Clinical trial NCT01410344: Allogeneic Transplant in HIV Patients (BMT CTN 0903)
Official title: Allogeneic Hematopoietic Cell Transplant for Hematological Cancers and Myelodysplastic Syndromes in HIV-Infected Individuals (BMT CTN #0903)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Lymphoma
HIV
Keywords: HIV
ALL
AML
MDS
Non-Hodgkin Lymphoma
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: National Cancer Institute (NCI)
name: Blood and Marrow Transplant Clinical Trials Network
name: National Marrow Donor Program
First posted: 2011-08-05
Enrollment: 20
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

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.

Primary outcomes:
measure: Percentage of Participants With Non-Relapse Mortality
timeFrame: Day 100, 1 Year, and 2 Years Post-transplant
Secondary outcomes:
measure: Percentage of Participants With Overall Survival
timeFrame: Six months, 1 Year, and 2 Years Post-transplant
measure: Percentage of Participants With Relapse/Progression
timeFrame: 1 Year Post-transplant
measure: Primary Cause of Death
timeFrame: Up to 2 Years Post-transplant
measure: Disease Status
timeFrame: Day 100 Post-transplant
measure: Percentage of Participants Recovering Hematologic Function
timeFrame: Days 28 and 100 Post-transplant
measure: Chimerism
timeFrame: Week 4, Day 100, and 6 months Post-transplant
measure: Percentage of Participants With Acute Graft-Versus-Host Disease (GVHD)
timeFrame: Day 100 Post-transplant
measure: Percentage of Participants With Chronic Graft-Versus-Host Disease (GVHD)
timeFrame: 1 Year Post-transplant
measure: Infection Severity
timeFrame: 1 Year Post-transplant
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic - Phoenix
state: Arizona
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: San Francisco
country: United States
facility: University of CA, SF
state: California
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Blood & Marrow Transplant Program at Northside Hospital
state: Georgia
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Philadelphia
country: United States
facility: University of Pennsylvania Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas/MD Anderson CRC
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Institute
state: Texas
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Center for International Blood and Marrow Transplant Research
name: Mary Horowitz, MD
role: STUDY_DIRECTOR
References:
citation: Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, Maziarz RT, Warlick ED, Fernandez HF, Alyea EP, Hamadani M, Bashey A, Giralt S, Geller NL, Leifer E, Le-Rademacher J, Mendizabal AM, Horowitz MM, Deeg HJ, Horwitz ME. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. 2017 Apr 10;35(11):1154-1161. doi: 10.1200/JCO.2016.70.7091. Epub 2017 Feb 13.
citation: Ambinder RF, Wu J, Logan B, Durand CM, Shields R, Popat UR, Little RF, McMahon DK, Cyktor J, Mellors JW, Ayala E, Kaplan LD, Noy A, Jones RJ, Howard A, Forman SJ, Porter D, Arce-Lara C, Shaughnessy P, Sproat L, Hashmi SK, Mendizabal AM, Horowitz MM, Navarro WH, Alvarnas JC. Allogeneic Hematopoietic Cell Transplant for HIV Patients with Hematologic Malignancies: The BMT CTN-0903/AMC-080 Trial. Biol Blood Marrow Transplant. 2019 Nov;25(11):2160-2166. doi: 10.1016/j.bbmt.2019.06.033. Epub 2019 Jul 4.