High-dose methotrexate-induced reversible grade 4 hyperbilirubinaemia and transaminitis in an adolescent with Burkitt Leukaemia

Background

High-dose methotrexate (HD-MTX) plays an important role in the curative therapy of haematological malignancies. HD-MTX alongside intrathecal MTX has been pivotal in ameliorating the need for prophylactic central nervous system irradiation.1 HD-MTX is associated with severe life-threatening toxicities in 2%–12% of cases.2 Predominant toxicities being renal dysfunction, myelosuppression, mucositis and hepatotoxicity. Hepatotoxicity is generally transient and includes reversible elevation of transaminase in up to 60% and associated hyperbilirubinaemia in 25% of courses. Unlike hepatotoxicity associated with oral low-dose MTX prescribed for inflammatory disorder, most cases of hepatotoxicity associated with HD-MTX are transient, reversible and do not lead to chronic liver disease.2 3 Severe grades of hepatotoxicity (grade ≥4) as per National Cancer Institute Common Toxicity Criteria (CTCAE V.4.0) are very rare with HD-MTX and mentioned as case reports.4 We describe a child with Burkitt leukaemia who had grade 4 drug-induced liver injury (DILI) including hyperbilirubinaemia postfirst course of HD-MTX.

Case presentation

Twelve-year-old male adolescent presented with history of fever, bone pains, headache and recurrent transfusions. On examination, he had generalised lymphadenopathy, hepatosplenomegaly and papilloedema. He underwent cervical lymph node biopsy, bone marrow biopsy and cerebrospinal fluid (CSF) examination and was diagnosed as CSF-positive Burkitt leukaemia. He was started on Intergroup protocol for high risk B-non Hodgkin’s lymphoma.5 He was given prephase regimen comprising of single dose of Vincristine 1 mg/m² and Cyclophosphamide 300 mg/m² and 7 days of oral Prednisolone 60 mg/m²/day along with triple intrathecal therapy (TIT) with Methotrexate, Cytarabine and Hydrocortisone. This was followed by two doses of Rituximab at 375 mg/m² on alternate days.

Immediately following prephase regimen, he was started on induction chemotherapy (COPADM-I) comprising of oral Prednisolone 60 mg/m²/day for 5 days, HD-MTX 8 gm/m² over 4 hours on day 1 followed by 16 doses of Leucovorin rescue 15 mg/m²/dose starting after 24 hours of HD-MTX, single dose of Vincristine 2 mg/m² on day 1 and Doxorubicin 60 mg/m² on day 2, Cyclophosphamide 500 mg/m²/day (days 2–4). He also received three doses of TIT on days 2, 4 and 6. We do not have in-house facility for monitoring serum MTX levels and send it to other centre. In view of lockdown due to COVID-19 pandemic, serum MTX levels were not monitored as per protocol. However, there was a rise of serum creatinine (ΔCr25) by >25% from baseline after 72 hours of administration of HD-MTX (38–51 µmol/L). ΔCr25 being a surrogate marker of MTX toxicities impelled us to give four extra doses of leucovorin and extra hydration for 24 hours.

He was noted to have progressive rise in aspartate transaminase (AST) and alanine transaminase (ALT) immediately following HD-MTX, which peaked on day 5 and normalised by day 10 post HD-MTX. In sharp contrast, he had deepening icterus (figure 1) and rise of serum bilirubin starting from day 6, peaking at day 18 and normalising after 7 weeks post HD-MTX. Serum alkaline phosphatase was normal throughout. The ALT/ALP ratio was >5 during day 4 to day 8 postexposure of HD-MTX indicating hepatocellular DILI (figure 2). He also developed fever on day 5 postHD-MTX with grade 3 mucositis. Grade 4 hepatotoxicity has been labelled in index child solely on the basis of CTCAE laboratory criteria. He did not have any CTCAE clinical criteria for signs of fulminant hepatic failure in form of bleed or features of encephalopathy.

Investigations

The investigations during hepatotoxicity in index child are as depicted in table 1.

Differential diagnosis

For grade 4, hepatotoxicity differential diagnoses considered were sepsis-induced hepatitis, viral hepatitis, viral reactivation post-Rituximab and DILI. After negative viral markers, undetectable viral load for HBV and HCV, multiple negative blood cultures, urine and sputum cultures, no organ dysfunction except liver and no apparent focus of infection in contrast enhanced computerized tomography (CECT) scan chest and ultrasound abdomen; DILI was considered the most likely cause of hepatotoxicity.

Treatment

During hyperbilirubinaemia, child was managed with supportive therapy with mega doses of fat soluble vitamins and oral Urso-deoxy cholic acid. He was managed for febrile neutropenia as per protocol with broad spectrum antibiotics and antifungals for 2 weeks duration. Mucositis was managed with analgesics and oral care. He did not require fresh frozen plasma or albumin for liver dysfunction.

Outcome and follow-up

With supportive therapy, transaminitis normalised by day 10 post HD-MTX and serum bilirubin normalised by D+55 post HD-MTX. He had lost 8 kg of weight during this period. He was rechallenged with next intensive course of chemotherapy (COPADM-II), which was exactly similar to COPADM-I. However, doses of HD-MTX were reduced to two-third in view of the malnourishment and previous DILI. He tolerated COPADM-II well and did not have recurrence of any of the previous complications. He is now gradually gaining weight and has completed the third intensive course of chemotherapy.