The current pharmacological treatment of myelofibrosis (MF) relies on the use of JAK inhibitors. These drugs are the only approved therapies for treating MF, and though they are effective for reducing spleen volume and managing the burden of disease, their effect on preventing disease progression to acute myeloid leukemia is limited. Patients who have cytopenia or whose disease is refractory to JAK inhibitor treatment also may not benefit from this therapeutic option.1

Several investigational drugs are being developed to treat MF that target pathways other than the JAK-STAT pathway. Some of them have immunomodulatory activity (pomalidomide); others target apoptosis (navitoclax, KRT-232, LCL-161, imetelstat), epigenetic modulation (CPI-0610, bomedemstat), the bone marrow microenvironment (PRM-151, AVID-200, alisertib), or signal transduction pathways (parsaclisib, everolimus).1,2

Pelabresib (CPI-0610)

Pelabresib (CPI-0610) is a selective small molecule with antitumor activity that inhibits the function of bromodomain and extraterminal domain (BET) proteins. Its activity downregulates nuclear factor kappa B (NF-κB) signaling and the expression of genes involved in the development of MF.2,3

CPI-0610 is under study in an open-label phase 2 clinical trial, MANIFEST (NCT02158858), and in a phase 3 clinical trial, MANIFEST-2 (NCT04603495), both sponsored by Constellation Pharmaceuticals, a MorphoSys company.4,5 In the MANIFEST trial, CPI-0610 is being evaluated as monotherapy for patients whose disease is resistant to Jakafi® (ruxolitinib), who cannot tolerate it, or who are ineligible for or no longer undergoing treatment with Jakafi. The trial is also evaluating CPI-0610 as add-on therapy in combination with Jakafi in patients with disease progression or suboptimal response to Jakafi, and in combination with Jakafi in patients who are JAK inhibitor-naïve.3 The phase 3 clinical trial is comparing CPI-0610 in combination with Jakafi vs placebo and Jakafi in patients with MF who are JAK inhibitor-naïve.3

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Everolimus is an mTOR inhibitor. The AKT/mTOR pathway is frequently activated in cancer, playing a role in the cell cycle and angiogenesis.6 Everolimus has been used as an immunosuppressant and has shown effectiveness in patients with renal cell carcinoma or mantle cell lymphoma.6 In MF, the AKT/mTOR pathway is also hyperactivated and is a potential therapeutic target in this disease.1,6 

A phase 1/2 clinical trial was conducted to evaluate the safety and efficacy of everolimus in the treatment of MF. The trial included patients with intermediate- or high-risk primary MF or secondary (post polycythemia vera/post essential thrombocythemia) MF.6

The results showed that everolimus was well tolerated and had a favorable safety profile. In addition, sustained splenomegaly reduction was noted in 44%, and constitutional symptoms were decreased in 69% of patients.6 

On the basis of these findings, everolimus may be a potential treatment option for MF, although more research is needed to acquire a full understanding of its effectiveness in this disease.6

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Pomalyst® (pomalidomide), a thalidomide analogue, is a second-generation immunomodulatory agent with anticytokine, anti-angiogenic and pro-erythroid activity.7,8 Pomalidomide is active in diseases such as multiple myeloma and myelodysplastic syndromes. In MF, it has been an effective treatment for anemia, thrombocytopenia, and splenomegaly.7

Various phase 1/2 clinical trials of pomalidomide alone or in combination with a corticosteroid have reported response rates of 10% to 36% in the treatment of anemia and/or thrombocytopenia, depending on the response criteria used.8 

The efficacy and tolerability of Pomalyst in patients with MF and significant anemia were first studied in a randomized, 4-arm, double-blind phase 2 clinical trial. Although the drug was well tolerated, the statistical design of the study did not allow a comparison of the response rates in the different arms of the study.7 

A phase 1/2 trial was performed later, also in patients with MF; however, no significant clinical efficacy was observed at the maximum tolerated dose.9 Modest activity of the drug administered in combination with prednisone was observed in patients who had MF with significant anemia in a phase 2 study.10

In the ongoing phase 1b/2 MPNSG-0212 clinical trial, a combination regimen of Jakafi and Pomalyst has been found to be safe and feasible in a cohort of patients at intermediate-2 risk or high risk presenting with primary or secondary MF and anemia.11

Read more about MF therapies


1. Tremblay D, Mascarenhas J. Next generation therapeutics for the treatment of myelofibrosis. Cells. 2021;10(5):1034. doi:10.3390/cells10051034

2. Harrison C, Kremyanskaya M, Bose P, et al. Pelabresib (CPI-0610) as add-on to ruxolitinib in myelofibrosis: durability of response and safety beyond week 24 in the phase 2 MANIFEST study. Blood. 2022;140 (Suppl 1):9659–9662. doi:10.1182/blood-2022-157735

3. MorphoSys presents new longer-term phase 2 results on pelabresib in myelofibrosis, including potential disease-modifying activity, at ASH 2022. Media Release. MorphoSys; December 11, 2022.

4. A phase 2 Study of CPI-0610 with and without ruxolitinib in patients with myelofibrosis. June 9, 2014. Updated December 7, 2022. Accessed December 21, 2022.

5. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2). October 26, 2020. Updated October 12, 2022. Accessed December 21, 2022.

6. Guglielmelli P, Barosi G, Rambaldi A, et al. Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. Blood. 2011;118(8):2069-2076. doi:10.1182/blood-2011-01-330563

7. Daver N, Shastri A, Kadia T, et al. Modest activity of pomalidomide in patients with myelofibrosis and significant anemia. Leuk Res. 2013;37(11):1440-1444. doi:10.1016/j.leukres.2013.07.007

8. Schlenk RF, Stegelmann F, Reiter A, et al. Pomalidomide in myeloproliferative neoplasm-associated myelofibrosis. Leukemia. 2017;31(4):889-895. doi:10.1038/leu.2016.299

9. Mesa RA, Pardanani AD, Hussein K, et al. Phase1/-2 study of pomalidomide in myelofibrosis. Am J Hematol. 2010;85(2):129-130. doi:10.1002/ajh.21598

10. Daver N, Shastri A, Kadia T, et al. Phase II study of pomalidomide in combination with prednisone in patients with myelofibrosis and significant anemia. Leuk Res. 2014;38(9):1126-1129. doi:10.1016/j.leukres.2014.06.015

11. Stegelmann F, Jahn E, Koschmieder S, et al. P1055: clinical and genetic results of the phase IB/II trial MPNSG-0212: ruxolitinib plus pomalidomide in myelofibrosis with anemia. Hemasphere. 2022;6(Suppl):945-946. doi:10.1097/01.HS9.0000847088.09306.08

Reviewed by Harshi Dhingra, MD, on 12/30/2022.