Impact of gene mutations on treatment response and prognosis of acute myeloid leukemia secondary to myeloproliferative neoplasms

Abstract

Acute myeloid leukemias secondary (sAML) to myeloproliferative neoplasms (MPN) have variable clinical courses and outcomes, but remain almost always fatal. Large cohorts of sAML to MPN are difficult to obtain and there is very little scientific literature or prospective trials for determining robust prognostic markers and efficient treatments. We analyzed event-free survival (EFS) and overall survival (OS) of 73 patients with MPN who progressed to sAML, based on their epidemiological characteristics, the preexisting MPN, the different treatments received, the different prognostic groups and the responses achieved according to the ELN, and their mutational status determined by next-generation DNA sequencing (NGS). For 24 patients, we were able to do a comparative NGS analysis at both MPN and sAML phase. After acute transformation EFS and OS were respectively of 2.9 months (range: 0-48.1) and 4.7 months (range: 0.1-58.8). No difference in EFS or OS regarding the previous MPN, the ELN2017 prognostic classification, the first-line therapy or the response was found. After univariate analysis, three genes, TP53, SRSF2 and TET2, impacted pejoratively sAML prognosis at sAML time. In multivariate analysis, TP53 (P = .0001), TET2 (P = .011) and SRSF2 (P = .018) remained independent prognostic factors. Time to sAML transformation was shorter in SRSF2-mutated patients (51.2 months, range: 14.7-98) than in SRSF2-unmutated patients (133.8 months, range: 12.6-411.2) (P < .001). Conventional clinical factors (age, karyotype, ELN2017 prognostic classification, treatments received, treatments response, Allo-SCT…) failed to predict the patients' outcome. Only the mutational status appeared relevant to predict patients' prognosis at sAML phase.

Secondary Acute Myeloid Leukemia and the Role of Allogeneic Stem Cell Transplantation in a Population-Based Setting

“…Mutated JAK2 defines PV, whereas mutated CALR or MPL are found in JAK2 negative ET and PMF. Post MPN-AML is associated with a very poor prognosis with a median OS of less than 6 months [63] where mutations in TP53, SRSF2 and TET2 have been shown to have an adverse impact on survival [64].…”

How I treat the blast phase of Philadelphia chromosome–negative myeloproliferative neoplasms

“…1 The mutational profile of MPN-BP is distinct from that of AML arising de novo and is characterized by mutations in IDH1/2, TET2, SRSF2, ASXL1, and TP53. 11,26,29,30,[40][41][42] By contrast, mutations in NPM1-FLT3, which are typical of AML de novo, are uncommon in MPN-BP. Retrospective analysis of After the acquisition of a JAK2 V617F or similar driver mutation by a hematopoietic stem cell (depicted in yellow), host genetic, epigenetic, and microenvironmental factors can facilitate the emergence of asymptomatic clonal hematopoiesis (depicted in green), subsequent clonal expansion, and emergence of an MPN phenotype (depicted as doublet of green cells).…”

“…Patients treated with a supportive care-only approach had short median survival, in the 6-week to 2-month range. 8,9,11,45 The outcomes reported with intensive chemotherapy have been generally poor (Table 2). 8,9,11,45 Allogeneic SCT has the potential to result in long-term survival (Table 2), [46][47][48][49][50] but only a minority of patients are able to proceed to transplantation.…”

“…32,41,53 The incidence increases with evolution to MPN-BP and is in the 13% to 31% range in published retrospective series. 11,26,40,41 Wild-type IDH1/2 enzymes catalyze the conversion of isocitrate to a-ketoglutarate. Mutant IDH1/2 results in conversion of isocitrate to R-2-hydoxyglutarate (2-HG), an oncometabolite that competitively inhibits a-ketoglutarate-dependent enzymes, including TET2 and the Jumanji enzymes, resulting in DNA and histone hypermethylation, epigenetic dysregulation, and differentiation block.…”

“…The median survival is in the 3-to 5-month range in published retrospective series, even in the context of intensive induction chemotherapy. [7][8][9][10][11] Allogeneic stem-cell transplantation (SCT) is the only approach reported to have the potential to significantly change the natural history of MPN-BP, but applicability has historically been limited by the refractory nature of these diseases and the older age (median age is in the mid 60s to early 70s) of patients at the time of presentation. Despite these disheartening outcomes, there is reason for a renewed sense of optimism based on our increasing understanding of the biologic mechanisms that drive these disparate group of disorders, as well as the increasing availability of new agents and approaches.…”