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This phase I study evaluated selective JAK2 inhibitor XL019 in 30 patients with myelofibrosis. The initial dose cohorts were 100, 200, and 300 mg orally on days 1-21 of a 28-day cycle. Central and/or peripheral neurotoxicity developed in all patients. Subsequently, patients were treated on lower doses; neurotoxicity was again observed, leading to study termination. Peripheral neuropathy resolved in 50%, and central neurotoxicity in all patients within months after therapy cessation. Myelosuppression was minimal. The terminal half-life of XL019 was approximately 21 h, with steady state reached by Day 8. International Working Group defined responses were seen in three (10%) patients.

We evaluated single agent pomalidomide for myelofibrosis-associated anemia. First, 21 patients received pomalidomide 3.0mg/day on 21-day-on/7-day-off schedule. Due to poor tolerance the study was quickly suspended. Second, 29 patients received pomalidomide 0.5mg/day continuously. Three patients (10%) experienced clinical improvement in hemoglobin per International-Working-Group criteria (median time to response 1.6 months; median response duration 6.7 months). Ten patients were RBC-transfusion-dependent per Delphi criteria; 2 (20%) achieved RBC-transfusion-independence (time to response 0.9 months in both; response duration of 8.3 and 15 months). One grade 3/4 toxicity (neutropenia) occurred. Pomalidomide at low dose is well tolerated but has modest clinical activity in myelofibrosis.

BCR::ABL1 -negative myeloproliferative neoplasms (MPNs) are classically represented by polycythemia vera, essential thrombocythemia, and primary myelofibrosis. BCR::ABL1 -negative MPNs are significantly associated with morbidity and mortality related to an increased risk of thrombo-hemorrhagic events. They show a consistent association with splanchnic vein thrombosis (SVT), either represented by the portal, mesenteric or splenic vein thrombosis, or Budd-Chiari Syndrome. SVT is also a frequent presenting manifestation of MPN. MPNs associated with SVT show a predilection for younger women, high association with JAK2V617F mutation, low JAK2V617F variant allele frequency (generally <10 %), and low rates of CALR , MPL , or JAK2 exon 12 mutations. Next-Generation Sequencing techniques have contributed to deepening our knowledge of the molecular landscape of such cases, with potential diagnostic and prognostic implications. In this narrative review, we analyze the current perspective on the molecular background of MPN associated with SVT, pointing as well future directions in this field. • Ph -negative MPNs are associated with splanchnic vein thrombosis (MPN-SVT). • MPN-SVT are associated with JAK2V617F mutation at low variant allele frequencies. • NGS unveils new molecular aspects with diagnostic and prognostic implications. • Accurate identification of MPN-SVT is crucial for proper treatment. [ABSTRACT FROM AUTHOR]

Highlights • Glasdegib had an acceptable toxicity profile in patients with myelofibrosis. • Most common adverse events were dysgeusia, muscle spasms, and alopecia. • Modest improvements in patient-reported symptoms were observed with glasdegib. • Spleen volume reduction (SVR) was noted in some patients, but no patient had ≥35% SVR. Abstract Glasdegib is a potent and selective oral inhibitor of the Hedgehog pathway. We report data from the single-arm, lead-in cohort of an open-label phase 1b/2 trial of glasdegib in patients with primary/secondary myelofibrosis (MF) previously treated with at least one Janus kinase inhibitor (JAKi). Patients received glasdegib 100 mg orally once daily until there was no further clinical benefit. Primary endpoints included adverse events (AEs). Secondary endpoints included patients with spleen volume reduction (SVR) ≥35% at week 24, patients with ≥50% total symptom score (TSS) reduction, and pharmacokinetics. All 21 treated patients had one or more AE and five (23.8%) had serious AEs. Most common (>30%) AEs were dysgeusia (61.9%), muscle spasms (57.1%), alopecia (38.1%), fatigue (33.3%), and decreased appetite (33.3%). Although no patient had ≥35% SVR at week 24, one patient previously treated with ruxolitinib had an SVR of 32.9%. At week 12, two (9.5%) patients had ≥50% reduction in TSS from baseline and ˜40% had ≥20% reduction. One patient had an anaemia response. Following administration of glasdegib 100 mg once daily, the median time to peak plasma concentrations at steady-state generally occurred at 1 h post-dose. The safety profile of glasdegib monotherapy was manageable in patients with primary/secondary MF. Further study of glasdegib in combination with JAKi in a MF population may be warranted. [ABSTRACT FROM AUTHOR]

Highlights • This is the largest and first cohort study of PD-1, PD-L1 in Ph (-) MPN patients. • PD-1, PD-L1 are increased in ET, PV, and MF when they grouped as MPN than controls. • Positive expression (>50%) of PD-1, PD-L1 in 20% in CD34+ cells, Low in other cells. • No correlation between PD-1, PD-L1 levels and other clinical features (JAK2 etc). Abstract Programmed Cell Death Receptor (PD-1) and its Ligand (PD-L1) pathway inhibitor therapy has been explored in the field of oncology treatment mainly for solid tumors. In hematologic malignancies, there is limited information except for Hodgkin's lymphoma, and there is even less information regarding myeloproliferative neoplasm (MPN). Therefore, we explored this by first measuring PD-1 and PD-L1 levels (percentage of positive cells) in 63 patients with Philadelphia chromosome-negative MPN (Ph(-) MPN), including 16 MF (12 PMF, 2 post-PV-MF, 2 post-ET-MF), 29 ET, and 18 PV. We found there was no significant difference in PD-1 or PD-L1 levels between the different MPN groups but that there was a significant difference when PV, ET and MF were grouped as MPN and compared with controls, of all immune cells including CD4+, CD8+, CD14+ and CD34+ progenitor cells. We further found a higher incidence of higher expression levels (more than 50% of cells with positive expression) of PD-1 and PD-L1 (20% and 26%, respectively) in the CD34+ cells; in contrast, we found a low incidence (0.08–1.8%) in the immune cells in MPN patients. PD-1 and PD-L1 levels were also measured by MFI methods, and we obtained similar results except the measurements by percentage appeared to be more sensitive than the MFI methods. We found no correlation between PD-1 and PD-L1 expression levels and clinical features including WBC, platelet counts, hemoglobin levels, presence or absence of the JAK2, MPL, or CALR gene mutation, or splenomegaly. Since MPN represents stem cell disorders, the presence of elevated expression of PD-1 and PD-L1 in these cells suggests that the exploration of PD-1 and PD-L1 pathway inhibitor therapy may be worthwhile in Ph(-) MPN. [ABSTRACT FROM AUTHOR]

Diagnosis of myelodysplastic syndromes (MDS) is often challenging and requires integration of clinical, morphologic, cytogenetics and molecular information. Flow cytometry immunophenotyping (FCIP) can support the diagnosis by demonstration of numerical and immunophenotypic abnormalities of progenitor and maturing myelomonocytic and erythroid populations. We have previously shown that comprehensive immunophenotypic analysis of the progenitor population is valuable in the diagnosis of MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). This study was designed to improve the analysis method and confirm its value in a larger cohort of patients. FCIP of bone marrow samples from 105 patients with cytopenia(s) (with or without leukocytosis) and clinical concern for MDS or MDS/MPN was performed using a single-tube/10-color/13-marker assay. A modified analysis approach was used to obtain 11 progenitor parameters and 2 myelomonocytic parameters. Significantly higher number of abnormalities were identified in MDS and MDS/MPN cases when compared to cytopenic patients not meeting the diagnostic criteria for MDS (Non-MDS). A FCIP score that combined the 13 parameters showed a sensitivity of 89.8% and specificity of 93.5% for the diagnosis of MDS and MDS/MPN. The sensitivity was 100% for both MDS/MPN and higher-risk MDS, and 81.3% for lower-risk MDS. This study confirms that detailed immunophenotypic analysis of the progenitor population is powerful in the diagnosis of MDS and MDS/MPN. The combination of markers used in the panel allowed for evaluation of two relatively new parameters, namely myeloid progenitor heterogeneity and stem cell aberrancy, which improved the sensitivity of the assay for lower-risk MDS. • Deep immunophenotypic analysis of progenitor cells is valuable in diagnosis of MDS. • MDS and MDS/MPN are associated with abnormal progenitor cell heterogeneity. • Stem cell aberrancy is commonly identified in myelodysplastic neoplasms. • CD371 and CD45RA combination is useful in flow cytometric evaluation of MDS. [ABSTRACT FROM AUTHOR]

