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Subsequent blast (BP) or accelerated phase (AP) is a severe complication of Philadelphia-negative myeloproliferative neoplasms (MPNs). The prognosis is generally dismal, but hypomethylating agents (HMAs) may induce a long-lasting response in a minority of patients. Here, we report a cohort of six patients with BP/AP-MPN who experienced MPN relapse after a leukemia response was obtained with azacytidine. Five of the patients achieved complete remission despite the presence of characteristics associated with poor prognosis, such as complex and monosomal karyotypes, TP53 mutations, and EVI1 overexpression. These remissions persisted for over five years in four of the 6 patients. All patients showed rapid reemergence of MPN within a median of two months with thrombocytosis requiring the addition of anagrelide, hydroxyurea, or ruxolitinib given continuously in parallel with the azacytidine cycle. Serial JAK2 V617F allelic burden measurements showed little variation. Thromboembolic events occurred in 3 patients, one leading to death. These findings confirm that HMA may reverse the disease course in AP/BP-MPN to a more chronic phase that may last for years but also lead to morbidity and mortality. Combining maintenance therapy with HMA and MPN-specific drugs appears to be a possible approach to avoiding leukemia relapse and controlling MPN disease.

In AML, approximately one-third of expressed genes are abnormally spliced, including aberrant TET2 exon 2 expression. In a discovery cohort (n=99), TET2 exon 2 skipping (TET2E2S) was found positively associated with a significant reduction in the cumulative incidence of relapse (CIR). Age, cytogenetics, and TET2E2S were independent prognostic factors for disease-free survival (DFS), and favorable effects on outcomes predominated in cytogenetic normal (CN)-AML and younger patients. Using the same cutoff in a validation cohort of 86 CN-AML patients, TET2E2Shigh patients were found to be younger than TET2low patients without a difference in the rate of complete remission. However, TET2E2Shigh patients exhibited a significantly lower CIR (p

EVI1 overexpression confers poor prognosis in acute myeloid leukemia (AML). Quantification of EVI1 expression has been mainly assessed by real-time quantitative PCR (RT-qPCR) based on relative quantification of EVI1-1D splice variant. In this study, we developed a RT-qPCR assay to perform quantification of EVI1 expression covering the different splice variants. A sequence localized in EVI1 exons 14 and 15 was cloned into plasmids that were used to establish RT-qPCR standard curves. Threshold values to define EVI1 overexpression were determined using 17 bone marrow (BM) and 31 peripheral blood (PB) control samples and were set at 1% in BM and 0.5% in PB. Samples from 64 AML patients overexpressing EVI1 included in the ALFA-0701 or -0702 trials were collected at diagnosis and during follow-up (n=152). Median EVI1 expression at AML diagnosis was 23.3% in BM and 3.6% in PB. EVI1 expression levels significantly decreased between diagnostic and post-induction samples, with an average variation from 21.6% to 3.56% in BM and from 4.0% to 0.22% in PB, but did not exceed 1 log10 reduction. Our study demonstrates that the magnitude of reduction in EVI1 expression levels between AML diagnosis and follow-up is not sufficient to allow sensitive detection of minimal residual disease.

In AML, approximately one-third of expressed genes are abnormally spliced, including aberrant TET2 exon 2 expression. In a discovery cohort (n=99), TET2 exon 2 skipping (TET2E2S) was found positively associated with a significant reduction in the cumulative incidence of relapse (CIR). Age, cytogenetics, and TET2E2S were independent prognostic factors for disease-free survival (DFS), and favorable effects on outcomes predominated in cytogenetic normal (CN)-AML and younger patients. Using the same cutoff in a validation cohort of 86 CN-AML patients, TET2E2S

FLT3 internal tandem duplication (FLT3-ITD) is usually considered as a bad marker for minimal residual disease (MRD) follow-up in acute myeloid leukemia (AML). Our objective was to evaluate the suitability of FLT3-ITD as a target for MRD detection by real-time quantitative PCR, in comparison with two other molecular MRD markers, NPM1 mutation and WT1 overexpression, in 20 adult AML patients treated in Acute Leukemia French Association (ALFA) trials. Overall, these 3 MRD markers showed comparable kinetics in 17/20 (85%) cases. Furthermore, we found that FLT3-ITD MRD levels after induction chemotherapy are predictive of complete remission duration.