Jakafi May Not Associate with Long-Term Benefits in Myelofibrosis Subset

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March 16, 2025

Author(s): Spencer Feldman

Fact checked by: Alex Biese

Among patients with calreticulin (CALR)-mutated myelofibrosis, real-world data reveal insights into those with splenomegaly and/or symptoms requiring therapy with Janus kinase 2 (JAK2) inhibitors.

The findings suggest that while Jakafi (ruxolitinib) shows some initial benefits, CALR-mutated patients may require more targeted and innovative therapeutic approaches for better long-term outcomes, according to study findings published in Annals of Hematology.

“Overall, despite the initial benefits of [Jakafi], CALR-mutated patients may require more innovative therapeutic interventions to achieve optimal outcomes. This further emphasizes the necessity of exploring alternative or adjunctive therapies tailored specifically for CALR-mutated individuals,” lead study author Dr. Francesca Palandri and colleagues wrote in the study.

Palandri is currently an adjunct professor primarily based in the Department of Experimental, Diagnostic and Specialty Medicine at the Università di Bologna, Bologna, Italy. She is also a junior researcher at Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology, Bologna, Italy.

Patients with CALR mutations began Jakafi with more severe disease, including higher peripheral blast counts, lower hemoglobin levels and worse marrow fibrosis, and after a longer median time from diagnosis (2.6 versus 0.7 years) compared to patients with JAK2 mutations. At six months, spleen responses were numerically lower in CALR-mutated patients, who also had lower rates of symptom responses (56.1% versus 66.7%, respectively). However, CALR-mutated patients experienced lower rates of high white blood cell counts.

Furthermore, in patients with delayed Jakafi initiation, anemia and reduced starting doses correlated with poorer survival. Managing anemia through interventions like danazol, erythropoiesis-stimulating agents, iron chelation and optimized Jakafi dosing may improve outcomes, according to study authors. The study also highlights the potential benefits of alternative JAK2 inhibitors with lower hematological toxicity.

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Topics of Interest in Women With Myeloproliferative Neoplasms

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March 2025

Natasha Szuber, Paola Guglielmelli, Naseema Gangat

Abstract

Overview
Sex and gender have emerged as central modifiers of disease biology, phenotype, and clinical outcomes in myeloproliferative neoplasms (MPNs). This review will uniquely highlight issues affecting women with MPN and articulate their relevant determinants.
Epidemiology and Diagnosis
A higher overall prevalence of MPN has been established in women. The incidence of essential thrombocythemia (ET) predominates, while, conversely, polycythemia vera (PV) and myelofibrosis (MF) are seen in lower frequencies as compared to men. Diagnostic criteria are dictated by sex‐driven physiological variances in hemoglobin and hematocrit levels in PV, mandating separate diagnostic thresholds, respectively: > 16.0 g/dL and > 48% in women vs. > 16.5 and > 49% in men. Genetic Framework and Phenotype Women with MPN harbor fewer acquired somatic mutations and a lower frequency of high‐risk mutations than their male counterparts; lower JAK2V617F driver variant allele frequency and attenuated allele burden kinetics have also been reported. Women with MPN are younger at diagnosis than men and, contingent on subtype, display more indolent disease features. Importantly, validated symptom burden assessments consistently disclose higher scores in women vs. men.
Thrombosis and Outcomes
Women with MPN have a unique thrombotic diathesis with respect to men, more frequently involving the splanchnic venous system in those ultimately diagnosed with PV. Outcomes data depict female sex as a variable associated with more favorable clinical trajectories, including lower rates of MF/leukemic transformation and secondary cancers, as well as improved overall survival rates vis‐à‐vis men. Life‐Cycle Windows, Pregnancy, and Postpartum Potential challenges at each significant life stage will be addressed: puberty, preconception and fertility, and perimenopause; these include issues surrounding oral contraceptives and hormone use. Prospective studies suggest overall favorable maternal and fetal outcomes with pregnancy in women with MPN. Full details on risks and reported outcomes will be discussed, as well as a risk‐adapted approach to management informed by obstetric and thrombosis history. Recommendations include aspirin 81 mg daily in all patients and cytoreduction with interferon‐α in those with antecedent thrombosis, as well as in low‐risk cases with higher‐risk features (e.g., poorly controlled hematocrit and recurrent fetal loss). Antepartum anticoagulation with low molecular weight heparin (LMWH) is recommended in cases with previous venous thromboembolism.
Conclusions and Future Directions
This review highlights female sex and gender as critical drivers of MPN incidence, presentation, and natural history. It further outlines the impact and management of MPN as related to unique female reproductive phases. A sex‐informed lens will be required in order to recalibrate current prognostic tools, a requisite to refining patient counselling and clinical decision‐making in line with precision medicine. Moreover, while several mechanisms underpinning sex‐defined discrepancies have been defined, these mandate further prospective study. Finally, sex and gender‐based differences must be weighted in clinical trials with systematized procedures to correct participation imbalances in favor of sex and gender equity.

