SEARCH:   Advanced

Blood, 15 January 2007, Vol. 109, No. 2, pp. 500-502. Prepublished online as a Blood First Edition Paper on September 21, 2006; DOI 10.1182/blood-2006-05-025049. This Article Abstract Full Text (PDF) All Versions of this Article: blood-2006-05-025049v1 109/2/500    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Giles, F. J. Articles by Freedman, S. J. Search for Related Content PubMed PubMed Citation Articles by Giles, F. J. Articles by Freedman, S. J. Related Collections Brief Reports Clinical Trials and Observations Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Brief report MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation Francis J. Giles1,, Jorge Cortes1, Dan Jones1, Donald Bergstrom2, Hagop Kantarjian1, and Steven J. Freedman2 1 Departments of Leukemia and Pathology, M. D. Anderson Cancer Center, Houston, TX; 2 Department of Clinical Oncology, Merck, Blue Bell, PA    Abstract Top Abstract Introduction Patients, materials, and methods Results and discussion References   MK-0457 (VX-680) is a small-molecule aurora kinase (AK) inhibitor with preclinical antileukemia activity. The T315I BCR-ABL mutation mediates resistance to imatinib, nilotinib, and dasatinib. MK-0457 has in vitro activity against cells expressing wild-type or mutated BCR-ABL, including the T315I BCR-ABL mutation. Three patients with T315I abl-mutated chronic myeloid leukemia (CML) or Philadelphia chromosome (Ph)–positive acute lymphocytic leukemia (ALL) have achieved clinical responses to doses of MK-04547 that are not associated with adverse events. Higher MK-0457 dose levels were associated with clinical responses and down-regulation of CrkL phosphorylation in leukemia cells. The possible role of AK inhibition in these clinical responses requires further investigation. The currently reported cases are the first observed clinical activity of a kinase inhibitor against the T315I phenotype. The observation of responses in 3 patients with T315I phenotype–refractory CML or Ph-positive ALL, at doses of MK-0457 associated with no significant extramedullary toxicity, is very encouraging.    Introduction Top Abstract Introduction Patients, materials, and methods Results and discussion References   The aurora kinases (AKs) are essential for the regulation of mitotic chromosome segregation and cytokinesis. Aberrant AK activity occurs in many human tumors.1 MK-0457 (VX-680) is a small-molecule AK and Janus kinase 2 (JAK-2) inhibitor that blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types.2,3 It causes profound inhibition of tumor growth in xenograft leukemia models.2 The T315I BCR-ABL mutation mediates clinical resistance to imatinib, nilotinib, and dasatinib.4 MK-0457 has in vitro activity against cells expressing wild-type and mutated BCR-ABL, including the T315I BCR-ABL mutation.5 To date, 3 patients with T315I abl-mutated chronic myeloid leukemia (CML) or Philadelphia chromosome (Ph)–positive acute lymphocytic leukemia (ALL) have been enrolled in an ongoing phase 1/2 study of MK-0457 for patients with refractory hematologic malignancies. We report here that MK-0457 is the first kinase inhibitor with clinical activity against this abl-mutated phenotype.    Patients, materials, and methods Top Abstract Introduction Patients, materials, and methods Results and discussion References   Patients receive a 5-day continuous intravenous infusion (CIV) at 2- to 3-week intervals with dose escalation of MK-0457 in successive cohorts of 3 patients per dose level. Maximum tolerated dose (MTD) has not been reached with the 8, 12, 16, 20, 24, 28, and 32 mg/m2/h dose levels. Intrapatient dose escalation is allowed. A nested polymerase chain reaction (PCR) strategy followed by direct DNA sequencing using the dideoxy-chain termination method was used to detect mutations in codons 221 to 500 of the BCR-ABL kinase domain. The protocol was approved by the MD Anderson Cancer Center (MDACC) Institutional Review Board and all patients provided written informed consent.    Results and discussion Top Abstract Introduction Patients, materials, and methods Results and discussion References   The first patient with a T315I BCR-ABL mutation treated on study is a 53-year-old male diagnosed with CML in November 2001. Therapy was commenced with imatinib 400 mg per day resulting in a 15-month complete hematologic response (CHR). In May 2003, he lost CHR and commenced imatinib at 600 mg per day. In June 2003, the white blood cell (WBC) count was 430 x 109/L despite additional hydroxyurea, and the patient was referred to MDACC. He declined stem cell transplantation (SCT) and was treated with imatinib, hydroxyurea, and pegylated alpha interferon until March 2005 without hematologic response. The patient returned to MDACC with accelerated-phase (AP) CML and commenced therapy with nilotinib 600 mg twice a day in April 2005.6 The patient had a transient response to nilotinib, which was discontinued in July 2005 when the T315I BCR-ABL mutation was detected. The patient was then treated with, and did not respond to, KOS-953 (17-allylamino-17-demethoxy-geldanamycin), an HSP-90 inhibitor.7 He commenced therapy with MK-0457 at a dose of 12 mg/m2/h in November 2005. By day 11 of cycle 1, the patient was pancytopenic with a WBC count of 0.4 x 109/L, hemoglobin (Hb) level of 76 g/L (7.6 g/dL), and platelet count of 31 x 109/L. These counts rapidly recovered, and 2 weeks later on day 1 of cycle 2 of therapy, the WBC count was 77 x 109/L, Hb level was 120 g/L (12 g/dL), and platelet count was 698 x 109/L. In the initial 4 cycles, this pattern was repeated (Figure 1) with an initial decrease in WBCs and a subsequent rise, with a steady increase, in platelet count to greater than 1000 x 109/L by end of cycle 4. Cycle 10 of therapy began in April 2006 at the 20 mg/m2/h dose level at which time the patient was in chronic phase. The patient continues on MK-0457 therapy and has decreasing levels of T315I, with the latest result (July 2006) showing that 90% of PCR product is T315I. View larger version (22K): [in this window] [in a new window]   Figure 1. WBC response to MK-0457 therapy in a patient with imatinib- and nilotinib-resistant T315I BCR-ABL–positive CML.   The second patient with a T315I BCR-ABL mutation treated on study was a 33-year-old female diagnosed with CML in 1997. Following 6 months of hydroxyurea and alpha interferon therapy, she commenced imatinib, which she received at doses up to 800 mg daily until August 2005, at which time she had failed to achieve CHR and commenced dasatinib therapy.8 After a transient response, she was taken off study in October 2005 secondary to lack of response. She was then referred to MDACC with refractory AP and was documented to have the T315I BCR-ABL mutation. The patient commenced therapy with MK-0457 at the 16 mg/m2/h dose level in January 2006. Repeat PCR-based DNA sequencing of BCR-ABL no longer detected the presence of the T315I mutation after cycles 1 and 2 of therapy. The patient achieved hematologic response in June 2006 when receiving the 24 mg/m2/h dose level and continues on MK-0457 single-agent therapy. The third patient with the T315I BCR-ABL mutation is a 63-year-old male diagnosed with Ph-positive ALL in December 2003. He achieved CHR to standard induction therapy and received both systemic and intrathecal consolidation therapy. No cytogenetic response was achieved, and in September 2005 relapse was evident. He commenced dasatinib (70 mg twice a day) therapy. He achieved CHR and a diploid karyotype by November 2005. In January 2006, responses were lost and the dasatinib dose increased to 90 mg twice a day. The patient suffered recurrent lower nonthrombocytopenia-related gastrointestinal bleeding and dasatinib was discontinued in February 2006. The patient was then