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The document explores inter-racial genetic differences in myelofibrosis, focusing on a diverse inner-city center analysis. The study conducted at Montefiore Medical Center in the Bronx, NY, with a predominantly Hispanic and Black population, aimed to identify high-risk mutations and their impact on clinical outcomes in a multi-ethnic cohort. Findings revealed higher prevalence of high molecular risk mutations in non-White patients, particularly Black and Hispanic cohorts, but no significant differences in leukemic transformation or overall survival between racial groups. The study highlights the importance of validating mutational risk profiles in diverse populations and calls for further investigation with larger-scale studies. [Extracted from the article]

The article discusses the use of JAK inhibitors in myelofibrosis treatment, focusing on when to treat, which agent to choose, and how to switch between medications. Ruxolitinib and momelotinib are approved as first-line therapies, with fedratinib as a second-line option. The text also highlights the importance of monitoring and managing side effects, as well as future directions in myelofibrosis treatment, including combination therapies and novel agents. The article provides valuable insights into navigating JAK inhibitors in myelofibrosis treatment for researchers and healthcare professionals. [Extracted from the article]

Introduction: Myelofibrosis (MF) is a clonal hematological disorder characterized by bone marrow fibrosis, splenomegaly, and inflammatory cytokine dysregulation. While the role of steroids in MF is not fully defined, their anti-inflammatory properties may offer therapeutic benefits, particularly in managing anemia and other cytopenias. Steroids exert their effects by suppressing pro-inflammatory cytokines such as IL1, IL6, and TNF, and by enhancing anti-inflammatory cytokines like IL4 and IL10. Elevated levels of IL6 and other cytokines in MF are associated with anemia and poor prognosis, suggesting that steroid therapy could mitigate these effects. Areas covered: In this manuscript, we review clinical studies which evaluated the safety and efficacy of steroids in MF patients. Moreover, we examine clinical data of the combination of steroids with immunomodulatory agents and JAK inhibitors. Our literature search consisted of an extensive review of PubMed and clinicaltrials.gov. Expert opinion: The role of steroids in the management of MF remains poorly defined, though emerging evidence suggests a potential therapeutic benefit, particularly in managing anemia and other cytopenias. The combination with IMIDs has also yielded positive outcomes as demonstrated in several studies. Steroids may also play a crucial role in managing cytopenias in MF patients receiving JAKi. [ABSTRACT FROM AUTHOR]

Background: Despite being one of the most populated and diverse countries in the world, there is a paucity of data on the prevalence of driver mutations in classical myeloproliferative neoplasms (MPN) in India. Aim: In the present study, we aimed to analyze somatic driver mutations such as JAK2 , CALR , and MPL in classical MPNs in a South Indian Tertiary Care Center. Patients and methods: Out of 185 suspected MPN patients screened, based on WHO 2016 criteria, 72 MPN patients were included in this study. JAK2 V617F and MPL mutations were screened using an allele-specific PCR assay. JAK2 exon 12 and CALR exon 9 mutations were screened by PCR Sanger sequencing. Results: In the present study, JAK2 V617F mutation was detected in 88.8% of polycythemia vera, 66.6% of essential thrombocythemia, and 53.3% of primary myelofibrosis (PMF) cases. CALR mutations were observed in 16.6% of essential thrombocythemia and 13.3% of PMF patients. In addition to the common type 2 mutation, we identified a rarely reported type 2-like mutation (c.1154_1155insATGTC) in a PMF patient. The identified mutations were mutually exclusive. We observed an absence of JAK2 exon 12 and MPL mutations in our study participants. Conclusion: In the present study, we observed JAK2 and CALR mutations in 77.7 and 5.5%, respectively, in classical MPNs. We identified a rare CALR type 2-like mutation in a PMF patient, a first report from India. [ABSTRACT FROM AUTHOR]

Summary: Myeloproliferative neoplasms (MPN) are characterized by a clonal proliferation of myeloid lineage cells within the bone marrow. The classical BCR‐ABL negative MPNs are comprised of polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Historically, the majority of MPNs are diagnosed in adults older than 60 years of age; however, in recent years, there has been recognition of MPNs in the adolescent and young adult (AYA) population. AYAs with MPN, typically defined as between the ages of 15 and 39 years old, may comprise up to 20% of patients diagnosed with MPN. They demonstrate unique patterns of driver mutations and thrombotic events and remain at risk for progression to more aggressive disease states. Given the likely long length of time they will live with their disease, there is a significant unmet need in identifying well‐tolerated and effective treatment options for these patients, particularly with the advent of disease modification. In this review, we provide a comprehensive overview of the clinical features, disease course and management of AYA patients with MPN and, in doing so, highlight key characteristics that distinguish them from their older counterparts. [ABSTRACT FROM AUTHOR]

Abstract Casitas B‐cell lineage (CBL) syndrome is a rare RASopathy known to predispose to CBL‐mutated juvenile myelomonocytic leukemia (JMML) in childhood. Adulthood acute myeloid leukemia arising out of a genetic aberrancies consistent with prior CBL‐mutated JMML has been twice previously described, but chronic myeloproliferative neoplasia has not. We present a case of progressive myeloproliferative neoplasm in adulthood in the context of CBL syndrome alongside a novel CSF3R variant. We also review pathogenic splice‐site mutations in CBL‐mutated JMML.

