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3382 Durable Leukemia and HIV Remission without Antiviral Therapy Following an Allogeneic Hematopoietic Stem Cell Transplantation (alloHCT) Using a Donor with CCR5-Δ32/Δ32 Homozygosity for an Acute Myeloid Leukemia (AML) Patient

Program: Oral and Poster Abstracts
Session: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Poster II
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, Diseases, Therapies, Myeloid Malignancies
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Ahmed Aribi, MD1, Elizabeth L. Budde, MD, PhD2, Joseph C. Alvarnas, MD1, Eileen P. Smith, MD3, Amandeep Salhotra, MD3, Monzr M. Al Malki, MD4, Wen Yi-Ping, NP5*, John Zaia, MD6,7*, Guido Marcucci, MD8,9, Jana Dickter1* and Stephen J Forman, MD4

1City of Hope National Medical Center, Duarte, CA
2Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
3Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
4Department of Hematology/HCT, City of Hope National Medical Center, Duarte, CA
5City of Hope Cancer Center, Duarte, CA
6Center for Gene Therapy, Hematological Malignancy and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
7Beckman Research Institute City of Hope, Duarte, CA
8Department of Hematologic Malilgnancies Translational Science, Beckman Research Institute, City of Hope, Duarte, CA
9Gehr Family Center for Leukemia Research, Medical Center and Comprehensive Cancer Center, City of Hope National Medical Center, Duarte, CA

Background: HIV patients has 2-fold higher incidence of AML compared to general population. We report an HIV-1 infected patient diagnosed in 1988 with nadir CD4 < 100 cells/µL on antiretroviral therapy (ART) with undetectable HIV viral load (VL) since 1990s. He was initially diagnosed with myelodysplastic syndrome (MDS) with trisomy 8 cytogenetic abnormalities and referred for alloHCT. However, his MDS transformed to AML. He received induction chemotherapy regimen of 7+3 (cytarabine plus idarubicin) and FLAG-IDA without achieving complete remission (CR). A salvage regimen consisting of 10-day decitabine and 21- day venetoclax 400 mg daily led to MRD negative CR with resolution of cytogenetic abnormalities. He tolerated the treatment well. A 10/10 HLA-matched CCR5-Δ32 homozygous donor was selected. He underwent a matched unrelated AlloHCT with the goal to treat his AML and HIV.

Method: Following nonmyeloblative conditioning using fludarabine and melphalan, he received infusion of GCSF mobilized unrelated 10/10 HLA-matched CCR5-Δ32 homozygous hematopoietic stem cells on 2/6/2019. The donor was blood group O+ and CMV negative; the recipient was B+ and CMV positive. The graft-versus-host disease (GVHD) prophylaxis was tacrolimus and sirolimus. At various timepoints, he had the following testing: HIV-1 viral envelope genotyping; pre-/post-HCT PBMC analyzed by ddPCR, qPCR; compartment testing for donor cells; ART levels; HIV-1 antibody quantification; and PBMC challenged with HIV-1; HIV, CMV T-cell responses. Antiretroviral therapy interruption (ATI) was started on 2/10/ 2021, 24 months post alloHCT.

Results: Days 30 and 100 bone marrow biopsies showed MRD-negative CR. Chimerism studies at days 30 and 100 showed 99.9% donor DNA. Transplant course was complicated by increasing creatinine, BK virus cystitis, pneumonia, and mild grade 1 chronic GVHD of the oral cavity developed 1-year post transplant and resolved after treatment.

HIV-1 coreceptor sequencing pre-HCT identified majority R5, possible X4 minority. HIV-1 VL was undetectable (< 20 copies/mL) pre-/post-HCT, and during 17 months(mo) since the start of ATI. ART drug levels were undetectable 7 mo, 12 mo post-ATI. The p18 antigen declined to equivocal detection at 37m post-HCT by western blot post-HCT, all other bands positive. PBMC DNA skGag copies/1 million CD4 cells were 80.25 pre-HCT, and stayed at 0 copies post-HCT (Day +57 to +1125). Gut biopsy contained 4.22 DNA skGag copies/1 million CD4 cells at day +175 and none on days +387, and +1126. Control CD8-depleted PMBC challenged with R5, X4, dual-tropic HIV-1 revealed detectable p24 antigen levels day 7. Patient’s CD8-depleted PBMC challenged with HIV strains reported undetectable p24 after R5 infection. Immunological studies at 37mo post-HCT and 12m post-ATI noted most CD8+ cells were terminally differentiated, CD4+ T cells had higher frequency naïve and memory subsets (Tcm, Tem, Ttm), and higher levels CD62L+ cells. Viral recall antigen analysis showed robust response to CMV stimulation, no response to HIV (CD4, CD8 T-cells), supporting HIV remission.

Conclusion: Our City of Hope AML patient with HIV-1 infection after alloHCT for AML using CCR5-Δ32/Δ32 donor cells, achieved durable remission for both AML (3.5 years post-transplant) and remission for HIV-1 infection (1.5-year post ATI), highlighting the feasibility and effectiveness of alloHCT as a meaningful approach for these patients. This is the 4th patient in the world with such success.

Disclosures: Aribi: SeaGen: Consultancy. Budde: Mustang Therapeutics: Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Merck: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ziopharm: Other: DMSC member for a phase 1 clinical; BeiGene: Membership on an entity's Board of Directors or advisory committees. Smith: Johnson and Johnson: Current equity holder in publicly-traded company. Salhotra: Orca Bio: Research Funding; Kadmon: Other: Advisory board meeting ; BMS: Research Funding. Al Malki: Hasna Biopharma: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; NexImmune: Consultancy, Research Funding; CareDx: Consultancy, Research Funding. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings.

*signifies non-member of ASH