Combination Chemotherapy With or Without Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To test whether the relapse-free survival after allogeneic stem cell transplantation among
Philadelphia chromosome positive and/or breakpoint cluster region (BCR)/Abelson murine
leukemia viral oncogene (ABL) positive acute lymphoblastic leukemia (ALL) patients given an
intensive short-term chemotherapy regimen of fractionated cyclophosphamide, vincristine
sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) in combination with the
tyrosine kinase inhibitor dasatinib is sufficiently high to warrant further investigation.

SECONDARY OBJECTIVES:

I. To test whether the continuous complete remission rate for previously untreated
Philadelphia chromosome positive and/or BCR/ABL positive acute lymphoblastic leukemia (ALL)
patients given an intensive short-term chemotherapy regimen of hyper-CVAD in combination with
the tyrosine kinase inhibitor dasatinib is sufficiently high to warrant phase III
investigation.

II. To investigate in a preliminary manner the relative effectiveness of minimal residual
disease (MRD) detection using real-time quantitative polymerase chain reaction (PCR) for
BCR/ABL versus flow cytometry to predict the outcome of patients treated by the hyper-CVAD +
dasatinib regimen and/or allogeneic stem cell transplant.

TERTIARY OBJECTIVES:

I. To estimate the frequency and severity of toxicities of the intensive short-term
chemotherapy regimen in these patients.

II. To estimate the overall survival of all patients on this study.

OUTLINE:

INDUCTION/CONSOLIDATION THERAPY: All patients receive both of the following regimens in
alternating courses:

COURSES 1, 3, 5, 7 or 3, 5, 7, 9: Patients receive cyclophosphamide intravenously (IV) over 3
hours twice daily (BID) on days 1-3; doxorubicin hydrochloride IV over 24 hours on day 4;
vincristine sulfate IV over 30 minutes on days 4 and 11; dexamethasone IV or orally (PO) once
daily (QD) on days 1-4 and 11-14; dasatinib PO QD on days 1-14; cytarabine intrathecally (IT)
on day 7; methotrexate IT on day 2; and filgrastim (G-CSF) subcutaneously (SC) QD or BID.

COURSES 2, 4, 6, 8: Patients receive high-dose methotrexate IV over 24 hours on day 1;
methylprednisolone IV over 30 minutes BID on days 1-3; dasatinib PO QD on days 1-14;
high-dose cytarabine IV over 2 hours BID on days 2-3; leucovorin calcium IV on days 2 or 3;
methotrexate IT on day 2; cytarabine IT on day 7; and G-CSF SC QD or BID.

Treatment repeats every 14-21 days for 8 courses in the absence of disease progression,
unacceptable toxicity, or if patient achieves complete remission (CR) or complete remission
with incomplete platelet recovery (CRi).

MAINTENANCE THERAPY*: Patients receive vincristine sulfate IV over 30 minutes on day 1,
prednisone PO QD on days 1-5, and dasatinib PO QD on days 1-28.

Treatment repeats every month for 24 courses in the absence of disease progression or
unacceptable toxicity or until the transplant is ready.

INTENSIFICATION: For courses 6 and 13, patients receive cyclophosphamide IV over 3 hours BID
on days 1-3; doxorubicin hydrochloride IV over 24 hours on day 4; vincristine sulfate IV over
30 minutes on days 4 and 11; dexamethasone IV or PO QD on days 1-4 and 11-14; dasatinib PO QD
on days 1-14; and G-CSF SC QD or BID.

NOTE: *Only if transplantation is not ready after induction/consolidation therapy or patients
are not undergoing a transplant.

ALLOGENEIC STEM CELL TRANSPLANTATION (FOR PATIENTS ACHIEVING CR OR CRi):

CONDITIONING REGIMEN: Patients receive 1 of the following regimens:

REGIMEN A: Patients receive total-body irradiation (TBI) QD on days -7 to -4 and
cyclophosphamide IV on days -3 and -2.

