Anthony M. Hunter, MD, discusses the development of, and future roles  for JAK, BET, and BCL2/BCL-XL inhibitors in myelofibrosis. 

Dr Hunter on the Development of Targeted Approaches Beyond JAK Inhibition in Myelofibrosis

“We’re already excited that we’ve got four JAK inhibitors to pick from, but now [we’re] moving beyond that pathway. [This] is great for trying to improve outcomes, [because] we know that JAK inhibitors do have their limitations. The 2 that have had the most press recently are pelabresib and navitoclax.”

Anthony M. Hunter, MD, assistant professor, Department of Hematology and Medical Oncology, Emory University School of Medicine, medical director, Immediate Care Center, Winship Cancer Institute of Emory University, shares his insights on the ongoing development of, and potential future roles for, JAK, BET, and BCL2/BCL-XL inhibitors in myelofibrosis.

Hunter begins by stating that 4 JAK inhibitors have been approved by the FDA for the treatment of patients with myelofibrosis: ruxolitinib (Jakafi), fedratinib (Inrebic), pacritinib (Vonjo), and momelotinib (Ojjaara). However, ongoing research aims to address the limitations associated with this drug class and improve patient outcomes, he notes.

Two inhibitors on the rise for myelofibrosis include the BET inhibitor pelabresib (CPI-0610), and the BCL2 and BCL-XL inhibitor navitoclax (ABT-263), Hunter details. He adds that both pelabresib and navitoclax have been explored in combination with ruxolitinib in prior phase 3 trials, including the MANIFEST-2 (NCT04603495) and TRANSFORM-1 (NCT04472598) studies, respectively.

 were presented, demonstrating a 35% or greater reduction in spleen volume at week 24 (SVR35W24) in 65.9% of patients treated with frontline pelabresib plus ruxolitinib (n = 214) vs 35.2% in those treated with ruxolitinib plus placebo (n = 216). 

 have shown that the navitoclax plus ruxolitinib produced significant reductions in spleen volume. At a median follow-up of 14.9 months (range, 0-29.5), 63.2% of patients treated with navitoclax/ruxolitinib had a SVR35W24 compared with 31.5% of those treated with ruxolitinib plus placebo. 

The MANIFEST-2 and TRANSFORM-1 trials both met their primary end points of SVR35W24, Hunter explains. Still, significant improvements regarding symptomatology were not established in these trials; therefore, more data and long-term follow-up are needed for both pelabresib and navitoclax, he concludes.

Videos

Anthony M. Hunter, MD, discusses challenges associated with ruxolitinib-based toxicities in patients with myelofibrosis.

Dr Hunter on the Management Ruxolitinib-Associated AEs in Myelofibrosis

Anthony M. Hunter, MD, assistant professor, Department of Hematology and Medical Oncology, Emory University School of Medicine, medical director, Immediate Care Center, Winship Cancer Institute of Emory University, discusses challenges associated with the management of ruxolitinib (Jakafi)-associated toxicities in patients with myelofibrosis.

Ruxolitinib-based regimens have been a cornerstone treatment for patients with myelofibrosis for over a decade. Prior research has demonstrated the agent's ability to significantly reduce splenomegaly and generally improve symptomatology, Hunter begins. However, one of the major limitations in routine clinical practice is the drug's propensity to cause cytopenias, Hunter says, adding that a considerable drop in both hemoglobin and platelet counts is observed in the majority of patients treated with ruxolitinib. Typically, hemoglobin levels can decrease by approximately 1.5 g within the first 8 to 12 weeks of treatment, after which they may stabilize and improve slightly, he explains. Nonetheless, some degree of persistent drug-related anemia is common, along with a dose-dependent decrease in platelet counts, Hunter notes.

These hematological adverse effects (AEs) can significantly impact treatment decisions, particularly in patients with different phenotypes of myelofibrosis, Hunter continues. For example, patients with a more proliferative phenotype characterized by significant splenomegaly and elevated counts may tolerate ruxolitinib better vs those with a cytopenic phenotype who already have low baseline blood counts, Hunter explains. In the latter group, exacerbating existing cytopenias complicates treatment.

