal numeral indicating the number of days from the 
start of that course of therapy (i.e., Day III-28 is the 28th day of Course III). 
Patients undergoing peripheral stem cell transplant on this protocol should receive this portion of their therapy at an Alliance,- 
SWOG-, ECOG-ACRIN- or FACT-credentialed transplant facility, experienced in the applicable techniques of stem cell 
procurement, storage, and administration in conjunction with high-dose, myeloablative chemotherapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 
CNS leukemia at time of entry on study or prior to the beginning of Course III will be treated only if symptomatic (see 
Sections 8.7 and 8.9). Testicular disease at time of entry onto study will be treated according to Section 8.10. 
** 
CNS leukemia either during hematologic remission (CR or PR) or after having completed protocol therapy without 
marrow relapse will be treated according to Sections 8.8 and 8.9. Testicular disease during therapy without marrow relapse will be 
treated according to Section 8.10. 
*** 
The treating physician should consult with the Study Chair regarding frail patients who may need to skip Course V and 
continue on to Course VI.
R 
E 
G 
I 
S 
T 
R 
A 
T 
I 
O 
N 
* 
Course I 
(Remission 
Induction) 
Bone marrow ≤20% blasts 
Cohort IIA: 
Course II  (Early Intensification) 
Bone marrow >20% blasts 
Cohort IIB: 
Course II  (Early Intensification) 
Course III  (Second 
Induction) 
Only for patients who do 
NOT achieve a CR based on 
Day II-22 bone marrow  
Course IV 
(CNS Prophylaxis) 
CR** 
No 
CR 
Course V*** 
Allogeneic Transplant:  
Patients ages 18-70 with an HLA-matched 
related or unrelated donor 
Autologous Transplant:  
Patients age 18-70 without an HLA-
matched related or unrelated donor 
Alternative Chemotherapy:  
Patients age >70 or who are not transplant 
candidates 
Course VI: 
Dasatinib maintenance begins 
approximately Day 30 post transplant 
(Course V)** 
Course VI: 
Dasatinib maintenance begins 
approximately Day 30 post transplant 
(Course V)** 
Course VI: 
Dasatinib maintenance + chemotherapy 
begins approximately Day 30 (Course 
V)** 
BM I-15 
BM II-22 
CR** 


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
5 
Update #11 
A PHASE II STUDY OF DASATINIB (SPRYCEL®) (IND #73969, NSC #732517) AS PRIMARY THERAPY FOLLOWED BY 
TRANSPLANTATION FOR ADULTS ≥ 18 YEARS WITH NEWLY DIAGNOSED PH+ ACUTE LYMPHOBLASTIC LEUKEMIA BY 
CALGB, ECOG AND SWOG 
Schema Page 2 of 7 
COURSE I  (Induction Therapy) 
Specimens submitted for quantitative polymerase chain reaction (Q-PCR) are required prior to initiation of protocol therapy. 
Specimens should be submitted to a CLIA-approved institutional laboratory. 
To control the peripheral blast count for as many as seven days while confirmation of t(9;22)(q34;q11) or BCR/ABL occurs, 
patients may receive dexamethasone 10 mg/m2/day PO or IV (either once daily or in divided doses) or similar corticosteroid 
regimen. Hydroxyurea also is permitted to control leukocytosis, although no other ALL-directed therapy is allowed. 
• Dasatinib 140 mg PO daily continuously during Course I. 
• Dexamethasone 10 mg/m2/day PO or IV (either once daily or in divided doses) on days I-1 through I-7. Round dose to 
nearest 0.75 mg. 
• Bone marrow examination on day I-15. 
• Lumbar puncture on day I-15 (and, in consenting patients, procure CSF for dasatinib levels; see Section 6.4). CNS 
leukemia at time of entry on study or prior to the beginning of Course III will only be treated if symptomatic. Give IT 
methotrexate 15 mg + hydrocortisone 50 mg twice weekly for at least 6 doses and until the CSF is clear. See Section 8.7 
for more detail. 
COURSE II  (Early Intensification Therapy) 
Treatment in this course will depend on the results from the bone marrow examination on day I-15. Patients with ≤ 20% 
blasts will be in Cohort IIA; patients with > 20% blasts will be in Cohort IIB. It is recommended that patients continue with 
dasatinib and onto Course II regardless of counts. 
Cohort IIA (≤ 20% blasts in Day I-15 bone marrow examination) 
 
Cotrimoxazole DS PO BID 3 days/week continuously during Course IIA   → 
 
Dasatinib continuously during Course IIA → 
 
Dex → 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
... 
22 
• Cotrimoxazole DS one tablet PO BID 3 days/week continuously during Course IIA, or if allergic to sulfonamides, 
inhaled pentamidine 300 mg once per month or dapsone 100 mg/day. Patients treated with dapsone should be ruled 
out for G6PD deficiency. 
• Dasatinib 140 mg PO daily continuously during Course IIA. 
• Dexamethasone (Dex)10 mg/m2/day PO or IV (either once daily or in divided doses) on days II-1 through II-7. 
Round dose to nearest 0.75 mg. 
• Bone marrow (BM) examination on day II-22 for all patients to assess response. 
Cohort IIB (> 20% blasts in Day I-15 bone marrow examination) 
 
Cotrimoxazole DS PO BID 3 days/week continuously during Course IIB   → 
 
Dasatinib continuously during Course IIB → 
 
Dex → 
 
 
 
 
 
 
 
 
 
 
 
 
VCR 
 
 
 
 
 
 
VCR 
 
 
 
 
 
 
VCR 
 
 
 
 
DNR 
 
 
 
 
 
 
DNR 
 
 
 
 
 
 
DNR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
... 
22 
• Cotrimoxazole DS one tablet PO BID 3 days/week continuously during Course IIB, or if allergic to sulfonamides, 
inhaled pentamidine 300 mg once per month or dapsone 100 mg/day. Patients treated with dapsone should be ruled 
out for G6PD deficiency. 
• Dasatinib 140 mg PO daily continuously during Course IIB. 
• Dexamethasone (Dex) 10 mg/m2/day PO or IV (either once daily or in divided doses) on days II-1 through II-7. 
Round dose to nearest 0.75 mg. 
• Vincristine (VCR) 2 mg (flat dose) IV on days II-1, II-8, and II-15. If use of an azole antifungal is necessary, it is 
recommended that an agent with the least inhibitory affect on CYP3A4 be selected if possible. The following 
azoles appear in order of strength of inhibition of CYP3A4: voriconazole, itraconazole, posaconazole, and 
fluconazole. Fluconazole at doses of 200 mg or less is not thought to be a significant inhibitor of CYP3A4. Azole 
antifungal agents should not be administered within 5 half lives of vincristine. 
• Daunorubicin (DNR) 30 mg/m2 IV on days II-1, II-8, and II-15. 
• Bone marrow (BM) examination on day II-22 for all patients to assess response.


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
6 
Update #11 
A PHASE II STUDY OF DASATINIB (SPRYCEL®) (IND #73969, NSC #732517) AS PRIMARY THERAPY 
FOLLOWED BY TRANSPLANTATION FOR ADULTS ≥ 18 YEARS WITH NEWLY DIAGNOSED PH+ ACUTE 
LYMPHOBLASTIC LEUKEMIA BY CALGB, ECOG AND SWOG 
Schema Page 3 of 7 
 
COURSE III  (Second Induction Therapy) 
(ONLY for patients not yet in CR or CRi by Day II-22) 
Treatment in this course will depend on the results from the bone marrow examination on day II-22. Until the 
results are available, patients will continue dasatinib 140 mg PO daily. 
If patients have not achieved a complete remission (CR) (see Section 12.1) based on day II-22 bone marrow they 
will receive Course III therapy. If, however, patients have achieved hematologic and morphologic CR based on 
day II-22 bone marrow, then they will proceed directly to Course IV without receiving Course III. 
 
Cotrimoxazole DS PO BID 3 days/week continuously during Course III → 
 
Dasatinib continuously during Course III → 
 
 
CTX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VCR 
 
 
 
 
 
 
 VCR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNR 
 
 
 
 
 
 
DNR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dex → 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
G-CSF to continue for at least 7 days and until ANC >1000/µL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM 
Day 
1 
2 3 
4 
5 
6 
7 
8 
9 10 
11 
12 
13 14 15 
16 
... 
22 
… 28 
29 
• Cotrimoxazole DS one tablet PO BID 3 days/week continuously during Course III, or if allergic to 
sulfonamides, inhaled pentamidine 300 mg once per month or dapsone 100 mg/day PO. Patients treated with 
dapsone should be ruled out for G6PD deficiency. 
• Dasatinib 140 mg PO daily continuously during Course III. 
• Cyclophosphamide (CTX) 1000 mg/m2 IV on day III-1. 
• Daunorubicin (DNR) 30 mg/m2 IV on days III-1 and III-8. 
• Vincristine (VCR) 2 mg (flat dose) IV on days III-1 and III-8. If use of an azole antifungal is necessary, it is 
recommended that an agent with the least inhibitory affect on CYP3A4 be selected if possible. The following 
azoles appear in order of strength of inhibition of CYP3A4: voriconazole, itraconazole, posaconazole, and 
fluconazole. Fluconazole at doses of 200 mg or less is not thought to be a significant inhibitor of CYP3A4. 
Azole antifungal agents should not be administered within 5 half lives of vincristine. 
• Dexamethasone (Dex) 10 mg/m2/day PO or IV (either once daily or in divided doses) on days III-1 through 
III-7. Round dose to nearest 0.75 mg. 
• G-CSF subcutaneously (SC) beginning on day III-9 and continuing for at least 7 days and then until ANC > 
1000/µL on any one determination after the nadir. For patients <78 kg use 300 mcg, and for patients ≥78 kg 
use 480 mcg. One dose of PEG-filgrastim (6 mg) on day III-9 may be substituted for G-CSF. 
• Bone marrow (BM) examination on day III-29 for all patients to assess response. 
 


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
7 
Update #11 
A PHASE II STUDY OF DASATINIB (SPRYCEL®) (IND #73969, NSC #732517) AS PRIMARY THERAPY FOLLOWED BY 
TRANSPLANTATION FOR ADULTS ≥ 18 YEARS WITH NEWLY DIAGNOSED PH+ ACUTE LYMPHOBLASTIC LEUKEMIA BY 
CALGB, ECOG AND SWOG 
Schema Page 4 of 7 
 
COURSE IV   (CNS Prophylaxis) 
It is recommended that IV vincristine be administered prior to the initiation of the high-dose IV methotrexate infusion. The 
IT methotrexate should be administered later in the day (at any time during the IV methotrexate infusion) to avoid any 
possible confusion between the IV vincristine and the IT methotrexate. 
 
Cotrimoxazole DS PO BID 3 days/week continuously during Course IV → 
 
VCR 
 
 
 
 
 
 
VCR 
 
 
 
 
 
 
 
IV MTX 
 
 
 
 
 
 
IV MTX  
 
 
 
 
 
 
IT MTX 
 
 
 
 
 
 
IT MTX 
 
 
 
 
 
 
 
PO MTX 
PO MTX 
 
 
 
 
 
PO MTX PO MTX  
 
 
 
 
 
 
SM 
 
SM 
 
 
 
 
SM 
 
SM 
 
 
 
 
 
IV LCV 
 
 
 
 
 
 
IV LCV 
 
 
 
 
 
 
 
 
PO LCV PO LCV  
 
 
 
 
PO LCV PO LCV  
 
 
Day 
1 
2 
3 
4 
5 
… 14 
15 
16 
17 
18 
19 20 21 
 
 
 
Cotrimoxazole DS PO BID 3 days/week continuously during Course IV → 
 
 
 
 
 
 
 
 
 
 
 
 
Dasatinib → 
 
 
 
 
 
 
 
 
VCR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IV MTX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IT MTX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PO MTX 
PO MTX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SM 
 
SM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IV LCV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PO LCV PO LCV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRD 
Day 22 23 24 25 26 27 28 
29 
30 
31 
32 
33 34 35 36 37 38 39 40 42 42 
43 
• Cotrimoxazole DS one tablet PO BID 3 days/week continuously for PCP prophylaxis during Course IV, or if allergic 
to sulfonamides, inhaled aerosolized pentamidine (300 mg once per month) or dapsone 100 mg/day. Patients treated 
with dapsone should be ruled out for G6PD deficiency. Cotrimoxazole should be stopped 3 days before and resumed 3 
days after each dose of methotrexate. 
• Dasatinib 140 mg PO daily beginning after recovery from the final methotrexate dose (methotrexate level <0.05 µM). 
• IT Methotrexate (IT MTX) 15 mg total intrathecal once every two weeks on Days IV-1, IV-15, and IV-29. 
Hydrocortisone 50 mg should be included with preservative free methotrexate.  
• Vincristine (VCR) 2 mg (flat dose) IV once every two weeks on Days IV-1, IV-15, and IV-29. If use of an azole 
antifungal is necessary, it is recommended that an agent with the least inhibitory affect on CYP3A4 be selected if 
possible. The following azoles appear in order of strength of inhibition of CYP3A4: voriconazole, itraconazole, 
posaconazole, and fluconazole. Fluconazole at doses of 200 mg or less is not thought to be a significant inhibitor of 
CYP3A4. Azole antifungal agents should not be administered within 5 half lives of vincristine. 
• IV Methotrexate (IV MTX) 500 mg/m2 in one liter of D5W or NS IV over 3 hours on days IV-1, IV-15, and IV-29). 
Prior to beginning IV Mtx, patients should be pre-hydrated with 500 mL - 1000 mL of D5W or NS plus 100 mEq/L of 
sodium bicarbonate. Continue vigorous hydration as tolerated over the course of the day to maintain hydration and urine 
pH>6. Please check with pharmacy to ensure that patients are not receiving any medications (e.g., sulfonamides, 
salicylates, penicillins, other organic acids, proton pump inhibitors) that may interfere with methotrexate clearance. 
During IV infusion, administer IT Mtx. See Section 8.4 for hydration instructions. 
• Oral Methotrexate (PO MTX) 25 mg/m2 PO q6 hours x 4 doses (total) beginning 6 hours after starting each dose of IV 
Mtx (Days 1 & 2, Days 15 & 16, and Days 29 & 30). The dose of oral methotrexate will be adjusted to maintain a serum 
methotrexate level between 1-2 µM according to the instructions in Section 8.4.2. 
• Serum Mtx (SM) levels should be obtained on Days 2, 4, 16, 18, 30, and 32 (i.e., two levels following each dose of IV 
Mtx, the first at 30 hours after the start of IV Mtx. See Section 8.4.2). 
• IV Leucovorin (IV LCV) 25 mg/m2 IV 6 hours after the 4th (last) PO Mtx dose (i.e., 30 hours after starting IV Mtx). 
• Oral Leucovorin (PO LCV) 5 mg/m2 PO q6 hours for a planned 8 doses or until serum Mtx level < 0.05 µM, beginning 
12 hours after IV Lcv. 
• Bone marrow (BM) examination must be obtained for all patients on Day IV-43 to assess response. 
• MRD assessment on peripheral blood and bone marrow aspirate by institutional Q-PCR.  


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
8 
Update #11 
A PHASE II STUDY OF DASATINIB (SPRYCEL®) (IND #73969, NSC #732517) AS PRIMARY THERAPY FOLLOWED BY 
TRANSPLANTATION FOR ADULTS ≥ 18 YEARS WITH NEWLY DIAGNOSED PH+ ACUTE LYMPHOBLASTIC LEUKEMIA 
BY CALGB, ECOG AND SWOG 
Schema Page 5 of 7 
 
COURSE V 
The treating physician should consult with the Study Chair regarding frail patients who may need to skip Course V 
and continue on to Course VI. 
This course include 3 different options: 
(1) Allogeneic Transplantation: for patients age 18-70 with an HLA-matched related or unrelated donor 
Discontinue dasatinib during Course V allogeneic transplant until approximately Day 30 (see Section 8.6.1). 
Patients must be treated at or referred to an Alliance-approved, ECOG-ACRIN-approved, SWOG-approved or FACT-
credentialed allogeneic transplant center to be eligible to receive this portion of the therapy. Course V should begin 
no later than 10 days following count recovery in Course IV. To receive allogeneic transplant, the patient must have 
adequate organ function (renal, liver, cardiac, and pulmonary) to meet institutional requirements. See Section 8.5.1.9 
for antibacterial, antifungal, and Pneumocystis pneumonia prophylaxis. 
Mobilization of allogeneic donor peripheral blood stem cells will be performed according to institutional guidelines. 
Peripheral blood stem cell collection should target an optimal CD34+ cell dose > 5 x 106 cells/kg (actual weight) with 
a maximum of 10 x 106 CD34+ cells/kg. Stem cells may be collected at any time prior to transplant. 
 
F 
F 
F 
F 
F 
 
 
 
 
 
 
 
 
 
 
 
 
A 
A 
A 
A 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tacrolimus   at varying doses (see below) contingent on levels → 
 
 
 
 
 
 
 
 
PBSCT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCSF  → 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRD 
Day 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
... 
30 
• Fludarabine (F) 30 mg/m2/day (actual body weight) IV on days -7, -6, -5, -4, and -3. At a minimum of one hour 
prior to the first dose, begin IV hydration to induce at least 100 mL/hr urine output. Fludarabine will be 
administered prior to alemtuzumab. 
• Alemtuzumab (A) 20 mg/day (flat dose) IV on days -7, -6, -5, -4, and -3. Alemtuzumab will be given within one 
hour of completion of fludarabine. Premedicate with acetaminophen, diphenhydramine (or equivalent), and 
methylprednisolone (or equivalent). 
• Melphalan (M) 140 mg/m2/day (corrected body weight) IV on day -2. 
• Allogeneic peripheral blood stem cell transplant (PBSCT) on day 0. 
• G-CSF 5 mcg/kg/day (actual body weight) subcutaneously (SC) on day +1 until at least ANC > 1500/µL for two 
consecutive days or > 5000/µL for one day. 
• Tacrolimus: 
In Matched Related Donors: 
• On day -2 through +3 tacrolimus 0.05 mg/kg/day by continuous IV infusion (CIVI). 
• On day +4 through +14 tacrolimus 0.03 mg/kg/day by CIVI. 
• On Day +15 through +100 tacrolimus 0.03 mg/kg/day by CIVI or in divided doses every 12 hours IV or oral. Oral 
dose is 3x the last IV dose. Adjust to maintain a trough level of ~ 10-20 ng/mL. 
• Beyond day +100, taper tacrolimus according to institutional guidelines. 
In Mismatched Related Donors or Unrelated Donors: 
• Initial tacrolimus dosing will be the same as in matched-related donors above (also Section 8.5.1.5). 
• Beyond day +180, taper tacrolimus by 20% per week. 
• Bone marrow (BM) examination on day V-30 for all patients. 
• MRD assessments on bone marrow aspirate by institutional Q-PCR on Day+30 and one year post transplant.  


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
9 
Update #11 
A PHASE II STUDY OF DASATINIB (SPRYCEL®) (IND #73969, NSC #732517) AS PRIMARY THERAPY FOLLOWED BY 
TRANSPLANTATION FOR ADULTS ≥ 18 YEARS WITH NEWLY DIAGNOSED PH+ ACUTE LYMPHOBLASTIC LEUKEMIA BY 
CALGB, ECOG AND SWOG 
Schema Page 6 of 7 
 
(2) Autologous Transplantation: for patients age 18-70 without an HLA-matched donor 
Patients must be treated at or referred to an Alliance-approved, ECOG-ACRIN-approved, SWOG-approved or FACT-
credentialed autologous transplant center to be eligible to receive this portion of the therapy. Course V should begin no later 
than 10 days following count recovery in Course IV. To receive autologous transplant, the patient must have adequate organ 
function (renal, liver, cardiac, and pulmonary) to meet institutional requirements. See Section 8.5.2.4 for antibacterial, 
antifungal, and Pneumocystis pneumonia prophylaxis.  
Discontinue dasatinib during Course V autologous transplant until after stem cells have been collected (see Section 8.5.2.8). 
Mobilization 
 
VP16 
VP16 
VP16 
VP16 
 
 
 
 
When WBC > 10,000/µL begin 
PBSC collection and MRD 
assessment of daily PBSC product. 
Continue GCSF until collection is 
complete or WBC > 50,000/µL 
↓ 
 
 
ara-C 
ara-C 
ara-C 
ara-C 
 
 
 
 
 
 
 
 
 
 
Antibiotic & 
Antifungal Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
G-CSF → 
 
 
 
 
 
 
 
 
 
 
 
Dasatinib 
Day 
1 
2 
3 
4 
5 
6 
7 
14  → 
• Etoposide (VP16): In patients age ≤ 65 years, 10 mg/kg/day (corrected body weight) by CIVI on days 1-4. Total dose 
is 40 mg/kg. In patients age > 65 years, 5 mg/kg/day (corrected body weight) by CIVI on days 1-4. Total dose is 20 
mg/kg. 
• Cytarabine (ara-C) In patients age ≤ 65 years, 2000 mg/m2 IV over 2 hours every 12 hours x 8 doses on days 1-4. In 
patients age > 65 years, 1000 mg/m2 IV over 2 hours every 12 hours x 8 doses on days 1-4. 
• G-CSFƒg-c 10 mcg/kg/day subcutaneously in one or two injections beginning on day +14. G-CSF must be continued 
until PBSC collection has been completed or WBC > 50,000/µL. Do not skip or dose reduce for bone pain. Round to 
nearest vial sizes. 
• Leukapheresis will begin when WBC > 10,000/µL. The target is ≥ 5 x 106 CD34+ cells/kg. Samples from each PBSC 
product (1 x 107 cells from each daily sample) must be sent for institutional Q-PCR. 
• Dasatinib Discontinue dasatinib until after stem cell collection is complete. Resume dasatinib 140 mg PO daily. 
Dasatinib must be continued until 3 days prior to autologous transplant. 
• It is recommended that patients remain in hospital until full hematologic recovery. 
Autologous Peripheral Blood Stem Cell Transplant (PBSCT) 
Peripheral blood stem cell transplantation should take place no earlier than 4 weeks following hospital discharge and after 
recovery from toxicity related to myelosuppression. The preparative regimen should begin no sooner than 72 hours after the 
last dose of dasatinib. Patients must meet institutional criteria for PBSCT and have neither active infection nor need for 
ongoing antibiotics. Patients must remain in complete remission as documented by normal bone marrow morphology with 
< 5% blasts within 2 weeks of transplant therapy, and have stable or improving peripheral blood counts. ANC must be > 
500/µL and platelet count > 50,000/µL. Patients with falling blood counts should be observed to exclude relapse as the cause 
of the change. Prior to autologous transplant, MRD assessment should be performed on bone marrow aspirate by institutional 
Q-PCR. 
 
 
 
 
M 
M 
 
 
 
 
 
 
 
 
 
 
 
PBSCT 
 
 
 
 
 
 
 
 
 
 
G-CSF   (see text below) → 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM 
 
 
 
 
 
 
 
 
 
 
MRD 
Day 
-5 
-4 
-3 
-2 
-1 
0 
1 
2 
... 
30 
• Melphalan (M) 100 mg/m2/day (corrected body weight) IV on days -2 and -1. Total dose is 200 mg/m2. 
• Autologous peripheral blood stem cell transplant (PBSCT) on day 0. 
• G-CSF 5 mcg/kg/day (actual body weight) SC beginning on day 0 and continued until ANC ≥ 1500/µL for two days or 
≥ 5000/µL for one day. 
• Bone marrow (BM) examination on day V-30 for all patients. 
• MRD assessment on bone marrow aspirate by institutional Q-PCR on Day+30 and one year post transplant. 


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
10 
Update #11 
A PHASE II STUDY OF DASATINIB (SPRYCEL®) (IND #73969, NSC #732517) AS PRIMARY THERAPY FOLLOWED BY 
TRANSPLANTATION FOR ADULTS ≥ 18 YEARS WITH NEWLY DIAGNOSED PH+ ACUTE LYMPHOBLASTIC LEUKEMIA BY 
CALGB, ECOG AND SWOG 
Schema Page 7 of 7 
(3) Alternative Chemotherapy Regimen: for those patients age > 70, or who are not candidates for transplantation, or those 
without transplant insurance coverage 
Patients who are age > 70, who are not candidates for transplantation or for those without transplant insurance coverage should 
not be removed from protocol therapy. Rather, these patients will receive an alternative chemotherapy regimen including etoposide 
and high-dose ara-C. Therapy should begin no sooner than 72 hours and no later than 10 days following the last dose of dasatinib 
in Course IV. 
 
 
VP16 
VP16 
VP16 
VP16 
 
 
 
 
 
 
 
 
 
ara-C 
ara-C 
ara-C 
ara-C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
G-CSF → 
 
 
 
 
 
 
 
 
 
 
 
 
BM 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
... 
14 
... 
30 
• Etoposide (VP16): In patients age ≤ 65 years, 10 mg/kg/day (corrected body weight) by CIVI on days 1-4. Total dose is 40 
mg/kg. In patients age > 65 years, 5 mg/kg/day (corrected body weight) by CIVI on days 1-4. Total dose is 20 mg/kg. 
• Cytarabine (ara-C): In patients age ≤ 65 years, 2000 mg/m2 IV over 2 hours every 12 hours x 8 doses on days 1-4. In patients 
age > 65 years, 1000 mg/m2 IV over 2 hours every 12 hours x 8 doses on days 1-4. 
• G-CSF 5 mcg/kg/day subcutaneously in one or two injections beginning on day +14.  
• Bone marrow (BM) examination on day V-30 for all patients. MRD assessment on bone marrow aspirate by institutional Q-
PCR at one year.  
COURSE VI  (Dasatinib Maintenance Therapy) 
Treatment in this course will depend on the treatment delivered in Course V.  
For Those Patients who Received Allogeneic Transplantation 
• Dasatinib 50 mg/day PO beginning on about day V-30 post transplant (if tolerable). Increase dose to 100 mg PO once daily 
after two weeks, if tolerated. Dasatinib maintenance to continue for a minimum of 12 months after the first dose of 
dasatinib. Discontinue dasatinib maintenance when any ONE of the following criteria are met: 1) Completion of 12 months 
of maintenance if two consecutive negative RT-PCR assays performed in a local CLIA-approved laboratory three months 
apart are documented; 2) After 12 months of maintenance when two consecutive negative RT-PCR assays performed in a 
local CLIA-approved laboratory three months apart are documented; or 3) At relapse. 
• Bone marrow examinations will occur every 3 months for 2 years and at relapse. Institutional Q-PCR should be performed 
on peripheral blood every 3 months for 5 years from study entry. At time of relapse, MRD assessment on bone marrow 
aspirate or peripheral blood by institutional Q-PCR should be performed.  
For Those Patients who Received Autologous Transplantation 
• Dasatinib 100 mg PO once daily beginning on about day V-30 post transplant (if tolerable). Dasatinib maintenance to 
continue for a minimum of 12 months after the first dose of dasatinib. Discontinue dasatinib maintenance when any ONE 
of the following criteria are met: 1) Completion of 12 months of maintenance if two consecutive negative RT-PCR assays 
performed in a local CLIA-approved laboratory three months apart are documented; 2) After 12 months of maintenance 
when two consecutive negative RT-PCR assays performed in a local CLIA-approved laboratory three months apart are 
documented; or 3) At relapse 
• Bone marrow examinations will occur every 3 months for 2 years and at relapse. Institutional Q-PCR should be performed 
on peripheral blood every 3 months for 5 years from study entry. At time of relapse, MRD assessment on bone marrow 
aspirate or peripheral blood by institutional Q-PCR should be performed.  
For Those Patients who Received Alternative Chemotherapy Regimen 
• Dasatinib 100 mg PO once daily beginning on day V-30 (30 days after starting etoposide/cytarabine). 
• Vincristine 2 mg IV every 4 weeks. 
• Dexamethasone 10 mg/day for 5 days every 4 weeks. 
• 6-Mercaptopurine 60 mg/m2/day PO in the evening. 
• Methotrexate 20 mg/m2 PO once per week. 
• Adjust doses of 6-mercaptopurine and methotrexate to keep the ANC > 1000/µL and the platelet count > 75,000/µL. 
• Dasatinib maintenance to continue for a minimum of 12 months after the first dose of dasatinib. Discontinue dasatinib 
maintenance when any ONE of the following criteria are met: 1) Completion of 12 months of maintenance if two consecutive 
negative RT-PCR assays performed in a local CLIA-approved laboratory three months apart are documented; 2) After 12 
months of maintenance when two consecutive negative RT-PCR assays performed in a local CLIA-approved laboratory three 
months apart are documented; or 3) At relapse 
• Bone marrow examinations will occur every 3 months for 2 years and at relapse. Institutional Q-PCR should be performed 
on peripheral blood every month for the first year, every 3 months for the following two years, and every six months for 5 
years from study entry. At time of relapse, MRD assessment on bone marrow aspirate or peripheral blood by institutional 
Q-PCR should be performed.  


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
11 
Update #11 
A PHASE II STUDY OF DASATINIB (SPRYCEL®) (IND #73969, NSC #732517) AS PRIMARY THERAPY FOLLOWED 
BY TRANSPLANTATION FOR ADULTS ≥ 18 YEARS WITH NEWLY DIAGNOSED PH+ ACUTE LYMPHOBLASTIC 
LEUKEMIA BY CALGB, ECOG AND SWOG  
Schema for Specimen Submission 
At diagnosis 
 
 
 
Alliance 
Patients 
 
Signed the CALGB 8461 model 
consent. * 
(See CALGB 8461) Submit to 
your local cytogeneticist: 
bone marrow 
peripheral blood 
 
Signed the CALGB 9665 model 
consent. 
(See CALGB 9665) Submit: 
bone marrow aspirate 
whole blood 
buccal cell sample  
 
ECOG-ACRIN 
Patients 
 
Signed the ECOG E3903 model 
consent. * 
(See ECOG E3903) Submit: 
blood 
bone marrow 
karyotypes 
 
 
 
 
Prior to 
initiation of 
remission 
induction 
therapy 
 
All 
Patients 
 
 
Signed the CALGB 10701 model 
consent. * 
(See section 6.3) Submit: 
3 unstained bone marrow smears 
3 unstained blood smears 
1 H&E stained biopsy slide 
4 unstained biopsy sections 
 
 
 
 
Course I,  
Day 15  
(+/- 1 day) 
 
All 
Patients 
Answered, “yes” to “I agree that my 
specimen(s) may be used for the 
research described above” 
(Question #1) in the model consent. 
(See section 6.4) Submit: 
3 mL peripheral blood 
3 mL of cerebrospinal fluid 
 
 
 
 
At Complete 
Remission 
 
 
Alliance 
Patients 
 
Signed the CALGB 8461 model 
consent. * 
(See CALGB 8461) Submit to 
your local cytogeneticist: 
bone marrow 
peripheral blood 
Signed the CALGB 9665 model 
consent.  
(See CALGB 9665) Submit: 
bone marrow aspirate 
whole blood 
 
 
 
 
At Relapse 
 
 
Alliance 
Patients 
 
Signed the CALGB 8461 model 
consent. * 
(See CALGB 8461) Submit to 
your local cytogeneticist: 
bone marrow 
peripheral blood 
Signed the CALGB 9665 model 
consent. 
(See CALGB 9665) Submit: 
bone marrow aspirate 
whole blood 
* 
Patient is not eligible for participation in CALGB 10701 if this model consent is not signed. 


