Helen T. Chifotides, PhD

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.

 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.

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.

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 inhibition

 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 symptoms

 in the ongoing pivotal phase 3 MOMENTUM trial (NCT04173494)

evaluating JAK-inhibitor treated, symptomatic, and anemic patients with MF. Momelotinib’s marked anemia benefits, including achievement of red blood cell (RBC) transfusion independence

appear to underlie prolongation of survival in those with MF.

 Momelotinib may receive regulatory approval as a treatment for anemic patients with MF in the near future.

Notwithstandingthe remarkable benefits of JAK inhibitors,

many novel treatments, acting through various mechanisms, are being explored either as single agents or in combination with ruxolitinib.

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.

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.

 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.

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.

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.

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.

 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

 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.

Navitoclax 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 (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 

 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 

 wild-type patients who are refractory or resistant to JAK inhibitors.

Lastly, imetelstat, a first-in-class potent telomerase inhibitor, yielded a median overall survival of 29.

 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).

The 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.

In addition to the transformative impact of JAK inhibitors in the MPN landscape and their central role in treating MF,

 several promising novel agents with various mechanisms of action—administered as monotherapies or in combination with ruxolitinib—are in advanced clinical development.

 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.

1. Masarova L, Bose P, Pemmaraju N, et al. Improved survival of patients with myelofibrosis in the last decade: single-center experience. 

. 2022;128(8):1658-1665. doi:10.1002/cncr.34103

2. Verstovsek S, Parasuraman S, Yu J, et al. Real-world survival of US patients with intermediate- to high-risk myelofibrosis: impact of ruxolitinib approval. 

. 2022;101(1):131-137. doi:10.1007/s00277-021-04682-x

3. Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure. 

. 2020;95(6):594-603. doi:10.1002/ajh.25777

4. Verstovsek S, Mesa R, Talpaz M, et al. Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia. 

 2022;107(7):1599-1607. doi:10.3324/haematol.2021.279415

5. Venugopal S, Mascarenhas J. The odyssey of pacritinib in myelofibrosis. 

. 2022;bloodadvances.2022007524. doi:10.1182/bloodadvances.2022007524

6. Chifotides HT, Bose P, Verstovsek S. Momelotinib: an emerging treatment for myelofibrosis patients with anemia. 

 2022;15(1):7. doi:10.1186/s13045-021-01157-4

7. Verstovsek S, Vannucchi A, Gerds A, et al. S195: MOMENTUM: phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. 

. 2022;6:96-97. doi:10.1097/01.HS9.0000843672.56808.41

8. Verstovsek S, Chen CC, Egyed M, et al. MOMENTUM: momelotinib vs danazol in patients with myelofibrosis previously treated with JAKi who are symptomatic and anemic. 

. 2021;17(12):1449-1458. doi:10.2217/fon-2020-1048

9. Mesa R, Oh ST, Gerds AT, et al. Momelotinib reduces transfusion requirements in patients with myelofibrosis. 

. 2022;63(7):1718-1722. doi:10.1080/10428194.2022.2043304

10. Mesa R, Harrison C, Oh ST, et al. Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis. 

 2022;10.1038/s41375-022-01637-7. doi:10.1038/s41375-022-01637-7

11. Venugopal S, Mascarenhas J. Novel therapeutics in myeloproliferative neoplasms. 

. 2020;13(1):162. doi:10.1186/s13045-020-00995-y

12. Chifotides HT, Bose P, Masarova L, Pemmaraju N, Verstovsek S. SOHO state of the art updates and next questions: novel therapies in development for myelofibrosis. 

. 2022;22(4):210-223. doi:10.1016/j.clml.2021.10.002

13. Newberry KJ, Patel K, Masarova L, et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. 

. 2017;130(9):1125-1131. doi:10.1182/blood-2017-05-783225

14. Bose P, Verstovsek S. SOHO state of the art updates and next questions: identifying and treating “progression” in myelofibrosis. 

. 2021;21(10):641-649. doi:10.1016/j.clml.2021.06.008

15. Shahin OA, Chifotides HT, Bose P, Masarova L, Verstovsek S. Accelerated phase of myeloproliferative neoplasms. 

. 2021;144(5):484-499. doi:10.1159/000512929

16. Mascarenhas JO, Verstovsek S. The clinical dilemma of JAK inhibitor failure in myelofibrosis: predictive characteristics and outcomes. 

