Among the challenges of treating women with chronic myeloid leukemia (CML) who may want to become pregnant is the lack of clear information regarding the dose of tyrosine kinase inhibitors (TKIs) and the exposure time. “The concept of stopping therapy is a relatively new one,” revealed Ellin Berman, MD, Professor of Medicine, Memorial Sloan Kettering Cancer Center, and panel member of the NCCN Guidelines for CML. “There are not, as yet, clear guidelines for who can safely stop therapy,” she told the audience at the NCCN 23rd Annual Conference.
Impact of Response to TKIs
With 4 TKIs currently used in first-line treatment—imatinib, dasatinib, nilotinib, and bosutinib—the question for clinicians managing women with CML who may want to become pregnant is which one to choose. “Many of us would choose a second-generation TKI, such as dasatinib or nilotinib, and more recently bosutinib, because the response is deeper and quicker, and faster response seems to be important,” 1 she stated. “However, all of these TKIs affect a spectrum of targets, which are important for reproduction.”2
Dr. Berman reviewed the types of molecular response to TKI therapy in patients with CML. The optimal response would be a molecular response of a 4.5-log reduction (MR4.5)—defined as BCR-ABL <0.0032 on the International Scale (IS)—which translates to no detectable disease that can be measured. However, Dr. Berman noted that only between 30% to 40% of patients achieve an MR4.5, and that may take up to 4 years of therapy.
As shown in Figure 2, imatinib is the slowest to provide an MR4.5. After 24 months of therapy, the incidence of MR4.5 with imatinib, dasatinib, and nilotinib is 8%, 9%, and 26%, respectively.3,4
Fetal Abnormalities Associated With TKIs
Few data are available regarding the effect of TKIs on the ovaries; however, Dr. Berman shared findings from 2 different studies on fetal abnormalities associated with these agents. The first study by Pye et al5 focused on the use of imatinib. Of 180 pregnant women with CML treated with imatinib, the timing of treatment was available for approximately 80% (n=146). During the first trimester, 103 women (71%) received imatinib therapy; during the first and second trimesters, 4 (26%) received imatinib. Approximately one-quarter (n=38) received imatinib throughout pregnancy. The investigators reported 8 cases (5%) of congenital abnormalities, including craniosynostosis, hypoplastic lung, duplex kidneys, hemivertebrae, cerebellar hypoplasia, premature closing of the skull, scoliosis, and cleft palate with polydactyly.
Incidence of major molecular response (MMR) and molecular response of a 4.5-log reduction (MR4.5).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 5S; 10.6004/jnccn.2018.0035
In the second study, 78 pregnant women with CML treated with dasatinib were reported to the drug manufacturer's database.6 Of the 46 women (59%) for whom outcomes were available, 8 (17%) had spontaneous abortions (2 with abnormalities) and 18 (39%) had elective abortions (3 with abnormalities).
Limited Long-Term Data on TKI Discontinuation Trials
For women undergoing treatment for CML who want to become pregnant, Dr. Berman explained that there are no clear data on when it is safe to stop therapy. Currently, she is guided by the “stop therapy” trials: to stop therapy, women should have at least MR4, and most trials have used MR4.5 for at least 2 years. “The bulk of data [on discontinuation] are with imatinib, because that's the drug that was licensed first, and the number of patients is substantial,” she reported.
However, she highlighted one preliminary trial (EURO-SKI) that suggested MR4.5 may not be necessary: Mahon et al7 demonstrated that patients with a deep molecular response (BCR-ABL <0.01% on the IS) had the same recurrence rate as those with MR4.5 (46%).
The 2018 NCCN Guidelines for CML provide a table of limited longer-term follow-up data from TKI discontinuation trials. Based on these studies, Dr. Berman noted, there is a recurrence rate of approximately 55% to 65%. “The time to relapse is consistent within the first 3 to 9 months of stopping therapy.” Women who opt to stop TKI therapy after at least 2 years of MR4.5 response should be monitored monthly with quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR), she suggested (Figure 2).