Abstract Erythrocytosis or polycythemia refers to a true or apparent increase in hemoglobin or hematocrit. When no etiology of erythrocytosis is identified, people are diagnosed with “idiopathic erythrocytosis” (IE). The identification of new contributing genes has recently improved the diagnostic workup of IE. As such mutations within the SH2B3 gene, which codes for the LNK protein and negatively regulates the JAK‐STAT pathway, have been identified in cases diagnosed as IE. This reports describes the presence of a previously undescribed germline SH2B3 variant p.(Thr335ArgfsTer4) within IE and emphasizes the advantages of gene panel sequencing as second step in the diagnostic work‐up.

Summary: Little is known about outcomes following interruption of targeted therapy in adult patients with histiocytic neoplasms. This is an IRB‐approved study of patients with histiocytic neoplasms whose BRAF and MEK inhibitors were interrupted after achieving complete or partial response by 18‐fluorodeoxyglucose positron emission tomography (FDG‐PET). 17/22 (77%) of patients experienced disease relapse following treatment interruption. Achieving a complete response prior to interruption, having a mutation other than BRAFV600E, and receiving MEK inhibition only were each associated with a statistically significant improvement in relapse‐free survival. Relapse is common following treatment interruption however some patients may be suitable for limited‐duration treatment. [ABSTRACT FROM AUTHOR]

Background: Patients with myeloproliferative neoplasms (MPNs) suffer from substantial symptoms and risk of debilitating complications, yet observational data on their labor market affiliation are scarce. Material and methods: We conducted a descriptive cohort study using data from Danish nationwide registries, including patients diagnosed with MPN in 2010-2016. Each patient was matched with up to ten comparators without MPN on age, sex, level of education, and region of residence. We assessed pre- and post-diagnosis labor market affiliation, defined as working, unemployed, or receiving sickness benefit, disability pension, retirement pension, or other health-related benefits. Labor market affiliation was assessed weekly from two years pre-diagnosis until death, emigration, or 31 December 2018. For patients and comparators, we reported percentage point (pp) changes in labor market affiliation crosssectionally from week - 104 pre-diagnosis to week 104 post-diagnosis. Results: The study included 3,342 patients with MPN and 32,737 comparators. From two years prediagnosis until two years post-diagnosis, a larger reduction in the proportion working was observed among patients than comparators (essential thrombocythemia: 10.2 [95% CI: 6.3-14.1] vs. 6.8 [95% CI: 5.5-8.0] pp; polycythemia vera: 9.6 [95% CI: 5.9-13.2] vs. 7.4 [95% CI: 6.2-8.7] pp; myelofibrosis: 8.1 [95% CI: 3.0-13.2] vs. 5.8 [95% CI: 4.2-7.5] pp; and unclassifiable MPN: 8.0 [95% CI: 3.0-13.0] vs. 7.4 [95% CI: 5.7-9.1] pp). Correspondingly, an increase in the proportion of patients receiving sickness benefits including other health-related benefits was evident around the time of diagnosis. Conclusion: Overall, we found that Danish patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN had slightly impaired labor market affiliation compared with a population of the same age and sex. From two years pre-diagnosis to two years post-diagnosis, we observed a larger reduction in the proportion of patients with MPN working and a greater proportion receiving sickness benefits compared with matched individuals. [ABSTRACT FROM AUTHOR]

The article focuses on investigating JAK2, CALR, and MPL gene mutations in Colombian patients with BCR-ABL Negative Myeloproliferative Neoplasms. It aims to determine the mutation frequencies in these genes, providing crucial molecular insights for accurate diagnosis and management of these neoplasms in the Colombian population. It further highlights the importance of molecular profiling in understanding and treating these diseases.

Background: In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT‐I) and COMFORT‐II clinical trials, adult patients with intermediate‐2 or high‐risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS). Methods: This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation. Results: The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0–70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p =.0610; 44.0% vs. 26.9% at Week 48, p =.0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p =.022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%‒73%] vs. 57% [95% CI, 49%‒64%]; hazard ratio, 1.53; 95% CI, 1.01‒2.31; p =.0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT. Conclusions: These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate‐2 and high‐risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS. Plain Language Summary: Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue.Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments.Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment.Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed. A pooled analysis of the Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT‐I) and COMFORT‐II phase 3 trials suggests that earlier ruxolitinib initiation in adult patients with intermediate‐2 or high‐risk myelofibrosis is associated with improved clinical outcomes, including significantly prolonged overall survival and improved spleen and symptom responses. These data suggest that patients with myelofibrosis may benefit from earlier intervention. [ABSTRACT FROM AUTHOR]

