Dr. Joseph G. Jurcic
Dr. Mark L. Heaney
Question: For how long should a patient with chronic myeloid leukemia who wants to become pregnant be removed from TKI therapy?
Answer: Imatinib, dasatinib, and nilotinib are teratogenic and cause embryonic or fetal toxicities in animals. Although tyrosine-kinase inhibitors (TKIs) do not appear to affect male fertility or pregnancy outcomes in female partners, these drugs are associated with a higher rate of miscarriage and fetal abnormalities when taken during pregnancy. In a report of 180 women with chronic myeloid leukemia (CML) exposed to imatinib during pregnancy, 14% had spontaneous abortions, and congenital abnormalities were seen in 10% of infants.1 Similar complication rates were observed with dasatinib.2 Based on these findings, conception while on TKI therapy is strongly discouraged, and these agents should be discontinued throughout pregnancy.
The best available data regarding discontinuation of treatment to attempt conception is derived from several TKI-stopping studies. In the STIM trial, among patients with undetectable minimal residual disease by BCR-ABL RQ-PCR analyses for at least 2 years, 41% remained in a treatment-free remission (TFR) 24 months after stopping imatinib. Most recurrences were seen within 6 months of treatment discontinuation, and resumption of imatinib produced undetectable minimal residual disease in nearly all patients.3 Similar results were reported in the Australasian Leukaemia & Lymphoma Group TWISTER study.4
Data on TFR after second-generation TKIs are limited, but large studies with nilotinib and dasatinib are in progress (NCT01743989, NCT01596114, NCT01744665, NCT01698905, NCT01627132, and NCT18500004). In the DADI trial conducted in patients taking dasatinib as second-line treatment who had a sustained deep molecular remission for more than 1 year, the TFR rate was 49% at 6 months.5 In the STOP 2G-TKI study, among patients receiving either nilotinib or dasatinib for at least 3 years and who maintained a 4.5-log reduction in BCR-ABL transcripts (MR4.5; BCR-ABL ≤ 0.0032% by International Scale [IS]) for 2 years, the 1-year probability of TFR without loss of major molecular response (BCR-ABL ≤ 0.1% IS) was 61%.6 Similarly, in a preliminary report of the ENEST freedom trial, 52% of patients on frontline nilotinib with sustained deep molecular response maintained a major molecular response without treatment for 12 months (NCT01784068).7 These data suggest that ideally TKIs should be stopped for patients to become pregnant when they meet stringent criteria for treatment discontinuation, namely a sustained MR4 (BCR-ABL ≤ 0.01% IS) for at least 2 years documented on at least four tests performed 3 months apart.8 However, given that sustained deep molecular remission is attained in approximately 40% of patients only after several years of treatment,9 this approach is not always feasible.
Outcomes of TKI discontinuation in pregnant patients without deep molecular remission are not as favorable. Ault et al. found that, after a median of 8 months of imatinib, five out of nine women in complete hematologic remission at the time of treatment interruption relapsed, and six experienced an increase in Philadelphia chromosome–positive metaphases. At a median of 18 months after resuming imatinib, eight patients had a cytogenetic response, but none achieved a major molecular response.10 Kuwabara et al. reported that, among seven women who had not achieved undetectable minimal residual disease at the time of imatinib discontinuation, all had disease progression. The three women who had achieved a major molecular response before stopping therapy attained it after restarting TKI, whereas the four remaining patients without a major molecular response did not regain responses.11 Therefore, a practical approach might be to advise temporary cessation of treatment after a major molecular response has been maintained for at least 2 years with monthly monitoring of peripheral blood by RQ-PCR.
It is not known how long TKI therapy should be stopped before attempting a natural pregnancy or oocyte retrieval, but recommended durations range from 2 weeks to 3 months.12 Because conception rarely occurs immediately following TKI cessation, patients will likely need to remain without TKI therapy for a minimum of 10 months. Therefore, if optimal disease control is not achieved prior to TKI cessation, patients will be at increased risk of losing response and experiencing disease progression. Initiation of treatment during pregnancy is recommended if BCR-ABL transcripts increase to 1.0% IS. Leukapheresis, interferon-a (but not pegylated interferon), and hydroxyurea after the first trimester have been used for disease control as safer alternatives to TKIs during pregnancy. Another strategy is to discontinue the TKI to allow ovarian hyperstimulation and oocyte retrieval followed by fertilization and embryo cryopreservation. TKI therapy could then be resumed with a goal of achieving a sustained deep molecular remission, at which time treatment might be stopped and the embryos implanted.13 Promising results from TKI-stopping trials coupled with newer TKI therapies that produce more rapid and deeper molecular responses will likely allow CML during pregnancy to be managed with fewer risks to both mother and fetus.