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Incidence and outcome of pancreatitis in children and young

adults with acute lymphoblastic leukaemia treated on a
contemporary protocol, UKALL 2003

Acute Pancreatitis is a well-known complication of the treat-
ment of childhood acute lymphoblastic leukaemia (ALL).
Pancreatitis is associated with significant complications, such
as multiorgan failure and pseudocysts. The incidence of pan-
creatitis following ALL treatment is 7–18% (Raja et al, 2012),
and this variation is due to differences in the definition of
pancreatitis and variations in the doses of anti-leukaemic
medications that cause pancreatitis. Whilst numerous anti-
leukaemic medications have been reported to cause pancrea-
titis, the most important is Asparaginase.
The development of pancreatitis is one of the common-
est causes for stopping Asparaginase, because re-exposure
is associated with recurrence. In contrast, stopping sched-
uled Asparaginase treatment because of previous pancreati-
tis has been linked to an increased relapse rate (Silverman
et al, 2001). Recently, recommendations for the reintroduc-
tion of Asparaginase based on clinical criteria were sug-
gested in attempt to minimize the risk of relapse without
compromising safety (Raja et al, 2012). We therefore con-
ducted a retrospective review of the clinical risk factors
and outcome of pancreatitis on the recently closed UKALL
2003 trial.
UKALL 2003 opened to patients aged 1–18 years with
previously untreated ALL in October 2003. The upper age
was increased to 20 years in September 2006 and 25 years
in June 2008. This analysis includes the 3101 eligible
patients who had entered the trial by 31 May 2011. Follow
up was to 31 October 2011 with median follow up of
3 years, 10 months (range 1
5 months to 8 years, 1 month).
Patients with pancreatitis were identified by the investiga-
tor-generated serious adverse report from the participating
centres. Further data was obtained from directed question-
naires relating to the event. All of the questionnaires were
returned. Pancreatitis was diagnosed according to the
Atlanta criteria (Bradley, 1993), which include at least
two of the following three features – clinical presentation
resembling pancreatitis, serum amylase and/or lipase >3
times the upper limit of normal and characteristic imaging
findings of acute pancreatitis. The severity of the episode
was graded according to the Common Terminology Criteria
for Adverse Events, version 4.03 (http://evs.nci.nih.gov/ftp1/
CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf).
Grade 3 was defined as severe pain, vomiting, medical inter-
vention required (e.g. analgesia) and grade 4 was life threat-
ening or urgent intervention required. Evaluated outcomes
measures included event-free survival (EFS), overall survival
(OS) and complications following pancreatitis. In view of
the potential for recurrence, the trial recommendation was
to avoid re-exposure to further Asparaginase, following pan-
creatitis. Details of the trial protocol and methods are
shown in Fig 1A and in the supplementary information.
The incidence of acute pancreatitis was 1
5%, and was
0
6%, 2
0% and 3
0% for treatment regimens A, B and C
respectively. Whilst several factors were significantly associ-
ated with the development of pancreatitis on univariate
analysis (Table IA), only treatment regimen given, (with
increasing intensity of treatment and asparaginase dose) was
associated with higher odds of developing pancreatitis and
remained significant on multivariate analysis (Table IB).
There was a suggestion that increasing age may also be
important but models including this variable did not reach
statistical significance. The CTCAE grade of pancreatitis was
grade 3 in 73% and grade 4 in 27% of cases. Pancreatitis was
more common in Asparaginase-containing blocks versus non-
Asparaginase containing blocks (83% vs. 17%; P < 0
0001;
Fig 1B). A median of 3 doses of Asparaginase was received
(cumulative dose 3000 iu/m2) before the onset of pancrea-
titis (range 1–10). The median interval between receiving the
last Asparaginase dose and developing pancreatitis was 10 d
(range 3–34). Six cases had further episodes of pancreatitis
(recurrence rate of 13%). Four patients with Asparaginase-
associated pancreatitis – were re-exposed to Asparaginase. Of

