Allogeneic Transplant in HIV Patients (BMT CTN 0903)

Medical College of Wisconsin

Status and phase: Completed; Phase 2

Conditions: HIV; Lymphoma; Leukemia

Treatments: Drug: Fludarabine and Melphalan; Drug: Busulfan and Fludarabine; Drug: Cyclophosphamide and Total Body Irradiation; Drug: Fludarabine and Busulfan

Study type: Interventional

Funder types: Other; NETWORK; NIH

Identifiers

NCT01410344

5U24CA076518 (U.S. NIH Grant/Contract)

BMT CTN 0903 (Other Identifier)

BMTCTN0903

U01HL069294 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 20 patients

Sex: All

Ages: 15+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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20 participants in 1 patient group

Allogeneic Transplant

Other group

Description:

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).

Treatment:

Drug: Fludarabine and Busulfan

Drug: Fludarabine and Melphalan

Drug: Cyclophosphamide and Total Body Irradiation

Drug: Busulfan and Fludarabine