Introduction

Severe Aplastic Anemia (SAA) is a life-threatening bone marrow failure disorder associated with pancytopenia, serious infections, and transfusion dependence. Although long term survival for SAA patients (pts) can be achieved with immunosuppressive therapy (IST), one quarter to one third will fail to respond and about half of responders relapse. Many refractory SAA pts lack an HLA matched donor for salvage allogeneic stem cell transplantation. Although umbilical cord blood transplantation (UCBT) is an alternative approach for SAA pts, the procedure is associated with delayed engraftment and high rejection rates. Further, a substantial portion of UCB units have an insufficient number of TNCs/CD34+ cells for optimal transplant outcomes. To address the need to improve UCBT outcomes for SAA, we instituted a phase II trial exploring the use of nicotinamide (NAM) ex-vivo expanded UCB [omidubicel] to transplant pts with refractory SAA.

Methods

Eligible pts were 4-55 years and had transfusion dependent SAA. Other criteria included a) failure or intolerance to IST, b) lack of an HLA matched donor, c) having a ≥ 4/8 HLA matched UCB unit with a minimum of 1.8 x 109 and at least 1.8x107/kg TNCs and at least 8 x 106 CD34+ cells, and d) absence of donor specific antibodies to mismatched alleles on the UCB unit. The study was designed to enroll up to 6 pts receiving omidubicel and CD34+ selected haploidentical cells (cohort 1), followed by enrollment of up to 23 pts receiving omidubicel only (cohort 2).

The conditioning regimen consists of hATG (40 mg/kg) on D -11 to -8, cyclophosphamide (60 mg/kg) on D -7 and -6, fludarabine (25 mg/m2) on D -5 to -1, and 2 Gy TBI on D -1. Tacrolimus and mycophenolate mofetil were given as GVHD prophylaxis. The primary end point of the study is sustained early engraftment. Secondary endpoints include treatment-related mortality, and standard transplant outcomes.

Results

A total of 8 pts with SAA refractory to IST and eltrombopag with a median age of 23 years (range 6-45) have been transplanted to date. Pts were heavily transfused (median ferritin 3745 µg/dL), had severe neutropenia with a median pre-transplant ANC of 115 (range 0-680), with 5 (63%) pts having HLA alloantibodies and 1 pt having an invasive fungal infection treated with multiple antifungals and granulocyte transfusions in the peri-transplant period. In cohort 1, the first 3 pts received omidubicel and ~3 x106 CD34+ cells/kg from a haploidentical donor. Since all 3 pts in cohort 1 had sustained engraftment with omidubicel, the study moved to cohort 2, where so far 5 pts have received omidubicel alone. UCB units were matched at a median of 5/8 HLA alleles (range 4-6). Before expansion, units contained a median 1.6 x105 CD34+ cells/kg. At time of transplantation, the expanded units contained a median 75.3 x105 CD34+ cells/kg, representing a median 42-fold expansion.

With a median follow-up of 10 months (range 1-35), 7/8 (88%) pts have had early and sustained cord engraftment. One pt in cohort 2 failed to engraft and was salvaged with a haploidentical transplant. Another pt in cohort 2 died on D+ 62 from disseminated adenovirus infection. This pt also developed grade 2 acute GVHD and his IST was stopped early in an effort to boost immunity against adenovirus. The other 7 pts are alive without evidence for acute or chronic GVHD and are transfusion independent. CMV reactivation requiring treatment occurred in 3/6 (50%) of pts at risk. Neutrophil and platelet recovery have been remarkably quick, occurring at a median of 10 days (range 6-14) and 31 days (15-40) respectively. Among the 7 pts with sustained engraftment, six pts had ≥ 95% cord myeloid chimerism by D+ 14 and ≥ 95% T-cell chimerism by D+ 26. Immune recovery has also been remarkably brisk: at D+ 100, the median absolute CD4 count was 186/µL (IQR, 118-340) and mean (±SD) IgG level was 522(±161) mg/dL, respectively (Figure).

Conclusions

These results provide the first evidence that omidubicel can result in rapid engraftment and sustained hematopoiesis in heavily transfused and allo-immunized SAA pts who are at high risk for graft failure with conventional UCBT. Data showing rapid recovery of IgG levels and rapid reconstitution of CD4, CD8, and NK cell subsets suggests immune recovery may occur quicker with omidubicel compared to conventional UBCT. Taken altogether, our preliminary data suggest omidubicel represents a promising new alternative graft source for SAA pts who lack HLA matched donors.

Disclosures

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.