Background. Myeloproliferative disorders define a vast and heteregenous group of neoplastic entities, characterized by malignant proliferation of blood cells. These may affect multiple tissues, some of these malignancies involving organs in which there is lymphoid tissue. Case report. A 81-year-old female patient was admitted to the Department of Internal Medicine with moderate-to-intense spontaneous pain in the left hypochondrial and in the left abdominal flank, associated with generalized fatigue and loss of appetite. According to the personal medical history, the patient is known with type II diabetes mellitus, being under treatment with oral antidiabetics (metformin 1000 mg), and arterial hypertension under treatment with candesartan. Upon admission, the physical examination revealed cutaneous and mucosal pallor and marked physical weakness. Abdominal palpation revealed pain in the left hypochondrial and in the left abdominal flank, associated with firm and massive splenomegaly, descending towards the umbilicus. Abdominal ultrasound confirmed massive splenomegaly, associated with moderate hepatomegaly. Blood analysis revealed several modifications, indicative of hypochromic normocytic anemia, associated with lymphocytosis, thrombocytopenia and neutropenia. C-reactive protein (CRP) serum levels were in normal range upon admission. All of these modifications suggested a possible leukemogenous or lymphoid malignancy, which resulted in the patient's transfer towards the Department of Hematology, for further investigations. Conclusions. Massive splenomegaly, associated with anemia and thrombocytopenia in elderly patients, should always indicate a leukemogenous or lymphoid malignancy and a thorough differential diagnosis and collaboration between internists and hematologists is required. [ABSTRACT FROM AUTHOR]

Background: Definitive treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN) involves allogeneic hematopoietic stem cell transplantation (allo‐HSCT), either with myeloablative (MAC) or reduced‐intensity conditioning (RIC). These diseases may arise in patients with a prior solid tumor. The impact of antecedent solid tumor on transplantation decision‐making and outcomes is not well defined. Methods: The authors performed a retrospective cohort study to address this question. A total of 1193 patients who underwent allo‐HSCT for AML, MDS, or MPN between January 1, 2010 and December 31, 2018 were included, 102 of whom had a history of prior solid tumor. Results: Patients with prior solid tumor were older (median age, 62.5 vs. 54.9 years; p <.00001) and more frequently were conditioned with RIC (52.5% vs. 27.2%; p <.00001). A higher incidence of acute graft‐versus‐host disease was observed in patients with prior solid tumor (73.5% vs 66.4%; adjusted odds ratio, 1.65; 95% confidence interval, 1.03–2.65; p =.037), yet overall survival and relapse did not significantly differ. Cytogenetic risk was the dominant risk factor for survival. Conclusions: Analysis by the authors suggests that patients with antecedent solid tumor and respective therapy can be transplanted successfully. Although selection bias is likely to be a factor, the results are encouraging for patients who come to transplantation after surviving a prior cancer. Among all patients who underwent allogeneic hematopoietic stem cell transplantation for myeloid neoplasms at the authors' center between 2010 and 2018, a history of antecedent solid tumor was associated with a higher incidence of acute graft‐versus‐host disease yet was not associated with worse overall survival or relapse rate. Analysis suggests that patients with antecedent solid tumor and respective therapy can be transplanted successfully. [ABSTRACT FROM AUTHOR]

Introduction: Chronic myeloid leukemia (CML) is characterized by Philadelphia chromosome resulting in the fusion between the BCR gene, located on chromosome 22, and the ABL gene on chromosome 9. The prognostic significance of BCR-ABL transcript variants in CML is controversial. The aim of the current study was to evaluate the clinico-hematological presentation and evolution of the disease, response to treatment and survival according to transcript type in chronic phase CML patients. Results: The median age of our population was 50 years with a slight female predominance (sex-ratio 0.78). Sixty percent had the b3a2 transcript and 34% had the b2a2 type. Patients with the co-expression of these two transcripts (4.5%) and those with e19a2 were excluded from the analysis. Patients with b3a2 subtype were associated significantly with thrombocytosis (p = 0.006) and higher Sokal score (p = 0.038) compared to those with b2a2 transcript. The two isolated transcripts were not significantly associated with gender, age group, blast cell percentage or the identified ranges of spleen size. Complete cytogenetic response at 12 months for b3a2 patients and b2a2 patients was 78.6% and 21.4% respectively. This difference was statistically significant (p = 0.001, HR = 9.5, 95% CI 6.5–13.7). Patients with b3a2 transcript had a higher rate of optimal molecular response at 3 months (p = 0.04, HR = 4.2, 95% CI 1–17.3) and major molecular response at 12 months (p = 0.004, HR = 4.9, 95%CI 1.5–15.1). At the date of last follow-up, most patients achieving deep molecular response (MR4 or deeper) belonged to b3a2 group (79%) (p = 0.003, HR = 5.2, 95% CI 1.6–16.4). We did not find a significant difference in OS and EFS between the two groups. Conclusion: Our study concluded that b2a2 transcript is a prognostic factor in cytogenetic and molecular response but further studies are needed to complete this aspect.

Few studies have assessed healthcare resource utilization (HRU) in patients with Philadelphia‐negative myeloproliferative neoplasms (MPN) using a matched cohort design. Further, no detailed assessment of HRU in the years preceding an MPN diagnosis exists. We conducted a registry‐based nationwide Danish cohort study, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN diagnosed between January 2010 and December 2016. HRU data were summarized annually from 2 years before MPN diagnosis until emigration, death, or end of study (December 2017). We included 3342 MPN patients and 32 737 comparisons without an MPN diagnosis, matched on sex, age, region of residence, and level of education. During the study period, the difference in HRU (rate ratio) between patients and matched comparisons ranged from 1.0 to 1.5 for general practitioner contacts, 0.9 to 2.2 for hospitalizations, 0.9 to 3.8 for inpatient days, 1.0 to 4.0 for outpatient visits, 1.3 to 2.1 for emergency department visits, and 1.0 to 4.1 for treatments/examinations. In conclusion, MPN patients had overall higher HRU than the matched comparisons throughout the follow‐up period (maximum 8 years). Further, MPN patients had substantially increased HRU in both the primary and secondary healthcare sector in the 2 years preceding the diagnosis. [ABSTRACT FROM AUTHOR]

Polyglobulia is secondary polycythaemia commonly due to underlying non haematological diseases like Chronic Obstructive Pulmonary Disease (COPD), obstructive sleep apnoea and also sometimes in people living in hilly or forest areas. It can occur in any venous or atrial thrombosis of the vessels, but cardiac, cerebral, and mesenteric vessels are usually involved. One of the rare causes of abrupt severe abdominal discomfort is portal vein thrombosis, usually associated with liver cirrhosis and thrombophilia. In this case report, the authors have highlighted a case of a 36-year-old male residing in the hilly area of Maharashtra, India, who reported to hospital with severe abdominal pain due to superior mesenteric vein thrombosis. On investigation, he had increased haemoglobin with raised haematocrit diagnosed as polyglobulia and became part of polycythaemia with positive JAK2 V617F mutation.

Myeloproliferative syndromes (MPS) are hematologic malignancies due to the expansion of an abnormal hematopoietic stem cell. They include chronic myeloid leukemia (CML) and non‐CML MPS such as polycythemia vera, essential thrombocythemia and primary myelofibrosis. The latter are distinguished by somatic pathogenic variants affecting JAK2, CALR, or MPL genes. Apparent germline pathogenic variants have been reported in the general population. Here, we found that two gnomAD data‐sets report more homozygotes than expected for the JAK2 c.1849G > T(Val617Phe) variant. We propose that somatic gene conversion can explain the presence of those unexpected homozygotes in normal populations. Consistently, homozygous individuals are older than 65 years. We also found a lower‐than‐expected frequency of the JAK2 variant in younger individuals suggesting that somatic mutation can underlie its presence in (at least some) heterozygotes. Regarding pathogenic variants in MPL and CALR, they are also present in the gnomAD data‐sets explored. However, we cannot conclude that such seemingly germline variants are in fact somatic alterations. These results suggest that apparently normal individuals bearing MPS‐related variants can be subclinical/undiagnosed MPS cases of somatic origin. It would be interesting to assess the hematologic phenotype of such individuals and the presence of the relevant variants in other tissues. [ABSTRACT FROM AUTHOR]

Objectives: Polycythaemia vera (PV) is a condition that may potentially put patients undergoing cardiac surgery at an increased risk of bleeding and thrombosis; however, there is currently a paucity of literature regarding the management of these patients. We aim to examine the literature in this systematic review to indicate the interventions that may be considered to minimise complications.Methods: We conducted a literature search using keywords and MeSH terms to identify articles discussing PV and cardiac surgery. The studies were identified and qualitatively analysed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol.Results: In total, 10 case reports representing 11 patients were identified for this systematic review and were included in qualitative analysis. 63.6% of patients had preoperative intermittent phlebotomy, and the majority of patients received postoperative therapy that involved one antiplatelet agent and one anticoagulant. Generous perioperative fluid management, phlebotomy, preservation of core body temperature, early extubation, monitoring of myocardial ischaemia, infarction and vascular events, intense chest physiotherapy and patient mobilisation are important to consider to reduce the risk of complications arising from surgery.Conclusion: These considerations should be systematically discussed in a multidisciplinary team, where the acute surgical need can be balanced appropriately against the risk of haemorrhage and thrombosis. [ABSTRACT FROM AUTHOR]

In the early era of COVID-19, characterization of long-term complications was unfeasible. But in early 2021, the authors came across a patient with a new diagnosis of Acute Myeloid Leukemia (AML) that was highly suspected as being secondary to a previous COVID-19 infection. The similarities of this anomaly to Hodgkin Lymphoma occurring after Epstein Barr Virus prompted the authors to perform a qualitative review of the literature for a possible pathway of how COVID-19 can cause AML., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Al-Midfai et al.)

Mesenchymal stem cells (MSCs) can become dysfunctional in patients with hematological disorders. An unanswered question is whether age-linked disruption of the bone marrow (BM) microenvironment is secondary to hematological dysfunction or vice versa. We therefore studied MSC function in patients with different hematological disorders and found decreased MHC-II except from one sample with acute myeloid leukemia (AML). The patients' MSCs were able to exert veto properties except for AML MSCs. While the expression of MHC-II appeared to be irrelevant to the immune licensing of MSCs, AML MSCs lost their ability to differentiate upon contact and rather, continued to proliferate, forming foci-like structures. We performed a retrospective study that indicated a significant increase in MSCs, based on phenotype, for patients with BM fibrosis. This suggests a role for MSCs in patients transitioning to leukemia. NFĸB was important to MSC function and was shown to be a potential target to sensitize leukemic CD34+/CD38− cells to azacitidine. This correlated with their lack of allogeneic stimulation. This study identified NFĸB as a potential target for combination therapy to treat leukemia stem cells and showed that understanding MSC biology and immune response could be key in determining how the aging BM might support leukemia. More importantly, we show how MSCs might be involved in transitioning the high risk patient with hematological disorder to AML. [ABSTRACT FROM AUTHOR]

Rationale: Chronic myeloid leukaemia is a myeloproliferative disorder due to clonal hyperproliferation of myeloid cells within the bone marrow. It can present both pro- and anti-thrombotic states. CML has different presentations within the gastrointestinal tract. Patient’s concern: A 40-year-old non-diabetic and non-hypertensive male complained of abdominal pain with nausea and emesis for 1 day. Besides, he had a history of abdominal distension and fever for 1 day. Diagnosis: Acute small bowel gangrene due to chronic myeloid leukaemia. Intervention: A limited resection of small intestine with ileostomy and mucus fistula. Outcome: After 3 months following surgery the patient underwent stoma closure. The patient was followed up for more than 3 years postoperatively. During the follow-up, the patient was asymptomatic without any recurrence of the disease. Lesson: Chronic myeloid leukaemia should be considered as one of the causes for small intestine gangrene when there is increased leukocyte count, splenomegaly without evidence of atherosclerotic occlusion or systemic emboli from the heart.

Hypereosinophilic syndrome (HES) encompasses numerous diverse conditions resulting in peripheral hypereosinophilia that cannot be explained by hypersensitivity, infection, or atopy and that is not associated with known systemic diseases with specific organ involvement. HES is often attributed to neoplastic or reactive causes, such as chronic eosinophilic leukemia, although a majority of cases remains unexplained and are considered idiopathic. Here, we review the current diagnosis and management of HES and present a unique case of profound hypereosinophilia associated with warm autoimmune hemolytic anemia requiring intensive management. This case clearly illustrates the limitations of current knowledge with respect to hypereosinophilia syndrome as well as the challenges associated with its classification and management.

Polyglobulia is secondary polycythaemia commonly due to underlying non haematological diseases like Chronic Obstructive Pulmonary Disease (COPD), obstructive sleep apnoea and also sometimes in people living in hilly or forest areas. It can occur in any venous or atrial thrombosis of the vessels, but cardiac, cerebral, and mesenteric vessels are usually involved. One of the rare causes of abrupt severe abdominal discomfort is portal vein thrombosis, usually associated with liver cirrhosis and thrombophilia. In this case report, the authors have highlighted a case of a 36-year-old male residing in the hilly area of Maharashtra, India, who reported to hospital with severe abdominal pain due to superior mesenteric vein thrombosis. On investigation, he had increased haemoglobin with raised haematocrit diagnosed as polyglobulia and became part of polycythaemia with positive JAK2 V617F mutation. [ABSTRACT FROM AUTHOR]

Summary: The seasonal influenza A vaccine is recommended for patients with myeloproliferative neoplasms (MPNs). We hypothesised that immune deregulation associated with MPNs may affect the immune response gained following vaccinations when compared to healthy controls. Using deep immunophenotyping with high‐dimensional single‐cell analysis and mass cytometry we could demonstrate an altered immune response in MPN patients following vaccination. We found that prior to vaccination, MPN patients had reduced numbers of naive CD4 T cells. Furthermore, at 3‐weeks and 3‐months post‐vaccination there was evidence of both delayed and impaired B‐ and T‐memory cells responses. Thus, although, the immune systems of MPN patients can 'recognise' the Influenza A vaccine, the response appears inferior compared to healthy controls. [ABSTRACT FROM AUTHOR]

Hydroxycarbamide, an antimetabolic agent used to treat myeloproliferative disorders, causes side effects, including myelosuppression, skin ulcers, and oral mucositis. Gastrointestinal ulcers are uncommon, and esophageal ulcers have not been previously reported. We present the case of a 74-year-old woman who developed esophageal and ileal ulcers after hydroxycarbamide treatment. Our case and previous reports suggest that hydroxycarbamide can cause ulcers throughout the gastrointestinal tract, which can improve rapidly after discontinuing medication. When new signs and symptoms occur, drug-induced etiologies should be considered as a potential cause. Timely diagnostic treatment with discontinuation of medication is crucial in such cases.

Abstract Background Noonan syndrome is an autosomal dominant disorder secondary to RASopathies, which are caused by germ‐line mutations in genes encoding components of the RAS mitogen‐activated protein kinase pathway. RIT1 (OMIM *609591) was recently reported as a disease gene for Noonan syndrome. Methods and Results We present a patient with RIT1‐associated Noonan syndrome, who in addition to the congenital heart defect, had monocytosis, myeloproliferative disorder, and accelerated idioventricular rhythm that was associated with severe hemodynamic instability. Noonan syndrome was suspected given the severe pulmonary stenosis, persistent monocytosis, and “left‐shifted” complete blood counts without any evidence of an infectious process. Genetic testing revealed that the patient had a heterozygous c.221 C>G (pAla74Gly) mutation in the RIT1. Conclusion We report a case of neonatal Noonan syndrome associated with RIT1 mutation. The clinical suspicion for Noonan syndrome was based only on the congenital heart defect, persistent monocytosis, and myeloproliferative process as the child lacked all other hallmarks characteristics of Noonan syndrome. However, the patient had an unusually malignant ventricular dysrhythmia that lead to his demise. The case highlights the fact that despite its heterogeneous presentation, RIT1‐associated Noonan syndrome can be extremely severe with poor outcome.

