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Article Type: Review Article ACUTE MYELOID LEUKEMIA IN THE PREGNANT PATIENT Xavier Thomas 1 1

Hospices Civils de Lyon, Hematology Department, Lyon-Sud Hospital, Pierre Bénite, France.

Correspondence:

Xavier Thomas, M.D., Ph.D. Hospices Civils de Lyon Hematology Department Lyon-Sud Hospital Bât.1G 165, chemin du Grand Revoyet 69495 Pierre Bénite cedex France

Phone: (33) 478862235 Fax: (33) 472678880 E-mail: [email protected]

Running title: AML in pregnancy.

ABSTRACT: Although acute myeloid leukemia (AML) mostly occurs in older patients, it could be seen in women of childbearing age. It is therefore not surprising that in some patients the management of AML will be complicated by a coexistent pregnancy. However, the association of leukemia and pregnancy is uncommon. Its incidence is estimated to be 1 in 75,000 to 100,000 pregnancies. During pregnancy, most leukemias are acute: two thirds are myeloid and one third are lymphoblastic. There is no standard approach for this clinical dilemma, in part because of This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ejh.12535 This article is protected by copyright. All rights reserved.

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variables such as the type of AML, the seriousness of the symptoms, and the patient's personal beliefs. In many cases, the diagnostic work up has to be altered because of the pregnancy, and often available treatments have varying risks to the fetus. While chemotherapy is reported to have some risks during the first trimester, it is admitted that it can be administered safely during the second and the third trimesters.

Key words: Acute myeloid leukemia, pregnancy, prognosis, teratogenicity, chemotherapy.

INTRODUCTION The occurrence of cancer in pregnant women ranges from 0.07% to 0.1% (1). Frequency and localization are comparable to those of nonpregnant woman of the same age. Acute leukemias rank third after breast and cervical cancer in association with pregnancy (1). The real incidence of leukemia during gestation is not well known. Its incidence is estimated to be 1 in 75,000 to 100,000 pregnancies (1-3). Since the first publication by Virchow in 1845, a rising number of patients with acute leukemia occurring during pregnancy have been reported. In 1943, McGoldrick and Lapp summarized the world literature on leukemia in pregnancy and reported 34 cases (4). In the 14 year period 1943-1956, Yahia et al. tabulated 32 additional cases (5). Since then, many case reports have been published. Acute myeloid leukemia (AML) accounts for more than two thirds of leukemias that are seen during pregnancy (6,7), and diagnosis is generally made during the last two trimesters (7). Treatment should adhere to the standard treatment, but due to this special situation, therapeutic approaches may be different from those usually used to treat the disease. Small adaptations can be considered, and should depend on the time of diagnosis, clinical tolerance of AML, and the toxic effects of the drugs on mother and child. The main goal will be to come to the end of the pregnancy with a viable healthy fetus and newborn and as little impairment as possible to the mother.

DIAGNOSIS OF AML DURING PREGNANCY Pregnancy often results in a delay in diagnosis. Because the early symptoms are non-specific, the diagnosis is generally made during the second and third trimester. It is estimated that 23% of acute leukemias diagnosed during pregnancy are detected in the first trimester, 37% in the second trimester and 40% in the third trimester (7). Unspecific symptoms such as fatigue,

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increased rate of fetal malformations (8,16,36,37). From the second trimester onwards, growth restriction is the main risk of chemotherapy. Fetal hematopoiesis was not adversely affected and no malformations were observed when chemotherapy was administered during the third trimester (38). However, some organs, including the eyes, genitalia, and hematopoietic and nervous systems, are still vulnerable after the first trimester (31), and transient myelosuppression and increased risk of prematurity or stillbirth have been demonstrated (16,21,39,40). When cytotoxic chemotherapy is administered near delivery, it is important to realize that the child might be born neutropenic and/or thrombocytopenic.

Treatment approaches and chemotherapeutic agents Hydroxyurea Hydroxyurea is a cytotoxic drug that inhibits DNA synthesis. This treatment is not curative. It is commonly used in AML at the time of diagnosis in case of hyperleukocytosis in order to control leukemic proliferation until chemotherapy regimen was started. Pre-clinical models have shown that hydroxyurea is teratogenic in all animal species (41,42). Congenital anomalies in the heart, central nervous system, skeleton as well as neural tube defects were described. In humans, cases of exposure to hydroxyurea during the course of pregnancy in chronic myeloid leukemia patients were recently reviewed (43). In spite of the severe teratogenicity in animals, none of the reports have shown any chromosomal abnormalities in the newborns or major malformations. Only one woman experienced spontaneous abortion (44). However, hydroxyurea should not be a treatment of choice during pregnancy.

Leukapheresis Leukapheresis may be used in AML for rapid reduction of hyperleukocytosis in patients with leucostasis-related symptoms. Experience with leukapheresis during pregnancy is limited.

