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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 -
Hematology (Amsterdam, Netherlands) Dec 2023The process of erythropoiesis is complex and involves the transfer of cells from the yolk sac to the fetal hepar and, ultimately, to the bone marrow during embryonic... (Review)
Review
The process of erythropoiesis is complex and involves the transfer of cells from the yolk sac to the fetal hepar and, ultimately, to the bone marrow during embryonic development. Within the bone marrow, erythroid progenitor cells undergo several stages to generate reticulocytes that enter the bloodstream. Erythropoiesis is regulated by various factors, with erythropoietin (EPO) synthesized by the kidney being the promoting factor and hepcidin synthesized by the hepar inhibiting iron mobilization. Transcription factors, such as GATA and KLF, also play a crucial role in erythropoiesis. Disruption of any of these factors can lead to abnormal erythropoiesis, resulting in red cell excess, red cell deficiency, or abnormal morphological function. This review provides a general description of erythropoiesis, as well as its regulation, highlighting the significance of understanding the process for the diagnosis and treatment of various hematological disorders.
Topics: Female; Pregnancy; Humans; Erythropoiesis; Erythrocytes; Erythroid Precursor Cells; Iron; Kidney
PubMed: 37639548
DOI: 10.1080/16078454.2023.2250645 -
The Lancet. Haematology Sep 2023The MOMENTUM study met all key endpoints at week 24, demonstrating symptom, spleen, and anaemia benefits with momelotinib versus danazol in patients with myelofibrosis.... (Randomized Controlled Trial)
Randomized Controlled Trial
Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an updated analysis of an international, double-blind, randomised phase 3 study.
BACKGROUND
The MOMENTUM study met all key endpoints at week 24, demonstrating symptom, spleen, and anaemia benefits with momelotinib versus danazol in patients with myelofibrosis. In this updated analysis, we report duration of week 24 responses and new responses with momelotinib through week 48.
METHODS
MOMENTUM is an international, double-blind, randomised, phase 3 study done at 107 sites across 21 countries. Patients were 18 years or older with primary, post-polycythaemia vera, or post-essential thrombocythaemia myelofibrosis, previously treated with an approved Janus kinase (JAK) inhibitor for 90 days or more (≥28 days with haematological complications), and had an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were randomly assigned (2:1) to either the momelotinib group (200 mg orally once per day) or danazol group (300 mg orally twice per day) through week 24 via non-deterministic biased coin minimisation and an interactive response system. Stratification factors were Total Symptom Score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), transfusion burden (0 units vs 1-4 units vs ≥5 units), and study site. After week 24, all patients initially randomly assigned to either group who remained on the study received open-label momelotinib. The primary endpoint, which has already been reported, was Myelofibrosis Symptom Assessment Form TSS response rate at week 24. Predefined secondary endpoints were duration of week 24 TSS and transfusion independence responses, safety, and survival, which are summarised post hoc at the week 48 data cutoff (May 17, 2022). TSS, transfusion independence, and splenic responses at week 48 were defined post hoc and assessed in all evaluable patients who entered the open-label period and provided sufficient data. The timing of this updated analysis was defined post hoc after all patients had the opportunity to complete their week 48 assessments, as most patients entered an extended access study (NCT03441113) after week 48. This study is registered with ClinicalTrials.gov, number NCT04173494, and is now complete.
FINDINGS
Between April 24, 2020, and Dec 3, 2021, a total of 195 patients were randomised (130 [67%] in the momelotinib group and 65 [33%] in the danazol group). 93 (72%) of 130 patients in the momelotinib group and 41 (63%) of 65 in the danazol group entered the momelotinib open-label extension period. Median follow-up was 48·4 weeks (IQR 40·6-55·7). Among TSS-evaluable patients at week 48, 30 (45%) of 67 patients in the momelotinib group who continued treatment and 15 (50%) of 30 in the danazol group who crossed over were responders. TSS responders at any time during the open-label period by week 48 were 46 (61%) of 75 evaluable patients in the momelotinib group who continued and 19 (59%) of 32 in the danazol group who crossed over, including most week 24 responders plus new responders after week 24. No new safety signals emerged with long-term follow-up. The most common non-haematological treatment-emergent adverse events in momelotinib-treated patients over the entire study period as of the data cutoff were diarrhoea (45 [26%] of 171) and asthenia (28 [16%]); the most common grades 3-4 treatment-emergent adverse events were thrombocytopenia (33 [19%]) and anaemia (19 [11%]). Serious treatment-emergent adverse events were reported in 79 (46%) of 171 patients, and fatal treatment-emergent adverse events were reported in 30 (18%); two fatal treatment-emergent adverse events were considered possibly related to momelotinib (rotaviral enteritis and Staphylococcus pneumonia).
