Leukemia & Lymphoma, June 2015; 56(6): 1581–1582 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.970549
COMMENTARY
Overcoming treatment challenges in imatinib-resistant chronic myelogenous leukemia Dany A. Curi1,2, Elspeth M. Beauchamp2 & Leonidas C. Platanias2,3
Leuk Lymphoma Downloaded from informahealthcare.com by University of Otago on 07/02/15 For personal use only.
¹Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Department of Pediatrics, Ann and Robert H. Lurie Children’s Hospital, Chicago, IL, USA,2Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA and 3Jesse Brown VA Medical Center, Chicago, IL, USA
Leukemia and Lymphoma, Yin et al. provide evidence of antileukemic effects in vitro in imatinib-resistant CML cells, by targeting the kinesin spindle protein (KSP) [20]. KSP has been shown to play an important role in mitotic progression, and is an attractive target in cancer cells due to high levels of expression [21]. Yin et al. show an increase in expression of KSP in BCR–ABL positive cells, including cells harboring the T315I mutation as well as CD34 ⫹ stem cells. In studies using the KSP inhibitor SB7433921, they found that KSP inhibition causes mitotic arrest and promotes apoptosis of Ph⫹ cell lines with or without the T315I mutation [20]. These data raise the possibility that targeting KSP may ultimately provide a new approach in the treatment of patients with BCR–ABL-positive CML with or without kinase domain mutations. Importantly, the authors also provide some evidence that KSP inhibitors are effective in targeting CD34 ⫹ stem cells and sensitize these cells to TKI treatment [20]. Although further studies are necessary to confirm these results, the data presented by Yin et al. raise the possibility of a unique way to target Ph⫹ cells, especially those resistant to current therapies. Further research in this direction is warranted. In conclusion, despite significant changes over the past decade or so in the standard of care of patients with Ph⫹ CML, a subset of patients continue to develop resistance or intolerance to multiple TKI agents. It remains crucial that alternative therapeutic targets are explored and new agents are developed in order to overcome resistance, possibly with less adverse effects. Future work should definitively establish whether targeting KSP provides a useful target in BCR–ABL transformed cells and whether KSP inhibitors have clinicaltranslational potential for the treatment of CML.
The treatment of chronic myelogenous leukemia (CML) in the era of tyrosine kinase inhibitors (TKIs) has significantly improved patient survival [1]. Imatinib mesylate was first introduced in 2001 for the treatment of Philadelphia-positive (Ph⫹) CML and inhibits BCR–ABL-regulated pathways involved in leukemogenesis [2,3]. TKIs have emerged as firstline agents for newly diagnosed patients with CML in chronic phase (CP) [4,5]. Despite remarkable responses to TKIs, a subset of patients develop resistance and/or intolerance. The most common cause of imatinib resistance is due to mutations at the BCR–ABL kinase domain, with over 90 mutations identified thus far [6,7]. An additional problem is that patients who are non-compliant with therapy are less likely to achieve major molecular and complete cytogenetic responses [8,9]. Furthermore, TKIs do not fully target CML stem cells, and these cells can induce disease relapse in patients after the withdrawal of therapy [10–12]. Recently, newer agents have been Food and Drug Administration (FDA) approved to treat patients with CML who have failed two or more TKIs or who have the T315I kinase domain mutation. Ponatinib, a multi-targeted TKI, was first introduced in 2012 for patients who have failed other TKIs or who have the T315I kinase domain mutation [13–16]. However, at least one-quarter of patients develop severe vascular narrowing or thrombosis, which in most cases is life-threatening [16]. Another agent currently FDA approved is omacetaxine mepesuccinate, a non-TKI that inhibits protein translation [17]. It has also been shown to be effective in patients with the T315I BCR–ABL kinase domain mutation or who have failed multiple TKIs. However, significant adverse effects have also been reported [18,19]. Therefore, both of these agents may have limited effectiveness in many patients due to toxicity related events. As more patients develop resistance to the current chemotherapeutic options available, newer agents that interact with other pathways need to be explored. In this issue of
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
Correspondence: Leonidas C. Platanias, Jesse Brown VA Medical Center, Chicago, IL 60612, USA. E-mail: [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
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Leuk Lymphoma Downloaded from informahealthcare.com by University of Otago on 07/02/15 For personal use only.
