Successful pregnancy occurring with interferon‐alpha therapy in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) occurs with an incidence of 1–2 cases per 100 000 population (1). The median age at onset of CML is in the sixth decade and only 10% of cases occur in women of childbearing age. Interferon-alpha (INF-α) is a biological agent used for the treatment of malignant conditions such as CML. We describe two cases of successful pregnancy before and during INF-α treatment and briefly review the literature relating to these situations. A 36-year-old woman (gravida 3, para 3) was discovered to have Philadelphia chromosome (Ph)-positive CML in the chronic phase. Therapy was initiated with INF-α at 7.5 million units daily subcutaneously. A major cytogenetic response was obtained in the second year of treatment (Table I). One year later the patient became pregnant while on therapy with INF-α. INF-α was continued during the pregnancy at the same dose. The pregnancy was uncomplicated and the patient's blood counts remained well controlled. The patient delivered a healthy female infant at 38 weeks of gestation. The baby's blood count was normal. The woman remains on INF-α therapy. The baby's growth and development have been normal to date (1 year later). The patient was a 33-year-old woman (gravida 1, para 1) who presented in 1992 with chronic phase Ph-positive CML. She was treated with INF-α at 3.0 million units daily subcutaneously. A major cytogenetic response was obtained in the fifth year and she stopped treatment 4 years later (Table I). Three months later she became pregnant. The pregnancy proceeded without complications and she delivered a full-term healthy male infant by cesarean section because of secondary arrest of dilatation. The baby's blood count was normal. She currently has a normal hemogram and is receiving no therapy. The baby is now 3 months old and has normal development. CML is a disorder of the hematopoietic stem cells, accounting for 15% of adult leukemias (2). CML classically progresses through three phases in which a chronic phase (leukocytosis, anemia, thrombocytosis and splenomegaly) precedes an accelerated and ultimately blastic phase. This disorder results from neoplastic transformation of hematopoietic progenitor cells. At the molecular level, CML is characterized by the bcr-abl fusion gene, which results from the reciprocal translocation t(9,22)(q34;q11), creating the Ph chromosome. INF-α is an effective agent in the treatment of CML in the chronic phase and has been shown to suppress the leukemic clone and prolong survival in patients with CML. The treatment of CML in the pregnant patient is a rare and controversial clinical situation as the risk of fetal complications must be considered when choosing a line of therapy. Nine cases of successful pregnancies in patients with CML treated with INF-α have been reported previously (3) and five of them conceived while they were on active treatment with INF-α, like patient one. Although it has been suggested that INF-α may impair fertility through a decrease in serum estradiol and progesterone levels (4), these findings suggest that INF-α does not interfere with female fertility. Because INF-α inhibits cell proliferation by effects on protein synthesis, RNA degradation and possibly the immune system, rather than by inhibition of DNA synthesis, it may be safe for the treatment of CML during pregnancy. Another reason may be related to the finding that INF-α does not cross the placental barrier to a great extent, so low levels can be detectable in the amniotic fluid and the fetal membranes (3). These cases provide further evidence in support of the safety of INF-α with respect to the fertility of women of childbearing age. STI571 (Gleevec, Novartis) is an inhibitor of the tyrosine kinase Bcr-Abl, C-Kit, and platelet-derived growth factor receptor (PDGFR), approved in 2001 by the Food and Drug Administration for patients with chronic-phase CML who are resistant to or intolerant of INF-α (2). A prospective study compared the efficacy of STI571 with that of INF-α combined with low-dose cytarabine in newly diagnosed chronic-phase CML and concluded that in terms of hematologic and cytogenetic responses, STI571 was superior to INF-α plus low-dose cytarabine (5). Because of the potential fetal toxicity of STI571 and a lack of knowledge of its use in pregnancy, we did not choose this drug. However, STI571 is recommended in patients with chronic-phase CML who have had no response to INF-α. With further experience with the treatment with STI571, we would be able to report the clinical experience in relation to pregnancy outcome.