Asciminib in chronic myeloid leukemia after Abl kinase inhibitor failure

Timothy P. Hughes, Michael J. Mauro, Jorge E. Cortes, Hironobu Minami, Delphine Rea, Daniel J. DeAngelo, Massimo Breccia, Yeow Tee Goh, Moshe Talpaz, Andreas Hochhaus, Philipp le Coutre, Oliver Ottmann, Michael C. Heinrich, Juan L. Steegmann, Michael W.N. Deininger, Jeroen J.W.M. Janssen, Francois Xavier Mahon, Yosuke Minami, David Yeung, David M. RossMartin S. Tallman, Jae H. Park, Brian J. Druker, David Hynds, Yuyan Duan, Christophe Meille, Florence Hourcade-Potelleret, K. Gary Vanasse, Fabian Lang, Dong Wook Kim

Research output: Contribution to journalArticle

Abstract

BACKGROUND Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome–positive leukemia are unknown. METHODS In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. RESULTS Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. CONCLUSIONS Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation.

Original languageEnglish (US)
Pages (from-to)2315-2326
Number of pages12
JournalNew England Journal of Medicine
Volume381
Issue number24
DOIs
StatePublished - Dec 12 2019

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Phosphotransferases
Protein-Tyrosine Kinases
Maximum Tolerated Dose
Cytogenetics
Leukemia, Myeloid, Accelerated Phase
Leukemia, Myeloid, Chronic Phase
Mutation
Poisons
Arthralgia
Lipase
Thrombocytopenia
Pancreatitis
Fatigue
Headache
Leukemia
Adenosine Triphosphate
Hypertension
Safety
Recurrence

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hughes, T. P., Mauro, M. J., Cortes, J. E., Minami, H., Rea, D., DeAngelo, D. J., ... Kim, D. W. (2019). Asciminib in chronic myeloid leukemia after Abl kinase inhibitor failure. New England Journal of Medicine, 381(24), 2315-2326. https://doi.org/10.1056/NEJMoa1902328

Asciminib in chronic myeloid leukemia after Abl kinase inhibitor failure. / Hughes, Timothy P.; Mauro, Michael J.; Cortes, Jorge E.; Minami, Hironobu; Rea, Delphine; DeAngelo, Daniel J.; Breccia, Massimo; Goh, Yeow Tee; Talpaz, Moshe; Hochhaus, Andreas; Coutre, Philipp le; Ottmann, Oliver; Heinrich, Michael C.; Steegmann, Juan L.; Deininger, Michael W.N.; Janssen, Jeroen J.W.M.; Mahon, Francois Xavier; Minami, Yosuke; Yeung, David; Ross, David M.; Tallman, Martin S.; Park, Jae H.; Druker, Brian J.; Hynds, David; Duan, Yuyan; Meille, Christophe; Hourcade-Potelleret, Florence; Vanasse, K. Gary; Lang, Fabian; Kim, Dong Wook.

In: New England Journal of Medicine, Vol. 381, No. 24, 12.12.2019, p. 2315-2326.

Research output: Contribution to journalArticle

Hughes, TP, Mauro, MJ, Cortes, JE, Minami, H, Rea, D, DeAngelo, DJ, Breccia, M, Goh, YT, Talpaz, M, Hochhaus, A, Coutre, PL, Ottmann, O, Heinrich, MC, Steegmann, JL, Deininger, MWN, Janssen, JJWM, Mahon, FX, Minami, Y, Yeung, D, Ross, DM, Tallman, MS, Park, JH, Druker, BJ, Hynds, D, Duan, Y, Meille, C, Hourcade-Potelleret, F, Vanasse, KG, Lang, F & Kim, DW 2019, 'Asciminib in chronic myeloid leukemia after Abl kinase inhibitor failure', New England Journal of Medicine, vol. 381, no. 24, pp. 2315-2326. https://doi.org/10.1056/NEJMoa1902328
Hughes, Timothy P. ; Mauro, Michael J. ; Cortes, Jorge E. ; Minami, Hironobu ; Rea, Delphine ; DeAngelo, Daniel J. ; Breccia, Massimo ; Goh, Yeow Tee ; Talpaz, Moshe ; Hochhaus, Andreas ; Coutre, Philipp le ; Ottmann, Oliver ; Heinrich, Michael C. ; Steegmann, Juan L. ; Deininger, Michael W.N. ; Janssen, Jeroen J.W.M. ; Mahon, Francois Xavier ; Minami, Yosuke ; Yeung, David ; Ross, David M. ; Tallman, Martin S. ; Park, Jae H. ; Druker, Brian J. ; Hynds, David ; Duan, Yuyan ; Meille, Christophe ; Hourcade-Potelleret, Florence ; Vanasse, K. Gary ; Lang, Fabian ; Kim, Dong Wook. / Asciminib in chronic myeloid leukemia after Abl kinase inhibitor failure. In: New England Journal of Medicine. 2019 ; Vol. 381, No. 24. pp. 2315-2326.
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abstract = "BACKGROUND Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome–positive leukemia are unknown. METHODS In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. RESULTS Patients were heavily pretreated; 70{\%} (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92{\%}) with a hematologic relapse had a complete hematologic response; 31 (54{\%}) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48{\%} of patients who could be evaluated, including 8 of 14 (57{\%}) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28{\%}) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. CONCLUSIONS Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation.",
author = "Hughes, {Timothy P.} and Mauro, {Michael J.} and Cortes, {Jorge E.} and Hironobu Minami and Delphine Rea and DeAngelo, {Daniel J.} and Massimo Breccia and Goh, {Yeow Tee} and Moshe Talpaz and Andreas Hochhaus and Coutre, {Philipp le} and Oliver Ottmann and Heinrich, {Michael C.} and Steegmann, {Juan L.} and Deininger, {Michael W.N.} and Janssen, {Jeroen J.W.M.} and Mahon, {Francois Xavier} and Yosuke Minami and David Yeung and Ross, {David M.} and Tallman, {Martin S.} and Park, {Jae H.} and Druker, {Brian J.} and David Hynds and Yuyan Duan and Christophe Meille and Florence Hourcade-Potelleret and Vanasse, {K. Gary} and Fabian Lang and Kim, {Dong Wook}",
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T1 - Asciminib in chronic myeloid leukemia after Abl kinase inhibitor failure

AU - Hughes, Timothy P.

AU - Mauro, Michael J.

AU - Cortes, Jorge E.

AU - Minami, Hironobu

AU - Rea, Delphine

AU - DeAngelo, Daniel J.

AU - Breccia, Massimo

AU - Goh, Yeow Tee

AU - Talpaz, Moshe

AU - Hochhaus, Andreas

AU - Coutre, Philipp le

AU - Ottmann, Oliver

AU - Heinrich, Michael C.

AU - Steegmann, Juan L.

AU - Deininger, Michael W.N.

AU - Janssen, Jeroen J.W.M.

AU - Mahon, Francois Xavier

AU - Minami, Yosuke

AU - Yeung, David

AU - Ross, David M.

AU - Tallman, Martin S.

AU - Park, Jae H.

AU - Druker, Brian J.

AU - Hynds, David

AU - Duan, Yuyan

AU - Meille, Christophe

AU - Hourcade-Potelleret, Florence

AU - Vanasse, K. Gary

AU - Lang, Fabian

AU - Kim, Dong Wook

PY - 2019/12/12

Y1 - 2019/12/12

N2 - BACKGROUND Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome–positive leukemia are unknown. METHODS In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. RESULTS Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. CONCLUSIONS Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation.

AB - BACKGROUND Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome–positive leukemia are unknown. METHODS In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. RESULTS Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. CONCLUSIONS Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation.

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