Lymphoma and Leukemia during Pregnancy

“Hematological malignancies occurring in pregnancy, although uncommon, present major diagnostic and therapeutic challenges.”

The diagnosis of malignancy during pregnancy is an extremely distressing event for the patient, her family and caregivers. The need to treat the patient for a potentially lethal disease, while minimizing potential risks to the developing fetus, raises significant therapeutic and ethical dilemmas.

Lymphoma presents the fourth most common malignancy in pregnancy, with an estimated prevalence of one in 6000 pregnancies [1–3], whereas leukemia, which is a relatively rare disease, is estimated to occur in one in 75,000–100,000 pregnancies [1,3]. Due to the increasing age of pregnancy in the western world and improved diagnostic techniques, the incidence of malignancy during pregnancy is expected to rise.

This editorial reviews unique medical challenges associated with the most common hematological cancers reported during pregnancy, addressing therapeutic dilemmas and current recommended approaches. Notably, the rarity of hematological cancers during pregnancy precludes conduction of prospective trials; hence, the information presented here is mainly based on small retrospective studies and case reports.

Lymphoma

Hodgkin's lymphoma (HL), followed by non-HL (NHL), represent the most common hematological cancers reported during pregnancy [4–7].

The presenting signs and symptoms of lymphoma during gestation are generally similar to those occurring in a nonpregnant woman. On the other hand, some lymphoma-related symptoms, such as fatigue and shortness of breath, imitate physiological changes associated with pregnancy; hence, this may result in a delayed diagnosis [7–9]. Moreover, the attempt to avoid imaging studies, which are potentially harmful to the fetus, especially if employed during first trimester [10,11], may further postpone diagnosis, resulting in an advanced disease at presentation, particularly in patients presenting with aggressive rather than indolent NHL or HL. However, the high incidence of advanced-stage NHL reported in women diagnosed while being pregnant could also be part of the biological features of pregnancy-related lymphoma, which is suggested to be characterized with highly aggressive histology and a strong predilection to the reproductive organs [12].

The management of lymphoma occurring during pregnancy ranges from a watch-and-wait approach, to an immediate need for therapeutic intervention depending on histological subtype and gestational stage at diagnosis [8]. Whereas most patients diagnosed with indolent, slow growing lymphoma (e.g., follicular lymphoma) can be watched carefully until delivery, some progress quite rapidly and need early initiation of single or combination chemotherapy [13,14]. Unless immediately required, chemotherapy should be deferred beyond first trimester due to its high teratogenicity. Pregnancy termination followed by conventional therapy should be seriously considered in this setting [14]. An alternative approach to multidrug chemotherapy, although less effective, but safer for the fetus, is the administration of an anti-CD20 monoclonal antibody – rituximab – as a single agent, which is highly effective in CD20 B-cell NHLs. A recent study on the outcome of 153 pregnancies occurring in women receiving rituximab (mostly administered in combination with other potentially teratogenic agents) [15] reported 90 live births (including 22 born prematurely and one who died at 6 weeks). Further findings included low incidence of anomalies (n = 2), a slightly higher likelihood for hematologic abnormalities, without significant increase in infections in these newborns, and a slightly elevated risk for neonatal infections (n = 4). Thus, the data indicate that rituximab may be relatively safe during pregnancy.

Patients presenting either with aggressive or highly aggressive forms of NHL (diffuse large cell and Burkitt lymphoma, respectively) should be treated promptly, employing therapeutic regimens known to be most appropriate for their specific histological subtypes. Therefore, women diagnosed during first trimester are considered for an early termination of pregnancy followed by immediate therapy, whereas those diagnosed at later gestational stages may continue their pregnancy and be treated conventionally.

The diagnosis of a highly aggressive lymphoma (e.g., Burkitt lymphoma) during the second trimester, but before week 20 of gestation, presents an exceptional condition, requiring pregnancy termination due to an urgent need for administration of methotrexate, a chemotherapeutic agent that remains highly teratogenic up to a relatively advanced gestational stage [8].

“The management strategy should primarily address the issue of the mother's survival, with an attempt to minimize therapy-related fetal toxicity.”

Whereas the outcome of pregnancy-associated HL appears to be similar to that reported in nonpregnant women, the outcome of women diagnosed during pregnancy, although essentially differing between histological subtypes, is generally inferior to that obtained in their nonpregnant counterparts, reflecting either a delay in diagnosis, suboptimal therapy or a more aggressive course of the disease.

In general, radiotherapy is not recommended during pregnancy; however, it may still be considered in early favorable HL patients if it involves cervical lymph nodes only [14].

Acute leukemia

Acute leukemias are characterized by a rapidly progressive clinical course and are fatal unless immediately treated with aggressive combination chemotherapy.

Treatment of acute myeloid leukemia includes intensive induction, followed by postremission therapy, which varies between a consolidative chemotherapeutic regimen and allogeneic stem cell transplantation [16].

Several retrospective studies reported on patients diagnosed and treated during the second and third trimesters of pregnancy, resulting in higher risk for spontaneous abortions, stillbirths, intrauterine growth restriction and cardiac toxicity, but with no evidence of significant increase in the risk for congenital anomalies [16]. According to the available data, if treated promptly and with appropriate regimens, pregnant women with acute myeloid leukemia have outcomes similar to those of nonpregnant women [16].

Acute lymphoblastic leukemia is rare among adults and data regarding its optimal management during pregnancy are very limited. However, as this is a highly aggressive, proliferative malignancy, necessitating immediate initiation of combinational chemotherapy, including CNS prophylaxis with high-dose methotrexate, treatment at early gestational stages is impossible, and pregnancy termination is recommended in all women considered for therapy before 20 weeks of gestation.

Chronic leukemias

Chronic myeloid leukemia, mainly occurring in elderly subjects, is rarely diagnosed during pregnancy. The disease is characterized by the presence of translocation 9;22, with the formation of the BCR–ABL chimeric protein, which acts as a constitutive tyrosine kinase. The employment of imatinib, a tyrosine kinase inhibitor, which becomes the standard of care in chronic myeloid leukemia, providing long-term survival, is prohibited during pregnancy, being associated with a remarkable risk for teratogenicity [17,18]. An asymptomatic woman diagnosed with low leukocyte count chronic myeloid leukemia during pregnancy may probably be closely watched, with a delay of imatinib treatment until after delivery. However, if therapy is needed, IFN-α, shown to be safe during pregnancy, should be administered. Hydroxyurea may be used during the second or third trimester for patients who do not tolerate interferon side effects, but it is prohibited at early gestational stages, due to potential teratogenicity.

Conclusion

Hematological malignancies occurring in pregnancy, although uncommon, present major diagnostic and therapeutic challenges. The management strategy should primarily address the issue of the mother's survival, with an attempt to minimize therapy-related fetal toxicity. Extensive collaborative efforts expanding basic and clinical research in this vital setting are warranted.