Chronic Lymphocytic Leukemia in Pregnancy: A Review of the Available Literature and the Pharmacological Challenges in Management

Chronic lymphocytic leukemia (CLL) is a hematologic malignancy that mostly affects adults over the age of 50, and more often men than women [1]. The epidemiology of CLL in pregnant women is poorly defined due to its rarity, estimated at 1 in 75,000 pregnancies [1]. Pregnant women with CLL face increased susceptibility to infections, due to a weakened immune system [2]. Higher risks of fetal malformations and death are associated with CLL treatment during pregnancy, emphasizing the need for careful consideration and management in these cases [3].

The etiology of CLL is generally considered multifactorial and has been hypothesized to be linked to family history, genetic mutations, and environmental factors. Genetic mutations, such as those affecting the regulation of cellular proliferation (e.g., TP53, ATM, SF3B1, BIRC3, and NOTCH1), are implicated in CLL development [4]. Environmental factors such as exposure to pesticides, herbicides, solvents, and ionizing radiation, as well as a family history of CLL, contribute to increased risk [5]. Immunodeficiency may also play a role in facilitating abnormal lymphocyte accumulation [4]. However, the alloimmunization during pregnancy may be linked to autoimmune onset in CLL [6].

This review aimed to explore and summarize the current evidence in the literature regarding the diagnosis, prognosis, and treatment of CLL pregnant cases. Furthermore, this review highlights the methods used for diagnosing and treating each case. For each case, the clinical presentation, complications throughout the pregnancy, and outcomes at both the maternal and t fetal levels will be demonstrated. Finally, some of the treatment options used in general for CLL and during pregnancy are discussed.

Our search strategy was generated using PubMed’s Medical Subject Headings (MeSH) terms, along with other title and abstract keywords. To include articles discussing CLL pregnant cases and their pregnancy outcomes and complications affecting both the mother and the fetus, the search terms included: “chronic B cell lymphocytic leukemia,” “lymphoid leukemia,” “pregnancy,” “gestation,” “pregnancy complications,” “pregnancy outcome,” “prenatal,” “maternal,” “fetal,” “obstetric,” “neonatal,” and “pregnancy complications neoplastic.” Utilizing a polyglot translator, the initial search strategy was converted to Embase; to maximize the number of articles regarding our research topic [7]. All studies identified by the search strategy were transferred to EndNote, where duplicates were automatically excluded. The remaining studies were then transferred to Rayyan to manually eliminate any remaining duplicates and initiate the screening process.

This review included case reports that discussed pregnant patients who were diagnosed with CLL and the impact of the disease on pregnancy outcomes for both the mother and fetus. Studies excluded from this review were: (1) animal studies, (2) reviews or non-original articles, and (3) non-English articles.

Across all four databases, the search strategy produced a total of 448 articles. A total of 58 duplicate studies were identified and excluded. Three hundred and seventy-six articles were excluded from the study for not meeting the inclusion criteria. Fourteen articles were included in the final review. Figure 1 depicts a schematic demonstration of the identification, selection, and inclusion processes. Tables 1 and 2 present a comprehensive summary of the studies that are included in this review, providing key details about each study.

Of the 14 studies, a total of 5 case studies involved pregnant women who were diagnosed with CLL during their pregnancy course. These findings provide valuable insights into the management and outcomes of this rare condition during pregnancy (Tables 1, 2). Chrisomalis et al. [1] reported a 30-year-old woman with asymptomatic stage (0-C) CLL diagnosed at 16 weeks gestation, managed with supportive care during pregnancy, and requiring no additional treatment 1 year post-delivery of a healthy infant. Ali et al. [8] described a 30-year-old woman diagnosed with advanced CLL at 17 weeks gestation, treated with transfusions and leukapheresis during pregnancy. She delivered a healthy neonate at term, but despite postpartum CHOP treatment, Richter transformation led to her death, while the baby showed normal development [8]. Crossette-Thambiah [9] reported a 30-year-old pregnant woman diagnosed with CLL at 14 weeks gestation, receiving no treatment during pregnancy. After delivering a healthy baby, CLL progressed, but remission was achieved FCR (Fludarabine, cyclophosphamide; in combination with rituximab) chemotherapy.

Furthermore, Welsh et al. [10] reported a pregnant woman diagnosed with CLL at 35 weeks gestation. The patient had an uncomplicated vaginal delivery and remained symptom-free with decreased white blood cell (WBC) 1 year postpartum without treatment. Hamad et al. [11] reported a pregnant woman diagnosed with CLL at 34 weeks gestation. Despite a herpes zoster infection, the patient had an uncomplicated vaginal delivery of a healthy infant. Placenta analysis showed no CLL, and the patient remained well without treatment 4 months postpartum. Overall, none of the five studies used CLL-targeting therapies, and Chrisomalis et al. [1] and Ali et al. [8] described the use of transfusion support and leukapheresis.