INTERPRETATION
Momelotinib was associated with durable symptom, spleen, and anaemia benefits, late responses after week 24, and favourable safety through week 48. These results highlight the potential benefits of treatment with momelotinib in patients with myelofibrosis, particularly those with anaemia.
FUNDING
Sierra Oncology, a GSK company.
Topics: Humans; Anemia; Antineoplastic Combined Chemotherapy Protocols; Danazol; Double-Blind Method; Janus Kinase Inhibitors; Primary Myelofibrosis; Adolescent; Adult
PubMed: 37517413
DOI: 10.1016/S2352-3026(23)00174-6 -
Hematology. American Society of... Dec 2023Thrombotic complications are the primary contributor to morbidity and mortality in essential thrombocythemia (ET) and polycythemia vera (PV). Cytoreductive therapy is... (Review)
Review
Thrombotic complications are the primary contributor to morbidity and mortality in essential thrombocythemia (ET) and polycythemia vera (PV). Cytoreductive therapy is the main tool for primary or tertiary thrombosis prevention in these diseases. In general, high-thrombotic-risk patients and those with symptoms that may be ameliorated from cytoreductive therapy are candidates for this treatment, although the decision is highly individualized. Approved options for cytoreduction in ET and PV include hydroxyurea, long-acting interferons, anagrelide in ET, and ruxolitinib in PV. Selecting the ideal agent requires careful consideration of the toxicity profiles and individual treatment goals. In this review the existing literature on cytoreductive decisions in ET and PV is summarized, with an emphasis on risk-stratification, highlighting the need for personalized care in order to maximize the benefit of these therapies while minimizing toxicities.
Topics: Humans; Polycythemia Vera; Thrombocythemia, Essential; Cytoreduction Surgical Procedures; Hydroxyurea; Thrombosis
PubMed: 38066871
DOI: 10.1182/hematology.2023000451 -
Biomedicines Sep 2023Dysregulated inflammatory signaling is a key feature of myeloproliferative neoplasms (MPNs), most notably of myelofibrosis (MF). Indeed, MF is considered the prototype... (Review)
Review
Dysregulated inflammatory signaling is a key feature of myeloproliferative neoplasms (MPNs), most notably of myelofibrosis (MF). Indeed, MF is considered the prototype of onco-inflammatory hematologic cancers. While increased levels of circulatory and bone marrow cytokines are a well-established feature of all MPNs, a very recent body of literature is intriguingly pinpointing the selective overexpression of cytokine receptors by MF hematopoietic stem and progenitor cells (HSPCs), which, by contrast, are nearly absent or scarcely expressed in essential thrombocythemia (ET) or polycythemia vera (PV) cells. This new evidence suggests that MF CD34 cells are uniquely capable of sensing inflammation, and that activation of specific cytokine signaling axes may contribute to the peculiar aggressive phenotype and biological behavior of this disorder. In this review, we will cover the main cytokine systems peculiarly activated in MF and how cytokine receptor targeting is shaping a novel therapeutic avenue in this disease.
PubMed: 37760903
DOI: 10.3390/biomedicines11092462 -
Blood and Lymphatic Cancer : Targets... 2023Polycythemia vera (PV) is a subtype of myeloproliferative neoplasms characterized by impaired quality of life and severe complications. Despite the increasingly in-depth... (Review)
Review
Polycythemia vera (PV) is a subtype of myeloproliferative neoplasms characterized by impaired quality of life and severe complications. Despite the increasingly in-depth knowledge of this condition, it necessitates a multifaceted management approach to mitigate symptoms and prevent thrombotic and hemorrhagic events, ensuring prolonged survival. The therapeutic landscape has been revolutionized in recent years, where venesection and hydroxycarbamide associated with antiplatelet therapy have a central role and are now accompanied by other drugs, such as interferon and Janus kinase inhibitors. Ongoing research and advancements in targeted therapies hold promise for further enhancing the therapeutic choice for PV management.
PubMed: 38146420
DOI: 10.2147/BLCTT.S409443 -
Vascular Health and Risk Management 2023Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by aberrant myeloid lineage hematopoiesis with excessive red blood cell and pro-inflammatory... (Review)
Review
Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by aberrant myeloid lineage hematopoiesis with excessive red blood cell and pro-inflammatory cytokine production. Patients with PV present with a range of thrombotic and hemorrhagic symptoms that affect quality of life and reduce overall survival expectancy. Thrombotic events, transformation into acute myeloid leukemia, and myelofibrosis are largely responsible for the observed mortality. Treatment of PV is thus primarily focused on symptom control and survival extension through the prevention of thrombosis and leukemic transformation. Patients with PV frequently experience thrombotic events and have elevated cardiovascular risk, including hypertension, dyslipidemias, obesity, and smoking, all of which negatively affect survival. To reduce the risk of thrombotic complications, PV therapy should aim to normalize hemoglobin, hematocrit, and leukocytosis and, in addition, identify and modify cardiovascular risk factors. Herein, we review what is currently known about the associated cardiovascular risk and propose strategies for diagnosing and managing patients with PV.