 

Risk for Specific Hematologic Cancers Down With GLP-1 Receptor Agonist Use in T2DM

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HealthDay News — For patients with type 2 diabetes (T2D), glucagon-like peptide-1 receptor agonist (GLP-1 RA) use is associated with a reduced risk for developing hematologic cancers compared with insulin and metformin use, according to a research letter published online March 6 in JAMA Network Open.

Omer S. Ashruf, from Northeast Ohio Medical University in Rootstown, and colleagues conducted a retrospective cohort study to compare the risks for hematologic cancers in patients with T2D treated with a GLP-1 RA versus metformin and insulin. The study included patients with T2D prescribed a GLP-1 RA, insulin, or metformin between April 30, 2005, and Oct. 31, 2023 (51,617; 611,115; and 938,602 patients, respectively). Groups were independently matched using a nearest neighbor greedy matching algorithm; 47,716 patients were included in the GLP-1 RA-insulin analysis and 50,590 were included in the GLP-1 RA-metformin analysis.

The researchers found that GLP-1 RA use was associated with significantly lower risks for of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) compared with metformin (hazard ratios, 0.61 and 0.67, respectively). No significant difference was seen in the risk for any other hematologic cancer. GLP-1 RA use was associated with significantly lower risks for myeloid leukemia, lymphoid leukemia, non-Hodgkin lymphoma, MDS, MPN, monoclonal gammopathy, multiple myeloma, and amyloidosis compared with insulin (hazard ratios, 0.39, 0.45, 0.42, 0.19, 0.50, 0.68, 0.49, and 0.52, respectively). GLP-1 RA use was associated with a 54 percent lower risk than that seen with insulin across all hematologic cancers.

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Optimizing Treatment in Patients With Myelofibrosis and Transfusion-Dependent Anemia

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By Clinical Content Hub

In patients with MF, greater anemia severity and transfusion dependency have been linked to worse overall survival and quality of life (QOL). Historically, the only available treatment strategies for MF-related anemia have shown limited efficacy and an increased risk for numerous adverse effects.1,2

In September 2023, the US Food and Drug Administration (FDA) approved momelotinib, an oral inhibitor of JAK1 and JAK2 as well as activin A receptor type 1 (ACVR1), for the treatment of adults with anemia and intermediate or high-risk MF. Momelotinib is currently the only FDA-approved therapy indicated for the treatment of MF patients with anemia.3 In clinical trials, this first-in-class treatment has shown efficacy in treating anemia and other key manifestations of MF.4

Douglas Tremblay, MD, is an assistant professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, New York, specializing in hematologic malignancies such as myelodysplastic/myeloproliferative overlap syndromes, myeloproliferative neoplasms, and acute myeloid leukemia. He serves as the principal investigator on multiple clinical trials focused on myeloid neoplasms. In this article, Dr Tremblay discusses treatment strategies for MF patients, with a particular focus on those with transfusion-dependent anemia, as well as emerging developments in the MF treatment landscape.

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Impact of treatment for adolescent and young adults with essential thrombocythemia and polycythemia vera

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12 March 2025

Yan Beauverd, Jean-Christophe Ianotto, Kyaw Htin Thaw, Marta Sobas, Parvis Sadjadian, Natalia Curto-Garcia, Lee-Yung Shih, Timothy Devos, Dorota Krochmalczyk, Serena Galli, Maria Bieniaszewska, Ilona Seferynska, Mary Frances McMullin, et al.