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
12 
Update #11 
TABLE OF CONTENTS 
 
SECTION 
 
 
 
 
 
 
 
 
 
 
  PAGE 
 
1.0 
INTRODUCTION ..................................................................................................................... 15 
1.1 
Acute Lymphoblastic Leukemia with t(9;22); Philadelphia (Ph) Chromosome Positive ALL.... 15 
1.2 
Imatinib Mesylate in Combination with Chemotherapy ......................................................... 15 
1.3 
Mechanisms of Resistance to Imatinib Mesylate ................................................................... 17 
1.4 
New Drugs to Overcome Resistance: Dasatinib for Ph+ ALL................................................. 18 
1.5 
Central Nervous System Prophylaxis .................................................................................... 19 
1.6 
Transplantation for Ph+ ALL ............................................................................................... 19 
1.7 
Dasatinib Maintenance ........................................................................................................ 20 
1.8 
The Rational for the Current Study ....................................................................................... 20 
1.9 
Inclusion of Women & Minorities ........................................................................................ 21 
2.0 
OBJECTIVES .......................................................................................................................... 21 
2.1 
Primary Objective ............................................................................................................... 21 
2.2 
Secondary Objectives .......................................................................................................... 21 
3.0 
ON-STUDY GUIDELINES ......................................................................................................... 22 
4.0 
ELIGIBILITY CRITERIA .......................................................................................................... 22 
4.1 
ALL Diagnosis ................................................................................................................... 22 
4.2 
Hemotopathology................................................................................................................ 22 
4.3 
Prior Therapy Status............................................................................................................ 22 
4.4 
Age Requirement ................................................................................................................ 22 
4.5 
Pregnancy and Nursing Status .............................................................................................. 22 
4.6 
Cardiac Function................................................................................................................. 23 
5.0 
REGISTRATION ...................................................................................................................... 23 
5.1 
Registration Requirements for CALGB 10701 ...................................................................... 23 
5.2 
Registration Procedures for CALGB 10701 .......................................................................... 23 
5.3 
Registration to Optional Substudy CALGB 61004................................................................. 24 
5.4 
CALGB Registration to CALGB Companion Studies ............................................................ 25 
5.5 
ECOG-ACRIN Registration to ECOG Companion Study ...................................................... 25 
6.0 
DATA AND SPECIMEN SUBMISSION ........................................................................................ 26 
6.1 
Data submission.................................................................................................................. 26 
6.2 
Specimen Submission Instructions ....................................................................................... 29 
6.3 
Central Morphology Review (For CTSU and Alliance).......................................................... 30 
6.4 
Dasatinib Pharmacokinetic (PK) Substudy CALGB 61004 (For CTSU and Alliance) .............. 30 
6.5 
CALGB Companion Studies Sample Submission (For Alliance only)..................................... 31 
6.6 
ECOG-ACRIN Companion Studies Sample Submission (For ECOG-ACRIN only) ................ 32 
7.0 
REQUIRED DATA ................................................................................................................... 33 
8.0 
TREATMENT PLAN ................................................................................................................. 35 
8.1 
Course I: Induction Therapy ................................................................................................ 35 
8.2 
Course II: Early Intensification Therapy (begins shortly after Day I-15) ................................. 36 
8.3 
Course III: Second Induction Therapy (only for patients not yet in CR or CRi) ....................... 36 
8.4 
Course IV: CNS Prophylaxis Therapy .................................................................................. 37 
8.5 
Course V ............................................................................................................................ 40 
8.6 
Course VI: Dasatinib Maintenance Therapy .......................................................................... 47 
8.7 
Treatment for CNS Leukemia .............................................................................................. 49 


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
13 
Update #11 
8.8 
CNS Leukemia Developing During Hematologic Remission (CR or PR) While Receiving or 
Having Completed Protocol Therapy .................................................................................. 49 
8.9 
Cranial Radiation Therapy ................................................................................................... 49 
8.10 
  Testicular Radiation: 2400 cGy in 12 Treatment Fractions ................................................... 51 
8.11    Quality Assurance Documentation ........................................................................................ 52 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY ..................................................... 53 
9.1 
Anticipated Toxicity and Management ................................................................................. 53 
9.2 
Treatment Delays ................................................................................................................ 53 
9.3 
Dasatinib Dose Modifications During Courses I - V .............................................................. 54 
9.4 
Dasatinib Dose Modifications During Course VI................................................................... 55 
9.5 
Course IV (CNS Prophylaxis) Dose Modifications ................................................................ 57 
9.6 
Course V High-Dose Ara-C Dose Modifications ................................................................... 58 
9.7 
Dose Modifications for Methotrexate and 6-Mercaptopurine in Course VI .............................. 59 
9.8 
Treatment of GVHD ........................................................................................................... 59 
10.0 
DRUG FORMULATION, AVAILABILITY AND PREPARATION .................................................. 60 
10.1 
Campath-1H (alemtuzumab, Campath) ................................................................................. 61 
10.2 
Cyclophosphamide (Cytoxan®; CTX; CPA; Neosar®; Cytoxan Lyophilized®) ...................... 61 
10.3 
Cytarabine, Ara-C (Cytosine Arabinoside) ............................................................................ 62 
10.4 
Dasatinib (Sprycel®) (IND #73969, NSC #732517) .............................................................. 63 
10.5 
Daunorubicin ...................................................................................................................... 67 
10.6 
Etoposide (VePesid®) ......................................................................................................... 67 
10.7 
Fludarabine (Fludara®) ....................................................................................................... 68 
10.8 
Melphalan Hydrochloride (Alkeran®) .................................................................................. 68 
10.9 
Methotrexate (Methotrexate Sodium; Amethopterin; MTX) ................................................... 69 
10.10 Vincristine sulfate (VCR, Oncovin)...................................................................................... 70 
10.11 Dexamethasone (Decadron®) .............................................................................................. 71 
10.12 6-Mercaptopurine (6-MP, Purinethol, mercaptopurine) .......................................................... 71 
10.13  Filgrastim (G-CSF: Granulocyte Colony-Stimulating Factor; Neupogen; recombinant-
methionyl human granulocyte-colony stimulating factor; r-methHuG-CSF; filgrastim-sndz, 
Zarxio(R)) ......................................................................................................................... 72 
10.14 PEG-filgrastim.................................................................................................................... 72 
10.15 Leucovorin Calcium (Citrovorum Factor, Folinic Acid, 5–Formyl Tetrahydrofolate) ............... 73 
10.16 Co-trimoxazole (Trimethoprim-sulfamethoxazole, Bactrim®, Septra®, Cotrim, Sulfatrim) ...... 73 
10.17 Pentamidine Isethionate (NebuPent® - oral inhalation solution) ............................................. 74 
10.18 Tacrolimus (Prograf®) ........................................................................................................ 74 
11.0 
ANCILLARY THERAPY ........................................................................................................ 75 
11.1 
Alliance Policy Concerning the Use of Growth Factors ......................................................... 76 
12.0 
CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE [43] ............................................ 76 
12.1 
Complete Remission (CR) ................................................................................................... 76 
12.2 
Complete Cytogenetic Remission (CCyR) ............................................................................ 76 
12.3 
Complete Molecular Remission ........................................................................................... 76 
12.4 
Major Molecular Remission................................................................................................. 77 
12.5 
Complete Remission with Incomplete Recovery of Counts (CRi) ........................................... 77 
12.6 
Partial Remission (PR) ........................................................................................................ 77 
12.7 
Refractory Disease .............................................................................................................. 77 
12.8 
Progressive Disease............................................................................................................. 77 
12.9 
Relapsed Disease ................................................................................................................ 77 
 


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13.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY ........................................................ 78 
13.1 
Duration of Treatment ......................................................................................................... 78 
13.2 
Relapse .............................................................................................................................. 78 
13.3 
Extraordinary Medical Circumstances: ................................................................................. 78 
14.0 
STATISTICAL CONSIDERATIONS ......................................................................................... 78 
14.1 
Statistical Objectives ........................................................................................................... 78 
14.2 
Accrual Plan ....................................................................................................................... 79 
14.3 
Study Monitoring ................................................................................................................ 79 
14.4 
CDUS ................................................................................................................................ 82 
15.0 
WRITING COMMITTEE ....................................................................................................... 82 
16.0 
ADVERSE EVENT REPORTING (AER).................................................................................. 82 
16.1 
 CALGB 10701 Adverse Event Reporting Requirements ....................................................... 83 
16.2 
 Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting Requirements for  
Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or non-CTEP IND: .................... 84 
16.3  Comprehensive Adverse Events and Potential Risks List (CAEPR) for Dasatinib (BMS-354825,      
NSC 732517) .................................................................................................................... 85 
16.4 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Alemtuzumab (NSC 
715969) ............................................................................................................................ 88 
17.0 
REFERENCES...................................................................................................................... 92 
APPENDIX I:  IDEAL BODY WEIGHT TABLE ........................................................................... 95 
APPENDIX II: GRAFT VERSUS HOST DISEASE GRADING..................................................... 96 
APPENDIX III:  EXAMPLES OF SUBSTRATES, INDUCERS AND INHIBITORS OF CYP3A4 97 
APPENDIX IV:  PATIENT INSTRUCTION SHEET ..................................................................... 99 
APPENDIX V A:  CRITERIA FOR EVALUATING ACUTE LEUKEMIA ................................. 100 
APPENDIX V B:  CRITERIA FOR EVALUATING ACUTE LEUKEMIA.................................. 101 


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Update #11 
1.0 
INTRODUCTION 
1.1 
Acute Lymphoblastic Leukemia with t(9;22); Philadelphia (Ph) Chromosome Positive 
ALL 
The oncogenic fusion gene BCR/ABL that results from the reciprocal translocation 
t(9;22)(q34;q11.2) is the sine qua non for chronic myeloid leukemia (CML). However, the 
Philadelphia chromosome (Ph) that results from the t(9;22) is also the single most frequent 
chromosome abnormality in adult acute lymphoblastic leukemia (ALL), detected in 11% to 34% 
of patients with ALL. The prevalence is increased in older adults, especially in individuals over 
60 years of age. The reciprocal translocation between chromosomes 9 and 22 results in the 
head-to-tail fusion of variable numbers of 5’ BCR exons on chromosome band 22q11.2 with the 
exon 2 of the ABL gene located on chromosome band 9q34. The protein product of the fusion 
gene resulting from the t(9;22) plays a central role in the development of this form of ALL. Two 
main fusion proteins, p190BCR/ABL and p210BCR/ABL, each containing NH2-terminal domains of 
Bcr and COOH-terminal domains of Abl, are produced depending on the location of the 
breakpoint within the BCR gene. The p190BCR/ABL product contains the first exon of BCR and 
occurs in 50-78% of the ALL cases with t(9;22). The p210BCR/ABL product contains either exon 
13 or exon 14 of BCR and is ubiquitous in CML and is considerably less frequent in ALL. Of 
note, p190BCR/ABL transcripts are frequently detected at a low level in p210BCR/ABL-positive ALL.  
Ph+ ALL has been associated with an unfavorable outcome but this has changed since the advent 
of imatinib mesylate. This introduction will describe the milestones achieved and why 
improvements are still needed beyond imatinib mesylate.  
1.2 
Imatinib Mesylate in Combination with Chemotherapy 
Imatinib mesylate. The first BCR-ABL inhibitor to gain clinical approval was imatinib mesylate, 
which partially blocks the adenosine triphosphate binding site of BCR-ABL, preventing a 
conformational switch of the oncogenic protein to the activated form [1]. Early studies showed 
that many previously-treated Ph+ ALL patients responded to imatinib monotherapy (400 mg2 or 
600 mg/day) initially (CR rates 20%) but then quickly (median treatment duration of 58 days) 
relapsed. Thus, although imatinib was well-tolerated and produced a modest response for 
previously-treated Ph+ ALL when used as single-agent therapy, responses were short-lived, and 
relapse was common [2, 3]. 
TKIs with steroids alone 
 
The treatment of elderly patients with Ph+ ALL has been limited by intolerance to 
chemotherapy, the inability to undergo alloSCT because of comorbidities, and the biological 
characteristics of the disease [4]. Several approaches to using TKI-based therapy have been 
explored in these patients, including a chemotherapy-free treatment based only on a TKI and 
steroids. In one study from the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA), 
61–83 years old Ph+ ALL patients received a 7-day steroid pretreatment followed by a 45-day 
induction of imatinib (800 mg/day) plus prednisone (40 mg/m2 per day) [5]. Therapy was well 
tolerated, and no major toxicities were reported. All 29 assessable patients (100%) experienced 
a CHR, and at 12 months, the OS and DFS probabilities were 74% and 48%. The GIMEMA 
prospective study LAL1205 has evaluated a similar regimen using dasatinib (70 mg) in adult 
Ph+ ALL patients (median age, 54 years) [6]. All 34 (100%) evaluable patients treated with this 
regimen achieved a CHR, and the OS rate at 10 months was 80.7%. Adding mixed-agent 
chemotherapy to TKI-steroid treatments does not appear to substantially increase 1-year OS or 
decrease relapse rates in elderly Ph+ ALL patients. The Group for Research in Adult Acute 
Lymphoblastic Leukemia AFR09 study, which combined standard induction therapy with 


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Update #11 
imatinib and prednisone, reported 1-year relapse and OS rates of 58% and 66% [7]. While these 
values were significantly improved from historical controls treated with chemotherapy without 
imatinib, they appear to be at par with chemotherapy-free regimens that include only TKIs and 
steroids. It would be of interest to combine TKIs and steroids with other established non-
myelotoxic agents, e.g., vincristine, in elderly Ph+ ALL patients. 
 
Table 1: Effect of Imatinib and Chemotherapy Combination on Outcome in Ph+ Adult and Elderly Patients  
Study 
No. 
patients 
Median 
age 
(range) 
Induction regimen 
CR, 
% 
DFS, 
% 
(yr) 
Benefit of 
alloSCT 
Survival, 
% (yr) 
Adult 
patients 
 
 
 
 
 
 
 
JALSG 
ALL 202 
[8] 
103 
45 
(15-64) 
Imatinib, CTX, 
daunorubicin, VCR, 
PRED 
97.1 
NA 
Relapse: 13% 
w/alloSCT; 
90% w/o 
alloSCT* 
56.8 (3) 
Modified 
Linker [9] 
19† 
37 
(15-67) 
Imatinib, 
daunorubicin, 
ASNase, VCR, 
PRED 
95 
NA 
 
NA 
GMALL 
[10] 
47-Alternate 
 
43.5 
(19-65) 
Concurrent or 
alternating imatinib 
with 
dexamethasone, 
VCR, daunorubicin, 
pegaspargase, CTX, 
Ara-C, 6-
mercaptopurine, 
methotrexate, G-
CSF 
NA 
52 
(2)‡ 
 
36 (2) 
45-
Concurrent 
95 
61 
(2)‡ 
 
43 (2) 
Hyper-
CVAD [11] 
54† 
51 
(17-84) 
Imatinib, CTX, 
VCR, doxorubicin, 
dexamethasone 
93 
76 vs. 
63═ 
(3) 
3 yr OS: 90% 
w/alloSCT ; 
33% w/o 
alloSCT║ 
NA 
GRAAPH-
2003 [12]§ 
45 
45 
(16-59) 
Daunorubicin, CTX, 
VCR, PRED, L-
asparaginase,  CTX, 
VCR, PRED, 
ASNase, triple 
intrathecal 
NA 
43 (4) 
4 yr OS: 55% 
w/alloSCT; 
80% w/auto-
SCT; 25% w/o 
SCT¶ 
52 (4) 
Elderly patients 
 
 
 
 
 
 
GRALL 
AFR 09 [7]† 
29† 
65.8 
(58-78) 
VCR, CTX, 
daunorubicin, PRED  
72 
58 (1) 
 
66 (1) 
GIMEMA 
[5] 
29† 
69 
(61-83) 
Imatinib, PRED 
100 
48 (1) 
 
74 (1) 
Abbreviations: Allo, allogeneic; Ara-C, cytarabine; Auto, autologous; CTX, cyclophosphamide; G-CSF, 
granulocyte-colony stimulating factor; GIMEMA, Gruppo Italiano Malattie EMatologiche dell'Adulto; 
GMALL, German Multicenter Trials of Adult ALL; GRALL, Group for Research in Adult Acute 
Lymphoblastic Leukemia (Ph-); GRAAPH, Group for Research on Adult Acute Lymphoblastic Leukemia 
(Ph+); hyper CVAD, fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone; 
JALSG, Japan Adult Leukemia Study Group; PRED, prednisone; SCT, stem cell transplant; VCR, 
vincristine; W, with; W/O, without; Yr, year;  


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Update #11 
* 
Relapsed occurred in 18 of 20 (90%) of patients in whom alloSCT was not performed in CR1 but in 
only seven of 54 (13%) who underwent alloSCT in CR1. 
† 
Evaluable patients. 
‡ 
Estimated probability of remission. 
§ 
Imatinib during consolidation therapy. 
═ The 3-year CR duration was 76% for 13 patients who achieved major molecular response prior to 
alloSCT compared with 63% for the 31 patients who did not, p=0.2. 
║ In de novo patients ≤40 years of age, 3-year overall survival was 90% with alloSCT (n=10) vs. 33% 
without alloSCT (n=6), p=0.005. 
¶ 
The 4-year OS in the alloSCT, autoSCT and no SCT groups were 55%, 80% and 25% (alloSCT versus 
autoSCT, p=0.16; alloSCT versus no SCT, p=0.05; autoSCT versus no SCT, p=0.008).  
1.3 
Mechanisms of Resistance to Imatinib Mesylate 
Four mechanisms of resistance to imatinib mesylate have been described to date. These are (1) 
mutations at the kinase site, (2) reduced intracellular imatinib mesylate concentration, (3) gene 
amplification, and (4) alternative signaling pathways functionally compensating for the 
imatinib-sensitive mechanisms.  
Mutations at the kinase domain impair imatinib’s binding to varying degrees and represent the 
most common (approximately 40-50%) mechanism of resistance. Recently, kinase domain 
mutations were found to precede imatinib-based therapy and gave rise to relapse in patients with 
de novo Ph+ ALL [13]. Of note, 12 (46%) of 26 patient samples harbored P-loop (e.g., G250E, 
Q252H, Y253H, E255K/V) mutations and 6 (23%) of 26 patient samples demonstrated 
gatekeeper (e.g., F311I, T315I, F317L) mutations at diagnosis. Interestingly, remission duration 
did not differ significantly between patients with or without a detectable early mutation in that 
study. At relapse, ten patients with mutations at diagnosis demonstrated the same mutation while 
one patient demonstrated a different mutation at relapse. These data suggest that, in contrast to 
CML, it may be worthwhile to consider mutational analysis at diagnosis in Ph+ ALL and tailor 
treatment accordingly. Novel drugs that overcome kinase domain mutations are discussed 
below. 
A previous study [13] concluded that other mechanisms of resistance also exist, as three patients 
with wild-type BCR-ABL at diagnosis relapsed without any mutations. Intracellular imatinib 
mesylate concentration has been shown to correlate with response in CML though no such data 
are yet available in Ph+ ALL. Briefly, drug efflux proteins, such as Permeability-glycoprotein 
(Pgp, the gene product of ABCB1, formerly MDR1) [14] and breast cancer resistance protein 
(Bcrp1, ABCG2) [15] were shown to lower intracellular imatinib mesylate concentrations in 
CML. Similarly, imatinib mesylate was shown to be a substrate for the organic cation influx 
transporter 1 (OCT1) and reduced OCT1 activity is the cause of low in vitro sensitivity to 
imatinib mesylate in CML [16]. Finally, plasma α1-acid glycoprotein concentrations had a 
marked influence on total imatinib mesylate concentrations in CML [17]. While in CML, 
decreased intracellular imatinib mesylate concentrations are addressed by intensifying the 
therapy with higher imatinib mesylate doses (up to 800 mg/day), this approach is not proved 
valid for Ph+ ALL. As discussed below, some of the novel Bcr-Abl kinase inhibitors are not 
subject to some of these mechanisms and are also markedly more potent than imatinib mesylate.  
BCR-ABL gene amplification is another mechanism of resistance to imatinib mesylate in CML. 
Though no such data exist so far in Ph+ ALL, duplication of the Ph chromosome was shown to 
be associated with worse outcome in Ph+ ALL in the pre-imatinib era [18]. Further, the effect 
of novel Bcr-Abl kinase inhibitors with significantly more potent anti-Bcr-Abl activity in 
imatinib-resistant cases suggests that this mechanism prevails in Ph+ ALL, too.  


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Update #11 
Alternative signaling pathways have been implicated in resistance to imatinib mesylate. 
Specifically, the Src (sarcoma) family kinase members, Lyn, Hck, and Fgr, have been shown to 
be elevated in the hematopoietic cells of mice with Ph+ ALL and these proteins are required for 
the induction of Ph+ ALL in mice [19]. Dasatinib (Sprycel®) and bosutinib (SKI-606) target 
the Src family kinase members in addition to Bcr/Abl as will be discussed below. Stromal 
support is another alternative pathway involved in imatinib resistance in Ph+ ALL. While the 
Bcr-Abl kinase continued to be inhibited by imatinib mesylate, resistant cells proliferated in the 
presence of stromal support [20]. The stromal effect did not require direct cell-cell contact, and 
stromal cell derived factor-1α substituted for the presence of the stromal cells. These data 
suggest that the stroma selects for imatinib mesylate resistant Bcr-Abl cells that are less 
dependent on the kinase activity; interrupting the interaction between lymphoblasts and the 
stroma may be of benefit in Ph+ ALL. 
Another recently identified mechanism of TKI resistance involves the expression of spliced 
isoforms of Ikaros (IKZF1) [21]. IKZF1 functions as a critical regulator of normal lymphocyte 
development and is involved in the rapid development of leukemia in mice expressing non-
DNA-binding isoforms [22]. The IK6 isoform, lacking all 4 N-terminal zinc fingers responsible 
for DNA-binding, was detected in 43 of 47 (91%) Ph+ ALL patients resistant to imatinib or 
dasatinib [21]. In addition, the expression level of IK6 correlated with the BCR-ABL transcript 
level. Hence, restoring Ikzf1 function may provide another approach to combating TKI 
resistance in the future. 
1.4 
New Drugs to Overcome Resistance: Dasatinib for Ph+ ALL 
Dasatinib, a dual SRC and ABL inhibitor, has a 325-fold greater potency than imatinib in cells 
transduced with unmutated BCR-ABL and is active against many of the BCR-ABL mutations 
conferring imatinib resistance [23]. Furthermore, dasatinib’s cellular uptake is not dependent on 
OCT-1 activity [24], though like imatinib, it is a substrate for efflux proteins [25].  
The START (SRC/ABL Tyrosine kinase inhibition Activity Research Trials of dasatinib) L 
(imatinib-resistant or -intolerant lymphoid blast crisis and ALL) reported that dasatinib (70 mg 
bid) was relatively well tolerated and produced a major hematological response (MHR) in 41% 
and major cytogenetic response (MCyR) in 57% of patients after a minimum follow-up of 12 
months [26]. The discrepancy between hematologic and cytogenetic responses likely stems from 
the high incidence of cytopenias induced by dasatinib. Median OS was 8.0 months. After 1 year 
of treatment, 22% of patients remained alive and progression-free [26]. A high proportion of 
patients with P- and A-loop mutation of the ABL domain achieved MHR and MCyR [27]. 
However, patients with the T315I and F317L gatekeeper mutations do not respond to dasatinib 
[27, 28].  Dasatinib is approved in the United States for Ph+ ALL patients who have failed to 
respond to imatinib, and clinical trials evaluating its efficacy in newly diagnosed Ph+ ALL are 
ongoing.  
Combining imatinib with conventional chemotherapy revolutionized the treatment of Ph+ ALL; 
CR rates now approach 95%, and 3-year OS can exceed 50% (Table 1) [5, 7-12]. Imatinib may 
be administered either concurrently or sequentially with chemotherapy. 
Combination chemotherapy with dasatinib 
Dasatinib combined with conventional chemotherapy is also efficacious and safe in Ph+ ALL 
patients. Combining hyper-CVAD with dasatinib (50 mg bid for the first 14 days of each cycle) 
led to CR in 93% of patients; after a median follow-up of 10 months, 75% were alive, and 64% 
remained in CR. A high incidence of T315I ABL mutation was noted among relapsed patients 
[29]. AFR 07 evaluated dasatinib in combination with the European Working Group on Adult 
ALL chemotherapy protocols for the treatment of ≥55 year old Ph+ ALL patients [30]. Dasatinib 
was administered with vincristine and dexamethasone during induction, sequentially with 


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Update #11 
methotrexate and L-asparaginase alternating with cytarabine during consolidation, and with 6-
mercaptopurine, methotrexate, and dexamethasone/vincristine during maintenance. A 95.2% 
CHR rate was observed, and the rate of serious adverse events was 40%, as expected in this 
population. Responses appeared to be durable; the level of minimal residual disease (MRD) has 
continued to decrease with prolonged therapy.  
This protocol will cover all age groups, 18 and above. 
1.5 
Central Nervous System Prophylaxis 
The central nervous system (CNS) is a sanctuary site for ALL, and relapses may occur first in 
the cerebrospinal fluid (CSF). CNS prophylaxis with intrathecal (IT) chemotherapy is routine. 
Imatinib does not cross the blood-brain barrier. Dasatinib has a potential advantage of 
penetrating into the CSF, but this has never been analyzed systematically. We therefore propose 
to measure dasatinib CSF levels at the time of the first intrathecal administration of 
chemotherapy. Since dasatinib is presumed to reach a maximal CSF level within 2 hours 
following its oral administration, the first intrathecal chemotherapy will be scheduled 
accordingly. Further, since we will be collecting the data prospectively, we will continue to 
administer standard intrathecal and systemic CNS prophylaxis throughout this study similar to 
the regimen previously used in CALGB C10001.  
1.6 
Transplantation for Ph+ ALL 
AlloSCT in first CR remains the standard of care for Ph+ ALL and the only established therapy 
that offers a possibility of cure [31]. However, prior treatment with TKIs can increase the 
feasibility of SCT in a greater proportion of Ph+ ALL patients by increasing remission rates and 
extending remission durations [4, 32].  In addition, TKIs have increased the proportion of 
patients experiencing sustained remissions and provides additional time to identify a suitable 
donor. Reducing BCR-ABL transcript levels after imatinib-based therapy has also resulted in a 
lower pre-SCT tumor burden [4]. Finally, three studies [8, 12, 32] demonstrated a clear benefit 
for alloSCT over chemotherapy alone (Table 1). Additional data with longer follow-up are 
necessary to determine whether alloSCT may still be necessary in Ph+ ALL patients treated with 
TKI-combination chemotherapy regimens. 
The German [12] and our preliminary experience with autologous (auto) SCT in CALGB 10001 
[33] suggest that this approach is at least as beneficial as allo-SCT but with less toxicity and 
therefore we propose to continue and study this treatment modality herein. 
1.6.2 Autologous Transplantation for Ph+ ALL 
Not all patients have a suitable donor for allo-HCT. Thus autologous HCT, using stem cells 
collected during the first CR, offers an alternative approach. Using conventional 
chemotherapy to eradicate residual disease prior to autologous transplantation in ALL 
resulted in poor outcomes with increased disease relapse in a recent study [34]. Therefore, 
it was concluded that “there was no evidence that a single autologous transplantation can 
replace consolidation/maintenance for any risk group.” However, using chemotherapy alone 
to eradicate residual Ph+ disease is suboptimal. We hypothesize that the combination of 
dasatinib with chemotherapy will achieve a better success rate in cleansing the marrow from 
residual disease prior to stem cell collection. As shown in Table 1, several groups [10, 35] 
including 
CALGB [36], have reported favorable outcomes following 
autologous 
transplantation for Ph+ ALL patients <60 years old without suitable allogeneic donors. 
Specifically, in one study [35], the outcomes of patients undergoing autologous versus 
allogeneic transplantation were similar. Even though the relapse rate was higher among 
patients who underwent autologous HCT, the higher TRM associated with allogeneic HCT 
balanced the final outcomes. We will build on our preliminary results from CALGB 10001 


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Update #11 
and pursue autologous transplantation for patients ≤70 years old without suitable allogeneic 
donors in the current study. 
We plan to evaluate the role of melphalan as the preparatory regimen for the autologous 
transplantation. Melphalan has been used before in the preparatory regimen for autologous 
transplantation in pediatric ALL [37, 38].  
1.7 
Dasatinib Maintenance 
Patients with CML who have had a good clinical response to imatinib are recommended to 
continue the drug life-long. Discontinuation of imatinib mesylate after allogeneic or autologous 
HCT continues to present a scientific dilemma for Ph+ ALL. Several studies continued imatinib 
until disease recurrence [5, 39, 40] while others had a set time [9, 41, 42] (one to two years) of 
imatinib maintenance. It is difficult to discern a difference between the studies based on patients’ 
outcomes because of the relatively short follow-up. In our clinical trial of imatinib and 
chemotherapy followed by autologous HCT (CALGB C10001) [36] we have continued imatinib 
maintenance for at least one year and then until two consecutive quantitative polymerase chain 
reaction (Q-PCR) tests 3 months apart were negative. However, long-term data from our study 
are not available yet. Two other studies claimed that molecular relapse did not predict 
hematologic relapse [9, 40]. We propose herein to continue patients on dasatinib for at least one 
year and monitor for molecular response and then discontinue dasatinib if two consecutive Q-
PCR tests (three months apart) are negative.  
1.8 
The Rational for the Current Study 
We hypothesize that dasatinib and dexamethasone, with minimal additional chemotherapy, will 
be well tolerated by older patients with newly diagnosed Ph+ ALL and will result in similar 
leukemia cytoreduction when compared historically to imatinib with either concomitant or 
sequential cytotoxic chemotherapy. We also hypothesize that a reduced-intensity preparatory 
regimen of fludarabine + melphalan + alemtuzumab followed by allogeneic HCT from HLA-
matched donors will result in low treatment-related mortality and significant improvement in 
disease-free survival compared to a no transplantation approach for Ph+ ALL patients ≤70 years 
old. In addition, we hypothesize that autologous CD34+ stem cell collection following dasatinib 
and dexamethasone treatment will result in similar or better collections of BCR/ABL-negative 
stem cells (by Q-PCR) as we observed following imatinib and standard dose chemotherapy in 
CALGB 10001, allowing autologous HCT for patients who lack allogeneic donors.  Given that 
the 3-year progression free survival was 50% for patients enrolled on the CALGB 10001 trial 
who under went autologous HCT after imatinib treatment, we anticipate that the DFS will be 
equal or better using the more potent TKI, dasatinib.  Finally, we hypothesize that dasatinib will 
be well tolerated as a maintenance therapy after HCT or chemotherapy and will result in 
favorable DFS compared with historical experience prior to TKI treatment.


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Update #11 
 
1.9 
Inclusion of Women & Minorities 
Although there is no evidence to suggest that the outcome will differ by gender or ethnicity and 
there is insufficient power to detect small or moderate effects, we will, in a secondary analysis, 
report the results by gender and ethnicity. Both men and women of all races and ethnic groups 
are eligible for this study. 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
2 
+ 
5 
= 
7 
Not Hispanic or Latino 
34 
+ 
25 
= 
59 
Ethnic Category: Total of all subjects 
36  (A1) 
+ 
30  (B1) = 
66  (C1) 
Racial Category 
 
American Indian or Alaskan Native 
1 
+ 
3 
= 
4 
Asian 
4 
+ 
1 
= 
5 
Black or African American 
4 
+ 
8 
= 
12 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
0 
White 
27 
+ 
18 
= 
45 
Racial Category: Total of all subjects 
36  (A2) 
+ 
30  (B2) = 
66  (C2) 
 
(A1 = A2) 
 
(B1 = B2)  
(C1 = C2) 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
Estimate the disease-free survival (DFS) and overall survival (OS) profiles in newly diagnosed 
patients 18 years or older who have Ph+ (BCR/ABL+) ALL receiving sequential dasatinib, 
followed by allogeneic or autologous HCT or chemotherapy followed by dasatinib maintenance. 
2.2 
Secondary Objectives 
2.2.1 Compare the OS and DFS profiles for each of the three cohorts to those from similar 
populations from other studies. 
2.2.2 Determine the ability of dasatinib to produce or maintain a BCR/ABL-negative status, as 
judged by Q-PCR following sequential dasatinib, chemotherapy, and HCT. 
2.2.3 Determine the feasibility of collecting adequate peripheral blood stem cells for autologous 
HCT following dasatinib therapy, and assess for residual Ph+ (BCR/ABL+) cells by Q-PCR. 
2.2.4 Study the safety and efficacy of autologous HCT following therapy with dasatinib. 
2.2.5 Study the safety and efficacy of reduced-intensity preparatory regimen followed by an 
allogeneic HCT following induction therapy with dasatinib. 
2.2.6 Study the safety and efficacy of dasatinib maintenance administered after allogeneic or 
autologous HCT or chemotherapy. 
2.2.7 Correlate plasma and CSF levels of dasatinib when given orally during induction. 


