TKIs and the treatment of CML in pregnant women

The use of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia has led to a transformation of chronic myeloid leukemia from a fatal disease without aggressive intervention to a disease that is a chronic condition, with patients having extended life expectancies.

CML has changed during the past decade to a disease requiring lifelong medication that provides substantial disease control, relatively few adverse effects and nearly normal lifestyles for most patients. Although the median age of diagnosis for patients with CML is 65 years, 20.2% of patients are diagnosed before the age of 44 years, with 17.6% aged 20 to 44 years. This younger subset of patients with CML can be faced with making decisions regarding child-bearing and continued control of their disease.

Tyrosine kinase inhibitors in pregnancy

In 2001, the first TKI for the frontline treatment of CML — imatinib (Gleevec, Novartis) — was introduced into the US market, offering durable remissions in up to 70% of patients. Dasatinib (Sprycel, Bristol-Myers Squibb) and nilotinib (Tasigna, Novartis) quickly followed as second-generation TKIs with additional receptor targets. Besides inhibiting the BCR-ABL gene, the second-generation TKIs may also inhibit other targets, including c-Kit, the platelet-derived growth factor receptors alpha and beta, Arg, c-Fms and Src. Several of these proteins are known to have functionality in gonadal development, implantation and fetal development.

Due to preclinical studies that found imatinib to be teratogenic in rats, resulting in defects such as exencephaly, encephaloceles and deformities of the skull bones, it has been recommended that women receiving treatment with imatinib use appropriate methods of contraception and to be aware of the potential teratogenic effects on fetuses. Published data of animal models with nilotinib and dasatinib also report increased risk of fetal toxicity, and similar warnings of use while pregnant have been issued. Therefore, there is scant data, other than case reports, on fertility and risks to the fetus in patients who continue treatment with a TKI during their pregnancies.

Published literature contains a number of case reports on the outcomes of pregnancy in patients who conceived while taking imatinib, dasatinib or nilotinib. The largest of such reports was a full outcome report of 125 of 180 women identified who conceived while on imatinib. Of these patients, 103 (71%) were exposed during the first trimester and 38 (26%) were exposed to imatinib throughout their pregnancy, until spontaneous or elective abortion or birth. The birth of a normal live infant occurred in 63 of the 125 pregnancies with a known outcome, with 18 of these patients receiving imatinib throughout their pregnancies. Elective terminations occurred in 35 women, three of which followed identification of fetal abnormalities. Eighteen pregnancies ended in spontaneous abortion; eight with known exposure during the first trimester and seven exposed throughout the pregnancy. Nine infants were reported to have congenital abnormalities, with eight live births and one stillbirth.

Of the 12 pregnancies that resulted in infants with fetal abnormalities, the dose of imatinib administered was recorded for 10 of these patients, with a range of 300 mg to 400 mg/day; however, the duration of therapy was not reported. It was noted that three of the infants had a similar defect, exomphalos, to that previously observed in rodent studies. Although the incidence of exomphalos in the general population is rare, occurring in one of 3,000 to 4,000 births, the findings in this report show a much higher incidence of three in 180 patients, which raises the concern of an imatinib-induced effect more likely than chance alone. Although the study was retrospective with data from spontaneous reports, the researchers concluded that imatinib should be avoided in pregnant patients due to the potential risk for serious developmental abnormalities, unless the risk of interrupting therapy is deemed unacceptable.

With shorter market exposures and fewer patients receiving treatment with dasatinib and nilotinib, there are very few reports of their use in pregnant patients. As of publication, only one case study of nilotinib exposure during pregnancy in a woman with CML has been published. In this case, an unplanned pregnancy was identified 7.4 weeks into gestation in a woman taking nilotinib 200 mg orally twice daily. Treatment was immediately held and no further treatment was given until delivery of a healthy baby.

The use of dasatinib during pregnancy has been reported in a report of two women with 5 to 8 weeks of exposure before discovery of pregnancy and subsequent discontinuation of therapy. One patient developed leukocytosis and mild thrombocytosis while off dasatinib and was subsequently treated with hydroxyurea and cytarabine starting around 12 weeks of gestation. Both cases reported normal fetal development with delivery of healthy babies. Another larger report describes eight women who conceived while receiving dasatinib. In these women, five abortions (three elected and two spontaneous) were reported in addition to three deliveries with no defects noted.

In most of the presented cases of TKI use during pregnancy, women had planned or unplanned pregnancies while being actively treated for CML. Although rare, the diagnosis of CML during pregnancy may place clinicians in a unique situation requiring the use of other therapeutic options for disease control while avoiding TKI therapy.

