Abstract
Most patients with chronic myeloid leukemia (CML) achieve clinically relevant hematologic and cytogenetic responses to imatinib. Patients who show resistance to imatinib need new therapeutic options. A range of options are being developed to treat imatinib-resistant patients who have CML. Promising results of early-phase clinical trials have been reported for new tyrosine kinase inhibitors, farnesyl transferase inhibitors, decitabine, homoharringtonine, and vaccines. Further clinical trials are needed to characterize the efficacy and safety profile of these new agents and to determine which agents improve the long-term prognosis for patients with CML who have shown resistance to imatinib.
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References
O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004.
Corbin AS, Rosee PL, Stoffregen EP, Druker BJ, Deininger MW. Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood. 2003;101:4611–4614.
Donato NJ, Wu JY, Stapley J, et al. Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia. Cancer Res. 2004;64:672–677.
Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129–141.
Kantarjian H, Ottman J, Cortes J, et al. AMN107, a novel aminopy-rimidine inhibitor of Bcr-Abl, has significant activity in imatinib-resistant bcr-abl positive chronic myeloid leukemia (CML) [abstract]. J Clin Oncol. 2005;16:195s. Abstract 3014.
Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47:6658–6661.
Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399–401.
Talpaz M, Kantarjian H, Paquette R, et al. A phase I study of BMS-354825 in patients with imatinib-resistant and intolerant chronic phase chronic myeloid leukemia (CML): results from CA180002 [abstract]. J Clin Oncol. 2005;16S:564s. Abstract 6519.
Sawyers CL, Shah NP, Kantarjian H, et al. A phase I study of BMS-354825 in patients with imatinib-resistant and intolerant accelerated and blast phase chronic myeloid leukemia (CML): results from CA180002 [abstract]. J Clin Oncol. 2005;16S:565s. Abstract 6520.
O’Hare T, Pollock R, Stoffregen EP, et al. Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML. Blood. 2004;104:2532–2539.
Golas JM, Arndt K, Etienne C, et al. SKI-606, a 4-anilino-3-quino-linecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 2003;63:375–381.
Warmuth M, Simon N, Mitina O, et al. Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant Bcr-Abl kinases. Blood. 2003;101:664–672.
Sun X, Layton JE, Elefanty A, Lieschke GJ. Comparison of effects of the tyrosine kinase inhibitors AG957, AG490, and STI571 on BCR-ABL-expressing cells, demonstrating synergy between AG490 and STI571. Blood. 2001;97:2008–2015.
Mow BM, Chandra J, Svingen PA, et al. Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro. Blood. 2002;99:664–671.
Gumireddy K, Baker SJ, Cosenza SC, et al. A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance. Proc Natl Acad Sci U S A. 2005;102:1992–1997.
Gumireddy K, Reddy MV, Cosenza SC, et al. ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anti-cancer agent. Cancer Cell. 2005;7:275–286.
Cortes J, Albitar M, Thomas D, et al. Efficacy of the farnesyl trans-ferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood. 2003;101:1692–1697.
Karp JE, Lancet JE, Kaufmann SH, et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood. 2001;97:3361–3369.
Cortes J, Daley GQ,Talpaz M, et al. Pilot study of SCH66336 (lon-afarnib), a farnesyl transferase inhibitor (FTI), in patients with chronic myeloid leukemia (CML) in chronic or accelerated phase resistant or refractory to imatinib [abstract]. Blood. 2002;100:164a. Abstract 614.
Cortes J, Garcia-Manero G, O’Brien S, et al. A phase I study of tip-ifarnib in combination with imatinib mesylate for patients with chronic myeloid leukemia in chronic phase who failed IM therapy [abstract]. Blood. 2004;104. Abstract 1011.
Gotlib J, Mauro MJ, O’Dwyer M, et al. Tipifarnib (Zarnestra) and imatinib (Gleevec) combination therapy in patients with advanced chronic myelogenous leukemia (CML): preliminary results of a phase I study [abstract]. Blood. 2003;102:909a. Abstract 3384.
Cortes J, O’Brien S, Verstovsek S, et al. Phase I study of lonafarnib (SCH66336) in combination with imatinib for patients with chronic myeloid leukemia (CML) after failure to imatinib [abstract]. Blood. 2004;104. Abstract 1009.
