Cord Blood Transplant With Dilanubicel for the Treatment of HIV Positive Hematologic Cancers

OUTLINE: Patients are assigned to 1 of 2 regimens.

REGIMEN A: Patients receive fludarabine intravenously (IV) over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 to -6, and undergo total body irradiation (TBI) twice daily (BID) on days -4 to -1. Patients then undergo umbilical cord blood transplant on day 0. Between 4-24 hours after transplant completion, patients receive dilanubicel IV over 5-10 minutes in the absence of disease progression or unacceptable toxicity.

REGIMEN B: Patients receive fludarabine IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 4 hours on days -5 to -4, and undergo TBI once daily (QD) on days -2 to -1. Patients then undergo umbilical cord blood transplant on day 0. Between 4-24 hours after transplant completion, patients receive dilanubicel IV over 5-10 minutes in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28, 80, and 180 days, and then at 1 and 2 years.

• Fludarabine (Drug), also known as 118218, 2-Fluoro-9-beta-arabinofuranosyladenine, 2-Fluorovidarabine, 9-Beta-D-arabinofuranosyl-2-fluoroadenine, Fluradosa: Given IV
• Cyclophosphamide (Drug), also known as Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan: Given IV
• Thiotepa (Drug), also known as STEPA, Tepadina, TESPA, Tespamin, Tespamine, Thiofosfamide, Thio-Tepa, Thiofozil, Thiophosphamide, Thiophosphoramide, Thiotef, Tifosyl, Triethylene thiophosphoramide, Triethylenethiophosphoramide, TSPA, WR 45312: Given IV
• Total-Body Irradiation (Radiation), also known as TBI, TOTAL BODY IRRADIATION, Whole Body Irradiation, Whole-Body Irradiation, SCT_TBI: Undergo TBI
• Umbilical Cord Blood Transplantation (Procedure), also known as Cord Blood Transplantation, UCB transplantation: Undergo UCBT
• Dilanubicel (Biological), also known as Allogeneic UCB-derived Hematopoietic Stem and Progenitor Cells NLA101, Allogeneic Umbilical Cord Blood-derived HSPCs NLA101, NLA101: Given IV

Primary outcomes

• Primary Graft Failure Rejection [Up to day 35 post-transplant]: Will be defined by no neutrophil recovery by day 45 (regardless of donor chimerism) or autologous recovery (neutrophil recovery but < 10% donor chimerism in blood and bone marrow) by day 36. This outcome was originally intended to be assessed for per the aforementioned definitions, but was only able to be assessed through 35 days post-transplant.

Secondary outcomes

• Incidence of Infusion Toxicities [Within the first 24 hours after infusion]: Defined as Common Terminology Criteria for Adverse Events version 5.0 grade >= 3 events.
• Median Number of Days Post-Transplant to Neutrophil Recovery Occurred [Up to Day 35 post-transplant]: Neutrophil recovery is defined as the first day of 2 consecutive days of absolute neutrophil count >= 500 after the first post-cord blood transplant nadir. This outcome was originally intended to be assessed for up to 45 days post-transplant, but was only able to be assessed through 35 days post-transplant.
• Platelet Engraftment [35 days post-transplant]: Will be defined as the first day of a platelet count > 20,000/ul with subsequent transfusions for 7 days. This outcome was originally intended to be assessed for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant.
• Incidence of Severe (Grades III-IV) Acute Graft Versus Host Disease (GVHD) [35 days post-transplant]: Will be defined by the 2014 National Institutes of Health (NIH) criteria. This outcome was originally intended to be assessed for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant.
• Incidence of Chronic GVHD [35 days post-transplant]: Will be defined by the 2014 NIH criteria. This outcome was originally intended to be assessed for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant.
• Incidence of Non-relapse Mortality [35 days post-transplant]: Will be defined as death without a prior relapse. This outcome was originally intended to be assessed for up to 180 days post-transplant, but was only able to be assessed through 35 days post-transplant.
• Human Immunodeficiency Virus (HIV) Plasma Viral Load [Baseline and weekly to 35 days post-transplant]: Assess CCR5Δ32 cord blood stem cell engraftment and its effect on biomarkers of HIV-1 infection, including plasma viral load and replication-competent reservoirs, as well as in gut and other sites (if tissue samples are available). This outcome was originally intended to be assessed weekly for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant.
• Immune Homeostasis [Up to 2 years]: Concentration of immunity cells per microliters after transplant
• Immune Reconstitution [Up to 2 years]: Concentration of immunity cells per microliters after transplant
• Change in HIV-1 Induced Inflammatory Immune Responses [Up to 2 years]: HIV viral load by PCR (copies per milliliter; mL)
• HIV Rebound Following Antiretroviral Therapy (ART) Cessation [Up to 2 years]: Count of participants with HIV rebound, measured by HIV viral load by PCR (copies per milliliter; mL)
• Viral Kinetics Following ART Cessation [Up to 2 years]: HIV viral load by PCR (copies per milliliter; mL)

Sex: All, ages: 6 Months to 65 Years

Inclusion Criteria:

* >= 6 months to =< 65 years
* Treatment with combination antiretroviral therapy (cART) for at least 1 month before enrollment
* Viral load < 5000 copies/ml plasma on cART
* Disease criteria

  * Acute myeloid leukemia

    * High risk in first complete remission (CR1), >= 2 cycles to obtain complete remission (CR), erythroblastic or megakaryocytic leukemia; >= in second complete remission (CR2)
    * All patients must be in CR as defined by hematologic recovery and < 5% blasts by morphology within the bone marrow and a cellularity of >= 15%
    * Patients for whom adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible. Specimen for morphologic assessment, including possible repeat procedures will be obtained (as possible). These patients must be discussed with the lead principal investigator, Filippo Milano prior to enrollment
  * Acute lymphoblastic leukemia

