Improved outcomes of octogenarians and nonagenarians with acute myeloid leukemia in the era of novel therapies
Authors: Mark Y. Jeng, Ritika Dutta, Irena T. Tan, Tian Y. Zhang, Gabriel N. Mannis
Journal: American Journal of Hematology (2020)

To the Editor: Acute myeloid leukemia (AML) is primarily a disease of the elderly, with the peak age-specific incidence rate occurring in individuals ≥80 years old.1 Because octogenarians and nonagenarians typically have more co-morbidities and higher rates of treatment-related morbidity/mortality, they are generally not considered candidates for intensive chemotherapy (ICT). As a result, elderly AML patients historically had few treatment options and poor survival. In a recent, large-scale observational study of octogenarians with AML diagnosed between 2003 and 2014 (n = 12 099), Bhatt et al reported that the majority of patients did not receive any form of chemotherapy, and had a one-month mortality of 41% and median overall survival (OS) of 1.5 months.2 However, with the recent approvals of several novel, targeted therapies that are better-tolerated and more effective, this paradigm is beginning to shift.3 For elderly patients deemed ineligible for standard ICT, monotherapy with hypomethylating agents (HMAs) such as azacitidine became the standard-of-care.4 Seeking to improve upon this regimen, numerous trials were initiated to test HMAs in combination with various novel agents. In particular, the addition of the potent B-cell lymphoma 2 (BCL2) inhibitor, venetoclax, demonstrated significant activity in the frontline treatment of patients deemed unfit for ICT.5 Concurrent advances in the molecular profiling of AML led to the development of targeted agents such as ivosidenib, the mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, and gilteritinib, the FMS-like tyrosine kinase 3 (FLT3) inhibitor.3 Despite these encouraging results, few studies to date have explored the effects of these novel therapies on outcomes of octogenarians and nonagenarians with AML. Here, we present single-institution, retrospective treatment patterns and survival outcomes for AML patients ≥80 years of age at the time of diagnosis, seen at Stanford between 2016 and 2020. This research used data provided by STARR, “STAnford medicine Research data Repository,” a clinical data warehouse containing live electronic medical record data from Stanford Health Care. The IRB approval was granted through STARR, which is operated by the Stanford Medicine Research IT team and funded by Stanford School of Medicine Research Office. Kaplan-Meier curves and survival analyses with log-ranked (Mantel-Cox) tests were performed using GraphPad Prism version 8.4.2. Patient/AML characteristics (n = 41) are presented in Table S1. The median age at AML diagnosis was 82 (range 80-99), with 9.8% of the cohort ≥90 years old. Patients received either best supportive care (BSC, 22.0%), HMA monotherapy (HMA mono, 19.5%), or novel therapies (58.5%), which includes venetoclax (n = 20), pevonedistat (n = 1), magrolimab (n = 1), ivosidenib (n = 1), or gilteritinib (n = 1), either as single-agents or in combination with an HMA; no patients received ICT. While the Eastern Cooperative Oncology Group (ECOG) score for the BSC group (median score = 2) was greater than either treatment group (median score = 1), the Charlson Comorbidity Index (CCI) was equivalent between all groups (median CCI = 1). The proportion of de novo (46.3%) vs secondary (46.3%) AML was similar, with most diagnoses classified as poor-risk (70.7%) per the 2017 ELN risk stratification. At the final analysis (cutoff date: 15 April 2020), 14 patients remained alive (34.1%), with a median OS of 336 days and a 30-day mortality rate of 14.6% for the entire cohort; individual survival plots are depicted in Figure 1A. Patients who received any treatment had a significant survival advantage relative to patients who received BSC (P < .001), with a longer median OS (441 vs 26 days) (Figure 1B). The OS analysis comparing either treatment subgroup individually to BSC also demonstrated a significant advantage in favor of treatment (HMA mono vs BSC, P = .013; novel therapies vs BSC, P < .001), with lower 30-day mortality rates (BSC = 55.6%; HMA mono = 0%; novel therapies = 4.2%) and longer median OS (BSC = 26 days; HMA mono = 261.5 days; novel therapies = 441 days) (Figure 1C). With further treatment subgroup analysis, the greatest median OS was observed in the other novel therapies group (626.5 days), which is comprised of patients receiving pevonedistat+HMA, magrolimab+HMA, ivosidenib, or gilteritinib (Figure 1D). For patients where a response was assessed (n = 20), the overall CR/CRi rate was 57.1%, with a greater CR/CRi and decreased time-to-response observed in the novel therapies group (CR/CRi = 62.5%; median time = 61 days) vs the HMA mono group (CR/CRi = 40.0%; median time = 143 days). Notably, for any patient receiving leukemia-directed therapy, univariate analysis showed no survival difference based on ECOG (score 0-1 vs 2+, P = .454), CCI (score 0-1 vs 2+, P = .172), or AML risk category (favorable-intermediate vs poor, P = .561). Prior studies of octogenarians and nonagenarians with AML have demonstrated very poor outcomes, with an estimated OS of ∼10% at 1-year.1, 2 In our study, while the patients receiving BSC had a median OS (26 days) similar to prior reports, the estimated OS at 1-year overall for the entire cohort was 3-fold higher (30%), likely due to the greater proportion (78%) of our patients receiving some form of leukemia-directed therapy.1, 2 A total of nine patients in our study were alive 1 year following their AML diagnosis, all of whom received leukemia-directed therapy. In summary, the management of octogenarians and nonagenarians with AML is particularly challenging due to the biology of their disease and their inability to tolerate ICT. Despite the historically very poor survival outcomes for elderly patients with AML, recent trials of lower-intensity AML therapies have expanded their treatment options.1-3 Here, we demonstrate that leukemia-directed therapies are associated with a significant survival advantage for AML patients ≥80 years old when compared to those who receive BSC only. We find that while HMA monotherapy is well tolerated and increases OS, the addition of novel, targeted therapies might potentially extend OS even further. While we cannot rule out the impact that treatment-selection bias has on survival outcomes in this retrospective study, our findings are supported by recent positive topline results announced from the phase three trial of azacitidine monotherapy vs azacitidine with venetoclax in newly diagnosed AML patients unfit for ICT.6 Collectively, these findings suggest that octogenarians and nonagenarians with newly diagnosed AML should increasingly be considered for AML-directed therapies, including those available through clinical trials. Larger, prospective studies that include not only survival, but also quality-of-life outcomes, will be essential to better guide the choice of AML therapy in this age group. The authors gratefully acknowledge all of the patients who contributed material and clinical information to this study. The authors declare no competing financial interests. Mark Y. Jeng, Ritika Dutta, and Irena T. Tan extracted and compiled patient data; Mark Y. Jeng conducted statistical analysis and wrote the manuscript; Tian Y. Zhang contributed to study design and patient care; Gabriel N. Mannis initiated and designed the study; and all authors contributed to the analysis of the data and review of the final manuscript. Supplementary Table S1 Patient demographics and AML characteristics. 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.