The Choice of Induction Regimen Affects Post Remission Survival of Acute Myelogenous Leukemia (AML) Patients with Intermediate or Poor Risk Disease
Authors: Solh Melhem , Solomon Scott R , Morris Lawrence E , Holland H. Kent , Zhang Xu , Bashey Asad 
Published: October 2019

Abstract
The fludarabine, high dose cytarabine and G_CSF with or without idarubicin combination regimen, referred to as FLAG+/-Ida, is commonly used as a salvage regimen for relapsed/refractory AML but its use as initial induction therapy has been more limited. The MRC trial 15 compared 2 induction courses of FLAG-Ida regimen to 3+7 (anthracycline plus cytarabine) regimens with etoposide (ADE) and found a higher relapse free survival among patients receiving FLAG-Ida. The findings of the MRC AML 15 trial are not widely applied in the United States as many experts use one course of induction followed by consolidation if patients achieve remission. The impact of choice of induction regimen on post remission survival in non-favorable risk AML patients remains unclear. To address this question, we assessed outcomes of 306 consecutive AML patients between aged 18 to75 years, with non-favorable NCCN risk who were received initial treatment at our center between January of 2009 and July of 2017 with either 3+7 (n=88) or FLAG+/-Ida (n=218). Our center's algorithm is to offer allogeneic HSCT as a consolidative therapy to all AML patients with non-favorable risk in CR1 who are considered transplant candidates. Patient characteristics were as follows: Median age 58(19, 75), male 55%, FLT-3 ITD positive 12%, NCCN risk ( intermediate 49%, poor 51%) and normal cytogenetics 45%. Baseline characteristics were similar between the two treatment groups with FLAG+/-Ida being younger at time of diagnosis (59 vs 66 years, P<0.001). A total of 240 (78%) patients achieved CR 1 after 3+7 (n=67, 76%) or FLAG+/-Ida (n=167, 79%) with no difference in the rate of achieving remission between the two groups. Patients in the FLAG-Ida group were more likely to achieve remission after one course of induction (74% vs 62%, p<0.001) and had a faster time to get into CR (30 days vs 37.5, p<0.001) compared to 3+7. CR was achieved in 84% and 73% of patients with intermediate and poor NCCN risk disease respectively. HSCT was performed in 172 patients accounting for 72% of the 240 patients who achieved CR post induction without any significant difference in transplant rates between FLAG+/-Ida and 3+7. The time from diagnosis to transplant was significantly shorter among CR patients after FLAG+/-Ida compared to 3+7 (FLAG+/- Ida 115 days vs 144 days for 3+7, p<0.001). After a median follow up of 41 months for patients achieving CR, the 3 year post remission OS and DFS was significantly better for patients receiving FLAG-Ida at 54% and 49% compared to 39% and 32% for patients receiving 3+7 respectively( P= 0.01 for both endpoints). In multivariate analysis, we analyzed factors associated with OS and DFS since achieving CR1 including age at CR1 (≤49, 50-64, ≥65), gender, race, NCCN risk, induction regimen, number of cycles to CR1, HSCT (yes, no) and year of CR1. HSCT was modelled as a time dependent covariate. A forward stepwise algorithm was implemented and variables were selected if p value was less than 0.05. Factors associated with r post remission survival included age at CR1 (≤49 vs50-64, HR 0.59, p=.02; ≤49 vs ≥65 HR 0.46, p=0.001), NCCN risk (intermediate vs poor HR 0.54, p<0.001), induction regimen (FlAG+/-Ida vs 3+7 HR 0.62, p=0.01) and receiving HSCT (yes vs no HR 0.68, p=0.02). Factors affecting DFS from time of CR also included age, NCCN risk, induction regimen (FlAG+/-Ida vs 3+7 HR 0.68, p=0.028) and receiving HSCT. This single center analysis shows that among patients with non-favorable risk AML, achieving CR after FLAG+/-Ida has better post remission survival than 3+7. This may be partially explained by the faster time to achieve CR and faster time to HSCT in the FLAG+/- Ida group.

Disclosures
Solh: Amgen: Speakers Bureau; Celgene: Speakers Bureau; ADC Therapeutics: Research Funding.