Elsevier

Blood Reviews

Volume 22, Issue 5, September 2008, Pages 247-259
Blood Reviews

Review
How I treat acute and chronic leukemia in pregnancy

https://doi.org/10.1016/j.blre.2008.03.006Get rights and content

Summary

The prevalence of pregnancy associated leukemia is approximately 1 case out of 10,000 pregnancies. This rare occurrence precludes the conducting of large, prospective studies to examine diagnostic, management and outcome issues. The treatment of a pregnant woman with leukemia may be associated with severe adverse fetal outcome including death and malformations, and therefore poses a difficult challenge for both the patient and the attending physician. Chemotherapy during the 1st trimester is associated with an increased risk for congenital malformations. However, this risk diminishes as pregnancy advances.

When acute leukemia is diagnosed during the 1st trimester, patients should be treated promptly similar to non-pregnant patients. However, the aggressive induction therapy should follow pregnancy termination. When the diagnosis is made later in pregnancy standard chemotherapy regimen should be considered and usually pregnancy termination is not mandatory. However, both the mother and the fetus should be under close observation and delivery should be postponed to a non-cytopenic period. Pregnancy associated chronic myelogenous leukemia (CML) can be treated with interferon throughout pregnancy with no apparent increase in adverse fetal outcome. In the very rare case of chronic lymphocytic leukemia (CLL) during pregnancy treatment can usually be delayed until after delivery.

Introduction

The diagnosis of leukemia during pregnancy is a dramatic event that poses challenges to the pregnant patient, her family and the medical team. The fact that an optimal anti-leukemia treatment may be associated with adverse fetal outcome including severe malformations or death raises a complicated maternal-fetal conflict. The dilemma is relevant especially in cases of acute leukemia. The aggressiveness of the disease requires immediate administration of intensive multi-drug chemotherapy and is further complicated by the disparity between the quality of the limited available clinical experience versus the dramatic decisions that has to be taken.

Due to its relative rarity, and the absence of a central registry, the epidemiology of leukemia occurring during pregnancy has never been well studied. Therefore, the prevalence of pregnancy associated leukemia is based on estimations and seems to be approximately 10,000 pregnancies.1, 2, 3 This occurrence may become higher, following the current trend to postpone pregnancy until later in life and the increase in the incidence of acute myelogenous leukemia (AML) in the last decade.

It has been estimated that the majority of leukemias diagnosed during pregnancy are acute.1, 2, 3, 4 Of the acute leukemias, two thirds are myelogenous and one third is lymphocytic. Chronic myelogenous leukemia (CML) occurs in up to 10% of pregnancy associated leukemias5 and chronic lymphocytic leukemia (CLL) is extremely rare.5, 6 The relative rarity of pregnancy-associated leukemia precludes conducting large prospective studies to examine diagnostic, management and outcome issues and the literature is largely composed of small retrospective studies and case reports. In this article we critically review the available data, identify clinical and ethical dilemmas and unresolved issues and suggest possible solutions regarding different aspects of leukemia diagnosed during pregnancy and lactation.

Section snippets

Design and Methods

We systematically searched English literature using the MEDLINE database for the years 1977-2007, the UptoDate and the NIH websites. The search terms were combinations of “pregnancy” and / or “leukemia” with each of the medications and treatment measures mentioned in this review. The literature search resulted in 5,212 articles, but only relevant data regarding the diagnosis and treatment of leukemia during pregnancy were analyzed. Letters were included when relevant cases were reported in

Diagnosis of leukemia during pregnancy

During pregnancy the woman’s body undergoes physiological changes that may make the diagnosis of leukemia more challenging. The diagnosis may be delayed since non-specific symptoms and signs of leukemia such as weakness, fatigue, pallor and dyspnea are sometimes attributed to gestation. Furthermore, pregnancy itself may be associated with anemia and leukocytosis that are common laboratory findings in patients with leukemia. Nevertheless, there is no evidence suggesting a delay in the diagnosis

Chemotherapy during pregnancy

Since the different cytotoxic agents have a molecular weight of 250–400 kDa, virtually all of them can cross the placenta and reach the fetus.8 However, only a few small trans-placental studies have been conducted to asses drug concentrations in the amniotic fluid, cord blood, placental and fetal tissues - with conflicting results. When treating pregnant patients with chemotherapy, it is crucial to consider the normal physiological changes that occur during pregnancy including up to 50% increase

Supportive treatment

Up to 70% of cancer patients may suffer from nausea or emesis following anti-cancer chemotherapy and may require anti-emetic treatment such as metoclopramide, anti-histamines or ondansetron-based drugs. No association was found between treatment with these medications and congenital malformations in both animal models and humans.14, 15

Pregnant women treated with anti-cancer chemotherapy, and especially patients with acute leukemia treated with high dose chemotherapy are at increased risk for

Long term fetal effect of the treatment of leukemia

The fact that the CNS continues to develop throughout gestation is a cause for concerns regarding the long term neurodevelopment outcome of children exposed to in-utero chemotherapy for different malignancies including leukemia. Childhood malignancy and long term fertility are other concerns in these children. Data regarding these issues are limited due to the rarity of pregnancy associated leukemia and the difficulties in long-term follow-up. A long term (up to age 6-29, average 18.7 years)

The treatment of acute leukemia during pregnancy

Acute leukemia is an extremely aggressive disease and is fatal unless treated promptly. There is evidence suggesting that treatment postponement until post partum is associated with an increased maternal mortality.22, 23 Therefore, following the diagnosis of acute leukemia, induction therapy with a carefully selected regimen must be administered as soon as possible.22

Acute myelgenous leukemia (AML)

The usual protocol for the treatment of acute myelogenous leukemia consists of a combination of cytarabine with an anthracycline for induction, and various intensive combinations for consolidation therapy.

Cytarabine

The experience with the administration of cytarabine during pregnancy is limited. However, the fact that it is an anti-metabolite raises concerns regarding its safety. Indeed, data from animal models suggest that cytarabine is teratogenic.24 A review of 93 cases of pregnant women exposed to cytarabine alone or in combination with one or more therapeutic agents (thioguanine, doxorubicin, vincristine, and prednisone), for the management of acute leukemia reported 4 cases of limb malformations

Anthracycline

Anthracyclines are an integral part of regimens used for the treatment of many malignancies besides leukemias, including lymphomas, breast and lung carcinomas and soft tissue sarcomas. The experience with the treatment of anthracyclines during pregnancy is limited mostly to doxorubicin and daunorubicin. Idarubicin, which is more lipophilic, has an increased placental transfer and affinity to the DNA, and therefore may be associated with higher rates of adverse fetal outcomes and should be

Consolidation therapy

Consolidation therapy protocols may include lower doses of cytarabine and anthracycline or different drugs such as etoposide. Experience with the topoisomerase inhibitors etoposide and teniposide is extremely poor and therefore their administration during pregnancy cannot be recommended.

Summary

Forty seven cases of pregnancy-associated acute leukemia reported of which 5 were diagnosed and treated during the 1st trimester (Table 1).

Given the paucity of experience and that cytarabine is an anti-metabolite, the administration of induction chemotherapy during the 1st trimester must follow a strong recommendation for pregnancy termination. In the 2nd and 3rd trimesters treatment with cytarabine and doxorubicin should be instituted promptly. The available limited data suggest that this

Acute promyelocytic leukemia (APL)

The induction therapy for patients with APL includes All Trans Retinoic Acid (ATRA) and chemotherapy (most commonly an anthracycline). As with all other vitamin A derivatives, ATRA exposure during the 1st trimester is associated with an extremely high rate (up to 85%) of teratogenicity, including severe neurological and cardiovascular malformations. It is commonly accepted that any administration of ATRA during the first trimester should follow pregnancy termination.