Impaired function of the endoplasmic stress (ER) response causes numerous pathological conditions, including tissue fibrosis. In the present study, we aimed to determine the pathological role of ER stress response systems in myeloproliferative neoplasms (MPNs). We found increased expression of the chaperone protein glucose-regulated protein (GRP) 78, a central regulator of ER stress, in megakaryocytes from primary myelofibrosis or postessential thrombocythemia myelofibrosis patients. GRP78 was overexpressed in JAK2V617F-harboring cell lines; however, inhibitors of ER stress did not affect the expression levels of GRP78. In contrast, ruxolitinib, a well-known inhibitor of JAK2V617F, clearly blocked GRP78 expression in these cells through downregulation of transcription factor 4 (ATF4). Interestingly, GRP78 was secreted from HEL and SET-2 cells into culture media. Coculture of these cells with HS-5 cells, a human bone marrow stroma-derived cell line, induced enhanced expression of lysyl oxidase (LOX), which mediates cross-linking of collagen fibers and induces tissue fibrosis, in HS-5 cells. An anti-GRP78 neutralizing antibody abrogated LOX elevation; in contrast, recombinant GRP78 protein induced LOX protein expression in HS-5 cells. Our observations suggest that the oncogenic protein JAK2V617F induces overexpression and release of GRP78, which may induce a fibrotic phenotype in surrounding bone marrow stromal cells. • GRP78, an endoplasmic response regulating chaperon is overexpressed in primary megakaryocytes derived from PMF or secondary MF patients. • JAK2V617F induced overexpression of GRP78 through activation of transcription factor ATF4. • JAK2V617F harboring HEL and SET-2 cells secreted GRP78 into microenvironment. • Secreted GRP78 work on bone marrow stromal cell line to activate JNK pathway leading to expression of lysyl oxidase. • Overexpression of lysyl oxidase in stromal cells were found in bone marrow biopsy specimens from PMF or secondary MF patients. [ABSTRACT FROM AUTHOR]

Background There is mounting evidence that Langerhans cell histiocytosis (LCH) and acute myeloid leukemia (AML) are hematopoietic neoplasms that arise from the same myeloid precursor cell. In addition, studies suggest a relationship between LCH and primary idiopathic myelofibrosis (MF). Furthermore familial LCH, AML, and MF have each been reported. Methods We examined more than 750 pedigrees of familial hematologic malignancies for evidence of familial LCH, AML, and/or MF and identified one family with all three neoplasms, which is presented here. Findings In four generations of this large family there are five cases of AML in three generations, two cases of LCH in two generations and three cases of MF in two generations. Anticipation of −18 and −6 years was present in the patients with MF, and −8 years in the patients with LCH. Anticipation was also identified between one AML patient pair in generations III and IV (−18 years) and three patients with AML in generations II, III, and IV (−5 years and −10 years). Interpretation This is the first report of familial LCH, AML, and MF in one family. The pedigree suggests a common basis for these entities, which is further suggested by the presence of anticipation in the pedigree. [ABSTRACT FROM AUTHOR]

Objectives Transferrin saturation (TSAT) 20% or less is considered to represent functional iron deficiency in the context of malignant disease, phenomenon mediated through inflammatory changes of iron homeostasis. We aimed to investigate clinical and prognostic significance of low TSAT in patients with primary (PMF) and secondary myelofibrosis (SMF), malignant diseases characterized by strong inflammatory milieu. Methods We retrospectively analyzed 87 patients with myelofibrosis and compared TSAT with disease specific parameters. Results One-third of patients had TSAT ≤20%. Lower TSAT was significantly associated with Janus-kinase-2 ( JAK2 ) mutation (P = 0.007), transfusion independency (P = 0.003), higher platelets (P = 0.004), lower mean-corpuscular-volume (P < 0.001), lower ferritin (P < 0.001), higher absolute-neutrophil-count (P = 0.027), lower absolute-lymphocyte-count (P = 0.041) and lower albumin (P = 0.018). PMF patients presenting with low TSAT (≤20%) experienced significantly shorter overall-survival (OS) (HR = 2.43; P = 0.017), whereas TSAT did not affect OS of SMF patients (HR = 1.48; P = 0.623). Low TSAT remained significantly associated with inferior OS in PMF in a series of multivariate Cox regression models comparing its properties to anemia, transfusion dependency, ferritin and Dynamic-International-Prognostic-System (DIPSS). Conclusions Low TSAT has detrimental effect on survival of PMF patients. This effect is independent of anemia and of ferritin levels that seem to be better at representing iron overload in PMF patients. [ABSTRACT FROM AUTHOR]

Myelofibrosis is a myeloproliferative neoplasm associated with progressive cytopenias and high symptom burden. MF patients with thrombocytopenia have poor prognosis but the presence of thrombocytopenia frequently precludes the use of JAK2 inhibitors. In this study, we assessed quality of life and symptom burden in 418 MF patients with (n = 89) and without (n = 329) thrombocytopenia using prospective data from the MPN-QOL study group database, including the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and Total Symptom Score (MPN10). Thrombocytopenia, defined as platelet count <100 × 10 9 /L (moderate 51–100 × 10 9 /L; severe ≤50 × 10 9 /L), was associated with anemia (76% vs. 45%, p < 0.001), leukopenia (29% vs. 11%, p < 0.001), and need for red blood cell transfusion (35% vs. 19%, p = 0.002). Thrombocytopenic patients had more fatigue, early satiety, inactivity, dizziness, sad mood, cough, night sweats, itching, fever, and weight loss; total symptom scores were also higher (33 vs. 24, p < 0.001). Patients with severe thrombocytopenia were more likely to have anemia (86% vs. 67%, p = 0.04), leukopenia (40% vs. 20%, p = 0.04), and transfusion requirements (51% vs. 20%, p = 0.002) but few differences in symptoms when compared to patients with moderate thrombocytopenia. These results suggest that MF patients with thrombocytopenia experience greater symptomatic burden than MF patients without thrombocytopenia and may benefit from additional therapies. [ABSTRACT FROM AUTHOR]

