Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome–positive (Ph1) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph1 ALL $60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and g-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade $3, 18.2%) and 27.3% (grade $3, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph1 ALL; however, a lower ponatinib dose may be more appropriate in this population.

INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph1 acute lymphoblastic leukemia / Martinelli, G.; Papayannidis, C.; Piciocchi, A.; Robustelli, V.; Soverini, S.; Terragna, C.; Marconi, G.; Lemoli, R. M.; Guolo, F.; Fornaro, A.; Lunghi, M.; de Fabritiis, P.; Candoni, A.; Selleri, C.; Simonetti, F.; Bocchia, M.; Vitale, A.; Frison, L.; Tedeschi, A.; Cuneo, A.; Bonifacio, M.; Martelli, M. P.; D'Ardia, S.; Trappolini, S.; Tosi, P.; Galieni, P.; Fabbiano, F.; Abbenante, M. C.; Granier, M.; Zhu, Z.; Wang, M.; Sartor, C.; Paolini, S.; Cavo, M.; Foa, R.; Fazi, P.; Vignetti, M.; Baccarani, M.. - In: BLOOD ADVANCES. - ISSN 2473-9529. - 6:6(2022), pp. 1742-1753. [10.1182/BLOODADVANCES.2021004821]

INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph1 acute lymphoblastic leukemia

Candoni A.;
2022

Abstract

Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome–positive (Ph1) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph1 ALL $60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and g-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade $3, 18.2%) and 27.3% (grade $3, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph1 ALL; however, a lower ponatinib dose may be more appropriate in this population.
2022
6
6
1742
1753
INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph1 acute lymphoblastic leukemia / Martinelli, G.; Papayannidis, C.; Piciocchi, A.; Robustelli, V.; Soverini, S.; Terragna, C.; Marconi, G.; Lemoli, R. M.; Guolo, F.; Fornaro, A.; Lunghi, M.; de Fabritiis, P.; Candoni, A.; Selleri, C.; Simonetti, F.; Bocchia, M.; Vitale, A.; Frison, L.; Tedeschi, A.; Cuneo, A.; Bonifacio, M.; Martelli, M. P.; D'Ardia, S.; Trappolini, S.; Tosi, P.; Galieni, P.; Fabbiano, F.; Abbenante, M. C.; Granier, M.; Zhu, Z.; Wang, M.; Sartor, C.; Paolini, S.; Cavo, M.; Foa, R.; Fazi, P.; Vignetti, M.; Baccarani, M.. - In: BLOOD ADVANCES. - ISSN 2473-9529. - 6:6(2022), pp. 1742-1753. [10.1182/BLOODADVANCES.2021004821]
Martinelli, G.; Papayannidis, C.; Piciocchi, A.; Robustelli, V.; Soverini, S.; Terragna, C.; Marconi, G.; Lemoli, R. M.; Guolo, F.; Fornaro, A.; Lunghi, M.; de Fabritiis, P.; Candoni, A.; Selleri, C.; Simonetti, F.; Bocchia, M.; Vitale, A.; Frison, L.; Tedeschi, A.; Cuneo, A.; Bonifacio, M.; Martelli, M. P.; D'Ardia, S.; Trappolini, S.; Tosi, P.; Galieni, P.; Fabbiano, F.; Abbenante, M. C.; Granier, M.; Zhu, Z.; Wang, M.; Sartor, C.; Paolini, S.; Cavo, M.; Foa, R.; Fazi, P.; Vignetti, M.; Baccarani, M.
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