Transplantation in AML CR1

In this issue of Blood, Gupta and colleagues report promising results using allo-SCT for patients with unfavorable cytogenetics in AML in CR1.¹  Their data show long-term outcomes for HLA well-matched URD are comparable with those from MSD transplantations. These findings suggest that the allo-SCT approach can be extended to all patients with an HLA-identical donor. The data encourage application of CBT or haploidentical transplantations to these high-risk patients because the outcome of these procedures is improving and expected to be better than chemotherapy alone.

For acute myeloid leukemia (AML) patients with unfavorable cytogenetics, even after achieving complete remission (CR), the probability of disease recurrence without allogeneic stem cell transplantation (allo-SCT) is 80%, and the likelihood of achieving subsequent CR is very low. Gupta et al¹  report improved outcome after allo-SCT in patients with high-risk (HR) AML in CR1 both in the matched sibling donor (MSD) and unrelated donor (URD) settings. As increasing numbers of allo-SCTs are performed from non-MSD stem cell sources, allo-SCT procedures will likely continue to improve (ie, reduced transplantation-related mortality), thereby allowing us to safely extend this curative treatment strategy to patients without MSD.^1,2  Transplants should preferentially be performed on time and not reserved for CR2 in HR patients. Fewer than 20% of HR patients will eventually be able to receive allo-SCT in CR2, as the patient will need to survive the relapse and then be fit enough to undergo allo-SCT in CR2.³  Although several reports of successful allo-SCT in CR2 with a curative potential of 25% to 30% have been reported, such data are highly selective and should not influence a decision against earlier allo-SCT especially at experienced transplant centers.³  Moreover, the risk of relapse after URD allo-SCT is higher for patients with unfavorable cytogenetics irrespective of whether the transplant is performed in CR1 or CR2. Because the probability of achieving CR2 after chemotherapy in this group of patients is low, early allo-SCT provides the optimal approach.

The largest and most challenging group of patients with de novo AML falls within the intermediate-risk category. Intermediate-risk patients who achieve CR1 after chemotherapy have a 50% probability of disease recurrence without allo-SCT, and the probability that CR2 can be attained is low. With advances in the molecular classification of AML, such as NPM1, FLT3-ITD, CEBPA, and c-kit, the indications for allo-SCT can now be extended to approximately 40% of patients with AML with no chromosomal abnormalities.^4,5  In a recent meta-analysis by Koreth et al of patients enrolled between 1982 and 2006, a significant overall survival benefit was reported for patients with poor-risk and intermediate-risk AML who received allo-SCT in CR1.⁶ 

In support of these findings, Gupta et al report a survival benefit for AML patients in CR1 with unfavorable cytogenetics with allo-SCT; most notably, there was no difference in outcome between MRD versus URD allo-SCT. This study also redemonstrates that older patients and patients receiving reduced-intensity conditioning (RIC) had an inferior outcome.¹  An aging population is increasing the proportion of persons susceptible to diseases for which SCT is indicated. However, with the median age of AML approaching 70 years, allo-SCT is not a treatment option for the majority of patients. Because relapse is the major cause of treatment failure after allo-SCT in patients with HR AML, new approaches to prevent disease recurrence are being explored. A question of practical importance is whether patients undergoing transplantation in CR1 will benefit from postremission chemotherapy before transplantation. There are no prospective studies demonstrating that any form of postremission chemotherapy further reduces the risk of posttransplantation relapse. However, results from 2 retrospective registry analyses suggest no benefit of adding further consolidation chemotherapy before allo-SCT; in both studies (transplant period 1980-mid 1990s), most patients were young and received full-intensity conditioning MRD allo-SCT.^7,8  In the study by Gupta et al, relapse occurred in 37% to 40% and was higher in patients receiving RIC regimens.¹  These findings highlight the importance of the depth-of-remission pre-SCT, especially in recipients of the RIC group. The role of postremission consolidation chemotherapy before RIC allo-SCT in HR AML has not been adequately addressed. Given that the majority of relapses occur within 1 year after transplantation, these patients should be enrolled in prospective studies to explore preemptive posttransplantation therapy to prevent early relapses. We speculate that, in the future, disease relapse may be further decreased by posttransplantation adjuvant therapies that could include chemotherapy (eg, azacitidine), leukemia vaccines, and adoptive transfer of natural killer cells or leukemia-specific T cells.

In patients with unfavorable cytogenetics in AML CR1, transplantation leads to improved long-term survival in the range of 34% to 42% versus less than 20% with nontransplantation therapy. Importantly, the outcome of transplantation appears to be comparable for recipients of URD versus MRD transplantation.^1,2  This is especially relevant in view of the fact that more than 20 000 allo-SCT procedures are performed annually throughout the world,⁹  and more than half are from non-MSD stem cell sources. The analysis by Gupta et al was performed for the transplantation period 1995 to 2006.¹  With improvements in transplantation procedures including better donor selection (with high-resolution HLA typing), excellent supportive care, and preemptive therapy in high-risk patients, we anticipate that outcomes will continue to improve.

Currently, a stem cell source can be found for virtually all patients who have an indication to receive allo-SCT. Haploidentical-related donor or cord blood transplantations (CBT) have emerged as alternatives to fill the gap for those patients who do not have MSD or URD and the outcome of these types of transplantations is expected to be better than chemotherapy alone in high-risk AML CR1. The results of 4 comparative studies together with meta-analyses of CBT versus URD–bone marrow transplantation (BMT) showed that despite increased disparity, the results of CBT appear to be as promising as those of matched URD-BMT in adults with hematologic malignancies.¹⁰  In the absence of an HLA-matched donor, both CBT and haploidentical-SCT strategies (center dependent) are suitable options to treat these HR patients.¹¹  An upcoming Blood and Marrow Transplant Clinical Trials Network study will compare haploidentical-SCT with CBT.

In summary, the current study provides insight into the applicability of expanding allo-SCT to all possible non-MRD stem cell sources to improve transplantation outcome in patients with AML in CR1 with unfavorable cytogenetics. While considering allo-SCT for AML in CR1, we need to make a judgment as to whether the relapse risk significantly exceeds the incremental mortality from allo-SCT over standard chemotherapy. The individual transplant center experience using URD, CBT, and haploidentical transplantation should also be taken into consideration. Enrollment in clinical trials should be encouraged, with the hope that the information from the current study will instigate studies evaluating various postremission strategies including CBT and haploidentical-SCT if no matched donor is available for HR AML CR1.