Juvenile myelomonocytic leukemia (JMML) is a life-threatening myeloproliferative neoplasm. The chemotherapeutic effect on survival remains unclear, and feasible standardized response criteria are yet to be established. We aimed to evaluate the chemotherapeutic response and its effect on survival in patients with JMML. A retrospective registry was reviewed for children diagnosed with JMML between 2000 and 2019. Response was assessed according to the criteria proposed by the International JMML Symposium in 2007 (criteria I) and the updated version in 2013 with its modifications (criteria II). A total of 73 patients were included in this study. Complete response (CR) rates were 46.6% and 28.8% using the criteria I and criteria II, respectively. A platelet count ≥ 40 × 109/L at diagnosis was associated with higher CR rates using the criteria II. Patients with criteria I-based CR had a better overall survival (OS) than those without CR (81.1% vs. 49.1% at 5 years). Patients with criteria II-based CR showed better OS (85.7% vs. 55.5% at 5 years) and event-free survival (EFS) (71.1% vs. 44.7% at 5 years) than those without CR. Additionally, a trend toward better EFS was observed in patients with criteria II-based CR than in those with criteria I-based CR but without criteria II-based CR (71.1% vs. 53.8% at 5 years). Chemotherapeutic response is associated with better survival outcomes. Along with splenomegaly, the addition of platelet count recovery, existence of extramedullary leukemic infiltration, and more stringent leukocyte counts to the response criteria allows for a more sensitive prediction of survival outcomes. • Standardized response criteria are yet to be established in treatment of JMML. • Complete response was assessed by the two criteria (criteria I and II). • A platelet count ≥40×109/L at diagnosis was associated with higher CR rates. • Patients with criteria II-based CR showed better OS and EFS than those without. • More stringent response criteria might be helpful in predicting survival outcomes. [ABSTRACT FROM AUTHOR]

Background Ruxolitinib is established as treatment for symptomatic myeloproliferative neoplasm (MPN)-associated myelofibrosis. The strict inclusion and exclusion criteria and dose modification rules that applied to the COMFORTI and II studies that led to the licensing of ruxolitinib are not always applicable to routine clinical practice. Thus physicians now face decisions regarding ruxolitinib use that were not addressed in these pivotal trials. Methods We performed an online survey of hematologists practicing in Europe, Israel, the United Kingdom and the United States. Demographic details regarding the physicians and their practice as relates to MPNs were collected. Management decisions pertaining to the use of ruxolitinib were obtained regarding 10 clinical scenarios relating to anemia, thrombocytopenia, frailty, infection and lack or loss of response to ruxolitnib in MF patients. Results 140 physicians responded to the survey. There were marked differences regarding their decisions for ruxolitinib administration in MF patients with or developing anemia or thrombocytopenia. Similarly there was little consensus regarding management of patients refractory or losing a response to ruxolitinib. There were differences between “MPN-focused” and “non-MPN-focused” physicians in certain areas. Conclusion Physician practices regarding management of MF patients experiencing ruxolitinib-related toxicities or in whom response to the drug is lost was variable. This was true of “MPN-focused” and “non-MPN-focused” physicians in certain cases. Physician education and experience in using ruxolitinib may improve patient management. [ABSTRACT FROM AUTHOR]

Mutations in Janus kinase 2 ( JAK2 ) are implicated in the pathogenesis of Philadelphia-chromosome negative myeloproliferative neoplasms, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Gandotinib (LY2784544), a potent inhibitor of JAK2 activity, shows increased potency for the JAK2 V617F mutation. The study had a standard 3 + 3 dose-escalation design to define the maximum-tolerated dose. Primary objectives were to determine safety, tolerability, and recommended oral daily dose of gandotinib for patients with JAK2 V617F -positive myelofibrosis, essential thrombocythemia, or polycythemia vera. Secondary objectives included estimating pharmacokinetic parameters and documenting evidence of efficacy by measuring clinical improvement. Thirty-eight patients were enrolled and treated (31 myelofibrosis, 6 polycythemia vera, 1 essential thrombocythemia). The maximum-tolerated dose of gandotinib was 120 mg daily, based on dose-limiting toxicities of blood creatinine increase or hyperuricemia at higher doses. Maximum plasma concentration was reached 4 h after single and multiple doses, and mean half-life on day 1 was approximately 6 h. Most common treatment-emergent adverse events were diarrhea (55.3%) and nausea (42.1%), a majority of which were of grade 1 severity. Best response of clinical improvement was achieved by 29% of myelofibrosis patients. A ≥50% palpable spleen length reduction was observed at any time during therapy in 20/32 evaluable patients. Additionally, ≥50% reduction in the Total Symptom Myeloproliferative Neoplasm Symptom Assessment Form Score was seen in 11/21 (52%) and 6/14 patients (43%) receiving ≥120 mg at 12 and 24 weeks respectively. Gandotinib demonstrated an acceptable safety and tolerability profile, and findings at the maximum-tolerated dose of 120 mg supported further clinical testing. Clinicaltrials.gov identifier: NCT01134120. [ABSTRACT FROM AUTHOR]

We measured plasma levels of high-sensitivity C-reactive protein (hs-CRP) in 526 subjects with primary myelofibrosis (PMF). Thirty-eight percent had an elevated hs-CRP level (≥ 0.3 mg/dL). Elevated hs-CRP levels were associated with a progressive disease phenotype, including anemia, high white blood cell count, low platelet count, increased splenomegaly, increased risk of blast transformation, and worse survival. Age ≥ 52 years, but no other demographic characteristics, was associated with an elevated hs-CRP level in multivariable logistic regression (odds ratio [OR], 4.29; 95% CI, 2.73-6.77; P < 0.001). Subjects with JAK2 V617F mutation and an allele burden ≥ 50% had an age-independent higher incidence of elevated hs-CRP level (OR = 1.97; 95% CI,1.21–3.22; P = 0.006) compared with a combined cohort of subjects with JAK2 V617F <50% allele burden, CALR, MPL mutations, or no detectable driver mutations. Neither ASXL1 or EZH2 sub-clonal mutations, nor JAK2 46/1 haplotype or the A3669G polymorphism of glucocorticoid receptor were significantly associated with increased hs-CRP levels. Subjects with age ≥ 52 years and JAK2 V617F with ≥ 50% allele burden had a phenotype of progressive disease. Our data indicate that older age and high JAK2 V617 allele burden are major determinants of inflammation in PMF, and are associated with disease progression. [ABSTRACT FROM AUTHOR]

Momelotinib is a potent inhibitor of JAK1 and JAK2 that demonstrated efficacy in patients with primary and secondary myelofibrosis. This phase 2, open-label, randomized study evaluated the efficacy and safety of oral once-daily momelotinib (100 mg and 200 mg) for the treatment of polycythemia vera (PV) and essential thrombocythemia (ET). The primary endpoint for PV was overall response rate (ORR), defined as the proportion of patients with hematocrit <45%, white blood cell count <10 × 10 9 /L, platelet count ≤400 × 10 9 /L, and resolution of palpable splenomegaly, each lasting ≥4 weeks. The definition of ORR for ET excluded the hematocrit component. A total of 39 patients (28 PV, 11 ET) were enrolled, with 28 patients receiving ≥12 weeks of treatment. The study was terminated due to limited efficacy. Two patients (ORR 5.1%) met the primary efficacy endpoint (both PV 200 mg). Predose plasma levels of momelotinib were stable over time. A total of 31 (79.5%) patients experienced momelotinib-related adverse events (AEs), the most frequent being headache (23.1%), dizziness (18.0%), somnolence (15.4%), nausea (15.4%), and fatigue (15.4%). Three patients experienced serious AEs (7.7%), with 1 considered related to momelotinib (dyspnea). Peripheral neuropathy occurred in 7 (17.9%) patients (4 PV, 3 ET). [ABSTRACT FROM AUTHOR]

