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Double-unit cord-blood transplant failed to extend survival in blood cancers
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Children and adolescents with hematologic malignancies who underwent double-unit cord-blood transplantation experienced similar survival rates as those who underwent single-unit transplants, according to results of a phase 3 randomized trial.
However, patients who received a single unit of cord blood achieved better platelet recovery and demonstrated a reduced risk for grade III and grade IV acute and extensive chronic graft-versus-host disease (GVHD).
John E. Wagner Jr., MD, director of blood and marrow transplantation in the department of pediatrics at the University of Minnesota, and colleagues sought to determine whether two units of cord blood would improve transplantation outcomes due to the limited number of hematopoietic cells in cord-blood units.
John E. Wagner Jr.
The multicenter study included 224 patients aged 1 to 21 years with high-risk acute leukemia, chronic myeloid leukemia or myelodysplastic syndrome. Wagner and colleagues randomly assigned 111 patients double-unit transplantation. The other 113 patients underwent single-unit transplantation. All patients underwent myeloablative conditioning and immunoprophylaxis for GVHD.
OS at 1 year served as the primary endpoint.
Patients in the double-unit cohort received a median of 7.2x107/kg infused nucleated cells, and 3.7x105/kg CD34-positive cells. Patients in the single-unit cohort received a median of 3.9x107/kg infused nucleated cells and 1.9x105/kg CD34-positive cells.
Researchers observed similar 1-year survival rates among double-unit (65%; 95% CI, 56-74) and single-unit (73%; 95% CI, 63-80) cord-blood recipients (
Double-unit and single-unit cord-blood transplantation also were associated with similar rates of 1-year DFS (64% vs. 70%;
Neutrophil recovery (88% vs. 89%;
Grade II to grade IV acute GVHD occurred in similar rates in both arms (
Ninety-one percent of all patients experienced at least one infectious episode, although the rate for infections was similar in both arms.
“These findings contrast with those reported in studies involving single centers and registries, in which platelet recovery was not affected or was marginally improved after double-unit transplantation, and rates of grade III and IV GVHD and extensive chronic GVHD were similar to those observed after single-unit transplantation,” Wagner and colleagues wrote. “Perhaps the poorer platelet recovery after double-unit transplantation in this study was due to the higher rate of GVHD. Still, it must be recognized that most previous studies of double-unit transplantation involved adults, for whom the graft cell doses were lower. Although CD3-positive cell dose has not been shown to affect the risk of GVHD, perhaps a threshold dose was achieved in these younger recipients, as compared with what can be achieved in larger adults, which resulted in higher rates of severe acute and chronic GVHD in these younger recipients.”
Disclosure: The study was funded by grants from the NCI and NHLBI. See the study for a list of the researchers’ relevant financial disclosures.
Perspective
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Edward Copelan, MD, FACP
This is an important study with straightforward clinical implications. Among children and adolescents with hematologic malignancies, there are no advantages — and important disadvantages (such as more grade 3 to grade 4 acute GVHD, and more extensive chronic GVHD) — to performing double-unit cord-blood transplantation compared with an “adequately dosed” single-unit transplant.These results conflict with the growing trend to use two cords when one might do. Non-randomized comparisons reporting significantly lower relapse rates and better survival following double- compared with single-cord transplants have generated immense enthusiasm for double-unit cord transplants, which now constitute 80% of cord transplants in the United States. According to data from the Center for International Blood and Marrow Transplant Research, the total nucleated cell dose of at least one of the two units exceeds 2.5x107/kg in half of these double-unit cord transplants. According to this randomized trial from the Blood and Marrow Transplant Clinical Trials Network, the second unit added risk of GVHD and expense without any benefit. Most double-unit transplants that include a primary unit dose ≥2.5x107/kg presumably result from the desire for a higher cell dose. Some centers have established a minimum threshold of 4x107/kg with HLA mismatched (4/6 to 5/6 matched) units. However, the reported lower rates of relapse with a second unit also have fueled much of the fervor. The current study strongly suggests that 2.5x107 cells/kg might be an acceptable threshold but, because the single-unit group received a much higher mean dose than this threshold (3.9x107/kg), this study does not definitively exclude a potential threshold above 2.5x107/kg, below which using a second unit in 4/6 or 5/6 HLA-matched cord transplants might be of benefit. Nevertheless, this study advances the field substantially, not only in its primary conclusion, but in again emphasizing the value of well-designed prospective randomized trials in transplantation to determine whether — and in what situations — new therapy options are of value.
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