Open-label study of oral CEP-701 (lestaurtinib) in patients with polycythaemia vera or essential thrombocythaemia with JAK2-V617F mutation

British Journal of Haematology

Volumn 164, Issue 1, 2014, Pages 83-93

  Hexner, Elizabeth ^a   Roboz, Gail ^b   Hoffman, Ron ^c   Luger, Selina ^a   Mascarenhas, John ^c   Carroll, Martin ^a   Clementi, Regina ^d   Bensen Kennedy, Debra ^e   Moliterno, Alison ^f  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b WEILL CORNELL MEDICAL COLLEGE   (United States)

^c MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^d Teva Branded Pharmaceutical Products R and D Inc   (United States)

^e Teva Branded Pharmaceutical Products RandD   (United States)

^f JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

CEP 701; Essential thrombocythaemia; JAK2 V617F mutation; Lestaurtinib; Polycythaemia vera

Indexed keywords

CEP 70; HEMOGLOBIN; HYDROXYUREA; JANUS KINASE 2; LESTAURTINIB; UNCLASSIFIED DRUG;

ABDOMINAL DISCOMFORT; ABDOMINAL PAIN; ADULT; AGED; ALLELE; ALLELE BURDEN; ARTICLE; CLINICAL ARTICLE; DIARRHEA; DIZZINESS; DOSE TIME EFFECT RELATION; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG FATALITY; DRUG RESPONSE; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSPEPSIA; FATIGUE; FEMALE; GASTROINTESTINAL SYMPTOM; HEMOGLOBIN BLOOD LEVEL; HUMAN; INCREASED APPETITE; JAK2 GENE; LIMB PAIN; MALE; MAXIMUM PLASMA CONCENTRATION; MULTICENTER STUDY; MUSCLE SPASM; MUTATION RATE; NAUSEA; NEUTROPHIL COUNT; OPEN STUDY; PERIPHERAL EDEMA; PHASE 1 CLINICAL TRIAL; PHLEBOTOMY; POLYCYTHEMIA VERA; PRIORITY JOURNAL; SOMATIC MUTATION; SPLEEN SIZE; THROMBOCYTE COUNT; THROMBOCYTHEMIA; THROMBOSIS; TIME TO MAXIMUM PLASMA CONCENTRATION; UNSPECIFIED SIDE EFFECT; VERY ELDERLY; VOMITING; WEIGHT GAIN;

CEP-701; ESSENTIAL THROMBOCYTHAEMIA; JAK2-V617F MUTATION; LESTAURTINIB; POLYCYTHAEMIA VERA;

ADULT; AGED; AGED, 80 AND OVER; CARBAZOLES; FEMALE; HUMANS; JANUS KINASE 2; MALE; MIDDLE AGED; MUTATION; POLYCYTHEMIA VERA; PROTEIN KINASE INHIBITORS; THROMBOCYTHEMIA, ESSENTIAL; TREATMENT OUTCOME;

EID: 84889596004     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/bjh.12607     Document Type: Article

References (31)

1. Antonioli, E., Carobbio, A., Pieri, L., Pancrazzi, A., Guglielmelli, P., Delaini, F., Ponziani, V., Bartalucci, N., Tozzi, L., Bosi, A., Rambaldi, A., Barbui, T. & Vannucchi, A.M. (2010) Hydroxyurea does not appreciably reduce JAK2 V617F allele burden in patients with polycythemia vera or essential thrombocythemia. Haematologica, 95, 1435-1438.
2. Baxter, E.J., Scott, L.M., Campbell, P.J., East, C., Fourouclas, N., Swanton, S., Vassiliou, G.S., Bench, A.J., Boyd, E.M., Curtin, N., Scott, M.A., Erber, W.N. & Green, A.R. (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet, 365, 1054-1061.
3. Berk, P.D., Goldberg, J.D., Silverstein, M.N., Weinfeld, A., Donovan, P.B., Ellis, J.T., Landaw, S.A., Laszlo, J., Najean, Y., Pisciotta, A.V. & Wasserman, L.R. (1981) Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. New England Journal of Medicine, 304, 441-447.
4. Cortelazzo, S., Finazzi, G., Ruggeri, M., Vestri, O., Galli, M., Rodeghiero, F. & Barbui, T. (1995) Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. New England Journal of Medicine, 332, 1132-1136.
5. Guglielmelli, P., Biamonte, F., Score, J., Hidalgo-Curtis, C., Cervantes, F., Maffioli, M., Fanelli, T., Ernst, T., Winkelman, N., Jones, A.V., Zoi, K., Reiter, A., Duncombe, A., Villani, L., Bosi, A., Barosi, G., Cross, N.C. & Vannucchi, A.M. (2011) EZH2 mutational status predicts poor survival in myelofibrosis. Blood, 118, 5227-5234.
6. Harrison, C.N., Campbell, P.J., Buck, G., Wheatley, K., East, C.L., Bareford, D., Wilkins, B.S., van der Walt, J.D., Reilly, J.T., Grigg, A.P., Revell, P., Woodcock, B.E. & Green, A.R. (2005) Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. New England Journal of Medicine, 353, 33-45.
7. Harrison, C., Kiladjian, J.J., Al-Ali, H.K., Gisslinger, H., Waltzman, R., Stalbovskaya, V., McQuitty, M., Hunter, D.S., Levy, R., Knoops, L., Cervantes, F., Vannucchi, A.M., Barbui, T. & Barosi, G. (2012) JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. New England Journal of Medicine, 366, 787-798.
8. Hexner, E.O., Serdikoff, C., Jan, M., Swider, C.R., Robinson, C., Yang, S., Angeles, T., Emerson, S.G., Carroll, M., Ruggeri, B. & Dobrzanski, P. (2008) Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood, 111, 5663-5671.
9. James, C., Ugo, V., Le Couedic, J.P., Staerk, J., Delhommeau, F., Lacout, C., Garcon, L., Raslova, H., Berger, R., Bennaceur-Griscelli, A., Villeval, J.L., Constantinescu, S.N., Casadevall, N. & Vainchenker, W. (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature, 434, 1144-1148.
10. Jones, A.V., Kreil, S., Zoi, K., Waghorn, K., Curtis, C., Zhang, L., Score, J., Seear, R., Chase, A.J., Grand, F.H., White, H., Zoi, C., Loukopoulos, D., Terpos, E., Vervessou, E.C., Schultheis, B., Emig, M., Ernst, T., Lengfelder, E., Hehlmann, R., Hochhaus, A., Oscier, D., Silver, R.T., Reiter, A. & Cross, N.C. (2005) Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood, 106, 2162-2168.
11. Kiladjian, J.J., Cassinat, B., Turlure, P., Cambier, N., Roussel, M., Bellucci, S., Menot, M.L., Massonnet, G., Dutel, J.L., Ghomari, K., Rousselot, P., Grange, M.J., Chait, Y., Vainchenker, W., Parquet, N., Abdelkader-Aljassem, L., Bernard, J.F., Rain, J.D., Chevret, S., Chomienne, C. & Fenaux, P. (2006) High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a. Blood, 108, 2037-2040.
12. Kiladjian, J.J., Cassinat, B., Chevret, S., Turlure, P., Cambier, N., Roussel, M., Bellucci, S., Grandchamp, B., Chomienne, C. & Fenaux, P. (2008) Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood, 112, 3065-3072.
13. Klco, J.M., Vij, R., Kreisel, F.H., Hassan, A. & Frater, J.L. (2010) Molecular pathology of myeloproliferative neoplasms. American Journal of Clinical Pathology, 133, 602-615.
14. Kralovics, R., Passamonti, F., Buser, A.S., Teo, S.S., Tiedt, R., Passweg, J.R., Tichelli, A., Cazzola, M. & Skoda, R.C. (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. New England Journal of Medicine, 352, 1779-1790.
15. Landolfi, R., Marchioli, R., Kutti, J., Gisslinger, H., Tognoni, G., Patrono, C. & Barbui, T. (2004) Efficacy and safety of low-dose aspirin in polycythemia vera. New England Journal of Medicine, 350, 114-124.
