A search of PubMed and the Cochrane Database of Systematic Reviews was performed in September of 2024. Search terms were separated by Boolean operators as follows: (“bortezomib”) AND (“pediatric” OR “children”). Article types were “adaptive clinical trials”, “case reports”, “clinical studies”, “clinical trials phase 1-4”, “controlled clinical trials”, “randomized controlled trials”, and “multi-center studies”. References of selected articles were searched for additional studies. In July 2025, clinical trial registries were searched on clinicaltrials.gov using the terms “bortezomib” and “pediatric”; “bortezomib” and “children”. Those registries with results posted were reviewed for inclusion or exclusion into our analysis. Findings were compared to the drug insert provided by Takeda for adult adverse events (AEs) where available (Takeda Pharmaceuticals, 2022).

Studies included for analysis are those that reported on pediatric patients ≤18 years of age treated with BTZ for all indication, as a single agent or in combination with other therapeutics. Patients ≤8 years of age were further stratified and defined as young pediatric patients for analysis. Studies were excluded if they met any of the following criteria: (1) review articles, (2) preclinical studies, (3) clinical studies that included adult patients where pediatric data could not be separated, (4) trial design only, (5) patient reported outcomes, (6) did not use BTZ, and (7) not available in English.

Full-text articles from the initial search were reviewed independently by two authors (Z.C.L., A.C.). Data extraction was performed independently by each author and compared for accuracy prior to inclusion. Data collected included study type, date of publication, number of enrolled patients, number of patients assessed for AEs, treatment indication, co-treatment, grade and incidence of complications, dose-limiting toxicities, and deaths attributable to BTZ.

The CTCAE system was used for toxicity classification. Identified AEs were classified by organ systems and included the neurological, bone marrow, infectious, respiratory, cardiac, and gastrointestinal systems. Toxicities are reported here as individual CTCAE terms or grouped by broader organ system category based on reporting of source documents. Toxicities from the same CTCAE group were tabulated as single event when it was clear that the toxicities occurred in a single patient. Dose limiting toxicity (DLT) was defined as AEs that required dose reduction, temporary or permanent cessation of BTZ. Treatment-related mortality was defined as death within 30 days of last BTZ dose that was possibly attributed to BTZ.

Data was collected and analyzed using Microsoft Excel (Version 16.0). Studies that did not report on certain categories of AEs were excluded from the corresponding tabulations of patients who experienced these complications. Finally, pediatric AEs incidences were compared to those reported for adults in the commercial packaging insert for BTZ.

Search criteria across PubMed and Cochrane databases identified 183 articles of which 23 were duplicates. Screening the abstract resulted in the exclusion of 22 that were trial registrations, 31 conference proceedings, and 2 articles not available in English (Figure 1). 105 full text articles were assessed for eligibility. An additional 25 were excluded because they combined both adult and pediatric patient data from which pediatric data could not be extracted, 8 that did not use BTZ, 8 containing only laboratory data, 9 with no discussion of adverse events, and 1 that addressed trial design theories with no reported patient interventions (n = 54). An additional 10 studies were found within references of identified articles. Articles were downloaded and reviewed in their entirety for data extraction and analysis. In total, 64 articles met inclusion criteria (Figure 1).

Search criteria across registered clinical trials matching “bortezomib” and “pediatric” returned 26 trials and “bortezomib” and “children” returned 10 trials. After removing duplicates 10 unique trials had posted results. Of trials with results, 3 trials were published and already included in our analysis (Figure 1), 6 trials encompassed both pediatric and adult patients and pediatric data could not be extracted, and 1 trial included only adult (≥18 years old) patients. Thus, clinical trials registry did not yield additional analyzable data for this review.

The studies that met inclusion criteria included 11 clinical trials, 5 clinical studies (>10 patients), and 48 case series/case reports (≤10 patients) (Supplementary Tables S1–S3). Clinical trials included phase 1 (n = 9), phase 2 (n = 1), and phase 3 (n = 1) trials. Treatment indications included solid tumors, new/relapsed acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) (Supplementary Table S1).

Treatment indications for the clinical studies and case series/case reports included B-ALL, T-ALL, solid tumors, MM, antibody-mediated transplantation rejection, proliferative glomerulonephritis, autoimmune cytopenias after hematopoietic stem cell or intestinal transplant, refractory Evan’s syndrome, refractory TTP, refractory anti-NMDA encephalitis, complications secondary to ERT for Pompe’s disease, and heparin induced thrombocytopenia (Supplementary Tables S2, S3). BTZ was used as a single agent in 2 clinical trials and 2 case series but was more frequently administered with other drugs including chemotherapeutic agents and corticosteroids (Supplementary Tables S1–S3).

Dose-dependent, reversible peripheral neuropathy (PN) is a known BTZ AE (Richardson et al., 2005; Argyriou et al., 2008; San Miguel et al., 2008; Moreau et al., 2011; Robak et al., 2018). In the BTZ drug insert, 38% of adult patients receiving BTZ experienced PN, with 11% experiencing ≥ grade 3 toxicity, leading to 8% of all patients to discontinue treatment (Takeda Pharmaceuticals, 2022). The overall incidence of PN in pediatric patients treated with BTZ was 8.56%, with 3.17% experiencing ≥ grade 3 toxicity (Tables 1, 2; Figure 2A). In young pediatric patients, defined as patients 8 years or younger, the overall incidence was 2.46% (Table 3). ALL and AML patients had a 10% incidence of PN. When ALL and AML were excluded, only 4.40% of pediatric patients and no young pediatric patients experienced PN (Tables 1, 3). Overall, pediatric patients experienced a lower incidence of PNs than adults, and PN improved or resolved completely after BTZ cessation.

