Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia

Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age

Cecilie U. Rank, MD; Benjamin O. Wolthers, MD, PhD; Kathrine Grell, PhD; Birgitte K. Albertsen, MD, PhD; Thomas L. Frandsen, MD, PhD; Ulrik M. Overgaard, MD; Nina Toft, MD, PhD; Ove J. Nielsen, MD, DrMedSci; Peder S. Wehner, MD, PhD; Arja Harila-Saari, PhD, MD; Mats M. Heyman, MD, PhD; Johan Malmros, MD, PhD; Jonas Abrahamsson, PhD, MD; Ulrika Norén-Nyström, MD, PhD; Beata Tomaszewska-Toporska, MD; Bendik Lund, MD, PhD; Kirsten B. Jarvis, MD; Petter Quist-Paulsen, MD, PhD; Goda E. Vaitkevičienė, MD, PhD; Laimonas Griškevičius, MD, PhD; Mervi Taskinen, MD, PhD; Ulla Wartiovaara-Kautto, MD, PhD; Kristi Lepik, MD; Mari Punab, MD; Ólafur G. Jónsson, MD; Kjeld Schmiegelow, MD, DrMedSci


J Clin Oncol. 2020;38(2):145-154. 

In This Article

Abstract and Introduction


Purpose: Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored.

Patients and Methods: We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0–45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol.

Results: Compared with patients aged 1.0–9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0–17.9 years) and adults (18.0–45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0–9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0–45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0–9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse.

Conclusion: Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse.


Because adult patients now more frequently receive pediatric-inspired acute lymphoblastic leukemia (ALL) treatment, their tolerance to such therapy has become an important issue.[1,2] Depending on the extent of asparaginase (ASP) exposure, larger trials report asparaginase-associated pancreatitis (AAP) in up to 11% of children with ALL.[3–16] Furthermore, premature withdrawal of ASP reduces cure rates,[3,4,17] and one of the commonest causes of ASP truncation in children is AAP because many experience a second AAP after ASP rechallenge.[3,5,18]

ASP depletes the body of asparagine,[19] interfering with the highly active pancreatic protein synthesis. Acute pancreatitis arises from premature activation of trypsin within pancreatic acinar cells, acinar cell destruction, concomitant local inflammation, and ultimately pancreatic autodigestion.[20] However, the direct mechanism behind AAP is unknown, and treatment is mainly supportive.[21] Although mortality is reported in only a small percentage of patients,[3,6,7,13,18,22] both acute and long-term morbidities after childhood AAP are common.[13,18,22–24]

Some clinical[3–9,15,18,25] and genetic[5,9,26] risk factors for acute pancreatitis have been proposed, including adolescent age. However, comparative studies of pediatric and adult patients with ALL, as well as studies exploring the AAP-related morbidity and impact on leukemic relapse risk, are missing. We investigated the cumulative incidence, clinical characteristics, and relapse risk in patients with ALL with AAP aged 1.0–45.9 years uniformly treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol.