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Abstract

Hematological malignancies during pregnancy are rare, which results in the absence of large prospective studies. The diagnosis is often delayed due to the symptom similarity to those of pregnancy and the recommendation to avoid imaging studies during gestation. Management of hematological malignancies during pregnancy poses challenges both to the patient and the medical team, given the therapy-attributable risks for mother and fetus and the need to consider patient's preferences regarding pregnancy continuation. Chemotherapy during the first trimester is associated with an increased risk for fetal demise and congenital malformations, while these risks diminish as pregnancy progresses. We hereby present a review of updated literature on the management of hematologic malignancies (Hodgkin and non-Hodgkin lymphomas, acute leukemia, multiple myeloma, chronic myeloid leukemia and myeloproliferative neoplasms) during pregnancy.

Keywords

chemotherapy congenital malformations hematologic malignancies

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Release date: 23 June 2014; Expiration date: 23 June 2015

LEARNING OBJECTIVES

Upon completion of this activity, participants should be able to:

Describe diagnosis and staging of hematologic malignancies during pregnancy, based on a review

Distinguish clinical features of hematologic malignancies during pregnancy

Discuss treatment of hematologic malignancies during pregnancy

Financial & competing interests disclosure

Editor: Phil Garner, Managing Director, Future Science Group.

Disclosure: Phil Garner has disclosed no relevant financial relationships.

CME author: Laurie Barclay, MD, Freelance writer and reviewer, Medscape, LLC.

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Author & credentials: Noa Lavi, MD, Department of Hematology & Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel; Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.

Disclosure: Noa Lavi, MD, has disclosed no relevant financial relationships.

Netanel A Horowitz, MD, Department of Hematology & Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel; Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.

Disclosure: Netanel A Horowitz, MD, has disclosed no relevant financial relationships.

Benjamin Brenner, MD, Department of Hematology & Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel; Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.

Disclosure: Benjamin Brenner, MD, has disclosed no relevant financial relationships.

No writing assistance was utilized in the production of this manuscript.

Background

Hematologic malignancy during pregnancy is a diagnostic, therapeutic and social challenge requiring a multidisciplinary team approach. Hematologic malignancies often necessitate prompt therapy and thus present a difficult clinical situation where the treatment effects on the fetus are to be weighed against the effects of disease progression on both the fetus and the mother. Therapy should be as close as possible to that of nonpregnant patients, but gestational age, disease stage and patient's choices regarding pregnancy continuation are to be taken into consideration.

Incidence

Cancer is diagnosed in approximately 0.1% of pregnant women and its prevalence is expected to rise in developed countries because of the increase in the average age at pregnancy. The most common malignancies associated with pregnancy are cervical and breast cancer, melanoma, lymphomas (1:1000–1:6000 pregnancies) and acute leukemias (1:75,000–1:100,000) [1]. Myeloproliferative neoplasms (MPNs) and multiple myeloma (MM), generally considered to be diseases of older age, are nowadays more frequently reported during pregnancy due to increasing age of pregnant women in the western world, advanced diagnostic molecular tools in MPNs and improved overall survival in MM. Chronic lymphocytic leukemia and myelodysplastic syndrome, generally considered diseases of older age, are very rarely reported during pregnancy.

Diagnosis & staging

Core needle or open excisional biopsies are safe to perform [2]. Bone marrow biopsy is required to be performed in the presence of constitutional symptoms, cytopenias or/and certain types of non-Hodgkin lymphoma (NHL),whereas it is rarely needed in Hodgkin lymphoma (HL). While evaluating lymphoma stage during pregnancy, CT or PET/CT should be avoided owing to radiation exposure of the fetus [3]. Chest radiography can be performed in pregnant women with abdominal shielding. Ultrasonography, particularly useful for abdominal assessment, can be safely used. The effect of MRI exposure in the prenatal period has not been fully assessed, although a small series has not demonstrated long-term adverse effects of the procedure [4]. Owing to the theoretical risk to the fetus, MRI scans should be avoided in the first trimester. Gadolinium is known to cross the placenta and was found to induce malformations in animal models [5]. Although scant available data in humans have not demonstrated its adverse effects on the fetus, gadolinium should not be administered at an early gestational stage. During second and third trimesters, gadolinium administration may be considered in selected cases [1]. MRI should only be performed if MRI results would significantly alter the management. Benefit should always outweigh the risk.

