Secondary acute myeloid leukaemia in elderly patients: Patient's fitness criteria and ELN prognostic stratification can be applied to guide treatment decisions. An analysis of 280 patients by the network rete ematologica lombarda (REL)
Authors: Erika Borlenghi, Chiara Pagani, Patrizia Zappasodi, Massimo Bernardi, Claudia Basilico, Elisabetta Todisco, Nicola Fracchiolla, Valentina Mancini, Mauro Turrini, Matteo Da Vià, Elisa Sala, Chiara Cattaneo, Marta Petullà, Federico Serana, Andrea Ferrario, Roberto Cairoli, Agostino Cortelezzi, Armando Santoro, Carlo Castagnola, Giuseppe Rossi
Journal: American Journal of Hematology (2017)

Secondary acute myeloid leukaemia (s-AML) includes AML deriving from antecedent haematologic disorders (AHD-AML), like myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) and AML therapy-related (t-AML).1 Patients with s-AML have higher median age, frequent unfavorable cytogenetics and their outcome has been considered invariably poorer compared to “de novo” AML.2, 3 Allogeneic stem cell transplantation (SCT) remains the only curative option. However, elderly patients are hardly eligible to SCT. Therefore elderly s-AML is still a therapeutic challenge and objective criteria to guide treatment decision are needed. To identify potential subgroups at different prognosis in relationship both to disease characteristics, like European Leukaemia Net (ELN) risk,4 to objectively defined patient's fitness and to the type of treatment received, we analyzed 280 s-AML patients diagnosed between 2008 and 2015 within a large series of 699 AML patients aged > 64 (APL excluded), consecutively seen at 8 centers of the REL Network. Clinical data were extracted from the electronic databases of the participating Institutions. The ELN-risk was calculated in 158 patients with available cytogenetic/molecular data. Patients were retrospectively categorized according to the fitness criteria to AML treatment, proposed by Ferrara et al.5 and recently validated6 which identifies patients candidates to standard intensive chemotherapy (fit), or to nonintensive treatments (unfit), or just to supportive care (BSC) (frail). The type of treatment actually received was intensive treatment (i-T) (3+7 like), non-intensive treatment (ni-T) (low-dose cytarabine, hypomethylating agents), or BSC. The characteristics of the subgroups were compared by the Fisher's exact test. Survival was evaluated using Kaplan–Meier method and compared using log-rank tests. Multivariable survival analysis was performed by the Cox proportional hazard regression model. The ethical review board of all Institutions approved the study. Patient's characteristics and treatment received by 280 s-AML and 419 de novo AML were no significantly different except for an overall higher ELN-risk in s-AML (Table 1 Supporting Information). Within s-AML subgroups, patients with t-AML were at lower ELN-risk and received more frequently i-T. The overall survival of s-AML patients was 5.2 ± 1.5 months, not significantly worse compared with de novo AML of similar age (6.0 ± 1.4 months) (P = .2) (Figure 1A). Among the subtypes of s-AML, median survival was 6.7, 3.7, and 8.8 months in post-MDS AML, in post-MPN AML, and in t-AML, respectively (Figure 1B). Post-MPN AML fared significantly worse than post-MDS AML (P = .021). Overall survival (Kaplan-Maier) A) OS in patients with s-AML compared to de-novo AML. Median survival was 5.2 (CI95% 3.7 to 6.8) months in s-AML and 6.0 (CI95% 4.6 to 7.4) months in de-novo AML (p = 0.2); B) OS in s-AML patients subdivided in three subgroups according to their diagnosis. Median survival was 6.7 months (CI95% 4.5 to 8.9) in post-myelodysplastic syndrome AHD-AML, 3.7 months (CI95% 2.6 to 4.7) in post-myeloproliferative neoplasm AHD-AML, and 8.8 months (CI95% 5.1 to12.6) in therapy-related AML (t-AML) (t-AML vs MDS p = 0.78; post MDS vs post MPN p = 0.021, t-AML vs post MPN p = 0.11). C) OS according to ELN risk classification: 9.7 months (CI95% 4.2 to 15.2), 13.3 months (CI95% 8.8 to 17.8), 8.7 months (CI95% 6.9 to 10.5) and 3.7 months (CI95% 2.5 to 4.9), in favourable, intermediate I, intermediate-II and adverse risk ELN, respectively (p = 0.001). D) OS according to the patient's fitness: median survival was was 10.1 (CI95% 8.2 to 12), 4.2 (CI95% 2.8 to 5.7) and 1.8 (CI95% 0.9 to 2.6) months in fit, unfit and frail patients, respectively (p = 0.001 fit vs unfit and p = 0.15 unfit vs frail). E) OS according to the type of treatment received: 9 months (CI95% 6.8 to 11.1) in i-T; 10.2 months (CI95% 8.3 to 12.2) in ni-T and 2.3 months (CI95% 1.5 to 3.0) in BSC (i-T vs niT p = 0.8- ni-T vs BSC or i-T vs BSC p = 0.01). F) OS according to complete remission achievement in 97 patients treated with i-T: 15.7 months (CI95% 3.4 to 27.9) vs 4.9 months (CI95% 3 to 6.7) (p = 0.001) According to ELN-risk, median survival in favorable/intermediate-I/intermediate-II patients was 11.1 vs. 3.7 months in adverse-risk (P ≤ .001) (Figure 1C), without differences among non-adverse risk subgroups. According to ‘fitness criteria', survival was significantly better in fit compared to unfit patients (P ≤ .001) (Figure 1D). According to treatment actually received, survival was similar between i-T and ni-T patients (9 vs. 10.2 months); patients receiving BSC fared significantly worse (median OS: 2.3 months: P ≤ .001) (Figure 1E). Complete remission (CR) achievement with i-T was associated with a median survival of 15.7 months, compared to 4.9 months of non-CR patients (P ≤ .001) (Figure 1F). It was 75%, 56%, 70%, in favorable, intermediate I and II-risk, respectively, compared to 16% in adverse ELN-risk group (P ≤ .001). In adverse ELN-risk patients, median survival was nonsignificantly longer, using ni-T or i-T (8.5 vs. 4.3 months P = .7). Conversely, with i-T, fit elderly patients with non-adverse ELN-risk, representing 15.3% of the entire population, had a 70.7% chance of achieving CR and a 2-year survival probability of 34%. Multivariable analysis confirmed that both ELN-risk, fitness category, and treatment had an independent impact on survival. Being fit, having non-adverse ELN-risk leukemia, and not receiving BSC only, were associated with a better outcome. Two recent studies have underscored the heterogeneity of s-AML and its different impact in younger compared to elderly AML patients.2, 3 Our study focused on elderly patients with s-AML. The frequency of s-AML was 40%, a markedly higher figure than the 18–25% recorded in epidemiological studies. This may be interpreted considering that patient's histories, particularly concerning previous hematological abnormalities, may have been more detailed and follow-up more strict in hematological units than in registry studies. We confirmed the similarity between the characteristics of elderly de novo AML and s-AML. In addition, the availability of molecular data in 66% of patients allowed to classify them also according to the ELN-risk criteria,4 commonly used to guide treatment decisions. Patients with AHD-AML were less frequently at favorable ELN-risk and more frequently at adverse ELN-risk (>50%) than de novo AML. The overall outcome of elderly s-AML does not differ from elderly de novo AML. However, among AHD-AML, patients with previous MPN fared significantly worse than those with previous MDS, confirming data from the Danish population-based study.2 We therefore agree that post-MPN AHD-AML should be considered as a separate entity from post-MDS AHD-AML warranting dedicated biological and clinical studies. Patient's fitness was analyzed according to the criteria of Ferrara et al.5 which consider comorbidities more important than classic geriatric parameters since in acute leukemia the probability of long-term survival mainly derives from the possibility of tolerating intensive antileukemic treatment. The distribution of patients among fitness categories was similar between s-AML or de novo AML, as well as within subgroups of s-AML including t-AML. The treatment intensity actually chosen by clinicians was in line with patient's fitness (P ≤ .001). Intensive chemotherapy was given to 69.1%, 15.4%, and 4.5% of patients classified as fit, unfit or frail, respectively. More importantly, fitness evaluation proved to independently predict the outcome of patients, showing a significantly better survival in fit compared to unfit or frail patients. We therefore confirm, as currently recommended in other hematologic disorders that in addition to age fitness evaluation should be mandatory in elderly AML patients. The type of treatment given was also independently associated with survival. Patients receiving BSC only, fared significantly worse than patients receiving either i-T or ni-T. While there were no differences between these two type of treatment overall, this result should be ascribed to the bad performance of i-T in the large subgroup of AML patients with adverse biological characteristics. Indeed, also the ELN-defined cytogenetic/molecular risk proved to independently impact on disease outcome. CR rates progressively decreased from favorable to intermediate and to adverse risk patients, a subgroup where CR rate with i-T was 16%, even lower than expected. More importantly patients at ELN adverse-risk fared no better with i-T than with ni-T, underscoring that, even among elderly s-AML patients, uniformly considered at dismal prognosis, the biological characteristics of the disease are important and their knowledge is essential for choosing the correct treatment strategy. Our study suggests that i-T should be spared in the large group of elderly patients with adverse biological characteristics, even if they would be considered fit. On the other hand, i-T should not be avoided in fit patients at favorable/intermediate ELN risk, even if elderly and with s-AML, considering the probability of CR achievement (70.7%) and of 2-year survival (34%) recorded in our series. With the limits of its retrospective nature and of the relatively small number of patients, our study confirms the conclusions achieved in studies with larger number of patients, showing the heterogeneity of s-AML, and supports the usefulness of an objective evaluation of every case of s-AML both concerning patient's fitness and the ELN biological risk of leukemia, in order to optimize the management of this difficult but not uniformly fatal disease. None. Additional Supporting Information may be found online in the supporting information tab for this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.