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Physiology International Sep 2023The classical myeloproliferative neoplasms are divided into chronic myeloid leukemia, and the Philadelphia negative polycythemia vera, essential thrombocythemia and... (Review)
Review
The classical myeloproliferative neoplasms are divided into chronic myeloid leukemia, and the Philadelphia negative polycythemia vera, essential thrombocythemia and primary myelofibrosis. These are heterogenous diseases, originating from the clonal proliferation of myeloid stem cells, resulting in increased mature cell numbers in one or more myeloid lineages. The most commonly seen mutations in the Philadelphia negative myeloproliferative neoplasms include those in Janus kinase, myeloproliferative leukemia protein and the calreticulin genes. Philadelphia negative myeloproliferative neoplasms occur infrequently, with a combined annual incidence of 2.58 per 100,000. There are many overlapping symptoms of Philadelphia negative MPNs, such as fatigue, night sweats, hepatosplenomegaly and circulatory symptoms due to increased cell numbers. Total Symptom Score of the MPN Symptom Assessment Form is used to assess symptom burden on patients. The most worrisome complications are thrombo-hemorrhagic events, and risk stratification is especially important as treatment of disease is based on their category. Phlebotomy and aspirin are the mainstay of treatment in low-risk polycythemia vera and essential thrombocythemia patients, whereas high-risk disease calls for additional cytoreduction, usually with hydroxyurea.
Topics: Humans; Polycythemia Vera; Thrombocythemia, Essential; Hydroxyurea; Aspirin; Mutation
PubMed: 37651280
DOI: 10.1556/2060.2023.00261 -
American Journal of Hematology Jan 2024Contemporary risk models in primary myelofibrosis (PMF) include the mutation (MIPSS70) and mutation/karyotype enhanced (MIPSS70 plus/v2.0) international prognostic...
The prognostic contribution of CBL, NRAS, KRAS, RUNX1, and TP53 mutations to mutation-enhanced international prognostic score systems (MIPSS70/plus/plus v2.0) for primary myelofibrosis.
Contemporary risk models in primary myelofibrosis (PMF) include the mutation (MIPSS70) and mutation/karyotype enhanced (MIPSS70 plus/v2.0) international prognostic scoring systems. High molecular risk (HMR) mutations incorporated in one or both of these models include ASXL1, SRSF2, EZH2, IDH1/2, and U2AF1Q157; the current study examines additional prognostic contribution from more recently described HMR mutations, including CBL, NRAS, KRAS, RUNX1, and TP53. In a cohort of 363 informative cases (median age 58 years; 60% males), mutations included JAK2 61%, CALR 24%, MPL 6%, ASXL1 29%, SRSF2 10%, U2AF1Q157 5%, EZH2 10%, IDH1/2 4%, TP53 5%, CBL 5%, NRAS 7%, KRAS 4%, and RUNX1 4%. At a median follow-up of 4.6 years, 135 (37%) deaths and 42 (11.6%) leukemic transformations were recorded. Univariate analysis confirmed significant survival impact from the original MIPSS70/plus/v2.0 HMR mutations as well as CBL (HR 2.8; p < .001), NRAS (HR 2.4; p < .001), KRAS (HR 2.1; p = .01), and TP53 (HR 2.4; p = .004), but not RUNX1 mutations (HR 1.8; p = .08). Multivariate analysis (MVA) that included both the original and more recently described HMR mutations confirmed independent prognostic contribution from ASXL1 (HR 1.8; p = .007), SRSF2 (HR 4.3; p < .001), U2AF1Q157 (HR 2.9, p = .004), and EZH2 (HR 2.4; p < .001), but not from IDH1/2 (p = .3), TP53 (p = .2), CBL (p = .3), NRAS (p = .8) or KRAS (p = .2) mutations. The lack of additional prognostic value from CBL, NRAS, KRAS, RUNX1, and TP53 was further demonstrated in the setting of (i) MVA of mutations and karyotype, (ii) MVA of MIPSS70/plus/v2.0 composite scores and each one of the recently described HMR mutations, except TP53, and iii) modified MIPSS70/plus/plus v2.0 that included CBL, NRAS, KRAS, and TP53 as part of the HMR constituency, operationally referred to as "HMR+" category. Furthermore, "HMR+" enhancement of MIPSS70/plus/plus v2.0 did not result in improved model performance, as measured by C-statistics. We conclude that prognostic integrity of MIPSS70/plus/plus v2.0, as well as their genetic components, was sustained and their value not significantly upgraded by the inclusion of more recently described HMR mutations, including CBL, NRAS, KRAS, and RUNX1. Additional studies are needed to clarify the apparent additional prognostic value of TP53 mutation and its allelic state.
