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Life‐threatening hemangiomatosis of the liver in an infant: Multimodal therapy including cyclophosphamide and secondary acute myeloid leukemia

To the Editor: We read with great interest the paper by Gottschling et al. [1] on two infants with life-threatening hemangiomatosis treated with cyclophosphamide.Wewould like to report another corresponding case treated at our institution. A 2-month-old female presented with abdominal enlargement due to massive hepatomegaly; there were no cutaneous hemangiomas. Imaging studies (sonography, CT, MRI) showed a grossly enlarged liver containing multiple contrast-enhancing lesions characteristic of hemangiomatosis of the liver (Fig. 1). Cardiomegalywas present on chest Xray. Steroid therapy was initiated which led to transient regression of the hemangiomas. On day 29 of steroid therapy the infant was readmitted with cardiac failure; sonography showed increasing hepatomegaly. Therapy was intensified with cyclophosphamide (10mg/kg/d 4 days). The patient’s condition promptly improved; a second and third course of cyclophosphamide was administered at 10-day intervals. In contrast to marked clinical improvement, liver size did not decrease. Thirty-six days after the last cyclophosphamide dose the patient again presented with cardiac failure. Since conservative treatment options had failed the patient was started on subcutaneous interferon and underwent partial hepatic embolization. Over three sessions at weekly intervals, the left hepatic artery and branches of the right hepatic artery (segments IV, VII, VIII) were occluded by embospheres of 300–500 and 500–700 mm, respectively. After the third intervention, echocardiographic parameters of cardiac function had normalized, whereas no regression of hepatic hemangiomas could be demonstrated on imaging. Five weeks later signs of cardiac failure re-occurred, a fourth embolization was done. Cardiac function stabilization was achieved and the child’s condition improved dramatically. At the age of 16 months the girl was developing normally, with her weight at the 50th percentile. Interferon therapy was stopped at 18 months when imaging studies showed marked regression of liver hemangiomas. At the age of 31 months the child was diagnosed with acute myeloid leukemia (AML) FAB M4/EO; cytogenetic analysis revealed inversion of chromosome 16. The patient was treated according to the AML-BFM 98 Interim (2003) study and achieved remission after the first induction cycle. Fifteen months after the end of therapy the patient is in 1st remission, developed normally,withweight and length above the 90th percentile. In contrast to the patients reported byGottschling et al. [2] we encountered two problems in the management of our patient: (1) The response to cyclophosphamide was only transient. The recurrent high-output cardiac failure could only be controlled by significantly reducing hepatic blood flow by means of hepatic artery embolization. (2) In a study on 24 children with therapy-induced AML [3] most followed the clinical pattern typified by exposure to epipodophyllotoxins with a mean time to onset of 42 months (range 5– 116 months) regardless of the chemotherapeutic agent(s) suspected of inducing the AML; 50% displayed FAB M4/5 morphology. Our patient received a cumulative dose of 140 mg/kg (2,330 mg/m) of cyclophosphamide in her 5th month of life. Twenty-six months later she developed AML FAB M4/EO which in the absence of exposure to any other leukemogenic agent was suspected to be secondary to treatment with cyclophosphamide.