Allogeneic Transplant in HIV Patients (BMT CTN 0903)

Study Overview
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Brief Summary
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The rationale for this trial is to demonstrate the feasibility and safety of allogeneic HCT for patients with chemotherapy-sensitive hematological malignancies and coincident HIV-infection. In particular, the trial will focus on the 100-day non-relapse mortality as an indicator of the safety of transplant in this patient population. Correlative assays will focus upon the incidence of infectious complications in this patient population, the evolution of HIV infection and immunological reconstitution. Where feasible (and when this can be accomplished without compromise of either the donor quality or the timeliness of transplantation), an attempt will be made to identify donors who are homozygotes for the delta32 mutation for CCR5.

Detailed Description
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The study is designed to evaluate the feasibility and safety of reduced-intensity and fully-ablative allogeneic hematopoietic cell transplantation (HCT) for patients with hematological malignancies or myelodysplastic syndromes (MDS) who have HIV infection. The goal of the study is to assess the 100 day Non-relapse Mortality as well as immunological reconstitution in this patient population. Where feasible, an attempt will be made to identify human leukocyte antigen (HLA)-compatible hematopoietic stem cell donors who are homozygotes for the delta32 mutation of the chemokine receptor 5 (CCR5delta32). Patients will undergo a treatment plan review prior to registration on the trial. All patients will undergo allogeneic HCT from a matched sibling or unrelated donor.

Official Title
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Allogeneic Hematopoietic Cell Transplant for Hematological Cancers and Myelodysplastic Syndromes in HIV-Infected Individuals (BMT CTN #0903)

Conditions
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HIV, Leukemia, Lymphoma

Intervention / Treatment
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* Drug: Fludarabine and Busulfan
* Drug: Fludarabine and Melphalan
* Drug: Busulfan and Fludarabine
* Drug: Cyclophosphamide and Total Body Irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection, as documented by a rapid HIV test or any FDA-Approved HIV-1 Enzyme or Chemiluminescence Immunoassay (E/CIA) test kit and confirmed by Western Blot at any time prior to study entry. HIV antigen, plasma HIV-1 RNA, or a secondary antibody test by a method other than rapid HIV and E/CIA is acceptable as an alternative test. Alternatively, if a rapid HIV test or any FDA-Approved HIV-1 Enzyme or Chemiluminescence Immunoassay (E/CIA) test is not available, two HIV-1 RNA values ≥ 2000 copies/mL at least 24 hours apart performed by any laboratory that has CLIA certification, or its equivalent, may be used to document infection. Patients must be willing to comply with effective Antiretroviral Therapy. Patients must be ≥ 15 years of age. Hematological malignancy associated with a poor prognosis with medical therapy alone. Diagnoses to be included: Patients with the diagnosis of Acute Myeloid or Lymphocytic Leukemia (AML or ALL) in first or second complete remission. Patients with advanced myelodysplastic syndromes (MDS), including those with International Prognostic Scoring System (IPSS) Int-2 and high-risk disease with less than 10% marrow blasts and no circulating myeloblasts after most recent therapy. Patients with acute leukemia that develops from a pre-existing MDS must meet the inclusion criteria for patients with AML detailed above. Hodgkin Lymphoma beyond first remission achieving at least a partial response to most recent therapy with no evidence of progression prior to transplant. Non-Hodgkin Lymphoma beyond first remission achieving at least a partial response to most recent therapy with no evidence of progression prior to transplant. Donor/Recipient HLA Matching: Related donor: must be an 8/8 match at HLA-A, -B, -C, (serologic typing or higher resolution) and -DRB1 (at high resolution using DNA based typing). A 7/8 related donor match is permitted only if an 8/8 unrelated donor cannot be identified. Unrelated donor: must be a 7/8 or 8/8 match at HLA-A, -B, -C, and -DRB1 (at high resolution using DNA based typing). Patients with adequate organ function as measured by: Cardiac: Left ventricular ejection fraction at rest ≥ 40% demonstrated by Multi Gated Acquisition Scan (MUGA) or echocardiogram. Patients with known heart disease must have a functional status no worse than American Heart Association Class I defined as patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. Hepatic: i. Total Bilirubin < 2.0 mg/dL (except for isolated hyperbilirubinemia attributed to Gilbert syndrome or antiretroviral therapy as specified in Appendix E) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5x the upper limit of normal. ii. Concomitant Hepatitis: Patients with chronic hepatitis B or C may be enrolled on the trial providing the above bilirubin and transaminase criteria are met. In addition, there must be no clinical or pathologic evidence of irreversible chronic liver disease, and there must be no active viral replication as evidenced by an undetectable hepatitis viral load by a PCR-based assay. c) Renal: Creatinine clearance (calculated creatinine clearance is permitted) > 40 mL/min. d) Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), or forced vital capacity (FVC) ≥ 45% of predicted (corrected for hemoglobin). Signed Informed Consent Exclusion Criteria: Karnofsky/Lansky performance score < 70%. Active central nervous system (CNS) malignancy; however, patients with a history of positive Cerebrospinal fluid (CSF) cytology that has become negative with intrathecal chemotherapy are eligible. Uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression or no clinical improvement). Active Cytomegalovirus (CMV) retinitis or other CMV-related organ dysfunction. AIDS related syndromes or symptoms that pose a perceived excessive risk for transplantation-related morbidity as determined by the principal investigator. Untreatable HIV infection due to multidrug antiretroviral resistance. Patients with a detectable viral load > 750 copies/ml should be evaluated with an HIV drug resistance test (HIV-1 genotype). The results should be included as part of the Antiretroviral Review (described in Appendix D). This Review Committee will make the final determination as to whether HIV viremia could potentially be suppressed with alternate antiretroviral therapy. . Pregnant (positive β-HCG) or breastfeeding. Fertile men or women unwilling to use contraceptive techniques from the time of initiation of mobilization until six-months post-transplant. Prior allogeneic HCT. Patients with psychosocial conditions that would prevent study compliance and follow-up, as determined by the principal investigator. T-cell depletion (including ATG or alemtuzumab) is not allowed. Use of cord blood as the source of hematopoietic cells is not allowed.

