Efficacy and safety of fedratinib in patients with myelofibrosis previously treated with ruxolitinib (FREEDOM2): results from a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Most patients with myelofibrosis develop ruxolitinib intolerance or disease that is relapsed or refractory, and survival rates after ruxolitinib discontinuation are poor. We aimed to evaluate the safety and efficacy of fedratinib versus best available therapy (BAT) in patients with myelofibrosis previously treated with ruxolitinib. METHODS: FREEDOM2 was a multicentre, open-label, randomised, controlled, phase 3 trial in 86 clinics in 16 countries, in which patients aged at least 18 years with intermediate-2 or high-risk myelofibrosis that was relapsed or refractory or intolerant to ruxolitinib with Eastern Cooperative Oncology Group performance status 0-2 were stratified by spleen size by palpation, platelet count, and previous ruxolitinib treatment, and randomly assigned 2:1 by interactive response technology to receive fedratinib 400 mg per day (4 × 100 mg capsules orally once daily, open-label) or BAT. Patients received prophylactic antiemetics and thiamine supplementation, and symptomatic antidiarrhoeals as required. Primary endpoint was proportion of patients reaching spleen volume reduction (SVR) of at least 35% (SVR35) at end of cycle 6 in the intention-to-treat population. This manuscript reports the primary analysis of the trial; follow-up is ongoing. This trial is registered at clinicaltrials.gov, NCT03952039. FINDINGS: Between Sept 9, 2019 and June 24, 2022, of 316 patients screened, 201 were randomly assigned and treated (134 to fedratinib, 67 to BAT [including 52 receiving ruxolitinib]); 46 patients from the BAT group crossed over to fedratinib. Approximately half of enrolled patients were male (fedratinib 75 [56%] of 134; BAT 30 [45%] of 67) and most were White (fedratinib 106 [79%] of 134; BAT 58 [87%] of 67). At data cutoff (Dec 27, 2022), median survival follow-up was 64·5 weeks (IQR 37·9-104·9). SVR35 at end of cycle 6 was seen in 48 (36%) of 134 patients receiving fedratinib versus four (6%) of 67 patients receiving BAT (30% difference; 95% CI 20-39; one-sided p-value <0·0001). During the first six cycles 53 (40%) of 134 patients in the fedratinib group and 8 (12%) of 67 patients in the BAT group had grade 3 or greater treatment-related adverse events, most frequently anaemia (fedratinib 12 [9%] of 134; BAT 6 [9%] of 67) and thrombocytopenia (fedratinib 16 [12%] of 134; BAT 2 [3%] of 67); one patient in the fedratinib group died from acute kidney injury suspected to be related to study drug (no treatment-related deaths in the BAT group). Gastrointestinal adverse events occurred more frequently in the fedratinib group compared with the BAT group, but were mostly grade 1-2 in severity and more frequent in early cycles, and were less frequent than in prior clinical trials. A total of 28 (21%) of 134 patients in the fedratinib group and 3 (4%) of 67 patients in the BAT group had thiamine levels below lower limit of normal per central laboratory assessment, with only one case of low thiamine in the fedratinib arm after the introduction of prophylactic thiamine supplementation. INTERPRETATION: Findings from FREEDOM2 support fedratinib as a second-line Janus kinase inhibitor option to reduce spleen size after ruxolitinib failure or intolerance in patients with myelofibrosis, and shows effective strategies for management of gastrointestinal adverse events and low thiamine concentrations through prophylaxis, monitoring, and treatment. FUNDING: Bristol Myers Squibb.

Proposals for Revised International Working Group-European LeukemiaNet Criteria for Anemia Response in Myelofibrosis.

With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate inter-study comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group-European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to i) account for gender-specific differences in determining hemoglobin levels for eligibility criteria, ii) revise definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices, and iii) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks prior to study enrollment) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs. non-TDA) and graded (major vs. minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment.

Identifying disease-modifying potential in myelofibrosis clinical trials.

