Myelofibrosis: Current unmet needs, emerging treatments, and future perspectives.

The current standard-of-care for treatment of myelofibrosis (MF) comprises inhibitors of the Janus kinase (JAK)/signal transducers and activators (STAT) pathway; however, despite their ability to alleviate symptoms, they do not appear to modify underlying disease and have not demonstrated substantial survival benefit. Allogeneic-hematopoietic stem cell transplantation remains the only curative option for patients with MF but is limited to a subset of high-risk and fit patients. Early disease modification could positively affect disease trajectory for lower risk patients with MF as well as those with conditions that can precede MF, such as polycythemia vera and essential thrombocythemia. Here, the authors discuss critical unmet needs in the MF treatment paradigm, including: the need for safe, impactful therapies for lower risk patients, thus allowing intervention when success is most likely; better development of first-line therapies (likely highly novel or combination strategies) for intermediate-risk/higher risk patients; and approved drugs to manage cytopenia. Finally, a consensus definition of disease modification is needed that informs trial design, allowing the development of clinical end points that enable understanding of therapies and responses and that facilitate the development of therapies that work according to this definition. Through close collaboration between clinicians, patients, and the pharmaceutical industry, better efforts to define benefit and identify patients most likely to benefit from a particular combination or treatment strategy should enable the development of more effective and safe treatments to extend and improve quality of life for patients with MF.

Meaningful Symptomatic Change in Patients With Myelofibrosis From the SIMPLIFY Studies.

OBJECTIVES: Patients with myelofibrosis develop symptoms due to bone marrow fibrosis, systemic inflammation, and/or organomegaly. Alleviating symptoms improves overall quality of life. Clinical trials have historically defined symptom response as a reduction of at least 50% in Total Symptom Score at week 24 compared with baseline. Whether 50% constitutes a meaningful benefit has not been established. This study determined the meaningful change threshold (MCT) for 2 momelotinib phase III trials, SIMPLIFY-1 and SIMPLIFY-2. METHODS: The absolute and percentage MCT was determined using anchor-based methods applied to the modified Myeloproliferative Neoplasm Symptom Assessment Form v2.0 and Patient Global Impression of Change. MCTs were applied retrospectively to determine responder rates. Generalized estimating equations estimated the treatment-related difference in likelihood of improvement. RESULTS: In SIMPLIFY-1, a Janus kinase inhibitor-naive population, the MCT was 8 points. In SIMPLIFY-2, a previously Janus kinase inhibitor-treated population, the MCT was 6 points. A 32% MCT was determined in both studies, showing that the historic 50% reduction threshold may be a conservative choice. In SIMPLIFY-1, a similar proportion of patients achieved responder status with 24 weeks of momelotinib or ruxolitinib therapy based on the absolute MCT (39% vs 41%, respectively). In SIMPLIFY-2, a significantly greater proportion of patients treated with momelotinib achieved responder states compared with best available therapy based on absolute and percent change MCTs. CONCLUSIONS: This study demonstrates that momelotinib provided clinically meaningful symptom benefit for patients with myelofibrosis and provides insight into the appropriateness of the symptom change threshold used in historical studies.

Diagnosis and evaluation of prognosis of myelofibrosis: a British Society for Haematology guideline

This document represents an update of the British Society for Haematology (BSH) guideline on myelofibrosis (MF) first published in 2012 and updated in 2015.1 This guideline aims to provide healthcare professionals with clear guidance on the diagnosis and prognostic evaluation of primary my-elofibrosis (PMF), as well as post-polycythaemia vera myelo-fibrosis (post-PV MF) and post-essential thrombocythaemia myelofibrosis (post-ET MF). A section on prefibrotic MF is also included. A separate BSH Guideline covers the manage-ment of MF and is published alongside this guideline.

The management of myelofibrosis: a British Society for Haematology guideline

This document represents an update of the British Society for Haematology guideline on Myelofibrosis first published in 2012 and updated in 2015 These guidelines aim to pro-vide healthcare professionals with clear guidance on stratified management for primary myelofibrosis (PMF), as well as post-polycythaemia myelofibrosis (post-PV MF) and postessential thrombocythaemia myelofibrosis (post-ET MF). A separate BSH guideline covers the diagnosis and prognostic evaluation of myelofibrosis and is published alongside this guideline

A randomized, double-blind study of zinpentraxin alfa in patients with myelofibrosis who were previously treated with or ineligible for ruxolitinib: Stage 2 of a phase II trial.

Not available.

Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are chronic cancers characterized by overproduction of mature blood cells. Their causative somatic mutations, for example, JAK2V617F, are common in the population, yet only a minority of carriers develop MPN. Here we show that the inherited polygenic loci that underlie common hematological traits influence JAK2V617F clonal expansion. We identify polygenic risk scores (PGSs) for monocyte count and plateletcrit as new risk factors for JAK2V617F positivity. PGSs for several hematological traits influenced the risk of different MPN subtypes, with low PGSs for two platelet traits also showing protective effects in JAK2V617F carriers, making them two to three times less likely to have essential thrombocythemia than carriers with high PGSs. We observed that extreme hematological PGSs may contribute to an MPN diagnosis in the absence of somatic driver mutations. Our study showcases how polygenic backgrounds underlying common hematological traits influence both clonal selection on somatic mutations and the subsequent phenotype of cancer.

Indication and management of allogeneic haematopoietic stem-cell transplantation in myelofibrosis: updated recommendations by the EBMT/ELN International Working Group.

New options for medical therapy and risk scoring systems containing molecular data are leading to increased complexity in the management of patients with myelofibrosis. To inform patients' optimal care, we updated the 2015 guidelines on indications for and management of allogeneic haematopoietic stem-cell transplantation (HSCT) with the support of the European Society for Blood and Marrow Transplantation (EBMT) and European LeukemiaNet (ELN). New recommendations were produced using a consensus-building methodology after a comprehensive review of articles released from January, 2015 to December, 2022. Seven domains and 18 key questions were selected through a series of questionnaires using a Delphi process. Key recommendations in this update include: patients with primary myelofibrosis and an intermediate-2 or high-risk Dynamic International Prognostic Scoring System score, or a high-risk Mutation-Enhanced International Prognostic Score Systems (MIPSS70 or MIPSS70-plus) score, or a low-risk or intermediate-risk Myelofibrosis Transplant Scoring System score should be considered candidates for allogeneic HSCT. All patients who are candidates for allogeneic HSCT with splenomegaly greater than 5 cm below the left costal margin or splenomegaly-related symptoms should receive a spleen-directed treatment, ideally with a JAK-inhibitor; HLA-matched sibling donors remain the preferred donor source to date. Reduced intensity conditioning and myeloablative conditioning are both valid options for patients with myelofibrosis. Regular post-transplantation driver mutation monitoring is recommended to detect and treat early relapse with donor lymphocyte infusion. In a disease where evidence-based guidance is scarce, these recommendations might help clinicians and patients in shared decision making.

Outcomes and characteristics of nonmelanoma skin cancers in patients with myeloproliferative neoplasms on ruxolitinib.

ABSTRACT: Nonmelanoma skin cancers (NMSCs) in ruxolitinib-treated patients with myeloproliferative neoplasms behave aggressively, with adverse features and high recurrence. In our cohort, mortality from metastatic NMSC exceeded that from myelofibrosis. Vigilant skin assessment, counseling on NMSC risks, and prospective ruxolitinib-NMSC studies are crucial.

Real-World Use of Fedratinib for Myelofibrosis Following Prior Ruxolitinib Failure: Patient Characteristics, Treatment Patterns, and Clinical Outcomes.

BACKGROUND: There is a lack of established clinical outcomes for patients with myelofibrosis (MF) receiving fedratinib following ruxolitinib failure. This study examined real-world patient characteristics, treatment patterns, and clinical outcomes of patients with MF treated with fedratinib following ruxolitinib failure in US clinical practice. PATIENTS AND METHODS: This retrospective patient chart review included adults with a physician-reported diagnosis of MF, who initiated fedratinib after discontinuing ruxolitinib. Descriptive analyses characterized patient characteristics, clinical outcomes, and treatment patterns from MF diagnosis through ruxolitinib and fedratinib treatment. RESULTS: Twenty-four physicians abstracted data for 150 eligible patients. Approximately 55.3% of the patients were male, 68.0% were White, and median age at MF diagnosis was 68 (range, 35-84) years. Median duration of ruxolitinib therapy was 7.6 (range, 0.7-65.5) months. At initiation of fedratinib, 88.0% of patients had palpable spleen and a mean spleen size of 16.0 (standard deviation [SD], 5.9) cm. Spleen size decreased by 19.4% to 13.2 (SD, 7.9) cm at month 3 (P = .0001) and by 53.4% to 7.2 (SD, 7.4) cm at month 6 (P = .01) of fedratinib treatment, respectively. Almost one-third (26.8%) of patients had achieved ≥ 50% spleen reduction by month 6. Mean number of symptoms also decreased significantly at month 3 (P < .0001) and month 6 (P = .01). CONCLUSION: Fedratinib appears to deliver spleen and symptom benefits in real-world patients with MF previously treated with ruxolitinib.

