妊娠期停用酪氨酸激酶抑制剂对慢性髓性白血病患者疾病状态及生育结果影响的观察

Effect of stopping tyrosine kinase inhibitors during pregnancy on disease status and reproductive outcomes among patients with chronic myeloid leukemia

目的探讨女性慢性髓性白血病（CML）患者妊娠期停用酪氨酸激酶抑制剂（TKI）对疾病状态及生育结果的影响。方法回顾性收集2004年11月至2017年11月期间，因妊娠停止TKI治疗的女性CML患者的临床资料，分析其临床特征、TKI停药前后的疾病状态变化及生育结果。结果共14例患者，均为慢性期（CP），12例Sokal评分低危。停药前TKI治疗中位时间46．5（15-123）个月。妊娠14次，妊娠时中位年龄为29（24-32）岁。12例意外妊娠者，妊娠期TKI中位暴露时间4（0-9）周。13例已获知生育结果，9例（69．2％）生产正常婴儿，1例（7．7％）生产多指畸形儿，3例（23．1％）自然流产。1例妊娠中（彩超未见器官畸形）。至随访截止日期，10例患者子女均生长发育正常，中位年龄14（0．7-65）个月。14例患者停药时疾病状态：完全分子学反应（CMR）7例，MR^4（BCR—ABL^IS≤0．01％，ABL转录本〉10000）3例，主要分子学反应（MMR）2例，完全细胞遗传学反应（CCyR）2例。妊娠期间停用TKI的中位时间为33．5（4-40）周。妊娠结束时疾病状态：4例为CMR，4例为MR^4，1例为MMR，4例为CCyR。无一例失去CCyR和血液学完全缓解。结论伊马替尼和尼洛替尼治疗期间，意外妊娠者可生育正常婴儿，但有自然流产和先天畸形风险。获得持续稳定MMR至少24个月的慢性期且Sokal评分低危的女性CML患者，妊娠期间停药安全系数较高，但仍有导致肿瘤负荷增加的风险，妊娠期间应每月监测外周血BCR—ABL水平变化。

Objective To explore the pregnancy outcome and disease status among patients with chronic myeloid leukemia （CML） treated with tyrosine kinase inhibitor （TKI） when they stopped TKI treatment during pregnancy. Methods The clinical characteristics, reproductive outcomes and disease status of the patients who stopped TKI due to pregnancy between November 2004 to November 2017 were retrospectively collected. Results A total of 14 CML patients in chronic phase （CML-CP）, 12 patients were Sokal-low-risk. The median time of TKI treatment was 46.5 （15-123） months before the drug was stopped. The median age at the time of pregnancy was 29 （24-32） years. The median time of TKI exposure was 4 （0-9） weeks in 12 accidental pregnancies. Outcomes were available for 13 pregnancies, 9 cases （69.2%） delivered healthy babies, 1 case （7.7%） delivered polydactylia malformation baby, 3 cases （23.1%） had spontaneous abortion. The last one was still in pregnancy （no organ malformations were observed in color Doppler ultrasound）. At the end of the follow up date, 10 children developed normal, the median age was 14 （0.7-65） months. Of the 14 patients who stopped TKI, 7 in complete molecular response （CMR）, 3 in MR^4 （BCR-ABL^IS 〈0.01%, ABL transcript 〉 10 000）, 2 in major molecular response （MMR）, 2 in complete cytogenetic response （CCyR）. The median time of TKI discontinuation during pregnancy was 33.5 （4-40） weeks. At the end of pregnancy, 4 cases were in CMR, 4 in MR4, 1 in MMR and 4 in CCyR. No patients lost CCyR and complete hematologic remission. Conclusions During the treatment of imatinib and Nilotinib, unplanned pregnancy may have a normal infant, but may lead to spontaneous abortion and congenital malformations. Female of CML-CP who had sustained and stable MMR at least 24 months and Sokal-low-risk had higher safety factor discontinued TKI during pregnancy, but still had a risk of increasing tumor load, so monitored the level of BCR-ABL of peripheral blood monthly during pregnancy is necessary.