Donor Peripheral Stem Cell Transplant in Treating Patients With Advanced Hematologic Cancer or Other Disorders

Study Overview
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Brief Summary
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RATIONALE: Giving chemotherapy and total-body irradiation before a donor peripheral stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving tacrolimus, methotrexate, cyclosporine, mycophenolate mofetil, and sirolimus before and after transplant may stop this from happening. PURPOSE: This phase II trial is studying how well donor peripheral stem cell transplant works in treating patients with advanced hematologic cancer or other disorders.

Detailed Description
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OBJECTIVES: Primary To evaluate hematopoietic recovery, using neutrophil and platelet engraftment as the primary criterion, in patients with advanced hematologic malignancies or other disorders undergoing allogeneic peripheral blood stem cell (PBSC) transplantation from matched unrelated donors. To evaluate the incidence of acute and chronic graft-versus-host-disease (GVHD) in patients undergoing allogeneic PBSC transplantation from matched unrelated donors. Secondary To evaluate the impact of HLA class I and class II allele-matching on the incidence of GVHD and on the survival outcome of these patients. To evaluate overall survival, disease-free survival, and relapse in these patients. OUTLINE: Patients are stratified according to type of conditioning regimen (myeloablative vs reduced-intensity myeloablative). Patients are assigned to a conditioning regimen according to diagnosis, age, disease status, prior radiotherapy, and prior autologous stem cell transplantation. Conditioning regimen: Regimen I: Patients undergo total body irradiation (TBI) on days -7 to -4 and receive cyclophosphamide IV on days -3 and -2. Alternatively, patients may receive cyclophosphamide on days -7 and -6 and undergo TBI on days -4 to -1. Regimen II: Patients receive busulfan IV over 2 hours once on day -8 and then every 6 hours on days -7 to -4. Patients also receive cyclophosphamide IV on days -3 and -2. Regimen III: Patients undergo TBI on days -7 to -4 and receive etoposide IV on day -3. Regimen IV: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and melphalan IV on day -2. Regimen V: Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and undergo TBI on day 0. Regimen VI: Patients receive busulfan IV over 3 hours and fludarabine phosphate IV over 30 minutes on days -5 to -2. Allogeneic peripheral blood stem cell (PBSC) transplantation: All patients undergo allogeneic PBSC transplantation on day 0. Graft-versus-host disease (GVHD) prophylaxis: Patients receive one of the following GVHD prophylaxis regimens: Regimen A: Patients receive tacrolimus IV or orally on days -1 to 180 and methotrexate IV on days 1, 3, 6, and 11. Regimen B: Patients receive cyclosporine IV or orally twice daily on days -1 to 180, mycophenolate mofetil IV over 2 hours or orally twice daily on days 0-27, and methotrexate IV on days 1, 3, and 6. Regimen C: Patients receive tacrolimus IV continuously or orally, and oral sirolimus beginning on day -3. Patients also receive methotrexate IV on days 1, 3, and 6. After completion of study therapy, patients are followed periodically.

Official Title
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A Phase II Trial of Allogeneic Peripheral Blood Stem Cell Transplantation From Matched Unrelated Donors in Patients With Advanced Hematologic Malignancies and Hematological Disorders

Conditions
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Chronic Myeloproliferative Disorders, Graft Versus Host Disease, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases, Precancerous/Nonmalignant Condition

