Clinical Outcomes in Myelodysplastic Syndrome Patients Treated with Orca-T or Post-Transplant Cyclophosphamide Patients: A Registry-Based Comparison

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Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only potentially curative intervention for myelodysplastic syndrome (MDS), but novel strategies are needed to reduce relapse and improve survival. Orca-T is an investigational precision cell therapy for treatment of hematological malignancies. In a Phase 1b clinical trial (NCT04013685), Orca-T exhibited an excellent safety profile and low rates of severe Graft-versus-Host disease (GVHD). In a Phase 3 prospectively randomized trial (NCT05316701), Orca-T met the primary endpoint of improving moderate-to-severe chronic GVHD-free survival in comparison to calcineurin inhibitor/methotrexate prophylaxis. The goal of the present study was to compare the clinical outcomes of myelodysplastic syndrome (MDS) patients who received either Orca-T or post-transplant cyclophosphamide (PTCy) for the control of GVHD. Methods The Orca-T patients in this study included all MDS patients in the Ph3 trial who received Orca-T and all MDS patients in the Ph1b trial who met the Ph3 eligibility criteria. For comparison to PTCy patients, a dataset was acquired from CIBMTR-NMDP. The PTCy patients in this study included those in the CIBMTR registry who had a diagnosis of MDS, received PTCy + tacrolimus ± mycophenolate, and had pre-transplant demographic and clinical profiles that were similar to the Orca-T patients. Additional inclusion criteria were ages 18-65, myeloablative conditioning regimen, and an 8/8 HLA-matched donor. We studied the following endpoints: overall survival (OS), relapse-free survival (RFS), GVHD and relapse-free survival (GRFS), moderate-severe chronic GVHD-free survival (cGFS), and the cumulative incidences of non-relapse mortality (NRM), relapse, grades 3-4 acute GVHD and moderate-severe chronic GVHD. Standard survival and competing risk methods were used; p <.05 defined significance. Results Orca-T MDS patients (n=25), in comparison to PTCy MDS patients (n=95), exhibited increased OS (p=.003), increased RFS (p=.005), and decreased relapse (p=.026) (Table 1 and Fig. 1). The 1-year estimates for NRM, GRFS and gr. 3-4 aGVHD favored Orca-T, but did not reach statistical significance. The cumulative incidence of moderate-to-severe cGVHD was lower in the PTCy group, but cGFS was similar. The analysis consistently showed lower overall survival estimates for PTCy patients across various subgroups, defined by recipient age, sex, HCT-CI, KPS, and donor type. Thus, differences in demographic and clinical characteristics between the treatment groups are unlikely to explain the overall observed difference in OS. Conclusions In conclusion, MDS patients treated with Orca-T, in comparison to PTCy, exhibited increased OS, increased RFS, decreased relapse, and decreased NRM. These observations provide evidence supporting the use of Orca-T for improved clinical outcomes.

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