Allogeneic Transplant in HIV Patients (BMT CTN 0903)
Condition: Leukemia; Lymphoma; HIV
MeSH terms: Lymphoma
Intervention: Fludarabine and Busulfan; Fludarabine and Melphalan; Busulfan and Fludarabine; Cyclophosphamide and Total Body Irradiation
Intervention description: 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.; 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.; 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.; 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.
Intervention MeSH terms: Vidarabine; Cyclophosphamide; Melphalan; Busulfan; Fludarabine; Fludarabine phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 15 Years
Healthy volunteers: No
Keywords: HIV; ALL; AML; MDS; Non-Hodgkin Lymphoma

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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.

          2. Patients must be willing to comply with effective Antiretroviral Therapy.

          3. Patients must be ≥ 15 years of age.

          4. Hematological malignancy associated with a poor prognosis with medical therapy alone.
             Diagnoses to be included:

               1. Patients with the diagnosis of Acute Myeloid or Lymphocytic Leukemia (AML or ALL)
                  in first or second complete remission.

               2. 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.

               3. Hodgkin Lymphoma beyond first remission achieving at least a partial response to
                  most recent therapy with no evidence of progression prior to transplant.

               4. Non-Hodgkin Lymphoma beyond first remission achieving at least a partial response
                  to most recent therapy with no evidence of progression prior to transplant.

          5. Donor/Recipient HLA Matching:

               1. 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.

               2. 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).

          6. Patients with adequate organ function as measured by:

               1. 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.

               2. 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).

          7. Signed Informed Consent

        Exclusion Criteria:

          1. Karnofsky/Lansky performance score < 70%.

          2. 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.

          3. Uncontrolled bacterial, viral or fungal infection (currently taking medication and
             with progression or no clinical improvement).

          4. Active Cytomegalovirus (CMV) retinitis or other CMV-related organ dysfunction.

          5. AIDS related syndromes or symptoms that pose a perceived excessive risk for
             transplantation-related morbidity as determined by the principal investigator.

          6. 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. .

          7. Pregnant (positive β-HCG) or breastfeeding.

          8. Fertile men or women unwilling to use contraceptive techniques from the time of
             initiation of mobilization until six-months post-transplant.

          9. Prior allogeneic HCT.

         10. Patients with psychosocial conditions that would prevent study compliance and
             follow-up, as determined by the principal investigator.

         11. T-cell depletion (including ATG or alemtuzumab) is not allowed.

         12. Use of cord blood as the source of hematopoietic cells is not allowed.