Regarding restarting therapy, the NCCN Guidelines recommend a BCR-ABL threshold of >1.0% on the IS. As for other cutoff guides, such as WBC or platelet count, Dr. Berman said “we don't know what cutoff to use. Most patients seem to recover their response quickly when restarted on a TKI, she added.
Natural Option: In Vitro Fertilization
As for the natural option of in vitro fertilization (IVF), Dr. Berman called it a personal decision. “For
Summary of limited longer-term follow-up data from the TKI discontinuation trials from the NCCN Guidelines.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 5S; 10.6004/jnccn.2018.0035
However, according to Dr. Berman, although IVF “seems a safer option,” it is not always a real alternative for some women. Time off from work, insurance issues, cost, and religious, legal, and cultural restrictions may complicate the matter for many women. “In having worked with numerous women [who want to become pregnant] through IVF, the best [strategy] is good communication among the patient, oncologist, gynecologist, and obstetrician,” she suggested.
Treatment Options During Pregnancy
Well established data regarding fetal and neonatal exposure to TKIs in pregnant women with CML are lacking, and thus caution is warranted. Dr. Berman briefly explored possible treatment options for women with CML during pregnancy. Although hydroxyurea is not indicated during any trimester of pregnancy, leukapheresis is a possibility during the first, second, and third trimesters.8 In addition, interferon-alfa is not indicated during the first trimester but may be considered during the second and third trimesters. As for TKIs, the use of these therapies during the first and second trimesters is not recommended, although they might be a possible option during the third trimester.
How About Men?
Dr. Berman mentioned that men being treated for CML with TKIs might ask about their fertility if their partner is interested in becoming pregnant. They tend to ask (1) what is the effect of TKI therapy on sperm, and (2) whether they have to stop therapy if their female partner wants to become pregnant.
Dr. Berman's answer to the first question is that TKI therapy seems to have no effect on sperm. However, TKIs do seem to inhibit platelet-derived growth factor and c-kit, she reported, which are important for Leydig cell development, as well as the proliferation, migration, and survival of sperm. According to Dr. Berman, findings on the impact of TKIs in men appear to be consistent: although there is a decrease in testosterone and sperm count, there is no effect on male fertility.6,9,10
As for the second question, Dr. Berman said that men do not need to stop therapy if their female partner wants to become pregnant. “The accumulated data from the drug companies suggest ‘no’; that it's safe for men to get their partner pregnant,” she added.
References
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Greuber EK, Smith-Pearson P, Wang J et al.. Role of ABL family kinases in cancer: from leukaemia to solid tumours. Nat Rev Cancer 2013;13:559–571.
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Cortes JE, Saglio G, Kantarjian HM et al.. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patient trials. J Clin Oncol 2016;34:2333–2340.
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Hochhaus A, Saglio G, Hughes TP et al.. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia 2016;30:1044–1054.
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Pye SM, Cortes J, Ault P et al.. The effects of imatinib on pregnancy outcome. Blood 2008;111:5505–5508.
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Cortes J, Mauro M, Steegmann JL et al.. Cardiovascular and pulmonary adverse events in patients treated with BCR-ABL inhibitors: data from the FDA Adverse Event Reporting System. Am J Hematol 2015;90:E66–72.
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Mahon FX, Richter J, Guilhot J et al.. Cessation of tyrosine kinase inhibitors treatment in chronic myeloid leukemia patients with deep molecular response: results of the EURO-SKI trial [abstract]. Blood 2016;128:787.
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Burwick RM, Kuo K, Brewer D et al.. Maternal, fetal, and neonatal imatinib levels with treatment of chronic myeloid leukemia in pregnancy. Obstet Gynecol 2017;129:831–834.
- 9.↑
Novartis: Gleevec (imatinib mesylate) tablets for oral use. Highlights of Prescribing Information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021588s024lbl.pdf. Accessed March 30, 2018.
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Novartis: Tasigna (nilotinib) capsules. Highlights of Prescribing Information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022068lbl.pdf. Accessed March 30, 2018.
