Single UM171 Expanded Cord Blood Transplant Is Feasible, Safe, and Permits Transplantation of Better HLA Matched Cords with Very Low Transplant Related Mortality

Cord blood (CB) transplants are hampered by low cell dose and high transplant related mortality (TRM). UM171, a novel and potent agonist of hematopoietic stem cell (HSC) self-renewal could solve this major limitation, allowing for CB's important qualities as lower risk of chronic GVHD and relapse to prevail. Hence, we initiated a clinical trial to test the safety and efficacy of UM171 expanded CB (eCB). The procedure was designed to be non-labor intensive and of short duration for it to be clinically viable.

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 day of transplant. 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. The first 3 pts also received a 2^nd nonmanipulated CB (neCB) to permit documentation of eCB engraftment. This fed-batch culture system allowed for small culture volumes, saving cost and labor.

Between 6/16-7/17, 16 adults with a median weight and age of 77 kg and 44 years, respectively, were transplanted with a single eCB (13 pts) or with an eCB and a neCB (3 pts). Median final culture volume was 609 mL. The median net viable (v)CD34 fold expansion was 36. Median 1st day of 100 and 500 neutrophils were D+10 and D+19, respectively. Achieving 100 neutrophils was faster than expected and 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 infused vCD34⁺ cell dose. More importantly, patients appeared to derive clinical benefit beyond neutrophil engraftment defined as the 1^st of 3 consecutive days of 500 neutrophils. Patients' last day of fever prior to neutrophil engraftment was Day +7, which occurred much earlier than D+19 of engraftment. We offer 2 hypotheses as explanation: i) 100 neutrophils, which are attained much earlier at D+10, provide significant defence against infection, ii) the graft contains a significant proportion of dendritic cell precursors (>25%) which offer protection during severe neutropenia. When compared to our pts who have received the same conditioning regimen with peripheral blood or marrow, eCB pts were free of fever much earlier (D+7 vs D+15 p<.001). Duration of hospitalization was reduced by 11 days when compared to our non UM171 CB transplants. In addition, because cell dose requirements were lower, 11/16 pts received a better HLA matched CB and 2 pts required a single CB instead of a double CB. Platelet engraftment occurred at a median of 42 days. With a median follow up of 4 months (range 1-13), there has been no CMV disease, no PTLD, 1 adenovirus cystitis, 1 grade 3-4 acute GVHD, 2 mild chronic GVHD and no TRM. Full donor chimerism was achieved in all cell subsets. These results favorably compare to those of other expansion trials which utilize much larger (up to 20L) and longer (up to 21 days) cultures. Moreover, and in contrast to others, we have already initiated our dose reduction study with smaller, better HLA matched CBs, proven to reduce TRM.

Despite preliminary data, it appears that a 7 day UM171 single eCB protocol is feasible and provides clinical benefit beyond faster engraftment with fewer infectious complications, better HLA matching and low TRM, all the while saving production and hospitalization costs. In conclusion, this 1^st trial documents the potency of UM171 and positions UM171-expanded CB as a viable HSC source.