Myelofibrosis is a myeloproliferative neoplasm that is characterized by splenomegaly, profound symptom burden, and cytopenias. JAK inhibitor therapy offers improvements in splenomegaly, symptom burden, and potentially survival; however, cytopenias remain a significant challenge. Danazol has previously demonstrated improvements in myelofibrosis-associated anemia. We conducted a phase II clinical trial evaluating the efficacy and tolerability of combination therapy with ruxolitinib, an oral JAK inhibitor, and danazol. Fourteen intermediate or high-risk MF patients were enrolled at 2 institutions. Responses per IWG-MRT criteria were stable disease in 9 patients (64.2%) clinical improvement in 3 (21.4%) all of which were spleen responses, partial response in 1 (7.1%) and progressive disease in 1 (7.1%). Despite limited IWG-MRT response, stabilization of anemia and thrombocytopenia was demonstrated. In JAK inhibitor naïve patients, 4/5 (80%) had stable or increasing hemoglobin. Of the 9 patients on prior JAK inhibitor, 5 patients (55.5%) and 8 patients (88.9%) had stable or increasing hemoglobin or platelet levels, respectively. Adverse events possibly related included grade 3 or greater hematologic toxicity in ten patients (71.4%) and non-hematologic toxicity in two patients (14.3%). Although combination therapy did not lead to increased hematologic response per IWG-MRT criteria, hematologic stabilization was observed and may be clinically useful. [ABSTRACT FROM AUTHOR]

Along with reducing spleen size, relieving symptom severity is a key objective of the treatment of myelofibrosis (MF). Several questionnaires have been developed for patient self-report of MF symptoms in clinical trials and each includes unique instructions, items, and/or response scales. This variability in questionnaire content increases uncertainty; it is unclear which questionnaire is the most appropriate for assessing MF symptoms and it makes comparisons across trials difficult. The Patient-Reported Outcome (PRO) Consortium’s MF Working Group (WG) was established to review existing MF symptom questionnaires and to develop a harmonized, consensus-based PRO questionnaire for use in future MF trials. The WG focused on the seven core symptoms of MF: fatigue, night sweats, pruritus, abdominal discomfort, pain under the ribs on the left side, early satiety, and bone pain. The resulting Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) asks respondents to report symptom severity at its worst for each of the seven items on a 0 (Absent) to 10 (Worst Imaginable) numeric rating scale. The MFSAF v4.0, for which there are 24-h and 7-day recall formats, will be maintained and licensed by the Critical Path Institute and made publicly available for use in future clinical trials. [ABSTRACT FROM AUTHOR]

Prognostic scoring systems for primary myelofibrosis (PMF) are not accurate in patients with post-essential thrombocythemia and post-polycythemia vera myelofibrosis (PET-MF; PPV-MF). Given the paucity of data describing the clinical characteristics, disease course and outcomes of these patients, we sought to describe and compare the clinical characteristics and outcomes of 755 patients with PMF, 181 with PPV-MF, and 163 with PET-MF referred to our institution between 1984 and 2013. The median follow-up was 31 months, and 56% (n = 616) patients had died. Over an observation period of 3502 person-years, 11% of patients had progression to AML, with similar rates among groups. The proportion of patients with transfusion dependency (higher in PMF), leukocytosis and systemic symptoms (higher in PPV-MF), and thrombocytopenia (higher in PMF, PPV-MF) differed among groups. Median overall survival (OS) was longest in PET-MF patients (73 mo vs 45 mo (PMF) vs 48 mo (PPV-MF), p < 0.001). Stratification of OS by DIPSS was only discriminatory in patients with PMF, and it failed to distinguish higher risk patients with PPV/PET-MF. In multivariate analysis, predictors of inferior OS were higher age, anemia, systemic symptoms, thrombocytopenia, and high peripheral blasts in PMF; age, anemia, and systemic symptoms for PPV-MF; and anemia, peripheral blasts and thrombocytopenia in PET-MF. Although the clinical characteristics of PPV/PET-MF patients are not substantially different from those with PMF, their outcomes differ and prognostic scoring systems for PET/PPV-MF should be improved. [ABSTRACT FROM AUTHOR]

Extreme thrombocytosis induces an acquired thrombotic-hemorrhagic diathesis, and left uncontrolled is a harbinger of potentially fatal vascular complications. Currently, cytoreduction with medical therapy remains the mainstay of hyperthrombocytosis management. However, it offers a less-than-ideal option in situations where a rapid reduction in platelets is urgently needed, as in the presence of vital end-organ ischemia or to ameliorate of life-threatening hemorrhage. The role of thrombocytapheresis, or plateletpheresis, in hyperthrombocytosis has become increasingly obsolete given the proactive titration of cytoreductive therapies and early identification and correction of reversible causes of reactive thrombocytosis. Despite its narrowed indications, plateletpheresis continues to offer a valuable temporizing measure in platelet count reduction before cytoreductive agents exert their maximal effect. In this context, it is important for the treating physician to be aware of the symptoms and risks associated with hyperthrombocytosis to inform best clinical practices. In this review, we discuss the role of plateletpheresis in the modern-day management of hyperthrombocytosis in patients with myeloproliferative neoplasms through a case based review of the literature. It becomes apparent throughout the discussion that the decision to perform plateletpheresis should be individualized based upon the clinical scenario, degree of thrombocytosis, available infrastructure and every patient’s risk profile. [ABSTRACT FROM AUTHOR]

The discovery that Philadelphia-negative classical myeloproliferative neoplasms (MPNs) present with several molecular abnormalities, including the mostly represented JAK2V617F mutation, opened new horizons in the diagnosis, prognosis, and monitoring of these disorders. However, the great strides in the knowledge on molecular genetics need parallel progresses on the best approach to methods for detecting and reporting disease-associated mutations, and to shape the most effective and rationale testing pathway in the diagnosis, prognosis and monitoring of MPNs. The MPN taskforce of the Italian Society of Hematology (SIE) assessed the scientific literature and composed a framework of the best, possibly evidence-based, recommendations for optimal molecular methods as well as insights about the applicability and interpretation of those tests in the clinical practice, and clinical decision for testing MPNs patients. The issues dealt with: source of samples and nucleic acid template, the most appropriate molecular abnormalities and related detection methods required for diagnosis, prognosis, and monitoring of MPNs, how to report a diagnostic molecular test, calibration and quality control. For each of these issues, practice recommendations were provided. [ABSTRACT FROM AUTHOR]

A recent study, showing the absence of paroxysmal nocturnal hemoglobinuria clones in myelofibrosis, has reopened the debate around the role of decreased haptoglobin in this disease. We present here a large prospective analysis of the clinical significance of low haptoglobin in 152 patients with myelofibrosis. Low haptoglobin (<32 mg/dL) was observed in 50 patients (33%). Decreased haptoglobin did not associate with low hemoglobin levels, positive Coombs test or abnormal liver function tests, suggesting it is not result of autoimmune hemolytic anemia or liver cirrhosis. Factors strongly correlating with decreased haptoglobin were high JAK2 allele burden and ongoing treatment with JAKi. Larger scale serial measurement and longer follow-up is needed to further explain our findings. [ABSTRACT FROM AUTHOR]

Abstracts Sole del(7p) is a rare finding in myeloid neoplasms and its clinical significance is largely unknown. Here we report 10 patients with isolated del(7p), 4 had acute myeloid leukemia (AML), 2 myelodysplastic syndromes (MDS), 1 chronic myelomonocytic leukemia (CMML), 1 primary myelofibrosis (PMF), and 2 AML in remission. Seven patients had large and 3 had small del(7p) clone. For patients with AML, 3 acquired del(7p) either at disease relapse or disease progression, then became refractory to therapy and died shortly thereafter (median 5 months). Detection of del(7p) in patients with MDS, CMML, or PMF appeared to predict poorer prognosis as all 4 patients experienced disease progression or transformation to AML after 5–24 months. In the remaining 3 patients (1 AML and 2 AML in remission), del(7p) was only detected in 10% to 30% of metaphases and was a transient finding that did not appear to have any clinical impact. We conclude that detection of del(7p) in myeloid neoplasms, when presents as a major clone, often poses a high risk for disease progression and refractoriness to therapy; whereas when del(7p) presents as a small clone, it may not carry any clinical significance. [ABSTRACT FROM AUTHOR]

