8,514 results on '"MYELOPROLIFERATIVE neoplasms"'
Search Results
2. A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms
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- 2024
3. A Study of VAC85135, a Neoantigen Vaccine Regimen, Concurrently Administered With Ipilimumab for the Treatment of Myeloproliferative Neoplasms
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Bristol-Myers Squibb
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- 2024
4. Ivosidenib and Ruxolitinib in Patients With Advanced Myeloproliferative Neoplasms (MPNs) That Have an IDH1 Gene Mutation (MPN)
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- 2024
5. Myeloablative Allo HSCT With Related or Unrelated Donor for Heme Disorders
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- 2024
6. A Study to Evaluate the Safety, Tolerability of INCB160058 in Participants With Myeloproliferative Neoplasms
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- 2024
7. Study of a Geriatric Assessment to Plan a Treatment Approach for Older People With Various Blood Disorders
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- 2024
8. Bone marrow findings post allogeneic transplant for myeloproliferative neoplasms and chronic myelomonocytic leukemia with increased fibrosis.
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Gupta, Srishti and Courville, Elizabeth L
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HEMATOPOIETIC stem cell transplantation , *SURGERY , *PATIENTS , *CHRONIC myeloid leukemia , *MYELOPROLIFERATIVE neoplasms , *HOMOGRAFTS , *CANCER patients , *DESCRIPTIVE statistics , *RETROSPECTIVE studies , *FIBROSIS , *MEDICAL records , *ACQUISITION of data , *COMPARATIVE studies ,BONE marrow examination - Abstract
Background Allogeneic hematopoietic stem cell transplant for myeloid neoplasms with increased fibrosis is uncommon; morphologic features posttransplant can be concerning for persistent disease. Methods In this retrospective study, we identified 22 patients transplanted for myeloproliferative neoplasms or chronic myelomonocytic leukemia with fibrosis at our institution, and reviewed slides from pretransplant and posttransplant bone marrow biopsies. Clinical features and results of molecular, chimerism, and cytogenetic studies were retrieved from the medical record. Results Pretransplant bone marrow biopsies commonly exhibited hypercellularity, atypical megakaryocytes, and reticulin fibrosis. At day 100, 36% of biopsies had reticulin grade >MF1 and 33% of those tested had positive molecular studies, with no significant associations between day 100 marrow characteristics and molecular profile or peripheral count recovery times. In the 1 year posttransplant biopsies (n = 12), 7 of 9 had negative molecular studies; of these, none had reticulin grade >MF1, 1 had trichrome 1+, 2 had atypical megakaryocytes, and 1 was hypercellular. Conclusions Supporting recent literature, our study indicates that persistent day 100 reticulin fibrosis/collagen deposition does not show an association with day 100 molecular status. Our study additionally provides data for 12 patients with 1 year posttransplant marrow biopsies, with the majority of those lacking either increased fibrosis or molecular evidence of persistent disease. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Predictors of clinical outcome in myeloproliferative neoplasm, unclassifiable: A Bone Marrow Pathology Group study.
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Crane, Genevieve M, Geyer, Julia T, Thakral, Beenu, Wang, Sa A, Wool, Geoffrey D, Li, Ke David, Davis, Adam R, Boiocchi, Leonardo, Bosler, David, Bueso-Ramos, Carlos E, Arber, Daniel A, George, Tracy I, Bagg, Adam, Hasserjian, Robert P, Orazi, Attilio, Hsi, Eric D, and Rogers, Heesun J
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OVERALL survival , *PROGNOSIS , *MYELOPROLIFERATIVE neoplasms , *TREATMENT effectiveness , *NUCLEOTIDE sequencing - Abstract
Objectives Myeloproliferative neoplasm, unclassifiable (MPN-U, revised to MPN, not otherwise specified in the fifth edition of the World Health Organization classification) is a heterogeneous category of primary marrow disorders with clinical, morphologic, and/or molecular features that preclude classification as a more specific MPN subtype due to stage at diagnosis, overlapping features between MPN subtypes, or the presence of coexisting disorders. Compared with other MPN subtypes, the contribution of the mutational landscape in MPN-U in conjunction with other clinical and morphologic biomarkers to prognosis has been less well investigated. Methods We performed a multicenter, retrospective study of MPN-U (94 cases) to better define the clinicopathologic features, genetic landscape, and clinical outcomes, including subgroups of early-stage, advanced-stage, and coexisting disorders. The Dynamic International Prognostic Scoring System (DIPSS) plus scoring system was applied to assess its relevance to MPN-U prognosis. Results Multivariate analysis demonstrated bone marrow blast count and DIPSS plus score as statistically significant in predicting overall survival. Univariate analysis identified additional potential poor prognostic markers, including abnormal karyotype and absence of JAK2 mutation. Secondary mutations were frequent in the subset analyzed by next-generation sequencing (26/37 cases, 70.3%) with a borderline association between high molecular risk mutations and overall survival. Conclusions This study, as one of the largest of MPN-U studies incorporating both clinicopathologic and molecular data, moves toward identification of biomarkers that better predict prognosis in this heterogeneous category. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Myeloproliferative Neoplasm Symptom Assessment Total Symptom Score (MPN-SAF TSS) in Chronic Myeloproliferative Neoplasms with Relation to Genetic Burden and Thrombosis.
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Ümit, Elif Gülsüm, Baysal, Mehmet, Kırkızlar, Hakkı Onur, and Demir, Ahmet Muzaffer
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THROMBOSIS diagnosis , *CROSS-sectional method , *PROTEINS , *WEIGHT loss , *T-test (Statistics) , *MEDICAL quality control , *SCIENTIFIC observation , *FATIGUE (Physiology) , *MYELOPROLIFERATIVE neoplasms , *SEVERITY of illness index , *DESCRIPTIVE statistics , *MANN Whitney U Test , *CHI-squared test , *MULTIVARIATE analysis , *PATIENT care , *RETROSPECTIVE studies , *CHRONIC diseases , *POLYCYTHEMIA vera , *ITCHING , *DATA analysis software , *COMPARATIVE studies , *THROMBOCYTOSIS , *THROMBOSIS , *ALLELES , *ECONOMIC aspects of diseases , *MEDICAL practice , *SYMPTOMS ,BONE marrow cancer - Abstract
The Myeloproliferative Neoplasm Symptom Assessment Total Symptom Score (MPN-SAF TSS) is a surrogate marker for symptom evaluation in chronic myeloproliferative neoplasms (MPNs). However, insufficient data are available regarding the relationship among the MPN-SAF TSS, JAK2 mutation allele burden, and thrombosis. In this retrospective analysis, we aimed to determine the genetic burdens, clinical features, and relationships with MPN-SAF TSS in MPN patients. One hundred thirty JAK2V617F-positive patients with MPNs were included in our study. We calculated the MPN-SAF TSS for all patients and compared it with their clinical characteristics. Patients with higher JAK2V617F mutation allele burden had higher MPN-SAF TSS values (p=0.008). Patients with thrombosis had higher MPN-SAF TSS than patients without thrombosis (p=0.003). The mean MPN-SAF TSS was higher in patients with primary myelofibrosis compared to those with polycythemia vera and essential thrombocythemia. Thrombosis was associated with increased symptom severity in several domains, including fatigue, abdominal discomfort, inactivity, night sweats, pruritus, weight loss, and early satiety. Additionally, an increase in JAK2 allele burden was observed with higher symptom scores. The MPNSAF TSS proved to be a reliable tool for assessing symptom burden in Turkish MPN patients. Furthermore, the significant association between thrombosis occurrence and symptom severity suggests that thrombotic events may contribute to symptom development. Notably, increasing JAK2 allele burden was correlated with more severe symptoms, highlighting its potential role in predicting disease burden. This study emphasizes the importance of symptom assessment in MPN patients and supports the incorporation of the MPN-SAF TSS in routine clinical practice to enhance patient care and management. [ABSTRACT FROM AUTHOR]
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- 2024
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11. JAK2V617F Mutation in Endothelial Cells of Patients with Atherosclerotic Carotid Disease.
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Diz-Küçükkaya, Reyhan, İyigün, Taner, Albayrak, Özgür, Eker, Candan, and Günel, Tuba
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PROTEINS , *EPITHELIAL cells , *MONONUCLEAR leukocytes , *BODY mass index , *MYOCARDIAL ischemia , *RESEARCH funding , *SMOKING , *HYPERTENSION , *FISHER exact test , *MANN Whitney U Test , *DESCRIPTIVE statistics , *ENDOTHELIAL cells , *CORONARY artery disease , *GENETIC mutation , *DATA analysis software , *CAROTID endarterectomy , *BIOMARKERS , *DIABETES , *DISEASE complications - Abstract
Objective: It has been shown that clonal mutations occur in hematopoietic stem cells with advancing age and increase the risk of death due to atherosclerotic vascular diseases, similarly to myeloproliferative neoplasms. Endothelial cells (ECs) and hematopoietic stem cells develop from common stem cells called hemangioblasts in the early embryonic period. However, the presence of hemangioblasts in the postnatal period is controversial. In this study, JAK2 gene variants were examined in patients with atherosclerotic carotid disease and without any hematological malignancies. Materials and Methods: Ten consecutive patients (8 men and 2 women) with symptomatic atherosclerotic carotid stenosis were included in this study. ECs (CD31+CD45-) were separated from tissue samples taken by carotid endarterectomy. JAK2 variants were examined in ECs, peripheral blood mononuclear cells, and oral epithelial cells of the patients with next-generation sequencing. Results: The median age of the patients was 74 (range: 58-80) years and the median body mass index value was 24.44 (range: 18.42- 30.85) kg/m2. Smoking history was present in 50%, hypertension in 80%, diabetes in 70%, and ischemic heart disease in 70% of the cases. The JAK2V617F mutation was detected in the peripheral blood mononuclear cells of 3 of the 10 patients, and 2 patients also had the JAK2V617F mutation in their ECs. The JAK2V617F mutation was not found in the oral epithelial cells of any of the patients. Conclusion: In this study, for the first time in the literature, we showed that the JAK2V617F mutation was found somatically in both peripheral blood cells and ECs in patients with atherosclerosis. This finding may support that ECs and hematopoietic cells originate from a common clone or that somatic mutations can be transmitted to ECs by other mechanisms. Examining the molecular and functional changes caused by the JAK2V617F mutation in ECs may help open a new avenue for treating atherosclerosis. [ABSTRACT FROM AUTHOR]
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- 2024
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12. BRAF mutation in myeloid neoplasm: incidences and clinical outcomes.