Topics: Male; Humans; Middle Aged; Female; Prognosis; Core Binding Factor Alpha 2 Subunit; Proto-Oncogene Proteins p21(ras); Primary Myelofibrosis; Mutation; Tumor Suppressor Protein p53; Membrane Proteins; GTP Phosphohydrolases
PubMed: 37846894
DOI: 10.1002/ajh.27136 -
Blood Cancer Journal Jul 2023
Topics: Humans; Primary Myelofibrosis; Thrombocythemia, Essential; Motivation; Thrombosis; Bone Marrow
PubMed: 37507408
DOI: 10.1038/s41408-023-00887-7 -
Expert Opinion on Investigational Drugs Jan 2024Myelofibrosis is a clonal myeloproliferative neoplasm associated with the proliferation of hematopoietic stem cells, increased bone marrow fibrosis, extramedullary... (Review)
Review
INTRODUCTION
Myelofibrosis is a clonal myeloproliferative neoplasm associated with the proliferation of hematopoietic stem cells, increased bone marrow fibrosis, extramedullary hematopoiesis, hepatosplenomegaly, abnormal cytokine production, and constitutional symptoms. These and many other factors contribute to the development of anemia in myelofibrosis patients.
AREAS COVERED
This review summarizes novel and promising treatments for anemia in myelofibrosis including transforming growth factor-β inhibitors luspatercept and KER-050, JAK inhibitors momelotinib, pacritinib, and jaktinib, BET inhibitors pelabresib and ABBV-744, antifibrotic PRM-151, BCL2/BCL-XL inhibitor navitoclax, and telomerase inhibitor imetelstat.
EXPERT OPINION
Standard approaches to treat myelofibrosis-related anemia have limited efficacy and are associated with toxicity. New drugs have shown positive results in myelofibrosis-associated anemia when used alone or in combination.
Topics: Humans; Primary Myelofibrosis; Janus Kinase Inhibitors; Antineoplastic Agents; Anemia; Protein Kinase Inhibitors
PubMed: 38073183
DOI: 10.1080/13543784.2023.2294324 -
Blood Advances Sep 2023Janus kinase inhibitors (JAKis) ruxolitinib, fedratinib, and pacritinib are the current standard of care in symptomatic myelofibrosis (MF). However, progressive disease...
Janus kinase inhibitors (JAKis) ruxolitinib, fedratinib, and pacritinib are the current standard of care in symptomatic myelofibrosis (MF). However, progressive disease and toxicities frequently lead to JAKi discontinuation. Preclinical data indicate that combining JAK and bromodomain and extraterminal (BET) domain inhibition leads to overlapping effects in MF. Pelabresib (CPI-0610), an oral, small-molecule BET1,2 inhibitor (BETi), in combination with ruxolitinib showed improvements in spleen volume reduction (SVR35) and total symptom score reduction (TSS50) from baseline in the phase 2 MANIFEST study (NCT02158858) in patients with MF. Given the absence of a head-to-head clinical comparison between JAKi monotherapy and JAKi with BETi combination therapy, we performed an unanchored matching-adjusted indirect comparison analysis to adjust for differences between studies and allow for the comparison of SVR35, TSS50, and TSS measured at several timepoints in arm 3 of MANIFEST (pelabresib with ruxolitinib in JAKi treatment-naive patients with MF), with data from the following JAKi monotherapy studies in JAKi treatment-naive patients: COMFORT-I and COMFORT-II (ruxolitinib), SIMPLIFY-1 (ruxolitinib and momelotinib), and JAKARTA (fedratinib). Response rate ratios >1 were observed for pelabresib with ruxolitinib vs all comparators for SVR35 and TSS50 at week 24. Improvements in TSS were observed as early as week 12 and were durable. These results indicate that pelabresib with ruxolitinib may have a potentially higher efficacy than JAKi monotherapy in JAKi treatment-naive MF.
