Management of myelofibrosis after ruxolitinib failure

References

• Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.
   PubMed Web of Science ®Google Scholar
• Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–798.
   PubMed Web of Science ®Google Scholar
• Al-Ali HK, Griesshammer M, Le Coutre P, et al. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. Haematologica. 2016;101(9):1065–1073.
   PubMed Web of Science ®Google Scholar
• Mead AJ, Milojkovic D, Knapper S, et al. Response to ruxolitinib in patients with intermediate-1-, intermediate-2-, and high-risk myelofibrosis: results of the UK ROBUST trial. Br J Haematol. 2015;170(1):29–39.
   PubMed Web of Science ®Google Scholar
• Palandri F, Tiribelli M, Benevolo G, et al. Efficacy and safety of ruxolitinib in intermediate-1 IPSS risk myelofibrosis patients: results from an independent study. Hematol Oncol. 2017;36(1):285–290.
   PubMed Web of Science ®Google Scholar
• Vannucchi AM, Te Boekhorst PAW, Harrison CN, et al. EXPAND, a dose-finding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis. Haematologica. 2019;104(5):947–954.
   PubMed Web of Science ®Google Scholar
• Talpaz M, Paquette R, Afrin L, et al. Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. J Hematol Oncol. 2013;6(1):81,8722-6-81.
   Google Scholar
• National comprehensive cancer network. bone cancer (version 3.2019). [Internet] 2019 [cited 2020 Mar 9]. Available from: http://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf.
   Google Scholar
• Verstovsek S, Mesa RA, Gotlib J, et al. The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo-controlled, phase III study in patients with myelofibrosis. Br J Haematol. 2013;161(4):508–516.
   PubMed Web of Science ®Google Scholar
• Barosi G, Klersy C, Villani L, et al. JAK2(V617F) allele burden 50% is associated with response to ruxolitinib in persons with MPN-associated myelofibrosis and splenomegaly requiring therapy. Leukemia. 2016;30(8):1772–1775.
   PubMed Web of Science ®Google Scholar
• Patel KP, Newberry KJ, Luthra R, et al. Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. Blood. 2015;126(6):790–797.
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55,017-0417-z.
   Google Scholar
• Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701–1707.
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117–1127.
   PubMed Web of Science ®Google Scholar
• Marchetti M, Barosi G, Cervantes F, et al. Which patients with myelofibrosis should receive ruxolitinib therapy? ELN-SIE evidence-based recommendations. Leukemia. 2017;31(4):882–888.
   PubMed Web of Science ®Google Scholar
• Kuykendall AT, Shah S, Talati C, et al. Between a rux and a hard place: evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation. Ann Hematol. 2018;97(3):435–441.
   PubMed Web of Science ®Google Scholar
• Mesa R, Jamieson C, Bhatia R, et al. Myeloproliferative neoplasms, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2016;14(12):1572–1611.
   PubMedGoogle Scholar
• Talpaz M, Erickson-Viitanen S, Hou K, et al. Evaluation of an alternative ruxolitinib dosing regimen in patients with myelofibrosis: an open-label phase 2 study. J Hematol Oncol. 2018;11(1):101,018-0642-0.
   Google Scholar
• Cervantes F, Gisslinger H, Radinoff A, et al. Safety and efficacy of ruxolitinib (rux) in patients with myelofibrosis (MF) and anemia (HB< 10 G/DL): results at week (WK) 24 of the realise trial: PS1465. Hemasphere. 2019;3:675–676.
   Google Scholar
• Bose P, Verstovsek S. Management of myelofibrosis-related cytopenias. Curr Hematol Malig Rep. 2018;13(3):164–172.
   PubMed Web of Science ®Google Scholar
• Gerds AT, Vannucchi AM, Passamonti F, et al. A phase 2 study of luspatercept in patients with myelofibrosis-associated anemia. Blood. 2019;134(Supplement_1):557–557.
   Google Scholar
• Verstovsek S, Kantarjian HM, Estrov Z, 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):1202–1209.
   PubMed Web of Science ®Google Scholar
• Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase 3 trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015;100(9):1139–1145.
   PubMed Web of Science ®Google Scholar
• Burton T, Parikh K, Patel M, et al. Real-world analysis of ruxolitinib treatment patterns and outcomes among patients with myelofibrosis. Blood. 2019;134(Supplement_1):4750–4750.
   Google Scholar
• Palandri F, Breccia M, Bonifacio M, et al. Life after ruxolitinib: reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. Cancer. 2020;126(6):1243–1252.
   PubMed Web of Science ®Google Scholar
• Koppikar P, Bhagwat N, Kilpivaara O, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012;489(7414):155–159.
