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
  1. Queudeville M, Ebinger M. Blinatumomab in Pediatric Acute Lymphoblastic Leukemia-From Salvage to First Line Therapy (A Systematic Review). J Clin Med . Jun 08 2021;10(12)doi:10.3390/jcm10122544
  2. 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.JAMA . 03 02 2021;325(9):833-842. doi:10.1001/jama.2021.0669
  3. Daly TM, Hill HR. Use and clinical interpretation of pneumococcal antibody measurements in the evaluation of humoral immune function.Clin Vaccine Immunol . Feb 2015;22(2):148-52. doi:10.1128/CVI.00735-14
  4. 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.Clin Vaccine Immunol . Jul 2014;21(7):982-8. doi:10.1128/CVI.00235-14
  5. Hathaway L, Sen JM, Keng M. Impact of blinatumomab on patient outcomes in relapsed/refractory acute lymphoblastic leukemia: evidence to date.Patient Relat Outcome Meas . 2018;9:329-337. doi:10.2147/PROM.S149420
  6. So W, Pandya S, Quilitz R, Shah B, Greene JN. Infectious Risks and Complications in Adult Leukemic Patients Receiving Blinatumomab.Mediterr J Hematol Infect Dis . 2018;10(1):e2018029. doi:10.4084/MJHID.2018.029
  7. 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. Front Immunol 2020, 11:611661.
Table 1: Pneumococcal Vaccination Titers Pre and Post Pneumovax 23 Booster