Abstract

Essential thrombocythemia (ET) and polycythemia vera (PV) are rare in adolescent and young adult (AYA). These conditions, similar to those in older patients, are linked with thrombotic complications and the potential progression to secondary myelofibrosis (sMF). This retrospective study of ET and PV patients diagnosed before age 25 evaluated complication rates and impact of cytoreductive drugs on outcomes. Among 348 patients (278 ET, 70 PV) with a median age of 20 years, the of thrombotic events was 1.9 per 100 patient-years. Risk factors for thrombosis included elevated white blood cell count (>11 × 109/L) (HR: 2.7, p = 0.012) and absence of splenomegaly at diagnosis (HR: 5.7, p = 0.026), while cytoreductive drugs did not reduce this risk. The incidence of sMF was 0.7 per 100 patient-years. CALR mutation (HR: 6.0, p < 0.001) and a history of thrombosis (HR: 3.8, p = 0.015) were associated with sMF risk. Interferon as a first-line treatment significantly improved myelofibrosis-free survival compared to other treatments or the absence of cytoreduction (p = 0.046). Although cytoreduction did not affect thrombotic event, early interferon use reduced sMF risk. These findings support interferon use to mitigate sMF risk in AYA ET and PV patients.

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JAK Inhibitors Reduce Thromboembolic Risk in Myeloproliferative Neoplasm Therapy

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March 11, 2025

Author(s): Alex Biese

Fact checked by: Ryan Scott

Treatment with Janus kinase inhibitors (JAKis) has been found to be associated with a reduction in risk of thromboembolic events among patients with myeloproliferative neoplasms (MPNs), according to research findings.

These findings were published in eJHaem, and are driven by observations of treatment with Jakafi (ruxolitinib) for patients with polycythemia vera and myelofibrosis, researchers noted.

“In this meta-analysis, JAKi [used for] MPN [treatment] was associated with a reduced risk of thromboembolic events compared [with] control, primarily driven by studies of [Jakafi] in polycythemia vera and myelofibrosis,” first study author Roberta Dunn and colleagues wrote in the study. “JAKi treatment was not associated with an increased risk of [major adverse cardiovascular events] or hypertension, adding to the existing body of evidence demonstrating the safety of JAKi in the treatment of MPNs. Further prospective clinical trials are warranted to confirm these findings and characterize the cardiovascular profile of other JAKis in all types of MPNs.”

Dunn is a medical student at the School of Medical Education, King’s College London, as well as a student researcher at Guy’s and St Thomas’ NHS Foundation Trust, in the United Kingdom.

MPNs, according to the Cleveland Clinic, are rare blood cancers that involve the patient’s body making too many red blood cells, white blood cells or platelets. JAKis, as explained by the National Cancer Institute, block the actions of enzymes which control cell signaling and growth, the number of blood cells and platelets made in the bone marrow, inflammation, and immune cell activity. Blocking these enzymes may help prevent abnormal blood cells or cancer cells from growing.

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Promising New Treatment for Myelofibrosis Blood Cancer Using a Combination Targeted Therapy 

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By Julie Grisham

An international phase 3 clinical trial of a new drug combination for treating the blood cancer myelofibrosis found that adding a second, experimental drug to standard treatment was more effective than the standard treatment alone. Further, adding the second drug did not significantly increase side effects. Memorial Sloan Kettering Cancer Center (MSK) enrolled the most patients in the trial.

“This is one of the largest myelofibrosis clinical trials to date,” says MSK leukemia specialist Raajit Rampal, MD, PhD, lead author of the study, published March 10 in Nature Medicine. “There is a real unmet need for patients with this disease, and the findings from this trial represent an exciting advance.”

This study looked at adding an experimental drug called pelebresib to the drug ruxolitinib (Jakafi®), which is the current treatment for myelofibrosis. Both drugs are targeted therapies. Pelebrisib blocks the action of proteins involved in inflammation and cancer; ruxolitinib blocks a protein called JAK. This combination approach was based on ongoing research from the lab of MSK leukemia specialist and physician-scientist Ross Levine, MD.

