1. Strategies of pregnancy management need further experience accumulation. Surely the most safe time for pregnancy in CML females is a period of stable CMR. Patients of childbearing potential should use all chances to get the best therapy response. For patients: please always be in contact with your doctor and discuss all possible decisions. Be aware, be responsible. Many aims become real now. The outcomes for 28 pregnancy cases in CML females on imatinib therapy and for 5 pregnancies on second generation TKI (TKI2) are shown in Table 1. No abnormalities of development were reported in the newborns. But we focus your attention on the fact that in 3 of 4 cases when females received imatinib during the whole pregnancy or from the 2 nd trimester there low-weight children were born (2400, 2159 and 2080 g). Also the low-weight infant was born in a female who received nilotinib 800 mg from the 10 th week of pregnancy (2500 g). In 2 cases those children were born in terms of premature delivery. Later we had an information that all the infants were developing well and the weight was rapidly restored during artificial feeding. Although there could be other reasons for low-weight these observations should be taken into consideration. Pregnancy in chronic myeloid leukemia. What a patient should know E.Yu.Chelysheva, A.G.Turkina Hematology Research Center, Federal State Institution of Ministry of Health and Social development, Moscow Tyrosine kinase inhibitors (TKI) therapy has improved a survival rate and a life quality for the majority of patients with chronic myeloid leukemia (CML). Therefore pregnancy management in CML is one of the important issues. Teratogenic events and spontaneous abortions on imatinib therapy have been reported [1,2]. On the other hand there is a risk of disease relapse if to discuss a treatment interruption for the period of pregnancy [3]. Pregnancy planning for partners of males on TKI therapy also needs to be clarified. CML patients for the patients of childbearing potential should be aware of the risks and current approaches of pregnancy management We provide an information from Russian CML Pregnancy database. The cases were captured in Hematology Research Center, Moscow, and in other clinics (the data updated in March 2012). Based on our proper experience we summarize answers for the most frequently asked questions for pregnancy planning and management. Table 1 Pregnancy outcomes in CML females on TKI therapy * Imatinib dose was from 400 to 600 mg daily. In 6 cases conceiving was at treatment interruption. In 2 cases imatinib was used during whole pregnancy, in 2 cases imatinib was administered from the 2 nd trimester. ** 3 of 28 pregnancies on imatinib were subsequent, with different outcomes. *** 2 of 3 pregnancies on dasatinib were subsequent in the same woman. **** in that 1 case on bosutinib conceiving was at treatment interruption uptake an early diagnostics by sensitive methods is required (HCG level) to stop TKI immediately if pregnancy is proved. 6 of reported here women interrupted TKI at conceiving. In other cases pregnancy occurred during TKI treatment. The drug was stopped after pregnancy diagnostics. The TKI exposure was from 4 to 10 weeks. Healthy children were delivered, in 3 cases spontaneous abortions took place. Q: What if woman wishes to prolong an unplanned pregnancy which occurred on TKI treatment? A: If a woman insists to keep the pregnancy she should stop TKI after early pregnancy approvement and immediately discuss the situation with the hematologist. We inform the woman about the possible risks and known pregnancy outcomes. We ask her to discuss the situation within her family. Usually we inform the females about the following facts: -potential teratogenic effects of TKIs (preclinical studies and data reported on imatinib usage in females) -risks of spontaneous abortion -observed cases of low-weight children on TKI therapy (our proper data) -still limited experience of pregnancy management on imatinib -very limited number of cases in literature and almost unknown effects of potent 2 nd generation of TKI during pregnancy -probability of loosing the remission in case of therapy interruption during pregnancy even with existing CMR (nearly 50%) -need of regular observation by gynecologists, obstetricians, hematologists. A female should strictly follow their indications We discuss approaches depending on the individual situation of every female. The key issue is the status of CML response at pregnancy diagnostics: hematologic, cytogenetic and molecular response. The terms and indications of supportive CML treatment during pregnancy highly depend on these data. Q: What kind of CML treatment can be used during pregnancy and when? A: These are highly individual and experience-based decisions. At 8-12 th week of gestation (during organogenesis) it’s better to avoid any drug exposure. After 15 th -16 th week a placenta barrier can be a border for possible drug influence. The start point for supportive treatment in most of our cases was the fact of cytogenetic or hematologic