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asciminib用于ABL激酶抑制剂治疗失败的慢性髓系白血病
Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure


Timothy P. Hughes ... 肿瘤 • 2019.12.12
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摘要


背景

asciminib是与BCR-ABL1蛋白的豆蔻酰位点相结合的别构抑制剂,它可通过不同于所有其他ABL激酶抑制剂的机制将BCR-ABL1锁定在非活性构象。asciminib同时靶向作用于天然和突变的BCR-ABL1,包括看门基因(gatekeeper)T315I突变体。asciminib用于费城染色体阳性白血病患者的安全性和抗白血病活性尚未明确。

 

方法

在这项1期剂量递增研究中,我们纳入了141例慢性期和9例加速期慢性髓系白血病(CML)患者,这些患者既往对至少两种ATP竞争性酪氨酸激酶抑制剂(TKI)耐药或发生不可接受的副作用。本试验的主要目的是确定asciminib的最大耐受剂量或推荐剂量(或这两者)。asciminib每日给药1次或2次(每次剂量为10~200 mg)。中位随访时间为14个月。

 

结果

患者既往接受过大量治疗,70%(105/150例患者)既往接受过至少3种TKI治疗。本试验未达到asciminib的最大耐受剂量。在慢性期CML患者中,基线时有血液学复发的34例(92%)患者达到了血液学完全缓解;基线时无细胞遗传学完全缓解的31例患者(54%)达到了细胞遗传学完全缓解。截至12个月时,在可评价的患者中,有48%达到或维持主要分子学缓解,包括被视为对普纳替尼(ponatinib)耐药或发生不可接受的副作用的14例患者中的8例(57%)。截至12个月时,在基线时有T315I突变的患者中,有5例(28%)达到或维持主要分子学缓解。临床缓解持久,44例患者中有40例维持主要分子学缓解。剂量限制性毒性作用包括无症状的脂肪酶水平升高和临床胰腺炎。常见不良事件包括疲劳、头痛、关节痛、高血压和血小板减少。

 

结论

在既往对TKI耐药或发生不可接受的副作用,并且接受过大量治疗的CML患者(包括普纳替尼治疗失败的患者和有T315I突变的患者)中,asciminib有活性(由诺华制药资助;在ClinicalTrials.gov注册号为NCT02081378)。





作者信息

Timothy P. Hughes, M.D., Michael J. Mauro, M.D., Jorge E. Cortes, M.D., Hironobu Minami, M.D., Delphine Rea, M.D., Daniel J. DeAngelo, M.D., Ph.D., Massimo Breccia, M.D., Yeow-Tee Goh, M.D., Moshe Talpaz, M.D., Andreas Hochhaus, M.D., Philipp le Coutre, M.D., Oliver Ottmann, M.D., Michael C. Heinrich, M.D., Juan L. Steegmann, M.D., Ph.D., Michael W.N. Deininger, M.D., Ph.D., Jeroen J.W.M. Janssen, M.D., Ph.D., Francois-Xavier Mahon, M.D., Yosuke Minami, M.D., Ph.D., David Yeung, M.D., David M. Ross, M.B., B.S., Ph.D., Martin S. Tallman, M.D., Jae H. Park, M.D., Brian J. Druker, M.D., David Hynds, M.S., Yuyan Duan, Ph.D., Christophe Meille, Ph.D., Florence Hourcade-Potelleret, Ph.D., K. Gary Vanasse, M.D., Fabian Lang, M.D., and Dong-Wook Kim, M.D., Ph.D.
From the South Australian Health and Medical Research Institute and the University of Adelaide, Adelaide, SA, Australia (T.P.H., D.Y., D.M.R.); Memorial Sloan Kettering Cancer Center, New York (M.J.M., M.S.T., J.H.P.); University of Texas M.D. Anderson Cancer Center, Houston (J.E.C.); Kobe University Graduate School of Medicine, Kobe (H.M.), and the National Cancer Center Hospital East, Chiba (Y.M.) — both in Japan; Hôpital Saint-Louis, Paris (D.R.), and the University of Bordeaux, Bordeaux (F.-X.M.) — both in France; Dana–Farber Cancer Institute, Boston (D.J.D.); Sapienza University, Rome (M.B.); Singapore General Hospital, Singapore (Y.-T.G.); University of Michigan Comprehensive Cancer Center, Ann Arbor (M.T.); Universitätsklinikum Jena, Jena (A.H.), Charité Hospital, Berlin (P.C.), and the Department for Hematology–Oncology, Goethe University Hospital, Frankfurt am Main (F.L.) — all in Germany; University of Cardiff, Cardiff, United Kingdom (O.O.); Veterans Affairs Portland Health Care System (M.C.H.) and Oregon Health and Science University Knight Cancer Institute (M.C.H., B.J.D.), Portland; Hospital de la Princesa and Instituto de Investigación Sanitaria Princesa, Madrid (J.L.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City (M.W.N.D.); Amsterdam University Medical Centers, VU University Medical Center, Amsterdam (J.J.W.M.J.); Novartis Pharma, Basel, Switzerland (D.H., Y.D., C.M., F.H.-P., K.G.V.); and Seoul St. Mary’s Hematology Hospital, Catholic University of Korea, Seoul, South Korea (D.-W.K.). Address reprint requests to Dr. Hughes at the South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA, Australia, or at tim.hughes@sahmri.com.

 

参考文献

1. Hughes TP, Saglio G, Quintás-Cardama A, et al. BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase. Leukemia 2015;29:1832-1838.

2. Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002;2:117-125.

3. Branford S, Rudzki Z, Walsh S, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003;102:276-283.

4. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012;119:1123-1129.

5. Cortes J, Jabbour E, Kantarjian H, et al. Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood 2007;110:4005-4011.

6. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 2011;12:841-851.

7. 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.

8. O’Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 2007;110:2242-2249.

9. O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009;16:401-412.

10. Valent P, Hadzijusufovic E, Schernthaner GH, Wolf D, Rea D, le Coutre P. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood 2015;125:901-906.

11. Moslehi JJ, Deininger M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol 2015;33:4210-4218.

12. Saussele S, Krauss MP, Hehlmann R, et al. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV. Blood 2015;126:42-49.

13. Caldemeyer L, Dugan M, Edwards J, Akard L. Long-term side effects of tyrosine kinase inhibitors in chronic myeloid leukemia. Curr Hematol Malig Rep 2016;11:71-79.

14. Steegmann JL, Baccarani M, Breccia M, et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia 2016;30:1648-1671.

15. Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature 2017;543:733-737.

16. Schoepfer J, Jahnke W, Berellini G, et al. Discovery of asciminib (ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1. J Med Chem 2018;61:8120-8135.

17. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009;27:6041-6051.

18. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome–positive leukemias. N Engl J Med 2006;354:2531-2541.

19. Branford S, Fletcher L, Cross NC, et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood 2008;112:3330-3338.

20. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645-652.

21. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003;21:4642-4649.

22. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28-37.

23. Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat Med 1998;17:1103-1120.

24. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med 2008;27:2420-2439.

25. Kantarjian H, O’Brien S, Jabbour E, et al. Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience. Blood 2012;119:1981-1987.

26. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome–positive leukemias. N Engl J Med 2012;367:2075-2088.

27. Quintás-Cardama A, Kantarjian HM, Cortes JE. Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia. Cancer Control 2009;16:122-131.

28. Apsel Winger B, Shah NP. PPARγ: welcoming the new kid on the CML stem cell block. Cancer Cell 2015;28:409-411.

29. Khorashad JS, Anand M, Marin D, et al. The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib. Leukemia 2006;20:658-663.

30. Lee BJ, Shah NP. Identification and characterization of activating ABL1 1b kinase mutations: impact on sensitivity to ATP-competitive and allosteric ABL1 inhibitors. Leukemia 2017;31:1096-1107.

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