Safety Study of Bone Marrow Transplant Using Mismatched Tissue Followed by Chemotherapy

Study Overview
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Brief Summary
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The purpose of this study is to see if giving high dose chemotherapy and total body irradiation before and repeating high dose chemotherapy after a bone marrow transplant could reduce the incidence of graft rejection and disease for patients with blood cancers

Detailed Description
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Allogeneic blood or marrow transplantation (alloBMT), following either marrow-ablative or nonmyeloablative conditioning, is a potentially curative treatment for a variety of hematologic malignancies and non-malignant hematologic disorders. Of all the potential sources of allografts, transplantation of stem cells from a human leukocyte antigen (HLA)-matched sibling has generally produced the best overall outcomes, i.e. overall and progression-free survival. Unfortunately, only about a third of candidates for alloBMT have HLA-matched siblings. For patients who lack HLA-matched siblings, there are three alternative sources of stem cells for alloBMT: 1) volunteer unrelated donors; 2) umbilical cord blood; and 3) partially HLA-mismatched, or haploidentical, related donors. Since any patient shares exactly one HLA haplotype with each biological parent or child and half of siblings, an eligible haploidentical donor can be identified rapidly in nearly all cases. However, haploidentical BMT has been associated with significant risks of graft rejection and severe GVHD, which are manifestations of excessive alloreactivity by host and donor T cells, respectively. The risk of severe GVHD may be reduced in intensively conditioned recipients of grafts that have been rigorously depleted of mature T cells or selectively depleted of alloreactive T cells, but the risks of serious infection and death from prolonged immune compromise in these patients remains high. Cyclophosphamide(Cy) is a highly immunosuppressive antineoplastic agent that has an established role in conditioning for alloBMT. Typically, the drug is administered prior to transplantation to prevent graft rejection by suppressing the host immune system. However, pre-transplantation conditioning with Cy increases the risk of GVHD following allogeneic T cell infusion in mouse models. In contrast, administration of a properly timed, high dose of Cy after BMT inhibits both graft rejection and GVHD.

Official Title
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A Phase II Trial of Myeloablative Conditioning and Transplantation of Partially HLA-mismatched Bone Marrow for Patients With Hematologic Malignancies

Conditions
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MDS, Leukemias, Lymphomas

Intervention / Treatment
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* Drug: Busulfan
* Drug: Cyclophosphamide
* Radiation: Total body irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute lymphocytic leukemia in high risk CR1 Acute myeloid leukemia in CR1 Therapy-related AML RAEB with >5% and <20% bone marrow blasts Chronic myelogenous leukemia beyond 1st chronic phase; Patients cannot be in blast crisis CMMoL JMML Chemotherapy-resistant Hodgkins Lymphoma or intermediate or high grade Non-Hodgkins lymphoma (Less than a PR after standard or salvage chemotherapy) Mantle cell lymphoma: chemotherapy refractory (Less than a PR after standard or salvage chemotherapy) or patients beyond CR1 with chemosensitive disease Follicular Lymphoma, Grade 3 Transformed indolent lymphomas Exclusion Criteria: Poor cardiac function: left ventricular ejection fraction <45% as determined by MUGA or ECHO. For pediatric patients LVEF <45% or a shortening fraction below normal limits for age. Poor pulmonary function: FEV1 and FVC <50% predicted for patients who have not received thoracic or mantle irradiation. For patients who have received thoracic or mantle irradiation, FEV1 and FVC <70% predicted or DLCO < 50 of predicted. For children unable to perform PFTs because of developmental stage pulse oximetry < 85% on RA Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert's or primary malignancy) Poor renal function: Creatinine >2.0mg/dl or creatinine clearance HIV-positive Positive leukocytotoxic crossmatch Women of childbearing potential who currently are pregnant or who are not practicing adequate contraception Uncontrolled viral, bacterial, or fungal infections Patients with symptoms consistent with RSV, influenza A, B, or parainfluenza at the time of enrollment will be assayed for the above viruses and if positive are not eligible for the trial until they are no longer symptomatic (patients may have continued assay positivity for a period of time post resolution of symptoms secondary to the nature of the assay. Indolent lymphomas (Follicular Grade 1 and 2, marginal zone, chronic lymphocytic leukemia, small lymphocytic lymphoma, MALT)

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: Myeloablative haploidentical BMT<br>All participants except those with acute lymphoblastic leukemia and lymphoblastic lymphoma: Busulfan will be administered 1 mg/kg oral (or 0.8 mg/kg IV) four times per day for four days, followed by cyclophosphamide 50 mg/kg once per day for two days. Participants with acute lymphocytic leukemia or lymphoblastic lymphoma: Cyclophosphamide will be administered 50 mg/kg once per day for two days, followed by total body irradiation at 300 cGy per day for four days. | Drug: Busulfan<br>* Participant will receive Busulfan injections, 4 times a day for 4 days with dilantin prophylaxis (in patients 10 years of age or older). Busulfan levels in the blood will be measured and dose adjusted, if needed.<br>Drug: Cyclophosphamide<br>* Patient will receive Cy by IV once a day for 2 days.<br>* Other names: CTX;Radiation: Total body irradiation<br>* Patients will receive TBI once a day for 4 days.<br>* Other names: TBI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Engraftment as Measured by Donor Chimerism | Percentage of participants who achieved donor chimerism >=95%. | Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-relapse Mortality | Number of participants deceased for reasons other than disease relapse or progression. | Day 100, 1 year | 
| Acute GVHD | Percentage of participants who experience grade II-IV or III-IV acute graft-versus-host-disease (GVHD) by Przepiorka criteria. The stages are defined as follows: Stage II: Rash on >50% of skin, bilirubin 2-3 mg/dL, or diarrhea 500-1000 mL/day Stage III: Bilirubin 3-15 mg/dL or diarrhea >1000 mL/day Stage IV: Generalized erythroderma with bullae or bilirubin >15 mg/dL This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999) | Day 100 | 
| Chronic GVHD | Percentage of participants who experience chronic GVHD. Chronic GVHD is graded using NIH consensus criteria and Seattle criteria. This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999) | 6 months, 12 months | 
| Survival | Percentage of participants alive (overall survival) and alive without disease relapse, progression, or diagnosis of myeloid malignancy (event-free survival). Estimated using Kaplan-Meier method. | 1 year, 2 years, 3 years | 
| Relapse | Percentage of participants who experienced disease progression or relapse. This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999) | 1 year, 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Lymphoma, Hematologic malignancies, ALL, AML, MDS, Transplantation, Mismatched, Haploidentical, Busulfan, Cyclophosphamide, Cellcept, Tacrolimus, TBI, CMMOL, CML, JMML