Of the 14 included studies, a total of nine case reports have explored the clinical presentations, management, and outcomes of pregnant women diagnosed with CLL before conception. Presentations included (Table 1) leukocytosis, lymphocytosis, with or without anemia [2, 11‒16]. Gurman [14], Tahmasebi et al. [16], and Murray et al. [13] reported patients who did not receive CLL-specific treatment during pregnancy, suggesting that careful management can lead to positive outcomes (Table 1). Complications included pneumonia, cholestasis, gestational diabetes, CLL-related skin lesions, and recurrent genital herpes infections [2, 12‒15, 17]. Four cases described pregnancy years following the completion of CLL therapy (cladribine-rituximab or fludarabine, cyclophosphamide with or without rituximab) with no fatal complications in the infants [2, 11, 17, 18]. Only Andrew et al. [17] described intrauterine growth restriction in 1 case. Two cases described CLL patients who were on chlorambucil when pregnancy was discovered, resulting in the discontinuation of chlorambucil [12, 15].

Historically, chlorambucil (an alkylating chemotherapeutic agent) was one of the mainstay treatment options. However, in recent years it has been largely replaced by chemoimmunotherapy, initially, and then novel and targeted agents due to superior efficacy [19, 20]. Nowadays, chlorambucil is only considered for patients with significant comorbidities [19, 20], and chemoimmunotherapy has become the standard treatment for CLL [21], despite carrying the risks of hematologic toxicities, and reduced efficacy in patients with high-risk disease or certain genetic mutations.

The advent of targeted therapies has transformed CLL management by focusing on mechanisms within CLL cells that reduce proliferation, induce apoptosis, and decrease cell survival (Fig. 2). Anti-CD20 antibodies, like rituximab and obinutuzumab, target the CD20 antigen on CLL cells and are typically used in combination with other therapies [22]. Bruton tyrosine kinase inhibitors (BTKIs) such as ibrutinib, acalabrutinib, and zanubrutinib inhibit BTK, reducing cell replication [23]. Ibrutinib and acalabrutinib can be combined with CD20 antibodies or used alone, while zanubrutinib is used as a monotherapy [24]. New strategies are exploring the combination of ibrutinib with venetoclax, a BCL-2 inhibitor, which can be used with a CD20 antibody, with ibrutinib, or alone [24]. Duvelisib and idelalisib, which inhibit phosphoinositide 3-kinases (PI3K), are typically reserved for relapsed/refractory CLL; duvelisib is usually administered as a monotherapy, while idelalisib may be combined with rituximab [24]. Table 3 illustrates novels agents approved for CLL and therapeutic targets [25].

The first trimester poses a high risk of drug-induced harm and birth defects, warranting the avoidance of chemotherapeutic agents, especially genotoxic ones. If immediate curative treatment is crucial, the risk of continuing the pregnancy versus termination should be discussed with the patient and a multidisciplinary team. In the second and third trimesters, chemotherapy exposure is less likely to cause birth defects but may lead to intrauterine growth restriction [26]. Chemotherapy may be considered for rapidly progressive or locally compressive diseases during these stages of pregnancy [27, 28]. Delaying chemotherapy until post-delivery minimizes risks [18]. Assessing medication safety and side effects during pregnancy is vital, and delivering before treatment, particularly in the third trimester, may be advantageous [29]. If chemotherapy is required during pregnancy, scheduling delivery 3–4 weeks posttreatment reduces maternal and neonatal risks [29]. CLL therapy is advancing with novel treatments and B-cell receptor blockade in clinical trials [27, 30], potentially changing the first-line therapy to avoid genotoxic drugs.

The available literature on CLL therapy during pregnancy is very scarce. However, the expert opinion from 2014 suggested a watch-and-wait approach for cases of CLL in pregnancy, which is reasonable as shown from the previously presented data [31]. On the other hand, in situations where treatment is required the expert opinion suggested leukapheresis [31]. When pharmacological therapy is unavoidable, rituximab and chlorambucil were suggested with the latter only in second and third trimesters [31]. Therefore, in addition to its lower comparative efficacy to other alternatives, the anticipated risk to fetuses further challenges the use of chlorambucil in pregnant CLL patients. As for more conventional chemotherapy options, such as FCR that is used for CLL treatment is not a promising option as fludarabine is also teratogenic and embryo-lethal [32].