referred to MDACC and documented to have the T315I BCR-ABL mutation. The patient commenced therapy with MK-0457 at the 20 mg/m2/h dose level in March 2006. At the time of study entry the patient had a WBC count of 15 x 109/L with 81% blasts. Following 2 cycles of therapy the patient had a CHR and stopped therapy to prepare for SCT, at which time the T315I was still dominant in the bone marrow. BCR-ABL inhibition was monitored by performing peripheral blood flow cytometry for phosphorylation of CrkL, a BCR-ABL substrate,9 at baseline and after the first MK-0457 cycle. In the CML patients treated initially at the 12 mg/m2/h and 16 mg/m2/h dose levels, the maximal plasma concentration of MK-0457 did not exceed 1 µM and no inhibition of pCrkL was detected. In the Ph-positive ALL patient dosed at 20 mg/m2, the peak plasma concentration of MK-0457 exceeded 1 µM and pCrkL inhibition was detected. Both CML patients went on to achieve objective responses at dose levels of 20 mg/m2/h and 24 mg/m2/h, respectively, at which dose-level exposures exceed 1 µM. Carter et al5 reported that with a 2-hour exposure to MK-0457, the 50% inhibitory concentration (IC50) for inhibition of T315I BCR-ABL autophosphorylation in Ba/F3 cells was approximately 5 µM, which was significantly higher than their reported binding constant and IC50 for ABL enzymatic inhibition in vitro. On our analysis in T315I cell lines and leukemia cells, the IC50 for inhibition of BCR-ABL autophosphorylation with a 6-hour MK-0457 exposure is approximately 400 nM. Further data are needed on the relationship between MK-0457 pharmacokinetics and its clinical activity. The only established therapeutic option for patients with the T315I BCR-ABL mutation is SCT.4,10 Young et al11 have presented a high-resolution crystal structure of the catalytic domain of a mutant form of Abl kinase (H396P), associated with imatinib resistance, in complex with MK-0457. MK-0457's binding to Abl accommodates the substitution of isoleucine for threonine at residue 315 (the "gatekeeper" position).4,11 MK-0457's avoidance of the innermost Abl kinase domain cavity may explain its activity against mutant forms of Bcr-Abl, including T315.11The currently reported cases document the first observed clinical responses to a kinase inhibitor in the T315I phenotype. The relative contributions of AK, BCR-ABL, and JAK-2 inhibition have not been established. Responses in patients with refractory CML or Ph-positive ALL at doses of MK-0457 associated with no significant extramedullary toxicity are very encouraging.    Acknowledgments   This work was supported by a research grant from Merck.    Footnotes   Submitted May 25, 2006; accepted August 27, 2006. Prepublished online as Blood First Edition Paper, September 21, 2006 DOI: 10.1182/blood-2006-05-025049 Contribution: F.J.G. designed research, performed research, analyzed data, and wrote the paper; J.C., D.J., and H.K. performed research, analyzed data, and wrote the paper; and D.B. and S.J.F. designed research, analyzed data, and wrote the paper. An Inside Blood analysis of this article appears at the front of this issue. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. Conflict-of-interest disclosure: D.B. and S.J.F. are employed by Merck, whose product (MK-0457) was studied in the present work. Correspondence: Francis J. Giles,The University of Texas M. D. Anderson Cancer Center, Department of Leukemia, 1400 Holcombe Blvd, Box 428, Houston, TX 77030; e-mail: frankgiles{at}aol.com.    References Top Abstract Introduction Patients, materials, and methods Results and discussion References   Matthews N, Visintin C, Hartzoulakis B, Jarvis A, Selwood DL. Aurora A and B kinases as targets for cancer: will they be selective for tumors? Expert Rev Anticancer Ther 2006; 6:109–120.[CrossRef][Medline] [Order article via Infotrieve] Harrington EA, Bebbington D, Moore J, et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 2004; 10:262–267.