Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic/Myeloproliferative Neoplasms, Myelodysplastic Syndromes
Conditions
Keywords
recurrent adult acute myeloid leukemia, adult acute myeloid leukemia in remission, recurrent adult acute lymphoblastic leukemia, adult acute lymphoblastic leukemia in remission, myelodysplastic/myeloproliferative neoplasm, unclassifiable, previously treated myelodysplastic syndromes, atypical chronic myeloid leukemia, BCR-ABL1 negative, chronic myelomonocytic leukemia, recurrent adult Burkitt lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent small lymphocytic lymphoma, recurrent marginal zone lymphoma, recurrent mantle cell lymphoma, recurrent adult lymphoblastic lymphoma, accelerated phase chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse large cell lymphoma, refractory chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, refractory multiple myeloma, secondary myelodysplastic syndromes, de novo myelodysplastic syndromes, adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with t(15;17)(q22;q12)
Brief summary
RATIONALE: Giving low doses of chemotherapy, monoclonal antibodies, and radiation therapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells when they do not exactly match the patient's blood. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil before transplant may stop this from happening. PURPOSE: This phase I/II trial is studying the side effects of alemtuzumab, fludarabine, and melphalan with or without cyclosporine, mycophenolate mofetil, and total-body irradiation before donor peripheral blood stem cell transplant and to see how well they work in treating patients with relapsed or refractory hematologic cancer.
Detailed description
OBJECTIVES: * Determine the ability of a reduced-intensity conditioning regimen comprising alemtuzumab, fludarabine, and melphalan with or without cyclosporine, mycophenolate mofetil, and low-dose total body radiotherapy followed by haplotype-mismatched, KIR class I epitope-mismatched CD34-positive allogeneic peripheral blood stem cell transplantation to facilitate engraftment by day 35 post-transplantation in at least 85% of patients with relapsed, refractory, or poor-risk hematological malignancies. * Determine the risk of graft-versus-host-disease in patients treated with these regimens. * Determine, preliminarily, the efficacy of these regimens, in terms of progression-free survival, in these patients. * Correlate outcomes, engraftment, and progression-free survival with the number of detectable alloreactive natural killer cell clones before transplantation and after engraftment in patients treated with these regimens. * Determine immune reconstitution in patients treated with these regimens. OUTLINE: This is a multicenter, pilot study. Patients are initially treated with conditioning regimen A. If adequate donor engraftment is not achieved, subsequent patients are treated with conditioning regimen B. * Conditioning regimen A: Patients receive alemtuzumab IV over 2 hours on days -14 to -12; fludarabine IV over 30 minutes on days -7 to -3; and melphalan IV over 20-30 minutes on day -2. * Conditioning regimen B: Patients receive oral or IV cyclosporine twice daily and oral or IV mycophenolate mofetil twice daily on days -15 to 0. Patients also receive alemtuzumab, fludarabine, and melphalan as in conditioning regimen A. Patients undergo low-dose total body irradiation twice daily on days -2 and -1. All patients undergo allogeneic, T-cell-depleted, CD34-positive peripheral blood stem cell transplantation on day 0. Patients receive sargramostim (GM-CSF) subcutaneously beginning on day 1 and continuing until blood counts recover. Patients are followed every 3 months for 1 year and then every 6 months for 5 years. PROJECTED ACCRUAL: A total of 14-56 patients (14-28 per regimen) will be accrued for this study.
Interventions
BIOLOGICALalemtuzumab
DRUGcyclosporine
DRUGfludarabine phosphate
DRUGmelphalan
DRUGmycophenolate mofetil
PROCEDUREperipheral blood stem cell transplantation
RADIATIONradiation therapy
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed hematological malignancy of 1 of the following types: * Acute myeloid leukemia meeting at least 1 of the following criteria: * Poor-risk cytogenetics, including -5, 5q-, -7, 7q-, 11q23, and Philadelphia (Ph) chromosome-positive in first or subsequent complete remission (CR) * Relapsed or primary refractory disease with ≤ 10% blasts in the peripheral blood and ≤ 20% blasts in the bone marrow * Standard-risk cytogenetics in second CR AND autologous transplantation is not feasible * Standard-risk cytogenetics in third or subsequent CR * Acute lymphoblastic leukemia meeting 1 of the following criteria: * Second or subsequent CR * High-risk cytogenetics, including Ph chromosome-positive and t(4:11) in first CR * Relapsed or primarily refractory disease with ≤ 10% blasts in the peripheral blood and ≤ 20% blasts in the bone marrow * High-risk myelodysplasia * International Prognostic Scoring System Score ≥ 2.5 * Chronic myeloid leukemia (CML)\* with an inadequate response to imatinib meeting 1 of the following criteria: * Second or subsequent chronic phase * Accelerated phase NOTE: \*Patients with CML in blast crisis (\> 30% promyelocytes and myeloblasts in the bone marrow) are not eligible * Non-Hodgkin's lymphoma meeting 1 of the following criteria: * Primarily refractory disease or in refractory relapse * Relapsed disease after autologous stem cell transplantation * Chemosensitive relapsed disease without CR to standard salvage therapy AND no option for autologous stem cell transplantation due to blood or marrow involvement or failure to harvest sufficient autologous stem cells * Chronic lymphocytic leukemia meeting both of the following criteria: * Stage III or IV disease * Refractory to fludarabine * Multiple myeloma meeting 1 of the following criteria: * Primarily refractory disease or in refractory relapse * Relapsed disease after autologous stem cell transplantation * No relapsed disease \< 6 months after autologous stem cell transplantation * No available eligible HLA-matched (i.e., 5 of 6 or 6 of 6 antigen match for HLA-A, -B, and -DR loci) family donor by serological or molecular typing * Available suitable family donor meeting the following criteria: * Parent, sibling, or child of the recipient * ≥ 16 years of age * Identical for only one HLA haplotype (i.e., haploidentical) AND incompatible at the HLA-A, -B, -C, and -DR loci of the unshared haplotype by serological or molecular typing * Mismatched with respect to KIR class I epitopes graft-vs-host directional activity * Mismatching that predicts both graft-vs-host and host-vs-graft bi-directional activity eligible * No mismatching that predicts only host-vs-graft directional activity PATIENT CHARACTERISTICS: Age * 18 to 60 Performance status * ECOG 0-1 Hepatic * Bilirubin \< 2 times upper limit of normal (ULN) * AST and ALT \< 2 times ULN Renal * Creatinine ≤ 2 mg/dL Cardiovascular * LVEF \> 40% (corrected) Pulmonary * DLCO \> 50% of predicted Other * No active infection requiring oral or IV antibiotics * HIV negative * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy * See Disease Characteristics Chemotherapy * See Disease Characteristics Endocrine therapy * Concurrent corticosteroids allowed for adrenal failure, treatment of graft-vs-host disease, or as premedication during study * No concurrent corticosteroids for antiemesis
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Engraftment rate | Up to 6 years |
| Risk of graft-vs-host disease | Up to 6 years |
| Progression-free survival (PFS) | Up to 6 years |
Countries
United States
Outcome results
None listed