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Abuasab, Tareq, Mohamed, Shehab, Pemmaraju, Naveen, Kadia, Tapan M., Daver, Naval, DiNardo, Courtney D., Ravandi, Farhad, Qiao, Wei, Montalban-Bravo, Guillermo, and Borthakur, Gautam
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HAIRY cell leukemia , *ACUTE myeloid leukemia , *CHRONIC myeloid leukemia , *MYELOPROLIFERATIVE neoplasms , *CHRONIC leukemia - Abstract
The presence of BRAF mutation in hematological malignancies, excluding Hairy cell leukemia, and its significance as a driver mutation in myeloid neoplasms (MNs) remains largely understudied. This research aims to evaluate patient characteristics and outcomes of BRAF-mutated MNs. Among a cohort of 6667 patients, 48 (0.7%) had BRAF-mutated MNs. Notably, three patients exhibited sole BRAF mutation, providing evidence supporting the hypothesis of BRAF's role as a driver mutation in MNs. In acute myeloid leukemia, the majority of patients had secondary acute myeloid leukemia, accompanied by poor-risk cytogenic and RAS pathway mutations. Although the acquisition of BRAF mutation during disease progression did not correlate with unfavorable outcomes, its clearance through chemotherapy or stem cell transplant exhibited favorable outcomes (median overall survival of 34.8 months versus 10.4 months, p = 0.047). Furthermore, G469A was the most frequently observed BRAF mutation, differing from solid tumors and hairy cell leukemia, where V600E mutations were predominant. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Evaluating targeted therapies in older patients with TP53-mutated AML.
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Sabile, Jean M.G., Swords, Ronan, and Tyner, Jeffrey W.
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MYELOPROLIFERATIVE neoplasms , *ACUTE myeloid leukemia , *MYELODYSPLASTIC syndromes , *OLDER patients , *TUMOR proteins - Abstract
Mutation of thetumor suppressor gene, TP53 (tumor protein 53), occurs in up to 15% of all patients with acute myeloid leukemia (AML) and is enriched within specific clinical subsets, most notably in older adults, and including secondary AML cases arising from preceding myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), patients exposed to prior DNA-damaging, cytotoxic therapies. In all cases, these tumors have remained difficult to effectively treat with conventional therapeutic regimens. Newer approaches fortreatmentofTP53-mutated AML have shifted to interventions that maymodulateTP53 function, target downstream molecular vulnerabilities, target non-p53 dependent molecular pathways, and/or elicit immunogenic responses. This review will describe the basic biology of TP53, the clinical and biological patterns of TP53 within myeloid neoplasms with a focus on elderly AML patients and will summarize newer therapeutic strategies and current clinical trials. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Myeloproliferative neoplasms: young patients, current data and future considerations.
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Sobas, Marta, Ianotto, Jean-Christophe, Kiladjian, Jean-Jacques, and Harrison, Claire
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MYELOPROLIFERATIVE neoplasms , *YOUNG adults , *HEMATOPOIETIC stem cells , *DISEASE risk factors , *ACUTE myeloid leukemia , *MYELOFIBROSIS - Abstract
The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders predominantly occurring in elderly, whereas in children and young adults are quite infrequent. Therefore, less is known about clinical presentation, genetic abnormalities, prognosis and best management strategies for this groups of patients. Currently, more cases of younger MPN patients are diagnosed. Nevertheless, diagnosis of MPNs, especially in childhood, may be difficult due to lower incidence of JAK2V617F and CALR mutations and differences in peripheral blood counts between adults and children. Challenges for younger MPN patients are longer life expectances, specific psychosocial need, fertility and pregnancy need and a long term therapy side effect (including second cancers). The most severe MPNs complication is transformation to secondary myelofibrosis (MF) or acute myeloid leukemia (AML). Optimal management of young MPNs remains a challenge as the classical risk scores fail in young MPNs. Moreover, the main objective of young MPNs therapy should be the disease outcome modification. Therefore, international collaborative work between pediatricians and "adult hematologists" is required to measure outcomes and generate protocol of management of young MPNs. [ABSTRACT FROM AUTHOR]
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- 2024
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15. A randomized, double-blind, placebo-controlled phase 3 study to assess efficacy and safety of ropeginterferon alfa-2b in patients with early/lower-risk primary myelofibrosis.
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Abu-Zeinah, Ghaith, Qin, Albert, Gill, Harinder, Komatsu, Norio, Mascarenhas, John, Shih, Weichung Joe, Zagrijtschuk, Oleh, Sato, Toshiaki, Shimoda, Kazuya, Silver, Richard T., and Mesa, Ruben
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CLINICAL trials , *MYELOPROLIFERATIVE neoplasms , *GENETIC mutation , *BONE marrow , *PATIENT safety - Abstract
Primary myelofibrosis (PMF) is the most aggressive of the myeloproliferative neoplasms and patients require greater attention and likely require earlier therapeutic intervention. Currently approved treatment options are limited in their selective suppression of clonal proliferation resulting from driver- and coexisting gene mutations. Janus kinase inhibitors are approved for symptomatic patients with higher-risk PMF. Additionally, most ongoing clinical studies focus on patients with higher-risk disease and/or high rates of transfusion dependency. Optimal treatment of early/lower-risk PMF remains to be identified and needs randomized clinical trial evaluations. Pegylated interferon alfa is recommended for symptomatic lower-risk PMF patients based on phase 2 non-randomized studies and expert opinion. Ropeginterferon alfa-2b (ropeg) is a new-generation pegylated interferon-based therapy with favorable pharmacokinetics and safety profiles, requiring less frequent injections than prior formulations. This randomized, double-blind, placebo-controlled phase 3 trial will assess its efficacy and safety in patients with "early/lower-risk PMF", defined as pre-fibrotic PMF or PMF at low or intermediate-1 risk according to Dynamic International Prognostic Scoring System-plus. Co-primary endpoints include clinically relevant complete hematologic response and symptom endpoint. Secondary endpoints include progression- or event-free survival, molecular response in driver or relevant coexisting gene mutations, bone marrow response, and safety. Disease progression and events are defined based on the International Working Group criteria and well-published reports. 150 eligible patients will be randomized in a 2:1 ratio to receive either ropeg or placebo. Blinded sample size re-estimation is designed. Ropeg will be administered subcutaneously with a tolerable, higher starting-dose regimen. The study will provide important data for the treatment of early/lower-risk PMF for which an anti-clonal, disease-modifying agent is highly needed. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Predictive significance of high neutrophil ratio for thrombosis in myeloproliferative neoplasms: JSH-MPN-R18 subanalysis.
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Nagaharu, Keiki, Ohya, Eiko, Edahiro, Yoko, Hashimoto, Yoshinori, Ito, Tomoki, Gotoh, Akihiko, Nakamae, Mika, Kimura, Fumihiko, Koike, Michiaki, Kirito, Keita, Wada, Hideho, Usuki, Kensuke, Tanaka, Takayuki, Mori, Takehiko, Wakita, Satoshi, Saito, Toshiki I., Saito, Akiko M., Shimoda, Kazuya, Kurokawa, Toshiro, and Tomita, Akihiro
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BLOOD cell count , *POLYCYTHEMIA vera , *MYELOPROLIFERATIVE neoplasms , *STATISTICAL software , *THROMBOSIS - Abstract
Thrombosis in myeloproliferative neoplasms (MPNs) is an important clinical problem, and risk-stratified management is essential. To identify the clinical characteristics of thrombosis in patients with MPNs, a nationwide multi-institutional retrospective analysis (JSH-MPN-R18) was conducted. The aim of the present study was to perform a sub-analysis of JSH-MPN-R18 findings to clarify the predictive parameters for thrombosis among complete blood count (CBC) results. Among the patients enrolled in JSH-MPN-R18, those with essential thrombocythemia (ET; n = 1152) and polycythemia vera (PV; n = 456) were investigated. We analyzed and compared CBC parameters between patients with and those without any thrombotic events using Welch's T-test. Statistical analyses were performed using the R statistical software. Thrombotic events were observed in 74 patients with ET. In multivariate analysis, only the neutrophil ratio was slightly but significantly higher for ET patients with thrombosis than for those without (p < 0.05). Of note, the absolute neutrophil count (aNeu) was considered a useful predictive tool for thrombosis among patients classified as low-risk according to the revised International Prognostic Score of Thrombosis for Essential Thrombocythemia. Among PV patients, those with thrombosis showed significantly higher hematocrit and aNeu than did those without thrombosis. As a thrombosis-associated factor, the neutrophil ratio was slightly but significantly elevated in patients with ET. This myeloid skew might reflect a higher value of JAK2 V617F allelic frequency in patients with ET with thrombosis; this was not clarified in JSH-MPN-R18. Further accumulation of evidence, including genetic information for JAK2 and other passenger mutations, is warranted. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Superior detection of low-allele burden Janus kinase 2 V617F mutation and monitoring clonal evolution in myeloproliferative neoplasms using chip-based digital PCR.