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Update #11 
3.0 
ON-STUDY GUIDELINES 
This clinical trial can fulfill its objectives only if patients appropriate for the trial are enrolled. All 
relevant medical and other considerations should be taken into account when deciding whether this 
protocol is appropriate for a particular patient. Management throughout the full duration of the 
protocol treatment at a medical facility having ready access to blood product support and adequate 
staff to care for the severely neutropenic patient with multiple therapy-induced toxicities will 
maximize patient safety. Physicians should consider the risks and the benefits of any therapy and 
therefore only enroll patients for which the agents administered are appropriate. Although they will 
not be considered as formal eligibility (exclusion) criteria, as part of this decision-making process 
physicians should recognize that the following problems may increase the risk to the patient entering 
this protocol:  
• Any other serious illness which would limit survival to <3 months, or psychiatric condition 
which would prevent compliance with treatment or informed consent. 
• Uncontrolled or severe cardiovascular disease. 
• Prior use of the agents administered in this protocol for other non-malignant disease may 
reduce the likelihood of beneficial outcome and should also be considered prior to enrolling 
patients. 
• Elevations of bilirubin, or creatinine that may suggest impaired hepatic or renal function 
must be considered as potentially serious obstacles for safe tolerance of the therapy 
prescribed in this protocol. 
• Physicians should be aware that dasatinib is a competitive inhibitor of CYP2C9, CYP2D6, 
and CYP3A4/5. Studies also show CYP3A4 is the major human p450 enzyme catalyzing 
biotransformation of dasatinib. Thus, co-administration of drugs which are inducers (e.g., 
phenytoin) or inhibitors (e.g., itraconazole, voriconazole, posaconazole) of this isoenzyme 
could decrease or increase dasatinib concentrations. A list of agents that may have potential 
drug interactions is included in Appendix III. 
4.0 
ELIGIBILITY CRITERIA 
All questions regarding eligibility should be directed to the Alliance Study Chair. Please note that the 
Study Chair may not grant waivers to eligibility requirements. 
4.1 
ALL Diagnosis 
Unequivocal histologic diagnosis of ALL. 
4.2 
Hemotopathology 
Detection of the t(9;22)(q34;q11) or 3-way variant by metaphase cytogenetics or BCR-ABL 
positive status by molecular analysis (Q-PCR or FISH) in a CLIA-approved laboratory. 
4.3 
Prior Therapy Status 
No prior therapy except up to one week of corticosteroids and/or hydroxyurea to enable time for 
the detection of t(9;22)(q34;q11) or BCR/ABL. 
4.4 
Age Requirement 
Age ≥ 18 years with no upper age limit. 
4.5 
Pregnancy and Nursing Status 
Non-pregnant and non-nursing. Treatment under this protocol would expose an unborn child 
to significant risks. Women and men of reproductive potential should agree to use an effective 
means of birth control and contraception should continue for three months after the last dose of 


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
23 
Update #11 
dasatinib to allow complete clearance of drug and its principal metabolites from the body. In 
women of childbearing potential, a pregnancy test will be required at study entry.  
4.6 
Cardiac Function 
• 
Left ventricular ejection fraction ≥ lower limit of institutional normal 
• 
No myocardial infarction within 6 months 
• 
No ventricular tachyarrhythmia within 6 months 
• 
No major conduction abnormality (unless a cardiac pacemaker is present) 
5.0 
REGISTRATION 
5.1 
Registration Requirements for CALGB 10701 
5.1.1 Informed Consent 
The patient must be aware of the neoplastic nature of his/her disease and willingly consent 
after being informed of the procedure to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side effects, risks, and discomforts. Human protection 
committee approval of this protocol and of its consent form are required. 
5.1.2 Study Monitoring Teleconferences 
A representative from each institution with one of the first 24* patients enrolled on the trial 
ARE REQUIRED to participate in a teleconference with members of the Alliance Statistics 
and Data Center and Alliance Protocol Operations Program Office staff.  
* 
Based on the results of the first interim analysis for feasibility and safety, it was 
decided that the monitoring teleconferences would be extended from 12 patients to 24 
patients.  
The CALGB 10701 study data coordinator will establish the teleconferences and notify 
participants. Institutions that do not participate in the teleconferences may be denied future 
registrations to this trial. 
5.2 
Registration Procedures for CALGB 10701 
5.2.1 CTSU Registration Requirements 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
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 (FDA Form 1572 with original signature, current 
CV, Supplemental Investigator Data Form with signature, and Financial Disclosure Form 
with original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI.  
These forms are available on the CTSU Web site (enter credentials at https://www.ctsu.org; 
then click on the Register tab) or by calling the PMB at 240-276-6575 Monday through 
Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
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 enroll patients. Study centers can check the status of their 
registration packets by querying the Regulatory Support System (RSS) site registration 
status page of the CTSU member web site by entering credentials at https://www.ctsu.org. 
Requirements for CALGB-10701 site registration: 


CALGB 10701/CTSU C10701 
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24 
Update #11 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
5.2.2 Patient Registration 
All institutions will use OPEN (Oncology Patient Enrollment Network) for registration of 
patients 
to 
CALGB 
10701. 
All 
institutions 
may 
access 
OPEN 
registration 
at 
https://open.ctsu.org. Alliance and CTSU registrars will direct all requests for registration to 
CALGB 10701 to occur through OPEN. 
If technical difficulties are experienced with OPEN during normal business hours, please contact 
the CTSU Help Desk (1-888-823-5925). 
To be able to enroll a patient, institution staff must have:  
• 
A valid and active CTEP-IAM account 
This the same user ID and password used for the CTSU website (for more information, 
see https://www.ctsu.org/public/CTEP-IAM_Factsheet.pdf). 
• 
A ‘Registrar’ role on in the Alliance or CTSU roster 
Assignment of the Alliance ‘Registrar’ role is managed through the Alliance Protocol 
Operations Program Office via submission of a roster update form signed by the 
Principal Investigator of the member network. 
Prior to accessing OPEN site staff should verify the following: 
• 
All eligibility criteria has been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group or CTSU web site as a tool to 
verify eligibility. 
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable).  
Site and/or Data Administrators can manage the CTSU roster roles via the new Site Roles 
maintenance feature under RSS on the CTSU members’ website. This will allow them to assign 
staff the ‘Registrar’ role. 
A training video and user guide is available on the CTSU members’ website, under the “OPEN” 
tab and within the OPEN application. Although the OPEN system is user-friendly and has many 
help features built in, we strongly encourage users to view the training demo for a quick 
overview of how OPEN works. OPEN has a “Practice Mode” which allows the user to switch 
from a “working” mode to practice mode to create registrations without updating live data. The 
user guide is also available to download and/or print as a reference tool. There are help icons 
within each of the OPEN screens to assist you with navigating the system. 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records.  
Further instructional information is provided on the OPEN tab of the CTSU members’ side of 
the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any additional 
questions contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
5.3 
Registration to Optional Substudy CALGB 61004 
Within CALGB 10701 there is one embedded substudy. This substudy must be offered to all 
patients enrolled on CALGB 10701. Although patient may opt not to participate, this substudy 
is strongly recommended for ALL patients. 
If a patient answers “yes” to “I agree that my specimen(s) may be used for the research described 
above” (Question #1) in the model consent, they have consented to participate in the embedded 


CALGB 10701/CTSU C10701 
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25 
Update #11 
companion CALGB 61004. Samples for CALGB 61004 should be submitted according to the 
instructions in Section 6.4. The rationale for performing the correlative substudy is described in 
Section 6.4. 
If a patient has also consented to the optional embedded companion study CALGB 61004, 
register the patient to CALGB 61004 within OPEN. Pre-registration to 61004 is not available. 
5.4 
CALGB Registration to CALGB Companion Studies  
5.4.1 Registration to REQUIRED CALGB 8461  
Enrollment in CALGB 8461 (Cytogenetic Studies in Acute Leukemia) is required for 
CALGB patients in order to achieve the scientific outcomes of this trial. Follow the 
instructions within CALGB 8461 for collection and submission of specimens (also see 
Section 6.5). 
Patients who register to CALGB 10701 must also register to CALGB 8461. Pre-registration 
to 8461 is no longer available.  
5.4.2 Registration to OPTIONAL CALGB 9665 (prior to February 28, 2014) 
Enrollment in the Leukemia Correlative Science Committee study CALGB 9665 (CALGB 
Leukemia Tissue Bank) is optional, but is strongly recommended for all Alliance patients. 
Pre-registration to CALGB 9665 is available. Follow the instructions within CALGB 9665 
for collection and submission of specimens (also see Section 6.5). 
If a patient has also consented to the optional companion study CALGB 9665, register the 
patient to CALGB 9665. Pre-registration to 9665 is not required. 
CALGB 9665 was temporarily suspended on February 28, 2014. Therefore, after 
February 28, 2014, Alliance institutions may not consent or enroll patients on CALGB 
9665. Patients already enrolled on CALGB 9665 should continue to submit specimens 
as required per protocol. 
5.5 
ECOG-ACRIN Registration to ECOG Companion Study  
5.5.1 Registration to REQUIRED E3903 
Prior to or at the time of registration to 10701, ECOG patients must be registered on and 
baseline samples submitted per ECOG E3903, “Ancillary laboratory protocol for collecting 
diagnostic material on patients considered for ECOG treatment trials for leukemia or related 
hematologic disorders.” 
The baseline eligibility assessments which will be reported back to the site for CALGB 
10701 include the results of the BCR/ABL status as determined by quantitative PCR. The 
assessments will be performed by the CLIA Certified Immunology Laboratory at 
Montefiore Medical Center-North Division. 
E3903 closed to new patient accrual on August 21, 2014. Therefore, after 8/21/14, ECOG-
ACRIN institutions may not consent or enroll patients on E3903. After 8/21/14, baseline 
eligibility assessments are to be performed by a local CLIA laboratory as per protocol 
(Section 4.2). 


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
26 
Update #11 
6.0 
DATA AND SPECIMEN SUBMISSION 
6.1 
Data submission 
Forms should be submitted to the Alliance Statistics and Data Center in compliance with the 
data submission schedule below. There are two options for submitting forms that use the 
Teleform barcode and cornerstones: 
• 
The preferred method is to submit the forms electronically using the “Submit to CALGB” 
button located at the bottom of the last page of each form. Forms submitted electronically 
should not be submitted by mail. 
• 
The forms may be mailed to the Alliance Statistics and Data Center, RO FF-3-24-CC/NW 
Clinic, 200 First Street Southwest, Rochester, MN 55905. Please note that the four 
cornerstones and the form id ("bitmap") must appear on the form. Copies must be 100% of 
the original form size.  
Supporting documentation for studies using Teleform can be mailed along with the Teleform 
forms. 
 
 
 
 
Form* 
 
Submission Schedule 
 
C10701 Registration Worksheet 
 
C-1944 
10701 On-Study Form 
 
C-1961 
10701 Molecular Results Form 
 
C-970 
Peripheral Blood & Bone Marrow Report Form 
Within 1 month of registration. 
C-972 
Leukemia Immunophenotyping Form 
 
C-1963 
10701 Prior Therapy Form 
 
 
Pathology Reports† 
 
 
 
 
 
C10701 BCR/ABL1 Transcripts Form 
With Update #10, this form was added. This 
form can be found on the study webpage on the 
Alliance and CTSU website under “Case Report 
Forms.” Complete this form for all patients, and 
mail to the Alliance Statistics and Data Center. 
 
C10701 ABL1 Mutational Analysis Form 
With Update #11, this form was added. This 
form can be found on the study webpage on the 
Alliance and CTSU website under “Case Report 
Forms.” Complete this form for all patients, and 
mail/e-mail to the Alliance Statistics and Data 
Center.  
During Treatment (Course I) 
C-1838 
Adverse Event Form** 
At end of Course I. 
C-1945 
10701 Treatment Form 
C-1834 
Acute Lymphoblastic Leukemia Follow-up 
Form 
C-664 
Infectious Complications Form 
C-028 
Acute Leukemia Flow Sheet 
C-970 
Peripheral Blood & Bone Marrow Report Form 
 
Pathology Reports‡ 
 
 
 
During Treatment (Course II) 


CALGB 10701/CTSU C10701 
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27 
Update #11 
C-1838 
Adverse Event Form** 
At end of Course II. 
C-1945 
10701 Treatment Form 
C-1834 
Acute Lymphoblastic Leukemia Follow-up 
Form 
C-664 
Infectious Complications Form 
C-028 
Acute Leukemia Flow Sheet 
C-970 
Peripheral Blood & Bone Marrow Report Form 
 
Pathology Reports‡ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
During Treatment (Course III) 
C-1838 
Adverse Event Form** 
At end of Course III. 
C-1945 
10701 Treatment Form 
C-1834 
Acute Lymphoblastic Leukemia Follow-up 
Form 
C-664 
Infectious Complications Form 
C-028 
Acute Leukemia Flow Sheet 
C-970 
Peripheral Blood & Bone Marrow Report Form 
 
Pathology Reports‡ 
 
 
 
During Treatment (Course IV) 
C-1838 
Adverse Event Form** 
At end of Course IV. 
C-1945 
10701 Treatment Form 
C-1834 
Acute Lymphoblastic Leukemia Follow-up 
Form 
C-664 
Infectious Complications Form 
C-028 
Acute Leukemia Flow Sheet 
C-970 
Peripheral Blood & Bone Marrow Report Form 
C-1833 
Serum Methotrexate Adjustment Record Form 
C-1961 
10701 Molecular Results Form 
 
During Treatment (Course V) 
C-1838 
Adverse Event Form** 
At end of Course V. 
C-1945 
10701 Treatment Form 
C-1834 
Acute Lymphoblastic Leukemia Follow-up 
Form 
C-664 
Infectious Complications Form 
C-028 
Acute Leukemia Flow Sheet (Alternative 
Chemotherapy Only) 
TR-1 
Allogeneic Transplant Flow Sheet (Allo 
Transplant only) 
TR-2 
Autologous Transplant Flow Sheet (Auto 
Transplant only) 
C-970 
Peripheral Blood & Bone Marrow Report Form  
C-1835 
Course V Follow-up Form 
C-939 
HLA Typing Form 
C-1839 
Peripheral Blood Stem Cell Collection Form 
C-1842 
Chimerism Analysis Form 
C-1961 
10701 Molecular Results Form 
 
Pathology Reports ‡ 


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
28 
Update #11 
 
 
 
 
 
During Treatment (Course VI) and Post-Treatment Follow-Up 
C-1838 
Adverse Event Form** 
Monthly for first year or until protocol 
treatment ends. 
C-1945 
10701 Treatment Form 
C-028 
Acute Leukemia Flow Sheet 
 
 
 
C-1961 
10701 Molecular Results Form 
At Day +30 post transplant or end of all Course 
V treatment, at one year post transplant or end 
of all Course V treatment, and at relapse 
 
 
 
C-1834 
Acute Lymphoblastic Leukemia Follow-up 
Form 
Every 3 months for two years and at relapse. 
C-970 
Peripheral Blood & Bone Marrow Report Form 
 
 
 
C-1961 
10701 Molecular Results Form 
For allogeneic and autologous transplantation 
arms, every 3 months for 5 years from study 
entry, and at relapse. For alternative 
chemotherapy arm, every month for 1 year, 
every 3 months for subsequent 2 years, then 
every 6 months for 5 years from study entry, and 
at relapse. 
 
 
 
 
C10701 ABL1 Mutational Analysis Form 
At relapse and at refractory disease. With 
Update #11, this form was added. This form can 
be found on the study webpage on the Alliance 
and CTSU website under “Case Report Forms.” 
Complete this form for all patients, and mail/e-
mail to the Alliance Statistics and Data Center. 
 
 
 
C-400 
CALGB Long-Term Follow-up Form 
Q6 months until year 5, then annually for a 
maximum of ten years from study entry. 
 
Other 
C-300 
CALGB: Off Treatment Notice 
At conclusion of treatment. 
 
 
 
C-113 
CALGB Notification of Death Form 
At time of death. 
 
 
 
C-1001 
New Malignancy Form 
At presentation of another malignancy. 
 
 
 
C-1820 
Adverse Events Addendum Form 
Complete if additional space is needed to report 
other adverse events. 
C-1742 
CALGB Confirmation of Lost to Follow-up 
Form 
See form for submission instructions. 
* 
Use the CALGB Remarks Addenda (C-260) if additional comments are necessary or additional writing 
space is needed. 
** 
Submit AE form until all protocol treatment related events have resolved or until non-protocol treatment 
begins. If patient death is reported via CTEP-AERS, report grade 5 event on AE form even is patient is off protocol 
treatment. 
† 
Submit legible copies of all pathology, cytochemistry, immunophenotyping, molecular, and cytogenetic 
reports documenting diagnosis to the Alliance Biorepository at Ohio State University (OSU) and the Alliance 
Statistics and Data Center. 


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
29 
Update #11 
‡ 
Submit legible copies of all pathology, cytochemistry, immunophenotyping, molecular, and cytogenetic 
reports documenting response, progression or relapse to the Alliance Biorepository at Ohio State University (OSU) 
and the Alliance Statistics and Data Center. 
 
S-069 and S-070 Medication Calendars are for institutional and patient use only. These forms are 
not required to be submitted to the Alliance Statistics and Data Center. 
 
Please refer to the Alliance web site to obtain up-to-date data forms for this study. 
6.2 
Specimen Submission Instructions 
Label the tubes with the CALGB study number, patient study ID number, patient initials, the 
date of collection, source of material, and the sample collection period. 
All submitted specimens must be labeled with the protocol number CALGB 10701, OPEN 
patient registration number, patient’s initials, and date and type of specimen collected (e.g., 
serum, whole blood). 
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS 
SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on Alliance 
trials. Authorized 
individuals 
may 
access 
BioMS 
at 
the 
following 
URL: 
http://bioms.wustl.edu/bioms, using most standard web browsers (Safari, Firefox, Internet 
Explorer).  For information on using the BioMS system, please refer to the ‘Help’ links on the 
BioMS web page to access the on-line user manual, FAQs, and training videos.  To report 
technical problems, such as login issues or application errors, please contact: 1-855-55-
BIOMS.  For assistance in using the application or questions or problems related to specific 
specimen logging, please contact: 1-855-55-BIOMS. 
After logging collected specimens in BioMS, the system will create a shipping manifest. This 
shipping manifest must be printed and placed in the shipment container with the specimens. 
Samples 
Sample Collection on CALGB 10701 
Prior to initiation of 
remission induction 
therapy 
During Treatment 
Ship to 
Course I, Day 15 (± 1 day) 
Bone marrow smears * 
(6.3.1) 
3 unstained slides 
 
OSU 
Whole blood smears 
(6.3.1) 
3 unstained slides 
 
OSU 
Bone marrow biopsy  
(6.3.1) 
1 stained section and 
4 unstained sections  
 
OSU 
Peripheral blood (plasma) 1 
(lavender top)  
(6.4.2) 
 
3 mL  
OSU 
Cerebrospinal fluid 1 
(lavender top) 
(6.4.2) 
 
3 mL  
OSU 
* 
See Section 6.3.4 for patients who have inaspirable bone marrow samples and/or for patients who have 
had a bone marrow examination (with extra slides available) within the past 8 days and refuse another 
examination prior to registration. 
1 
For patients who consent (model consent question #1) to substudy 61004.  


CALGB 10701/CTSU C10701 
Version Date: 02/21/2017 
30 
Update #11 
6.3 
Central Morphology Review (For CTSU and Alliance)  
6.3.1 At entry on this study, slides that were obtained prior to any protocol induction treatment 
must be submitted. Send three (3) air-dried, unstained bone marrow smears (films) and three 
(3) unstained blood smears (films), one (1) H & E stained biopsy slide, and four (4) 
unstained biopsy sections for confirmatory cytologic and cytochemical studies. These 
should be submitted together with the final institutional pathology, cytochemistry, and 
immunophenotyping reports (if possible). 
6.3.2 There must be an adequate amount of marrow in each smear. The above requirements are 
considered minimal. Contact the Alliance Study Chair with any questions. 
6.3.3 Identify each slide with the patient’s study ID number and protocol number, pack carefully 
in protective slide cartons (not cardboard folders). Samples must be logged and shipped via 
BioMS, see Section 6.2 for instructions. A copy of the shipping manifest produced by 
BioMS must be printed and placed in the shipment with the specimens. Promptly mail 
(slides must arrive within one week of sampling) to:  
Alliance Biorepository at Ohio State University (OSU) 
Department of Pathology 
Polaris Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Phone: 614-293-7073 Fax: 614-293-7967 
Send a copy of your institutional bone marrow aspiration and biopsy report, cytochemistry, 
cytogenetic, and flow cytometry reports as soon as complete to the Alliance Statistics and 
Data Center and to the Alliance Biorepository at Ohio State University. This report must 
include differential cell counts, cytochemistry results, and FAB/WHO classification.  
6.3.4 Inaspirable Bone Marrow Cases 
Patients who have inaspirable bone marrow samples (“dry tap”) can be enrolled if there are 
adequate numbers of circulating 
blast cells 
in the blood to allow 
complete 
immunophenotyping, cytogenetic and molecular analysis. One H&E stained biopsy slide 
and four unstained biopsy sections must be submitted for central morphology review 
together with six air-dried unstained peripheral blood smears. 
A patient who has had an adequate diagnostic bone marrow examination within the past 8 
days (with extra slides available) and refuses another aspiration prior to registration can be 
enrolled on the study if their previous bone marrow slides are submitted for central 
morphology review and if their absolute lymphoblast count is > 10,000/µL in the peripheral 
blood. Three unstained prior bone marrow aspirate smears, one H&E stained biopsy slide 
and four unstained biopsy sections must be submitted for Central Review together with six 
fresh air-dried unstained peripheral blood smears. Adequate volumes of peripheral blood 
must be submitted for the companion studies as described in those protocols to meet the 
objectives of those studies. 
6.4 
Dasatinib Pharmacokinetic (PK) Substudy CALGB 61004 (For CTSU and Alliance) 
6.4.1 Cerebrospinal Fluid and Plasma Specimen Collection (Course I Day 15) 
A lumbar puncture will be performed in all patients on Course I Day 15 (± 1 day). In 
consenting patients (model consent question #1), a CSF and peripheral blood sample will 
be collected to determine dasatinib cerebrospinal fluid (CSF) and plasma levels. The lumbar 


CALGB 10701/CTSU C10701 
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31 
Update #11 
puncture should be performed between 2 and 3 hours after dasatinib administration, and the 
timing of the dasatinib administration. 
6.4.2 Cerebrospinal Fluid and Plasma Specimen Submission 
• 
Peripheral Blood: Collect 3 mL of peripheral blood in a 3 mL lavender top tube. After 
collection, invert specimen gently 8-10 times for complete mixing 
with the 
anticoagulant. Place the lavender tube on wet ice for a minimum of 10 minutes. 
Centrifuge within 30 minutes of collection at 4 degrees for 5 minutes at 2000 x g. 
Transfer plasma into a labeled, screw-cap, polypropylene plasma drug tube, or 
equivalent. Specimens should be stored at or below -20°C. 
 
Label the tube with the patient study ID#, protocol number, date of collection, nominal 
collection time and cycle, actual sample time, and source of material. 
• 
CSF: Collect CSF in a lavender top tube. After collection, invert specimen gently 8-10 
times for complete mixing with the anticoagulant. Place the lavender tube on wet ice for 
a minimum of 10 minutes. Centrifuge within 30 minutes of collection at 4 degrees for 5 
minutes at 2000 x g. Transfer into a labeled, screw-cap, polypropylene plasma drug 
tube, or equivalent. Specimens should be stored at or below -20°C. 
 
Label the tube with the patient study ID#, protocol number, date of collection, nominal 
collection time and cycle, actual sample time, and source of material. 
It is essential that all specimens are thoroughly frozen prior to packing for shipment and that 
all tubes are securely capped. All specimens should be shipped on dry ice by overnight 
express courier. Samples must be logged and shipped via BioMS, see Section 6.2 for 
instructions. A copy of the shipping manifest produced by BioMS must be printed and 
placed in the shipment with the specimens. Shipment on Monday through Thursday by 
overnight service to assure receipt is encouraged. Do not ship specimens on Fridays or 
Saturdays. Specimens may be shipped to: 
Alliance Biorepository at Ohio State University (OSU) 
Department of Pathology 
Polaris Innovation Center 
2001 Polaris Parkway  
Columbus, OH  43240  
Phone: 614-293-7073  
Fax: 614-293-7967  
path.calgb@osmu.edu  
 
Plasma and cerebrospinal fluid samples will be de-identified and sent to Dr. Jan Beumer’s lab 
at University of Pittsburgh Cancer Institute for pharmacokinetics analyses. 
6.5 
CALGB Companion Studies Sample Submission (For Alliance only) 
Follow instructions in the protocols below for collection and submission of specimens. 
6.5.1 CALGB 8461 (Cytogenetic Studies in Acute Leukemia): Patients are required to be 
enrolled on CALGB 8461 in order to meet the objectives of this clinical trial. A bone 
marrow aspirate and/or peripheral blood sample are required at the following 
intervals: 
• 
At diagnosis;  
• 
At complete remission, if diagnostic specimen is abnormal;  
• 
At relapse. 


CALGB 10701/CTSU C10701 
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32 
Update #11 
6.5.2 CALGB 9665 (CALGB Leukemia Tissue Bank) (prior to February 28, 2014): All 
patients are strongly encouraged to be enrolled on CALGB 9665. A marrow aspirate, 
whole blood sample, and buccal smear are required at the following intervals: 
• 
At the time of diagnosis;  
• 
At the time of remission (bone marrow and blood sample only);  
• 
At the time of relapse (bone marrow and blood sample only). 
6.6 
ECOG-ACRIN Companion Studies Sample Submission (For ECOG-ACRIN only) 
Follow instructions in E3903 for collection and submission of specimens. 
6.6.1 ECOG E3903 (Ancillary laboratory protocol for collecting diagnostic material on 
patients considered for ECOG treatment trials for leukemia or related hematologic 
disorders): Patients are required to be enrolled on ECOG E3903. Blood, bone marrow and 
karyotypes are to be submitted as outlined in E3903. After 8/21/2014, no new patients may 
be enrolled on E3903 (see Section 5.5.1). 
 


CALGB 10701/CTSU C10701 
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33 
Update #11 
7.0 
REQUIRED DATA 
Laboratory and clinical parameters during the treatment courses are to be followed using individual 
institutional guidelines and the best clinical judgment of the responsible physician. It is expected that 
patients on this protocol will be cared for by physicians experienced in the treatment and supportive 
care of patients with acute leukemia and transplantation. 
Treatment courses are specified using a roman numeral, followed by a cardinal numeral indicating 
the number of days from the start of that course (e.g., Day III-28 is the 28th day of Course III). 
Guidelines For Pre-Study Testing 
To be completed within 8 DAYS prior to study: 
All bloodwork; bone marrow examinations; history & physical exam; any X-ray, scan of any 
type, or ultrasound of uninvolved organs which is not utilized for tumor measurement. 
Tests & Observations 
Prior 
to 
Study 
Prior to 
Each 
Treatment 
Course (I-
V) 
During Each 
Treatment 
Course (I-V) 
Prior to & 
During Course VI & 
Post- Treatment 
Follow-Up* 
History and Progress Notes 
X 
X 
Weekly 
X 
Physical Examination*** 
X 
X 
A 
X 
Pulse, Blood Pressure, Temperature 
X 
X 
A 
 
Height 
X 
X 
 
 
Weight/Body Surface Area† 
X 
X 
 
X 
Performance Status 
X 
X 
 
X 
Tumor Measurements** 
X 
X 
 
X 
Drug Toxicity Assessment 
 
X 
X 
X 
Laboratory Studies 
 
 
 
 
CBC, Differential, Platelets 
X 
X 
Weekly 
X 
Serum Creatinine, BUN, Electrolytes 
X 
X 
A,L 
 
PT, PTT 
X 
G 
A 
 
AST, ALT, Alk. Phos., Bilirubin, LDH 
X 
X 
A 
 
Uric acid, PO4 
X 
 
A 
 
Total Protein, Albumin 
X 
 
A 
 
Glucose, Amylase, Fibrinogen 
 
 
A 
 
ECHO or MUGA 
 
F, G 
 
 
DLCO (PFTs) 
 
G 
 
 
Hepatitis A, B, C, HIV serology 
 
G 
 
 
EKG 
X 
G 
 
 
u-HCG or Serum HCG 
X 
 
 
 
CMV DNA titer 
 
G,M 
 
 
Staging 
 
 
 
 
Central Morphology Review 
X 
 
 
 
Chest X-ray, PA & Lateral 
X 
O 
 
 
CSF Cell Count, CSF Protein & Glucose 
A 
 
B 
 
CSF for Dasatinib level 
 
 
C 
 
Serum Methotrexate Levels 
 
 
D 
 
Cytogenetics 
X 
E (until 
CCyR) 
 
Relapse 
Chimerism analysis 
 
 
H 
 
Institutional Q-PCR for BCR/ABL 
X 
J 
K 
N 
ABL Mutation Analysis 
X 
 
 
Relapse 
Bone Marrow Asp & Bx 
X 
E 
 
I 


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* 
Monthly for the first year, then every 3 months for 2 years, then every 6 months for 2 years, then yearly for a 
maximum of 10 years from study entry, or at relapse, whichever occurs first. 
** 
Note specifically by physical exam the size of the liver, spleen, lymph nodes and, if applicable, mediastinal 
mass by chest x-ray. 
*** 
Including assessment for symptoms of pulmonary arterial hypertension (PAH). Right heart catheterization can 
confirm the diagnosis of PAH. 
† 
Drug doses need not be changed unless the calculated dose changes by ≥ 10%. 
A 
As clinically indicated using good clinical practice. 
B 
CSF should be obtained on Days I-15, IV-1, IV-15, IV-29, or if clinically indicated (see Sections 8.7 and 
Section 8.8). 
C 
In consenting patients only, CSF + plasma for dasatinib level on day I-15. 
D 
On Days IV-2, IV-4, IV-16, IV-18, IV-30, IV-32 (see Section 8.4.2). 
E 
Required at the end of Courses I, II, III, IV, V (patients undergoing autologous transplant will need BM test 
after Step I and before Step II). 
F 
Required prior to Day 1 of course IIB and III. 
G 
Required prior to Course V allogeneic HCT.  
H 
Institutional chimerism analysis on peripheral blood from donor and recipient prior to registration and from 
recipient on day +30, +90-+100, +180, +365 and at time of relapse. Perform T-cell chimerism on Day +120. 
I 
Every 3 months for 2 years and at relapse.  
J 
Perform institutional Q-PCR on peripheral blood and bone marrow aspirate prior to Course V. 
K 
For allogeneic transplant during Course V, perform institutional Q-PCR on bone marrow on Day +30 and one 
year post transplant. For autologous transplant during Course V, perform institutional Q-PCR on each day’s 
PBSC product, on bone marrow aspirate prior to autologous stem cell transplant, on bone marrow aspirate on 
day +30 post transplant and one year post transplant. For chemotherapy only during Course V, perform 
institutional Q-PCR on bone marrow one year after initiation of chemotherapy. 
L 
Daily during the four days of high-dose ara-C during Course V for autologous transplant and non-transplant 
patients. 
M 
Patients undergoing allogeneic HCT should be screened weekly for CMV viremia until day +120 (see Section 
8.5.1.9). 
N 
For patients who underwent Allogeneic HCT, institutional Q-PCR should be performed on peripheral blood 
every 3 months for 5 years from study entry. For patients who underwent Autologous HCT, institutional 
quantitative RT-PCR should be performed on peripheral blood every 3 months for 5 years from study entry. 
For patients who received the Alternative Chemotherapy Regimen, perform institutional Q-PCR on peripheral 
blood monthly for the first year, every 3 months for 2 years, then every 6 months for 5 years from study entry. 
At time of relapse, perform institutional Q-PCR on peripheral blood or bone marrow aspirate for all patients on 
study. 
O 
Required prior to Course V allogeneic HCT. Required within 72 hours of Course IV day 1 methotrexate IV 
dose to rule out pleural effusion. Repeat chest X-ray prior to each IV methotrexate dose if clinically indicated. 
 
