ELEVATED BLOOD PRESSURE (BP) AND ADVERSE EVENTS OF HYPERTENSION (HTN) IN PHASE 1, 2, AND 3 TRIALS OF PONATINIB IN LEUKEMIA
(Abstract release date: 05/21/15)
EHA Library. GUILHOT F. 06/12/15; 102683; PB1746
Disclosure(s): Université de Poitiers CHU de PoitiersOncology Hematology and Cell Therapy
François GUILHOT
Contributions
Contributions
Abstract
Abstract: PB1746
Type: Publication Only
Background
Ponatinib is a potent, multitargeted tyrosine kinase inhibitor with proven efficacy in resistant Philadelphia chromosome–positive (Ph+) leukemia.
Aims
This analysis reports elevated BP and adverse events of HTN in phase 1, 2, and 3 trials of ponatinib in patients with leukemia.
Methods
Ponatinib safety and efficacy were evaluated in patients with relapsed/refractory hematologic malignancies in the ongoing phase 1 trial, in heavily pretreated chronic myeloid leukemia (CML)/Ph+ acute lymphoblastic leukemia (ALL) patients in the ongoing PACE (phase 2) trial, and in newly diagnosed chronic-phase CML patients in the terminated EPIC (phase 3) trial of ponatinib vs imatinib. All patients gave informed consent. Phase 1 and EPIC, but not PACE, excluded patients with uncontrolled HTN (defined as untreated systolic/diastolic >150/>100 mm Hg in phase 1 and >140/>90 mm Hg in EPIC). Elevated BP was defined by the single highest BP measurement (systolic/diastolic): grade (G) 1/pre-HTN 120–139/80–89 mm Hg, G2 140–159/90–99 mm Hg, G3 ≥160/≥100 mm Hg. HTN adverse events were reported by investigators.
Results
Elevated BP was frequent at trial entry (Table 1). G1/G2–3 rates were 44%/42% in phase 1, 37%/47% in PACE, and 51%/19% with ponatinib vs 52%/12% with imatinib in EPIC. Any increase in BP grade from baseline was also frequent, with rates of 74% in phase 1, 68% in PACE, and 68% with ponatinib vs 51% with imatinib in EPIC. In PACE, estimated systolic/diastolic BP increases over time were low, at 2.3/0.7 mm Hg per year. HTN adverse events were reported in 38%, 28%, 18%, and 2% of patients in phase 1, PACE, and the EPIC ponatinib and EPIC imatinib arms, respectively. Hypertensive crisis was reported in 2 patients in PACE and in 2 patients in the EPIC ponatinib arm. HTN adverse events did not lead to discontinuation or death. Few patients had dose modifications for HTN adverse events (0% in phase 1, 5% in PACE, and 3% with ponatinib vs 0% with imatinib in EPIC). A retrospective multivariate analysis of pooled patients showed that HTN adverse events were significantly associated with ponatinib dose intensity.
Summary
Increase in BP was frequently observed in ponatinib trials, including in patients on imatinib. Rates of HTN adverse events were relatively lower and seen primarily with ponatinib. While associated with ponatinib dose intensity, HTN adverse events rarely led to change in leukemia therapy. Given BP variability, investigator reporting of HTN adverse events may be a more reliable indicator of clinically meaningful HTN.
Keyword(s): Chronic myeloid leukemia, Tyrosine kinase inhibitor
Session topic: Publication Only
Type: Publication Only
Background
Ponatinib is a potent, multitargeted tyrosine kinase inhibitor with proven efficacy in resistant Philadelphia chromosome–positive (Ph+) leukemia.
Aims
This analysis reports elevated BP and adverse events of HTN in phase 1, 2, and 3 trials of ponatinib in patients with leukemia.
Methods
Ponatinib safety and efficacy were evaluated in patients with relapsed/refractory hematologic malignancies in the ongoing phase 1 trial, in heavily pretreated chronic myeloid leukemia (CML)/Ph+ acute lymphoblastic leukemia (ALL) patients in the ongoing PACE (phase 2) trial, and in newly diagnosed chronic-phase CML patients in the terminated EPIC (phase 3) trial of ponatinib vs imatinib. All patients gave informed consent. Phase 1 and EPIC, but not PACE, excluded patients with uncontrolled HTN (defined as untreated systolic/diastolic >150/>100 mm Hg in phase 1 and >140/>90 mm Hg in EPIC). Elevated BP was defined by the single highest BP measurement (systolic/diastolic): grade (G) 1/pre-HTN 120–139/80–89 mm Hg, G2 140–159/90–99 mm Hg, G3 ≥160/≥100 mm Hg. HTN adverse events were reported by investigators.
