Acute myeloid leukemia after age 70 years: A retrospective comparison of survival following treatment with intensive versus <scp>HMA</scp> ± venetoclax chemotherapy
Authors: Kebede H. Begna, Naseema Gangat, Aref Al‐Kali, Mark R. Litzow, William J. Hogan, Mrinal M. Patnaik, Animesh Pardanani, C. Christopher Hook, Alexandra P. Wolanskyj, Michelle A. Elliott, Curtis A. Hanson, Rhett P. Ketterling, Ayalew Tefferi
Journal: American Journal of Hematology (2021)

Population-based studies indicate a median age of over 65 years for newly diagnosed adult patients with acute myeloid leukemia (AML).1 The particular scenario is of utmost practical importance considering that such patients, especially those above age 70 years (i.e., "older old" as opposed to "younger old" patients between ages 60–70 years),1 are typically not offered allogeneic hematopoietic stem cell transplantation (AHSCT), thus compromising their chance for long-term survival. Instead, an increasing number of oncologists are currently preferring to use low-intensity chemotherapy (e.g., hypomethylating agents ± venetoclax) in older old patients with AML, with the intent to prolong short-term survival while at the same time avoid treatment-related morbidity from intensive induction chemotherapy.2-4 However, while any form of treatment might be better than supportive care in prolonging survival in such patients, the possibility of additional survival benefit from intensive chemotherapy cannot be excluded and should not be ignored.5 The current study seeks to provide additional information in this regard, based on retrospective analysis of data from 360 newly diagnosed AML patients above age 70 years, seen at our institution between January, 2004 and December, 2017. In addition, we included survival data from a more recent group of 28 newly-diagnosed AML patients above age 70 years (seen between April, 2018 and December, 2019) treated upfront with HMA + venetoclax. Our specific objectives included treatment-annotated survival analysis and determination of prognostic factors. The current study was approved by the Mayo Clinic institutional review board and included AML patients above age 70 years, who were recruited from institutional databases of cytogenetically annotated patients with World Health Organization classification system-compliant diagnosis of AML, excluding acute promyelocytic leukemia.6 The diagnosis of AML was further subcategorized into primary, secondary (i.e., with antecedent history of a chronic myeloid neoplasm) and therapy-related. In all instances, bone marrow examination and cytogenetic studies were performed or reviewed at the Mayo Clinic. Cytogenetic risk stratification into favorable, intermediate and adverse groups was based on the 2017 European LeukemiaNet (ELN) recommendations.6 Commonly available molecular information included FLT3-ITD, NPM1 and CEBPA mutational status, in a subset of patients. Follow up information was updated as of November 2020. Type of therapy included induction (or intensive) chemotherapy (often "7 + 3" or equivalent), less intensive chemotherapy often including HMA, and supportive care alone ± hydroxyurea. Information with regard to marrow recovery was collected to evaluate complete remission (CR) or CR with incomplete count recovery (CRi).6 Statistical analysis considered clinical and laboratory variables at the time of diagnosis and as necessary at the time of follow up or remission. Categorical variables were compared using chi-square statistics. Overall survival was calculated from date of diagnosis to death regardless of cause, and patients who were alive were censored at last follow-up. Survival curves were prepared using Kaplan-Meier method and compared using log-rank test. Multivariable Cox-regression analyses were used to identify independent risk factors. The JMP Pro 13.0.0 software (SAS Institute, Cary, NC, USA) was used for all calculations. The core group of study patients was comprised of 360 consecutive cases seen between 2004 and 2017 (i.e., before the introduction of venetoclax into our clinical practice); median age at diagnosis was 76 years (range 71–94; males 69%). The AML subtype was primary in 171 (48%) patients, therapy-related in 37 (10%) and secondary in 152 (42%); the latter included post-myelodysplastic syndromes (MDS) in 110 (31%) patients, post-myeloproliferative neoplasm (MPN) in 27 (8%) and post-MDS/MPN in 15 (4%). Cytogenetic information was available in all 360 study patients and included adverse (135 patients; 38%), intermediate (220 patients; 61%) and favorable (five patients; 1.4%) risk categories. FLT3-ITD/NPM1 mutation information was available in 113 patients and included FLT3-ITD-/NPM1- in 77 (68%) patients, FLT3-ITD-/NPM1+ in 20 (18%), FLT3-ITD+/NPM1- in nine (8%) and FLT3-ITD+/NPM1+ in seven (6%). Mostly single CEBPA mutations were seen in eight (13%) of 64 patients tested. Table S1 outlines these clinical characteristics of the study patients above age 70 years ("older old" group; n = 360); compared to their younger counterparts recruited from the same institutional database, including patients age <60 years ("younger group"; n = 404) and those ages 60–70 years ("younger old" group; n = 359). Older patients in both the >70 and 60–70 age categories were more likely to be males and present with secondary or therapy-related AML (p < .01; Table S1); similarly, favorable karyotype was almost exclusively seen in patients below age 60 years (p < .01). Whereas, the distribution of adverse and intermediate-risk karyotype as well as that of FLT3-ITD/NPM1 mutation profiles were similar among all three