-
Journal of Hematology & Oncology Jul 2023Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, extramedullary hematopoiesis, and splenomegaly. Patients with... (Review)
Review
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, extramedullary hematopoiesis, and splenomegaly. Patients with MF are at risk for reduced survival versus the general population and often experience burdensome signs and symptoms that reduce quality of life. The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was initially approved by the US Food and Drug Administration in 2011 for the treatment of patients with intermediate or high-risk MF, including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF, based on efficacy and safety findings from the randomized, controlled, phase 3 COMFORT trials. Over a decade later, ruxolitinib continues to be the standard of care in higher-risk MF, and dose optimization and management remain crucial for safely maximizing clinical benefits of ruxolitinib. This review summarizes the safety profile of ruxolitinib in patients with MF in the COMFORT trials leading up to approval and in the subsequent JUMP, ROBUST, EXPAND, and REALISE trials; in pooled analyses; and in postmarketing analyses in the 10 years following approval. There is a focus on the occurrence of common hematologic and nonhematologic adverse events, with guidance provided on the management of patients with anemia or thrombocytopenia, including dosing strategies based on findings from the REALISE and EXPAND trials. Finally, to ensure a greater understanding of the safety profile of ruxolitinib, practical considerations are discussed.
Topics: Humans; Primary Myelofibrosis; Quality of Life; Janus Kinase 2; Nitriles; Pyrimidines
PubMed: 37501130
DOI: 10.1186/s13045-023-01471-z -
Blood Advances Oct 2023In patients with cytopenic myelofibrosis, treatment with the JAK2/IRAK1 inhibitor pacritinib was associated with anemia benefit in the phase 3 PERSIST-2 study. The...
In patients with cytopenic myelofibrosis, treatment with the JAK2/IRAK1 inhibitor pacritinib was associated with anemia benefit in the phase 3 PERSIST-2 study. The impact of pacritinib on transfusion independence (TI) has not been previously described, nor has the mechanism by which pacritinib improves anemia been elucidated. Because it has been previously postulated that inhibition of activin A receptor, type 1 (ACVR1)/activin receptor-like kinase-2 improves anemia in patients with myelofibrosis via suppression of hepcidin production, we assessed the relative inhibitory potency of pacritinib compared with other JAK2 inhibitors against ACVR1. Pacritinib inhibited ACVR1 with greater potency (half-maximal inhibitory concentration [IC50] = 16.7 nM; Cmax:IC50 = 12.7) than momelotinib (IC50 = 52.5 nM; Cmax:IC50 = 3.2), fedratinib (IC50 = 273 nM; Cmax:IC50 = 1.0), or ruxolitinib (IC50 > 1000; Cmax:IC50 < 0.01). Pacritinib's inhibitory activity against ACVR1 was corroborated via inhibition of downstream SMAD signaling in conjunction with marked suppression of hepcidin production. Among patients on PERSIST-2 who were not transfusion independent at baseline based on Gale criteria, a significantly greater proportion achieved TI on pacritinib compared with those treated on best available therapy (37% vs 7%, P = .001), and significantly more had a ≥50% reduction in transfusion burden (49% vs 9%, P < .0001). These data indicate that the anemia benefit of the JAK2/IRAK1 inhibitor pacritinib may be a function of potent ACVR1 inhibition.
Topics: Humans; Primary Myelofibrosis; Hepcidins; Janus Kinase 2; Anemia; Janus Kinase Inhibitors; Activin Receptors, Type I
PubMed: 37552106
DOI: 10.1182/bloodadvances.2023010151 -
EJHaem Aug 2023Primary myelofibrosis (PMF) and polycythaemia vera (PV) are rare -negative myeloproliferative neoplasms, associated with an increased risk of thrombosis, haemorrhagic... (Review)
Review
Primary myelofibrosis (PMF) and polycythaemia vera (PV) are rare -negative myeloproliferative neoplasms, associated with an increased risk of thrombosis, haemorrhagic complications and progression to fibrosis or leukaemia or fibrosis for PV. Both diseases are characterised by biological and clinical heterogeneity, leading to great variability in their management in routine clinical practice. In this review, we present an updated overview of the diagnosis, prognosis and treatment of PMF and PV, and we discuss how our multidisciplinary expert group based across France translates this evidence-based knowledge into routine clinical practice.