Institutional normal laboratory values must be recorded on flow sheets. 
 


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8.0 
TREATMENT PLAN 
All questions regarding treatment or dose modifications should be directed to the Alliance Study 
Chair. 
Patients must be enrolled on this study without prior enrollment on any other treatment protocol. A 
lumbar puncture prior to treatment is not required and should not be performed in the absence of 
significant CNS symptoms or signs. CNS leukemia at time of entry on study will only be treated if 
symptomatic (see Section 8.7). 
Alliance institutions should submit peripheral blood and bone marrow aspirate specimens for the 
appropriate companion studies CALGB 8461 (required) and CALGB 9665 (in consenting patients). 
See Section 6.5. 
ECOG-ACRIN institutions should submit blood and bone marrow specimens as described in protocol 
ECOG E3903. As of 8/21/2014, no new patients may be enrolled on E3903. See Section 6.6. 
Treatment courses are specified using a roman numeral, followed by a cardinal indicating the number 
of days from the start of that course (e.g., Day III-28 is the 28th day of Course III). 
8.1 
Course I: Induction Therapy 
8.1.1 Pre-Study Phase 
Course I must begin only after confirmation of the presence of t(9;22)(q34; q11) or 
BCR/ABL. During this pre-study phase, dexamethasone 10 mg/m2/day orally (or IV) once 
daily or in divided doses or equivalent corticosteroid regimen can be administered to control 
the peripheral blast count for a maximum of 7 days (Days -7 – 0). Hydroxyurea also is 
permitted to control leukocytosis, although no other ALL-directed therapy is allowed. 
8.1.2 Course I Treatment 
8.1.2.1 Dasatinib 140 mg PO daily. H2 blockers or proton pump inhibitors are prohibited. Use 
of antacids separated by more than 2 hours from dasatinib should be considered.  
8.1.2.2 Dexamethasone 10 mg/m2/day PO or IV (once daily, or in divided doses) on days I-1 
to I-7. Round dose to nearest 0.75 mg. 
8.1.2.3 Day I-15 Bone Marrow Examination 
A bone marrow aspiration and biopsy must be obtained for all patients on day I-15 to 
assess initial response. The day of this bone marrow exam can be moved up or back 
one day to accommodate weekends or holidays. 
8.1.2.4 Day I-15 Cerebrospinal Fluid (CSF) Examination 
A lumbar puncture will be performed on day I-15. The day of this lumbar puncture 
can be moved up or back one day to accommodate weekends or holidays. The lumbar 
puncture (LP) should be performed between 2 to 3 hours after dasatinib 
administration. CSF obtained on day I-15 should be analyzed by cytocentrifuge exam. 
Record the cell count and differential cell count and results of cytocentrifuge 
examination. If the patient has a platelet count <20,000/µL, it is recommended to 
transfuse platelets during the LP. Please see Section 8.7 for treatment of CNS 
leukemia. 
Additionally, in consenting patients (see model consent question #1), a sample will 
be collected for dasatinib level and sent to a central reference laboratory (see Section 
6.3).  


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8.2 
Course II: Early Intensification Therapy (begins shortly after Day I-15) 
The treatment plan for this course will depend on the bone marrow results on day I-15. Until 
these results are available, patients will continue on dasatinib as a single agent at 140 mg/day. It 
is recommended that patients continue with dasatinib and onto Course II regardless of counts. 
All patients will begin cotrimoxazole DS one tablet PO BID 3 days per week continuously 
during Course II, or, if allergic to sulfonamides, inhaled aerosolized pentamidine (300 mg once 
per month) or dapsone 100 mg PO daily.  
8.2.1 If ≤ 20% blasts in the Day I-15 marrow (Cohort IIA) 
8.2.1.1 Dasatinib 140 mg PO daily. H2 blockers or proton pump inhibitors are prohibited. Use 
of antacids separated more than 2 hours from dasatinib should be considered.  
8.2.1.2 Dexamethasone 10 mg/m2/day PO or IV (once daily, or in divided doses) on days II-
1 to II-7. Round dose to nearest 0.75 mg. 
8.2.1.3 Day II-22 Bone Marrow Examination 
A bone marrow aspiration and biopsy must be obtained for all patients on day II-22 
to assess response. Institutions should submit peripheral blood and bone marrow 
aspirate specimens for relevant Alliance companion studies (CALGB 8461 
[required]).  
8.2.2 If > 20% blasts in the Day I-15 marrow (Cohort IIB) 
8.2.2.1 Dasatinib 140 mg PO daily. H2 blockers or proton pump inhibitors are prohibited. Use 
of antacids separated more than 2 hours from dasatinib should be considered.  
8.2.2.2 Dexamethasone 10 mg/m2/day PO or IV (once daily, or in divided doses) on days II-
1 to II-7. Round dose to nearest 0.75 mg. 
8.2.2.3 Daunorubicin 30 mg/m2/day IV on days II-1, II-8 and II-15. 
8.2.2.4 Vincristine 2 mg (flat dose) IV on days II-1, II-8, and II-15. If use of an azole 
antifungal is necessary, it is recommended that an agent with the least inhibitory affect 
on CYP3A4 be selected if possible. The following azoles appear in order of strength 
of inhibition of CYP3A4: voriconazole, itraconazole, posaconazole, and fluconazole. 
Fluconazole at doses of 200 mg or less is not thought to be a significant inhibitor of 
CYP3A4. Azole antifungal agents should not be administered within 5 half lives of 
vincristine. Please note vincristine dose modifications in Section 9.5.5. 
8.2.2.5 Day II-22 Bone Marrow Examination 
A bone marrow aspiration and biopsy must be obtained for all patients on day II-22 
to assess response. Institutions should submit peripheral blood and bone marrow 
aspirate specimens for relevant Alliance companion studies (CALGB 8461 
[required]).  
8.3 
Course III: Second Induction Therapy (only for patients not yet in CR or CRi) 
The treatment plan for this course will depend on the bone marrow results from day II-22 for 
cohorts IIA and IIB. Until these results are available, patients will continue dasatinib at 140 
mg/day.  
If patients have achieved hematologic and morphologic complete remission (please see Section 
12.1 for definition of complete remission) based on day II-22 bone marrow examination, they 


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will proceed directly to Course IV without receiving the second induction therapy in Course 
III below. Those patients who have not achieved CR, however, will receive Course III below. 
All patients will continue cotrimoxazole DS one tablet PO BID 3 days per week continuously 
during Course III, or, if allergic to sulfonamides, inhaled aerosolized pentamidine (300 mg once 
per month) or dapsone 100 mg/day.  
8.3.1 Dasatinib 140 mg PO daily. 
8.3.2 Cyclophosphamide 1000 mg/m2 IV on day III-1. Hydrate intravenously and induce 
diuresis. 
8.3.3 Daunorubicin 30 mg/m2/day IV on days III-1 and III-8. 
8.3.4 Vincristine 2 mg (flat dose) IV on days III-1 and III-8. Concomitant voriconazole or 
posaconazole are contraindicated due to increased neurotoxicity. If use of an azole 
antifungal is necessary, it is recommended that an agent with the least inhibitory affect on 
CYP3A4 be selected if possible. The following azoles appear in order of strength of 
inhibition 
of CYP3A4: voriconazole, itraconazole, posaconazole, and fluconazole. 
Fluconazole at doses of 200 mg or less is not thought to be a significant inhibitor of 
CYP3A4. Azole antifungal agents should not be administered within 5 half lives of 
vincristine. Please note vincristine dose modifications in Section 9.5.5. 
8.3.5 Dexamethasone 10 mg/m2/day PO or IV (once daily, or in divided doses) on days III-1 to 
III-7. Round dose to nearest 0.75 mg. 
8.3.6 G-CSF subcutaneously daily beginning on day III-9 and continuing for at least 7 days and 
then until neutrophil recovery (≥ 1000/µL) on any one determination after the nadir. Use the 
nearest vial size for administration: for patients <78 kg use 300 mcg and for patients ≥78 kg 
use 480 mcg vial. One dose of PEG-filgrastim (6 mg) may be substituted for G-CSF on day 
III-9. 
8.3.7 Day III-29 Bone Marrow Examination 
A bone marrow aspiration and biopsy must be obtained for all patients on day III-29 or as 
soon thereafter as the ANC recovers to >1000/µl to assess response. Alliance institutions 
should submit peripheral blood and bone marrow aspirate specimens for relevant companion 
studies (8461 [required]).  
8.4 
Course IV: CNS Prophylaxis Therapy 
Do not begin Course IV therapy until dasatinib has been interrupted for at least 7 days prior to 
administration of the day 1 IV methotrexate dose. 
It is recommended that patients be hospitalized during the high-dose IV methotrexate 
administration for continuous IV hydration. 
The goal of this treatment course is to maintain serum methotrexate concentrations of >1 µM 
for 30 continuous hours during 3 treatments. It is recommended that IV vincristine be 
administered prior to the initiation of the IV methotrexate infusion. The IT methotrexate 
should be administered later in the day (at any time during the IV methotrexate infusion) to 
avoid any possible confusion between the IV vincristine and the IT methotrexate. 
All patients will continue cotrimoxazole DS one tablet PO BID 3 days per week until the 
completion of all therapy, or, if allergic to sulfonamides, inhaled aerosolized pentamidine (300 
mg once per month). Cotrimoxazole should be stopped 3 days before and resumed 3 days 
after each dose of methotrexate. 


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• 
Dasatinib 140 mg PO daily beginning after recovery from the final methotrexate dose 
(methotrexate level <0.05 µM). 
• 
IT Methotrexate (IT Mtx) 15 mg intrathecal once every two weeks on days IV-1, IV-15, 
and IV-29. Use preservative-free methotrexate. Hydrocortisone 50 mg should be included 
with the methotrexate. The LP can be done anytime during the 3-hour IV methotrexate 
infusion on these days, but it is recommended that it be done at the end of the 3-hour IV 
methotrexate infusion, well after the IV vincristine has been given.  
• 
Vincristine (VCR) 2 mg (flat dose) IV once every two weeks on days IV-1, IV-15, and IV-
29. If use of an azole antifungal is necessary, it is recommended that an agent with the least 
inhibitory affect on CYP3A4 be selected if possible. The following azoles appear in order 
of strength of inhibition of CYP3A4: voriconazole, itraconazole, posaconazole, and 
fluconazole. Fluconazole at doses of 200 mg or less is not thought to be a significant 
inhibitor of CYP3A4. Azole antifungal agents should not be administered within 5 half lives 
of vincristine. Please note vincristine dose modifications in Section 9.5.5. 
• 
IV Methotrexate (IV Mtx) 500 mg/m2 IV in one liter of D5W or NS over 3 hours once 
every two weeks days IV-1, IV-15, and IV-29. Prior to beginning IV-Mtx, patients should 
be pre-hydrated with 500 mL - 1 liter of D5W plus 100 mEq/L of sodium bicarbonate. 
Continue vigorous hydration as tolerated over the course of the day to maintain hydration 
and urine pH >6. Please check with pharmacy to ensure that patients are not receiving any 
medications (e.g., sulfonamides, salicylates, penicillins, other organic acids, proton pump 
inhibitors) that may interfere with methotrexate clearance.  
• 
It is strongly recommended that additional hydration (with NS or D5W containing 100 
mEq/L of sodium bicarbonate per liter) be given on days 2, 16 and 30 when patient returns 
for IV leucovorin. If patients remain on PO leucovorin for a prolonged period of time 
because of slow methotrexate clearance, then the subsequent dose of methotrexate 
(scheduled on days IV-15 and IV-29) must be delayed, as necessary, to ensure that no 
leucovorin has been administered for at least 72 hours prior to beginning the next 
methotrexate infusion. 
• 
PO Methotrexate (PO Mtx) 25 mg/m2 PO every 6 hours x 4 doses (total) beginning 6 hours 
after starting each dose of IV Mtx (on days 1 and 2, days 15 and 16, and days 29 and 30). 
See Section 8.4.2 for dose adjustment levels. Doses should be rounded to the nearest 2.5 mg 
tablet size. 
• 
IV Leucovorin (IV Lcv) 25 mg/m2 IV 6 hours after the 4th (last) PO Mtx dose (i.e., 30 hours 
after starting IV Mtx; on days 2, 16, and 30).  
• 
PO-Leucovorin (PO Lcv) 5 mg/m2 PO every 6 hours for a planned 8 doses or until serum 
methotrexate level <0.05 µM, beginning 12 hours after IV Lcv. (Calculated doses of 7.5 mg 
to 12.5 mg may be rounded to nearest 10 mg.)


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Update #11 
8.4.1 Timing of Chemotherapy 
The following is a recommended schedule of chemotherapy administration: 
Day  
IV-1 
Monday, 9 AM: 
Monday, 9 AM-12 PM: 
IV Vincristine. 
IV Mtx 3-hour infusion with hydration. During IV infusion, 
administer IT Mtx.* 
Monday, 3 PM: 
Monday, 9 PM: 
Begin PO Mtx. 
PO Mtx at home. 
Day  
IV-2 
Tuesday, 3 AM: 
Tuesday, 9 AM: 
Tuesday, 3 PM: 
PO Mtx at home. 
PO Mtx at home. 
Obtain serum Mtx level (see Section 8.4.2). Give IV Lcv. 
Day  
IV-3 
Wednesday, 3 AM: 
Wednesday, 9 AM: 
Wednesday, 3 PM: 
Wednesday, 9 PM: 
PO Lcv at home. 
PO Lcv at home. 
PO Lcv at home. 
PO Lcv at home. 
Day  
IV-4 
Thursday, 3 AM: 
Thursday, 9 AM: 
Thursday, 3 PM: 
Thursday, 9 PM: 
Thursday: 
PO Lcv at home. 
PO Lcv at home. 
PO Lcv at home. 
PO Lcv at home. 
Obtain serum Mtx level at any time during the day on Thursday. Stop 
leucovorin if serum Mtx <0.05 mM. 
* It is recommended that patients be hospitalized during the high-dose IV methotrexate 
administration for continuous IV hydration. 
8.4.2 Serum Methotrexate Levels 
Serum methotrexate levels should be obtained on days IV-2 (exactly 30 hours after starting 
the IV Mtx infusion) and IV-4, days IV-16 and IV-18, and days IV-30 and IV-32. 
On day IV-15 and day IV-29, the oral methotrexate dose will be adjusted to try to achieve a 
level between 1-2 mM at 30 hours. The adjustment will be performed on day IV-15 and IV-
29 based on the 30-hour serum methotrexate level obtained during the previous week on 
Days IV-2 or IV-16. Please refer to the tables below for instructions on methotrexate dose 
adjustments. 
Note: All patients should begin PO Mtx at Level 0 (25 mg/m2 PO every 6 hours x 4). 
Subsequent adjustments will be made according to the table below. Each adjustment will be 
made according to the previous week’s methotrexate level at 30 hours. 
Note: Patients must be off leucovorin for a minimum of 3 days (72 hours) prior to beginning 
the next dose of methotrexate. 
Note: For methotrexate renal toxicity see Section 9.5.4. See Section 16.2 for additional 
reporting requirements. 
The PO methotrexate dose should be adjusted according to the following tables:  
30 hour Mtx level (µM) from 
Day 2 or Day 16 
Dose Adjustment for Day 15 or Day 29 
< 1.0 
Increase one dose level from previous week 
1 – 2 
No adjustment 
2.1 - 10 
Decrease one dose level from previous week 
> 10 
No oral methotrexate 
 
 
 
 


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Update #11 
Dose Level 
Adjusted MTX Dose 
2 
60 mg/m2 every 6 hours x 4 
1 
40 mg/m2 every 6 hours x 4 
0 (Starting Level) 
25 mg/m2 every 6 hours x 4 
-1 
18 mg/m2 every 6 hours x 4 
-2 
13 mg/m2 every 6 hours x 4 
8.4.3 Day IV-43 Bone Marrow Examination 
A bone marrow aspiration and biopsy must be obtained for all patients on about day IV-43 
to assess response, and perform institutional Q-PCR on peripheral blood and bone marrow 
aspirate. Alliance institutions should submit peripheral blood and bone marrow aspirate 
specimens for relevant companion studies (CALGB 8461 [required]).  
8.5 
Course V 
This course includes three different options: allogeneic transplantation for patients ages 18-70 
with an HLA-matched donor (see Section 8.5.1); autologous transplantation for patients age 18-
70 without an HLA-matched donor or not a candidate for allogeneic transplantation (see Section 
8.5.2); and for patients age > 70, or who are not transplant candidates, or without insurance 
coverage, an alternative chemotherapy regimen without transplantation (see Section 8.5.3). 
The treating physician should consult with the Study Chair regarding frail patients who may 
need to skip Course V and continue on to Course VI. 
8.5.1 Course V: Allogeneic Transplantation (for patients ages 18-70 with an HLA-matched 
donor) 
Discontinue dasatinib during Course V (Allogeneic Transplantation) until approximately 
day V-30. 
Patients must be treated at or referred to an Alliance-approved, ECOG-ACRIN-approved, 
SWOG-approved, or FACT-credentialed allogeneic transplant center to be eligible to 
receive this portion of the therapy. Course V therapy should begin no later than 10 days 
following count recovery in Course IV. 
To receive allogeneic transplant, patients must have adequate organ function (renal, liver, 
cardiac, and pulmonary) to meet institutional requirements for allogeneic transplantation. 
8.5.1.1 Donor Mobilization 
Any consenting healthy individual who fulfills the donor (FAHCT) criteria will be 
considered for peripheral blood stem cell mobilization and collection. Sibling donors 
must be matched at 6/6 or 5/6 HLA antigens (HLA A, B and DR). Unrelated donors 
will be matched for HLA A, B, C and DRB1 antigens by molecular sequencing 
techniques. Syngeneic donors are acceptable. 
• 
Mobilization of allogeneic peripheral blood stem cells will be performed 
according to institutional guidelines. Peripheral blood stem cell collection should 
target an optimal CD34+ cell dose > 5 x 106 cells/kg (actual weight) with a 
maximum of 10 x 106 CD34+ cells/kg. Stem cells may be collected at any time 
prior to transplant. 
• 
In instances where the cells harvested from the donor are <5 x 106 CD34+ cells/kg 
recipient, the clinical investigator may elect to collect a bone marrow backup 
product. 


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Update #11 
8.5.1.2 Fludarabine 30 mg/m2/day (actual body weight) IV over 30 minutes on days –7, –6, 
–5, –4, –3. At a minimum of one hour prior to the first dose, begin IV hydration to 
induce at least 100 mL/hr urine output. Fludarabine will be administered prior to 
alemtuzumab. 
8.5.1.3 Alemtuzumab 20 mg/day (flat dose) IV over 30 minutes on days –7, –6, –5, –4, –3. 
Alemtuzumab will be given within one hour of completion of fludarabine. Prior to each 
alemtuzumab infusion, patients will receive acetaminophen 650 mg orally, 
diphenhydramine 50 mg IV (or equivalent), and methylprednisolone 2 mg/kg IV (or 
equivalent) to prevent alemtuzumab toxicity. Premedication may be repeated as 
necessary. Patients who develop infusion-related symptoms, such as fever, or rigors, 
despite treatment with diphenhydramine, acetaminophen and methylprednisolone, will 
receive meperidine at investigator discretion. 
8.5.1.4 Melphalan 140 mg/m2/day (corrected body weight) IV over 30 minutes on day –2. It 
is recommended that the patient be hydrated with normal saline (150 mL/hour) starting 
one hour prior to the melphalan dose and continuing for 24 hours after the melphalan 
dose.  
Corrected weight = ideal weight (see Appendix I) + 25% of the difference between 
ideal and actual weight. If actual weight is less than ideal, use actual weight rather 
than corrected weight. The corrected weight should then be used to calculate Body 
Surface Area (BSA) for dosing. 
8.5.1.5 GVHD Prophylaxis with Tacrolimus for Matched Sibling Donors 
• 
GVHD prophylaxis should be per institutional guidelines. The following is a 
recommendation for the use of tacrolimus. 
• 
Tacrolimus 0.05 mg/kg/day on Day -2 through +3 (6 days total) given via 
continuous IV infusion. The scheduling of tacrolimus administration should be 
such that a full 48 hours has been given before the donor stem cells are infused.  
• 
Tacrolimus 0.03 mg/kg/day on Day +4 through +14 (11 days total) via continuous 
IV infusion. 
• 
Tacrolimus 0.03 mg/kg/day on Day +15 through +100 via continuous IV infusion 
or in divided doses every 12 hours or oral. Oral dose is 3x the last IV dose.  
• 
Tacrolimus blood concentration should be maintained between 10 - 20 ng/mL as 
a steady state during continuous IV infusion or as trough levels during divided 
doses. 
• 
Following Day +100, tacrolimus will be tapered according to institutional 
guidelines. 
8.5.1.6 GVHD Prophylaxis with Tacrolimus for Mismatched (5/6) Related and Matched 
Unrelated Donors (MUD)  
• 
GVHD prophylaxis should be per institutional guidelines. The following is a 
recommendation for the use of tacrolimus. 
• 
Initial tacrolimus dosing will be the same as in Section 8.5.1.5. 
• 
In recipients of mismatched related or unrelated donor transplants, tacrolimus 
should continue until day +180. Thereafter, tacrolimus will be tapered by 20% 
per week in the absence of GVHD. 
8.5.1.7 Allogeneic peripheral blood stem cells will be infused on day 0. 


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Update #11 
8.5.1.8 G-CSF 5 mcg/kg/day (actual body weight) SC beginning on day +1. 
It is recommended that G-CSF be started on day +1. If no ANC recovery has 
been achieved by Day 14, G-CSF must be administered.  
• 
G-CSF should continue daily until ANC > 1500/µL for 2 consecutive days or 
5000/µL for 1 day. G-CSF can be restarted if the ANC falls to < 500/µL. 
• 
G-CSF doses should be rounded as follows: 300 mcg for patients ≤60 kg, 480 
mcg for weight 61-95 kg, 600 mcg if weight >95 kg. IV administration of 
each dose over 15-60 minutes is permissible if patient cannot tolerate 
subcutaneous injections. 
8.5.1.9 Infectious Disease Prophylaxis 
• 
Antibacterial prophylaxis is required. For example, levofloxacin 500 mg or 
gatifloxacin 400 mg orally or institutional equivalent until resolution of 
neutropenia. 
• 
Antifungal prophylaxis is required. For example, posaconazole 200 mg three 
times daily orally or voriconazole 200 mg two times daily orally (or IV) or 
institutional equivalent until day +180. Azole antifungal agents should not be 
administered within 5 half lives of vincristine. 
• 
Pneumocystis 
pneumonia 
prophylaxis 
is 
required. 
For 
example, 
cotrimoxazole double-strength BID twice a week from engraftment until 1 year 
after transplantation.  
• 
CMV viremia monitoring and prophylaxis are required. For example, 
cytomegalovirus (CMV) positive patients or those who had a CMV-seropositive 
donor can be given ganciclovir 5 mg/kg from day -8 until day -3, followed by 
receive acyclovir 10 mg/kg every 8 hours IV/orally until discharge. Then continue 
acyclovir 800 mg orally three times a day will be continued until day 210. 
Alternatively, 
and based on institutional 
practice, patients can receive 
valacyclovir 2,000 mg four times daily from discharge until day +210. Patients 
who are CMV negative and had a CMV-negative donor can follow institutional 
guidelines. 
• 
Patients should be screened weekly for CMV viremia until day +120 and treated 
with ganciclovir upon detection of CMV viremia. 
• 
Monitoring for EBV viremia by DNA PCR is strongly encouraged througout the 
first 100 days. 
• 
Antifungal, antiviral, and Pneumocystis prophylaxis and screening for CMV 
viremia should continue indefinitely for those with active GVHD or those 
receiving immunosuppressive treatment. 
• 
In institutions that do not provide CMV-negative blood products for CMV-
negative donor/recipient pairs, CMV-negative donor/recipient pairs should be 
screened weekly for CMV viremia. 
8.5.1.10 On Day 30 post-transplant in Course V all patients will undergo a bone marrow 
examination. Perform institutional Q-PCR on bone marrow aspirate on Day +30 and 
one year post-transplant to assess for minimal residual disease.  


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Update #11 
8.5.2 Course V: Autologous Transplantation (for patients ages 18-70 without an HLA-
matched donor or not a candidate for allo-HCT) 
Patients must be treated at or referred to an Alliance-approved, ECOG-ACRIN-approved, 
SWOG-approved or FACT-credentialed autologous transplant center to be eligible to 
receive this portion of the therapy. Course V therapy should begin no later than 10 days 
following count recovery in Course IV. 
To receive autologous transplant, patients must have adequate organ function (renal, liver, 
cardiac, and pulmonary) to meet institutional requirements for autologous transplantation. 
Discontinue dasatinib 24 hours prior to the initiation of Course V and restart after 
completion of stem cell collection (see Section 8.5.2.8). 
8.5.2.1 Step I – Peripheral Blood Stem Cell (PBSC) Mobilization and Leukapheresis 
Patients will receive therapy as follows: 
1) Begin the etoposide continuous IV infusion at hour 0 (Hours 0 - 96, days 1-4); 
2) Start the high-dose ara-C (HiDAC) 2-hour IV infusion at hour 0 (every 12 hours 
x 8 doses on days 1-4); 
3) Start the G-CSF on day 14 at a dose of 10 mcg/kg/day SC. G-CSF must be 
continued until PBSC collection has been completed or WBC >50,000/µL. 
4) It is recommended that patients remain in hospital until full hematologic recovery. 
8.5.2.2 Etoposide 
• 
In patients age ≤ 65 years, etoposide 10 mg/kg/day (corrected weight) via 
continuous IV infusion over 96 hours (days 1-4). Total dose is 40 mg/kg. 
Corrected weight = ideal weight (see Appendix I) + 25% of the difference 
between ideal and actual weight. If actual weight is less than ideal, use actual 
weight rather than corrected weight. 
During etoposide infusion, other IV fluids should be kept to a minimum and blood 
products should not be given except in an emergency. 
• 
In patients age > 65 years, etoposide 5 mg/kg/day (corrected weight) via 
continuous IV infusion over 96 hours (days 1-4). Total dose is 20 mg/kg. 
Corrected weight = ideal weight (see Appendix I) + 25% of the difference 
between ideal and actual weight. If actual weight is less than ideal, use actual 
weight rather than corrected weight. 
During etoposide infusion, other IV fluids should be kept to a minimum and blood 
products should not be given except in an emergency. 
8.5.2.3 HiDAC 
In patients ≤ 65 years of age: 
• 
Cytarabine 2000 mg/m2 in 250 mL D5W IV over 2 hours every 12 hours x 8 doses 
(days 1-4). 
• 
Prior to each dose of cytarabine, evaluate for the presence of nystagmus or other 
signs of cerebellar dysfunction. (Assessments are more accurate if the patient has 
not recently, i.e., in approximately the last hour, been medicated with anti-
emetics.) If these symptoms are present, stop cytarabine and do not resume this 
drug. Corticosteroid eye drops should be used prophylactically. Please note dose 
modification in Section 9.6. 


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• 
Cytarabine doses should be given while the etoposide continuous infusion is 
running. 
• 
Actual body weight should be used in Body Surface Area (BSA) calculations for 
dosing. 
In patients > 65 years of age: 
• 
Cytarabine 1000 mg/m2 in 250 mL D5W IV over 2 hours every 12 hours x 8 doses 
(days 1-4). 
• 
Prior to each dose of cytarabine, evaluate for the presence of nystagmus or other 
signs of cerebellar dysfunction. (Assessments are more accurate if the patient has 
not recently, i.e., in approximately the last hour, been medicated with anti-
emetics.) If these symptoms are present, stop cytarabine and do not resume this 
drug. Corticosteroid eye drops should be used prophylactically. Please note dose 
modification in Section 9.6. 
• 
Cytarabine doses should be given while the etoposide continuous infusion is 
running. 
• 
Actual body weight should be used in Body Surface Area (BSA) calculations for 
dosing. 
8.5.2.4 Prophylactic Anti-Fungal, Anti-Bacterial Antibiotic and Anti-Viral Therapy 
Prophylactic anti-fungal and anti-bacterial antibiotic therapy beginning on day 5 of 
this regimen are required. An institutional equivalent, or any of the following 
commonly used regimens may be used: ciprofloxacin 
500 mg PO BID, 
amoxicillin/clavulanate (Augmentin) 875 mg PO BID, acyclovir 400 mg PO BID, 
posaconazole 200 mg PO TID, fluconazole 200 BID or voriconazole 200 mg BID. 
Such therapy may be discontinued once the ANC is >500/µL, unless otherwise 
clinically indicated. 
8.5.2.5 Granulocyte Colony Stimulating Factor (G-CSF) 
G-CSF 10 mcg/kg/day (total dose) subcutaneously in one or two divided doses 
starting on day 14. Continue until PBSC collection has been completed or WBC 
>50,000/µL. Do not skip or reduce dose for bone pain. 
G-CSF doses should be rounded to the nearest vial size. IV administration of each 
dose over 15-60 minutes is permissible if patient cannot tolerate subcutaneous 
injections. 
8.5.2.6 Peripheral Blood Stem Cell (PBSC) Collection 
• 
Begin PBSC collections when the WBC >10,000/µL. This usually occurs about 
day 18 after starting HiDAC/etoposide. Waiting until the WBC >30,000/µL may 
increase the CD34+ yield. 
• 
Aim for a total of 1-5 collections with a goal of collecting ≥ 5 x 106 CD34+ 
cells/kg and not more than 10 x 106 CD34+ cells/kg. This would be an adequate 
collection even if the mononuclear (MNC) collection is <12 x 108/kg. In the 
absence of a reliable measurement of CD34+ cells, the MNC collection should be 
>12 x 108 cells/kg. 
• 
If the CD34+ collection on the first day of apheresis is poor, it is recommended 
to continue G-CSF, delay apheresis 1-3 days, and resume once the WBC has 
increased to > 15,000-20,000/µL. 