   PubMed Web of Science ®Google Scholar
• Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: international working group-myeloproliferative neoplasms research and treatment (IWG-MRT) and european LeukemiaNet (ELN) consensus report. Blood. 2013;122(8):1395–1398.
   PubMed Web of Science ®Google Scholar
• Gerds A, Su D, Martynova A, et al. Ruxolitinib rechallenge can improve constitutional symptoms and splenomegaly in patients with myelofibrosis: a case series. Clin Lymphoma Myeloma Leuk. 2018;18(11):e463–e468.
   PubMed Web of Science ®Google Scholar
• Newberry KJ, Patel K, Masarova L, et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood. 2017;130(9):1125–1131.
   PubMed Web of Science ®Google Scholar
• Gerds AT, Savona MR, Scott BL, et al. Results of PAC203: a randomized phase 2 dose-finding study and determination of the recommended dose of pacritinib in patients with myelofibrosis. Blood. 2019;134(Supplement_1):667–667.
   Google Scholar
• Mascarenhas J, Komrokji RS, Cavo M, et al. Imetelstat is effective treatment for patients with intermediate-2 or high-risk myelofibrosis who have relapsed on or are refractory to janus kinase inhibitor therapy: results of a phase 2 randomized study of two dose levels. Blood. 2018;132(Supplement 1):685–685.
   Google Scholar
• Tefferi A, Mudireddy M, Mannelli F, et al. Blast phase myeloproliferative neoplasm: Mayo-Agimm study of 410 patients from two separate cohorts. Leukemia. 2018;32(5):1200–1210.
   PubMed Web of Science ®Google Scholar
• Odenike O. How I treat the blast phase of philadelphia chromosome-negative myeloproliferative neoplasms. Blood. 2018;132(22):2339–2350.
   PubMed Web of Science ®Google Scholar
• Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643–651.
   PubMed Web of Science ®Google Scholar
• Harrison CN, Mesa RA, Jamieson C, et al. Case series of potential wernicke’s encephalopathy in patients treated with fedratinib. Blood. 2017;130:4197.
   Web of Science ®Google Scholar
• Giacomini MM, Hao J, Liang X, et al. Interaction of 2,4-diaminopyrimidine-containing drugs including fedratinib and trimethoprim with thiamine transporters. Drug Metab Dispos. 2017;45(1):76–85.
   PubMed Web of Science ®Google Scholar
• Hazell AS, Afadlal S, Cheresh DA, et al. Treatment of rats with the JAK-2 inhibitor fedratinib does not lead to experimental wernicke’s encephalopathy. Neurosci Lett. 2017;642:163–167.
   PubMed Web of Science ®Google Scholar
• Zhang Q, Zhang Y, Diamond S, et al. The janus kinase 2 inhibitor fedratinib inhibits thiamine uptake: a putative mechanism for the onset of wernicke’s encephalopathy. Drug Metab Dispos. 2014;42(10):1656–1662.
   PubMed Web of Science ®Google Scholar
• Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4(7):e317–24.
   PubMed Web of Science ®Google Scholar
• 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. Am J Hematol. 2020. DOI:10.1002/ajh.25777
   Web of Science ®Google Scholar
• Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib induces spleen responses and reduces symptom burden in patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) and low platelet counts, who were either ruxolitinib-naïve or were previously treated with ruxolitinib. Blood. 2019;134(Supplement_1):668–668.
   PubMedGoogle Scholar
• Asshoff M, Petzer V, Warr MR, et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production and ameliorates anemia of chronic disease in rodents. Blood. 2017;129(13):1823–1830.
   PubMed Web of Science ®Google Scholar
• Oh ST, Talpaz M, Gerds AT, et al. Hepcidin suppression by momelotinib is associated with increased iron availability and erythropoiesis in transfusion-dependent myelofibrosis patients. Blood. 2018;132(Supplement 1):4282–4282.
   Google Scholar
• Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor-naive patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844–3850.
   PubMed Web of Science ®Google Scholar
• Harrison CN, Vannucchi Am Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017;5(2):e73–e81.
   PubMed Web of Science ®Google Scholar
• Mesa RA, Vannucchi Am Mead A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol. 2017;4(11):e508–e509.
   PubMedGoogle Scholar
• Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652.
   PubMed Web of Science ®Google Scholar
• CTI BioPharma provides update on clinical hold of investigational agent pacritinib and new drug application in U.S.[Internet]. Seattle, WA. 2016 [ cited 2016 Feb 9]. Available from: http://investors.ctibiopharma.com/phoenix.zhtml?c=92775&p=RssLanding&cat=news&id=2137027.
   Google Scholar
• CTI BioPharma announces removal of full clinical hold on pacritinib[Internet]; 2017 [cited 2017 Feb 15]. Available from: http://www.prnewswire.com/news-releases/cti-biopharma-announces-removal-of-full-clinical-hold-on-pacritinib-300386115.html.