RUNX1 associated familial platelet disorder (FPD) is a rare autosomal dominant hematologic disorder characterized by thrombocytopenia and/or altered platelet function. There is an increased propensity to develop myeloid malignancy (MM) - acute myeloid leukemia, myeloproliferative neoplasms or myelodysplastic syndrome often in association with secondary somatic variants in other genes. To date, 23 FPD-MM pediatric cases have been reported worldwide. Here, we present two new kindreds with novel RUNX1 pathogenic variants in which children are probands. The first family is a daughter/mother diad, sharing a heterozygous frameshift variant in RUNX1 gene (c.501delT p.Ser167Argfs*9). The daughter, age 13 years, presented with features resembling juvenile myelomonocytic leukemia - severe anemia, thrombocytopenia, high white cell count with blast cells, monocytosis, increased nucleated red cells and had somatic mutations with high allele burden in CUX1, PHF6, and SH2B3 genes. She also had increased fetal hemoglobin and increased LIN28B expression. The mother, who had a long history of hypoplastic anemia, had different somatic mutations- a non-coding mutation in CUX1 but none in PHF6 or SH2B3. Her fetal hemoglobin and LIN28B expression were normal. In the second kindred, the proband, now 4 years old with thrombocytopenia alone, was investigated at 3 months of age for persistent neonatal thrombocytopenia with large platelets. Molecular testing identified a heterozygous intragenic deletion in RUNX1 encompassing exon 5. His father is known to have increased bruising for several years but is unavailable for testing. These two cases illustrate the significance of secondary mutations in the development and progression of RUNX1-FPD to MM. [ABSTRACT FROM AUTHOR]

The following case report and literature review will emphasize the individualized therapeutic management of a complex prothrombotic pathology. The onset of acute portal vein thrombosis in a patient with atrial fibrillation and good compliance to anticoagulation with a direct oral anticoagulant, who associates significant thrombocytosis, after excluding predisposing inflammations, infections or solid neoplasia, raises the diagnostic suspicion of myeloproliferative disorder, and imposes a complex interdisciplinary approach. [ABSTRACT FROM AUTHOR]

Myeloproliferative neoplasms (MPNs) are classified as chronic myeloid leukemia (CML) and Philadelphia chromosome-negative MPN. In MPN cases, the presence of a BCR-ABL1 translocation with a coexisting mutation is exceptionally rare. Herein, we report the first documented patient with CML harboring CALR mutation in Korea. A 33-year-old woman was referred to our hospital in February 2015 with splenomegaly, leukocytosis, and thrombocytosis. She was diagnosed with CML and started receiving nilotinib. In October 2015, a major molecular response was observed, but thrombocytosis persisted. A repeat bone marrow (BM) examination revealed no specific findings. However, as thrombocytosis worsened, we changed nilotinib to dasatinib. In May 2019, owing to persistent thrombocytosis, we repeated the BM examination and found CALR mutation (15.97%) on the MPN-next generation sequencing (NGS) test. We then retrospectively performed repeat MPN-NGS testing using the BM aspirate sample obtained in 2015 and found CALR mutation (10.64%). [ABSTRACT FROM AUTHOR]

Background: Noonan syndrome is an autosomal dominant disorder secondary to RASopathies, which are caused by germ‐line mutations in genes encoding components of the RAS mitogen‐activated protein kinase pathway. RIT1 (OMIM *609591) was recently reported as a disease gene for Noonan syndrome. Methods and Results: We present a patient with RIT1‐associated Noonan syndrome, who in addition to the congenital heart defect, had monocytosis, myeloproliferative disorder, and accelerated idioventricular rhythm that was associated with severe hemodynamic instability. Noonan syndrome was suspected given the severe pulmonary stenosis, persistent monocytosis, and "left‐shifted" complete blood counts without any evidence of an infectious process. Genetic testing revealed that the patient had a heterozygous c.221 C>G (pAla74Gly) mutation in the RIT1. Conclusion: We report a case of neonatal Noonan syndrome associated with RIT1 mutation. The clinical suspicion for Noonan syndrome was based only on the congenital heart defect, persistent monocytosis, and myeloproliferative process as the child lacked all other hallmarks characteristics of Noonan syndrome. However, the patient had an unusually malignant ventricular dysrhythmia that lead to his demise. The case highlights the fact that despite its heterogeneous presentation, RIT1‐associated Noonan syndrome can be extremely severe with poor outcome. [ABSTRACT FROM AUTHOR]

Chronic neutrophilic leukemia is a rare leukemia seen in middle aged and elderly people, characterized by neutrophilic leukocytosis with no significant increase in granulocytic precursors. The chief criteria for diagnosis include total leukocyte count ≥25 × 109/L, >80% of white blood cells being mature neutrophils (segmented and band forms), immature granulocytic precursors ≥10% in the peripheral blood, and hypercellular marrow. In addition to this, there must be no evidence of dysplasia, monocytosis or BCR-ABL1, PDGFR-A, PDGFR-B, or FGRF-1 rearrangements. Moreover, the cause of neutrophilia should not be attributed to any other myeloproliferative disorders or to physiologic neutrophilia.We present two patients with this rare disorder who presented with gout as the initial symptom. [ABSTRACT FROM AUTHOR]

The article reports that neonate diagnosed with Noonan syndrome with myeloproliferative change. Topics include myeloproliferative neoplasm in early childhood, characterized by excessive myelomonocytic cell proliferation and granulocyte-macrophage colony-stimulating factor hypersensitivity; and Hematopoietic stem cell transplantation remains the only curative treatment for JMML.