The administration of ATRA

Acute lymphoblastic leukemia (ALL)

Acute lymphoblastic leukemia is relatively rare among adults and therefore only 19 cases of pregnant patients with ALL have been reported (Table 1).37, 38, 39, 40 Since ALL is highly aggressive, adequate chemotherapy must be administered immediately after its diagnosis.

The scanty data regarding treatment of ALL during pregnancy does not allow firm recommendations. This issue is further complicated since methotrexate, which is a crucial component of most intensification protocols of ALL, is

Treatment of chronic myelogenous leukemia during pregnancy (CML)

The incidence of CML is about 1–2 per 100,000 cases per year accounting for 15% of adult leukemias.50 The median age at onset of CML is in the sixth decade and only 10% of cases occur in women in childbearing age.51 Traditionally, therapeutic options for CML included bone marrow transplantation, interferon alpha and chemotherapy. However, in recent years the treatment of the disease has evolved dramatically with the introduction of imatinib mesylate which has emerged as the treatment of choice

Imatinib mesylate

Imatinib mesylate (STI571, Gleevec, Glivec) is a tyrosine kinase inhibitor that entered clinical trials in 1998 and has since been shown to induce dramatic hematological and cytogenetic responses in CML patients in chronic and accelerated phase.53 Several reports of animal models have suggested that imatinib may be teratogenic and therefore the present recommendation for women treated with imatinib is to use appropriate methods of contraception.

Twenty three cases of pregnant women with CML

Interferon-alpha

Prior to the development of Imatinib mesylate, interferon alpha was the non-transplant treatment of choice for most patients with CML. Interferon alpha inhibits cell proliferation by its effect on protein synthesis, RNA degradation and possibly by immune system modulation. It does not inhibit DNA synthesis. Due to its high molecular weight (19 kDa) interferon alpha does not cross the placental barrier to a great extent.65 Neither mutagenicity in vitro nor teratogenicity have been observed in

Hydroxyurea

Hydroxyurea is a cytotoxic drug that inhibits DNA synthesis. It was commonly administered to patients with CML prior to the introduction of imatinib mesylate. Although up to 90 percent of CML patients treated with hydroxyurea may experience clinical and hematological remission, this treatment is not curative, does not prolong overall survival, and only rarely results in attaining cytogenetic response.73

Several cases of hydroxyurea administration during pregnancy have been reported.74, 75, 76, 77

Leukapheresis

Leukapheresis may be used in the management of acute and chronic leukemias for rapid reduction of high white blood cells counts in patients with impending vascular occlusion. The experience with leukapheresis during pregnancy is extremely limited and is composed of only 2 case reports.81, 82 In both cases leukapheresis was the only treatment for CML and was well tolerated by the mother and fetus. CML patients treated with leukapheresis have an advanced disease and therefore require additional

Stem cell transplantation

Allogeneic stem cell transplantation remains an important treatment option for patients with CML, particularly younger individuals who failed treatment with imatinib and have an HLA-identical donor. Given that there are no reports regarding stem cell transplantation in pregnancy and the aggressiveness of this treatment, it should be contra indicated during pregnancy.

Treatment of chronic phase

A suggested algorithm for the treatment of chronic phase CML is presented in Fig. 2. Treatment of CML is recommended as soon as diagnosis is attained and throughout pregnancy. Interferon alpha seems to be the only safe treatment during pregnancy and is therefore the treatment of choice in all trimesters. However, for patients treated with imatinib before conception continuation of imatinib may be considered due to the high risk of disease progression following its cessation. Still, the scanty

Treatment of accelerated and blastic phase

Only one case of accelerate phase CML during pregnancy has been reported.57 The treatments of choice for accelerated phase are imatinib and BMT. In the 2nd and 3rd trimesters imatinib treatment may be offered with a close follow-up of both the mother and fetus.

