Head-to-Head Comparison of Haploidentical HSCT Strategies for Hematologic Malignancies: Phase III Hatcy Study of T-Cell-Depleted HSCT with Adjunctive ATIR101 Versus T-Cell-Replete HSCT with Post‐Transplant Cyclophosphamide

Rationale: Haploidentical allogeneic hematopoietic stem cell transplantation (haplo HSCT) is increasingly used for the treatment of high-risk hematologic malignancies and overcomes limitations of finding a human leukocyte antigen (HLA)-matched donor in a timely manner. Although the most frequently used approach is a T-cell-replete stem cell source followed by in vivo depletion of alloreacting T cells using post-transplant chemotherapy with cyclophosphamide (PTCy), several other approaches have emerged, providing selected or manipulated donor-derived T cells to a T-cell-depleted or alpha/beta T-cell-CD19-depleted stem cell backbone. Here, we present the approach involving T-cell-depleted haplo HSCT complemented by ATIR101, an adjunctive infusion consisting of ex vivo selectively allodepleted, donor-derived, T-cell-enriched leukocytes. ATIR101 can facilitate early immune protection and provide anti-infectious and anti-leukemic activity while minimizing the risk of acute and chronic graft-versus-host disease (GVHD) without the need for post-transplant immunosuppression. ATIR101 is manufactured through the ex vivo use of TH9402 (a rhodamine derivative) and photodynamic treatment, selectively depleting the donor T cells that were activated by the recipient cells. The safety and efficacy of ATIR101 treatment following T-cell-depleted haplo HSCT have been investigated in Phase I and II studies in patients with hematologic malignancies (Roy DC et al. Br J Haematol 2019; ASH 2016, 2018). This strategy is currently being explored in a large, global, randomized Phase III study against a strategy of T-cell-replete HSCT with PTCy as the most commonly applied approach in haplo HSCT.

Trial Overview: A randomized, multicenter, open-label Phase III trial (HATCY; CR‐AIR‐009; NCT02999854) is currently enrolling 250 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) to undergo either T-cell-depleted haplo HSCT with adjunctive ATIR101 treatment or T-cell-replete haplo HSCT with PTCy.

Trial Design and Methods: Inclusion and exclusion criteria are listed in Table 1. All patients undergo total body irradiation (TBI) or non-TBI myeloablative conditioning. Patients in the ATIR101 arm receive anti-thymocyte globulin (Sanofi, 2.5 mg/kg once daily for 4 days) prior to HSCT and an ATIR101 infusion at a dose of 2 × 10⁶ viable T cells/kg between 28 and 32 days post HSCT. In this group, no post-HSCT immune suppression is administered. Patients in the PTCy arm receive cyclophosphamide (50 mg/kg) on Day 3 and 4 (or 5) post HSCT, with subsequent use of immune suppression for GVHD prophylaxis based on institutional guidelines. The primary endpoint of the study is GVHD- and relapse-free survival (GRFS), a composite endpoint defined as time from randomization until Grade III/IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, disease relapse, or death, whichever occurs first. GRFS was selected because it encompasses overall post-transplant health status, thereby closely reflecting a successful transplant outcome (Holtan SG, Blood 2015). Key secondary endpoints are overall survival, progression‐free survival, relapse‐related mortality, and transplant‐related mortality. A further objective of the study is to compare the effects of the two treatment strategies on quality of life. Approximately 50 sites are planned globally. The analysis is event driven: an interim analysis is planned at 105 GRFS events and the final analysis at 156 GRFS events. All patients will be followed up for at least 24 months post HSCT.

Conclusion: This study will determine whether a strategy with a T-cell-depleted HSCT with adjunctive ex vivo selectively allodepleted, donor-derived, T-cell-enriched leukocytes (ATIR101) results in improved outcomes over a strategy with T-cell-replete HSCT with PTCy in patients undergoing haploidentical transplantation. The use of GRFS as a composite endpoint involving freedom of relapse and severe GVHD will allow a unique health-economic assessment and definition of value-based healthcare.

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