Profound Hyperbilirubinemia during Induction of Adult Acute Lymphoblastic Leukemia: Capping L-Asparaginase Dose to 10,000 Units Attenuates It without Compromising Remission Rate.

Introduction: Hyperbilirubinemia is a well known side-effect of L-asparaginase. Grade 4 hyperbilirubinemia (bilirubin > 3) results in delayed chemotherapy; compromising dose intensity. Hence a strategy to prevent this is important.

Materials & Methods: At our center, we see around 125 cases of newly diagnosed adult acute lymphoblastic leukemia (age>24 years) every year. Since 2005, we have started treating these adult patients on modified BFM 90 protocol. This protocol includes 8 doses of L-asparaginase at 10,000 units/m2 during induction. Hyperbilirubinemia of grade 4 (median bilirubin upto 20) was encountered in the first few patients. To avoid delay in chemotherapy, we modified the protocol to cap L-asparaginase dose at 10,000 u for all patients.

Results: A total of 64 patients with ALL was treated on this modified protocol in 18 months. We compared the degree of hyperbilirubinemia in this group of patients with the first 20 patients who were treated with the standard dose of L-asparaginase. Median age of the full cohort (All 84 patients) was 34 years (24–60). Fifty four patients had precursor B-cell ALL while 30 patients had T-cell ALL. Male: Female ratio was 4.1:1. All the analysed patients have completed induction. In first group of 20 patients who had received standard dose of L-asparaginase, 6 patients developed grade 4 hyperbilirubinemia (median bilirubin 23). SGPT, SGOT and SAP were either normal or borderline elevated. Viral markers at diagnosis and at the onset of hyperbilirubinemia were negative. No significant hepatic abnormality was seen on USG abdomen. In four out of 6 patients’ bilirubin returned to normal after conservative management, over a period of 3 weeks. The two remaining patients developed sepsis, had deranged coagulation parameters and succumbed to sepsis. Of the second group of 64 patients ( L-asparaginase at 10,000 fixed dose), 5 patients developed hyperbilirubinemia (highest value of bilirubin 4). All other investigations (listed above) were normal.All patients’ bilirubin came back to normal within 1 week of interruption of chemotherapy. Complete remission rates were 90% in the first group of 20 patients and 92% in the second group of 64 patients.

Conclusion: In the cohort of 64 patients (second group), capping of L-asparaginase resulted in significant reduction in intensity, incidence and duration of hyperbilirubinemia. This modification did not affect CR rate, though we are currently evaluating long term survival to confirm sustained efficacy.