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• 
While 5 x 106 CD34+ cells/kg represents an acceptable minimum, infusion of a 
larger collection may improve engraftment. It is not recommended, however, to 
continue the leukapheresis for more than 5 aphereses in order to exceed the 
minimum required collection once that amount of PBSC has been collected. 
• 
If the CD34 collection is inadequate after 5 aphereses, allow a two-week rest 
period. Bone marrow and peripheral blood criteria for CR must then be 
redocumented after which an attempt may be made to remobilize PBSC using G-
CSF at doses ≥ 10 µg/kg daily. Physician discretion is permitted at this juncture 
with respect to using higher G-CSF doses and allowing the use of GM-CSF. The 
remobilization attempt must take place no later than two weeks after bone marrow 
and peripheral blood criteria for CR have been documented. 
• 
Patients who cannot be mobilized following HiDAC/etoposide because of 
therapy-related complications may remain on study and receive autologous 
transplantation following mobilization at a later date using the methods outlined 
above. Bone marrow and peripheral blood criteria for CR must be met within two 
weeks of the mobilization. 
• 
Patients unable to undergo PSCT after HiDAC/etoposide may continue as 
outlined in Section 8.5.3. 
• 
PBSC processing should occur per institutional criteria. Ex vivo “purging” 
procedures are not permitted.  
• 
An aliquot of each day’s stem cell collection (1 x 107 cells) must be sent for 
institutional Q-PCR.  
8.5.2.7 Backup Bone Marrow Harvest - This is not a requirement if stem cell collection 
is adequate. 
• 
Total nucleated cell count collection should be >1 x 108/kg. 
• 
Cells will be processed as per institutional criteria. 
• 
An aliquot of each day’s stem cell collection (1 x 107 cells) must be sent for 
institutional Q-PCR.  
8.5.2.8 Dasatinib  
Restart dasatinib at 140 mg PO daily after completion of stem cell collection. 
Dasatinib must then be continued until 3 days prior to the autologous transplant. 
8.5.2.9 Step II - Autologous Peripheral Blood Stem Cell Transplant (PBSCT) 
• 
Peripheral blood stem cell transplantation should take place no earlier than 4 
weeks following hospital discharge and after recovery from toxicity related to 
myelosuppression following mobilization and leukapheresis. The preparative 
regimen should begin no sooner than 72 hours after the last dose of dasatinib in 
Section 8.5.2.8. 
• 
Patients must meet institutional criteria for PBSCT and have neither active 
infection nor need for ongoing antibiotics. 
• 
A bone marrow examination must be performed prior to autologous HCT to 
assess response. Patients must remain in complete remission as documented by 
normal bone marrow morphology with < 5% blasts within 2 weeks of transplant 
therapy, and have stable or improving peripheral blood counts. ANC must be > 
500/µL and platelet count > 50,000/µL. Patients with falling blood counts should 
be observed to exclude relapse as the cause of the change. Perform institutional 


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Q-PCR on bone marrow aspirate prior to autologous HCT. Procure specimens for 
relevant companion studies (CALGB 8461 [required]). 
8.5.2.10 Melphalan 100 mg/m2/day (corrected weight) IV over 30 minutes on days -2 and -1. 
It is recommended that the patient be hydrated with normal saline (150 mL/hour) 
starting one hour prior to the melphalan dose and continuing for 24 hours after the 
melphalan dose. Diurese vigorously to keep at baseline weight. 
Corrected weight = ideal weight (see Appendix I) + 25% of the difference between 
ideal and actual weight. If actual weight is less than ideal, use actual weight rather 
than corrected weight. The corrected weight should then be used to calculate Body 
Surface Area (BSA) for dosing. 
8.5.2.11 Autologous PBSC infusion on Day 0. Peripheral stem cells should be thawed in a 
37°C water bath and infused IV immediately without an in-line filter. 
8.5.2.12 G-CSF 5 mcg/kg (actual body weight) subcutaneously daily starting on day 0 and 
continued daily until ANC >1500/µL for 2 days or >5000/µL for one day. G-CSF 
should be restarted if the ANC falls to <500/µL and continued until the ANC >5000/µL 
for two days. 
G-CSF doses should be rounded off to nearest vial sizes. IV administration of each 
dose over 15-60 minutes is permissible if patient can not tolerate subcutaneous 
injections. 
8.5.2.13 On Day 30 post-transplant following Course V all patients will undergo a bone 
marrow examination. Perform institutional Q-PCR on bone marrow aspirate on 
Day+30 and one year post-transplant.  
8.5.3 Course V: Alternative Chemotherapy Regimen without Transplantation (for those 
patients age > 70, those who are not candidates for any transplant, or those without 
insurance coverage) 
Patients who are age > 70, who are not candidates for transplantation, or those without 
insurance coverage should not be removed from protocol therapy. Rather, they will receive 
an alternative chemotherapy regimen consisting of etoposide and high-dose ara-c. 
Dasatinib is to be discontinued until initiation of Course VI. 
Chemotherapy should begin no less than 72 hours and no more than 10 days after the last 
dose of dasatinib in Course IV. 
8.5.3.1 Etoposide 
• 
In patients age ≤ 65 years, etoposide 10 mg/kg/day (corrected weight) via 
continuous IV infusion over 96 hours (days 1-4). Total dose is 40 mg/kg. 
Corrected weight = ideal weight (see Appendix I) + 25% of the difference 
between ideal and actual weight. If actual weight is less than ideal, use actual 
weight rather than corrected weight. 
During etoposide infusion, other IV fluids should be kept to a minimum and blood 
products should not be given except in an emergency. 
• 
In patients age > 65 years, etoposide 5 mg/kg/day (corrected weight) via 
continuous IV infusion over 96 hours (days 1-4). Total dose is 20 mg/kg. 


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Corrected weight = ideal weight (see Appendix I) + 25% of the difference 
between ideal and actual weight. If actual weight is less than ideal, use actual 
weight rather than corrected weight. 
During etoposide infusion, other IV fluids should be kept to a minimum and blood 
products should not be given except in an emergency. 
8.5.3.2 HiDAC 
• 
In patients age ≤ 65 years, cytarabine 2000 mg/m2 in 250 mL D5W IV over 2 
hours every 12 hours x 8 doses (days 1-4). Prior to each cytarabine dose, evaluate 
for the presence of nystagmus or other signs of cerebellar dysfunction. 
(Assessments are more accurate if the patient has not recently, i.e., in 
approximately the last hour, been medicated with anti-emetics.) If these 
symptoms are present, stop cytarabine and do not resume this drug. Corticosteroid 
eye drops should be used prophylactically. Cytarabine doses should be given 
while the etoposide continuous infusion is running. Actual body weight should be 
used in Body Surface Area (BSA) calculations for dosing. 
• 
In patients age > 65 years, cytarabine 1000 mg/m2 in 250 mL D5W IV over 2 
hours every 12 hours x 8 doses (days 1-4). Prior to each cytarabine dose, evaluate 
for the presence of nystagmus or other signs of cerebellar dysfunction. 
(Assessments are more accurate if the patient has not recently, i.e., in 
approximately the last hour, been medicated with anti-emetics.) If these 
symptoms are present, stop cytarabine and do not resume this drug. Corticosteroid 
eye drops should be used prophylactically. Cytarabine doses should be given 
while the etoposide continuous infusion is running. Actual body weight should be 
used in Body Surface Area (BSA) calculations for dosing. 
8.5.3.3 Prophylactic Anti-Fungal, Anti-Bacterial Antibiotic, and Antiviral Therapy 
Prophylactic anti-fungal and anti-bacterial antibiotic therapy beginning on day 5 of 
this regimen are required. A commonly used regimen is ciprofloxacin 500 mg PO 
BID, amoxicillin/clavulanate (Augmentin) 875 mg PO BID, acyclovir 400 mg PO 
BID and posaconazole 200 mg PO TID. Such therapy may be discontinued once the 
ANC is >500/µL, unless otherwise clinically indicated. 
8.5.3.4 Granulocyte Colony Stimulating Factor (G-CSF) 
G-CSF 5 mcg/kg/day subcutaneously starting on day 14, and continued until WBC 
>5000/µL for one day or >1500 for two days. 
G-CSF doses should be rounded to the nearest vial size. IV administration of each 
dose over 15-60 minutes is permissible if patient can not tolerate subcutaneous 
injections. 
8.5.3.5 On Day 30 of Course V all patients will undergo a bone marrow examination. 
Perform institutional Q-PCR on bone marrow aspirate approximately one year 
after initiating Course V.  
8.6 
Course VI: Dasatinib Maintenance Therapy 
8.6.1 In Patients Who Underwent Allogeneic HCT 
Patients who underwent allogeneic HCT will receive dasatinib for at least twelve months 
after the initial dose of dasatinib. Dasatinib maintenance is to be discontinued when any 
ONE of the following criteria are met: 


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(1) Completion of 12 months of maintenance if two consecutive negative RT-PCR 
assays performed in a local CLIA-approved laboratory three months apart are 
documented. 
(2) After 12 months of maintenance when two consecutive negative RT-PCR assays 
performed in a local CLIA-approved laboratory three months apart are documented. 
(3) At relapse. 
Dasatinib maintenance administered as follows: 
• 
Dasatinib 50 mg/day PO beginning on about day V-30 post-transplant (if tolerable). 
• 
Dasatinib dose should be increased to 100 mg PO once daily after two weeks if 
tolerated. Report accurately in the flow sheets. 
• 
Bone marrow examinations will occur every 3 months for 2 years and at relapse. 
Institutional Q-PCR should be performed on peripheral blood every 3 months for 5 years 
from study entry. At time of relapse, MRD assessment on bone marrow aspirate or 
peripheral blood by institutional Q-PCR should be performed.  
8.6.2 In Patients Who Underwent Autologous HCT 
Patients who underwent autologous HCT will receive dasatinib for at least twelve months 
after the initial dose of dasatinib. Dasatinib maintenance is to be discontinued when any 
ONE of the following criteria are met: 
(1) Completion of 12 months of maintenance if two consecutive negative RT-PCR 
assays performed in a local CLIA-approved laboratory three months apart are 
documented. 
(2) After 12 months of maintenance when two consecutive negative RT-PCR assays 
performed in a local CLIA-approved laboratory three months apart are documented. 
(3) At relapse. 
Dasatinib maintenance administered as follows: 
• 
Dasatinib 100 mg PO once daily beginning on about day V-30 post-transplant (if 
tolerable). 
• 
Bone marrow examinations will occur every 3 months for 2 years and at relapse. 
Institutional quantitative RT-PCR should be performed on peripheral blood every 3 
months for 5 years from study entry. At time of relapse, MRD assessment on bone 
marrow aspirate or peripheral blood by institutional Q-PCR should be performed.  
8.6.3 In Patients Who Did Not Undergo HCT 
Patients who did not undergo HCT will receive dasatinib and chemotherapy for at least 
twelve months after the initial dose of dasatinib. Dasatinib maintenance is to be discontinued 
when any ONE of the following criteria are met: 
(1) Completion of 12 months of maintenance if two consecutive negative RT-PCR 
assays performed in a local CLIA-approved laboratory three months apart are 
documented. 
(2) After 12 months of maintenance when two consecutive negative RT-PCR assays 
performed in a local CLIA-approved laboratory three months apart are documented. 
(3) At relapse. 
Dasatinib and chemotherapy maintenance administered as follows: 


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• 
Dasatinib 100 mg PO once daily beginning on day V-30 (30 days after starting 
etoposide/cytarabine). 
• 
Vincristine 2 mg IV every 4 weeks. 
• 
Dexamethasone 10 mg/day for 5 days every 4 weeks. 
• 
6-mercaptopurine 60 mg/m2/day PO in the evening. Doses of 6-mercaptopurine may 
be rounded to the next 25 mg. 
• 
Methotrexate 20 mg/m2 PO once per week. Doses of methotrexate may be rounded to 
the next 2.5 mg. 
• 
Bone marrow examinations will occur every 3 months for 2 years and at relapse. 
Institutional Q-PCR should be performed on peripheral blood every month for the first 
year, every 3 months for the following two years, and every six months for 5 years from 
study entry. At time of relapse, MRD assessment on bone marrow aspirate or peripheral 
blood by institutional Q-PCR should be performed.  
8.7 
Treatment for CNS Leukemia 
CNS leukemia at time of entry on study or up to the beginning of Course III will only be treated 
if symptomatic. Give IT methotrexate 15 mg twice weekly (hydrocortisone 50 mg should be 
included with preservative free methotrexate) for at least 6 doses and until the CSF is clear. 
Begin cranial radiation therapy (see Section 8.9) for symptomatic patients with CNS leukemia 
at time of entry (or promptly after day of CNS diagnosis for symptomatic patients diagnosed 
after entry into this protocol). Concurrent with cranial radiation therapy, continue weekly IT 
methotrexate (15 mg). Use minimal doses of leucovorin as necessary to prevent mucositis or 
severe myelosuppression. If CNS remission is achieved, then continue to give intrathecal 
methotrexate monthly for 12 months. 
8.8 
CNS Leukemia Developing During Hematologic Remission (CR or PR) While Receiving 
or Having Completed Protocol Therapy 
Continue protocol therapy for patients who experience CNS failure without marrow relapse. 
Give 15 mg IT methotrexate weekly or twice weekly until CNS is clear of leukemia cells and 
then monthly for 12 months. Give concurrent cranial radiation (see Section 8.9). These patients 
continue to receive protocol therapy until bone marrow relapse occurs. Consult with the Alliance 
Study Chair if CSF leukemia persists, regarding the use of intrathecal cytarabine. 
8.9 
Cranial Radiation Therapy 
Cranial radiation therapy is intended only for patients with CNS leukemia at presentation, 
symptomatic CNS disease prior to beginning Course III, or for patients who develop symptoms 
of CNS disease during remission (as described in Sections 8.7 and 8.8). IMRT and proton RT 
will not be allowed on this study. 
8.9.1 Equipment 
Modality: Co-60 or X-ray beams with a nominal energy between 4 and 6 MV. 
Calibration: The calibrations of therapy units used in this protocol shall be verified by the 
Radiological Physics Center. 
8.9.2 Target Volume 
The target volume consists of the entire brain and meninges, including the frontal lobe as 
well as the posterior halves of the globes of the eyes, with the optic disk and nerve superior 


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to the vertex and posterior to the occiput. The caudal border shall be below the skull base at 
the C2 vertebral level (see discussion of field matching in Section 8.9.4). 
Localization: The planning target volumes shall be defined by means of a simulator. 
8.9.3 Target Dose 
Prescription Point: The prescription point in each target volume is at or near the center*. 
For multi-convergent beams, the prescription point is usually at the intersection of the beam 
axes. 
*Note: This follows the recommendations of ICRU Report 50. If your institution’s practice 
differs, a conversion may be necessary. For instance, if you prescribe to a certain isodose 
line, adjust this (departmental) prescription so that the (protocol) prescribed dose is given to 
the (protocol) prescription point. 
Dose Definition: The absorbed dose is specified below in centigray (cGy)-to-water. 
Tissue Heterogeneity: No corrections for bone attenuation shall be made. Institutions that 
customarily correct of heterogeneities must calculate monitor units or time of irradiation 
without this option. 
Prescribed dose and fractionation: The total dose to the prescription point shall be 2400 
cGy in 12 fractions. The patient shall be treated with one fraction per day of 200 cGy. 
Dose Uniformity: The dose variations in each target volume shall be within +7%,-5% of 
the prescription dose (In accordance with ICRU Report 50, small high-dose volumes can be 
excluded from the evaluation of the dose uniformity but not small low-dose volumes). 
Treatment Interruptions: No corrections shall be made for treatment interruptions less 
than seven days. For interruptions greater than seven days, please contact the radiation 
oncology co-chair. 
8.9.4 Treatment Technique 
Patient Position: The patient shall be treated in the supine position. 
Beam Configuration: The cranial volume is treated with two lateral, equally weighted 
photon beams. 
Field Shaping: Field-shaping shall be done with blocks which are at least 5 HVL thick. 
Eye Protection: A simple method to minimize lens irradiation, while irradiating the 
posterior halves of the eyes, is to let the central axes of the horizontal cranial beams go 
through both orbits. The anterior edges of the beams are defined by an external block or by 
an independently controlled collimator and meet at a point 1 cm anterior to the frontal lobe 
meninges. Shielding blocks cover the anterior halves of the eyes and protect the nose and 
mouth. 
Essentially the same geometry can be achieved with the central axes through the center of 
the head by angling the lateral fields so that the rays through the eyes lie in the same 
horizontal plane. It is acceptable to use a parallel-opposed beam-pair, without such angling, 
with shielding blocks that cover the anterior half of the proximal eye. The dose to the 
contralateral lens will then increase, however. 
8.9.5 Dose Calculations and Reporting 
Prescription Point: The monitor units or time or irradiation required to deliver the 
prescribed dose to the prescription points shall be calculated and submitted using the “RT-
1 Dosimetry Summary” form. 


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Dose Uniformity: The maximum and minimum doses in the target volumes shall be 
calculated and reported on the RT-1 form. These may be extracted from isodose diagrams 
or calculated separately. 
Isodose Distributions: For single beams (electrons or photons) and equally-weighted, 
parallel-opposed photon beams, isodose distributions are not required. In all other cases, a 
plot of the dose distribution in the central transverse plane through the target volume shall 
be submitted. The prescription point and the outlines of the target volume and critical organs 
shall be shown. Isodose values must be clearly labeled. The effects of shielding blocks shall 
be included. 
8.9.6 Cranial Radiation Therapy Definitions of Deviation of Performance 
Prescription Dose: 
• 
Minor Deviation: The dose to the prescription point differs from that in the protocol 
by between ±6% and ± 10%. 
• 
Major Deviation: The dose to the prescription point differs from that in the protocol 
by more than 10%. 
Dose Uniformity: 
• 
Minor Deviation: The variation in dose in one target of the volumes exceeds +7%/-5%. 
8.10 
Testicular Radiation: 2400 cGy in 12 Treatment Fractions 
Testicular disease at time of entry on study or during therapy without marrow relapse will be 
treated by radiation and the patient will continue on study therapy. IMRT and proton RT will 
not be allowed on this study. 
8.10.1 Equipment: 
Modality: High-energy photon electron beams. The selection of energy is determined by 
the dose uniformity criterion, and with electrons, the lowest possible energy should be used 
to spare tissues outside the target volume. 
Calibration: The calibrations of therapy machines in this protocol shall be verified by the 
Radiological Physics Center. 
8.10.2 Planning Target Volume: The planning target volume consists of the testes in the 
scrotal sac. Use margins of at least 1/2 cm. 
8.10.3 Target Dose 
Prescription Point: The prescription point is at or near the center of the planning target 
volume. 
Note: This follows the recommendations of ICRU Report 50. If your institution’s practice 
differs, a conversion may be necessary. For instance, if you prescribe to a certain isodose 
line, adjust this (departmental) prescription so that the (protocol) prescribed dose is given to 
the (protocol) prescription point. 
Dose Definition: The absorbed dose is specified as centigray (cGy)-to-water. 
Prescribed Dose and Fractionation: The total dose to the prescription point shall be 2400 
cGy in 12 fractions. The patient shall be treated with one fraction per day of 200 cGy. 
Dose Uniformity: The variations of dose within the planning target volume shall be within 
+7%, -5% of the dose prescription point (In accordance with ICRU Report 50, small high-
dose volumes can be excluded from the evaluation of the dose uniformity but not small low-
dose volumes). The uniformity requirement can in general be met with an electron beam of 


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appropriate energy provided bolus is used, which is the simplest technique. Bolus may also 
be needed for photon beams to fulfill the dose uniformity requirement. 
Treatment Interruptions: No corrections shall be made for treatment interruptions less 
than seven days. For interruptions greater than seven days, please contact the radiation 
oncology co-chair. 
8.10.4 Treatment Technique 
Patient Position: The patient shall be treated in the supine position. 
Field-Shaping: Field-shaping can be done with blocks of at least 5 HVL thick. 
8.10.5 Normal Tissue Sparing and Dose Specification Points 
Perineum: The testes shall be supported posteriorly and, if possible, extended caudally in 
order to minimize perineal irradiation. The field shall not be angled towards the perineum. 
Penis: The penis shall be excluded from the field by fixing it to the skin over the symphysis 
pubis. 
Dose Specification Points: To ensure dose uniformity specified in Section 8.10.3, the dose 
at two points shall be calculated and submitted with the Quality Assurance Documentation. 
Point A: 0.5 cm from the anterior surface of the testes. 
Point B: 0.5 cm from the posterior surface of the testes. 
Note: Points A and B are defined with respect to the surface of the testis itself, and not the 
bolus material. 
8.10.6 Dose Calculations and Reporting 
Prescription Point: The monitor units or time of irradiation required to deliver the 
prescribed dose to the prescription points shall be calculated and submitted using the “RT-
1 Dosimetry Summary” form. 
Dose Uniformity: The maximum and minimum doses in the target volumes shall be 
calculated and reported on the “RT-1 Dosimetry Summary” form. These may be extracted 
from isodose diagrams or calculated separately. 
Dose Specification Points: The daily dose to dose specification points shall be calculated 
and reported on the “RT-2 Radiotherapy Total Dose Record.” 
8.10.7 Testicular Radiation Therapy Definitions of Deviation of Performance 
Prescription Dose: 
• 
Minor Deviation: The dose to the prescription point differs from that in the protocol by 
between ±6% and ± 10%. 
• 
Major Deviation: The dose to the prescription point differs from that in the protocol 
by more than 10%. 
Dose Uniformity: 
• 
Minor Deviation: The variation in dose in one target of the volumes exceeds +7%/-5%. 
8.11 
Quality Assurance Documentation 
8.11.1 Within one week of the completion of radiotherapy, the following data shall be 
submitted: 


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• 
A copy of the patient’s radiotherapy record including prescription, and the daily and 
cumulative doses to the prescription point and specified dose points. 
• 
Documentation of the treatment field: This may consist of a photograph of the patient 
in the treatment position, taken in a darkened room with the light field on, to demonstrate 
that the treatment field completely includes the patient. Alternatively, verification films 
that show the patient with respect to the radiation field may be submitted. 
8.11.2 Submission of Quality Assurance Documentation 
• 
Submit data to: 
Quality Assurance Review Center 
272 West Exchange Street, Suite 101 
Providence, RI 02903-1025 
Tel: 401-454-4301 
Fax: 401-454-4683 
calgb@qarc.org 
• 
Direct questions regarding the radiotherapy in this study to: 
Jeffrey Bogart, MD 
CALGB 10701 Radiation Oncology Co-Chair 
Tel: 315-464-5276 
bogartj@upstate.ed 
 
 
CALGB 10701 Protocol Dosimetrist 
Quality Assurance Review Center 
272 West Exchange Street, Suite 101 
Providence, RI 02903-1025 
Tel: 401-454-4301 
Fax: 401-454-4683 
physics@QARC.org 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
9.1 
Anticipated Toxicity and Management 
Should unanticipated circumstances arise that might require minor variances from the prescribed 
dosing and schedule of protocol therapy in order to ensure safety and allow patients to continue 
to receive treatment on study, the Alliance Study Chair should be contacted in advance for 
discussion and approval. If the following signs or symptoms are medically manageable, they are 
not to be a consideration with respect to the patient’s dosing or continuation on study: nausea, 
mild vomiting, diarrhea, drug-related fever or chills, alopecia. 
It is the intent of this protocol to administer the maximum tolerated dose intensity of designated 
therapy to adults with ALL even though hospitalization, blood transfusions, and parenteral 
antibiotics may be routinely required. Antibacterial, antiviral, and antifungal prophylaxis and 
treatment are required.  
9.2 
Treatment Delays 
Doses may be delayed because of marked mucositis, hepatic toxicity, renal toxicity, or infection. 
Continue treatment, starting at the point where it had been suspended, after toxicity resolves to 
≤grade 2 or when infection is eradicated. Document on study report forms. 


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9.3 
Dasatinib Dose Modifications During Courses I - V 
Dasatinib Dose Level 
Dasatinib Dose 
Dose Level 0 (Starting Dose) 
140 mg once daily 
Dose Level -1 
100 mg once daily 
Dose Level -2 
50 mg once daily 
If dose reduction below dose level -2 is required, please contact the Alliance Study Chair 
regarding further use of dasatinib in subsequent treatment modules. 
9.3.1 Dasatinib Dose Modifications for Hepatic Toxicity 
• 
For bilirubin ≥ 3 mg/dL but < 5 mg/dL, decrease dasatinib by one dose level until 
bilirubin improves to < 3 mg/dL, then resume dasatinib at the previous dose level. 
• 
For bilirubin ≥ 5 mg/dL, interrupt dasatinib until bilirubin improves to < 5 mg/dL, then 
resume dasatinib with one dose level reduction for the remainder of that course. At the 
next course, re-escalate to the previous dose level. If bilirubin does not improve to < 5 
mg/dL after four weeks, contact the Study Chair.  
• 
For grade 3 or 4 ALT or AST, interrupt dasatinib until ALT/AST improves to ≤ grade 
1, then resume dasatinib with one dose level reduction for the remainder of that course. 
At the next course, re-escalate to the previous dose level. 
9.3.2 Other Non-Hematologic Toxicity 
• 
During Course I, dasatinib will only be modified for non-hematologic grade 3/4 
toxicity (as described below). 
• 
Grade 2 (Courses II-V) 
For grade 2 non-hematologic toxicity due to dasatinib that does not resolve despite 
symptom-oriented therapeutic intervention, interrupt dasatinib until toxicity resolves to 
≤ grade 1. Dasatinib may then be resumed at the previous dose. If grade 2 toxicity recurs, 
interrupt dasatinib until toxicity resolves to ≤ grade 1, then resume dasatinib with one 
dose level reduction for the remainder of that course. For the next course, re-escalate to 
the previous dose level. 
• 
Grade 3/4 
For ≥ grade 3 non-hematologic toxicity at least possibly due to dasatinib, interrupt 
dasatinib until toxicity resolves to ≤ grade 1. Then resume dasatinib with a one level 
dose reduction for the remainder of that course. For the next course, re-escalate to the 
previous dose level. For recurrent grade 4 non-hematologic toxicity, discontinue 
dasatinib and contact the Alliance study chair. 
9.3.3 Hematologic Toxicity 
• 
Grade 3 or 4 (Courses II-V) 
For ANC < 1000/µL or platelet count <50,000/µL, interrupt dasatinib until ANC > 
1000/µL and platelet count > 50,000/µL.  
• 
If toxicity resolves within 2 weeks, then resume dasatinib at previous dose level.  
• 
If toxicity does not resolve within 2 weeks or recurs, interrupt dasatinib until ANC 
>1000/µL and platelet count > 50,000/µL, then resume dasatinib with one dose 
level reduction for the remainder of that course. For the next course, re-escalate 
to the previous dose level.  


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• 
Patients with recurrent cytopenia but no evidence of relapse should be discussed with 
the Alliance Study Chair with regard to ancillary support with G-CSF during dasatinib 
therapy. Ph+ ALL lymphoblasts often express G-CSF receptors. 
9.4 
Dasatinib Dose Modifications During Course VI 
9.4.1 In Patients Who Underwent Allogeneic HCT 
9.4.1.1 Dasatinib Dose Levels 
Dose Level 
Dasatinib Dose 
Dose Level 0 
50 mg once daily 
Dose Level +1 
100 mg once daily 
9.4.1.2 Dasatinib Dose Modifications for Hepatic Toxicity 
• 
For bilirubin > 1.5 mg/dL du eto dasatinib, interrupt dasatinib until bilirubin 
improves to ≤ 1.5 mg/dL, then resume dasatinib at the previous dose level. 
• 
If bilirubin does not improve to ≤ 1.5 mg/dL after four weeks, contact the Study 
Chair. 
• 
For ≥ grade 2 ALT or AST due to dasatinib, interrupt dasatinib until ALT/AST 
improves to ≤ grade 1, then resume dasatinib at the previous dose. If ALT/AST 
does not improve to ≤ grade 1 after four weeks, contact the Study Chair. 
• 
When tolerated, an attempt should be made to increase the dasatinib dose to 100 
mg once daily. Once increased to 100 mg once daily, the dose modifications for 
patients who underwent autologous HCT or alternative chemotherapy will apply 
to these patients. 
9.4.1.3 Dasatinib Dose Modifications for Other Non-hematologic and Hematologic 
Toxicity 
• 
For ≥ grade 2 hematologic toxicity or ≥ grade 2 non-hematologic toxicity due to 
dasatinib, interrupt dasatinib until toxicity resolves to ≤ grade 1, then resume 
dasatinib at the same dose level. 
• 
When tolerated an attempt should be made to increase the dasatinib dose to 100 
mg once daily. Once increased to 100 mg once daily, the dose modifications for 
patients who underwent autologous HCT/alternative chemotherapy (Section 
9.4.2) will apply to these patients. 
9.4.2 In Patients Who Underwent Autologous HCT or Alternative Chemotherapy 
9.4.2.1 Dasatinib Dose Levels 
Dose Level 
Dasatinib Dose 
Dose Level 0 
100 mg once daily 
Dose Level -1 
50 mg once daily 
9.4.2.2 Dasatinib Dose Modifications 
Hepatic Toxicity 
• 
For bilirubin >1.5 mg/dL –3 mg/dL due to dasatinib, interrupt dasatinib until 
bilirubin improves to ≤ 1.5 mg/dL, then resume dasatinib at the previous dose 
level. 


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• 
For recurrent bilirubin >1 mg/dL – 3 mg/dL due to dasatinib, interrupt dasatinib 
until bilirubin improves to ≤ 1.5 mg/dL, then resume dasatinib with one dose level 
reduction for the remainder of that cycle (1 cycle = 4 weeks). For the next cycle, 
re-escalate dasatinib to the previous dose level. 
• 
For bilirubin >3 mg/dL due to dasatinib, interrupt dasatinib until bilirubin 
improves to ≤ 1.5 mg/dL, then resume dasatinib with one dose level reduction for 
the remainder of that cycle (1 cycle = 4 weeks). For the next cycle, re-escalate 
dasatinib to the previous dose level. 
• 
If bilirubin does not improve to ≤ 1.5 mg/dL after four weeks, contact the Study 
Chair. 
• 
For recurrent bilirubin > 10 mg/dL, discontinue dasatinib and contact the Study 
Chair. 
• 
For ALT/AST > 2.5–5x ULN due to dasatinib, interrupt dasatinib until ALT/AST 
improve to ≤2.5x ULN, then resume dasatinib at the previous dose level. 
• 
For recurrent ALT or AST >2.5 – 5x ULN due to dasatinib, interrupt dasatinib 
until ALT/AST improves to ≤2.5x ULN, then resume dasatinib with one dose 
level reduction for the remainder of that cycle (1 cycle = 4 weeks). For the next 
cycle, re-escalate dasatinib to the previous dose level. 
• 
For ALT/AST > 5x ULN due to dasatinib, interrupt dasatinib until ALT/AST 
improve to ≤2.5x ULN then resume dasatinib with one dose level reduction for 
the remainder of that cycle (1 cycle = 4 weeks). For the next cycle, re-escalate 
dasatinib to the previous dose level. 
• 
If ALT/AST does not improve to ≤2.5x ULN after four weeks, contact the Study 
Chair. 
• 
For recurrent ALT/AST >20x ULN, discontinue dasatinib and contact the Study 
Chair. 
Other Non-Hematologic Toxicity 
• 
For grade 2 non-hematologic toxicity due to dasatinib that does not resolve 
despite symptom-oriented therapeutic intervention, interrupt dasatinib until 
toxicity resolves to ≤ grade 1. Dasatinib may then be resumed at the previous dose 
level. If grade 2 toxicity recurs, interrupt dasatinib until toxicity resolves to ≤ 
grade 1, then resume dasatinib with a one dose level reduction for the remainder 
of that cycle (1 cycle = 4 weeks). For the next cycle, re-escalate to the previous 
dose level. 
• 
For ≥ grade 3 non-hematologic toxicity at least possibly due to dasatinib, interrupt 
dasatinib until the toxicity resolves to ≤ grade 1. Then resume dasatinib with one 
level dose reduction for the remainder of that cycle. For the next cycle, re-escalate 
to the previous dose level. For recurrent grade 4 non-hematologic toxicity 
discontinue further dasatinib and contact the Alliance study chair. 
• 
If dose modification below dose level -1 is required, please contact the Alliance 
Study Chair regarding further use of dasatinib in subsequent treatment modules. 
Hematologic Toxicity 
• 
For ANC < 1000/µL or platelet count <50,000/µL, interrupt dasatinib until ANC 
> 1000/µL and platelet count > 50,000/µL. If toxicity resolves within 2 weeks, 
then resume dasatinib at previous dose level. If toxicity does not resolve within 2 
weeks or recurs, interrupt dasatinib until ANC >1000/µL and platelet count > 


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50,000/µL, then resume dasatinib with one dose level reduction. For the next 
course, re-escalate the previous dose level.  
• 
Patients with recurrent cytopenia and yet no evidence of relapse should be 
discussed with the Alliance Study Chair with regard to ancillary support with G-
CSF during dasatinib therapy. Ph+ ALL lymphoblasts often express G-CSF 
receptors. 
• 
If dose modification below dose level -1 is required, please contact the Alliance 
Study Chair regarding further use of dasatinib in subsequent treatment modules. 
9.5 
Course IV (CNS Prophylaxis) Dose Modifications 
9.5.1 Neutropenic Fever 
For neutropenic fever (ANC < 500/µL and temperature ≥ 101°F) delay methotrexate until 
ANC ≥1000/µL and infection resolves. 
 
9.5.2 Hyperbilirubinemia 
Give the following doses: 
Bilirubin (mg/dL) 
VCR 
PO-MTX 
High-Dose 
IV-MTX 
<1.5 
2 mg (flat dose) 
25 mg/m2 
500 mg/m2 
≥1.5 but <3.0 
1 mg (flat dose) 
25 mg/m2 
500 mg/m2 
≥3.0 but <5.0 
0 
18.0 mg/m2 
 0* 
≥5.0 
0 
0 
 0* 
* 
Delay treatment for up to two weeks. Contact the Alliance Study 
Chair if toxicity does not resolve. 
9.5.3 Oral Mucositis 
For ≥ grade 3 oral mucositis, hold treatment until toxicity resolves to ≤ grade 2. If delay is 
greater than two weeks, then notify the Alliance Study Chair. 
9.5.4 Renal Toxicity 
• 
Patients with elevated serum creatinine (≥1.8 mg/dL) who have met all other criteria for 
initiation of Course IV treatment should have therapy held for as many as two weeks to 
allow for normalization of renal function (serum creatinine <1.8 mg/dL). If creatinine 
remains elevated after two weeks, notify Study Chair. 
• 
Patients who experience nephrotoxicity should discontinue all methotrexate (IV, IT, 
oral). Substitute IV cytarabine (1000 mg/m2) for IV methotrexate and IT cytarabine (50 
mg total dose) for IT methotrexate. There is no substitute for oral methotrexate; it is 
simply discontinued. 
9.5.5 Neurologic Toxicity 
9.5.5.1 Dose Modification for Seizures 
• 
For grade 2 seizures, hold next VCR dose. Reinstitute at previous dose at time of 
next planned VCR dose. For recurrent grade 2 seizures, please contact the Study 
Chair. 
• 
For ≥ grade 3 seizures, please contact the Study Chair. 


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9.5.5.2 Dose Modification for Constipation 
For grade 3 or 4 constipation, hold VCR dose, and institute aggressive hydration and 
laxative treatment. When toxicity resolves to ≤ grade 1, resume VCR at 50% of 
previous dose. VCR should then be re-escalated to previous dose, as tolerated. 
9.5.5.3 Dose Modification for Sensory or Motor Neuropathy from Vincristine 
For grade 3 or 4 sensory or motor neuropathy, hold VCR. Upon resolution of toxicity 
to ≤ grade 1, resume VCR at 50% of previous dose at time of next scheduled dose. 
Document on study report forms. 
9.5.5.4 Dose Modification for Arachnoiditis 
If CSF granulocytosis or pleocytosis, increased CSF pressure, fever, or localized signs 
of arachnoiditis occur following IT Mtx, skip IT Mtx. After resolution of symptoms, 
intrathecal treatment can be resumed with methotrexate (15 mg) or cytarabine (50 mg) 
at the point where it had been suspended. 
9.5.5.5 Dose Modification for Methotrexate Neurotoxicity 
If a patient develops neurological symptoms, including malaise, headaches, 
somnolence, focal neurologic deficits or seizures following administration of 
methotrexate, treatment with dextromethorphan may result in rapid improvement of 
symptoms. 
Prompt 
treatment 
of 
neurologic 
symptoms 
with 
45-90 
mg 
dextromethorphan (e.g., as found in 15-30 mL Robitussin DM) every 4-6 hours x 24-
48 hours should be considered. For grade 3 or 4 neurotoxicity, hold the methotrexate 
and discuss the patient with the Study Chair. 
9.5.5.6 Dose Modification for Psychosis 
If signs or symptoms of psychosis caused by steroids are present, steroid treatment 
should be discontinued. 
9.5.6 Pleural Effusions 
Patients with pleural effusions who have met all other criteria for initiation of Course IV 
treatment should have therapy held for as many as two weeks to allow pleural effusions to 
resolve. If pleural effusions persist, notify Study Chair. 
9.6 
Course V High-Dose Ara-C Dose Modifications 
9.6.1 Cerebellar Toxicity 
Neurologic assessments should be performed before and after each dose of ara-C for 
cerebellar toxicities. If signs or symptoms of cerebellar toxicity occur during or following 
ara-C, infusion should be terminated and no further ara-C should be administered. Notify 
the Study Chair. 
9.6.2 Creatinine Elevation 
• 
In patients ≤ 65 years 
For creatinine > 1.5 mg/dL and ≤ 2 mg/dL decrease cytarabine to 1000 mg/m2. For 
creatinine > 2.0 mg/dL decrease cytarabine to 200 mg/m2. 
• 
In patients > 65 years 
For creatinine > 1.5 mg/dL and ≤ 2 mg/dL decrease cytarabine to 400 mg/m2. For 
creatinine > 2.0 mg/dL decrease cytarabine to 200 mg/m2. 


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9.7 
Dose Modifications for Methotrexate and 6-Mercaptopurine in Course VI 
9.7.1 Dose Levels 
Dose Level 
6-MP 
MTX 
Dose Level 0 
60 mg/m2 
20mg/m2 
Dose Level -1 
45 mg/m2 
15 mg/m2 
 
9.7.2 Dose Modifications for Hematologic Toxicity in Course VI 
• 
For ANC ≤ 1000, skip methotrexate and interrupt 6-MP until ANC improves to > 
1000, then resume methotrexate and 6-MP at the previous dose. 
• 
For recurrent ANC ≤ 1000, skip methotrexate and interrupt 6-MP until ANC 
improves to > 1000, then resume methotrexate and 6-MP with one dose level 
reduction of each. Re-escalate methotrexate and 6-MP at 2-4 week intervals, as 
allowed, to maintain ANC > 1000. 
• 
For platelets ≤ 75,000, skip methotrexate and interrupt 6-MP until platelets improve 
to > 75,000, then resume methotrexate and 6-MP at the previous dose.  
• 
For recurrent platelets ≤ 75,000, skip methotrexate and 6-MP until platelets improve 
to > 75,000, then resume methotrexate and 6-MP with one dose level reduction of 
each. Re-escalate methotrexate and 6-MP at 2-4 week intervals, as allowed, to 
maintain platelets > 75,000. 
9.7.3 Dose Modifications for Bilirubin in Course VI 
• 
For bilirubin ≥ 3mg/dL but < 5 mg/dL, decrease methotrexate and 6-MP by one 
dose level until bilirubin improves to < 3 mg/dL. 
• 
For bilirubin ≥ 5 mg/dL, skip methotrexate and interrupt 6-MP until bilirubin 
improves to < 5 mg/dL. 
• 
Re-escalate methotrexate and 6-MP at 2-4 intervals, as allowed. If bilirubin does 
not improve to < 5 mg/dL after 4 weeks, contact the Study Chair. 
9.7.4 Dose Modifications for ALT and AST Course VI 
• 
For grade ≥ 3 ALT or AST, skip methotrexate and interrupt 6-MP until ALT/AST 
improves to ≤ grade 2, then resume methotrexate and 6-MP with one dose level 
reduction of each. 
• 
Re-escalate methotrexate and 6-MP at 2-4 week intervals, as allowed. 
• 
IF ALT/AST does not improve to ≤ grade 2 after 4 weeks, contact the Study Chair. 
9.8 
Treatment of GVHD 
Acute GVHD generally develops at time of engraftment or within the first three months after 
transplantation. It is a clinico-pathological syndrome involving the skin, the liver, and the gut. 
Serial biopsies and observations are used to help establish the diagnosis and severity of GVHD. 
The clinical appearance of skin GVHD can be mimicked by toxicity of the conditioning regimen 
and by drug reaction; therefore, documentation by skin biopsy should be performed when 
possible. Hepatic GVHD cannot be assessed solely on clinical grounds in patients who have 
concurrent drug toxicity, viral hepatitis, or toxicity caused by the conditioning regimen, and liver 
biopsy is helpful when possible. Gastrointestinal GVHD can be difficult to distinguish from 


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infectious enteritis, and endoscopic biopsy should be done whenever possible. Appendix II 
presents the staging and grading system for acute GVHD. 
9.8.1 Acute GVHD 
• 
Indications for initial treatment of acute GVHD 
In general, treatment for GVHD should be started when grade 2 GVHD criteria have 
been met (Appendix II). Grade 2 GVHD is moderately severe disease and usually 
consists of multiorgan disease. The decision to treat is based on the clinical assessment 
of the patient’s condition, the onset time relative to the day of transplant, and the rapidity 
with which symptoms progress. 
• 
Agents to be used for initial treatment of acute GVHD 
Acute 
GVHD 
usually 
is treated with 
a corticosteroid-containing 
regimen. 
Methylprednisolone can be administered at a dose of at least 1 mg/kg body weight every 
12 hours for 10-12 days. Tapering should begin between 10-20 days after starting initial 
treatment. The tapering of steroids can be determined by the institution guidelines. 
Record treatment information on flow sheets. 
Patients may be eligible for other agents for the treatment of GVHD per institutional 
protocols. Salvage regimens 
may include antithymocyte globulin, 
anti-T-cell 
antibodies, or psoralen and ultraviolet A irradiation (PUVA).  
9.8.2 Chronic GVHD 
• 
Diagnosis of chronic GVHD 
Manifestations of chronic GVHD typically do not occur until one to three months after 
transplantation. The patients will be diagnosed with either limited or extensive chronic 
GVHD. Biopsies of the liver are recommended for patients who present with abnormal 
liver function tests in the absence of overt involvement of the skin, eyes, or mouth. 
Endoscopy and biopsy are recommended to establish gut involvement.  
• 
Agents to be used for treatment of chronic GVHD 
Patients diagnosed with extensive chronic GVHD are often treated for 9-12 months with 
tacrolimus and prednisone but should be managed according to institutional protocols. 
Suggested dosages are prednisone 1 mg/kg/day given as an oral dose in the morning. 
Record treatment information on flow sheets. 
10.0 DRUG FORMULATION, AVAILABILITY AND PREPARATION 
Qualified personnel who are familiar with procedures that minimize undue exposure to themselves 
and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents in a self-contained, protective environment. 
Discard unused portions of injectable chemotherapeutic agents that do not contain a bacteriostatic 
agent or are prepared with unpreserved diluents (i.e., Sterile Water for Injection USP or 0.9% Sodium 
Chloride for Injection USP) within eight hours of vial entry to minimize the risk of bacterial 
contamination. 
The total administered dose of chemotherapy may be rounded up or down within a range of 5% of 
the actual calculated dose. 


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10.1 
Campath-1H (alemtuzumab, Campath) 
AVAILABILITY 
Campath is provided through the US Campath Distribution Program. It is no longer 
commercially available (as of September 2012). To request Campath supplies, call 1-877-422-
6728. Campath is supplied in 1 mL single-use vials containing 30 mg/mL in 1 mL. Please refer 
to the agent’s package insert for additional information.  
STORAGE & STABILITY 
Intact vials should be stored, protected from light, under refrigeration. Do not freeze.  
Alemtuzumab was physically and chemically stable at room temperature for up to 24 hours after 
dilution at concentrations between 20 and 4800 mcg/mL in 0.9% sodium chloride and 5% 
dextrose infusion bags. However, since the product does not contain any preservatives, solutions 
diluted for infusion must be used within 8 hours of preparation. Infusion solutions may be stored 
at room temperature or under refrigeration. 
PREPARATION 
Withdraw the desired volume of alemtuzumab (0.67 mL) and inject into 100 mL of normal saline 
or 5% dextrose for IV infusion. Gently invert the bag to mix the solution. 
ADMINISTRATION 
In this study, alemtuzumab will be administered IV over 30 minutes within one hour after 
fludarabine. Premedicate with 50 mg diphenhydramine IV (or equivalent), 650 mg 
acetaminophen PO, and 2 mg/kg methylprednisolone (or equivalent) 30 minutes prior to each 
alemtuzumab dose. Patients who develop infusion-related symptoms, such as fever, or rigors, 
despite treatment with diphenhydramine, acetaminophen and methylprednisolone, will receive 
meperidine at the investigator discretion.  
TOXICITY 
Infusion reactions occur in most patients. They commonly consist of rigors, fever, headache, 
nausea, vomiting, diarrhea, rash, pruritus, dyspnea and hypotension. Acute infusion reactions 
may also include chills, abdominal and back pain, bronchospasm, angioedema, tachyarrhythmia, 
etc.  
Autoimmune hemolytic anemia, neutropenia, autoimmune thrombocytopenia, lymphopenia, 
bacterial and opportunistic infections (e.g., Pneumocystis jiroveci pneumonia, oral candidiasis, 
herpes zoster, CMV reactivation, cryptococcosis), allergic reactions, fatigue, hypertension, 
syncope, angina and myocardial infarction, anorexia, nausea, vomiting, diarrhea, constipation, 
dyspepsia, mucositis, thrombocytopenia, myalgia, bone pain, tremor, tumor lysis syndrome, 
insomnia, interstitial pneumonitis, pruritus, urticaria, peripheral edema are also seen. 
CAUTION: Women of child-bearing age and fertile men must use adequate and effective 
contraception during treatment with alemtuzumab and for at least 3 months after all therapy in 
this study is completed. The effects of alemtuzumab on embryogenesis, reproduction, and 
spermatogenesis are unknown. Breast feeding should be discontinued during this study and for 
3 months after study treatment is completed.  
10.2 
Cyclophosphamide (Cytoxan®; CTX; CPA; Neosar®; Cytoxan Lyophilized®) 
AVAILABILITY 
Commercially available as a powder for reconstitution in 100 mg, 200 mg, 500 mg, 1 gram, and 
2 gram vials. 
STORAGE & STABILITY 


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Intact vials should be stored at room temperature. Reconstituted and diluted solutions are stable 
for 24 hours at room temperature and 6 days if refrigerated. 
PREPARATION 
Reconstitute 100 mg, 200 mg, 500 mg, 1 gram and 2 gram vials with 5, 10, 25, 50, or 100 mL 
of SWI or NS to give a final concentration of 20 mg/mL. 
Vigorous shaking, gentle warming may be necessary for non–lyophilized preparation. 
Bacteriostatic water for injection (paraben preserved only) may be used; benzyl alcohol 
derivatives may NOT be used. May be further diluted in 100 - 250 mL of D5W or NS for IV 
infusion. 
ADMINISTRATION 
IV.  
TOXICITY 
Myelosuppression, hemorrhagic cystitis, SIADH, fatigue, alopecia, anorexia, nausea, vomiting, 
azoospermia, amenorrhea, cardiotoxicity (myocardial necrosis) - with high doses (such as those 
used in PBSCT), anaphylaxis (rare). 
Please refer to the package insert for a comprehensive list of adverse events. 
DRUG INTERACTIONS 
Cyclophosphamide undergoes metabolic activation via cytochrome P450 3A4 in the liver and 
may potentially interact with any drug affecting the same enzyme systems. Inhibitors of 3A4, 
e.g., itraconazole, could theoretically inhibit activation and inducers of 3A4, e.g., phenytoin, 
could theoretically enhance activation of cyclophosphamide to active alkylating species. For the 
most part, such interactions have not yet been documented clinically. 
10.3 
Cytarabine, Ara-C (Cytosine Arabinoside) 
AVAILABILITY 
Commercially available as a sterile powder for reconstitution in vials of 100 mg, 500 mg, 1000 
mg, and 2000 mg, or a preservative free 20 mg/mL solution in 5 mL, 25 mL, and 50 mL vials, 
or a 100 mg/mL solution in 20 mL vials. 
PREPARATION 
Cytarabine powder is reconstituted with sterile water for injection or 0.9% sodium chloride for 
injection. Solutions reconstituted with bacteriostat should not be used for IV administration of 
high dose cytarabine (> 1 gm/m2), as are used in this study. Solutions for parenteral 
administration should be reconstituted to a concentration  of 100 mg/mL. Reconstituted 
solutions are further diluted in D5W or 0.9% sodium chloride for IV infusion. 
STORAGE & STABILITY 
Intact vials should be stored at room temperature. Solutions reconstituted with bacteriostatic 
diluents are stable for 8 days at room temperature, but solutions without preservatives should be 
used within 8 hours. 
ADMINISTRATION 
Cytarabine will be administered intravenously over 2 hours in Course V for patients no 
undergoing transplant. 
TOXICITY 
The most common adverse reactions reported with cytarabine (“usual dosage” e.g., ≤ 200 
mg/m2/day) include hematologic, gastrointestinal, dermatologic, and hepatic. Myelosuppression 


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includes neutropenia, thrombocytopenia and anemia. Cytarabine is considered highly 
emetogenic. In addition to nausea and vomiting, diarrhea and mucositis are reported in > 10% 
of patients receiving cytarabine. Alopecia is common. Rash, including hand-foot syndrome, is 
reported also. Mild jaundice, and elevated transaminase levels also are reported in > 10% of 
patients. Fever (non-infectious) is also reported among the most common adverse reactions 
associated with cytarabine. 
Less commonly, a “cytarabine syndrome” or “ara-C syndrome” has been reported. The 
syndrome may be characterized by fever, myalgia, bone pain, rash, malaise, and chest pain. 
In addition to the above, the following adverse reactions have been described with high dose (≥ 
1 gm/m2/day) cytarabine. Neurologic toxicity is primarily cerebellar (nystagmus, dysarthria, 
dysdiadochokinesia, ataxia, abnormal gait) but cerebral toxicity (somnolence, confusion, 
psychosis, seizures) may also be seen. Ocular toxicity including photophobia and conjunctivitis 
are described with high dose cytarabine. Steroid ophthalmic solution should be administered, 
beginning 6-12 hours before cytarabine and continuing for 24 hours after the last “high dose”, 
to prevent conjunctivitis. Pulmonary edema has been rarely reported in association with high 
dose cytarabine. 
Please refer to the package insert for a comprehensive list of adverse events. 
10.4 
Dasatinib (Sprycel®) (IND #73969, NSC #732517) 
AVAILABILITY 
Dasatinib (Sprycel®) is available in 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, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, 
and polyethylene glycol (in the 20 mg tablets and 50 mg tablets).  
AGENT ORDERING 
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) policy 
requires that agent be shipped directly to the institution where the patient is to be treated.  PMB 
does not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained).  The CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 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. 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status and a 


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Update #11 
“current” password.  For questions about drug orders, transfers, returns, or accountability, call 
(240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
ACCOUNTABILITY 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of all agents received from DCTD using the NCI Drug 
Accountability Record Form (DARF).  (See the NCI Investigator’s Handbook for Procedures 
for Drug Accountability and Storage.) 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, Agent-CRADA, CTA, CSA) between the 
Pharmaceutical Company(ies) (hereinafter referred to as a “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/default.htm) contained within the terms of 
award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing investigational Agents contain confidential information and should not be shared 
or distributed without the permission of the NCI. If a copy of this protocol is requested by a 
patient or patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements, 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as “Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order. Additionally, all Clinical 
Data and Results and Raw Data will be collected, used, and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects including, if 
applicable, the Standards for Privacy of Individually Identifiable Health Information set 
forth in 45 C.F.R. Part 164. 


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4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication. Collaborator(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 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: 
 
 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
NCI Shady Grove 
Room 5W520, MSC 9740 
9609 Medical Center Drive 
Bethesda, Maryland  20892 
FAX 240-276-7894 
Email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information.” 
STORAGE & STABILITY 
Store the intact bottles at controlled room temperature (15°C-25°C) and protect from light. 
Excursions are permitted up to 30°C. Shelf life testing of the intact bottles is on-going. 
ADMINISTRATION 
Oral. The tablets may be taken with or without a meal. Tablets should not be crushed or cut; 
they should be swallowed whole. Please refer to the protocol text for dasatinib doses during each 
course of therapy. During the first month, subjects will be instructed to take dasatinib in the 
morning. Subsequently, subjects may adjust the time they take dasatinib as long as they take the 
drug approximately every 24 hours. If a scheduled dose is missed for more than 12 hours or 
dosing is interrupted for toxicity or for any other reason, these doses should be omitted. 
TOXICITY 
Common adverse events with dasatinib are myelosuppression, bleeding events, fluid retention 
and QT prolongation. Treatment with dasatinib is associated with grade 3/4 thrombocytopenia, 
neutropenia and anemia. Myelosuppression is managed by dose interruption, dose reduction, or 
discontinuation. Dasatinib can cause platelet dysfunction in vitro and thrombocytopenia in 
humans. Severe CNS hemorrhage, including fatalities occurred in 1% of patients. Severe GI 
hemorrhage occurred in 7% of patients and generally required treatment interruptions and 
transfusions. Other cases of severe hemorrhage occurred in 4% of patients. Most bleeding events 
were associated with severe thrombocytopenia. Fluid retention was severe in 9% of patients, 


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including pleural and pericardial effusions reported in 5% and 1%, respectively. Severe ascites 
and generalized edema were each reported in 1%. Severe pulmonary edema was reported in 1% 
of patients. Patients who develop symptoms suggestive of pleural effusion (dyspnea or dry 
cough) should be evaluated by chest x-ray. Severe pleural effusion may require oxygen therapy 
and thoracentesis. Fluid retention is typically managed by supportive care measures that include 
diuretics or short courses of steroids. Dasatinib has the potential to prolong cardiac ventricular 
repolarization (QT interval). Dasatinib should be administered with caution in patients who have 
or may develop prolongation of QTc, including patients with hypokalemia, hypomagnesemia, 
or congenital long QT syndrome and patients taking anti-arrhythmic drugs or other medical 
products that lead to QT prolongation. Hypokalemia or hypomagnesemia should be corrected 
prior to dasatinib administration.  
In October 2011, the FDA issued a Drug Safety Communication describing the risk of 
pulmonary arterial hypertension (PAH) associated with dasatinib. At least twelve cases of PAH 
have been confirmed by right heart catheterization (normal pulmonary capillary wedge pressure, 
but elevated pulmonary artery pressure) with dasatinb considered the most likely cause. The 
onset of PAH was variable, including the occurrence after more than one year of treatment. 
Symptoms of PAH include dyspnea, fatigue, hypoxia, and fluid retention. No fatalities were 
reported, and PAH may be reversible upon discontinuation of dasatinib. Because dasatinib is 
associated with other adverse events that can cause pulmonary symptoms, it is suggested that 
these other events (e.g., pleural effusion, pulmonary edema, anemia, lung infiltration) be ruled 
out prior to performing right heart catheterization. 
POTENTIAL DRUG INTERACTIONS 
Potent CYP3A4 inducers and inhibitors are prohibited on CALGB 10701. Dasatinib is primarily 
metabolized by the human CYP3A4 enzyme.   
CYP3A4 substrates known to have a narrow therapeutic index should be administered with 
caution in patients receiving dasatinib.  
Systemic antacids (both H2 receptor antagonists and proton pump inhibitors) are prohibited on 
CALGB 10701.  
Dasatinib may prolong the QT/QTc interval. Use caution when administering dasatinib with 
other potential QTc-prolonging medications. 
Due to the possibility of CNS, gastrointestinal, cardiac, and cutaneous hemorrhage, avoid using 
medications that inhibit platelet function or anticoagulants with dasatinib.  
Long-term suppression of gastric acid secretion by use of H2 blockers or proton pump inhibitors 
(e.g., famotidine and omeprazole) is likely to reduce dasatinib exposure. Therefore, concomitant 
use of H2 blockers or proton pump inhibitors with dasatinib is not recommended. If antacid 
therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours 
after the dose of dasatinib. 
Specifically in this study, tacrolimus is metabolized by CYP3A4 and dasatinib may inhibit 
tacrolimus metabolism. Patients who have undergone allogeneic transplant and are continuing 
to receive tacrolimus should be carefully monitored for a rise in tacrolimus levels and 
consequent toxicities, such as renal and hepatic toxicities, as well as myelosuppression. 
Examples of substrates, inducers, and inhibitors of CYP3A4 may be found in Appendix III. 


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10.5 
Daunorubicin 
AVAILABILITY 
Daunorubicin is commercially available (or available as required in non North American 
countries) as a powder for reconstitution in 20 mg vials, and in vials of solution at a concentration 
of 5 mg/mL in 20 mg vials. Please refer to the package insert for additional information. 
PREPARATION 
Reconstitute the 20 mg vial with 4 mL of sterile water for injection to attain a 5 mg/mL 
concentration. 
Storage & Stability 
Intact vials should be stored at room temperature. Reconstituted solutions are stable for 48 hours 
under refrigeration. Daunorubicin contains no preservative and should be used with 24 hours. 
ADMINISTRATION 
Give IV push or as a short IV infusion through a well-established IV site. AVOID 
EXTRAVASATION, as severe necrosis may result. 
TOXICITY 
The most common adverse reactions associated with daunorubicin include hematologic, 
gastrointestinal, and cardiovascular. Leukopenia and thrombocytopenia are often dose-limiting. 
Daunorubicin causes nausea and vomiting, but is generally considered moderately emetogenic. 
Stomatitis is also common. Acute cardiovascular reactions include EKG abnormalities which 
are usually asymptomatic and self-limiting. Chronic cardiomyopathy manifests as congestive 
heart failure. Risk factors include age (> 70 years), mediastinal irradiation and cumulative 
lifetime dose (e.g., > 450 mg/m2). Dermatologic reactions (alopecia, “radiation recall”) are also 
common.  
Less common are red/orange urine (more alarming than of notable consequence to patients) and 
skin “flare.” The flare consists of redness and itching along the distribution of the vessel through 
which daunorubicin was administered. It is usually self-limiting and of short duration, but should 
be distinguished from an extravasation reaction. 
Extravasation of daunorubicin does not occur very often, but can result in severe skin and tissue 
necrosis. Cold should be applied to the site of a suspected or actual extravasation of 
daunorubicin. 
10.6 
Etoposide (VePesid®) 
AVAILABILITY 
Etoposide is commercially available in 5 mL, 7.5 mL, 25 mL, and 50 mL vials containing 20 
mg/mL. 
STORAGE & STABILITY 
Unopened vials should be stored at room temperature and protected from light. Solutions of 0.2 
or 0.4 mg/mL are stable for 96 and 24 hours, respectively, at room temperature under normal 
light. 
PREPARATION 
The dose of etoposide is usually diluted with D5W or Normal Saline for Injection to a final 
concentration of no more than 0.4 mg/mL. If the volume required to prepare etoposide to ensure 
stability for a desired amount of time is too large, then drug should be given undiluted. 


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ADMINISTRATION 
Etoposide will be administered via continuous intravenous infusion over 96 hours (mobilization 
for autologous transplant, and alternative chemotherapy in patients not undergoing transplant). 
NOTE: DO NOT ADMINISTER CLOUDY OR PRECIPITATED DRUG. 
TOXICITY 
Myelosuppression, anorexia, nausea, vomiting (mildly emetogenic), alopecia, peripheral 
neuropathy, hypersensitivity reactions (chills, fever, bronchospasm, dyspnea, hypotension).  
Please refer to the package insert for a comprehensive list of adverse events. 
10.7 
Fludarabine (Fludara®) 
AVAILABILITY 
Fludarabine is commercially available as a white, lyophilized powder. Each vial contains 50 mg 
of fludarabine phosphate, 50 mg of mannitol and sodium hydroxide to adjust pH.  
STORAGE & STABILITY 
Intact vials should be stored under refrigeration. Reconstituted vials are stable for 16 days at 
room temperature or under refrigeration. Solutions diluted in D5W or NS are stable for 48 hours 
at room temperature or under refrigeration. Solutions of fludarabine phosphate contain no 
preservatives and should be used within 24 hours of reconstitution. 
PREPARATION 
Fludarabine should be reconstituted with 2 mL SWI. Each mL of the resulting solution will 
contain 25 mg of fludarabine, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7-
8.5. The product should be further diluted for intravenous administration in 5% Dextrose for 
Injection, USP, or in 0.9% Sodium Chloride, USP. 
ADMINISTRATION 
Fludarabine will be administered IV over a period of 30 minutes. In this study, fludarabine will 
be administered prior to alemtuzumab for patients undergoing allo transplant in Course V. 
TOXICITY 
Myelosuppression (dose limiting toxicity), fever, mild nausea and/or vomiting, skin rashes, 
myalgia, fatigue, autoimmune hemolytic anemia (may be life threatening), peripheral 
neuropathy and pulmonary toxicity (both pneumonia and pulmonary hypersensitivity reactions 
have been reported; fatal pulmonary toxicity has been described, especially when fludarabine 
was used in combination with pentostatin). Severe fatal CNS toxicity presenting with loss of 
vision and progressive deterioration of mental status as encountered almost exclusively after 
very high doses of fludarabine. Such toxicity has only been rarely demonstrated at the 25-30 
mg/m2 dosage of fludarabine monophosphate. Very rarely described complications include 
transfusion-associated graft versus host disease, thrombotic thrombocytopenic purpura, and 
liver failure. Tumor lysis syndrome has been observed, especially in patients with advanced 
bulky disease. Opportunistic infections (protozoan, viral, fungal, and bacterial) have been 
observed. 
10.8 
Melphalan Hydrochloride (Alkeran®)  
AVAILABILITY 
Melphalan for IV use is commercially available in 50 mg vials. The product is a lyophilized 
powder with 20 mg povidone per vial. Also provided is 10 mL of diluent for use in 
reconstitution. The diluent contains 0.2 gm sodium citrate, 6 mL propylene glycol, 0.5 mL 95% 
ethanol, and sterile water. 


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STORAGE & STABILITY 
Intact vials should be stored at room temperature (15-30ºC) and protected from light. 
Reconstituted solutions are chemically and physically stable for at least 90 minutes at room 
temperature. Solutions further diluted in 0.9% sodium chloride to a concentration of 0.1 mg/mL 
to 0.45 mg/mL are stable for at least 60 minutes. Solutions diluted to 1 mg/mL are reported to 
be physically stable for at least 4 hours at room temperature-chemical stability of this dilution is 
not known. Because of the relative instability of melphalan solutions, it is recommended that 
administration of the diluted solution be completed within 60 minutes of reconstitution. 
Reconstituted solutions should not be refrigerated.  
PREPARATION 
Melphalan should be prepared immediately before intended use. Each vial is reconstituted with 
10 mL of the supplied diluent to yield a concentration of 5 mg/mL. The reconstituted solution 
may be diluted with 0.9% sodium chloride to a concentration of 0.1 mg/mL to 0.45 mg/mL. 
Alternatively, when the required concentration necessitates an unacceptable volume of fluid, the 
reconstituted solution may be administered undiluted.  
ADMINISTRATION 
Melphalan will be administered IV in patients undergoing autologous transplant in Course V. 
TOXICITY 
The major toxicity of melphalan is bone marrow suppression, usually lasting four to eight weeks. 
Other toxicities include venoocclusive disease, nausea, vomiting, and mucositis. Less common 
toxicities include pulmonary fibrosis, alopecia, and allergic reactions.  
10.9 
Methotrexate (Methotrexate Sodium; Amethopterin; MTX) 
AVAILABILITY 
Commercially available in 2.5 mg tablets, or 2 mL, 4 mL, 8 mL, 10 mL vials, containing 25 
mg/mL, with or without preservative; and powder for reconstitution in 20 mg, 25 mg, 50 mg, 
100 mg, 250 mg, or 1,000 mg vials. 
STORAGE & STABILITY 
Intact vials and tablets should be stored at room temperature and protected from light. Solutions 
for intrathecal use should be administered within 8 hours. Hydrocortisone and methotrexate may 
be mixed in the same syringe for IT administration. Solutions for IV administration are stable 
for 8 days, but for this study, they should be used sooner, since they do not contain preservative. 
PREPARATION 
IT: Reconstitute to a concentration of 1-5 mg/mL with an appropriate sterile, preservative-free 
medium. 
IV: The 1 gm vial should be reconstituted with 19.4 mL of preservative free SWFI, saline or 
D5W to a concentration of 50 mg/mL. Solutions should be further diluted in D5W or NS for IV 
infusion. 
ADMINISTRATION 
Oral: Course IV. 
IT: 15 mg mixed with 50 mg hydrocortisone (Course IV). 
IV: Infusion over 3 hours; administer after IV hydration and urinary alkalinization (Course IV). 
TOXICITY 
Hematologic including leukopenia (1.5%), thrombocytopenia (5%) (nadir 5–12 days; recovery 
15–27 days), anemia (nadir 6–13 days), pancytopenia (1.5%); gingivitis, glossitis, pharyngitis, 


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stomatitis, enteritis; nausea/vomiting, anorexia, diarrhea; hematemesis, melena; acute and 
chronic hepatotoxicity: reversible transaminase increase within 1–3 days after administration, 
hepatic fibrosis and cirrhosis with long term therapy; pulmonary toxicity including pneumonitis; 
pruritus, photosensitivity; CNS: seizures, dizziness, confusion; nephropathy: azotemia, renal 
failure; when administered IT may cause headache, back pain, rigidity. 
Please refer to the package insert for a comprehensive list of adverse events. 
DRUG INTERACTIONS 
Sulfonamides, salicylates, penicillins, other organic acids, and proton pump inhibitors may 
interfere with renal elimination of methotrexate which can lead to enhanced toxicity. 
10.10 Vincristine sulfate (VCR, Oncovin) 
AVAILABILITY 
Commercially available in 1, 2, and 5 mg vials containing 1 mg/mL. 
Storage & Stability 
Intact vials should be stored under refrigeration and protected from light. 
PREPARATION 
The desired volume (2 mL) should be withdrawn and injected into 0.9% NaCl for IV infusion, 
or administered as a bolus injection. Care must be taken to avoid inadvertent IT injection. The 
2 mL volume may be further diluted to 30 mL with 0.9% NaCl in a syringe for bolus IV injection. 
ADMINISTRATION 
Note: The maximum single dose of vincristine IV bolus injection, prior to starting IV 
methotrexate infusion in this study is 2 mg. 
Administer intravenously only. Intrathecal administration is fatal. Vincristine preparations 
must be wrapped and labeled with the following warnings: “Fatal if given intrathecally. For 
IV use only.” 
Vincristine is a vesicant which if extravasated can cause tissue necrosis. Inject over 1 minute 
through a freely flowing IV line or direct IV push after ensuring good blood return. 
TOXICITY 
Neurotoxicity including peripheral mixed sensorimotor neuropathy, loss of deep tendon 
reflexes, peripheral numbness, tingling and pain is the major and dose-limiting toxicity. May 
also see foot drop, cranial palsy, atrophy, ataxia, difficulty walking, jaw pain, and headaches. 
Also hoarseness and vocal cord paresis, optic or extraocular neuropathy and peripheral neuritis 
and neuralgia. Autonomic nervous system effects include severe constipation, abdominal 
cramps and ileus. Urinary retention, bladder atony, incontinence, orthostatic hypotension and 
myoclonal jerks may also occur. CNS effects may include mental status changes, seizures, 
progressive encephalopathy and coma. Rarely SIADH has been seen. 
Please refer to the package insert for a comprehensive list of adverse events. 
DRUG INTERACTIONS 
Vincristine is metabolized by CYP3A4/3A5. Inhibitors of CYP3A4/3A5 can result in increased 
vincristine neurotoxicity. Multiple reports describe increases neurotoxicity (e.g., constipation) 
in patients receiving concurrent azole antifungals, especially itraconazole. 