REGIMEN B: Patients receive TBI BID on days -6 to -4 and cyclophosphamide IV on days -3 and
-2.

REGIMEN C: Patients receive cyclophosphamide IV on days -7 and -6 and TBI QD on days -4 to
-1.

REGIMEN D: Patients receive cyclophosphamide IV on days -6 and -5 and TBI BID on days -3 to
-1.

REGIMEN E: Patients receive TBI QD on days -7 to -4 and etoposide IV on day -3.

REGIMEN F: Patients receive TBI BID on days -6 to -4 and etoposide IV on day -3.

ALLOGENEIC STEM CALL TRANSPLANTATION: Patients undergo allogeneic stem cell transplantation
on day 0.

GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive 1 of the following regimens:

REGIMEN A: Patients receive sirolimus PO and tacrolimus IV continuously (changing to PO BID)
beginning on day -3 and continuing for 6 months.

REGIMEN B: Patients receive tacrolimus IV continuously (changing to PO BID) and continuing
for 6 months, and methotrexate IV on days 1, 3, 6, and 11.

SINGLE-AGENT THERAPY: After completion of maintenance therapy or beginning on day 100
post-transplantation, patients receive dasatinib PO QD for up to 5 years.

After completion of study therapy, patients are followed every 6 months for up to 5 years.

Inclusion Criteria:

- INDUCTION/CONSOLIDATION REGISTRATION:

- Patients must have a morphologic diagnosis of acute lymphoblastic leukemia (ALL), with
evidence of ALL involvement in bone marrow and/or blood; patients with only
extramedullary disease in the absence of bone marrow or blood involvement are not
eligible; patients with M0 acute myeloid leukemia (AML) or mixed lineage leukemia are
not eligible for this study; patients with L3 (Burkitts) are also not eligible

- For ALL in marrow or peripheral blood, immunophenotyping of the blood or marrow
lymphoblasts must be performed to determine lineage (B cell, T-cell, or mixed B/T
cell); NOTE: appropriate marker studies including cluster of differentiation
(CD)19 (B cell), CD10, CD5, and CD7 (T cell) must be performed; co-expression of
myeloid antigens (CD13 and CD33) will not exclude patients; if possible, the
lineage specific markers cytoplasmic CD22 or CD79a (B cells), cytoplasmic CD3 (T
cells) and cytoplasmic myeloperoxidase (MPO) (myeloid cells) must be determined

- Patients may have received no more than one course of remission induction therapy for
ALL; patients who have received any post-remission therapy for ALL or who have
relapsed from complete remission are not eligible; (patients with previously untreated
ALL can be eligible, and patients who have received one course of remission induction
therapy for ALL can be eligible, regardless of their response to therapy); patients
may have received no more than 14 days of tyrosine kinase inhibitor therapy prior to
registration; any prior induction chemotherapy must have been completed no more than
28 days prior to registration

- NOTE: If the patient has been initiated on the protocol defined regimen (i.e. the
hyper-CVAD regimen without a tyrosine kinase inhibitor) before the Philadelphia
chromosome (Ph)/BCR-ABL status was known, the patient may be registered on the
protocol and start dasatinib; in this first course, dasatinib will be
administered up to day 14 (i.e. if the patient is registered on day 5 and starts
therapy on day 6, only 8 days of dasatinib will be administered and dasatinib
will be completed on day 14)

- For patients who have received any prior therapy that was NOT remission induction
therapy, one of the following must be true:

- At least 6 weeks must have elapsed since any monoclonal antibodies were given, at
least 7 days must have elapsed since any other treatment was given, and all
toxicities of the remission induction therapy must have resolved to grade =< 2

- The patient must have rapidly progressive disease (per institutional guidelines)

- For previously treated patients, the study chair must be contacted before
registration, in order to determine the regimen to be given in the first course of
induction/consolidation therapy, based on prior therapy

