Antineoplastic
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of cladribine in human pregnancy have been located. However, other drugs that inhibit DNA synthesis (e.g., methotrexate and aminopterin) are known human teratogens. If possible, the drug should be avoided in pregnancy, especially during the 1st trimester. Because hairy cell leukemia usually has an indolent disease course, deferring treatment until after delivery may be appropriate (1).
FETAL RISK SUMMARY
The prodrug cladribine is a synthetic antineoplastic agent that is administered as a single course given by continuous IV infusion for 7 consecutive days. It is indicated for the treatment of active hairy cell leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms. The drug is classified as an antimetabolite in the same subclass of purine analogs and related agents as clofarabine, fludarabine, mercaptopurine, pentostatin, and thioguanine. Cladribine undergoes intracellular metabolism to its active metabolite. About 20% is bound to plasma proteins and the mean terminal half-life is 5.4 hours (2).
Reproduction studies have been conducted in mice and rabbits (routes not specified but assumed to be oral). In mice, a significant increase in fetal variations was observed with a daily dose that was about 17 times the human dose based on body weight. The drug was embryotoxic in mice when given at doses equivalent to the human dose. When the daily dose was doubled, increased resorptions, reduced litter size, and fetal malformations were observed. Fetal death and malformations were observed in rabbits given a daily dose that was about 33 times the human dose based on body weight. The no-observed-effect-dose (NOEL) in these species was about 6 and 11 times the human dose, respectively (2).
Carcinogenic studies have not been conducted with cladribine. The drug was not mutagenic in various assays but was clastogenic. When given IV to monkeys, the drug caused suppression of rapidly generating cells, including testicular cells. The effect on human fertility is unknown (2).
It is not known if cladribine crosses the human placenta. The molecular weight (about 286), low plasma protein binding, terminal half-life, and long infusion time suggest that the drug will cross to the embryo–fetus.
In a letter correspondence, a woman at 10 week’s gestation was diagnosed with hairy cell leukemia (3). Because she wished to continue her pregnancy, treatment was deferred until after delivery. At 16 weeks’ gestation, during an otherwise normal pregnancy, she underwent a splenectomy for an enlarged spleen that was causing abdominal discomfort. She gave birth at term to a healthy female infant. Treatment was again deferred for 6 months while she breastfed her infant. Six weeks after treatment, a repeat bone marrow biopsy specimen and aspirate were normal (3).
A 37-year-old woman with hairy cell leukemia was treated with a 7-day infusion of cladribine and obtained a complete remission (4). Eleven months after completion of therapy, she became pregnant. Her pregnancy was uncomplicated and she gave birth to a term, healthy, female infant whose birth weight (actual birth weight not specified) was appropriate for gestational age. At 9 months of age, the infant was developing normally and meeting all developmental milestones (4).
BREASTFEEDING SUMMARY
No reports describing the use of cladribine during human lactation have been located. The molecular weight (about 286), low plasma protein binding (about 20%), terminal half-life (5.4 hours), and long infusion time (7 consecutive days) suggest that the drug will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. However, because of the risk for significant toxicity in a nursing infant, women receiving this antineoplastic agent should not breastfeed. Hairy cell leukemia usually has an indolent disease course and deferring treatment until breastfeeding is stopped appears to be an option (see above case report).
References
1.Robak T. Current treatment options in hairy cell leukemia and hairy cell leukemia variant. Cancer Treat Rev 2006;32:365–76.
2.Product information. Leustatin. Centocor Ortho Biotech, 2007.
3.Alothman A, Sparling TG. Managing hairy cell leukemia in pregnancy. Ann Intern Med 1994;120:1048–9.
4.Orlowski RZ. Successful pregnancy after cladribine therapy for hairy cell leukemia. Leuk Lymphoma 2004;45:187–8.