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10.11 Dexamethasone (Decadron®) 
AVAILABILITY 
Dexamethasone is commercially available in 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 
mg, and 6 mg tablets, and in vials for injection at a concentration of 4 mg/mL or 10 mg/mL. 
Please refer to the agent’s package insert for additional information. 
STORAGE & STABILITY 
Dexamethasone tablets and vials should be stored at room temperature. 
ADMINISTRATION 
Dexamethasone will be administered orally or by IV. 
TOXICITY 
Short-term use of dexamethasone (e.g., ≤ 4 weeks) may be associated with gastrointestinal side 
effects (dyspepsia, ulceration); insomnia, nervousness, and occasionally, psychosis; and 
hyperglycemia. Immunosuppression with increasing risk of infection also is seen. More 
prolonged use may be associated with, in addition to the above, muscle weakness and muscle 
wasting; osteoporosis and factures; hirsutism, acnea, skin atrophy, and easy bruising; sodium 
and water retention; adrenal suppression can occur with long term use necessitating tapering 
rather than abrupt discontinuation and the need for steroid coverage during stress. Occasionally 
a withdrawal syndrome manifest by muscle aches and pains is seen upon discontinuation, even 
following short-term use. 
10.12 6-Mercaptopurine (6-MP, Purinethol, mercaptopurine)  
AVAILABILITY 
Commercially available as a scored 50 mg tablet. 
Please refer to the FDA-approved package insert for 6-mercaptopurine for product information 
and a comprehensive list of adverse events. 
STORAGE & STABILITY 
Store at room temperature and protected from light. 
ADMINISTRATION 
Oral. Round daily dose to the nearest 25 mg (half tablet). Adjust daily doses so that the correct 
total dose is given each week of therapy. Note that absorption of 6-MP from the GI tract is 
variable and incomplete with a bioavailability of approximately 50%. Absorption is improved 
if given one-half hour before or 1 hour after meals. Concurrent milk products can decrease 
absorption and 6-MP effect is enhanced if given at bedtime on an empty stomach.  
Patients with severe myelosuppression should have their thiopurine methyltransferase (TPMT) 
status and/or their thiopurine metabolite concentrations evaluated, so that the dose of 6-MP can 
be reduced in patients with a TPMT defect. Patients with the rare homozygous deficient TPMT 
phenotype may tolerate only 1/10 to 1/20th the average 6-MP dose. TPMT testing and thiopurine 
metabolite measurements are commercially available. 
TOXICITY 
Myelosuppression, primarily leukopenia and thrombocytopenia; GI toxicities include stomatitis, 
diarrhea, abdominal pain, nausea and vomiting; anorexia; hepatotoxicity, rash, and fever. 
DRUG INTERACTIONS 
Allopurinol - Do NOT give with mercaptopurine unless specifically allowed on protocol. 
Allopurinol, a xanthine oxidase inhibitor, will enhance the toxicity of 6-MP by inhibiting the 


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oxidative metabolism of 6-MP. If 6-MP is given with allopurinol the dose should be reduced to 
25% to 33% of the planned dose of 6-MP initially with subsequent dosage based on patient 
response and toxicity. 
10.13 Filgrastim (G-CSF: Granulocyte Colony-Stimulating Factor; Neupogen; recombinant-
methionyl human granulocyte-colony stimulating factor; r-methHuG-CSF; filgrastim-
sndz, Zarxio(R)) 
AVAILABILITY 
G-CSF is commercially available in 1 mL and 1.6 mL vials containing  300 mcg or 480 mcg, 
and in pre-filled syringes containing 300 mcg/0.5 mL and 480 mcg/0.8 mL. 
Storage & Stability 
Intact vials and prefilled syringes should be stored under refrigeration. Do not allow the drug to 
freeze. 
PREPARATION 
The desired dose (rounded as described in the protocol) is withdrawn from a vial, or already 
available in a pre-filled syringe for injection. Filgrastim may be diluted in D5W to a 
concentration ≥15 µg/mL for IV administration 
ADMINISTRATION 
The daily dose should be injected subcutaneously in one or two sites. If subcutaneous 
administration is not possible, filgrastim may be administered as a short IV infusion over 15-60 
minutes. 
TOXICITY 
The most common adverse event associated with G-CSF is bone pain. Bone pain is usually 
reported as mild or moderate, and, if necessary, may be treated with non-opioid or opioid 
analgesics. 
Please refer to the package insert for a comprehensive list of adverse events. 
10.14 PEG-filgrastim 
Please refer to the FDA-approved package insert for pegfilgrastim for product information and 
a comprehensive list of adverse events. 
AVAILABILITY 
Pegfilgrastim is commercially available as a preservative-free solution containing 6 mg/0.6 mL 
(concentration 10 mg/mL) of pegfilgrastim in a prefilled single-dose syringe. 
STORAGE & STABILITY 
Intact syringes should be stored under refrigeration and protected from light. Pegfilgrastim 
syringes are reportedly stable at room temperature for up to 48 hours prior to injection, if 
protected from light. Syringes that are frozen intentionally may be allowed to thaw in the 
refrigerator. Pegfilgrastim syringes that have been frozen a second time should be discarded. 
ADMINISTRATION 
Pegfilgrastim should be injected subcutaneously at a dose of 6 mg (0.6 mL). Pegfilgrastim will 
be administered only one time per course, 24 to 72 hours after completion of chemotherapy. If 
pegfilgrastim is given, the patient should not receive additional filgrastim. 
TOXICITIES 


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The most common side effect associated with pegfilgrastim is bone pain. Bone pain is usually 
reported as mild or moderate, and, if necessary, may be treated with non-opioid or opioid 
analgesics. 
Other reported side effects include reversible elevations in LDH, alkaline phosphatase and uric 
acid. These laboratory abnormalities are not usually of clinical significance and do not usually 
require any intervention. 
10.15 Leucovorin Calcium (Citrovorum Factor, Folinic Acid, 5–Formyl Tetrahydrofolate) 
AVAILABILITY 
Leucovorin calcium is commercially available as a powder for reconstitution in 50 mg, 100 mg  
200 mg, 350 mg, and 500 mg vials, and as a solution for injection in 500 mg vials (10 mg/mL). 
Leucovorin calcium is also available in 5 mg, 10 mg, 15 mg, and 25 mg tablets. 
STORAGE & STABILITY 
Intact vials and tablets should be stored at room temperature and protected from light. 
Reconstituted solutions prepared with bacteriostatic water are stable for at least 7 days at room 
temperature. 
PREPARATION 
Leucovorin powder may be reconstituted with SWFI or bacteriostatic water for injection. 
ADMINISTRATION 
The first dose of leucovorin will be given as a bolus IV injection or short IV infusion in D5W or 
0.9% NaCl. Subsequent doses will be administered orally. If oral administration is precluded, 
the subsequent doses can be given IV. 
TOXICITY 
The only adverse reaction is rare reports of allergic reactions to parenteral injections of 
leucovorin. However, these are extremely uncommon. 
Please refer to the package insert for a comprehensive list of adverse events. 
10.16 Co-trimoxazole (Trimethoprim-sulfamethoxazole, Bactrim®, Septra®, Cotrim, 
Sulfatrim) 
AVAILABILITY 
Commercially available as a single strength scored tablet containing 80 mg trimethoprim and 
400 mg sulfamethoxazole, a double strength scored tablet containing 160 mg trimethoprim and 
800 mg sulfamethoxazole, or an oral suspension containing 40 mg/5 mL of trimethoprim and 
200 mg/5 mL of sulfamethoxazole. 
STORAGE & STABILITY 
Tablets and suspension should be stored at room temperature in airtight, light-resistant package.  
ADMINISTRATION 
Oral.  
TOXICITY 
Allergic reactions include epidermal necrolysis, exfoliative dermatitis, serum sickness, and 
Stevens-Johnson Syndrome (rare) and more commonly, mild to moderate skin rashes 
(erythematous, maculopapular, morbilliform and/or pruritic). GI: nausea, vomiting anorexia. 
Hematologic: myelosuppression, hemolysis (with G-6-PD deficiency). Miscellaneous: elevated 
liver function tests, fever, chills, renal toxicity, and rarely pulmonary infiltrates with cough and 
shortness of breath. 


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Please refer to the package insert for a comprehensive list of adverse events. 
INTERACTIONS 
Folate - Co-trimoxazole can enhance folate deficiency which can contribute to megaloblastic 
anemia or myelosuppression. Leucovorin may be given for serious bone marrow suppression to 
reverse this effect. 
Warfarin - Co-trimoxazole may prolong prothrombin time by inhibiting metabolic clearance of 
warfarin. Monitor PT/INR and evidence of bleeding when these agents are used together. 
10.17 Pentamidine Isethionate (NebuPent® - oral inhalation solution) 
AVAILABILITY 
Commercially available as a powder for reconstitution containing 300 mg of pentamidine 
isethionate for use with Respirgard® nebulizer. 
PREPARATION 
Reconstitute with 6 mL of SWFI. Place entire contents of vial in nebulizer reservoir for 
administration. 
COMPATIBILITY 
Saline will cause the drug to precipitate in the vial. Do not mix with any other drugs for 
inhalation. 
STORAGE & STABILITY 
Intact vials should be stored at room temperature. Reconstituted solutions are stable for 48 hours 
at room temperature. Use immediately upon preparation is recommended due to lack of 
preservatives in the solution. 
ADMINISTRATION 
Administer aerosolized pentamidine over 30 to 45 minutes. Pentamidine administration in this 
study is intended for PCP prophylaxis in patients unable to tolerate cotrimoxazole. 
TOXICITIES 
Cough (38%) and bronchospasm are the most common side effects associated with inhalation 
of pentamidine. Other effects associated with inhalation include pharyngitis, fatigue, chest pain. 
Other systemic effects which are also much less likely with inhalational therapy include 
hypotension, 
dizziness, 
maculopapular 
pruritic 
rash, 
hypoglycemia, 
hyperglycemia, 
gastrointestinal side effects, and increased liver function tests. 
Please refer to the package insert for a comprehensive list of adverse events. 
10.18 Tacrolimus (Prograf®) 
AVAILABILITY 
Tacrolimus is commercially available as an injection (5 mg/mL) and as oral capsules (0.5 mg, 1 
mg, or 5 mg).  
STORAGE & STABILITY 
Store tacrolimus capsules and injection at controlled room temperature, 15-30°C (59-86°F).  
PREPARATION 
Tacrolimus injection must be diluted prior to IV infusion with 0.9% sodium chloride or 5% 
dextrose injection to a concentration of 0.004 to 0.02 mg/mL. Solutions should be prepared in 
non-PVC plastic or glass. Tacrolimus injection and diluted solutions of the drug should be 


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inspected visually for particulate matter and discoloration prior to administration whenever 
solution and container permit.  
ADMINISTRATION 
Oral therapy should be started as soon as possible as per protocol and 12 hours after stopping 
intravenous therapy. Oral doses will be administered twice a day. IV tacrolimus may be 
administered as a continuous infusion or in divided doses every 12 hours.  
TOXICITY 
Most of the adverse event information described below comes from studies of tacrolimus in 
solid organ transplantation. In patients receiving tacrolimus, 5% to 47% experienced anemia, 
8% to 32% experienced leukocytosis, and 14% to 24% experienced thrombocytopenia. Mild to 
moderate hypertension was reported in 38% to 50% of patients receiving tacrolimus. Chest pain 
was reported in 19%. Antihypertensive therapy may be required. The most common adverse 
effects of tacrolimus have involved the central nervous system, and include headache (37% to 
64%), tremors (48% to 56%), insomnia (32% to 64%), paresthesia (17% to 40%); and dizziness 
(19%). Tremor and headache may respond to dosage reduction. Agitation, anxiety, confusion, 
seizures, depression, hallucinations, myoclonus, neuropathy, psychosis, incoordination, and 
abnormal dreams have been reported in 3% to 15% of tacrolimus-treated patients. Hyperkalemia 
(13% to 45%), hypokalemia (13% to 29%) hypophosphatemia (49%) and hypomagnesemia 
(16% to 48%) have been associated with tacrolimus therapy. In addition, hirsutism occurs only 
rarely with tacrolimus. Gastrointestinal adverse effects of tacrolimus have included nausea (32% 
to 46%), vomiting (14% to 29%), anorexia (7% to 34%), constipation (23% to 35%) and diarrhea 
(37% to 72%). Nephrotoxicity was reported in 36% to 40% and 52% of liver and kidney 
transplant patients receiving tacrolimus. Overt nephrotoxicity is usually seen early after 
transplantation and is characterized by an increased serum creatinine and a decrease in urine 
output. Hematuria has been reported in greater than 3% of tacrolimus-treated patients. Abnormal 
liver function tests have been reported in 6% to 36% of patients; ascites was reported in 7-27% 
of these patients.  
Other miscellaneous effects that have occurred in clinical trials include pain (24% to 63%), fever 
(19% to 48%), back pain (17% to 30%), and peripheral edema (12% to 36%). The incidence of 
hyperglycemia is 17% and may require therapy with insulin. Other less frequently occurring 
effects (greater than 3%) include peritonitis, and photosensitivity reactions. Anaphylaxis has 
been reported in a few patients receiving intravenous tacrolimus. 
DRUG INTERACTIONS 
Tacrolimus is metabolized by cytochrome P450 3A4. Drugs that are inhibitors (e.g., 
itraconazole) or inducers (e.g., phenytoin) of 3A4 might increase or decrease tacrolimus 
concentrations respectively. This could result in increased or decreased effect of tacrolimus. 
Tacrolimus dose will be adjusted based on blood levels. 
11.0 ANCILLARY THERAPY 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc., when appropriate. 
Treatment with hormones (other than the required dexamethasone) or other chemotherapeutic agents 
may not be administered except for steroids given for adrenal failure; and hormones administered for 
non-disease-related conditions (e.g., insulin for diabetes). 
Palliative radiation therapy may not be administered except for whole-brain irradiation for 
documented CNS disease or testicular radiation for documented testicular involvement. Do not hold 
protocol chemotherapy during CNS irradiation. 


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11.1 
Alliance Policy Concerning the Use of Growth Factors 
The following guidelines are applicable unless otherwise specified in the protocol. 
11.1.1 Epoetin (EPO) 
Use of epoetin (epoetin, darbepoetin, EPO) in this protocol is permissible but not 
recommended. A baseline serum Epo level should be measured first. 
11.1.2 Filgrastim (G-CSF), PEG-filgrastim, and sargramostim (GM-CSF) 
1. Filgrastim (G-CSF) or PEG-filgrastim should be used as indicated in Course V. 
2. For the treatment of febrile neutropenia the use of CSFs should not be routinely 
instituted as an adjunct to appropriate antibiotic therapy. However, the use of CSFs may 
be indicated in patients who have prognostic factors that are predictive of clinical 
deterioration such as pneumonia, hypotension, multi-organ dysfunction (sepsis 
syndrome) or fungal infection, as per the ASCO guidelines. Investigators should 
therefore use their own discretion in using the CSFs in this setting. The use of CSF 
(PEG-filgrastim, filgrastim or sargramostim) must be documented and reported on flow 
sheets. 
3. When PEG-filgrastim, filgrastim or sargramostim are used, they must be obtained from 
commercial sources. 
12.0 CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE [43] 
The assessment of response after treatment for acute leukemia requires a physical examination, 
complete blood count, platelet count, differential count, and bone marrow aspiration and biopsy. 
Extramedullary sites known to be involved by leukemia prior to treatment (e.g., mediastinal 
lymphadenopathy or CSF) must be reexamined as well. Immunophenotyping, cytochemistry, and 
cytogenetic analyses are supportive data for clinical assessment.  
Investigators are cautioned that the bone marrow cytology and peripheral blood differential count in 
patients who are recovering from chemotherapy or who have received hematopoietic growth factors 
or cytokines may be shifted to immaturity, reflecting regenerating hematopoiesis; this should not be 
misinterpreted as residual or recurrent leukemia. Whenever the initial morphological result is 
ambiguous, a second bone marrow examination should be performed ≥ one week later, and 
confirmatory data should be gathered from cytogenetic analyses, immunophenotyping, or 
cytochemistry. 
12.1 
Complete Remission (CR) 
A CR requires the following: an absolute neutrophil count (segs and bands) >1000/µL, no 
circulating blasts, platelets >100,000/µL; adequate bone marrow cellularity with trilineage 
hematopoiesis, and <5% marrow leukemia blast cells. All previous extramedullary 
manifestations of disease must be absent (e.g., lymphadenopathy, splenomegaly, skin or gum 
infiltration, testicular masses, or CNS involvement). 
12.2 
Complete Cytogenetic Remission (CCyR)  
No clonal abnormal metaphase cells in ≥ 20 bone marrow karyotypes. 
12.3 
Complete Molecular Remission  
No evidence of BCR/ABL transcripts in a Q-PCR assay with a sensitivity of 1:1000 or greater, 
typically performed on blood. 


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12.4 
Major Molecular Remission  
Ratio of BCR/ABL transcript to ABL transcript is ≤ 0.1% in a Q-PCR assay with a sensitivity 
of 1:1000 or greater, typically performed on blood. 
12.5 
Complete Remission with Incomplete Recovery of Counts (CRi) 
CRi is identical to criteria for CR except for recovery of platelets <100,000/µL or recovery of 
ANC <1000/µL. Patients must be transfusion independent. 
12.6 
Partial Remission (PR) 
A PR requires all of the CR criteria except that the marrow may still contain 5-25% leukemia 
blast cells. An absolute neutrophil count (segs and bands) > 1000/µL, no circulating blasts, and 
platelets > 100,000/µL are required as for a CR. 
12.7 
Refractory Disease 
Failure to achieve a CR or PR with persistence of leukemia cells after treatment. 
12.8 
Progressive Disease 
An increase of at least 25% in the absolute number of circulating or bone marrow leukemic 
blasts, or development of extramedullary disease. 
12.9 
Relapsed Disease 
The reappearance of unequivocal leukemia blast cells in the blood or the bone marrow (>5%) or 
in the CNS (positive cytospin examination of CSF) or in any other extramedullary site after a 
CR; or progression to >25% leukemia blasts cells in the marrow after a PR.


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13.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
13.1 
Duration of Treatment 
Day on Study 
 
Clinical Status*† 
 
Action 
II-22 
M0, M1 
M2, M3 
relapse 
Proceed to course IV. 
Continue treatment (course III). 
Remove from protocol therapy. 
III-29 
M0, M1 
M2, M3, relapse 
Continue treatment. 
Remove from protocol therapy. 
IV-43 
M0, M1 
M2, M3, relapse 
Continue treatment. 
Remove from protocol therapy. 
V-30 
M0, M1 
M2, M3, relapse 
Continue treatment. 
Remove from protocol therapy. 
* If marrow cellularity is inadequate for diagnosis, repeat weekly until determination can be made. 
† Please see Appendix V for definitions of clinical status (i.e., M0, M1, etc.). 
13.2 
Relapse 
Patients who achieve complete remission (M0, M1) will continue on protocol therapy until the 
appearance of hematologic relapse as defined by the reappearance of unequivocal leukemia blast 
cells in the blood or the bone marrow (>5%) or in the CNS (positive cytospin examination of 
CSF) or in any other extramedullary site after a CR; or progression to >25% leukemia blasts 
cells in the marrow after a PR. Cytogenetics, FISH, or Q-PCR may be useful to identify recurrent 
Ph+ ALL cells. 
At the time of documented relapse, institutions should submit bone marrow or peripheral blood 
for institutional Q-PCR.  
13.3 
Extraordinary Medical Circumstances:  
If, at any time the constraints of this protocol are detrimental to the patient’s health or the patient 
no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In this 
event: 
• 
Document the reason(s) for discontinuation of therapy in patient records. 
• 
Submit C-300 (Off Treatment Notice) and follow the data submission requirements, 
including submission of appropriate follow-up forms at time of relapse and death, as well 
as C-300, and C-113, as detailed in Sections 6.1 (Data Submission) and 7.0 (Required Data). 
• 
Notify the Study Chair. 
• 
Continue to follow the patient for relapse, second malignancies, and survival endpoints. 
14.0 STATISTICAL CONSIDERATIONS 
14.1 
Statistical Objectives 
The primary objective of this study is the construction of a historical database to provide 
leukemia investigators relevant baseline data useful for the design of follow-up studies in this 
rare patient population. Consequently, the primary statistical objectives of this protocol 
primarily relate to estimation rather than inference. More specifically, the primary statistical 
objective of this study is the estimation of the disease-free survival (DFS) at the three-year 


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landmark for the combined as well as each of the three individual patient cohorts.  Disease-free 
survival (DFS) is measured from the date of first induction CR to relapse, or death due to any 
cause, with patients last known to be alive and disease-free censored at the date of last contact. 
The analysis population will consist of all eligible patients who receive at least one dose of 
dasatinib. The manuscripts reporting the results will report the effect of excluding any patients 
on the results. 
A secondary clinical endpoint of this study is achievement of BCR-ABL negativity. The 
corresponding statistical endpoint of this study is the probability of being BCR-ABL negative in 
the bone marrow and peripheral blood in a CLIA-approved clinical laboratory at the completion 
of the CNS prophylaxis course (Course IV). Patients who discontinue the protocol-specified 
treatment before completing the CNS prophylaxis course on this study will be counted as non-
responders (i.e., be qualified as not having reached BCR-ABL negative status). Another 
secondary clinical endpoint of this study will be the feasibility of maintenance therapy in this 
patient population. This analysis will be restricted to those patients achieving CR. For both 
secondary endpoints, the proportions will be estimated based on the combined and individual 
cohorts. 
Other clinical endpoints of interest include overall survival, disease-free survival and response. 
All time-to-event distributions will be estimated using the Kaplan-Meier estimator. Proportions 
will be estimated using point as well as interval estimators. All interval estimators will be 
constructed using the finite sample size sampling distribution at the unadjusted two-sided level 
of 0.05.  
For each endpoint, whenever scientifically plausible, the cohorts may be compared in an 
exploratory fashion. To this end, a three sample log-rank test will be used for time-to-event 
profiles and a randomized test for contingency will be used for binary outcomes. These tests will 
be conducted at the unadjusted 0.05 level. 
14.2 
Accrual Plan 
We plan to evaluate 60 patients. Any eligible patient who receives at least one dose of dasatinib 
will be deemed evaluable in the sense of being included in the primary analyses. We may have 
to register up to 66 patients to meet this goal. As the projected accrual rate is 2 patients per 
month, the projected accrual period is 33 months. Given that the last patient may need to be 
followed for up to three years, the total projected study period is expected to last up to 69 
(=33+36) months.  
14.3 
Study Monitoring 
We will formally monitor, by virtue of using statistical decision rules, the following feasibility 
and safety endpoints for all treated patients. Each decision rule is designed so as to have high 
probability of early crossing if the probability of the realization of the event of concern is about 
an unacceptable threshold and a low probability of early crossing if the event probability is 
below an acceptable threshold. 
1. Hematologic toxicity preventing administration of dasatinib at 70 mg BID during Courses 
I-IV. A drop-out rate exceeding 0.4 will be considered unacceptable. A drop-out rate of 0.2 
will be considered acceptable. The decision rule and its operating characteristics are shown 
in Tables 1 and 5, respectively. 
2. Dasatinib-related pleural effusion necessitating drainage (thoracentesis). A toxicity rate 
exceeding 0.3 will be considered unacceptable.  A drop-out rate of 0.1 will be deemed 
acceptable. The decision rule and its operating characteristics are shown in Tables 2 and 6, 
respectively. 


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3. Dasatinib-related pericardial effusion necessitating drainage (pericardiocentesis). A toxicity 
rate exceeding 0.15 will be considered unacceptable. The decision rule and operating 
characteristics are shown in Tables 3 and 7, respectively. 
4. Treatment-related mortality (TRM). A TRM rate exceeding 0.4 will be considered 
unacceptable. The decision rule and its operating characteristics are shown in Tables 4 and 
8, respectively. 
We will monitor the first 12, 24, 36, 48 and 60 patients. Monitoring will begin after the 12th 
patient completes Course V. If any of the bounds are crossed, we will initiate a review of the 
study to determine whether the study needs to be amended (for example, changing eligibility 
requirements or modifying the treatment regimens) or closed. In addition to the statistical 
decision rules, we will monitor the first twelve patients by holding regular teleconferences to be 
attended by the study investigators or their representatives, as well as the Alliance Protocol 
Operations Program Office and Alliance Statistics and Data Center. The first six patients will 
be monitored on a bi-weekly basis while the next six will be monitored on a monthly basis. 
Based on the results of the first interim analysis for feasibility and safety, we may decide to 
extend the teleconferences for the next 12 patients. These rules are primarily intended to help 
the study team to formally monitor the study from a safety and feasibility standpoint. 
k 
1 
2 
3 
4 
5 
nk 
12 
12 
12 
12 
12 
Nk 
12 
24 
36 
48 
60 
rk 
4 
7 
11 
14 
16 
Table 1: Monitoring design for assessing the inability to administer dasatinib at 70 mg BID due 
to hematologic toxicity. The stage is denoted by k. The number of patients accrued during and 
up to stage k are denoted by  nk and  Nk respectively. The critical value at stage k is denoted by 
rk. 
k 
1 
2 
3 
4 
5 
nk 
12 
12 
12 
12 
12 
Nk 
12 
24 
36 
48 
60 
rk 
4 
5 
7 
8 
9 
Table 2: Monitoring design for assessing pleural effusion necessitating drainage (thoracentesis). 
The stage is denoted by k. The number of patients accrued during and up to stage k are denoted 
by  nk and  Nk respectively. The critical value at stage k is denoted by rk. 
 
k 
1 
2 
3 
4 
5 
nk 
12 
12 
12 
12 
12 
Nk 
12 
24 
36 
48 
60 
rk 
2 
3 
4 
5 
6 
Table 3: Monitoring design for assessing pericardial effusion necessitating drainage 
(pericardiocentesis). The stage is denoted by k. The number of patients accrued during and up 
to stage k are denoted by  nk and  Nk respectively. The critical value at stage k is denoted by rk. 
 
k 
1 
2 
3 
4 
5 
nk 
12 
12 
12 
12 
12 
Nk 
12 
24 
36 
48 
60 
rk 
4 
7 
11 
14 
16 


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Table 4: Monitoring design for assessing treatment related mortality. The stage is denoted by k. 
The number of patients accrued during and up to stage k are denoted by nk and  Nk respectively. 
The critical value at stage k is denoted by rk. 
 
p 
p1 
p2 
p3 
p4 
p5 
Early Exit 
Probability 
Exit 
Probability 
0.20 
0.205 
0.073 
0.012 
0.012 
0.027 
0.303 
0.330 
0.30 
0.507 
0.177 
0.045 
0.051 
0.073 
0.780 
0.852 
0.40 
0.775 
0.152 
0.031 
0.023 
0.014 
0.980 
0.994 
Table 5: The operating characteristics for the monitoring rule illustrated in Table 1. The 
probability of not being able to administer dasatinib at 70 mg BID due to hematologic toxicity 
is denoted by p. The first exit probability at stage k is denoted by pk. An "exit" would initiate a 
safety assessment. The probability of early exit is equal to p1+…+p4. The exit probability is 
equal to p1+…+p5. 
 
p 
p1 
p2 
p3 
p4 
p5 
Early Exit 
Probability 
Exit 
Probability 
0.10 
0.026 
0.065 
0.021 
0.038 
0.044 
0.150 
0.195 
0.20 
0.205 
0.344 
0.120 
0.137 
0.088 
0.806 
0.894 
0.30 
0.507 
0.385 
0.067 
0.032 
0.007 
0.991 
0.998 
Table 6: The operating characteristics for the monitoring rule illustrated in Table 2. The 
probability of experiencing an episode of pleural effusion necessitating drainage (thoracentesis) 
is denoted by p. The first exit probability at stage k is denoted by pk. An "exit" would initiate a 
safety assessment. The probability of early exit is equal to p1+…+p4. The exit probability is 
equal to p1+…+p5. 
P 
p1 
p2 
p3 
p4 
p5 
Early Exit 
Probability 
Exit 
Probability 
0.05 
0.118 
0.051 
0.028 
0.017 
0.011 
0.215 
0.226 
0.10 
0.341 
0.160 
0.096 
0.065 
0.048 
0.662 
0.710 
0.15 
0.557 
0.205 
0.098 
0.053 
0.031 
0.913 
0.944 
Table 7: The operating characteristics for the monitoring rule illustrated in Table 3. The 
probability 
experiencing 
an episode 
of pericardial 
effusion 
necessitating 
drainage 
(pericardiocentesis). of not being able to administer dasatinib at 70 mg BID due to hematologic 
toxicity is denoted by p. The first exit probability at stage k is denoted by pk. An "exit" would 
initiate a safety assessment. The probability of early exit is equal to p1+…+p4. The exit 
probability is equal to p1+…+p5. 
 
P 
p1 
p2 
p3 
p4 
p5 
Early Exit 
Probability 
Exit 
Probability 
0.20 
0.205 
0.073 
0.012 
0.012 
0.027 
0.303 
0.330 
0.30 
0.507 
0.177 
0.045 
0.051 
0.073 
0.780 
0.852 
0.40 
0.775 
0.152 
0.031 
0.023 
0.014 
0.980 
0.994 
Table 8: The operating characteristics for the monitoring rule illustrated in Table 4. The 
probability of experiencing a treatment-related mortality is denoted by p. The first exit 
probability at stage k is denoted by pk. An "exit" would initiate a safety assessment. The 
probability of early exit is equal to p1+…+p4. The exit probability is equal to p1+…+p5. 