Donor leukocyte infusion (DLI) can induce graft-versus-leukemia (GvL) reactions in patients with chronic myeloid leukemia (CML) relapsing after allogeneic bone marrow transplantation (BMT), but the mechanisms of the antileukemic effect of DLI are unknown, and the procedure is complicated by graft-versus-host disease (GvHD) and graft failure. Here, we adapted a murine retroviral BMT model of Philadelphia(+) leukemia by combining allogeneic bone marrow (BM) from C57Bl/6 (H-2(b)) mice with BCR-ABL-transduced Balb/c (H-2(d)) BM, inducing mixed chimerism and myeloproliferative disease in recipients resembling relapse of CML following allogeneic BMT. Infusions of allogeneic splenocytes eliminated BCR-ABL-induced CML-like disease in the majority of mixed chimeras, with significant GvL effects mediated by both CD4(+) and CD4(-) cells. BCR-ABL-induced acute B-lymphoblastic leukemia was also eradicated by DLI in major histocompatibility complex (MHC)-mismatched chimeras. Most DLI-treated mice converted to full allogeneic chimerism but succumbed frequently to GvHD or graft failure. When MHC-matched B10.D2 (H-2(d)) mice were the allogeneic donors, CML-like disease was more resistant to DLI. These results suggest that depletion of CD8(+) cells from DLI could impair GvL against CML, while increased MHC disparity between donor and recipient may improve the responsiveness of Philadelphia(+) B-lymphoblastic leukemia to DLI.

Tyrosine kinase fusion oncogenes that occur as a result of chromosomal translocations have been shown to activate proliferative and antiapoptotic pathways in leukemic cells, but the importance of autocrine and paracrine expression of hematopoietic cytokines in leukemia pathogenesis is not understood. Evidence that leukemic transformation may be, at least in part, cytokine dependent includes data from primary human leukemia cells, cell culture experiments, and murine models of leukemia. This report demonstrates that interleukin (IL)-3 plasma levels are elevated in myeloproliferative disease (MPD) caused by the TEL/tyrosine kinase fusions TEL/platelet-derived growth factor beta receptor (PDGFbetaR), TEL/Janus kinase 2 (JAK2), and TEL/neurotrophin-3 receptor (TRKC). Plasma granulocyte-macrophage colony-stimulating factor (GM-CSF) levels were elevated by TEL/PDGFbetaR and TEL/JAK2. However, all of the fusions tested efficiently induced MPD in mice genetically deficient for both GM-CSF and IL-3, demonstrating that these cytokines are not necessary for the development of disease in this model system. Furthermore, in experiments using normal marrow transduced with TEL/PDGFbetaR retrovirus mixed with marrow transduced with an enhanced green fluorescent protein (EGFP) retrovirus, the MPD induced in these mice demonstrated minimal stimulation of normal myelopoiesis by the TEL/PDGFbetaR-expressing cells. In contrast, recipients of mixed GM-CSF-transduced and EGFP-transduced marrow exhibited significant paracrine expansion of EGFP-expressing cells. Collectively, these data demonstrate that, although cytokine levels are elevated in murine bone marrow transplant models of leukemia using tyrosine kinase fusion oncogenes, GM-CSF and IL-3 are not required for myeloproliferation by any of the oncogenes tested.

Summary: Standard first‐line therapy choice for essential thrombocythaemia (ET) requiring cytoreduction, supported by randomized trials, is low‐dose aspirin with hydroxycarbamide, but the role of recombinant interferon‐alfa (IFNα)‐2a/2b and pegylated (PEG)‐IFN‐α‐2a/2b is increasingly highlighted. Longer‐term outcome data, however, remains somewhat scarce, particularly in the 'real world'. We hereby report on a large, well‐annotated cohort of ET patients from a single referral centre undergoing therapy with either IFNα or (PEG)‐IFN‐α‐2a/2b and demonstrate high rates of complete haematological responses, good tolerability and safety, low rates of thromboembolic events in compliant patients and confirm feasibility of long‐term therapy in a significant proportion of patients. [ABSTRACT FROM AUTHOR]

