Mgta-456, an Aryl Hydrocarbon Receptor (AHR) Antagonist Based Expansion of CD34+ Hematopoietic Stem Cells (HSC), Permits Selection of Better HLA Matched Cord Blood Units (CBUs) and Promotes Faster Neutrophil Recovery and Uniform Engraftment with Potentially Less Acute Graft-Vs-Host Disease (GVHD)

Background. HSC dose and HLA match are independent risk factors that impact non-relapse mortality in children and adults undergoing umbilical cord blood (UCB) transplant for acute leukemia (Eapen et al. Blood 2014 123:133-140). Low number of CD34+ HSCs results in prolonged periods of cytopenia and higher risk of graft failure. To reduce these risks, a minimum cell dose threshold, e.g. 3.0 x 10⁷ total nucleated cells (TNC)/kilogram (kg), has generally been required in CBU selection. While beneficial in terms of hematopoietic recovery, this cell dose threshold markedly limits the number of available cord blood units (CBUs) particularly for larger adolescent and adult recipients, thus reducing the probability of identifying a 7-8/8 HLA-matched graft. In addition, a second UCB unit is often required for adults as a single unit may not meet the cell dose threshold. MGTA-456 is an expanded CD34+ HSC product utilizing an AHR antagonist in the presence of SCF, Flt-3L, IL-6 and TPO. In previous studies with fresh MGTA-456, 36 patients with hematologic malignancies demonstrated rapid neutrophil recovery and sustained engraftment in all patients. The aims of this study (NCT03674411) were to evaluate the safety and efficacy of cryopreserved MGTA-456 as well as the effectiveness of lowering the minimum cell dose threshold of the selected CBU from 3.0 x 10⁷ to 1.0 x 10⁷ TNC/kg to improve donor-recipient HLA match.

Patients and Methods: Ten patients with high-risk hematologic malignancy were enrolled with 9 transplanted to date. Conditioning consisted of cyclophosphamide 120 mg/kg, fludarabine 75 mg/m2 and total body irradiation 1320 cGy (total doses) with cyclosporine and mycophenolate mofetil as immunoprophylaxis. G-CSF was initiated on the day after infusion and continued until the neutrophil count exceeded 2500/uL for 3 consecutive days.

Results: Cryopreserved MGTA-456 contained a median of 1.9 x 10⁹ CD34+ cells (range, 1.1-6.2) after expansion culture (a 491-fold expansion of CD34+ cells [range, 219-672]). As shown in Table 1, neutrophil recovery occurred in 100% of patients (with one pending after recent transplant) at a median of 15 days (range, 0-31), similar to recipients of fresh MGTA-456 in a prior study (median 14 days, range 7-32) and significantly faster than in recipients of unmodified UCB (median 25 days). Platelet recovery (>20,000/uL for 7 days without transfusion) was also comparable in recipients of cryopreserved and fresh MGTA-456 (median 42 [range 27-53] vs 45 days [range 28-54], respectively), and again faster relative to recipients of unmodified CBUs (median 64 days). In line with preclinical experiments in NSG murine recipients that demonstrates all engrafting cells are retained in the CD34+CD90+ subpopulation, CD34+CD90+ content strongly correlated with speed of neutrophil recovery in recipients of MGTA-456 (cryopreserved and fresh) as shown in Figure 1. As expected, lowering the cell dose requirement from 3.0 x 10⁷ to 1.0 x 10⁷ TNC/kg for UCB unit selection prior to expansion culture improved HLA match and/or eliminated the need for double UCB transplant in 5 of 6 adults (Table 1). As a result, all but one patient received an 8/8 (n=5) and 7/8 (n=4) HLA matched UCB graft, potentially contributing to the low incidence of acute GVHD with only one patient of the 7 out >42 days having grade 2 acute GVHD. This low rate of GVHD compares favorably to that observed in the prior study of fresh MGTA-456. With a follow-up of 19-187 days (median 89), all patients are alive.

Conclusion: Transplantation of cryopreserved MGTA-456 resulted in complete engraftment and rapid recovery with speed of neutrophil recovery correlating with the CD34+CD90+ cell dose. Based on the marked expansion that is now possible, units with fewer cells can now be considered, increasing the probability of finding a better HLA matched unit, particularly for adults. Availability of MGTA-456 could reduce the barriers associated with cell dose and poor HLA match previously limiting the successful use of UCB in transplantation.

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