Polycythemia vera, essential thrombocytosis, and myelofibrosis are chronic Philadelphia-negative myeloproliferative neoplasms that are characterized by clonal hematopoiesis, splenomegaly, risk of hemorrhagic and thrombotic sequelae, and profound symptom burden. We review the outcomes of 75 myeloproliferative neoplasm patients treated with pegylated interferon alpha 2a off study at an academic medical center. In the 56 treated polycythemia vera and essential thrombocytosis patients, a complete or partial response was obtained in 78.6% of patients per ELN/IWG-MRT revised criteria, with >80% of polycythemia vera patients becoming phlebotomy independent and 60% of essential thrombocytosis patients having platelet normalization with therapy. In the 19 treated myelofibrosis patients, stable disease was seen in 63.2% of patients. Vascular events occurred in 2/75 (2.6%) of treated patients while on therapy. Grade 3 toxicity was uncommon with leukopenia noted in 1 patient (1.3%). The most common adverse event overall was grade 1 fatigue in 18.7%. This retrospective single center analysis demonstrates pegylated interferon alpha 2a is active and well-tolerated therapy outside the support of a clinical trial. These results substantiate the previously reported efficacy of pegylated interferon alpha 2a in myeloproliferative neoplasms. Further prospective and randomized clinical trial data is required to better delineate pegylated interferon alpha 2a’s use in myeloproliferative disease, with emphasis placed on comprehensive molecular characterization, allelic burden quantification, and measurement of histologic response. [ABSTRACT FROM AUTHOR]

Myelofibrosis is a chronic and progressive myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating symptoms and leukemic transformation. Ruxolitinib, an oral JAK1/2 inhibitor, is highly effective in ameliorating systemic symptoms and reducing splenomegaly. Current clinical research is focused on the evaluation of agents based on pre-clinical rationale that can result in disease course modification. Panobinostat is a pan-histone deacetylase inhibitor that has demonstrated clinical activity as a single agent in early phase trials of myelofibrosis. We previously conducted a phase I trial of panobinostat monotherapy in patients with myelofibrosis and determined 25 mg thrice weekly as the recommended phase II dose. We then completed an investigator initiated, Simon 2-stage, phase II trial of 22 myelofibrosis patients at our single institution. After 6 cycles of therapy, the overall response rate by IWG-MRT criteria was 36% (8/22; 95% CI: 16–56%). The median percent reduction in spleen volume was 34% (range, 1.6%–73%) in eight evaluable patients. The average reduction in JAK2V617F allele burden was 6.8% (Range; −4.0% to 20.2%) and one patient obtained a complete molecular response. Six patients remained on therapy in the extension phase for a median of 18 months (range, 7–44). Treatment discontinuation was frequent due to patient/physician perception of therapy ineffectiveness. The optimal dosing of panobinostat for the treatment of MF remains somewhat ill-defined but appears to be most effective and better tolerated when administered at lower doses over a prolonged duration of therapy. [ABSTRACT FROM AUTHOR]

The presence of JAK2 exon 12 mutation was included by the 2016 World Health Organization (WHO) Classification as one of the major criteria for diagnosing polycythemia vera (PV). Few studies have evaluated the clinical presentation and bone marrow morphology of these patients and it is unclear if these patients fulfill the newly published criteria of 5th edition WHO or The International Consensus Classification (ICC) criteria for PV. Forty-three patients with JAK2 exon 12 mutations were identified from the files of 7 large academic institutions. Twenty patients had complete CBC and BM data at disease onset. Fourteen patients met the diagnostic criteria for PV and the remaining six patients were diagnosed as MPN-U. At diagnosis, 9/14 patients had normal WBC and platelet counts (isolated erythrocytosis/IE subset); while 5/14 had elevated WBC and/or platelets (polycythemic /P subset). We found that hemoglobin and hematocrit tended to be lower in the polycythemia group. Regardless of presentation (P vs IE), JAK2 deletion commonly occurred in amino acids 541–544 (62 %). MPN-U patients carried JAK2 exon 12 mutation, but did not fulfill the criteria for PV. Half of the patients had hemoglobin/hematocrit below the diagnostic threshold for PV, but showed increased red blood cell count with low mean corpuscular volume (56–60 fL). Three cases lacked evidence of bone marrow hypercellularity. In summary, the future diagnostic criteria for PV may require a modification to account for the variant CBC and BM findings in some patients with JAK2 exon 12 mutation. • A significant proportion of studied patients with JAK2 exon 12 mutation did not fulfill the current WHO/ICC criteria for PV. • JAK2 exon 12 analysis is required in all patients with elevated RBC values when JAK2 V617F mutation is negative. • Awareness of the variable bone marrow morphology findings in PV remains key to correct diagnosis. [ABSTRACT FROM AUTHOR]

EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250 mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190 mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion. [ABSTRACT FROM AUTHOR]

Lenalidomide, with or without prednisone, is an active therapy for patients with myelofibrosis (MF). We provide an update of a phase II study of lenalidomide plus prednisone in patients with MF, after median follow up of 9 years. Forty patients were enrolled in the study and all patients were evaluable for response. Response to the treatment was reevaluated using IWG response criteria published in 2013: quality of response improved over time and overall response rate was 35%. Response in splenomegaly was seen in 39% of patients and anemia response in 32%. The median time to treatment failure (TTF) in all patients was 8.2 months and the median duration of response was 34.6 months. Response was highly durable in some patients: six patients (15%) had TTF for more than 60 months (5 years) and three patients are still on the treatment beyond 109 months (9 years). Complete and partial responses were seen in one and five patients, respectively, but achieving deeper response was not necessary for the response to be durable. New clinical studies are needed to explore safe and well tolerated lenalidomide-based combination strategies for patients with MF. [ABSTRACT FROM AUTHOR]

Although BCR-ABL negative myeloproliferative neoplasms (MPN) – and especially myelofibrosis (MF) – are recognized to be associated with autoimmune phenomena, immune derangements in MPN have been much less studied. Myeloid-derived suppressor cells (MDSC) are one type of important immune modulator cell. Therefore, we studied MDSCs in MPN disease. MDSCs were studied in two cohorts: the first cohort was 55 patients including 16 primary myelofibrosis (PMF), 7 post-polycythemia vera (PV)-MF, 2 post-essential thrombocythemia (ET)-MF, 11 ET, 17 PV, 2 undefined MPN disorder, and 23 normal controls; the second cohort included 38 patients: 17 ET, 7 PMF, 3 ET-MF, 2 PV-MF, 9 PV patients, and 20 normal volunteers. The second cohort was studied using freshly collected specimens and a comparable age group as controls. CD11b + , CD14 − , and CD33 + cells were defined as MDSCs in both cohorts by flow cytometry. Since there are no differences in MDSC levels among different MPN categories, they were grouped as MPNs. The results showed that MDSCs were significantly elevated in MPNs compared with controls in both cohorts. We also performed RT-PCR and found that MPN patients have significantly elevated arginase-1 mRNA compared with controls, and sorted MDSCs were found to have suppressor T cell activity in MPNs, substantiating the hypothesis that levels of MDSCs are, in fact, deranged in MPNs. MDSC levels were not correlated with JAK2 status, white blood cells, Hb levels, platelet counts, splenomegaly, or the degree of bone marrow fibrosis (in MF). Further studies in immune therapy involving MDSC inhibitors or differentiation may be developed to treat MPN disease. [ABSTRACT FROM AUTHOR]

