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\begin{document}

\title{Symptomatic Hyperammonemia Secondary to Recombinant Erwinia Asparaginase}



\author[1]{Catherine E. Martin}%
\author[1]{Mira Kohorst}%
\author[1]{Asmaa Ferdjallah}%
\author[1]{Jessica L. Kalmes}%
\author[1]{Heather M. Johnson}%
\author[1]{Paul Galardy}%
\author[1]{Shakila Khan}%
\author[1]{Alexis Kuhn}%
\affil[1]{Mayo Clinic Minnesota}%


\vspace{-1em}



  
  \date{May 20, 2024}


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Title: Symptomatic Hyperammonemia Secondary to Recombinant Erwinia
Asparaginase

Catherine E. Martin, Pharm.D., Department of Pharmacy -- Ambulatory
Service, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

Mira A. Kohorst, M.D., Department of Pediatric and Adolescent Medicine,
Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street
SW, Rochester, MN 55905, USA

Asmaa Ferdjallah, M.D., M.P.H, Department of Pediatric and Adolescent
Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, 200
First Street SW, Rochester, MN 55905, USA

Jessica L. Kalmes, APRN, C.N.P., M.S.N, Department of Pediatric and
Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905, USA

Heather M. Johnson, APRN, C.N.P., M.S.N, Department of Pediatric and
Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905, USA

Paul J. Galardy, M.D., Department of Pediatric and Adolescent Medicine,
Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street
SW, Rochester, MN 55905, USA

Shakila P. Khan, M.D., Department of Pediatric and Adolescent Medicine,
Division of Pediatric Hematology/Oncology, Mayo Clinic, 200 First Street
SW, Rochester, MN 55905, USA

Alexis K. Kuhn, Pharm.D., Department of Pharmacy -- Ambulatory Service,
Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

Corresponding author: Catherine E. Martin; address: 200 First Street SW,
Rochester, MN 55905; phone: 507-284-2695; fax: 507-266-4912; email:
martin.catherine3@mayo.edu

Main text word count: 967

Number of tables, figures, and supporting information: None

Short running title: Hyperammonemia after recombinant Erwinia
asparaginase

Keywords: Asparaginase, hyperammonemia, pediatrics, Erwinia, leukemia

Abbreviations\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Abbreviation & Full term\tabularnewline
\midrule
\endhead
ALL & Acute lymphoblastic leukemia\tabularnewline
IM & Intramuscular\tabularnewline
NSAA & Nadir serum asparaginase activity\tabularnewline
ULN & Upper limit of normal\tabularnewline
\bottomrule
\end{longtable}

Asparaginase is well recognized as a crucial element in the treatment of
pediatric acute lymphoblastic leukemias (ALL).\textsuperscript{1} It is
an enzyme that exerts its anti-leukemic effects by catalyzing the
breakdown of asparagine to aspartic acid and
ammonia.\textsuperscript{1}The \emph{E. coli} -derived asparaginase
formulations, L-asparaginase and pegaspargase, have high rates of
antibody development that can ultimately lead to inadequate asparaginase
activity.\textsuperscript{2}To combat this, \emph{Erwinia chrysanthemi}
-derived asparaginase was developed, of which several products exist:
conventional Erwinia asparaginase (Erwinaze), and, the newest
formulation, recombinant Erwinia asparaginase
(Rylaze).\textsuperscript{2,3}

As ammonia is a byproduct of asparaginase's mechanism, acute, transient
hyperammonemia is expected.\textsuperscript{4,5} Symptomatic
hyperammonemia may present as headache, nausea, vomiting, lethargy, or
in severe cases, encephalopathy, coma, or
death.\textsuperscript{6--8}There are several case reports describing
symptomatic hyperammonemia in patients receiving pegaspargase and
conventional Erwinia asparaginase, but herein we describe two patients
who developed symptomatic hyperammonemia secondary to recombinant
Erwinia asparaginase.\textsuperscript{6,9,10}

\textbf{Patient 1:}

Patient 1 is an 18-year-old male with very high-risk B-cell ALL. During
his third dose of pegaspargase, he experienced a grade 3
hypersensitivity reaction. Though he clinically tolerated a
desensitization protocol, resultant asparaginase activity levels were
undetectable; therefore, his therapy was modified to substitute
recombinant Erwinia asparaginase for all future doses of pegaspargase.

