Treating the Patient With CML Who Is Pregnant or Trying to Become Pregnant

White blood cells in leukemia, AI generative: © Катерина Євтехова - stock.adobe.com

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML), significantly enhancing patient survival.¹ As patients now approach normal lifespans, the issue of parenthood has garnered considerable interest. Conceiving and carrying a pregnancy to term has become more feasible, although it necessitates careful management by a team of experts,² because all TKIs can be teratogenic and must be stopped during pregnancy. Unfortunately, not all pregnancies can be safely carried to term without treatment for the entire gestation.

At our institution, since 1990, a multidisciplinary team consisting of hematologists, gynecologists, the fertility and reproductive medicine team (assisted reproductive technology [ART]), neonatologists, and psychologists has managed fertility and pregnancy in patients with hematologic diseases. Since 2007, we have overseen 50 pregnancies in 27 female patients and 25 conceptions in 18 male patients.³ Focusing on the pregnancies, 10 ended in abortion (3 voluntary and 7 spontaneous within the first 9 weeks of gestation). There were 7 medically assisted pregnancy attempts, with embryos implanted in 3 patients aged 41, 40, and 26 years. Two of these attempts were successful, resulting in the birth of 2 girls to the youngest patient, who was 26 and 28 years old at the time. Seven patients were diagnosed with CML during pregnancy, and the remaining 21 became pregnant after starting treatment. Among this group, 5 pregnancies began while patients were in treatment-free remission (TFR) and 1 pregnancy began for a patient while being treated with interferon (IFN). All other patients stopped taking TKIs upon the first positive pregnancy test, between the third and sixth weeks of gestation.

Fifteen pregnancies required therapy: 11 were treated with IFN, 2 with imatinib mesylate (Gleevec), 1 with nilotinib (Tasigna), and 1 was initially treated with IFN at 7 weeks but had to restart imatinib at 21 weeks due to lack of response to IFN. Among the 41 babies born (including 1 twin pregnancy), no major problems were reported and their growth and development were comparable to that of the general pediatric population. Notably, 4 mothers on IFN breastfed their children for periods ranging from 4 weeks to 12 months.

Pregnancy Period

Considering the pregnancy period and the timing of CML diagnosis and treatment, 3 scenarios are possible.^4,5 During pregnancy, the 2 most susceptible periods for malformations are the embryonic period from weeks 5 to week 10 and the early fetal period during weeks 11 to 12. Indeed, the eligibility to TFR makes the 2-year threshold crucial for the pharmacological decision of pregnancy.

• Early pregnancy during initial CML treatment: When pregnancy occurs within 2 years of starting treatment, it is difficult to maintain TFR throughout the pregnancy. Treatment plans need adjustment to balance effective disease control with minimization of risks to the fetus.
• Late pregnancy without eligibility for TFR: Patients who become pregnant after a longer treatment period but without achieving deep molecular response and TFR criteria require accurate monitoring to avoid disease progression after stopping treatment.
• Late pregnancy with eligibility for TFR: Patients meeting TFR criteria are less likely to experience relapse, but more than 40% may lose their molecular response within the first 3 months of TFR. This requires vigilant monitoring to ensure the disease remains controlled without active treatment during pregnancy.

Conversely, the diagnosis of CML during pregnancy requires immediate and careful consideration of treatment options to ensure both maternal and fetal health, especially if white blood cell count exceeds 100,000/mm³ and platelet count is more than 1,000,000/mm³. In all these scenarios, careful evaluation of therapy must consider the gestational period status, the leukemic burden, the kinetics of transcript rise, and the different drugs that can be used.

Drug Choice

In the past 10 years, findings from pharmacological studies along with initial reports of patients with CML who are pregnant have helped to clarify the risks and safety profiles of drugs—both TKIs and non-TKIs—used during pregnancy.^5,6 Among the drugs from the pre-TKI era, hydroxyurea poses significant risks of teratogenic and mutagenic effects whereas IFN and its pegylated form present a safer profile and can be considered for maintaining the response achieved by TKIs. IFN is also the preferred choice during breastfeeding.

TKIs are all associated with teratogenic effects; therefore, they must be avoided up to week 16, after the embryonic and early fetal periods. Once the placenta is formed and organs developed, the use of imatinib and nilotinib can be permitted because findings from several studies have suggested that these 2 TKIs, but not dasatinib (Sprycel), do not significantly cross the placenta. Contrariwise, male conception was not affected by TKI therapy, but caution should be used, especially with newer drugs.