Staging of a pregnant patient with lymphoma is limited and should include chest x-ray with abdominal shielding, abdominal ultrasonography and bone marrow biopsy when indicated.

During second and third trimesters of pregnancy, MRI can be performed in case of strong indication.

Clinical aspects

HL

HL is more frequent than NHL in pregnant women. Approximately 3% of HL patients are diagnosed during pregnancy [6]. HL in pregnant women is usually initially diagnosed at the same disease stage as in nonpregnant counterparts. Moreover, the outcome in women who were diagnosed in pregnancy, does not appear to be worse than that in age-matched nonpregnant patients [7]. In a recent retrospective cohort study, nulliparous status and ‘B’ symptoms predicted inferior progression-free survival in pregnant women with HL [8].

NHL

Pregnancy itself may obscure symptoms and clinical findings of lymphoma. Pregnant women with aggressive lymphomas may present with an advanced stage disease due to delay in diagnosis. Highly aggressive lymphomas (Burkitt or Burkitt-like) developing during pregnancy may be characterized with a fulminant course and unfavorable prognosis attributable to a delay in diagnosis, worse natural history or insufficient therapy. When adequate chemotherapy regimens are administered, survival rates of pregnant patients with NHL are similar to those of nonpregnant controls [9].

Reproductive organs are more commonly involved in pregnancy-associated NHL than in age-matched nonpregnant patients diagnosed with a similar lymphoma subtype. This may be attributed either to the increased blood flow to reproductive organs during gestation or to expression of gestational hormone receptors [8]. In a recent analysis of 121 clinical cases of pregnancy-associated NHL, 75% had stage IV disease at diagnosis and reproductive organ involvement was revealed in 49% of patients, most of them having breast involvement. Of note, placental and fetal involvements were rare [10].

Acute leukemia

Acute leukemia can affect both the pregnant woman and the fetus. Problems associated with this condition include maternal severe pancytopenia associated with bleeding and infections, disseminated intravascular coagulation, which may significantly complicate the treatment of the mother and the delivery, placental effects of leukemic cells such as decreased blood flow, and decreased exchange of oxygen and nutrients [11]. Acute leukemia in pregnancy increases the risk of abortion, perinatal mortality, intrauterine growth retardation and preterm delivery [12].

MM

The median age at diagnosis of MM is 70 years; accordingly, there are few case reports of MM during pregnancy. Disease features such as low back pain and anemia are frequent during normal pregnancies, which may cause delay in diagnosis [13].

Chronic myeloid leukemia

Chronic myeloid leukemia (CML), a relatively slow-growing tumor, can present with severe leukostasis and vascular complications, adversely affecting maternal and fetal outcomes [13,14].

MPNs

The most common Philadelphia chromosome negative MPNs are polycythemia vera (PV), essential thrombocytosis (ET) and myelofibrosis. These diseases are typically observed in older adults; however, 20% of ET patients and 15% of PV patients are younger than 40 years at diagnosis [15]. Accordingly, most cases of MPN during pregnancy are those of ET, and less frequently of PV.

MPNs are associated with an elevated risk of thrombosis. The hypercoagulable state associated with pregnancy further increases this risk. Pregnant women with MPN are at an increased risk of developing thrombosis and other gestational complications (including recurrent abortion, premature delivery, fetal growth restriction or loss and pre-eclampsia).

The live birth rate in patients with ET and PV is only 60%, with first-trimester loss occurring in up to 30% of pregnancies [15].

Treatment of hematologic malignancy coexistent with pregnancy

Treatment of cancer during pregnancy remains a challenge because the common treatment modalities including chemotherapy and radiotherapy may produce detrimental effects on the fetus, including fetal demise, congenital malformations, carcinogenesis, intrauterine growth restriction and mental retardation. The decision to employ chemotherapy or radiotherapy during pregnancy should be weighed against the pregnancy stage and the effect of delaying treatment on maternal survival.

