No Survival Advantage After Double Umbilical Cord Blood (UCB) Compared to Single UCB Transplant in Children with Hematological Malignancy: Results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501) Randomized Trial

On the basis of pilot data in adults with acute leukemia suggesting that the co-infusion of two UCB units was safe and associated with survival rates comparable to that in children, a randomized trial was proposed to determine whether the transplantation of two units might confer a survival advantage since cell dose is a critical determinant of hematopoietic recovery, non relapse mortality (NRM) and survival. Because adults are not as likely to have an adequate single unit, the study was performed in children.

The BMT CTN, sponsored by NHLBI and NCI, conducted a multi-center, randomized, phase III trial with a primary objective of comparing one-year overall survival in the two study arms using an intent-to-treat analysis. Secondary objectives included comparisons of engraftment, acute and chronic graft-versus-host disease (GVHD), NRM, relapse and disease-free survival (DFS). Thirty-eight BMT CTN, PBMTC or COG centers enrolled patients between December 2006 and February 2012. All patients had to have available two UCB units; unit 1 was the best available HLA-matched unit to the patient with ≥2.5 × 10⁷ total nucleated cell/kg patient weight; unit 2 was the next best HLA-matched unit with ≥1.5 × 10⁷ total nucleated cell/kg. Each unit had to be at least 4/6 HLA-matched to the patient and 3/6 matched between units (at intermediate resolution for HLA-A, -B and allele-level for HLA-DRB1). Patients were randomized to receive a conventional single (n=113) or double (n=111) UCB transplant with randomization stratified by transplant center and patient age. Compliance was >95% in both treatment groups. Of those randomized to a single UCB transplant, 2.7% crossed over to a double and of those randomized to a double UCB transplant, 1.0% crossed over to single; 1.8% in both groups were not transplanted. Patient primary disease (AML, ALL, MDS, CML), disease risk, gender, age, race, ethnicity, CMV serology, performance score and HLA-match were balanced between the two study groups; ALL was the predominant diagnosis (half) in both study groups. All patients received a uniform conditioning regimen (fludarabine 75mg/m², TBI 1320 cGy, cyclophosphamide 120 mg/kg) and GVHD prophylaxis (cyclosporine and mycophenolate mofetil).

The median follow-up of surviving patients is 25 months (both study arms). Overall, 92% patients were in remission with 60% of these in second or subsequent remission. Most units were mismatched at one or two HLA-loci (45% and 40% of single UCB and 42% and 45% of double UCB transplants, respectively). The median pre-cryopreserved total nucleated cell dose was 4.8 and 8.9 × 10⁷/kg for recipients of single and double UCB transplants, respectively. Except for a higher risk of grade III-IV acute GVHD in recipients of a double UCB transplant, all outcomes were similar between the two groups (Table 1). The primary causes of death on both arms were similar with most due to relapse and GVHD.

In children with hematological malignancies, outcomes were similar with no survival advantage in recipients of a double UCB transplant as compared to those transplanted with an adequately dosed single UCB unit. While recipients of two units had a higher incidence of acute GVHD, relapse risk was unchanged. Therefore, on the basis of these results, single UCB transplant should be the standard approach in children for whom a single unit containing ≥2.5 × 10⁷nucleated cells/kg matched at zero, one or two HLA-loci is available. Double UCB transplant however remains a suitable alternative in the absence of an adequately dosed single UCB unit in children with hematologic malignancies.

No relevant conflicts of interest to declare.