Chemotherapy, Imatinib Mesylate, and Peripheral Stem Cell Transplantation in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well giving imatinib mesylate together with chemotherapy and peripheral stem cell transplantation works in treating patients with newly diagnosed acute lymphoblastic leukemia. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Imatinib mesylate may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth. Giving imatinib mesylate together with chemotherapy and peripheral stem cell transplantation may be an effective treatment for acute lymphoblastic leukemia.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine the activity of imatinib mesylate (Gleevec) to prolong disease-free survival (DFS) and overall survival in acute lymphoblastic leukemia (ALL) patients with t(9;22). II. Determine the ability of imatinib mesylate (Gleevec) to produce or maintain a BCR-ABL-negative status, as judged by real-time-polymerase chain reaction (RT-PCR) following sequential chemotherapy, imatinib mesylate (Gleevec) and transplantation. III. Determine the feasibility of collecting adequate peripheral blood stem cells for autologous transplantation following imatinib mesylate (Gleevec) therapy. IV. Study the safety and efficacy of autologous peripheral stem cell transplantation following therapy with imatinib mesylate (Gleevec). V. Study the safety and efficacy of allogeneic stem cell transplantation following therapy with imatinib mesylate (Gleevec). VI. Study the safety and efficacy of imatinib mesylate (Gleevec) administered after allogeneic or autologous stem cell transplant. OUTLINE: COURSE I (remission induction): Patients receive 1 course of front-line induction therapy on a Cancer and Leukemia Group B (CALGB)/Southwest Oncology Group (SWOG) protocol prior to enrollment. COURSE II (imatinib mesylate): Patients receive imatinib mesylate orally (PO) twice daily on days 1-28. COURSE III (CNS prophylaxis): Within 7 days after completing course II, patients receive methotrexate intrathecally (IT), methotrexate intravenously (IV) over 3 hours, and vincristine sulfate IV on days 1, 8, and 15; methotrexate PO every 6 hours on days 1-2, 8-9, and 15-16; leucovorin calcium IV on days 2, 9, and 16; and leucovorin calcium PO every 6 hours on days 3, 4, 10, 11, 17, and 18. COURSE IV (imatinib mesylate): After blood counts recover after completion of course III, patients receive imatinib mesylate as in course II. COURSE V: Patients undergo allogeneic peripheral blood stem cell transplantation (PBSCT), autologous PBSCT, or no PBSCT. COURSE Va (allogeneic PBSCT for patients with human leukocyte antigen [HLA]-matched sibling donor): Beginning 3-10 days after completion of course IV, patients with an HLA-matched sibling donor undergo total body irradiation (TBI) 2-3 times daily on days -7 to -4. Patients receive etoposide IV over 4 hours on day -3. Patients then undergo PBSCT on day 0. Patients then receive graft-vs-host disease prophylaxis with tacrolimus IV continuously on days -1 to 56 (or IV continuously on days -1 to 14 and then PO or IV every 12 hours on days 15-56) followed by a taper. Patients also receive methotrexate IV on days 1, 3, and 6, and filgrastim subcutaneously (SC) beginning on day 4 and continuing until blood counts recover. COURSE Vb (autologous PBSCT for patients without HLA-matched sibling donor): Beginning 3-10 days after completion of course IV, patients without an HLA-matched sibling donor receive etoposide IV continuously and cytarabine IV over 2 hours on days 1-4. Patients also receive filgrastim SC beginning on day 14 and continuing until PBSC collection is complete. Patients receive imatinib mesylate PO twice daily beginning after completion of PBSC collection and continuing until 3 days before PBSCT. Patients then undergo TBI 2-3 times daily on days -8 to -5. Patients receive etoposide IV over 4 hours on day -4 and cyclophosphamide IV over 2 hours on day -2. Patients undergo PBSCT on day 0. Patients receive filgrastim SC beginning on day 0 and continuing until blood counts recover. COURSE Vc (no transplantation for patients who are not transplant candidates): Beginning 3-10 days after completion of course IV, patients who are not candidates for PBSCT receive etoposide IV over 4 hours and cytarabine IV over 2 hours on days 1-4. Patients also receive filgrastim SC once or twice a day beginning on day 14 and continuing until blood counts recover. COURSE VI: Patients receive imatinib mesylate PO once or twice daily beginning on day 30 post transplantation or on day 30 if no transplantation received and continuing for at least 1 year or until patient has 2 consecutive negative reverse transcriptase-polymerase chain reaction assays at least 3 months apart or until relapse. After completion of study treatment, patients are followed up monthly for 1 year, every 3 months for 2 years, every 6 months for 2 years, then yearly for 5 years.

Official Title
-----------------
A Phase II Trial of Sequential Chemotherapy, Imatinib Mesylate (Gleevec, STI571) (NSC # 716051), and Transplantation for Adults With Newly Diagnosed Ph+ Acute Lymphoblastic Leukemia by the CALGB and SWOG

Conditions
-----------------
Adult Acute Lymphoblastic Leukemia in Remission

Intervention / Treatment
-----------------
* Drug: imatinib mesylate
* Drug: methotrexate
* Drug: vincristine sulfate
* Drug: leucovorin calcium
* Procedure: peripheral blood stem cell transplantation
* Procedure: autologous hematopoietic stem cell transplantation
* Procedure: allogeneic hematopoietic stem cell transplantation
* Radiation: total-body irradiation
* Drug: tacrolimus
* Biological: filgrastim
* Drug: etoposide
* Drug: cyclophosphamide
* Drug: cytarabine
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Unequivocal histologic diagnosis of ALL Detection of the t(9;22)(q34;q11) or 3-way variant by metaphase cytogenetics or BCR-ABL positive by molecular analysis (RT-PCR or fluorescence in situ hybridization [FISH}) Prior Therapy: Complete or partial remission following one course of induction chemotherapy with an intensive 4 or 5 drug regimen (with or without imatinib mesylate) on a CALGB or SWOG ALL protocol for previously untreated ALL patients Note: The double induction regimen of SWOG S0333 is considered to be one course of induction chemotherapy for the purpose of this eligibility criterion; therefore, patients from S0333 may be eligible for this study only after completing the entire double induction regimen Complete or partial remission following one course of therapy on any standard induction regimen (with or without imatinib mesylate) without prior enrollment on a cooperative group frontline protocol; in these instances, documentation of Philadelphia chromosome (Ph)+ positivity may occur outside a CALGB or SWOG laboratory Note: CALGB institutions must enroll patients on CALGB 9862 and submission of an initial sample for the companion trial must occur at time of enrollment on CALGB C10001; enrollment on companion studies CALGB 8461 and 9665 is not required No more than six weeks of prior imatinib mesylate during induction therapy before study enrollment 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 imatinib mesylate (Gleevec) to allow complete clearance of drug and its principle metabolites from the body; in women of childbearing potential, a pregnancy test will be required at study entry

Ages Eligible for Study
-----------------
Minimum Age: 15 Years
Maximum Age: 59 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (imatinib mesylate, chemotherapy, PBSCT)<br>See Detailed Description. | Drug: imatinib mesylate<br>* Given PO<br>* Other names: Glivec;Drug: methotrexate<br>* Given IT and IV<br>* Other names: MTX;Drug: vincristine sulfate<br>* Given IV<br>* Other names: Vincasar PFS;Drug: leucovorin calcium<br>* Given IV and PO<br>* Other names: LV;Procedure: peripheral blood stem cell transplantation<br>* Undergo PBSCT<br>* Other names: transplantation, peripheral blood stem cell;Procedure: autologous hematopoietic stem cell transplantation<br>* Undergo autologous PBSCT<br>Procedure: allogeneic hematopoietic stem cell transplantation<br>* Undergo allogeneic PBSCT<br>Radiation: total-body irradiation<br>* Undergo TBI<br>* Other names: TBI;Drug: tacrolimus<br>* Given IV or PO<br>* Other names: Prograf;Biological: filgrastim<br>* Given SC<br>* Other names: Neupogen;Drug: etoposide<br>* Given IV<br>* Other names: VP-16-213;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival | Disease-free survival (DFS) was measured as the interval from achievement of complete remission (CR) until relapse or death, regardless of cause; patients alive and in CR were censored at last follow-up. DFS was estimated using the Kaplan Meier method. A complete remission (CR) was defined as recovery of morphologically normal bone marrow and blood counts (i.e., neutrophils >= 1.5 x 10^9/L and platelets > 100 x 10^9/L) and no circulating leukemic blasts or evidence of extramedullary leukemia and persisting for at least one month. | Duration of treatment (up to 10 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival (OS) as the interval from the on-study date until death. OS was estimated using the Kaplan Meier method. | Duration of study (up to 10 years) | 
| Number of Participants Who Achieved a BCR-ABL Response at 12 Months | BCR-ABL response is defined in two ways: complete molecular response (CMR) and major molecular response (MMR). Complete Molecular Response is defined as a Bcr-Abl (a fusion of gene of Bcr and ABl genes) ratio ≤0.0032% on the International Scale Bcr = breakpoint cluster gene Abl = abelson proto-oncogene MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region [Bcr] gene and Abelson proto-oncogene [Abl] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction [RT-PCR] (performed centrally). | 12 months | 
| 5 Year Disease-free Survival for Autologous & Allogeneic Transplant Groups | Percentage of patients who achieved a complete remission (CR) and were alive and relapse free at 5 years. The 5-year progression free survival was estimated using the Kaplan Meier method. | 5 years from CR | 
| 5 Year Overall Survival for Autologous & Allogeneic Transplant Groups | Percentage of patients who were alive at 5 years. The 5-year progression free survival was estimated using the Kaplan Meier method. | 5 years from registration |