This large registry analysis describes trends in patient characteristics, transplant strategies and outcome after alloSCT2 for patients with AML relapsing after a first alloSCT over the last two decades. As shown for alloSCT111, the number of second transplants has increased considerably over time, which may be due to an easier availability of alternative donors such as matched unrelated (MUD) and haploidentical donors. The formation of different RIC regimen12 and improved supportive care might be other reasons.13 Further significant changes over time comprised increasing patient age, longer remission after alloSCT1, more frequent use of alternative donors and donor change for alloSCT2, changes in GVHD prophylaxis, more intensive conditioning as well as improved disease control and improved KPS at alloSCT2. Fortunately, 2-year OS after alloSCT2 has continuously increased over time, reaching 35% in the most recent cohort. This was mainly due to a marked decrease in 2-year RI. In contrast, both rates of 2-year NRM and GVHD remained stable over the years, despite increased patient age and more frequent use of alternative donors. Better performance score at alloSCT2 might have counterbalanced the increased risk for NRM associated with increasing age and alternative donors. Besides alloSCT2 in earlier years, identified risk factors for inferior outcome after alloSCT2 included established variables such as older age, shorter remission after alloSCT1, donor type other than a matched sibling donor (MSD), RIC for alloSCT2, as well as active disease and lower KPS at time of alloSCT2.
Considering the analysis of changes over time together with risk factors for outcome, some lessons can be learned for planning and performing alloSCT2 for AML relapse after alloSCT1. These strategies include both measures to be taken before, during, and after alloSCT2:
The duration of remission between alloSCT1 and relapse is probably the most relevant risk factor for outcome, as seen in our analysis as well as in previous studies.5,6,14–16 Early relapse is thought to mainly represent an aggressive nature of the leukemia with low sensitivity to both the conditioning and the allogeneic immune reaction.17 However, due to limited time for recovery from the physical and mental toxicities of alloSCT1, the need for salvage therapy shortly after alloSCT1 might also increase toxicity, decrease patients’ general conditions and hence diminish the resilience to another transplant, as well as their motivation to undergo the procedure for a second time. Therefore, prolongation of the remission after alloSCT1 is of benefit also for those finally developing relapse. More frequent use of maintenance therapy in recent years might be an explanation for the prolonged remission observed in the later period of our study, although we cannot prove this from our data, since the treatment applied between alloSCT1 and 2 is not covered by the EBMT registry. Nevertheless, both targeted therapies18–20, unspecific pharmaceutical approaches21–24 and prophylactic or preemptive donor lymphocyte infusion25–27 have been increasingly used for maintenance post-transplant after showing their potential to reduce the relapse rate and lengthen remission duration after alloSCT.
Second, our data as well as observations from other studies14,17,28 including a recent meta-analysis16, showed that initial disease control and, at best, achieving CR after post-transplant relapse is a major factor for final success of alloSCT2. Therefore, timely and effective medical treatment shortly after diagnosis of post-transplant relapse is mandatory, which, however, must avoid disproportionate side effects, to which patients in this situation are highly sensitive. Carefully adapting treatment toxicity to the individual patient is of particular relevance, given that a better KPS was another factor being independently associated with outcome from alloSCT2 in the present study. As a limitation of our analysis, we did not have enough details on therapies applied between relapse and alloSCT2 in the registry to draw meaningful conclusions concerning the optimized strategy. Fortunately, modern antileukemic therapies offer a better balance between efficacy and toxicity than classical chemotherapy. In particular, the use of hypomethylating agents +/- venetoclax29–31 or application of targeted therapies32–37 represent promising options in that sense.
