Abstract

Background

The introduction of BCR-ABL inhibitors revolutionized the treatment of chronic myeloid leukemia (CML) which is now a manageable, chronic disease. As BCR-ABL inhibitors are used more widely and for longer, some distinctly different or late occurring adverse events (AEs) have become apparent from clinical studies and literature reports (e.g. pulmonary arterial hypertension, PAOD). PAOD has been described in a varying percentage of pts receiving nilotinib across the ENESTnd phase 3 trial of nilotinib versus imatinib (1.2%) and the literature (0.5%–12.5%). Arterial thrombotic events have also been reported in pts receiving ponatinib (11%). To assess whether PAOD may be a class effect, a pooled database of over 2700 pts in clinical trials of dasatinib was assessed.

Methods

Bristol-Myers Squibb clinical trial safety databases were examined using specific search-terms to identify cases of PAOD or PAOD-related events based on the mapped MedDRA preferred terms. In total, 11 clinical trials of first-line (n=2) and second-line (n=9) single-agent dasatinib in pts with CML (any phase) or Philadelphia chromosome-positive acute lymphoblastic leukemia were evaluated. Dasatinib 100 mg once daily (QD) was received in first-line trials while doses received in second-line trials varied: 15–240 mg QD or twice daily (BID), 20 mg BID, 50 mg BID, 70 mg BID, 100 mg QD, 140 mg QD.

Results

Across 11 clinical trials, 2705 pts received dasatinib with a cumulative 5890 pt years exposure. 6 pts (0.2%) were identified with either PAOD (n=1) or a PAOD-related event (n=5). See Table for details. In the dasatinib and imatinib arms of the phase 3 DASISION study (the only study with an imatinib control arm using the standard 400 mg QD dose) no cases of PAOD or related events were identified. For the 6 pts receiving dasatinib with PAOD or a related event the median age was 67.5 years (range: 54.0–80.0). All pts received dasatinib following imatinib resistance (n=4) or intolerance (n=2) after 20.0 months median duration of prior imatinib therapy (range: 2.4 – 53.1). Pts received dasatinib treatment for a median of 39.1 months (range: 9.9 – 74.4); 5/6 received a starting dose of 70 mg BID. All of the 6 PAOD or related events were grade 3 or lower in severity; no grade 4 or serious AEs were reported. None of the 6 pts discontinued dasatinib due to PAOD or a related event. Dose interruptions occurred in 2/6 pts; the remaining pts continued to receive dasatinib. All pts had risk factors for PAOD including cardiovascular events (n=3) such as coronary/ischemic heart disease, tricuspid regurgitation, hypertension, and heart failure; endocrine/metabolic events (n=2) such as obesity and diabetes mellitus; or other events such as hyperlipidemia (n=1). 3/6 pts were or had been smokers. PAOD or related events were newly diagnosed in 5/6 pts; 1 pt with femoral artery occlusion had a prior history of right leg angioplasty indicating a preexisting condition (pt 5 in the Table). Common concomitant medications included acetylsalicylic acid (n=3) and erythropoietin (n=3).

Table
 Event Grade CML Age, years Gender Imatinib status PAOD risk factors Dasatinib starting dose, mg BID Duration on dasatinib, months Dasatinib dose modification Treatment received 
Femoral artery occlusion CP 73 Coronary heart disease Angioplasty Previous smoker 25 for 5 days then no dose for 2 days 74.4 Interrupted No 
Intermittent claudication/claudication BP 54 Obesity 70 11.9 None Yes 
Intermittent claudication/claudication AP 68 Previous smoker 70 29.9 None No 
PAOD CP 63 Diabetes mellitus Smoker 70 35.0 None Yes 
Femoral artery occlusion AP 80 Hypertension Right leg angioplasty Hyperlipidemia 70 9.9 Interrupted Yes 
Atherosclerosis of lower extremities CP with clonal evolution 67 Ischemic heart disease Hypertension Heart failure 70 13.8 None Yes 
 Event Grade CML Age, years Gender Imatinib status PAOD risk factors Dasatinib starting dose, mg BID Duration on dasatinib, months Dasatinib dose modification Treatment received 
Femoral artery occlusion CP 73 Coronary heart disease Angioplasty Previous smoker 25 for 5 days then no dose for 2 days 74.4 Interrupted No 
Intermittent claudication/claudication BP 54 Obesity 70 11.9 None Yes 
Intermittent claudication/claudication AP 68 Previous smoker 70 29.9 None No 
PAOD CP 63 Diabetes mellitus Smoker 70 35.0 None Yes 
Femoral artery occlusion AP 80 Hypertension Right leg angioplasty Hyperlipidemia 70 9.9 Interrupted Yes 
Atherosclerosis of lower extremities CP with clonal evolution 67 Ischemic heart disease Hypertension Heart failure 70 13.8 None Yes 

R=resistant I=intolerant

Conclusion

The incidence of PAOD in pts receiving dasatinib is low and as expected for the target population. In the dasatinib clinical trials assessed here, PAOD occurred in pts who had received prior imatinib treatment and had significant predisposing risk factors for PAOD. These results suggest that PAOD is most likely not an effect of dasatinib treatment. In conclusion, confronting possible vascular AEs, pt baseline risk factors, AE profiles, and off-target profiles of therapeutic alternatives should be considered individually when choosing the most appropriate BCR-ABL inhibitor.

Disclosures:

le Coutre:Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Hughes:Ariad: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Mahon:Ariad: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Kim:Ilyang: Research Funding, Speakers Bureau; Ariad: Research Funding; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau, Support for travel to meetings Other. Steegmann:Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Shah:Bristol-Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Wallis:Bristol-Myers Squibb: Employment. Cortes:Novartis: Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding; Tragara: Membership on an entity’s Board of Directors or advisory committees; Ambit: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Arog: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.