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PURPOSE: Thrombocytopenia is a relatively common dose-limiting toxicity during peptide receptor radionuclide therapy (PRRT) in patients with NET. Although uncommon, some patients develop persistent cytopenia and eventually therapy-related myeloid neoplasm (t-MN), which has a dismal prognosis. As the indications for PRRT are expanding, it is important to investigate factors that may predict cytopenias during/after PRRT. We prospectively evaluated the prevalence of clonal hematopoiesis (CH) and cytopenia in patients with NET undergoing PRRT. MATERIALS AND METHODS: Patients with metastatic NET with plan to receive four cycles of lutetium-177 were enrolled. CH was evaluated before PRRT using a panel of 220 genes with a targeted depth of ≥1,000×. Patients were followed during PRRT and every 3 months thereafter. RESULTS: Of 37 patients enrolled, the median age was 68 years and 51.4% were male. Previous treatment exposures included alkylating agents in 30%, platinum agents in 8%, and external radiation in 13%. CH was detected in 35.1% using a variant allele frequency (VAF) cutoff of ≥2% and 45.9% with a VAF of ≥1%. The most common mutations were in age-related genes (DNMT3A , TET2). CH was not associated with anemia or neutropenia; however, it was associated with lower platelet count at baseline and more time spent in a thrombocytopenic state during/after PRRT. Five patients had bone marrow biopsies (BMBs) because of sustained hematologic dysfunction post-PRRT, and of those, diagnoses included clonal cytopenia of undetermined significance (CCUS) in three and idiopathic cytopenia of undetermined significance (ICUS) in two. CONCLUSION: CH is present in 35.1% of patients with NET and is associated with thrombocytopenia risk during PRRT. Future studies with long-term follow-up will delineate whether CH might be a predictor for higher risk of t-MN after PRRT. [ABSTRACT FROM AUTHOR]

Myeloid neoplasms are clonal hematopoietic stem cell disorders driven by the sequential acquisition of recurrent genetic lesions. Truncating mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with a high-risk disease phenotype with increased proliferation, epigenetic therapeutic resistance, and poor survival outcomes. We performed a multi-omics interrogation to define gene expression and chromatin remodeling associated with ASXL1MT in chronic myelomonocytic leukemia (CMML). ASXL1MT are associated with a loss of repressive histone methylation and increase in permissive histone methylation and acetylation in promoter regions. ASXL1MT are further associated with de novo accessibility of distal enhancers binding ETS transcription factors, targeting important leukemogenic driver genes. Chromatin remodeling of promoters and enhancers is strongly associated with gene expression and heterogenous among overexpressed genes. These results provide a comprehensive map of the transcriptome and chromatin landscape of ASXL1MT CMML, forming an important framework for the development of novel therapeutic strategies targeting oncogenic cis interactions. 'Mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with poor clinical outcome, however, their impact on chromatin dynamics remains unexplored. Here the authors use a multi-omics approach for chronic myelomonocytic leukemia (CMML) and investigate the transcriptome and chromatin landscape of ASXL1MT CMML. [ABSTRACT FROM AUTHOR]

Response to erythropoiesis-stimulating agents in patients with WHO-defined myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) Keywords: MDS/MPN-RS-T; myeloid leukaemia; erythropoiesis stimulating agents; ESA; MDS-RS; sideroblastic anaemia EN MDS/MPN-RS-T myeloid leukaemia erythropoiesis stimulating agents ESA MDS-RS sideroblastic anaemia e104 e108 5 04/30/20 20200501 NES 200501 To the Editor, In the 2016 iteration of the World Health Organisation (WHO) classification of myeloid neoplasms, myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) has been included as a unique entity, defined by the presence of erythroid lineage dysplasia in the presence or absence of multilineage dysplasia and persistent thrombocytosis (platelet count >=450 × 10 SP 9 sp /l), without other disease-defining genetic abnormalities (Arber I et al i ., [1]). We conducted a single institution retrospective study to assess ESA responses among WHO-defined patients with MDS/MPN-RS-T. After Institutional Review Board approval, adult patients with WHO-defined MDS/MPN-RS-T, diagnosed from years 2002 to 2014 at our institution, were included in the study. While ESA therapy has long been used to manage anaemia in MDS/MPN-RS-T, ours is the first study to meticulously document ESA response rates in these patients by using the IWG MDS/MPN overlap syndrome response criteria (Savona I et al i ., [14]). [Extracted from the article]

