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ASXL1 and SETBP1 Mutations and Their Prognostic Contribution in Chronic Myelomonocytic Leukemia: a Two-Center Study of 466 Patients

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ASXL1 and SETBP1 Mutations and Their Prognostic Contribution in Chronic Myelomonocytic Leukemia: a Two-Center Study of 466 Patients Leukemia (2014) 28, 2206–2212 & 2014 Macmillan Publishers Limited All rights reserved 0887-6924/14 www.nature.com/leu ORIGINAL ARTICLE ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients MM Patnaik1, R Itzykson2,3,4, TL Lasho1, O Kosmider2,5, CM Finke1, CA Hanson6, RA Knudson7, RP Ketterling7, A Tefferi1 and E Solary3,4,8 In a cohort of 466 patients, we sought to clarify the prognostic relevance of ASXL1 and SETBP1 mutations, among others, in World Health Organization-defined chronic myelomonocytic leukemia (CMML) and its added value to the Mayo prognostic model. In univariate analysis, survival was adversely affected by ASXL1 (nonsense and frameshift) but not SETBP1 mutations. In multivariable analysis, ASXL1 mutations, absolute monocyte count 410 Â 10(9)/l, hemoglobin o10 g/dl, platelets o100 Â 10(9)/l and circulating immature myeloid cells were independently predictive of shortened survival: hazard ratio (95% confidence interval (CI)) values were 1.5 (1.1–2.0), 2.2 (1.6–3.1), 2.0 (1.6–2.6), 1.5 (1.2–1.9) and 2.0 (1.4–2.7), respectively. A regression coefficient-based prognostic model based on these five risk factors delineated high (Z3 risk factors; HR 6.2, 95% CI 3.7–10.4) intermediate-2 (2 risk factors; HR 3.4, 95% CI 2.0–5.6) intermediate-1 (one risk factor; HR 1.9, 95% CI 1.1–3.3) and low (no risk factors) risk categories with median survivals of 16, 31, 59 and 97 months, respectively. Neither ASXL1 nor SETBP1 mutations predicted leukemic transformation. The current study confirms the independent prognostic value of nonsense/frameshift ASXL1 mutations in CMML and signifies its added value to the Mayo prognostic model, as had been shown previously in the French consortium model. Leukemia (2014) 28, 2206–2212; doi:10.1038/leu.2014.125 INTRODUCTION Notably, a Mayo Clinic study analyzed several clinical and Chronic myelomonocytic leukemia (CMML) is a clonal, hematopoietic laboratory parameters, including ASXL1 mutations, in 226 10 stem cell disorder, with overlapping features of myelodysplastic patients with CMML; on multivariable analysis, risk factors syndromes (MDS) and myeloproliferative neoplasms.1 The World for survival included hemoglobin o10 g/dl, platelet count Health Organization (WHO) diagnostic criteria for CMML include o100 Â 10(9)/l, AMC 410 Â 10(9)/l and the presence of 10 persistent peripheral blood (PB) absolute monocyte count (AMC) circulating immature myeloid cells (IMCs). In this study, ASXL1 of 41 Â 10(9)/l, absence of BCR-ABL1 or PDGFRA/B mutations, mutations were detected in 49% of patients and did not affect o20% myeloblasts or promonocytes in PB or bone marrow (BM) either overall (P ¼ 0.08) or leukemia-free (P ¼ 0.4) survival. The and presence of dysplasia in one or more myeloid lineages.1 study resulted in the development of the Mayo prognostic model, In addition, the WHO system recognizes CMML-1 (o5% PB blasts with three risk categories, low (0 risk factor), intermediate (1 risk and o10% BM blasts) and CMML-2 (5–19% PB blasts, 10–19% BM factor) and high (Z2 risk factors), with median survivals of 32, 18.5 blasts, or presence of Auer rods). and 10 months, respectively.10 Somatic mutations are detected in 490% of patients with In contrast to the findings from the above-discussed CMML and include involvement of the following genes: TET2 Mayo Clinic study, a GFM (Groupe Francais des Myelodysplasies) (50–60%), ASXL1 (40–50%), SRSF2 (40–50%), RUNX1 (10–15%), study demonstrated an adverse prognostic effect for ASXL1 KRAS (10%), NRAS (10%), SETBP1 (5–10%), CBL (5–10%), SF3B1 mutations in 312 patients with CMML;5 additional risk factors on (5–10%), ZRSF2 (5–10%), U2AF1 (5–10%), EZH2 (5–10%), IDH2 multivariable analysis included age 465 years, white blood (5–10%), JAK2 (5–10%), FLT3 (o5%), NPM1 (o5%), DNMT3A count (WBC) 415 Â 10(9)/l, platelet count o100 Â 10(9)/l and 5 (o5%), IDH1 (o5%) and TP53 (1%).2 Among these, only ASXL1 hemoglobin level o10 g/dl in females and o11 g/dl in males. and SETBP1 mutations have been prognostically implicated.3–7 The GFM prognostic model assigns three adverse points for ASXL1 (additional sex combs like 1) maps to chromosome 20q11 WBC 415 Â 10(9)/ l and two adverse points for each one and regulates chromatin by interacting with the polycomb-group of the remaining risk factors, resulting in a three-tiered risk repressive complex proteins (PRC1 and PRC2).8 SETBP1 is located stratification, low (0–4 points), intermediate (5–7 points) and on chromosome 18q21.1 and encodes the SET binding protein 1. high (8–12 points), with respective median survivals of 56, 27.4 Recurrent somatic SETBP1 mutations are also seen in patients with and 9.2 months. It should be noted that all nucleotide variations atypical chronic myeloid leukemia (B25%)3,6,9 and are identical to (missense, nonsense and frameshift) were regarded as ASXL1 changes seen in patients with the Schinzel–Giedion syndrome.9 mutations in the Mayo study,10 whereas only nonsense and Some,4,5,7 but not all,10 studies have demonstrated a negative frameshift ASXL1 mutations were considered in the French prognostic impact for ASXL1 mutations in patients with CMML. study.5 1Division of Hematology, Mayo Clinic, Rochester, MN, USA; 2Universite´ Paris Descartes, Paris, France; 3Institut Gustave Roussy, Villejuif, France; 4Universite´ Paris-Sud 11, Orsay, France; 5Institut Cochin, Paris, France; 6Division of Hematopathology, Mayo Clinic, Rochester, MN, USA; 7Division of Cytogenetics, Mayo Clinic, Rochester, MN, USA and 8INSERM U1009, Villejuif, France. Correspondence: Professor A Tefferi, Division of Hematology, Department of Medicine, Mayo Clinic, Rochester 55905, MN, USA or Professor E Solary, Inserm UMR 1009, Institut Gustave Roussy, 114, Rue Edouard Vaillant, Villejuif 94805, France. Received 10 March 2014; revised 25 March 2014; accepted 28 March 2014; accepted article preview online 3 April 2014; advance online publication, 9 May 2014 Molecular prognostication in CMML MM Patnaik et al 2207 More recently, SETBP1 mutations were seen in 12 (6.2%) of 195 French consortium CMML registry.5 The median age of the entire French patients with CMML and were reported to affect both patient cohort was 73 years (range, 20–93 years), with 66% of the overall and leukemia-free survival.3 Similar observations were patients being males (Table 1). A total of 395 (85%) patients had made by a Mayo Clinic study where SETBP1 mutations were seen CMML-1 with a median OS of 38 months, whereas 71 (15%) in 8 (4.5%) of 179 patients with CMML.6 Meggendorfer et al.11 patients had CMML-2 with a median OS of 24 months. The French identified SETBP1 mutations in 52 (9.4%) of 551 patients with patient cohort displayed significantly higher hemoglobin level MDS/myeloproliferative neoplasm overlap features, and specifically (Po0.0001), platelet counts (P ¼ 0.0009) and lower BM blast % in 21 (7.1%) of 294 patients with CMML, and demonstrated no (P ¼ 0.04) (Supplementary Table 1). In addition, a higher propor- impact of these mutations on survival. The SETBP1 mutations were tion of the French patients presented with lower risk disease found to strongly overlap with ASXL1 and CBL mutations and were based on the Spanish cytogenetic stratification system (P ¼ 0.01), mutually exclusive with JAK2 and TET2 mutations. The current MDAPS (P ¼ 0.04), GFM model (Po0.002) and the Mayo prognostic study sought to further clarify the prognostic relevance of ASXL1 model (P ¼ 0.001). The distribution of ASXL1 (P ¼ 0.05), SETBP1 and and SETBP1 mutations in a larger group of CMML patients and spliceosome component mutations was similar between the two examine the additional value of incorporating molecular patient cohorts (Supplementary Table 1). information to the Mayo prognostic model, as has been demonstrated previously by the GFM, in their specific prognostic ASXL1 mutations model.5 Archived DNA was available for ASXL1 mutation screening in 420 of the 466 study patients; 164 (39%) patients harbored ASXL1 MATERIALS AND METHODS mutations, excluding missense variations. In the Mayo Clinic cohort, 96 (43%) of 225 patients harbored nonsense/frameshift The current study was a collaborative effort between the Mayo Clinic in ASXL1 mutations and 20 (7%) had ASXL1 missense mutations. Minnesota, USA, and the French consortium for CMML.5,10 Patient data and outcomes from the French consortium for CMML had been used to help ASXL1 mutations in the French cohort did not include missense develop the GFM CMML prognostic model.5 The study was approved by mutations. Table 1 outlines presenting clinical and laboratory the institutional review boards of the Mayo Clinic and the Cochin hospital features and subsequent events stratified by ASXL1 mutational in Paris, France, respectively. Study eligibility criteria included availability of status. ASXL1-mutated patients displayed lower hemoglobin level PB smear, BM histology and cytogenetic information at the time of referral. (P ¼ 0.0007), higher WBC (Po0.0001), higher AMC (Po0.0001) and The diagnoses of CMML, including subclassification into CMML-1 or were more likely to display circulating IMCs (P ¼ 0.0006), U2AF1 CMML-2, and documentation regarding the presence or absence of ring mutations (P ¼ 0.0009) and higher risk categories based on the sideroblasts and leukemic transformation were according to the 2008 1 Spanish cytogenetic risk stratification system (P ¼ 0.01), MDAPS WHO criteria. All complete blood count differentials and PB smears were (P 0.0003), GFM model (P 0.0001) and the Mayo prognostic evaluated for presence of circulating IMCs, defined by the presence of any ¼ o of the following cells in the PB: myeloblasts, promyelocytes, myelocytes or model (P ¼ 0.009).
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