However, the therapy is tolerated well by the mother and the fetus, and may be used as a shortterm temporizing measure (45,46).

Cytarabine Cytarabine as an antimetabolite is teratogenic in animal models. Cytarabine carries a significant risk to the fetus. Cytarabine use is not advocated in the first trimester. Cases of limb

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than in those treated after delivery (25). Data related to the main studies reported in the literature are presented in Table 1.

Chemotherapy during pregnancy has been associated with congenital malformations and neonatal bone marrow suppression, suggesting that at least one fraction of these drugs is passing the placenta (26). Chemotherapy raises the percentage of miscarriages to 20% compared to an average of 3 – 4% in the general population (27). Studies in animal models showed that transplacental transfer of chemotherapeutics varies substantially among drugs (28). Transfer mainly occurs by passive diffusion, but also can involve active transporters (29). Chemotherapy exerts physical changes on the placenta. Exposure to chemotherapy early in pregnancy (1st

trimester) induces excessive polyploidization of the chorion leave trophoblast (30). Further exposure also predisposes to placental underdevelopment. In another hand, physiological changes in the mother during pregnancy can alter the effectiveness of antineoplastic agents by modifying their metabolism or clearance (31,32). Although most cytotoxic drugs are 250 – 400 kDa and can cross the placenta (33), only a limited number of drugs have been proven to be human teratogenic. A review in 1988 showed 86% of fetuses exposed to alkylating agents, 81% of fetuses exposed to an anti-metabolite, and 83% of the fetuses exposed to anti-tumor antibiotics, during the first trimester, to be free of malformations (8). The standard combination of cytarabine with an anthracycline (except idarubicin) has not been associated with the occurrence of teratogenicity. However, combination therapy engenders a greater risk than single-agent therapy (34). In cases treated during the first trimester of pregnancy, the rate of fetal malformation was higher with a combination (25%) than with single agents (17%) (8). The risk of birth defects may also vary according to the time at which the drug is administered during pregnancy and with the dose. The risk of fetal injury induced by the administration of cytotoxic chemotherapy during the first trimester of pregnancy is real but actually occurs in a minority of patients (8). Teratogenic potential of chemotherapeutic agents is highest between the fifth and tenth week of gestation and then decreases until organogenesis is completed in the 13th week of pregnancy. Therapeutic abortion should therefore be offered to all patients developing AML during the first semester (35). However, successful treatment of AML in pregnant mothers is possible with the fetus in utero. Cytotoxic agents appear to be increasingly safer as the

pregnancy approaches its term. Chemotherapy after the second trimester is not associated with an

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OBSTETRICAL ISSUES A near term delivery (> 35 – 37 weeks) remains the main goal. Delivery should take place in a hospital with a neonatal care unit. As treatment options will be dependent on the gestational age, it appears very important to have a correct dating of the pregancy. A careful fetal examination by ultrasonographic screening is essential to ensure that there are no pre-existing fetal anomalies. Ultrasound scans should be repeated every 2 – 3 weeks to evaluate the fetal growth, development and well-being. Pregnancy-related complications should be treated according to the standard obstetrical care. If treatment is started during pregnancy, fetal well-being after AML therapy should be considered and women should be counselled to be alert when contractions occur because of an increased incidence in preterm contractions (83). The possibility of fetal anemia has to be considered and checked before and after chemotherapy. When delivery is inevitable before 34 weeks, fetal lung maturation by corticosteroids should be considered (84). The mode of delivery is determined based on obstetrical indications. Delivery should be planned at least 3 weeks after the last dose of chemotherapy to allow bone marrow recovery and minimize the risks for the mother and the fetus (85). Chemotherapy should not be administered after 35 weeks. Due to liver and renal immaturity, neonates have limited capacity to metabolize and eliminate drugs. The delay of delivery after chemotherapy will allow fetal drug excretion via the placenta (86). Consolidation chemotherapy can be administered when needed after delivery or after an interval of one week after an uncomplicated caesarean section. Although concentrations of chemotherapeutic agents vary in breast milk, breastfeeding during or shortly after chemotherapy is contra-indicated (1).

SHORT- AND LONG-TERM FETAL EFFECT OF THE TREATMENT OF AML Leukemia in a pregnant patient is supposed to increase the risk of abortion, fetal wastage, and perinatal mortality (6,7,39). Fetal growth restriction and spontaneous preterm delivery have been reported to occur in about 40 – 50% of cases. The effects of cytostatic drugs on the fetus may be studied from two perspectives: immediate effects (corresponding to the first three months of pregnancy known as the embryonic phase when all organs form), which are well known in terms of abortion and teratogenicity; and late effects (corresponding to the fetal phase characterized by

growth and development of all organs), which are less well known with potential gonadal and other endocrine disorders, growth and developmental problems, and genetic and teratogenic

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36. Schafer AI. Teratogenic effects of antileukemic chemotherapy. Arch Intern Med 1981;141:514-515.

37. Buekers TE, Lallas TA. Chemotherapy in pregnancy. Obstet Gynecol Clin North Am 1998;25:323-329.

38. Morishita S, Imai A, Kawabaa I, Tamaya T. Acute myelogenous leukemia in pregnancy: Fetal blood sampling and early effects of chemotherapy. Int J Gynecol Obstet 1994;44:273-277.

39. Catanzarite VA, Ferguson JE II. Acute leukemia and pregnancy. A review and management of outcome, 1972-1982. Obstet Gynecol Surv 1984;39:663-678.

40. Lishner M, Koren G. Cancer chemotherapy during pregnancy. Consortium of cancer in pregnancy evidence. Can Fam Phys 2001;47:41-42.

41. Millicovsky G, Desesso JM, Kleiman L, Clark K. Effects of hydroxyurea on hemodynamics of pregnant rabbits: a maternally mediated mechanism of embryotoxicity. Am J Obst Gynecol 1981;140:747-752.

42. Chaube S, Murphy ML. The effects of hydroxyurea and related compounds on the rat foetus. Cancer Res 1996;20:1448-1457.

43. Azim HA Jr, Pavlidis N, Peccatori FA. Treatment of the pregnant mother with cancer: A systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part II: Hematological tumors. Cancer Treat Rev 2010;36:110-121.

44. Thauvin-Robinet C, Maingueneau C, Robert E, et al. Exposure to hydroxyurea during pregnancy: a case series. Leukemia 2001;15:1309-1311.

45. Meyer RJ, Cuttner J, Truog P, Ambinder EP, Holland JF. Therapeutic leukopheresis of acute myelo-monocytic leukemia in pregnancy. Med Pediatr Oncol 1978;4:77-83.

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46. Fitzgerald D, Rowe JM, Heal J. Leukapheresis for control of chronic myelogenous leukemia during pregnancy. Am J Hematol 1986;22:213-218.

47. Turchi JJ, Villasis C. Anthracyclines in the treatment of malignancy in pregnancy. Cancer 1988;61:425-440.

48. Achtari C, Hohlfeld P. Cardiotoxic transplacental effect of idarubicin administered during the second trimester of pregnancy. Am J Obstet Gynecol 2000;183:511-512.

49. Hahn KM, Johnson PH, Gordon N, et al. Treatment of pregnant breast cancer patients and

outcomes of children exposed to chemotherapy in utero. Cancer 2006;107:1219-1226.

50. Shapira T, Pereg D, Lishner M. How I treat acute and chronic leukemia in pregnancy. Blood Rev 2008;22:247-259.

51. Aviles A, Neri N, Nambo MJ. Long term evaluation of cardiac function in children who received anthracyclines during pregnancy. Ann Oncol 2006;17:286-288.

52. Sieber SM, Adamson RH. Toxicity of antineoplastic agents in man: Chromosomal aberrations, antifertility effects, congenital malformations and carcinogenic potential. Adv Cancer Res 1975;22:57-109.

53. Nicholson HO. Leukemia and pregnancy: A report of five cases and discussion of management. J Obstet Gynaecol Br Commonw 1968;75:517-520.

54. Doney RC, Kraemer KG, Shepard TM. Combination chemotherapy for acute myelocytic leukemia during pregnancy: Three case reports. Cancer Treat Rep 1979;61:369-371.

55. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009;113:1875-1891.

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76. Stentoft J, Lanng Nielsen J, Hvidman LE. All-trans retinoic acid in acute promyelocytic leukaemia in late pregnancy. Leukemia 1994;8:1585-1588.

77. Culligan DJ, Merriman L, Kell J, et al. The management of acute promyelocytic leukemia presenting during pregnancy. Clin Leukemia 2007;1:183-191.

78. Fenaux P, Chastang C, Chevret S, et al. A randomized comparison of ATRA followed by chemotherapy and ATRA plus chemotherapy, and the role of maintenance chemotherapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1999;94:1192-1200.

79. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukaemia. N Engl J Med 1997;337:1201-1208.

80. Fadilah SAW, Hatta AZ, Keng CS, Jamil MA, Singh S. Successful treatment of acute myelocytic leukemia in pregnancy with all-trans retinoic acid. Leukemia 2001;15:1665-1666.

81. Antunez de Mayolo JA, Ahn YS, Temple JD, Harrington WJ. Spontaneous remission of acute leukemia after the termination of pregnancy. Cancer 1989;63:1621-1623.

82. Siddiqui T, Elfenbein GJ, Noyes WD, Moreb JS, Oblon D, Weiner RS. Myelodysplastic syndromes presenting in pregnancy. A report of five cases and the clinical outcome. Cancer 1990;66:377-381.

