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.

Adult acute lymphoblastic leukaemia

“…Indeed, four/five-drug regimens were associated with response rates >80% in several uncontrolled studies [244,279,287]. Induction programs of this kind (German multicentre ALL/GMALL phase 1, CALGB, MDACC) [244,279,288] can currently be regarded as appropriate for clinical use on a type 3 level of evidence for patients at low risk (see Section 5.5) and standard treatment on a type R basis for patients at intermediate and high risk (see Section 5.5) [141,242,244,265,269,279,283,[288][289][290]. With these regimens, remission should be achieved in at least 75% of patients at intermediate risk (see Section 5.5) and in almost 90% of patients with low risk (see Section 5.5).…”

“…Subsequent trials have addressed the role of a fourth, fifth or sixth drug in this phase, namely l-asparaginase, cyclophosphamide, cytarabine (high dose), etoposide, topotecan [242,244,[269][270][271][272][273][274][275][276][277][278][279][280][281][282][283]. Despite superimposable remission rates between study and control, cyclophosphamide and l-asparaginase are commonly included in remission schedules, since they are believed to increase the quality of remissions, if not their number, or at least affect outcome in some subgroups with a poorer prognosis.…”

Changes in antithrombin and fibrinogen levels during induction chemotherapy with L-asparaginase in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma. Use of supportive coagulation therapy and clinical outcome: the CAPELAL study

“…3,4 This drug induces a relative asparagine deficiency that leads to the death of human lymphoblasts. L-asparaginase has, however, also been shown to be toxic to the liver, pancreas, central nervous system (CNS) and kidneys, particularly when derived from E. coli.…”

Autologous stem cell transplantation in adults with acute lymphoblastic leukemia in first complete remission: analysis of the LALA-85, -87 and -94 trials

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] Riskadapted strategies based on initial prognostic grouping are currently applied in these patients. Intensive strategies, including allogeneic and autologous stem cell transplantation (SCT), are generally offered to high-risk patients after achievement of the first CR.…”