How I treat myeloproliferative neoplasms in pregnancy.

ABSTRACT: Although myeloproliferative neoplasms (MPNs) are traditionally considered diseases of adults in their sixth or seventh decade, these conditions do occur in young patients; for example, for essential thrombocythemia, in particular, there is a second peak in women of reproductive age. Therefore, pregnancy is an uncommon but not rare occurrence and clinical challenge in some scenarios. Here, we discuss in detail our local approach to the management of pregnancy in patients with MPN while taking a case-based approach. We include relevant updates in the field and point to a future research strategy that should be internationally focused to obtain as much information in as short a time as possible.

Polycythemia Vera: Barriers to and Strategies for Optimal Management.

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.

Momelotinib in Myelofibrosis Patients With Thrombocytopenia: Post Hoc Analysis From Three Randomized Phase 3 Trials.

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 × 109/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.

Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis.

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen's safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study's A'herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.

Patient-reported Outcomes and Quality of Life in Anemic and Symptomatic Patients With Myelofibrosis: Results From the MOMENTUM Study.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that typically manifests with debilitating symptoms that progressively worsen, negatively impacting patients' quality of life. Fatigue is a multifactorial and burdensome MF-related symptom due to its severity, persistence, and prevalence, with anemia a contributing factor and major unmet need. Clinical trials of the Janus kinase (JAK)1/JAK2/activin A receptor type 1 inhibitor momelotinib have shown consistent anemia benefits, in addition to improvements in MF-related symptoms. The phase 3 MOMENTUM trial in symptomatic and anemic patients met its primary end point, with a greater proportion having a Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score (TSS) reduction ≥50% at week 24 with momelotinib versus danazol. To support the positive primary end point result, we conducted longitudinal, responder, and time-to-event analyses of patient-reported outcomes from MOMENTUM, as measured by the MFSAF, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Patient-Reported Outcomes Measurement Information System (PROMIS) assessments. These analyses demonstrated rapid and durable response benefits with momelotinib, with achievement of first TSS response by day 29 and continued improvement over time. Improvements favored momelotinib versus danazol for each MFSAF individual item, and greater improvements were observed for disease- and cancer-related fatigue and physical functioning at week 24, with significant results for multiple items/domains across the 3 assessments. These findings are consistent in demonstrating that momelotinib provides substantial symptom benefit.

Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution.

Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis of hematopoietic stem/progenitor cells (HSPCs) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukemia (sAML). All patients showed dominant TP53 'multihit' HSPC clones at transformation, with a leukemia stem cell transcriptional signature strongly predictive of adverse outcomes in independent cohorts, across both TP53-mutant and wild-type (WT) AML. Through analysis of serial samples, antecedent TP53-heterozygous clones and in vivo perturbations, we demonstrate a hitherto unrecognized effect of chronic inflammation, which suppressed TP53 WT HSPCs while enhancing the fitness advantage of TP53-mutant cells and promoted genetic evolution. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukemia, and are of broad relevance to other cancer types.

Teaching digital interprofessional collaboration.

BACKGROUND: Interprofessional communication in Australian clinical practice has recently shifted from paper records to electronic medical records (EMRs), and there is therefore a need for universities to prepare health graduates for digital communication. APPROACH: An interprofessional team co-designed and co-facilitated an online interprofessional activity for third year pharmacy and fifth year medical students utilising a simulated EMR (EHR Go™). Students completed a series of profession-specific tasks relating to a simulated patient, then came together in interprofessional groups of 10-12 to establish a collaborative medication charting plan. EVALUATION: A total of 640 students participated in the activity, of which 60% (386/640) were medical students. Immediately after the interprofessional workshop, students were invited to complete a voluntary anonymous evaluation. Five-point Likert scales were used to rate the relevance to practice, achievement of learning outcomes, organisation and overall quality of the activity. Students were also asked to contribute qualitative feedback. Of the participants, 28% (180/640) completed the survey, and 53% (96/180) of respondents were medical students. A majority of survey respondents agreed or strongly agreed that the activity was relevant to practice (94%; 170/180), achieved the learning outcomes (84%; 151/180), was well organised (74%; 133/180) and was a quality learning experience (79%; 143/180). The positive feedback focused on appreciating the opportunity to discuss with interdisciplinary colleagues the rationale for admission medications. Constructive feedback included the need for clearer directives regarding pre-workshop activities. IMPLICATIONS: This interprofessional education (IPE) activity presents a feasible, innovative approach to teaching pharmacy and medical students digital communication and collaboration using a simulated EMR. Overall, a majority of learners were satisfied with the learning experience and felt that the IPE activity achieved the learning outcomes and was relevant to practice.