Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Other Diseases

OBJECTIVES:

Primary

• Determine the feasibility (i.e., risk of treatment-related mortality during the first 6 months after transplantation) of administering reduced-intensity allogeneic hematopoietic stem cell transplantation to patients with hematologic cancer or other diseases.

Secondary

• Determine the response rate (partial and complete response), 6- and 12-month probabilities of response, and time to progression in patients treated with this regimen.
• Determine the risk of acute and chronic graft-versus-host disease in patients treated with this regimen.
• Determine other toxicities of this regimen in these patients.
• Determine the overall survival and disease-free survival of patients treated with this regimen.
• Determine the impact of iron status on overall and disease-free survival.
• Determine the influence of quality of life (at time of transplantation) on overall survival.

OUTLINE:

• Preparative regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3. Patients also receive busulfan IV over 2 hours every 6 hours on days -4 and -3 or melphalan IV over 2 hours on day -3.
• Graft-versus-host disease (GVHD) prophylaxis: Patients with matched related donors receive oral tacrolimus twice daily on days -1 to 90 followed by a taper until day 180. Patients also receive methotrexate IV on days 1, 3, and 6. Patients with matched unrelated and 9/10 matched related donors receive oral tacrolimus twice daily on days -1 to 180 followed by a taper; methotrexate IV on days 1, 3, 6, and 11; and oral mycophenolate mofetil twice daily on days -2 to 60 followed by a taper. All patients also receive antithymocyte globulin IV over 4 to 6 hours once a day on days -4 to -1.
• Allogeneic stem cell transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. Patients receive filgrastim (G-CSF) beginning on day 7 and continuing until blood counts recover.
• Lymphocyte infusion: Patients with progressive or stable disease while off immunosuppression and no active GVHD may receive up to 3 donor lymphocyte infusions from the original donor at 8-week intervals beginning on day 180 or 210 .

Quality of life is assessed at baseline.

After completion of study therapy, patients are followed every 3 months for 2 years and then every 6 months for up to 3 years.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Inclusion criteria

• Histologically confirmed hematological disease, including any of the following:

• Chronic lymphocytic leukemia

• Absolute lymphocytosis > 5,000/µL
• Morphologically mature lymphocytes with < 55% prolymphocytes
• Lymphocyte phenotype with expression of CD19 and CD5
• Absence of CD23 expression allowed provided disease is morphologically distinguished from mantle cell lymphoma
• Prolymphocytic leukemia

• Absolute lymphocytosis > 5,000/µL
• Morphologically mature lymphocytes with > 55% prolymphocytes
• Non-Hodgkin's or Hodgkin's lymphoma

• Any WHO classification histologic subtype
• Diagnosis by core biopsy allowed provided there is adequate tissue for diagnosis and immunophenotyping
• Diagnosis by bone marrow biopsy not acceptable for follicular lymphomas
• Multiple myeloma

• Has received ≥ 1 prior treatment regimen
• Has a partial response or greater by the Blade Criteria
• Patients who achieved complete remission are eligible
• Acute myeloid leukemia

• Documented control (i.e., < 10% bone marrow blasts and no circulating blasts)
• Myelodysplastic syndromes

• Documented disease as defined by WHO or French-American-British Cooperative group criteria
• Chronic myelogenous leukemia
• Patients with atypical chronic myelogenous leukemia (i.e., absent Philadelphia chromosome) are eligible
• Polycythemia vera

• Documented disease as defined by WHO criteria (i.e., A1 + A2, and any other category A, OR A1 + A2, and any 2 category B):

• A1: Total red blood cell mass > 25% above mean normal predicted value OR hemoglobin > 18.5 g/dL in males, 16.5 g/dL in females (hematocrit ≥ 60% in males or ≥ 56% in females)
• A2: No cause of secondary erythrocytosis (absence of familial erythrocytosis, no elevation of epoetin alfa [EPO] due to hypoxia, high oxygen affinity hemoglobin, truncated EPO receptor, or inappropriate ectopic EPO production)
• A3: Splenomegaly
• A4: Clonal genetic abnormality other than the Philadelphia chromosome
• A5: Endogenous erythroid colony formation in vitro
• B: Platelet count > 400,000/mm³, WBC > 12,000/mm³, bone marrow biopsy with prominent erythroid and megakaryocytic proliferation, and low serum EPO
• Chronic idiopathic myelofibrosis

• Documented disease as defined by WHO criteria
• Must have a HLA-identical donor, a matched unrelated donor, or a HLA 9/10 related donor meeting the following criteria:
• HLA-identical sibling (6/6)

• Serologic typing for class I (A, B)
• Molecular typing for class II (DRB1)
• 9/10 matched related donor

• High-resolution molecular typing at HLA-A, B, C, DRB1, and DQB1
• Only a single mismatch at one class I or II allele allowed
• 10/10 matched unrelated donor

• Molecular identity at HLA-A, B, C, DRB1, and DQB1 by high-resolution typing
• Syngeneic donors are not eligible
• Creatinine clearance ≥ 40 mL/min
• Bilirubin ≤ 3 times upper limit of normal (ULN)
• AST ≤ 3 times ULN
• DLCO ≥ 40% with no symptomatic pulmonary disease
• LVEF ≥ 30% by cardiac MRI or echocardiogram with no symptomatic cardiac disease
• Fertile patients willing to use effective contraception

Exclusion criteria

• Uncontrolled diabetes mellitus
• Active serious infection
• Known hypersensitivity to E. coli-derived products
• Known HIV positivity
• History of another malignancy*, meeting the following criteria:

• Non-skin malignancy or melanoma within the past 5 years
• Concomitant malignancy that has not been curatively treated
• NOTE: *However, cancer survivors who have undergone potentially curative therapy for a prior malignancy at least 5 years before enrollment and are deemed at low risk of < 30% for recurrence by their treating physicians is considered
• Pregnant or nursing