Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial

Abstract

IntroductionChronic myelomonocytic leukemia (CMML), which is the most frequent myelodysplastic/myeloproliferative disorder, 1 is characterized by the accumulation of monocytes and a variable proportion of immature dysplastic granulocytes in the PB and the BM. 2 Clonal cytogenetic abnormalities are detected in ϳ 40%, 3 and a copyneutral uniparental disomy in leukemic cells of ϳ 50% of the patients. 4 Mutations in ASXL1, TET2, and RUNX1 genes are detected in 25% to 50% of patients, RAS and CBL gene mutations in 10% to 25% of patients, and mutations in JAK2, FLT3, LNK, UTX, EZH2, IDH1, and IDH2 in Ͻ 10% of patients. 5 Epigenetic changes could also play a role in the disease pathogenesis. 6 For example, transcription-intermediary factor-1␥ gene (TIF1␥), whose disruption in myeloid cells induces an age-dependent CMML phenotype in the mouse, is down-regulated in leukemic cells of ϳ 35% of CMML patients because of the gene promoter hypermethylation. 7 The prognosis of this disease of the elderly is quite variable, with an approximately 2.5-year median survival. 3 BM and PB blast percentages have major prognostic value and distinguish CMML-1, with Ͻ 10% BM and Ͻ 5% PB blasts, from CMML-2 with Ն 10% BM and/or Ն 5% PB blasts. 1 Other well-documented prognostic factors include white blood cell (WBC) count, splenomegaly (SMG), extramedullary disease (EMD), cytopenias, and cytogenetic abnormalities. [8][9][10][11] ASXL1 and EZH2 mutations negatively affect the disease outcome, whereas the prognostic influence of TET2 mutation is more controversial. [12][13][14][15][16] The short survival of patients with poor prognostic factors is related to the limited availability of effective treatments. 3 The only The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on March 24, 2019. by guest www.bloodjournal.org From potentially curative therapeutic option is allogeneic stem cell transplantation, however excluded in most patients by age and comorbidities. 17 In the only randomized trial conducted specifically in CMML, to our knowledge, hydroxyurea appeared more efficient than oral etoposide 18 but still associated with short survival; whereas in other reports, the response rate of CMML to low-dose cytarabine, 19 oral topotecan, 20 and intensive chemotherapy 21 remained low. The hypomethylating agents, 5-azacitidine (AZA) and 5-aza-2Ј-deoxycytidine (decitabine [DAC]) received Federal Drug Administration approval for treatment of myelodysplastic syndrome, including CMML, AZA being also approved in the European Union for CMML with marrow blasts Ͼ 10%. Pooled AZA and DAC published studies suggest an overall response rate of 39% to 45% and an overall survival (OS) benefit for responders. [22][23][24][25][26] However, CMML patient populations included in those series were generally heterogeneous. ...

The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML

“…Indeed, both agents exert potent antileukemic effects in MDS and CMML. 42,43 Therefore, it is tempting to speculate that part of their antileukemic effect might also involve an induction of autophagy and myeloid differentiation. Nevertheless, the data presented herein deciphers the signaling pathways involved in CSF1-mediated induction of autophagy and monocyte differentiation, as well as paves a new research avenue for future therapeutic interventions through PRKAA reactivation in the context of CMML.…”

CMML: Clinical and molecular aspects

“…Limited prospective data is available: AZA is licensed in Europe in CMML-2 patients with WBC <12 G/L, on the basis of the MDS AZA-001 trial where only few CMML patients were randomized [27]. A phase II study of DAC in high risk population of MP-CMML provided interesting results [71] prompting an ongoing randomized phase III trial addressing the role of DAC as upfront treatment of MP-CMML in the presence of adverse prognostic features (NCT02214407). As in other myeloid neoplasms, response to HMA remains difficult to predict in CMML with clinical variables or with gene mutations.…”

“…The hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DAC) seem active in CMML, though they have mostly been explored retrospectively [69,70], reporting overall response rates in the 40-70% range. In retrospective studies controlling for biases, there does seem to be a significant difference between DAC and AZA in this population (Duchmann et al, manuscript in preparation), even though several authors have suggested that DAC could be beneficial in proliferative CMML [70,71], possibly because standard regimens of DAC are slightly more myelotoxic than AZA regimens. HMA also seem active in patients with extra-medullary disease [71].…”

“…In retrospective studies controlling for biases, there does seem to be a significant difference between DAC and AZA in this population (Duchmann et al, manuscript in preparation), even though several authors have suggested that DAC could be beneficial in proliferative CMML [70,71], possibly because standard regimens of DAC are slightly more myelotoxic than AZA regimens. HMA also seem active in patients with extra-medullary disease [71]. Limited prospective data is available: AZA is licensed in Europe in CMML-2 patients with WBC <12 G/L, on the basis of the MDS AZA-001 trial where only few CMML patients were randomized [27].…”

Management recommendations for chronic myelomonocytic leukemia: consensus statements from the SIE, SIES, GITMO groups

“…22 Most important, a recently concluded phase II trial in which 39 CMML patients were treated with decitabine suggested that lower CJUN and CMYB gene expression levels were independently associated with an improved overall outcome and survival. 43 However, the value of somatic gene mutations in the prognosis of CMML has not been validated and no scoring system including such molecular aberrations has been developed. …”