Effect of Dose and Schedule of L-Asparaginase Administration on Early Minimal Residual Disease in Acute Lymphoblastic Leukemia

Abstract

Background and Objectives: L-asparaginase has become the backbone of acute lymphoblastic leukemia induction. In Berlin–Frankfurt–Munster (BFM) 95/2000 protocols, L-asparaginase was given twice weekly for initial 4 weeks. While sufficient L-asparaginase levels are important, there is no apparent correlation between high L-asparaginase levels and minimal residual disease (MRD). In view of toxicities of L-asparaginase, we planned to study the effect of dose and schedule of Escherichia coli-derived L-asparaginase on early MRD by phasing the same total dose, once a week over 8 weeks. Methods: This prospective, observational study enrolled 45 children and young adults ≤40 years. Modified BFM 95 protocol was followed. Weekly 5000 IU/m² L-asparaginase was given intravenously, and MRD was analyzed at the end of 4 weeks (MRD1) and at 8 weeks (MRD2), using multicolor flow cytometry. MRD positive was defined as residual blasts ≥0.01%. Results: Thirty-one patients were eligible for final analysis. Nine could receive scheduled eight doses of L-asparaginase and 22 patients received less than eight doses. We analyzed age, gender, diagnosis, prednisone response, cytogenetics, central nervous system status, BFM risk group, MRD2, and relapse. L-asparaginase dose association was not statistically significant with respect to MRD2 (P = 0.237). There were no cases of pancreatitis, hypersensitivity, bleeding, or thrombosis. Reasons for patients receiving less than the scheduled eight doses were low serum fibrinogen levels and liver dysfunction. This study revealed 8 MRD1-negative and 13 MRD2-negative patients. Conclusion: L-asparaginase dose intensity does not affect early MRD. Phasing L-asparaginase over 8 weeks could lead to the achievement of more MRD2-negative status and thereby improve long-term outcome. This strategy may also reduce the incidence of adverse drug events.

Keywords

Acute lymphoblastic leukemia - Berlin–Frankfurt–Munster - flow cytometry - L-asparaginase - minimal residual disease

Publication History

Received: 05 May 2018

Accepted: 21 June 2018

Article published online:
03 June 2021

• References

• 1 Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet 2013; 381: 1943-55
• 2 Campana D. Minimal residual disease in acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2010; 2010: 7-12
• 3 Bartram CR, Schrauder A, Köhler R, Schrappe M. Acute lymphoblastic leukemia in children: Treatment planning via minimal residual disease assessment. Dtsch Arztebl Int 2012; 109: 652-8
• 4 Piatkowska-Jakubas B, Krawczyk-Kuliś M, Giebel S, Adamczyk-Cioch M, Czyz A, Lech Marańda E. et al. Use of L-asparaginase in acute lymphoblastic leukemia: Recommendations of the polish adult leukemia group. Pol Arch Med Wewn 2008; 118: 664-9
• 5 Riccardi R, Holcenberg JS, Glaubiger DL, Wood JH, Poplack DG. L-asparaginase pharmacokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys and humans. Cancer Res 1981; 41: 4554-8
• 6 Schrey D, Borghorst S, Lanvers-Kaminsky C, Hempel G, Gerss J, Möricke A. et al. Therapeutic drug monitoring of asparaginase in the ALL-BFM 2000 protocol between 2000 and 2007. Pediatr Blood Cancer 2010; 54: 952-8
• 7 Nesbit ME, Ertel I, Hammond GD. L-asparaginase as a single agent in acute lymphocytic leukemia: Survey of studies form childrens cancer study group. Cancer Treat Rep 1981; 65 (04) Suppl 101-7
• 8 Chessells JM, Richards SM, Bailey CC, Lilleyman JS, Eden OB. Gender and treatment outcome in childhood lymphoblastic leukaemia: Report from the MRC UKALL trials. Br J Haematol 1995; 89: 364-72
• 9 Pession A, Valsecchi MG, Masera G, Kamps WA, Magyarosy E, Rizzari C. et al. Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia. J Clin Oncol 2005; 23: 7161-7
• 10 Stow P, Key L, Chen X, Pan Q, Neale GA, Coustan-Smith E. et al. Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood 2010; 115: 4657-63
• 11 Samra MA, Mahmoud HK, Abdelhamid TM, El Sharkawy NM, Elnahass YH, Elgammal M. et al. The prognostic significance of minimal residual disease in adult Egyptian patients with precursor acute lymphoblastic leukemia. J Egypt Natl Canc Inst 2013; 25: 135-42