Intervention / Treatment
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* Drug: busulfan
* Drug: cyclophosphamide
* Drug: cyclosporine
* Drug: etoposide
* Drug: fludarabine phosphate
* Drug: melphalan
* Drug: methotrexate
* Drug: mycophenolate mofetil
* Drug: sirolimus
* Drug: tacrolimus
* Procedure: allogeneic hematopoietic stem cell transplantation
* Procedure: peripheral blood stem cell transplantation
* Radiation: total-body irradiation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of one of the following: Acute lymphocytic leukemia (ALL), meeting one of the following criteria: In first relapse or beyond High-risk ALL, defined by any of the following: Hypoploidy (≤ 44 chromosomes) Pseudodiploidy with translocations or molecular evidence of t(9;22), 11q23, or t(8;14), excluding B-cell ALL Elevated WBC at presentation (WBC > 20,000/mm³ [for patients > 18 years of age]; WBC > 200,000/mm³ [for patients 12-18 years of age]) Acute myeloid leukemia (AML), meeting one of the following criteria: In first complete remission Failed to achieve remission In first relapse or beyond Secondary AML (> 30% blasts in marrow aspirate) Should receive induction chemotherapy to obtain remission, if possible, before transplant Chronic myelogenous leukemia, meeting one of the following criteria: In first or second chronic phase or accelerated phase In blast crisis, defined as > 30% promyelocytes plus blasts in the bone marrow Myelodysplastic syndromes, including any of the following: Refractory anemia with excess blasts (RAEB) Chronic myelomonocytic leukemia RAEB in transformation Refractory non-Hodgkin lymphoma, chronic lymphocytic leukemia, Hodgkin lymphoma, or multiple myeloma Received and failed front-line therapy, high-dose therapy and autologous stem cell transplantation, or salvage therapy Myeloproliferative disorders/myelofibrosis may be allowed on a case by case basis Severe aplastic anemia, paroxysmal nocturnal hemoglobinuria, or any other hematologic disorder requiring transplantation Patients > 55 years of age with hematologic diseases treatable by allogeneic stem cell transplantation who are not eligible for IRB 99190 are eligible No uncontrolled CNS involvement of disease No matched (6/6) related donor available HLA-identical unrelated donor available HLA-phenotypically identical for HLA-A and HLA-B alleles and identical for DRB1 alleles by DNA typing for both class I and class II antigens Allele mismatch for HLA class I (i.e., B 2701 vs B 2702) allowed if no alternative donors Allele mismatch for class II (i.e., DRB1 0401 vs 0402) or minor mismatch for class I cross reactive group (CREG) (i.e., A 2 vs A 28) allowed in patients ≤ 35 years of age requiring urgent transplant PATIENT CHARACTERISTICS: Karnofsky performance status 50-100% Life expectancy > 8 weeks LVEF ≥ 45% at rest AST ≤ 2 times normal (unless liver function abnormality is due to underlying disease) Total bilirubin < 1.5 times normal (unless liver function abnormality is due to underlying disease) Creatinine ≤ 1.5 times normal OR creatinine clearance ≥ 60 mL/min DLCO ≥ 40% of predicted (corrected for hemoglobin) No coexisting medical problem that would significantly increase the risk of the transplant procedure HIV negative Not pregnant PRIOR CONCURRENT THERAPY: See Disease Characteristics

