Donor Stem Cell Transplant in Treating Patients With Relapsed Hematologic Malignancies or Secondary Myelodysplasia Previously Treated With High-Dose Chemotherapy and Autologous Stem Cell Transplant

Study Overview
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Brief Summary
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RATIONALE: Giving chemotherapy, such as busulfan and fludarabine phosphate, before a peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving methotrexate, tacrolimus, and antithymocyte globulin before and after the transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them (called graft-versus-tumor effect). Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) may boost this effect. PURPOSE: This phase II trial is studying how well donor stem cell transplant works in treating patients with relapsed hematologic malignancies or secondary myelodysplasia previously treated with high-dose chemotherapy and autologous stem cell transplant .

Detailed Description
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OBJECTIVES: Primary To demonstrate the efficacy of performing reduced-intensity conditioning allogeneic hematopoietic cell transplantation in patients with relapsed hematologic malignancies or secondary myelodysplasia after completion of prior high-dose chemotherapy and autologous hematopoietic stem cell transplantation. To compare the strategy of this regimen with the strategy used in CALGB-100002. Secondary To describe the response rate at 6 and 12 months in patients treated with this regimen. To describe the time-to-progression in patients treated with this regimen. To determine the ability to use pharmacokinetic-directed busulfan to achieve AUC within 20% of target AUC in > 80% of patients. To determine percent of donor chimerism in T-cell, myeloid and B-cell populations achieved with this regimen compared with CALGB-100002. To determine the risk of acute and chronic graft-versus-host disease and other toxicities of this regimen in these patients. To describe the overall survival and disease-free survival of patients treated on this regimen. To determine the rate of viral, bacterial, and fungal opportunistic infections occurring in the first year after transplantation compared with CALGB-100002. OUTLINE: This is a multicenter study. Preparative Regimen: Busulfan test dose: Patients receive busulfan IV over 45 minutes once during days -14 and -9. Busulfan treatment dose: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV over 3 hours on days -6 to -3. Graft-vs-Host Disease (GVHD) Prophylaxis: HLA-identical donor: Patients receive antithymocyte globulin IV over 6-10 hours on days -6 to -5; oral tacrolimus twice daily on days -2 to 90 followed by a taper* as tolerated until day 150 or 180; and methotrexate IV on days 1, 3, and 6. NOTE: * Tacrolimus may be tapered on days 60-90 if donor chimerism of CD3+ cells is < 50% at day 60 or patient has progressive disease. Matched-unrelated donor: Patients receive antithymocyte globulin, tacrolimus, and methotrexate as in HLA-identical donor regimen. Patients also receive oral mycophenolate mofetil twice daily on days 0 to 60. Allogeneic Stem Cell Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on days 0 and 1. Patients then receive filgrastim subcutaneously daily beginning on day 7 and continuing until blood counts recover. Donor Lymphocyte Infusion (DLI): After day 180 (or day 210 for patients without an HLA-identical donor), patients with stable or progressive disease and no active GVHD may receive up to 3 DLIs every 8 weeks. Blood samples are collected at baseline and then periodically during study therapy for pharmacokinetic studies. After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for up to 5½ years.

Official Title
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Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation as Second Transplantation for Patients With Disease Relapse or Myelodysplasia After Prior Autologous Transplantation

Conditions
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Leukemia, Lymphoma, Lymphoproliferative Disorder, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms

Intervention / Treatment
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* Biological: anti-thymocyte globulin
* Biological: donor lymphocytes
* Biological: filgrastim
* Biological: therapeutic allogeneic lymphocytes
* Drug: busulfan
* Drug: fludarabine phosphate
* Drug: methotrexate
* Drug: mycophenolate mofetil
* Drug: tacrolimus
* Other: reduced-intensity transplant conditioning procedure
* Procedure: allogeneic hematopoietic stem cell transplantation
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed hematologic malignancies: Chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL) Absolute lymphocytosis of > 5,000/μL Lymphocytes must appear morphologically mature with < 55% prolymphocytes (CLL) Patients with > 55% prolymphocytes are considered as having PLL Lymphocyte phenotype with expression of CD20, CD19, and CD5 (CLL) Non-Hodgkin lymphoma Any WHO classification of histologic subtype Core biopsies acceptable for primary diagnosis and immunophenotyping Bone marrow biopsies as sole means of diagnosis not allowed for follicular lymphoma Hodgkin lymphoma Any WHO classification of histologic subtype Core biopsies acceptable for primary diagnosis and immunophenotyping Bone marrow biopsy is required Multiple myeloma Patients must have active disease requiring treatment (Durie-Salmon stage I-III) Acute myeloid leukemia Must have < 10% bone marrow blasts and no circulating blasts Myelodysplastic syndrome (MDS) MDS as define by WHO criteria Must have < 10% marrow blasts Relapsed or progressive disease or myelodysplasia ≥ 6 months after prior high-dose chemotherapy with autologous hematopoietic cell support Prior syngeneic transplantation allowed Healthy donor meeting one of the following criteria: HLA-identical sibling (6/6) Serologic typing for class I (A, B) and molecular typing for class II (DRB1) required 8/8 matched-unrelated donor Molecular identity at HLA A, B, C, and DRB1 by high-resolution typing required No syngeneic donors PATIENT CHARACTERISTICS: Creatinine clearance ≥ 40 mL/min Total bilirubin ≤ 2 mg/dL AST ≤ 3 times upper limit of normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception DLCO ≥ 40% with no symptomatic pulmonary disease LVEF ≥ 30% by MUGA or ECHO No uncontrolled diabetes mellitus or active serious infection No known hypersensitivity to E.coli-derived products No HIV infection PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 4 weeks should elapse between prior standard cytotoxic chemotherapy, radiation therapy, or surgery and the planned start of the preparative regimen on day -7

