Abstract
INTRODUCTION: Although early clearance of leukemic blasts following induction chemotherapy for acute myeloid leukemia (AML) has been associated with improvement in outcomes (Kern et al. 2003), it remains unclear if a strategy of day 14 marrows with early intervention for residual leukemia (Day14 strategy) is superior to a strategy of no day14 marrows with delayed chemotherapy (noDay14 strategy). To compare these strategies we conducted a single centre retrospective analysis of patients receiving standard ‘3+7‘ induction chemotherapy for AML (APL excluded) treated from 2004-2017. Prior to 2014 all patients were treated with a Day14 strategy, but due to a change in institutional policy all patients thereafter were treated using a noDay14 strategy. Outcomes were assessed using an intention-to-treat approach.
RESULTS: Patient characteristics are as in Table 1. Gender, age, WBC and cytogenetic risk category were similar between the Day14 and noDay14 cohorts, but there were more patients with age >60 and secondary AML in the noDay14 cohort. NPM1 and FLT-3 testing were not routinely available prior to 2008.
Of patients intended to have a day 14 marrow, 229 (91%) underwent a marrow at a median of 14 days (9-22) with others not receiving one due to induction complications (n=16), death (n=4) or other reasons (n=3). Of these, 59 (25.8%) had residual leukemia (i.e. >5% blasts) and 51 received chemotherapy. Response was not evaluated for 2 patients, there were 3 deaths, 19 had persistent disease and 27 had complete remission (CR) or CR with incomplete count recovery (CRi).
An end-of-induction (EOI) marrow (after single induction in the noDay14 cohort and single induction ± intensification in the Day14 cohort) was performed in 331 (91%) patients. Median time to a marrow was longer in the Day14 cohort (p=0.001). At EOI there was no difference within the Day14 and noDay14 cohorts in mortality (8.3 vs. 3.6%, p=0.12), CR/CRi rates (75.4 vs. 83%, p=0.13) or induction failure (14.3 vs. 13.4%, p=0.87). Majority of the patients with induction failure went on to receive reinduction chemotherapy. After all reinductions; mortality and rates of CR/CRi and persistent leukemia were similar between the two cohorts.
There was no difference in the allogeneic stem cell transplantation rates for the Day14 and noDay14 cohorts (39.8 vs. 41.2%, p=0.90). Median follow-up for the entire cohort was 509 days. Amongst non-transplanted patients, relapse rates were similar in the Day14 and noDay14 cohorts (62.1 vs. 51.7%, p=0.2) as was relapse free survival (RFS, 378 vs. 381 days, p=0.47). When censored for transplant patients in the Day14 and noDay14 cohorts had similar rates of relapse (37.4 vs. 30.4%, p=0.26) and RFS (443 vs. 395 days, p=0.45, Fig. 1A). RFS was also not different for the two cohorts amongst patients aged>60 (p=0.90), aged <60 (p=0.40) or favourable (p=0.17), intermediate (p=0.69) or unfavourable risk karyotype (p=0.87).
The 5 year overall survival (OS) of the entire cohort was 43% and median OS was 856 days with no difference in the Day14 and noDay14 cohorts (758 days vs. not reached, p=0.11, Fig. 1B). There was no difference in the OS amongst the two cohorts when stratified by the diagnostic karyotype (favorable, p=0.24, intermediate, p=0.34 and unfavorable, p=0.50). For patients aged >60, OS was similar in the Day14 and noDay14 cohorts (413 vs. 569 days, p=0.47) but amongst patients aged <60 there was a trend toward better OS with treatment under a noDay14 strategy (median not reached vs. 1215 days, p=0.055). In subgroup analysis, patients treated under the Day14 strategy having residual leukemia at Day14 had worse OS relative to those without leukemia (328 vs. 1507 days, p<0.001).
To minimize the impact of changes in care occurring over the duration of the study we evaluated patients treated from 2010 - 2017 during which supportive care and anti-fungal prophylaxis was similar. Overall results were similar to when the entire cohort was considered; however, patients treated using a Day14 strategy had a significantly higher mortality than those treated using a noDay14 strategy at EOI (11.1 vs. 3.6%, p=0.047).
CONCLUSIONS: Although patients with residual leukemia at day 14 have worse OS, our data suggest that there is no advantage to performing routine day 14 marrows supplemented by early intensification treatment. Additionally, this approach may be associated with a higher early mortality and, amongst patients aged<60 years old, with worse OS.
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No relevant conflicts of interest to declare.