Background: Based on pilot study data demonstrating safety and excellent survival [Blood 2014 124:46] in acute leukemia patients undergoing myeloablative cord blood transplant (CBT) plus infusion of an off-the-shelf non-HLA matched expanded CB unit (OTS) for bridging hematopoiesis, a randomized trial was conducted to determine whether myeloablative CBT with or without an OTS would confer more rapid neutrophil (ANC) engraftment and therefore a survival advantage.

Methods: We conducted a multi-center, randomized controlled phase II trial (RCT) with a primary endpoint of ANC engraftment defined as the first of 2 consecutive days in which neutrophil count ≥ 500 cells/μL. Secondary endpoints included platelet engraftment, overall survival (OS), disease free-survival (DFS), acute/chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), and relapse. 160 patients were enrolled between February 2013 and June 2018. Patients were randomized to receive either a conventional single or double CBT (SOC group) (n=78) or SOC + OTS (OTS group) (n=82). Unmanipulated CB units had to be at least 4/6 HLA-matched to the patient (intermediate resolution for HLA-A, -B and allele-level for HLA-DRB1) with no HLA matching required for the OTS. Patient disease (AML=68, ALL=77, MDS=7, CML/other=8), disease risk, gender, age, race, ethnicity, CMV serology, performance score and HLA-match were balanced between the two study groups. Patients received conditioning with either FLU 75mg/m2, TBI 13.2 Gy, CY120 mg/kg or with FLU 150mg/m2, TBI 4Gy, CY 50 mg/kg and Thiotepa 10 mg/kg. Cyclosporin and MMF were used for GVHD prophylaxis in all patients (Table 1).

Results: The median follow-up of surviving patients was 15 months. Approximately 30% of patients enrolled were <18 years and most patients received the high dose TBI (13.2Gy) regimen (85% in OTS group and 91% in SOC group). The median pre-cryopreserved total nucleated cell dose was 5.4 × 107/kg for both groups while the median pre-cryopreserved CD34 cell dose was 0.30 and 0.28 × 106/kg for the OTS and SOC group, respectively. Patients in the OTS group received an additional median CD34+ cell dose of 10.5x106/kg. Median time to ANC engraftment was similar between the 2 groups, at 20 days (range 7-46) in the OTS group and 19 days (13-51) in the SOC group. Five patients experienced graft failure, 2 in the OTS group and 3 in the SOC group. Similarly, no difference was seen for median time to platelet engraftment [38 days (35-43) vs. 40 days (30-42) for the OTS and the SOC group]. Peripheral blood chimerisms performed weekly (day 7-28) revealed that the initial circulating myelomonocytes present in the peripheral blood of OTS patients at day 7 were nearly all generated from the OTS product. Contribution to engraftment of the OTS graft was transient, and generally undetectable after day 21. All outcomes were similar between the two groups. OS and DFS at 2 years were 70% and 60% vs 61% and 55% for the OTS and the SOC groups, respectively. Cumulative incidence of relapse and NRM at 2 years were 18% and 21% in the OTS group and 21% and 22% in the SOC group. Grade III-IV aGVHD was 16% and 14% for the and the SOC group, respectively. The OTS product was well tolerated, and serious adverse events rates similar between the 2 groups. Patients continue to be followed through 2 years to assess cGVHD, and graft-relapse-free-survival.

Conclusion: In this multi-center RCT, no significant difference was observed in the primary or secondary endpoints. Importantly, while the median time to ANC recovery in the OTS group was unchanged (20 days) from our pilot study, the observed time to neutrophil recovery in the SOC group was 7 days quicker than expected based on previously observed outcomes following myeloablative CBT (median 26 days). During the 5 years that this study was open to accrual, the criteria for CB donor selection have improved, now regularly utilizing CD34+ cell content and high-resolution HLA-typing where available, as has the quality of the CB inventory. This RCT highlights that delayed engraftment should no longer be a barrier in the consideration of SOC CBT for patients with hematological malignancies. As expected, and observed consistently following CBT, both groups demonstrated low incidence of severe acute GVHD and relapse at 2 years. Interventions in CBT should focus on improving immune reconstitution and reducing the risk of NRM but must be easily adopted into SOC in order to be adopted clinically.


Milano:ExCellThera: Research Funding; Amgen: Research Funding. Rezvani:Kaleido: Membership on an entity's Board of Directors or advisory committees, Other: one-time compensation from advisory boards; Nohla Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: one-time compensation from advisory boards; AbbVie: Other: Principal investigator ; U.S. Department of Justice: Other: Expert medical witness; Johnson & Johnson: Employment, Other: Brother is employed. Delaney:Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees.

Author notes


Asterisk with author names denotes non-ASH members.