References [1] O’Hare T, Deninger MW, Eide CA , et al. Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosomepositive leukemia. Clin Cancer Res 2011;17:212–221. [2] Chen Y, Fu L. Mechanisms of acquired resistance to tyrosine kinase inhibitors. Acta Pharm Sin B 2011;1:197–207. [3] Bixby DL. Managing inadequate responses to frontline treatment of chronic myeloid leukemia:a case-based review. Cancer Treat Rev 2013;39:241–251. [4] Milojkovic D, Apperley J. Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin Cancer Res 2009;15:7519–7527. [5] Goldman JM, Melo JV. Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med 2003 ; 349:1451–1464. [6] Lange T, Park B, Willis SG, et al. BCR-ABL kinase domain mutations in chronic myeloid leukemia not quite enough to cause resistance to imatinib therapy? Cell Cycle 2005;4:1761–1766. [7] Agarwal MB, Rathi SA . Will kinase domain mutations dictate the terms. Indian J Med Paediatr Oncol 2013;34:151–153. [8] Marin D, Bazeos A , Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010;28:2381–2388. [9] Ibrahim AR, Eliasson L, Apperley JF, et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood 2011;117:3733–3736. [10] Jorgensen HG, Holyoake TL. Characterization of cancer stem cells in chronic myeloid leukaemia. Biochem Soc Trans 2007;35:1347–1351. [11] Bhatia R, Holtz M, Niu N, et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 2003;101:4701–4707.
[12] Graham SM, Jorgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002;99:319–325. [13] Huang WS, Metcalf CA , Sundaramoorthi R, et al. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J Med Chem 2010;53:4701–4719. [14] O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a panBCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009;16:401–412. [15] Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in philadelphia chromosome-positive leukemias. N Engl J Med 2013;369:1783–1796. [16] National Cancer Institue. FDA approval for ponatinib hydrochloride. Available from: www.cancer.gov/cancertopics/ druginfo/fda-ponatinibhydrochloride [17] Wetzler M, Segal D. Omacetaxine as an anticancer therapeutic: what is old is new again. Curr Pharm Design 2011;17:59–64. [18] National Cancer Institute. FDA approval for omacetaxine mepesuccinate. Available from: www.cancer.gov/cancertopics/ druginfo/fda-omacetaxinemepesuccinate [19] Quintás-Cardama A , Kantarjian H, Cortes J. Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009. Cancer 2009:115:5382–5393. [20] Yin Y, Sun H, Xu J, et al. Kinesin spindle protein inhibitor SB743921 induces mitotic arrest and apoptosis and overcomes imatinib resistance of chronic myeloid leukemia cells. Leuk Lymphoma 2015;56: 1813–1820. [21] Sarli V, Giannis A . Targeting the kinesin spindle protein: basic principles and clinical implications. Clin Cancer Res 2008;14: 7583–7587.
COMMENTARY
Overcoming treatment challenges in imatinib-resistant chronic myelogenous leukemia Dany A. Curi1,2, Elspeth M. Beauchamp2 & Leonidas C. Platanias2,3
Leuk Lymphoma Downloaded from informahealthcare.com by University of Otago on 07/02/15 For personal use only.
¹Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Department of Pediatrics, Ann and Robert H. Lurie Children’s Hospital, Chicago, IL, USA,2Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA and 3Jesse Brown VA Medical Center, Chicago, IL, USA
Leukemia and Lymphoma, Yin et al. provide evidence of antileukemic effects in vitro in imatinib-resistant CML cells, by targeting the kinesin spindle protein (KSP) [20]. KSP has been shown to play an important role in mitotic progression, and is an attractive target in cancer cells due to high levels of expression [21]. Yin et al. show an increase in expression of KSP in BCR–ABL positive cells, including cells harboring the T315I mutation as well as CD34 ⫹ stem cells. In studies using the KSP inhibitor SB7433921, they found that KSP inhibition causes mitotic arrest and promotes apoptosis of Ph⫹ cell lines with or without the T315I mutation [20]. These data raise the possibility that targeting KSP may ultimately provide a new approach in the treatment of patients with BCR–ABL-positive CML with or without kinase domain mutations. Importantly, the authors also provide some evidence that KSP inhibitors are effective in targeting CD34 ⫹ stem cells and sensitize these cells to TKI treatment [20]. Although further studies are necessary to confirm these results, the data presented by Yin et al. raise the possibility of a unique way to target Ph⫹ cells, especially those resistant to current therapies. Further research in this direction is warranted. In conclusion, despite significant changes over the past decade or so in the standard of care of patients with Ph⫹ CML, a subset of patients continue to develop resistance or intolerance to multiple TKI agents. It remains crucial that alternative therapeutic targets are explored and new agents are developed in order to overcome resistance, possibly with less adverse effects. Future work should definitively establish whether targeting KSP provides a useful target in BCR–ABL transformed cells and whether KSP inhibitors have clinicaltranslational potential for the treatment of CML.
The treatment of chronic myelogenous leukemia (CML) in the era of tyrosine kinase inhibitors (TKIs) has significantly improved patient survival [1]. Imatinib mesylate was first introduced in 2001 for the treatment of Philadelphia-positive (Ph⫹) CML and inhibits BCR–ABL-regulated pathways involved in leukemogenesis [2,3]. TKIs have emerged as firstline agents for newly diagnosed patients with CML in chronic phase (CP) [4,5]. Despite remarkable responses to TKIs, a subset of patients develop resistance and/or intolerance. The most common cause of imatinib resistance is due to mutations at the BCR–ABL kinase domain, with over 90 mutations identified thus far [6,7]. An additional problem is that patients who are non-compliant with therapy are less likely to achieve major molecular and complete cytogenetic responses [8,9]. Furthermore, TKIs do not fully target CML stem cells, and these cells can induce disease relapse in patients after the withdrawal of therapy [10–12]. Recently, newer agents have been Food and Drug Administration (FDA) approved to treat patients with CML who have failed two or more TKIs or who have the T315I kinase domain mutation. Ponatinib, a multi-targeted TKI, was first introduced in 2012 for patients who have failed other TKIs or who have the T315I kinase domain mutation [13–16]. However, at least one-quarter of patients develop severe vascular narrowing or thrombosis, which in most cases is life-threatening [16]. Another agent currently FDA approved is omacetaxine mepesuccinate, a non-TKI that inhibits protein translation [17]. It has also been shown to be effective in patients with the T315I BCR–ABL kinase domain mutation or who have failed multiple TKIs. However, significant adverse effects have also been reported [18,19]. Therefore, both of these agents may have limited effectiveness in many patients due to toxicity related events. As more patients develop resistance to the current chemotherapeutic options available, newer agents that interact with other pathways need to be explored. In this issue of
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
Correspondence: Leonidas C. Platanias, Jesse Brown VA Medical Center, Chicago, IL 60612, USA. E-mail: [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
1581
1582
D. A. Curi et al.
Leuk Lymphoma Downloaded from informahealthcare.com by University of Otago on 07/02/15 For personal use only.
References [1] O’Hare T, Deninger MW, Eide CA , et al. Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosomepositive leukemia. Clin Cancer Res 2011;17:212–221. [2] Chen Y, Fu L. Mechanisms of acquired resistance to tyrosine kinase inhibitors. Acta Pharm Sin B 2011;1:197–207. [3] Bixby DL. Managing inadequate responses to frontline treatment of chronic myeloid leukemia:a case-based review. Cancer Treat Rev 2013;39:241–251. [4] Milojkovic D, Apperley J. Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin Cancer Res 2009;15:7519–7527. [5] Goldman JM, Melo JV. Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med 2003 ; 349:1451–1464. [6] Lange T, Park B, Willis SG, et al. BCR-ABL kinase domain mutations in chronic myeloid leukemia not quite enough to cause resistance to imatinib therapy? Cell Cycle 2005;4:1761–1766. [7] Agarwal MB, Rathi SA . Will kinase domain mutations dictate the terms. Indian J Med Paediatr Oncol 2013;34:151–153. [8] Marin D, Bazeos A , Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010;28:2381–2388. [9] Ibrahim AR, Eliasson L, Apperley JF, et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood 2011;117:3733–3736. [10] Jorgensen HG, Holyoake TL. Characterization of cancer stem cells in chronic myeloid leukaemia. Biochem Soc Trans 2007;35:1347–1351. [11] Bhatia R, Holtz M, Niu N, et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 2003;101:4701–4707.
[12] Graham SM, Jorgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002;99:319–325. [13] Huang WS, Metcalf CA , Sundaramoorthi R, et al. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J Med Chem 2010;53:4701–4719. [14] O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a panBCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009;16:401–412. [15] Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in philadelphia chromosome-positive leukemias. N Engl J Med 2013;369:1783–1796. [16] National Cancer Institue. FDA approval for ponatinib hydrochloride. Available from: www.cancer.gov/cancertopics/ druginfo/fda-ponatinibhydrochloride [17] Wetzler M, Segal D. Omacetaxine as an anticancer therapeutic: what is old is new again. Curr Pharm Design 2011;17:59–64. [18] National Cancer Institute. FDA approval for omacetaxine mepesuccinate. Available from: www.cancer.gov/cancertopics/ druginfo/fda-omacetaxinemepesuccinate [19] Quintás-Cardama A , Kantarjian H, Cortes J. Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009. Cancer 2009:115:5382–5393. [20] Yin Y, Sun H, Xu J, et al. Kinesin spindle protein inhibitor SB743921 induces mitotic arrest and apoptosis and overcomes imatinib resistance of chronic myeloid leukemia cells. Leuk Lymphoma 2015;56: 1813–1820. [21] Sarli V, Giannis A . Targeting the kinesin spindle protein: basic principles and clinical implications. Clin Cancer Res 2008;14: 7583–7587.
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