Allogeneic Hematopoietic Cell Transplantation in Septuagenarians

Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) are diseases that affect predominantly older adults, and it is precisely this group of patients that continues to suffer from particularly poor outcomes [1-4]. Although hematopoietic cell transplantation (HCT) has emerged as an important treatment strategy for patients with high-risk hematologic malignancies, as recently as 2 decades ago this modality was limited mainly to patients under age 50 [5]. This arbitrary age restriction was related primarily to concerns about early nonrelapse mortality (NRM) and morbidity. Initial studies of HCT using myeloablative conditioning regimens suggested that patients over age 50 may experience increased toxicity from chemo-therapy, as well as higher rates of graft-versus-host disease (GVHD) [6]. Several factors, including improved supportive care and the development of a decrease in intensity conditioning (RIC) regimens, have led to reduced mortality after allogeneic HCT [7]. This progress, along with the lack of effective alternative treatment strategies for many patients, has rekindled interest in HCT for older adults with hemato-logic malignancies and has led to an increase in the use of HCT in these individuals [5,8-11].

Although little is known about quality of life after RIC HCT in older patients [12], recent studies have reported somewhat promising survival results. A large database analysis of patients age >40 undergoing RIC-HCT for AML or MDS uncovered no adverse effect of age on NRM, disease-free survival, or overall survival (OS) [8]. In addition, a recent study of patients ages 60 to 70 with high-risk MDS or secondary AML receiving RIC-HCT versus azacitidine therapy also revealed fairly encouraging outcomes for the HCT group, with a 2-year OS of 39%, NRM of 33%, and relapse rate of 30% [10]. Although RIC-HCT has become an accepted strategy for treating patients age >50, this approach is currently used in only a relatively small proportion of older adults with AML and MDS [13]. Moreover, while an increasing number of studies have focused on patients age >60, few studies have focused on patients age >70 [14].

In this issue of Biology of Blood and Marrow Transplantation, Brunner et al [15] report a retrospective analysis of 54 patients age >70 undergoing HCT at 2 affiliated institutions [15]. The patients had a heterogeneous group of diseases, but more than two-thirds had AML or MDS. All patients received an RIC regimen, mostly busuflan and fludarabine, and most patients received their grafts from matched unrelated donors. Two-year OS and progression-free survival in the entire population were both 39%, with reasonable rates of GVHD. Two-year OS was 53% in patients with AML or MDS with favorable or intermediate-risk cytogenetics (only 1 patient had favorable cytogenetics), compared with 30% in those with adverse cytogenetics or other hematologic malignancies. Perhaps the most encouraging finding is the low overall NRM of 3.7% at day 100 and 5.6% at 2 years post-HCT, contradicting the hypothesis that NRM precludes HCT in older patients. The low rate of rehospitalization after HCT in the study population is also a reason for optimism. In fact, similar to an earlier study of older adults undergoing HCT, a sizeable proportion of patients (36%) never required hospitalization after the initial inpatient stay for transplantation [14].

Of course, as the authors themselves acknowledge, their study is subject to all of the shortcomings that accompany any database investigation of patients undergoing HCT. The transplant recipient population comprised patients considered sufficiently robust to undergo HCT. Moreover, as should often be the case, the vast majority of patients with AML or MDS had received therapy before undergoing HCT, and patients who had responded poorly to chemotherapy were unlikely to be selected for HCT. In addition, the lack of a control arm in the study represents a significant limitation. Despite the restrictions inherent to this sort of study, the authors make a convincing case that carefully selected adults age 70 and older can safely undergo HCT, and that HCT merits further exploration as a treatment option for these patients. The authors speculatedperhaps correctlydthat because many patients had relatively high disease risk index scores, they would have had poor outcomes without HCT. Naturally, however, this study does not tell us whether any of the specific patients selected for HCT by their physicians would have done as well or better with less aggressive therapies or supportive care. Nevertheless, it does indicate that HCT seems to be a sensible option for certain patients.

Even if selected older patients with AML and MDS patients can indeed undergo HCT with reasonable survival rates, a number of questions still remain: What conditioning regimen(s) should be used? Which older patients should undergo HCT? How should the general health of the patient and also the details of the patient's hematologic neoplasm be taken into account?

Regarding patient selection, if some vigorous older adults can safely undergo RIC-HCT, perhaps a subset of these older adults are sufficiently fit to derive further benefit from more aggressive conditioning regimens [16-18]. This issue has not yet been fully explored. Patients with poor performance status (ECOG 2) and those with significant pretransplantation comorbidities do not appear to fare as well as others [15,19,20]. In addition, investigators are currently evaluating novel measures pertaining to frailty in older patients being considered for HCT [5].

Finally, there is the challenging problem of disease-related risk factors, which the disease risk index will help address. It is well-known that outcomes after HCT depend in part on the disease, as well as on the patient's remission status [21]. On the one hand, if older patients with AML and MDS with favorable and intermediate cytogenetics had better outcomes with RIC-HCT compared to those with unfavorable cytogenetics, then one might argue that the former had diseases more amenable to this particular therapy. On the other hand, these better outcomes might be related to the selection of a particularly fit group of patients with less aggressive disease, who were more likely to be in complete remission at the time of HCT. Perhaps this group of patients was bound to do equally well regardless of the treatment administered. Similarly, those with unfavorable cytogenetics were less likely to be in complete remission at the time of HCT and perhaps were more likely to have worse outcomes irrespective of the treatment they received. At present, at least 2 prospective clinical trials are planned to examine further the role of RIC-HCT in the older population by biological assignment to HCT versus other treatment modalities [22]. Such studies should provide insight into which older patients are most suited for HCT.

The development of strategies to allow for alternative sources of hematopoietic cells, including haploidentical bone marrow and umbilical cord blood, is expanding the ability to perform HCT in older patients. As logistical barriers to HCT in these patients fade away, it is becoming increasingly imperative that oncologists learn when to apply this modality. Multiple studies show that early NRM and frequent hospitalization do not appear to be obstacles to HCT in relatively robust older patients. We must now turn our attention to optimizing patient selection, as well as to examining how quality of life is affected in older patients undergoing allogeneic HCT.