relapse. We consider a BCR-ABL level by PCR more than 1% a relative border to discuss a supportive treatment. All the drugs that can be used in CML pregnancy have the category “D” by FDA: the drug can be used if it benefits in the life-threatening situation. Interferon alpha (IFNα) is comparatively safe, it does not cross placenta and has no teratogenic effects. But in cases of huge leukemic mass it does not allow to control the leukemia As to our experience IFNα was effective in 4 of 6 cases. A CHR was maintained only in those patients who had CCyR and low BCR-ABL transcript levels at pregnancy diagnostics. In 2 of 6 cases CHR was lost and hydroxyurea was added at the 2 nd -3d trimester. Imatinib is reported not able to cross placenta [4]. We have 2 reports of using it during whole pregnancy and 2 cases when it was used since 2 nd trimester. CML was well controlled. The children were healthy, but low weight was marked. The effects of TKI2 at pregnancy are not well described. We had a patient exposed to dasatinib in 1 st trimester twice at 2 pregnancies who continued on hydroxyurea. Healthy children were born in both cases. One female received nilotinib since the 10 th week of gestation due to rapid CML progression. She achieved a CHR and delivered a low-weight child by premature delivery. Hydroxyurea is able to cross placenta; teratogenic effects were reported on it Leukaferesis has been described as possible approach but we did not use it. Q: What about breastfeeding? A: TKIs, interferon-alpha and hydroxyurea can be found at the breast milk Therefore an artificial feeding should be used. Breastfeeding is acceptable only if a female continues treatment interruption. We observed 2 women with treatment interruption for 1 and 3 months for safe breastfeeding. Q: What recommendations would be for the males on TKIs? A: All the known cases in literature were with favorable outcomes, so there are no contraindications for conceiving for CML males. The only issue is to examine a spermogram in case of suspected infertility because there were some reports informing that imatinib can impair spermatogenesis. As to our data: 14 healthy children were born in partners of CML males on imatinib, 1 from male on nilotinib. Imatinib dose was from 400 to 600 mg daily with no treatment interruption at conception. One man already became a father on imatinib for two times. denve@bk.ru Ekaterina Chelysheva, Hematology Research Center, Moscow, Russia Pregnancy outcomeTKI Imatinib*NilotinibDasatinibBosutinib**** Delivery at term, healthy infants162 Premature delivery11 Ongoing pregnancy21 Spontaneous abortion3 Neonatal death1 Medical abortion51 Total number of cases28**13***1 LITERATURE: 1.Pye S., Cortes J., Ault P. et al. The effects of imatinib on pregnancy outcome. Blood, 15 June 2008, Vol. 111, No. 12, pp. 5505-5508. 2. Cole S., Kantarjian H., Ault P., Cortes J. Successful completion of pregnancy in a patient with chronic myeloid leukemia without active intervention: a case report and review of literature Clinical Lymphoma & Myeloma, Vol. 9, No. 4, 324-327, 2009; 3.Mahon FX, Réa D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. The Lancet Oncology, 2010, 11(11): 1029-1035 4. Russell M.A., Carpenter M.W., Akhtar M.S. et al. Imatinib mesylate and metabolite concentrations in maternal blood, umbilical cord, placenta and breast milk. J Perinatol 2007; 27:241-243. Q: When a woman with CML can plan pregnancy? A: For today’s knowledge the period after 2 years of stable complete molecular response (CMR) is the best time due to safety reasons. CMR means negative results by quantitative polymerase chain reaction (Q-PCR). The woman can be monitored by Q-PCR and without treatment. She avoids the possible TKI influence on fetus. Also she has the lowest risk of disease progression and the chance to re- achieve the remission after restarting therapy in case of molecular repalse. We observed without treatment 5 women with CMR at the start of pregnancy. 4 of 5 had molecular relapses during pregnancy but a complete hematologic response (CHR) was kept. After delivery and returning to treatment major molecular response (MMR) and CMR were restored. 1 of 5 females had a hematologic relapse without treatment but she had no stable and long-lasting CMR at the pregnancy start. Only complete cytogenetic response (CCyR) was restored after 3 month of treatment re-introduction, further monitoring is needed. Q: Should a woman interrupt the TKI at the time of conceiving? A: This question is discussable. Pros. A TKI influence on fetus can be excluded totally Contra. Even in healthy partners the chance of conceiving is nearly 25-30%. Treatment interruption can take a considerably long period if a reproductive function is impaired. If a CML relapse occurs a woman should restart TKI, and conceiving would be postponed. The gynecologists confirm the fact that during very early stages of pregnancy the embryo is not much effected by external factors. In case of pregnancy during TKI Conclusions : Questions and Answers (Q&A) : Results: Aims and Methods: Background: