Comparison of Efficacy and Safety of Two Types of E.coli Asparaginase (Native or Pegylated) for Treatment of Adult Patients with High-Risk (HR), Philadelphia (Ph) Chromosome-Negative ALL Included in the Prospective MRD-Oriented Protocol ALL-HR-11 from the Spanish Pethema Group

Background and objective. Asparaginase (ASP) is an essential drug for ALL treatment. Two types of E.coli ASP (native and pegylated) are used in clinical trials for treatment of children and adults with ALL, but to our knowledge direct comparison between these two types of ASP in the same protocol has not been performed. This study aimed to compare the efficacy and safety of native vs. PEG-ASP in adult patients with HR, Ph-negative ALL.

Patients and methods. HR ALL included one or more of the following parameters at baseline: age 30-60 yr., WBC count >30x10⁹/L for B-cell precursor ALL or >100x10⁹/L for thymic T-ALL, pro-B, early or mature T-ALL, 11q23 or MLL rearrangements or complex karyotype. Induction therapy consisted of vincristine, prednisone, daunorubicin and ASP (native 10,000 IU/m², i.v., days 16-20 and 23-27 or PEG 2,000 IU/m², iv, day 15 depending on center decision) for 4 weeks (Induction-1). FLAG-Ida was administered as intensified induction (Induction-2) in patients not achieving CR or in those in CR with MRD≥0.1% at the end of induction, and those patients proceeded to allogeneic HSCT if CR was attained. Patients in CR and MRD<0.1% proceeded to early consolidation therapy including 3 cycles with rotating cytotoxic drugs with high-dose methotrexate, high-dose ARA-C and ASP (native 20,000 IU/m² on day 3 of each cycle or PEG 2,000 IU/m² on day 3 of each cycle). Patients continued with delayed consolidation (identical to that of early consolidation) followed by maintenance therapy up to 2 yr. in continuous CR if MRD levels after consolidation were <0.01%, otherwise they were assigned to allogeneic HSCT. The cumulated doses of native ASP and PEG-ASP for patients who completed the induction and early+delayed consolidation were 220,000 IU/m² and 14,000 IU/m², respectively. No ASP levels were assessed.

Results. Ninety-onepatients received native ASP and 35 PEG-ASP in Induction-1. The two groups of patients were comparable for the main clinical and hematologic ALL parameters. No differences were observed in the CR rate (86% vs. 86%), in the frequency of MRD level <0.1% after Induction-1 (63% vs. 70%), and that of MRD level <0.01% after early consolidation (74% vs. 92%, p=0.19), as well as in the proportion of patients submitted to allogeneic HSCT (20% vs. 14%). No differences were found in overall survival or disease-free survival probabilities at 3-years according to the type of ASP (OS: 60% [95%CI: 47% ; 73%] vs. 57%[95%CI: 36% ; 78%], p=0.872 and DFS: 40% [95%CI: 25% ; 55%] vs. 58% [95%CI: 36% ; 80%], p=0.302). Abnormalities in the coagulation parameters were significantly more frequent in patients receiving PEG-ASP in Induction-1 (18% vs. 35%, p=0.045). These abnormalities, together with hepatic toxicity were significantly more frequent in patients receiving PEG-ASP in early consolidation (1% vs. 13%, p=0.003, and 5% vs. 34, p<0.001, respectively). A trend for more allergic reactions was seen in patients receiving native ASP (18% vs. 5%, p=0.1) No differences in the frequency of ASP discontinuation rate were observed (6 % vs. 3%).

Conclusions. In HR, Ph-negative adult ALL patients included in the PETHEMA ALL-HR 11 protocol the type of E.coli ASP (native vs. PEG) did not have impact on response and outcome. Allergic reactions were more frequently seen with native ASP and coagulation abnormalities and hepatic toxicity were most frequent with PEG-ASP. Most of the differences in toxicity can be explained by the schedule of ASP given in consolidation (single dose of native ASP vs. single dose of PEG-ASP in each cycle).

Supported in part by grants RD12/0036/0029 (RTICC, FEDER), PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain