TY - JOUR
T1 - Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia
T2 - a randomized, open-label phase 2 clinical trial
AU - Cortes, Jorge
AU - Apperley, Jane
AU - Lomaia, Elza
AU - Moiraghi, Beatriz
AU - Undurraga Sutton, Maria
AU - Pavlovsky, Carolina
AU - Chuah, Charles
AU - Sacha, Tomasz
AU - Lipton, Jeffrey H.
AU - Schiffer, Charles A.
AU - McCloskey, James
AU - Hochhaus, Andreas
AU - Rousselot, Philippe
AU - Rosti, Gianantonio
AU - de Lavallade, Hugues
AU - Turkina, Anna
AU - Rojas, Christine
AU - Arthur, Christopher Kevin
AU - Maness, Lori
AU - Talpaz, Moshe
AU - Mauro, Michael
AU - Hall, Tracey
AU - Lu, Vickie
AU - Srivastava, Shouryadeep
AU - Deininger, Michael
N1 - Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/11/25
Y1 - 2021/11/25
N2 - In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.
AB - In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.
UR - http://www.scopus.com/inward/record.url?scp=85119599791&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85119599791&partnerID=8YFLogxK
U2 - 10.1182/blood.2021012082
DO - 10.1182/blood.2021012082
M3 - Article
C2 - 34407543
AN - SCOPUS:85119599791
SN - 0006-4971
VL - 138
SP - 2042
EP - 2050
JO - Blood
JF - Blood
IS - 21
ER -