Eilon Krashin1 and Michael Lishner1, 2
(1)
Department of Medicine A, Meir Medical Center, Kfar Saba, Israel
(2)
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Michael Lishner
Email: michael2@clalit.org.il
Keywords
LeukemiaPregnancyChemotherapyMalformationsFetus
Introduction
The incidence of leukemia during pregnancy is relatively low, estimated to be about 1 in every 75,000–100,000 pregnancies [9]. This incidence may increase concomitant with the trend to postpone pregnancy until later years. It is estimated that the majority of cases diagnosed in pregnancy are acute, with acute myeloid leukemia (AML) accounting for two-thirds of cases and acute lymphocytic leukemia (ALL) accounting for one-third. Chronic leukemia, generally considered a disease of old age, is uncommon during pregnancy. Chronic myeloid leukemia (CML) occurs in up to 10 % of pregnancy-associated leukemias, and chronic lymphocytic leukemia (CLL) is extremely rare [24]. Due to the relative rarity of pregnancy-associated leukemia, most of the relevant literature is based on small, retrospective studies and case reports rather than on large, prospective studies.
The physiological changes a woman’s body undergoes during pregnancy may obscure the diagnosis of leukemia. The nonspecific symptoms and signs of leukemia such as weakness, fatigue, and pallor and laboratory findings such as anemia and leukocytosis may be erroneously attributed to gestation. Nonetheless, there is no evidence suggesting a delay in the diagnosis of leukemia in pregnant patients compared to nonpregnant controls. Most cases of CML and CLL presenting during pregnancy are diagnosed due to abnormal routine blood counts.
The diagnosis of leukemia requires a morphologic, immunophenotypic, and cytogenetic examination of bone marrow. A bone marrow biopsy can be performed safely during pregnancy without harming the fetus [28].
Management of Acute Leukemia During Pregnancy
Acute leukemia is an extremely aggressive disease and fatal unless treated promptly. It is associated with complications affecting both the pregnancy and the fetus, including cytopenia associated with infection and bleeding, leukostasis, decreased placental blood flow and oxygen exchange, and disseminated intravascular coagulopathy (DIC). Acute leukemia may increase the risk of miscarriage, fetal growth restriction, and perinatal mortality [2]. Some studies suggest that postponing treatment until the postpartum period is associated with increased maternal mortality [14]. Therefore, a diagnosis of acute leukemia mandates immediate, full treatment regardless of gestational stage.
In light of the toxic effects of therapy on the fetus and the mother, it is recommended that women diagnosed with acute leukemia during the first trimester terminate the pregnancy. However, if leukemia presents during the second or third trimester, the application of standard chemotherapy protocols will usually allow both disease remission and delivery of a normal infant. Whenever chemotherapy is required, delivery should be timed for 2–3 weeks after treatment to coincide with recovery of the maternal blood count. Overall, the outcomes for pregnant patients with AML are similar to those of nonpregnant women [9].
Treatment approaches for acute leukemia in pregnancy are summarized in Table 15.1.
Table 15.1
Treatment approaches for acute leukemia in pregnancy
|
Acute myeloid leukemia |
|
|
First trimester |
Pregnancy termination, then conventional chemotherapy |
|
Second/third trimester |
Treat as nonpregnant women, early delivery if allogeneic stem cell transplantation is recommended |
|
Acute promyelocytic leukemia |
|
|
First trimester |
Pregnancy termination, then conventional therapy (ATRA with anthracycline) |
|
Second/third trimester |
Treat as nonpregnant women including ATRA |
|
Acute lymphoblastic leukemia |
|
|
First trimester |
Pregnancy termination, then conventional chemotherapy |
|
Second trimester |
Consider protocols excluding methotrexate until third trimester |
|
Third trimester |
Treat as nonpregnant women, early delivery if allogeneic stem cell transplantation is recommended |
ATRA all-trans retinoic acid
Acute Myeloid Leukemia
The standard protocol for the treatment of acute myeloid leukemia (AML) consists of a combination of cytosine arabinoside (cytarabine) with an anthracycline for induction, followed by various intensive combinations for consolidation therapy. Experience with administration of cytarabine during pregnancy is relatively limited. A review of 93 cases of pregnant women exposed to cytarabine alone or in combination with one or more therapeutic agents (thioguanine, doxorubicin, vincristine, or prednisone) for the management of acute leukemia reported four cases of limb malformations associated with first trimester exposure. Among 89 cases where cytarabine was used during all trimesters, there were 6 cases of intrauterine fetal death (IUFD), 12 cases of intrauterine growth retardation (IUGR), 5 cases of transient neonatal cytopenias, and 2 cases of neonatal death secondary to severe infections [11].
