Statistically Significant Differences In Toxicities Between L- and PEG Asparaginase In Adult Patients with Acute Lymphoblastic Leukemia

The use of asparaginase (ASP) in treatment regimens for adult acute lymphoblastic leukemia (ALL) patients (pts) is a challenge due to its toxicity profile. Adverse events associated with ASP use include hypersensitivity reactions, coagulation disorders, hepatotoxicity, pancreatitis and hyperglycemia. Life-threatening complications compromise completion of treatment, and even pt suitability for bone marrow transplantation if required. We report our single institution experience with ASP acute toxicities in adult pts diagnosed with ALL.

From 1993–2007, 135 pts (median age 38 years; range 18–76) were treated with ASP as part of their ALL directed regimen, of which 84 (62%) and 51 (38%) received L and Peg-ASP, respectively. Approximately 794 and 51 doses of L- and Peg-ASP were given, respectively. Acute toxicities were graded according to CTCAE version 3.0 at pre, peak (7d) and post (14d) ASP treatment. Grade 1 (G1) through grade 4 (G4) toxicities were evaluated during both induction and intensification. For each patient, the number and proportion of all toxicities (G1-G4) were calculated.

There was a higher frequency of toxicities with L- compared to Peg-ASP after controlling for age and gender. The average proportion of G2-G4 toxicities was 25% for L-ASP pts compared to 13% for Peg-ASP (p < 0.001). G3 toxicities were seen in 78% (65/82) of pts receiving L-ASP and 50% (26/52) with Peg-ASP (p=0.02), and G4 toxicities were seen in 23% (19/83) and 8% (4/52) of L-ASP and Peg-ASP pts, respectively (p=0.07). Additionally, a greater proportion of L-ASP vs Peg-ASP pts (42% v 3%) had elevation of liver function test (ALT) at the post-induction time point (p < 0.001). Similar results were seen for AST, Alk phos and glucose levels (all p values < 0.05). Decreased fibrinogen levels were also seen more frequently in patients receiving L-ASP (57%) vs Peg-ASP (30%) patients (NS).

The proportion of laboratory measurements that were G2 toxicity or higher increased with age for L-ASP (0.2% per year, p=0.05) but not Peg-ASP pts (0.06% per year, p=0.55). However, when adjusting for dose agent, the proportion of G2-G4 toxicities was 0.14% higher with each increasing year of age (p=0.05). Furthermore, males also had a greater proportion of G2-G4 toxicities since there was a 4.4% lower rate of toxicities reported for females as compared to males (p=0.05).

Notably, higher grade toxicities were seen in pts with increasing age with either L- or Peg-ASP. The median ages for L-ASP pts with a G2, G3 and G4 were 40.5, 41 and 55 years. The median age for those pts who received L-ASP and experienced a G4 toxicity vs those pts who received L and had no G4 toxicities was 55 years old vs 39 (p=0.018). The median ages for Peg-ASP pts with G2, G3, and G4 toxicities were 32, 34 and 57 years respectively. With both L- and Peg-ASP groups combined, the median age for those pts having a G3 toxicity vs those pts without any G3 toxicities was 40 vs 32 years (p=0.012) and for G4 toxicity was 55 vs 36 years (p=0.001).

In adult ALL pts who receive ASP, therapy with L-ASP was associated with (1) increased liver function tests including ALT, AST and alk phos as well as a trend for lower fibrinogen levels post induction therapy and (2) a higher likelihood of G4 toxicities as compared to therapy with Peg-ASP. Regardless of the dosing agent, higher grade toxicities were seen in pts with increasing age, although this was most notable in patients who received L-ASP. Male pts receiving ASP were also more likely to suffer from G2 or higher toxicities as compared to female pts. The use of either L- or Peg ASP should be closely monitored in adult patients with ALL and if toxicities arise, it is likely that the older patients will suffer from higher grade toxicities.

No relevant conflicts of interest to declare.