Third, since despite recent achievements, long-term remission is a rarity after conventional treatment for post-transplant relapse, the identification of a donor for an eventual alloSCT2 should be part of the management immediately after relapse, to allow alloSCT2 at the optimal time point, defined by best disease response and a high KPS. Although intuitive, change to an alternative donor for alloSCT2 does not seem to be mandatory, since a variety of studies including our own could not demonstrate an advantage (although no disadvantage either) after alloSCT2 from a different donor.14–16 Due to missing information in one third of patients, donor switch could not be included in the multivariate analysis in our study. However, an exploratory analysis on 1006 patients revealed no hint towards a significant influence, suggesting that the observed trend to more frequent donor change in recent years did not decisively contribute to improved outcome over time. In contrast, an improved outcome was observed among patients receiving alloSCT2 from a MSD, who in the vast majority did not undergo donor change. This indirectly might suggest that at least after alloSCT1 from a MSD, using the same donor for alloSCT2 remains an option. Nevertheless, beyond unavailability of the original donor, switching to a different one might be reasonable under certain conditions. For instance, the situation of HLA loss by the malignant blasts, particularly after haploidentical or mismatched unrelated alloSCT138, justifies change to an alternative donor39, although unequivocal clinical evidence is missing. Furthermore, as described above, optimized timing for alloSCT2 to the point of maximum control of the leukemia and the patient being in good clinical condition, is mandatory. In that sense, the most easily available donor, including mismatched relatives, might be preferable, given that the general feasibility of alloSCT2 from a haploidentical donor has been demonstrated.40,41
Forth, according to our data a MAC regimen should be considered for alloSCT2 in all patients who might tolerate it. Similar findings have been described by others28 and are supported by data obtained both after alloSCT142 and in a prospective trial in alloSCT2.43 Recent developments in the field of conditioning have identified myeloablative regimen with reduced toxicity and hence improved outcome.44 Beyond, although not validated for alloSCT2, the EBMT transplant conditioning intensity (TCI) score12 may support the selection of less toxic, but still myeloablative regimen also for alloSCT2. Unfortunately, the huge variety of conditioning regimens applied in our cohort precluded a reasonable comparison and hence the definition of an optimized regimen.
Finally, an optimized GVHD prophylaxis might improve the results after alloSCT2. In our analysis, the use of in-vivo TCD was associated with a markedly decreased incidence of both acute and chronic GVHD, leading to a reduction of NRM. Although this did not translate into improved survival, using in-vivo TCD might be preferable in alloSCT2, rather than omitting it in the interest of an eventually stronger graft-versus-leukemia effect. The use of PTCY might be an alternative to in-vivo TCD, even in the matched donor setting. However, since this strategy has only been introduced very recently, data are not mature enough to draw any conclusion on its use in the setting of alloSCT2.
Apart from the retrospective nature, several limitations of our study need to be considered. As discussed above, we are lacking sufficient data on maintenance therapy after alloSCT1 and initial disease control strategies after post-transplant relapse. Beyond, we missed information on the quality of remission before alloSCT2, since minimal residual disease (MRD) status was reported only recently and therefore in about 20% of our patients. Data from alloSCT1 have shown an advantage for patients transplanted in MRD-negative CR45,46, although this seems not to be true for all molecular markers used for MRD detection47. Hence the role of MRD negativity before alloSCT2 remains to be elucidated. As discussed above, the influence of PTCY as GVHD prophylaxis could not be evaluated either in the multivariable analysis because it was mainly used in the later period. Last, the contribution of maintenance treatment after alloSCT2 to overall outcome cannot be estimated since these data have not been captured in the registry for many years.
In summary, according to this large registry analysis on > 1500 patients, outcome after alloSCT2 has continuously improved over the last two decades, despite increasing patient age. In particular, decreased RI did not come at the cost of increased toxicity. This might be a result of better disease control and improved performance score at time of alloSCT2, as well as an increasing use of MAC, in-vivo TCD and eventually PTCY in alloSCT2 over time. These data encourage to perform alloSCT2 in relapsed AML after first transplant. Factors that were associated with improved outcome may help to optimize the procedure, which at present represents the most effective therapy in this setting. In detail, maintenance strategies after alloSCT1, early identification of a donor for alloSCT2, application of less toxic strategies for initial disease control, timely implementation of alloSCT2 when the best response status has been achieved, as well as the use of intensive, but toxicity-reduced conditioning regimen and in-vivo T-cell depletion for GVHD prophylaxis are treatment elements that might contribute to improved results.
Nevertheless, with still half of the patients relapsing again and only one third being cured by alloSCT2, there is still a lot of room for improvement. Preclinical research has largely increased our understanding of the biology of post-transplant relapse.48,49 It is hoped that specific and individualized treatment will be based on this knowledge in the future to improve outcome after relapse after alloSCT.