Roxanne Nelson

December 13, 2011

December 13, 2011 (San Diego, California) — For leukemia and lymphoma patients who require a stem cell transplant but do not have a matched donor, the use of peripheral blood stem cells (PBSCs) from an unrelated donor has become a popular option, and has taken over bone marrow as the source of transplantation.

Dr. Claudio Anasetti

The use of PBSCs has increased to 75% of unrelated living donor transplants, but there are no real data to support this shift, noted Claudio Anasetti, MD, chair of the Department of Blood & Marrow Transplant at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida.

Now, the first trial to compare PBSC with bone marrow transplants from unrelated donors has found that the 2 approaches result in similar survival, but that the PBSC transplants are associated with higher rates of chronic graft-vs-host-disease (GVHD).

Dr. Anasetti presented these data at a plenary session here at the American Society of Hematology 53rd Annual Meeting.

Although engraftment is faster in patients receiving PBSCs, the incidence of overall chronic GVHD in these patients is higher than in those transplanted with bone marrow stem cells (53% vs 40%), he reported.

"Acute GVHD was not significantly different between the 2 arms," he said. "Extensive chronic GVHD was higher in the PBSC arm — about 48% vs 32% — which is approximately a 16% point difference."

Which is Better?

Dr. Anasetti explained that most patients currently receive unrelated donor transplants. "Why would anyone want a 16% increase in the chance of living with chronic GVHD for years?" he asked.

Some patients will benefit from PBSCs over bone marrow, Dr. Anasetti surmised. As far as the standard of care, both stem cell sources are acceptable. "Peripheral cells may be preferred for patients at risk for graft failure or early serious infection, and bone marrow more acceptable for others," he said. "Patient and donor preferences also need to be considered."

This is a very large randomized trial that reviewed phase 2 data and asked if the conclusions from those data would hold up in a randomized study, said Stephanie J. Lee, MD, MPH, professor of medicine at the University of Washington School of Medicine in Seattle.

"What the results show is that the survival is about the same between the 2 different types; peripheral cells weren't better, as many people had expected," said Dr. Lee, who moderated a press briefing in which the highlights of the study were presented.

"It also showed the relative trade-offs between one stem cell source and another," she added. "This is asking people to go back and look at our previous assumptions" — to ask ourselves again what the source of stem cells should be.

Mixed Results

Previous studies of PBSCs have been encouraging, but these transplants have come from related donors. A meta-analysis of 12 randomized trials of human leukocyte antigen (HLA)-identical sibling transplants concluded that PBSCs result in better engraftment, better survival, and less relapse than bone marrow, but increased acute and chronic GVHD.

"The graft-vs-host disease was a problem, but the balance was that relapse was less and that survival was improved," Dr. Anasetti explained.

However, retrospective analyses of unrelated donor transplants did not demonstrate the same improvement in survival with PBSCs. These trials were not randomized, and they suggested that the benefits seen with siblings weren't there with unrelated donors, Dr. Anasetti pointed out. "With retrospective studies, we are never sure that the groups are comparable," he added.

No Survival Difference, Increased GVHD

Because of the uncertainties, Dr. Anasetti and colleagues designed a prospective controlled trial to compare outcomes of PBSC and marrow from unrelated donor transplants only. In the phase 3 randomized multicenter trial, sponsored by the National Heart, Lung, and Blood Institute and the National Cancer Institute, the primary objective was to compare 2-year survival probabilities in both study groups using an intent-to-treat analysis.

Patients were enrolled from March 31, 2004 to September 9, 2009, and the accrual was 550 donor-recipient pairs. Randomization was performed in a 1:1 ratio to either PBSC or bone marrow. Patients were stratified by transplant center and disease risk. Of the 278 patients randomized to the bone marrow group, 5% did not have a transplant and 4.3% crossed over to the PBSC group. Of the 273 patients randomized to the PBSC group, 4% did not undergo transplant and 0.4% crossed over to the bone marrow group. Thus, patients in both groups had greater than 90% compliance with the assigned therapy.

The vast majority of patients (90%) were older than age 20 years of age. Almost half (47%) had acute myeloid leukemia, 28% had high-risk disease, 48% were conditioned with cyclophosphamide plus total body irradiation, and 71% received tacrolimus plus methotrexate for GVHD prophylaxis.

"The findings confirm that PBSCs in unrelated donors are associated with faster engraftment and a higher probability of keeping the graft. Acute graft-vs-host disease was just about the same," said Dr. Anasetti, "but chronic disease was increased."

In particular, extensive chronic GVHD was higher in the PBSC group, he added. "The bad news was that relapse was not less and survival was the same."

Two-Year Outcomes of Transplantation

2-Year Outcomes PBSC (%) Bone Marrow (%) P value
Overall survival (transplanted patients) 52.0 52.0 0.37
Disease-free survival (transplanted patients) 47.0 44.0 0.60
Relapse rate 28.0 28.0 0.88
Acute GVHD II to IV by day 100 47.0 46.0 0.87
Acute GVHD III to IV by day 100 16.0 14.0 0.37
Chronic GVHD (limited) 5.0 9.1 <0.001
Chronic GVHD (extensive) 47.7 31.8 <0.001
Patients alive at 2 years on therapy 62.6 42.6 0.026


There were also no survival differences according to graft sources in the planned subset analyses of low- and high-risk malignancy or among patients who received HLA-matched or mismatched grafts.

The primary causes of death in the bone marrow and PBSC groups were relapse (54% vs 49%), graft failure (7% vs 0%), acute or chronic GVHD (22% vs 34%), and other causes (16% vs 16%).

The study was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute. Coauthor Daniel J. Weisdorf, MD, from the blood and marrow transplant program at the University of Minnesota Medical Center in Minneapolis, reports a financial relationship with Genzyme. Coauthor Peter Westervelt, MD, PhD, from the Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, reports being on the speakers bureaus of Novartis.

American Society of Hematology (ASH) 53rd Annual Meeting: Abstract 1. Presented December 11, 2011.

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