Cardio-Vascular Events Occurring On Ponatinib In Chronic Phase Chronic Myeloid Leukemia Patients, Preliminary Analysis Of a Multicenter Cohort
Authors: Nicolini Franck E. , Gagnieu Marie-Claude , Heiblig Mael , Blond Emilie , Legros Laurence , Guillermin Yann , Morisset Stephane , Barraco Fiorenza , Etienne Madeleine , Le Borgne Oriane , Ruby Jeremy , Sobh Mohamad , Richard-Colmant Gaelle , Fettig Celine , Michallet Mauricette , Rea Delphine 
Published: October 2019

Abstract
Ponatinib represents an alternative option for chronic phase (CP) chronic myeloid leukemia (CML) patients (pts) failing 2 or more tyrosine kinase inhibitors (TKI) or developing a T315I mutation. This TKI induces high rates of cytogenetic and molecular responses in a highly TKI-resistant patient population (Cortes et al. ASCO 2013). However, the tolerability of Ponatinib might not be optimal in this setting, as number of cardiovascular (CV) events might occur or recur, but the analysis remains complicated in such a population of pts already exposed to Nilotinib for the majority of them, and possessing their own CV risk factors as well. In order to clarify this question, we rationally and prospectively analysed a 3-center cohort of 19 CP CML pts on Ponatinib within trials or used as compassionate use. We measured standard clinical assessments [height, weight, body mass index (BMI)], and basic routine metabolic laboratory assessments (fasting total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glycosylated hemoglobin), homocysteine, an amino acid linked to arterial disorders, VEGF (ELISA), and BCR-ABL (IS). Ponatinib plasma concentrations were determined by UPLC with mass tandem detection at any time for all, expressed as µg/l and 24H concentrations (C24h, expressed ad mg/kg/d) were estimated according to the average half-life calculated for the entire cohort. The median age at diagnosis was 49 (7-82) and 56 (20-86) yrs at Ponatinib initiation. The Sokal score was low for 21%, intermediate for 10%, high for 53%, unknown for 3 (10%) pts. Median CML duration prior to Ponatinib was 53 (1.5-228) months. Prior to Ponatinib, 9 pts had 3 TKI, 6 2 TKI, 2 Imatinib only, and 2 none. Overall 10/19 pts (53%) had Nilotinib for a median of 12 (6-35) months, and 5/19 pts (26%) had CV risk factors prior to Ponatinib initiation (3 hypertension, 1 myocardial infarction (MI), 1 coronary arterial disease (CAD) on Nilotinib). Median BMI was 25.5 (16-34) with 4 pts >30 at Ponatinib initiation. Two pts were in CP at diagnosis, 2 in hematologic progression in CP, 13 in cytogenetic resistance, 1 in molecular progression, and 1 with extra-hematologic intolerance at Ponatinib initiation. The median duration of Ponatinib was 24 (1.5-27) months. At latest follow-up, 6 pts were in CHR, 2 in PCyR, 5 in CCyR, 6 pts were in MMR. Overall 8/19 pts (42%) had arterial -combined or not- CV events on Ponatinib (1 PAOD, 2 CAD, 2 MI, 4 newly diagnosed or destabilised hypertension, 1 renal artery thrombosis, 1 transient brain ischemia) after a median of 8.5 (4-17) months on drug. On Ponatinib, high values of total cholesterol (>2 g/l) were seen in 8 pts (4 unknown), LDL cholesterol (>1.5 g/l) in 3 pts (5 unknown), triglycerides (>1.48 g/l) in 7 pts (5 unknown), glycosylated hemoglobin (>6%) in 2 (7 unknown), and homocysteinemia (≥13 mmol/l) in 5 (5 unknown), but did not statistically differ from that of Ponatinib initiation. Median C24h of Ponatinib did not exceed the therapeutic range [i.e. ≥21 mg/l (according to J. Cortes et al. NEJM 2012): 23.3 (15-39) mg/l] except for 3 pts (all in CCyR). VEGF data will be presented. The only variable associated with CV events was older age at Ponatinib initiation (64 vs 47 years, p=0.019). We went on matching the Ponatinb cohort with an unselected cohort of Ponatinib-free CP CML pts treated with Nilotinib as first (19% of pts) or ≥2nd line in one center, sharing similar age at Nilotinib initiation (54 years), Nilotinib treatment duration (26.5 months), but with a longer disease duration (67 months). We analysed the cumulative incidence of CV events occurring on the TKI of interest (but not after), since its initiation (Figure 1).Figure 1 Cumulative incidences of cardio-vascular events occurring in CP CML pts on Ponatinib or on Nilotinib since TKI initiation and on each TKI.Figure 1. Cumulative incidences of cardio-vascular events occurring in CP CML pts on Ponatinib or on Nilotinib since TKI initiation and on each TKI.
In conclusion, despite the small size and the relative heterogeneity of this Ponatinib cohort, the obvious caveats and bias of such a study, despite high efficacy rates, Ponatinib induces significant high CV events in CP CML pts, after a relatively short period of exposure to this compound as compared to a historical cohort of Nilotinib-treated pts. The role of prior Nilotinib exposure remains to be determined. These results should promote an extreme vigilance especially in older pts with known CV risk factors that will need to be strictly controlled and monitored. A preventive anti-thrombotic prophylaxis might be useful since Ponatinib initiation.

Disclosures:
Nicolini: Novartis, Ariad, Teva, BMS and Pfizer: Honoraria. Legros:Novartis, BMS, Pfizer: Honoraria. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria.