Older Patients with Acute Myeloid Leukemia (AML) in First Relapse: Impact of Genetics and of Salvage Therapy. A Study of the Acute Leukemia French Association (ALFA)
Authors: Sarkozy Clémentine , Gardin Claude , Gachard Nathalie , Merabet Fatiha , Turlure Pascal , Malfuson Jean-Valère , Pautas Cécile , Micol Jean-Baptiste , Thomas Xavier , Quesnel Bruno , Celli-Lebras Karine , Preudhomme Claude , Terré Christine , Chevret Sylvie , Michallet Mauricette , Cordonnier Catherine , Fenaux Pierre , Bordessoule Dominique , Castaigne Sylvie , Dombret Hervé 
Published: October 2019

Abstract
Abstract 253

Aim.
AML in older patients constitutes the majority of AML cases, still associated with a high relapse rate after intensive chemotherapy (ICT). Relapsing patients are frequently targeted for new drug development, but few data are available on their outcome and optimal management. With the aim to provide historical data for future drug evaluation, we retrospectively analyzed a cohort of 393 patients aged ≥50 years in first relapse after prospective inclusion in ALFA 9801 (NCT00931138) and 9803 (NCT00363025) ICT trials.

Patients.
Median age was 64 years (50–82). Median duration of first complete remission (CR1) was 9 months (1–69). Twelve patients had prior allogeneic stem cell transplantation. At diagnosis, cytogenetics was as follows: 16 favorable (4%), 240 intermediate (61%), 76 adverse (19%), and 61 failed or not done (16%), 173 patients having a normal karyotype (NK). Twenty-nine of 174 patients tested at diagnosis had FLT3-ITD (17%), while the incidence of NPM1, CEBPA, IDH1, IDH2 or WT1 mutation was 24%, 4%, 9%, 10% and 2%, respectively. Among 86 NK-AML patients tested, 24 had a favorable genotype (NPM1 or CEBPA mutation without FLT3-ITD). At relapse, median WBC was 3.4 × 109/L and ECOG-PS >1 in 28% of patients. Relapse management was best supportive care (BSC, 32%), low-dose cytarabine (LDAC, 12%), ICT (38%), ICT combined with gemtuzumab ozogamicin (GO, 5%), or GO alone (10%). As expected, patients who received LDAC or BSC were significantly older and tended to have more frequent unfavorable karyotype. Conversely, patient and AML characteristics were comparable in the ICT, ICT+GO, and GO subsets.

Results.
Complete remission (CR) rate was 31% and median post-relapse survival was 6.8 months (0%, 17%, 53%, 80%, 42.5% and 3.2, 5.6, 9, 19.8, 8.9 months in BSC, LDAC, ICT, ICT+GO, and GO subsets, respectively). CR2 rate and post-relapse survival were comparable in both GO and ICT subsets, while CR2 rate was higher (P=0.02) and survival longer (P=0.04) in the ICT+GO versus the ICT subset. Median post-relapse survival was 17.3 months in patients who achieved CR2 versus 4.2 months in those who did not (p<0.001). In univariate analysis, age, CR1 duration, WBC, ECOG-PS, and favorable karyotype influenced both CR2 rate and post-relapse survival. Median post-relapse survival reached 16.2 months in patients with favorable karyotype versus 6.2 months in other patients (P<0.001). The presence of FLT3-ITD at diagnosis was associated with shorter post-relapse survival (3 versus 7 months, P=0.03). Interestingly, outcome was similar in NK patients with or without a favorable genotype, as well as in patients with an intermediate or even an adverse karyotype. Besides favorable karyotype, multivariate analysis allowed to identify CR1 duration <12 months (HR, 1.8; P<0.001), ECOG-PS ≥2 (HR, 2.0; P>0.001), age (P=0.001) and WBC (P=0.03), but not FLT3-ITD, as independent factors for shorter survival. To evaluate the role of the different management options, which were dependent of patient and disease characteristics as well as physician's choice, we matched patients treated intensively (ICT/ICT+GO/GO) to those not treated intensively (LDAC/BSC) using a propensity score. This methodology allows comparing both approaches by reducing the multidimensional covariates associated with the intensive option to a single one-dimensional score used for patient matching. In 76 patient pairs, intensive salvage (HR, 0.49, P<0.001), good ECOG-PS (HR, 0.44, P<0.001), and CR1 duration ≥12 months (HR, 0.55, P=0.001) were associated with longer post-relapse survival. The benefit associated with intensive treatment was more marked in patients with CR1 duration ≥12 months (1-year post-relapse survival, 58% versus 24%; P=0.001) than in those with CR1 duration <12 months (1-year post-relapse survival, 25% versus 13%; P=0.09).

Conclusion.
If, as expected, favorable karyotype and longer CR1 duration predicted better post-relapse outcome in older AML patients, other karyotypes or genotypes did not. Patients with CR1 duration ≥12 months did benefit from intensive salvage. Intensive treatment should thus remain the current control arm in trials evaluating new alternatives in late relapsing patients, while LDAC/BSC may still be considered as an adequate control arm in patients relapsing within the first year of CR1. Results observed with GO-containing salvage also suggest that GO studies should be actively pursued in this setting.

Disclosures:
No relevant conflicts of interest to declare.