- Patients must be Philadelphia (Ph) positive and/or BCR/ABL positive as confirmed by
standard cytogenetics, fluorescent in situ hybridization (FISH), and/or polymerase
chain reaction (PCR) testing performed by local laboratory; NOTE: samples will be
submitted centrally for verification of results

- Patients must have a bilirubin =< 3.0 x institutional upper limit of normal (IULN)
within 14 days prior to registration

- Patients must have serum glutamic oxaloacetic transaminase (SGOT) (aspartate
aminotransferase [AST]) =< 3.0 x IULN and/or serum glutamate pyruvate transaminase
(SGPT) (alanine aminotransferase [ALT]) =< 3.0 x IULN within 14 days prior to
registration; if both tests are done then both values must be =< 3.0 x IULN

- Patients must have a serum creatinine =< 3.0 x IULN within 14 days prior to
registration

- Patients must not have active pericardial effusion, ascites, or pleural effusion of
any grade; exception: if the effusion is suspected to be related to the leukemia, the
patient may have pericardial effusion of =< grade 2 or pleural effusion =< grade 1

- Patients may not have any clinically significant cardiovascular disease including the
following:

- Myocardial infarction or ventricular tachyarrhythmia within 6 months

- Prolonged corrected QT (QTc) >= 480 msec (Fridericia correction)

- Ejection fraction less than institutional normal

- Major conduction abnormality (unless a cardiac pacemaker is present)

- Patients with any cardiopulmonary symptoms of unknown cause (e.g. shortness of
breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with
or without stress test as needed in addition to electrocardiogram (EKG) to rule
out QTc prolongation; the patient may be referred to a cardiologist at the
discretion of the principal investigator; patients with underlying
cardiopulmonary dysfunction should be excluded from the study

- Patients must have Zubrod performance status of 0-2

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease-free for 5 years

- Collection and submission of pre-treatment cytogenetic specimens must be completed
within 28 days prior to registration on S0805

- Collection and submission of pretreatment marrow and/or peripheral blood specimens for
cellular and molecular studies, including verification of BCR/ABL status must be
completed within 28 days prior to registration

- Patients must not be pregnant or nursing; women/men of reproductive potential must
have agreed to use an effective contraceptive method; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures outlined in the protocol, he/she is
responsible for beginning contraceptive measures

- Patients must not have prior history of known type I hypersensitivity or anaphylactic
reactions to doxorubicin

- Patients or their legally authorized representative must be informed of the
investigational nature of this study and must sign and give written informed consent
in accordance with institutional and federal guidelines

- At the time of patient registration, the treating institution's name and
identification (ID) number must be provided to the Data Operations Center in Seattle
in order to ensure that the current (within 365 days) date of institutional review
board approval for this study has been entered into the data base

- MAINTENANCE/INTENSIFICATION:

- Patient must have achieved CR or CRi within 2 courses of Induction/Consolidation
Chemotherapy; patient must remain in CR or CRi until beginning Maintenance
Chemotherapy and this must be re-documented by bone marrow and peripheral blood
examination within 28 days prior to registration to Step 2

- All treatment related toxicities must have resolved to =< grade 2

- Patients must not have received allogeneic stem cell transplant

- TRANSPLANT REGISTRATION:

- Patients must have an available completely matched sibling donor or a 10/10 matched
non-sibling donor

- Patients must have allogeneic stem cell transplant arranged prior to registration to
Step 3

- Patients must have documented CR or CRi within 14 days prior to registration to Step 3

- Patients must not be HIV + (human immunodeficiency virus); a negative HIV test must be
obtained within 14 days prior to registration

- POST TRANSPLANT/POST-MAINTENANCE SINGLE-AGENT DASATINIB THERAPY:

- Patients must have reached day 100 post transplant or must have completed protocol
maintenance/intensification (or must have been approved by the Study Chair after early
removal from maintenance/intensification)

- Patients must be in CR or CRi based on bone marrow and peripheral blood examination
within 28 days prior to registration to Step 4

- Patients must have recovered to =< grade 2 from all treatment related toxicity