The Outcomes of Pregnancies in Japanese Patients with CML in the TKI Era; A Result of Nationwide Survey

Abstract

Background The introduction of tyrosine kinase inhibitors (TKIs) has dramatically improved the survival of patients with chronic myeloid leukemia (CML). Although the median age at diagnosis of CML is around 55 years, CML affects all generations, rendering a substantial population of women of childbearing potential. Therefore, issues related to conception and pregnancy are becoming increasingly important, because TKIs have the potential risk of fetal abnormalities and spontaneous abortion. Planned pregnancy during treatment-free remission (TFR) is an ideal way to avoid exposure of the embryo and fetus to a TKI. However, in real-life situations, not all conceptions are planned, not all patients fulfill the eligibility criteria for TFR, and some cases develop CML during pregnancy. Information about pregnancy in patients with CML is still limited in the TKI era. Study Design and Methods We designed a retrospective observational study of female patients with CML in the chronic phase who experienced pregnancy. We conducted a nationwide survey to collect data associated with CML treatment, conception, and pregnancy outcomes. This study was approved by the institutional review boards of Aiiku Hospital and each hospital participating in the survey. This study is registered in the University Medical Information Network (UMIN000042762). Results We sent questionnaires to 463 hematological centers to ask whether they made a diagnosis of CML in female patients of childbearing age and we received replies from 206 centers (recovery rate: 44.5%). A total 853 female patients aged 45 years or younger were diagnosed as having CML between 2002 and 2020, and 78 patients became pregnant by December 2020. Information of 70 pregnancies in 49 patients was obatained for analysis. The median age at CML diagnosis was 26 (range, 9-40) years and the median age at pregnancy was 33 (range, 21-42) years. Times of pregnancy varied from once to five times, and times of childbirth ranged from zero to three times. There were three types of pregnancies: CML onset during pregnancy (n=9), unplanned pregnancy during treatment or stopping treatment with TKI (n=25), and planned pregnancy during TFR or treatment with interferon (IFN)-α (n=36). The median durations from CML diagnosis to first pregnancy were 4.1 years in patients with unplanned pregnancies and 9.1 years in patients with planned pregnancies. Nine pregnancies in patients with CML onset during pregnancy resulted in seven births and two elective abortions. Twenty-five unplanned pregnancies led to 14 births, eight elective abortions and three spontaneous abortions. In 36 planned pregnancies, there were 27 births, one stillbirth and seven spontaneous abortions, and one case was during pregnancy at the time of the search. Elective abortions were chosen in 10 pregnancies, possibly due to exposure of the embryo to a TKI (n=9) or due to not achieving MMR at the time of a positive pregnancy test (n=6). TFR was chosen in 31 pregnancies, resulting in 26 births and five spontaneous abortions. MMR or deeper response was sustained in 18 of 26 (69%) pregnancies with childbirth and 15 of 18 (83%) pregnancies with DMR at the time of a positive pregnancy test. Treatment with IFN-α was chosen in 23 pregnancies and resulted in 20 births and three spontaneous abortions. Among the 13 patients with MMR or a deeper response at the time of pregnancy, only one patient (7.7%) lost MMR during pregnancy. Treatment with IFN-α was commenced after loss of MMR was experienced during pregnancy with TFR in four cases, with MMR being regained in two cases and CCyR being sustained in the other two cases until delivery. Conclusions Although our analysis was based on a limited number of patients, TFR could be a reasonable option for patients who achieve DMR and desire childbearing. Treatment with IFN-α might be another option for pregnancy in patients who achieved MMR or a deeper response.