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Allogeneic transplantation for -5/5q- AML
genetic features, such as MK (67%), which may have been confounded with the true impact of -5/5q-. Moreover, inferior outcomes of this cohort may also be explained by the fact that about 30% of our patients had active disease at the time of SCT, which appears, as expected, to be a strong predictor for worse outcomes in multivariate analysis.8 Nevertheless, even when focusing on patients in CR1, the observed outcomes in the current cohort are still in the range of 25% at two years, suggest- ing that our population represents a higher-risk group. Not surprisingly, younger age and a better performance status were both associated with better OS and LFS in line with previously published data,1,27,28 but this observa- tion should be weighed against the underlying selection bias inherent in such a registry-based study. Conditioning intensity lost all impact on outcomes in multivariate analysis. This observation has been confirmed in other studies where the benefit of conditioning intensity was lost in chemorefractory disease, such as MK AML and those involving TP53 deregulation.26,29
The main objective of our study was to evaluate the impact of additional cytogenetic abnormalities in a cohort of AML patients with -5/5q-. The presence of -5/5q- is rarely an isolated event in AML as it is frequently associ- ated with other adverse cytogenetic features, such as CK, MK, -7/7q- or abn(17p).5,22,30 The independent impact of -5/5q- was questioned by Breems et al. in the first report on MK, in which any single monosomy carried a better outcome than the full definition of MK,13,15,31 with no spe- cific effect for -5/5q-. More recently, Middeke et al. described 236 high-risk AML patients after SCT, and found that -5/5q- was associated with worse outcomes compared to CK and/or MK AML, and that abn(17p) translated into the worst survival after SCT.32 Those data suggested that the bad prognosis of MK AML after SCT was mainly related to the presence of -5/5q- and/or abn(17p), but these observations have not been complete- ly confirmed by others.15,33 In our multivariate Cox model, we found that either the presence of MK or abn(17p) were both significantly associated with worse OS and LFS, while CK and -7/7q- had no impact on any outcome parameter. Most of those additional cytogenetic abnor- malities and/or characteristics are typically not present as a single additional event to -5/5q- (Figure 1) making it dif- ficult to weigh the impact of each individual additional event. To avoid the confounding effect of largely overlap- ping cytogenetic categories, we decided to define four well-delimited groups based on a hierarchical prognostic effect of MK and additional abn(17p) in -5/5q- AML: the “5q sole group”, “CK group”, “MK group”, and “abn(17p) group”. These cytogenetic categorizations allowed us to confirm the strong deleterious prognostic effect of addi- tional MK and abn(17p) in this entity in multivariate analysis. In contrast, we did not observe differences in any outcome parameters between the “5q sole group” and the “CK group” with a relatively better 2-year OS (close to 40% for patients transplanted in CR1). The addi- tional cytogenetic abnormalities found in both of those groups could only be numerical abnormalities and some structural abnormalities. The weaker prognostic impact of numerical abnormalities such as trisomy has already been suggested in other studies.13,34 On the contrary, the
presence of -5/5q- within MK is translated into worse LFS and OS, which is in agreement with most published data,24,33 but different from the report from Middeke et al.32 Finally, we confirmed the deleterious effect on outcomes of the combination of -5/5q- with any abn(17p), which has been suggested from our previous dataset.16 The impact of abn(17p) clearly appears stronger than MK, as MK did not impact outcomes within the “abn(17p)” group.
Patients with -5/5q- AML in CR1 without MK and/or abn(17p) appear to benefit from allogeneic SCT, with long-term survival achieved in more than 40% of the patients. In contrast, patients harboring the combination of -5/5q- with abn(17p) represent a very poor subgroup due to an intrinsic and well-known chemoresistance and to a potential lack of sensitivity to a GvL effect.16 If SCT remains the only option for those high-risk patients in CR1, it should be integrated into a post-transplant inter- vention program including low-dose decitabine,35 prophy- lactic donor leukocyte infusions,36,37 a combination of both or other P53-independent therapeutic agents. Lenalidomide has been shown to have a specific effect on myelodysplastic syndrome (MDS) with isolated 5q- through inhibition of the 5q- clone, leading to 60% hema- tologic response and 40% cytogenetic response.38-40 However, responses have been much lower in patients with higher-risk MDS and AML, especially if harboring CK or MK.38 Combinations with standard chemotherapy or hypomethylating agents are associated with objective responses even in patients harboring high-risk features38,41 with the exception of TP53 mutated clones.42,43 Another option might be to integrate lenalidomide as maintenance therapy after SCT, but previous experiences raised seri- ous concerns about an increased risk of acute GvHD.44,45 However, interesting results from the combination of lenalidomide and azacytidine have been recently pub- lished.46
In conclusion, our study, based on a large cohort of patients with AML and -5/5q- undergoing SCT, showed that this strategy led to long-term survival in about 20% of the patients, which seems inferior to other high-risk AML subsets. One of the largest limitations in this study might be the lack of centralized cytogenetic analysis and the selection of patients with an available full cytogenetic report; an essential requirement for the proposed analy- sis. Active disease at the time of SCT remains the strongest prognostic factor of worse survival and precau- tions have to be taken when bridging these patients to SCT. Novel therapeutic pre-transplant strategies must be developed to increase the proportion of patients in remis- sion before SCT. Finally, we found that the benefit from SCT in this cytogenetic entity is highly dependent on the presence of particular additional adverse cytogenetic fea- tures. Indeed, patients without MK or abn(17p) benefit the most from SCT, whereas the additional presence of MK and/or abn(17p) leads to a very poor outcome. SCT is therefore questionable in this subgroup of patients with the current standard approach, especially if they are not in CR1 at the time of SCT. Development of pre-transplant and post-transplant pharmacological and immunological interventions to sustain a response in a larger proportion of patients is urgently needed in these patients.
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