Overall, the need to manage cytopenias carefully while maintaining effective dosing of ruxolitinib poses a challenge for clinicians. In real-world clinical practice, especially in community settings, these cytopenias often necessitate dose reductions and sometimes early cessation of therapy, which can adversely affect patient outcomes and survival, Hunter concludes.

Dr Hunter on the Management Ruxolitinib-Associated AEs in Myelofibrosis  

Dr Hunter on the Evolution of Pathology in Myelofibrosis

Anthony M. Hunter, MD, assistant professor, Department of Hematology and Medical Oncology, Emory University School of Medicine, medical director, Immediate Care Center, Winship Cancer Institute of Emory University, discusses 

the evolution of pathology in myelofibrosis

 based on outcomes from ongoing clinical trials.

It has long been established that the key biological or cell-signaling pathway involved in myeloproliferative neoplasms (MPNs) and myelofibrosis is the JAK-STAT pathway, Hunter begins. This understanding significantly advanced in 2005 with the discovery of the 

 mutation present in a large percentage of patients with these diseases, he says. Regardless of these specific mutations, all patients with MPNs or myelofibrosis exhibit activation of the JAK-STAT signaling pathway, which affects various aspects of hematopoiesis, or blood cell production, Hunter explains.

In addition to its role in hematopoiesis, the JAK-STAT pathway is linked to increased inflammatory cytokine signaling, he continues. This pathway signals through numerous cytokine and inflammatory receptors, leading to elevated levels of inflammatory signaling and various cytokines in myelofibrosis, Hunter says. Understanding this biological pathway has been crucial and has driven the development of JAK inhibitors as a treatment strategy, according to Hunter. JAK inhibitors have become a cornerstone in the management of myelofibrosis, providing significant symptom relief and improving the quality of life for many patients, he notes.

However, current research is expanding beyond the JAK-STAT pathway, Hunter expands. New agents being explored in clinical trials focus on non–JAK inhibitor treatments that target additional pathways, such as BET inhibitors, various other signaling molecules, and anti-fibrotic compounds, he adds. These emerging therapies may complement the role of the JAK-STAT pathway in myelofibrosis, offering broader treatment options and addressing other aspects of the disease, Hunter says. By exploring these alternative pathways, researchers hope to develop more comprehensive treatment strategies that can better manage the complex biology of myelofibrosis and improve outcomes for patients, Hunter concludes.

Anthony M. Hunter, MD, discusses the evolution of pathology in myelofibrosis based on outcomes from clinical trials.

Anthony M. Hunter, MD, assistant professor, Department of Hematology and Medical Oncology, Emory University School of Medicine, medical director, Immediate Care Center, Winship Cancer Institute of Emory University, discusses the evolution of JAK inhibitors in myelofibrosis, a topic that 

was highlighted in a presentation at the 2023 SOHO Annual Meeting

The primary objective of the presentation was to delve into the historical and emerging data regarding JAK inhibitors, he begins. JAK inhibitors have had a part in the therapeutic arsenal for myelofibrosis for approximately 12 years, starting with the introduction of ruxolitinib (Jakafi). However, there has been a notable expansion in the range of available options, such as 

momelotinib (Ojjaara), which was approved by the FDA in September 2023

 for patients with intermediate- or high-risk primary or secondary myelofibrosis and anemia.

In the presentation, Hunter assessed the data related to the clinically available and forthcoming JAK inhibitors, exploring the unique distinctions among them and identifying their potential roles within specific patient subgroups, as well as the practical aspects of utilizing these drugs. One of the key elements of JAK inhibitors that sets them apart from other agents is their suitability for patients with baseline low blood counts or cytopenias, Hunter emphasizes. Treatment alternatives are emerging for patients with cytopenias, who have historically been difficult to treat with original JAK inhibitors. Pacritinib (Vonjo) is designed for patients with lower platelet counts, specifically those with platelet counts less than 50 x 109/L, a group that had been historically excluded from JAK inhibitor treatment, he explains. Furthermore, data indicate that pacritinib may have the potential to ameliorate anemia in these patients. In addition, data have shown improved outcomes with momelotinib vs danazol in patients with anemia, Hunter continues.

