scholarly journals Incidence of Autoimmune Diseases, Molecular Characteristics and Clinical Outcomes of Chronic Myelomonocytic Leukemia in an Asian Population: A Single-Center Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4653-4653
Author(s):  
Ben Ponvilawan ◽  
Pattaraporn Tunsing ◽  
Sanya Sukpanichnant ◽  
Weerapat Owattanapanich
Keyword(s):  
Overall Survival ◽  
Autoimmune Diseases ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Laboratory Data ◽  
Chronic Myelomonocytic Leukemia ◽  
Comprehensive Cancer Center ◽  
Genetic Mutations ◽  
Molecular Characteristics ◽  
Myelomonocytic Leukemia

Abstract Background: Chronic myelomonocytic leukemia (CMML) is the most common subtype of the rare myelodysplastic/myeloproliferative neoplasms. Some studies have described the possible association with autoimmune disease. With the potential transformation into acute myeloid leukemia, it is known to have an unfavorable prognosis. Previous studies reported TET2, SRSF2, ASXL1, and KRAS/NRAS as the most occurring somatic mutations in CMML. However, the clinical and molecular characteristics of CMML patients in Asia remained fairly unknown. Materials and Methods: Patients with CMML who were diagnosed in Siriraj Hospital, which is the largest comprehensive cancer center in Thailand, from 2010 to 2020 were identified from the hospital database. Clinical and laboratory data, along with pathological results, were collected from the same database. The results of the 25-gene targeted DNA sequencing panel designed for myeloid neoplasms were also extracted if the results were available. Continuous variables were represented as medians and their associated ranges. Overall survival (OS) was determined using Kaplan-Meier estimator and log-rank test. Results: A total of 67 patients with CMML were included in our study. The median age of the cohort was 67 years old with a similar number of male and female patients in the cohort. Thirteen (19.4%) patients were diagnosed with autoimmune diseases, mainly autoimmune hemolytic anemia and immune thrombocytopenic purpura. According to cytogenetic risk for CMML, 35 (64.8%), 6 (11.1%), and 13 (24.1%) patients were classified as low, intermediate, and high risk, respectively. The clinical characteristics and laboratory results of patients were shown in Table 1. For the 15 patients with available molecular results, 13 had at least 1 somatic abnormality with TET2 (46.7%), ASXL1, NRAS, SRSF2 (each 26.7%), and KRAS (20.0%) being the common genetic mutations. The median mutation number was 4 (range, 0-6). The molecular landscape was demonstrated in Figure 1. Overall survival (OS) rates at 1 and 2 years were 74% and 57%, respectively. Patients with MDS-CMML tended to have longer median OS compared to MPN-CMML [37.9 (13.6-62.2) months vs. 19.7 (10.1-29.4) months] but did not reach statistical significance (p=0.124) (Figure 2). Conclusions: Asian patients with CMML had a considerable amount of associated autoimmune diseases. The genetic mutations contributing to CMML in our cohort also differed from previous reports. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Clinical Phenotype of Myeloproliferative Neoplasms with Activating CBL-mutations Resembles Chronic Myelomonocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3895-3895
Author(s):  
Juliana Popa ◽  
Susanne Schnittger ◽  
Philipp Erben ◽  
Tamara Weiss ◽  
Ayalew Tefferi ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Clinical Phenotype ◽  
Myeloproliferative Neoplasms ◽  
Direct Sequencing ◽  
Jak2 V617f ◽  
Chronic Myelomonocytic Leukemia ◽  
A Genome ◽  
Length Mutations ◽  
Myelomonocytic Leukemia

