Novel Targets Beyond the JAK-STAT Pathway Aim to Push Myelofibrosis Treatment Forward

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Jax DiEugenio

Ongoing research in myelofibrosis continues to focus on agents directed at novel targets with the hope of expanding treatment options beyond the host of JAK inhibitors used in this treatment paradigm, according to Anthony M. Hunter, MD.

“[There are] a lot of novel agents on the horizon [that could] work in combination with JAK inhibitors to hopefully continue to move that bar forward for patients [with myelofibrosis,” said Hunter, who is an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and the medical director of the Immediate Care Center at Winship Cancer Institute of Emory University in Atlanta, Georgia.

In an interview with OncLive®, Hunter explained the evolving understanding of the biology of myelofibrosis, detailed the growth of JAK inhibitors being used for the treatment of these patients, and expanded on novel targets and agents currently being tested in clinical trials.

OncLive: How has our understanding of the pathology of myelofibrosis evolved in recent years as more research studies have been conducted?

Hunter: What has been well documented for years now is that the key biologic pathway or cell-signaling pathway actually involved in myeloproliferative neoplasms [MPN] or myelofibrosis is the JAK-STAT pathway. That [understanding] was advanced in 2005 when we found out about the JAK2 mutation in a large percentage of these patients, [and we] subsequently [found out about] the MPL and CALR mutations, as well. We find that in all patients with MPN or myelofibrosis, irrespective of those mutations, we see activation of this JAK-STAT signaling pathway, which has a lot of different effects and we can break those up into effects on hematopoiesis, or how they affect sort of blood cell production.

Then we also see increases in inflammatory cytokine signaling. The JAK/STAT pathway signals through a lot of cytokine and inflammatory receptors, so we see a lot of inflammatory signaling increase in a number of different cytokine levels and in myelofibrosis, which impacts the disease and the symptoms that we see. That has been key to [understanding] the biology [of myelofibrosis] and has led to the development of JAK inhibitors.

We’ve started to move beyond [the JAK-STAT] pathway a little bit, as well. A lot of the research now and new agents that are being explored in clinical trials are largely looking at non–JAK inhibitor agents, combining other pathways such as BET inhibitors, various other signaling molecules, and anti-fibrotic type compounds. All of those have additional roles, along with the JAK-STAT pathway in myelofibrosis.

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Pooled Analysis Shows Cytoreduction to Be Safe, Tolerable in Younger Patients With PV

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Ashling Wahner

Cytoreductive therapy with interferon alfa (rIFNα) or hydroxyurea is safe and well tolerated in patients with polycythemia vera (PV) under the age of 60 years and induces annualized discontinuation rates comparable to those reported with these agents in older patients with PV, for whom cytoreductive therapy is routinely used, according to findings from a meta-analysis that were published in Blood Advances.1

Across the 14 studies included in this analysis, rIFNα discontinuation rates ranged from 4.6% to 37% over median durations of 0.4 to 6.3 years. Hydroxyurea discontinuation rates ranged from 2.6% to 17% over median durations of 0.5 to 14 years.

Although the use of cytoreductive agents, such as rIFNα and hydroxyurea, is associated with reduced thrombosis risk in PV, these agents are not routinely recommended by the European LeukemiaNet (ELN) or the National Comprehensive Cancer Network (NCCN) for patients with PV under the age of 60 years. The ELN recommends cytoreductive therapy for patients with PV who are younger than 60 years of age and have not had prior thrombotic events provided that they have strictly defined phlebotomy intolerance, symptomatic progressive splenomegaly, persistent or progressive leukocytosis, extreme thrombocytosis, persistently high cardiovascular risk, inadequate hematocrit control requiring phlebotomies, and/or persistently high symptom burden.2 The NCCN does not recommend cytoreductive therapy as initial treatment for patients with low-risk disease.3

“Unfortunately, effective and potentially life-prolonging cytoreductive therapy is often deferred in younger patients who are considered ‘low-risk’ because of their age and lack of thrombosis history,” senior study author Ghaith Abu-Zeinah, MD, an instructor in medicine at Weill Cornell Medical College and an assistant attending physician at the NewYork Presbyterian Hospital in New York, New York, and coauthors, wrote in the paper.1 “The rationale for withholding cytoreductive therapy is data-sparse and driven by theoretical concerns for toxicity and unknown benefits from early treatment. Yet, there is some evidence that early treatment is both well tolerated and potentially useful.”

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Momelotinib Improves Anemia in JAK Inhibitor-Naive Myelofibrosis

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Sabrina Serani

Treatment with momelotinib (Ojjaara) delivered benefits to anemia among patients with myelofibrosis who were naive to JAK inhibitors, regardless of their baseline hemoglobin level. Further, momelotinib provided significant anemia benefits compared with ruxoltinib (Jakafi), according to an analysis from the phase 3 SIMPLIFY-1 study (NCT01969838).

SIMPLIFY-3 randomized 432 patients with myelofibrosis who had not received JAK inhibitors toreceive momelotinib or ruxolitinib.In patients who were anemic and received momelotinib, mean hemoglobin levels increased by weeks 2 to 4 of treatment, and hemoglobin levels remained stable among patients who were not anemic.

Comparatively, patients who were anemic and nonanemictreated with ruxolitinib experienced an initial decrease in mean hemoglobin. This decrease stabilized after weeks 4 to 6 as patients received red blood cell transfusions. Patients receiving ruxolitinib were permitted to cross over to the momelotinib group, and mean hemoglobin levels increased after this change.

The study also evaluated patients at different levels of anemia. Among patient who were mildly anemic, with ahemoglobin levelbetween 10 and 12 g/dL, 90.4% of patients were transfusion-free at baseline, 93.9% of these patients remained transfusion-free while receiving momelotinib. Four patients who were not transfusion-free at baseline became transfusion-free while on treatment. In contrast, patients who were mildly anemic in the ruxolitinib arm became more dependent on transfusion; 50% of patients who were transfusion-free at baseline required a transfusion while on ruxolitinib.

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Serum Albumin Levels May Predict Survival Among Patients With Myelofibrosis Treated With Ruxolitinib

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Jonathan Goodman, MPhil

Serum albumin may function as a dynamic surrogate marker for clinical outcomes among patients with myelofibrosis treated with ruxolitinib, according to research published in JCO Precision Oncology. The utility of this surrogate measure may, however, vary by a given patient’s treatment status.

Previous work has established ruxolitinib, a JAK inhibitor, as a standard of care among patients with myelofibrosis. Yet although this treatment may help to reduce spleen size and symptom burden, it is unclear whether it improves overall survival (OS) rates.

New models, such as the RR6 model, have aimed to provide a prognostic surrogate measure for OS, though whether these models effectively distinguish high-risk disease from cases where there is no response to treatment is unclear. For this study, researchers aimed to evaluate whether serum albumin — which is linked with an anti-inflammatory response to treatment — is an effective surrogate marker for OS among patients with myelofibrosis.

Overall, data from 396 patients were included. In the cohort, among evaluable patients, 91 had received ruxolitinib while 305 were naïve to treatment, 58% of patients were male sex, and 72% of patients had primary myelofibrosis.

Analysis suggested that serum albumin levels frequently dropped among all patients, though this was less pronounced among patients treated with ruxolitinib. Relatedly, patients with a high serum albumin level at baseline had improved median OS periods (53.5 months) compared to patients with low levels (29.8 months; odds ratio, 1.95; P <.001).

The link between serum albumin levels and OS was independent of variables included in the dynamic international prognostic scoring system, though only among patients who were naïve to ruxolitinib.

Future efforts to incorporate serum albumin with other inflammatory markers into an inflammatory index and assess its relevance in the context of other JAK inhibitors and combinations are ongoing.

Furthermore, among patients treated with ruxolitinib, changes in serum albumin levels predicted OS. Among patients with stable levels or an increase, median OS was 82.7 months, compared with 64.1 months among patients with a decrease (P =.04).

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Individualized Approaches and Challenges in Myelofibrosis

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Raajit Rampal, MD, PhD

Raajit K. Rampal, MD, PhD, hematologic oncologist at Memorial Sloan Kettering Cancer Center, discusses how the field of gene therapy and precision medicine is evolving in the context of myelofibrosis treatment. He also explains how treatment decisions are individualized for patients with myeloproliferative neoplasms, including myelofibrosis.

Rampal presented on this topic and more at the Fifth Annual Miami Cancer Institute Global Summit on Immunotherapies for Hematologic Malignancies, hosted by Dr. Guenther Koehne and Miami Cancer Institute.

In addition, Rampal discusses some of the unmet needs that exist in this space, including the need for disease-modifying therapy in this interview with Targeted OncologyTM.

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Genetics and Genetic Testing to Inform Myelofibrosis Clinical Management

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by Charles Bankhead, Senior Editor, MedPage Today May 1, 2024

The history of primary myelofibrosis dates back to 1951 and the description of four distinct clinicopathologic entitiesopens in a new tab or window that came to be known as myeloproliferative neoplasms (MPNs): chronic myeloid leukemia (CML), polycythemia vera, essential thrombocythemia, and myelofibrosis.

Discovery of the Philadelphia (Ph) chromosome in 1960opens in a new tab or window paved the way to identification of BCR/ABL as the principal genetic driver of CML. Another 45 years passed before the discovery of a first genetic driver of non-Ph MPNs, a mutation in the Janus kinase 2 (JAK2) gene,opens in a new tab or window which occurs in 50-60% of myelofibrosis cases.

“The identification of that particular pathway was foundational, and it has changed the face of how we treat patients,” said James Rossetti, DO, of the University of Pittsburgh. “The JAK2 mutation is not present in everyone with myelofibrosis, and there are other mutations as well.”

Researchers identified a third key driver in 2013opens in a new tab or window: calreticulin gene (CALR). The mutation is associated with about 25% of myelofibrosis cases.

Most studies have shown that JAK2, MPL, and CALR are mutually exclusiveopens in a new tab or window and do not occur together. However, a few studies have shown co-occurrence of the three key mutations. Even though JAK2, MPL, and CALR usually do not occur together, numerous other mutations have been identified in association with the three primary mutations. As many as 80% of patients with myelofibrosisopens in a new tab or window have one or more other mutations.

Historically, myelofibrosis treatment was palliative in nature, aimed at relieving specific symptoms. The discovery of the JAK2 driver mutation has transformed treatment. Since 2011 four JAK2 inhibitors have received FDA approval: ruxolitinib (Jakafi)opens in a new tab or window, fedratinibopens in a new tab or window (Inrebic), pacritinibopens in a new tab or window (Vonjo), and momelotinibopens in a new tab or window (Ojjaara). All four drugs demonstrated ability to reduce splenomegaly, a major clinical manifestation of myelofibrosis, as well as symptoms.

Some of the co-occurring mutations are targetable, creating interest in combination therapies that simultaneously target different signaling pathways, said Aaron Gerds, MD, of the Cleveland Clinic. One such combination was evaluated in a clinical trial that paired a JAK2 inhibitor with an IDH2 inhibitor.

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Direct and indirect costs for patients with myeloproliferative neoplasms

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Jingbo Yu, James Nelson, Taylor Marlin, Evan Braunstein, & Michelle Jerry

Abstract

Myeloproliferative neoplasms (MPNs) are associated with substantial healthcare resource use and productivity loss. This retrospective cohort analysis used disability leave and medical claims data to measure direct and indirect healthcare costs associated with MPNs. The analysis included 173 patients with myelofibrosis (MF), 4477 with polycythemia vera (PV), 6061 with essential thrombocythemia (ET), and matched controls (n = 519, n = 13,431, and n = 18,183, respectively). Total healthcare costs were significantly higher for cases versus controls in each cohort (mean cost difference: MF, $67,456; PV, $10,970; ET, $22,279). Cases were more likely than controls to take disability leave and incurred higher disability-related costs. Among subgroups with thrombotic events, direct and indirect costs were higher for cases versus controls. Thrombotic events substantially increased direct costs and disability leave for patients with PV or ET compared with the full PV or ET cohorts. These findings demonstrate increased economic burden for patients with MPNs.

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Lack of Mutations Associated With Favorable Prognosis in MPN-U

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Laura Joszt, MA

Among patients with myeloproliferative neoplasm, unclassifiable (MPN-U), bone marrow blast and the Dynamic International Prognostic Scoring System (DIPSS) plus score can predict overall survival (OS), according to a study published in American Journal of Clinical Pathology.1 In addition, the study found that the lack of certain mutations seemed to be associated with a better prognosis.

MPN-U is a type of MPN that doesn’t fit one of the other types of MPNs, such as chronic myelogenous leukemia (CML), myelofibrosis (MF), essential thrombocythemia (ET), or polycythemia vera (PV).2 Janus kinase (JAK) mutations are often present in PV, ET, and primary MF; MPL or CALR mutations are often present in ET and primary MF; and chromosome errors are present in patients with CML.2

This study identified additional potential poor prognostic markers for patients with MPN-U, which is important as MPN-U is a heterogeneous category with features that typically preclude classification. MPN-U cases show “a range of clinicopathologic presentations and differences in prognosis depending on the stage of disease,” the authors explained. “Creating further challenges, MPN-U cases remain relatively understudied.”