83. Van Calsteren K, Heyns L, De Smet F, et al. Cancer during pregnancy: an analysis of 215

patients emphasizing the obstetrical and the neonatal outcomes. J Clin Oncol 2010;28:683-689.

84. Crowley P, Chalmers I, Keirse MJ. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1990;97:11-25.

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cleft and altered neuronal development (34), which is consistent with animal studies (69). The administration of corticosteroids to pregnant women may be associated with intra-uterine growth retardation, low birth weight and increased infant morbidity (70). In the pregnant woman, complications related to corticosteroids are the same as in non pregnant patients and mainly include premature rupture of membranes and exacerbation of gestational diabetes and hypertension.

Pain control Paracetamol can be administered safely throughout pregnancy. Non-steroidal anti-inflammatory drugs are preferably not used during pregnancy, but may be considered during the first and second trimester of pregnancy. They are contra-indicated in the third trimester because of their potential association with premature closure of the ductus arteriosus, oligohydramnion and prolonged gestation and labor (26).

Special situations Acute promyelocytic leukemia APL during pregnancy is a challenging situation. APL is considered a medical emergency. Management of APL during pregnancy represents a significant problem to the obstetrician because it is usually associated with coagulopathy, which may severely complicate the management of pregnancy, labor and delivery. Main cases reported from the literature are summarized in Table 2. Patients should be closely monitored for clinical and laboratory manifestations of this coagulopathy. Prior to the ATRA era, APL treated with standard chemotherapy did not always result in live birth (71,72). However, the current management of APL during pregnancy remains potentially complicated by the potential teratogenic effect of chemotherapy, ATRA, and arsenic trioxide (ATO). Recent guidelines have been published and address separatly the management of APL during the first trimester of pregnancy from that of APL arising during the second and third trimester (55). Therapeutic options during the first trimester are extremely limited in terms of chances of successful outcome for the fetus. ATRA is highly teratogenic and should be avoid during this period (73). Similarly ATO, given its high potential embryotoxicity, cannot be recommended at any stage of pregnancy (74,75). When using chemotherapy alone, there will be an increased risk of hemorrhage due to release of

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1994;86:681-682.

134. Tsuda H, Doi H, Inada T, Shirono K. Successful treatment of acute promyelocytic leukemia in a pregnant woman by using all-trans retinoic acid. Rinsho Ketsueki 1994;35:717-719.

135. Celo JS, Kim HC, Houlihan C, Canavan BF, Manzullo GP, Saidi P. Acute promyelocytic leukaemia in pregnancy: all-trans retinoic acid as a newer therapeutic option. Obstet Gynecol

1994;83:808-811.

136. Watanabe R, Okamoto S, Moriki T, Kizaki M, Kawai Y, Ikeda Y. Treatment of acute promyelocytic leukemia with all-trans retinoic acid during the third trimester of pregnancy. Am J Hematol 1995;48:210-211.

137. Nakamura K, Dan K, Iwakiri R, Gomi S, Nomura T. Successful treatment of acute promyelocytic leukemia in pregnancy with all-trans retinoic acid. Ann Hematol 1995;71:263-

264.

138. Simone MD, Stasi R, Venditti A, et al. All-trans retinoic acid (ATRA) administration

during pregnancy in relapsed acute promyelocytic leukemia. Leukemia 1995;9:1412-1413.

139. Requena A, Velasco JG, Pinilla J, Gonzales-Gonzales A. Acute leukemia during pregnancy: obstetric management and perinatal outcome of two cases. Eur J Obstet Gynecol Reprod Biol 1995;63:139-141.

140. Heistinger M, Schumer J, Isak E. Acute promyelocytic leukemia (APL) in late pregnancy: Successful treatment with all-trans retinoic acid (ATRA) – a case report. Onkologie 1995;18:137.

141. Morton J, Taylor K, Wright S, et al. Successful maternal outcome following the use of ATRA for the induction of APL late in the first trimester. Blood 1995;86(suppl.1):772a.

142. Sham RL. All-trans retinoic acid-induced labor in a pregnant patient with acute

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OBSTETRICAL ISSUES A near term delivery (> 35 – 37 weeks) remains the main goal. Delivery should take place in a hospital with a neonatal care unit. As treatment options will be dependent on the gestational age, it appears very important to have a correct dating of the pregancy. A careful fetal examination by ultrasonographic screening is essential to ensure that there are no pre-existing fetal anomalies. Ultrasound scans should be repeated every 2 – 3 weeks to evaluate the fetal growth, development and well-being. Pregnancy-related complications should be treated according to the standard obstetrical care. If treatment is started during pregnancy, fetal well-being after AML therapy should be considered and women should be counselled to be alert when contractions occur because of an increased incidence in preterm contractions (83). The possibility of fetal anemia has to be considered and checked before and after chemotherapy. When delivery is inevitable before 34 weeks, fetal lung maturation by corticosteroids should be considered (84). The mode of delivery is determined based on obstetrical indications. Delivery should be planned at least 3 weeks after the last dose of chemotherapy to allow bone marrow recovery and minimize the risks for the mother and the fetus (85). Chemotherapy should not be administered after 35 weeks. Due to liver and renal immaturity, neonates have limited capacity to metabolize and eliminate drugs. The delay of delivery after chemotherapy will allow fetal drug excretion via the placenta (86). Consolidation chemotherapy can be administered when needed after delivery or after an interval of one week after an uncomplicated caesarean section. Although concentrations of chemotherapeutic agents vary in breast milk, breastfeeding during or shortly after chemotherapy is contra-indicated (1).