Abstract Abstract 3895 Poster Board III-831 A genome-wide single nucleotide polymorphism (SNP) screen led to the identification of 11q aUPD in patients diagnosed with various subtypes of myeloproliferative neoplasms (MPN), e.g. chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML) and myelofibrosis (MF) (Grand et al., Blood 2009;113:6182). Further molecular analyses revealed acquired activating point and length mutations in CBL exons 8 and 9 in 10% of CMML, 8% of aCML and 6% of MF cases. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. In this study, 160 patients with BCR-ABL and JAK2 V617F negative MPNs were screened for CBL mutations by PCR and direct sequencing. Eighteen known (Y371H, L380P [2x], C381R, C381Y [2x], C384Y, C396Y, H398P, H398Q, W408C, P417H, F418L, R420Q [5x]) and four new (F378L, G397V, I423N, V430M) missense mutations affecting fourteen residues were identified in 20 patients. Two patients harbored two different mutations. The clinical phenotype could be characterized more precisely in 17 patients. Median age was 68 years (range 59–85) with a slight female predominance (f, n=10; m, n=7). Striking hematological features were leukocytosis (14/17; 82%; median 29,000/μl, range 4,500-141,000) with continuously left-shifted granulopoiesis (blasts, promyelocytes, myelocytes, metamyelocytes) in 85% and elevated monocytes (median 2,500/μl, range 630-10,656) >1,000/μL in 88% (15/17) of patients. Eosinophilia (>1,500/μL) was rare (3/17, 18%). Anemia (normal values: f, Hb <12g/dL; m, Hb <14g/dL) was present in all 17 patients (f, median 10g/dL, range 8.7-11.8; m, median 11.2g/dL, range 8.6-12.9). Platelets did not exceed 300,000/μL in any patient while 11/17 (65%) patients presented with thrombocytopenia (median 125,000/μL, range 18,000-271,000). Splenomegaly was present in 11/17 patients (65%) and LDH was elevated (median 304U/L, range 189-729) in 9/17 patients (52%). Bone marrow histology and immunohistochemistry were available from 12 patients. Relevant features were hypercellularity, marked granulopoiesis and microlobulated megakaryocytes without clusters in 11/12 patients (92%), respectively. Increased fibres were seen in 8/12 (67%) patients of whom one showed severe fibrosis. Clinical follow-up was available from 17 patients. Thirteen patients (76%) have died because of progression to secondary acute myeloid leukemia/blast phase (n=7), cytopenia-related complications (n=2) or for unknown reasons (n=4) after a median of 23 months (range 3-60) following diagnosis. In conclusion, point mutations of CBL exons 8 and 9 are present in approximately 6-12% of BCR-ABL and JAK2 V617F negative MPNs. They are associated with a distinct clinical and hematological phenotype presenting with myeloproliferative features allowing diagnosis of a proliferative subtype of CMML rather than aCML or MF in the majority of cases. Patients with left-shifted leukocytosis, monocytosis, anemia and lack of thrombocytosis who are negative for BCR-ABL and point or length mutations of JAK2 should be routinely screened for CBL mutations. Disclosures: No relevant conflicts of interest to declare.

Concomitant Analysis of EZH2 and ASXL1 Mutations In Myelofibrosis, Chronic Myelomonocytic Leukemia and Blast-Phase Myeloproliferative Neoplasms

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3070-3070 ◽  
Author(s):  
Omar Abdel-Wahab ◽  
Animesh Pardanani ◽  
Jay Patel ◽  
Terra Lasho ◽  
Adriana Heguy ◽  
...  
Keyword(s):  
Mutation Analysis ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Normal Karyotype ◽  
Chronic Myelomonocytic Leukemia ◽  
Blast Phase ◽  
Idh Mutations ◽  
Myelomonocytic Leukemia

Abstract Abstract 3070 Background: EZH2 and ASXL1 mutations were recently described in a spectrum of myeloid malignancies; mutational analysis of small patient cohorts has suggested the highest mutational frequency in myelofibrosis (MF) and chronic myelomonocytic leukemia (CMML). The current study seeks to determine i) EZH2 and ASXL1 mutational frequencies in WHO-defined subcategories of MF, CMML and blast-phase myeloproliferative neoplasm (MPN), ii) if these mutations are mutually exclusive of TET2, IDH, JAK2 and MPL mutations and iii) clinical correlates of ASXL1 and EZH2 mutations in primary MF (PMF) and CMML. Methods: The study population included 94 patients: 46 PMF, 22 post-polycythemia vera/essential thrombocythemia MF (post-PV/ET MF), 11 blast-phase MPN and 15 CMML (10 CMML-1 and 5 CMML-2). High throughput DNA resequencing was used to screen archived bone marrow for EZH2, ASXL1, TET2, IDH, JAK2 and MPL mutations. Results: ASXL1 mutations were identified in all disease categories, including PMF (13%), post-PV/ET MF (23%), blast phase MPN (18%), and CMML (20%). We identified somatic mutations in TET2 in 15%, 14%, 18%, and 13% of PMF, post-PV/ET MF, blast phase MPN, and CMML, respectively. By contrast, mutations in EZH2 and IDH1/2 were less frequent. EZH2 mutations were seen in 3 out of 46 PMF patients (7%) and were not observed in patients with post-PV/ET MF or blast phase MPN. Mutations in IDH1/2 were restricted to blast-phase MPN (36%) and PMF (7%). No mutations in EZH2 or IDH1/2 were seen in CMML. Although we identified frequent TET2 and ASXL1 mutations, we only identified one patient with concurrent mutations in both genes. Three ASXL1 mutation-positive patients also had mutations in EZH2 or IDH and one patient had concurrent ASXL1, TET2 and IDH mutations. In addition, 7 ASXL1, 7 TET2, and 1 IDH mutated patients were JAK2V617F-positive. MPL mutations were also documented in all three mutation categories. All EZH2- and ASXL1-mutated PMF patients displayed normal karyotype and none underwent leukemic transformation during follow-up. Furthermore, mutated versus unmutated patients, in both instances, were not significantly different in age and sex distribution or clinical characteristics. The 3 EZH2-mutated PMF patients died after 29, 48 and 67 months from the time of mutation analysis. In univariate analysis, the presence of mutant ASXL1 in PMF was associated with worse survival (p=0.06) but the borderline significance was lost during multivariable analysis that included risk stratification according to DIPSS (Passamonti et al. Blood 2010; 115: 1703–1708). The 3 ASXL1 mutated CMML cases were alive after 40, 34 and 12 months from time of mutation analysis and none of them had progressed to acute leukemia; karyotype was normal in two of the patients and showed isolated trisomy 8 in one. Conclusions: ASXL1 mutations are as frequent as TET2 mutations in MF and CMML. In contrast, EZH2 mutations are infrequent and cluster with PMF. ASXL1 and EZH2 mutations are not mutually exclusive events, seem to be associated with normal karyotype and do not appear to be leukemogenic or prognostically detrimental in PMF or CMML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Spectrum of Myeloid Mutations in Patients with Elevated Hemoglobin

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2577-2577
Author(s):  
Pratibha Bhai ◽  
Benjamin Chin-Yee ◽  
Ian Cheong ◽  
Maxim Matyashin ◽  
Michael A. Levy ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Prognostic Significance ◽  
Laboratory Data ◽  
Gene Mutations ◽  
Jak2 V617f ◽  
Driver Mutations ◽  
Genetic Mutations ◽  
World Population ◽  
Age Related

