Clofarabine, Melphalan, and Thiotepa Followed By a Donor Stem Cell Transplant in Treating Patients With High-Risk and/or Advanced Hematologic Cancer or Other Disease

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of clofarabine when administered with melphalan and thiotepa followed by allogeneic stem cell transplantation in patients with high-risk and/or advanced hematologic malignancies. (Phase I)
• Determine the 1-year disease-free survival of patients treated with this regimen. (Phase II)
• Determine the efficacy of this regimen, in terms of antileukemic potential and relapse rate, in these patients.

Secondary

• Evaluate the incidence and severity of nonhematologic toxicity of this regimen in these patients.
• Evaluate the incidence and severity of graft-versus-host disease in patients treated with this regimen.

OUTLINE: This is a phase I, dose-escalation study of clofarabine followed by an open-label, phase II study. Patients are stratified according to HLA-compatible donor type (related vs unrelated).

• Cytoreductive therapy: Patients receive clofarabine IV over 2 hours once daily on days -9 to -5, thiotepa IV over 4 hours on day -4, and melphalan IV over 30 minutes once daily on days -3 and -2.

Cohorts of 3-6 patients receive escalating doses of clofarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Graft-versus-host disease (GVHD) prophylaxis: Patients who undergo bone marrow or peripheral blood stem cell transplantation receive tacrolimus IV continuously over 24 hours or orally every 8-12 hours beginning on day -3 and methotrexate IV on days 1, 3, 6, and 11. Patients who undergo UCB transplantation receive tacrolimus IV continuously over 24 hours or orally every 8-12 hours beginning on day -3 and mycophenolate mofetil (MMF) IV or orally 2 or 3 times daily on days -3 to 45 followed by a taper until day 100 (unless there are signs of acute GVHD). Patients who undergo UCB transplantation without GVHD continue tacrolimus for 6 months followed by a taper and discontinued 1 year after transplantation.
• Allogeneic hematopoietic stem cell transplantation (HSCT) or allogeneic umbilical cord blood (UCB) transplantation: Patients undergo allogeneic HSCT (bone marrow or peripheral blood stem cells) or double UCB transplantation on day 0. Patients also receive filgrastim (G-CSF) IV or subcutaneously beginning on day 7 and continuing until blood counts recover.
• Maintenance therapy: Approximately 2 months after transplantation patients with ALL, M4 or M5 AML, and those transplanted with AML in bone marrow relapse receive cytarabine intrathecally (IT) monthly for up to 5 doses. Patients with a history of CNS leukemia receive cytarabine IT once monthly during months 2-12 after HSCT.

After completion of study therapy, patients are followed periodically for at least 4 years.

PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed diagnosis of 1 of the following:

• Acute myelogenous leukemia, meeting 1 of the following criteria:

• In first complete remission (CR), meeting 1 of the following criteria:

• Poor risk [no t(15,17), inv 16, or t(8,21)]
• Not a candidate for total body irradiation (TBI)
• Any infant in first CR
• In second CR, meeting the following criteria:

• All patients
• In more than second CR OR relapsed/refractory disease, meeting the following criteria:

• All patients
• Blast percentage > 5% and < 25% in bone marrow (BM) at the time of stem cell transplantation (SCT)
• Acute lymphoblastic leukemia, meeting 1 of the following criteria:

• In first CR, meeting 1 of the following criteria:

• Poor risk [t(9;22), t(4;11) AND no CR after 7-28 days of induction]
• Not a candidate for TBI
• Any infant in first CR
• In second CR, meeting the following criteria:

• All patients
• In more than second CR OR relapsed/refractory disease, meeting the following criteria:

• All patients
• Blast percentage > 5% and < 25% in BM at the time of SCT
• Acute undifferentiated or biphenotypic leukemia, meeting the following criteria:

• All patients
• Blast percentage > 5% and < 25% in BM at the time of SCT
• Chronic myelogenous leukemia, meeting the following criteria:

• All patients
• In first chronic phase
• Myelodysplastic syndrome, meeting 1 of the following criteria:

• Primary high risk disease

• Stage > RAEB1
• Secondary high risk disease

• All patients
• Any stage
• Juvenile myelomonocytic leukemia

• All patients
• No doubling of peripheral blast counts within a period of 2 weeks
• No active CNS disease
• HLA-compatible donor available meeting 1 of the following criteria:

• Related donor

• Genotypically or phenotypically matched at ≥ 7 or 8 of HLA-A, -B, -C and -DRB1 alleles
• Unrelated donor meeting 1 of the following criteria:

• 8 of 8 alleles matched
• For patients < 18 years old only: 7 or 8 alleles matched with the mismatch at only 1 HLA-A, -B, -C, or -DRB1 allele
• Two HLA-compatible unrelated cord blood (UCB) units available meeting the following criteria:

• HLA-matched minimally at 4 of 6 HLA-A, HLA-B, and DRB1 allele

• HLA-A and HLA-B matched at intermediate resolution by molecular technique
• DRB1 allele matched at high resolution by molecular technique
• Both matched UCB units with cryopreserved nucleated cell dose ≥ 1.5 x 10^7/kg

PATIENT CHARACTERISTICS:

• Karnofsky OR Lansky performance status 70-100%
• SGOT < 2 times upper limit of normal
• Bilirubin < 1.5 mg/dL (unless there is liver disease involvement)
• Creatinine normal OR creatinine clearance > 60 mL/min
• LVEF > 50% at rest OR shortening fraction ≥ 29%
• Patients with asymptomatic pulmonary disease with no prior risk factors OR symptomatic pulmonary disease with diffusion capacity > 50% of predicted (corrected for hemoglobin) are eligible
• No active uncontrolled viral, bacterial, or fungal infection
• No known HIV I or II positivity
• No known human T-cell lymphotrophic virus I or II positivity
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• No hydroxyurea within the past 2 weeks
• No allogeneic or autologous stem cell transplantation within the past 6 months