Results of a Prospective Multi-Center Myeloablative Double-Unit Cord Blood Transplantation Trial in Adult Patients with Acute Leukemia and Myelodysplasia (submitted on behalf of the RCI BMT 05-DCB Protocol Team)

Background: Retrospective studies suggest that double-unit cord blood (CB) grafts may improve engraftment and protect against relapse as compared with that observed after single-unit CB transplantation (CBT). However, whether the promising disease-free survival (DFS) reported in single center series can be replicated in a multi-center setting has not been established.

Methods: We performed a prospective multi-center study of myeloablative double-unit CBT in adults. Eligible patients were 22-50 years and had acute leukemia in morphologic remission or MDS (< 10% bone marrow blasts at work-up). CB grafts were 4-6/6 HLA-A,B antigen, -DRB1 allele matched to the recipient with a cryopreserved TNC ≥ 1.5 x 10⁷/kg/unit and units were 3-6/6 HLA-matched to each other. Conditioning consisted of cyclophosphamide 120 mg/kg, fludarabine 75 mg/m², and total body irradiation 1320 cGy with cyclosporine-A and mycophenolate mofetil 1 gram every 12 hours as GVHD prophylaxis.

Results: Fifty-six patients [median 35 years (range 18-49), median weight 78 kg (range 53-127), and 33 (59%) CMV seropositive] were transplanted at 10 centers between 2007 and 2011. Thirty patients had AML (13 CR1, 17 CR2), 19 had ALL (11 CR1, 8 CR2), 4 had acute biphenotypic or undifferentiated leukemia (3 CR1, 1 CR2), and 3 had MDS. The median infused TNC doses were 2.9 x 10⁷/kg and 2.1 x 10⁷/kg for the larger and smaller units, respectively, and 4 (3%) units were 6/6, 40 (36%) 5/6, and 68 (61%) 4/6 HLA-matched to the recipient. The cumulative incidence of sustained donor neutrophil engraftment was 90% (95%CI: 82-96) at day 42 and 91% (95%CI: 82-97) at day 100 with a median time to neutrophil recovery of 22 days (range 13-94). Seventy percent (95%CI: 58-82) of patients had platelet recovery at day 180. The incidences of grade II-IV and III-IV acute graft-versus-host disease (GVHD) by day 100 were 66% (95%CI: 53-78) and 39% (95%CI: 27-52), respectively, and 21% (95%CI: 12-33) had chronic GVHD by 1-year. Day 180 transplant-related mortality (TRM) was 32% (95%CI: 21-45), and the 2-year relapse incidence was 10% (95%CI: 3-20). With a median follow-up of survivors of 24 months (range 11-26), 1-year and 2-year Kaplan-Meier estimates of DFS are 57% (95%CI: 44-70) and 50% (95%CI: 37-64), respectively. Of 26 patients who have died, 21 died of TRM which was most commonly due to GVHD (n = 9) followed by graft failure (n = 4), infection (n = 4), and organ failure (n = 4).

Conclusions: Double-unit CBT is a viable alternative treatment for high-risk acute leukemia and MDS, especially in those lacking a matched unrelated donor. However, our results highlight the need for further improvement in this therapy. The major challenges for patients were delayed or failed engraftment, infection, organ toxicity, and GVHD, whereas the relapse incidence was low. Strategies to further ameliorate the TRM after myeloablative double-unit CBT are needed.