American Journal of Hematology 69:281±284 (2002)
Clinical Severe Hepatic Venoocclusive Disease During Induction Treatment of Acute Monoblastic Leukemia Managed With Defibrotide 1
Osnat Bairey,1* Ilia Kirgner,1 Moshe Yakobi,2 Ashraf Hamdan,2 Ziv Ben-Ari,3 and Mati Shaklai1
Institute of Hematology, Rabin Medical Center, Beilinson Campus, Petah Tikva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 2 Internal Medicine Department B, Rabin Medical Center, Beilinson Campus, Petah Tikva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3 Liver Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Hepatic venoocclusive disease (VOD) is the most common complication of cytoreductive therapy used for stem cell transplantation, but it is rarely encountered during induction treatment of acute leukemia. We describe a patient in whom severe clinical VOD developed shortly after induction treatment for acute monoblastic leukemia. Administration of intravenous defibrotide for 19 days induced complete resolution of the VOD. Further consolidation treatment was resumed including high-dose cytosine arabinoside without further complications. Am. J. Hematol. 69:281±284, 2002. ã 2002 Wiley-Liss, Inc. Key words: venoocclusive disease; acute monoblastic leukemia; induction treatment; cytosine arabinoside; defibrotide
INTRODUCTION
Hepatic venoocclusive disease (VOD) is a nonthrombotic obliteration of small intrahepatic veins by loose connective tissue [1]. The clinical triad of jaundice, hepatomegaly, and/or upper right quadrant pain and ascites (or unexplained weight gain of more than 5% of basic weight) is sufficient to suspect this diagnosis. Definitive diagnostic tests are not available. VOD is a common complication of cytoreductive therapy used for blood or bone marrow transplantation [2,3]. However, it has rarely been encountered during conventional-dose treatment of acute leukemia [4], and even more rarely, during induction treatment. We describe a patient in whom clinical severe VOD developed during induction treatment for acute monoblastic leukemia. The patient showed a dramatic response to defibrotide, and consolidation treatments were continued without further toxicity.
mia was admitted to RabinMedical Center, on 2/01/ 2000 with fever, acute tonsillitis, and weigh loss of 9 kg. Physical examination disclosed gingival hyperplasia, cervical lymphadenopathy, and mild splenomegaly. Peripheral blood values were as follows: hemoglobin 7.7 g/dL, leukocyte count 34,000 cells/lL with 58% monocytes, 8% segmented neutrophils, 25% lymphocytes, 3% band neutrophils, 1% metamyelocytes, 3% myelocytes, 2% eosinophils, and 1% blasts; platelet count 127,000/lL. Bone marrow aspiration and biopsy showed hypercellularity with predominant (90%) monoblasts that stained with Sudan-black, specific and nonspecific esterases. Immunophenotyping of bone marrow aspirate cells by fluorescence-
*Correspondence to: Osnat Bairey, Institute of Hematology, Rabin Medical Center, Beilinson Campus, Petah Tiqva 49100, Israel. E-mail:
[email protected]
CASE PRESENTATION
Received for publication 16 April 2001; Accepted 15 November 2001
A 49-year-old female with a past history of recurrent abortions, hysterectomy, and hypertriglyceride-
Published online in Wiley InterScience (www.interscience.wiley. com). DOI: 10.1002/ajh.10072
ã 2002 Wiley-Liss, Inc.
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Case Report: Bairey et al.
activated cell sorter (FACS) showed positivity for CD33, CD13, CD14, CD15, CD11C, HLA-DR, and CD7 differentiation antigens. Cytogenetic studies revealed two populations: one with del(17)(q25) and the other with del(17)(q25) and t(13q;20q). Serum lysozyme level was markedly elevated: 87 mg/mL (normal £10.27 mg/mL). The diagnosis was acute monoblastic leukemia subtype M5b. Induction treatment was initiated on 4/01 with idarubicin 12 mg/m2 for 3 days, cytosine arabinoside 100 mg/m2 continuous infusion for 7 days, and etoposide 75 mg/m2 for 4 days. There were several treatment complications: pancytopenia, for which the patient received transfusions of red blood cells and platelets; severe neutropenia which lasted from 7/01 to 25/01 and was treated with subcutaneous injections of granulocyte growth factor (GCSF); severe diarrhea, which lasted from 8/01 to 23/ 01 and was treated with subcutaneous injections of octreotide; severe hypoalbuminemia of 2.0 g/dL (lowest value on 17/01); fever, which lasted from 8/01 to 25/01; and isolation of enterococci in blood cultures on 21/01. The patient was treated with amoxycillin, metronidazole, ceftazidime, meropenem vancomycin, and fluconazole. Acyclovir was administered for oral herpetic lesions. The patient began induction treatment at a weight of 64 kg, lost 4 kg during the first week but gained 7 kg during the second week of the treatment. At that time, painless hepatomegaly appeared, with a liver span of 21 cm; ascites and bilateral pleural effusion were noted. Liver function tests revealed marked serum hyperbilirubinemia, which rapidly peaked to 15.1 mg/dL (direct 11.3 mg/dL), with only mild elevation of serum transaminase and alkaline phosphatase levels (less then twice the normal values). Hepatobilliary ultrasound showed normal appearance of the gallbladder and bile ducts. Doppler ultrasound performed on 21/01 showed normal flow in portal vein and hepatic artery. The patient did not develop renal dysfunction or pulmonary infiltrates but did require oxygen support for 4 days. An attempt to perform a transjugular liver biopsy on 18/01 failed due to narrowing of her the right jugular vein. The patient was treated with fluid restriction and spironolactone and furosemide diuretics with no improvement. She fulfilled the clinical criteria for severe VOD. On 19/01 therapy for VOD was initiated, consisting of intravenous defibrotide on a compassionate-use basis (Crinos S.p.A, Como, Italy) at a dose of 800 mg/day (12 mg/kg) in 4 divided doses, which was increased gradually to 2,000 mg/day (30 mg/kg) until 6/02. Within 3 weeks, liver function tests returned to baseline, the ascites fluid disappeared, and the patient lost 14 kg. Percutaneous liver biopsy performed on 2/02 showed signs of mild sinusoidal chronic inflammation and fibrosis with no evidence of
leukemic infiltration or infectious cause. Complete remission was achieved. The patient was further treated with 3 consolidation schedules: the first, with daunorubicin 45 mg/m2 for 3 days and cytosine arabinoside 100 mg/m2 for 7 days, and the second and third with cytosine arabinoside 3 g/m2 twice daily on days 1, 3, and 5. There were no further complications other than a short bout of neutropenic fever, and serum bilirubin remained within the normal range. Mild transient elevation of serum transaminase and alkaline phosphatase levels followed each consolidation course. Due to a history of recurrent abortions, a full procoagulant profile was performed that showed an increased level of antiphospholipid antibody IgA isoform to 49 U/mL (normal