Summary: Survival prediction in essential thrombocythaemia (ET) and polycythaemia vera (PV) is currently based on clinically‐derived variables; we examined the possibility of integrating genetic information for predicting survival. To this end, 906 molecularly‐annotated patients (416 Mayo Clinic; 490 University of Florence, Italy), including 502 ET and 404 PV, were recruited. Multivariable analysis identified spliceosome mutations to adversely affect overall (SF3B1, SRSF2 in ET and SRSF2 in PV) and myelofibrosis‐free (U2AF1, SF3B1 in ET) survival; TP53 mutations predicted leukaemic transformation in ET; "adverse" mutations occurred in 51 (10%) ET and 8 (2%) PV patients. We confirmed the independent survival effect of adverse mutations [hazard ratio (HR) 2·4, 95% CI 1·6–3·5], age >60 years (6·6, 4·6–9·7), male sex (1·8, 1·3–2·4) and leukocytosis ≥11 × 109/l (1·6, 1·1–2·2), in ET, and adverse mutations (7·8, 3·1–17·0), age >67 years (5·4, 3·6–8·1), leukocytosis ≥15 × 109/l (2·8, 1·8–4·2) and thrombosis history (2·0, 1·4–2·9), in PV. HR‐based risk point allocation allowed development of three‐tiered mutation‐enhanced international prognostic systems (MIPSS) which were validated in both cohorts and performance was shown to be superior to conventional scoring systems. Spliceosome mutations enhance survival prediction in ET and PV and identify patients at risk for fibrotic progression. TP53 mutations predict leukaemic transformation in ET. [ABSTRACT FROM AUTHOR]

Primary myelofibrosis (PMF)-associated pruritus is often severe and requires treatment. Fifty-one patients with bone marrow-proven PMF with associated pruritus were identified from a primary cohort of patients with PMF (n = 566) seen at our institution. We conducted a retrospective review of the clinical characteristics, severity of pruritus, type of treatment, and response of these patients. Thirty-two out of 51 patients (63 %) reported severe PMF-associated pruritus and required a total of 108 treatment episodes, with complete response (CR), partial response (PR) and no response (NR) observed in 22, 23, and 55 % of episodes, respectively. The most common treatment categories included JAK inhibitors (n = 19), anti-depressants (n = 18), and antihistamines (n = 17). Highest CR rates were observed in patients treated with a JAK inhibitor (53 %) and immunomodulatory drugs (IMiDS (50 %)). Emerging targeted therapies may result in better symptom control and higher response rates in patients suffering from severe PMF-associated pruritus. [ABSTRACT FROM AUTHOR]

The article discusses a study which examines the nonhepatosplenic extramedullary manifestations (EMM) of chronic myelomonocytic leukemia (CMML). The study is the first to describe the frequency and spectrum of nonhepatosplenic EMM present at the time of CMML diagnosis. Nonhepatosplenic EMM were seen in 6% of patients at diagnosis.

A letter to the editor is presented which discusses the study on the clinical spectrum and outcomes of autoimmune diseases (AID) and/or systemic inflammatory syndromes (SIS) in patients with chronic myelomonocytic leukemia (CMML).

The article discusses a study which describes the frequency and molecular characteristics of double/compound KIT mutations in systemic mastocytosis (SM). The study involves patients with diagnosis of SM per 2008 World Health Organization criteria who were screened for mutations targeting KIT coding regions. The study found mutations distributed across exons, suggesting an incomplete annotation of KIT mutations in SM.

Among 826 patients with primary myelofibrosis ( PMF) and analysable metaphases on cytogenetic studies, 352 (42·6%) had abnormal karyotype, of which 240 (68·2%) were sole aberrations and 48 (13·6%) were complex; the most frequent abnormalities were 20q− (23·3%), 13q− (18·2%), +8 (11·1%), +9 (9·9%), chromosome 1q+ (9·7%) and −7/7q− (7·1%). Phenotypic correlates included: abnormal karyotype with anaemia ( P = 0·02), leucopenia ( P < 0·01) and thrombocytopenia ( P < 0·01); complex karyotype with younger age ( P = 0·04) and thrombocytopenia ( P < 0·01); leucopenia with 20q−, +8 and −7/7q− and thrombocytopenia with 20q− and −7/7q−. Cytopenias were less likely to occur with 13q−. 476 patients were annotated for JAK2/ CALR/ MPL mutations; abnormal karyotype frequencies were 43% in JAK2, 42% CALR, 33% MPL mutated and 34% triple-negative cases ( P = 0·3). A proportion of patients were also screened for ASXL1, EZH2, IDH1, IDH2, SRSF2, U2 AF1 and SF3B1 mutations; in all instances, mutational frequencies were higher in patients with normal karyotype, reaching significance for ASXL1 ( P = 0·02) and U2 AF1 ( P = 0·01). 13q− was associated with mutant CALR ( P = 0·03), +9 with mutant JAK2 ( P = 0·02) and 20q− with mutant SRSF2 ( P = 0·02). The current PMF study provides detailed cytogenetic information and correlations with mutations and clinical phenotype. [ABSTRACT FROM AUTHOR]

