Introduction

Allogeneic hematopoietic stem cell transplantation (alloHCT) with a T-cell depleted (TCD) graft has been demonstrated to be an effective method to prevent graft versus host disease (GVHD) when used with high intensity myeloablative conditioning regimens. However its utility is not established in older patients and those with significant comorbidities in whom reduced intensity conditioning (RIC) regimens are preferred. To further enhance the tolerability of TCD in this population, an alternative method of TCD with co-administration of both CD34+ selected product and an α/β T lymphocyte depleted product enriched for TCR-γδ T lymphocytes has been explored as a technique to potentially improve the anti-tumor effect and hasten immune reconstitution. This pilot study aimed to establish whether a RIC regimen is sufficient to allow engraftment of an α/β TCD graft.

Methods

We conducted a prospective study with the primary end point of ability to achieve sustained donor stem cell engraftment of a TCD graft following a RIC regimen (NCT03531736). Patients were conditioned with rabbit anti-thymocyte globulin (ATG) 2mg/kg/daily x3, fludarabine 30mg/m2 daily x5 and TBI 2Gy daily x2 and received post-transplant cyclophosphamide (PT-Cy) 50mg/kg/daily x2 with aim to further reduce host T cells to enhance engraftment, and rituximab 200mg/m2 x1 to reduce risk of EBV-driven post-transplant lymphoproliferative disorder (PTLD). The grafts were depleted of T-cells using the CliniMACS device and were composed of a TCR- α/β + lymphocyte depleted portion and CD34+ selected peripheral blood stem cell (PBSC) graft from HLA-matched related and unrelated donors. No additional immune suppressive medications were used for GVHD prophylaxis. Patients received routine infection prophylaxis as per standard of care, including letermovir in all CMV seropositive patients.

Results

Between May 2018 and September 2023, 17 were enrolled, and 15 are evaluable on study. Patient median age was 72 (range 59-81), 9 (60%) were female and they were treated for myeloid hematologic malignancies; MDS (n = 5), AML (n = 9) or CMML (n = 1). Patients had a median HCT-CI of 3 (range 0-9).

Median follow up was 35.9 months post-transplant (range 9.6 - 59.9). Median CD34 dose was 8.75 x10^6 cells/kg (5.16-12.8), and the median dose of the TCR-a/b+ was 7.09 x10(3) cells/kg (0-164.7). All patients engrafted with a median time of 15 days for neutrophils (range 13-17) and 19 days for platelet engraftment (range 17-28). There was one late graft rejection, and the patient underwent a successful second transplant.

The OS was 100% at 1 year and 86% at 3 years post-transplant. The PFS was 80% at 1 year and 65% at 3 years post-transplant. The cumulative incidence of relapse was 20% at 1 year and 35% at 3 years post-transplant. Seven patients experienced acute GVHD; six were grade II (skin and/or upper gut) and 1 with grade 3 lower gut GVHD which required systemic steroids. There were no cases of chronic GVHD.

Median CD4 and CD8 counts were 99.5 cells/mcL (range 4-528) and 70 cells/mcL (range 2-727) at 3 months, 132 cells/mcL (range 51-538) and 45 cells/uL (range 12-833) at 6 months and 165 cells/mcL (range 83-366) and 231 cells/mcL (range 51-2412) at 12 months, respectively. By 6 months, 30.8% (4/13) and by 12 months 72.7% (8/11) of assessable patients had achieved a CD19+ count greater than 50 cells/mcL.

Five patients developed EBV reactivation, of which 3 required treatment with rituximab and all resolved. Two patients developed non-life threatening bacterial infections requiring hospital admission. CMV viremia was detected in four patients; all were CMV seropositive recipients who received letermovir prophylaxis. Of these, two cases required treatment and resolved rapidly. There were no cases of CMV disease. There were no deaths due to infection.

Conclusions

In this prospective study we demonstrated that a lymphodepleting RIC regimen is sufficient to allow engraftment of an α/β depleted TCD graft and resulted in high survival rates in an older and vulnerable patient population.

Sufficient immune recovery was seen in this population, with a low incidence of serious infections. The low incidence of severe acute GVHD and absence of chronic GVHD allowed patients to be treated successfully even at time of disease relapse. Based on the promising outcomes of this pilot study, future research will focus on validating these findings in a larger cohort through a phase II study.

Disclosures

Shaffer:Hansa Biopharma: Consultancy. Papadopoulos:AbbVie: Research Funding; EpiKast: Current Employment; Exelixis: Current Employment, Current equity holder in publicly-traded company, Honoraria; Apellis Pharmaceuticals: Current equity holder in publicly-traded company; Biogen: Current Employment, Current equity holder in publicly-traded company, Honoraria; Graviton Bioscience Corp: Current Employment; Leap Therapeutics: Current equity holder in publicly-traded company; Regulus Therapeutics: Current Employment, Current equity holder in publicly-traded company, Honoraria; Actio Biosciences Inc: Consultancy, Current equity holder in private company. Perales:Omeros: Current Employment, Current equity holder in publicly-traded company; Allogene: Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Miltenyi: Research Funding; Biotec: Research Funding; Nektar: Research Funding; Novartis: Research Funding; OrcaBio: Current equity holder in private company; NexImmune: Current Employment, Current equity holder in publicly-traded company. Tamari:Orca Bio: Research Funding.

Off Label Disclosure:

CD34+ cell enrichment has been performed via magnetic cell separation techniques using the CliniMACS device (Miltenyi Biotec, Auburn, CA). The CliniMACS CD34 Reagent System has been approved by the FDA as a Humanitarian Use Device for the prevention of GVHD in patients with AML in first complete remission undergoing matched sibling donor allo HCT, but not approved yet for other types of T cell depletion, which is being studied on this protocol.

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2024
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