Incidence of Adverse Effects in Patients with Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia in Lymphoid Blast Crisis Receiving Ponatinib with or without Concomitant Azole Antifungals

Presenter: Kayleigh R. Marx, RPh, PharmD, BCOP, Clinical Pharmacy Specialist, Leukemia, University of Texas MD Anderson Cancer Center Division of Pharmacy

Co-Authors: Caitlin R. Rausch, MD Anderson Cancer Center Division of Pharmacy; Jenessa Lee, MD Anderson Cancer Center Division of Pharmacy; Alex R. Lovell, MD Anderson Cancer Center Division of Pharmacy; Shilpa Paul, MD Anderson Cancer Center Division of Pharmacy; Jonathan M. Savoy, MD Anderson Cancer Center Division of Pharmacy; Elias J. Jabbour, MD Anderson Cancer Center Division of Leukemia

Background: Ponatinib combined with hyper-CVAD for patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) has yielded an estimated 5-year event-free survival and overall survival of 68% and 73%, respectively.^1,2 A pooled multivariate analysis of phase 1-3 data demonstrated that ponatinib dose intensity was significantly associated with increased incidence of adverse effects (AEs), including arterial occlusive events.³ The combination of ponatinib and azole antifungals or other strong CYPA4 inhibitors may increase the risk of AEs because of increased serum levels of ponatinib.⁴ Given the necessity of azole use and the desire to increase utilization of ponatinib in this patient population, it is prudent to understand the impact of azoles on the incidence of AEs.

Objectives: To describe the incidence and severity of AEs, specifically the composite measure of arterial and venous occlusive events (AVOEs), in patients with Ph+ ALL or chronic myelogenous leukemia (CML) in lymphoid blast crisis (BC) who received ponatinib, with or without azoles or other strong CYP3A4 inhibitors. Secondary end points include time of onset of AEs.

Methods: This retrospective cohort study included newly diagnosed adults (≥18 years) with Ph+ ALL or CML-BC who received treatment with a ponatinib-based regimen at the University of Texas MD Anderson Cancer Center from March 6, 2016, to January 1, 2020. Patients with less than 12 months of follow-up were excluded. Pertinent medical history, laboratory studies, chemotherapy treatments, risk factors for AVOEs, and concomitant medications were collected from the electronic medical records. The results are reported using descriptive statistics.

Results: A total of 53 patients received ponatinib in combination with intensive (N = 39; 74%) or low-intensity chemotherapy (N = 14; 26%) for the treatment of newly diagnosed Ph+ ALL (N = 47; 89%) or CML-BC (N = 6; 11%). A total of 48 (91%) patients received a concomitant azole. Twenty-six (49%) patients had at least 1 grade 3 AE that was possibly related to ponatinib, after a median of 52 days of treatment, at a median dose of 30 mg of ponatinib. In addition, 8 (15%) patients had an occlusive event after a median of 86 days of treatment. Among these patients, 4 (50%) received an azole at the time of the event (ie, 2 received posaconazole, 1 isavuconazole, 1 fluconazole). One patient had both a venous and an arterial occlusive event.

Conclusion: The rate of venous occlusive events in this cohort is similar to rates reported with ponatinib monotherapy and does not appear to be increased in patients receiving concomitant azoles. Further analysis of the impact of concomitant non-azole CYP3A4 inhibitors and pharmacologic thromboprophylaxis on these outcomes is ongoing.

1. Jabbour E, Short NJ, Ravandi F, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study. Lancet Haematol. 2018;5:e618-e627.
2. Short NJ, Kantarjian HM, Ravandi F, et al. Long-term safety and efficacy of hyper-CVAD plus ponatinib as frontline therapy for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2019;134(suppls 1):283.
3. Dorer DJ, Knickerbocker RK, Baccarani M, et al. Impact of dose intensity of ponatinib on selected adverse events: multivariate analyses from a pooled population of clinical trial patients. Leuk Res. 2016;48:84-91.
4. Narasimhan NI, Dorer DJ, Niland K, et al. Effects of ketoconazole on the pharmacokinetics of ponatinib in healthy subjects. . 2013;53:974-981.