Changes in RT-qPCR Levels during and after TKI Interruptions for Attempted Conceptions in Women with CML

Introduction: Amongst the benefits of tyrosine kinase inhibitors (TKI) for chronic myeloid leukemia (CML) is the ability for younger patients to consider parenthood. TKI are contraindicated in pregnancy, so for women attempting pregnancy therapy is interrupted. Although successful pregnancy outcomes are well-recognised there are limited data on the likelihood of relapsing off-treatment, and the impact on the disease long-term. This observational study included 28 women who interrupted TKI on 38 occasions, for either planned interruptions to attempt conception or stopping on discovering pregnancy. Our data suggest that although disease and pregnancy outcomes were less good in patients with unplanned interruptions, good outcomes are still possible. Furthermore, the outcome for patients with MMR or better at stopping is so favourable that current recommendations regarding approaches to conception could be revised to address actual rather than optimal behaviour in this unique circumstance

Methods: Using our comprehensive database of 935 TKI-treated patients with CML we identified all women of child-bearing age, and then those who interrupted TKI therapy in the context of planned or unplanned pregnancy. Irrespective of subsequent pregnancy, we collected information regarding previous obstetric history, TKI, RT-qPCR level, line and date at stopping, three monthly RT-qPCR levels during time off treatment, RT-qPCR level at restarting treatment, best RT-qPCR response after restarting, and TKI and RT-qPCR at most recent follow up.

Results: Of 174 women aged <46yrs at diagnosis, 28 discontinued TKI on at least one occasion to attempt or continue pregnancy (total attempts =38). There were 18 planned attempts by 14 women to conceive off-treatment, of which 8 were successful. Women were advised to limit their attempt at conception to 6 months, to allow for a maximum time off-treatment of 15 months should pregnancy occur. The median time off-treatment prior to conception or re-starting was 193 (61-223) days. The 8 conceptions, resulted in 6 healthy babies and two spontaneous abortions. The median time off-treatment for successful conception attempts was 373 (173-1131) days. Four further women used assisted conception because of some combination of older age, history of unsuccessful conception prior to diagnosis and less deep response levels. IVF was unsuccessful in 2 cases (29/32 days off-treatment), the remaining 2 women progressed to term and had three healthy babies (one twin pregnancy) each with 304/658 days off-treatment. Responses at stopping were MR3 or deeper in 20/22 (91%). Eight women remained in MMR or better while 12 lost MMR, eight also lost CCyR, but none lost CHR. Ten of the 12 have regained MR3 and the remaining 2 cases have only recently restarted TKI.

Thirteen women discovered on 16 occasions that they were pregnant on TKI, and all stopped treatment beyond 5 weeks gestation but within the first trimester. There were 3 abortions (1 elective and 2 spontaneous), and 13 live births (10 healthy, 2 with perinatal problems and 1 with a congenital abnormality). At stopping, 9/16 were in MR3 or deeper: 8 lost MMR, 7 lost CCyR and 1 lost CHR. Seven of 8 regained MMR but the remaining case has not regained CCyR 1933 days after re-starting treatment. Of the 7 patients not in MMR at stopping, 6 obtained MMR or deeper on re-starting therapy and the remaining case is in CHR, 123 days from re-starting TKI.

Conclusion: By considering the outcomes of 38 attempts at pregnancy in women taking TKI treatment, we found first and foremost that temporary cessation of therapy can allow women with CML to have a baby. Twenty-nine women were in MMR at time of stopping, of whom 9 remained in MMR off therapy, which suggests that advice pertaining to time off TKI should be tailored to RT-qPCR results and not to arbitrary time-limits. Of 20 women who lost MMR, 18 regained this level on re-starting (remaining 2 women too early after re-starting to assess response), which supports the general advice that stopping therapy should be delayed until MMR is obtained, However of the 9 women who were not in MMR at stopping, 6 have subsequently obtained MMR with 3 achieving MR4, suggesting that good responses can still be obtained and the possibility of more flexible approaches (assisted conception, pulsed TKI treatment, TKI holidays etc) for women unable to obtain optimal responses in a biologically timely manner.