Asparaginase-Associated Pancreatitis in ALL: Results from the NOPHO ALL2008 Treatment of Patients 1-45 Years
Authors: Rank Cecilie Utke , Wolthers Benjamin Ole , Grell Kathrine , Albertsen Birgitte Klug , Frandsen Thomas Leth , Overgaard Ulrik Malthe , Toft Nina , Nielsen Ove Juul , Wehner Peder Skov , Harila-Saari Arja , Heyman Mats , Abrahamsson Jonas , Norén-Nyström Ulrika , Tomaszewska-Toporska Beata , Lund Bendik , Jarvis Kirsten Brunsvig , Quist-Paulsen Petter , Vaitkeviciene Goda Elizabeta , Griškevičius Laimonas , Taskinen Mervi , Wartiovaara-Kautto Ulla , Lepik Kristi , Punab Mari , Jónsson Ólafur Gísli , Schmiegelow Kjeld 
Published: November 2019

Premature discontinuation of asparaginase reduces cure rate in contemporary acute lymphoblastic leukemia (ALL) treatment. One of the commonest causes of asparaginase truncation is asparaginase-associated pancreatitis (AAP). We prospectively registered AAP during treatment of 2,448 consecutive Nordic/Baltic ALL patients aged 1.0-45.9 years treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol (7/2008-10/2018).
The Day 280 cumulative incidence of first-time AAP (including 99% (167/168) of AAP events at this time point) was 8.3% (95% confidence interval (CI) 7.0-9.9) with a median time of 104 days (interquartile range (IQR) 70-145) from ALL diagnosis to AAP, with a median of 10 days (IQR 6-13) from last asparaginase exposure, and after a median number of five asparaginase doses (IQR 3-7, max 14 doses). All patients received polyethylene glycol conjugated Escherichia coli-derived asparaginase as standard treatment. Eighty-five percent (140/164, unknown in N=4) of AAP events were severe (AAP-associated symptoms and/or pancreatic enzymes >3x upper normal limit lasting >72 hours or with hemorrhagic pancreatitis, pancreatic abscess, or pseudocyst). Four age groups were defined: 1.0-4.9, 5.0-8.9, 9.0-16.9, and 17.0-45.9 years-each containing approximately 25% of the AAP events. Compared with patients aged 1.0-4.9 years, adjusted (sex, immunophenotype, and white blood cell count) hazard ratios (HR) of AAP were associated with higher age (5.0-8.9 years: HR 2.3, 95% CI 1.5-3.6, P<.0001; 9.0-16.9 years: HR 2.5, 95% CI 1.6-3.8, P<.0001; and 17.0-45.9 years: HR 2.5, 95% CI 1.6-3.8, P<.0001). When analyzing the odds of developing any AAP-related complication among patients with ≥100 days of follow-up after the AAP diagnosis, older children (≥5.0 years) and adolescents had increased odds of developing any complication compared with younger children aged 1.0-4.9 years, notably a more than six-fold increase among adolescents (5.0-8.9 years: odds ratio (OR) 2.67, 95% CI 1.07-6.68, P=.04 and 9.0-16.9 years: OR 6.52, 95% CI 2.35-18.1, P=.0003)-including acute and permanent insulin need; intensive care unit admission; pancreatic pseudocyst development; recurrent abdominal pain; elevated pancreatic enzymes at last-follow-up; imaging compatible with pancreatitis (pancreatic inflammation/edema/pseudocysts/hemorrhage) at last follow-up; and AAP-related death. Adult age was not associated with development of any AAP-related complication (17.0-45.9 years: OR 2.3, 95% CI 0.9-5.9, P=.07). Three patients aged 8.6, 17.3, and 18.6 years died of first-time AAP within 0-29 days from AAP diagnosis.
Of 168 AAP patients, 34 (20%) were re-challenged with asparaginase. Fifty percent (17/34) developed a second episode of AAP-41% being severe (7/17). The median time to a second AAP event from asparaginase re-exposure was 29 days (IQR 16-94) and occurred after a median of two asparaginase doses (range 0-7). Neither age group nor severity of the first AAP was associated with increased hazard of a second AAP event. None of the patients with a second AAP were further re-exposed to asparaginase, and none died of the second AAP. Among a total of 196 ALL relapses, 21 patients have had AAP including 17 patients with asparaginase truncation. However, the hazard of relapse (age- and sex-adjusted) was not increased among AAP patients with asparaginase truncation versus AAP patients with asparaginase re-exposure (5.0-year cumulative incidence of relapse: 13.2% versus 14.2%) (HR 1.0, 95% CI 0.3-3.1, P=1.0). When analyzing time to relapse among AAP patients versus non-AAP patients, no difference in hazard of relapse was found (HR 2.0, 95% CI 0.8-4.9, P=.2).
In conclusion, adolescents and young adults tolerated asparaginase treatment as well as children; however, the risk of AAP was higher for patients older than 5.0 years of age with no difference with increasing age. Despite a low AAP-related mortality, the morbidity was considerable and most profound for patients aged 9.0-16.9 years. Since asparaginase re-exposure was associated with a high risk of a second AAP event and neither AAP development nor AAP-related asparaginase truncation was associated with increased relapse risk, asparaginase re-exposure should be attempted only in patients with a high risk of leukemic relapse. Finally, there is an unmet need for preventive strategies toward AAP.

Disclosures
Wolthers: Novo Nordisk: Employment.