PF553 CLONES WITH COMPLEX ABERRATIONS AND TP53 MUTATIONS RESPOND TO AZACITIDINE IN MYELODYSPLASTIC SYNDROMES AND ACUTE MYELOID LEUKEMIA

Abstract

Background:Mutations in TP53 are associated with poor outcome in pts with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This holds also true for allogeneic stem cell transplantation (Lindsley et al, NEJM, 2017). Regarding hypomethylating agents, it was suggested that pts with TP53 mutations preferentially respond to decitabine (Welch et al, NEJM, 2016), although more recent studies also suggest response to azacitidine (AZA) (Döhner et al, Leukemia, 2018).Aims:Our aim was to retrospectively study real life data in terms of response to AZA in pts with TP53 mutations.Methods:We included 34 pts diagnosed with MDS or AML that were analyzed by banding analysis, fluorescence in situ hybridization (FISH‐panel, 10 probes), and sequencing (54 genes). The cohort comprised pts with TP53 mutations (N = 16, all with complex aberrant karyotypes, 9/16 with additional mutations) and without TP53 mutations (N = 18, 6x normal karyotype, 10x 1–2 cytogenetic aberrations, 2x complex aberrations, 17/18 with mutations other than TP53). For 6 pts with TP53 mutations treated with AZA at least two sequential genetic analyses (before and during treatment) were available. For the other 10 pts with TP53 mutations clinical but not genetic follow up was available or they received other treatment than AZA. All 18 pts without TP53 mutations received at least four cycles of AZA and genetic analyses were available from at least two time points. The IWG criteria (Cheson et al, Blood, 2006) for cytogenetic response were adapted and genetic response was defined as 50% reduction in FISH clone size or in variant allele frequency (VAF).Results:Clones with a TP53 mutation responded to AZA (50% VAF reduction) in 6/6 pts with TP53 mutations and genetic follow up (Figure 1A). Two of these pts were subjected to allogeneic transplantation, best clinical response for the other four pts was 3x hematologic improvement and 1x stable disease.From the other 10 pts with TP53 mutations, two responded to induction chemotherapy and were subjected to allogeneic transplantation; six started or intended to start treatment with AZA (5x) or decitabine (1x); two received best supportive care.At least one clone responded to AZA (50% reduction in FISH or VAF) in 10/18 pts (56%) without TP53 mutations. Aberrations that responded were: ASXL1, IDH2, RUNX1, SF3B1, SRSF2, TET2, U2AF1, +1, t(3;3), 5q‐, −7, i(12q), 17p‐, 17q‐, 20q‐. Although med. overall survival (OS) was shorter in pts with responding TP53 mutations than in pts without TP53 mutations but other responding clones (432 vs 682 days, P = 0.02, Figure 1B), it was longer than in pts with TP53 mutations where no genetic follow up analysis was available that could prove genetic response (266 days, P = 0.08).Summary/Conclusion:While pts without proven reduction of the TP53 clone size showed the poor outcome (med. OS 266 days) expected due to the presence of this high‐risk genetic abnormality, pts with documented reduction of the TP53 clone size also clinically profited with a med. OS of 432 days. We want to emphasize that a TP53‐mutated clone responded in 6/6 pts with TP53 mutations and genetic follow up analysis. This response rate of 100% is remarkably, as only 56% of pts with other mutations than TP53 had genetic aberrations responding to AZA. Although a retrospective analysis on a small patient number was performed, our observation supports the suggestion that pts with TP53 mutations not only respond to decitabine, but also to AZA. Even though response is not persistent, treatment with AZA could gain survival time, postpone progression and bridge interval until transplantation.image