Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial

Jorge E. Cortes, Dong Wook Kim, Javier Pinilla-Ibarz, Philipp D. le Coutre, Ronald Paquette, Charles Chuah, Franck E. Nicolini, Jane F. Apperley, H. Jean Khoury, Moshe Talpaz, Daniel J. DeAngelo, Elisabetta Abruzzese, Delphine Rea, Michele Baccarani, Martin C. Müller, Carlo Gambacorti-Passerini, Stephanie Lustgarten, Victor M. Rivera, Frank G. Haluska, François GuilhotMichael W. Deininger, Andreas Hochhaus, Timothy P. Hughes, Neil P. Shah, Hagop M. Kantarjian

Research output: Contribution to journalArticle

Abstract

Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph1 ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n 5 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ‡90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.

Original languageEnglish (US)
Pages (from-to)393-404
Number of pages12
JournalBlood
Volume132
Issue number4
DOIs
StatePublished - Jul 26 2018

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Emitter coupled logic circuits
Leukemia
Safety
Cytogenetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid, Chronic Phase
Skin
ponatinib
Incidence
Constipation
Exanthema
Thrombocytopenia
Abdominal Pain
Headache
Survival

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Cortes, J. E., Kim, D. W., Pinilla-Ibarz, J., le Coutre, P. D., Paquette, R., Chuah, C., ... Kantarjian, H. M. (2018). Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial. Blood, 132(4), 393-404. https://doi.org/10.1182/blood-2016-09-739086

Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia : final 5-year results of the phase 2 PACE trial. / Cortes, Jorge E.; Kim, Dong Wook; Pinilla-Ibarz, Javier; le Coutre, Philipp D.; Paquette, Ronald; Chuah, Charles; Nicolini, Franck E.; Apperley, Jane F.; Khoury, H. Jean; Talpaz, Moshe; DeAngelo, Daniel J.; Abruzzese, Elisabetta; Rea, Delphine; Baccarani, Michele; Müller, Martin C.; Gambacorti-Passerini, Carlo; Lustgarten, Stephanie; Rivera, Victor M.; Haluska, Frank G.; Guilhot, François; Deininger, Michael W.; Hochhaus, Andreas; Hughes, Timothy P.; Shah, Neil P.; Kantarjian, Hagop M.

In: Blood, Vol. 132, No. 4, 26.07.2018, p. 393-404.

Research output: Contribution to journalArticle

Cortes, JE, Kim, DW, Pinilla-Ibarz, J, le Coutre, PD, Paquette, R, Chuah, C, Nicolini, FE, Apperley, JF, Khoury, HJ, Talpaz, M, DeAngelo, DJ, Abruzzese, E, Rea, D, Baccarani, M, Müller, MC, Gambacorti-Passerini, C, Lustgarten, S, Rivera, VM, Haluska, FG, Guilhot, F, Deininger, MW, Hochhaus, A, Hughes, TP, Shah, NP & Kantarjian, HM 2018, 'Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial', Blood, vol. 132, no. 4, pp. 393-404. https://doi.org/10.1182/blood-2016-09-739086
Cortes, Jorge E. ; Kim, Dong Wook ; Pinilla-Ibarz, Javier ; le Coutre, Philipp D. ; Paquette, Ronald ; Chuah, Charles ; Nicolini, Franck E. ; Apperley, Jane F. ; Khoury, H. Jean ; Talpaz, Moshe ; DeAngelo, Daniel J. ; Abruzzese, Elisabetta ; Rea, Delphine ; Baccarani, Michele ; Müller, Martin C. ; Gambacorti-Passerini, Carlo ; Lustgarten, Stephanie ; Rivera, Victor M. ; Haluska, Frank G. ; Guilhot, François ; Deininger, Michael W. ; Hochhaus, Andreas ; Hughes, Timothy P. ; Shah, Neil P. ; Kantarjian, Hagop M. / Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia : final 5-year results of the phase 2 PACE trial. In: Blood. 2018 ; Vol. 132, No. 4. pp. 393-404.
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AU - Cortes, Jorge E.

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AU - Paquette, Ronald

AU - Chuah, Charles

AU - Nicolini, Franck E.

AU - Apperley, Jane F.

AU - Khoury, H. Jean

AU - Talpaz, Moshe

AU - DeAngelo, Daniel J.

AU - Abruzzese, Elisabetta

AU - Rea, Delphine

AU - Baccarani, Michele

AU - Müller, Martin C.

AU - Gambacorti-Passerini, Carlo

AU - Lustgarten, Stephanie

AU - Rivera, Victor M.

AU - Haluska, Frank G.

AU - Guilhot, François

AU - Deininger, Michael W.

AU - Hochhaus, Andreas

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AU - Shah, Neil P.

AU - Kantarjian, Hagop M.

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N2 - Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph1 ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n 5 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ‡90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.

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