UM171 Modified Cord Blood Achieves Excellent Survival and Disease Control after 2 Years of Follow-up in High and Very High Risk Malignancies

Background Benefits of cord blood (CB) transplantation include low rates of relapse and chronic graft-versus-host disease (cGVHD). However, CB use is rapidly declining because of delayed neutrophil recovery, high rates of infections and severe acute GVHD leading to high transplant-related mortality (TRM) and prolonged hospitalization. Several of these complications are related to the low cell number of CB grafts, compromising early engraftment and optimal HLA matching. In order to improve these limitations, we initiated a phase II clinical trial exploiting UM171 expanded CB. This molecule has previously been shown to efficiently expand stem and progenitor cells in 7-day ex vivo cultures. More recent studies have also documented the dominant expanding effect of UM171 on several immuno-modulatory cells, thus profoundly changing graft composition and possibly further reducing relapse and GVHD. Methods Patients (pts) received a myeloablative conditioning regimen. On day (D)-7 of transplant, CB was thawed and CD34+ selected. The CD34- lymphocyte containing fraction was cryopreserved and infused on D+1. The CD34+ component was placed in a closed culture system with UM171 and media was injected once a day until D0, when cells were washed and infused. This fed-batch culture system allowed for small culture volumes, saving cost and labor. Moreover, the short duration of expansion made the process practical and clinically viable. Findings Between 9/16-11/18, 22 adults with a median age of 44 years and high- to very high-risk hematologic malignancies were transplanted with a single UM171 CB. Five pts (23%) had already failed a prior allogeneic transplant and 5 (23%) had refractory/relapsed acute leukemia or aggressive lymphoma. Median co-morbidity index was 2 and 36% of pts had an index ≥3. Because minimal cell dose requirements were lower, we had access to 47% of the CBs in the banks instead of 5% for a 70 kg pt. Consequently, >80% of pts received a ≥6/8 HLA matched CB. UM171 profoundly changed graft composition, including a 600 and 8000-fold increase in dendritic and mast cells, respectively. Median 1st day of 100 and 500 neutrophils were D+10 and D+18, respectively. Achieving 100 neutrophils was 5 days faster than seen with pts receiving peripheral blood (PB) or marrow (BM) at same institution and appeared cell dose independent, suggesting that clinically meaningful expansion of an early repopulating myeloid progenitor is at saturation even with smaller CBs. In contrast, attaining 500 neutrophils was accelerated but dependent on cell dose and similar to our BM-PB pts. More importantly, pts appeared to derive clinical benefit beyond neutrophil engraftment as median last day of fever was D+8, much earlier than engraftment and 4 days earlier than seen with our PB-BM pts, translating into a shorter duration of admission, similar to that with BM-PB. Median CD4 count was 218/μL and 413/μL at 3 and 12 months, respectively. Cumulative incidences (CI) of grade 2-4 and 3-4 acute GVHD were 60% and 9%, respectively. We observed no steroid refractory acute GVHD, no moderate/severe cGVHD and 91% of patients were off immunosuppressive therapy by 12 months. One patient died of TRM (<5%) and 5 pts (CI 24% at 2 years) had progressive disease. With a median follow-up of 26 months, 2-year progression-free, GVHD-and-relapse-free survival (GRFS), and chronic GRFS were excellent for such a high-risk group at 72%, 62% and 72%, respectively. Interpretation A 7-day UM171 expansion CB protocol is feasible and provides clinical benefits beyond engraftment, such as very low TRM and severe GVHD with prompt withdrawal of immunosuppression resulting in excellent GRFS. Hypotheses to explain this could be earlier achievement of 100 neutrophils, protective effect of the immuno-modulatory dendritic cells on mucosal integrity and relapse, and mast cells on gut GVHD, as well as better HLA matching. If confirmed, UM171 expansion may overcome the shortcomings of CB transplants while maintaining its benefits of low risk of cGVHD and relapse. Encouraged by our observation that several pts with very high-risk disease (e.g. refractory leukemia) remain in CR, we have now embarked on a Canadian and US trial to ascertain if indeed UM171 modified grafts will have a potent antileukemia effect in extremely high-risk disease pts such as those with refractory acute leukemias and high-risk molecular anomalies like p53 mutation and EVI-1 rearrangement. Figure Disclosures Cohen: ExCellThera: Consultancy, Equity Ownership, Patents & Royalties: Royalities from sales of UM171, Research Funding. Roy:Celgene: Consultancy, Honoraria, Research Funding; ExCellThera: Patents & Royalties: Royalties from sales of UM171, Research Funding; Amgen Canada: Honoraria; Janssen Canada: Honoraria; Sanofi Canada: Research Funding. Delisle:ExCellThera: Patents & Royalties, Research Funding. Bambace:ExCellThera: Patents & Royalties: royalities. Ahmad:ExCellThera: Patents & Royalties. Lachance:ExCellThera: Patents & Royalties. Bernard:ExCellThera: Patents & Royalties. Kiss:ExCellThera: Patents & Royalties. Busque:Paladin: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; ExCellThera: Patents & Royalties; BMS: Consultancy. Roy:Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent; Hopital Maisonneuve-Rosemont: Patents & Royalties: Author on patent. Milano:ExCellThera: Research Funding; Amgen: Research Funding. Sauvageau:ExCellThera: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. OffLabel Disclosure: None of the medications listed are approved for this indication.

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