The ultimate goal of bringing most new drugs to the clinic in hematological malignancy is to improve overall survival. However, the use of surrogate endpoints for overall survival is increasingly considered standard practice, since a well validated surrogate endpoint can accelerate the outcome assessment and facilitate better clinical trial design. Established examples include monitoring minimal residual disease in chronic myeloid leukemia and acute leukemia, and metabolic response assessment in lymphoma. However, what happens when a clinical trial endpoint that is not a good surrogate for disease-modifying potential becomes ingrained as an expected outcome, and new agents are expected or required to meet this endpoint to demonstrate "efficacy"? JAK inhibitors for myelofibrosis have a specific impact on reducing symptom burden and splenomegaly, but limited impact on the natural history of the disease. Since the introduction of ruxolitinib more than a decade ago there has been modest incremental success in clinical trials for myelofibrosis, but no major leap forward to alter the natural history of the disease. We argue that the clinical development of novel agents for myelofibrosis will be accelerated by moving away from using endpoints that are specifically tailored to measure the beneficial effects of JAK inhibitors. We propose that specific measures of relevant disease burden, such as reduction in mutation burden as determined by molecular endpoints, should replace established endpoints. Careful re-analysis of existing data and trials in progress is needed to identify the most useful surrogate endpoints for future MF trials and better serve patient interest.

Clinical utility of investigations in triple-negative thrombocytosis: A real-world, multicentre evaluation of UK practice.

Diagnosis of essential thrombocythaemia (ET) is challenging in patients lacking JAK2/CALR/MPL mutations. In a retrospective evaluation of 320 patients with 'triple-negative thrombocytosis', we assessed utility of bone marrow histology (90.9% of patients) and myeloid gene panel (MGP, 55.6%). Supportive histology ('myeloproliferative neoplasm-definite/probable', 36.8%) was associated with higher platelet counts and varied between centres. 14.6% MGP revealed significant variants: 3.4% JAK2/CALR/MPL and 11.2% other myeloid genes. Final clinical diagnosis was strongly predicted by histology, not MGP. 23.7% received cytoreduction (17.6% under 60 years). Real-world 'triple-negative' ET diagnosis currently depends heavily on histology; we advocate caution in MGP-negative cases and that specific guidelines are needed.

Momelotinib versus Continued Ruxolitinib or Best Available Therapy in JAK Inhibitor-Experienced Patients with Myelofibrosis and Anemia: Subgroup Analysis of SIMPLIFY-2.

INTRODUCTION: Some Janus kinase (JAK) inhibitors such as ruxolitinib and fedratinib do not address and may worsen anemia in patients with myelofibrosis. In these cases, the JAK inhibitor may be continued at a reduced dose in an effort to maintain splenic and symptom control, with supportive therapy and/or red blood cell (RBC) transfusions added to manage anemia. This post hoc descriptive analysis of the phase 3 SIMPLIFY-2 trial evaluated the relative benefits of this approach versus switching to the JAK1/JAK2/activin A receptor type 1 inhibitor momelotinib in patients for whom anemia management is a key consideration. METHODS: SIMPLIFY-2 was a randomized (2:1), open-label, phase 3 trial of momelotinib versus best available therapy (BAT; 88.5% continued ruxolitinib) in JAK inhibitor-experienced patients with myelofibrosis (n = 156). Patient subgroups (n = 105 each) were defined by either baseline (1) hemoglobin (Hb) of < 100 g/L or (2) non-transfusion independence (not meeting the criteria of no transfusions and no Hb of < 80 g/L for the previous 12 weeks); outcomes have been summarized descriptively. RESULTS: In both subgroups of interest, week 24 transfusion independence rates were higher with momelotinib versus BAT/ruxolitinib: baseline Hb of < 100 g/L, 22 (33.3%) versus 5 (12.8%); baseline non-transfusion independent, 25 (34.7%) versus 1 (3.0%). Mean Hb levels over time were also generally higher in both subgroups with momelotinib, despite median transfusion rates through week 24 with momelotinib being comparable to or lower than with BAT/ruxolitinib. Spleen and symptom response rates with momelotinib in these subgroups were comparable to the intent-to-treat population, while rates with BAT/ruxolitinib were lower. CONCLUSION: In patients with moderate-to-severe anemia and/or in need of RBC transfusions, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using anemia supportive therapies. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02101268.