Chemotherapy

Physiological changes during pregnancy affect drug distribution, metabolism and excretion. However, no pharmacokinetic studies have been conducted that aim to assess whether pregnant women should be treated with different chemotherapy doses [16].

Most cytotoxic agents are known to cross the human placenta and reach the fetus circulation [17].

The first trimester is the most critical period for chemotherapeutic drug exposure, as implantation (weeks 1 to 2) and embryogenesis proceed (weeks 3 to 8) during that time. The major manifestations of drug toxicity at this time are spontaneous abortions during implantation and major malformations during embryogenesis. Exposure to chemotherapy during the first trimester has been associated with a 10–20% risk of major congenital malformations and a 33% risk of adverse pregnancy outcomes [17].

It is recommended that folate antagonists (e.g., methotrexate) be avoided during first and second trimesters of pregnancy owing to a high risk of congenital malformations. The risk seems to diminish as pregnancy advances [18]. While cytarabine, an antimetabolite, was found to be associated with a higher risk for limb deformities [16,19 –21], and anthracyclines were shown to interfere with eye and limb development [22]. In terms of the different types of chemotherapy, alkylating agents may be less teratogenic. Exposure of adult patients to anthracyclines is known to be associated with development of heart failure. However, the question whether in utero exposure to anthracyclines is cardiotoxic to the fetus remains debatable. To the best of our knowledge, no reports have been published regarding fetal pulmonary damage related to bleomycin or neurotoxicity associated with vinca alkaloids.

The use of chemotherapy during the first trimester of pregnancy is considered dangerous to the fetus. In low-risk patients, such as those with HL (stage I, II and even III), low-grade NHL, and perhaps other nonleukemic hematologic malignancies, therapy can be deferred until the end of the first trimester or even further into the later stages of pregnancy if the patient is closely monitored. If chemotherapy is required in the first trimester, pregnancy termination is to be recommended. When termination of pregnancy is not acceptable to the patient, a single-agent followed by multiagent therapy at the end of the first trimester can be considered.

Overall, the risk of teratogenesis after cancer therapy appears to be lower than is commonly estimated based on findings obtained from animal models. However, the available data documenting the immediate postpartum period, and delayed effects of chemotherapy come from case reports and limited retrospective studies only.

Recently, Aviles et al. retrospectively reported prolonged follow-up clinical outcomes of 54 newborns who were born to pregnant women treated with chemotherapy during the first trimester of pregnancy [23]. Doses and schedules of chemotherapy were the same as those applied in nonpregnant patients. Low birthweight was the most frequent finding, while no congenital abnormalities were detected. Cardiac function and chromosomal examination appeared to be normal and no neoplasms were revealed in these children. Their physical, psychological and neurological development was also normal and educational attainment correlated with economic and social factors. The authors also analyzed retrospective data from the literature, including women with hematologic malignancies treated during the first trimester. In contrast to these data, out of 196 evaluable newborns reported in other publications, 48% were premature, 40% had low birthweight and 13% had different congenital abnormalities. Thus, the issue of chemotherapy administration during the first trimester still remains highly controversial.

However, among the possible toxic effects of chemotherapy on the fetus during the second and third trimesters are low birthweight, intrauterine growth restriction, premature birth and stillbirth. The CNS continues to evolve throughout the gestation period and therefore, impaired functional development, intellectual disability and diminished learning capability may occur [17]. There are strong concerns about a potential increase in the incidence of malignancies and long-term fertility problems in chemotherapy-exposed fetuses.

A long-term (average 18.7 years) follow-up of 84 children born to mothers with hematologic malignancies reported normal physical, neurological and psychological development [24]. Malignancy rate was similar to that of the general population and 12 of these children became parents.

Given these data, chemotherapy could be administered during the second and third trimesters. However, extreme caution is warranted and detailed discussion with the patient of associated risks should always take place. Delivery should be postponed for 2–3 weeks following treatment to allow bone marrow recovery and fetal drug elimination via the placenta.

Chemotherapeutic agents vary in their concentration in breast milk and dose-dependent and -independent effects of these drugs cannot be ruled out. Most authorities recommend avoiding breastfeeding until at least 2 weeks following the completion of chemotherapy [9,25].

