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Skip Navigation LinksHome > March 25, 2013 - Volume 35 - Issue 6 > Doing More with Less in Cord Blood Transplants
Oncology Times:
doi: 10.1097/01.COT.0000428629.46174.aa
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Doing More with Less in Cord Blood Transplants

Carlson, Robert H.

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ATLANTA—Cell dose is a critical determinant of hematopoietic recovery, non-relapse mortality, and survival in stem cell transplantation, and so it would seem intuitive that two transplants of umbilical cord blood would be better than a single transplant.

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But a Phase III trial reported here at the American Society of Hematology Annual Meeting showed no survival advantage to double umbilical cord-blood transplantation vs. single transplantation in children with hematological malignancies (Abstract 359).

In the randomized trial by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) of 224 patients, overall and disease-free survival, relapse rate, and non-relapse mortality were all similar for both study groups, and recipients of two units did have a higher incidence of acute graft vs. host disease (GvHD).

The overall one-year survival rates were 71 percent for patients receiving single cord grafts and 66 percent for patients having double grafts. Disease-free survival at one year was 68 percent for single transplants vs. 64 percent for double transplants; relapse rates at one year were 12 and 14 percent, respectively; and the non-relapse mortality rates were 20 vs. 22 percent.

Adverse events were generally equivalent: neutrophil recovery was 89 vs. 87 percent, respectively; and platelet recovery was 80 and 72 percent.

While any-grade chronic GvHD at one year was approximately the same—32 percent for the single-graft group vs. 30 percent for double graft—acute grade 3/4 GvHD was significantly different, at 14 percent for single vs. 23 percent for double grafts.

The trial was a collaboration between BMT CTN—which is sponsored by the National Heart, Lung, and Blood Institute and the National Cancer Institute—the Pediatric Blood and Marrow Transplant Consortium, and the Children's Oncology Group.

JOHN WAGNER, MD: Sin...
JOHN WAGNER, MD: Sin...
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The first author, John E. Wagner, MD, Professor of Pediatrics and Director of the Pediatric Blood and Marrow Transplant Program at the University of Minnesota, performed the first umbilical cord blood transplant in the world for leukemia, in 1990. In his presentation here, he noted that pilot data in adults with acute leukemia suggested that the co-infusion of two umbilical cord blood units was safe and associated with survival rates comparable to that in children. On the basis of those data, a randomized trial was proposed to determine whether the transplantation of two units might confer a survival advantage.

But because adults are not as likely to have an adequate single unit, the study was performed in children, he explained.

Patients were randomly assigned to receive a conventional single (113 patients) or double (111 patients) umbilical cord blood transplant. The patients' primary diseases were acute myelogenous leukemia, acute lymphocytic leukemia (ALL), myelodysplastic syndromes, and chronic myelogenous leukemia, with ALL accounting for approximately half of each study arm.

All patients had to have available two umbilical cord blood units:

* Unit 1 was the best available HLA-matched unit to the patient with at least 2.5×107 total nucleated cells/kg patient weight;

* Unit 2 was the next best HLA-matched unit with at least 1.5×107 total nucleated cells/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. The median number of cells actually administered in the trial was 3.9×107/kg for the single graft, and 7.2×107/kg for two grafts.

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Conditioning Regimen as for Adults

Wagner noted that the children in the study received the same uniform conditioning regimen that is standard for adult patients—“that may be the reason the outcomes for both arms of the study were superior than what would have been expected based on the historical data set,” he said. “It is not just receiving a double [graft] perhaps that added some benefit to some patients, it was also the conditioning regimen itself.”

The conditioning regimen included fludarabine at 75 mg/m2, total body irradiation of 1,320 cGy, cyclophosphamide at 120 mg/kg, and GVHD prophylaxis with cyclosporine and mycophenolate mofetil.

At a median follow-up of 25 months for both study arms, 92 percent of patients were in remission, with 60 percent of those in second or subsequent remission.

Wagner concluded that on the basis of the study results, single umbilical cord blood transplant should be the standard approach in children for whom a single unit containing at least 2.5×107 nucleated cells/kg matched at zero, one, or two HLA-loci is available. “But we also showed that a double umbilical cord blood transplant remains an acceptable alternative, particularly for patients who do not have an adequate single cord blood unit based on the cell dose,” he added.

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Cell Dose a Major Limitation

Cell dose is a major limitation for umbilical cord blood transplantation in adults, since units containing a minimum of 2.5×107 total nucleated cells/kilogram of patient body weight are frequently not available, he said.

“This [pediatric data] allows us to extend the transplant experience to adults who otherwise would not have an adequate single.”

Wagner referred to a recent article he coauthored, published online ahead of print in Blood (doi: 10.1182/blood-2012-08-449108first author was Andromachi Scaradavou) the day before his ASH presentation, reporting on a study of 409 adult patients with hematologic malignancies randomly assigned to receive a single or double umbilical cord blood transplant showing the double transplant to be safe, effective, and comparable to a single transplant.

ASH Immediate Past President Armand Keating, MD, Professor of Medicine and Director of the Division of Hematology at the University of Toronto, called the study an important observation underscoring that less is more—“This study indicates that if you have an adequate number of stem cells in a single graft, results are no better than if you end up with more cells in a double transplant,” he said at a news briefing before the meeting. But he added that if there aren't enough stem cells in the first graft, it is entirely appropriate to obtain a second graft because the results are no worse other than for the increased GvHD.

Keating also said that he anticipated there will be a similar trial in the near future for adults. “We will be seeing more of these re-evaluations of very successful therapies to achieve the same results using less treatment,” he said.

Also speaking at the news briefing, ASH 2012 Secretary Charles Abrams, MD, Professor of Medicine and Associate Chief of the Hematology/Oncology Division at the University of Pennsylvania, called cord blood transplantation an example of a “real success story in a deadly disease.

“But when it became possible to cure patients, we are learning now that we probably swung a little too far. We were dealing with such deadly diseases that the treatments were perhaps more toxic than they need to be.”

© 2013 Lippincott Williams & Wilkins, Inc.

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