16. Levine, R.L., Wadleigh, M., Cools, J., Ebert, B.L., Wernig, G., Huntly, B.J., Boggon, T.J., Wlodarska, I., Clark, J.J., Moore, S., Adelsperger, J., Koo, S., Lee, J.C., Gabriel, S., Mercher, T., D'Andrea, A., Frohling, S., Dohner, K., Marynen, P., Vandenberghe, P., Mesa, R.A., Tefferi, A., Griffin, J.D., Eck, M.J., Sellers, W.R., Meyerson, M., Golub, T.R., Lee, S.J. & Gilliland, D.G. (2005) Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell, 7, 387-397.
17. Levis, M., Ravandi, F., Wang, E.S., Baer, M.R., Perl, A., Coutre, S., Erba, H., Stuart, R.K., Baccarani, M., Cripe, L.D., Tallman, M.S., Meloni, G., Godley, L.A., Langston, A.A., Amadori, S., Lewis, I.D., Nagler, A., Stone, R., Yee, K., Advani, A., Douer, D., Wiktor-Jedrzejczak, W., Juliusson, G., Litzow, M.R., Petersdorf, S., Sanz, M., Kantarjian, H.M., Sato, T., Tremmel, L., Bensen-Kennedy, D.M., Small, D. & Smith, B.D. (2011) Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood, 117, 3294-3301.
18. Li, J., Spensberger, D., Ahn, J.S., Anand, S., Beer, P.A., Ghevaert, C., Chen, E., Forrai, A., Scott, L.M., Ferreira, R., Campbell, P.J., Watson, S.P., Liu, P., Erber, W.N., Huntly, B.J., Ottersbach, K. & Green, A.R. (2010) JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Blood, 116, 1528-1538.
19. Moliterno, A.R., Williams, D.M., Rogers, O. & Spivak, J.L. (2006) Molecular mimicry in the chronic myeloproliferative disorders: reciprocity between quantitative JAK2 V617F and Mpl expression. Blood, 108, 3913-3915.
20. Moliterno, A.R., Williams, D.M., Rogers, O., Isaacs, M.A. & Spivak, J.L. (2008) Phenotypic variability within the JAK2 V617F-positive MPD: roles of progenitor cell and neutrophil allele burdens. Experimental Hematology, 36, 1480-1486.
21. Pardanani, A., Gotlib, J.R., Jamieson, C., Cortes, J.E., Talpaz, M., Stone, R.M., Silverman, M.H., Gilliland, D.G., Shorr, J. & Tefferi, A. (2011) Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. Journal of Clinical Oncology, 29, 789-796.
22. Santos, F.P., Kantarjian, H.M., Jain, N., Manshouri, T., Thomas, D.A., Garcia-Manero, G., Kennedy, D., Estrov, Z., Cortes, J. & Verstovsek, S. (2010) Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood, 115, 1131-1136.
23. Scott, L.M., Scott, M.A., Campbell, P.J. & Green, A.R. (2006) Progenitors homozygous for the V617F mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. Blood, 108, 2435-2437.
24. Stein, B.L. & Moliterno, A.R. (2010) Primary myelofibrosis and the myeloproliferative neoplasms: the role of individual variation. JAMA: the Journal of the American Medical Association, 303, 2513-2518.
25. Stein, B.L., Williams, D.M., Wang, N.Y., Rogers, O., Isaacs, M.A., Pemmaraju, N., Spivak, J.L. & Moliterno, A.R. (2010) Sex differences in the JAK2 V617F allele burden in chronic myeloproliferative disorders. Haematologica, 95, 1090-1097.
26. Stein, B.L., Williams, D.M., O'Keefe, C., Rogers, O., Ingersoll, R.G., Spivak, J.L., Verma, A., Maciejewski, J.P., McDevitt, M.A. & Moliterno, A.R. (2011) Disruption of the ASXL1 gene is frequent in primary, post-essential thrombocytosis and post-polycythemia vera myelofibrosis, but not essential thrombocytosis or polycythemia vera: analysis of molecular genetics and clinical phenotypes. Haematologica, 96, 1462-1469.
27. Ugo, V., Marzac, C., Teyssandier, I., Larbret, F., Lecluse, Y., Debili, N., Vainchenker, W. & Casadevall, N. (2004) Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera. Experimental Hematology, 32, 179-187.
28. Vannucchi, A.M., Antonioli, E., Guglielmelli, P., Pardanani, A. & Tefferi, A. (2008) Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia, 22, 1299-1307.
29. Verstovsek, S. (2009) Therapeutic potential of JAK2 inhibitors. Hematology: American Society of Hematology Education Program, 2009, 636-642.
30. Verstovsek, S., Mesa, R.A., Gotlib, J., Levy, R.S., Gupta, V., DiPersio, J.F., Catalano, J.V., Deininger, M., Miller, C., Silver, R.T., Talpaz, M., Winton, E.F., Harvey, J.H. Jr, Arcasoy, M.O., Hexner, E., Lyons, R.M., Paquette, R., Raza, A., Vaddi, K., Erickson-Viitanen, S., Koumenis, I.L., Sun, W., Sandor, V. & Kantarjian, H.M. (2012) A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. New England Journal of Medicine, 366, 799-807.
31. Zalcberg, I.R., Ayres-Silva, J., de Azevedo, A.M., Solza, C., Daumas, A. & Bonamino, M. (2011) Hydroxyurea dose impacts hematologic parameters in polycythemia vera and essential thrombocythemia but does not appreciably affect JAK2-V617F allele burden. Haematologica, 96, e18-e20.