Ages Eligible for Study
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Minimum Age: 15 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 |
| --- | --- |
| Other: Allogeneic Transplant<br>One regimen from either reduced-intensity conditioning (RIC) (Fludarabine and Busulfan; or Fludarabine and Melphalan) or myeloablative conditioning (MAC) (Busulfan and Fludarabine; or Cyclophosphamide and Total Body Irradiation) will be administered prior to allogeneic hematopoietic cell transplantation (HCT). | Drug: Fludarabine and Busulfan<br>* RIC Regimen (Flu/Bu): Fludarabine total dose: 120-180 mg/m^2, Busulfan: ≤ 8 mg/kg PO or 6.4 mg/kg IV). Recommended regimen: Days -6 to -2: Flu (30 mg/m^2/day, total dose of 150 mg/m^2) Days -5 to -4: Busulfan (4mg/kg/day PO or 3.2 mg/kg IV, 130 mg/m^2/day, total dose of 8 mg/kg PO or 6.4 mg/kg IV, or 260 mg/m^2 IV, respectively) Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage. Busulfan will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs more than 125 percent of IBW, in which case the drug will be dosed according to the adjusted IBW.<br>* Other names: Fludara and Busulfex;Drug: Fludarabine and Melphalan<br>* RIC Regimen (Flu/Mel): Fludarabine total dose: 120-180 mg/m^2, Melphalan total dose: less than or equal to 150 mg/m^2. Recommended regimen: Days -5 to -2: Flu (30mg/m^2/day, total dose of 120 mg/m^2) Day -1: Mel (140mg/m^2) Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage.<br>* Other names: Fludara and Alkeran;Drug: Busulfan and Fludarabine<br>* MAC Regimen (Bu/Flu): Fludarabine total dose: 120-180mg/m^2 Busulfan total dose less than or equal to 16mg/kg PO or 12.8 mg/kg IV. Recommended regimen: Days -5 to -2: Busulfan (4 mg/kg/day PO with Bu Css 900 plus/equal to 100 ng/mL (or per institutional standard), 3.2 mg/kg/day IV or 130 mg/m^2/day IV; total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m^2, respectively) Days -5 to -2: Flu (30 mg/m^2/day, total dose of 120 mg/m^2) Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage. Busulfan will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs more than 125 percent of IBW, in which case the drug will be dosed according to the adjusted IBW.<br>* Other names: Busulfex and Fludara;Drug: Cyclophosphamide and Total Body Irradiation<br>* MAC Regimen (Cy/TBI): Cyclophosphamide total dose: 120 mg/kg, Fractionated TBI total dose: 1200-1420 cGy Recommended regimen: Days -7 to -4: TBI (total dose of 1200-1420 cGy) Days -3 to -2: Cy (60 mg/kg/day, total dose of 120 mg/kg) Cyclophosphamide will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs less than IBW, in which case the drug will be dosed according to the actual body weight.<br>* Other names: Cytoxan® and radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Non-Relapse Mortality | The events for non-relapse mortality are death due to any cause other than relapse of the underlying malignancy. | Day 100, 1 Year, and 2 Years Post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Survival | Overall survival is defined as the time from transplant to death from any cause. | Six months, 1 Year, and 2 Years Post-transplant | 
| Percentage of Participants With Relapse/Progression | Relapse/Progression is defined as relapse or progression of the primary malignancy. | 1 Year Post-transplant | 
| Primary Cause of Death |  | Up to 2 Years Post-transplant | 
| Disease Status | Patients will be assessed for disease status at Day 100 post-HCT, classified as complete remission, partial remission, stable disease, and relapse/progressive disease. | Day 100 Post-transplant | 
| Percentage of Participants Recovering Hematologic Function | Recovery of hematologic function is described by the time to neutrophil and platelet recovery. Time to neutrophil recovery will be the first of three consecutive days of > 500 neutrophils/μL following the expected nadir. Time to platelet engraftment will be described by the date when platelet count is > 20,000/μL for the first of three consecutive labs with no platelet transfusions 7 days prior. | Days 28 and 100 Post-transplant | 
| Chimerism | Donor T-cell and myeloid chimerism will be described separately by conditioning regimen intensity (myeloablative or reduced intensity) according to proportions with mixed chimerism (5-95% donor cells out of all), full chimerism (>95% donor cells), or graft rejection (<5% donor cells). | Week 4, Day 100, and 6 months Post-transplant | 
| Percentage of Participants With Acute Graft-Versus-Host Disease (GVHD) | Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash Rash <25% of body surface area Rash on 25-50% of body surface area Rash on > 50% of body surface area Generalized erythroderma with bullous formation Liver stage (based on bilirubin level)*: 0: <2 mg/dL 1.2-3 mg/dL 2.3.01-6 mg/dL 3.6.01-15.0 mg/dL 4.>15 mg/dL GI stage*: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus * If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1. GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4 | Day 100 Post-transplant | 
| Percentage of Participants With Chronic Graft-Versus-Host Disease (GVHD) | Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification. | 1 Year Post-transplant | 
| Infection Severity | The maximum grade of infections reported by participants are described, as defined in the BMT CTN Technical MOP. | 1 Year Post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALL, HIV, AML, MDS, Non-Hodgkin Lymphoma