Chronic myeloid leukemia (CML) is a chronic myeloproliferative neoplasm characterized by a reciprocal translocation between the long arms of chromosomes 9:22 t(9:22)(q34,q11), which results in the BCR-ABL fusion gene that encodes a protein with tyrosine kinase activity. Today, the standard of care for this condition is targeted therapy with tyrosine kinase inhibitors (TKIs).1 CML may occur in women in their fertile age, meaning that pregnancy may occur at diagnosis or during the CML treatment.2,3 Rarely, the diagnosis of CML may occur during pregnancy. The management of this situation is challenging, due to the potential adverse effects of TKIs in the mother and the fetus,4 such as increased risk of placental failure, low weight of the newborn (NB), increased prematurity rate, perinatal morbidity and mortality.5 The TKIs are potentially teratogenic.3,4,6 Therefore, they are not recommended during pregnancy. Little is known about their potential toxicity to human embryos,7 but there are reports of cases that have been successfully treated with TKIs.7,8

This study aimed to analyze all cases of pregnancy in patients with CML at a single center.

From January 2000 to June 2016, we analyzed all cases of pregnancy in patients with CML. At our center, patients are advised to use adequate contraception methods during treatment with TKIs. Data were collected from medical records and prenatal care: age, disease phase at diagnosis and at start of pregnancy, Sokal and Hasford score, treatments for CML before, during and after pregnancy, adverse events, responses at the onset of pregnancy, evolution of disease during pregnancy, type of delivery and complications during or after birth. The Local Research Ethics Committee approved the project, and all patients signed informed consent. Definitions for the classification of the deliveries were: early term: 37 0/7 weeks through 38 6/7 weeks of gestation, full term: 39 0/7 weeks through 40 6/7 weeks, late term: 41 0/7 weeks through 41 6/7 weeks; post-term: 42 0/7 weeks of gestation and beyond.9

Between January 2000 and August 2016, we treated 497 patients (including 203 females) with CML at our center. There were ten pregnancies in 7 women. Pregnant patients had a median age of 29 years (13–38 years) at diagnosis, five were in the chronic phase (CP) and two in the accelerated phase (AP). Clinical and laboratory data at diagnosis are described in Table 1. Data from diagnosis was not available for one patient (patient 2), who had started treatment at another hospital. In 3 patients (1, 2 and 7), CML was diagnosed during pregnancy. All patients were Ph-positive, without any additional abnormality and presented the p210 BCR-ABL transcript. All pregnancies were not planned and TKIs were interrupted after diagnosis of the pregnancy. Five patients received TKIs between the 6th and 21st week of pregnancy.

The presence of pregnancy during the CML is a rare condition5 since the disease is more common between 40 and 60 years,2 and female patients are advised not to conceive while on TKI treatment. Reports are showing the increase in prevalence during the reproductive phase.10 In our series, we observed ten pregnancies in seven patients in fifteen years, all of them not planned, resulting in exposure to TKIs in the first weeks. Besides this short exposure to TKIs in the first trimester, there were no congenital malformations. The TKI was discontinued according to literature recommendation, to avoid the risk of teratogenic effects, as reported in animals.3,4,6,8 Some reports have shown favorable outcomes in patients who were treated with TKIs during pregnancy.13–16 Additionally, we did not observe any abnormality in the newborns exposed to HU during pregnancy.

Leukapheresis was used in two patients with newly diagnosed CML and was well tolerated. This therapy is described as safe in this population, but should be performed in individual cases of hyperleukocytosis.17

All patients used Interferon-alpha as standard therapy during pregnancy, doses from 3 million U/day three times a week to 9 million/day, which was well tolerated, although two patients had headache reports. However, the adverse effects were not significant for drug discontinuation. Five out of nine deliveries were preterm, but no malformation was reported, which corroborates the literature reports on the safety of the drug in pregnancy.14,15 Adverse-event profiles were similar among those described in the literature.13

We observed in our series that the TKI interruption in patients with stable MMR did not affect the patient's outcome. A recent review reported that TKI discontinuation among patients who have achieved very deep and prolonged molecular remission is safe, and that TKIs may be reintroduced after delivery in case of a loss of MMR.17

On the other hand, early discontinuation of imatinib, without achieving a stable response, increases the risk of loss of hematological response and progression, as described in patients 4 and 6. Patient 6 was resistant to imatinib and was receiving dasatinib as second-line therapy, with CHR as the best response, in 7 years of TKI treatment. She progressed to the accelerated phase and died seven months after the last delivery. In this particular case, the presence of the sickle cell disease corroborated a worse prognosis and a poor outcome. Pregnancy itself did not prove to be an aggravating factor of the disease, as suggested in the literature.6

Hydroxyurea, interferon and leukapheresis are safe options for patients with hyperleukocytosis. The use of TKIs is not recommended in pregnancy because of the risk of teratogenicity and should be started as soon as possible after delivery. In some cases, TKIs can be used during pregnancy, depending on the risk of the disease. Patients who wish to conceive should be advised to interrupt TKIs, with the recommendation that they achieve a stable and deep molecular response or at least a stable MMR before discontinuation. Those patients have less risk of MMR loss or disease progression after TKI discontinuation.

Katia B Pagnano: consultancy: Novartis. The other authors have no conflict to declare.