   Google Scholar
• Bhagwat N, Koppikar P, Keller M, et al. Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms. Blood. 2014;123(13):2075–2083.
   PubMed Web of Science ®Google Scholar
• Fisher DAC, Malkova O, Engle EK, et al. Mass cytometry analysis reveals hyperactive NF kappa B signaling in myelofibrosis and secondary acute myeloid leukemia. Leukemia. 2017;31(9):1962–1974.
   PubMed Web of Science ®Google Scholar
• Fisher DAC, Miner CA, Engle EK, et al. Cytokine production in myelofibrosis exhibits differential responsiveness to JAK-STAT, MAP kinase, and NFkappaB signaling. Leukemia. 2019;33(8):1978–1995.
   PubMed Web of Science ®Google Scholar
• Nieborowska-Skorska M, Maifrede S, Dasgupta Y, et al. Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms. Blood. 2017;130(26):2848–2859.
   PubMed Web of Science ®Google Scholar
• Nath D, Dutta A, Yang Y, et al. The PIM kinase inhibitor TP-3654 in combination with ruxolitinib exhibits marked improvement of myelofibrosis in murine models. Blood. 2018;132(Supplement 1):54–54.
   Google Scholar
• Stivala S, Codilupi T, Brkic S, et al. Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms. J Clin Invest. 2019;129(4):1596–1611.
   PubMed Web of Science ®Google Scholar
• Bogani C, Bartalucci N, Martinelli S, et al. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms. PLoS One. 2013;8(1):e54826.
   PubMed Web of Science ®Google Scholar
• Fiskus W, Verstovsek S, Manshouri T, et al. Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells. Mol Cancer Ther. 2013;12(5):577–588.
   PubMed Web of Science ®Google Scholar
• Daver NG, Kremyanskaya M, O'Connell C, et al. A phase 2 study of the safety and efficacy of INCB050465, a selective PI3Kδ inhibitor, in combination with ruxolitinib in patients with myelofibrosis. Blood. 2018;132(Supplement 1):353–353.
   Google Scholar
• Moyo TK, Palmer J, Huang Y, et al. Resurrecting response to ruxolitinib: a phase I study of ruxolitinib and umbralisib (TGR-1202) in ruxolitinib-experienced myelofibrosis. Haemasphere. 2018;2:133.
   Google Scholar
• Zaware N, Zhou MM. Bromodomain biology and drug discovery. Nat Struct Mol Biol. 2019;26(10):870–879.
   PubMed Web of Science ®Google Scholar
• Kleppe M, Koche R, Zou L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(1):29–43 e7.
   PubMed Web of Science ®Google Scholar
• Mascarenhas J, Kremyanskaya M, Hoffman R, et al. MANIFEST, a phase 2 study of CPI-0610, a bromodomain and extraterminal domain inhibitor (BETi), as monotherapy or “add-on” to ruxolitinib, in patients with refractory or intolerant advanced myelofibrosis. Blood. 2019;134(Supplement_1):670–670.
   Google Scholar
• Tse C, Shoemaker AR, Adickes J, et al. ABT-263: a potent and orally bioavailable bcl-2 family inhibitor. Cancer Res. 2008;68(9):3421–3428.
   PubMed Web of Science ®Google Scholar
• Waibel M, Solomon VS, Knight DA, et al. Combined targeting of JAK2 and bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors. Cell Rep. 2013;5(4):1047–1059.
   PubMed Web of Science ®Google Scholar
• Harrison CN, Garcia JS, Mesa RA, et al. Results from a phase 2 study of navitoclax in combination with ruxolitinib in patients with primary or secondary MyelofibrosisResults from a phase 2 study of navitoclax in combination with ruxolitinib in patients with myelofosis. Blood. 2019;134(Supplement_1):671–671.
   Google Scholar
• Mason KD, Carpinelli MR, Fletcher JI, et al. Programmed anuclear cell death delimits platelet life span. Cell. 2007;128(6):1173–1186.
   PubMed Web of Science ®Google Scholar
• Gerds AT, Tauchi T, Ritchie E, et al. Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib. Leuk Res. 2019;79:38–44.
   PubMed Web of Science ®Google Scholar
• Sasaki K, Gotlib JR, Mesa RA, et al. Phase II evaluation of IPI-926, an oral hedgehog inhibitor, in patients with myelofibrosis. Leuk Lymphoma. 2015;56(7):2092–2097.
   PubMed Web of Science ®Google Scholar
• Yan D, Pomicter AD, Tantravahi S, et al. Nuclear-cytoplasmic transport is a therapeutic target in myelofibrosis. Clin Cancer Res. 2019;25(7):2323–2335.