The experience with anthracycline treatment during pregnancy is limited mostly to doxorubicin and daunorubicin. Idarubicin, which is more lipophilic, has increased placental transfer and an affinity to DNA and may be associated with higher rates of adverse fetal outcomes. Therefore, it should be avoided during pregnancy. Daunorubicin and doxorubicin are not associated with an increased risk for severe congenital malformations beyond the first trimester [18], although daunorubicin is more commonly used for the treatment of AML. A major concern is whether anthracyclines are cardiotoxic to the developing fetus. A long-term follow-up study of 81 children whose mothers were treated with chemotherapeutic regimens including anthracyclines found no myocardial damage in both gestational and postnatal echocardiograms [5]. While in utero exposure to anthracyclines does not produce significant changes in cardiac systolic function based on conventional echocardiographic parameters, children exposed to anthracyclines during gestation have a lower normal fractional shortening and mildly decreased left ventricular wall thickness [15], findings of yet undetermined clinical significance.
Given the risk of significant fetal malformations, the need for prompt administration of induction chemotherapy during the first trimester should follow a strong recommendation for pregnancy termination. The available data suggest that a combination regimen consisting of cytarabine with daunorubicin or doxorubicin may be administered safely after the first trimester. Close fetal follow-up is recommended, especially cardiac function monitoring and assessment of limb development. Since aggressive chemotherapy may cause severe complications such as infections, nausea, and cytopenias, adequate maternal supportive treatment is essential.
Consolidation therapy protocols in AML may include lower doses of cytarabine and an anthracycline or other drugs, such as etoposide. Consolidation with cytarabine and anthracyclines is preferred over etoposide, where experience is extremely limited. Treatment of AML in relapse consists of high-dose chemotherapy, bone marrow transplantation (BMT), or experimental drugs. None of these therapeutic options can be administered safely during pregnancy.
Acute Promyelocytic Leukemia
Induction therapy for patients with acute promyelocytic leukemia (APL) includes all-trans retinoic acid (ATRA) and chemotherapy, most commonly an anthracycline. As with all other vitamin A derivatives, ATRA should be avoided during the first trimester owing to extremely high teratogenicity associated with retinoid use (up to 85 %), including severe neurological and cardiovascular malformations. It is commonly accepted that pregnancy termination should precede administration of ATRA during the first trimester.
Normal pregnancy outcomes without congenital malformations were reported after administration of ATRA in combination with an anthracycline during the second and third trimesters [18]. Due to the risk of fetal cardiac toxicity, stringent fetal monitoring is recommended, with specific emphasis on cardiac function.
Arsenic trioxide is an established teratogen. Thus, it is contraindicated throughout pregnancy [24].
APL is of special importance to the obstetrician because of its association with disseminated intravascular coagulopathy (DIC), which may severely complicate management of pregnancy, labor, and delivery. Patients should be closely monitored for clinical and laboratory manifestations of DIC.
Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) is rare among adults, and less than 30 cases during pregnancy have been reported [26]. Since ALL is a highly aggressive disease, adequate chemotherapy must be administered immediately after diagnosis.
