Outcome of Elderly Patients after Failure to Hypomethylating Agents Given As Frontline Therapy for Acute Myeloid Leukemia (AML): Single Institution Experience
Authors: Nanah Rama , McCullough Kristen B. , Hogan William J , Begna Kebede H. , Gangat Naseema , Patnaik Mrinal M , Elliott Michelle Ann , Litzow Mark , Al-Kali Aref 
Published: October 2019

Abstract
Background: AML outcome in elderly patients unfit for intensive chemotherapy continues to be challenging. Hypomethylating agents (HMA) can be effective in these patients but responses are short-lived (Fenaux et al, JCO 2009; Dombret et al Blood 2015). Even though HMAs achieve superior response rates to supportive care alone, complete remissions (CR) are rarely achieved and often quickly lost when they occur. The majority of patients will either have stable disease or progress through therapy. We hereby describe the outcome of these patients at our institution after they fail HMAs.
Methods: A total of 56 AML patients' data from Feb 2007 to June 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our institution. Patients were considered for our study if they received HMA as frontline therapy for their AML. Patients who received HMAs after induction chemotherapy failure or for their MDS were excluded. Response was identified based on IWG AML criteria (Cheson et al, JCO 2003). Prognostic factors were analyzed by univariate and multivariate analyses. Survival estimates were calculated using Kaplan-Meier curves and univariate and multivariate analyses was based on log-rank testing using JMP software version 10.
Results:
i) Characteristics at Diagnosis: We identified 56 AML patients treated with HMA as frontline therapy with median age of 76 years (range, 59-91), 68% of which were males. Cases were classified as AML with myelodysplasia related changes in 25%, and therapy related myeloid neoplasm in 2%, and not otherwise specific in 73%. Out of 56 cases, 23% were secondary to MDS, 2% ET (Essential Thrombocytopenia), 5% PV (Polycythemia Vera), 5% MF (Myelofibrosis), 4% from CMML (Chronic Myelomonocytic Leukemia); while 61% were de novo AML. Per cytogenetics data, 2% were considered favorable risk, 62% intermediate, and 36% poor (34% had complex karyotype).
ii) Clinical outcome to Frontline HMA: Out of 56 patients, 15(27%) patients received azacitidine (AZA) and 41 (73%) received decitabine (DAC) with a median number of cycles of 4 (range 1-62). Median number of cycles was higher for AZA vs DAC (8 vs 4, p =0.3). CR was found in 10 (18%), CR with incomplete count recovery in 3 (5%), partial remission (PR) in 3 (5%) patients, with overall response of 28% and median response duration of 10 months (range, 1-78 months). Thirteen (81%) out of 16 responders relapsed. Therefore, only 53 patients were included in primary or secondary failure analysis.
iii) Clinical outcome to Frontline HMA failure: Out of 53 patients, 12 (23%) received subsequent treatments. Out of the 12 patients, 3 (25%) received another HMA (switch), 2 (17%) subcutaneous low dose cytarabine, 4 (33%) intensive chemotherapy, while 3 (25%) received either therapy on a clinical trial or targeted therapy. None of the 12 patients who got first salvage therapy achieved remission. Five out of the 12 patients received second salvage therapy, 2 (40%) of which achieved CR. Only one patient had third salvage therapy and did not respond. No patient was able to proceed to allogenic hematopoietic cell transplantation. Median overall survival (mOS) for this group was 2 months. Median OS for patients who received subsequent salvage therapies was better than those who did not receive any subsequent therapy after failing HMA (9.5 vs 2 months, p = 0.0009).
Conclusions: Elderly patients diagnosed with AML who are unfit for intensive chemotherapy have a poor prognosis. HMA can get some patients into remission but most patients will ultimately fail. Outcome for patients who have primary or secondary (relapse) failure is very poor with a median OS of 2 months. Switch of HMA did not result in any response. Response to salvage therapy continues to be low but offering salvage therapies seem to improve OS. Our study provides historical data for future novel therapies, which are sorely needed for these patients.
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Disclosures
Al-Kali: Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.