Patients with the rare blood cancer myelofibrosis often experience symptoms such as tiredness, an increase in the size of their spleens (an organ involved in filtering the blood), and anemia (too few red blood cells). One type of treatment for myelofibrosis, called a Janus kinase (JAK) inhibitor, can help patients to feel better and reduce the size of their spleens, but some JAK inhibitors do not help with anemia and may make it worse. In those situations, patients may continue to take their JAK inhibitor but also receive another type of treatment, called an anemia supportive therapy, and may also receive red blood cell transfusions. This study compared 2 treatment approaches, continuing the JAK inhibitor ruxolitinib and adding an anemia supportive therapy and/or transfusions versus switching to another treatment called momelotinib, in 2 groups of patients from a clinical trial: (1) patients with levels of hemoglobin (a red blood cell protein) at the start of the trial that indicated that they had anemia, and (2) patients who were already receiving red blood cell transfusions at the start of the trial. In both groups, more patients did not need red blood cell transfusions anymore at week 24 with momelotinib, and their hemoglobin levels on average became higher over time. More patients also had improvements in spleen size and symptoms with momelotinib. Overall, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using supportive therapies and/or red blood cell transfusions to treat anemia.

How I Treat Low-risk Polycythemia Vera Patients who Require Cytoreduction.

Polycythemia vera (PV) was first described by Vaquez in 1892. This is a chronic hematological malignancy which affects both older and young patients. Perhaps due to lack of a curative treatment and the perceived toxicities of prior therapies our focus in the past was to intensify treatment only for patients at higher risk of thrombosis. Recent triggers to challenge this approach include: a recognition that low-risk PV is not "no-risk", our ability to better recognize patients who would benefit from more intensive therapy from the perspective of thrombosis, and data showing that some treatments may reduce risk of transformation to myelofibrosis. Furthermore, there is emergent evidence that molecular monitoring may identify an improvement in disease state translating to improved overall survival. Here we describe clinical situations that would trigger the use of cytoreductive treatment for low-risk PV patients as well as our approach to choosing a specific cytoreductive agent and how to effectively monitor treatment.

Safety and efficacy of fedratinib in patients with myelofibrosis previously treated with ruxolitinib: primary analysis of FREEDOM trial.

The phase 3b FREEDOM trial (ClinicalTrials.gov: NCT03755518) evaluates efficacy/safety of fedratinib in intermediate- or high-risk myelofibrosis patients with platelet count ≥50 × 109/L, previously treated with ruxolitinib. The trial design included protocol specified strategies to mitigate the risk for gastrointestinal (GI) adverse events (AEs), thiamine supplementation, and encephalopathy surveillance. Due to COVID-19, accrual was cut short with 38 patients enrolled. In the efficacy evaluable population (n = 35), nine (25.7%; 95% confidence interval 12.5-43.3) patients achieved primary endpoint of ≥35% spleen volume reduction (SVR) at end of cycle (EOC) 6; and 22 (62.9%) patients showed best overall response of ≥35% SVR up to end of treatment. Sixteen (44.4%) patients showed ≥50% reduction in total symptom score at EOC6 (n = 36). Compared to previously reported JAKARTA-2 trial, rates of GI AEs were lower, and no patient developed encephalopathy. Overall, FREEDOM study showed clinically relevant spleen and symptom responses with fedratinib, and effective mitigation of GI AEs.

Erythrocytosis: Diagnosis and investigation.

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.

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.

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

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.

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.

Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis.

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.

Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms.

Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver.