Treatment of Blood Cancer During Pregnancy

Introduction

Hematological cancer during pregnancy presents a significant risk to both the mother and the fetus. Hodgkin’s lymphoma is the most prevalent, followed by non-Hodgkin lymphoma and acute leukemia. The diagnosis of hematological cancers is challenging due to the overlap of disease and pregnancy-related symptoms, along with limitations in imaging studies during pregnancy. There is limited data on the safety and effectiveness of therapy. The primary objective of treatment is to preserve the mother's health.

Consequently, early-stage pregnancy termination is often recommended to facilitate the administration of appropriate therapy. However, during later stages of gestation, treatment is frequently feasible. The heightened risk of thrombosis associated with both cancer and pregnancy often necessitates thromboprophylaxis. The intricate management and consequences of hematological cancer during pregnancy underscore the importance of collaborative research, particularly focusing on fundamental disease mechanisms and prospective epidemiological studies. This article offers updated management guidance, specifically focusing on chemotherapy and biological agents.

What Is Hematological Cancer?

Hematological cancer refers to a type of cancer that occurs in blood cells. The bone marrow is the origin where blood cells are generated. Therefore, bone marrow cancer also affects blood cells. Leukemia, multiple myeloma, and lymphoma are other types of blood cancers. Cancer is identified in approximately 0.1 percent of pregnancies, ranking as the second most common cause of maternal mortality after pregnancy-related vascular complications. The prevalence of cancer during pregnancy is anticipated to increase in developed countries due to the rising average age of pregnancy. Solid tumors account for the majority of cases, with hematological cancers being less frequent. The low incidence of hematological cancers during pregnancy has hindered the conduct of large prospective controlled trials, limiting available data to retrospective series and case reports. This limitation complicates the establishment of stringent management guidelines. Existing evidence does not indicate a causative link between pregnancy and hematological cancers. Epidemiological studies have not established an association between non-Hodgkin lymphoma and exposure to hormonal therapy (estrogen, progesterone, or both). Nonetheless, certain non-Hodgkin lymphoma subtypes express hormone-related receptors, potentially contributing to tumor growth and disease progression. The diagnosis of cancer during pregnancy is a distressing experience that presents a significant challenge to the patient, family, and the medical team. Moreover, the immunosuppressive environment characteristic of pregnancy, primarily induced by the expansion of regulatory T cells, may enhance tumor progression. However, there are no reliable animal models or robust clinical data supporting the involvement of these mechanisms in gestation-associated hematological cancers.

What Is the Treatment of Blood Cancer During Pregnancy?

The following are the treatment of blood cancer during pregnancy:

• Chemotherapy

  1. The numerous physiological changes accompanying pregnancy, such as increased plasma volume, the creation of a third space by amniotic fluid, hepatic oxidation, and renal clearance, impact the distribution, metabolism, and excretion of drugs. Limited pharmacokinetic data exist from studies involving pregnant women. Although plasma and tumor concentrations of certain chemotherapeutic agents may decrease during pregnancy, clinical evidence suggests a comparable prognosis for pregnant and non-pregnant women.

  2. Chemotherapy can hinder the migration and growth of cells of a growing baby in the first trimester in the mother’s womb. It is only the cause of lower birth weights in babies whose mothers received chemotherapy.

  3. Most cytotoxic drugs, typically ranging from 250 to 400 kDa, can cross the placenta. While some animal studies have examined drug concentrations in amniotic fluid, cord blood, placenta, and fetal tissues, human doses are usually lower than those found to be fetotoxic in animals.

  4. Data for patients mainly involve combination therapies, in contrast to animal models using single agents.

  5. The fetus is most vulnerable to drug-related teratogenicity during organogenesis (the first two to eight weeks of gestation).

  6. However, certain organs, including the eyes, genitalia, and hematopoietic and nervous systems, remain vulnerable after the first trimester.

  7. Non-ionized, low-molecular-weight drugs with high lipid solubility and low protein binding have an increased ability to transfer from the mother to the fetus. Genetic predisposition may influence teratogenic susceptibility, as fewer than a quarter of fetuses are adversely affected when mothers are treated during the first trimester.

  8. Chemotherapeutic agents, especially when administered in combination, are generally advised against during the first trimester. If immediate therapy is essential for the mother's condition, pregnancy termination is strongly recommended.

  9. Exposure to chemotherapy in the second and third trimesters is less likely to result in teratogenic effects, though it does increase the risk of intrauterine growth restriction.

