Our study indicates very favorable long term survival for patients with AML in CR1 or CR2 who receive an autologous HCT and survive in remission for 2-years or more post-transplant. Mortality rates of these 2-year survivors are similar to general population mortality rates.
In an analysis from the Bone Marrow Transplant Survivor Study, Bhatia et al have also described long-term mortality after autologous HCT for AML (13
). Their study included 158 patients with AML who had received an autologous HCT and survived for 2-years after transplantation. The overall relative mortality of their cohort was higher than that of the general population with a standardized mortality ratio of 6.4 (95% confidence intervals, 4.1-9.3). However, mortality rates declined with time since HCT and were no different that the general population in a subgroup of patients who had survived for more than 10 years after HCT. A more recent study from the Fred Hutchinson Cancer Research Center has also shown that patients receiving autologous HCT for hematologic malignancies who survive in remission for at least 5 years have mortality rates that are higher than the general population.(19
) In contrast, our study shows that patients with AML who receive an autologous HCT in CR1 and CR2 have relative mortality rates similar to that of the general population starting at 4-years after HCT. In comparison to other studies, our analysis only included patients in CR1 and CR2 and the majority of patients included in our cohort had good or intermediate risk cytogenetics. Hence, in contrast to other studies where relapse was the most common cause of late mortality, patients included in our study had a relatively lower probability of late relapse and were able to enjoy survival rates similar to the general population.
Advanced disease stage (CR2 vs. CR1), older age at HCT, and presence of high-risk cytogenetic abnormalities are known adverse prognostic factors for AML and it is not surprising that these factors were associated with higher risks of overall mortality and adverse DFS in our patient cohort. A lower Karnofsky performance status score at transplant, which may be a surrogate for comorbidities and intensity and toxicity of prior therapy, was associated with increased risks of late NRM.
The use of hematopoietic growth factors to promote engraftment was the only factor associated with increased risks of relapse. This observation is intriguing and has been reported previously among autologous HCT recipients for lymphoma (20
). In a recent retrospective cohort study from the European Group for Blood and Marrow Transplantation, Gorin et al have also reported a higher incidence of relapse with peripheral blood versus bone marrow transplantation among 2,165 AML patients receiving autologous HCT in CR1 (22
). The cumulative incidence of relapse was 56%, 46% and 39% among early peripheral blood (≤80 days of CR1), delayed peripheral blood (>80 days from CR1) and bone marrow graft recipients, respectively (P<0.001). These higher risks for relapse with peripheral blood transplantation persisted even after adjusting for other important risk factors in multivariate analyses. The authors postulated that recruitment of tumor cells following mobilization with growth factors with subsequent higher leukemic contamination of the peripheral blood grafts may have accounted for this higher incidence of relapse. The impact of growth factors on outcomes of allogeneic transplantation for leukemia is also controversial, with some studies associating their use with inferior overall and leukemia-free survival while the majority of studies show no impact on outcomes.(23
) In our study, the adverse effect of growth factors on relapse could be secondary to patient selection factors that we could not account for in our analysis. For instance, our cohort consisted of patients who received their transplant in the 1990’s when the use of growth factors in HCT was emerging and patients at higher risk of relapse may have received growth factors preferentially (e.g. among patients who had received greater prior therapy to achieve CR and may have been considered to be at higher risk of delayed engraftment). However, this observation may warrant further investigation in future studies.
It is reassuring that the mortality rates of AML patients who receive an autologous HCT and stay in remission for 2-years are similar to that of the general population. However, late effects of transplantation such as second cancers and other organ specific late complications can take many years to develop and studies that include an adequate number of very long-term survivors are still needed to realize the complete risks and impact of late mortality following autologous HCT for AML.
Our study has the limitations of a retrospective cohort design. Our results are also not generalizable to all patients who receive an autologous HCT for AML since our study was restricted to patients who received their transplant in CR1 and CR2. Also, only 4% of patients had poor-risk cytogenetics. Cytogenetic risk information from diagnosis was missing for 22% of patients; this was comprised primarily of patients from the earliest time period when cytogenetics were not routinely assessed in AML. In addition, the choice of autologous HCT as consolidation therapy over chemotherapy only or allogeneic HCT was determined by physicians at transplant centers. Factors that may have determined choice of therapy were not available to us for analysis.
Our study was not designed to determine the general outcomes of autologous HCT for AML since our cohort was restricted to AML patients in CR1 and CR2 who survived in remission for 2-years or more after autologous HCT. A large number of patients who receive an autologous HCT for AML relapse within the first 2-years post-transplant; in fact, among the 958 patients who received an autologous HCT for AML in CR1 or CR2 and were reported to the CIBMTR during the study period, 56% had treatment failure (relapse or death) within the first two years. Our specific objective was to determine long-term outcomes in patients who had survived 2-years or more and had presumably overcome the risks of initial relapse.
In conclusion, our study highlights the very favorable long-term survival among AML patients who receive an autologous HCT in CR1 or CR2 and survive in continuous complete remission for at least 2 years. Their mortality rates are similar to that of the general population.