Combination Chemotherapy, Bone Marrow Transplant, and Post Transplant Cyclophosphamide for Hematologic Cancer

Study Overview
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Brief Summary
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RATIONALE: Giving chemotherapy before a donor bone marrow transplant helps stop the growth of cancer and abnormal cells and 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 cyclophosphamide, mycophenolate mofetil, or tacrolimus after transplant may stop this from happening. PURPOSE: This clinical trial is studying how well giving combination chemotherapy together with tacrolimus and mycophenolate mofetil works in treating patients who are undergoing a donor bone marrow transplant for hematologic cancer.

Detailed Description
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OBJECTIVES: Primary Determine the optimal dose of post-transplant immunosuppression comprising high-dose cyclophosphamide, tacrolimus, and mycophenolate mofetil administered after myeloablative conditioning chemotherapy comprising busulfan and cyclophosphamide followed by allogeneic bone marrow transplantation in patients with high-risk hematologic malignancies. Determine the incidence and severity of acute graft-versus-host disease in patients treated with this regimen. Determine other toxic effects of this regimen in these patients. Secondary Determine immune reconstitution in patients treated with this regimen. Determine disease control in patients treated with this regimen. OUTLINE: This is a pilot study. Patients are stratified according to age (≤ 19 years old vs > 19 years old). Myeloablative conditioning chemotherapy: Patients receive busulfan IV or orally 4 times daily on days -7 to -4 OR days -6 to -3 and cyclophosphamide IV over 1 hour once daily on days -3 to -1 OR days -2 and -1. Allogeneic bone marrow transplantation: Patients undergo allogeneic bone marrow transplantation on day 0. Immunosuppression therapy: Patients receive high-dose cyclophosphamide IV over 1 hour on days 3 and 4. After completion of study transplantation, patients are followed at 30 and 60 days, 6 months, 1 year, and then annually thereafter.

Official Title
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HLA Matched Related and Unrelated Bone Marrow Transplantation With Busulfan/Cyclophosphamide and Post Transplantation Cyclophosphamide for Hematological Malignancies

Conditions
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Chronic Myeloproliferative Disorders, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Busulfan
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of 1 of the following hematologic malignancies: Acute myeloid leukemia (AML), meeting 1 of the following criteria: AML beyond first complete remission (CR1) Refractory AML AML arising from myelodysplastic syndromes (MDS) Secondary AML MDS Refractory anemia with excess blasts with > 10% blasts in bone marrow Acute lymphoblastic leukemia (ALL), meeting 1 of the following criteria: ALL in CR1 with 1 of the following high-risk features: Philadelphia chromosome (Ph)-positive disease Less than 1 year of age at diagnosis Cytogenetic abnormalities involving chromosome 11q23 ALL beyond CR1 Refractory ALL Chronic myeloid leukemia beyond first chronic phase Chronic myelomonocytic leukemia Chronic lymphocytic leukemia Stage III-IV disease Does not meet criteria for other bone marrow transplantation (BMT) studies Myeloproliferative disorders Ph-negative disease Hodgkin's or non-Hodgkin's lymphoma Chemotherapy-resistant disease Paroxysmal nocturnal hemoglobinuria with life-threatening thrombosis Multiple myeloma Stage II or III disease Very high-risk disease Having an unrelated donor is considered a high-risk condition Meets medical criteria for myeloablative BMT for the Sidney Kimmel Comprehensive Cancer Center Bone marrow donor available, meeting 1 of the following criteria: Genotypically HLA-identical sibling Phenotypically matched first-degree relative Unrelated donor molecularly matched at HLA-A, -B, -C, -DRB1, and -DQB1 PATIENT CHARACTERISTICS: Age 6 months to 65 years Performance status Not specified Life expectancy Not specified Hematopoietic See Disease Characteristics Hepatic Not specified Renal Not specified Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy See Disease Characteristics Endocrine therapy No concurrent dexamethasone as an antiemetic during immunosuppression therapy Radiotherapy Not specified Surgery Not specified Other No concurrent immunosuppressants until ≥ 24 hours after the completion of cyclophosphamide (post-transplantation)

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 65 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: Bone marrow transplant<br>Myeloablative bone marrow transplant with a busulfan (Bu), cyclophosphamide (Cy), preparative regimen and post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis | Drug: Busulfan<br>* Days -7 to -4: 4 mg/kg PO daily OR 3.2 mg/kg IV daily OR 160 mg/m^2 daily (for pediatric recipients)<br>* Other names: Busulfex;Drug: Cyclophosphamide<br>* Days -3, -2, +3, +4: 50 mg/kg IV daily<br>* Other names: CTX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Develop Acute Graft-versus-host Disease (GVHD) | Percentage of participants who developed grades II-IV and grades III-IV acute GVHD. Acute GVHD is defined by the Przepiorka criteria, which stages the degree of organ involvement in the skin, liver, and gastrointestinal (GI) tract, based on severity, with Stage 1+ being least severe and stage 4+ being the most severe. Grading of acute GVHD is as follows: Grade I (skin involvement stages 1+ to 2+, with no liver or GI involvement), Grade II (skin involvement stages 1+ to 3+, liver 1+, GI tract 1+), Grade III (skin involvement stages 2+ to 3+, liver 1+, GI tract 2+ to 4+), Grade IV (skin involvement stages 4+, Liver 4+). | Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days to Engraftment | Median number of days to neutrophil and platelet engraftment. | Up to one year | 
| Chimerism | Number of patients who achieved 100% donor chimerism. | Day 30, Day 60 | 
| Non-relapse Mortality | Percentage of participants who died for BMT-related reasons. | Day 100, 2 years | 
| Relapse | Percentage of participants who developed relapse or progressive disease. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute myeloid leukemia in remission, refractory anemia with excess blasts, 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), childhood acute myeloid leukemia in remission, recurrent adult acute myeloid leukemia, recurrent childhood acute myeloid leukemia, secondary acute myeloid leukemia, de novo myelodysplastic syndromes, adult acute lymphoblastic leukemia in remission, childhood acute lymphoblastic leukemia in remission, recurrent adult acute lymphoblastic leukemia, recurrent childhood acute lymphoblastic leukemia, accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, childhood chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, relapsing chronic myelogenous leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, chronic eosinophilic leukemia, chronic idiopathic myelofibrosis, chronic neutrophilic leukemia, stage III adult Hodgkin lymphoma, stage IV adult Hodgkin lymphoma, stage II multiple myeloma, stage III multiple myeloma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma, previously treated myelodysplastic syndromes, 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 childhood large cell lymphoma, recurrent childhood lymphoblastic lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent childhood small noncleaved cell lymphoma, recurrent/refractory childhood Hodgkin lymphoma, recurrent adult Hodgkin lymphoma, recurrent small lymphocytic lymphoma, recurrent marginal zone lymphoma, stage III adult Burkitt lymphoma, stage III adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage IV adult Burkitt lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage III marginal zone lymphoma, stage IV mantle cell lymphoma, stage IV marginal zone lymphoma, stage III small lymphocytic lymphoma, stage IV small lymphocytic lymphoma, chronic myelomonocytic leukemia, refractory chronic lymphocytic leukemia, refractory multiple myeloma, secondary myelodysplastic syndromes, stage IV adult lymphoblastic lymphoma, childhood myelodysplastic syndromes