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\begin{document}

\title{Vaccine Preventable Illness After Blinatumomab Therapy: A Case Report}



\author[1]{Katie Voelz}%
\author[1]{Anthony Salvatore}%
\author[1]{Sudarshawn Damodharan}%
\author[1]{Cathy Lee-Miller}%
\affil[1]{University of Wisconsin-Madison Department of Pediatrics}%


\vspace{-1em}



  
  \date{June 16, 2024}


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Title: Vaccine Preventable Illness After Blinatumomab Therapy: A Case
Report

Authors: Katie Voelz MD\textsuperscript{1,2}, Anthony Salvatore
DO\textsuperscript{1}, Sudarshawn Damodharan DO\textsuperscript{1,2} \&
Cathy Lee-Miller MD\textsuperscript{1,2}

\textsuperscript{1}Department of Pediatrics, University of Wisconsin
School of Medicine \& Public Health, Madison, WI, USA

\textsuperscript{2}Division of Pediatric Hematology, Oncology and Bone
Marrow Transplant, University of Wisconsin School of Medicine \& Public
Health, Madison, WI, USA

Correspondence:

Cathy Lee-Miller

University of Wisconsin School of Medicine \& Public Health

1111 Highland Ave, WIMR 4105

Madison, WI 53705

Email: calee4@wisc.edu

Word Count: Main Text: 848

Manuscript contains 1 Table

Short running Title: Vaccine-preventable, ALL, immunotherapy

Keywords: Blinatumomab, ALL, vaccination, pediatrics\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
AE & Adverse Event\tabularnewline
ALL & Acute Lymphoblastic Leukemia\tabularnewline
ANC & Absolute Neutrophil Count\tabularnewline
COG & Children's Oncology Group\tabularnewline
ED & Emergency Department\tabularnewline
IVIG & Intravenous Immunoglobulin G\tabularnewline
MRD & Minimal Residual Disease\tabularnewline
SR & Standard Risk\tabularnewline
\bottomrule
\end{longtable}

To The Editor:

Blinatumomab is a bispecific T-cell engaging monoclonal antibody that
targets the CD19 antigen on B-cells and the CD3 antigen on T-cells,
resulting in close linkage of T-cells with B-cells and subsequent
redirected lysis.\textsuperscript{1} This immunotherapy has demonstrated
efficacy in patients with relapsed/refractory cases of B-cell acute
lymphoblastic leukemia (ALL) and is being studied in patients with
standard risk (SR) B-cell ALL with minimal residual disease (MRD) after
induction. While blinatumomab use in pediatric patients has been shown
to have decreased rates of sepsis and infection when compared to
chemotherapy, there is scant data describing specific adverse events
(AEs) in pediatrics.\textsuperscript{1,2} We describe a patient with SR
B-cell ALL in first remission who received blinatumomab and then
developed recurrent \emph{Streptococcus pneumoniae} bacteremias during
maintenance. This case raises the possibility that blinatumomab
increases the risk of vaccine preventable illnesses in children with
B-cell ALL.

