Elderly patients &gt; 65 years of age with acute myeloid leukemia and normal karyotype benefit from intensive therapeutic programs
Authors: Massimo Bernardi, Matteo Carrabba, Carlo Messina, Raffaella Milani, Elisa Sala, Francesca Pavesi, Bernhard Gentner, Jacopo Peccatori, Andrea Assanelli, Sarah Marktel, Consuelo Corti, Alessandra Forcina, Luca Vago, Fabio Ciceri
Journal: American Journal of Hematology (2016)

To the Editor: The outcome of elderly patients (pts) with acute myeloid leukemia (AML) is unsatisfactory. Median overall survival (OS) of pts older than 65 after intensive treatments is about 6 months and 5-year overall survival is 5–25% 1, 2. Cytogenetics is the most important factor affecting the prognosis of younger pts who receive an intensive treatment. The majority of AML pts presents intermediate-risk (INT) cytogenetics, including normal karyotype (NK) AML which represents about 50% of total cases. Most common molecular abnormalities, NPM1 or CEBPA mutations and/or internal tandem duplication of FLT3, affect the prognosis in younger pts 3. For clinical practice, the European LeukemiaNet (ELN) proposed a four group standardized genetic prognostic system correlating cytogenetic and molecular data with clinical data, with the INT categories representing 49% of cases of the older pts population 3. As information about the prognostic impact of genetic abnormalities is limited in older pts the decision to treat them with intensive programs according to their genetic risk is still controversial, in particular for cases with INT characteristics. We retrospectively analyzed data from 77 elderly pts treated at the San Raffaele Institute, fulfilling the following inclusion criteria: age > 65 years, new diagnosis of AML, consecutively considered "fit" for aggressive treatment according to local criteria, receiving at least one cycle of induction chemotherapy between October 2001 and August 2015. General criteria for elegibility were PS (ECOG) ≤ 2, renal and hepatic parameters < 2 ULN, left ventricular ejection fraction ≥ 50%, absence of uncontrolled infections and concomitant malignancies. Response evaluations were defined according to the IWG revised recommendations 4. We compared the outcome of pts according to the cytogenetic and ELN genetic risk-groups. Categorical data were compared using the Fisher's exact test, survival was estimated using the Kaplan–Meier method, the log-rank test was used to compare the survival distributions of different groups of pts. Cytogenetic analysis was evaluable in 68 pts (88%), according to the revised MRC classification 5. ELN genetic classification could be defined in 46 cases (60%) (Table 1). Outcome analysis: 44 pts with NK AML were compared to pts with INT karyotype (other than NK), adverse (ADV), and not evaluable (NE) cytogenetics, analyzed together (no-NK, 31 pts), the 2 only pts with FAV cytogenetics were excluded from this analysis; 24 ELN FAV + INT I cases were compared to 22 INT II + ADV ones. Complete remission (CR) after induction: 70% (54 pts) overall, NK 82% (36 pts) and no-NK 58% (18 pts) (P = 0.036), FAV + INT I 87% (21 pts) and INT II + ADV 54% (12 pts) (P = 0.021). Fifty-five pts received post-remission treatments, 54 pts with high-dose cytarabine (HDARAC, ≥ 8 g/sqm total dose) with or without subsequent autologous (AUTO) or allogeneic (ALLO) transplantation (SCT). Pts alive at last follow-up: overall 22/77 (29%) 19 in CR, NK 16/44 (36%) 13 in CR, no-NK 5/31 (16%) 4 in CR (P = 0.07), FAV + INT I 13/24 (54%) 12 in CR, INT II + ADV 4/22 (18%) all in CR (P = 0.015). Median OS from diagnosis for all 77 pts was 437 days (12–4,621), for NK and no-NK pts was 675 (20–4351) and 298 (12–1,585) days, respectively, projected 5 years OS was 40% and 27%, respectively (P = 0.0019) (Fig. 1A). The difference remained significative also excluding from the analysis the 8 pts with ADV cytogenetics (P = 0.0044). Median and estimated 5-year OS were still significatively better for NK than for no-NK AML pts excluding from the analysis cases with FAV (P = 0.0040) or FAV and ADV (P = 0.0084) molecular abnormalities. Median disease free survival (DFS) for NK and no-NK pts was 519 and 311 days, respectively (P = ns). Median OS from diagnosis for FAV + INT I and INT II + ADV pts was 614 (42–4,638) and 313 (12–1453) days and projected 5 years OS was 48% and 0%, respectively (P = 0.035) (Fig. 1B). Median DFS for FAV + INT I and INT II + ADV pts was 293 and 379 days, respectively (P = ns). A: Overall survival from diagnosis of 44 NK-AML pts and 31 no NK-AML pts, median OS for NK-AML was 675 days, no NK-AML 298 days, P = 0.0019. B: Overall survival from diagnosis of 24 FAV/INT I pts and 22 INT II/ADV pts, according to ELN genetic risk classification, median OS for FAV/INT I was 614 days, INT II/ADV 313 days, P = 0.035. A major challenge for clinicians is identification of elderly pts who would likely benefit from intensive treatments. Our retrospective analysis was aimed in particular to evaluate the outcomes of cases with INT genetic characteristics. Initial selection of our pts was based according to simple clinical and functional evaluations. Pts considered "fit" and with ADV risk cytogenetics were not excluded from intensive treatment programs. Of note, the relatively low frequency of ADV cytogenetics in the study population may reflect an impact of genetic characteristics on the fitness at diagnosis. Our analysis evidenced a better response to induction and better OS for pts with NK AML, either compared to other cytogenetic-risk groups or when evaluated within the ELN classification. In fact, 92% of lower-risk ELN cases (22/24 FAV + INT I) were NK AML, while only 25% (11/44) of NK AML cases had documented concomitant FAV molecular abnormalities. Data derived from the HOVON43 study investigating the value of high-dose daunorubicin in pts above 60 years showed a probability of 5-year OS < 20% in patients with NK AML 6. We documented a 40% long-term survival for NK pts with a significative advantage compared to pts with other INT cytogenetics abnormalities. DFS was not statistically different. The significative better CR rate obtained in NK pts could explain their OS advantage. In fact, in the entire population, median OS of pts who obtained the CR and who did not was 892 and 157 days, respectively (P < 0.0001). Further comparison of outcomes according to different post-remission approaches was not feasible due to the small numbers of pts who received an ALLO or AUTO SCT in the different groups. In conclusion, our observations suggest that the absence of cytogenetic abnormalities per se could define in the elderly a AML subtype with favorable prognosis after intensive treatments, behaving differently from other AML cases with INT genetic characteristics. The concomitant presence of favorable molecular abnormalities can further improve the outcome. As the CR rate in our NK AML pts was very high we think that further intensification of induction CHT should not be pursued, whereas strategies to prevent the high incidence of disease relapse, including new targeted agents, should be explored. Massimo Bernardi,* Matteo Carrabba,1 Carlo Messina,1 Raffaella Milani, Elisa Sala, Francesca Pavesi, Bernhard Gentner, Jacopo Peccatori, Andrea Assanelli, Sarah Marktel, Consuelo Corti, Alessandra Forcina, Luca Vago, Fabio Ciceri 1Haematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy; 2 University Vita-Salute, Milan 20132, Italy