SHORT- AND LONG-TERM FETAL EFFECT OF THE TREATMENT OF AML Leukemia in a pregnant patient is supposed to increase the risk of abortion, fetal wastage, and perinatal mortality (6,7,39). Fetal growth restriction and spontaneous preterm delivery have been reported to occur in about 40 – 50% of cases. The effects of cytostatic drugs on the fetus may be studied from two perspectives: immediate effects (corresponding to the first three months of pregnancy known as the embryonic phase when all organs form), which are well known in terms of abortion and teratogenicity; and late effects (corresponding to the fetal phase characterized by

growth and development of all organs), which are less well known with potential gonadal and other endocrine disorders, growth and developmental problems, and genetic and teratogenic

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disorders affecting future generations (16,37,87,88). Of note, during the time from conception until implantation (6 to 10 days after fertilization), the embryo is undifferentiated, and repair and recovery are possible through multiplication of multipotential cells to replace those that might have been lost. Exposure of embryos to teratogens during this phase does not necessary cause congenital malformations unless the agent persists in the body beyond this period (34). The most critical period for teratogenicity is between the third and tenth weeks because this period correlates with the stage of active organogenesis. The occurrence of teratogenicity when chemotherapy is administered during the first trimester is reported to be 10 – 20% (16,37).

Fetal hematopoiesis In adults, hematopoiesis normally occurs in the bone marrow. Hematopoietic stem cells encountered in adults arise by replication and amplification of a stock of hematopoietic stem cells that emerged early in ontogenesis, when the bone marrow has not already been formed. The earliest hematopoietic activity is first indicated by the appearance of blood islands in the mesoderm of the extraembryonic yolk sac. Hematopoiesis is initiated in the yolk sac during the third week of gestation. The existence of an ancestral precursor common to both lineages has been postulated: the angioblast, later renamed hemangioblast designates a group of blood- and vessel-forming mesoderm cells (89). Clonogenic progenitors have been identified at 4.5 weeks of development, including pluripotent (CFU-GEMM), early (BFU-E), or late (CFU-E) erythoid and granulo-macrophage (CFU-GM) progenitors. By the fifth week of development, hematopoietic cells can be detected in aorta-gonad-metanephros region, liver, thymus, and spleen (89). Their role in blood cell production varies along phylogeny. By the eleventh week of gestation, hematopoietic activity begins to shift toward the bone marrow, such that by the time of birth, the marrow remains the major location for hematopoiesis.

Short-term fetal effects of chemotherapy Experimentally, abortive and teratogenic effects have been demonstrated for all cytostatic drugs.

The potential fetal effects depend on the gestational age at exposure. During the implantation period (first 10 days after conception), the number of surviving omnipotent stem cells will determine whether a miscarriage occurs or a normal embryo will develop. Organogenesis occurs between 10 days and 8 weeks after the conception. This period is therefore at risk for congenital

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malformations. The administration of chemotherapy is therefore contra-indicated until a gestational age of 10 weeks. Respecting a 4-week safety period, chemotherapy may start from a gestational age of 14 weeks (68). During the second and third trimester, no major malformations due to cytotoxic agents are expected. However, cases of growth restriction, prematurity, intrauterine and neonatal death, and hematopoietic suppression have been reported (26). Chromosomal aberrations have been described in newborns whose mother received cytotoxic treatment during pregnancy (87).

Metastases of maternal malignant cells to placenta and fetus Although maternal cells do reach the fetus, vertical transmission of malignant cells is exceptionally rare. While dissemination is through hematogenous route, dissemination is limited

by the placental barrier and the fetal immune system. The placenta possesses very effective protective mechanisms against circulating malignant cells (90). Nevertheless the placenta is not an absolute barrier and leukemic cells can pass from mother to fetus (91). Cases of documented maternal malignancy metastatic to the placenta and fetus have been recently reviewed (1). Acute leukemia represented the second most frequent malignancy with such localizations after malignant melanoma (92,93). The placenta should be systematically analyzed histopathologically after delivery (94).

