Prolonged versus standard native E. coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951

Abstract

Asparaginase is an essential component of combination chemotherapy for childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma. The value of asparaginase was further addressed in a group of non-very high-risk patients by comparing prolonged (long-asparaginase) versus standard (short-asparaginase) native E. coli asparaginase treatment in a randomized part of the phase III 58951 trial of the European Organization for Research and Treatment of Cancer Children’s Leukemia Group. The main endpoint was disease-free survival. Overall, 1,552 patients were randomly assigned to long-asparaginase (775 patients) or short-asparaginase (777 patients). Patients with grade ≥2 allergy to native E. coli asparaginase were switched to equivalent doses of Erwinia or pegylated E. coli asparaginase. The 8-year disease-free survival rate (±standard error) was 87.0±1.3% in the long-asparaginase group and 84.4±1.4% in the short-asparaginase group (hazard ratio: 0.87; P=0.33) and the 8-year overall survival rate was 92.6±1.0% and 91.3±1.2% respectively (hazard ratio: 0.89; P=0.53). An exploratory analysis suggested that the impact of long-asparaginase was beneficial in the National Cancer Institute standard-risk group with regards to disease-free survival (hazard ratio: 0.70; P=0.057), but far less so with regards to overall survival (hazard ratio: 0.89). The incidences of grade 3–4 infection during consolidation (25.2% versus 14.4%) and late intensification (22.6% versus 15.9%) and the incidence of grade 2–4 allergy were higher in the long-asparaginase arm (30% versus 21%). Prolonged native E. coli asparaginase therapy in consolidation and late intensification for our non-very high-risk patients did not improve overall outcome but led to an increase in infections and allergy. This trial was registered at www.clinicaltrials.gov as #NCT00003728.

Results of successive EORTC‐CLG 58 881 and 58 951 trials in paediatric T‐cell acute lymphoblastic leukaemia (ALL)

“…Importantly, trial 58951 showed that prolongation of native E. coli asparaginase therapy in consolidation and late intensification did not result in an additional gain in outcome. On the contrary, prolonged asparaginase treatment can lead to an increased risk of infections and allergy (Mondelaers et al, 2017). Noteworthy, supportive care changes over time which may also impact outcome results of successive trials.…”

“…Both trials investigated three questions in a randomized manner. These were, in trial 58881: (i) Medac Escherichia coli asparaginase versus Erwinia asparaginase (Duval et al, 2002), (ii) addition of high-dose IV cytarabine (HD IV Ara-C) during postinduction-consolidation therapy in increased-risk patients (Millot et al, 2001), and (iii) addition of monthly IV 6-mercaptopurine (IV 6-MP) to conventional continuation therapy (van der Werff Ten Bosch et al, 2005), and, in trial 58951: (i) dexamethasone versus prednisolone during induction and maintenance (Domenech et al, 2014), (ii) increasing the number of administrations of asparaginase during consolidation and late intensification (Mondelaers et al, 2017), (iii) vincristine + corticosteroid pulses or no pulses during continuation treatment (De Moerloose et al, 2010). From 1989From to 1998From and from 1998From to 2008 18 years of age with previously untreated ALL or lymphoblastic NHL were included in two successive EORTC-CLG trials, trial 58881 and 58951, respectively.…”

“…However, this meta‐analysis was hampered by limited sample sizes in the included studies, so caution needs to be applied (Kelly et al , ). At present, the administration of CRT for T‐ALL varies across international paediatric oncology groups, with some protocols including (low‐dose) CRT for all patients and some including CRT for a subset of patients, while other protocols omit CRT entirely (Moghrabi et al , ; Kamps et al , ; Moricke et al , ; Pui et al , ; Schrappe et al , ; Mondelaers et al , ). In addition, no improved survival in children with B‐ALL could be demonstrated with administration of CRT (Clarke et al , ; Richards et al , ; Vora et al , ).…”

Pediatric randomized trial EORTC CLG 58951: Outcome for adolescent population with acute lymphoblastic leukemia

“…The treatment scheme (Figure 1 25 The second assessed the value of prolonged courses of asparaginase throughout consolidation and late intensification for non-VHR patients. 26 The third question evaluated the advantage of six vincristine-corticosteroid pulses added to continuation therapy for AR patients in CR at the end of the late intensification. 27 All VHR patients were eligible for allogeneic hematopoietic stem cell transplantation (a-HSCT) if they had an HLA (Human Leukocyte Antigen) identical donor.…”

Asparaginase: an old drug with new questions

“… 10 Hypersensitivity reactions are more likely to appear with increasing numbers of administrations within the same cycle but may appear in discontinuous administration regimens. 27 These reactions are more common in the first doses of asparaginase and after a break in treatment. The risk of antibody formation increases with repeated exposure to ASNase, especially in the consolidation and re-induction phases of the treatment.…”