The need for re-induction based on D14-residual acute myeloid leukemia in patients achieving complete remission predicts higher relapse rate and inferior post-remission survival

Abstract Background: The primary goal of induction therapy in acute myeloid leukemia (AML) is to induce complete remission with (CR) or without (CRi) hematologic recovery. In order to accomplish this, re-induction might be necessary based on D14-residual AML. The current study examines the impact of re-induction on relapse, transplant-censored survival, and post-transplant survival in a consecutive series of AML patients who have achieved CR/CRi following intensive chemotherapy. The study also examined the impact of variations in consolidation chemotherapy including the use of anthracycline-based chemotherapy (AC) in the first consolidation cycle and the use of high (HiDAC) vs. intermediate (IDAC) dose cytarabine. Methods: The current study was conducted under IRB-approved minimum risk protocols that allowed retrospective collection and analysis of patient data. Formal criteria were used for AML diagnosis, genetic risk stratification, and adjudication of response (Blood 2022;140:1345). Patients who received less intensive induction regimens or failed to achieve CR/CRi were excluded. Relapse-free (RFS) and overall survival (OS) analysis was calculated from the date of documented CR/CRi. Patients who underwent allogeneic stem cell transplant (ASCT) were censored at the time of transplant. Conventional statistical methods were utilized (JMP Pro 17.1.0, SAS Institute, Cary, NC, USA). Results: A total of 279 AML patients diagnosed between 2004 and 2020 were included: median age 58 years, males 60%, de novo 75%, post-chronic myeloid neoplasm (post-CMN) 16%, and therapy-related 9%. Induction regimens included idarubicin (Ida) + cytarabine (Cyt) in 183 (66%) patients, daunorubicin (Da) 60 mg/m² + Cyt in 76 (27%), and Da 90 mg/m2 + Cyt in 19 (7%). Re-induction was utilized to achieve CR/CRi in 72 (27%) at a median of 18 days from start of first induction regimen. The indication for re-induction was based on residual bone marrow blast (median 30%; range 4-90) on day14 (N=53) or day 21-28 (N=15), persistent extramedullary disease (N=2) or the presence of circulating blast (N=2). At a median transplant censored follow-up of 26 months (mos), 93 (33%) deaths, 117 (42%) relapses, and 134 (48%) ASCTs were documented; ASCTs were performed in CR1 (50%) or CR2 (50%). Median RFS was 18 mos, with respective 1-, 2-, 3- year RFS of 63%, 42% and 35%. In multivariable analysis (MVA), age ≥65 years (HR 1.5, p=0.04), European LeukemiaNet (ELN) adverse karyotype (vs. intermediate HR 1.7, p=0.02; vs. favorable HR 2.8, p<0.01), and the need for re-induction to achieve CR/CRi (HR 1.7, p=0.01) were independently predictive of relapse. RFS was not impacted by NPM1 mutation ( HR 0.5, p=0.09) or FLT3-ITD (HR 1.3, p=0.3). The median OS was 80 mos, with 5-year OS of 53%. In MVA, age ≥65 years (HR 2, p=0.01), ELN adverse karyotype (vs. intermediate HR 3.3, p<0.01; vs. favorable HR 4.7, p<0.01), FLT3-ITD (HR 1.9, p=0.04), and the need for re-induction (HR 1.9, p=0.03) independently predicted inferior OS. RFS was similar among patients who received AC (N=84; Idarubicin 9 mg/m2 or Da 60 mg/m2 days 1 to 2/3 + 100 mg/m2 Cyt days 1 to 5/7; median 18 mos) as their first consolidation cycle vs. those who received HiDAC (N=99; 3 g/m2 q12 hours on days 1,3 and 5; median 16 mos) or IDAC (N=58; IDAC; 1-2 g/m2 q12 hours on days 1, 3 and 5; median 24 mos; p=0.9); the corresponding median OS were 125, 85, and 40 mos (p=0.4). In patients aged ≥65 years, but not younger patients, both RFS (p<0.01; median 23 (N=36) vs. 8 (N=24) mos) and OS (median 40 vs. 12 mos, p<0.01) were significantly longer with IDAC vs. AC as their first consolidation cycle. In the AC consolidation cohort, patients who received 2-3 additional HiDAC/IDAC cycles displayed longer OS (p<0.01) and RFS (p=0.047), compared to those who received less. In both the HiDAC and IDAC cohorts, RFS and OS were not significantly different between those who received 3-4 versus 1-2 consolidation cycles. The need for re-induction did not affect post-transplant survival (p=0.5), which was superior in patients receiving Ida + Cyt induction (vs. Da 60mg/m2 + Cyt, HR 0.6, p=0.04) and in those transplanted in CR1 (HR 0.5, p<0.01). Conclusions: The current study signals the need for re-induction to achieve CR1 as a negative predictor of outcome in AML patients achieving CR/CRi following intensive induction chemotherapy. The particular information is potentially actionable in terms of the choice of consolidation strategy.