. 2022;128(14):2717-2727. doi:10.1002/cncr.34222

17. Bose P, Verstovsek S. Management of myelofibrosis-related cytopenias. 

. 2018;13(3):164-172. doi:10.1007/s11899-018-0447-9

18. Vachhani P, Verstovsek S, Bose P. Disease modification in myelofibrosis: an elusive goal?. 

. 2022;40(11):1147-1154. doi:10.1200/JCO.21.02246

19. Gerds AT, Vannucchi AM, Passamonti F, et al. Duration of response to luspatercept in patients (Pts) requiring red blood cell (RBC) transfusions with myelofibrosis (MF) – Updated data from the phase 2 ACE-536-MF-001 study. 

 2020;136(Suppl 1):47-48. doi.10.1182/blood-2020-137265

20. Mascarenhas J, Gerds A, Verstovsek S. Paradigm shift: combination BET and JAK inhibition in myelofibrosis. 

. 2021;35(12):3361-3363. doi:10.1038/s41375-021-01405-z

21. Mascarenhas J, Kremyanskaya M, Patriarca A, et al. S198: BET inhibitor pelabresib (CPI-0610) combined with ruxolitinib in patients with myelofibrosis – JAK-inhibitor naïve or with suboptimal response to ruxolitinib – preliminary data from the MANIFEST study. 

2022;6:99-100. doi:10.1097/01.HS9.0000843684.97625.7e

22. Harrison C, Gupta V, Gerds AT, et al. Phase III MANIFEST-2: pelabresib + ruxolitinib vs. placebo + ruxolitinib in JAK-inhibitor treatment-naïve myelofibrosis. 

23. Passamonti F, Foran J, Tandra A, et al. S197: Navitoclax plus ruxolitinib in JAK-inhibitor naïve patients with myelofibrosis: preliminary safety and efficacy in a multicenter, open-label phase 2 study. 

 2022;6:98-99. doi:10.1097/01.HS9.0000843680.94912.c5

24. Harrison CN, Garcia JS, Somervaille TCP, et al. Addition of navitoclax to ongoing ruxolitinib therapy for patients with myelofibrosis with progression or suboptimal response: phase II safety and efficacy. 

. 2022;40(15):1671-1680. doi:10.1200/JCO.21.02188

25. Pemmaraju N, Garcia JS, Potluri J, et al. Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study. 

. 2022;9(6):e434-e444. doi:10.1016/S2352-3026(22)00116-8

26. Mascarenhas J, Komrokji RS, Palandri F, et al. Randomized, single-blind, multicenter phase II study of two doses of imetelstat in relapsed or refractory myelofibrosis. 

. 2021;39(26):2881-2892. doi:10.1200/JCO.20.02864

Articles

Srdan Verstovsek, MD, PhD, highlighted recent advancements in developing novel therapeutic strategies for myelofibrosis during SOHO 2022.

Novel Therapies in Development for Myelofibrosis Show Promise

Building on the transformative impetus from the first Food and Drug Administration (FDA)-approved Janus kinase (JAK) 1/2 inhibitor, ruxolitinib (Jakafi), in the clinical landscape of myeloproliferative neoplasms (MPNs), we are entering a new era of multiple JAK inhibitors and other diverse classes of drugs in rapid clinical development. Advancements in elucidating the pathophysiology of MPNs have spurred significant progress in developing novel promising agents or combination regimens with ruxolitinib to treat patients who are unresponsive to standard treatments or have specific clinical needs.

In myelofibrosis (MF), the most aggressive MPN, with an average survival of 5 to 7 years, abnormal clonal hematopoietic stem cell proliferation in the bone marrow (BM) leads to liberation of pro-inflammatory cytokines and extensive fibrosis, causing progressive pancytopenia, especially anemia and thrombocytopenia, along with splenomegaly and other symptoms, compromising quality of life.

For nearly a decade, ruxolitinib has been the centerpiece therapy for patients with MF, markedly improving splenomegaly and constitutional symptoms and providing survival benefit.2 The second FDA-approved JAK2 inhibitor, fedratinib (Inrebic), may actually be a good second-line option for patients who are ruxolitinib-resistant with intermediate-2 and high-risk MF (primarily thrombocytopenic and characterized by platelet counts 50−100 × 109/L).3 At present, 2 ongoing phase 3 clinical trials, the single-arm FREEDOM trial (NCT03755518) and the double-arm FREEDOM 2 trial (NCT03952039), are assessing the efficacy and safety of fedratinib in patients with MF who are resistant/refractory/intolerant to ruxolitinib. The FREEDOM trials are important because the previous JAKARTA studies (NCT01523171, NCT01437787) were placed on hold or terminated given concerns for the development of Wernicke encephalopathy. Pacritinib is a potent inhibitor of both JAK2 and fms-related receptor tyrosine kinase 

3, or FLT3, but does not affect JAK1. Pacritinib is being evaluated in comparison with the physician’s choice in an ongoing phase 3 trial (PACIFICA; NCT03165734) in patients with MF and severe thrombocytopenia (baseline platelet count < 50 × 10

/L) at the optimal dose determined in the PAC203 study (200 mg twice daily; NCT03165734).

 Successful clinical development of pacritinib will provide a non-myelosuppressive JAK2 inhibitor for frontline treatment of patients with MF who have severe thrombocytopenia, a setting currently lacking approved drugs. Another JAK1/2 inhibitor that is in advanced clinical development and complements its predecessors is momelotinib, possessing the exclusive attribute to improve anemia, which becomes severe in patients with MF.

 At present, momelotinib is undergoing evaluation in patients who are symptomatic and anemic with advanced MF, previously treated with a JAK inhibitor, in a phase 3 trial (MOMENTUM; NCT04173494); the comparator drug is danazol.

Given that patients with MF experience disease-associated and JAK inhibitor-induced anemia, several clinical trials have been evaluating drugs counteracting anemia, as monotherapies or in combination with ruxolitinib, in patients with MF-associated anemia.

Currently, a global, multicenter phase 2 trial is under way to evaluate the safety and efficacy of luspatercept-aamt (Reblozyl), an activin receptor ligand trap that enhances late-stage erythropoiesis in patients with anemia and MF, including ruxolitinib-treated, transfusion-dependent individuals; a phase 3 trial (INDEPENDENCE) is planned for 2020. Interim results of the phase 2 study demonstrated significant efficacy of luspatercept-aamt, achieving reduction in red blood cell transfusion burden in ruxolitinib-treated patients with MF. Thalidomide (Thalomid), an immunomodulatory agent, significantly improved anemia and thrombocytopenia (platelet counts increased in 60% of patients) in a phase 2 trial evaluating ruxolitinib-treated patients with MF and baseline thrombocytopenia (NCT03069326).

Synergistic combinations with ruxolitinib targeting epigenetics and JAK2 

CPI-0610 is a selective bromodomain and extraterminal protein inhibitor that improved spleen volume, anemia, BM fibrosis, total symptom score, and transfusion dependence (alone or with ruxolitinib) in patients with MF who are enrolled in the global phase 2 MANIFEST study (NCT02158858).

 Furthermore, a phase 1 clinical trial combining an inhibitor of heat shock protein 90 (JAK2 is its chaperone protein), PU-H71, with ruxolitinib in patients with primary/secondary MF is under way (NCT03935555).

 The previous 2 trials are supported by preclinical data showing drug synergism. In a phase 2 trial of ruxolitinib/azacitidine (hypomethylating agent) in patients with MF, synergism was demonstrated in spleen length reduction and BM fibrosis improvement compared with ruxolitinib monotherapy (NCT01787487).

Synergistic combinations with ruxolitinib targeting antiapoptotic proteins and JAK2. 

Navitoclax is an orally bioavailable inhibitor of the antiapoptotic B-cell lymphoma 2 (BCL2) family of proteins (primarily BCL extra-large [XL]). In preclinical studies, the nonclinical analogue of navitoclax, ABT-737, in combination with ruxolitinib showed synergism in inducing apoptosis of 

V617F-driven MPN cell lines. Interim data from an ongoing phase 2 clinical trial evaluating navitoclax in combination with ruxolitinib in ruxolitinib-treated patients with MF (with baseline platelet count ≥ 100 × 10

/L) showed reduction in spleen volume and BM fibrosis (≥1 grade) and improvement in total symptom score in a proportion of the patients (NCT03222609).