Long-term fetal effects of chemotherapy Potential problems of neurodevelopmental delay, sterility, carcinogenesis and genetic defects have to be considered. A study of 84 children born from mothers treated by chemotherapy for hematological malignancies did not show any congenital, neurological, immunological and psychological abnormalities (18). Although acute myocardial dysfunction can appear in the fetus during pregnancy with anthracyclines (26,95), follow-up with cardiac ultrasound in a large series was reassuring (51). In a few cases, secondary malignancies, growth retardation, intellectual impairment and reduced fertility have been reported (6,27).

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FERTILITY IN YOUNG WOMEN LEUKEMIA SURVIVORS As patients continue to survive longer after chemotherapy, previously unrecognized toxic effects are becoming manifest, such as infertility, which is of particular concern for patients hoping to return to a normal lifestyle (96). The number of primordial follicules in the ovaries is defined during embryonal life and deceases gradually with postnatal aging. The process of follicular growth and maturation is most likely to be affected by cytotoxic chemotherapy. Clinically, amenorrhea ensues and is accompanied by elevation of serum FSH and LH levels and by a fall in serum estradiol. Vaginal epithelial atrophy and endometrial hypoplasia occur, and patients may complain of menopausal symptoms. The onset and duration of amenorrhea is both dose- and agerelated. Younger patients are able to tolerate larger cumulative drug doses and have a greater likelyhood of resumption of menses. Efforts to protect the ovary from the toxic effects of chemotherapy have focused on the use of oral contraceptives to induce ovarian suppression (97). In absence of complete remission for at least 2 – 3 years, pregnancy is avoided in patients who presented AML. However, any association between pregnancy and risk of relapse remains unclear (10). Pregnancy in female cancer survivors displays a significantly higher risk for preterm delivery and low birth weight (98). Pretreatment cryopreservation of ovarian tissue is today increasingly offered, particularly when SCT is planned as consolidation therapy (99).

ETHICAL CONSIDERATIONS A desired pregnancy is a priori a positive event. The diagnosis of AML during pregnancy places the patient and her family into a severe conflict requiring the medical personnel support and professional accompaniment. The situation leads to a potential maternal-fetal conflict. At an early stage of pregnancy, the prolongation of pregnancy depends on the prognosis of the disease. Chemotherapy during the first trimester very often causes intrauterine death of the fetus. During the second and third trimesters, chemotherapy is the only available therapy. However, decision about treatment must be case-specific. It is essential to provide the pregnant woman with a multidisciplinary team of physicians including gynecologists, hematologists, neonatalogists and obstetricians as well as psychologists. Every decision should be made together with the patient after consideration of risks and benefits.

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CONCLUSIONS Overall, attention must be paid to the drugs used and the age of pregnancy. Each case should be examined individually, considering both the aggressiveness of leukemia and the stage of the pregnancy when the therapy is applied. Recommendations for the management of AML and APL in pregnancy are summarized in Table 3. Pregnant women in the first trimester should be offered termination of pregnancy because of the potentially fetal consequences of chemotherapy and the maternal complications of leukemia. Chemotherapy treatment combining cytarabine and doxorubicin, with fetal surveillance and monitoring for adequate growth, during the second to third trimester may not require termination as remission of AML and delivery of a normal infant seem likely. Delivery should be planned after the 32nd week of gestation and 2 – 3 weeks

following treatment to allow bone marrow recovery. During the last trimester, a slight delay in treatment should be considered to allow for delivery before institution of chemotherapy. It remains important to keep in mind that spontaneous abortion ranges from 10% to 20% and live birth with congenital anomalies arises in 3 – 4% in the general population (100,101). This should be considered in the interpretation of the outcome of leukemia patient during pregnancy.

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105. Manoharan A, Leyden MJ. Acute non-lymphocytic leukaemia in the third trimester of pregnancy. Aust N Z J Med 1979;9:71-74.