Biological therapy

Rituximab

Several cases of rituximab used during pregnancy have been reported, mostly in nonmalignant disorders [26,27]. In these reports the administration of rituximab seems to be safe, without increased risk of adverse fetal outcome. A case report of a pregnant woman, receiving rituximab together with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) in early pregnancy, described transient complete fetal B-cell depletion; however, B-cell recovery was rapid [28]. A retrospective analysis evaluated the outcomes of 253 pregnancies with preconceptional or antepartum rituximab exposure. In 153 cases, pregnancy outcomes were reported, 90 of these cases resulted in live births. The majority of the births were uncomplicated. Only several cases of neonatal infection and some cases of transient neonatal leukopenia without related infections were reported [29]. Based on the available limited data, it seems that the benefits of rituximab treatment of life-threatening hematologic malignancies during the second and third trimesters of pregnancy may outweigh its risks. Data on teratogenicity are limited and, until further information emerges, the use of rituximab cannot be widely recommended during the first trimester.

Imatinib

Imatinib is the standard of care for nonpregnant patients with CML. In a study by Pye et al., 50% (63 of 125) of women, exposed to imatinib during pregnancy, gave birth to healthy babies [30]. However, 12 infants exposed to imatinib during the first trimester had congenital abnormalities; of note, the abnormalities were similar in three of them. Second-generation tyrosine kinase inhibitors also appear to be teratogenic. Data on prognosis upon cessation of imatinib are limited to only a small number of patients, most of whom developed rapid disease recurrence but achieved remission with reinstitution of imatinib [31,32].

Radiotherapy

Fetus exposure to radiation during the first trimester is associated with teratogenesis and an increased risk of childhood malignancy. The incidence of these effects depends upon the fetal dose of exposure [33].

A total of 10–20 cGy of radiation, when given during organogenesis, is considered to be the threshold dose for severe congenital malformations. If standard doses of radiotherapy are used and the distance of the fetus from the field edges is over 30 cm, the total exposure of the fetus is not teratogenic [34].

Radiotherapy given in the second and third trimesters is associated with an increased risk for the development of leukemia and solid tumors within the first decade of life [35] and increased risk of neurodevelopmental impairment [36].

Radiation should be avoided during pregnancy, apart from highly selected cases such as stage I–II lymphoma confined to the neck or axillary lymph nodes, in the absence of alternative therapies. An expert radio-oncologist must evaluate fetal radiation exposure in each case.

Supportive treatment

Antiemetics

There has been no association found between therapy with metoclopramide, antihistamines or ondansetron-based antiemetics and congenital malformations in either animal models or humans [37,38]. The same is true regarding the new antiemetic drug, aprepitant (Emend®), which is classified by the US FDA as category B.

Growth factors

Experience regarding the treatment of chemotherapy-induced cytopenias with granulocyte colony-stimulating factor and erythropoietin is restricted; however, no teratogenic effects have been reported to date [36].

Anti-infective agents

The safety of penicillins and cephalosporins for the fetus is well established. Aminoglycosides and metronidazole do not appear to be teratogenic; however, this assumption is based on limited data. Quinolones and tetracyclines should be avoided during pregnancy. Sulfonamides should be avoided when possible. The systemic antifungal drug most widely used in pregnancy is amphotericin B. There have been no reports of teratogenicity attributed to this agent, resulting in it being the antifungal drug of choice during pregnancy [18]. Fluconazole teratogenicity is dose dependent; accordingly, it appears to be safe at a low dose of 150 mg per day [18]. Ketoconazole and voriconazole may cause serious fetal malformations and are contraindicated in pregnancy. There are no sufficient data about the safety of caspofungin during pregnancy [39].

Disease-specific therapy

HL

Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD), the most common chemotherapy regimen for HL, is not recommended during the first trimester as data regarding its safety during pregnancy are limited (although some evidence suggests that this regimen is safe in this clinical setting). No information is available about the safety of doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide and prednisone (Stanford V) or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (BEACOPP) regimens during gestation.

Patients with advanced HL diagnosed at an early pregnancy stage should start chemotherapy immediately and pregnancy termination should be strongly recommended in these cases.

