1. Living with CML – Fertility and Pregnancy Dr Graeme Smith St. James’s Hospital Leeds National CML Patient & Carer Meeting, November 2015

2. Fertility and Pregnancy The transformation of CML from a fatal disease with a median life expectancy of 6 to 7 years to a chronic condition has raised issues for CML patients of child bearing age about their ability to have children Cortes J. et al. Hematol Oncol Clin NorthAm 2004, 18:569-84 National CML Patient & Carer Meeting, November 2015

3. Fertility Studies in male rats showed imatinib treatment in early life reduces testicular size, sperm mobility and alters reproductive hormones, leading to the conclusion that imatinib before puberty has deleterious effects Other animal studies suggest spermatogenesis is impaired in rats, dogs and monkeys leading to concerns that men treated with imatinib may have decreased sperm counts Effects on the ovaries are unremarkable and hence female fertility not affected Nilotinib and Dasatinib – little evidence of adverse effect on male or female fertility in rats and rabbits However, most studies and case reports in man have focused on pregnancy outcome rather than fertility National CML Patient & Carer Meeting, November 2015

4. Pregnancy Preclinical models have shown that imatinib has teratogenic effects, leading to the manufacturer’s recommendation that women should avoid pregnancy National CML Patient & Carer Meeting, November 2015

5. Imatinib and Pregnancy Pye et al, The Effects of Imatinib on Pregnancy Outcome Blood. 2008; 111(12): 5505-8 Timing of exposure to imatinib by trimester known in 146/180 cases (81%). 71% of these were exposed in the 1 st trimester (includes 4 cases exposed in 1 st & 2 nd trimesters) 26% exposed throughout pregnancy 3% exposed after 1 st trimester National CML Patient & Carer Meeting, November 2015

6. Outcome known for 125/180 (63%) Pye et al. Blood. 2008; 111(12):5505-8, * Includes 3 terminated following identification of foetal abnormalities Pregnancy outcome Total number (%) of those with known outcome n=125 (%) of total n=180 Normal live infant 635035 Elective Termination* 352819.5 Foetal Abnormality 129.66.7 Spontaneous Abortion 1814.410 National CML Patient & Carer Meeting, November 2015

7. Pregnancy outcome in Imatinib treated patients (2) Abruzzese et al, 2014 210 pregnancis with known outcome 24 (14%) ended in spontaneous abortion 43 (20%) underwent elective termination 15 (9%) born with fetal abnormality 128 (60%) had uneventful pregnancy with normal live infant (77% if exclude elective terminations) National CML Patient & Carer Meeting, November 2015

8. What about the other TKIs? Nilotinib - 3 cases in the literature, 1 with development of a foetal abnormality (omphalocele) - 2/45 cases in investigator’s brochure Dasatinib - 17 cases in the literature inc. a series of 13 (Cortes et al, 2008) of whom 4 had elective terminations, 2 had spontaneous abortions, 1 had a healthy newborn, and one a premature delivery. 5 still pregnant! National CML Patient & Carer Meeting, November 2015

9. Paternity No increased risk of congenital malformations or increased abortion have been reported in > 150 cases in the literature where father was on Imatinib Similarly – no reported concerns with Nilotinib (1/36 cases of congenital abnormality), or Dasatinib (0/9 cases) National CML Patient & Carer Meeting, November 2015

10. Conclusions: the Dad Due to the possible adverse effects on male fertility, sperm banking should be discussed at diagnosis as an option However, studies show no suggestion of any problems in pregnancy, delivery or any increase in congenital abnormalities when the father is being treated for CML For male patients, fathering children can be achieved without interruption of treatment National CML Patient & Carer Meeting, November 2015

11. Unplanned Pregnancy In cases of accidental pregnancy, a risk/ benefit evaluation should be made, with careful counselling of patients. The needs of mothers who require optimal cancer therapy need to be balanced against the potential teratogenicity to foetus Pregnancy itself does not appear to affect CML prognosis National CML Patient & Carer Meeting, November 2015

12. Options Continue imatinib with close monitoring of pregnancy (consider termination if significant abnormalities are found) The greatest risk to the foetus occurs in the first trimester since this correlates with organ development National CML Patient & Carer Meeting, November 2015

13. Options (2) Discontinue imatinib (but possibility of CML relapse and ultimately a less good long term disease outcome) Discontinue imatinib, but use alternative therapies such as interferon-α (not associated with any teratogenic effects in animals) and/or leucapheresis to control the white cell and platelet counts National CML Patient & Carer Meeting, November 2015

14. Planned Pregnancy – A management algorithm Apperly, J ‘CML in pregnancy and childhood’, 2009 Pre – conception - effective contraception! - planned pregnancy when achieved stable MMoR for 18-24/12 - Liase with Ob/Gyn team National CML Patient & Carer Meeting, November 2015

15. Management of fertility For patients of childbearing age who have yet to start or complete their family, provision for maintenance of fertility should be considered Options include: Sperm freezing (cryopreservation) Embryo freezing Egg Freezing Ovarian Tissue Freezing National CML Patient & Carer Meeting, November 2015

16. Management algorithm (2) TKI interruption - should be stopped immediately before or after conception - not at all during foetal organogenesis (5-13 weeks) Disease monitoring - Monthly PCR ( ?2 monthly if MR4.5) - Risk assess if loss of MMoR - ? Restart treatment - ? interferon-  National CML Patient & Carer Meeting, November 2015

17. Management algorithm (3) Post delivery NB -Breast feeding: imatinib, nilotinib and dasatinib have all been found to be excreted in the milk of rats and hence breast feeding is not recommended - continue off TKI for first 2-5 days of breast feeding (benefits of colustrum) - consider longer period off Rx if stable MMoR to facilitate breastfeeding - Restart same TKI National CML Patient & Carer Meeting, November 2015

18. Conclusions TKI therapy probably does not significantly effect the fertility of men and women with CML who want to start a family. Children of fathers who have CML do not have an increased risk of birth defects Mothers with CML can have a successful pregnancy with a healthy baby at the end, but this needs careful planning and monitoring Unplanned pregnancies should be avoided (if at all possible!) National CML Patient & Carer Meeting, November 2015