Comment on Deeg et al, page 1485
In this issue of Blood, Deeg and colleagues address the problem of unrelated BMTs for patients with acquired SAA.
The background of the study is the high incidence of rejection in this setting, the efficacy of radiation to overcome the problem, and the potential long-term sequelae of radiation, such as second tumors. For these reasons, Deeg and colleagues have designed a prospective trial to assess the minimal dose of total body irradiation (TBI) that would allow sustained engraftment in matched or mismatched unrelated bone marrow transplants (BMTs) when used in conjunction with cyclophosphamide (CY) 200 mg/kg and antithymocyte globulin (ATG). The good news from this multicenter trial is that 2 Gy of TBI produces encouraging survival in patients with a matched donor, with a rejection rate of 2%. The bad news is that lung toxicity still occurred also when lowest TBI dose (2 Gy) was used and, together with other complications, produced significant mortality both in the matched (39%) and especially in the mismatched patients (60%). Deeg and colleagues discuss the potential toxic role of high-dose CY (200 mg/kg) also based on the fact that 9 patients receiving CY 120 mg/kg and TBI 12 Gy did not experience acute pulmonary toxicity. In keeping with this hypothesis, the Seattle team has shown great variability in CY metabolites and strong correlation with transplant mortality.
For the past 3 decades, cyclophosphamide 200 mg/kg has been standard conditioning for sibling transplants in young patients with acquired aplastic anemia (SAA). It was Rainer Storb et al1 who published the first encouraging results in the 1970s, which were then confirmed in large multicenter trials in the United States and Europe.2 The 2 major complications, graft rejection and graft-versus-host disease (GvHD), were controlled in young patients by modified conditioning regimens and combined cyclosporine (CsA)-methotrexate (MTX) GvHD prophylaxis. Currently, a sibling transplant with CY 200 mg/kg-ALG as conditioning, followed by unmanipulated marrow and CsA-MTX after transplantation, would produce survival in excess of 80% to 90% in patients younger than 30 years of age.
However,when patients are older than 30, or if the donor is an identical sibling (European Group for Blood and Marrow Transplantation, unpublished data), survival does not exceed 60%, suggesting that CY 200 mg/kg is not well tolerated in older patients. Deeg and colleagues confirm in this paper that age remains a very significant predictor: survival was 73% in young patients (< 20 years) compared with 46% in patients older than 20 years.
These results are important because they suggest the need for modified conditioning regimens in older patients, both those grafted from siblings and those from unrelated donors; fludarabine (FLU), introduced in the transplant arena by the Perugia group (Aversa et al3 ) some 10 years ago, is now being increasingly used in combination with low-dose cyclophosphamide for SAA patients. Several reports have already been published using FLU-CY with or without low-dose radiation, both in the related and unrelated settings, in Europe, the United States, and Japan. Prospective trials are ongoing: we hope they will show that we can allograft older SAA patients with fludarabine-based regimens, from siblings or volunteer donors, as successfully as young patients with cyclophosphamide. Until then, unrelated transplants, especially in adults, will have to be considered second-line treatment. ▪