Imetelstat is a short oligonucleotide telomerase inhibitor that possibly prolonged median overall survival in patients with MF in the higher-dose (9.4-mg/kg) arm of the phase 2 IMbark study (NCT02426086).

A phase 3 trial comparing imetelstat to best available therapy in patients with refractory MF is planned for early 2021.

PRM-151, a plasma-derived analogue of the human antifibrotic protein pentraxin 2, improved BM fibrosis in mice models and patients with MF in preclinical and phase 1/2 clinical studies, respectively.

 The promising results merit a phase 3 trial, especially given the scarcity of antifibrotic agents.

Polycythemia Vera and Essential Thrombocythemia

The two relatively indolent MPN subtypes, polycythemia vera (PV) and essential thrombocythemia (ET), are characterized by abnorabnormal proliferation of myeloid cells, resulting in elevated blood counts (erythrocytosis and thrombocytosis in PV and ET, respectively), considerable risk of thrombosis and hemorrhage, and progression to secondary MF and acute myeloid leukemia (more common in PV than ET).

 In PV and ET, therapies are aimed at reducing risk of thrombosis, which is higher in patients over 60 years old or with a history of thrombosis, and in ET, when the calreticulin gene, 

is absent. A particularly promising agent for the two indolent MPNs is the long-acting ropeginterferon α-2b, which was approved in Europe for frontline treatment of high-risk patients with PV and without symptomatic splenomegaly on the basis of the PROUD/CONTINUATION-PV studies [EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357- 17 (CONTINUATION-PV)].

 The previous investigations demonstrated superiority of ropeginterferon α-2b versus hydroxyurea after 3 years of therapy. Besides awaiting possible approval of ropeginterferon α-2b to treat patients with PV in the United States, a phase 3 trial of ropeginterferon α-2b versus anagrelide in hydroxyurea-resistant/intolerant patients with ET has been planned to start in 2020. Givinostat, an inhibitor of histone deacetylases, demonstrated promising clinical responses (reduction in pruritus and thrombosis, and normalization of hematological parameters) in phase 1/2 studies in patients with 

V617F– positive PV and is entering a phase 3 trial in 2021.

 Currently, hydroxyurea and ruxolitinib are the first- and second-line treatments for high-risk patients with PV, respectively, and hydroxyurea is the first-line treatment for ET.

Herein we highlighted an array of drugs— ranging from new JAK inhibitors to an antifibrotic agent, epigenetic modifiers, and telomerase and BCL-XL/BCL2 inhibitors—that are in early or advanced clinical development in MPN. We are looking forward to enrichment of the MPN arsenal with new disease-modifying agents complementing the clinical benefits of ruxolitinib and fulfilling unmet needs in this population.

1. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. 

. 2017;10(1):156. doi:10.1186/s13045-017-0527-7

2. Bose P, Verstovsek S. Management of myelofibrosis after ruxolitinib failure. Leuk Lymphoma. Published online April 16, 2020. doi:10.1080/1 0428194.2020.1749606

3. Bose P, Verstovsek S. Management of myelofibrosis-related cytopenias. 

. 2018;13(3):164-172. doi:10.1007/s11899- 018-0447-9

3. Bose P, Alfayez M, Verstovsek S. New concepts of treatment for patients with myelofibrosis. 

. 2019;20(1):5. doi:10.1007/s11864-019-0604-y

4. Bose P, Verstovsek S. Updates in the management of polycythemia vera and essential thrombocythemia. 

. 2019;10:2040620719870052. doi:10.1177/2040620719870052

5. Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. 

. 2020;7(3):e196-e208. doi:10.1016/S2352- 3026(19)30236-4

6. Chifotides HT, Bose P, Verstovsek S. Givinostat: an emerging treatment for polycythemia vera. 

. 2020;29(6):525- 536. doi:10.1080/13543784.2020.1761323

Building on the transformative impetus from the first FDA-approved JAK 1/2 inhibitor, ruxolitinib, in the clinical landscape of myeloproliferative neoplasms, we are entering a new era of multiple JAK inhibitors and other diverse classes of drugs in rapid clinical development. 

Helen T. Chifotides, PhD | Authors

Articles

Novel Therapies in Development for Myelofibrosis Show Promise

New Therapies in Development for Myelofibrosis