Therapy with JAK 1/2 inhibitors for myelofibrosis

review
  • 76 Downloads

Abstract

Purpose

Myelofibrosis (MF) is currently the myeloproliferative disorder with the most severe prognosis. A mutation of the JAK2 (V617F) enzyme is present in about 65 % of patients. Inhibition of JAK-kinases was therefore a proposed treatment for the disease. The purpose of this article is to give an updated overview about the recent developments in the therapy of MF with JAK-inhibitors.

Materials and methods

We did a research through the literature to identify the JAK 1/2 inhibitors which are already approved for treating MF or currently undergoing clinical trials. The most important clinical data concerning ruxolitinib, TG101348, SAR302503, CYT387, and SB1518 are described in more detail.

Results

Most of the relevant data documented clinical benefits of JAK inhibitors, particularly in terms of reducing splenomegaly and constitutional symptoms. However, there might also be a trend for better overall survival. The efficacy of ruxolitinib has been demonstrated in two large Phase III trials. In September 2012, the European Medicines Agency (EMA) approved ruxolitinib for the treatment of patients with intermediate or high-risk MF. The other drugs discussed here are still investigated in Phase II or III studies.

Conclusion

There is emerging evidence that supports the use of JAK-inhibitors for MF in clinical practice, especially for patients with splenomegaly and constitutional symptoms. Nevertheless, possible side effects such as anemia and thrombopenia must be considered when prescribing these substances.