Patients with early-stage HL diagnosed in the first trimester can be closely followed-up for signs of disease progression and start chemotherapy in the second trimester. Alternatively, single-agent chemotherapy (preferably vinca alkaloids or anthracyclines) may be given until the second trimester, as proposed by some experts; however, the efficacy of this approach is unclear [9,17,25,36].

Patients with HL diagnosed in the second or third trimester can be treated with ABVD, based on limited available data [36]. Some patients may be candidates for deferred therapy until after delivery. This allows a full staging evaluation and selection of appropriate therapy following delivery. Potential candidates include patients with ‘limited’ clinical stage IA or IIA HL presenting during the late second and third trimester. There have been no prospective trials comparing the outcome of deferred and immediate treatment in this setting.

When imaging studies during pregnancy do not give accurate data regarding the initial stage of disease, patients receiving therapy during pregnancy should proceed with further treatment as if they initially had an advanced stage disease.

A case–control study of 48 pregnant women with HL demonstrated a 20-year survival rate, which was similar to that of matched nonpregnant women with HL [7]. Furthermore, the incidence of preterm delivery or intrauterine growth retardation was not higher in pregnant women with HL [7].

NHL

Indolent lymphoma

Owing to the indolent course of these lymphomas, treatment may usually be postponed until delivery or at least until the second trimester. If there is an indication for therapy during the first trimester, single-agent rituximab should be carefully considered. Rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) or rituximab plus cyclophosphamide, vincristine and prednisone (R-CVP) regimens may be used for the management of these lymphomas during the second or third trimester, while fludarabine-based chemotherapy should be avoided.

Aggressive lymphoma (including large B-cell lymphomas, mantle cell lymphoma & mature T-cell neoplasms)

In the majority of patients with aggressive lymphoma prompt administration of intensive combination chemotherapy is required. Information on the safety of the CHOP regimen, if used during the first trimester, is limited and based on case reports. In these instances, the incidence of severe fetal malformation was not reported to be increased [9,24].

Until further studies evaluate the safety of the CHOP regimen during the first trimester, pregnancy termination is recommended. In some patients with stage I–II NHL and low disease burden who are diagnosed close to the end of the first trimester, careful observation up to the end of the trimester followed by proper immunochemotherapy may be considered.

Limited information suggests that CHOP in conjunction with rituximab could be used for the management of lymphoma during the second and third trimesters of pregnancy. [9,24,40]. A multicenter collaborative study that evaluated the outcomes of 90 patients diagnosed with lymphoma during pregnancy demonstrated that standard chemotherapy regimens for lymphoma administered during the second and third trimester resulted in a low incidence of maternal and fetal complications.

Highly aggressive lymphoma (including precursor [B or T] lymphoblastic leukemia/lymphoma & Burkitt's lymphoma)

The fulminant nature of the disease and its rapid progression require prompt initiation of therapy. The chemotherapeutic regimens employed in patients with highly aggressive lymphoma comprise high-dose methotrexate, which is highly teratogenic to the fetus during the first trimester, including skull and limb abnormalities as well as neural tube defects [41]. Therefore, pregnancy termination should be strongly recommended in such cases. Data regarding the use of methotrexate during the second and third trimesters are very limited and suggest that although not teratogenic the drug is associated with severe fetal myelosuppression [9]. The safety of these chemotherapy regimens during the second and third trimesters remains unclear.

Acute leukemia

Acute leukemia requires immediate full treatment, regardless of gestational stage as a delay or modification of treatment results in poorer maternal prognosis [12].

Leukopharesis in the presence of a significantly high white cell count and leukostasis-related symptoms appears to be tolerated well by both the fetus and mother.

Acute myeloid leukemia

The standard induction regimen for acute myeloid leukemia (AML) patients includes cytarabine and an anthracycline.

Cytarabine, being an antimetabolite, is known to be teratogenic in animal models [18] and has been recently found to be associated with a higher risk for limb deformities in humans [16,19 –21]. In 89 reported cases of cytarabine treatment during various trimesters of pregnancy, intrauterine growth retardation (13%), intrauterine fetal death (6%), cytopenia (5%) and two cases of neonatal death were revealed [16].

