The prognosis of most leukemia patients treated with BCR-ABL tyrosine kinase inhibitors (TKIs) is favorable, and a more precise understanding of serious and potentially irreversible treatment-related toxicities is essential to properly inform treatment choice. Few cases of pulmonary arterial hypertension (PAH) have been reported in patients with leukemia treated with dasatinib, a second-generation BCR-ABL TKI. To better understand characteristics and outcomes of dasatinib-treated patients with PAH, all clinical cases of PAH confirmed by right-heart catheterization in the Bristol-Myers Squibb pharmacovigilance database (N 5 41), including 22 previously unpublished cases, were examined for previous treatments for leukemia, patient characteristics, time to PAH onset, and outcomes. Our analysis shows that compared with PAH due to other etiologies, dasatinib-related PAH is atypical, in that it is associated with partial to complete reversibility upon treatment discontinuation. The incidence of dasatinib-related PAH appears to be low. Most PAH cases were observed in patients who had received prior treatments for leukemia. No specific patient attributes appear to be associated with an increased risk of developing PAH while receiving dasatinib. Symptoms of PAH in dasatinib-treated leukemia patients should prompt a thorough workup, including consideration of confirmatory right-heart catheterization. In cases of confirmed PAH, dasatinib should be discontinued.

Prolonged survival in patients with chronic myeloid leukemia treated with BCR-ABL1-targeted tyrosine kinase inhibitors allows consideration of parenthood for patients on chronic therapy, but there are limited data about the effects of dasatinib on pregnancy. Pregnancy-related outcomes in dasatinib-treated patients or their partners reported to Bristol–Myers Squibb from clinical trials or healthcare providers through December 2013 were reviewed. Outcomes were available in 46/78 dasatinib-treated women (59%) and 33/69 partners of dasatinib-treated men (48%). Fifteen women (33%) delivered a normal infant; 18 (39%) and 8 (17%) had an elective or spontaneous abortion; and 5 (11%) had an abnormal pregnancy. There were 7 reports of fetal/infant abnormalities (encephalocele, renal tract abnormalities, and hydrops fetalis). Thirty of 33 (91%) infants fathered by dasatinib-treated men were reported normal at birth. Also, animal studies evaluated the impact of dasatinib on fertility, embryo-fetal toxicity, and development, suggesting that dasatinib may be a selective developmental toxicant. The outcomes of most pregnancies conceived by men treated with dasatinib were normal, but due to the small number of cases, further monitoring is required. Significant effects on pregnancy outcomes in women treated with dasatinib were found, supporting current recommendations that women avoid becoming pregnant during dasatinib treatment and be informed of fetal risks.

Rare but serious cardiovascular and pulmonary adverse events (AEs) have been reported in patients with chronic myeloid leukemia treated with BCR-ABL inhibitors. Clinical trial data may not reflect the full AE profile of BCR-ABL inhibitors because of stringent study entry criteria, relatively small sample size, and limited duration of follow-up. To determine the utility of the FDA AE Reporting System (FAERS) surveillance database for identifying AEs possibly associated with the BCR-ABL inhibitors imatinib, dasatinib, and nilotinib in the postmarketing patient population, we conducted Multi-Item Gamma Poisson Shrinker disproportionality analyses of FAERS reports on AEs in relevant system organ classes. Signals consistent with the known safety profiles of these agents as well as signals for less well-described AEs were detected. Bone marrow necrosis, conjunctival hemorrhage, and peritoneal fluid retention events were uniquely associated with imatinib. AEs that most commonly reached the threshold for dasatinib consisted of terms relating to hemorrhage and fluid retention, including pleural effusion and pericardial effusion. Most terms that reached the threshold solely with nilotinib were related to peripheral and cardiac vascular events. Although this type of analysis cannot determine AE incidence or establish causality, these findings elucidate the AEs reported in patients treated with BCR-ABL inhibitors across multiple clinical trials and in the community setting for all approved and nonapproved indications, suggesting drug-AE associations warrant further investigation. These findings emphasize the need to consider patient comorbidities when selecting amongst BCR-ABL inhibitors.

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In the adjuvant setting, the third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane are recommended at some point during treatment, either in the upfront, switch after tamoxifen or extended treatment setting after tamoxifen in postmenopausal patients with hormone receptor-positive early breast cancer. AIs have demonstrated superior disease-free survival and overall benefit-to-risk profiles compared with tamoxifen. Potential adverse events, including cardiovascular (CV) side effects, should be considered in the long-term management of patients undergoing treatment with AIs. AIs reduce estrogen levels by inhibiting the aromatase enzyme, thus reducing the levels of circulating estrogen. This further reduction in estrogen levels may potentially increase the risk of developing CV disease. This systematic review evaluated published clinical data for changes in plasma lipoproteins and ischaemic CV events during adjuvant therapy with AIs in patients with hormone receptor-positive early breast cancer. The electronic databases MEDLINE, EMBASE, Derwent Drug File and BIOSIS were searched to identify English-language articles published from January 1998 to 15 April 2011 that reported data on AIs and plasma lipoproteins and/or ischaemic CV events. Overall, available data did not show any definitive patterns or suggest an unfavourable effect of AIs on plasma lipoproteins from baseline to follow-up assessment in patients with hormone receptor-positive early breast cancer. Changes that occurred in plasma lipoproteins were observed soon after initiation of AI therapy and generally remained stable throughout the studies. Available data do not support a substantial risk of ischaemic CV events associated with adjuvant AI therapy; however, studies with longer follow-up are required to better characterize the CV profile of AIs.

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The results of these studies indicated that dasatinib did not induce physiological changes or molecular signatures consistent with PAH when compared to positive controls. Instead, dasatinib induced changes consistent with imatinib. Both dasatinib and imatinib induced biochemical and structural changes consistent with a protective effect for PAH. These data suggest that other factors of unclear etiology contributed to the development of PAH in patients treated with dasatinib.

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). 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.