Nation-wide randomized comparative study of doxorubicin, vincristine and prednisolone combination therapy with and without L-asparaginase for adult acute lymphoblastic leukemia

Abstract

A randomized clinical trial of combination chemotherapy for adult acute lymphoblastic leukemia (ALL) with doxorubicin, vincristine and prednisolone with and without L-asparaginase (AdVP vs L-AdVP) was conducted, involving 58 institutions throughout Japan. After reaching complete remission (CR), patients were treated with the same regimen for more than 2 years. Among 166 evaluable cases of the 198 cases enrolled, CR rates were 63.1% (53/84) with AdVP and 64.6% (53/82) with L-AdVP (P = 0.837). Median survival times and 7-year survival rates were 12.7 months and 21.2% with AdVP, and 16.0 months and 22.3% with L-AdVP (P = 0.955 by generalized Wilcoxon test [GW], P = 0.952 by log-rank test [LR]). Median disease-free survival times and 7-year survival rates were 13.5 months and 23.8% with AdVP and 17.0 months and 30.6% with L-AdVP, showing some increments for L-AdVP but no statistical significance (P = 0.141 by GW, P = 0.300 by LR). Among the cases of extramurally confirmed FAB subtypes, CR rates were 75.9% (63/83) for the L1 subtype and 51.3% (39/76) for the L2 subtype (P = 0.001). As to adverse effects, pancreatitis was complicated more frequently in L-AdVP than in AdVP (P = 0.039). Other side effects such as hyperbilirubinemia, diabetes mellitus, diarrhea and hypofibrinogenemia were observed more frequently with L-AdVP, but with no statistical significance. Thus, addition of a single course of L-asparaginase in the induction phase of combination chemotherapy with doxorubicin, vincristine and prednisolone did not significantly enhance the effect of antileukemic treatment of adult ALL.

Incidence of asparaginase-related hepatotoxicity, pancreatitis, and thrombotic events in adults with acute lymphoblastic leukemia treated with a pediatric-inspired regimen

“…A wide range of rates of toxicities associated with PEG-ASP have been published. 5,6,17–20 A historical cohort of patients from University of Southern California, Cleveland Clinic, and MD Anderson Cancer Center receiving PEG-ASP (median age: 33 years, range: 17–68) demonstrates that the rates of toxicity reported in the literature were much lower than we observed. These authors report 36% hepatotoxicity, 5% pancreatitis, and 8% thrombosis (all grades 3–4) in a cohort of 76 adult patients.…”

Acute lymphoblastic leukemia: a comprehensive review and 2017 update

“…The role of L-asparaginase, while standard in pediatric protocols, is a challenge in adults at times due to the increased rate of adverse events. 41 In fact, in the UKALL 14 Trial, Patel et al 42, 43 demonstrated that asparaginase toxicity was the leading cause of induction-related mortality and the protocol was amended to omit asparaginase for patients over the age of 40. The MRC UKALL XII/ECOG 2993 23 regimen utilizes a similar structure to CALGB 8811.…”

Recent approaches in acute lymphoblastic leukemia in adults

“…Only one randomized trial (47) has analyzed the role of l‐asparaginase in induction therapy. No effect on CR rate was found, but L ‐asparaginase may have contributed to a longer remission duration.…”