  10. Specific cytotoxic drugs, especially antimetabolites, are highly teratogenic and should be avoided during pregnancy.

  11. High-dose Methotrexate is linked to the aminopterin syndrome, while Anthracycline-induced fetal cardiotoxicity varies, with liposomal doxorubicin having a higher placental penetration and theoretically posing a greater risk of fetal toxic effects, including cardiac effects.

  12. Anthracyclines and Cyclophosphamide, commonly used in the later stages of pregnancy, appear to be safe.

  13. Delivery should be planned at least two to three weeks after chemotherapy cessation to facilitate bone marrow recovery and fetal drug excretion via the placenta.

  14. The late side effects of chemotherapy can be seen in babies, as mothers who are under chemotherapy have fertility and nervous disturbances.

  15. Follow-up studies on children exposed to chemotherapy in utero have reported normal neurological development, school performance, sexual maturation, and reproduction.

• Targeted Therapies

  1. The current landscape of treating hematological cancers is undergoing significant changes due to the emergence of targeted therapies.

  2. There are three classes of biological therapies that exert a substantial influence on the treatment of individuals with hematological cancers.

  3. Tretinoin is recommended for addressing acute promyelocytic leukemia (blood cancer). When combined with anthracyclines, this drug markedly enhances the prognosis for patients with acute promyelocytic leukemia, resulting in a highly favorable long-term outcome.

  4. However, the use of retinoids in the first trimester is linked to considerable toxic effects, including central nervous system and cardiovascular malformations (retinoid embryopathy). Therefore, women diagnosed early in gestation should opt for pregnancy termination.

  5. Administering Tretinoin during the second or third trimester appears to have no adverse effects on outcomes, although instances of preterm deliveries and reversible cardiac symptoms have been reported.

  6. Imatinib stands as the standard treatment for non-pregnant patients with chronic myeloid leukemia. In a particular study, 50 percent (63 out of 125) of women treated with Imatinib gave birth to healthy babies. Nevertheless, 12 infants exposed to Imatinib during the first trimester exhibited congenital abnormalities, especially affecting the kidneys, skeleton, heart, brain, and gut (for example, exomphalos).

  7. Consequently, if treatment is deemed necessary during this period, interferon alfa should be considered. Additionally, women who become pregnant after a prolonged molecular remission might be candidates for Imatinib discontinuation or substitution with interferon.

  8. Women with an inferior response should delay pregnancy until achieving a better response or, at the very least, consider treatment with interferon alfa during early gestational stages.

  9. The impact of Imatinib cessation on the disease course is still a matter of debate. While most studies report disease relapse after Imatinib discontinuation, only a small fraction of patients achieve complete remission upon reintroducing Imatinib, underscoring the importance of using interferon during pregnancy.

  10. Second-generation tyrosine kinase inhibitors, increasingly utilized, especially in cases where Imatinib has proven ineffective, also appear to be teratogenic. Furthermore, women are advised to avoid breastfeeding while taking tyrosine kinase inhibitors.

• Supportive Therapy During Pregnancy

  1. Chemoimmunotherapy frequently leads to unwanted effects, such as nausea, allergic reactions, and significant neutropenia, potentially elevating the susceptibility to infections.

  2. Antiemetics, including the serotonin receptor antagonist Ondansetron and the D2 receptor antagonist Metoclopramide, are considered safe.

  3. Similarly, prior research supports the safety of antihistamines and phenothiazines. While a comprehensive examination of antibiotic use during pregnancy is beyond the scope of this report, Macrolides (for example, Clarithromycin), Cephalosporins, Metronidazole, and Penicillin are generally considered safe.

  4. Conversely, aminoglycosides, quinolones, trimethoprim, and tetracyclines should be avoided. Regarding growth factors commonly employed in individuals undergoing chemotherapy, particularly focusing on pregnant women receiving granulocyte colony-stimulating factors for severe chronic neutropenia, available data indicate the safety of this therapy.

  5. Anagrelide and Hydroxyurea should preferably be avoided, especially during the first trimester of gestation. Interferon alfa is the preferred drug in this context and should be administered with an appropriate antiplatelet agent, typically Aspirin. The role of additional low-molecular-weight heparin remains unclear.

Conclusion

In conclusion, there are few treatment options available for blood cancer in pregnancy. However, it is clear that treatment comes with complications and risks for the children. Also, the children may be affected, or organs may be compromised due to chemotherapy. A demanding and careful personalized approach is needed to ensure the well-being of both the mother and the developing fetus. The available treatment options have evolved over time, allowing for more tailored and nuanced strategies. Clinical trials and ongoing research efforts aim to expand the knowledge and refine therapeutic approaches, providing optimism for improved outcomes in the future.