Kantarjian HM, O’Brien S, Cortes J, et al. Results of decitabine (5-aza-2′deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer. 2003;98:522–528.
Issa JP, Garcia-Manero G, Giles FJ, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103:1635–1640.
Issa JP, Garcia-Manero G, Talpaz M, et al. Phase II Study of 5-aza-2′-deoxycytidine (decitabine) in patients with Philadelphia chromosome positive chronic myelogenous leukemia resistant or intolerant to imatinib mesylate [abstract]. Blood. 2003;102:910a. Abstract 3385.
O’Brien S, Kantarjian H, Keating M, et al. Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Blood. 1995;86:3322–3326.
O’Brien S, Giles F, Talpaz M, et al. Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase. Cancer. 2003;98:888–893.
Cortes J, O’Brien S, Verstovsek S, et al. Phase I study of subcutaneous (SC) homoharringtonine (HHT) for patients (pts) with chronic myelogenous leukemia (CML) [abstract]. In: program and abstracts of the 45th Annual Meeting and Exposition of the American Society of Hematology; December 6–9,2003; San Diego, Calif, USA. Abstract 5010.
Marin D, Kaeda JS, Andreasson C, et al. Phase I/II trial of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib. Cancer. 2005;103:1850–1855.
Pinilla-Ibarz J, Cathcart K, Korontsvit T, et al. Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses. Blood. 2000;95:1781–1787.
Cathcart K, Pinilla-Ibarz J, Korontsvit T, et al. A multivalent bcr-abl fusion peptide vaccination trial in patients with chronic myeloid leukemia. Blood. 2004;103:1037–1042.
Bocchia M, Gentili S, Abruzzese E, et al. Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial. Lancet. 2005;365:657–662.
Qazilbash MH, Wieder E, Rios R, et al. Vaccination with the PR1 leukemia-associated antigen can induce complete remission in patients with myeloid leukemia [abstract]. Blood. 2004;104:77a. Abstract 259.
Li Z, Qiao Y, Laska E, et al. Combination of imatinib mesylate with autologous leukocyte-derived heat shock protein 70 vaccine for chronic myelogenous leukemia [abstract]. Proc Am Soc Clin Oncol. 2003;22:166. Abstract 664.
Choi YJ, Wang Q, White S, Gorre ME, Sawyers CL, Bollag G. Ima-tinib-resistant cell lines are sensitive to the Raf inhibitor BAY 43-9006 [abstract]. Blood. 2002;100:369a. Abstract 1427.
Yu C, Krystal G, Varticovksi L, et al. Pharmacologic mitogen-activated protein/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase inhibitors interact synergisti-cally with STI571 to induce apoptosis in Bcr/Abl-expressing human leukemia cells. Cancer Res. 2002;62:188–199.
Sattler M, Mohi MG, Pride YB, et al. Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell. 2002;1:479–492.
Sekulic A, Hudson CC, Homme JL, et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 2000;60:3504–3513.
Mohi MG, Boulton C, Gu TL, et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci U S A. 2004;101:3130–3135.
Yu C, Krystal G, Dent P, Grant S. Flavopiridol potentiates STI571-induced mitochondrial damage and apoptosis in BCR-ABL-positive human leukemia cells. Clin Cancer Res. 2002;8:2976–2984.
Scherr M, Battmer K,Winkler T, Heidenreich O, Ganser A, Eder M. Specific inhibition of bcr-abl gene expression by small interfering RNA. Blood. 2003;101:1566–1569.
Wohlbold L, van der Kuip H, Miething C, et al. Inhibition of bcr-abl gene expression by small interfering RNA sensitizes for ima-tinib mesylate (STI571). Blood. 2003;102:2236–2239.
Nimmanapalli R, O’Bryan E, Bhalla K. Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts. Cancer Res. 2001;61:1799–1804.
Gorre ME, Ellwood-Yen K, Chiosis G, Rosen N, Sawyers CL. BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood. 2002;100:3041–3044.
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Kantarjian, H.M., Cortes, J. New Strategies in Chronic Myeloid Leukemia. Int J Hematol 83, 289–293 (2006). https://doi.org/10.1532/IJH97.06024
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DOI: https://doi.org/10.1532/IJH97.06024