His next scheduled dose of pegaspargase was substituted with 6 doses of
recombinant Erwinia asparaginase 50 mg (25 mg/m2) intramuscularly (IM)
every 48 hours.\textsuperscript{11} Within minutes of his fourth dose,
he reported feeling nauseous and light-headed. He was treated with a
fluid bolus and promethazine. A post-dose ammonia level resulted at 275
\selectlanguage{greek}µ\selectlanguage{english}mol/L (upper limit of normal (ULN) 60 \selectlanguage{greek}µ\selectlanguage{english}mol/L). Given the symptomatic
hyperammonemia with the previous dose, an ammonia level and a nadir
serum asparaginase activity (NSAA) were measured prior to the next dose
(dose \#5 of 6). His pre-dose ammonia level remained elevated at 248
\selectlanguage{greek}µ\selectlanguage{english}mol/L, and his NSAA was 0.54 IU/mL (goal NSAA [?]0.1
IU/mL).\textsuperscript{12} His ammonia level immediately following dose
5 was 321 \selectlanguage{greek}µ\selectlanguage{english}mol/L. He reported feeling fatigued and nauseous for about 24
hours after each recombinant Erwinia asparaginase dose.

With the sixth recombinant Erwinia asparaginase dose, the patient
received lactulose 20 grams by mouth three times daily (titrated to
three soft stools per day) with symptomatic improvement noted within a
few days of initiation. Four days after starting lactulose, and with no
further asparaginase, ammonia normalized. Due to the high NSAA during
the previous course, and to prevent further accumulation of ammonia, the
recombinant Erwinia asparaginase dose was decreased by 20\% and the
frequency was changed to every 72 hours for the next course. Repeat NSAA
after the first dose of this new dosing schedule was undetectable, and
the dose was increased to 50 mg every 72 hours with a resultant NSAA of
0.34 IU/mL. With the dose adjustment, he has been able to discontinue
the lactulose without recurrence of symptomatic hyperammonemia. At the
time of publication, the plan for patient 1 is to continue an every
72-hour dosing schedule with NSAA monitoring.

\textbf{Patient 2:}

Patient 2 is a 17-year-old male with T-cell ALL. During his third dose
of pegaspargase, he had a grade 3 hypersensitivity reaction. An
asparaginase activity panel was drawn 7 days after the dose, and he had
undetectable asparaginase activity with anti-asparaginase antibodies
present. He clinically tolerated a pegaspargase desensitization, but
like patient 1, was unable to regain sufficient asparaginase activity.
For every dose of pegaspargase, 6 doses of recombinant Erwinia
asparaginase 40 mg (25 mg/m2) IM every 48 hours was
substituted.\textsuperscript{11}

Due to complaints of nausea during and after receiving his recombinant
Erwinia asparaginase injections, an ammonia level was obtained prior to
the second dose of the fifth and final course and was found to be 325
\selectlanguage{greek}µ\selectlanguage{english}mol/L (ULN 30 \selectlanguage{greek}µ\selectlanguage{english}mol/L). He was also initiated on lactulose 20 grams by
mouth 4 times daily titrated to three soft stools per day. He reported
improvement of symptoms after initiation of lactulose, and subsequent
ammonia decreased to 136 \selectlanguage{greek}µ\selectlanguage{english}mol/L. An NSAA was measured before dose five
and was markedly elevated at 0.84 IU/mL, however this level was not
resulted in time to modify his final remaining dose.

\textbf{Discussion:}

We present two patients receiving recombinant Erwinia asparaginase who
developed symptomatic hyperammonemia concurrent with robust asparaginase
activity levels. Fortunately our patients had relatively minor symptoms,
but hyperammonemia can be severe.\textsuperscript{7,8} These are the
first reported cases of hyperammonemia with recombinant Erwinia
asparaginase and will hopefully bring awareness to this potentially
serious complication. Minimal literature is available regarding
appropriate treatment for asparaginase-induced hyperammonemia, and
sodium benzoate and arginine have been trialed without
success.\textsuperscript{13} Our experience, coupled with the case
series published by Nussbaum and colleagues, support the use of
lactulose.\textsuperscript{9} Interestingly, both of our patients and
the patients presented by Nussbaum were all adolescents/young
adults.\textsuperscript{9}

Our report has several limitations. First, the latency with which our
asparaginase activity levels resulted, in the context of every 48-72
hour dosing, presented a challenge in clinical practice. Second, due to
its retrospective nature, we cannot assure ourselves that the ammonia
levels were handled appropriately (e.g. placed on ice
immediately)---which could falsely elevate the
levels.\textsuperscript{14} However, our institutional laboratory
catalog does instruct immediately placing the sample on ice, and the
symptoms that our patients reported were consistent with hyperammonemia.

Recombinant Erwinia asparaginase is relatively new, and its use is
reserved for patients with hypersensitivity to \emph{E.
coli}asparaginase products. This limited use may explain a lack of data
outlining symptomatic hyperammonemia. Secondly, while there are no
head-to-head trials, published literature supports that there may be a
lower incidence of symptomatic hyperammonemia with Erwinia asparaginase
products compared to pegaspargase.\textsuperscript{6,10} Further
research is needed to provide guidance on which patients receiving
recombinant Erwinia asparaginase warrant ammonia and asparaginase
activity level monitoring and recommended management.

Dr. Kuhn discloses recent participation on an advisory board for Rylaze
for Jazz Pharmaceuticals. No other authors have any conflicts of
interest.

References:

1. Egler RA, Ahuja SP, Matloub Y. L-asparaginase in the treatment of
patients with acute lymphoblastic leukemia. \emph{J Pharmacol
Pharmacother} . 2016;7(2):62-71. doi:10.4103/0976-500X.184769

2. Salzer W, Bostrom B, Messinger Y, Perissinotti AJ, Marini B.
Asparaginase activity levels and monitoring in patients with acute
lymphoblastic leukemia. \emph{Leuk Lymphoma} . 2018;59(8):1797-1806.
doi:10.1080/10428194.2017.1386305

3. Maese LD, Loh ML, Choi MR, et al. Recombinant Erwinia Asparaginase
(JZP458) in Acute Lymphoblastic Leukemia: Results from the Phase 2/3
AALL1931 Study. \emph{Blood} . Published online September 15,
2022:blood.2022016923. doi:10.1182/blood.2022016923

4. J\selectlanguage{ngerman}örck C, Kiess W, Weigel JFW, Mütze U, Bierbach U, Beblo S. Transient
hyperammonemia due to L-asparaginase therapy in children with acute
lymphoblastic leukemia or non-Hodgkin lymphoma. \emph{Pediatr Hematol
Oncol} . 2011;28(1):3-9. doi:10.3109/08880018.2010.484852

5. Steiner M, Attarbaschi A, Kastner U, et al. Distinct fluctuations of
ammonia levels during asparaginase therapy for childhood acute
leukemia.\emph{Pediatr Blood Cancer} . 2007;49(5):640-642.
doi:10.1002/pbc.21022

6. Gossai N, Richards M, Boman L, et al. Symptomatic Hyperammonemia With
Erwinia chrysanthemi-derived Asparaginase in Pediatric Leukemia
Patients. \emph{J Pediatr Hematol Oncol} . 2018;40(4):312-315.
doi:10.1097/MPH.0000000000001062

7. Clay AS, Hainline BE. Hyperammonemia in the ICU. \emph{Chest} .
2007;132(4):1368-1378. doi:10.1378/chest.06-2940

8. Strickler N, Balabanov S, Casauro K, Schanz U, Manz MG, Gerber B.
Acute central nervous system complications and ammonium levels in adult
patients with acute lymphoblastic leukemia receiving
l-asparaginase.\emph{Leuk Lymphoma} . 2018;59(4):855-862.
doi:10.1080/10428194.2017.1352090

9. Nussbaum V, Lubcke N, Findlay R. Hyperammonemia secondary to
asparaginase: A case series. \emph{J Oncol Pharm Pract Off Publ Int Soc
Oncol Pharm Pract} . 2016;22(1):161-164. doi:10.1177/1078155214551590

10. Heitink-Pollé KMJ, Prinsen BHCMT, de Koning TJ, van Hasselt PM,
Bierings MB. High incidence of symptomatic hyperammonemia in children
with acute lymphoblastic leukemia receiving pegylated
asparaginase.\emph{JIMD Rep} . 2013;7:103-108.
doi:10.1007/8904\_2012\_156

11. RYLAZE (asparaginase erwinia chrysanthemi
(recombinant)-rywn){[}package insert{]}. Leinster, Ireland: Jazz
Pharmaceuticals Ireland Limited; June 2021.

12. van der Sluis IM, Vrooman LM, Pieters R, et al. Consensus expert
recommendations for identification and management of asparaginase
hypersensitivity and silent inactivation. \emph{Haematologica} .
2016;101(3):279-285. doi:10.3324/haematol.2015.137380

13. Leonard JV, Kay JD. Acute encephalopathy and hyperammonaemia
complicating treatment of acute lymphoblastic leukaemia with
asparaginase. \emph{Lancet Lond Engl} . 1986;1(8473):162-163.
doi:10.1016/s0140-6736(86)92304-4

14. Tong WH. Comment on Ammonia level as a proxy of asparaginase
inactivation in children: A strategy for classification of infusion
reactions. \emph{J Oncol Pharm Pract} . 2021;27(4):1054-1056.
doi:10.1177/10781552211007553

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