Topics: Humans; Polycythemia Vera; Cardiovascular Diseases; Quality of Life; Janus Kinase 2; Risk Factors; Thrombosis; Heart Disease Risk Factors
PubMed: 38025519
DOI: 10.2147/VHRM.S429995 -
International Journal of Laboratory... May 2024An absolute erythrocytosis is present when the red cell mass is greater than 125% of the predicted. This is suspected when the hemoglobin or hematocrit is above the... (Review)
Review
An absolute erythrocytosis is present when the red cell mass is greater than 125% of the predicted. This is suspected when the hemoglobin or hematocrit is above the normal range. An erythrocytosis can be classified as primary or secondary and congenital or acquired. The commonest primary acquired disorder is polycythemia vera. The diagnostic criteria for PV have evolved over time and this is the main diagnosis managed in hematology clinics. There are a variety of rare congenital causes both primary and secondary. In particular in young patients and/or those with a family history a congenital cause is suspected. There remains a larger cohort with acquired erythrocytosis mainly with non-hematological pathology. In order to explore for a cause of erythrocytosis, measurement of the erythropoietin level is a first step. A low erythropoietin level indicates a primary cause and a normal or elevated level indicates a secondary etiology. Further investigation is then dictated by initial findings and includes mutational testing with PCR and NGS for those in whom a congenital cause is suspected. Following this possibly bone marrow biopsy, scans, and further investigation as indicated by history and initial findings. Investigation is directed toward the identification of those with a hematological disorder which would be best managed following guidelines in hematology clinics and referral elsewhere in those for whom there are non-hematological reasons for the elevated hemoglobin.
Topics: Humans; Polycythemia; Erythropoietin; Hemoglobins; Polycythemia Vera
PubMed: 38695361
DOI: 10.1111/ijlh.14298 -
Expert Opinion on Investigational Drugs 2023Myeloproliferative neoplasm (MPN) is a heterogeneous group of hematopoietic stem cell disorders characterized by clonal proliferation of one of more of the hematopoietic... (Review)
Review
INTRODUCTION
Myeloproliferative neoplasm (MPN) is a heterogeneous group of hematopoietic stem cell disorders characterized by clonal proliferation of one of more of the hematopoietic stem cell lineages. Clinical manifestations result from uncontrolled myeloproliferation, extramedullary hematopoiesis with splenomegaly and excessive inflammatory cytokine production. Currently available therapy improves hematologic parameters and symptoms but does not adequately address the underlying neoplastic biology. Bomedemstat has thus far demonstrated clinical efficacy and tolerability in the treatment of MPNs with recent evidence of impacting the malignant stem cell population.
AREAS COVERED
This review summarizes the mechanisms of action, pharmacokinetics and pharmacodynamics, safety and efficacy of bomedemstat in MPN with specific emphasis on essential thrombocythemia (ET) and myelofibrosis (MF).
EXPERT OPINION
In patients with MPNs, bomedemstat appears effective and well tolerated. The signs and symptoms of these diseases are managed as a reduction in the frequency of mutant cells was demonstrated in patients with ET and MF. Ongoing and planned studies of bomedemstat in MPN will establish the position of bomedemstat in MPNs and may help to redefine treatment endpoints of MPNs in the future.
Topics: Humans; Myeloproliferative Disorders; Primary Myelofibrosis; Thrombocythemia, Essential; Enzyme Inhibitors; Neoplasms
PubMed: 37804041
DOI: 10.1080/13543784.2023.2267980 -
British Journal of Haematology Oct 2023Management approaches for accelerated and blast phase myeloproliferative neoplasms remain challenging for clinicians and patients alike. Despite many therapeutic... (Review)
Review
Management approaches for accelerated and blast phase myeloproliferative neoplasms remain challenging for clinicians and patients alike. Despite many therapeutic advances, outcomes for those patients who are not allogeneic haematopoietic cell transplant eligible remain, in general, very poor. Estimated survival rates for such blast phase patients is frequently reported as less than 6 months. No specific immunological, genomic or clinicopathological signature currently exists that accurately predicts the risk and timing of transformation, which frequently induces a high degree of anxiety among patients and clinicians alike. Within this review article, we provide an up-to-date summary of current understanding of the underlying pathogenesis of accelerated and blast phase disease and discuss current therapeutic approaches and realistic outcomes. Finally, we discuss how the horizon may look with the introduction of more novel agents into the clinical arena.
Topics: Humans; Blast Crisis; Hematopoietic Stem Cell Transplantation; Mutation; Myeloproliferative Disorders
PubMed: 37527977
DOI: 10.1111/bjh.19010