Methotrexate, a crucial component of most ALL chemotherapeutic protocols, is highly teratogenic. First trimester methotrexate exposure is associated with an increased risk of miscarriage. Exposure to high-dose methotrexate (>10 mg/week) during the first trimester was associated with the fetal aminopterin syndrome—cranial dysostosis, delayed ossification, hypertelorism, wide nasal bridge, micrognathia, and ear anomalies [8]. The most sensitive period for malformations appears to be from 6 to 8 weeks of gestation, with risk diminishing as pregnancy advances [19]. Previously, termination of pregnancy was recommended when ALL was diagnosed prior to the twentieth week of gestation due to concern for methotrexate-induced malformations [24]. However, reports from recent years have not shown a significant risk of developmental side effects associated with second trimester methotrexate exposure [18]. Evidence however is relatively scarce. When ALL is diagnosed during the first trimester, termination of pregnancy should be strongly recommended, followed by immediate administration of an adequate treatment regimen. In the second trimester, treatment protocols excluding methotrexate should be considered. Chemotherapeutic regimens including L-asparaginase, vincristine, anthracyclines, cyclophosphamide, and cytarabine have previously been used in the second trimester [26]. During the third trimester, protocols similar to those employed with nonpregnant patients are applied, with close observation of mother and fetus and delivery planned for a non-cytopenic period.
The Philadelphia chromosome (chromosome 9:22 translocation) is found in 15–30 % of all cases of adult ALL. Current treatment for Philadelphia chromosome-positive ALL consists of chemotherapy and a tyrosine kinase inhibitor (TKI). The potential teratogenicity of TKIs as well as chemotherapy must be considered. There are few reports of treatment of Philadelphia chromosome-positive ALL in pregnancy. In two cases, chemotherapy was administered during pregnancy, with TKIs initiated after delivery [26]. Given the available data on the effects of TKIs on the fetus, use during pregnancy in Philadelphia-positive ALL should be based on risk–benefit analysis for both mother and fetus. However, some authors recommend avoidance of TKIs throughout pregnancy [21].
Chronic Myeloid Leukemia
The incidence of chronic myeloid leukemia (CML) is about 1–2 cases per 100,000 per year, yet only 10 % of cases occur in women in childbearing age. The disease is characterized by abnormal myeloid cell proliferation caused by activation of an abnormal fusion gene, BCR-ABL. Overall, pregnancy does not appear to effect on disease outcomes.
Traditional therapeutic options have included interferon alpha, chemotherapy, and bone marrow transplantation. Imatinib mesylate (STI571, Gleevec, Glivec) is a TKI that has been shown to induce dramatic hematological and cytogenetic responses in CML patients. Today, more potent second-generation (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) TKIs are available for imatinib-resistant patients.
Interferon alpha (IFN-α) is a large (19 kDa) protein that does not cross the placental barrier to a great extent. Neither mutagenicity in vitro nor teratogenicity has been observed in animal studies. Two major case reports [17, 27] reported the outcomes of 40 pregnant patients, 8 of whom with CML, who were treated with IFN-α in various trimesters. There were no reports of congenital malformations when IFN-α was given as monotherapy. It is therefore considered safe throughout pregnancy [20].
Hydroxyurea is a cytotoxic drug which may induce clinical and hematological remission in CML patients. Hydroxyurea exposure is known to produce congenital anomalies in animals. A review of 31 pregnant women treated with hydroxyurea (22 in the first trimester) reported 3 minor congenital abnormalities, 2 cases of intrauterine fetal death, and 9 premature deliveries. Second and third trimester exposure was associated with increased risk of preeclampsia [25]. Based on the available information, hydroxyurea administration should be avoided during the first trimester.
Imatinib
Several studies reported significant complications when imatinib was administered during the first trimester. A series of 125 patients who conceived while on imatinib reported a 14.4 % rate of spontaneous abortions and a 9.6 % rate of fetal abnormalities, including a 100-fold greater-than-expected incidence of exomphalos (three cases), as well as renal, bony, and pulmonary abnormalities [22]. A recent series of 167 patients exposed to imatinib during organogenesis displayed similar results [1]. It is hypothesized that these malformations may be due to the inhibition of “off-target” tyrosine kinases such as PDGFR-α. Little information is available on imatinib use in later trimesters. In a report of two patients exposed to imatinib during the third trimester, the concentrations of imatinib and its active metabolite, CGP74588, were found to be higher in the placenta than in maternal blood but low or undetectable in the umbilical cord, suggesting limited placental transfer in late pregnancy, with no observed fetal complications [23].
