Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial

B Patel, A A Kirkwood, A Dey, D I Marks, A K McMillan, T F Menne, L Micklewright, P Patrick, S Purnell, C J Rowntree, P Smith, A K Fielding, B Patel, A A Kirkwood, A Dey, D I Marks, A K McMillan, T F Menne, L Micklewright, P Patrick, S Purnell, C J Rowntree, P Smith, A K Fielding

Abstract

Safety and efficacy data on pegylated asparaginase (PEG-ASP) in adult acute lymphoblastic leukaemia (ALL) induction regimens are limited. The UK National Cancer Research Institute UKALL14 trial NCT01085617 prospectively evaluated the tolerability of 1000 IU/m2 PEG-ASP administered on days 4 and 18 as part of a five-drug induction regimen in adults aged 25-65 years with de novo ALL. Median age was 46.5 years. Sixteen of the 90 patients (median age 56 years) suffered treatment-related mortality during initial induction therapy. Eight of the 16 died of sepsis in combination with hepatotoxicity. Age and Philadelphia (Ph) status were independent variables predicting induction death >40 versus ⩽40 years, odds ratio (OR) 18.5 (2.02-169.0), P=0.01; Ph- versus Ph+ disease, OR 13.60 (3.52-52.36), P<0.001. Of the 74 patients who did not die, 37 (50.0%) experienced at least one grade 3/4 PEG-ASP-related adverse event, most commonly hepatotoxicity (36.5%, n=27). A single dose of PEG-ASP achieved trough therapeutic enzyme levels in 42/49 (86%) of the patients tested. Although PEG-ASP delivered prolonged asparaginase activity in adults, it was difficult to administer safely as part of the UKALL14 intensive multiagent regimen to those aged >40 years. It proved extremely toxic in patients with Ph+ ALL, possibly owing to interaction with imatinib.

Conflict of interest statement

Fielding received lab funding from Medac GmBH to carry out part of this work and that company were the supplier of PEG-ASP at the time of this work. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic of UKALL14 treatment protocol. High risk features: karyotypes: t(9;22) t(4;11), low hypodiploidy near triploidy or complex, age >40 years, WBC ⩾30 × 109/l (precursor B lineage ALL), ⩾100 × 109/l (T-cell-ALL), molecular minimal residual disease positivity (>1 × 10−4) after induction phase 2.
Figure 2
Figure 2
Flow chart of progress of the 91 patients enrolled. Grade 4 sepsis n=4, grade IV organ toxicity n=4 (hepatotoxicity n=1, pancreatitis n=1, hepatotoxicity plus neurological event n=1, hepatotoxicity plus thromboembolism together with sepsis n=1 and wrong diagnosis n=1, withdrawal of consent, n=1.

References

    1. Sallan SE, Hitchcock-Bryan S, Gelber R, Cassady JR, Frei E 3rd, Nathan DG. Influence of intensive asparaginase in the treatment of childhood non-T-cell acute lymphoblastic leukemia. Cancer Res 1983; 43: 5601–5607.
    1. Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ et al. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 2002; 99: 1986–1994.
    1. Seibel NL. Treatment of acute lymphoblastic leukemia in children and adolescents: peaks and pitfalls. Hematology Am Soc Hematol Educ Program 2008, 374–380.
    1. Avramis VI, Spence SA. Clinical pharmacology of asparaginases in the United States: asparaginase population pharmacokinetic and pharmacodynamic (PK-PD) models (NONMEM) in adult and pediatric ALL patients. J Pediatr Hematol Oncol 2007; 29: 239–247.
    1. Kurtzberg J, Asselin B, Bernstein M, Buchanan GR, Pollock BH, Camitta BM. Polyethylene glycol-conjugated L-asparaginase versus native L-asparaginase in combination with standard agents for children with acute lymphoblastic leukemia in second bone marrow relapse: a Children's Oncology Group Study (POG 8866). J Pediatr Hematol Oncol 2011; 33: 610–616.
    1. 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: 7161–7167.
    1. Asselin BL, Whitin JC, Coppola DJ, Rupp IP, Sallan SE, Cohen HJ. Comparative pharmacokinetic studies of three asparaginase preparations. J Clin Oncol 1993; 11: 1780–1786.
    1. Douer D. Is asparaginase a critical component in the treatment of acute lymphoblastic leukemia? Best Pract Res Clin Haematol 2008; 21: 647–658.
    1. Douer D, Yampolsky H, Cohen LJ, Watkins K, Levine AM, Periclou AP et al. Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia. Blood 2007; 109: 2744–2750.
    1. Stock W, Douer D, Deangelo DJ, Arellano M, Advani A, Damon L et al. Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma 2011; 52: 2237–2253.
    1. Wetzler M, Sanford BL, Kurtzberg J, Deoliveira D, Frankel SR, Powell BL et al. Effective asparagine depletion with pegylated asparaginase results in improved outcomes in adult acute lymphoblastic leukemia — Cancer and Leukemia Group B Study 9511. Blood 2007; 109: 4164–4167.
    1. Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005; 106: 3760–3767.
    1. Fabry U, Korholz D, Jurgens H, Gobel U, Wahn V. Anaphylaxis to L-asparaginase during treatment for acute lymphoblastic leukemia in children—evidence of a complement-mediated mechanism. Pediatr Res 1985; 19: 400–408.
    1. DeAngelo DJ, Stevenson KE, Dahlberg SE, Silverman LB, Couban S, Supko JG et al. Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia. Leukemia 2015; 29: 526–534.
    1. Boissel N, Auclerc MF, Lheritier V, Perel Y, Thomas X, Leblanc T et al. Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol 2003; 21: 774–780.
    1. de Bont JM, Holt B, Dekker AW, van der Does-van den Berg A, Sonneveld P, Pieters R. Significant difference in outcome for adolescents with acute lymphoblastic leukemia treated on pediatric vs adult protocols in the Netherlands. Leukemia 2004; 18: 2032–2035.
    1. Ramanujachar R, Richards S, Hann I, Goldstone A, Mitchell C, Vora A et al. Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer 2007; 48: 254–261.
    1. Stock W, La M, Sanford B, Bloomfield C, Vardiman J, Gaynon P et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies. Blood 2008; 112: 1646–1654.
    1. Sive JI, Buck G, Fielding A, Lazarus HM, Litzow MR, Luger S et al. Outcomes in older adults with acute lymphoblastic leukaemia (ALL): results from the international MRC UKALL XII/ECOG2993 trial. Br J Haematol 2012; 157: 463–471.
    1. Douer D, Aldoss I, Lunning MA, Burke PW, Ramezani L, Mark L et al. Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia. J Clin Oncol 2014; 32: 905–911.
    1. Goekbuget N. PEG-asparaginase intensification in adult acute lymphoblastic leukemia (ALL): significant improvement of outcome with moderate increase of liver toxicity in the German Multicenter Study Group for Adult ALL (GMALL) Study 07/2003. ASH Annu Meeting Abstr 2010; 116: 494.
    1. Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 2009; 27: 911–918.
    1. Vignetti M, Fazi P, Cimino G, Martinelli G, Di Raimondo F, Ferrara F et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol. Blood 2007; 109: 3676–3678.
    1. Foa R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris MS et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2011; 118: 6521–6528.

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