Contributions
Abstract: PS1122
Type: Poster Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00
Location: Poster area
Background
The third generation tyrosine kinase inhibitor ponatinib is effective as salvage treatment for chronic phase (CP) Ph+ chronic myeloid leukemia (CML) patients resistant or intolerant to prior TKIs. Considering the demonstrated impact of ponatinib dose on the incidence of cardiovascular adverse events, a dose reduction to 15 mg daily is recommended in CP after the achievement of treatment milestones. Lower than 45 mg ponatinib dose strategies are currently under investigation in prospective clinical trials. There is a strong interest on independent data describing the efficacy and the safety of 15 mg daily ponatinib.
Aims
Describe and assess the efficacy and toxicity of low doses of ponatinib in CML-CP resistant or intolerant to previous TKIs.
Methods
A retrospective analysis of consecutive, CML-CP patients treated with ponatinib 15 mg as starting or de-escalated dose has been performed. No pre-specified criteria to switch to ponatinib or to reduce the dose were indicated.
Results
62 patients are included, 53% males. Median age at ponatinib start was 57 (28-87) years. The median time from CML diagnosis to ponatinib treatment was 53.2 months (4.8-230). ABL1 mutations were detected in 29.3% patients (being 41% of them positive for the T315I mutation). Roughly half of the patients (45%) received ponatinib as 4th or 5th line of treatment. Ponatinib was started at 45, 30 and 15 mg, in 24, 13 and 25 patients, respectively. Resistance to prior TKIs was the reason for switch in all patients treated with higher than 15 mg dose, while 12/25 patients starting with 15 mg were purely intolerant or intolerant and resistant. The median treatment duration at any dose was 21.2 months, with 45/62 (72%) patients exposed to ponatinib for more than 12 months. Overall, 68% of patients improved response status. In patients treated with 45 or 30 mg the CCyR, MR3 and MR4/MR4.5 rates were 76%, 55% and 32% respectively. Responses were achieved after a median of 3.5, 4.3 and 6.7 months, respectively. Dose reduction to 15 mg was decided after a median time of 10 months, mostly due to adverse events (73%) and less frequently, to prevent toxicity and/or following response attainment (27%). Median duration of treatment was 32.4 months, with a discontinuation rate of 5/37 (1 cerebrovascular accident, 2 severe hematologic toxicities, two cases of resistance/progression). Two deaths were registered (both in the 45 mg group), one after blast crisis and one for a fatal cardiovascular event. Focusing the 25 patients started with ponatinib 15 mg, median duration of treatment was 15 months (4.3-58.1). CCyR was obtained in 55% of patients lacking CCyR and MR3 in 50% without MMR with a median time of 3.8 and 3.4 months, respectively. During follow-up, MR3 or deeper responses were maintained or improved in 80% of cases, while 7 patients lost their best acquired response (4 MR4/4.5 to MR3, 1 MR3 to MR2, 1 CCyR to PHR and 1 progression to accelerated phase). Three patients of this group discontinued the treatment (1 coronary vasospasm-induced acute coronary syndrome, 2 muscle skeletal pain). After a median follow-up of 21 months, 35/54 (65%) patients on ponatinib mantain a MR3 or deeper response; 48 (89%) are taking 15 mg or lower.
Conclusion
This analysis confirms the efficacy of de-escalated ponatinib dose in CML patients resistant to prior TKIs, with acceptable toxicity profile. Promising data on 15 mg as a starting dose in selected patients (intolerant or with low level resistance) warrant further investigation in larger prospective trials.
Session topic: 8. Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, Dose intensity, Tyrosine kinase inhibitor
Abstract: PS1122
Type: Poster Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00
Location: Poster area
Background
The third generation tyrosine kinase inhibitor ponatinib is effective as salvage treatment for chronic phase (CP) Ph+ chronic myeloid leukemia (CML) patients resistant or intolerant to prior TKIs. Considering the demonstrated impact of ponatinib dose on the incidence of cardiovascular adverse events, a dose reduction to 15 mg daily is recommended in CP after the achievement of treatment milestones. Lower than 45 mg ponatinib dose strategies are currently under investigation in prospective clinical trials. There is a strong interest on independent data describing the efficacy and the safety of 15 mg daily ponatinib.
Aims
Describe and assess the efficacy and toxicity of low doses of ponatinib in CML-CP resistant or intolerant to previous TKIs.
Methods
A retrospective analysis of consecutive, CML-CP patients treated with ponatinib 15 mg as starting or de-escalated dose has been performed. No pre-specified criteria to switch to ponatinib or to reduce the dose were indicated.
Results
62 patients are included, 53% males. Median age at ponatinib start was 57 (28-87) years. The median time from CML diagnosis to ponatinib treatment was 53.2 months (4.8-230). ABL1 mutations were detected in 29.3% patients (being 41% of them positive for the T315I mutation). Roughly half of the patients (45%) received ponatinib as 4th or 5th line of treatment. Ponatinib was started at 45, 30 and 15 mg, in 24, 13 and 25 patients, respectively. Resistance to prior TKIs was the reason for switch in all patients treated with higher than 15 mg dose, while 12/25 patients starting with 15 mg were purely intolerant or intolerant and resistant. The median treatment duration at any dose was 21.2 months, with 45/62 (72%) patients exposed to ponatinib for more than 12 months. Overall, 68% of patients improved response status. In patients treated with 45 or 30 mg the CCyR, MR3 and MR4/MR4.5 rates were 76%, 55% and 32% respectively. Responses were achieved after a median of 3.5, 4.3 and 6.7 months, respectively. Dose reduction to 15 mg was decided after a median time of 10 months, mostly due to adverse events (73%) and less frequently, to prevent toxicity and/or following response attainment (27%). Median duration of treatment was 32.4 months, with a discontinuation rate of 5/37 (1 cerebrovascular accident, 2 severe hematologic toxicities, two cases of resistance/progression). Two deaths were registered (both in the 45 mg group), one after blast crisis and one for a fatal cardiovascular event. Focusing the 25 patients started with ponatinib 15 mg, median duration of treatment was 15 months (4.3-58.1). CCyR was obtained in 55% of patients lacking CCyR and MR3 in 50% without MMR with a median time of 3.8 and 3.4 months, respectively. During follow-up, MR3 or deeper responses were maintained or improved in 80% of cases, while 7 patients lost their best acquired response (4 MR4/4.5 to MR3, 1 MR3 to MR2, 1 CCyR to PHR and 1 progression to accelerated phase). Three patients of this group discontinued the treatment (1 coronary vasospasm-induced acute coronary syndrome, 2 muscle skeletal pain). After a median follow-up of 21 months, 35/54 (65%) patients on ponatinib mantain a MR3 or deeper response; 48 (89%) are taking 15 mg or lower.
Conclusion
This analysis confirms the efficacy of de-escalated ponatinib dose in CML patients resistant to prior TKIs, with acceptable toxicity profile. Promising data on 15 mg as a starting dose in selected patients (intolerant or with low level resistance) warrant further investigation in larger prospective trials.
Session topic: 8. Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, Dose intensity, Tyrosine kinase inhibitor