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Lu, Yiyi, Lin, Lin, Lin, Jiafei, Wu, Beiying, Cai, Gang, Wang, Xuefeng, and Ma, Xuefei
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LEUKOCYTE count , *MYELOPROLIFERATIVE neoplasms , *CHRONIC myeloid leukemia , *PROTEIN-tyrosine kinase inhibitors , *LACTATE dehydrogenase - Abstract
The JAK2 V617F is a prevalent driver mutation in Philadelphia chromosome-negative myeloproliferative neoplasms (Ph−MPNs), significantly affecting disease progression, immunophenotype, and patient outcomes. The World Health Organization (WHO) guidelines highlight the JAK2 V617F mutation as one of the key diagnostic criterions for Ph−MPNs. In this study, we analyzed 283 MPN samples with the JAK2 V617F mutation to assess the effectiveness of three detection technologies: chip-based digital PCR (cdPCR), real-time quantitative PCR (qPCR), and next-generation sequencing (NGS). Additionally, we investigated the relationship between JAK2 V617F mutant allele burden (% JAK2 V617F) and various laboratory characteristics to elucidate potential implications in MPN diagnosis. Our findings demonstrated high conformance of cdPCR with qPCR/NGS for detecting % JAK2 V617F, but the mutant allele burdens detected by qPCR/NGS were lower than those detected by cdPCR. Moreover, the cdPCR exhibited high sensitivity with a limit of detection (LoD) of 0.08% and a limit of quantification (LoQ) of 0.2% for detecting % JAK2 V617F in MPNs. Clinical implications were explored by correlating % JAK2 V617F with various laboratory characteristics in MPN patients, revealing significant associations with white blood cell counts, lactate dehydrogenase levels, and particularly β2-microglobulin (β2-MG) levels. Finally, a case report illustrated the application of cdPCR in detecting low-allele burdens in a de novo chronic myeloid leukemia (CML) patient with a hidden JAK2 V617F subclone, which expanded during tyrosine kinase inhibitor (TKI) treatment. Our findings underscore the superior sensitivity and accuracy of cdPCR, making it a valuable tool for early diagnosis and monitoring clonal evolution. [ABSTRACT FROM AUTHOR]
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- 2024
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18. Socio-demographic determinants of myelofibrosis outcomes in an underserved center and the SEER national database.
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Yan, John, Hammami, M. Bakri, Wei, John X., Shah, Nishi, Goldfinger, Mendel, Mantzaris, Ioannis, Kornblum, Noah, Gritsman, Kira, Sica, Alejandro, Cooper, Dennis, Feldman, Eric, Konopleva, Marina, Pradhan, Kith, Thakur, Rahul, Vegivinti, Charan, Qasim, Asma, Verma, Amit, and Goel, Swati
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OVERALL survival , *MYELOPROLIFERATIVE neoplasms , *SURVIVAL rate , *DEMOGRAPHIC characteristics , *SOCIAL determinants of health , *MYELOFIBROSIS - Abstract
The influence of demographic characteristics and social determinants on cancer outcomes is widely recognized in various malignancies but remains understudied in myelofibrosis (MF). This study aims to investigate social and demographic variables associated with MF survival. We retrospectively reviewed data of biopsy-proven MF patients from the Surveillance, Epidemiology and End Results (SEER) database (2000–2021) and Montefiore Medical Center (2000–2023), an underserved inner-city hospital. The SEER cohort included 5,403 MF patients and was predominantly Non-Hispanic (NH) White (82%) with a median age of 69 years. The age-adjusted incidence rate of MF was 0.32 cases per 100,000 person-years, increasing annually by 1.3% from 2000 to 2021. Two- and five- year overall survival rates were 69% and 42%, respectively. Worse cause-specific survival was associated with older age, male sex, and diagnosis before 2011 (year of Ruxolitinib approval). NH-Black ethnicity, unmarried status and lower median income were independent predictors of worse overall survival. The single-center analysis included 84 cases, with a median age of 66 years. NH-White patients comprised 37% of the sample, followed by NH-Black (28.5%). Two- and five- year overall survival rates were 90% and 61%, respectively, with NH-Black patients exhibiting the lowest median survival, although the difference was not statistically significant. Age was a significant predictor of worse survival in this cohort. NH-Black and Hispanic patients lived in areas with higher socioeconomic and demographic stress compared to NH-White patients. Overall, this study highlights the association of social and demographic factors with MF survival and emphasizes the need for equitable healthcare and further exploration of social-demographic factors affecting MF survival. [ABSTRACT FROM AUTHOR]
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- 2024
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19. The application of JAK inhibitors in the peri-transplantation period of hematopoietic stem cell transplantation for myelofibrosis.
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Wang, Zerong, Jin, Xuelian, Zeng, Jiajia, Xiong, Zilin, and Chen, Xinchuan
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HEMATOPOIETIC stem cell transplantation , *MYELOPROLIFERATIVE neoplasms , *GRAFT versus host disease , *OVERALL survival , *RUXOLITINIB , *MYELOFIBROSIS - Abstract
Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with a poor prognosis, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential. Ruxolitinib, a JAK1/2 inhibitor, has shown promising results in improving patients' symptoms, overall survival, and quality of life, and can be used as a bridging therapy to HSCT that increases the proportion of transplantable patients. However, the effect of this and similar drugs on HSCT outcomes is unknown, and the reports on their efficacy and safety in the peri-transplantation period vary widely in the published literature. This paper reviews clinical data related to the use of JAK inhibitors in the peri-implantation phase of hematopoietic stem cell transplantation for primary myelofibrosis and discusses their efficacy and safety. [ABSTRACT FROM AUTHOR]
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- 2024
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20. Red Palms' Syndrome and Red Fingers' Syndrome: A Mini Review.
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Bilancini, Salvino, Lucchi, Massimo, Tucci, Sandro, Pomella, Federica, Vittori, Giulia, Mollo, Pierluigi Edgard, and Trevisan, Giusto
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COMMUNICABLE diseases , *FINGERS , *ERYTHEMA , *RARE diseases , *ASPIRIN , *HIV infections , *MYELOPROLIFERATIVE neoplasms , *POLYCYTHEMIA vera , *HAND , *HEPATITIS B , *HEPATITIS C , *THROMBOCYTOSIS , *TOES , *SYMPTOMS - Abstract
Red palms syndrome consists of an intense redness on the palms of the hands and, occasionally, the soles of the feet. This infrequent condition may be primary or secondary. The primary forms are either familial or sporadic. They are always benign and do not require treatment. The secondary forms may have a poor prognosis related to the underlying disease, for which early identification and treatment are imperative. Red fingers syndrome is also rare. It manifests as a persistent redness on the fingers or toes pulp. It is typically secondary either to infectious diseases like human immunodeficiency virus, hepatitis C virus and chronic hepatitis B or to Myeloproliferative Disorders, such as Thrombocythemia and Polycythemia vera. Manifestations spontaneously regress over months or years without trophic alterations. Treatment is limited to that of the underlying condition. Aspirin has been shown effective in Myeloproliferative Disorders. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Concurrent myelodysplastic malignancies and plasma cell neoplasms; a clinicopathological study with prognostic implications.
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Adekunle, Folashade, Ko, Kyungmin, Craig, Jeffrey, Courville, Elizabeth, Williams, Eli, Aguilera, Nadine, and Obiorah, Ifeyinwa E.
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PLASMA cell diseases , *MYELOPROLIFERATIVE neoplasms , *PROGNOSIS , *PLASMA cells , *MYELOID leukemia - Abstract
AbstractPlasma cell neoplasms (PCN) have infrequently been reported in patients with myelodysplastic syndrome (MDS) and even more rarely in those with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN). We report the clinicopathologic features of 26 patients with bone marrow myelodysplasia accompanied by PCN, including 21 patients with MDS and 5 with MDS/MPN. The clinicopathologic features of the MDS/MPN-PCN were compared to those of the MDS-PCN group and 68 cases of MDS/MPN without PCN, respectively. The MDS/MPN-PCN group was notable for increased reticulin fibrosis > grade 1 when compared to both the MDS/MPN (
p = 0.007) and MDS-PCN (p = 0.02) groups. MDS/MPN-PCN was associated with worse overall survival when compared with MDS-PCN (p = 0.03) and but not with MDS/MPN. Notably, hemoglobin level <8 g/dl (p = 0.008), andIDH2 somatic mutation (p = 0.003) were independent predictors of poor overall survival in all patients with MDS/MPN. Analysis of larger cohorts is required to confirm these associations and provide an insight into the pathogenesis. [ABSTRACT FROM AUTHOR]- Published
- 2024
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22. The CALR mutations enhance the expression of the immunosuppressive proteins GARP and LAP on peripheral blood lymphocytes through increased binding of activated platelets.
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Holmström, Morten Orebo, Ruders, Josephine Hallundbæk, Riley, Caroline Hasselbalch, Larsen, Morten Kranker, Grauslund, Jacob Handlos, Kjær, Lasse, Skov, Vibe, Ellervik, Christina, Guo, Belinda B., Linden, Matthew, Hasselbalch, Hans Carl, and Andersen, Mads Hald
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TRANSFORMING growth factors-beta , *GENE expression , *PLATELET count , *MYELOPROLIFERATIVE neoplasms , *PEPTIDES - Abstract
Summary Recently, an antibody which inhibits the glycoprotein A repetitions predominant (GARP)‐mediated release of active transforming growth factor beta (TGFβ) from the TGFβ propeptide latency‐associated peptide (LAP) showed preclinical activity in a murine model of the chronic myeloproliferative neoplasms (MPN). Consequently, we investigated the expression of the immunosuppressive molecules LAP and GARP on peripheral blood lymphocytes from 56 MPN patients and 11 healthy donors (HD). We found that lymphocytes from patients with MPN express higher levels of LAP and GARP with no strong differences found between the different MPN diagnoses. The impact of clinical parameters on the expression of LAP and GARP by lymphocytes showed that patients with calreticulin (CALR)mut MPN have increased expression compared with HD and patients with the Januskinase2 (JAK2) mutation. The fraction of lymphocytes bound to activated platelets (aPLT) strongly correlate to LAP and GARP expression suggesting that it is not the lymphocytes themselves but aPLT, which confer the increased expression of GARP and LAP on MPN patient lymphocytes. Notably, no differences in neither platelet counts nor anti‐thrombotic therapy was identified between patients with JAK2‐ and CALRmut patients. Analysis of platelet gene expression failed to identify differences in expression of relevant genes between JAK2‐ and CALRmut patients. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Transformation into acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 from JAK2-mutated essential thrombocythemia: a case report.
