Session: 732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Clinical Outcome: Real World Studies Based on Database Analyses
Hematology Disease Topics & Pathways:
clinical trials, Research, ALL, AML, Acute Myeloid Malignancies, Lymphoid Leukemias, Clinical Research, Diseases, Therapies, Lymphoid Malignancies, Myeloid Malignancies, Minimal Residual Disease
Allogeneic hematopoietic stem cell transplants (alloHSCT) remain the only curative treatment for many advanced hematologic malignancies; however, despite improvements in donor matching and supportive care, these transplants are associated with significant toxicity and reduced quality of life. Strategies to maintain or enhance the graft-vs-tumor and graft-vs-infection effects while eliminating graft-vs-host disease (GVHD) have long been a key goal in the field.
Orca-T is a high-precision, immunotherapy consisting of stem and immune cells, derived from allogeneic donors, that leverages highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses. Orca-T has demonstrated a favorable safety profile and promising control of both relapse and GVHD.
As of 15 July 2022, 180 patients have received Orca-T. Of those patients, 127 have ≥180 days of follow-up and a diagnosis of acute leukemia in CR [AML (n=62), ALL (n=42), mixed phenotype acute leukemia(n=4), CML with prior blast crisis (n=4)], or high risk MDS (n=15). Patients received Orca-T as part of a single-center Phase 2 study (n=32, NCT01660607) or a multicenter Phase 1b study (n=95, NCT04013685). Median follow-up was 387 days (range 41-2062); 72 and 36 patients have > 1 year and >18 months of follow-up, respectively. Patients were aged 19-69 (median 48) and 57% male. Donors were HLA-matched related (n=66) or unrelated (n=61). Patients received investigator’s choice of myeloablative conditioning regimens (busulfan-based, n=98; TBI-based, n=29) prior to Orca-T, followed by single-agent GVHD prophylaxis with either tacrolimus (n=124) or sirolimus (n=3). For comparison purposes, an independent CIBMTR-based cohort was identified which consisted of patients with AML, ALL, or MDS who received myeloablative alloHSCT with a PBSC source between 2016-2018 followed by tac/methotrexate PPX. Matching for relapse risk was based on minimal residual disease (MRD) status in acute leukemia patients; development of an additional risk matched CIBMTR comparator based on DRI score and MRD status is ongoing.
Orca-T was successfully manufactured in a single, centralized GMP manufacturing facility, distributed throughout the U.S., and infused for all patients enrolled.
The relapse-free survival was 81% at both 1 year and 18 months in Orca-T recipients. MRD status was determined for 77 patients with acute leukemia by multicolor flow cytometry; of these patients, 31% were MRD+ when they received Orca-T. Amongst MRD- patients (n=53), RFS with Orca-T was 90% at both 1 year as compared to 66% in the CIBMTR cohort (n=324 MRD- patients). Amongst MRD+ patients (n=24), RFS was 68% at one year with Orca-T as compared to 48% in the comparator cohort (n=104).
Relapse prevention with Orca-T appeared to be enhanced further with a conditioning regimen consisting of busulfan, fludarabine, and thiotepa (“BFT”, n=56 patients, median f/u 342 days); RFS was 90% at 12 months in this group. This included patients with MDS (n=6, 100% RFS at 1 yr), MRD+ acute leukemia (n=14, RFS 73% at 1 yr), MRD- acute leukemia (n=26, RFS 96% at 1 year), and acute leukemia with unknown MRD status (n=11, 91% RFS at 1 yr) (Figure 1).
As with relapse, severe infections were low following Orca-T with 11% of patients developing Grade 3 infections per the BMT-CTN grading scale.
Median times to neutrophil and platelet engraftment were rapid with Orca-T at 13 and 16 days, respectively; graft failure was rare at 1.6%. Grade ≥ 3 aGVHD and mod/severe cGVHD rates were low with Orca-T at 5% and 6%, respectively, through 1 year post-transplant. Non-relapse mortality was low at 5% at 1 year; NRM with BFT was 0%. Overall, Orca-T shows GRFS of 76% and 69% at 1 year and 18 months post-transplant, respectively; OS was 91% and 86% at these time points post-transplant. No formal statistical comparison to the CIBMTR cohort was performed (Table 1).
At more than 1 year of median follow-up, outcomes with Orca-T, a high-precision immunotherapy, demonstrate robust graft-vs-leukemia and graft-vs-infection effects while markedly reducing GVHD and NRM despite MAC. These outcomes were accomplished with consistent and reliable cell manufacturing and distribution of Orca-T at a national scale. A multi-center randomized controlled phase 3 trial comparing Orca-T to SOC, utilizing BFT or TBI-based conditioning, is currently enrolling across the US (NCT05316701).
Disclosures: Oliai: Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Orca Bio: Research Funding; Arog: Research Funding; Seagen: Research Funding. Hoeg: Orca Bio: Research Funding. Pavlova: Orca Bio: Current Employment, Current holder of stock options in a privately-held company, Research Funding. Gandhi: Orca Bio: Research Funding; Gamida: Honoraria; CareDx: Consultancy. Muffly: Kite: Consultancy, Research Funding; Jasper: Research Funding; BMS: Research Funding; Astellas: Consultancy, Research Funding; Adaptive: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Consultancy; Medexus: Consultancy; CTI Biopharma: Consultancy. Mehta: Orca Bio: Research Funding; Syndax: Research Funding. Srour: Orca Bio: Research Funding. Waller: Orca Bio: Research Funding; Verastem Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lowsky: Orca Bio: Research Funding. Patel: Medexus Pharma: Honoraria; CareDx: Honoraria; Orca Bio: Research Funding; Kite: Honoraria. Dholaria: Molecular Templates: Research Funding; Takeda: Research Funding; Wugen: Research Funding; MJH Biosciences: Honoraria; BEAM Therapeutics: Consultancy; Orca Bio: Research Funding; Poseida: Research Funding; Pfizer: Research Funding; Arivan: Consultancy; Janssen: Research Funding; Gamida Cell: Consultancy; Vanderbilt University Medical Center: Current Employment; Angiocrine: Research Funding; BMS: Research Funding; MEI Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy. Pantin: NKARTA: Consultancy; Omeros Corporation: Consultancy, Speakers Bureau; Cardinal Health: Honoraria; Orca Bio: Research Funding. Salhotra: Kadmon: Other: Advisory board meeting ; Orca Bio: Research Funding; BMS: Research Funding. McGuirk: CRISPR Therapeutics: Consultancy; Sana: Honoraria; Orca Bio: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding, Speakers Bureau; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Nextar: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau; In8bio, Inc.: Other: IIT Clinical Trial. Fernhoff: Orca Bio: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. McClellan: Orca Bio: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Abedi: Celgene: Consultancy, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Orca Bio: Research Funding; AbbVie: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau; CytoDyn: Current equity holder in publicly-traded company. Negrin: CoImmune: Current equity holder in private company, Current holder of stock options in a privately-held company; University of Pennsylvania: Other: DSMB or Advisory Board; Novartis: Consultancy; UptoDate: Honoraria; Amgen: Consultancy; Kuur: Consultancy; Garuda: Consultancy; BioEclipse Therapeutics: Current equity holder in private company, Current holder of stock options in a privately-held company; Magenta: Consultancy, Current equity holder in publicly-traded company. Meyer: GigaGen: Other: Co-founder, scientific advisor; indee labs: Membership on an entity's Board of Directors or advisory committees; Triursus Therapeutics: Other: Co-founder, scientific advisor; Orca Bio: Research Funding.
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