PubMed: 37601853
DOI: 10.1002/jha2.734 -
Nature Communications Oct 2023Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either...
Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either JAK2 or Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment.
Topics: Humans; Primary Myelofibrosis; Myeloproliferative Disorders; Mutation; Hematopoietic Stem Cells; Homozygote; Calreticulin; Janus Kinase 2
PubMed: 37828014
DOI: 10.1038/s41467-023-42101-z -
Therapeutic Advances in Hematology 2024Interferons are cytokines with immunomodulatory properties and disease-modifying effects that have been used to treat myeloproliferative neoplasms (MPNs) for more than... (Review)
Review
Interferons are cytokines with immunomodulatory properties and disease-modifying effects that have been used to treat myeloproliferative neoplasms (MPNs) for more than 35 years. The initial use of interferons was limited due to difficulties with administration and a significant toxicity profile. Many of these shortcomings were addressed by covalently binding polyethylene glycol to the interferon structure, which increases the stability, prolongs activity, and reduces immunogenicity of the molecule. In the current therapeutic landscape, pegylated interferons are recommended for use in the treatment of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We review recent efficacy, molecular response, and safety data for the two available pegylated interferons, peginterferon alfa-2a (Pegasys) and ropeginterferon alfa-2b-njft (BESREMi). The practical management of interferon-based therapies is discussed, along with our opinions on whether to and how to switch from hydroxyurea to one of these therapies. Key topics and questions related to use of interferons, such as their safety and tolerability, the significance of variant allele frequency, advantages of early treatment, and what the future of interferon therapy may look like, will be examined. Pegylated interferons represent an important therapeutic option for patients with MPNs; however, more research is still required to further refine interferon therapy.
PubMed: 38380373
DOI: 10.1177/20406207241229588 -
Journal of Translational Medicine Oct 2023Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not... (Review)
Review
Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not well established except in its primary form. The present review consolidates current understanding of marrow fibrosis. We searched PubMed without time restriction using key words: bone marrow and fibrosis as the main stem against the terms: growth factors, cytokines and chemokines, morphology, megakaryocytes and platelets, myeloproliferative disorders, myelodysplastic syndrome, collagen biosynthesis, mesenchymal stem cells, vitamins and minerals and hormones, and mechanism of tissue fibrosis. Tissue marrow fibrosis-related papers were short listed and analysed for the review. It emerged that bone marrow fibrosis is the outcome of complex interactions between growth factors, cytokines, chemokines and hormones together with their facilitators and inhibitors. Fibrogenesis is initiated by mobilisation of special immunophenotypic subsets of mesenchymal stem cells in the marrow that transform into fibroblasts. Fibrogenic stimuli may arise from neoplastic haemopoietic or non-hematopoietic cells, as well as immune cells involved in infections and inflammatory conditions. Autoimmunity is involved in a small subset of patients with marrow fibrosis. Megakaryocytes and platelets are either directly involved or are important intermediaries in stimulating mesenchymal stem cells. MMPs, TIMPs, TGF-β, PDGRF, and basic FGF and CRCXL4 chemokines are involved in these processes. Genetic and epigenetic changes underlie many of these conditions.
Topics: Humans; Bone Marrow; Primary Myelofibrosis; Cytokines; Fibrosis; Chemokines; Hormones
PubMed: 37814319
DOI: 10.1186/s12967-023-04393-z -
Haematologica Feb 2024
Topics: Humans; Primary Myelofibrosis; Pyrimidines; Nitriles; Janus Kinase 2; Benzamides; Pyrazoles
PubMed: 37259556
DOI: 10.3324/haematol.2023.283106 -
EJHaem Aug 2023Myelofibrosis (MF) is a clonal malignancy frequently characterized by anemia and in 10%-20% of cases it can evolve into blast phase (BP). Anemia in MF is associated with...
