Background: Allogeneic stem cell transplantation (allo SCT) is the only potentially curative therapy for patients with intermediate-2 and high-risk myelofibrosis (MF). Allo SCT for MF has historically been challenging as many patients are transplanted with active or advanced disease and immune reconstitution in MF patients is often hindered by inflammation and bone marrow fibrosis. When compared to non-SCT therapies, MF patients who receive allo SCT achieve long-term survival benefits. However, it comes with an upfront cost of an increased risk of non-relapse mortality in the first year after allo SCT (Gowin K et al, Blood Av 2020). Therefore, there is an unmet need to improve on the early outcomes of transplantation for MF.

Methods: We reviewed MF patients who underwent myeloablative allo SCT with Orca-T derived from HLA matched donors on NCT01660607 and NCT04013685. Orca-T is an investigational cellular product comprising stem and immune cells that leverages highly purified donor regulatory T cells to control alloreactive immune responses. Single agent GVHD prophylaxis was administered as tacrolimus or sirolimus.

Results: We present outcomes for 7 MF patients with DIPSS risk of int-1 (n=1), int-2 or higher risk MF (n=6) treated with the Orca-T graft and compared this to 6 MF patients who underwent standard of care (SOC) allo SCT at Stanford, between 2017 - 2021 (Table 1). All patients were high or very high-risk based on MIPSS70 plus score v, 2.0. All patients had 10/10 HLA-matched donors, except 1 of 7 Orca-T patients who had 9/10 HLA-matched donor. All but 1 patient in both, Orca-T and SOC, recipients had prior Jakafi exposure.

All Orca-T recipients had splenomegaly with spleen size of 16.3 - 23 cm. Engraftment occurred at median of D+13 (range 10-29) and 6 of 7 patients had 100% CD3 donor chimerism at D+100. 1 patient was 90% CD3 donor chimerism at D+100 but achieved 100% CD3 donor chimerism at D+180. All patients had significant marrow fibrosis, MF grade 2 or 3, before allo SCT. Regression of marrow fibrosis to MF grade 0 or 1 was noted by D+ 100 in 7 of 7 Orca-T recipients but only in 1 of 6 SOC patients. Orca-T recipients did not have grade 2-4 acute GVHD and 1 of 7 recipients had extensive chronic GVHD. Tacrolimus was tapered off in 3 of 7 patients at D+180. SOC recipients had 2 of 6 recipients with grade 2-4 acute GVHD, 3 of 6 recipients with extensive chronic GVHD and only 1 recipient was taken off tacrolimus at D+180. There were no deaths in Orca-T recipients and 2 deaths in SOC recipients before D+180, cause of death was acute GVHD and relapse. Finally, when compared to standard allo SCT, Orca-T recipients may have a reduced frequency and severity of infections without significant consequences while the SOC patients had severe and often multiple infections.

Conclusion: Our data indicates that Orca-T graft was well tolerated and potentially efficacious in MF patients undergoing allo SCT. We observed early regression of marrow fibrosis at D+100 in all Orca-T recipients. This limited data suggests that Orca-T may afford an early resolution of an inflammatory microenvironment that allows for robust immune reconstitution and potentially lower incidence of serious infections. Orca-T is under continued investigation to reduce early non-relapse mortality for MF.

Figure 1
Figure 1.
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Disclosures

Gandhi: CareDx Inc: Honoraria; Gamida Cell: Consultancy, Membership on an entity's Board of Directors or advisory committees. Muffly: Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding. Shiraz: Kite Pharma-Gilead: Research Funding. Fernhoff: Orca Bio: Current Employment. McClellan: Orca Bio: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Gotlib: Allakos: Consultancy; Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Meyer: Triursus Therapeutics: Current holder of stock options in a privately-held company; GigaImmune: Current holder of stock options in a privately-held company; Orca Biosystems: Research Funding; Indee, Jura: Consultancy.

© 2021 by The American Society of Hematology
2021
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