[CrossRef][Medline] [Order article via Infotrieve] Samanta AK, Lin H, Sun T, Kantarjian H, Arlinghaus RB. Janus kinase 2: a critical target in chronic myelogenous leukemia. Cancer Res 2006; 66:6468–6472.[Abstract/Free Full Text] O'Hare T, Corbin AS, Druker BJ. Targeted CML therapy: controlling drug resistance, seeking cure. Curr Opin Genet Dev 2006; 16:92–99.[CrossRef][Medline] [Order article via Infotrieve] Carter TA, Wodicka LM, Shah NP, et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A 2005; 102:11011–11016.[Abstract/Free Full Text] Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006; 354:2542–2551.[Abstract/Free Full Text] Georgakis GV and Younes A. Heat-shock protein 90 inhibitors in cancer therapy: 17AAG and beyond. Future Oncol 2005; 1:273–281. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006; 354:2531–2541.[Abstract/Free Full Text] Singer CF, Hudelist G, Lamm W, et al. Active (p)CrkL is overexpressed in human malignancies: potential role as a surrogate parameter for therapeutic tyrosine kinase inhibition. Oncol Rep 2006; 15:353–359.[Medline] [Order article via Infotrieve] Jabbour E, Cortes J, Kantarjian HM, et al. Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after BCR-ABL kinase mutation-related imatinib failure. Blood 2006; 108:1421–1423.[Abstract/Free Full Text] Young MA, Shah NP, Chao LH, et al. Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680. Cancer Res 2006; 66:1007–1014.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: MK-0457: a light at the end of the tunnel? Giovanni Martinelli, Simona Soverini, Ilaria Iacobucci, and Michele Baccarani Blood 2007 109: 396-397. [Full Text] [PDF] This article has been cited by other articles: E. Jabbour, H. Kantarjian, D. Jones, M. Breeden, G. Garcia-Manero, S. O'Brien, F. Ravandi, G. Borthakur, and J. Cortes Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy Blood, July 1, 2008; 112(1): 53 - 55. [Abstract] [Full Text] [PDF] I. Samudio, S. Kurinna, P. Ruvolo, B. Korchin, H. Kantarjian, M. Beran, K. Dunner Jr., S. Kondo, M. Andreeff, and M. Konopleva Inhibition of mitochondrial metabolism by methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate induces apoptotic or autophagic cell death in chronic myeloid leukemia cells Mol. Cancer Ther., May 1, 2008; 7(5): 1130 - 1139. [Abstract] [Full Text] [PDF] A. M. D'Alise, G. Amabile, M. Iovino, F. P. Di Giorgio, M. Bartiromo, F. Sessa, F. Villa, A. Musacchio, and R. Cortese Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells Mol. Cancer Ther., May 1, 2008; 7(5): 1140 - 1149. [Abstract] [Full Text] [PDF] A. Gontarewicz, S. Balabanov, G. Keller, R. Colombo, A. Graziano, E. Pesenti, D. Benten, C. Bokemeyer, W. Fiedler, J. Moll, et al. Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I Blood, April 15, 2008; 111(8): 4355 - 4364. [Abstract] [Full Text] [PDF] T. O'Hare, C. A. Eide, J. W. Tyner, A. S. Corbin, M. J. Wong, S. Buchanan, K. Holme, K. A. Jessen, C. Tang, H. A. Lewis, et al. SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib PNAS, April 8, 2008; 105(14): 5507 - 5512. [Abstract] [Full Text] [PDF] L. K. Kenealy, C. B. Christenson, and C. B. Williams Current Therapies for Chronic Myeloid Leukemia Journal of Pharmacy Practice, April 1, 2008; 21(2): 116 - 125. [Abstract] [PDF] P. Ramirez and J. F. DiPersio Therapy Options in Imatinib Failures Oncologist, April 1, 2008; 13(4): 424 - 434. [Abstract] [Full Text] [PDF] O. Gautschi, J. Heighway, P. C. Mack, P. R. Purnell, P. N. Lara Jr., and D. R. Gandara Aurora Kinases as Anticancer Drug Targets Clin. Cancer Res., March 15, 2008; 14(6): 1639 - 1648. [Abstract] [Full Text] [PDF] X.-F. Huang, S.-K. Luo, J. Xu, J. Li, D.-R. Xu, L.-H. Wang, M. Yan, X.-R. Wang, X.-B. Wan, F.-M. Zheng, et al. Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia Blood, March 1, 2008; 111(5): 2854 - 2865. [Abstract] [Full Text] [PDF] H. M Marshall and J. M Hammond Treatment Options in Imatinib-Resistant Chronic Myelogenous Leukemia Ann. Pharmacother., February 1, 2008; 42(2): 259 - 264. [Abstract] [Full Text] [PDF] M. Wetzler Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia: On Target to Improve Outcome ASCO Educational Book, January 1, 2008; 2008(1): 275 - 279. [Abstract] [Full Text] [PDF] J. McLaughlin, D. Cheng, O. Singer, R. U. Lukacs, C. G. Radu, I. M. Verma, and O. N. Witte Sustained suppression of Bcr-Abl-driven lymphoid leukemia by microRNA mimics PNAS, December 18, 2007; 104(51): 20501 - 20506. [Abstract] [Full Text] [PDF] P. Carpinelli, R. Ceruti, M. L. Giorgini, P. Cappella, L. Gianellini, V. Croci, A. Degrassi, G. Texido, M. Rocchetti, P. Vianello, et al. PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer Mol. Cancer Ther., December 1, 2007; 6(12): 3158 - 3168. [Abstract] [Full Text] [PDF] J. M. Goldman How I treat chronic myeloid leukemia in the imatinib era Blood, October 15, 2007; 110(8): 2828 - 2837. [Abstract] [Full Text] [PDF] H. de Lavallade, J. S. Khorashad, H. P. Davis, D. Milojkovic, J. S. Kaeda, J. M. Goldman, J. F. Apperley, and D. Marin Interferon-{alpha} or homoharringtonine as salvage treatment for chronic myeloid leukemia patients who acquire the T315I BCR-ABL mutation Blood, October 1, 2007; 110(7): 2779 - 2780. [Full Text] [PDF] T. O'Hare, C. A. Eide, and M. W. N. Deininger Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia Blood, October 1, 2007; 110(7): 2242 - 2249. [Abstract] [Full Text] [PDF] E. L. Kwak, J. W. Clark, and B. Chabner Targeted Agents: The Rules of Combination Clin. Cancer Res., September 15, 2007; 13(18): 5232 - 5237. [Abstract] [Full Text] [PDF] J. Yang, T. Ikezoe, C. Nishioka, T. Tasaka, A. Taniguchi, Y. Kuwayama, N. Komatsu, K. Bandobashi, K. Togitani, H. P. Koeffler, et al. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo Blood, September 15, 2007; 110(6): 2034 - 2040. [Abstract] [Full Text] [PDF] J. E. Ballard, T. Prueksaritanont, and C. Tang Hepatic Metabolism of MK-0457, a Potent Aurora Kinase Inhibitor: Interspecies Comparison and Role of Human Cytochrome P450 and Flavin-Containing Monooxygenase Drug Metab. Dispos., September 1, 2007; 35(9): 1447 - 1451. [Abstract] [Full Text] [PDF] F. E. Nicolini, S. Hayette, S. Corm, E. Bachy, D. Bories, M. Tulliez, F. Guilhot, L. Legros, F. Maloisel, J.-J. Kiladjian, et al. Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a T315I BCR-ABL mutation Haematologica, September 1, 2007; 92(9): 1238 - 1241. [Abstract] [Full Text] [PDF] G. Dasmahapatra, N. Yerram, Y. Dai, P. Dent, and S. Grant Synergistic Interactions between Vorinostat and Sorafenib in Chronic Myelogenous Leukemia Cells Involve Mcl-1 and p21CIP1 Down-Regulation Clin. Cancer Res., July 15, 2007; 13(14): 4280 - 4290. [Abstract] [Full Text] [PDF] T. Ikezoe, J. Yang, C. Nishioka, T. Tasaka, A. Taniguchi, Y. Kuwayama, N. Komatsu, K. Bandobashi, K. Togitani, H. P. Koeffler, et al. A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia Mol. Cancer Ther., June 1, 2007; 6(6): 1851 - 1857. [Abstract] [Full Text] [PDF] S. O'Brien Dasatinib in accelerated phase Blood, May 15, 2007; 109(10): 4110 - 4110. [Full Text] [PDF] S. Soverini, S. Colarossi, A. Gnani, F. Castagnetti, G. Rosti, C. Bosi, S. Paolini, M. Rondoni, P. P. Piccaluga, F. Palandri, et al. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain Haematologica, March 1, 2007; 92(3): 401 - 404. [Abstract] [Full Text] [PDF] N. P. Shah Medical Management of CML Hematology, January 1, 2007; 2007(1): 371 - 375. [Abstract] [Full Text] [PDF] S. Branford Chronic Myeloid Leukemia: Molecular Monitoring in Clinical Practice Hematology, January 1, 2007; 2007(1): 376 - 383. [Abstract] [Full Text] [PDF] D. A. Thomas Philadelphia Chromosome Positive Acute Lymphocytic Leukemia: A New Era of Challenges Hematology, January 1, 2007; 2007(1): 435 - 443. [Abstract]