Ages Eligible for Study
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Maximum Age: 69 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Matched-unrelated donor: Patients receive antithymocyte globulin, tacrolimus, and methotrexate as in HLA-identical donor regimen. Patients also receive oral mycophenolate mofetil twice daily on days 0 to 60. Allogeneic Stem Cell Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on days 0 and 1. Patients then receive filgrastim subcutaneously daily beginning on day 7 and continuing until blood counts recover. Donor Lymphocyte Infusion (DLI): After day 180 (or day 210 for patients without an HLA-identical donor), patients with stable or progressive disease and no active GVHD may receive up to 3 DLIs every 8 weeks. Blood samples are collected at baseline and then periodically during study therapy for pharmacokinetic studies. After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for up to 5½ years. | Biological: anti-thymocyte globulin<br> <br> Biological: donor lymphocytes<br> <br> Biological: filgrastim<br> <br> Biological: therapeutic allogeneic lymphocytes<br> <br> Drug: busulfan<br> <br> Drug: fludarabine phosphate<br> <br> Drug: methotrexate<br> <br> Drug: mycophenolate mofetil<br> <br> Drug: tacrolimus<br> <br> Other: reduced-intensity transplant conditioning procedure<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 |
| --- | --- | --- |
| Event-free Survival (EFS) | EFS was defined as the date of transplant to date of progression or develop myelodysplasia after autologous transplant. EFS was estimated using the Kaplan Meier method. | Duration of study (up to 5.5 years) | 
| Comparison of EFS Distribution to That of CALGB-100002 | EFS distributions between CALGB-100002 and this study will be compared using the two-sample log-rank test. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate | Complete response (CR) rate is reported as the percentage of participants who achieved a CR. | Up to 5.5 years | 
| Overall Survival | Overall survival (OS) was defined as the transplant from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% confidence interval (CI) was estimated using the Kaplan Meier method. | Up to 5.5 years | 
| Rate of Opportunistic Infections | Percent of participants who have an opportunistic (viral, bacterial and fungal) infection in the first year following transplant. | 1 year post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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), juvenile myelomonocytic leukemia, prolymphocytic leukemia, recurrent adult acute myeloid leukemia, recurrent adult T-cell leukemia/lymphoma, recurrent childhood acute myeloid leukemia, refractory chronic lymphocytic leukemia, recurrent adult Hodgkin 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 grade III lymphomatoid granulomatosis, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent childhood grade III lymphomatoid granulomatosis, recurrent childhood large cell lymphoma, recurrent childhood lymphoblastic lymphoma, recurrent childhood small noncleaved cell lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent mycosis fungoides/Sezary syndrome, 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, recurrent/refractory childhood Hodgkin lymphoma, childhood diffuse large cell lymphoma, childhood grade III lymphomatoid granulomatosis, childhood immunoblastic large cell lymphoma, childhood nasal type extranodal NK/T-cell lymphoma, post-transplant lymphoproliferative disorder, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, refractory multiple myeloma, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, childhood myelodysplastic syndromes, recurrent childhood anaplastic large cell lymphoma, adult acute myelomonocytic leukemia (M4), childhood acute myelomonocytic leukemia (M4), adult acute minimally differentiated myeloid leukemia (M0), childhood acute minimally differentiated myeloid leukemia (M0), adult acute myeloblastic leukemia without maturation (M1), childhood acute myeloblastic leukemia without maturation (M1), adult acute myeloblastic leukemia with maturation (M2), childhood acute myeloblastic leukemia with maturation (M2), adult acute promyelocytic leukemia (M3), childhood acute promyelocytic leukemia (M3), adult acute monoblastic leukemia (M5a), adult acute monocytic leukemia (M5b), childhood acute monoblastic leukemia (M5a), childhood acute monocytic leukemia (M5b), adult erythroleukemia (M6a), adult pure erythroid leukemia (M6b), childhood acute erythroleukemia (M6), adult acute megakaryoblastic leukemia (M7), childhood acute megakaryocytic leukemia (M7), childhood Burkitt lymphoma, atypical chronic myeloid leukemia, BCR-ABL1 negative, chronic myelomonocytic leukemia, cutaneous B-cell non-Hodgkin lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, myelodysplastic/myeloproliferative neoplasm, unclassifiable