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Table 1. Main literature regarding AML diagnosed in pregnant women. Reference No. of cases Patient’s Pregnancy and fetal outcome outcomes Raich et al. 1975 1 pt with AML 1 CR 1 SVD with no CM (102) Durie et al. 1977 1 pt with AML 1 CR 1 SVD with no CM (103) Lowenthal et al. 1 pt with AML 1 CR 1 IL, no CM 1978 (104) Manoharan et al. 1 pt with AML 1 CR 1 SVD with no CM 1979 (105) Hamer et al. 1979 1 pt with AML 1 CR 1 SVD with no CM (106) Doney et al. 1979 3 pts with AML 2 CR, 1 toxic 1 TA, 2 SVD with PB (54) death and 1 transient myelosuppression Pizzuto et al. 1980 9 pts with AL ND 6 SVD, 3 FD (15) Colbert et al. 1980 2 pts with AML 1 PR, 1 CR 1 LI, 1 fetal distress with (107) transient neutropenia Awidi et al. 1983 5 pts with AL ND 1 SA, 4 SVD (108) Catanzarite et al. 47 pts with AL 40 pts treated 5 TA, 3 perinatal 1984 (39) (OS > 12 months) demises, 1 liveborn infant, 31 LI 7 pts not treated (1 1 TA, 2 perinatal survivor) demises, 4 LI Fassas et al. 1984 4 pts with AML 3 CR, 1 PR 1 CS, 1 TA, 2 SVD (109) No CM Reynoso et al. 1987 3 pts with AML No mortality 3 SVD, 1 IL (6) 1 pt with CML-BC 1PR, 3 CR 1 mild thrombocytopenia Feliu et al. 1988 (16) 4 pts with AML 1 CR, 1 death 4 SVD, no CM from cerebral hemorrhage Aviles et al. 1988 17 pts with AL No mortality No CM or late side (110) effects Fukuoka et al. 1989 1 pt with AML 1 CR 1 SVD with no CM (111) Caligiuri et al. 1989 40 pts with AML 72% CR in AML 13 fetus in 1st trimester, 8 (7) PB, 2 SA Siddiqui et al. 1990 5 pts with MDS 1 CR 3 SVD (1 Down (82) syndrome), 1 TA, 1 hysterectomy Zuazu et al. 1991 8 pts with AML 2 deaths 2 SA, 1 FD, 2 CS (1PB), (112) 2 SVD, 1 IL Tomizuka et al. 1992 1 pt with AML 1 PR 1 CS with no CM

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(113) Artlich et al. 1994 (114) Aragona et al. 1995 (115) RadosevicRadojkovic et al. 1995 (116) Hsu et al. 1995 (117)

Veneri et al. 1996 (118) Nakayama et al. 1996 (119) Greenlund et al. 2001 (11) Ali et al. 2003 (120)

Yucebilgin et al. 2003 (121) Matsuo et al. 2004 (122)

1 pt with AML

1 CR

Malformations (BallerGerald syndrome) 1 SVD

1 pt with AML 1 pt with AML

1 death (hemorrhage) 1 resistant disease 1 CS with no CM

1 pt with AML

1 CR

1 pt with AML

1 CR

1 pt with AML

1 CR

13 pts with AML

9 CR (69%)

4 pts with AML 1 pt with AML

1 CR, 3 deaths during therapy 1 CR

1 pt with AML

1 CR

1 CS with LBW, pancytopenia, and intermittent sinusoidal fetal heart rate pattern 1 CS with no CM 1 IL with LBW and respiratory distress 29% fetal loss, no CM 1 SA, 2 TA, 1 intrauterine death 1 CS with signs of fetal distress 1 CS with no CM, transient myelosuppression 11 SVD, 1 SA, 8 TA, 7 CS with no CM and 4 PB 2 LBW, 1 TA, no CM

Chelghoum et al. 27 pts with AML 25 CR (93%), 1 2005 (24) toxic death Dilek et al. 2006 3 pts with AML 1 CR (123) Aboujaoude et al. 1 pt with AML 1 death (stroke 1 intrauterine fetal 2007 (124) postpartum) demise Menezes et al. 2008 3 pts with AML No CR 1 TA, 2 CS, no CM (125) Sabty Firas et al. 2 pts with AML 2 CR 1 CS, 1 SVD, no CM 2008 (126) Pailoor et al. 2010 1 pt with AML 1 CR 1 TA (127) Tashiro et al. 2011 1 pt with AML 1 CR 1 CS with LBW (128) Aviles et al. 2012 14 pts with AL 10 CR (71%) 1 TA, 13 LI with no CM (129) Abbreviations: AL, acute leukemia; CM, congenital malformation; CML-BC, chronic myeloid leukemia in myeloid blast crisis; CR, complete remission; CS, Cesarean section; FD, fetal death; IL, induced labor; LI, living infant; MDS, myelodysplastic syndrome; ND, not done; PB, premature birth; PR, partial remission; Pts, patients; SA, spontaneous abortion; SVD, spontaneous vaginal delivery; TA, therapeutic abortion.

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Table 2. Main literature regarding APL diagnosed in pregnant women. Reference Patients Treatment Patient’s outcome Gstöttner et al. 1 pt (28 w) DNR + AraC 1 CR 1978 (130) D’Emilio et al. 1 pt (22 w) Chemotherapy 1 CR 1989 (131) Takatsuki et al. 1 pt (14 w) BHAC + DNR 2 CR 1992 (132) 1 pt (29 w) + 6MP + steroid Harrison et al. 1994 (133)

1 pt (26 w)

Tsuda et al. 1 pt (28 w) 1994 (134) Celo et al. 1994 1 pt (31 w) (135) Watanabe et al. 1 pt (28 w) 1995 (136)

Nakamura et al. 1 pt (30 w) 1995 (137) Simone et al. 1 pt (3 w) 1995 (138) Stentoft et al. 1 pt (23 w) 1995 (76) Aragona et al. 1995 (115) Requena et al. 1995 (139) Heistinger et al. 1995 (140) Morton et al. 1995 (141) Sham 1996 (142) Lipovsky et al. 1996 (143) Lin et al. 1996 (59) Incerpi et al. 1997 (144) Terada et al. 1997 (145)