Transformation of essential thrombocythemia (ET) to myelodysplastic syndromes or acute myeloid leukemia is infrequent, comprising 1–5% of cases with dismal clinical outcome. Studies on prognosis in ET patients with leukemic transformation are limited. The large cohort included 40 patients (1990–2014) with ET transformation (median age of 59 years, M:F of 1:1). Median time from ET diagnosis to transformation was 76 months (26–481) with median follow-up time of 15 years. Advanced age, myelofibrosis (grade 2–3), and leukocytosis at the time of transformation were associated with inferior OS from transformation ( p < 0.05). Given rarity of the clinical scenario, multicenter efforts are encouraged. [ABSTRACT FROM AUTHOR]

We previously demonstrated that peripheral blood (PB) is a reliable source for testing JAK2 V617F mutation in patients with myelofibrosis (MF); saliva has also been tested to detect such mutation, however its diagnostic accuracy as compared to PB has not been validated. In this study, we prospectively tested 167 patients with MF for JAK2 V617F mutation, using both saliva and PB collected at the same time from each patient. The concordance between the 2 sources was 96%, with a sensitivity of 100% and a specificity of 90%. The only factor associated with false positivity on saliva was ongoing transfusion dependency. JAK2 V617F testing using saliva is a simple, non-invasive, and potentially a more reliable method than PB for measuring JAK2 status and assessing V617F allelic burden in patients with transfusion dependency. [ABSTRACT FROM AUTHOR]

Smoking may be associated with accelerated erythropoiesis, leukocytosis and thrombocytosis, which are also hallmarks in patients with polycythemia vera, essential thrombocythemia and early stages of myelofibrosis (MPNs). The JAK-STAT and NF-κB signaling pathways are activated in both smokers and in patients with MPNs. Additionally, both share elevated levels of several proinflammatory cytokines, in vivo activation of leukocytes and platelets, endothelial dysfunction and increased systemic oxidative stress. Based upon experimental, epidemiological and clinical data it is herein argued and discussed, if smoking may be involved in MPN pathogenesis, considering most recent studies and reviews which are supportive of the concept that chronic inflammation with NF-κB activation and oxidative stress may have a major role – both as triggers but also as the driving force for clonal expansion in MPNs. [ABSTRACT FROM AUTHOR]

Ruxolitinib has been shown in two randomized clinical trials to be effective in alleviating systemic symptoms and reducing spleen size in patients with myelofibrosis (MF). We retrospectively evaluated efficacy and tolerability of ruxolitinib in a cohort of unselected MF patients treated in routine clinical practice. One hundred and two patients who began ruxolitinib therapy were identified in 13 participating centers. Ninety three of the patients receiving ruxolitinib for at least 3 months were evaluated for treatment efficacy and toxicity. Median age at ruxolitinib initiation was 67 years. Indications for treatment were constitutional symptoms (15%), symptomatic splenomegaly (6%) or both (76%). Two patients received ruxolitinib for other indications. The median initial ruxolitinib dose was 30 mg/day. Median duration of therapy was 11 months. Eighty two patients (88.2%) responded to therapy, 76 (84.4%) patients had improvement in constitutional symptoms and 60 patients (70.6%) had reduction in spleen length. While on ruxolitinib, 30% of patients had grade 3–4 anemia and 12.9% of patients had grade 3–4 thrombocytopenia. Thirteen patients (14%) discontinued therapy. This analysis of a cohort of MF patients treated with ruxolitinib in routine clinical practice demonstrates the efficacy and tolerability of this drug outside of a highly monitored clinical trial setting. [ABSTRACT FROM AUTHOR]

Myeloproliferative neoplasm (MPN) transformed to acute myeloid leukemia (MPN-AML), MPN in accelerated phase (MPN-AP), and high-risk primary myelofibrosis (PMF) are associated with a poor response to therapy and very short survival. Several reports have suggested clinical activity of hypomethylating agents in these patients. We conducted a retrospective study of 21 patients with MPN-AML, 13 with MPN-AP and 11 with DIPSS-plus high-risk PMF treated with decitabine at our institution over the last 7 years and evaluated their clinical outcomes. Six patients (29%) with MPN-AML responded to decitabine (3 CR, 2 CRi, and 1 PR); median response duration was 7 months. The median overall survival (OS) was significantly higher in those who responded (10.5 vs 4 months). Among patients with MPN-AP, 8 patients (62%) benefited; the median response duration was 6.5 months. The median OS was 11.8 months in responders vs 4.7 months in non-responders. Among patients with DIPSS-plus high-risk PMF, 9 (82%) benefited; the median response duration was 9 months. The median OS was 32 months in responders vs 16.3 months in non-responders. Decitabine is a viable therapeutic option for patients with MPN-AML, MP-AP and high-risk PMF. Prospective clinical studies combining decitabine with other clinically active agents are needed to improve overall outcome. [ABSTRACT FROM AUTHOR]

The co-occurrence of myeloproliferative and lymphoproliferative neoplasms (MPN/LPN) has been reported, mostly in case reports. The aim of this study was to assess the characteristics and clinical course of the coexistent diseases. Among 9866 patients who presented to our institution from 1960 to 2014, 34 (0.3%) were diagnosed with MPN/LPN. LPN was diagnosed first in 16 patients, second in 15, and at the same time in 3. The time to secondary malignancy was longer when LPN was diagnosed first (119 vs 98 months). Myelofibrosis (41%), polycythemia vera (24%), and essential thrombocythemia (18%) were the most common MPNs, and non-Hodgkin lymphoma (50%) and chronic lymphocytic leukemia (32%) were the most common LPNs. Seventy-three percent of patients treated for MPN and 72% of those treated for LPN achieved a complete response. After a median follow-up from MPN diagnosis of 84 months, 16 patients are alive and 18 died (4 related to MPN and 2 LPN). Coexistent MPN/LPN is a rare event that does not appear to predict worse outcomes. Treatment choice is generally oriented towards controlling the prevalent disease; the other malignancy may influence treatment strategies in selected cases. [ABSTRACT FROM AUTHOR]

Background The clinical phenotype of patients with myeloproliferative neoplasms (MPNs) including primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET) whom manifest WHO grade 1 marrow fibrosis is poorly defined. Current IWG-MRT criteria require 2+ marrow fibrosis for diagnosis of post PV/ET myelofibrosis (MF). In contrast, the 2008 WHO definition of PMF does not require a minimum fibrosis threshold. Methods We retrospectively analyzed the clinical characteristics of 91 MPN patients with 1+ marrow fibrosis. We compared the clinical phenotype of sub threshold fibrosis PV/ET with that manifested by PMF. We applied the IWG-MRT criteria for post-PV/ET MF with the fibrosis component omitted and evaluated for percentage of criteria fulfillment. Results When IWG-MRT criteria were applied to the PV/ET group, 38/58 (66%) of patients fulfilled criteria for diagnosis of post-PV/ET myelofibrosis except for the 2+ fibrosis requirement. Comparison of sub threshold fibrotic PV/ET clinical phenotype to PMF revealed similar characteristics including heavy symptomatic burden (57% and 52%), presence of splenomegaly (43% and 55%), leukoerythroblastic blood smear (38% and 45%), and median hemoglobin (12.8 g/dL and 11.1 g/dL). Conclusion MPN progression represents a biological spectrum and definitions of progression in ET/PV may benefit from criteria not restricted by degree of fibrosis. [ABSTRACT FROM AUTHOR]

