Rasburicase in the prevention of laboratory/clinical tumour lysis syndrome in children with advanced mature B-NHL: a Children's Oncology Group Report

Abstract

Laboratory (LTLS) and clinical (CTLS) tumour lysis syndrome (TLS) are frequent complications in newly diagnosed children with advanced mature B cell non-Hodgkin lymphoma (B-NHL). Rasburicase, compared to allopurinol, results in more rapid reduction of uric acid in paediatric patients at risk for TLS. However, the safety and efficacy of rasburicase for the treatment or or prevention of TLS has not been prospectively evaluated. Children with newly diagnosed stage III-IV, bone marrow(+) and/or central nervous system(+) mature B-NHL received hydration and rasburicase prior to cytoreductive therapy. Rasburicase was safe and well-tolerated and there were no grade III-IV toxicities probably or directly related to rasburicase. Patients with an initial lactate dehydrogenase ≥2× upper limit of normal had a significantly elevated uric acid level (P = 0·005), increased incidence of TLS (P-0·005) and lower glomerular filtration rate (GFR; P < 0·001). Following rasburicase, there was only a 9% and 5% incidence of LTLS and CTLS, respectively. Furthermore, there was a significant improvement in estimated GFR from Day 0 to Day 7 following rasburicase (P = 0·0007) and only 1·3% of patients required new onset renal assisted support after rasburicase administration. A TLS strategy incorporating rasburicase prior to cytoreductive chemotherapy proved safe and effective in preventing new onset renal failure and was associated with a significant improvement in GFR.

Keywords: Burkitt lymphoma; Rasburicase; diffuse large B-cell lymphoma; paediatric; tumour lysis syndrome.

Figure 1. Patient characteristics

A. Numbers of patients in each treatment group stratified by normal lactate dehydrogenase (NL LDH; < 2x upper limit of normal [ULN]) or high LDH (HI LDH; > 2x ULN) initial LDH levels. B. Incidence of increased LDH by treatment group. C. Incidence of Group C treatment group stratified by bone marrow only [B-ALL (CNS−)], central nervous system (CNS) only and combined [B-ALL (CNS+)].

Figure 2. Incidence and magnitude of hyperuricaemia

A. Mean ± standard error of the mean (SEM) uric acid (UA) levels at initial measurement in each treatment group. B. Mean ± SEM initial UA values and associated initial lactate dehydrogenase (LDH) values. LDH <2x upper limit of normal (ULN) vs. LDH ≥2x ULN, p = 0.005 (unpaired t test). C. Incidence of hyperuricaemia in each treatment group. D. Incidence of hyperuricaemia associated with initial LDH values. LDH <2x ULN vs. LDH ≥2x ULN, p = 0.02 (Fisher’s exact test). E. Time course of UA level decline for all 29 episodes of hyperuricaemia in 25 patients. Time 0 represents the time of peak UA. The dashed line represents a level of 475.8 μmol/l – the cut-off point for hyperuricaemia. F. Percentage of episodes of hyperuricaemia that resolve within 24, 48, or 72 h after rasburicase administration.

Figure 3. Incidence of tumour lysis syndrome in all analysis groups

A. Incidence of laboratory tumour lysis syndrome (LTLS) and clinical tumour lysis syndrome (CTLS) associated with initial lactate dehydrogenase (LDH) values. LDH <2x upper limit of normal (ULN)vs. LDH ≥2x ULN, p = 0.005 (Fisher’s exact test). B. Incidence LTLS or CTLS by treatment group and LDH values. C. Incidence of LTLS, or CTLS at any time prior to the initiation or following chemotherapy (COP-R; cyclophosphamide, vincristine, prednisone, rituximab).

Figure 4. Incidence and time course of renal impairment

A. Mean estimated glomerular filtration rate (GFR) at initial presentation in those with normal or elevated lactate dehydrogenase (LDH). The horizontal line represents the mean, the box represents the 25^th–75^th percentile, and the bars represent the minimum and maximum values. LDH <2x upper limit of normal (ULN) vs. LDH ≥2x ULN, p < 0.0001 (unpaired t test). B. Mean estimated GFR at initial presentation in all analysis groups. P value calculated with the unpaired t test. Group B LDH <2x ULN vs. LDH ≥2x ULN, p < 0.002 (unpaired t test). Group C LDH <2x ULN vs. LDH ≥2x ULN, p < 0.015 (unpaired t test). C. Mean estimated GFR at initial presentation in those with normal or elevated uric acid (UA). UA <475.8 μmol/l vs. ≥475.8 μmol/l p = 0.0003. D. Mean estimated GFR for patients with initial GFR < 60 ml/min/1.73m² over the observation period. The box and whiskers are defined as in (a). The dashed line represents a GFR of 60 ml/min/1.73m². P = 0.0007 (unpaired t test) comparing day −1 to day 7. E. Daily estimated GFR for individual patients with renal impairment any time before COP-R (cyclophosphamide, vincristine, prednisone, rituximab). The dashed line indicates 60 ml/min/1.73m².