1 pt (3rd tr) 1 pt (25 w) 1 pt (20 w) 1 pt (31 w) 1 pt (13 w) 1 pt (29 w) 1 pt (34 w) 1 pt (14 w) 1 pt (24 w) 1 pt (29 w)

Pregnancy and fetal outcome 1 CS (34w) with no CM 1 CS (28 w) with no CM 1 FD (19 w) 1 CS (35 w) with no CM ATRA 1 CR 1 CS (30 w) with cardiac arrest, no CM ATRA + 1 CR 1 CS (29 w) chemotherapy with no CM ATRA 1 CR 1 CS (31 w) with no CM ATRA 1 CR 1 CS (31 w) with respiratory distress, no CM ATRA 1 CR 1 CS (32 w) with no CM ATRA + steroid 1 CR but relapse 1 CS (32 w) with LBW ATRA 1 CR 2 SVD (twins) (32 w) with no CM Chemotherapy 1 CR 1 FD after delivery (hemorrhage) AraC + 6TG 1 CR 1 CS (34 w) +DNR + Mitox 1 CR 1 CS (34 w) ATRA 1 CR 1 CS (34 w) with no CM ATRA 1 CR 1 SVD (32 w) with no CM ATRA 1 CR 1 IL (29 w) with FD ATRA 1 CR 1 IL (38 w) with no CM ATRA + G-CSF 1 CR 1 CS (40 w) + Epo with no CM ATRA + DNR 1 CR 1 IL (33 w) with no CM ATRA 1 CR 1 CS (34 w) with cardiac arrhythmia, no

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1 pt (29 w)

ATRA + steroid 1 CR

Leong et al. 2000 (147)

1 pt (3rd tr)

ATRA

Giagounidis et al. 2000 (72) Fadilah et al. 2001 (80) Siu et al. 2002 (148)

1 pt (21 w) 1 pt (25 w)

ATRA + 6TG + 1 CR DNR + AraC ATRA 1 CR

1 pt (13 w)

ATRA + Ida

1 CR

Carradice et al. 2002 (149)

1 pt (25 w)

ATRA + chemotherapy

1 CR

Ali et al. 2003 (120) Murrin et al. 2004 (150)

1 pt (26 w) 1 pt (19 w) 1 pt (34 w)

1 toxic death 1 CR 1 CR

Chelghoum et al. 2005 (24)

1 pt (7 w) 1 pt (9 w) 1 pt (5 w)

DNR + AraC ATRA + Ida ATRA + chemotherapy after delivery ATRA + DNR + AraC

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Maeda et al. 1997 (146)

1 pt (28 w)

Dilek et al. 2006 1 pt (25 w) (123) Park et al. 2009 1 pt (13 w) (151) Ganzitti et al. 1 pt (25 w) 2010 (152) Aoki et al. 2011 1 pt (38 w) (153)

1 CR

3 CR

ATRA + 1 CR chemotherapy after delivery ATRA + DNR + Toxic death AraC (intracranial bleeding) ATRA + Ida 1 CR

CM 1 CS (32 w) with apnoea, no CM 1 CS (37 w) because fetal distress 1 IL (35w) with no CM 1 CS (34 w) with no CM 1 SVD (37 w) with transient congestive heart failure 1 IL (28 w) with pulmonary complications 1 SA 1 TA (FD) 1 SVD with no CM 1 SA 2 TA

1 SVD with no CM 1 PB with death from pulmonary hemorrhage 1 TA

ATRA + 1 CR 1 SVD with no chemotherapy CM ATRA + Ida + 1 CR 1 SVD (38 w) AraC after with no CM delivery Abbreviations: AraC, cytarabine; ATRA, all-trans retinoic acid; BHAC, behenoylcytosine arabinoside; CM, congenital malformation; CR, complete remission; CS, Cesarean section; DNR, daunorubicin; Epo, erythropoietin; FD, fetal death; G-CSF, granulocyte colony stimulating factor; Ida, idarubicin; IL, induced labor; LI, living infant; LBW, low birth weight; Mitox, mitoxantrone; PB, premature birth; Pts, patients; SA, spontaneous abortion; SVD, spontaneous vaginal delivery; TA, therapeutic abortion; tr, trimester; w, weeks; 6MP, 6-mercaptopurine; 6TG, 6-thioguanine.

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Table 3. Recommendations for the management of AML and APL in pregnancy. Type of leukemia AML

APL

1st trimester Pregnancy termination, then conventional therapy Pregnancy termination, then conventional therapy

2nd trimester Cytarabine + Doxorubicin

3rd trimester Cytarabine + Doxorubicin

ATRA + anthracycline

ATRA + anthracycline

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Acute myeloid leukemia in the pregnant patient.

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