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Asou, Chie, Sakamoto, Tomoyuki, Suzuki, Kodai, Okuda, Itoko, Osaki, Atsushi, Abe, Ryohei, Ito, Yoshihiro, Kakegawa, Emi, Miyakawa, Yoshitaka, Terui, Yasuhito, and Nakamura, Yuichi
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ACUTE myeloid leukemia , *MYELOPROLIFERATIVE neoplasms , *LEUCOCYTES , *ORAL drug administration , *GENETIC mutation - Abstract
Background: Blast transformation is a rare but well-recognized event in Philadelphia-negative myeloproliferative neoplasms associated with a poor prognosis. Secondary acute myeloid leukemias evolving from myeloproliferative neoplasms are characterized by a unique set of cytogenetic and molecular features distinct from de novo disease. t(8;21) (q22;q22.1); RUNX1::RUNX1T1, one of the most frequent cytogenetic abnormalities in de novo acute myeloid leukemia, is rarely observed in post-myeloproliferative neoplasm acute myeloid leukemia. Here we report a case of secondary acute myeloid leukemia with t(8;21) evolving from JAK2-mutated essential thrombocythemia. Case presentation: The patient was a 74-year-old Japanese woman who was referred because of thrombocytosis (platelets 1046 × 109/L). Bone marrow was hypercellular with increase of megakaryocytes. Chromosomal analysis presented normal karyotype and genetic test revealed JAK2 V617F mutation. She was diagnosed with essential thrombocythemia. Thrombocytosis had been well controlled by oral administration of hydroxyurea; 2 years after the initial diagnosis with ET, she presented with leukocytosis (white blood cells 14.0 × 109/L with 82% of blasts), anemia (hemoglobin 91 g/L), and thrombocytopenia (platelets 24 × 109/L). Bone marrow was hypercellular and filled with 80% of myeloperoxidase-positive blasts bearing Auer rods. Chromosomal analysis revealed t(8;21) (q22;q22.1) and flow cytometry presented positivity of CD 13, 19, 34, and 56. Molecular analysis showed the coexistence of RUNX1::RUNX1T1 chimeric transcript and heterozygous JAK2 V617F mutation in leukemic blasts. She was diagnosed with secondary acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 evolving from essential thrombocythemia. She was treated with combination chemotherapy with venetoclax and azacytidine. After the first cycle of the therapy, blasts disappeared from peripheral blood and decreased to 1.4% in bone marrow. After the chemotherapy, RUNX1::RUNX1T1 chimeric transcript disappeared, whereas mutation of JAK2 V617F was still present in peripheral leukocytes. Conclusions: To our best knowledge, the present case is the first one with JAK2 mutation preceding the acquisition of t(8;21). Our result suggests that t(8;21); RUNX1::RUNX1T1 can be generated as a late event in the progression of JAK2-mutated myeloproliferative neoplasms. The case presented typical morphological and immunophenotypic features associated with t(8;21) acute myeloid leukemia. [ABSTRACT FROM AUTHOR]
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- 2024
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24. Impact of Phlebotomy on Quality of Life in Low-Risk Polycythemia Vera.
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Visweshwar, Nathan, Fletcher, Bradley, Jaglal, Michael, Laber, Damian A., Patel, Ankita, Eatrides, Jennifer, Rathnakumar, Geetha Rajasekharan, Iyer, Keshav Visweswaran, Ayala, Irmel, and Manoharan, Arumugam
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POLYCYTHEMIA vera , *ACUTE myeloid leukemia , *MYELOPROLIFERATIVE neoplasms , *CORONARY artery disease , *VENOUS thrombosis - Abstract
Polycythemia vera is an indolent myeloproliferative disorder that predisposes patients to venous and arterial thrombosis and can transform into myelofibrosis and acute myeloid leukemia. Consistent phlebotomy prevents life-threatening cerebrovascular and coronary artery disease and prolongs survival in low-risk polycythemia vera (patients under 60 years without thrombosis). However, despite its effectiveness in preventing serious complications, phlebotomy does not necessarily enhance the quality of life (QoL). This review assesses QoL issues associated with low-risk PV, explores alternative management strategies such as erythrocytapheresis, and discusses the roles of hydroxyurea, peginterferon, ruxolitinib, and other novel agents in potentially improving disease management and patient outcomes. [ABSTRACT FROM AUTHOR]
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- 2024
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25. C-Mannosyl tryptophan is a novel biomarker for thrombocytosis of myeloproliferative neoplasms.
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Tabata, Shotaro, Yamashita, Yusuke, Inai, Yoko, Morita, Shuhei, Kosako, Hideki, Takagi, Tomoyuki, Shide, Kotaro, Manabe, Shino, Matsuoka, Taka-aki, Shimoda, Kazuya, Sonoki, Takashi, Ihara, Yoshito, and Tamura, Shinobu
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MYELOPROLIFERATIVE neoplasms , *HYDROPHILIC interaction liquid chromatography , *BLOOD diseases , *THROMBOCYTOSIS , *JAPANESE people , *SECRETION , *PROTEOLYSIS - Abstract
C-Mannosyl tryptophan (CMW), a unique glycosylated amino acid, is considered to be produced by degradation of C-mannosylated proteins in living organism. Although protein C-mannosylation is involved in the folding and secretion of substrate proteins, the pathophysiological function in the hematological system is still unclear. This study aimed to assess CMW in the human hematological disorders. The serum CMW levels of 94 healthy Japanese workers were quantified using hydrophilic interaction liquid chromatography. Platelet count was positively correlated with serum CMW levels. The clinical significance of CMW in thrombocytosis of myeloproliferative neoplasms (T-MPN) including essential thrombocythemia (ET) were investigated. The serum CMW levels of the 34 patients with T-MPN who presented with thrombocytosis were significantly higher than those of the 52 patients with control who had other hematological disorders. In patients with T-MPN, serum CMW levels were inversely correlated with anemia, which was related to myelofibrosis (MF). Bone marrow biopsy samples were obtained from 18 patients with ET, and serum CMW levels were simultaneously measured. Twelve patients with bone marrow fibrosis had significantly higher CMW levels than 6 patients without bone marrow fibrosis. Collectively, these results suggested that CMW could be a novel biomarker to predict MF progression in T-MPN. [ABSTRACT FROM AUTHOR]
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- 2024
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26. Mechanobiology and Primary Cilium in the Pathophysiology of Bone Marrow Myeloproliferative Diseases.
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Tiberio, Federica, Coda, Anna Rita Daniela, Tosi, Domiziano Dario, Luzi, Debora, Polito, Luca, Liso, Arcangelo, and Lattanzi, Wanda
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BONE marrow diseases , *BONE marrow cells , *STEM cell niches , *HEMATOPOIETIC stem cells , *POLYCYTHEMIA vera , *CILIA & ciliary motion - Abstract
Philadelphia-Negative Myeloproliferative neoplasms (MPNs) are a diverse group of blood cancers leading to excessive production of mature blood cells. These chronic diseases, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), can significantly impact patient quality of life and are still incurable in the vast majority of the cases. This review examines the mechanobiology within a bone marrow niche, emphasizing the role of mechanical cues and the primary cilium in the pathophysiology of MPNs. It discusses the influence of extracellular matrix components, cell-cell and cell-matrix interactions, and mechanosensitive structures on hematopoietic stem cell (HSC) behavior and disease progression. Additionally, the potential implications of the primary cilium as a chemo- and mechanosensory organelle in bone marrow cells are explored, highlighting its involvement in signaling pathways crucial for hematopoietic regulation. This review proposes future research directions to better understand the dysregulated bone marrow niche in MPNs and to identify novel therapeutic targets. [ABSTRACT FROM AUTHOR]
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- 2024
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27. Epidemiology and disease characteristics of myelofibrosis: a comparative analysis between Italy and global perspectives.
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Breccia, Massimo, Palandri, Francesca, Polverelli, Nicola, Caira, Morena, Berluti, Michela, Palumbo, Giuseppe A., and De Stefano, Valerio
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HEMATOPOIETIC stem cells ,MYELOPROLIFERATIVE neoplasms ,BONE marrow ,MYELOFIBROSIS ,EPIDEMIOLOGY ,PHENOTYPES - Abstract
Myelofibrosis (MF) is a clonal disorder of hematopoietic stem cells characterized by altered bone marrow function and fibrosis. The aim of this narrative review is to report on the most recent epidemiologic data and to discuss features of MF and current strategies for the management of this condition in clinical practice. MF features covered by our review will include: characteristics of patients with MF; myeloproliferative and myelodepletive phenotypes; MF-associated thrombosis and bleeding; risk of infections; prefibrotic and overt PMF; secondary MF. Finally, we will discuss a few aspects of MF management in clinical practice and suggest strategies for its optimization and standardization. The focus of our paper is on Italy, but relevant data from other countries will also be reviewed. [ABSTRACT FROM AUTHOR]
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- 2024
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28. Molecular biomarkers of leukemia: convergence-based drug resistance mechanisms in chronic myeloid leukemia and myeloproliferative neoplasms.
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Kaehler, Meike, von Bubnoff, Nikolas, Cascorbi, Ingolf, and Gorantla, Sivahari Prasad
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HEMATOLOGIC malignancies ,CHRONIC myeloid leukemia ,MYELOPROLIFERATIVE neoplasms ,DEUBIQUITINATING enzymes ,PROTEIN-tyrosine kinase inhibitors - Abstract
Leukemia represents a diverse group of hematopoietic neoplasms that can be classified into different subtypes based on the molecular aberration in the affected cell population. Identification of these molecular classification is required to identify specific targeted therapeutic approaches for each leukemic subtype. In general, targeted therapy approaches achieve good responses in some leukemia subgroups, however, resistance against these targeted therapies is common. In this review, we summarize molecular drug resistance biomarkers in targeted therapies in BCR::ABL1-driven chronic myeloid leukemia (CML) and JAK2-driven myeloproliferative neoplasms (MPNs). While acquisition of secondary mutations in the BCR::ABL1 kinase domain is the a common mechanism associated with TKI resistance in CML, in JAK2-driven MPNs secondary mutations in JAK2 are rare. Due to high prevalence and lack of specific therapy approaches in MPNs compared to CML, identification of crucial pathways leading to inhibitor persistence in MPN model is utterly important. In this review, we focus on different alternative signaling pathways activated in both, BCR::ABL1-mediated CML and JAK2-mediated MPNs, by combining data from in vitro and in vivo-studies that could be used as potential biomarkers of drug resistance. In a nutshell, some common similarities, especially activation of PDGFR, Ras, PI3K/Akt signaling pathways, have been demonstrated in both leukemias. In addition, induction of the nucleoprotein YBX1 was shown to be involved in TKI-resistant JAK2-mediated MPN, as well as TKI-resistant CML highlighting deubiquitinating enzymes as potential biomarkers of TKI resistance. Taken together, whole exome sequencing of cell-based or patients-derived samples are highly beneficial to define specific resistance markers. Additionally, this might be helpful for the development of novel diagnostic tools, e.g., liquid biopsy, and novel therapeutic agents, which could be used to overcome TKI resistance in molecularly distinct leukemia subtypes. [ABSTRACT FROM AUTHOR]
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- 2024
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29. Systemic Inflammatory Index in Polycythemia Vera and Its Prognostic Implications.