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14.4 
CDUS 
This study will be monitored by the Complete Clinical Data System (CDUS) Version 3.0. The 
Alliance Statistics and Data Center will submit quarterly reports to CTEP by electronic means 
using the Clinical Data Update System (CDUS). 
15.0 WRITING COMMITTEE 
A Writing Committee will be responsible for the publication of a manuscript that will describe the 
results of this study in a peer-reviewed journal. The members of this Writing Committee will be the 
co-authors of this manuscript, Dr. Wieduwilt, the Study Chair, will be the primary author; the 
CALGB 10701 Statistician will be the second author; and the Leukemia Committee Chair of the 
Alliance will be the senior (last) author.  
The other members of the Writing Committee will be determined according to the level of 
participation in the study as measured by the patient accrual from each group. The number of 
investigators on the Writing Committee from each of the participating cooperative groups (Alliance, 
ECOG-ACRIN, and SWOG) will be based on the following accrual formula. Each Group enrolling 
1-5% of the total number of patients accrued will nominate one member of the Writing Committee. 
Each group will be entitled to an additional member of the Writing Committee for each additional 
10% of the overall accrual. For example, if a group enrolled 15% of the study patients, that group 
would have 2 co-authors on the Committee; if 25% of the study patients were enrolled, that group 
would have 3 co-authors. The Alliance will be assigned additional members of the Writing 
Committee only after that group accrues >15% of the total study patients. It will be the responsibility 
of each cooperative group to name the individual clinical or laboratory investigators to fill their 
allotted positions. By this method, it is anticipated that the final Writing Committee will include 
approximately 8-10 of the clinical and/or laboratory investigators who have been most involved in 
the design, conduct, and analysis of this study. 
16.0 ADVERSE EVENT REPORTING (AER) 
Investigators are required by Federal Regulations to report serious adverse events as defined in the 
table below. This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0 to determine the severity of the reaction for adverse event reporting. All reactions 
determined to be “reportable” in an expedited manner must be reported using the CTEP Adverse 
Event Reporting System (CTEP-AERS). Reporting of cases of secondary AML/MDS/ALL is to be 
performed using CTEP-AERS. New primary malignancies should be reported using Study Form C-
1001. 
Expedited AE reporting for this study must use CTEP-AERS, accessed via the CTEP Web site 
(http://ctep.cancer.gov).  The reporting procedures to be followed are presented in the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and 
DCP INDs and IDEs” which can be downloaded from the CTEP Web site (http://ctep.cancer.gov).  
These requirements are briefly outlined in the tables below. 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to CTEP 
by telephone at 301-897-7497.  Once Internet connectivity is restored, the 24-hour notification 
phoned in must be entered electronically into CTEP-AERS by the original submitter at the site. 


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16.1 
CALGB 10701 Adverse Event Reporting Requirements 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE 
within 
30 Days of the Last Administration 
of the Investigational 
Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
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 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Note: All deaths on study require both routine and expedited reporting regardless of causality. 
Attribution to treatment or other cause should be provided. 


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• 
Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS 
report within 5 calendar days of the initial 24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted 
within 10 calendar days of the investigator learning of the event.  
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions (see below). 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under a CTEP IND. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
16.2 
Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting Requirements 
for Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or non-CTEP IND: 
• 
CALGB 10701 is conducted under a CTEP-held IND for dasatinib. Therefore, the reporting 
requirements for investigational agents under a CTEP-held IND should be followed for all 
enrolled patients. 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
• 
A discussion of adverse events associated with agents used in this trial can be found in 
Section 10.0 (Drug Formulation, Availability, and Preparation). For the purposes of 
expedited adverse event reporting, the CAEPR for dasatinib may be found in Section 16.3. 
Note: that the ASAEL column of the CAEPR has been replaced with the specific protocol 
exceptions to expedited reporting (SPEER) list. This list now includes “expected” severity 
grades in addition to event terms.” 
• 
Grade 3/4 myelosuppression and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. All other grade 3, 4, or 5 adverse 
events that precipitate hospitalization or prolong an existing hospitalization must be reported 
via CTEP-AERS. 
• 
Grade 3/4 nausea or vomiting and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. All other grade 3, 4, or 5 adverse 
events that precipitate hospitalization or prolong an existing hospitalization must be reported 
via CTEP-AERS. 
• 
Grade 3/4 febrile neutropenia and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. All other grade 3, 4, or 5 adverse 
events that precipitate hospitalization or prolong an existing hospitalization must be reported 
via CTEP-AERS. 
• 
Grade 3/4 infection and hospitalization resulting from such do not require CTEP-AERS, but 
should be submitted as part of study results. All other grade 3, 4, or 5 adverse events that 
precipitate hospitalization or prolong an existing hospitalization must be reported via CTEP-
AERS. 
• 
CTEP-AERS report should be submitted for creatinine level that doubles within a 24-hour 
period. 


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• 
CTEP-AERS report should be submitted if Course IV day 4, 18, or 32 serum methotrexate 
level is >0.05 µM. 
• 
CTEP-AERS reports should be submitted electronically to the Alliance Protocol Operations 
Program Office (https://eapps-ctep.nci.nih.gov/ctepaers/). 
• 
The reporting of adverse events described in the table above is in addition to and does not 
supplant the reporting of adverse events as part of the reporting of the results of the clinical 
trial, e.g., study summary forms, or cooperative group data reporting forms (see Section 6.1 
for required forms). 
16.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Dasatinib (BMS-
354825, NSC 732517) 
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 2937 patients. Below is the CAEPR for 
Dasatinib (BMS-354825, Sprycel). 
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. 
Version 2.6, September 1, 20151 
 
 Adverse Events with Possible  
 Relationship to Dasatinib (BMS-354825, Sprycel) 
 (CTCAE 4.0 Term) 
[n= 2937] 
 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
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 
 Abdominal pain (Gr 2) 
 
Anal mucositis 
  
 
Constipation 
  
Diarrhea 
 Diarrhea (Gr 3) 
 
Dyspepsia 
  
 
Gastrointestinal hemorrhage2 
  
 
Mucositis oral 
  


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 Adverse Events with Possible  
 Relationship to Dasatinib (BMS-354825, Sprycel) 
 (CTCAE 4.0 Term) 
[n= 2937] 
 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
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 site conditions 
- Other (generalized edema) 
  
 
General disorders and 
administration site conditions 
- Other (superficial edema) 
 General disorders and 
administration site conditions - 
Other (superficial edema) (Gr 2) 
 
Non-cardiac chest pain 
  
 
Pain 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection3 
 Infection3 (Gr 3) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
  
 
Aspartate aminotransferase 
increased 
  
 
Electrocardiogram QT 
corrected interval prolonged 
  
Neutrophil count 
decreased 
 Neutrophil count decreased (Gr 3) 
Platelet count decreased 
 Platelet count decreased (Gr 4) 
 
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 
 Hypophosphatemia (Gr 3) 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
  
Myalgia 
 Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
  
Headache 
 Headache (Gr 3) 
 
Intracranial hemorrhage 
  
 
Leukoencephalopathy 
  
 
Reversible posterior 
leukoencephalopathy syndrome 
  


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 Adverse Events with Possible  
 Relationship to Dasatinib (BMS-354825, Sprycel) 
 (CTCAE 4.0 Term) 
[n= 2937] 
 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
  
Dyspnea 
 Dyspnea (Gr 3) 
 
Laryngeal mucositis 
  
 
Pharyngeal mucositis 
  
Pleural effusion 
 Pleural effusion (Gr 3) 
 
Pneumonitis 
  
 
Pulmonary hypertension 
  
 
Tracheal mucositis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
  
 
Erythema multiforme 
  
 
Pruritus 
  
 
Rash acneiform 
  
Rash maculo-papular 
 Rash maculo-papular (Gr 2) 
 
Stevens-Johnson syndrome 
  
 
Toxic epidermal necrolysis 
  
VASCULAR DISORDERS 
  
 
Flushing 
  
 
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.  
 
2Gastrointestinal 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. 
 
3Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
4Gastrointestinal 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: 
 
CARDIAC DISORDERS - Acute coronary syndrome; 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; Conjunctivitis; Dry eye; Eye disorders - Other (optic nerve neuritis) 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Dry mouth; Dysphagia; Enterocolitis; Esophagitis; 
Flatulence; Gastritis; Gastrointestinal disorders - Other (anal fissure); Gastrointestinal disorders - Other 
(hematemesis); Gastrointestinal disorders - Other (mouth ulceration); Gastrointestinal disorders - Other (oral soft 
tissue disorder); Gastrointestinal disorders - Other (oropharyngeal pain); Gastrointestinal disorders - Other (tongue 
eruption); Gastrointestinal ulcer4; 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 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (herpes virus infection) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Cardiac troponin T increased; 
CD4 lymphocytes decreased; CPK increased; Creatinine increased; GGT increased; Investigations - Other (bone 
densitometry); Investigations - Other (EKG T-wave inversion); Investigations - Other (pancytopenia); 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; Musculoskeletal and connective tissue disorder - Other (epiphyses delayed 
fusion); Musculoskeletal and connective tissue disorder - Other (muscle spasm); Musculoskeletal and connective 
tissue disorder -  Other (muscle stiffness); Musculoskeletal and connective tissue disorder - Other (nuchal rigidity); 
Musculoskeletal and connective tissue disorder - Other (rhabdomyolysis); Musculoskeletal and connective tissue 
disorder - Other (tendonitis); Myositis; Osteoporosis; Pain in extremity 
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 - Gynecomastia; Irregular menstruation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Bronchospasm; Epistaxis; Hypoxia; Pulmonary edema; Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin; Hyperhidrosis; Nail loss; 
Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Periorbital edema; Photosensitivity; Purpura; Skin and 
subcutaneous tissue disorders - Other (acute febrile neutrophilic dermatosis); Skin and subcutaneous tissue disorders 
- Other (hair color changes); Skin and subcutaneous tissue disorders - Other (panniculitis); Skin ulceration; Urticaria 
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. 
 
16.4 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Alemtuzumab 
(NSC 715969) 
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 Agent 
Specific Adverse Event List (ASAEL), appears in a separate column and is identified with bold 


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and italicized text. This subset of AEs (ASAEL) contains events that are considered 'expected' 
for expedited reporting purposes only. Refer to the CTEP, NCI Guidelines for Adverse Event 
Reporting Requirements: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events 
Frequency is provided based on 346 patients. Below is the CAEPR for alemtuzumab. 
Version 2.1, March 23, 20101 
 
 Adverse Events with Possible  
 Relationship to Alemtuzumab  
 (CTCAE 4.0 Term) 
[n= 346] 
 
 
 
 EXPECTED AEs FOR 
CTEP-AERS 
REPORTING  
 
Agent Specific Adverse 
Event List 
(ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
Expected 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 Anemia 
 
Blood and lymphatic system 
disorders - Other (bone 
marrow aplasia) 
  
 
Disseminated intravascular 
coagulation 
 
  
 
Febrile neutropenia 
 
 Febrile neutropenia 
 
Hemolysis 
  
CARDIAC DISORDERS 
  
 
Atrial fibrillation 
 
  
 
Cardiac arrest 
 
  
 
Left ventricular systolic 
dysfunction 
  
 
Myocardial infarction 
 
  
 
Sinus tachycardia 
 
  
 
Ventricular arrhythmia 
 
  
 
Ventricular tachycardia 
 
  
ENDOCRINE DISORDERS 
  
 
Hyperthyroidism 
 
  
 
Hypothyroidism 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
  
 
Diarrhea 
 
  
 
Dyspepsia 
 
  
 
Mucositis oral 
 
  
Nausea 
 
 Nausea 
 
Small intestinal mucositis 
 
  
Vomiting 
 
 Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Chills 
 
 Chills 
 
Edema limbs 
 
  
Fatigue 
 
 Fatigue 
Fever 
 
 Fever 
 
Flu like symptoms 
 
 Flu like symptoms 
 
Injection site reaction 
 
 Injection site reaction 


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Non-cardiac chest pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
 Allergic reaction 
 
Autoimmune disorder 
 
  
 
Cytokine release syndrome 
 
 Cytokine release syndrome 
 
Serum sickness 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
 Infection2 
Infections and infestations – 
Other (Opportunistic infection 
with ≥Grade 2 Lymphopenia) 
 
 
  
INVESTIGATIONS 
  
 
Alkaline phosphatase 
increased 
 
  
 
Aspartate aminotransferase 
increased 
 
  
Lymphocyte count decreased 
 
 Lymphocyte count decreased 
Neutrophil count decreased 
 
 Neutrophil count decreased 
Platelet count decreased 
 
 Platelet count decreased 
 
White blood cell decreased 
 
 White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia 
 
Hypoalbuminemia 
 
 Hypoalbuminemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthritis 
 
  
 
Back pain 
 
  
 
Generalized muscle weakness  
  
 
Myalgia 
 
 Myalgia 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness 
 
Dysgeusia 
 
 Dysgeusia 
 
Headache 
 
 Headache 
 
Peripheral sensory neuropathy  
  
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Allergic rhinitis 
 
 Allergic rhinitis 
 
Bronchospasm 
 
  
 
Cough 
 
 Cough 
 
Dyspnea 
 
 Dyspnea 
 
Hypoxia 
 
 Hypoxia 
 
Pneumonitis 
 
  
 
Pulmonary edema 
 
  
 
Stridor 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Pruritus 
 
 Pruritus 
 
Purpura 
 
  
 
Rash acneiform3 
 
  
 
Urticaria 
 
 Urticaria 
VASCULAR DISORDERS 
  
 
Flushing 
 
 Flushing 
 
Hypertension 
 
  
 
Hypotension 
 
 Hypotension 


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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 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
3 Also may include desquamation. 
4 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. 
5 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 
GASTROINTESTINAL DISORDERS SOC. 
6 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 
 
Also reported on alemtuzumab trials but with the relationship to alemtuzumab still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(lymphadenopathy) 
CARDIAC DISORDERS - Pericarditis 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Tinnitus 
ENDOCRINE DISORDERS - Endocrine disorders - Other (aggravated diabetes mellitus) 
EYE DISORDERS - Optic nerve disorder 
GASTROINTESTINAL 
DISORDERS - Ascites; Colitis; Gastrointestinal hemorrhage4; Gastrointestinal 
perforation5; Gastrointestinal ulcer6; Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Gait disturbance; 
General disorders and administration site conditions - Other (Goodpasture's syndrome); General disorders and 
administration site conditions - Other (Guillain-Barre syndrome); General disorders and administration site conditions 
- Other (Hemophagocytic syndrome); General disorders and administration site conditions - Other (Syndrome of 
Inappropriate Antidiuretic Hormone Secretion [SIADH]) 
INVESTIGATIONS - Blood bilirubin increased; Creatinine increased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hypercalcemia; Hyperglycemia; 
Hypocalcemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Joint range of motion decreased; 
Musculoskeletal and connective tissue disorder - Other (muscle atrophy); Myositis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment 
related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Intracranial hemorrhage; Ischemia cerebrovascular; Leukoencephalopathy; 
Seizure; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Depression; Personality change; Psychosis 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other (toxic 
nephropathy); Urinary frequency; Urinary retention; Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; Reproductive system and breast 
disorders - Other (cervical dysplasia); Reproductive system and breast disorders - Other (ovarian failure) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Bronchial obstruction; Bronchopulmonary hemorrhage; Pulmonary fibrosis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme 
VASCULAR DISORDERS - Vascular disorders - Other (increased capillary fragility); Vascular disorders - Other 
(splenic infarction) 
  
 
Note: Alemtuzumab in combination with other agents could cause an exacerbation of any adverse event currently 
known to be caused by the other agent, or the combination may result in events never previously associated with either 
agent. 


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CALGB 10701/CTSU C10701 
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leukemia. Blood, 2008. 112(8): p. 3348-54. 
25. 
Hiwase, D.K., et al., Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: 
therapeutic implications. Clin Cancer Res, 2008. 14(12): p. 3881-8. 
26. 
Porkka K, S.B., et al., Efficacy of dasatinib in patients with Philadelphia-chromosome-positive 
acute lymphoblastic leukemia who are resistant or intolerant to imatinib: 2-year follow-up data 
from START-L (CA180-015). Blood (ASH Annual Meeting Abstracts), 2007.  p. 2810. 
27. 
Ottmann, O., et al., Dasatinib induces rapid hematologic and cytogenetic responses in adult 
patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance 
or intolerance to imatinib: interim results of a phase 2 study. Blood, 2007. 110(7): p. 2309-15. 
28. 
Soverini S., et al., Resistance to dasatinib in Philadelphia-positive leukemia patients and the 
presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. 
Haematologica, 2007. 92(3): p. 401-404. 
29. 
Ravandi F.,  et al., Phase II study of combination of hyperCVAD with dasatinib in frontline 
therapy of patients with Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia 
(ALL).  Blood (ASH Annual Meeting Abstracts), 2008. 112: p. 2941. 
30. 
Rousselot P., et al., Dasatinib (Sprycel®) and chemotherapy for first-line treatment in elderly 
patients with de novo Philadelphia positive ALL: results of the first 22 patients included in the 
EWALL-Ph-01 trial (on behalf of the European Working Group on Adult ALL [EWALL]). 
Blood, 2008. 112:Abstract 2920. 


CALGB 10701/CTSU C10701 
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Update #11 
31. 
Fielding, A.K. and A.H. Goldstone, Allogeneic haematopoietic stem cell transplant in 
Philadelphia-positive acute lymphoblastic leukaemia. Bone Marrow Transplant, 2008. 41(5): 
p. 447-53. 
32. 
Thomas D, O.B.S., et al., Long-term outcome after hyper-CVAD and imatinib (IM) for de novo 
or minimally treated Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-
ALL). . J Clin Oncol, 2010. 28: p. 6506. 
33. 
Wetzler M., et al., Imatinib and autologous stem cell transplantation for Philadelphia Positive 
acute lymphoblastic leukemia (Ph+ ALL) – study 10001. Ann Hematol, 2008. 87: p. S92-4. 
34. 
Goldstone, A.H., et al., In adults with standard-risk acute lymphoblastic leukemia, the greatest 
benefit is achieved from a matched sibling allogeneic transplantation in first complete 
remission, 
and an autologous 
transplantation 
is less effective 
than conventional 
consolidation/maintenance chemotherapy in all patients: final results of the International ALL 
Trial (MRC UKALL XII/ECOG E2993). Blood, 2008. 111(4): p. 1827-33. 
35. 
de Labarthe, A., et al., Imatinib combined with induction or consolidation chemotherapy in 
patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results 
of the GRAAPH-2003 study. Blood, 2007. 109(4): p. 1408-13. 
36. 
Wetzler, M., et al., Autologous stem cell transplanation (SCT) following sequential 
chemotherapy and imatinib for adults with newly diagnosed Philadelphia chromosome positive 
acute lymphoblastic leukemia (Ph+ ALL)-CALGB study 10001.  
37. 
Schroeder, H., et al., High dose melphalan and total body irradiation with autologous marrow 
rescue in childhood acute lymphoblastic leukaemia after relapse. Bone Marrow Transplant, 
1991. 7(1): p. 11-5. 
38. 
Mehta, J., et al., Autologous transplantation with CD52 monoclonal antibody-purged marrow 
for acute lymphoblastic leukemia: long-term follow-up. Leuk Lymphoma, 1997. 25(5-6): p. 
479-86. 
39. 
Ottmann, O.G., et al., Imatinib compared with chemotherapy as front-line treatment of elderly 
patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). 
Cancer, 2007. 109(10): p. 2068-76. 
40. 
Potenza, L., et al., Efficacy of imatinib mesylate as maintenance therapy in adults with acute 
lymphoblastic leukemia in first complete remission. Haematologica, 2005. 90(9): p. 1275-7. 
41. 
Thomas, D., et al., Long-term follow-up after frontline therapy with hyper CVAD and imatinib 
mesylate regimen in adults with Philadelphia (Ph) positive acute lymphocytic leukemia (ALL). 
Blood (ASH Annual Meeting Abstracts), 2007. 110: p.2869 
42. 
Yanada, M., et al., High complete remission rate and promising outcome by combination of 
imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic 
leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol, 2006. 
24(3): p. 460-6. 
43. 
Cheson, B.D., et al., Revised recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol, 2003. 21(24): p. 
4642-9. 
44. 
Przepiorka, D., et al., Consensus Conference on Acute GVHD Grading. Bone Marrow 
Transplant, 1994. 15(6): p. 825-8. 
 


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APPENDIX I:  IDEAL BODY WEIGHT TABLE 
 
 
 
 
 
 
 
 
 
 
 
Height (Feet/Inch) 
Small Frame (kg) 
Medium Frame (kg) 
Large Frame (kg) 
 
 
 
 
 
MEN 
 
 
 
 
 
5’2” 
54 
59 
64 
 
5’3” 
56 
60 
65 
 
5’4” 
57 
62 
67 
 
5’5” 
59 
63 
69 
 
5’6” 
60 
65 
71 
 
5’7” 
62 
67 
73 
 
5’8” 
64 
69 
75 
 
5’9” 
66 
71 
77 
 
5’10” 
68 
73 
79 
 
5’11” 
70 
75 
81 
 
6’0” 
72 
77 
84 
 
6’1” 
74 
79 
86 
 
6’2” 
76 
82 
88 
 
6’3” 
78 
84 
90 
 
6’4” 
79 
86 
93 
 
 
 
 
 
WOMEN 
 
 
 
 
 
4’10” 
45 
49 
54 
 
4’11” 
46 
50 
55 
 
5’0” 
47 
51 
57 
 
5’1” 
49 
53 
58 
 
5’2” 
50 
54 
59 
 
5’3” 
51 
55 
61 
 
5’4” 
53 
57 
63 
 
5’5” 
54 
59 
64 
 
5’6” 
56 
61 
66 
 
5’7” 
58 
63 
68 
 
5’8” 
59 
65 
70 
 
5’9” 
61 
67 
72 
 
5’10” 
64 
69 
74 
 
5’11” 
65 
70 
76 
 
6’0” 
67 
72 
79 
 
 


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APPENDIX II: GRAFT VERSUS HOST DISEASE GRADING 
To assess graft versus host disease (GVHD), use the scale below rather than the NCI CTCAE. 
I. 
Keystone Convention for Grading GVHD [44] 
 
 
 
 
 
Organ 
 
 
Gut Changes 
 
Grade 
Skin* 
Bilirubin (mg/dL) 
(diarrhea [mL/day]) 
 
 
 
 
 
 
1 
Rash < 25% 
2.0 - < 3.0 
> 500 - 999 or biopsy-
proven upper GI 
involvement 
 
 
 
 
 
 
2 
Rash 25-50% 
3.1 - 6 
≥ 1000 - < 1499 
 
 
 
 
 
 
3 
Rash > 50% 
6.1 - 15 
≥ 1500  
 
 
 
 
 
 
4 
Generalized 
erythroderma with 
bullae 
> 15 
Severe abdominal pain 
with or without ileus 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Organ Grade (see table above) 
 
Skin 
Hepatic 
Gut Changes 
OVERALL 
GRADE 
 
1 or 2 
0 
0 
1 
 
1, 2, 3 
1 
1 
2 
 
2 or 3 
2 or 3 
2 or 3 
3 
 
Grade 4 toxicity in any organ system is considered overall Grade 4. 
 
 
 
 
 
 
 
 
 
 
* Use “rule of nines” to determine body surface area 
 
II. Clinical Grading of Chronic GVHD 
A. 
Limited Chronic GVHD: 
1. Localized skin involvement, 
and/or 
2. Hepatic dysfunction due to chronic GVHD. 
B. 
Extensive Chronic GVHD: 
1. Generalized skin involvement, 
or 
2. Localized skin involvement and/or hepatic dysfunction due to chronic GVHD 
Plus 
3a. Liver histology showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis, or  
3b. Involvement of eye (Schirmer’s test with less than 5 mm wetting), or 
3c. Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy, or 
3d. Involvement of any other target organ. 


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APPENDIX III:  EXAMPLES OF SUBSTRATES, INDUCERS AND INHIBITORS OF CYP3A4 
CYP3A4 Substrates 
 
Albuterol 
Alfentanil 
Alprazolam 
Amiodarone 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Budesonide 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazepine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cilostazol 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Dasatinib (1) 
Delavirdine 
Diazepam 
Dihydroergotamine  
Diltiazem  
Disopyramide  
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, 
conj., 
synthetic 
Estrogens, conj., equine 
Estrogens, 
conj., 
esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestane 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fluticasone 
Fosamprenavir 
Gefitinib 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine  
Itraconazole 
Ketamine  
Ketoconazole 
Lansoprazole 
Letrozole 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Pipotiazine 
Primaquine 
Progesterone 
Quetiapine 
Quinidine 
Rabeprazole  
Ranolazine 
Repaglinide 
Rifabutin 
Ritonavir 
Salmeterol 
Saquinavir 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Spiramycin 
Sufentanil 
Sunitinib 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tipranavir 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamide 
Zopiclone 
 


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CYP3A4 Inhibitors 
Acetominophen 
Acetazolamide 
Amiodarone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffeine 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetidine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Danazol 
Dasatinib (1) 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice (2) 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan  
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol  
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Ranolazine 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Voriconazole 
Zafirlukast 
Ziprasidone 
 
CYP3A4 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin  
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital  
Phenytoin 
Primidone 
Rifabutin 
Rifampin  
Rifapentine 
St. John’s wort (3) 
When drugs classified as ‘substrates’ are co-administered with (Study Agent), there is the potential for higher concentrations of 
the ‘substrate’. When (Study Agent)  is co-administered with compounds classified as ‘inhibitors’, increased plasma 
concentrations of (Study Agent) is the potential outcome. The co-administration of ‘inducers’ would potentially lower plasma 
(Study Agent) concentrations. 
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, Goldman MP, 
Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; LexiComp Inc. 2007: 1899-1912.   
Only major substrates and effective inducers are listed.   
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at 
http://medicine.iupui.edu/flockhart/. 
(1)   Investigator’s Brochure: Dasatinib (BMS 354825). Bristol-Myers Squibb. October 2006. 
(2)  Malhotra et al. (2001). Clin Pharmacol Ther. 69:14-23. 
(3)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249. 
      Frye et al. (2004). Clin Pharmacol Ther. 76:323-329. 
 
Updated on May 1, 2007 


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APPENDIX IV:  PATIENT INSTRUCTION SHEET 
 
Course IV Drug Administration Schedule 
 
After Course III if there is no evidence of persistent leukemia in your bone marrow, that is, your bone 
marrow shows a remission from leukemia, you will receive a course of treatment, referred to as “Course 
IV” to try to further prevent recurrence of your leukemia. This treatment is specifically designed to 
decrease the risk of leukemia recurring in the brain and spinal cord (the central nervous system), known 
sites of recurrence in patients with your disease. After you have recovered sufficiently from Course III the 
following chemotherapy drugs will be given during the next month of therapy: 
 
The following is meant to serve as a schedule of when chemotherapy drugs are to be given during Course 
IV. 
 
 
For Example 
Actual Date & Time: 
Instructions 
Day 1 
Monday at 9 AM: 
 
Vincristine in clinic. 
 
Monday at 9 AM-12 
PM: 
 
Intravenous (IV) Methotrexate in clinic. 
During IV Methotrexate, Intrathecal 
Methotrexate will be given in clinic. 
 
Monday at 3 PM: 
 
Begin Oral Methotrexate. 
 
Monday at 9 PM: 
 
Oral Methotrexate at home. 
Day 2 
Tuesday at 3 AM: 
 
Oral Methotrexate at home. 
 
Tuesday at 9 AM: 
 
Oral Methotrexate at home. 
 
Tuesday at 3 PM: 
 
Return to clinic for blood sample. 
Intravenous Leucovorin in clinic. 
Day 3 
Wednesday at 3 AM: 
 
Oral Leucovorin at home. 
 
Wednesday at 9 AM: 
 
Oral Leucovorin at home. 
 
Wednesday at 3 PM: 
 
Oral Leucovorin at home. 
 
Wednesday at 9 PM: 
 
Oral Leucovorin at home. 
Day 4 
Thursday at 3 AM: 
 
Oral Leucovorin at home. 
 
Thursday at 9 AM: 
 
Oral Leucovorin at home. 
 
Thursday at 3 PM: 
 
Oral Leucovorin at home. 
 
Thursday at 9 PM: 
 
Oral Leucovorin at home. 
 
Thursday: 
 
Return to clinic for blood sample at any 
time during the day on Thursday. Oral 
Leucovorin will be stopped depending on 
results of blood sample. 
 
In addition to the drugs discussed above, an oral antibiotic, known as Bactrim® will be taken. One 
Bactrim tablet will be taken twice daily for three days every week to prevent Pneumocystis pneumonia. If 
you are allergic to this medication, a different antibiotic (pentamidine) can be prescribed. 
 
Bactrim should be stopped 3 days before and resumed 3 days after each dose of methotrexate. 
 
 
 


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APPENDIX V A:  CRITERIA FOR EVALUATING ACUTE LEUKEMIA 
 
(Excerpted from the June 1974 Modification of the December 1969 Criteria) 
 
 
Category M-Bone Marrow 
 
Specify Marrow Cellularity 
 
Marrow cellularity is to be defined as follows (for purposes of judging toxicity and response): 
 
0 
Aplastic (severely hypocellular) bone marrow 
1+ 
Hypocellular bone marrow 
2+ 
Normocellular bone marrow 
3+ 
Hypercellular bone marrow 
4+ 
Packed (intensely hypercellular bone marrow) 
 
 
It is recognized that assessment of marrow cellularity based on aspiration alone is not always accurate. 
Where the aspirates are normocellular, further investigation of cellularity is not indicated. When the 
pretreatment marrow is hypocellular or when decisions concerning further therapy hinge on whether or 
not hypocellular aspirate is truly representative, marrow biopsy should be done. 
 
 
 
TYPE OF LEUKEMIA 
 
Acute Lymphocytic 
Acute Myelocytic 
 
Rating 
Blast Cells (%)* 
Lymphocytes & Blast 
Cells (%) 
Blast Cells (%)** 
Blast Cells & 
Promyelocytes (%) 
M0 
0 - 5.0 
0 - 40.0 
0 - 5.0 
0 - 10.0 
M1 
0 - 5.0 
0 - 40.0 
0 - 5.0 
0 -10.0 
M2 
5.1 - 25.0 
40.1 - 70.0 
5.1 - 25.0 
10.1 - 30.0 
M2x 
0 - 25.0 
< 70.0 
0 - 25.0 
0 - 30.0 
M3 
25.0 - 50.0 
> 70.0 
25.0 - 50.0 
30.1 - 55.0 
M4 
> 50.0 
 
> 50.0 
> 55.0 
 
* 
The term “blast cell” includes any cell which cannot be classified as a more mature normal element, and 
includes “leukemic cells,” pathologic lymphocytes, and stem cells. 
 
** 
The term “blast cell” includes any cell which cannot be classified as a more mature normal element, and 
includes “leukemic cells,” nucleolated granulated cells, and monocytoid leukemic cells. It does not include 
pathologic erythroid cells. 


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APPENDIX V B:  CRITERIA FOR EVALUATING ACUTE LEUKEMIA 
 
(Excerpted from the June 1974 Modification of the December 1969 Criteria) 
 
Category H-Hemogram 
 
 
Rating 
Hemoglobin 
M 
F 
Neutrophilic 
Granulocytes/µl** 
Blasts* % 
Platelets/µl 
H0 
≥ 14 
≥ 13 
≥ 3,500 
0 
≥ 200,000 
H1 
≥ 12 
≥ 11 
 ≥ 2,000† 
0 
100 - 199,000 
H2 
≥ 9.0 
≥ 500 
≤ 5 
50 - 99,000 
H3 
7.0 - 8.9 
≥ 500 
5.1 - 20 
25 - 49,000 
H4 
< 7.0 
< 500 
> 20 
< 25,000 
 
* 
In acute lymphocytic leukemia, the term blast cell includes any cell which cannot be classified as a more mature 
normal element and includes “leukemic cells,” “pathologic lymphocytes,” and stem cells. 
 
 
In acute myelocytic leukemia, the term blast cell includes any cell which cannot be classified as a more mature 
normal element and includes “leukemic cells,” nucleolated cells, monocytoid leukemic cells and promyelocytes. 
 
** Term here includes segmented polys, stabs, and metamyelocytes. 
 
† 
And at least 50% of total number of leukocytes. 
 
Overall “H” rating is to be determined by the worst subcategory present; i.e., hemogram cannot be considered H0 if 
any subcategory worse than 0, cannot be H1 if any subcategory worse than 1, etc. 
 
Ratings indicating improvement in an “H” category must not be ascribable to transfusion of any blood elements. 
 
Mononuclear cells must not exceed 5000 cells/cm2 (7000 for patients <4 years) for an H0, H1 rating. 
 
The appearance of 1 or 2% blast cells on an isolated count does not preclude an H1 rating but cannot be allowed in 
an H0 rating.