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

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.

Use of PEG-asparaginase in newly diagnosed adults with standard-risk acute lymphoblastic leukemia compared with E. coli-asparaginase: a retrospective single-center study

“…Other side effects, such as thrombosis, pancreatitis, hyperglycemia, hepatotoxicity, and abnormalities of lipid metabolism, also contribute to the limitations121718. Compared with E. coli -asparaginase, PEG-asparaginase produces prolonged depletion of asparagine and is associated with reduced incidence of certain toxicities (i.e., hypersensitivity reactions), thereby making it preferable for use in ALL treatment192021.…”

Toward the potential cure of leukemias in the next decade

“…Recent progress in adult ALL therapy can be attributed to several things, including 1) the implementation of the pediatric regimens in adolescents and young adults up to ages 30 to 40 years (these regimens rely on asparaginase-vincristine-steroids (intensification of nonmyelosuppressive agents [98][99][100] ; however, asparaginase is associated with serious toxicities [liver dysfunction, thrombosis, pancreatitis, disseminated intravascular coagulopathy, hip necrosis], which may not be well tolerated among patients aged ≥40 years) 101 ; 2) the incorporation of BCR-ABL1 TKIs into combination regimens in Ph-positive ALL; 3) the incorporation of rituximab into chemotherapy regimens in CD20-positive ALL; 4) the recent discovery of the high activity of conjugated monoclonal antibodies targeting CD22 (inotuzumab ozogamicin, which is bound to calicheamicin) and of bispecific antibody constructs targeting CD19 (blinatumomab, which targets CD3-CD19); and 5) the discovery of the high activity of CD19 chimeric antigen receptor T (CAR-T) cellular therapy in ALL salvage.…”

Exposure-adjusted adverse events comparing blinatumomab with chemotherapy in advanced acute lymphoblastic leukemia

“…15,16,21 Infection has been a clinical challenge in treating patients with r/r ALL and is a common cause of morbidity and mortality with SOC. [11][12][13] There was a notable difference in the EAERs for grade $3 infections between blinatumomab and SOC (1.63 vs 6.49 events per patient-year), which corresponded to a lower EAER of fatal AEs for blinatumomab compared with SOC (0.57 vs 1.28 events per patient-year, respectively). In addition, the rate of infections decreased from .50% during induction to ;40% during blinatumomab maintenance therapy, which corresponded to a similar decrease in cytopenias from .50% to ;11%.…”

“…2,10 Because of the myelosuppressive nature of some regimens and the underlying disease, patients are susceptible to serious and sometimes fatal infections. [11][12][13] Thus, prolonged therapy with multiagent chemotherapy for patients with r/r ALL remains a clinical challenge due to the potential for cumulative toxicity.…”