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Krecak, Ivan, Lekovic, Danijela, Arsenovic, Isidora, Bogdanovic, Andrija, Holik, Hrvoje, Zekanovic, Ivan, Moric Peric, Martina, and Lucijanic, Marko
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PLATELET lymphocyte ratio , *NEUTROPHIL lymphocyte ratio , *POLYCYTHEMIA vera , *PLATELET count , *MYELOPROLIFERATIVE neoplasms - Abstract
Background: This study aimed to evaluate the clinical and prognostic associations of the systemic inflammatory index (SII) in polycythemia vera (PV) patients. SII integrates information on absolute neutrophil (ANC), lymphocyte (ALC), and platelet counts into one index (calculated as ANCxALC/platelet count) and was previously shown to predict thrombotic and mortality risks in the general population. Methods: A total of 279 PV patients treated in several hematologic centers in Croatia and Serbia was retrospectively evaluated. Results: The median SII for the overall cohort was 1960. Higher SII stratified at the specific cut-off points was significantly associated with shorter time to thrombosis (TTT; p = 0.004) driven by arterial thrombotic events, and shorter overall survival (OS; p < 0.001). Higher SII was able to refine the European Leukemia Net-defined high-risk patient subgroup for both thrombotic and survival risks, especially in individuals over 60 years of age. SII and all other evaluated CBC components and indices (leukocytes, ANC, ALC, platelets, neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR)) demonstrated low-to-modest prognostic properties, whereas SII outperformed other parameters with respect to TTT and OS prognostications. Discussion: The presented results complement prior studies evaluating the prognostic performance of different CBC components for thrombotic and survival risk predictions and offer more options to personalize PV treatments. [ABSTRACT FROM AUTHOR]
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- 2024
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30. A comparative analysis of the clinical and genetic profiles of blast phase BCR::ABL1‐negative myeloproliferative neoplasm and acute myeloid leukemia, myelodysplasia‐related.
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Chen, Dong, Geyer, Julia, Bagg, Adam, Hasserjian, Robert, and Weinberg, Olga K.
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MYELODYSPLASTIC syndromes , *PROTEINS , *PLATELET count , *MYELOPROLIFERATIVE neoplasms , *SYMPTOMS , *DESCRIPTIVE statistics , *GENETIC mutation , *OVERALL survival - Abstract
Introduction: The classic Philadelphia chromosome–negative myeloproliferative neoplasms (Ph (‐) MPNs), have variable potential for progression to the blast phase (MPN‐BP) of the disease. Except initiated by distinct driver mutations, MPN‐BP frequently carry similar genetic abnormalities defining acute myeloid leukemia myelodysplasia‐related (AML‐MR). Because of dissimilar initial pathogenesis, MPN‐BP and AML‐MR are retained under different disease categories. To determine if separately classifying these entities is justified, we compare MPN‐BP with AML‐MR patients based on mutational landscape and clinical parameters. Methods: 104 MPN‐BP patients and 145 AML‐MR patients were identified with available clinical, cytogenetic, and genetic data. Results: AML‐MR patients presented with a higher blast count (median, 51% vs. 30%) while MPN‐BP patients had higher WBC counts, platelet counts and bone marrow cellularity (all p<0.0001). Patients with MPN‐BP showed similar genetic mutations with similar mutation pattern (functional domain, hotspot and locus involved by the mutations) but a different mutation rate from AML‐MR, with more frequent JAK2, CALR, MPL, ASXL1, IDH2, SETBP1 and SRSF2 mutations and less frequent TP53 and DNMT3A mutations. The overall survival (OS) of MPN‐BP (OS post‐BP‐progression) is comparable to that of AML‐MR (median OS, 9.5 months vs. 13.1 months, p=0.20). In addition, the subgroups of MPN‐BP show similar OS as AML‐MR. When harboring certain mutation such as TP53, ASXL1, DNMT3A, TET2, RUNX1, IDH1, IDH2, EZH2, U2AF1, BCOR and SRSF2, MPN‐BP and AML‐MR patients carrying the same somatic mutation show no difference in OS. Conclusion: MPN‐BP and AML‐MR harbor similar somatic mutations and clinical outcomes, suggesting a unified clinical disease entity. [ABSTRACT FROM AUTHOR]
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- 2024
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31. Myeloproliferative Neoplasms Transcriptome Reveals Pro-Inflammatory Signature and Enrichment in Peripheral Blood Monocyte-Related Genes.
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Bassan, Vitor Leonardo, de Freitas Martins Felício, Rafaela, Ribeiro Malmegrim, Kelen Cristina, and Attié de Castro, Fabíola
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MONOCYTES , *RESEARCH funding , *NEUTROPHILS , *MYELOPROLIFERATIVE neoplasms , *DESCRIPTIVE statistics , *GENES , *POLYCYTHEMIA vera , *BLOOD platelets , *INTERFERONS , *GENE expression profiling , *INFLAMMATION , *GENETIC mutation , *THROMBOCYTOSIS , *MYELOFIBROSIS - Abstract
Myeloproliferative neoplasms (MPN) are hematological diseases associated with genetic driver mutations in the JAK2, CALR, and MPL genes and exacerbated oncoinflammatory status. Analyzing public microarray data from polycythemia vera (n = 41), essential thrombocythemia (n = 21), and primary myelofibrosis (n = 9) patients' peripheral blood by in silico approaches, we found that pro-inflammatory and monocyte-related genes were differentially expressed in MPN patients' transcriptome. Genes related to cell activation, secretion of pro-inflammatory and pro-angiogenic mediators, activation of neutrophils and platelets, coagulation, and interferon pathway were upregulated in monocytes compared to controls. Together, our results suggest that molecular alterations in monocytes may contribute to oncoinflammation in MPN. [ABSTRACT FROM AUTHOR]
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- 2024
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32. Observation and Management of Juvenile Myelomonocytic Leukemia and Noonan Syndrome-Associated Myeloproliferative Disorder: A Real-World Experience †.
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Lucas, Bryony J., Connors, Jeremy S., Wang, Heping, Conneely, Shannon, Cuglievan, Branko, Garcia, Miriam B., and Rau, Rachel E.
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THERAPEUTIC use of antineoplastic agents , *THERAPEUTIC use of antimetabolites , *MYELOID leukemia genetics , *CYTOGENETICS , *NOONAN syndrome , *GERM cells , *AZACITIDINE , *MYELOPROLIFERATIVE neoplasms , *TREATMENT effectiveness , *RETROSPECTIVE studies , *CANCER chemotherapy , *MEDICAL records , *ACQUISITION of data , *MYELOID leukemia , *GENETIC mutation , *GENETICS , *ALLELES , *DISEASE complications , *CHILDREN - Abstract
Simple Summary: Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Given its rarity, management is not standardized and varies widely, ranging from observation to bone marrow transplant depending on genomic and clinical features. We describe the course of JMML or Noonan Syndrome-associated Myeloproliferative Disorder in 22 pediatric patients treated at three institutions to provide guidance for monitoring versus intervention, including transplant, supported by patient outcomes. We provide additional insight into the expected time to spontaneous resolution in those with germline PTPN11 mutations and treatment approaches for patients with germline CBL mutations where no standard exists. Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Treatment is not uniform, with management varying from observation to stem cell transplant. The aim of our retrospective review is to describe the treatment and outcomes of a cohort of patients with JMML or Noonan Syndrome-associated Myeloproliferative Disorder (NS-MPD) to provide management guidance for this rare and heterogeneous disease. We report on 22 patients with JMML or NS-MPD managed at three institutions in the Texas Medical Center. Of patients with known genetic mutations and cytogenetics, 6 harbored germline mutations, 12 had somatic mutations, and 9 showed cytogenetic abnormalities. Overall, 14/22 patients are alive. Spontaneous clinical remission occurred in one patient with somatic NRAS mutation, as well as two with germline PTPN11 mutations with NS-MPD, and two others with germline PTPN11 mutations and NS-MPD remain under surveillance. Patients with NS-MPD were excluded from treatment analysis as none required chemotherapeutic intervention. All patients (5/5) treated with 5-azacitidine alone and one of the four treated with 6-mercaptopurine monotherapy had a reduction in mutant variant allele frequency. Transformation to acute myeloid leukemia was seen in two patients who both died. Among patients who received transplants, 7/13 are alive, and relapse post-transplant occurred in 3/13 with a median time to relapse of 3.55 months. This report provides insight into therapy responses and long-term outcomes across different genetic subsets of JMML and lends insight into the expected time to spontaneous resolution in patients with NS-MPD with germline PTPN11 mutations. [ABSTRACT FROM AUTHOR]
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- 2024
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33. Direct and indirect costs for patients with myeloproliferative neoplasms.
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Yu, Jingbo, Nelson, James, Marlin, Taylor, Braunstein, Evan, and Jerry, Michelle
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MYELOPROLIFERATIVE neoplasms , *DIRECT costing , *POLYCYTHEMIA vera , *MEDICAL care costs , *MYELOFIBROSIS - Abstract
Myeloproliferative neoplasms (MPNs) are associated with substantial healthcare resource use and productivity loss. This retrospective cohort analysis used disability leave and medical claims data to measure direct and indirect healthcare costs associated with MPNs. The analysis included 173 patients with myelofibrosis (MF), 4477 with polycythemia vera (PV), 6061 with essential thrombocythemia (ET), and matched controls (n = 519, n = 13,431, and n = 18,183, respectively). Total healthcare costs were significantly higher for cases versus controls in each cohort (mean cost difference: MF, $67,456; PV, $10,970; ET, $22,279). Cases were more likely than controls to take disability leave and incurred higher disability-related costs. Among subgroups with thrombotic events, direct and indirect costs were higher for cases versus controls. Thrombotic events substantially increased direct costs and disability leave for patients with PV or ET compared with the full PV or ET cohorts. These findings demonstrate increased economic burden for patients with MPNs. [ABSTRACT FROM AUTHOR]
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- 2024
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34. Myeloproliferative neoplasm with eosinophilia and coexisting BCR::ABL1 and PDGFRB rearrangement: favorable and rapid response to imatinib.
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Yao, Sun, Na, Liu, and Liangding, Hu
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MYELOPROLIFERATIVE neoplasms , *EOSINOPHILIA , *IMATINIB , *PROTEIN-tyrosine kinase inhibitors , *CHRONIC myeloid leukemia - Abstract
Here, we present a rare case of myeloproliferative neoplasms (MPN) with eosinophilia harboring both BCR::ABL1 and PDGFRB rearrangements, posing a classification dilemma. The patient exhibited clinical and laboratory features suggestive of chronic myeloid leukemia (CML) and myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK), highlighting the diagnostic challenges associated with overlapping phenotypes. Despite the complexity, imatinib treatment swiftly achieved deep molecular remission, underscoring the therapeutic efficacy of tyrosine kinase inhibitors in such scenarios. Furthermore, the rapid attainment of deep remission by this patient in response to imatinib closely resembles that observed in MLN-TK patients with PDGFRB rearrangements. Further research is warranted to elucidate the underlying mechanisms driving the coexistence of multiple oncogenic rearrangements in MPNs and to optimize therapeutic strategies for these complex cases. [ABSTRACT FROM AUTHOR]
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- 2024
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35. FRACTION: protocol of a phase II study of Fedratinib and Nivolumab combination in patients with myelofibrosis and resistance or suboptimal response to JAK-inhibitor treatment of the German MPN study group (GSG-MPN).
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Isfort, Susanne, von Bubnoff, Nikolas, Al-Ali, Haifa Kathrin, Becker, Heiko, Götze, Thorsten, le Coutre, Philipp, Griesshammer, Martin, Moskwa, Claudia, Wohn, Luisa, Riedel, Johanna, Palandri, Francesca, Manz, Kirsi, Hochhaus, Andreas, Döhner, Konstanze, and Heidel, Florian H.
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MYELOFIBROSIS , *NIVOLUMAB , *MYELOPROLIFERATIVE neoplasms , *REMISSION induction , *MYELOID cells , *IMMUNE checkpoint proteins - Abstract
Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be effectively reduced for the first time. However, JAK-inhibitor treatment is limited in several aspects: 1) duration of response: 3 years after initiation of therapy more than 50% of patients have discontinued JAK-inhibitor treatment due to lack of efficacy or resistance; 2) reduction of disease burden: while effective in reducing inflammation and constitutional symptoms, JAK-inhibitors fail to reduce the malignant clone in the majority of patients and therefore lack long-term efficacy. Early clinical trials for patients with myelofibrosis (MF) have tried to address these issues for patients with suboptimal response to Ruxolitinib therapy while combination therapies with Fedratinib are rare. Recent reports provided first evidence on how the JAK2-V617F mutated myeloid cells may influence T-cell responses. JAK2-V617F promoted the synthesis of PD-L1 in MPN cells leading to limited anti-neoplastic T-cell responses, metabolic changes in T-cells and eventually JAK2-V617F-driven immune-escape of MPN cells. These findings may facilitate the use of immunotherapeutic approaches for JAK-mutated clones. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. The FRACTION study is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with myelofibrosis and suboptimal or lack of response to JAK-inhibitor therapy. Over a 12 months period the trial assesses longer term outcomes, particularly the effects on clinical outcomes, such as induction of clinical remissions, quality of life and improvement of anemia. No prospective clinical trial data exist for combinations of JAK- and immune-checkpoint-inhibitors in the planned MF study population and this study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives. Trial registration: EudraCT Number 2021-004757-23. [ABSTRACT FROM AUTHOR]
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- 2024
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36. Hematocrit control and thrombotic risk in patients with polycythemia vera treated with ruxolitinib in clinical practice.
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Chojecki, Aleksander, Boselli, Danielle, Dortilus, Allison, Hamadeh, Issam, Begley, Stephanie, Chen, Tommy, Bose, Rupali, Podoltsev, Nikolai, Zeidan, Amer M., Balmaceda, Nicole Baranda, Yacoub, Abdulraheem, Ai, Jing, Knight, Thomas Gregory, Ragon, Brittany Knick, Shah, Nilay Arvind, Sanikommu, Srinivasa Reddy, Symanowski, James, Mesa, Ruben, and Grunwald, Michael Richard
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POLYCYTHEMIA vera , *RUXOLITINIB , *MYELOFIBROSIS , *ERYTHROCYTES , *HEMATOCRIT , *KINASE inhibitors , *MYELOPROLIFERATIVE neoplasms - Abstract
Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by unregulated red blood cell production resulting in elevated hemoglobin and/or hematocrit levels. Patients often have symptoms such as fatigue, pruritus, and painful splenomegaly, but are also at risk of thrombosis, both venous and arterial. Ruxolitinib, a selective Janus kinase inhibitor, is approved by the US Food and Drug Administration as second-line cytoreductive treatment after intolerance or inadequate response to hydroxyurea. Although ruxolitinib has been widely used in this setting, limited data exist in the literature on ruxolitinib treatment patterns and outcomes among patients with PV in routine clinical practice. We report a retrospective, observational, cohort study of patients treated for PV with ruxolitinib across three US centers (academic and regional practice) from December 2014-December 2019. The study included 69 patients, with a median follow-up duration of 3.7 years (95% CI, 2.9–4.4). Our data demonstrate very high rates of hematocrit control (88% of patients by three months and 89% by six months); few patients required dose adjustments or suspension. No arterial thromboses were observed; however, the follow-up duration does not allow for the generation of meaningful conclusions from this. Three patients had thrombotic events; one was in the setting of a second malignancy, one post-operative, and a third related to prolonged immobility. We also found that 28% of patients initiated ruxolitinib as a result of poorly controlled platelet counts, second only to hydroxyurea intolerance (46%) as a reason to start therapy. In clinical practice, ruxolitinib continues to be effective in controlling hematocrit levels after three and six months of treatment in patients and is associated with low thrombotic risk. [ABSTRACT FROM AUTHOR]
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- 2024
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37. Research progress of additional pathogenic mutations in chronic neutrophilic leukemia.
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Gao, Jiapei, Han, Shuai, Deng, Bin, Deng, Yifan, and Gao, Xiaohui
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CHRONIC leukemia , *MOLECULAR biology , *TRANSCRIPTION factors , *RNA splicing , *RNA metabolism , *PRELEUKEMIA , *PAROXYSMAL hemoglobinuria - Abstract
Chronic neutrophilic leukemia (CNL) is a rare type of myeloproliferative neoplasm (MPN). Due to its nonspecific clinical symptoms and lack of specific molecular markers, it was previously difficult to distinguish it from other diseases with increased neutrophils. However, the discovery of the CSF3R mutation in CNL 10 years ago and the update of the diagnostic criteria by the World Health Organization (WHO) in 2016 brought CNL into a new era of molecular diagnosis. Next-generation sequencing (NGS) technology has led to the identification of numerous mutant genes in CNL. While CSF3R is commonly recognized as the driver mutation of CNL, other mutations have also been detected in CNL using NGS, including mutations in other signaling pathway genes (CBL, JAK2, NARS, PTPN11) and chromatin modification genes (ASXL1, SETBP1, EZH2), DNA methylation genes (DNMT3A, TET2), myeloid-related transcription factor genes (RUNX1, GATA2), and splicing and RNA metabolism genes (SRSF2, U2AF1). The coexistence of these mutated genes and CSF3R mutations, as well as the different evolutionary sequences of clones, deepens the complexity of CNL molecular biology. The purpose of this review is to summarize the genetic research findings of CNL in the last decade, focusing on the common mutated genes in CNL and their clinical significance, as well as the clonal evolution pattern and sequence of mutation acquisition in CNL, to provide a basis for the appropriate management of CNL patients. [ABSTRACT FROM AUTHOR]
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- 2024
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38. Momelotinib: Mechanism of action, clinical, and translational science.
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Vlasakakis, Georgios, McCabe, Michael T., Ho, Yu Liu, Ferron‐Brady, Geraldine, Martin, Paul, Bentley, Darren, Ellis, Catherine, Antonysamy, Mary, and Visser, Sandra A. G.
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MYELOPROLIFERATIVE neoplasms , *PROGNOSIS , *MYELOFIBROSIS , *SURVIVAL rate , *BONE marrow - Abstract
Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis‐related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK–STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady‐state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUCtau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite‐to‐parent AUC ratio of 1.4–2.1. This review describes momelotinib's mechanism of action, detailing how the JAK–STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment. [ABSTRACT FROM AUTHOR]
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- 2024
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39. Empfohlene Diagnostik bei Pruritus auf primär unveränderter Haut.
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Düll, M. M. and Kremer, A. E.
- Abstract
Copyright of Die Dermatologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2024
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40. Type II mode of JAK2 inhibition and destabilization are potential therapeutic approaches against the ruxolitinib resistance driven myeloproliferative neoplasms.
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Gorantla, Sivahari P., Prince, Gerin, Osius, Jasmin, Dinesh, Dhurvas Chandrasekaran, Boddu, Vijay, Duyster, Justus, and von Bubnoff, Nikolas
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POLYCYTHEMIA vera ,MOLECULAR docking ,MYELOPROLIFERATIVE neoplasms ,SITE-specific mutagenesis ,RUXOLITINIB - Abstract
Background: Ruxolitinib has been approved by the US FDA for the treatment of myeloproliferative neoplasms such as polycythemia vera and primary myelofibrosis. Ruxolitinib will remain a main stay in the treatment of MPN patients due to its effective therapeutic benefits. However, there have been instances of ruxolitinib resistance in MPN patients. As JAK2 is a direct target of ruxolitinib, we generated ruxolitinib-resistant clones to find out the mechanism of resistance. Methods: Cell-based screening strategy was used to detect the ruxolitinibresistant mutations in JAK2. The Sanger sequencing method was used to detect the point mutations in JAK2. Mutations were re-introduced using the site-directed mutagenesis method and stably expressed in Ba/F3 cells. Drug sensitivities against the JAK2 inhibitors were measured using an MTS-based assay. JAK2 and STAT5 activation levels and total proteins were measured using immunoblotting. Computational docking studies were performed using the Glide module of Schrodinger Maestro software. Results: In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. All the ruxolitinib-resistant JAK2 variants displayed sensitivity towards type II JAK2 inhibitor CHZ-868. In this study, we also found that JAK1-L1010F (homologous JAK2-L983F) is highly resistant towards ruxolitinib suggesting the possibility of JAK1 escape mutations in JAK2-driven MPNs and JAK1 mutated ALL. Finally, our study also shows that HSP90 inhibitors are potent against ruxolitinibresistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors. Conclusion: Our study identifies JAK1 and JAK2 resistance variants against the type I JAK2 inhibitors ruxolitinib, fedratinib, and lestaurtinib. The sensitivity of these resistant variants towards the type II JAK2 inhibitor CHZ-868 indicates that this mode of type II JAK2 inhibition is a potential therapeutic approach against ruxolitinib refractory leukemia. This also proposes the development of potent and specific type II JAK2 inhibitors using ruxolitinib-resistance variants as a prototype. [ABSTRACT FROM AUTHOR]
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- 2024
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41. The utility of next generation sequencing-based minimal residual disease monitoring in a post-myeloproliferative neoplasm acute myeloid leukemia patient: a case report.
