Practice-Changing Transplant Study in Blood Cancers

Nick Mulcahy

October 17, 2012

Peripheral blood should not be the default source of stem cells for transplantation in blood cancer patients without a family donor, according to a first-of-its-kind study.

In this population, peripheral-blood stem cells did not improve survival, compared with bone-marrow cells, but were significantly associated with a highly undesirable adverse effect — chronic graft-vs-host disease (GVHD).

The first randomized phase 3 trial to compare stems cells from bone marrow with those from peripheral blood in allogeneic transplantation is published in the October 18 issue of New England Journal of Medicine.

Peripheral blood — not bone marrow — has become the go-to source for stem cells in this setting, the authors explain.

"Over the past decade, the use of peripheral-blood stem cells has increased and now accounts for 75% of stem-cell transplants from unrelated adult donors, without clinical data to support this shift," write the authors, led by Claudio Anasetti, MD, from the H. Lee Moffitt Cancer Center in Tampa, Florida.

But this study provides "data that should change current practice," writes Frederick Appelbaum, MD, from the Fred Hutchinson Cancer Center in Seattle, Washington, in an accompanying editorial.

"Peripheral-blood stem cells should be used in only the minority of patients for whom the benefits outweigh the risks," he writes.

Hematologic Malignancies

The study was conducted by the Blood and Marrow Transplant Clinical Trials Network (in North America and Germany). It involved 551 patients younger than 66 years with acute leukemia, myelodysplasia, chronic myeloid or myelomonocytic leukemia, or myelofibrosis.

"These diseases accounted for approximately 75% of unrelated-donor transplantations in the United States during the study period," the study authors note.

Bone-marrow cells were collected from the donors using standard procedures.

Peripheral-blood stem-cell donors were prescribed filgrastim at the North American centers and lenograstim at the German centers, at a dose of 10 μg/kg of body weight per day for 5 days. They then underwent a single large-volume apheresis on day 5, or 2 smaller-volume apheresis procedures on days 5 and 6.

At 2 years, there was no significant difference in overall survival between the peripheral-blood group and the bone-marrow group (51% vs 46%; P = .29). Median follow-up for surviving patients was 36 months.

There were also no significant differences between the 2 groups in the incidence of acute GVHD or relapse.

However, there were significant differences for 2 other key measures, and these should help identify which patients are best suited for which stem-cell source.

At 2 years, the incidence of chronic GVHD was higher in the peripheral-blood group than in the bone-marrow group (53% vs 41%; P = .01).

This negative outcome might be expected because peripheral blood has "at least" 2 times as many T cells as bone marrow, observes Dr. Appelbaum.

On the plus side, the overall incidence of graft failure was lower in the peripheral-blood group than in the bone-marrow group (3% vs 9%; P = .002).

Therefore, Dr. Appelbaum believes that peripheral blood is appropriate for patients in need of rapid engraftment (including those with life-threatening infections) and for those at high risk for graft rejection. This includes patients undergoing reduced-intensity conditioning without previous exposure to intensive chemotherapy.

However, he sees the specter of chronic GVHD, which can be "debilitating," as a critical factor affecting decision-making.

"For the majority of unrelated-donor transplantations performed after the patient has undergone a standard, high-dose preparative regimen, bone marrow should be used," he writes.

Dr. Anasetti and colleagues make the same observations, but they are less definitive about the implications for practice. They say that peripheral-blood stem cells "may be recommended" for patients at higher risk for graft failure, and that bone marrow "may be recommended for all other patients."

Their reticence might be related to the fact that the study was not powered "to support firm conclusions" about the secondary outcome measures (i.e., anything other than survival).

The authors also acknowledge the importance of donor preference. "In our trial, 30% of screened donors declined to undergo randomization, preferring one donation source over the other," they write.

Although Dr. Appelbaum believes that these results should change practice, he has doubts that this will take place.

"The benefits of peripheral blood are seen early, under the watchful eyes of the transplantation physician, whereas the deleterious effects occur late, often after the patient has left the transplantation center," he writes.

Study Details

"The new findings are somewhat different from previous studies of HLA-identical siblings," the authors point out.

"In some of these studies, the use of peripheral-blood stem cells improved survival among patients with advanced disease, predominantly by decreasing the risk of relapse," they write.

This discrepancy might be related to differences in the study populations, they explain. Their study population only included 12% of patients with chronic myeloid leukemia, which is "the disease most sensitive to the antileukemia effect of peripheral-blood stem-cell transplantation from siblings," they write.

All study patients received 1 of 4 typical conditioning regimens (at the minimum dose of each agent defined in the protocol): cyclophosphamide plus total-body irradiation; cyclophosphamide plus busulfan; fludarabine, busulfan, plus antithymocyte globulin; or fludarabine plus melphalan. The cyclophosphamide-containing regimens are myeloablative, whereas the fludarabine-containing regimens are reduced-intensity conditioning regimens. Patients received 1 of 2 GVHD-prophylaxis regimens (tacrolimus plus methotrexate or cyclosporine plus methotrexate), with or without additional agents.

The study was supported by funding from the National Heart, Lung, and Blood Institute; the National Cancer Institute; the Office of Naval Research; and the National Marrow Donor Program. Some the study authors and Dr. Appelbaum report financial ties to industry, as detailed in the paper.

N Engl J Med. 2012;367:1487-1496, 1555-1556. Abstract, Editorial