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A Toolkit for Healthcare Transition for Adolescents With Classical Myeloproliferative Neoplasms

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March 2025

Nicole Kucine1, Holger Cario2, Ghaith Abu-Zeinah1, Maria Caterina Putti3, Nicolas Boissel4, Maria Luigi Randi3, Linda Resar5, Martin Griesshammer6, Jean-Jacques Kiladjian4

Abstract

Classical myeloproliferative neoplasms (MPNs) are being identified more frequently in adolescents. There is no guidance on the healthcare transition of young MPN patients from pediatric to adult medicine. Therefore, we convened an international panel of experts in both pediatric and adult MPN care to develop three tools to facilitate high-quality healthcare transition: a physician education tool, a transition readiness assessment tool, and a consensus statement of practice recommendations to ensure a more seamless transition in the care adolescents receive. These tools can help ensure a better healthcare transition for young patients. The next steps include evaluating the readiness assessment tool with adolescent patients.

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The role of psychosocial adjustment in the quality of life of patients with myeloproliferative neoplasms

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March 7, 2025

A.A.M. Eppingbroek, L. Lechner, E.C. Bakker, M.D. Niijkamp, M.A. de Witte, C.A.W. Bolman

Abstract

Purpose

Myeloproliferative neoplasms (MPNs) can cause a high symptom burden that negatively affects quality of life (QoL). The way patients deal with their disease and how this impacts their QoL is important to understand, yet virtually unknown. The aim of this study is to investigate whether and how psychosocial adjustment affects QoL in MPN patients.

Methods

A longitudinal study was conducted in 338 MPN patients to investigate whether and how baseline measurements of psychosocial adjustment could predict QoL outcomes six months later. Psychosocial adjustment to illness was operationalized by: coping, self-management, resilience and illness identity (II). We tested the hypotheses that high scores on respectively problem-solving coping, self-management, resilience, II-subscales acceptance and enrichment, and low scores on II-subscales rejection and engulfment are associated with high scores on QoL. We performed a multiple hierarchical regression analysis including sociodemographic and disease-related variables and baseline QoL as control variables.

Results

II-subscale engulfment had the most pronounced negative impact on QoL (β.47, p<.001). After the introduction of the control variables, the effect of engulfment remained statistically significant (β.16, p<.01). Additionally, baseline QoL (β.32, p<.001), treatment option wait-and-see (β.11, p<.05), and MPN symptom burden at T2 (β.36, p<.001) demonstrated significance. The other variables measuring psychosocial adjustment did not relate significantly to QoL.

Conclusion

The findings of this study illustrate the significant adverse effect of engulfment on patients’ QoL, underscoring the importance of providing psychosocial guidance to mitigate the patients’ feelings of being overwhelmed by the disease.

New MF Study Recruiting Participants for Its Phase 3 Portion

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Özge Özkaya, MSc, PhD
Publish Date

A phase 1/3 clinical trial testing the safety and efficacy of selinexor plus ruxolitinib in patients with myelofibrosis (MF) who are Janus kinase (JAK) inhibitor-naïve is now recruiting participants for its phase 3 portion.

The global, multicenter, 2-part study aims to recruit an estimated 350 participants with MF. Participants were all at least 18 years of age.

The study consists of an experimental phase 1a, experimental phase 1b, and experimental phase 3 portion.

In the experimental phase 1a portion, 1 group of patients were given 40 mg of oral selinexor once a week on days 1, 8, 15, and 22 of each 28-day cycle together with 15 or 20 mg of ruxolitinib twice a day based on their platelet count at baseline while another group was given 60 mg of oral selinexor on the same days and the same dose of ruxolitinib as the first group.

In the experimental phase 1b, patients were given either 40 or 60 mg of oral selinexor once a week on days 1, 8, 15, and 22 of each 28-day cycle and the same dose of ruxolitinib.

In the experimental phase 3 portion, patients will either be given a fixed starting dose of 60 mg of oral selinexor or a placebo once a week on days 1, 8, 15, and 22 of each 28-day cycle together with the same dose of ruxolitinib.

The primary outcome measures of the phase 1 portion of the trial was the maximum tolerated dose and recommended phase 2 dose of selinexor and the number of participants with adverse events by severity, nature, and occurrence.

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