age groups (p = NS; Table S1). The core study population of 360 patients was followed to death (n = 341; 95%) or a minimum of 3 years for living patients (n = 19; 6%). During this period, 147 (40.8%) patients were managed with supportive care ± hydroxyurea therapy as needed, whereas the remaining patients received some form of chemotherapy including intensive chemotherapy including "7cytarabine+3anthracycline" or equivalent (n = 109; 30.3%), or less intensive chemotherapy including HMA ± other drugs not including venetoclax (n = 96; 26.7%) and other miscellaneous agents of variable intensity (n = 8; 2.2%). Among 107 patients receiving intensive chemotherapy and were evaluable for response, 66 (62%) achieved either CR (32%) or CRi (30%); the corresponding documented CR + CRi, CR and CRi rates in the HMA-based therapy group were 32%, 22% and 10%. Median durations of CR/CRi were 23/20 months in the intensive and 22/14 months in the less intensive chemotherapy groups. Consolidation chemotherapy was variable and not consistently employed and included AHSCT in only three (<1%) patients. Overall median survival was 6.3 months (1-year, 3-year and 5-year survival rates were 33%, 12% and 7%, respectively) (Figure 1(A)). Multivariable analysis of pre-treatment variables identified adverse karyotype (p < .001), increasing age (p < .001), decreased platelet count (p = .005), increased leukocyte count (p = .006), increased peripheral blood blast % (p = .008) and secondary/therapy-related vs primary AML (p = .02) as independent risk factors for overall survival; NPM1/FLT3ITD mutation profile was borderline significant (0.07) but the number of informative cases was too low (n = 113) to be conclusive. The aforementioned variables, with the exception of the AML subtype, retained their significance when the type of treatment was introduced into the multivariate model, which identified treatment type (HR 3.0 for intensive vs. supportive care; 1.6 for intensive vs HMA-based; 1.8 for HMA-based vs supportive care) and karyotype (HR 2.0 for adverse vs. intermediate) as the two most prominent risk factors; Figure 1(B), (C) depict survival data stratified by karyotype or treatment received, respectively. Figure 1(D) depicts survival of patients receiving either intensive chemotherapy or HMA-based chemotherapy not including venetoclax, stratified by karyotype. For this particular analysis, we excluded patients with favorable karyotype because of their small sample size (n = 5) as well as the 147 patients treated with supportive care. Taken together, these figures confirm that any form of therapy was better than supportive care in prolonging short-term survival (i.e., median survival and 1-year survival). But, intensive chemotherapy might be necessary to secure longer-term survival (i.e., 3-year survival), especially in patients with intermediate risk karyotype, as illustrated in Figure 1(D). Furthermore, in patients treated with intensive chemotherapy, survival in patients achieving CR (median 23 months; 1-year survival 70%; 3-year survival 39%) was similar to those with CRi (median 25 months; 1-year survival 67%; 3-year survival 32%) and both produced significantly longer survival compared to patients not achieving CR or CRi. The same was true for patients receiving HMA-based therapy not including venetoclax. Finally, in order to determine if the above-stated observations were significantly altered by the addition of venetoclax to HMA, we included, in our survival analysis, 28 AML patients above age 70 years (median age 75 years; range 71–92) who were more recently diagnosed (between April 2018 and December 2019) and were treated upfront with HMA + venetoclax; the latter group of patients displayed survival data that were similar to their counterparts treated with HMA-based therapy that did not include venetoclax but inferior to those receiving intensive chemotherapy (Figure 2). However, more patients in the HMA + venetoclax group carried unfavorable karyotype (72%), compared to patients treated with either intensive chemotherapy (35%) or HMA without venetoclax (22%; p < .001), thus making the comparison less valid. The value of the current study is limited by its retrospective nature, which did not allow accounting for differences in performance score and high risk mutations between the different treatment groups. Nevertheless, our observations suggest that intensive chemotherapy, as opposed to HMA-based therapy, might be necessary to secure long-term survival in patients above age 70 years and with intermediate-risk karyotype, whereas its additional benefit in patients with unfavorable karyotype was not apparent. Therefore, until additional information from prospective controlled studies that are stratified for cytogenetic risk groups becomes available, it is reasonable to consider intensive chemotherapy for fit AML patients over age 70 years and with favorable or intermediate risk karyotype. Whereas, HMA-based combinations with venetoclax or other mutation-targeted agents are reasonable alternatives for those with unfavorable karyotype.2, 7 Whether or not combining venetoclax or other mutation targeting agents with intensive chemotherapy extends additional value remains to be determined. Theauthors declare no conflict of interest. None. Table S1. Clinical and laboratory characteristics of 360 consecutive patients with acute myeloid leukemia (AML) and age >70 years; the table also includes the corresponding findings in younger age groups recruited from the same database and seen during the same time period. 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.