Transient abnormal myelopoiesis (TAM) is a neonatal preleukemic syndrome that occurs exclusively in neonates with Down syndrome (DS). Most affected infants spontaneously resolve, although some patients culminate in hepatic failure despite the hematological remission. It is impossible to determine the patients who are at high risk of progressive liver disease and leukemic transformation. The objective is to search for biomarkers predicting the development of hepatic failure in DS infants with TAM. Among 60 newborn infants with DS consecutively admitted to our institutions from 2003 to 2016, 41 infants with or without TAM were enrolled for the study. Twenty-two TAM-patients were classified into "progression group" (n = 7) that required any therapy and "spontaneous resolution group" (n = 15). Serum concentrations of chemokines (CXCL8, CXCL9, CXCL10, CCL2 and CCL5) and transforming growth factor (TGF)-β1 were measured at diagnosis of TAM for assessing the outcome of progressive disease. Three patients developed leukemia during the study period (median, 1147 days; range, 33–3753). Three died of hepatic failure. All patients in the progression group were preterm birth <37 weeks of gestational age and were earlier than those in the spontaneous resolution group (median, 34.7 vs. 37.0 weeks, p < 0.01). The leukocyte counts and CXCL8 and CCL2 levels at diagnosis in the progression group were higher than those in the spontaneous resolution group (leukocyte: median, 81.60 vs. 27.30 × 109/L, p = 0.01; CXCL8: 173.8 vs. 34.3 pg/ml, p < 0.01; CCL2: 790.3 vs. 209.8 pg/mL, p < 0.01). Multivariate analyses indicated that an increased CCL2 value was independently associated with the progression and CXCL8 with the death of liver failure, respectively (CCL2: standardized coefficient [sc], 0.43, p < 0.01; CXCL8: sc = −0.46, p = 0.02). High levels of circulating CXCL8 and CCL2 at diagnosis of TAM may predict progressive hepatic failure in DS infants. [ABSTRACT FROM AUTHOR]

The transcription factor GATA2 regulates normal hematopoiesis, particularly in‐ stem cell maintenance and myeloid differentiation. Various heteroallelic GATA2 gene mutations are associated with a variety of hematological neoplasms, including myelodysplastic syndromes and leukemias. Here, we report that impaired GATA2 expression induces myelodysplastic and myeloproliferative neoplasm development in elderly animals, and this neoplasm resembles chronic myelomonocytic leukemia in humans. GATA2 hypomorphic mutant (G2fGN/fGN) mice that were generated by the germline insertion of a neocassette into the Gata2 gene locus avoided the early embryonic lethality observed in Gata2‐null mice. However, adult G2fGN/fGN mice suffered from exacerbated leukocytosis concomitant with progressive anemia and thrombocytopenia and eventually developed massive granulomonocytosis accompanied by trilineage dysplasia. The reconstitution activity of G2fGN/fGN mouse stem cells was impaired. Furthermore, G2fGN/fGN progenitors showed myeloid lineage‐biased proliferation and differentiation. Myeloid progenitor accumulation started at a younger age in G2fGN/fGN mice and appeared to worsen with age. G2fGN/fGN mice showed increased expression of transcripts encoding cytokine receptors, such as macrophage colony‐stimulating factor receptor and interleukin‐6 receptor, in granulocyte‐monocyte progenitors. This increased expression could be correlated with the hypersensitive granulomonocytic proliferation reaction when the mice were exposed to lipopolysaccharide. Taken together, these observations indicate that GATA2 hypomorphism leads to a hyperreactive defense response to infections, and this reaction is attributed to a unique intrinsic cell defect in the regulation of myeloid expansion that increases the risk of hematological neoplasm transformation. GATA2 hypomorphism causes a hyperreactive defense response to infections in mice, thus increasing the risk of hematological neoplasm. In elderly animals, GATA2 hypomorphism induces myelodysplastic/myeloproliferative neoplasm development, which resemble chronic myelomonocytic leukemia in humans. [ABSTRACT FROM AUTHOR]

Kris Vaddi,1 Srdan Verstovsek,2 Jean-Jacques Kiladjian3 1Drug Discovery, Incyte Corporation, Wilmington, DE, 2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Clinical Investigations Center, Hôpital Saint-Louis et Université Paris Diderot, Paris, France Abstract: Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis and the presence of Janus kinase (JAK) 2V617F or similar mutations. This review summarizes the pathophysiology of PV, the challenges associated with traditional treatment options, and the scientific rationale and supportive clinical evidence for targeted therapy with ruxolitinib. Accumulating evidence indicates that activating mutations in JAK2 drive the PV disease state. Traditional PV treatment strategies, including aspirin, phlebotomy, and cytoreductive agents such as hydroxyurea, provide clinical benefits for some but not all patients and may not adequately treat PV-related symptoms. Furthermore, traditional treatment approaches are associated with potential side effects that may limit their usage and lead some patients to discontinue the treatment. Ruxolitinib is an orally available small-molecule tyrosine kinase inhibitor that is a potent and selective inhibitor of JAK1/JAK2. Ruxolitinib is approved in the US for patients with PV with an inadequate response or intolerance to hydroxyurea and in Europe for adults with PV who are resistant to or intolerant of hydroxyurea. In the Phase III RESPONSE registration trial, ruxolitinib was superior to the best available therapy in patients with PV who were resistant to or intolerant of hydroxyurea in controlling hematocrit levels, reducing spleen volume, and improving PV-related symptoms and quality-of-life measures. The most common nonhematologic adverse events in ruxolitinib-treated patients were headache, diarrhea, pruritus, and fatigue in the RESPONSE trial; hematologic adverse events were primarily grade 1 or 2. In the Phase IIIb nonregistration RELIEF trial, there were nonsignificant trends toward an improved symptom control in patients with PV on a stable hydroxyurea dose who were generally well controlled but reported disease-associated symptoms and switched to ruxolitinib vs those who continued hydroxyurea therapy. Updated treatment guidelines will be important for educating physicians about the role of ruxolitinib in the treatment of patients with PV. Keywords: myeloproliferative disorder, polycythemia vera, Janus kinase inhibitor