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Background: In the past year, multiple studies have demonstrated the drastically increased risk of relapse and death in patients with Acute Myeloid Leukemia (AML) who have persistent FLT3 internal tandem duplication (ITD) mutations detectable in clinical remission by next generation sequencing (NGS). Translating this evidence into a change in clinical practice requires both widely available testing and a clear understanding of the clinical implications of FLT3-ITD detection at defined threshold levels. In the largest of the recent studies (Pre-MEASURE, PMID: 36881031), we performed FLT3-ITD MRD detection in blood DNA collected from 608 patients at the time of first remission (CR1) prior to allogeneic hematopoietic cell transplant (alloHCT). To evaluate cross-assay comparability and the impact of residual disease burden levels, we performed analysis on this cohort using a commercially available FLT3-ITD MRD NGS assay. Methods: Of the 608 patients aged 18 or older from the Pre-MEASURE study who received an alloHCT for FLT3-ITD mutated AML during CR1 at a CIBMTR reporting site in the USA between the years of 2013-2019, patients not experiencing non-relapse mortality and with sufficient DNA from pretransplant blood available were included in this analysis. A commercially available testing kit (IVS, Invivoscribe, San Diego, CA), which can detect FLT3-ITD MRD by NGS for up to 21 patients on one Illumina MiSeq flow cell, was used to establish a workflow following clinical testing standards and validated to detect ITDs down to a variant allele fraction (VAF) of at least 0.005%. Results were compared to those previously reported using an anchored multiplex PCR-based (AMP) targeted NGS assay. Overall survival (OS) and cumulative incidence of relapse were estimated with the day of transplant as time 0 using Kaplan-Meier estimation (log-rank tests) and Cox proportional hazards models. Results: A total of 451 patients were included in this study, of which 173 (38%) experienced relapse (median: 5.2 months; range 0.7-52.1) and 133 (29%) died (median: 10.7 months; range 2-53.8) post-alloHCT. The IVS assay identified 232 FLT3-ITD variants with a median VAF of 0.005% (range 0.0002-44%) and length of 51bp (range 5-228). IVS positive patients had a median of 1 FLT3-ITD variant (range 1-15) and median maximum VAF of 0.01% (range 0.0003-44%). Utilizing the same VAF cutoff of 0.01% for MRD positivity for the IVS test as used in the Pre-MEASURE study, patients testing positive prior to alloHCT exhibited higher rates of relapse (79% vs 31%, p<0.0001) and decreased survival (29% vs 77%, p<0.0001) at 3 years compared to testing negative. These results closely align with those previously reported using the AMP assay (Figure A). The IVS test has a superior limit of detection compared with the AMP test, allowing investigation of alternative VAF thresholds. In total, 151 patients (33.5%) were FLT3-ITD MRD positive by IVS of which only 75 (17%) had VAF ≥0.01%. A threshold-free approach for the IVS test improved the ability to identify patients at risk of relapse, predicting 63% of relapses within 6 months of transplant compared to 43% with the 0.01% cutoff, but resulted in decreased specificity as 42% of all positive patients relapsed within 6 months vs. 57% with the 0.01% VAF cutoff. In multivariable analysis, IVS FLT3-ITD MRD status was associated with both relapse and overall survival (Figure B). Additionally, stratifying patients by their level of residual FLT3-ITD disease burden prior to alloHCT revealed a dose-dependent increase in risk for death (Figure B) and relapse. Any detectable level of residual FLT3-ITD over 0.001% VAF exhibited increased risk, with VAFs ≥0.01% being the highest. Conclusions: In this analysis of patients with AML from the Pre-MEASURE study, we show cross-assay evidence that the detection of residual FLT3-ITD variants in pre-transplant blood during CR1 is associated with significantly increased risk of relapse and death after alloHCT. The highly sensitive assay used in this study could identify ~2/3 of patients who relapsed within 6 months and demonstrated that a dose-dependent correlation between residual FLT3-ITD level and adverse clinical outcomes exists, with VAF ≥0.01% representing the highest risk. This evidence provides strong justification for NGS-based AML MRD clinical testing for persistent FLT3-ITD prior to alloHCT to identify patients at high risk of post-transplant relapse and death.

Abstract Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.

SummaryVenetoclax (VEN) is an FDA‐approved selective inhibitor of B‐cell leukaemia/lymphoma‐2 (BCL‐2), used for treating elderly or unfit acute myeloid leukaemia (AML) patients unable to undergo intensive chemotherapy. Combining VEN with hypomethylating agents (HMAs) has shown impressive response rates in high‐risk myelodysplastic syndromes (MDS) and relapsed/refractory AML. However, the efficacy of VEN and HMAs in treating DDX41‐mutated (mDDX41) MDS/AML patients remains uncertain. Despite the favourable prognostic nature of mDDX41 MDS/AML patients, there is a lack of clinical experience regarding their response to different treatment regimens, leading to an unknown optimal therapeutic approach.