Non‐Promyelocytic Acute Myeloid Leukaemia With Budd–Chiari Syndrome: A Rare Concurrence in a Child

To the Editor, A 13-year-old girl presented with fever, cough, and vomiting for one week. There was no significant past history. On examination, she was pale with no significant organomegaly or lymphadenopathy. Her blood investigations at presentation showed a haemoglobin of 6.4 gm/dL, total leucocyte count of 15,710/mm3, platelet count of 26,000/mm3, and lactate dehydrogenase of 626 IU/mL. The peripheral smear showed 35% blasts. A bone marrow aspiration performed showed 70% blasts, and the flowcytometry of the blasts was positive for human leucocyte antigen (HLA)-DR, cluster of differentiation (CD) 34, MPO, CD 13, CD 33, CD 177, CD 64, and CD11C, with aberrant CD 7 suggestive of acute myeloid leukaemia(AML). The karyotype was normal. The molecular analysis by polymerase chain reaction was positive for nucleophosmin 1 (NPM1) mutation and FMS-like tyrosine kinase 3–internal tandem duplication (FLT3–ITD), and negative for promyelocytic leukaemia–retinoic acid receptor alpha (PML–RARA) fusion. Further tests for rare translocations in promyelocytic leukaemia, such as promyelocytic leukaemia zinc finger (PLZF-RARa), could not be done due to financial constraints. Prior to initiation of chemotherapy, she developed acute severe abdominal pain with generalised abdominal distension. Her abdominal examination revealed gross free fluid (Figure 1A). She also developed tingling of the right toes with cyanosis of the little toe (Figure 1B). Her liver function tests revealed a total bilirubin of 1.9 mg/dL, aspartate aminotransferase of 326 IU/mL, alanine transaminase of 156 IU/mL, albumin of 3.2 mg/dL, and international normalised ratio of 1.5. Her ascitic fluid analysis revealed a straw coloured fluid with occasional mesothelial cells and no growth on culture. The serum ascites albumin ratio was more than 1.1. Contrast-enhanced computed tomography (CECT) of the abdomen showed a filling defect in the right middle and left hepatic vein with enlarged enhancing caudate lobe and hypo-enhancing periphery of liver, massive ascites, mild splenomegaly suggestive of Budd–Chiari syndrome (BCS) (Figure 2). Her echocardiogram showed thrombi in the right ventricle and the arch of the aorta. She thus had anatomically distinct thrombi, that is, intracardiac and in the hepatic veins. She was started on enoxaparin at 1 mg/kg twice a day, under the cover of platelet transfusions, and was given induction chemotherapy using the 3 + 7 protocol of daunomycin and cytarabine [1]. She had to undergo therapeutic paracentesis along with intravenous albumin infusion on a daily basis, in order to relieve the massive ascites. She was also started on spironolactone at a dose of 2.5 mg/kg/day. Stent placement in the hepatic veins was deferred due to her underlying coagulopathy. She received frequent fresh frozen plasma and single-donor platelet transfusions. Her need for frequent platelet transfusions was attributed to myelosuppression due to chemotherapy and/or portal hypertension. However, 10 days after starting enoxaparin, she developed a large hematoma over the right thigh, prompting its stoppage. Around two weeks after the initiation of chemotherapy, her clinical condition improved, and her ascites subsided. Once her platelet count recovered, she was restarted on enoxaparin. Her post-induction measurable residual disease (MRD) by flow cytometry was 0.1%. The family of the child was counselled about the option of allogenic bone marrow transplant, but they opted to continue chemotherapy in view of financial constraints. After the second cycle of induction of the 3 + 7 regimen, the MRD was negative, and she further received two cycles of consolidation with high-dose cytarabine, which were uneventful. An abdominal Doppler scan done two months later showed recanalisation of the hepatic veins. However, the echocardiogram showed persistence of the cardiac thrombus, and hence enoxaparin was switched to oral rivaroxaban. A thrombophilia profile for acquired and inherited predisposition to thrombosis, performed at treatment completion, was negative. She is currently 12 months post-treatment completion, on rivaroxaban, and is doing well. BCS denotes hepatic venous outflow tract obstruction, which may involve one or more hepatic veins, the inferior vena cava at the hepatic segment, or the junction to the right atrium [2]. The clinical presentation of BCS is heterogeneous, from asymptomatic to the classic triad of ascites, abdominal pain, and hepatomegaly [3]. Aetiological factors of BCS in children include inherited thrombophilia (protein C/S deficiency, antithrombin deficiency, and hyperhomocysteinaemia), myeloproliferative disorders (rare), and idiopathic causes [4]. The type of AML most frequently associated with disseminated intravascular coagulation (DIC) and thrombosis is the promyelocytic type [5]. AML-related thrombosis can be arterial or venous, but hepatic vein thrombosis causing BCS, in non-promyelocytic paediatric AML is very rare and has been previously reported by very few case reports, although all patients were more than 18 years of age [6-9]. One case, reported by Sarah Greenfeld [7], was of a 19-year-old who presented with AML and multiple thromboses of both arterial and venous types, including two intracardiac thrombi, IVC thrombosis, pulmonary embolus, hepatic vein thrombosis, and splenic infarcts. Leukaemias can predispose to thrombosis via multiple mechanisms, like elevated blast burden, vascular invasion, leukostasis, cytokine release, DIC syndrome, chemo-induced prothrombotic states, immobilisation, central lines, and infections [6]. The general management paradigm includes anticoagulation and endovascular intervention (angioplasty, stenting– direct intrahepatic portosystemic shunt) if feasible [10]. This case highlights the rare occurrence of BCS in a child with AML and emphasises the importance of its early recognition and multidisciplinary management for a favourable outcome. Anticoagulation therapy in these patients must be initiated cautiously, due to the risk of bleeding from AML. Treatment of the underlying leukaemia should be initiated promptly. The authors declare no conflicts of interest. According to our Institutional Ethics Committee, ethical approval is not required for single case reports. However, written informed consent was obtained from the patient's parents/legal guardians for publication of this report and images of the patient. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.