Excessive Toxicity After Treatment of Congenital Acute Myeloid Leukemia

Introduction

Congenital leukemias are exceedingly rare with a birth prevalence of 1 to 5 in a million (van der Linden et al.,Semin Fetal Neonatal Med 2012; 192–195) and manifest with a variety of symptoms including respiratory distress, hepatosplenomegaly and skin infiltrates. The most common type is monoblastic leukemia (FAB M5) with rearrangements of chromosome 11q23/MLL (van der Linden et al., Semin Fetal Neonatal Med 2012; 192–195, Kang et al.,Obstet Gynecol Sci 2014; 325–329).

Congenital leukemias are associated with poor prognosis including stillbirth, early death, and a high rate of relapse after treatment.

Case Description

Our patient was born at a gestational age of 39 weeks and 5 days by secondary caesarian section due to a pathologic pattern in cardiotocography (tachycardia and narrow oscillation). She was the first child of a non-consanguineous marriage. Regular examinations during pregnancy had demonstrated normal fetal growth and development, no history of exposure to radiation, teratogens, smoking, drinking or drugs. Postnatal adaptation was difficult, required vigorous resuscitation and ventilator support. Umbilical cord pH 7,14/ 7,19, base excess – 9 mmol/l, APGAR score 4/5/5. Already at birth multiple blueberry muffin-like spots were present ([Fig 2a]). The blood count showed a hyperleukocytosis of 302.000 /µl, an anemia (Hb 8,0 g/dl) and low thrombocytes of 118/nl. Coagulation profile showed an activated partial thromboplastin time>120 sec and INR<10%. The blood smear was cytologically congruent with an AML FAB M5. The karyogram displayed a normal karyotype (46, XX), fluorescence in situ hybridization (FISH) revealed a complex t (4:11;19)-rearrangement involving the MLL locus. Furthermore, amplicon sequencing detected a mutation in the CCAAT/enhancer binding protein α (CEBPA). Lumbar puncture confirmed an involvement of the central nervous system.

Fig. 2 a Photographs of the initial postnatal presentation shows widespread leukemic infiltrates (“blueberry muffin spots”) b Skin toxicity after administration of chemotherapy.

On the first day of life, hyperleukocytosis was treated by exchange transfusion. At the same time we initiated cytoreduction with cytarabine 3 mg/kg*24 h. However, 36 h after initiation of chemotherapy, leukocyte counts rose despite an increase in the cytarabine dose to 6 mg/kg*24 h. For this reason, Daunoxome was added according to the AML-BFM 2012 Registry recommendations and resulted in a rapid decline of leukocyte numbers. Cell lysis syndrome was avoided by the application of rasburicase, by maintaining adequate urine output and by withholding further chemotherapy until the 5^th day of life when leukocyte counts decreased below 2/nl. In comparison to standard ADxE infant doses, daunoxome was reduced by 50% and cytarabine by approximately 30% because of concerns about the detoxification capacity of the neonatal liver ([Fig. 1]).

Fig. 1 Schematic representation of the therapeutic regimen (upper panel) and the course of leukocytes and bilirubin measured in the peripheral blood.

The blueberry muffin spots disappeared after the first dose of Daunoxome. Leukocyte counts below 2/nl were achieved on the 5th day of life, at the same time the need for ventilatory support subsided. After a period of clinical recovery, adverse drug effects affected multiple organs: Skin alterations appeared as an erythema that transformed to necrotic epidermolysis on day 18 covering the whole body, only sparing the hands and feet ([Fig 2]). Intensive analgesia and surgical debridement were required. From day 16, progressive hepatic failure fulfilling the criteria for venoocclusive disease occurred: Bilirubin levels rose up to a maximum of 12,2 mg/dl accompanied by an increase in liver enzymes and cholestasis parameters as well as a decrease in the synthesis performance and a decrease in the hepatic vein blood flow. From day 18, renal function declined continuously. Due to progressive renal failure with anuria, serum urea>220 mg/dl and serum phosphate>2.5 mmol/l, continuous venovenous hemofiltration (CVVH) was initiated on day 24. Due to pronounced hemodynamic instability (noradrenalin and adrenalin 1 μg/kg/min), efficacy of CVVH was low. A bone marrow smear on day 26 showed no signs of regeneration. Due to irreversible multi-organ failure, life-sustaining treatment was withdrawn.