Among all the agents, rituximab seems to be the most promising agent in terms of use in pregnancy (Fig. 3). Neither rituximab nor obinutuzumab has shown teratogenic patterns in animal studies [33‒35]. However, transient B-cell depletion was observed in the animal fetuses post-delivery with both agents in addition to opportunistic infections with obinutuzumab. There were no human data identified for obinutuzumab.

BTKIs have shown fetal malformations in animal studies and are therefore labeled by the FDA to possibly cause fetal harm [36‒38]. Idelalisib was found to be teratogenic in animal studies and duvelisib can increase embryo-fetal mortality in animals when administered during organogenesis [39, 40]. Hence, none of those agents have any data in humans.

In other hematologic settings, the administration of venetoclax during pregnancy has been reported. Although its prescribing information and animal studies has indicated possible fetal harm [41], a case by Karagiannis et al. [42] has reported a pregnant refractory AML patient who received venetoclax with high dose cytarabine and mitoxantrone at 24 weeks of gestation. The infant had hyperbilirubinemia, transient B-cell depletion and required ventilation. The baby recovered from all complications, although possible long-term effects remain unclear. The mother underwent allogeneic hematopoietic stem cell transplant.

The rare incidence of CLL during pregnancy has been attributed to multiple hypotheses. Sex hormones have been suggested by Tahmasebi et al. [16] as potential regulators of the immune system. Notably, females have a lower incidence and a lower risk of progressive disease in CLL compared to males [43, 44]. The male-to-female incidence ratio at CLL diagnosis is typically 2:1, with a ratio of 3–4:1 for patients requiring therapy. The immunomodulatory effects of female sex hormones have led to speculation that reproductive factors and exogenous hormones may influence the risk of lymphoid malignancies [16, 45‒47]. A multicenter case-control study involving females with CLL or small lymphocytic lymphoma revealed that parity conferred a protective effect, with an odds reduction of 21% for each additional child [46]. Similarly, another review indicated a trend of decreased CLL risk with increasing parity, but this was not statistically significant [45]. However, the immunological alterations during pregnancy seem to have limited relevance to the etiology of CLL [45, 47].

Furthermore, during early pregnancy, many cases showed an increase in WBC that is primarily attributed to an absolute rise in neutrophil numbers as well as a normalization of WBC a week following delivery [1, 8, 10, 11, 14, 16]. The reason for the decrease in WBC following delivery remains unclear, but it may involve an increase in immunotolerance during pregnancy, which allows the expansion of a monoclonal population of B-lymphocytes [10]. This suggests a pattern of increase in the CLL count in the blood as a result of redistribution during pregnancy. In addition, the prognosis for young CLL patients is significantly better than for older patients, and any CLL patient with a WBC that is apparently returning to normal can be considered to have a better prognosis than a CLL patient with an increasing WBC as reported by Welsh et al. [10].

Given the rare incidence in pregnant females and the usually indolent course of CLL [2], the preferred approach in initial stages is the “watch and wait” approach. This is to minimize any potential treatment-related risks to the fetus. This approach was implemented in most of the cases who got pregnant before presenting with CLL manifestations [1, 8‒11]. Most of the patients who followed this approach had normal outcomes with no treatment required after delivery except for three cases. However, two cases demonstrated heavy bone marrow infiltration few months after delivery requiring chemotherapy [9, 16]. While leukapheresis has been suggested in some of the cases [8, 11], it has many drawbacks (inconvenient, expensive, time-consuming, and does not improve survival outcomes) that hinder its use as a maintenance therapy.

None of the cases identified in the literature required immediate pharmacological therapy. As shown, the pharmacological standard of care (BTK inhibitors/venetoclax with or without CD20 inhibitors) [24], are either contraindicated in pregnancy based on animal data or has no reports of use among pregnant CLL patients [36‒38, 42]. Moreover, despite the availability of some literature on each of rituximab and venetoclax in pregnant patients with other non-CLL diagnoses, it is unclear whether long-term results would support their safety [42]. Furthermore, the field of CLL therapy is rapidly evolving, and individualized treatment decisions should consider patient-specific factors, including age, fitness, genetic mutations, comorbidities, and patient preferences, to optimize the treatment response and minimize side effects. Therefore, more specialized data on those agents is still required to draw solid conclusions on possible therapeutic alternatives in this population when treatment is indicated.

On another note, CLL is frequently associated with compromised immune function, which increases the risk of infections affecting various elements of the immune system [48]. Alarmingly, infectious complications have long been recognized as a major contributor to morbidity and mortality, often accounting for the primary cause of death in various studies, with infectious mortality rates ranging from 30 to 50% [49, 50]. The predisposition of CLL patients to infections stems from both humoral immunodepression associated with the stage and duration of CLL and additional immunosuppression induced by treatments such as steroids, cytotoxic drugs, and monoclonal antibodies [50, 51].

Seven out of the fourteen reported cases (2 reported by Hamad et al. [11]) in this review developed infections throughout the course of their pregnancies [1, 2, 11, 14, 16, 17]. This immune compromise has been linked to adverse pregnancy outcomes, including stillbirth, spontaneous abortion, lower birth weight, and preterm birth [52]. Perinatal infections are a significant cause of fetal and neonatal morbidity and mortality [53]. Among the concerning infections in the TORCH group (toxoplasma, rubella, cytomegalovirus [CMV], and herpes simplex virus [HSV]), CMV and HSV pose particular risks due to their higher likelihood of reactivation in CLL and potential severe complications in newborns [54].

As seen in the case reported by Hamad et al. [11] in young women of childbearing age or during prenatal screening, it is important to determine whether immunity to rubella is a result of natural or passive immunity from IVIG. If the immunity is passive and IVIG is no longer necessary, re-immunization is recommended at least 1 month or more before conception, if feasible. Alternatively, passive immunity can be maintained using IVIG. It is important to assess specific anti-rubella and antiviral antibody titers rather than relying solely on normal or near-normal IgG levels [11]. There should be a detailed discussion about the results and how they can be interpreted from the perspective of previous studies and of the working hypotheses. It is evidently crucial to promptly identify and treat infections and, whenever possible, take preventive measures [53]. These preventive measures include vaccination, such as influenza vaccination (excluding live vaccines), prophylactic antibiotics, and immunoglobulin replacement for recurrent infections [55‒57].

Overall, it is very challenging given the current scarcity of literature and level of evidence to recommend specific therapeutic pathways for pregnant patients with CLL. Furthermore, adequate emphasis should be given to contraception in female CLL patients in childbearing age. Given the absolute lack of guidance on the most appropriate contraceptive method in these patients, especially for those on CLL therapy, there is room for future research to close this gap.

Meanwhile, clinicians may consider weighing the benefits and risks of active treatment (being pharmacologic or leukapheresis) compared with a watch-and-wait approach with pregnant patients and multidisciplinary teams. Unless there is high ALC, intrauterine growth restriction, placental insufficiency, and other CLL-related antenatal complications, the “watch and wait” approach may be the best to adapt in early stage disease [11]. Leukapheresis was suggested in the cases presented here and when ineffective, it seems that rituximab seems to have the relatively safest outcomes in the cases presented in CLL and other hematological malignancies. That is not to say that it should be used in all pregnant CLL patients as data are not robust enough yet for this recommendation, especially considering the B-cell-depleting properties reported in animal and human data.

On the other hand, patients who became pregnant after completion of CLL therapy developed various complications with some of them requiring chemotherapy post-delivery. The potential risk of CLL relapse during following complete remission should be considered [58]. Thus, it can be implied that the main factor affecting the pregnancy outcome is not the pregnancy itself rather than the stage and severity of the disease as well as the infectious events during pregnancy [59].

CLL is not frequently observed in women of childbearing age, making its occurrence during pregnancy quite rare and, as such, no specific guidelines are available. However, the fourteen cases discussed in this review highlight the evidence-based approaches for pregnancy-related concerns in CLL patients. CLL is typically a slow-growing disease that allows for a watchful waiting approach during pregnancy. However, each case should be evaluated and treated individually. In situations where treatment cannot be avoided, delaying therapy until the second or third trimesters may help reduce but not eliminate the risk of fetal malformations. It is important to consider the development of infections throughout pregnancy due to the combined immunosuppressive effects of CLL, pregnancy, and CLL therapy.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder. However, we have applied for the Qatar National Library (QNL) open access agreement which could cover all the funding and publication fees. If our request is accepted by QNL, they will have no role in the design, data collection, data analysis, and reporting of this study.

A.B.: conceptualization, formal analysis, methodology, project administration, writing – original draft, and writing – review and editing. M.B.: methodology, validation, and writing – original draft. B.E. and A.M.E.: methodology, writing – original draft, and writing – review and editing. M.E.: methodology, validation, writing – original draft, and writing – review and editing. R.G.: review and editing. R.M.E., O.M., and S.A.: validation, writing – original draft, and writing – review and editing. M.M. and K.A.: writing – original draft and writing – review and editing. M.Y.: conceptualization, project administration, supervision, writing – original draft, and writing – review and editing.