Allogeneic Hematopoietic Cell Transplantation for Patients With Busulfex-based Regimen

OBJECTIVES:

Primary

• Phase I Objective: To identify the maximum tolerated dose of continuous infusion IV busulfan based on blood levels derived from a test dose in conjunction with fludarabine, ATG and methotrexate plus tacrolimus for GVHD prophylaxis
• Phase II Objective: To determine the one-year disease-free survival (DFS) rate at the maximum tolerated dose identified during Phase I of the trial (target AUC 6912)

Secondary

• Determine the overall and disease-free survival of patients treated with this regimen.
• Determine the dose-limiting toxicities of this regimen in these patients.
• Determine the capacity of test dosing of busulfan that would result in the desired area under the curve concentration exposure of patients receiving a full-dose busulfan regimen.
• Determine the incidence of graft-vs-host disease and DNA chimerism between 1 month and 2 years post-transplantation in these patients.
• Compare the overall survival (OS) and disease-free survival (DFS) rates for patients treated with Campath vs. patients treated with ATG/Methotrexate for GVHD control

OUTLINE: This is a non-randomized, open-label, parallel group study of busulfan. Patients are stratified according to donor relationship - matched related donor (MRD) vs matched unrelated donor (MUD).

• Conditioning regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV over 2 hours once within days -15 to -10 and then IV continuously over 90 hours on days -7 to -4. Patients with a MRD also receive Methotrexate (MTX) on Days +1, +3, and +6. Patients with a MUD receive ATG on Days -3 and -2 and MTX on Days +1, +3 and +6.

Phase I portion only: Cohorts of 3-6 patients receive escalating doses of busulfan 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.

• Allogeneic peripheral blood stem cell transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously beginning on day 5 and continuing until blood counts recover.
• Graft-vs-host disease (GVHD) prophylaxis: Patients receive oral tacrolimus twice daily on days -1 to 180 or days -1 to 240.
• Donor lymphocyte infusion (DLI): Patients who do not achieve CR, do not have GVHD, and have been off immunosuppressants for at least 30 days may receive up to 3 DLIs, at least 8 weeks apart, after completion of tacrolimus.

After the completion of study treatment, patients are followed periodically for up to 5 years.

Inclusion criteria

Histologically confirmed diagnosis of any of the following:

Chronic lymphocytic leukemia or prolymphocytic leukemia Chemotherapy-refractory or advanced disease after ≥ 3 prior treatments Chronic myelogenous leukemia Diagnosis based on t(9;22) or related t(9;12) cytogenetic abnormalities AND characterized by elevated white blood counts (WBC) in peripheral blood or marrow Patients with progressive disease on imatinib mesylate or other protein tyrosine kinase inhibitors; less than a major cytogenetic or fluorescent in situ hybridization (FISH) complete response (CR) after a minimum of 6 months of targeted therapy; or less than a complete FISH or cytogenetic response after 12 months of targeted therapy are eligible Patients with other cytogenetic abnormalities, such as t(9;12), that are associated with an aggressive clinical course are eligible Non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma Any World Health Organization (WHO) classification histologic subtype allowed Must have advanced disease as defined by relapse after initial CR or failure to achieve CR OR deemed to have less than a 30% likelihood of durable response with an autologous stem cell transplant Refractory low-grade NHL histologies or any intermediate or aggressive large cell or mantle cell lymphoma allowed Acute myeloid leukemia (AML) High-risk disease in first CR (CR1) OR evidence of any recurrent disease beyond CR1 High-risk individuals are those requiring more than 1 course of induction therapy to achieve remission; those with extra-medullary disease at presentation; or those with high-risk cytogenetic abnormalities (abnormalities of chromosomes 5, 7, 2, trisomy 8, or 3) or > 2 cytogenetic abnormalities

• Multiple myeloma
• Myelodysplastic syndromes (MDS) Must have MDS defined by WHO criteria with > 5% blasts or high-risk cytogenetic abnormalities (abnormalities of chromosomes 5, 7, 2, trisomy 8, or 3)
• Acute lymphoblastic leukemia (ALL) High-risk disease in CR1 OR beyond CR1 High-risk disease includes the following: t(9;22) or t(4;11); WBC > 30,000/mm³ at presentation; non-T-cell phenotype; or more than 30 years of age
• Myelofibrosis/agnogenic myeloid metaplasia

• Patients must be transfusion dependant or have evidence of evolving AML as evidenced by an excess of blasts or a state of marrow failure/fibrosis
• Myeloproliferative disorders with advanced disease (e.g., progressive or spent phase polycythemia vera, myelofibrosis, or essential thrombocythemia)

• Any of the following categories of donors are acceptable*:
• Human Leucocyte Antigen (HLA)-identical or 1 antigen-mismatched sibling (5/6, 6/6, or 8/10) donor

• Minimal serologic typing required for class I (A, B); molecular typing required for class II (DRB1)
• 8/10 matched unrelated donor (MUD)

• Molecular analysis at HLA-A, -B, -C, -DRB1 and -DQB1 (8/10 match) by high resolution typing is required
• 5/6 MUD

• Molecular analysis at HLA-A, -B, and -DRB1 required Note: *No syngeneic donors

PATIENT CHARACTERISTICS:

• Performance status 0-2
• Bilirubin ≤ 2 times upper limit of normal (ULN)
• Aspartate aminotransferase (AST) ≤ 2 times ULN
• Creatinine clearance ≥ 50 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Diffusing capacity of the lungs for carbon monoxide (DLCO) > 60% with no symptomatic pulmonary disease
• Left ventricular ejection fraction (LVEF) ≥ 50% by multigated acquisition (MUGA) scan

Exclusion criteria

Uncontrolled or severe cardiovascular disease, pulmonary disease, or infection that, in the opinion of the treating physician, would make this study unreasonably hazardous to the patient Other serious illness that would limit survival to < 2 years Psychiatric condition that would preclude study compliance Uncontrolled diabetes mellitus or active serious infection Active second malignancy except for nonmelanomatous skin cancer Known hypersensitivity to E. coli-derived products HIV positivity

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 4 weeks since prior chemotherapy, radiotherapy, or surgery

• Cranial radiotherapy or intrathecal therapy as prophylaxis against central nervous system (CNS) recurrence within the past 4 weeks allowed (in high-risk patients)