We observed a decline over time in the unadjusted probability of TRM after allogeneic transplantation using myeloablative conditioning for patients with AML who were younger than age 50 years. Since our primary objective was to estimate the collective impact of changes in transplantation practice on the risk for TRM, we calculated rates that were adjusted for changes in relevant patient and disease characteristics. Reductions in TRM remained significant in three of the four groups (MRD/CR1, MRD/CR2, URD/CR2), suggesting that changes in practice rather than patient characteristics were the primary factors driving the decrease in risk for TRM.
An alternative explanation for the decrease in the incidence of TRM is that improvements in the pretransplantation health of HCT recipients occurred over time, making them less susceptible to complications. Such an improvement could have arisen either through advances in supportive care during chemotherapy or perhaps through more discriminating selection of patients for transplantation. Although such an improvement could have contributed to the reduction in TRM, it is unlikely to be the sole cause. First, the proportions of patients with poor performance status or a comorbid condition in each group either increased over time or remained stable. Second, we adjusted for changes in patient and disease characteristics over time to isolate the effect of changes in practice. Finally, recognizing the potential selection bias that the increase in the use of reduced-intensity conditioning regimens for patients who are marginal candidates for myeloablative conditioning might engender, we chose to study younger patients for whom myeloablative conditioning remains the norm.
An important finding in our study is that for the three groups in which the adjusted risk for TRM decreased over time, there was an accompanying improvement in survival. Although the reduction in TRM and improvement in survival are encouraging, our results also draw attention to the fact that the risk for TRM after allogeneic HCT remains high, especially after URD transplantation.
Since the 1980s, there has been a steady succession of innovations designed to reduce the risk of TRM. More effective cyclosporine-based GVHD prophylaxis was adopted in the 1980s.27
In the 1990s, another calcineurin inhibitor, tacrolimus, was introduced,28
and other innovations occurred, including the introduction of fluconazole prophylaxis to prevent invasive fungal infections,29,30
leukocyte reduction of blood products, new screening assays to prevent CMV disease,16,19
and busulfan pharmacokinetic testing.17
Since 2000 there have been other advances, including the adoption of broader, molecularly defined HLA matching for the selection of URDs.18
In addition, in the last decade, PBPCs have largely supplanted BM for adults undergoing MRD HCT for hematologic malignancies, although its overall impact on TRM has been ambiguous.31,32
A limitation of our study, which relied on data from the CIBMTR, was the inability to directly gauge the impact of these and other individual innovations. We were able to indirectly estimate the effect of a limited set of changes by subgroup analysis and other means and did not identify any specific advance or advances that were primarily responsible for the reduction in TRM.
We believe that our results in AML can be generalized to other diseases in which HCT with myeloablative conditioning is performed since the causes of TRM are largely the same regardless of indication for transplantation. This is substantiated by the results of a large Italian single-center trial that demonstrated reductions in TRM over time in patients with a variety of hematologic malignancies.
Advances that hold the potential to further reduce the risk of TRM in patients undergoing HCT continue to be made. The recent identification of risk factors based on comorbidity and serum levels of biomarkers of inflammation, for example, now permits more careful patient selection.33,34
Ongoing studies may yield further gains. For example, genome-wide testing for genetic susceptibilities to the various causes of TRM is being performed using URD-recipient pair samples and data from the CIBMTR (personal communication, Theresa Hahn, August 2010). Such research may make it possible to minimize TRM by tailoring the transplantation approach to individual patients.
Our results indicate that the risk of leukemic relapse, unlike TRM, has not improved over time. Therefore, continued research toward enhancing the antileukemic effect of HCT is needed.
In conclusion, the risk for TRM in patients receiving myeloablative conditioning and allogeneic transplantation for AML has decreased since the 1980s, and this reduction appears to be primarily attributable to changes in practice.