CALR mutations are detected in about 50% of persons of predominately European descent with essential thrombocythemia (ET) or primary myelofibrosis (PMF) with wild-type alleles of JAK2 and MPL. We studied 1088 Chinese with diverse myeloproliferative neoplasms including ET ( N = 234) and PMF ( N = 50) without JAK2 V617F or MPL exon 10 mutations. CALR mutation was detected in 53% (95% CI, 46–60%) of subjects with ET and 56% (95% CI, 41–70%) of subjects with PMF. 152 CALR mutations were identified clustering into 15 types including deletions ( N = 8), insertions ( N = 3) and complex indels ( N = 4). We also identified 9 new mutations. Mean (±SD) mutant allele burden was 31 ± 12% (range, 0.5–69%). Persons with PMF had higher CALR mutant allele burdens than those with ET (38 ± 8% vs. 29 ± 12%; P < 0.001). Amongst persons with CALR mutations, those with PMF had different clinical features from those with ET. These data may be useful for diagnosing ET and PMF in Chinese who are about 40% of all persons with ET and PMF and for monitoring therapy-response. They also highlight similarities and differences in CALR mutations between Chinese and persons of predominately European descent with these diseases. [ABSTRACT FROM AUTHOR]

Chromosome 12 (Chr12) abnormalities have been described for individual patients with Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPN), however the frequency, characteristics, and outcomes of such patients as a whole have not been investigated. We reviewed a database of 1787 consecutive Ph-neg MPN patients seen at our institution and determined that 2% of Ph-neg MPN patients harbored an alteration involving Chr12 by cytogenetic evaluation. Retrospective chart review revealed that patients with Chr12 abnormalities had a higher likelihood of having myelofibrosis (MF) compared to patients without a Chr12 abnormality, and were more likely to have post-polycythemia vera MF. The most common alterations in Chr12 in MF patients involved 12q13, 12q15, 12q24, and trisomy 12, and >40% of Chr12 Ph-neg MPN patients had cytogenetic evolution. Chr12 abnormalities did not significantly correlate with JAK2 status, progression to acute myeloid leukemia, or survival, however patients with 12q24 abnormalities trended toward poorer outcomes. [ABSTRACT FROM AUTHOR]

To predict leukemic transformation (LT), we evaluated easily detectable diagnostic parameters in 338 patients with primary myelofibrosis (PMF) followed in the Latium region (Italy) between 1981 and 2010. Forty patients (11.8%) progressed to leukemia, with a resulting 10-year leukemia-free survival (LFS) rates of 72%. Hb (<10 g/dL), and circulating blasts (≥1%) were the only two independent prognostic for LT at the multivariate analysis. Two hundred-fifty patients with both the two parameters available were grouped as follows: low risk (none or one factor) = 216 patients; high risk (both factors) = 31 patients. The median LFS times were 269 and 45 months for the low and high-risk groups, respectively ( P < .0001). The LT predictive power of these two parameters was confirmed in an external series of 270 PMF patients from Tuscany, in whom the median LFS was not reached and 61 months for the low and high risk groups, respectively ( P < .0001). These results establish anemia and circulating blasts, two easily and universally available parameters, as strong predictors of LT in PMF and may help to improve prognostic stratification of these patients particularly in countries with low resources where more sophisticated molecular testing is unavailable. [ABSTRACT FROM AUTHOR]

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterised by the clonal proliferation of the haematopoietic precursors together with the progressive development of bone marrow fibrosis. This stromal alteration is an important clinical issue and specific prognostic markers are not currently available. In bone marrow biopsies from 58 PMF patients, we explored the methylation pattern of genes encoding cytokines involved in the stromal reaction, namely platelet-derived growth factor-beta ( PDGFB ), transforming growth factor-beta ( TGFB ) and basic fibroblast growth factor ( FGF2 ). We also evaluated the methylation profile of the Long Interspersed Nucleotide Element 1 (LINE-1). PDGFB , FGF2 and LINE-1, but not TGFB , were significantly differently methylated in PMF compared to controls. Significantly, PDGFB hypomethylation (<16%) was correlated with a favourable PMF prognosis (grade of marrow fibrosis, p = 0.03; International Prognostic Scoring Systems p = 0.01 and Dynamic International Prognostic Scoring Systems, p = 0.02). Although the basis of the association of PDGFB hypomethylation with favourable prognosis remains to be clarified, we speculate that hypomethylation in PMF could represent the effect of acquired somatic mutations in genes involved in epigenetic regulation of the genome. [ABSTRACT FROM AUTHOR]

The anti-tumor activity of AZD1480, a potent, selective inhibitor of Janus-associated kinases 1 and 2, was demonstrated in preclinical models of myeloproliferative neoplasms. In a phase I clinical study, 35 patients with myelofibrosis received 2.5–70 mg AZD1480 orally once daily (QD) or 10 or 15 mg twice daily (BID) continuously during repeated 28-day cycles. Two patients experienced dose-limiting toxicities: one patient in the 2.5 mg QD cohort had a grade 3 lung infiltration/acute pneumonia, and one patient receiving 50 mg QD had grade 3 presyncope. Dosing was stopped at 70 mg QD after the first patient experienced an adverse neurological event (AE) and evidence of low-grade neurological toxicity in patients on lower doses after the initial month of therapy became apparent. The most common AZD1480-related AEs were dizziness and anemia. AZD1480 was absorbed quickly and eliminated from the plasma rapidly, with a mean terminal half-life of 2.45–8.06 h; accumulation was not observed after repeated daily dosing for 28 days. Four patients showed evidence of clinical improvement based on IWG-MRT 2006 criteria. AZD1480 was relatively well tolerated, however, low-grade, reversible neurological toxicity was therapy limiting and led to study termination. [ABSTRACT FROM AUTHOR]

Cyclic AMP-response element-binding protein 3-like 1 (CREB3L1) is a gene involved in the unfolded protein response (UPR). Recently, we demonstrated that CREB3L1 is specifically overexpressed in the platelets of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). In this study, we aimed to show the clinical and biological relevance of CREB3L1 in these hematological diseases. Overexpression of CREB3L1 was specific to platelets in MPNs and associated with a higher risk of thrombosis and fibrotic transformation in essential thrombocythemia (ET) and polycythemia vera (PV) cases, respectively. Furthermore, we found that UPR genes were downregulated in platelets of patients with ET and PV, which were more pronounced in patients harboring the JAK2 V617F mutation. However, CREB3L1 overexpression does not alter UPR gene expression or cell proliferation in UT-7/TPO/CALRm cells exogenously expressing mutated calreticulin and HEL cells harboring endogenous JAK2 V617F. Furthermore, CREB3L1 overexpression did not modulate sensitivity to endoplasmic reticulum stress in these cell lines. Taken together, our data show 1) a potential role of CREB3L1 expression in platelets as a new marker of high-risk MPNs and 2) an association between CREB3L1 overexpression and UPR gene downregulation in these patients' platelets, with CREB3L1 not altering UPR in our in vitro models and possibly further in vivo mechanisms being involved. • CREB3L1 expression is specific for MPN platelets. • CREB3L1 expression is associated with higher risk ET and PV. • UPR genes are downregulated in ET and PV platelets. • UPR genes expression is independent of CREB3L1 expression in cell line models. • CREB3L1 does not alter cell proliferation/ER stress sensitivity in cell line models. [ABSTRACT FROM AUTHOR]

• Post-PV SMF patients experience highest risk of arterial thrombotic events in comparison to PMF and post-ET SMF. • High thrombotic risk persists in the multivariate model adjusted for relevant predictors. • Post-ET SMF patients experience most favorable survival in comparison to other subsets. [ABSTRACT FROM AUTHOR]

