S135: NEXT-GENERATION SEQUENCING-BASED MEASURABLE RESIDUAL DISEASE MONITORING IN ACUTE MYELOID LEUKEMIA WITH FLT3 INTERNAL TANDEM DUPLICATION TREATED WITH INTENSIVE CHEMOTHERAPY PLUS MIDOSTAURIN

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Background: Internal tandem duplications of the FLT3 gene (FLT3-ITD) occurring in 10-25% of adult acute myeloid leukemia (AML) patients (pts) represent an attractive target for monitoring of measurable residual disease (MRD), particularly in pts treated with a FLT3 inhibitor. So far, MRD monitoring in FLT3-ITD mutated (FLT3-ITD+) AML was limited by the heterogeneity of ITD length and insertion site and the number of ITD clones. We recently developed a next-generation sequencing (NGS)-based MRD assay to monitor FLT3-ITD at very high sensitivity (Blätte et al, Leukemia 2019). Aims: To evaluate the prognostic impact of the MRD status in pts 18-70 years with FLT3-ITD+ AML enrolled on the AMLSG16-10 trial (NCT01477606) combining intensive chemotherapy with midostaurin (mido) followed by mido maintenance. Methods: Using FLT3-ITD paired-end NGS (Illumina MiSeq) with a variant allele frequency (VAF) sensitivity of 10-4-10-5, 497 bone marrow (BM) and 66 blood samples from 157 FLT3-ITD+ AML were analyzed at diagnosis (Dx, n=157), after two cycles of chemotherapy (Cy2, n=142), at end of treatment (EOT, n=116), and during 3-12 months follow-up (FU, n=148). All pts achieved complete remission (CR) at Cy2. Allogeneic hematopoietic-cell transplantation in first CR (HCT_CR1) was performed in 121 (77%) pts. NPM1 and DNMT3A mutation status were available for all pts (NPM1mut, n=111; DNMT3Amut, n=74). Results: 465 ITDs were identified at Dx. Median length was 51 nucleotides (range, 9-284), median VAF 0.312% (0.006-92.26), median total VAF per pt 31.54% (0.46-92.26), and 69% of pts exhibited >1 ITD (median 2; range, 1-16). At Cy2 and EOT pts’ total ITD VAF significantly decreased (median log10 reduction: 4.6 and 4.7; P<.001, each), and MRD negativity (MRD-) was achieved in 78% and 94%, respectively. Concurrent NPM1mut favorably impacted on log10 VAF reduction (median, 4.7 vs 3.7; P<.001) and MRD- (88% vs 53%; P<.001) at Cy2. Median follow-up was 3.9 years. Achievement of MRD- at Cy2 predicted for superior 4-year rates of cumulative incidence of relapse (CIR) (4y-CIR, 29% vs 51%; P<.001) and overall survival (OS) (4y-OS, 70% vs 42%; P=.004) (Figure 1A and B), also for pts undergoing HCT_CR1 (4y-CIR, 16% vs 40%; P<.001; 4y-OS, 74% vs 48%; P=.014). Multivariate models for CIR and OS, including age, white blood cell count, BM blasts, NPM1mut, DNMT3Amut, FLT3-ITD allelic ratio, FLT3-ITD MRD+ at Cy2 and HCT_CR1 as time-dependent variable, revealed FLT3-ITD MRD- as the only consistent favorable variable for CIR (HR, 0.22; P<.001) and OS (HR, 0.37; P=.005); NPM1mut (HR, 0.17; P<.001) and HCT_CR1 (HR, 0.08; P<.001) were favorable for CIR. No significant benefit was observed at EOT mainly due to the high rate of MRD-. During FU, 16 pts converted from MRD- to MRD+ (MRDconv) and 13/16 pts relapsed within a median time of 7 days (range, 0-197 days), translating into a significantly increased relapse risk (2y-CIR, 81% vs 14%; P<.001) and inferior OS (2y-OS, 31% vs 83%; P<.001) (Figure 1C and D). In Cox regression MRDconv as time-dependent variable was of adverse impact for CIR (HR, 10.99; P<.001) and OS (HR, 4.27; P<.001). Summary/Conclusion: NGS-based FLT3-ITD MRD monitoring allows for the identification of pts at high risk of relapse and death. Combining mido with intensive chemotherapy MRD- at Cy2 and EOT was achieved in a high proportion of pts; at Cy2 MRD- was the strongest independent favorable prognostic factor for relapse risk and OS. Concurrent NPM1mut correlated with deeper molecular responses and higher rates of MRD-..During FU, MRDcon was the strongest unfavorable factor for both CIR and OS.Keywords: Flt3-ITD, Acute myeloid leukemia, MRD

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