In cases of an unresponsive disease or blast crisis, patients should be treated as acute leukemia.

Treatment of hairy cell leukemia (HCL)

Hairy cell leukemia accounts for approximately 2-3% of all adult leukemias in the western world. Due to its median age of diagnosis and the male predominance, HCL is very rare during pregnancy.83 The disease is characterized by an indolent course which enables a delay of treatment. Of the 6 cases of pregnancy associated HCL that have been reported,84, 85, 86, 87, 88 in 2 cases treatment was delayed until after delivery,85, 87 2 patients were treated with interferon alpha86 and one patient with

Treatment of chronic lymphocytic leukemia during pregnancy (CLL)

Chronic lymphocytic leukemia is the predominant leukemia among the elderly and affects men twice as often as women. The median age at diagnosis is 60 years, with only 10-15% of patients are younger than 50 years. Therefore, it has been very rarely associated with pregnancy.81

In contrast to acute leukemias, CLL is characterized by an indolent clinical course and therefore treatment can usually be delayed until post partum.89

Only four cases of pregnancy associated CLL have been reported.81, 90, 91

Chlorambucil

Data from animal models have demonstrated that exposure to chlorambucil during pregnancy has been associated with neural tube defects, limb malformations and renal hypoplasia.93, 94, 95 Eight cases of pregnant patients exposed to chlorambucil have been reported in the literature.96, 97, 98, 99, 100 First trimester exposure has been associated with congenital abnormalities including renal agenesis, ureteral malformations and cardiovascular anomalies.100 The few cases of 2nd and 3rd trimester

Corticosteroids

Corticosteroids may be indicated for treating the autoimmune complications of CLL. The short acting agents – prednisone, prednisolone and methyl-prednisolone are metabolized by placental 11-hydroxygenase and therefore the fetus is exposed to approximately 10% of the maternal dose.101 Studies on animal model have shown that antenatal exposure to glucocorticoids is associated with cleft palate and altered neuronal development, ultimately resulting in complex behavioral abnormalities.102 Moreover,

Fludrabine

The use of fludarabine for treating young patients with CLL has been gaining popularity lately. There are no reports regarding the administration of fludarabine during pregnancy. However, since anti-metabolites seem to be more teratogenic than other anti-cancer drugs, its use during pregnancy should be avoided if possible.

Summary

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. When treatment is indicated cytoreduction may be accomplished mechanically with leukapheresis. There is no information regarding cytotoxic treatment for pregnancy associated CLL. Chlorambucil is contraindicated during the 1st trimester of pregnancy because of its

Breastfeeding and chemotherapy

The different chemotherapeutic agents vary in their concentration in breast milk and so dose-dependent as well as dose-independent effects of these drugs cannot be ruled out. Although it is unclear how much toxicity can be attributed to these drugs during lactation, most authorities recommend avoiding breastfeeding until at least 2 weeks following the completion of chemotherapy.1, 2, 3

Ethical considerations

The diagnosis of leukemia during pregnancy raises complex ethical dilemmas. The fact that an adequate anti-leukemia treatment may be associated with poor fetal outcome including severe congenital malformations or death, leads to a potential maternal-fetal conflict. The dilemma is relevant especially in cases of acute leukemia, since the aggressiveness of the disease requires prompt administration of high dose chemotherapy, and is further complicated by the disparity between the limited

Future perspectives

There are no prospective studies on pregnant patients with cancer and data regarding the teratogenic effects of chemotherapy derives mainly from animal models. However, chemotherapy doses used in humans are lower than the minimum teratogenic doses applied in animals, making it difficult to extrapolate data from animals to humans. Recently, there has been a growing interest in studying the effect of different drugs, including chemotherapeutic agents, on the placenta.106, 107, 108 For example,

Conflict of interest statement

None of the authors has a conflict of interest or any affiliation with any organization with a financial interest in the subject matter in the manuscript. The manuscript is not sponsored by any company.

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