Asciminib and pregnancy in CML: Preliminary human data and clinical implications from 47 reported outcomes Free

Asciminib (ASC) is a first-in-class allosteric BCR::ABL1 tyrosine kinase inhibitor (TKI), specifically targeting the myristoyl pocket. It has shown promising efficacy and a favorable safety profile in patients with chronic phase (CP) chronic myeloid leukemia (CML). As ASC use expands, including frontline therapy, clinicians will face complex questions about pregnancy planning and treatment.

Preclinical studies revealed no adverse effects on male or female fertility at exposures equivalent to human dosing, and no increased risk of embryo-fetal harm from paternal exposure. In female rats and rabbits, a low incidence of embryotoxic and teratogenic effects (e.g., cardiac malformations, anasarca) occurred only at high doses, above therapeutic levels.

Given the limited human data on pregnancy during ASC treatment, we aimed to provide an overview of pregnancy outcomes in CML patients with confirmed paternal or maternal ASC exposure.

This analysis includes cases collected from two sources: data provided by the manufacturer upon our request (from clinical trials and post-marketing) and physician reports, encompassing both retrospective and prospective data.

A total of 47 pregnancies were identified: 13 with paternal exposure and 34 with maternal exposure, in 32 women (1 with 2 pregnancies, 1 with twins). In the paternal exposure group, 8 men were receiving ASC as monotherapy at the time of conception, while 5 were treated with ASC in combination with nilotinib or imatinib. Among the 11 cases with known outcomes, 8 resulted in live births (including one twin pregnancy), while 2 ended in miscarriage and 1 in an ectopic pregnancy. The ASC dose in mg was reported in 6 cases: 40 QD (ectopic pregnancy), 40 BID (miscarriage); 80 QD in 3 (childbirth, one medically assisted with egg donor), ASC 40 QD+imatinib 400 mg in one (childbirth).

All newborns were reported as healthy, with no congenital anomalies.

The maternal exposure group included 33 cases treated with ASC monotherapy and one case of combination with imatinib. In one instance, the patient transitioned to interferon after discontinuing ASC at 6 weeks (W) of gestation. Among the 23 pregnancies with known outcomes, 10 ended in elective abortion, mostly due to the patient's preference to continue therapy or uncertainty about fetal safety, 3 resulted in miscarriage, and 11 in 12 live births (one twin pregnancy).

Few embryo-fetal data were available. In one elective termination at 14–15W with ASC stopped at 4W, the fetus exhibited anasarca and monosomy 45, considered unrelated to ASC. Another case of miscarriage at 9W involved a non-developing gestational sac, with no direct association to the treatment. In 6 cases, the pregnancy outcome was unknown due to loss to follow-up or missing consent, while 4 pregnancies were still ongoing at the time of reporting. Among the ongoing cases, three women had discontinued ASC early in pregnancy while exposed to 40 to 80 QD.

In total, 10/12 normal newborns were reported following maternal exposure. In most cases, ASC had been discontinued during the first trimester, often between 4 and 9W, with daily doses ranging from 20 to 120 mg, and one ASC 40 QD+imatinib 400 mg. One woman used ASC 200 QD until the third month of pregnancy without reported complications. Another case involved continued ASC use into the 2^nd and 3^rd trimesters; the child was born healthy (transient aspiration pneumonia resolved fully). Two cases of congenital anomalies were documented, one with ventricular septal defect, coarctation of the aorta, fetal growth restriction (40 BID discontinued at 5W) and another with a non-specified major anomaly (80 QD discontinued at 6W) both considered unrelated to ASC and possibly linked to other factors, including concurrent medications.

This series represents the largest collection of pregnancy outcomes related to ASC to date. Despite limited data, these findings suggest that paternal ASC exposure appears uneventful, and early treatment discontinuation during pregnancy in women is feasible. Notably, one case of 2^nd and 3^rd trimester exposure was recorded. However, contraception is advised for women on ASC, especially if previously failing other treatments; no contraception is needed for men. The presentation will provide updated clinical details, including CML management during gestation and reproductive outcomes, offering insights to improve patient counseling, support informed reproductive choices, and guide personalized treatment.