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Choi, Yu Jeong, Kook, Hye Won, Lee, Seung-Tae, Song, Jaewoo, Choi, Jong Rak, Cheong, June-Won, and Shin, Saeam
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POLYCYTHEMIA vera , *ACUTE myeloid leukemia , *HEMATOPOIETIC stem cell transplantation , *LEUKOCYTE count , *MYELOPROLIFERATIVE neoplasms - Abstract
This document discusses the relevance of next-generation sequencing (NGS)-based minimal residual disease (MRD) monitoring in the context of post-myeloproliferative neoplasm (MPN) acute myeloid leukemia (AML). It highlights a case study of a patient with secondary AML from an MPN who has remained healthy for over a year since diagnosis, suggesting that not all secondary AMLs have a poor prognosis. The presence of a specific mutation, SF3B1 K666N, throughout the patient's pre-hematopoietic stem cell transplantation (HSCT) period raises questions about its germline nature, but subsequent analysis confirmed it as somatic. The case emphasizes the importance of analyzing both cancerous and germline material to determine the origin of a mutation and underscores the complex dynamics of clonal evolution during disease progression. Further research is needed to validate these findings. [Extracted from the article]
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- 2024
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42. Non-canonical FLT3 alterations reveal novel germline FLT3 variants leading to somatic gene rescue mutations.
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Gordon, Jaymeson, Bravo-Perez, Carlos, Guarnera, Luca, Unlu, Serhan, Kawashima, Naomi, Ahmed, Arooj, Haddad, Christopher, Kubota, Yasuo, Nautiyal, Ishani, Ullah, Fauzia, Dima, Danai, Williams, Nakisha D., Kewan, Tariq, Bahaj, Waled, Carraway, Hetty E., Yang, Chao-Yie, Gurnari, Carmelo, Visconte, Valeria, and Maciejewski, Jaroslaw P.
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SOMATIC mutation ,TRANSMEMBRANE domains ,GAIN-of-function mutations ,MYELOPROLIFERATIVE neoplasms ,MYELODYSPLASTIC syndromes - Abstract
This article discusses the molecular landscape of FLT3 gene alterations in myeloid neoplasms (MNs), specifically acute myeloid leukemia (AML). FLT3 mutations, including internal tandem duplications (ITD) and mutations in the activation loop (AL), are common in AML and have been associated with poor prognosis. However, the presence and clinical implications of non-canonical FLT3 mutations (FLT3NC) have been less explored. The study analyzed a cohort of MN patients and found that FLT3NC alterations were more prevalent in non-AML MNs compared to AML. Additionally, the study identified three cases of germline FLT3NC, suggesting a potential role of hypomorphic germline FLT3 mutations in somatic gene rescue and leukemogenesis. The findings provide new insights into the complexity of FLT3 mutations in MNs. [Extracted from the article]
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- 2024
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43. DARS expression in BCR/ABL1-negative myeloproliferative neoplasms and its association with the immune microenvironment.
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Xiong, Hao, Liao, Minjing, Zhang, Huitao, Li, Yanhong, Bai, Jun, Zhang, Jinping, Li, Lijuan, and Zhang, Liansheng
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MYELOPROLIFERATIVE neoplasms , *THROMBOPOIETIN receptors , *RENAL cell carcinoma , *COLON cancer , *IMMUNOHISTOCHEMISTRY , *T cells - Abstract
DARS, encoding for aspartyl-tRNA synthetase, is implicated in the pathogenesis of various cancers, including renal cell carcinoma, glioblastoma, colon cancer, and gastric cancer. Its role in BCR/ABL1-negative myeloproliferative neoplasms (MPNs), however, remains unexplored. This study aimed to elucidate the expression of DARS in patients with MPNs (PV 23, ET 19, PMF 16) through immunohistochemical analysis and to examine the profiles of circulating immune cells and cytokines using flow cytometry. Our findings indicate a significant overexpression of DARS in all MPNs subtypes at the protein level compared to controls (P < 0.05). Notably, elevated DARS expression was linked to splenomegaly in MPNs patients. The expression of DARS showed a negative correlation with CD4+ T cells (R = − 0.451, P = 0.0004) and CD4+ T/CD8+ T cell ratio (R = − 0.3758, P = 0.0040), as well as with CD68+ tumor-associated macrophages (R = 0.4037, P = 0.0017). Conversely, it was positively correlated with IL-2 (R = 0.5419, P < 0.001), IL-5 (R = 0.3161, P = 0.0166), IL-6 (R = 0.2992, P = 0.0238), and IFN-γ (R = 0.3873, P = 0.0029). These findings underscore a significant association between DARS expression in MPNs patients and specific clinical characteristics, as well as immune cell composition. Further investigation into the interplay between DARS and the immune microenvironment in MPNs could shed light on the underlying mechanisms of MPNs pathogenesis and immune dysregulation. [ABSTRACT FROM AUTHOR]
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- 2024
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44. The Burden of symptoms and Quality of life of Filipino patients with Myeloproliferative neoplasm: A Multicenter Cross‐sectional survey.
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Mesina, Flordeluna Z., Dumagay, Teresita E., and Alejandria, Marissa M.
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SYMPTOM burden , *MYELOPROLIFERATIVE neoplasms , *MYELOFIBROSIS , *QUALITY of life , *FILIPINOS , *POLYCYTHEMIA vera - Abstract
Background Methodology Results Conclusion Myeloproliferative neoplasms (MPN) are hematologic malignancies characterized by cellular proliferation of one or more hematopoietic cell lines. Management has been focused on blood count control but addressing relief from symptoms and providing a better quality of life (QOL) are equally important in the care of these patients. The MPN Symptom Assessment Form‐Total Symptom Score (MPN‐SAF TSS) is used to determine symptoms at baseline and during treatment. Understanding the symptom burden is important in developing a holistic management plan for MPN. Hence, this study aimed to determine the symptom burden and QOL of Filipino patients with MPN.Using a validated Filipino version of the MPN‐SAF‐TSS questionnaire and the University of the Philippines‐Department of Health QOL (UP‐DOH QOL) questionnaire, a cross‐sectional survey of consecutive patients with MPN from two public and two private tertiary hospitals was conducted. We purposively sampled adults, newly diagnosed or previously diagnosed with polycythemia vera (PV), essential thrombocythemia (ET), or myelofibrosis (MF). The mean scores were compared with the type of MPN using analysis of variance. Linear regression was done to determine the association of patients' characteristics to the mean symptom burden and QOL scores, while logistic regression was used to determine the association of patient and disease characteristics with the level of symptom severity and QOL.A total of 167 (63 PV, 66 ET, and 38 MF) patients were surveyed from four centers. The mean overall symptom burden score was 24.41 (standard deviation [SD] = 18.91) with MF having the highest score at 28.53, followed by PV at 23.75 and ET at 22.67. The majority (80.24%) had a high QOL with a mean global QoL score of 84.92 (SD = 16.75). Comparison of individual scores showed bone pain and weight loss were significantly higher in patients with MF compared to PV (
p = 0.0002) and ET (p = 0.032); while pruritus was significantly higher in PV compared to ET and MF (p = 0.043). Logistic regression analysis showed female sex and being newly diagnosed (adjusted odds ratio [aOR] 11.22, 95% confidence interval [CI] 2.32–54.25) were associated with high symptom burden while having a controlled blood count (aOR 0.26, 95% CI 0.10–0.71) was associated with low symptom burden and high QOL.The majority of the participants were symptomatic with moderate to severe symptom burden. While no statistically significant difference was seen among the three types of MPN in terms of overall mean symptom score, patients with MF were more likely to have a severe symptom burden while patients with ET had the least symptoms. Despite having symptoms, QOL was regarded as high. QoL was significantly higher among those with PV or ET than those with MF. Our study highlighted the utility of a validated symptom scoring system in determining the symptom burden and who would benefit from pharmacologic/non‐pharmacologic symptom management. Results emphasized incorporating symptom scoring in clinical practice and going beyond blood counts in caring for our patients with MPN. [ABSTRACT FROM AUTHOR]- Published
- 2024
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45. Circulating Polymorphonuclear Myeloid-Derived Suppressor Cells (PMN-MDSCs) Have a Biological Role in Patients with Primary Myelofibrosis.