    * High risk CR1 (for example, but not limited to: t(9;22), t(1;19), t(4;11) or other mixed-lineage leukemia \[MLL\] rearrangements, hypodiploid); greater than 1 cycle to obtain CR; >= CR2
    * All patients must be in CR as defined by hematologic recovery and < 5% blasts by morphology within the bone marrow and a cellularity of >= 15%
    * Patients in which adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible. Specimen for morphologic assessment, including possible repeat procedures will be obtained (as possible). These patients must be discussed with the lead principal investigator, Filippo Milano prior to enrollment
  * Chronic myelogenous leukemia excluding refractory blast crisis. To be eligible in first chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate
  * Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate (Int)-2 or high risk (i.e., refractory anemia with excess blasts \[RAEB\], refractory anemia with excess blasts in transformation \[RAEBt\]) or refractory anemia with severe pancytopenia or high-risk cytogenetics. Blasts must be < 10% by a representative bone marrow aspirate morphology
  * Other hematologic malignancy such as non-Hodgkin lymphomas. Fred Hutch site: These patients must be presented at Patient Care Conference (PCC) prior to enrollment, given potential competing eligibility on auto-transplant protocols. Participating centers: These patients must be discussed with the lead principal investigator, Filippo Milano prior to enrollment
* Karnofsky (>= 16 years old) >= 70%
* Lansky (< 16 years old) >= 50%
* Adults: Calculated creatinine clearance must be > 60 mL and serum creatinine =< 2 mg/dL
* Children (< 18 years old): Calculated creatinine clearance must be > 60 mL/min
* Total serum bilirubin must be < 3 mg/dL
* Transaminases must be < 3 x the upper limit of normal
* Diffusion capacity of the lung for carbon monoxide (DLCO) corrected > 50% normal or for pediatric patients in whom DLCO cannot be measured has adequate pulmonary function
* Left ventricular ejection fraction > 45% OR
* Shortening fraction > 26%
* Ability to understand and the willingness to sign a written informed consent document (adult subject or parent/legal guardian of minor subject)

Exclusion Criteria:

* Uncontrolled viral or bacterial infection at the time of study enrollment
* Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval
* Pregnant or breastfeeding
* Prior myeloablative transplant within the last 6 months
* Extensive prior therapy including > 12 months alkylator therapy or > 6 months alkylator therapy with extensive radiation
* Central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy. Diagnostic lumbar puncture to be performed

Participant flow

Outcome results

• Primary Graft Failure Rejection (Primary), Count of participants, Participants: Regimen A (Fludarabine, Cyclophosphamide, TBI, Dilanubcel) ; Regimen B (Anticancer Drugs, TBI, Dilanubicel) 0
• Incidence of Infusion Toxicities (Secondary), Number, infusion toxicity events: Regimen A (Fludarabine, Cyclophosphamide, TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) ; Regimen B (Anti-cancer Drugs Plus TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) 0
• Median Number of Days Post-Transplant to Neutrophil Recovery Occurred (Secondary), Median, Days post-transplant: Regimen A (Fludarabine, Cyclophosphamide, TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) ; Regimen B (Anti-cancer Drugs Plus TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) 16 (16 to 16)
• Platelet Engraftment (Secondary), Count of participants, Participants: Regimen A (Fludarabine, Cyclophosphamide, TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) ; Regimen B (Anti-cancer Drugs Plus TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) 0
• Incidence of Severe (Grades III-IV) Acute Graft Versus Host Disease (GVHD) (Secondary), Number, Number of Grade 3/4 aGVHD Events: Regimen A (Fludarabine, Cyclophosphamide, TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) ; Regimen B (Anti-cancer Drugs Plus TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) 0
• Incidence of Chronic GVHD (Secondary), Number, Number of cGVHD Events: Regimen A (Fludarabine, Cyclophosphamide, TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) ; Regimen B (Anti-cancer Drugs Plus TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) 0
• Incidence of Non-relapse Mortality (Secondary), Count of participants, Participants: Regimen A (Fludarabine, Cyclophosphamide, TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) ; Regimen B (Anti-cancer Drugs Plus TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) 1
• Human Immunodeficiency Virus (HIV) Plasma Viral Load (Secondary), Number, percentage of viral load change: Regimen A (Fludarabine, Cyclophosphamide, TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) ; Regimen B (Anti-cancer Drugs Plus TBI, Followed by Unmanipulated Cord Blood and Dilanubicel) 0
• Immune Homeostasis (Secondary)
• Immune Reconstitution (Secondary)
• Change in HIV-1 Induced Inflammatory Immune Responses (Secondary)
• HIV Rebound Following Antiretroviral Therapy (ART) Cessation (Secondary)
• Viral Kinetics Following ART Cessation (Secondary)

Adverse events

Time frame: Assessed from start of conditioning until participant death on study at Day 35 post-transplant.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The study was originally intended to be multi-site but ended up only being conducted at the lead site. Due to the rarity of the subject population and the smaller number of enrolling sites, we were not able to reach accrual goals. Once the funding period ended, the study had to be closed to accrual.

• Study Protocol and Statistical Analysis Plan (PDF, 2023-07-12)
• Informed Consent Form (PDF, 2022-09-28)

• Filippo Milano, Principal investigator, Fred Hutch/University of Washington Cancer Consortium

NIH grants: R34HL142322