Pregnancy During CML Treatment Requires Judicious Use of TKIs, Interferon

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Although the use of tyrosine kinase inhibitors (TKIs) has emerged as a staple in the treatment of chronic myeloid leukemia (CML), their use during pregnancy garners special attention requiring the expertise of a multidisciplinary team, according to Elisabetta Abruzzese, MD, PhD, of Sant'Eugenio University Hospital in Rome, Italy.

Overall, all TKIs are teratogenic, embryotoxic, and can result in post-implantation loss when administered in high doses, although animal studies have not demonstrated genotoxicity or mutagenicity, said Abruzzese, during a Breakfast With the Expert session at the 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023).¹

Most of the concern exists with female patients; however, in the literature, about 450 pregnancies in partners of men on therapy have been described, with most men taking imatinib (Gleevec®; Novartis; n = 327), nilotinib (Tasigna®; Novartis; n = 50), and dasatinib (Sprycel®; Bristol Myers Squibb; n = 45). Investigators have noted no problems in conception, pregnancy, delivery, or any increase in congenital abnormalities in men taking TKIs but later-generation TKIs have not been extensively evaluated.

The use of TKIs in female patients with CML who become pregnant or who are pregnant at diagnosis has also been extensively reported. Pregnancy outcomes range from some fetal abnormalities reported for imatinib (n > 300) to unremarkable outcomes reported for bosutinib (Bosulif®; Pfizer; n = 16). Thirteen pregnant patients were administered asciminib (Scemblix®; Novartis) with 2 pregnancies having reached term, 3 were ongoing, 3 were electively terminated, 3 were spontaneous, and 3 were therapeutically terminated (1 for Turner syndrome and 2 were unknown).¹

Three factors to consider when treating female patients with CML who are pregnant include, first, illness-related factors, ie, biology of the illness (chronic phase vs advanced phase), CML status (onset, remission, depth of remission), pregnancy status (weeks of gestation and progress of pregnancy), timing and duration of embryo-fetus TKI exposition, and type of TKI used. Second, patient-related factors, including psychophysiological issues (age of patient, sociocultural and religious environment, and willingness of the patient). The third set of factors to consider are pregnancy-related, ie, a pregnant patient diagnosed with CML, a patient with CML who plans to get pregnant, and a patient with CML with an unplanned pregnancy.

“Regardless, each case of pregnancy must be individually considered,” Abruzzese said.

In the case of managing the pregnant patient with CML, Abruzzese said prenatal development plays a major role when considering the use of TKIs. “During the first 4 to 5 weeks of pregnancy after [medical] confirmation, the embryo has not implanted yet; there’s no contact with the mother’s blood or placenta,” Abruzzese said. “The use of TKIs can be suspended if pregnancy is diagnosed early,” Abruzzese continued. Weeks 6 through 10 of gestation are marked by organogenesis in the fetus. The most sensitive time for malformation is observed during weeks 12 through 16 of gestation, Abruzzese added.

Regarding studies focused on specific TKIs, Abruzzese noted that imatinib teratogenicity is mostly observed during organogenesis. According to 1 study,² 51 patients were treated with imatinib beyond the second trimester and experienced no events. Further, placental transfer to the fetus was minimal.

Abruzzese noted that nilotinib occasionally crosses the placenta (1 in 3 patients) and a study from European LeukemiaNet (ELN)2 reported on 7 patients treated with nilotinib after 21 weeks, most of whom received a reduced dose (400 mg/d) of the agent.

“Dasatinib also passes the placenta and should not be used at any time,” Abruzzese said. She noted that ELN reported 1 case of intrauterine death at 27 weeks.

In general, “monitoring is very important and should follow treatment-free remission (TFR) indications,” Abruzzese said. “The kinetics of transcript rise is variable and should determine when to restart TKI treatment,” said Abruzzese.

A potential alternative to TKIs is the use of interferon as it is reported safe throughout pregnancy and can be used to maintain remission when transcript levels start to rise, Abruzzese said.

For patients in deep molecular remission (DMR), defined as BCR-ABL of 0.01% or lower, no treatment is necessary if TFR criteria are met. The clinician should monitor BCR-ABL levels/kinetics every 4 to 8 weeks. If the patient is in major molecular response (MMR), defined as BCR-ABL less than 0.1% and greater than 0.01%, no TKI treatment is recommended, or interferon could be considered. The clinician should monitor complete blood counts (CBC), BCR-ABL levels/kinetics every 4 to 8 weeks.

For patients in MR2, defined as BCR-ABL greater than 0.1% but less than or equal to 1%, the clinician should consider interferon and measure BCR-ABL at week 15. If complete hematological response (CHR) is confirmed the clinician can consider imatinib or nilotinib if the patient is resistant to imatinib, and after placenta formation.

For patients with no MR2 and CHR, defined as BCR-ABL greater than 1% to 10%, consider interferon or no treatment if CHR is constant and measure BCR-ABL level and CBC at week 15. Imatinib and nilotinib are TKI options for consideration.

“For the patient with CML who is pregnant, we need to balance the care of the mother, the baby, as well disease burden,” Abruzzese concluded.

_REFERENCES

_{1. Abruzzese E. Chronic myeloid leukemia and pregnancy. Presented at: 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023). September 8, 2023. Houston, TX}

_{2. Abruzzese E, Mauro M, Apperley J, Chelysheva E. Tyrosine kinase inhibitors and pregnancy in chronic myeloid leukemia: opinion, evidence, and recommendations. Ther Adv Hematol. 2020;11:2040620720966120. doi:10.1177/2040620720966120}