Background Vascular events in essential thrombocythemia ( ET) are associated with advanced age and thrombosis history. Recent information suggests additional effect from the presence of specific mutations. Objectives To examine the influence of age and thrombosis history on the reported association between mutational status and thrombosis-free survival in ET. Patients and Methods Analysis was performed using a Mayo Clinic cohort of 300 ET patients, and key findings were reanalyzed by including additional 102 Italian patients. Results Among 300 Mayo patients with ET (median age 55 yr, 60% females), mutational frequencies were 53% JAK2, 32% CALR, 3% MPL, and 12% JAK2, CALR and MPL wild type. One hundred and six (35%) patients experienced arterial ( n = 75) or venous ( n = 43) events, before ( n = 55) or after ( n = 71) diagnosis. In univariate analysis, compared to JAK2-mutated cases, JAK2, CALR and MPL wild type ( HR 0.31, 95% CI 0.11-0.86), and CALR-mutated (0.53, 95% CI 0.30-0.92) patients displayed better thrombosis-free survival. JAK2, CALR, and MPL wild type remained significant ( P = 0.03; HR 0.32, 95% CI 0.11-0.9) during multivariable analysis that included age ( P = 0.01) and thrombosis history ( P = 0.0006); a favorable impact from CALR mutations was of borderline significance ( P = 0.1; HR 0.62, 95% CI 0.35-1.1), but became significant ( P = 0.02) when multivariable analysis including thrombosis history ( P = 0.02) was performed on patients younger than 60 yr of age. Conclusions The favorable impact of mutational status on thrombosis-free survival in ET might be most evident for JAK2, CALR, and MPL wild type patients, whereas the favorable effect from CALR mutations might be confined to young patients. [ABSTRACT FROM AUTHOR]

The article discusses findings of a study on inferior survival in advanced systemic mastocytosis associated with mutation of ASXL1 and CBL genes. It states that KIT D816V mutation is considered as the driver mutation in systemic mastocytosis (SM), and mentions that patients with conditions like chronic myelomonocytic leukaemia (CMML), and acute myeloid leukaemia (AML) were analyzed. It notes that mutations in the non-KIT genes ASXL1, CBL and SETBP1 were associated with overall survival.

The prognostic significance of cytogenetic findings at diagnosis in polycythemia vera (PV) was investigated in a retrospective series of 137 patients. Cytogenetics were normal in 117 patients (85%) and displayed a −Y abnormality in five patients (7% of male patients), and other chromosomal abnormalities in 15 patients (11%). The most frequent cytogenetic anomalies were trisomy 8 ( n = 4), trisomy 9 ( n = 2), deletion 20q ( n = 2) and chromosomal 1 abnormalities ( n = 2). Parameters that were significantly associated with abnormal cytogenetics included age ≥60 yr ( P = 0.02), but not JAK2V617F allele burden, thrombosis, hemorrhage, leukemic/fibrotic transformation, or survival. We conclude that cytogenetic anomalies occur infrequently at PV diagnosis and do not confer an adverse outcome. [ABSTRACT FROM AUTHOR]

JAK2V617F and MPLW515L/K are myeloproliferative disorder (MPD)-associated mutations. We genotyped 552 individual hematopoietic colonies obtained by CD34+ cell culture from 16 affected patients (13 JAK2V617F and 3 MPLW515L/K) to determine (a) the proportion of colonies harboring a particular mutation in the presence or absence of cytokines, (b) the lineage distribution of endogenous colonies for each mutation, and (c) the differences (if any) in the pattern of mutation among the various MPDs, as established by genotyping of individual colonies. Genotyping analysis revealed cohabitation of mutation-negative and mutationpositive endogenous colonies in polycythemia vera as well as other MPDs. Culture of progenitor cells harboring MPLW515L/K yielded virtually no endogenous erythroid colonies in contrast to JAK2V617F-harboring progenitor cells. The mutation pattern (i.e., relative distribution of homozygous, heterozygous, or wild-type colonies) was not a distinguishing feature among the MPDs, and MPLW515 mutations were detected in B and/or T lymphocytes in all three patients tested. These observations suggest that clonal myelopoiesis antedates acquisition of JAK2V617F or MPLW515L/K mutations and that the latter is acquired in a lympho-myeloid progenitor cell. [ABSTRACT FROM AUTHOR]

The article discusses a study which aimed to investigate the association between JAK2V617F and advanced age, higher hemoglobin level, higher leukocyte count and lower platelet count in patients with essential thrombocythemia (ET). The study also considered the possible association of JAK2V617F with thrombocythemia complication. Allele-specific, quantitative polymerase chain reaction (PCR) analysis for JAK2V617F was performed in ET patients using genomic DNA from archived bone marrow.