Asparaginase-Associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia: A Ponte Di Legno Toxicity Working Group Report on Clinical Presentation and Outcome

Background: Asparaginase-associated pancreatitis (AAP) is a well-known and frequent toxicity of childhood acute lymphoblastic leukemia (ALL) therapy. Diagnostic criteria have varied among international ALL study groups, impairing international comparison of incidence, severity and complications, and limiting the knowledge on the risk of re-exposure to asparaginase.

Objectives and Methods: This questionnaire study reports AAP data from 19 collaborative groups on children (1.0-17.9 years) treated with ALL from 1/2000-4/2015. To define AAP, the Ponte di Legno toxicity working group (PTWG) consensus definition was used: At least two of i) amylase, pancreatic amylase, or pancreatic lipase >3x upper normal limit (UNL), ii) abdominal pain, iii) imaging compatible with AAP (Lancet Oncology, 2016; 6: 231-239). AAP was graded as mild or severe (persisting abdominal pain and pancreatic enzymes ≥3xUNL more than 72 hours after AAP diagnosis and/or pseudocyst, abscess, or hemorrhagic APP at imaging).

Results: Of 633 patients registered with AAP, 459 patients fulfilled the PTWG criteria for AAP; 96% had abdominal pain, 92% had a rise in at least one pancreatic enzyme >3xUNL, and 75% had imaging (72 MRI, 239 CT, 320 ultrasound) compatible with AAP. Of the remaining 174 patients, 29 had >35 days from injection of asparaginase to diagnosis of pancreatitis, 41 fulfilled only one diagnostic criteria, and 104 had insufficient data in the groups' registries. The median age was 8.3 years (75%-range: 4.2-13.3), 53% were male, and 80% had B-cell precursor ALL. At AAP diagnosis, 41% presented with fever, 68% had tachycardia, 29% had hypotension, and 77% presented with systemic inflammatory response syndrome (SIRS) defined as fulfilling a minimum of two of four criteria: i) body temperature >38 ^◦C or <36 ^◦C; ii) heart rate >90 beats per minute; iii) respiratory rate >20 breaths per minute or PaCO2 <4.2 kPa; iv) white blood cell count >12 x 10⁹/L or <4 x 10⁹/L. Seven percent required mechanical ventilation, including 5 of the 7 patients who died due to AAP.

Twenty-six percent of the 459 study patients developed pseudocysts. These patients were older than those who did not (median age 10.8 years vs 7.1 years; p=0.0003), and more frequently presented with SIRS (30% with SIRS vs 16% without SIRS; p=0.015). Five percent of patients with abdominal pain that ceased within 72 hours developed pseudocysts vs 33% of patients with pain persisting >72 hours (p<0.0001). Twenty percent required insulin within ten days of AAP diagnosis, and 6% still received insulin at last follow-up (median: 5 years from diagnosis of AAP). Persisting need of insulin therapy was associated with older age (median: 13 years vs 7.6 years; P=0.001) and presence of pseudocysts (13% vs 3% for those without pseudocysts; p=0.0001). Five percent of all patients had recurrent abdominal pain at last follow-up. 103 patients (22%) were re-exposed to asparaginase, and 45% of these developed a second AAP. 24% were re-exposed after a mild AAP, and no difference in risk of second AAP was found among mild and severe first AAP episodes (47% vs 45%, P=1). Risk of a second AAP was not significantly associated with presence of SIRS at first AAP episode (56% vs 30%; P=0.1), CRP level, or pancreatic enzyme levels at diagnosis of first AAP. Of the 43 patients who developed a second AAP, this was graded as a mild second AAP in 48%. Severity of second AAP was not associated to SIRS or severity of first AAP.

Conclusion: AAP is associated with a high frequency of both acute and persisting complications. The risk of complications was associated with older age and presence of SIRS at diagnosis of AAP. Almost half of those re-exposed to asparaginase developed a second episode of AAP, however the risk of recurrent AAP was not predictable based on characteristics of the first episode. To improve prediction of AAP, exploration of other risk factors, including host genome variants, is indicated.