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Campanelli, Rita, Carolei, Adriana, Catarsi, Paolo, Abbà, Carlotta, Boveri, Emanuela, Paulli, Marco, Gentile, Raffaele, Morosini, Monica, Albertini, Riccardo, Mantovani, Stefania, Massa, Margherita, Barosi, Giovanni, and Rosti, Vittorio
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RESEARCH funding , *MYELOID-derived suppressor cells , *MYELOPROLIFERATIVE neoplasms , *OXIDATIVE stress , *IMMUNE system , *CHRONIC diseases , *BONE marrow diseases , *SEPSIS , *MYELOFIBROSIS , *INFLAMMATION , *CYTOKINES , *GENETICS - Abstract
Simple Summary: Myeloid-derived suppressor cells (MDSCs) are immature cells that expand in the circulation of patients with cancer, sepsis or chronic inflammation, modulate the immune response against cancer (favoring tumor onset and progression) and promote neoangiogenesis. These premises suggest that MDSCs could be involved in the pathogenesis of primary myelofibrosis (PMF) (a myeloproliferative neoplasm characterized by chronic inflammation and extensive neoangiogenesis in bone marrow and spleen). In this paper, we found that (1) MDSCs are increased both in the circulation and in the spleen of PMF patients and strongly correlate with disease progression; and (2) reduced CXCR4 expression on MDSCs along with increased plasmatic SDF-1α can be involved in their mobilization. These findings suggest that circulating MDSCs can be considered a parameter of disease severity and set MDSCs as potential new targets for cancer therapy. Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by a chronic inflammatory state that plays a relevant role in the disease pathogenesis (as proven by high levels of inflammatory cytokines with prognostic significance and by a persistent oxidative stress) and by extensive neoangiogenesis in bone marrow (BM) and spleen. Myeloid-derived suppressor cells (MDSCs) are immature cells that expand in patients with cancer, sepsis or chronic inflammation, favoring tumor onset and progression mainly through the decrease in immune surveillance and the promotion of neoangiogenesis. In this paper, we evaluated the presence of circulating MDSCs in PMF patients, the plasmatic factors involved in their mobilization/expansion and the correlations with laboratory, genetic and clinical parameters. The data indicated that MDSCs could have a relevant role in PMF as a new pathogenic mechanism contributing to explaining the phenotypic diversity observed during the clinical course of the disease, or a potential new target for personalized treatment. [ABSTRACT FROM AUTHOR]
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- 2024
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46. Dermatomyositis‐like skin eruptions under hydroxyurea therapy conceal TP53‐mutated atypical keratinocytes: A histopathologic and molecular pathologic case series.
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Pruessmann, Wiebke, Kirfel, Jutta, Sailer, Verena‐Wilbeth, and Rose, Christian
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HYDROXYUREA , *KERATINOCYTES , *DNA synthesis , *MYELOPROLIFERATIVE neoplasms , *NUCLEOTIDE sequencing ,KERATINOCYTE differentiation - Abstract
Hydroxyurea is an antimetabolite that inhibits DNA synthesis and is used as a treatment option in chronic myeloproliferative disorders. Rarely, “dermatomyositis (DM)‐like” skin lesions are observed after long‐term therapy. In this case series, five skin biopsies of four patients were evaluated by histology, immunohistochemistry, and next‐generation sequencing of the TP53 gene locus. All biopsies showed focal basal pleomorphic keratinocytes and suprabasal aberrant p53 expression as well as sparse to severe vacuolar interface dermatitis. Histopathologically, “DM‐like” skin lesions can be clearly distinguished from DM by marked subepidermal fibrosis, vascular proliferation, and the absence of dermal mucin deposits. In 75% of the specimens multiple, partly inactivating and/or pathogenic point mutations of TP53 were found in low frequencies. “DM‐like” skin eruptions as a long‐term consequence of hydroxyurea therapy are possibly not chemotherapy‐associated benign toxic changes, but rather inflammatory reactions to complex keratinocyte alterations that clinically mimic the picture of DM. Synergistic mutagenic effects of hydroxyurea and sunlight might be responsible for this unique drug side effect and could provide a pathogenic link to the known increased risk of skin cancer in these patients. [ABSTRACT FROM AUTHOR]
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- 2024
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47. The Variation in the Traits Ameliorated by Inhibitors of JAK1/2, TGF-β, P-Selectin, and CXCR1/CXCR2 in the Gata1 low Model Suggests That Myelofibrosis Should Be Treated by These Drugs in Combination.
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Gobbo, Francesca, Martelli, Fabrizio, Di Virgilio, Antonio, Demaria, Elena, Sarli, Giuseppe, and Migliaccio, Anna Rita
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TRANSFORMING growth factors-beta , *MYELOFIBROSIS , *HEMATOPOIETIC stem cells , *MYELOPROLIFERATIVE neoplasms , *THERAPEUTICS , *THROMBOPOIETIN receptors - Abstract
Studies conducted on animal models have identified several therapeutic targets for myelofibrosis, the most severe of the myeloproliferative neoplasms. Unfortunately, many of the drugs which were effective in pre-clinical settings had modest efficacy when tested in the clinic. This discrepancy suggests that treatment for this disease requires combination therapies. To rationalize possible combinations, the efficacy in the Gata1low model of drugs currently used for these patients (the JAK1/2 inhibitor Ruxolitinib) was compared with that of drugs targeting other abnormalities, such as p27kip1 (Aplidin), TGF-β (SB431542, inhibiting ALK5 downstream to transforming growth factor beta (TGF-β) signaling and TGF-β trap AVID200), P-selectin (RB40.34), and CXCL1 (Reparixin, inhibiting the CXCL1 receptors CXCR1/2). The comparison was carried out by expressing the endpoints, which had either already been published or had been retrospectively obtained for this study, as the fold change of the values in the corresponding vehicles. In this model, only Ruxolitinib was found to decrease spleen size, only Aplidin and SB431542/AVID200 increased platelet counts, and with the exception of AVID200, all the inhibitors reduced fibrosis and microvessel density. The greatest effects were exerted by Reparixin, which also reduced TGF-β content. None of the drugs reduced osteopetrosis. These results suggest that future therapies for myelofibrosis should consider combining JAK1/2 inhibitors with drugs targeting hematopoietic stem cells (p27Kip1) or the pro-inflammatory milieu (TGF-β or CXCL1). [ABSTRACT FROM AUTHOR]
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- 2024
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48. Momelotinib - a promising advancement in the management of myelofibrosis in adults with anemia.
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Furqan, Muhammad and Oduoye, Malik O.
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MYELOFIBROSIS ,BONE marrow examination ,ANEMIA ,STEM cell transplantation ,ADULTS ,MYELOPROLIFERATIVE neoplasms - Abstract
Myelofibrosis (MF) is a rare BCR-ABL negative myeloproliferative neoplasm characterized by clonal proliferation of stem cells, with mutations in JAK2, CALR, or MPL genes. MF presents in primary and secondary forms, with common symptoms including splenomegaly, anemia, and thrombocytopenia. Diagnostic criteria involve bone marrow examination and mutation studies. Current treatments are limited, with allogeneic stem cell transplant as the only curative option. Recent FDA approval of Momelotinib (MMB) offers new promise for MF patients with anemia. MMB, a JAK1/2 and ACVR1 inhibitor, effectively reduces spleen size, improves hemoglobin levels, and decreases transfusion dependency. The MOMENTUM trial compared MMB to danazol in JAK inhibitortreated MF patients with anemia, showing MMB's superior symptom relief and transfusion independence rates. Additionally, the SIMPLIFY-1 and SIMPLIFY-2 trials evaluated MMB in JAK inhibitor-naïve and experienced patients, respectively, confirming MMB's non-inferiority to ruxolitinib in spleen volume reduction and highlighting its benefits in transfusion requirements. MMB's unique dual inhibition mechanism addresses anemia by suppressing hepcidin production, thus enhancing erythropoiesis. These trials collectively suggest MMB as an effective treatment for MF, improving quality of life and offering a survival advantage for patients with anemia. Despite challenges, such as trial design limitations and adverse events, MMB represents a significant advancement in MF management, providing a new therapeutic option for a previously underserved patient population. [ABSTRACT FROM AUTHOR]
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- 2024
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49. Atypical chronic myeloid leukemia found in a patient with eosinophilia for six years: a case report.
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Jiang, Moqin, Chen, Meng, Yan, Lixiang, Zhang, Ying, Yang, Xiangdong, and Zhang, Weifeng
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CHRONIC myeloid leukemia ,EOSINOPHILIA ,LEUCOCYTES ,MYELOPROLIFERATIVE neoplasms ,CHRONIC leukemia ,PULMONARY eosinophilia ,TUMOR classification - Abstract
Background: Atypical chronic myeloid leukemia (aCML) is a highly aggressive type of blood cancer that falls under the category of myelodysplastic/myeloproliferative neoplasms (MDS/MPN). In the fifth edition of the WHO classification of tumors, this category has been renamed MDS/MPN with neutrophilia. Although eosinophilia is commonly observed in blood cancers, it is rarely seen in aCML. Case presentation: This study presents a case of aCML that was diagnosed six years after the patient developed eosinophilia. The patient had undergone tests to rule out other primary and secondary diseases, but the eosinophilia remained unexplained. Treatment with corticosteroids and hydroxyurea had proven ineffective. Six years later, the patient experienced an increase in white blood cells, primarily neutrophils. After ruling out other possible diagnoses, a combination of morphologic and molecular genetic findings led to the diagnosis of aCML. The patient responded well to treatment with azacitidine. Conclusions: This study summarizes the current state of aCML diagnosis and management and discusses the possible connection between eosinophilia and aCML. [ABSTRACT FROM AUTHOR]
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- 2024
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50. Decreased spermatogonial numbers in boys with severe haematological diseases.
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Lahtinen, Atte K., Funke, Miriam, Krallmann, Claudia, Wyrwoll, Margot J., Jarisch, Andrea, Yang, Yifan, Bjarnason, Ragnar, Romerius, Patrik, Sundin, Mikael, Norén‐Nyström, Ulrika, Langenskiöld, Cecilia, Cremers, Jann‐Frederik, Kliesch, Sabine, Stukenborg, Jan‐Bernd, Neuhaus, Nina, and Jahnukainen, Kirsi
- Subjects
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HEMATOPOIETIC stem cell transplantation , *FANCONI'S anemia , *FERTILITY preservation , *APLASTIC anemia , *MYELOPROLIFERATIVE neoplasms , *MYELOFIBROSIS - Abstract
Summary: This study examines spermatogonial numbers in testicular samples from 43 prepubertal patients undergoing haematopoietic stem cell transplantation (HSCT). High‐dose chemotherapy and/or radiation during HSCT can impact spermatogenesis requiring fertility preservation. Results show that 49% of patients have decreased and 19% severely depleted spermatogonial pool prior to HSCT. Patients with Fanconi anaemia exhibit significantly reduced spermatogonial numbers. Patients with immunodeficiency or aplastic anaemia generally present within the normal range, while results in patients with myelodysplastic syndrome or myeloproliferative neoplasm vary. The study emphasizes the importance of assessing spermatogonial numbers in patients with severe haematological diseases for informed fertility preservation decisions. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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