Reduced-intensity, Related-donor Bone Marrow Transplantation Followed by High-dose Cyclophosphamide for Hematologic Cancers

Study Overview
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Brief Summary
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This research is being done to learn more about reduced-intensity bone marrow transplantation (BMT), also known as a mini transplant for patients with blood cancers, using bone marrow from a relative. The main goal of the study is to determine how quickly the donor's bone marrow takes in your body. Other goals include describing how many people accept the bone marrow and how quickly the blood counts come up; describing Graft-versus-host disease (GVHD) and other complications; and describing how many people survive without progressive cancer and survive overall

Detailed Description
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At the present time there are few or no cures for people with cancer of the blood or lymph glands outside of a bone marrow transplant (BMT). BMT has developed over several decades of research as an effective treatment of various malignant and nonmalignant hematologic diseases. This research is being done to learn more about reduced-intensity bone marrow transplantation (BMT), also known as a mini transplant for patients with blood cancers, using bone marrow from a relative. The bone marrow for this transplant comes from a relative who is a half-match or haplo match to you. Possible donors include parents, siblings, and children. Mini transplants have been given to many people with various cancers but are considered experimental. Over 200 people at Johns Hopkins have received mini transplants with high doses of cyclophosphamide after the transplant. However, the chemotherapy combination and other treatment given before those transplants were different from what is in this study. Although all of the chemotherapy and immune-lowering drugs used in this study are approved by the Food and Drug Administration (FDA), the combination of medications used in this study are not FDA approved and are experimental.

Official Title
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Reduced-intensity, Related-donor Allogeneic BMT With Fludarabine, Busulfan, and High-dose Posttransplantation Cyclophosphamide for Hematologic Malignancies

Conditions
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Lymphoma, Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Busulfan
* Drug: Cyclophosphamide
* Drug: Mycophenolate Mofetil
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: First-degree related donor who is at minimum HLA haploidentical Eligible diagnoses: Low-grade non-Hodgkin's lymphoma or plasma cell neoplasm that has progressed during multiagent therapy, failed at least two prior therapies (excluding single agent rituximab and single agent steroids), or in the case of lymphoma undergone histological conversion: Follicular grade 1 or 2 lymphoma Follicular lymphoma not otherwise specified Marginal zone (or MALT) lymphoma Lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia Hairy cell leukemia Small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL) Prolymphocytic leukemia Low grade B-cell lymphoma, unspecified Multiple myeloma Plasma cell leukemia Poor-risk SLL or CLL, defined by an 11q or 17p deletion, histological conversion, or disease progression < 6 months after a purine analog-containing regimen Aggressive lymphoma that has failed at least one prior regimen of multiagent chemotherapy, and patient is either ineligible for autologous BMT or autologous BMT is not recommended: Hodgkin lymphoma Follicular grade 3 lymphoma Mantle cell lymphoma or leukemia Diffuse large B-cell lymphoma (excluding primary CNS lymphoma). Eligible subtypes include primary mediastinal large B-cell lymphoma, T-cell rich large B-cell lymphoma, and large B-cell lymphoma not otherwise specified. Burkitt's lymphoma/leukemia Atypical Burkitt's lymphoma/leukemia (high grade B-cell lymphoma, unclassified, including that with features intermediate between Burkitt's and diffuse large B-cell lymphoma) Anaplastic large cell lymphoma Plasmablastic lymphoma Peripheral T-cell lymphoma Relapsed or refractory acute leukemia in second or subsequent remission Poor-risk acute leukemia in first remission AML with at least one of the following: AML arising from MDS or a myeloproliferative disorder, or secondary AML Presence of Flt3 internal tandem duplications Poor-risk cytogenetics Primary refractory disease ALL (leukemia and/or lymphoma) with at least one of the following: Adverse cytogenetics Clear evidence of hypodiploidy Primary refractory disease Biphenotypic leukemia MDS with at least one of the following features: Poor-risk cytogenetics IPSS score of INT-2 or greater Treatment-related MDS MDS diagnosed before age 21 years Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy Life-threatening cytopenias, including those generally requiring greater than weekly transfusions Interferon- or imatinib-refractory CML in first chronic phase, or non-blast crisis CML beyond first chronic phase Philadelphia chromosome negative myeloproliferative disease (including myelofibrosis) Chronic myelomonocytic leukemia Juvenile myelomonocytic leukemia For patients with SLL, CLL, or prolymphocytic leukemia, < 20% of bone marrow cellularity involved by this process Adequate end-organ function: Left ventricular ejection fraction greater than or equal to 35% Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST < 5 x ULN FEV1 and FVC > 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation >92% on room air ECOG performance status < 2 or Karnofsky or Lansky score > 60 Exclusion Criteria: Pregnant or breast-feeding Uncontrolled infection Note: Infection is permitted if there is evidence of response to medication. Eligibility of HIV infected patients will be determined on a case-by-case basis. Any previous BMT within 3 months prior to start of conditioning Active extra-medullary leukemia or known active Central Nervous System (CNS) involvement by malignancy. Such disease treated into remission is permitted.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 75 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: Transplant<br>Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil. | Drug: Fludarabine<br>* 30 mg/m^2 IV daily on Day -6 through Day -2.<br>* Other names: Flu;Drug: Busulfan<br>* 1 mg/kg PO OR 0.8 mg/kg IV four times daily on Day -6 through Day -3.<br>* Other names: Myleran;Drug: Cyclophosphamide<br>* 50 mg/kg IV daily on Day +3 and Day +4.<br>* Other names: Cy;Drug: Mycophenolate Mofetil<br>* 15 mg/kg PO three times daily (max daily dose of 3g) starting on Day +5.<br>* Other names: CellCept;Drug: Tacrolimus<br>* Dosed based on drug levels; begin on Day +5 at 1 mg IV daily.<br>* Other names: Prograf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chimerism in Unsorted Peripheral Blood | Percentage of participants achieving full-donor chimerism in unsorted peripheral blood. | Day 60 | 
| Chimerism in CD3+ Sorted Peripheral Blood | Percentage of participants achieving full-donor chimerism in CD3+ sorted peripheral blood | Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Percentage of participants alive | 1 year | 
| Progression-free Survival | Percentage of participants alive without disease relapse or progression. | 1 year | 
| Incidence of Relapse | Percentage of participants experiencing disease relapse or progression | 1 year | 
| Non-relapse Mortality | Percentage of participants who died due to BMT-related reasons | 1 year | 
| Incidence of Graft-versus-host-disease (GVHD) | Percentage of participants experiencing acute and chronic GVHD. Acute GVHD is graded by Przepiorka criteria. Chronic GVHD is graded by NIH consensus criteria and Seattle criteria. | 1 year | 
| Graft Failure | Percentage of participants who failed to engraft. | Day 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, Hodgkin's lymphoma, Non hodgkin's lymphoma, Leukemia, Acute myeloid leukemia (AML), Acute lymphoblastic leukemia(ALL), Chronic myeloid leukemia (CML), Chronic Myelomonocytic (CMML), Myelodysplastic syndrome (MDS), High-risk acute leukemia in first remission, Relapsed leukemia in remission, Cyclophosphamide, High-dose cyclophosphamide, Fludarabine, Busulfan, Allogeneic, Nonmyeloablative, Reduced intensity, Haploidentical, Bone marrow transplant (BMT)