Myelofibrosis (MF), the most aggressive myeloproliferative neoplasm (MPN), is witnessing a meteoric rise in the clinical development of novel treatments in light of the dramatic impact of ruxolitinib (Jakafi) and other advancements. Ruxolitinib was the first JAK1/2 inhibitor that received regulatory approval and became the cornerstone MF treatment by improving quality of life and significantly prolonging survival of patients with MF.^1,2 Fedratinib (Inrebic), the second JAK2 inhibitor that received regulatory approval in 2019, may be a good second-line option for ruxolitinib-resistant patients with intermediate-2 and high-risk MF.³ Notably, the unmet need of severely thrombocytopenic patients with intermediate- or high-risk MF was addressed with the recent regulatory approval of pacritinib (Vonjo), a JAK2/IRAK1 inhibitor.^4,5

Splenomegaly, anemia, and constitutional symptoms are hallmarks of MF. Momelotinib, the first JAK1/2 inhibitor with the exclusive attribute to simultaneously improve anemia by suppressing hepcidin expression in the liver via ACVR1/ALK2 inhibition⁶ while also improving splenomegaly and constitutional symptoms, is in advanced clinical development for anemic and symptomatic patients with MF. Momelotinib demonstrated significant improvements in anemia measures, spleen size, and symptoms⁷ in the ongoing pivotal phase 3 MOMENTUM trial (NCT04173494)⁸ evaluating JAK-inhibitor treated, symptomatic, and anemic patients with MF. Momelotinib’s marked anemia benefits, including achievement of red blood cell (RBC) transfusion independence^7,9 appear to underlie prolongation of survival in those with MF.¹⁰ Momelotinib may receive regulatory approval as a treatment for anemic patients with MF in the near future.

Notwithstandingthe remarkable benefits of JAK inhibitors,¹¹ many novel treatments, acting through various mechanisms, are being explored either as single agents or in combination with ruxolitinib.¹² Design and development of new strategies to treat MF aim at addressing unmet therapeutic needs, including suboptimal response or resistance to JAK inhibitors, cytopenias, progressive disease, achieving deeper spleen and symptom responses, prolongation of survival, and disease modification.^13-18

During the MPN session at the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022), Srdan Verstovsek, MD, PhD, United Energy Resources, Inc, Professor of Medicine and hematologist oncologist at The University of Texas MD Anderson Cancer Center, will highlight recent advancements in developing novel therapeutic strategies for MF during the Myeloproliferative Neoplasms Session on September 29, 2022.

Therapies Combined with Ruxolitinib in the Frontline

Luspatercept (Reblozyl) is an activin receptor-ligand trap molecule. In the phase 2 trial on luspatercept (NCT03194542) in patients with transfusion-dependent MF, 46% of them on a stable dose of ruxolitinib also receiving luspatercept had a 50% or greater decrease in RBC transfusion burden and 36% achieved transfusion-independence for 12 or more consecutive weeks.¹⁹ Currently, luspatercept is being evaluated in the registrational phase 3 INDEPENDENCE trial (NCT04717414) in patients with MF who are concomitantly treated with ruxolitinib and require RBC transfusions.

Dual inhibition of the JAK/STAT and BET pathways demonstrated synergism in preclinical studies and may be a promising strategy to enhance the efficacy of ruxolitinib in MF.²⁰ In the phase 2 MANIFEST study (NCT02158858), pelabresib (formerly CPI-0610), a first-in-class, oral, selective BET (epigenetic modifier) inhibitor, was combined with ruxolitinib. The combination elicited 35% or greater spleen volume reductions (SVR35) and 50% or greater improvement in total symptom score (TSS50) from baseline in 68% and 56% of the enrolled JAK inhibitor-naïve patients with MF (Arm 3), respectively, at 24 weeks.²¹ Responses were significantly higher than historical data reported for ruxolitinib monotherapy in phase 2 and 3 trials. Pelabresib in combination with ruxolitinib is being evaluated in the global, registrational phase 3 MANIFEST-2 trial (NCT04603495) in JAK inhibitor-naïve patients.²²

Navitoclax (formerly ABT-263) inhibits the anti-apoptotic BCL-2 family of proteins (primarily BCL-XL) and may enhance the clinical activity of ruxolitinib based on preclinical studies. In the phase 2 REFINE study (NCT03222609; cohort 3), navitoclax combined with ruxolitinib achieved spleen and symptom responses, and improved anemia and bone marrow fibrosis in a significant number of JAK inhibitor-naïve patients.²³ Currently, navitoclax combined with ruxolitinib is being evaluated in JAK inhibitor-naïve patients in the phase 3 trial TRANSFORM-1 (NCT04472598).

“Add-on” Agents to Ruxolitinib in the Second-Line Setting

Navitoclax in combination with ruxolitinib has also been evaluated in the second-line setting in MF patients. In the phase 2 REFINE trial (cohort 1a), a significant number of patients with MF treated with the combination navitoclax/ruxolitinib achieved SVR35 and TSS50 compared with baseline at week 24, and bone marrow fibrosis improved by at least 1 grade in about one-third of ruxolitinib-treated patients^.24 Patients who had 1 grade or higher improvement in bone marrow fibrosis and 20% or greater reduction in allele burden of driver mutations demonstrated prolonged survival.²⁵Navitoclax in combination with ruxolitinib is undergoing investigation in the randomized phase 3 trial TRANSFORM-2 (NCT04468984) in the second line.

A potent and highly selective inhibitor of PI3 kinase, parsaclisib, was assessed as an “add-on” agent to ruxolitinib in patients with MF and a suboptimal response to ruxolitinib. The combination parsaclisib/ruxolitinib will be explored in the phase 3 trial, LIMBER-304 (NCT04551053), in those with MF who had suboptimal response to ruxolitinib.

Navtemadlin

Navtemadlin (formerly KRT-232) is a first-in-class, potent, bioavailable inhibitor of HDM2, a key negative regulator of p53. This drug demonstrated encouraging clinical efficacy and tolerability in TP53 wild-type patients with MF who failed ruxolitinib in a phase 2 study. Navtemadlin will be compared to best available therapy (BAT), excluding JAK inhibitors, in the global phase 3 BOREAS trial (NCT03662126) in TP53 wild-type patients who are refractory or resistant to JAK inhibitors.

Imetelstat

Lastly, imetelstat, a first-in-class potent telomerase inhibitor, yielded a median overall survival of 29.⁹ months (dose, 9.4 mg/kg) in patients with intermediate-2 or high-risk MF relapsed/refractory to JAK inhibitors in the phase 2 IMbark study (NCT02426086).²⁶The overall survival benefit from imetelstat compared favorably with matched historical data for treatment with BAT after JAK inhibitor failure. The international, registrational phase 3 trial IMpactMF (NCT04576156) is underway to evaluate the potential survival advantage—an unprecedented trial end point for investigational MF therapies—of imetelstat in intermediate-2 or high-risk JAK inhibitor–refractory MF.

Future Outlook

In addition to the transformative impact of JAK inhibitors in the MPN landscape and their central role in treating MF,¹¹ several promising novel agents with various mechanisms of action—administered as monotherapies or in combination with ruxolitinib—are in advanced clinical development.¹² These strategies are poised to expand the armamentarium of MF therapeutics with novel disease-modifying agents that complement the clinical benefits of ruxolitinib (eg, depth and duration of spleen, symptom responses), improve other aspects of the disease besides splenomegaly and constitutional symptoms (eg, bone marrow fibrosis, driver mutation burden), address unmet needs in MF (eg, cytopenias, resistance to ruxolitinib), and prolong survival.

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