1. Fuerst, Mark L.

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NEW YORK-Younger patients with chronic myelogenous leukemia (CML) can plan to start a family if they take proper precautions and receive appropriate counseling.

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Since the introduction of the first-generation tyrosine kinase inhibitor (TKI) imatinib, the life expectancy of CML patients has improved dramatically and now approaches normal. Clinicians have the opportunity to focus more on quality of life, including childbearing.


"Younger CML patients are interested in starting a family. Two main challenges for clinicians are pregnancy and management of CML and, if CML is present, pregnancy planning," noted Marlise R. Luskin, MD, MSCE, of Dana-Farber Cancer Institute and Harvard Medical School, Boston, while at the 2018 Great Debates and Updates in Hematologic Malignancies meeting.


TKIs & Fertility

The success of CML treatment is predicated on lifelong TKI therapy and, rarely still, allogeneic stem cell transplant. Fertility may also be affected by TKIs, transplant, and delay in childbearing.


An estimated 9,000 cases of CML were diagnosed in 2017, and approximately 20 percent of new cases are patients under age 45 years, or about 2,000 cases per year. CML represents about 10 percent of pregnancy-associated leukemias, or one in 100,000 pregnancies, Luskin said.


TKIs that target BCR-ABL also inhibit other tyrosine kinases. Off-target tyrosine kinase inhibition impacts gonadal development, embryonic implantation, and fetal development, although TKIs do not appear to be mutagenic.


The direct impact of TKIs on human fertility is not well-established, although preclinical studies show TKIs affect fetal development. One large retrospective study of imatinib exposure shows fetal toxicity during pregnancy, but no prospective clinical trials have collected data on pregnancy outcomes in women exposed to TKIs, noted Luskin.


Distinctive, overlapping congenital abnormalities have been described after imatinib exposure during early pregnancy, including skeletal malformations and renal, respiratory, and gastrointestinal abnormalities. "These retrospective studies make it impossible to define exact correlation between timing and dose of TKI exposure and abnormalities," she explained. Second-generation TKI exposure in pregnancy is less known and their safety is not established.


Is it safe for men on imatinib to conceive a pregnancy? she asked. "Studies suggest it is reasonable to continue imatinib with counseling regarding uncertainty. There is no data on safety for men on second-generation TKIs," she said. Limited case reports exist of successful, healthy pregnancies conceived by men taking dasatinib and nilotinib, but there are no reports of successful pregnancies of partners of men on bosutinib or ponatinib.


Once a pregnancy has been established during CML treatment, pregnancy termination is not mandated. Factors to consider include stage of pregnancy, stage of the disease, and if the pregnancy was desired. If the pregnancy is maintained, closely monitor the patient and fetus along with a maternal fetal medicine specialist, Luskin said.


A discussion of TKI cessation is appropriate, balancing risks versus benefits for the patient and fetus. It's generally recognized that patients should stop TKIs once pregnancy is recognized, and the TKI may be safely reintroduced later. Most patients who lose response during stopping reinitiate the response after pregnancy.


"There is evidence that TKIs do not cross to the placenta efficiently, but there is no data for the safety of this approach," said Luskin. Clinical experience suggests interferon is safe in the second and third trimesters; however, pegylated interferon may accumulate polyethylene glycol. Hydroxyurea should be avoided because of possible teratogenicity.


Need for Planning

Fertility counseling for men and women should occur at CML diagnosis, with a referral to a fertility specialist. Women should know the risks to the fetus of TKI exposure and men should know the possible risks to conceiving while on TKIs, particularly second-generation TKIs. She stressed the importance of contraception while receiving TKIs.


If a couple desires fertility, discuss options for fertility preservation prior to treatment and fertility during TKI treatment interruption. Fertility preservation prior to TKI initiation should include semen cryopreservation for men to facilitate partner pregnancy, current or future, and egg retrieval or embryo cryopreservation for women. Discuss with an experienced maternal-fetal medicine team to facilitate surrogate pregnancy and optimal timing of pregnancy, she said.


TKI discontinuation without deep remission carries risks. Most data are for imatinib. "Stopping trials in patients with excellent control is increasingly accepted. Patient selection is important," noted Luskin.


NCCN guidelines for stopping include a minimum 3 years of TKI, no history of TKI resistance, stable molecular response, and close monitoring every 1-2 months. The majority of molecular relapses occur within 6 months; almost all are within the first 1-2 years.


Most patients will not meet standard criteria for TKI stopping during the period of desired fertility. "Only 25 percent of patients are eligible for coming off TKIs," she said. Some experts propose the CML patient achieve a major molecular response for 2 years. An option is to organize a brief treatment cessation to complete embryo harvesting to allow fertility at a better time, or with a surrogate, said Luskin.


Breastfeeding is not recommended for patients receiving TKIs since the infant may be exposed to a therapeutic dose. Again, most data are from imatinib. Two case reports confirm imatinib and its metabolites are present in breast milk. The effects of infant exposure to imatinib are unknown.


Pregnancy is possible for CML patients, with precautions about the safety of TKIs. "No TKI is established as safe for the developing fetus, and women are recommended to avoid conceiving or carrying a pregnancy while taking a TKI. The impact of TKIs on spermatogenesis is not established, and men are not recommended to conceive while taking a TKI, with the possible exception [of] imatinib," Luskin emphasized.


Mark L. Fuerst is a contributing writer.