   PubMed Web of Science ®Google Scholar
• Varricchio L, Mascarenhas J, Migliaccio AR, et al. AVID200, a potent trap for TGF-β ligands inhibits TGF-β1 signaling in human myelofibrosis. Blood. 2018;132(Supplement 1):1791–1791.
   Google Scholar
• Tefferi A, Lasho TL, Begna KH, et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N Engl J Med. 2015;373(10):908–919.
   PubMed Web of Science ®Google Scholar
• Wang X, Hu CS, Petersen B, et al. Imetelstat, a telomerase inhibitor, is capable of depleting myelofibrosis stem and progenitor cells. Blood Adv. 2018;2(18):2378–2388.
   PubMed Web of Science ®Google Scholar
• Kuykendall A, Wan Y, Mascarenhas J, et al. Favorable overall survival of imetelstat-treated relapsed/refractory myelofibrosis patients compared with closely matched real world data. Hemasphere. 2019;3:669–670.
   Google Scholar
• Gilles L, Arslan AD, Marinaccio C, et al. Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis. J Clin Invest. 2017;127(4):1316–1320.
   PubMed Web of Science ®Google Scholar
• Wen QJ, Yang Q, Goldenson B, et al. Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition. Nat Med. 2015;21(12):1473–1480.
   PubMed Web of Science ®Google Scholar
• Gangat N, Marinaccio C, Swords R, et al. Aurora kinase a inhibition provides clinical benefit, normalizes megakaryocytes, and reduces bone marrow fibrosis in patients with myelofibrosis. Clin Cancer Res. 2019;25(16):4898–4906.
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Manshouri T, Pilling D, et al. Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis. J Exp Med. 2016;213(9):1723–1740.
   PubMed Web of Science ®Google Scholar
• Raghu G, van den Blink B, Hamblin MJ, et al. Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis: a randomized clinical trial. JAMA. 2018;319(22):2299–2307.
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Hasserjian RP, Pozdnyakova O, et al. PRM-151 in myelofibrosis: efficacy and safety in an open label extension study. Blood. 2018;132(Supplement 1):686–686.
   Google Scholar
• Verstovsek S, Talpaz M, Wadleigh M, et al. A randomized, double blind phase 2 study of 3 different doses of prm-151 in patients with myelofibrosis who were previously treated with or ineligible for ruxolitinib. Hemasphere. 2019;3(S1):S828.
   Google Scholar
• Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380(17):1628–1637.
   PubMed Web of Science ®Google Scholar
• Pemmaraju N, Gupta V, Ali H, et al. Results from phase 1/2 clinical trial of tagraxofusp (SL-401) in patients with intermediate, or high risk, relapsed/refractory myelofibrosis. Blood. 2019;134(Supplement_1):558–558.
   Google Scholar
• Patnaik MM, Ali H, Gupta V, et al. Results from ongoing phase 1/2 clinical trial of tagraxofusp (SL-401) in patients with relapsed/refractory chronic myelomonocytic leukemia (CMML). J Clin Oncol. 2019;37(15_suppl):7059–7059.
   Web of Science ®Google Scholar
• Jutzi JS, Kleppe M, Dias J, et al. LSD1 inhibition prolongs survival in mouse models of MPN by selectively targeting the disease clone. Hemasphere. 2018;2:e54.
   PubMed Web of Science ®Google Scholar
• Niebel D, Kirfel J, Janzen V, et al. Lysine-specific demethylase 1 (LSD1) in hematopoietic and lymphoid neoplasms. Blood. 2014;124(1):151–152.
   PubMed Web of Science ®Google Scholar
• Sprussel A, Schulte JH, Weber S, et al. Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. Leukemia. 2012;26(9):2039–2051.
   PubMed Web of Science ®Google Scholar
• Pettit K, Gerds AT, Yacoub A, et al. Phase 1/2 study of the LSD1 inhibitor IMG-7289 in patients with myelofibrosis. Blood. 2019;134(Supplement_1):556–556.
   Google Scholar
• Fleischman AG, Aichberger KJ, Luty SB, et al. TNFalpha facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms. Blood. 2011;118(24):6392–6398.
   PubMed Web of Science ®Google Scholar
• Heaton WL, Senina AV, Pomicter AD, et al. Autocrine tnf signaling favors malignant cells in myelofibrosis in a Tnfr2-dependent fashion. Leukemia. 2018;32(11):2399–2411.
   PubMed Web of Science ®Google Scholar
• Pemmaraju N, Carter BZ, Kantarjian HM, et al. Final results of phase 2 clinical trial of LCL161, a novel oral SMAC Mimetic/IAP antagonist for patients with intermediate to high risk myelofibrosis. Blood. 2019;134(Supplement_1):555–555.
   Google Scholar