A pivotal factor in choosing between JAK inhibitors for patients with myelofibrosis is the presence of baseline cytopenias. Overall, these agents exhibit substantial spleen response and symptom reduction, he says. However, there is a lack of comprehensive data to guideoncologists on which specific patient subgroups should transition between JAK inhibitors, aside from patients with cytopenias in the frontline setting, Hunter says. Therefore, the rest of these agents remain viable options across the myelofibrosis population, he concludes.

Anthony M. Hunter, MD, discusses the evolution of JAK inhibitors in myelofibrosis, a topic that was highlighted in a presentation at the 2023 SOHO Annual Meeting.


Dr Hunter on the Ongoing Investigation into JAK Inhibitors in Myelofibrosis

Following the FDA approvals of the JAK inhibitors (JAKi) ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo), the treatment landscape of myelofibrosis (MF) continues to grow with the use of these agents with an additional FDA review planned for momelotinib in September 2023.

With multiple JAKi now options in this treatment space , patient- and disease-specific factors are vital when determining the most appropriate therapy plans. Symptom and spleen assessments, the presence of cytopenias, and risk stratification are key factors to consider prior to treatment with a JAKi. Moreover, hematopoietic stem cell transplant candidacy should be considered at diagnosis, as this remains the only potentially curative therapy for patients with MF. Patients with significant symptomatology, should be assessed for clinical trials. However, in the absence of a suitable clinical trial, treatment with a JAKi is the standard of care in this setting.

JAKi have consistently demonstrated improvements in splenomegaly and disease-related symptoms, with long-term follow-up also showing an overall survival benefit. Ruxolitinib has the longest track record of both safety and success, initially demonstrated by the COMFORT trials (NCT00952289, NCT00934544).1,2 However, cytopenias can be a challenge, and real-world data have highlighted the frequency of ruxolitinib dose interruptions and early treatment discontinuation. In the COMFORT studies, half of patients had discontinued treatment by 3 years,3 whereas real-world data have demonstrated a median duration of treatment as low as 13 months.4 Novel ruxolitinib dosing strategies in patients with anemia may improve tolerability,5 and anemia-directed therapies can also be employed. Nonetheless, pretreatment or treatment-emergent anemia and/or thrombocytopenia remain complicating factors.

Excitingly, new JAKi are emerging, with the potential to extend the benefit of JAKi to cytopenic patients with MF. Pacritinib has recently been approved for patients with a platelet count of less than 50, a group for whom prior JAKi were contraindicated based on the FDA label. Momelotinib is an emerging agent that inhibits ACVR1, in addition to JAK1 and JAK2, resulting in improvements in erythropoiesis. Indeed, the MOMENTUM study (NCT04173494) has demonstrated improvements in anemia, as well as MF-associated symptoms and spleen size, compared with danazol in patients previously treated with a JAKi.6 Recently, inhibition of ACVR1 has also been demonstrated with pacritinib, with potential for anemia improvement with this agent.

Although outcomes following ruxolitinib discontinuation are historically poor, several studies have demonstrated efficacy in JAKi-pretreated patients. Fedratinib, pacritinib, and momelotinib have all demonstrated activity in patients previously treated with ruxolitinib, as well as the frontline setting.6-9 As the armamentarium of JAKi grows, further investigation will be needed to determine appropriate treatment selection within subgroups of patients, as well as optimal sequencing of these agents.

Although additional JAKi remain in development, such as jaktinib, innovative approaches using a JAKi as a backbone in combination with agents targeting pathways beyond the JAK/STAT pathway have become a primary focus in MF drug development. Numerous studies are ongoing, including several phase 3 trials evaluating novel combination strategies compared with ruxolitinib alone in JAKi-naïve patients. Promising agents include those targeting BET proteins (pelabresib; CPI-0610), BCL-XL/BCL-2 (navitoclax; ABT-263), and MDM2 (navtemadlin; KRT-232). Telomerase inhibitors (imetelstat; Geron) and agents targeting the bone marrow microenvironment or alternative signaling pathways are also under investigation. Importantly, moving beyond classical end points of spleen and symptom reduction, trials are beginning to incorporate overall survival and other potential markers of disease-modifying activity, such as reductions in bone marrow fibrosis and clonal burden.

