Back to the OR?

A study by Eapen and coworkers in this issue of Blood shows that unrelated donor transplantations for patients with aplastic anemia (AA) yield superior outcome when bone marrow (BM) is used as the stem cell source compared with peripheral blood (PB).¹  Recently, a combined European Group for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Research analysis found that AA patients receiving an HLA identical sibling transplantation had superior outcome when patients were grafted with BM instead of PB.² 

The reasons for the superiority of BM in the HLA identical sibling transplant setting were that PB grafts did not reduce graft failure (15% and 16%, respectively), but did increase chronic graft-versus-host disease (cGVHD); this led to an actuarial survival rate of 85% in BM versus 73% in PB grafts for patients under the age of 20 and 64% versus 52% for patients over the age of 20.²  Despite this 2007 report, the use of PB grafts in Europe for AA patients has not change; remaining 38% of the graft source before and after the 2007 report (unpublished data from European Group for Blood and Marrow Transplantation database). Last year a second study by the Center for International Blood and Marrow Transplant Research reported on AA patients grafted from HLA identical siblings using different stem cell sources: granulocyte-colony stimulating factor (G-CSF)–stimulated bone marrow (G-BM), unstimulated BM, or PB progenitor cells between 1997 and 2003.³  Grades II-IV and III-IV acute GVHD and cGVHD were significantly higher after PB transplant compared with BM. Mortality was lower after BM transplant compared with G-BM and PB. This study also concluded that BM is the preferred stem cell source for HLA-matched sibling transplantations for AA.³ 

The present study by Eapen and coworkers confirms the same results when looking at unrelated donor transplantations. The excess death rate in PB grafts was attributed to significantly more acute GVHD. All 3 studies with identical siblings or unrelated donors confirmed other negative predictors of survival, such as delayed transplantation and older patient age.^1-3  Will the present report change the use of PB as a stem cell source for patients with AA? If one considers the effect of the 2007 report on HLA identical sibling transplantations the answer is no. So the next question is, why do transplant practitioners favor PB grafts to the extent that 30% or more still choose PB for a patient with AA, despite data indicating worse outcome? The initial answer is usually to prevent graft rejection, but we have seen that this is not the case.^1-3  PB transplants do speed up hematologic recovery but do not reduce graft rejection, possibly because of the immune pathogenesis of the disease and the use of nonmyeloablative regimens.⁴ 

The second reason to prefer PB grafts could be donor safety, because donation of PB avoids the need for general anesthesia, allows for more rapid recovery after donation, and several international registries offer PB as a default stem cell source. But donor safety is not improved after PB donation. A recent report on over 50 000 donations in Europe documented a significantly higher rate of severe adverse events, 10.76 per 10 000 donations for PB and 4.32 per 10 000 donations for BM.⁵  Fatalities were higher, though not significantly, in PB versus BM donors (4 vs 1 fatality).⁵  Therefore, safety is not a convincing donor issue.

The last reason for selecting PB grafts is logistics: it is easier for the transplantation center to organize a PB harvest in a different unit—usually the blood bank—compared with booking an operating room and harvesting marrow for a couple of hours. The latter is cumbersome, no question, but the data tell us this is best for AA patients and probably also for the donors. This is true for a conventional transplantation in a patient with AA, possibly after a conditioning regimen with cyclophosphamide 200 mg/kg when the donor is a matched sibling⁶  and a combination of cyclophosphamide and fludarabine with or without low-dose total body irradiation when the donor is unrelated.^7,8  Of course, an adequate cell dose of at least 3 × 10⁸/kg of the recipient's weight should be harvested, and the technique matters.⁹  It's possible that semiautomatic marrow harvesting devices will have a place in the clinic in the near future.

If PB is selected as a stem cell source for a first transplantation in patients with AA, a prospective clinical trial should be done with appropriate measures, such as antithymocyte globulin¹⁰  or alemtuzumab,¹¹  should be used to prevent acute and chronic GVHD.