Management of CML during pregnancy

In the rare event in which women are newly diagnosed with CML during their pregnancies, observation and close monitoring are an appropriate initial strategy to the management of these patients. For most women with chronic-phase disease, initiation of treatment can be deferred until after delivery and cessation of breast-feeding, if appropriate. Several strategies, including interferon alpha (INF-alpha), hydroxyurea and apheresis, have been suggested for the management of leukocytosis (white blood cell count >100 × 10⁹/L) and/or thrombocytosis (>500 × 10⁹/L) in these patients in which the avoidance of initiation of TKIs is desired.

INF-alpha was the non-transplant treatment of choice before the development of imatinib in 1998. By inhibiting cell proliferation through its ability to enhance or inhibit the synthesis of specific proteins, RNA degradation, modification of cell surface antigen expression, and possibly immune system modulation, INF-alpha differs from other therapeutic agents by eliciting no effect on DNA synthesis. Because of its large molecular weight (19 kilodalton), crossing of the placental barrier is not observed to a great extent. In animal studies, neither mutagenicity in vitro nor teratogenicity have been observed. Numerous case reports have been published reporting successful pregnancies in women receiving INF-alpha for the treatment of CML in all stages of pregnancy. No reports have been associated with congenital malformation, and all pregnancies have resulted in healthy babies. Based on these results, INF-alpha is considered a safe drug to be administered throughout pregnancy.

Hydroxyurea has primarily found a role in the management of CML as a method to control leukocytosis and thrombocytosis in patients waiting to start treatment with TKIs. Before the discovery of imatinib, hydroxyurea was commonly administered to patients with CML — with a significant portion of patients obtaining a hematologic remission — but did not show an improvement in OS and only rarely showed cytogenic responses. As a cell cycle-phase specific antineoplastic agent, it exhibits its effects by blocking ribonucleotide reductase, the rate-limiting enzyme of DNA synthesis.

Animal models have demonstrated hydroxyurea to be a potent teratogen, causing fetal malformations and embryotoxicity in rats and rabbits. Several cases of administration of hydroxyurea at discovery of pregnancy in patients with CML have been reported, with four of the five women delivering normal infants and one reported stillborn infant after eclampsia. Additional published case reports describing the use of hydroxyurea during pregnancy, particularly after the first trimester, have shown successful deliveries with no reported effect on fetal development. However, most guidelines suggest avoiding the use of hydroxyurea unless no alternative therapy exists.

Apheresis is another option in the control of CML, particularly leukocytosis, due to the avoidance of drug therapy and the ability to be used during the first trimester of pregnancy. By rapidly reducing the white blood cell counts to reduce the risk for leukocyte-induced vascular occlusion, leukopheresis serves as a short-term treatment modality but is not recommended as maintenance therapy. Unlike other treatment options for CML, leukopheresis does not carry the potential for teratogenic or leukomogenic adverse effects in pregnant patients.

Published experiences using leukopheresis as a viable alternative to cytotoxic agents and INF-alpha have reported it to be well tolerated by the mother and fetus with normal fetal development and delivery. Based on these case reports, it is reasonable to utilize leukopheresis as a temporary measure of control in patients not only in the first trimester, but also for those who do not wish to be exposed to other CML treatments during their pregnancies, with the intention of initiating more aggressive therapy after delivery.

Summary

During the past decade, the treatment of CML has been revolutionized by the development of TKI therapies. This rapid change in the disease course has forced many clinicians to adapt treatment regimens for that select patient population who are of child-bearing age and may wish to have a family. Case reports of TKI use during pregnancy have shown favorable outcomes in most cases; however, the risk of fetal harm still remains, thus prompting strict warnings on the use of TKIs during pregnancy.

Other therapeutic options, including INF-alpha, hydroxyurea (after the first trimester) and leukopheresis have been shown in numerous case studies to be safe alternatives when therapy is warranted during pregnancy. A thorough discussion with the patient before conception or after discovery of pregnancy is prudent to review the various treatment options available and the risks involved.

Starla J. Sweany, PharmD, BCOP, is a Clinical Pharmacy Specialist in Leukemia at MD Anderson Cancer Center. Disclosure: Dr. Sweany reports no relevant financial disclosures.

For more information:

• Apperley J. Best Pract Res Clin Haematol. 2009;22:455-474.
• Apperley J. J Natl Compr Canc Netw. 2009;7:1050-1058.
• Ault P. J Clin Oncol. 2006;24:1204-1208.
• Mubarak AA. Am J Hematol. 2002;69:115-118.
• Pye SM. Blood. 2008;111:5505-5508.
• Shapira T. Blood Rev. 2008;22:247-259.