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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]

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]

Among spliceosome component mutations, those involving SF3B1 are most frequent in myelodysplastic syndromes with ring sideroblasts (MDS-RS; ~ 75% incidence) and SRSF2 in chronic myelomonocytic leukemia (~ 28% incidence). We recently reported on the lack of prognostic significance for SF3B1 mutations in both MDS-RS and primary myelofibrosis (PMF). In the current study, we examined the prevalence and prognostic relevance of SRSF2 mutations in PMF. Among 187 patients screened, 32 (17%) harbored SRSF2 monoallelic mutations affecting residue P95. Significant associations were demonstrated between SRSF2 mutations and advanced age (P < .01), IDH mutations (P < .01), and higher DIPSS-plus risk category (P = .03). SRSF2 mutations were associated with shortened overall (P < .01) and leukemia-free (P < .01) survival; the adverse effect on survival was independent of DIPSS-plus (P = .01; HR = 1.9; 95% CI, 1.1-3.0) and IDH mutations (P < .01; HR = 2.3; 95% CI, 1.4-3.8). In conclusion, SRSF2 mutations are relatively common in PMF, cluster with IDH mutations, and are independently predictive of poor outcome. [ABSTRACT FROM AUTHOR]

The article discusses the study results on the use of telomerase inhibitor imetelstat for the treatment of myelofibrosis. Topics include the Janus kinase (JAK) inhibitors used for myeloproliferative neoplasm-associated myelofibrosis, the allogeneic stem-cell transplantation with its long-term disease-free remission but with the chronic graft-versus-host disease complications and induced significant myelosuppression with the use of the imetelstat drugs.

Janus kinase 2 (JAK2) mutations define polycythemia vera (PV). Calreticulin (CALR) and myeloproliferative leukemia virus oncogene (MPL) mutations are specific to JAK2-unmutated essential thrombocythemia (ET) and primary myelofibrosis (PMF). We examined the effect of these mutations on long-term disease outcome. One thousand five hundred eighty-one patients from the Mayo Clinic (n = 826) and Italy (n = 755) were studied. Fifty-eight percent of Mayo patients were followed until death; median survivals were 19.8 years in ET (n = 292), 13.5 PV (n = 267; hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.4-2.2), and 5.9 PMF (n = 267; HR, 4.5; 95% CI, 3.5-5.7). The survival advantage of ET over PV was not affected by JAK2/CALR/MPL mutational status. Survival in ET was inferior to the age- and sex-matched US population (P < .001). In PMF (n = 428), but not in ET (n = 576), survival and blast transformation (BT) were significantly affected by mutational status; outcome was best in CALR-mutated and worst in triple-negative patients: median survival, 16 vs 2.3 years (HR, 5.1; 95% CI, 3.2-8.0) and BT, 6.5% vs 25% (HR, 7.6; 95% CI, 2.8-20.2), respectively. We conclude that life expectancy in morphologically defined ET is significantly reduced but remains superior to that of PV, regardless of mutational status. In PMF, JAK2/CALR/MPL mutational status is prognostically informative. [ABSTRACT FROM AUTHOR]

Abstract: Comparative genomic hybridization (CGH), using oligo arrays with either 44,000 or 105,000 oligonucleotides, was performed on granulocyte-derived DNA from 71 patients with BCR-ABL-negative classic myeloproliferative neoplasms (MPNs): 32 primary myelofibrosis (PMF), 26 polycythemia vera (PV) and 13 essential thrombocythemia (ET). Copy number changes (CNCs) were detected in 44%, 35%, and 15% of the cases with PMF, PV and ET, respectively. In ET and PMF, CNCs were more frequently detected in the presence of JAK2V617F (50% vs. 19%; p =0.05). Conventional chromosome analysis was obtained in 57 patients either at diagnosis or within 1 year of the array CGH study; all 21 patients with PV and 11 with ET displayed normal cytogenetic findings despite the presence of CNCs in 29% and 18%, respectively. In PMF, the respective rates of CNCs and abnormal karyotype were 48% and 36%; karyotypic abnormalities, including unbalanced translocations, were often detected by array CGH as chromosomal gains or losses. This preliminary report suggests a potential value for array CGH in terms of both clinical diagnostics and genomic research in MPNs. [Copyright &y& Elsevier]

A letter to the editor is presented which discusses the prognostic advantage of calreticulin mutations in myelofibrosis.