The Impact of Ponatinib on Pregnancy Outcomes

Introduction: Ponatinib (PON), a third-generation tyrosine kinase inhibitor (TKI) with pan-BCR::ABL1 inhibition, is indicated for treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+-ALL). A high proportion of patients with CML and Ph+-ALL are of childbearing age, and because treatment with BCR::ABL1 TKIs can prolong survival, parenthood should be considered during chronic therapy. Preclinical studies have shown teratogenic and embryofetal toxic effects with PON, but little is known about its use during pregnancy in humans. The aim of this retrospective review is to describe pregnancy outcomes during PON use in patients to allow prescribers to manage this aspect of disease management. Methods: A search of the Incyte Global Safety Database was performed to identify all reports of pregnancy in PON-treated women or female partners of PON-treated men received worldwide from December 21, 2007, to December 13, 2022. We used the standardized Medical Dictionary for Regulatory Activities query “Pregnancy and Neonatal Topics” (broad scope with adjudication) to extract reports from patients, health care professionals, interventional and noninterventional clinical trials, literature, regulatory authorities, and license partners. As per standard pharmacovigilance practice, follow-up data were sought in all cases. Results: As of December 13, 2022, a total of 67 pregnancies were identified, including 35 (52.2%) with paternal and 32 (47.8%) with maternal PON exposure. Among the 35 pregnancies with paternal exposure, 25 (71.4%), 2 (5.7%), and 8 (22.9%) fathers had CML, Ph+-ALL, or another/unknown disease, respectively. Twenty-two (62.9%) pregnancies had known outcomes. Of these, 4 (18.2%) resulted in spontaneous abortions and 18 (81.8%) in live births, with the delivery of 14 (63.6%) healthy infants, 1 (4.5%) infant with congenital anomaly (fatal Patau syndrome; trisomy 13), and 3 (13.6%) infants with no other information. Most pregnancies resulting in delivery of healthy infants (n=9; 64.3%) and the 1 resulting in fatal Patau syndrome had paternal PON exposure >3 months at time of conception. In most cases of spontaneous abortions, duration of PON treatment at time of conception was unknown (n=3; 75%). Among the 32 pregnancies with maternal exposure, 28 (87.5%), 2 (6.3%), and 2 (6.3%) mothers had CML, Ph+-ALL, and another/unknown disease, respectively. Nineteen (59.4%) pregnancies had known outcomes. Eleven (57.9%) pregnancies resulted in abortion, of which 4 were spontaneous, 6 were elective, and 1 was an unspecified type. Eight (42.1%) pregnancies resulted in 9 live births, with the delivery of 4 healthy infants, 2 infants with a congenital anomaly, 1 infant with low birth weight, and 1 set of twins with no other information. Both infants with congenital anomalies had Hirschsprung's disease (HD), of whom 1 also had renal insufficiency. These infants were exposed to PON until the seventh and ninth gestational weeks (GWs), respectively. The infant with low birth weight was exposed until the fourth GW. Two women who had spontaneous abortions with known time of exposure during pregnancy were treated until the fourth GW and <20 GW. Of 4 women who delivered healthy infants, 1 was treated with PON until the fourth GW; 1 was treated until the sixth GW; 1 was treated intermittently during the pregnancy, pausing between weeks 6 and 20; and 1 had an unknown duration of exposure. Conclusion: Most pregnancies with paternal exposure to PON that had known outcomes led to healthy infants, suggesting minimal risk to the offspring. However, definite conclusions are limited by the small number of reports, limited information, and retrospective review. In contrast, in pregnancies with maternal exposure, 2 pregnancies resulted in infants born with the rare congenital malformation of HD. However, the limited information available does not provide sufficient support for a causal association between PON exposure and risk of HD. These results concur with the current recommendations that pregnancy should be avoided in women taking PON. In case of accidental or planned pregnancy, risk/benefit evaluations must be carried out on an individual basis, with careful counseling of the parents.