Our patient presented as a fully immunized 27-month-old male with B-cell
ALL, CNS 1 and neutral cytogenetics. He was treated per Children's
Oncology Group (COG) protocol AALL1731, on study, for SR B-cell ALL. His
day 8 peripheral blood flow cytometry minimal residual disease (MRD) was
0.007\% and his end of induction bone marrow MRD was negative. However,
high throughput sequencing MRD was detectable at 0-4 clones per million
cells. Therefore, he was stratified as SR-average disease, and was
randomized to two cycles of blinatumomab in addition to standard
chemotherapy for SR B-cell ALL. He received intravenous immunoglobulin G
(IVIG) twice for hypogammaglobulinemia (IgG \textless{} 400mg/dL); first
dose was three days before initiation of blinatumomab and second dose
six weeks after completion of immunotherapy. Approximately nineteen
months after completion of blinatumomab, during cycle one of
maintenance, he presented to the emergency department (ED) with an
elevated temperature (100.2F) without neutropenia (absolute neutrophil
count (ANC) of 2940/uL); blood cultures were drawn
and\emph{Streptococcus pneumoniae} grew within 12.3 hours. The patient
was overall well-appearing with only mild fatigue. He remained afebrile
for \textgreater{}24 hours and S. \emph{pneumoniae} was pan-sensitive
therefore he was discharged home after 48 hours and completed seven days
of ceftriaxone. His IgG one week prior to positive blood culture was
713mg/dL. Ten weeks later during cycle two of maintenance therapy, he
again presented to the ED with fever (100.5F), abdominal pain and
fatigue; he was not neutropenic at presentation (ANC 4130/uL). Blood
cultures were obtained, and \emph{Streptococcus pneumonia} grew at 12.1
hours. He was treated with a 10-day course of ceftriaxone. Notably, he
had three negative blood cultures between bacteremic episodes. With this
second episode of \emph{S. pneumoniae} bacteremia, serotyping was
conducted revealing serotype 35B. IgG at the time of this second
bacteremia was 601 mg/dL. Pneumococcal titers were low so he was
re-vaccinated with Pneumovax 23. Four weeks later, vaccine titers
demonstrated a normal humoral response with a greater than 4-fold
increase in \textgreater{}50\% of serotypes (Table
1)\textsuperscript{3,4}

This case represents a rare occurrence of recurrent bacteremia of a
vaccine-preventable illness in a fully immunized pediatric patient who
received blinatumomab therapy for SR B-cell ALL. Hypogammaglobulinemia
is a known complication of blinatumomab however, there is incomplete
understanding of blinatumomab activity on immunity in pediatric
patients.\textsuperscript{5,6} Blinatumomab depletes B-cells, which play
a key role in developing immunity. Normal B-cells produce an
anti-protein antibody that is a major component of naturally-acquired
IgG adaptive immunity against \emph{S. pneumoniae}
.\textsuperscript{7}By depleting the B-cell population and the natural
ability to produce protective antibodies for an undetermined amount of
time, blinatumomab may put patients at higher risk of serious infections
than those receiving standard chemotherapy. Despite the known increased
infectious risk, there is little data on how B-cell therapy affects
subsets of specific antibodies. Studies with rituximab (anti-CD20
monoclonal antibody) show that B-cell depletion does not eliminate
B-cell immunity.\textsuperscript{7} CD20-negative plasma cells and
circulating antibodies appear to be maintained, however CD20-positive
and memory B-cells are reduced. Upon restimulation, these cell
populations rapidly expand and differentiate into antibody-producing
cells.\textsuperscript{7} It appears that the main risk-determining
factors are the duration of B-cell depleting therapy and length of
sustained B-cell lymphopenia; the latter of which is not known for
patients receiving blinatumomab.

Data from adult studies cannot be directly applied to the pediatric
setting given the biological and genetic differences between pediatric
and adult B-cell ALL. There are also unique aspects of developing immune
systems that could alter the activity of blinatumomab and its AE profile
in children.\textsuperscript{1} Our patient's response to Pneumovax 23
indicates proper humoral function, and his lack of neutropenia or
hypogammaglobulinemia at the time of bacteremia episodes raises the
likelihood that blinatumomab contributed to our patient's susceptibility
to \emph{S.pneumoniae} .

Our patient's recurrent bacteremias following immunotherapy raises the
question of blinatumomab potentially decreasing the durability of
immunity in fully vaccinated children. This immunity decrement may lead
to an increased risk of vaccine-preventable illnesses. Due to biologic
and genetic differences in both disease processes and immune system
function, a knowledge gap exists for consequences of blinatumomab in
children. This case highlights the importance of further research on
blinatumomab activity and potential AEs in pediatric patients, including
the need to check vaccine titers and create re-vaccination strategies in
children who have received blinatumomab.

Conflict of Interest

The authors declare that there is no conflict of interest

References

\begin{enumerate}
\tightlist
\item
  Queudeville M, Ebinger M. Blinatumomab in Pediatric Acute
  Lymphoblastic Leukemia-From Salvage to First Line Therapy (A
  Systematic Review). \emph{J Clin Med} . Jun 08
  2021;10(12)doi:10.3390/jcm10122544
\item
  Brown PA, Ji L, Xu X, et al. Effect of Postreinduction Therapy
  Consolidation With Blinatumomab vs Chemotherapy on Disease-Free
  Survival in Children, Adolescents, and Young Adults With First Relapse
  of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical
  Trial.\emph{JAMA} . 03 02 2021;325(9):833-842.
  doi:10.1001/jama.2021.0669
\item
  Daly TM, Hill HR. Use and clinical interpretation of pneumococcal
  antibody measurements in the evaluation of humoral immune
  function.\emph{Clin Vaccine Immunol} . Feb 2015;22(2):148-52.
  doi:10.1128/CVI.00735-14
\item
  Daly TM, Pickering JW, Zhang X, Prince HE, Hill HR. Multilaboratory
  assessment of threshold versus fold-change algorithms for minimizing
  analytical variability in multiplexed pneumococcal IgG
  measurements.\emph{Clin Vaccine Immunol} . Jul 2014;21(7):982-8.
  doi:10.1128/CVI.00235-14
\item
  Hathaway L, Sen JM, Keng M. Impact of blinatumomab on patient outcomes
  in relapsed/refractory acute lymphoblastic leukemia: evidence to
  date.\emph{Patient Relat Outcome Meas} . 2018;9:329-337.
  doi:10.2147/PROM.S149420
\item
  So W, Pandya S, Quilitz R, Shah B, Greene JN. Infectious Risks and
  Complications in Adult Leukemic Patients Receiving
  Blinatumomab.\emph{Mediterr J Hematol Infect Dis} .
  2018;10(1):e2018029. doi:10.4084/MJHID.2018.029
\item
  Ercoli G, Ramos-Sevillano E, Nakajima R, de Assis RR, Jasinskas A,
  Goldblatt D, Felgner P, Weckbecker G, Brown J: The Influence of B Cell
  Depletion Therapy on Naturally Acquired Immunity to Streptococcus
  pneumoniae. \emph{Front Immunol} 2020, 11:611661.
\end{enumerate}

Table 1: Pneumococcal Vaccination Titers Pre and Post Pneumovax 23
Booster\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Serotype & Pre-Booster (ug/mL) & 4 weeks Post-Booster
(ug/mL)\tabularnewline
1 & 0.19 & 3.30\tabularnewline
2 & 0.14 & 0.35\tabularnewline
3 & 0.07 & 0.71\tabularnewline
4 & 0.05 & \textgreater{}13.92\tabularnewline
5 & 0.19 & 21.67\tabularnewline
6B & 0.10 & 11.18\tabularnewline
7F & 0.29 & 1.73\tabularnewline
8 & 0.09 & 3.46\tabularnewline
9N & 0.06 & \textgreater{}30.40\tabularnewline
9V & 0.09 & \textgreater{}16.50\tabularnewline
10A & 0.00 & 0.02\tabularnewline
11A & 0.17 & 0.15\tabularnewline
12F & 0.04 & 0.16\tabularnewline
14 & 0.29 & 7.88\tabularnewline
15B & 0.10 & 0.13\tabularnewline
17F & 0.46 & 1.07\tabularnewline
18C & 0.33 & \textgreater{}33.28\tabularnewline
19A & 0.48 & 0.15\tabularnewline
19F & 0.31 & 0.4\tabularnewline
20 & 0.19 & 0.17\tabularnewline
22F & 0.05 & 0.11\tabularnewline
33F & 0.06 & 0.07\tabularnewline
\bottomrule
\end{longtable}

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