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Regimen I<br>Patients undergo total body irradiation (TBI) on days -7 to -4 and receive cyclophosphamide IV on days -3 and -2. Alternatively, patients may receive cyclophosphamide on days -7 and -6 and undergo TBI on days -4 to -1. | Drug: cyclophosphamide<br> <br> Drug: cyclosporine<br> <br> Drug: methotrexate<br> <br> Drug: mycophenolate mofetil<br> <br> Drug: sirolimus<br> <br> Drug: tacrolimus<br> <br> Procedure: allogeneic hematopoietic stem cell transplantation<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> Radiation: total-body irradiation<br> <br> |
| Active Comparator: Regimen II<br>Patients receive busulfan IV over 2 hours once on day -8 and then every 6 hours on days -7 to -4. Patients also receive cyclophosphamide IV on days -3 and -2. | Drug: busulfan<br> <br> Drug: cyclophosphamide<br> <br> Drug: cyclosporine<br> <br> Drug: methotrexate<br> <br> Drug: mycophenolate mofetil<br> <br> Drug: sirolimus<br> <br> Drug: tacrolimus<br> <br> Procedure: allogeneic hematopoietic stem cell transplantation<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> |
| Active Comparator: Regimen III<br>Patients undergo TBI on days -7 to -4 and receive etoposide IV on day -3. | Drug: cyclosporine<br> <br> Drug: etoposide<br> <br> Drug: methotrexate<br> <br> Drug: mycophenolate mofetil<br> <br> Drug: sirolimus<br> <br> Drug: tacrolimus<br> <br> Procedure: allogeneic hematopoietic stem cell transplantation<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> Radiation: total-body irradiation<br> <br> |
| Active Comparator: Regimen IV<br>Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and melphalan IV on day -2. | Drug: cyclosporine<br> <br> Drug: fludarabine phosphate<br> <br> Drug: melphalan<br> <br> Drug: methotrexate<br> <br> Drug: mycophenolate mofetil<br> <br> Drug: sirolimus<br> <br> Drug: tacrolimus<br> <br> Procedure: allogeneic hematopoietic stem cell transplantation<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> |
| Active Comparator: Regimen V<br>Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and undergo TBI on day 0. | Drug: cyclosporine<br> <br> Drug: fludarabine phosphate<br> <br> Drug: methotrexate<br> <br> Drug: mycophenolate mofetil<br> <br> Drug: sirolimus<br> <br> Drug: tacrolimus<br> <br> Procedure: allogeneic hematopoietic stem cell transplantation<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> Radiation: total-body irradiation<br> <br> |
| Active Comparator: Regimen VI<br>Patients receive busulfan IV over 3 hours and fludarabine phosphate IV over 30 minutes on days -5 to -2. | Drug: busulfan<br> <br> Drug: cyclosporine<br> <br> Drug: fludarabine phosphate<br> <br> Drug: methotrexate<br> <br> Drug: mycophenolate mofetil<br> <br> Drug: sirolimus<br> <br> Drug: tacrolimus<br> <br> Procedure: allogeneic hematopoietic stem cell transplantation<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutrophil Engraftment - The Days Till ANC Recovery | The primary engraftment endpoint, neutrophil engraftment, is defined as the first of three consecutive days on which the absolute neutrophil count is > 500/µL. The duration and extent of neutrophil engraftment is the time from transplant to neutrophil engraftment. | Up to 180 days post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Two-year Overall Survival | Overall survival (OS) was measured from peripheral stem cell infusion to death from any cause. It was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula. Participants were followed up to 2 years after transplant and Kaplan-Meier survival analysis was used to generate the two-year Overall Survival estimate presented. | Up to 2 years post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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graft versus host disease, recurrent adult acute lymphoblastic leukemia, recurrent childhood acute lymphoblastic leukemia, untreated adult acute lymphoblastic leukemia, untreated childhood acute lymphoblastic leukemia, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, refractory anemia with excess blasts in transformation, refractory anemia with excess blasts, atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, myelodysplastic/myeloproliferative disease, unclassifiable, recurrent adult acute myeloid leukemia, recurrent childhood acute myeloid leukemia, adult acute myeloid leukemia in remission, childhood acute myeloid leukemia in remission, secondary acute myeloid leukemia, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, childhood chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, relapsing chronic myelogenous leukemia, chronic eosinophilic leukemia, chronic idiopathic myelofibrosis, chronic neutrophilic leukemia, essential thrombocythemia, polycythemia vera, Waldenstrom macroglobulinemia, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, splenic marginal zone lymphoma, recurrent childhood grade III lymphomatoid granulomatosis, childhood nasal type extranodal NK/T-cell lymphoma, recurrent childhood large cell lymphoma, childhood diffuse large cell lymphoma, childhood immunoblastic large cell lymphoma, recurrent childhood lymphoblastic lymphoma, Burkitt lymphoma, recurrent childhood small noncleaved cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, recurrent adult T-cell leukemia/lymphoma, recurrent adult grade III lymphomatoid granulomatosis, adult nasal type extranodal NK/T-cell lymphoma, recurrent adult Hodgkin lymphoma, recurrent/refractory childhood Hodgkin lymphoma, refractory chronic lymphocytic leukemia, refractory multiple myeloma, stage III multiple myeloma, aplastic anemia, paroxysmal nocturnal hemoglobinuria, adult acute lymphoblastic leukemia in remission, childhood acute lymphoblastic leukemia in remission, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent mycosis fungoides/Sezary syndrome, stage II multiple myeloma