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Correspondence

(A)

(B)

Fig 1. (A) Outline of Treatment regimens on UKALL 2003. Clinical risk groups were defined by National Cancer Institute Criteria (Smith et al,
1996), cytogentics and early response criteria. Timings of Peg-Asparaginase are indicated by arrows (B) Occurrence of acute pancreatitis according
to treatment block on UKALL2003. Acute pancreatitis was more common in Asparagainse containing blocks (83% vs. 17% P < 0
0001).

these, one case had recurrent pancreatitis with severe pancre-
atitis on both occasions (grade 4).
There was significant morbidity (29% required admission
to the intensive therapy unit, 25% developed pseudocysts,
13% developed diabetes mellitus, 8% pleural effusions and
2% renal failure). As the majority of patients were not
re-exposed again to Asparaginase, most received half their
scheduled Asparaginase [median scheduled Asparaginase dose
received in the pancreatitis cohort was 50% (5000 iu/m2);
range 17–100% (2–12 000 iu/m2)]. Despite these omissions,
there was no significant difference in EFS and OS between
those who did and did not develop pancreatitis (5-year EFS
in the pancreatitis cohort 84%; 95% confidence interval (CI):
69–99% vs. 87%; 95%CI: 86–89% in the non-pancreatitis

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Correspondence

Table I. Table of Associations of Pancreatitis with Patient Characteristics (A) Univariate Analysis and (B) Multivariate Analysis.

(A)
Characteristic Pancreatitis (n = 48) No pancreatitis (n = 3053) P-value (heterogeneity)

Patient demographics
Sex Male 24 (50
0%) 1739 (57
0%) 0
3
Female 24 (50
0%) 1314 (43
0%)
Age (years) Median (range) 9 (2–23) 5 (1–24) <0
0001
<2 0 (0
0%) 208 (6
8%) 0
002
2–9 25 (52
1%) 2041 (66
9%)
10–15 19 (39
6%) 581 (19
0%)
16+ 4 (8
3%) 223 (7
3%)
Race Black 0 (0
0%) 74 (2
5%) 0
6
White 38 (84
4%) 2470 (84
6%)
Asian 5 (11
1%) 227 (7
8%)
Other 2 (4
4%) 149 (5
1%)
Disease characteristics
WBC Median (range) 13
8 (0
7–282
5) 12
0 (0
4–881
0) 0
8
<10 22 (45
8%) 1376 (45
1%) 0
4
10 8 (16
7%) 487 (16
0%)
20 4 (8
3%) 518 (17
0%)
50 8 (16
7%) 303 (9
9%)
100+ 6 (12
5%) 369 (12
1%)
NCI risk Standard 17 (35
4%) 1787 (58
5%) 0
001
High 31 (64
6%) 1266 (41
5%)
Immunophenotype B/N 37 (77
1%) 2674 (87
8%) 0
03
T 11 (22
9%) 372 (12
2%)
Regimen given A 9 (18
8%) 1524 (49
9%) <0
0001
B 17 (35
4%) 825 (27
0%)
C 22 (45
8%) 704 (23
1%)
Slow early response No 35 (72
9%) 2709 (88
7%) 0
0007
Yes 13 (27
1%) 344 (11
3%)
MRD High (H) 22 (45
8%) 996 (33
0%) 0
2 (0
08: H vs. L)
Indeterminate 13 (27
1%) 953 (31
5%)
Low (L) 13 (27
1%) 1072 (35
5%)

(B)
P-
Characteristic Odds ratio (95%CI) value

Regimen A 1
00 0
0002

given B 3
49 (1
55–7
86)
C 5
29 (2
42–11
55)

Table IA: Univariate analysis of patient characteristics with and without acute pancreatitis. WBC, white blood cell count; NCI risk, National Can-
cer Institute risk (Smith et al, 1996); MRD, minimal residual disease. Table IB: Multivariate analysis of significant patient characteristics associ-
ated with the development of acute pancreatitis. Treatment regimen given was the only significant predictor for the development of acute
pancreatitis in a multivariate analysis. See the Supporting Information for details of the regimens used.

group; Odds ratio for EFS in the pancreatitis cohort
compared to no pancreatitis = 1
36 95% CI: 0
50–3
74
P = 0
5; 5 year OS in pancreatitis cohort 92%; 95% CI:
82–100% vs. 92%; 95% CI:90–93% in non pancreatitis
group; Odds ratio for OS in the pancreatitis cohort com-
pared to no pancreatitis was 1
26 95% CI:0
36–4
45 P = 0
6).
There were no deaths as a result of pancreatitis.
The incidence of pancreatitis in our analysis was lower than
previously reported in other studies. Potentially, differences in
the incidence may reflect differences in the criteria used to
diagnose pancreatitis. However in order to make definitive
comparisons on the incidence of pancreatitis between different
leukaemia protocols, a consensus classification is required on
the definition on pancreatitis. As this does not currently exist,
we used the Atlanta criteria to diagnose pancreatitis, as
recently recommended. (Raja et al, 2012).
An additional reason for the difference in pancreatitis seen
on UKALL 2003 and other series may reflect differences in
the cumulative dose of Asparaginase used. Thus Regimen A/B
patients were exposed to a relatively small amount of
amount of Peg-Asparaginase (3000 - 4000 iu/m2) and Regi-
men C received 12 000 iu/m2. In contrast, the Dana Farber

712 ª 2013 John Wiley & Sons Ltd

British Journal of Haematology, 2013, 162, 706–718

Cancer Institute ALL 91-01 Consortium used a higher cumu-
lative dose of Peg- Asparaginase (30 000 iu/m2) (Kearney
et al, 2009). Asparaginase dose intensity is however, not the
only factor likely to be important in the pathogenesis of
pancreatitis. Regimen B patients had a three-fold higher
incidence of pancreatitis compared to Regimen A despite
having a similar Asparaginase exposure. This suggests that
anthracycline induction and the additional cylophosphamide/
cytarabine exposure in the Berlin-Frankf€urt-M€unster consoli-
dation in Regimen B may be risk factors for the development
of pancreatitis.
In our series, Asparaginase withdrawal due to pancreatitis
did not affect EFS and OS, though the overall numbers of
cases with pancreatitis was small. However, in the current
UKALL 2011 trial, we continue to recommend that Aspara-
ginase be withheld following pancreatitis. Our analysis
demonstrates that increasing treatment intensity and Aspara-
ginase exposure are the biggest risk factors for developing
pancreatitis.
Acknowledgements
The authors are grateful to Professor Josef Vormoor for his
comments.
Authorship contributions
RW, SD, PI and JS collected data and helped write the man-
uscript. RW performed the statistical analyses. AJ, NG and
SS supervised the writing of the manuscript.
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British Journal of Haematology, 2013, 162, 706–718
13652141, 2013, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.12407 by CAPES, Wiley Online Library on [10/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Correspondence
Conflict of interest
The authors declare no conflict of interest.
Sujith Samarasinghe1
Sunita Dhir1
James Slack1
Prasad Iyer1
Rachel Wade2
Rachel Clack2
Ajay Vora3
Nicholas Goulden4
1
Department of Paediatric and Adolescent Haematology and Oncology,
Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS
Foundation Trust, Newcastle Upon Tyne, 2Clinical Trial Service Unit,
University of Oxford, Oxford, 3Department of Paediatric Haematology,
Sheffield Children’s Hospital, Sheffield, and 4Department of
Haematology, Great Ormond Street Hospital, London, UK
E-mail: sujith.samarasinghe@nuth.nhs.uk
Keywords: acute pancreatitis, Asparaginase, childhood acute
lymphoblastic leukaemia
First published online 10 June 2013
doi: 10.1111/bjh.12407
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Additional Supporting Information may be found in the
online version of this article:
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713