In summary, JAKi have remained the foundation in MF therapy, with numerous studies demonstrating their efficacy. Dose-limiting cytopenias and limited disease-modifying activity have contributed to treatment discontinuation due to disease evolution or adverse effects. Novel JAKi and combination approaches have emerged or are currently under investigation to overcome these shortcomings. Additional research will be paramount to establish the optimal frontline and subsequent treatment approaches in patients with MF in this new era.

Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. 

. 2012;366(9):799-807. doi:10.1056/NEJMoa1110557

Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. 

. 2012;366(9):787-798. doi:10.1056/NEJMoa1110556

Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. 

. 2017;10(1):55. doi:10.1186/s13045-017-0417-z

Passamonti F, Heidel FH, Parikh RC, et al. Real-world clinical outcomes of patients with myelofibrosis treated with ruxolitinib: a medical record review. 

. 2022;18(18):2217-2231. doi:10.2217/fon-2021-1358

Cervantes F, Ross DM, Radinoff A, et al. Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study. 

. 2021;35(12):3455-3465. doi:10.1038/s41375-021-01261-x

Verstovsek S, Gerds AT, Vannucchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. 

. 2023;401(10373):269-280. Published correction appears in 

Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. 

. 2017;4(7):e317-e324. doi:10.1016/S2352-3026(17)30088-1

Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. 

. 2018;5(2):e73-e81. doi:10.1016/S2352-3026(17)30237-5

Gerds AT, Savona MR, Scott BL, et al. Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis. 

. 2020;4(22):5825-5835. doi:10.1182/bloodadvances.2020003314

Articles

Following the FDA approvals of the JAK inhibitors ruxolitinib, fedratinib, and pacritinib, the treatment landscape of myelofibrosis continues to grow with the use of these agents with an additional FDA review planned for momelotinib in September 2023.

JAK Inhibitors Continue to Shape the Treatment Landscape of Myelofibrosis 

Anthony M Hunter, MD, assistant professor, Department of Hematology and Medical Oncology Emory University School of Medicine, medical director, Immediate Care Center, Winship Cancer Institute of Emory University, discusses the current treatment landscape with JAK inhibitors in myelofibrosis.

At the 2023 SOHO Annual Meeting, Hunter presented factors to consider when selecting a JAK inhibitor when treating a patient with myelofibrosis. Hunter explains that not all patients require a JAK inhibitor. For those who do require a JAK inhibitor, Hunter emphasizes that the optimal JAK inhibitor use remains ruxolitinib (Jakafi) in the frontline proliferative setting, pacritinib (Vonjo) in the frontline cytopenic setting, and either fedratinib (Inrebic), momelotinib, pacritinib, or other novel agents following ruxolitnib progression.

Patients could become intolerant to a JAK inhibitor or become resistant or refractory to a treatment, Hunter says, adding that, historically, these patients have poor overall survival outcomes. Although the JAK/STAT pathway is critical in the pathogenesis of myelofibrosis, the overall mechanisms for JAK inhibitors in the treatment of these patients are not fully understood yet, he explains. However, there are many other viable signaling pathways to target for this patient population, including the PI3K or the RAS/MAPK pathway, which are activated in myelofibrosis, Hunter emphasizes.

Historically, following progression on or after ruxolitinib, patients typically have a very short overall survival prognosis, specifically with the previous lack of beneficial treatment options within this landscape, Hunter continues. With the advent of multiple emerging JAK inhibitors that have been approved or are under development, the future remains bright, with many of these new agents now being investigated in the second-line, post-ruxolitinib setting. With more options available, there is now a chance to treat some patients with another JAK inhibitor. Ongoing clinical trials are also an option for patients following ruxolitinib, and these studies remain important for this patient population, he concludes.

Anthony M Hunter, MD, discusses the current treatment landscape with JAK inhibitors in myelofibrosis.


Anthony M Hunter, MD

Articles

Dr Hunter on the Development of Targeted Approaches Beyond JAK Inhibition in Myelofibrosis

Dr Hunter on the Management Ruxolitinib-Associated AEs in Myelofibrosis

Dr Hunter on the Evolution of Pathology in Myelofibrosis

Dr Hunter on the Ongoing Investigation into JAK Inhibitors in Myelofibrosis

JAK Inhibitors Continue to Shape the Treatment Landscape of Myelofibrosis

Dr Hunter on the Current Treatment Landscape of JAK Inhibitor Treatment in Myelofibrosis