Dasatinib
There have been 17 case reports on dasatinib exposure during pregnancy [7, 10, 12]. In one series of 8 women who conceived while on dasatinib treatment, 3 underwent termination of pregnancy, 2 had spontaneous abortions, and 3 delivered healthy babies. In one reported case of dasatinib treatment during pregnancy, termination was required in the second trimester due to fetal hydrops [10]. Other reports showed normal pregnancy outcomes when dasatinib was discontinued during the first trimester following pregnancy confirmation.
Nilotinib
Of the two published reports of nilotinib exposure in early pregnancy, one resulted in a normal delivery, while the other required pregnancy termination at 3 months due to a large exomphalos [1].
All TKIs are assigned pregnancy category D (evidence of human fetal risk, yet potential benefits may warrant use despite potential risk). The present recommendation for women treated with imatinib and other TKIs is to use appropriate methods of contraception. Women wishing to conceive should remain off TKI therapy prior to conception and preferably throughout pregnancy.
Leukapheresis may be used in the management of acute and chronic leukemia for rapid reduction of elevated white blood cell counts in patients with impending vascular occlusion. The treatment can be performed safely in pregnancy [24], and there have been no reports of adverse events to mother or fetus associated with this procedure. However, leukapheresis is not readily available in all centers, is costly and time consuming, and may be limited by the need for good venous access.
Allogeneic stem cell transplantation remains a treatment option for CML patients who have failed treatment with imatinib and have an HLA-identical donor. Given the aggressiveness of this treatment and lack of reports on stem cell transplantation during pregnancy, it is absolutely contraindicated.
CML Diagnosed During Pregnancy
CML is usually diagnosed incidentally during pregnancy by observation of abnormal blood counts. For many patients, the “watch-and-wait” approach is adequate, with treatment reserved for those with elevated white blood cell counts (>100 × 109/l) or platelet counts (>500 × 109/l). Leukapheresis can be particularly useful during the first trimester and may avoid drug therapy. Low-dose aspirin or low molecular weight heparin, both safe during pregnancy, may also be required to prevent thrombotic events. If leukapheresis is not well tolerated or if counts are poorly controlled despite treatment, IFN-α is the drug of choice.
In cases where there is poor response or intolerance to IFN-α, one approach is to initiate treatment with hydroxyurea. Another approach is the introduction of a TKI. Although there are isolated reports on imatinib safety during late pregnancy [23], there is limited evidence to support this approach. Therefore, most experts recommend avoiding use of imatinib and other TKIs throughout pregnancy [21], aside from patients who present with accelerated disease who reject pregnancy termination. Treatment options per trimester in CML are displayed in Table 15.2.
Table 15.2
Treatment options in CML per trimester
|
First trimester |
Leukapheresis for WBC >100 × 109 IFN-α |
|
Second trimester |
Leukapheresis for WBC >100 × 109 IFN-α Consider hydroxyurea if IFN-α cannot be tolerated |
|
Third trimester |
IFN-α Interferon alpha
Pregnancy in Established CML
Given the association of congenital abnormalities with first trimester exposure to imatinib, it is recommended that patients with established CML discontinue imatinib before attempting to conceive. The advisability of discontinuing treatment prior to planned pregnancy depends on the molecular response to imatinib. The ideal scenario for stopping a TKI is in a patient with sustained complete molecular response, defined as undetectable BCR-ABL transcripts (using sensitive RT-PCR test) or a 4.5 log reduction in transcript load for at least 2 years. About 40 % of patients who have achieved sustained complete molecular response can remain off TKI therapy for at least two more years, and those who relapse usually regain their previous excellent disease response upon reintroduction of TKIs [13]. However, if there is less than a major molecular response to TKI, cessation of treatment may lead to cytogenetic or hematological relapse. Even among patients who have achieved sustained molecular negativity, approximately 60 % will experience an increase in BCR-ABL transcript level. Therefore, all patients who stop their TKI in order to become pregnant should be cautioned that their tumor load may rise off treatment. When therapy is stopped, it is recommended that the period from imatinib cessation to pregnancy not exceed 6 months in order to prevent very prolonged periods off treatment. A few days are required between cessation of treatment and unprotected intercourse to permit imatinib washout from the body. BCR-ABL transcripts should be monitored at baseline and at 6–8-week intervals, with more frequent monitoring if transcript levels increase. Imatinib should be resumed as soon as possible after delivery. Because of the potential for adverse reactions from imatinib in nursing infants, breastfeeding is strongly discouraged [23].