Topics: Humans; Primary Myelofibrosis; Pyrimidines; Nitriles
PubMed: 37530627
DOI: 10.1182/bloodadvances.2023010628 -
Cancers Jan 2024Myelofibrosis (MF) is an essential element of primary myelofibrosis, whereas secondary MF may develop in the advanced stages of other myeloid neoplasms, especially... (Review)
Review
Myelofibrosis (MF) is an essential element of primary myelofibrosis, whereas secondary MF may develop in the advanced stages of other myeloid neoplasms, especially polycythemia vera and essential thrombocythemia. Over the last two decades, advances in molecular diagnostic techniques, particularly the integration of next-generation sequencing in clinical laboratories, have revolutionized the diagnosis, classification, and clinical decision making of myelofibrosis. Driver mutations involving , , and induce hyperactivity in the JAK-STAT signaling pathway, which plays a central role in cell survival and proliferation. Approximately 80% of myelofibrosis cases harbor additional mutations, frequently in the genes responsible for epigenetic regulation and RNA splicing. Detecting these mutations is crucial for diagnosing myeloproliferative neoplasms (MPNs), especially in cases where no mutations are present in the three driver genes (triple-negative MPNs). While fibrosis in the bone marrow results from the disturbance of inflammatory cytokines, it is fundamentally associated with mutation-driven hematopoiesis. The mutation profile and order of acquiring diverse mutations influence the MPN phenotype. Mutation profiling reveals clonal diversity in MF, offering insights into the clonal evolution of neoplastic progression. Prognostic prediction plays a pivotal role in guiding the treatment of myelofibrosis. Mutation profiles and cytogenetic abnormalities have been integrated into advanced prognostic scoring systems and personalized risk stratification for MF. Presently, JAK inhibitors are part of the standard of care for MF, with newer generations developed for enhanced efficacy and reduced adverse effects. However, only a minority of patients have achieved a significant molecular-level response. Clinical trials exploring innovative approaches, such as combining hypomethylation agents that target epigenetic regulators, drugs proven effective in myelodysplastic syndrome, or immune and inflammatory modulators with JAK inhibitors, have demonstrated promising results. These combinations may be more effective in patients with high-risk mutations and complex mutation profiles. Expanding mutation profiling studies with more sensitive and specific molecular methods, as well as sequencing a broader spectrum of genes in clinical patients, may reveal molecular mechanisms in cases currently lacking detectable driver mutations, provide a better understanding of the association between genetic alterations and clinical phenotypes, and offer valuable information to advance personalized treatment protocols to improve long-term survival and eradicate mutant clones with the hope of curing MF.
PubMed: 38339265
DOI: 10.3390/cancers16030514 -
Cancers Apr 2024Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal... (Review)
Review
Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal proliferation of hematopoietic stem cells leading to an overproduction of hematopoietic cells. The last two decades have seen significant advances in our understanding of the molecular pathogenesis of these diseases, with the discovery of key mutations in the , , and genes being pivotal. This review provides a comprehensive update on the molecular landscape of PV, ET, and PMF, highlighting the diagnostic, prognostic, and therapeutic implications of these genetic findings. We delve into the challenges of diagnosing and treating patients with prognostic mutations, clonal evolution, and the impact of emerging technologies like next-generation sequencing and single-cell genomics on the field. The future of MPN management lies in leveraging these molecular insights to develop personalized treatment strategies, aiming for precision medicine that optimizes outcomes for patients. This article synthesizes current knowledge on molecular diagnostics in MPNs, underscoring the critical role of genetic profiling in enhancing patient care and pointing towards future research directions that promise to further refine our approach to these complex disorders.
PubMed: 38730632
DOI: 10.3390/cancers16091679 -
SAGE Open Medicine 2023Myelofibrosis is a rare disease. There is currently no published data reporting the demographics and outcome of myelofibrosis patients in Malaysia. We aimed to study...
Myelofibrosis is a rare disease. There is currently no published data reporting the demographics and outcome of myelofibrosis patients in Malaysia. We aimed to study the demographics, clinical characteristics, and outcome of our patients in Sarawak. : This non-interventional, retrospective, and multi-center study was conducted on secondary data of medical records collected at four Sarawak Public Hospitals. All adult myelofibrosis patients diagnosed between January 2001 and December 2021 were included. : A total of 63 patients (male 31) with myelofibrosis were included-47 (74.6%) primary and 16 (25.4%) secondary myelofibrosis. Eleven had antecedent polycythaemia vera, whereas five transformed from essential thrombocythaemia. The combined annual incidence rate was 0.182 per 100,000 population. The period prevalence per 100,000 population over the entire study duration was 2.502. The median age was 59.0 years (33.0-93.0). Majority had high-risk (34/63(54.0%)) and intermediate-2 risk disease (19/63(30.2%)). JAK2V617F mutation was identified in 52 patients (82.5%), followed by CALR mutation in 6 (9.5%) and negative for both mutations in 5 (7.9%). Hydroxyurea was used as first-line therapy in 41/63 (65.1%), followed by interferon (8/63(12.7%)) and ruxolitinib (4/63(6.3%)). Out of 46 patients who received second-line therapy, 18 (39.1%) were switched to ruxolitinib and 9 (19.6%) to interferon. The median age of survival for overall patients was 6.8 years. The use of ruxolitinib in myelofibrosis patients showed a better overall 5-year survival compared to the no ruxolitinib arm, despite no statistical significance ( = 0.34). Patients who had good performance status had lower hazard of death than patients who had poor performance status (high-risk (95% confidence intervals): 0.06(0.013-0.239), < 0.001). Patients with intermediate risk disease had better overall survival compared to those in high-risk group (95% confidence intervals): 0.24(0.082-0.695), = 0.009). : This registry provides a real-world overview of myelofibrosis patients in our state and highlights the key insight into the unmet clinical need.
PubMed: 37705719
DOI: 10.1177/20503121231194433 -
Blood Apr 2024SETBP1 mutations are found in various clonal myeloid disorders. However, it is unclear whether they can initiate leukemia, because SETBP1 mutations typically appear as...
SETBP1 mutations are found in various clonal myeloid disorders. However, it is unclear whether they can initiate leukemia, because SETBP1 mutations typically appear as later events during oncogenesis. To answer this question, we generated a mouse model expressing mutated SETBP1 in hematopoietic tissue: this model showed profound alterations in the differentiation program of hematopoietic progenitors and developed a myeloid neoplasm with megakaryocytic dysplasia, splenomegaly, and bone marrow fibrosis, prompting us to investigate SETBP1 mutations in a cohort of 36 triple-negative primary myelofibrosis (TN-PMF) cases. We identified 2 distinct subgroups, one carrying SETBP1 mutations and the other completely devoid of somatic variants. Clinically, a striking difference in disease aggressiveness was noted, with patients with SETBP1 mutation showing a much worse clinical course. In contrast to myelodysplastic/myeloproliferative neoplasms, in which SETBP1 mutations are mostly found as a late clonal event, single-cell clonal hierarchy reconstruction in 3 patients with TN-PMF from our cohort revealed SETBP1 to be a very early event, suggesting that the phenotype of the different SETBP1+ disorders may be shaped by the opposite hierarchy of the same clonal SETBP1 variants.
Topics: Animals; Mice; Humans; Primary Myelofibrosis; Myeloproliferative Disorders; Mutation; Myelodysplastic-Myeloproliferative Diseases; Hematopoietic System; Carrier Proteins; Nuclear Proteins
PubMed: 38194688
DOI: 10.1182/blood.2023021349 -
Annals of Hematology Jan 2024There are few prospective studies on patients with post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera myelofibrosis (PPV-MF). Therefore, we...
There are few prospective studies on patients with post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera myelofibrosis (PPV-MF). Therefore, we conducted a nationwide longitudinal prospective survey to clarify the clinical characteristics of these diseases. A total of 197 PET-MF and 117 PPV-MF patients diagnosed between 2012 and 2021 were analyzed. The median age at diagnosis was 70.0 years for both diseases. The time from diagnosis of ET or PV to that of MF was 9.6 and 10.4 years, respectively, with no significant difference. Patients with PPV-MF had higher hemoglobin levels and white blood cell counts than those with PET-MF, whereas those with PET-MF had higher platelet counts than those with PPV-MF. Although splenomegaly was more frequent in patients with PPV-MF at diagnosis, there was no difference in the frequency of constitutional symptoms. Ruxolitinib was the most common treatment administered to 74.6% and 83.8% of patients with PET-MF and PPV-MF, respectively. Patients with PET-MF and PPV-MF had similar prognoses, with 3-year overall survival (OS) of 0.742 in PET-MF and 0.768 in PPV-MF patients. In both diseases, leukemic transformation was the leading cause of death, followed by infection. The 3-year OS for patients with PET/PPV-MF and primary MF diagnosed during the same period was 0.754 and 0.626, respectively, with no significant difference. This survey provides real-world clinical features and prognostic data on secondary myelofibrosis in the ruxolitinib era.
Topics: Humans; Aged; Polycythemia Vera; Thrombocythemia, Essential; Primary Myelofibrosis; Prospective Studies
PubMed: 37946031
DOI: 10.1007/s00277-023-05528-4