Subsequent blast (BP) or accelerated phase (AP) is a severe complication of Philadelphia-negative myeloproliferative neoplasms (MPNs). The prognosis is generally dismal, but hypomethylating agents (HMAs) may induce a long-lasting response in a minority of patients. Here, we report a cohort of six patients with BP/AP-MPN who experienced MPN relapse after a leukemia response was obtained with azacytidine. Five of the patients achieved complete remission despite the presence of characteristics associated with poor prognosis, such as complex and monosomal karyotypes, TP53 mutations, and EVI1 overexpression. These remissions persisted for over five years in four of the 6 patients. All patients showed rapid reemergence of MPN within a median of two months with thrombocytosis requiring the addition of anagrelide, hydroxyurea, or ruxolitinib given continuously in parallel with the azacytidine cycle. Serial JAK2 V617F allelic burden measurements showed little variation. Thromboembolic events occurred in 3 patients, one leading to death. These findings confirm that HMA may reverse the disease course in AP/BP-MPN to a more chronic phase that may last for years but also lead to morbidity and mortality. Combining maintenance therapy with HMA and MPN-specific drugs appears to be a possible approach to avoiding leukemia relapse and controlling MPN disease. • MPNs may reemerge after treatment of the accelerated phase (AP) or blast phase (BP) with hypomethylating agents (HMAs). • Leukemia remission in these patients may persist for many years despite poor prognosis characteristics. • The successive evolution of MPN and BP/AP had no significant impact on JAK2 V617F allelic burden. • MPN reemergence required active treatment in addition to HMA. • Thromboembolic events may occur, showing that reversion to a more chronic phase may also lead to morbidity and mortality. [ABSTRACT FROM AUTHOR]

Poor graft function (PGF) and secondary failure of platelet recovery (SFPR) are significant causes of transplant related morbidity and mortality. Although thrombopoietin receptor agonists (TPO-RA), particularly Eltrombopag (EPAG), have been reported to be efficacious in the treatment of prolonged thrombocytopenia, potential long term adverse effects remain to be elucidated. This retrospective study was performed to determine the efficacy and toxicity profile of TPO-RAs in allogeneic hematopoietic stem cell transplant (alloHCT) recipients. Medical records of 27 patients [median age: 55(21−73) years; male/female: 15/12] who received posttransplant EPAG for SFPR or PGF were analysed. Eltrombopag was started on day 110(33−670) after transplant. Median initial dose was 25(25−50) mg/day which was properly escalated to a maximum dose of 75(50−100) mg/day. Duration of the treatment was median 120(31−377) days. Overall response rate (ORR) was 59.3% in the study population. Time-to-treatment response was 42(3−170) days. Mild-to-moderate bone marrow fibrosis was detected in the posttreatment biopsies of 12/22 patients (54.5%), 9 of whom did not represent any grade of myelofibrosis in their inital biopsies. The grade of posttreatment fibrosis was significantly increased when time-to-treatment response was longer (p = 0.008). Long term use of TPO-RAs may be considered as a potential cause of myelofibrosis in alloHCT recipients. [ABSTRACT FROM AUTHOR]

Leukemic transformation (LT) is the main cause of death for patients with myeloproliferative neoplasms (MPNs). To study genetic changes associated with the LT, we performed targeted sequencing in 26 MPN patients including 21 with paired samples. We observed that, besides three driver genes, IDH2 (19%) and ASXL1 (14%) were also frequently mutated at MPN diagnosis. Although variant allele frequencies (VAFs) of mutations in DNA methylation and spliceosome did not expand during LT, they were enriched in patients with LT (the LT group). At follow-up, we also observed acquisition of mutations, mostly in the LT group. When considering dynamics of VAF from diagnosis to follow-up, VAFs in the LT group expanded (median VAF, 36.7–43.7%, p = 0.045). In contrast, mutations in patients with no clinical progression was stable (median VAF, 36.3–35.7%, p = 0.739). Overall, the present study demonstrates genetic changes during LT and provides the potential for prognostic application. • Mutations in DNA methylation/spliceosome genes are enriched in the LT group. • Newly detected mutations are common during leukemic transformation. • Allelic burdens of pre-existing mutations increase during leukemic transformation. [ABSTRACT FROM AUTHOR]

Recent studies have provided evidence that the Philadelphia-negative chronic myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera and myelofibrosis (MPNs), may be preceded or accompanied by chronic inflammation and are associated with an increased risk of second cancers, both hematological and non-hematological. Thrombocythemia is one of the hallmarks in the early stages of these neoplasms. Several non-hematological cancers are associated with reactive thrombocythemia, which has been shown to have a major negative impact upon survival. In regard to treatment of MPNs a “wait and watch” strategy is recommended in patients with low-risk disease. Another strategy implies early treatment with interferon-alpha2 (IFN) to prohibit clonal evolution. Based upon experimental and clinical studies of the important role of platelets for cancer invasiveness and metastasis it is herein argued, that these detrimental platelet effects further support the “Early Interferon Concept” in MPNs to normalize elevated leukocyte and platelet counts. In the context of the known increased risk of second cancer in MPNs the prevailing “wait and watch” strategy is seriously challenged, when taking into account that this strategy may actually worsen prognosis of second cancers in MPNs due to elevated platelet counts, enhancing cancer invasiveness and its metastatic potential. [ABSTRACT FROM AUTHOR]

Microcytosis is a relatively frequent finding in primary myelofibrosis (PMF); however its prognostic significance is unknown. We identified factors associated with microcytosis in PMF and measured its impact on outcomes. Among 725 patients with PMF, 140 (19%) showed microcytosis. In multivariate analysis, factors associated with microcytosis were absence of prior therapy, low iron, low transferrin saturation (satTF), and splenomegaly. Among 375 untreated patients, low satTF and splenomegaly were associated with microcytosis. Overall, microcytosis was associated with a higher risk of transformation to leukemia ( p = 0.03), but not shorter leukemia-free survival. Microcytosis in PMF may be related to dysregulation of iron homeostasis. [ABSTRACT FROM AUTHOR]

Predicting survival in persons with primary myelofibrosis (PMF) is typically based on the International Prognostic Scoring System (IPSS), the Dynamic IPSS (DIPSS) or the DIPSS-Plus. These scoring systems use clinical and laboratory data developed predominately in persons of European descent. Splenomegaly is not a prognostic variable in any of these scoring systems. Recently, we reported differences in clinical and laboratory features between Chinese vs. persons of European descent with PMF. Based on this we developed a modified prognostic model to predict survival of Chinese subjects in which splenomegaly is an independent favorable prognostic factor. In the current study, we analyzed data from 874 Chinese with PMF including 495 with splenomegaly. Subjects with splenomegaly had significantly higher hemoglobin concentrations ( P < 0.001), higher levels of WBCs ( P < 0.001), platelets ( P < 0.001), excess blood blasts (≥1%; P = 0.012), less RBC-transfusion-dependence ( P < 0.001) and lower DIPSS risk distribution ( P = 0.024). Frequency of JAK2 V617F (62% v s. 50%; P = 0.003) was also different. In univariate analyses subjects without splenomegaly had briefer survival (median, 64 mo [95% CI, 43–85] vs. 110 mo [95% CI, 67–153]; P < 0.001). In multivariate analyses, splenomegaly was a favorable prognostic correlate of survival independent of DIPSS risk-cohort (hazard ratio [HR] = 1.445; [95% CI, 1.101–1.895]; P = 0.008). Our data suggest including splenomegaly improves the predictive accuracy of the prognostic model to estimate survival of Chinese with PMF. [ABSTRACT FROM AUTHOR]