Among women who have discontinued treatment after achieving a complete molecular response, no treatment may be required throughout pregnancy. IFN-α therapy can be introduced when loss of cytogenetic response has occurred. Introduction of IFN-α should be considered sooner in women who have stopped a TKI without achieving a major molecular response [21].
Accelerated Disease
Only one case of accelerated phase CML during pregnancy has been reported [3]. The treatment of choice for accelerated phase is imatinib and allogeneic stem cell transplantation. In cases of an unresponsive disease or blast crisis, patients should be treated as in acute leukemia. Due to the need for prompt initiation of aggressive treatment, pregnancy termination should be strongly considered.
Hairy Cell Leukemia
Hairy cell leukemia accounts for approximately 2–3 % of all adult leukemias in the Western world and is very rare during pregnancy. The disease is characterized by an indolent course; therefore, treatment should preferably be delayed until after delivery. When indicated, IFN-α is the treatment of choice. Due to scant data regarding its use during pregnancy, cladribine is not recommended. Splenectomy is reserved for those who fail medical therapy.
Chronic Lymphocytic Leukemia
There are seven case reports of chronic lymphocytic leukemia (CLL) in pregnancy, and only one patient required treatment (leukapheresis) due to advanced disease with severe cytopenias. In all reported cases, patients gave birth to healthy infants with no congenital malformations. There are no data regarding the spread of CLL cells to the fetus. Two cases of placental invasion have been described, but the clinical significance of this is unclear [16].
Since CLL is an incurable disease with an indolent clinical course, treatment should be delayed unless the patient is symptomatic. Most patients can be monitored closely without treatment until delivery or disease progression.
There are several options for treating CLL. The most common drugs are chlorambucil, corticosteroids, and fludarabine. First trimester exposure to chlorambucil has been associated with congenital abnormalities including renal agenesis, ureteral malformations, and cardiovascular anomalies. The few cases of second and third trimester chlorambucil exposure have not been associated with congenital malformations. Corticosteroids may be indicated for treating the autoimmune complications of CLL. There are no reports on the administration of fludarabine during pregnancy. However, since antimetabolites seem to be more teratogenic than other chemotherapeutic agents, their use during pregnancy should be avoided, if possible [16]. Leukapheresis should be offered in case of placental insufficiency associated with severe leukocytosis (>100 × 109/l). There is no chemotherapeutic protocol for CLL which has been shown to be safe during the first trimester. However, CVP (cyclophosphamide, vincristine, prednisone) is an acceptable option from the second trimester onward. As rituximab treatment from the second trimester onward has been reported for other conditions [18], its apparent safety makes it a potential treatment for CLL in pregnant patients.
Outcomes
Several small studies suggest that outcomes for infants born to leukemic mothers may not differ significantly from those of infants born to healthy mothers. One study retrospectively followed the clinical outcomes of 54 infants born to pregnant women who received chemotherapy for hematological malignancies during the first trimester of pregnancy, 14 of whom had acute leukemia. Low birth weight was the most frequent finding (18.5 %), yet all children recovered normal weight within 10 weeks. Physical, psychological, and neurological development were normal [6].
The available literature on late outcomes of antileukemia chemotherapy is limited and is mainly based on retrospective data. A long-term follow-up study (average 18.7 years) of 84 children born to mothers with hematological malignancies, of whom 29 had acute leukemia, reported normal physical, neurological, and psychological development [4]. The malignancy rate was similar to that of the general population, and 12 of these children became parents.
Ethical Considerations
The maternal–fetal ethical conflict, inherent in any case of cancer during pregnancy, is especially relevant in acute leukemia due to the need for prompt administration of high-dose chemotherapy. It is further complicated by limited clinical experience in the face of the dramatic decisions that need to be made. Treatment of pregnancy-associated leukemia must be case specific. Every decision should be made together with the patient and her significant other after careful consideration of the risks and benefits. However, when there is a clear risk to the mother, her safety must supersede fetal risk.
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