Haematologica 2002; 87:(02)ELT12
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AIDA treatment for high-risk acute promyelocytic leukemia in a pregnant woman at 21 weeks of gestation
Massimo Breccia, Giuseppe Cimino, Giuliana Alimena, Sara De Carolis,* Francesco Lo Coco, Franco Mandelli.
Departments of Human Biotechnology and Hematology -University La Sapienza of Rome; * Department of Obstetrics and Gynecology- University Cattolica-S.Cuore, Rome, Italy

Correspondence: Massimo Breccia, MD; Dept. of Human Biotechnology and Hematology of the University La Sapienza of Roma, Via Benevento 6, 00161 Roma, Italy. Phone: 39.06.857951; Fax: 39.06.44241984. Email: mbreccia@hotmail.com
We describe a case of high risk acute promyelocytic leukemia diagnosed in a woman at 21 weeks of gestation. The patient was successfully induced into hematologic and molecular remission by all-trans-retinoic acid (ATRA) and chemotherapy (CHT). The role of combined ATRA and chemotherapy in APL during midterm gestation is discussed. A 35-year-old woman was admitted in May 2001 because of leucocytosis (16.5x109/L) and thrombocytopenia (38.5x109/L) diagnosed during pregnancy ( 21 weeks of gestation). Laboratory tests disclosed signs of disseminated intravascular coagulation (PT 1.3, PTT 1.4, fibrinogen 50 mg/dL, fibrinogen split products 1748 microg/L). Bone marrow and peripheral blood morphologic analysis showed infiltration with >80% dysplastic promyelocytes with bundles of Auer rods, consistent with a diagnosis of hypergranular APL. A PML/RARa bcr1 type transcript was detected in leukemic blast RNA by RT-PCR.1 After informed consent, the patient was enrolled in the AIDA protocol, consisting of i.v. idarubicin (12 mg/m2 day 2,4,6,8) and oral ATRA (45 mg/m2/d) until hematologic remission.2 Supportive antihemorrhagic treatment included platelet transfusions to maintain platelet count above 30x109/L, tranexamic acid (100 mg/kg/d continuos infusion) and prednisone 0.5 mg/kg until the end of induction. A rapid normalization of the coagolopathy was observed after 4 days of treatment, in conjunction with early morphologic signs of leukemia cell maturation. The patient achieved complete hematologic remission at day +31 with no major toxicities being recorded during induction. She then received a consolidation CHT course with idarubicin (5 mg/m2 day 1,2,3,4), cytarabine (1000 mg/m2 day 1,2,3,4) and ATRA (45 mg/m2/d for 15 days), according to the AIDA 2000 trial for high risk APL. The marrow hypoplastic phase following consolidation was complicated by Pseudomonas aeruginosa septicemia successfully managed with piperacillin/tazobactam and amikacin. Molecular analysis of residual disease by RT-PCR of PML/RARalpha (sensitivity 10-4 ) showed absence of detectable hybrid transcript after the 1st consolidation course. At this time, in agreement with the the patient's obstetrician, it was decided to postpone further anti-leukemic therapy, and to perform a Caesarian section. At 34 weeks of gestation, the patient who was in complete remission gave birth to a normal 1950 g. body weight premature girl. Physical examination and routine laboratory tests showed no apparent abnormalities of the newborn. APL is of special importance to the obstetrician because of its well known association with disseminated intravascular coagulation (DIC), which may severely complicate the management of pregnancy, labor and delivery. By reviewing the pertinent literature, we have identified 34 cases of APL developing during pregnancy who were treated with various approaches including CHT alone, ATRA alone and combined ATRA plus chemotherapy.3-8 Among 15 receiving CHT, 13 were diagnosed in late pregnancy and yielded live newborns, whereas 2 patients in the 6th and 10th week of gestation at the time of APL diagnosis, had an abortion.4 Anthracycline-based chemotherapy appears reasonably safe for APL patients in the second or third trimester of pregnancy and in particular the association of idarubicin and cytarabine in late pregnancy does not seem to be associated with increased toxicity for either the pregnant woman or the fetus. Concerning ATRA, its use seems to be safe only during the second and third trimesters of gestation, while during the first three months it has been associated with fetal malformations due to its potential teratogenicity.5 To the best of our knowledge, 17 APL patients in advanced pregnancy were treated with ATRA alone: only one report describes the occurrence of cardiac arrhythmia in an infant who, however, responded well to specific antiatrhythmic therapy.6 In recent years, data from large cooperative studies have shown that the combination of ATRA and chemotherapy and in particular their simultaneous administration provide the best results in terms of long term outcome. Moreover, molecular follow-up studies have demonstrated that, despite the initial benefit provided by ATRA, this latter as a single agent does not result in PCR-negativity, whereas the addition of chemotherapy is essential for sustained molecular and clinical remission.2 Our patient, like the ones reported by Delgado-Lamas7 and Giagounidis,8 developed APL during the second trimester of pregnancy, and received ATRA plus chemotherapy. She achieved molecular remission and gave birth to an apparently healthy newborn. However, distinct from the cases mentioned above,7,8 the disease described here showed aggressive features, including signs of DIC and hyperleukocytosis. Based on a risk assessment model recently developed by the Gimema and Pethema group,9 APL patients with WBC counts greater than 10x109/L are defined as having high risk disease and assigned to receive intensified consolidation. In conclusion, simultaneous ATRA and chemotherapy seem safe and effective for the management of high risk APL diagnosed during advanced pregnancy. In fact, ATRA provided amelioration of coagulation parameters and probably counteracted, together with specific supportive measures, the hemorrhagic risk, while the combination of ATRA and CHT resulted in rapid achievement of molecular remission and did not compromise the delivery of a healthy newborn. We believe that this report may add clinically useful information to the scant data available on APL managed during midterm pregnancy.

Acknowledgments
Supported by ROMAIL (Associazione Italiana contro le Leucemie, Sez. di Roma) and AIRC (Associazione Italiana per la Ricerca sul Cancro)

References

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