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A Grand Time in Grand Rapids

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MPN Advocacy & Education International held an in-person patient/caregiver event in Grand Rapids, Michigan on April 25th. The room buzzed with excitement and camaraderie as patients and caregivers had the opportunity to engage with each other and MPN experts on a wide range of topics. 

Dr. Anas Al-Janadi gave an overview of the history of MPNs and defined where we are in our current understanding of the disease and what the future may hold. While exciting discoveries were made that supported the development of drug therapies for MPN patients; such as the JAK2 mutation in 2005 and later the MPL and CALR mutations, the MPN community is still working to better understand the reasons for disease progression and ways to reduce symptom burden.

Dr. Kristin Pettit, on the heels of her wedding (Congrats, Dr. Pettit), discussed the challenges MPN patients have flying, having elective or emergency surgeries, symptom management, and some critical women’s issues. Each topic had the following take-aways: check with your doctor and practice good self-care. Dr. Pettit emphasized hydration, healthy eating, exercise and reducing stress.

Dr. Aaron Gerds shared a play-by-play of diagnosing and treating MPNs. He began by situating ET, PV, and MF on the greater spectrum of Myeloid Neoplasms. Dr. Gerds, along with the other experts that presented, stressed the importance of a good clinical examination including a thorough history and a hands-on physical examination. Gerds went on to describe the testing required to make a proper MPN diagnosis, such as; blood counts, chemistries, infectious disease, bone marrow biopsy, and molecular testing. Afterwards, he walked us through the process of navigating individual risk and treatment options using the National Comprehensive Cancer Network (NCCN) Guidelines for Myelofibrosis. 

Justin Grinell, owner and head trainer of State of Fitness, reminded us that our health is not our fault, but it is our responsibility. He shared some ways to move toward a healthy lifestyle by incorporating an 11 min movement break in our day. To take just 11 minutes each day doing something active at your own Zone 2 (when your heart rate is 180 minus your age) can have an accumulative positive effect on not just your body but on your brain as well. Be sure to look for Justin this summer during our Healthy Summer Series webinars where you can join Justin for a quick lunch-time workout. 

Finally, Dr. Craig Kessler implored patients to ask questions. Ask your doctor questions about the treatment plan they create for you. Ask what component of MPN symptoms they are focusing on, and how the treatment they recommend will address that component (anemia, blood counts, spleen reduction, etc.). He stressed getting your COVID-19 vaccine and boosters. He also made clear that your questions matter and not to be afraid to ask.

We want to thank the specialists for sharing their valuable information and spending their time away from their respective institutions. We also want to thank our patients and their family members and friends for joining us and asking such thought-provoking questions. We hope that you will have a chance to join us at our next MPN Advocacy and Education International in-person event in Asheville, NC on Thursday August 22nd. To learn more, please visit www.mpnadvocacy.com/events-list.

Dr Sekeres on the Rationale for the FDA Approval of Momelotinib in Myelofibrosis

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Mikkael A. Sekeres, MD, MS

Mikkael A. Sekeres, MD, MS, professor, medicine, chief, Division of Hematology, Leukemia Section, the University of Miami Health System, Sylvester Comprehensive Cancer Center, discusses the background on the FDA approval of momelotinib (Ojjaara) for the treatment of patients with anemic myelofibrosis.

At a recent OncLive® State of the Science Summit™ on hematologic malignancies, Sekeres and colleagues provided updates in the realm of myelodysplastic syndromes. Notably, one of these updates includes the FDA approval of momelotinib for the treatment of adult patients with intermediate or high-risk myelofibrosis with anemia. Originally, the phase 3 SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268) trials investigated momelotinib compared with ruxolitinib (Jakafi) and momelotinib compared with best available therapy, respectively, Sekeres begins. In SIMPLIFY-2, although patients receiving momelotinib didn’t show a significant improvement in spleen response, they experienced a notable enhancement in symptom score, a benefit that is crucial for patients with myelofibrosis, he reports.

Subsequently, the phase 3 MOMENTUM trial (NCT04173494) was initiated, randomly assigning symptomatic patients with myelofibrosis in a 2:1 ratio to receive either momelotinib or danazol. Notably, significant improvement in symptom scores was observed with momelotinib, Sekeres states, saying that furthermore, substantial improvement in spleen size reduction was noted, forming the basis for momelotinib’s FDA approval. Additionally, there was a trend toward enhanced red blood cell transfusion independence rates among patients, Sekeres adds.

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