Combination Chemotherapy With or Without Imatinib Mesylate and/or Peripheral Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia

2014-08-27 03:39:11 | BioPortfolio


RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. A peripheral stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. When the healthy stem cells are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving combination chemotherapy together with imatinib mesylate and peripheral stem cell transplant may be an effective treatment for acute lymphoblastic leukemia.

PURPOSE: This phase II trial is studying how well giving combination chemotherapy together with or without imatinib mesylate and/or peripheral stem cell transplant works in treating patients with acute lymphoblastic leukemia.




- Evaluate the role of post-remission therapy intensification comprising combination chemotherapy with or without imatinib mesylate and/or peripheral blood stem cell transplantation, in terms of improving the probability of 1-year disease-free survival, in patients with Philadelphia chromosome (Ph)-positive or high-risk Ph-negative acute lymphoblastic leukemia.


- Evaluate the efficacy of high-dose cytarabine and mitoxantrone hydrochloride as second-line treatment, in terms of achieving complete remission, in patients refractory, but not with disease progression, after the second or third induction course (blasts > 20% and blasts > 5%, respectively).

- Determine the feasibility of minimal residual disease (MRD) monitoring in patients treated with this regimen.

- Determine the negative prognostic role of MRD positivity in patients treated with this regimen.

- Determine toxicity of this regimen in these patients.

- Determine the efficacy of imatinib mesylate, in terms of complete hematologic remission rate, in Ph-positive patients.

- Determine the molecular response in Ph-positive patients treated with this regimen.

- Assess molecular monitoring of BCR/ABL after induction treatment and during maintenance therapy in these patients.

- Determine the overall survival of patients treated with this regimen.

OUTLINE: This is a multicenter, nonrandomized, prospective study.

- Induction therapy: Patients receive vincristine IV on days 1, 8, 15, 22, and 36; daunorubicin hydrochloride IV on days 1-3, 22-24, and 36-38; asparaginase intramuscularly (IM) or IV on days 10, 13, 16, 19, and 22; oral prednisone or methylprednisolone IV on days -6 to 24, followed by a taper; and methotrexate intrathecally (IT) 3 times daily on days 21 and 35. Patients with Philadelphia chromosome (Ph)-positive disease also receive oral imatinib mesylate daily on days 4-50.

Patients proceed to consolidation, reinduction, and maintenance therapy. Patients are stratified according to risk (standard risk vs high risk), which is based on WBC at diagnosis, response to induction therapy, and/or cytogenetic features.

- Standard risk (WBC ≤ 50,000/mm3 at diagnosis, responded to steroid treatment [blasts reduced ≥ 75%], remission after induction therapy, AND no molecular translocation [t(9;22, t(4;11), t(1;19)] or molecular equivalent [BCR/ABL, ALL-1/AF4, E2A/PBX1]):

- Consolidation therapy: Patients receive high-dose cytarabine IV over 2 hours twice daily on days 1 and 2 and etoposide IV over 1 hour on days 1-3. Treatment may repeat after 30 days for a second course.

- Maintenance therapy: Beginning 20 days after completion of consolidation therapy, patients undergo cranial radiotherapy, 5 days a week, for 2 weeks. This regimen may be repeated once. Patients also receive methotrexate IT once a month, methotrexate IM once a week, and oral mercaptopurine daily (beginning concurrently with cranial radiotherapy) for 3 years.

- Reinduction therapy: During the same 3 years that maintenance therapy is being delivered, patients receive alternating courses of chemotherapy. The alternating courses are administered monthly for 6 months, every 3 months for the 6 months, and then every 6 months for 2 years.

- Course A: Patients receive vincristine IV on day 1, daunorubicin hydrochloride IV on days 1 and 2, and oral prednisone on days 1-7.

- Course B: Patients receive vincristine IV and cyclophosphamide IV on day 1 and oral prednisone on days 1-7.

- High risk (WBC > 50,000/mm3 at diagnosis OR no response to steroid pretreatment OR resistant to second course [blasts increased > 20%] or third course [blasts increased > 5%] of induction therapy OR unfavorable cytogenetics [i.e., translocations present (t(9;22), t(4;11), t(1;19)) or molecular equivalent (BCR/ABL, ALL-1/AF4, E2A/PBX1)]):

- Salvage therapy: Patients receive salvage therapy comprising high-dose cytarabine IV over 3 hours twice daily on days 1-4, mitoxantrone IV over 30 minutes once daily on days 3-5, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 6 and continuing until blood counts recover. Patients with Ph-positive disease also receive oral imatinib mesylate on days 4-50.

Patients achieving remission after induction or salvage therapy proceed to consolidation therapy.

- Consolidation therapy: Patients receive high-dose cytarabine IV over 3 hours on days 1-5, idarubicin IV on day 3, and G-CSF SC beginning on day 7 and continuing until blood counts recover. Patients with Ph-positive disease also receive oral imatinib mesylate on days 4-50.

- Allogeneic or autologous hematopoietic stem cell transplantation (HSCT): Patients with a HLA-identical family member donor or a nonrelated HLA-matched donor undergo allogeneic peripheral blood stem cell (PBSC) transplantation (PBSCT) within 3 months after completion of consolidation therapy. Patients who do not have an eligible donor available undergo PBSC harvest after consolidation therapy and then undergo autologous HSCT comprising CD34+ cells after a second conditioning regimen.

- Maintenance therapy: Patients with Ph-positive disease receive oral imatinib mesylate daily after transplantation.

- Meningeal leukemia: Patients receive triple intrathecal therapy comprising methylprednisolone, cytarabine, and methotrexate twice a week until CNS is negative.

After completion of study treatment, patients are followed every 2 months for 1 year, every 3 months for 1 year, every 4 months for 2 years, and then every 6 months for 1 year.

PROJECTED ACCRUAL: A total of 253 patients will be accrued for this study.

Study Design

Allocation: Non-Randomized, Primary Purpose: Treatment




filgrastim, asparaginase, cyclophosphamide, cytarabine, daunorubicin hydrochloride, etoposide, idarubicin, imatinib mesylate, mercaptopurine, methotrexate, methylprednisolone, mitoxantrone hydrochloride, prednisone, vincristine sulfate, allogeneic hematop


Ospedale Civile Alessandria




National Cancer Institute (NCI)

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:39:11-0400

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Medical and Biotech [MESH] Definitions

A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.

Congener of CYTARABINE that is metabolized to cytarabine and thereby maintains a more constant antineoplastic action.

A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472)

Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the LIVER to form the active aldophosphamide. It has been used in the treatment of LYMPHOMA and LEUKEMIA. Its side effect, ALOPECIA, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer.

A hydrolase enzyme that converts L-asparagine and water to L-aspartate and NH3. EC

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