Results
Elevated BP was frequent at trial entry (Table 1). G1/G2–3 rates were 44%/42% in phase 1, 37%/47% in PACE, and 51%/19% with ponatinib vs 52%/12% with imatinib in EPIC. Any increase in BP grade from baseline was also frequent, with rates of 74% in phase 1, 68% in PACE, and 68% with ponatinib vs 51% with imatinib in EPIC. In PACE, estimated systolic/diastolic BP increases over time were low, at 2.3/0.7 mm Hg per year. HTN adverse events were reported in 38%, 28%, 18%, and 2% of patients in phase 1, PACE, and the EPIC ponatinib and EPIC imatinib arms, respectively. Hypertensive crisis was reported in 2 patients in PACE and in 2 patients in the EPIC ponatinib arm. HTN adverse events did not lead to discontinuation or death. Few patients had dose modifications for HTN adverse events (0% in phase 1, 5% in PACE, and 3% with ponatinib vs 0% with imatinib in EPIC). A retrospective multivariate analysis of pooled patients showed that HTN adverse events were significantly associated with ponatinib dose intensity.
Table 1. Baseline BP and Any Increase in BP Gradea on Study
| Normal BPb at Baseline | G1 BP at Baseline | G2 BP at Baseline | G3 BP at Baseline | ||||||
| n | Increase to G1 | Increase to G2 | Increase to G3 | n | Increase to G2 | Increase to G3 | n | Increase to G3 | n |
Phase 1, N=81 | 11 | 18% | 45% | 27% | 36 | 47% | 39% | 27 | 70% | 7 |
PACE, N=449 | 70 | 34% | 31% | 23% | 167 | 53% | 35% | 157 | 62% | 55 |
EPIC/ponatinib, n=154 | 46 | 57% | 22% | 7% | 78 | 51% | 14% | 30 | 50% | 0 |
EPIC/imatinib, n=152 | 54 | 65% | 13% | 2% | 79 | 35% | 5% | 12 | 17% | 6 |
aBased on single highest BP measurement; b<120/<80 mm Hg
Baseline BP was missing for 1 patient in the EPIC imatinib arm
Summary
Increase in BP was frequently observed in ponatinib trials, including in patients on imatinib. Rates of HTN adverse events were relatively lower and seen primarily with ponatinib. While associated with ponatinib dose intensity, HTN adverse events rarely led to change in leukemia therapy. Given BP variability, investigator reporting of HTN adverse events may be a more reliable indicator of clinically meaningful HTN.
Keyword(s): Chronic myeloid leukemia, Tyrosine kinase inhibitor
Session topic: Publication Only
Abstract: PB1746
Type: Publication Only
Background
Ponatinib is a potent, multitargeted tyrosine kinase inhibitor with proven efficacy in resistant Philadelphia chromosome–positive (Ph+) leukemia.
Aims
This analysis reports elevated BP and adverse events of HTN in phase 1, 2, and 3 trials of ponatinib in patients with leukemia.
Methods
Ponatinib safety and efficacy were evaluated in patients with relapsed/refractory hematologic malignancies in the ongoing phase 1 trial, in heavily pretreated chronic myeloid leukemia (CML)/Ph+ acute lymphoblastic leukemia (ALL) patients in the ongoing PACE (phase 2) trial, and in newly diagnosed chronic-phase CML patients in the terminated EPIC (phase 3) trial of ponatinib vs imatinib. All patients gave informed consent. Phase 1 and EPIC, but not PACE, excluded patients with uncontrolled HTN (defined as untreated systolic/diastolic >150/>100 mm Hg in phase 1 and >140/>90 mm Hg in EPIC). Elevated BP was defined by the single highest BP measurement (systolic/diastolic): grade (G) 1/pre-HTN 120–139/80–89 mm Hg, G2 140–159/90–99 mm Hg, G3 ≥160/≥100 mm Hg. HTN adverse events were reported by investigators.
Results
Elevated BP was frequent at trial entry (Table 1). G1/G2–3 rates were 44%/42% in phase 1, 37%/47% in PACE, and 51%/19% with ponatinib vs 52%/12% with imatinib in EPIC. Any increase in BP grade from baseline was also frequent, with rates of 74% in phase 1, 68% in PACE, and 68% with ponatinib vs 51% with imatinib in EPIC. In PACE, estimated systolic/diastolic BP increases over time were low, at 2.3/0.7 mm Hg per year. HTN adverse events were reported in 38%, 28%, 18%, and 2% of patients in phase 1, PACE, and the EPIC ponatinib and EPIC imatinib arms, respectively. Hypertensive crisis was reported in 2 patients in PACE and in 2 patients in the EPIC ponatinib arm. HTN adverse events did not lead to discontinuation or death. Few patients had dose modifications for HTN adverse events (0% in phase 1, 5% in PACE, and 3% with ponatinib vs 0% with imatinib in EPIC). A retrospective multivariate analysis of pooled patients showed that HTN adverse events were significantly associated with ponatinib dose intensity.