Keywords

JAK2 Myelofibrosis JAK2 inhibitor Ruxolitinib 

References

  1. 1.
    Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood. 2007;110(4):1092–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Cervantes F, Passamonti F, Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia. 2008;22(5):905–14.PubMedCrossRefGoogle Scholar
  3. 3.
    Passamonti F, Rumi E, Pungolino E, Malabarba L, Bertazzoni P, Valentini M, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med. 2004;117(10):755–61.PubMedCrossRefGoogle Scholar
  4. 4.
    Tefferi A. Medical progress: myelofibrosis with myeloid metaplasia. N Engl J Med. 2000;342(17):1255–65.PubMedCrossRefGoogle Scholar
  5. 5.
    Tefferi A. Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Oncol. 2005;23(33):8520–30.PubMedCrossRefGoogle Scholar
  6. 6.
    Tefferi A, Vainchenker W. Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol. 2011;29(5):573–82.PubMedCrossRefGoogle Scholar
  7. 7.
    Barbui T, Carobbio A, Cervantes F, Vannucchi AM, Guglielmelli P, Antonioli E, et al. Thrombosis in primary myelofibrosis: incidence and risk factors. Blood. 2010;115(4):778–82.PubMedCrossRefGoogle Scholar
  8. 8.
    Passamonti F, Rumi E, Arcaini L, Castagnola C, Lunghi M, Bernasconi P, et al. Leukemic transformation of polycythemia vera—a single center study of 23 patients. Cancer. 2005;104(5):1032–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Mesa RA, Li CY, Kettering RP, Schroeder GS, Knudson RA, Tefferi A. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 2005;105(3):973–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Ballen KK, Shrestha S, Sobocinski KA, Zhang MJ, Bashey A, Bolwell BJ, et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2010;16(3):358–67.PubMedCrossRefGoogle Scholar
  11. 11.
    Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779–90.PubMedCrossRefGoogle Scholar
  12. 12.
    Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7(4):387–97.PubMedCrossRefGoogle Scholar
  13. 13.
    Quintas-Cardama A, Kantarjian H, Cortes J, Verstovsek S. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov. 2011;10(2):127–40.PubMedCrossRefGoogle Scholar
  14. 14.
    Quintas-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115(15):3109–17.PubMedCrossRefGoogle Scholar
  15. 15.
    Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117–27.PubMedCrossRefGoogle Scholar
  16. 16.
    Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. Long-term outcome of ruxolitinib treatment in patients with myelofibrosis: durable reductions in spleen volume, improvements in quality of life, and overall survival advantage in COMFORT-I. ASH Ann Meet Abstr. 2012;120(21):800.Google Scholar
  17. 17.
    Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.PubMedCrossRefGoogle Scholar
  18. 18.
    Cervantes F, Kiladjian JJ, Niederwieser D, Sirulnik A, Stalbovskaya V, McQuity M, et al. Long-term safety, efficacy, and survival findings from Comfort-II, a Phase 3 study comparing ruxolitinib with best available therapy (BAT) for the treatment of myelofibrosis (MF). ASH Ann Meet Abstr. 2012;120(21):801.Google Scholar
  19. 19.
    Harrison C, Kiladjian JJ, Al Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–98.PubMedCrossRefGoogle Scholar
  20. 20.
    Talpaz M, Hamburg SI, Jamieson K, Terebelo HR, Afrin L, Winton EF, et al. Preliminary safety and efficacy of ruxolitinib in patients (pts) with primary and secondary myelofibrosis (MF) with platelet counts (PC) of 50–100×109/L. ASCO Meet Abstr. 2012;30(Suppl 15):6630.Google Scholar
  21. 21.
    Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A. TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia. 2008;22(9):1790–2.PubMedCrossRefGoogle Scholar
  22. 22.
    Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE, et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell. 2008;13(4):311–20.PubMedCrossRefGoogle Scholar
  23. 23.
    Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011;29(7):789–96.PubMedCrossRefGoogle Scholar
  24. 24.
    Pardanani AD, Caramazza D, George G, Lasho TL, Hogan WJ, Litzow MR, et al. Safety and efficacy of CYT387, a JAK-1/2 inhibitor, for the treatment of myelofibrosis. ASCO Meet Abstr. 2011;29(Suppl 15):6514.Google Scholar
  25. 25.
    Deeg HJ, Odenike O, Scott BL, Estrov Z, Cortes JE, Thomas DA, et al. Phase II study of SB1518, an orally available novel JAK2 inhibitor, in patients with myelofibrosis. ASCO Meet Abstr. 2011;29(Suppl 15):6515.Google Scholar
  26. 26.
    Komrokji RS, Wadleigh M, Seymour JF, Roberts AW, To LB, Zhu HJ, et al. Results of a Phase 2 study of pacritinib (SB1518), a novel oral JAK2 inhibitor, in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis. Blood. 2011;118(21):130–1.Google Scholar
  27. 27.
    Mesa RA, Verstovsek S, Cervantes F, Waltzman RJ, Mendelson ET, Martin N, et al. Comparison of the efficacy of placebo and best available therapy for the treatment of myelofibrosis in the COMFORT studies. Blood. 2011;118(21):765.Google Scholar
  28. 28.
    Mesa RA, Gotlib J, Gupta V, DiPersio JF, Catalano J, Deininger MW, et al. Associations between improvements in myelofibrosis (MF) symptoms and quality of life measures with splenomegaly reduction in COMFORT-I: a randomized, double-blind, Phase III trial of the JAK1 and JAK2 inhibitor ruxolitinib versus placebo in patients with MF. Blood. 2011;118(21):1642–3.Google Scholar
  29. 29.
    Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc. 2011;86(12):1188–91.PubMedCrossRefGoogle Scholar
  30. 30.
    Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA working party on chronic myeloid leukemia. Clin Cancer Res. 2006;12(24):7374–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Deshpande A, Reddy MM, Schade GOM, Ray A, Chowdary TK, Griffin JD, et al. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia. 2012;26(4):708–15.PubMedCrossRefGoogle Scholar
  32. 32.
    Baffert F, Evrot E, Ebel N, Roelli C, Andraos R, Qian ZY, et al. Improved efficacy upon combined JAK1/2 and pan-deacetylase inhibition using ruxolitinib (INC424) and panobinostat (LBH589) in preclinical mouse models of JAK2V617F-driven disease. Blood. 2011;118(21):363.Google Scholar
  33. 33.
    Santos FP, Verstovsek S. What is next beyond janus kinase 2 inhibitors for primary myelofibrosis? Curr Opin Hematol. 2013;20(2):123–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  1. 1.Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases , Rheumatology , Oncologic Center, Laboratory for Immunological and Cancer ResearchParacelsus Medical University SalzburgSalzburgAustria

Personalised recommendations