Double-Unit Cord Blood Transplantation Not Superior to Single-Unit in Reducing Risk of Transplant Failure in Children and Young Adults

The strategy of using two unrelated cord blood (UCB) units is no better than the standard single-unit approach in preventing hematopoietic cell transplantation (HCT)-related mortality or engraftment failure, according to a report published in Blood.

For patients who need to undergo HCT but lack a human leukocyte antigen (HLA)-identical donor, use of UCB units has been proposed as an alternative hematopoietic cell source. However, UCB units contain a limited number of these cells, which may lead to poorer post-HCT outcome. Doubling UCB units was thought to increase cell dose, Gérard Michel, MD, from La Timone Hospital in Marseille, France, and co-authors of the report explained.

Dr. Michel and authors enrolled 151 patients (children and young adults ≤35 years) from 22 French transplant centers in a prospective, multi-center, randomized trial comparing the single- and double-UCB strategies. Patients had acute leukemia in remission or myelodysplastic syndromes (MDS; with <20% bone marrow blasts): 74 received single-UCB transplant, and 77 received double-UCB transplant. All underwent a myeloablative conditioning regimen.

Patients were included in the study if they:

  • required unrelated HCT
  • did not have an acceptable unrelated donor, according to the transplant center, based on HLA compatibility and donor availability
  • had at least two UCB units that were a 4-6 HLA match to the patient

Patients were excluded if they had a history of allogeneic HCT (alloHCT) or a poor health status that precluded the use of a myeloablative conditioning regimen. This regimen included:

  • Busulfan (administered from days 9-5 prior to transplant and dosed depending on patient weight), clophosphamide (50 mg/kg/day on days 5-2 prior to transplant), and anti-thymocyte globulin (2.5 mg/kg/day from days 3-1 prior to transplant)
  • Fludarabine (25 mg/m2/day from days 9-7 prior to transplant, total body irradiation (from days 6-4 prior to transplant), and clophosphamide (60 mg/kg/day on days 3-2 prior to transplant)

The study’s primary endpoint was cumulative incidence of transplant strategy failure, which was defined as the first of the following four events to occur: transplant-related mortality (TRM), autologous recovery (defined as hematopoietic recovery with >80% blood recipient chimerism), second alloHCT, or infusion of an autologous hematopoietic cell rescue for engraftment failure. Secondary endpoints included hematologic recovery, relapse risk, incidence and grading of acute and chronic graft-versus-host disease (GVHD), immune recovery, TRM, disease-free survival, and overall survival (OS).

The majority of the patients were <18 years (79.5%); 59.6 percent had acute lymphocytic leukemia, and the remaining 40.4 percent had acute myeloid leukemia or MDS. The mean interval from randomization to transplantation was 39.3 days, and the mean follow-up from UCB transplant was 798 days.

Fourteen patients (six in the single-unit group and eight in the double-unit group) relapsed and could not receive transplant. Of the remaining 137 transplanted patients in both groups, none crossed over to the other treatment group.

In the intent-to-treat analysis, the cumulative incidence of transplant failure (in which patients who relapsed before their planned graft could not be transplanted due to refractory disease) was 14.9 percent in the single-unit group and 23.4 percent in the double-unit group (p=0.21). In the per-protocol analysis, which included only patients who received a transplant, the cumulative incidence was 7.3 percent in the single-unit group versus 14.5 percent in the double-unit group (p=0.20).

Of the five patients who experienced transplantation strategy failure after single-unit UCB transplant, the first classifying event was TRM (n=3), followed by autologous recovery (n=1), and secondary transplant for engraftment failure (n=1). This was similar in the 10 patients in the double-unit UCB transplant group who experienced a transplant strategy failure: eight patients experienced TRM, one had autologous recovery (n=1), and one underwent second transplant for engraftment failure.

The median times to neutrophil recovery (24.8 days after single-UCB unit and 23.5 days after double-UCB unit) and platelet recovery also were similar (58.1 days and 55.9 days). The 60-day probability of post-transplant recovery was 92.6 percent in the single-unit group and 94.2 percent in the double-unit group.

“OS two years after transplantation was 74.8 percent in our double-unit arm and 68.8 percent in the single-unit arm, a difference that was not significant,” the authors wrote. “The incidence of any degree of chronic GVHD at two years was similar in our two treatment arms, but we found a higher incidence of extensive disease after double-unit transplantation.” (See TABLE for a detailed comparison of outcomes.)

In the entire study population, 35 patients died after HCT: 19 in the single-unit arm and 16 in the double-unit arm. Causes of death in the single-unit group included disease-related relapse (n=15), engraftment failure (n=2), infectious complication (n=1), and veno-occlusive disease (n=1), while causes of death in the double-unit cohort included disease-related relapse (n=8), infectious complications (n=5), adult respiratory distress (n=1), GVHD (n=1), and thrombotic microangiopathy (n=1).

The authors also proposed that double-unit UCB be reserved for patients who lack an UCB unit with adequate cell dose. “Double-unit transplantation is ineffective at improving outcome when a single-unit UCB containing more than 3 x 107 TNC/kg can be used,” they wrote.

Because this study was conducted in a largely pediatric patient population, the results may not be generalizable to the adult patient population. Differing quality and cell dose of selected cord blood units could have influenced the study results and, in addition, Dr. Michel and authors noted that “the results in the single-unit arm may be favorably influenced by the degree of UCB recipient HLA compatibility [given that there was] a relatively high proportion of 6/6 HLA-identical UCB in the single-unit arm (19.1% vs. 7.2%).”

“A double-unit strategy proved ineffective at improving the outcome of a UCB transplant when a single cord has an adequate cell dose,” the authors concluded. “Approaches to facilitate engraftment and to improve patient survival may include better HLA matching with high-resolution typing of eight instead of six loci, as well as in vivo cord blood priming or expansion.”


Reference

Michel G, Galambrun C, Sirvent A, et al. Single versus double-unit cord blood transplantation for children and young adults with acute leukemia or myelodysplastic syndrome. Blood. 2016 April 20. [Epub ahead of print]

TABLE. Outcomes of Single- Versus Double-Unit UCB Transplant
  Single-unit UCBn=68 Double-unit UCBn=69 p value
2-year CI of relapse 23.5% 17.4% 0.31
Day 100 acute GVHDGrade ≥2

Grade ≥3

41.2%

25%

44.9%

18.8%

0.76

0.40

2-year chronic GVHDOverall

Extensive only

50%

14.7%

52.6%

31.9%

0.70

0.02

2-year transplant-related mortality 5.9% 11.6% 0.25
2-year disease-free survival 67.6% 68.1% 0.74
2-year OS 68.8% 74.8% 0.56
UCB = unrelated cord blood; CI = cumulative incidence; GVHD = graft-versus-host disease; OS = overall survival

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