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Paradigm shift: combination BET and JAK inhibition in myelofibrosis

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Fig. 1: Inhibitors targeting Janus Associated Kinase 2 (JAK2) and bromodomain and extraterminal domain (BET) proteins cooperate to downregulate NFκB activity as well as expression of target genes that contribute to the underlying pathologic features of myelofibrosis.


  1. Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000;342(17):1255–65.

    Article  CAS  Google Scholar 

  2. Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood 2017;129(6):667–79.

    Article  CAS  Google Scholar 

  3. Fisher DAC, Malkova O, Engle EK, Miner CA, Fulbright MC, Behbehani GK, et al. Mass cytometry analysis reveals hyperactive NF Kappa B signaling in myelofibrosis and secondary acute myeloid leukemia. Leukemia 2017;31(9):1962–74.

    Article  CAS  Google Scholar 

  4. Cervantes F, Pereira A. Does ruxolitinib prolong the survival of patients with myelofibrosis? Blood 2017;129(7):832–7.

    Article  CAS  Google Scholar 

  5. Barosi G, Rosti V, Gale RP. Critical appraisal of the role of ruxolitinib in myeloproliferative neoplasm-associated myelofibrosis. Onco Targets Ther. 2015;8:1091–102.

    Article  Google Scholar 

  6. Venugopal S, Mascarenhas J. Current clinical investigations in myelofibrosis. Hematol Oncol Clin North Am. 2021;35(2):353–73.

    Article  Google Scholar 

  7. Newberry KJ, Patel K, Masarova L, Luthra R, Manshouri T, Jabbour E, et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood 2017;130(9):1125–31.

    Article  CAS  Google Scholar 

  8. Mascarenhas J, Mehra M, He J, Potluri R, Loefgren C. Patient characteristics and outcomes after ruxolitinib discontinuation in patients with myelofibrosis. J Med Econ. 2020;23(7):721–7.

    Article  Google Scholar 

  9. Kuykendall AT, Shah S, Talati C, Al Ali N, Sweet K, Padron E, et al. Between a rux and a hard place: evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation. Ann Hematol. 2018;97(3):435–41.

    Article  CAS  Google Scholar 

  10. Pemmaraju N, Garcia JS, Potluri J, Holes L, Harb J, Jung P, et al. The addition of navitoclax to ruxolitinib demonstrates efficacy within different high-risk populations in patients with relapsed/refractory myelofibrosis. Blood. 2020;136:39–40.

  11. Yacoub A, Wang E, Rampal R, Borate U, Kremyanskaya M, Ali H, et al. Addition of parsaclisib (INCB050465), a PI3K delta inhibitor, in patients with suboptimal response to ruxolitinib: a phase 2 study in patients with myelofibrosis. Br J Haematol. 2021;193:9.

    Article  Google Scholar 

  12. Pettit K, Gerds AT, Yacoub A, Watts JM, Tartaczuch M, Bradley TJ, et al. A phase 2a study of the LSD1 inhibitor Img-7289 (bomedemstat) for the treatment of myelofibrosis. Blood. 2019;134:556.

  13. Mascarenhas J, Komrokji RS, Cavo M, Martino B, Niederwieser D, Reiter A, et al. Potential disease-modifying activity of imetelstat demonstrated by reduction in cytogenetically abnormal clones and mutation burden leads to clinical benefits in relapsed/refractory myelofibrosis patients. Blood. 2020;136:39–40.

  14. Sanchez R, Zhou MM. The role of human bromodomains in chromatin biology and gene transcription. Curr Opin Drug Discov Dev. 2009;12(5):659–65.

    CAS  Google Scholar 

  15. Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell. 2014;54(5):728–36.

    Article  CAS  Google Scholar 

  16. Kleppe M, Koche R, Zou L, van Galen P, Hill CE, Dong L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(4):785–7.

    Article  CAS  Google Scholar 

  17. Fiskus W, Cai TY, DiNardo CD, Kornblau SM, Borthakur G, Kadia TM, et al. Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells. Blood Cancer J. 2019;9:1–13.

  18. Albrecht BK, Gehling VS, Hewitt MC, Vaswani RG, Cote A, Leblanc Y, et al. Identification of a benzoisoxazoloazepine inhibitor (CPI-0610) of the bromodomain and extra-terminal (BET) family as a candidate for human clinical trials. J Med Chem. 2016;59(4):1330–9.

    Article  CAS  Google Scholar 

  19. Somervaille T, Verstovsek S, Mascarenhas J, Kremyanskaya M, Hoffman R, Rampal R, et al. CPI-0610, bromodomain and extraterminal domain protein (BET) inhibitor, as “add-on” to ruxolitinib, in advanced myelofibrosis patients with suboptimal response: update of MANIFEST phase 2 study. Br J Haematol. 2021;193:98–9.

    Google Scholar 

  20. Mead A, Mascarenhas J, Talpaz M, Patriarca A, Devos T, Palandri F, et al. CPI-0610, a bromodomain and extraterminal domain protein (bet) inhibitor, in combination with ruxolitinib, in jak-inhibitor-naive myelofibrosis patients: update of manifest phase 2 study. Br J Haematol. 2021;193:96-.

    Google Scholar 

  21. Verstovsek S, Kantarjian HM, Estrov Z, Cortes JE, Thomas DA, Kadia T, et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood 2012;120(6):1202–9.

    Article  CAS  Google Scholar 

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JM, AG, and SV conceived the work that led to the submission, drafted the paper, approved the final version, and agreed to be accountable for all aspects of the work.

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Correspondence to John Mascarenhas.

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JM has received research support paid to his institution from PharmaEssentia, Abbvie, CTI Bio, Merck, Roche, Novartis, BMS, Forbius, Kartos, Incyte, Geron, Sierra Oncology; consulting or advisory board fees from Kartos, CTI Bio, Constellation, Incyte, Roche, Novartis, BMS, Abbvie, PharmaEssentia, and Geron. AG has received advisory board fees from PharmaEssentia, BMS, Novartis, AbbVie, Sierra Oncology. SV has received research support paid to his institution from Incyte, Roche, NS Pharma, Celgene, Gilead, Promedior, CTI BioPharma, Blueprint Medicines Corp., Novartis, Sierra Oncology, PharmaEssentia, Constellation, Protagonist, Kartos; advisory board fees from Constellation, BMS, Sierra Oncology, Incyte, Novartis, Celgene, PharmaEssentia.

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Mascarenhas, J., Gerds, A. & Verstovsek, S. Paradigm shift: combination BET and JAK inhibition in myelofibrosis. Leukemia 35, 3361–3363 (2021).

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