Practice-Changing Trials

A great contribution in the management of pregnancy in CML derived from the experience of a single center and also from national and international databases. In 2019, Assi et al described the outcome of 51 pregnancies in 37 patients: 30 female and 7 male. Focusing on pregnancies, the investigators immediately stopped TKI after pregnancy confirmation.⁷ The researchers observed that TKI interruption resulted in a loss of molecular response, which could be regained postpartum with treatment resumption. The Gruppo Italiano Malattie EMatologiche database collected data on conception in male patients and pregnancies in female patients. A total of 193 pregnancies have been registered: 109 pregnancies from 83 male patients and 84 pregnancies from 74 female patients. Fourteen (7 female and 7 male) conceptions were medically assisted, all spontaneous. One hundred ninety-four children were born (with 1 twin pregnancy). Regarding pregnancy, all patients stopped TKI at the first pregnancy test (FPT). Fifteen of 84 pregnancies required antileukemic therapy. IFN was administered in 13 gestations, and one of these shifted to nilotinib at 21 weeks due to poor disease control. One patient was treated with imatinib at 20 weeks, and another one was treated with nilotinib at 23 weeks. An update presented at the 65th American Society of Hematology Annual Meeting and Exposition in San Diego, California, illustrated that all children born from patients with CML presented a development comparable to those in the same age group. Similarly, the European LeukemiaNet registry reported data on 400 pregnancies of female patients, demonstrating that the early interruption of TKI at FPT is not associated with congenital abnormalities.⁸

Next Steps and Ongoing Trials

Different aspects deserve future investigations; first, our data suggest that fertility preservation and ART are valid strategies for patients wishing to conceive and should be incorporated into clinical practice. This field will be explored in the future.

Another field of growth will be the pharmacological studies and clinical data about asciminib (Scemblix), the progenitor of the new class of drugs, the allosteric inhibitors, which should soon be available in the first line. Finally, we will collect data about a longer follow-up of children born to patients with CML, which will validate the results obtained.⁹

REFERENCES:

1. Efficace F, Vignetti M, Sparano F, Scalzulli E, Breccia M. Optimizing health-related quality of life in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Expert Rev Hematol. 2021;14(3):293-302. doi:10.1080/17474086. 2021.1886918

2. Robertson HF, Apperley JF. Treatment of CML in pregnancy. Hematology Am Soc Hematol Educ Program. 2022;2022(1):123128. doi:10.1182/hematology.2022000330

3. Abruzzese E, Aureli S, Bondanini F, et al. Chronic myeloid leukemia and pregnancy: when dreams meet reality: state of the art, management and outcome of 41 cases, nilotinib placental transfer. J Clin Med. 2022;11(7):1801. doi:10.3390/jcm11071801

4. Abruzzese E, Apperley JF. Managing pregnancy in chronic myeloid leukemia. In: Hehlmann R, ed. Chronic Myeloid Leukemia. 2nd ed. Springer; 2021.

5. Abruzzese E, Mauro M, Apperley J, Chelysheva E. Tyrosine kinase inhibitors and pregnancy in chronic myeloid leukemia: opinion, evidence, and recommendations. Ther Adv Hematol. 2020;11:2040620720966120. doi:10.1177/2040620720966120

6. Abruzzese E, Trawinska MM, Perrotti AP, De Fabritiis P. Tyrosine kinase inhibitors and pregnancy. Mediterr J Hematol Infect Dis. 2014;6(1):e2014028. doi:10.4084/MJHID.2014.028

7. Assi R, Kantarjian H, Keating M, et al. Management of chronic myeloid leukemia during pregnancy among patients treated with a tyrosine kinase inhibitor: a single-center experience. Leuk Lymphoma. 2021;62(4):909-917. doi:10.1080/10428194.202 0.1849672

8. Chelysheva E, Apperley J, Turkina A, et al. Chronic myeloid leukemia diagnosed in pregnancy: management and outcome of 87 patients reported to the European LeukemiaNet international registry. Leukemia. 2024;38(4):788-795. doi:10.1038/ s41375-024-02183-0

9. Abruzzese E, Trawinska MM, De Fabritiis P, Bernardi S. SOHO state of the art updates and next questions: chronic myeloid leukemia and pregnancy: “per aspera ad astra”. Clin Lymphoma Myeloma Leuk. 2024;24(4):214-223. doi:10.1016/j.clml.2023.11.011