Abstract Background: JAK2 V617F and exon 12 mutations are the characteristic driver mutations in polycythemia vera (PV), identified in more than 95% of patients. In addition, other genetic mutations have previously been described in JAK2-positive PV that appear to have prognostic significance (Tefferi et al., Blood 2016). The incidence of other driver mutations in unselected patients referred for elevated hemoglobin is less well studied. This study aims to characterize the genetic mutational landscape in a real-world population of patients referred for elevated hemoglobin using a targeted Next-Generation Sequencing (NGS)-based assay. Methods: We reviewed all patients referred for elevated hemoglobin levels (&gt;160 g/L in females or &gt;165 g/L in males) between 2018 and 2020 to hematology clinics at London Health Sciences Centre in Southwestern Ontario, Canada who underwent testing for genetic variants using the NGS-based Oncomine Myeloid Research Assay (ThermoFisher Scientific, MA, USA). This assay targets 40 key genes with diagnostic and prognostic implications in several myeloid malignancies (17 full genes and 23 genes with clinically relevant "hotspot" regions) and a panel of 29 fusion driver genes (&gt;600 fusion partners). Patient demographics, laboratory data and final diagnosis were extracted from the electronic medical record. For all patients with genetic mutations, clinical diagnosis was confirmed by three independent reviewers. Results: A total of 529 patients underwent genetic testing for elevated hemoglobin levels: 389 (73.5%) were males (mean age 58; range 18-95) and 140 (26.5%) were female (mean age 60; range 24-85). JAK2 mutations were detected in 10.9% (58/529) of patients and a diagnosis of PV was confirmed. The majority of JAK2-mutated PV patients (n=57) were positive for JAK2 V617F, while one patient had an exon 12 mutation. Additional single myeloid mutations were detected in 34.5% (20/58) of JAK2-positive patients and involved the following genes: TET2 (11; 19%), DNMT3A (2; 3.4%), ASXL1 (2; 3.4%), SRSF2 (2; 3.4%), BCOR (1; 1.7%), TP53 (1; 1.7%) and ZRSR2 (1; 1.7%) (Figure 1A). JAK2 mutations were not detected in 89.0% (471/529) of our cohort. A diagnosis of PV was confirmed in 2 JAK2-negative patients based on clinical features and myeloid mutations were detected in both: SRSF2 and TET2 gene mutations in 1 patient and SRSF2, IDH2, ASXL1 gene mutations in the other patient. Three JAK2-negative patients tested positive for the BCR-ABL fusion and were diagnosed with chronic myeloid leukemia. The remaining 466 JAK2-negative patients were diagnosed with secondary erythrocytosis and myeloid mutations were found in 6% (28/466) of these cases. Mutations were detected in DNMT3A (12; 2.6%), TET2 (5; 1.1%), ASXL1 (5; 1.1%), TP53 (2; 0.4%), NF1 (2; 0.4%), KIT (1; 0.2%), U2AF1 (1; 0.2%) (Figure 1B). All patients with JAK2-negative secondary erythrocytosis had only one myeloid gene mutation detected. Conclusion: Additional myeloid mutations other than JAK2 mutations are frequently identified in patients referred for erythrocytosis, with the highest frequencies observed in the TET2, DNMT3A and ASXL1 genes. The spectrum of myeloid mutations and overall incidence in JAK2-negative patients with secondary erythrocytosis is similar to the reported incidence of Clonal Hematopoiesis of Indeterminate Potential (CHIP) (Jaiswal et al., NEJM 2014), and suggests that these may represent incidental age-related mutations. By contrast, among the JAK2-positive patients, 34.5% had at least one additional myeloid mutation supporting a pathogenic role in these patients with myeloproliferative neoplasms. While concomitant myeloid mutations in patients with PV are well-described, further research is required to elucidate the significance of variants identified in JAK2-negative patients classified as secondary erythrocytosis in order to determine whether these mutations contribute to clinical phenotype or represent background CHIP. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical, Hematologic, Biologic and Molecular Characteristics of Patients with Myeloproliferative Neoplasms and a Chronic Myelomonocytic Leukemia-Like Phenotype

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1891
Author(s):  
Sonja Heibl ◽  
Bettina Gisslinger ◽  
Eva Jäger ◽  
Agnes Barna ◽  
Michael Gurbisz ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Chronic Myelomonocytic Leukemia ◽  
Molecular Characteristics ◽  
Molecular Features ◽  
Cell Counts ◽  
Myelomonocytic Leukemia

Patients with a myeloproliferative neoplasm (MPN) sometimes show a chronic myelomonocytic leukemia (CMML)-like phenotype but, according to the 2016 WHO classification, a documented history of an MPN excludes the diagnosis of CMML. Forty-one patients with an MPN (35 polycythemia vera (PV), 5 primary myelofibrosis, 1 essential thrombocythemia) and a CMML-like phenotype (MPN/CMML) were comprehensively characterized regarding clinical, hematologic, biologic and molecular features. The white blood cell counts in MPN/CMML patients were not different from CMML patients and PV patients. The hemoglobin values and platelet counts of these patients were higher than in CMML but lower than in PV, respectively. MPN/CMML patients showed myelomonocytic skewing, a typical in vitro feature of CMML but not of PV. The mutational landscape of MPN/CMML was not different from JAK2-mutated CMML. In two MPN/CMML patients, development of a CMML-like phenotype was associated with a decrease in the JAK2 V617F allelic burden. Finally, the prognosis of MPN/CMML (median overall survival (OS) 27 months) was more similar to CMML (JAK2-mutated, 28 months; JAK2-nonmutated 29 months) than to PV (186 months). In conclusion, we show that patients with MPN and a CMML-like phenotype share more characteristics with CMML than with PV, which may be relevant for their classification and clinical management.

scholarly journals Myeloproliferative/Myelodysplastic Neoplasms Presenting All Diagnostic Criteria of Chronic Myelomonocytic Leukemia but with Absolute Peripheral Blood Monocytosis 0.5-1× 109/L Should be Classified As CMML

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Sandra Castaño-Díez ◽  
Monica Lopez-Guerra ◽  
Daniel Esteban ◽  
Francesca Guijarro ◽  
Alex Bataller Torralba ◽  
...  
Keyword(s):  
Overall Survival ◽  
Diagnostic Criteria ◽  
Median Time ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Chronic Myelomonocytic Leukemia ◽  
Transformation Rate ◽  
Monocyte Count ◽  
Myelomonocytic Leukemia

Introduction Current diagnosis of chronic myelomonocytic leukemia (CMML) requires peripheral blood (pb) monocytosis ≥1×109/L. Accordingly, cases which fulfill other diagnostic criteria of CMML but not reaching the required pb monocytosis threshold would be classified as MDS or unclassifiable MPN/MDS according to WHO classification (Arber et al, Blood 2016) Recently, a group of authors (Geyer et al, Modern Pathology 2017) proposed the term oligomonocytic CMML (OM-CMML) for these patients with blood monocytes ≥10% of the WBCs, but only accounting for 0.5-1 × 109/L as an absolute value and fulfilling all other criteria of CMML and suggested that they should be managed as other patients with classical CMML despite lacking pb monocytosis ≥1×109/L. To address clinical value of this proposed newly entity, we analyzed the incidence, clinico-biological characteristics and outcome of a series of patients fulfilling the proposed criteria for OM-CMML from a single center with a long follow-up. Methods We included patients diagnosed between 1997 and 2019 who gathered the proposed criteria for OM-CMML (Geyer et al, Modern Pathology 2017). These patients were compared with a cohort of patients from the same study period diagnosed with classical CMML. Statistical analyses were performed using Rv3.1 and SPSS v20. Next generation targeted sequencing (NGS) was performed with Ion Ampliseq AML Research and Oncomine Myeloid Research Assay panel Results Overall, we included in the study 213 patients, including 35 (16%) who fulfilled the proposed criteria for OM-CMML. Median follow-up of alive patients was 42 months. In the OM-CMML group, 71% were males, median age was 74 years (51-92). OM-CMML patients presented at diagnosis with a lower leucocyte count (WBC) (median value, 4.6(2.2-7.5)x109/L vs 10(3-119)x109/L, p&lt;0.001), neutrophil count (2(0.7-5.7)x109/Lvs5.1(0.5-57)x109/L; p&lt;0.001), and monocyte count, both in terms of absolute figures (0.75(0.5-0.9)x109/Lvs1.9(0.6-33)x109/L;p&lt;0.001) and relative percentage (15% (10-30) vs 20% (1.8-51);p&lt;0.001). All OM-CMML patients corresponded to FAB non-leucocytosis, CMML-Myelodysplastic type (CMML-MD), whereas 62% of c-CMML patients were diagnosed as a CMML-MD subtype p&lt;0.001). No other different clinical characteristic were observed (Table 1). Cytogenetic analysis showed an abnormal karyotype in 23% of OM-CMML patients. NGS at diagnosis was available in 26 pt, without observing significant differences regarding gene mutation frequency. At diagnosis 17% of OM-CMML patients were transfusion-dependent and the distribution according to CPSS categories was: low (48%), int-1 (23%), int-2 (26%) and high (3%) risk, without difference with c-CMML (Table 1). Progression to a c-CMML was observed in 67% (24) of OM-CMML pts with a median time to progression of 7 months (m) (1-149 m). We did not observe differences in transformation rate to AML (AML-t; 10 (28.5%) vs 44 (24.7%) among OM-CMML and c-CMML group, p=0.6) or cumulative incidence (CI) of AML-t between OM-CMML and c-CMML patients (50m-CI AML-t: 35%±7 vs 21±12, p=0.3) (Fig 1). Eight out of the 10 pt (80%) who developed an AML previously presented a c-CMML phase. Median time to AML-t was longer in OM-CMML pt: 60m (3-219) vs 13.7m (0.8-124), p=0.011. The percentage of patients who received treatment in OM-CMML cohort was similar to that of c-CMML pts: (28% vs 21%, p=0.37, respectively). Moreover, time to treatment requirement was similar in both patient cohorts (15m (0.9-211m) vs 10m (0.1-112), p=0.5, respectively). Finally, overall survival of OM-CMML did not differ from that of c-CMML (5-year Overall Survival: 45±16% vs 30±7%; p=0.31, Figure 2). Conclusion: Clinical features and evolution of patients with OM-CMML were comparable to that of patients with c-CMML, supporting similar classification and management criteria. Acknowledgement: PI16/01027 (JE; MDB), PI19/01476 (JE; MDB) Disclosures No relevant conflicts of interest to declare.

Phenotypic and Prognostic Correlates of Spliceosome Mutations (SRSF2, SF3B1, U2AF35) in Chronic Myelomonocytic Leukemia with ≥ 1% Ring Sideroblasts.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2803-2803
Author(s):  
Mrinal M. Patnaik ◽  
Terra L Lasho ◽  
Curtis A Hanson ◽  
Janice M Hodnefield ◽  
Ryan A Knudson ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Univariate Analysis ◽  
Significant Risk ◽  
Chronic Myelomonocytic Leukemia ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Mutational Hotspots ◽  
Ring Sideroblasts ◽  
Myelomonocytic Leukemia

Abstract Abstract 2803 Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms. Ring sideroblasts (RS) represent abnormal mitochondrial iron accumulation in MDS; with ≥15% RS necessary for the conventional diagnosis of MDS-RS. Somatic spliceosome mutations are recurrent in MDS, with SF3B1 mutations being the most frequent in MDS-RS (∼75%) and SRSF2 in CMML (∼28%). The distribution of these mutations in the presence of both RS and monocytosis is unknown and their prognostic relevance, in the particular setting, undetermined. Methods: Using the Mayo Clinic database for myeloid malignancies (1997–2007), we identified patients who met the 2008 WHO criteria for CMML, and who also displayed at least 1% RS in their bone marrow (BM). All patients underwent BM examination and cytogenetic evaluation at diagnosis and the pathology slides, including iron stains, were centrally re-reviewed to accurately quantify BM RS. DNA was interrogated in the three most frequent spliceosome genes with somatic mutations; SF3B1, SRSF2 and U2AF35. Results: Sixty four patients met the above stipulated criteria for CMML with ≥1% RS; 46 (72%) were males and median age was 71 years (range, 17–90 years). Fifty three (83%) had CMML-1 and the remainder CMML-2. The percentage of patients with ≥15% RS was 41%: 30% had 15–49% RS and 11% had >50% RS. Thirty patients (47%) displayed SRSF2 mutations (mutational frequencies were 58% in the presence of <15% RS, 42% with 15–49% RS and 0% with >50% RS), 9 (14%) SF3B1 mutations (3% with <15% RS, 26% with 15–49% RS and 43% with >50% RS), and 5 (8%) U2AF35 mutations (8% with <15% RS, 11% with 15–49% RS and 0% with >50% RS). Mutational hotspots were P95 for SRSF2 (93%), K700 for SF3B1 (67%) and Q157 for U2AF35 (60%). The three spliceosome mutations were mutually exclusive. At a median follow-up of 26 months, 49 (77%) deaths and 11 (17%) leukemic transformations were documented. In univariate analysis, significant risk factors for survival included increased levels of white blood cell (WBC), absolute neutrophil (ANC), absolute monocyte (AMC), absolute lymphocyte (ALC) counts, the Spanish cytogenetics risk stratification system (Haematologica 2011;96:375), and the presence of circulating blasts. Neither the presence of spliceosome mutations (SF3B1/SRSF2/U2AF35) nor the percentage of RS (considered both as a continuous and a categorical variable), had an impact on either overall or leukemia-free survival. Conclusions: Among spliceosome mutations in CMML, those involving SRSF2 are by far the most frequent, even in the presence of ring sideroblasts. However, in patients with >50% RS, only SF3B1 mutations were seen whereas in those with 15–49% RS, SRSF2 mutations were more common. These observations suggest that SF3B1 mutations play a dominant but not exclusive role in the pathogenesis of RS. Regardless, the current study did not suggest prognostic impact from either the presence of the spliceosome mutations studied or the percentage of RS. Disclosures: No relevant conflicts of interest to declare.

Myelodysplastic/Myeloproliferative Neoplasms

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 264-272 ◽  
Author(s):  
Mario Cazzola ◽  
Luca Malcovati ◽  
Rosangela Invernizzi
Keyword(s):  
Clinical Laboratory ◽  
Myeloproliferative Neoplasms ◽  
Chronic Myelomonocytic Leukemia ◽  
World Health ◽  
Refractory Anemia ◽  
Molecular Diagnostic ◽  
Juvenile Myelomonocytic Leukemia ◽  
Lymphoid Tissues ◽  
Ring Sideroblasts ◽  
Myelomonocytic Leukemia

Abstract According to the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, myelodysplastic/myeloproliferative neoplasms are clonal myeloid neoplasms that have some clinical, laboratory, or morphologic findings that support a diagnosis of myelodysplastic syndrome, and other findings that are more consistent with myeloproliferative neoplasms. These disorders include chronic myelomonocytic leukemia, atypical chronic myeloid leukemia (BCR-ABL1 negative), juvenile myelomonocytic leukemia, and myelodysplastic/myeloproliferative neoplasms, unclassifiable. The best characterized of these latter unclassifiable conditions is the provisional entity defined as refractory anemia with ring sideroblasts associated with marked thrombocytosis. This article focuses on myelodysplastic/myeloproliferative neoplasms of adulthood, with particular emphasis on chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts associated with marked thrombocytosis. Recent studies have partly clarified the molecular basis of these disorders, laying the groundwork for the development of molecular diagnostic and prognostic tools. It is hoped that these advances will soon translate into improved therapeutic approaches.

Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia In Patients up to Age 75: Comparison of Survival In Patients with An Available Donor Compared to Patients without a Donor

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2381-2381
Author(s):  
Teresa Field ◽  
Janelle Perkins ◽  
Taiga Nishihori ◽  
Joseph Pidala ◽  
Hugo F. Fernandez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Analysis ◽  
Myelodysplastic Syndrome ◽  
Cell Transplantation ◽  
Research Funding ◽  
Chronic Myelomonocytic Leukemia ◽  
No Donor ◽  
Hematopoietic Stem ◽  
Myelomonocytic Leukemia

Abstract Abstract 2381 Allogeneic hematopoietic cell transplantation (HCT) remains the only curative treatment strategy for patients with Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML). Recent reduction of the transplant related toxicity has permitted the expansion of empiric age limitations for HCT up to 75 years. There has been limited comparative data on HCT focusing on donor availability in patients with MDS/CMML. Between January 2004 and September 2009, a total of 255 new patients (NP) with a diagnosis of MDS or CMML were evaluated for HCT at Moffitt Cancer Center. This report describes the outcomes of these patients with emphasis on donor availability. Donor Search Results: Of the 255 NP, 58 did not undergo a donor search. Reasons for not proceeding were as follows: Medicare declined coverage due to age >65 (18), waiting as have low risk disease (15), patient declined (6), patient seen as second opinion only (7) and patient was not eligible for HCT (12). These patients were not included in the survival analysis. Of the 197 patients who had a donor search initiated, a sibling (SIB) matched unrelated (MUD) or single HLA antigen/allele mismatch (mMUD) unrelated adult donor was found in 173 patients. A suitable adult donor was not identified in the remaining 24 patients. To mitigate bias due to factors giving a survival advantage to patients who were stable enough to survive the donor and proceed to HCT, the survival analysis included only those patients alive 90 days after the donor search was initiated. We have been able to identify donors within this time frame for 99% of the patients who ever found one, although time to transplant is longer. At the 90 days landmark, there were 164 patient in the Donor cohort, and 19 patients in the No Donor cohort. Donor Cohort: The median age was 56.6 yrs (18.5 – 73.5). Ninety-seven patients (59%) were older than 55 yrs and 26 (16%) were above 65 yrs. At the time of the transplant consult, IPSS risk was Low (10), Int-1 (44), Int-2 (48), High (25), AML (21), CMML (13), or not evaluable (NE) (3). Donors included SIB (60), MUD (75) and mMUD (29). Median follow-up of surviving patients is 27.7months (7.2 – 70.7). No Donor Cohort: Median age was 57.4 yrs (32.6 – 68.1) with 12 patients (63%) older than 55 yrs and 3 (16%) patients older than 65 years of age. IPSS at initiation of the donor search was Int-1 (5), Int-2 (6), High (5), AML (1) and CMML (2). Median follow-up is 9.2 months (1.4 – 61.5). Of the 19 patients with no donor, 3 patients received an umbilical cord blood HCT elsewhere and were analyzed by intent to treat. Outcomes: Patients with a donor had significantly improved overall survival from time of donor search vs. patients with no donor (P=0.007) with 2 year OS of 48% vs. 23%, respectively. Median survival for the donor group was 22.2 months [95% CI 14.7 – 35.7] vs. 10.1 months for those without a donor [95% CI 2.3 – 14.7]. Transplant: Of the 164 patients with a donor, 121 (74%) patients received the planned allogenic transplants. The 2-year overall survival (OS) after transplantation is similar for SIB (51%), MUD (39%) or mMUD (68%) transplant recipients (P=0.4), and also similar by age below or above 55 years (P=0.7). These data demonstrate that most patients with MDS or CMML can have a suitable donor identified and proceed to HCT. Overall survival is significantly improved for those patients who have a suitable sibling or unrelated donor. Disclosures: Lancet: Eisai: Consultancy; Celgene: Honoraria. Alsina: Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. List: Celgene: Research Funding.