Myelofibrosis (MF) is a clonal malignancy frequently characterized by anemia and in 10%-20% of cases it can evolve into blast phase (BP). Anemia in MF is associated with reduced survival and -in primary MF- also with an increased probability of BP. Conventional treatments for anemia have limited effectiveness in MF. Within a dataset of 1752 MF subjects largely unexposed to ruxolitinib (RUX), BP incidence was 2.5% patients per year (p-y). This rate reached respectively 4.3% and 4.5% p-y in case of patients with common terminology criteria for adverse events (CTCAE) grade 3/4 and grade 2 anemia, respectively, that represented together 32% of the cohort. Among 273 MF cases treated with RUX, BP incidence was 2.89% p-y and it reached 4.86% p-y in subjects who started RUX with CTCAE grade 2 anemia (one third of total). Within patients with red blood cell transfusion-dependency at 6 months of RUX (21% of the exposed), BP rate was 4.2% p-y. Our study highlights a relevant incidence of BP in anemic MF patients, with a similar rate whether treated with or without RUX. These findings will help treating physicians to make decisions on the safety profile of innovative anemia treatments.
PubMed: 37601878
DOI: 10.1002/jha2.745 -
HemaSphere Nov 2023The oral activin A receptor type I, Janus kinase 1 (JAK1), and JAK2 inhibitor momelotinib demonstrated symptom, spleen, and anemia benefits in intermediate- and...
The oral activin A receptor type I, Janus kinase 1 (JAK1), and JAK2 inhibitor momelotinib demonstrated symptom, spleen, and anemia benefits in intermediate- and high-risk myelofibrosis (MF). Post hoc analyses herein evaluated the efficacy and safety of momelotinib in patients with MF and thrombocytopenia (platelet counts <100 × 10/L) from randomized phase 3 studies: MOMENTUM (momelotinib versus danazol; JAK inhibitor experienced); SIMPLIFY-1 (momelotinib versus ruxolitinib; JAK inhibitor naïve); and SIMPLIFY-2 (momelotinib versus best available therapy; JAK inhibitor experienced); these studies were not statistically powered to assess differences in thrombocytopenic subgroups, and these analyses are descriptive. The treatment effect of momelotinib versus ruxolitinib on week 24 response rates (spleen volume reduction ≥35%/Total Symptom Score reduction ≥50%/transfusion independence) was numerically comparable or better in thrombocytopenic patients versus the overall JAK inhibitor naive population; rates were preserved with momelotinib in thrombocytopenic patients but attenuated with ruxolitinib (momelotinib: 27%/28%/67% overall versus 39%/35%/61% in thrombocytopenic group; ruxolitinib: 29%/42%/49% overall versus 0%/22%/39% in thrombocytopenic group, respectively). In contrast to ruxolitinib, momelotinib maintained high dose intensity throughout the treatment. In the JAK inhibitor experienced population, thrombocytopenic patients had the following: (1) numerically higher symptom and transfusion independence response rates with momelotinib than in control arms; and (2) preserved spleen, symptom, and transfusion independence response rates with momelotinib relative to the overall study populations. The safety profile of momelotinib in thrombocytopenic patients was also consistent with the overall study population. In summary, momelotinib represents a safe and effective treatment option for patients with MF and moderate-to-severe thrombocytopenia.
PubMed: 37908862
DOI: 10.1097/HS9.0000000000000963 -
Frontiers in Genetics 2023The classical -negative myeloproliferative neoplasms such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal diseases with the... (Review)
Review
The classical -negative myeloproliferative neoplasms such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal diseases with the presence of characteristic "driver mutations" in one of the genes: JAK2, CALR, or MPL. The search for mutations in these three genes is required for the diagnosis of MPNs. Nevertheless, the progress that has been made in the field of molecular genetics has opened a new era in medicine. The search for additional mutations in MPNs is helpful in assessing the risk stratification, disease progression, transformation to acute myeloid leukemia (AML), or choosing the right treatment. In some cases, advanced technologies are needed to find a clonal marker of the disease and establish a diagnosis. This review focuses on how the use of new technologies like next-generation sequencing (NGS) helps in the diagnosis of -negative myeloproliferative neoplasms.
PubMed: 37745842
DOI: 10.3389/fgene.2023.1241912