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.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.1,2 We describe a patient with SR
B-cell ALL in first remission who received blinatumomab and then
developed recurrent 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 < 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 andStreptococcus pneumoniae grew within 12.3 hours. The patient was
overall well-appearing with only mild fatigue. He remained afebrile for
>24 hours and S. 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 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 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 >50% of serotypes (Table
1)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.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 S. pneumoniae .7By 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.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.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.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 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
- Queudeville M, Ebinger M. Blinatumomab in Pediatric Acute
Lymphoblastic Leukemia-From Salvage to First Line Therapy (A
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Consolidation With Blinatumomab vs Chemotherapy on Disease-Free
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of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.JAMA . 03 02 2021;325(9):833-842. doi:10.1001/jama.2021.0669
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Table 1: Pneumococcal Vaccination Titers Pre and Post Pneumovax 23
Booster