Successful Planned Pregnancy through Vitrified-Warmed Embryo Transfer in a Woman with Chronic Myeloid Leukemia: Case Report and Literature Review
1 Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima 960-1295, Japan.
2 Fukushima Medical Center for Children and Women, Fukushima Medical University, Fukushima 960-1295, Japan.
Received: September 14, 2019
Accepted: November 18, 2019
Mediterr J Hematol Infect Dis 2020, 12(1): e2020005 DOI 10.4084/MJHID.2020.005
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
35-year-old female patient with chronic myeloid leukemia (CML) wanted
to have a child. She had been treated with imatinib and had achieved
major molecular remission, after which imatinib was intentionally
discontinued, and interferon-α treatment was initiated. After three
failed cycles of artificial insemination with her husband's semen, the
patient underwent treatment with assisted reproductive technology.
After two cycles of in vitro fertilization, two embryos (8-cell stage
and blastocyst) were cryopreserved. The patient again had elevated
major BCR-ABL mRNA levels; thus, infertility treatment was
discontinued. After 18 months of dasatinib treatment, major molecular
remission was again observed, and the patient underwent
vitrified–warmed embryo transfer with a single blastocyst. After that,
she became pregnant. Discontinuation of tyrosine kinase inhibitors
combined with the timely initiation of infertility treatments,
including assisted reproductive technology, might thus be useful for
treating women with CML who wish to become pregnant.
Tyrosine kinase inhibitors (TKIs) can be used as a standard treatment for chronic myeloid leukemia (CML) instead of chemotherapy with multiple anticancer drugs. For example, imatinib improves the prognosis for women with CML and preserves fertility, unlike conventional anticancer drugs; however, it is contraindicated in women of childbearing age due to its teratogenic effects. Moreover, intentional imatinib withdrawal has been reported to restore the possibility of spontaneous pregnancy in previous infertile women with CML;[1-7] however, there have been no reports of successful pregnancies following assisted reproductive technology (ART) treatment for infertile women with CML. Here, we report a successful planned pregnancy through vitrified–warmed embryo transfer in a woman with CML showing molecular remission.
Recently, a guideline regarding TKI discontinuation in female CML patients who wish to have children was revised and published. The guideline recommends that such individuals should discontinue TKI treatment before conceiving and maintain TKI discontinuation during pregnancy. However, the major problem associated with this strategy is CML relapse during TKI discontinuation. There have been several reports on TKI discontinuation criteria and relapse rates following TKI interruption in CML patients. According to reports from TKI discontinuation trials, the recurrence rate is approximately 50–60% in CML patients with complete MMR or a deep molecular response. Moreover, if untreated after TKI discontinuation, recurrence is generally observed within six months. Therefore, female CML patients who wish to become pregnant must switch from imatinib to another CML treatment and have a limited amount of time to achieve pregnancy successfully.
Treatment options during TKI withdrawal or pregnancy include the administration of hydroxyurea and INF-α.[10-13] Hydroxyurea is not a safe option due to observed teratogenic effects in an animal model. However, INF-α is safe for women who wish to have children or for pregnant women. In this case, INF-α was administered after TKI withdrawal and was continued during infertility treatment. Due to prolonged infertility treatment, interferon-α monotherapy was unable to suppress the CML disease state. Therefore, another TKI, dasatinib, was administered for disease control.
There are multiple ways to achieve pregnancy and, subsequently, delivery, such as natural pregnancy and infertility treatment. Although natural pregnancy is ideal, infertility treatment (particularly ART) is effective in achieving pregnancy in a limited time. As shown in Table 1, 11 cases of planned pregnancy have been reported in female CML patients with TKI interruption, including this case.[1-7] Besides one, all cases exhibited MMR at the time of TKI interruption. IFN-α therapy was performed in three of the 11 cases, including ours, after TKI discontinuation. Four of the cases conceived naturally, and two underwent infertility treatment without ART. However, there have been no previous reports of ART treatment for planned pregnancy in female CML patients; therefore, our report might be the first case in which pregnancy was achieved via vitrified–warmed embryo transfer.
|Table 1. Reported cases of planned pregnancy in patients with CML with TKI interruption.|
ART treatment with frozen embryos increases the chance of pregnancy in women with CML as well as other AYA cancer survivors. It might also be appropriate even if infertility treatment is interrupted due to CML relapse. In this case, ART treatment was administered after six months of non-ART infertility treatment. During this time, levels of CML molecular markers started to increase, forcing the infertility treatment to be interrupted when frozen embryos were obtained after two cycles of ART treatment. The patient was then treated with dasatinib, another TKI, in addition to IFN-α treatment. After MMR had been confirmed after more than 12 months, vitrified–warmed embryo transfer was scheduled, and pregnancy was established. Thus, ART, particularly with frozen embryos, could be a useful treatment option for female CML patients who have a limited period to achieve pregnancy.
Given that there is currently no effective strategy to prevent age-related fertility declines in women, cryopreservation of eggs or ovarian tissue to preserve fertility for women who wish to have children is an important issue. In this case, the patient was already 35 years old when she was referred to our hospital, having been diagnosed with CML at 27 years when she was already married to her partner. The patient might have been able to undergo embryo cryopreservation by ART as soon as she was judged to be in MMR. Recently, Gazdaru et al. reported successful embryo cryopreservation for a TKI-resistant female CML patient who changed from TKI to IFN-α treatment prior to conditioning chemotherapy with hematopoietic stem cell transplantation. Accordingly, all female CML patients who wish to have children, even those who are unmarried without a partner, should consider undergoing embryo or oocyte cryopreservation to preserve their fertility.
Another critical issue to consider in such cases is the teratogenicity of treatment drugs during pregnancy in women with CML.[6,17] In this case, we stopped dasatinib, a TKI, and IFN-α before the scheduled vitrified–warmed embryo transfer; nonetheless, the child was born with a meningocele despite the long drug-free period. There have been previous reports of meningoceles occurring in the children of female CML patients who became pregnant during imatinib treatment.[17,18] Moreover, Cortes et al. reported that an infant with encephalocele, a type of neural tube defect, was observed in a woman treated with dasatinib. In this case, since the pregnancy was established more than three months after the discontinuation of dasatinib administration, there might be almost no drug-related effects on the fetus. In contrast, IFN-α has not been reported to exhibit teratogenicity and can be used safely during pregnancy.
Neural tube defects, such as meningoceles are associated with folate deficiency. Generally, hematological malignancies, such as leukemia and pregnancy, require large amounts of folate for cell growth.[21,22] Moreover, polymorphisms in the gene encoding methylenetetrahydrofolate reductase, an enzyme involved in folate metabolism, have been associated with CML in Asian patients. In this case, additional folate supplementation might be required in addition to that generally recommended.
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