Spliceosome GENE MUTATIONS ARE Also PRESENT In the Diverse Mutational Spectrum of CHRONIC Myelomonocytic LEUKEMIA

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1402-1402
Author(s):  
Hideki Makishima ◽  
Anna M Jankowska ◽  
Valeria Visconte ◽  
Ramon V. Tiu ◽  
Kathryn M Guinta ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Gene Mutations ◽  
P53 Mutation ◽  
Chronic Myelomonocytic Leukemia ◽  
Homozygous Mutation ◽  
Myelomonocytic Leukemia

Abstract Abstract 1402 Chronic myelomonocytic leukemia (CMML) is characterized by monocytic proliferation, cytomorphologic dysplasia and frequent progression to acute myelogeneous leukemia (AML). The molecular basis of CMML is poorly defined, although somatic mutations in a number of genes have recently been identified in a proportion of patients (epigenetic regulatory genes, spliceosomal genes, apoptosis genes, growth signal transducers and others). We performed a comprehensive analysis of molecular lesions, including somatic mutations detected by sequencing and chromosomal abnormalities investigated by metaphase and SNP-array karyotyping. We have selected a cohort of 72 patients (36 CMML1, 16 CMML2 and 20 sAML evolved from CMML). Our mutational screen performed in stages (as new mutations were discovered by our and other groups) and currently reveals mutations in UTX in 8%, DNMT3A in 9%, CBL in 14%, IDH1/2 in 4%, KRAS in 2.7%, NRAS in 4.1%, JAK2 in 1%, TET2 in 48%, ASXL1 in 43%, EZH2 in 5.5%, RUNX1 37%. Based on the discovery of various spliceosomal mutations in myeloid malignancies, novel mutations were also found in CMML, in U2AF1 in 12%, SF3B1 in 14%, SFRS19 in 6 % of cases tested. Chromosomal defects were detected in 60% of patients. In particular, a high frequency of somatic uniparental disomy (sUPD) were identified 71% of patients with abnormal cytogenetics, including UPD1p (N=3), UPD7q (N=8), UPD4q (N=6), UPD2p (N=2), UPD17q (N=2), UPD11q (N=5), UPDX (N=1), UPD21q (N=2). Some of the detected mutations were homozygous through their association with sUPD as for example for 3 EZH2, 1 UTX, 6 TET2, 2 DNMT3A, 5 CBL, 1 NRAS, 1 U2AF1 mutations. Furthermore, UPD17p implies that a P53 mutation is also present in this case as previously LOH17p was shown to be invariably associated with P53 mutations. Similarly, 2 cases of UPD17q imply that homozygous mutation of SRSF2, which is one of the Serine/arginine-rich splicing factor, may be present in this location and the mutation analysis is ongoing. In over 90% of >1 mutation was found but many patients harbored multiple mutations with frequent combinations of TET2/CBL or TET2/ASXL1 as well as RUNX1 and U2AF1 serving as examples. There was an accumulation of mutations from sAML, CMML2 and CMML1 suggesting stepwise accumulation of lesions. In serial studies, some of the mutations were present at the inception (e.g., TET2, ASXL1 and DNMT3A) in some cases originally heterozygous mutations were also while other can occur in the course of disease (e.g. CBL). RAS and DNMT3A mutations were associated with a higher blasts count. In sum, combined analysis of molecular lesions in CMML reveals that similar phenotype may be a result of diverse mutations associated with seemingly unrelated pathways and that clinical phenotype may be a result of a combination of mutations which accumulate as the disease progresses. Survival analyses will require large cohorts to account for various confounding factors including the presence of multiple chromosomal abnormalities and mutations in one patient, however currently EZH2, DNMT3 and CBL mutations appear to convey less favorable prognosis. Disclosures: No relevant conflicts of interest to declare.

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