The anthracycline idarubicin, is more lipophilic and therefore has an elevated placental transfer; it is also known to have higher affinity to DNA. Hence, idarubicin should be avoided during pregnancy, as it is associated with a higher prevalence of adverse fetal outcomes. Daunorubicin is more commonly used than doxorubicin in the treatment of AML despite the latter agent having similar activity in AML and the fact that its effects on pregnant women with breast cancer have been extensively studied. Therefore, doxorubicin is the preferred anthracycline for AML management during pregnancy [16]. Although just several cases of fetal cardiac toxicity related to anthracyclines have been documented, fetal cardiac function should be monitored during pregnancy.

The administration of induction chemotherapy during the first trimester should be preceded by a strong recommendation for pregnancy termination. The limited available data suggest that cytarabine and doxorubicin can be administered safely after the first trimester.

Consolidation with cytarabine and anthracyclines is preferred over topoisomerase inhibitors (etoposide) where experience is extremely limited [11]. Just a few cases of postremission therapy for AML in pregnancy have been reported [12,42] and the regimens used are typically not described. According to previous publications [11], ‘lower doses’ of cytarabine should be used as consolidation; however, the exact dose has not been mentioned. Another publication [13] has recommended the use of high-dose cytosar at the later stages of pregnancy.

Acute promyelocytic leukemia

Acute promyelocytic leukemia induction therapy comprises all-trans-retinoic acid (ATRA) and anthracyclines. ATRA should be avoided during the first trimester owing to its very high (up to 85%) teratogenicity. Normal pregnancy outcomes were reported following the administration of ATRA in conjunction with an anthracycline during the second and third trimesters [18] and this is the recommended induction therapy to be used in second and third trimesters. Arsenic trioxide is established to be teratogenic and is contraindicated throughout pregnancy [18].

Acute lymphoblastic leukemia

Prior to the 20th week of gestation, termination of pregnancy is recommended followed by immediate chemotherapy. After the 20th week of pregnancy, the treatment protocol, not including methotrexate, can be used before the third trimester. In the third trimester, the protocols similar to those employed in nonpregnant patients are applicable [11,18]. Cytarabine, cyclophosphamide, Vinca alkaloids, L-asparaginase, anthracyclines and steroids have all been used in pregnancy.

MM

Pregnant women diagnosed with progressive disease need immediate treatment. As thalidomide and lenalidomide may cause severe birth defects, they are contraindicated throughout gestation [43]. To date, minimal information regarding the safety of bortezomib during pregnancy is available, therefore it cannot be recommended. Steroids have proven to be the safest therapy in gestation, and pregnant women with symptomatic myeloma should be treated with steroids until delivery; however, a more intensive therapy would be required in a rapidly progressing disease. In these cases, while in first trimester, combination therapy should be given and termination of pregnancy is to be recommended. In rapidly progressive cases later in pregnancy, chemotherapy is advisable, although standard of care has not been established. Brisou et al. identified 28 case reports of MM associated with pregnancy: 15 patients were diagnosed with MM during pregnancy, five of them received treatment against myeloma while pregnant, three were treated with steroids, one received cyclophosphamide, vincristine, melphalan, prednisone and one was treated with cyclophosphamide [44].

In patients with extensive pelvic or spinal involvement, cesarean section should be used to avoid further trauma resulting from a vaginal delivery [11].

CML

As CML is a chronic disease, two scenarios may occur. The first is when a woman with CML treated with imatinib or other tyrosine kinase inhibitors wishes to become pregnant; the other is when CML is newly diagnosed during pregnancy.

Imatinib exposure in pregnancy poses an increased risk for significant congenital malformations. Therefore, it should be avoided during pregnancy. As far as the first scenario is concerned, it is debatable whether imatinib should be stopped, since discontinuation of therapy may be associated with an elevated risk of disease progression. The decision should be individualized for each patient.

Two major reports evaluating interferon therapy during pregnancy [45,46] described 40 patients, eight of them treated during the first trimester. There were no cases of fetal malformation when interferon was administered as monotherapy. Therefore, IFN-α should be considered for newly diagnosed CML patients during pregnancy [16].

Patients in the second or third trimesters who do not tolerate interferon may be treated with hydroxyurea or possibly imatinib. Leukapheresis may also be used as a transient tool for leukoreduction.

MPNs

The European LeukemiaNet published consensus-based recommendations for MPN treatment during pregnancy according to patient specific risk factors [47].

MPN patients at a high risk for pregnancy-related complications include women who had a prior thrombotic or hemorrhagic event; women who had pregnancy-related complications in previous pregnancies; and a platelet count ≥1500 × 10⁹/l.

During pregnancy, phlebotomies should be carried out, if indicated, to keep hematocrit level less than 45%.

Executive summary

Incidence

The most common hematologic malignancies associated with pregnancy are lymphomas. The prevalence is expected to increase in developed countries.

Diagnosis & staging

Core needle or open excisional biopsies are safe to perform.

Staging of a pregnant patient with lymphoma should be based on medical history, physical examination, bone marrow biopsies if indicated and chest x-ray with abdominal shielding. Intra-abdominal disease can be evaluated with ultrasound. MRI should be performed only if the results may influence treatment decisions.

PET and gallium scans are not safe during pregnancy.

Treatment principles in pregnancy

Most cytotoxic agents cross the human placenta and reach the fetus.

In the first trimester, major drug toxicities include spontaneous abortions and major morphological abnormalities.

If chemotherapy is required in the first trimester, pregnancy termination should be considered.

Adverse effects of chemotherapy on the fetus during the second and third trimesters include low birthweight, intrauterine growth restriction, premature birth, stillborn fetus, impaired functional development, intellectual disability and diminished learning capability.

Chemotherapy could be administered during the second and third trimester.

Radiation exposure of the fetus during the first trimester is associated with teratogenesis and carcinogenesis.

Radiation exposure during the second and third trimesters is associated with carcinogenesis.

Radiation should be avoided during pregnancy.

Disease-specific therapy

Hodgkin lympholia

– For women with advanced disease at an early stage of pregnancy, treatment with an appropriate chemotherapy protocol should be promptly initiated and pregnancy termination should be considered.

– Patients who have early stage Hodgkin lymphoma (HL) diagnosed in the first trimester can be followed-up without any treatment until the second trimester.

– Patients presenting in the second or third trimesters can be treated with adriamycin, bleomycin, vinblastine, dacarbazine (ABVD). Some patients may be candidates for deferred therapy until after delivery.

Non-liL

– Rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) or rituximab plus cyclophosphamide, vincristine and prednisone (R-CVP) regimens may be used for the management of these non-HL during the second or third trimester.

Acute myeloid leukemlia

– Given the paucity of experience and the fact that cytarabine is an antimetabolite, the administration of induction chemotherapy during the first trimester must be accompanied by a strong recommendation for pregnancy termination. The available limited data suggest that cytarabine and doxorubicin may be administered safely after the first trimester.

Acute promyelocytic leukemlia

– Any administration of all-trans-retinoic acid during the first trimester should follow pregnancy termination.

– Limited data may suggest all-trans-retinoic acid with anthracycline as a therapeutic option for acute promyelocytic leukemia during the second and third trimesters.

Acute lymphoblastic leukemlia

– Prior to the 20th week of gestation, termination is suggested followed shortly thereafter by chemotherapy.

– After the 20th week, a modified protocol that does not include methotrexate may be used until the third trimester.

– In the third trimester, treatment protocols similar to those for nonpregnant patients should be employed.

Chronic myeloid leukemlia

– IFN-α should be considered for newly diagnosed chronic myeloid leukemia patients during pregnancy.

Myeloproliferative neoplaslis

– The recommended management of pregnant women with myeloproliferative neoplasms should include aspirin, phlebotomy when hematocrit is >45%, and prophylaxis with low molecular weight heparin during puerperium.

– Women with a history of a thrombotic event or an essential complication in a previous pregnancy should be treated with low molecular weight heparin throughout the pregnancy and during puerperium.

– If cytoreduction should be given IFN-α is the safest option.

Future perspective

The relative rarity of pregnancy-associated hematologic malignancies precludes conduction of large prospective studies. International collaboration is needed in order to conduct thorough epidemiologic and follow-up studies.

If not contraindicated, all pregnant women with MPN should take aspirin throughout the pregnancy period and prophylactic low molecular weight heparin during the postpartum period.

In the high-risk group, women who had a prior thrombotic event or a pregnancy-related complication in previous pregnancies should receive aspirin throughout the pregnancy, if not contraindicated, while patients with a platelet count ≥1500 × 10⁹/l or those with a previous major bleeding event in the presence of a relatively high platelet count should be treated with IFN-α during pregnancy. Aspirin should be avoided.

However, the indications for the use of platelet-lowering drugs in pregnant women with MPN are controversial. According to the guidelines of the Italian Society of Hematology and expert judgment [48,49], candidates for IFN-α therapy during pregnancy are women with a previous history of major thrombosis or major bleeding; platelet count >100 0–1500 × 10⁹/l; and when familial thrombophilia or cardiovascular risk factors are documented.

Hydroxyurea, busulfan and anagrelide should be avoided, particularly during the first trimester.

There are no data regarding the safety of ruxolitinib or other JAK2 inhibitors during pregnancy.

Conclusion

Most women diagnosed with hematologic malignancies during pregnancy have a prognosis similar to that of age-matched nonpregnant women. If chemotherapy is mandatory during the first trimester, pregnancy termination is usually recommended. The majority of women receiving therapy during the second and third trimester have good outcomes.

Therapy of pregnant women with hematological malignancies should be personalized, with a treatment plan taking into account the aggressiveness of the disease, patient preference and the currently available therapies. Chemotherapy should be delayed until the second trimester if possible; otherwise, termination of pregnancy is recommended during the first trimester. Consideration should be given to postponing delivery for 2–3 weeks following treatment to allow bone marrow recovery and fetal drug elimination via the placenta. In general, radiation should be avoided during pregnancy with some exceptions. Long-term follow-up of offspring exposed to chemotherapy is needed.

Future perspective

Hematologic malignancies during pregnancy are comparatively rare and therefore large prospective studies are absent. Most available data are based on small retrospective analyses and case reports. There is significant under-reporting of negative outcomes after pregnancy (pregnancy loss etc). The lack of systematic registries collecting data on the outcome of pregnant patients treated with chemotherapy most probably misleads pregnancy results and underscores the negative results, which are hardly ever published. International collaboration is needed to conduct thorough epidemiological and follow-up studies.

Animal models are the main tool for studying the teratogenic effects of chemotherapy. However, it is difficult to apply these data to pregnant women as the chemotherapy doses given to humans are lower than those used in animals, potentially leading to differences in teratogenic effects.

Moreover, data from animal experiments cannot be extrapolated to humans because the placenta is the most species-specific mammalian organ [50].

Recently, there has been an increasing interest in investigating the effect of different drugs on the placenta. Placental perfusion studies can serve as a model for the assessment of placental transfer and the effect of cancer chemotherapy and targeted therapy and thus add important information regarding fetal safety [51 –53].

The normal physiological changes that occur during pregnancy may influence pharmacokinetics and pharmacodynamics of chemotherapeutic agents. There is a need for pharmacokinetic studies in pregnant women receiving chemotherapy [16].

Footnotes

An update on the management of hematologic malignancies in pregnancy

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An Update on the Management of Hematologic Malignancies in Pregnancy

Abstract

Keywords

Financial & competing interests disclosure

Background

Incidence

Diagnosis & staging

Clinical aspects

HL

NHL

Acute leukemia

MM

Chronic myeloid leukemia

MPNs

Treatment of hematologic malignancy coexistent with pregnancy

Chemotherapy

Biological therapy

Rituximab

Imatinib

Radiotherapy

Supportive treatment

Antiemetics

Growth factors

Anti-infective agents

Disease-specific therapy

HL

NHL

Indolent lymphoma

Aggressive lymphoma (including large B-cell lymphomas, mantle cell lymphoma & mature T-cell neoplasms)

Highly aggressive lymphoma (including precursor [B or T] lymphoblastic leukemia/lymphoma & Burkitt's lymphoma)

Acute leukemia

Acute myeloid leukemia

Acute promyelocytic leukemia

Acute lymphoblastic leukemia

MM

CML

MPNs

Conclusion

Future perspective

Footnotes

An update on the management of hematologic malignancies in pregnancy

References