Summary
Increase in BP was frequently observed in ponatinib trials, including in patients on imatinib. Rates of HTN adverse events were relatively lower and seen primarily with ponatinib. While associated with ponatinib dose intensity, HTN adverse events rarely led to change in leukemia therapy. Given BP variability, investigator reporting of HTN adverse events may be a more reliable indicator of clinically meaningful HTN.
Keyword(s): Chronic myeloid leukemia, Tyrosine kinase inhibitor
Session topic: Publication Only
Type: Publication Only
Background
Ponatinib is a potent, multitargeted tyrosine kinase inhibitor with proven efficacy in resistant Philadelphia chromosome–positive (Ph+) leukemia.
Aims
This analysis reports elevated BP and adverse events of HTN in phase 1, 2, and 3 trials of ponatinib in patients with leukemia.
Methods
Ponatinib safety and efficacy were evaluated in patients with relapsed/refractory hematologic malignancies in the ongoing phase 1 trial, in heavily pretreated chronic myeloid leukemia (CML)/Ph+ acute lymphoblastic leukemia (ALL) patients in the ongoing PACE (phase 2) trial, and in newly diagnosed chronic-phase CML patients in the terminated EPIC (phase 3) trial of ponatinib vs imatinib. All patients gave informed consent. Phase 1 and EPIC, but not PACE, excluded patients with uncontrolled HTN (defined as untreated systolic/diastolic >150/>100 mm Hg in phase 1 and >140/>90 mm Hg in EPIC). Elevated BP was defined by the single highest BP measurement (systolic/diastolic): grade (G) 1/pre-HTN 120–139/80–89 mm Hg, G2 140–159/90–99 mm Hg, G3 ≥160/≥100 mm Hg. HTN adverse events were reported by investigators.
Results
Elevated BP was frequent at trial entry (Table 1). G1/G2–3 rates were 44%/42% in phase 1, 37%/47% in PACE, and 51%/19% with ponatinib vs 52%/12% with imatinib in EPIC. Any increase in BP grade from baseline was also frequent, with rates of 74% in phase 1, 68% in PACE, and 68% with ponatinib vs 51% with imatinib in EPIC. In PACE, estimated systolic/diastolic BP increases over time were low, at 2.3/0.7 mm Hg per year. HTN adverse events were reported in 38%, 28%, 18%, and 2% of patients in phase 1, PACE, and the EPIC ponatinib and EPIC imatinib arms, respectively. Hypertensive crisis was reported in 2 patients in PACE and in 2 patients in the EPIC ponatinib arm. HTN adverse events did not lead to discontinuation or death. Few patients had dose modifications for HTN adverse events (0% in phase 1, 5% in PACE, and 3% with ponatinib vs 0% with imatinib in EPIC). A retrospective multivariate analysis of pooled patients showed that HTN adverse events were significantly associated with ponatinib dose intensity.
Table 1. Baseline BP and Any Increase in BP Gradea on Study
| Normal BPb at Baseline | G1 BP at Baseline | G2 BP at Baseline | G3 BP at Baseline | ||||||
| n | Increase to G1 | Increase to G2 | Increase to G3 | n | Increase to G2 | Increase to G3 | n | Increase to G3 | n |
Phase 1, N=81 | 11 | 18% | 45% | 27% | 36 | 47% | 39% | 27 | 70% | 7 |
PACE, N=449 | 70 | 34% | 31% | 23% | 167 | 53% | 35% | 157 | 62% | 55 |
EPIC/ponatinib, n=154 | 46 | 57% | 22% | 7% | 78 | 51% | 14% | 30 | 50% | 0 |
EPIC/imatinib, n=152 | 54 | 65% | 13% | 2% | 79 | 35% | 5% | 12 | 17% | 6 |
aBased on single highest BP measurement; b<120/<80 mm Hg
Baseline BP was missing for 1 patient in the EPIC imatinib arm
Summary
Increase in BP was frequently observed in ponatinib trials, including in patients on imatinib. Rates of HTN adverse events were relatively lower and seen primarily with ponatinib. While associated with ponatinib dose intensity, HTN adverse events rarely led to change in leukemia therapy. Given BP variability, investigator reporting of HTN adverse events may be a more reliable indicator of clinically meaningful HTN.
Keyword(s): Chronic myeloid leukemia, Tyrosine kinase inhibitor
Session topic: Publication Only
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