Other neurological AEs have also been reported in adults. Headaches were reported in 15% of patients, with <1% experiencing ≥ grade 3 toxicity. Transient ischemic attack, hemorrhagic stroke, coma, and Posterior Reversible Encephalopathy Syndrome were also reported although the incidences were not available (Takeda Pharmaceuticals, 2022). The overall incidence of other neurological AEs in pediatric patients treated with BTZ was 1.62%, with 1.69% of evaluable patients experiencing ≥ grade 3 toxicity (Tables 1, 2). Toxicities included headache, confusion, depressed level of consciousness, and seizures. In young pediatric patients, the overall incidence was 0.88% (Table 3). ALL and AML patients had a 1.2% incidence of other neurological AEs. When ALL and AML patients were excluded, 2.84% of pediatric patients and no young pediatric patients experienced other neurological AEs (Tables 1, 3; Figure 2A). Pediatric patients experienced fewer neurological AEs than adults.

Bone marrow suppression has been reported for PIs in adults (Richardson et al., 2003a; Jagannath et al., 2004; Murai et al., 2014; Kim et al., 2015). Reported bone marrow toxicities in the BTZ clinical trial data for Mantle Cell Lymphoma and Multiple Myeloma included anemia, neutropenia/febrile neutropenia, thrombocytopenia, leukopenia, and lymphopenia (Takeda Pharmaceuticals, 2022). Pediatric studies reviewed in this systematic review similarly reported high incidences of bone marrow suppression.

The incidence of anemia in adults was 18%, with 6% experiencing ≥ grade 3 toxicity (Takeda Pharmaceuticals, 2022). Pediatric incidence was higher than adults at 35.56%, with 24.74% experiencing ≥ grade 3 toxicity (Tables 1, 2; Figure 2B). In young pediatric patients, the incidence of any grade anemia was 3.13% (Table 3). The majority of ALL patients (61.43%) experienced anemia. When ALL patients were excluded, 23.87% of pediatric patients and 3.45% of young pediatric patients experienced anemia (Tables 1, 3; Figure 2B).

The rate of neutropenia in adults was 15%, with 10% experiencing ≥ grade 3 toxicity (Takeda Pharmaceuticals, 2022). Pediatric incidence of neutropenia was higher at 46.62%, with 43.70% experiencing ≥ grade 3 toxicity (Tables 1, 2; Figure 2B). In young pediatric patients, the incidence of any grade neutropenia was 3.13% (Table 3). The majority of ALL patients (76.92%) experienced neutropenia. When patients with ALL were excluded, 24.20% of pediatric patients and 3.45% of young pediatric patients experienced neutropenia (Tables 1, 3; Figure 2B).

Febrile neutropenia, not described in the adult drug insert, was observed in 16.67% of pediatric patients, with 11.46% experiencing ≥ grade 3 toxicity (Tables 1, 2; Figure 2B). In young pediatric patients, the incidence of any grade febrile neutropenia was 11.11% (Table 3). ALL and AML patients had a 34.65% incidence of febrile neutropenia. When patients with ALL and AML were excluded, 2.36% of all pediatric patients and no young pediatric patients experienced febrile neutropenia (Tables 1, 3; Figure 2B).

The incidence of thrombocytopenia in adults was 32%, with 25% experiencing ≥ grade 3 toxicity (Takeda Pharmaceuticals, 2022). Pediatric incidence was higher at 49.82%, with 46.15% experiencing ≥ grade 3 toxicity (Tables 1, 2; Figure 2B). In young pediatric patients, the incidence of any grade thrombocytopenia was 6.25% (Table 3). The majority of ALL patients (77.87%) experienced thrombocytopenia. When patients with ALL were excluded, 28.03% of pediatric patients and 6.90% of young pediatric patients experienced thrombocytopenia (Tables 1, 3; Figure 2B).

While not reported in the combined adult drug insert (Takeda Pharmaceuticals, 2022), Robak et al. reported a rate of leukopenia in adults with previously untreated mantle cell lymphoma of 48% for all grades, with 43% experiencing ≥ grade 3 toxicity (Robak et al., 2018). Pediatric incidence was comparable at 42.78%, with 32.98% experiencing ≥ grade 3 toxicity (Tables 1, 2; Figure 2B). In young pediatric patients, the incidence of any grade leukopenia was 3.13% (Table 3). The majority of ALL patients (80%) experienced leukopenia. When patients with ALL were excluded, 21.77% of pediatric patients and 3.45% of young pediatric patients experienced leukopenia (Tables 1, 3; Figure 2B).

Similarly, Robak et al. found that 28% adults with previously untreated mantle cell lymphoma experienced lymphopenia, with 25% experiencing ≥ grade 3 toxicity (Robak et al., 2018). Pediatric lymphopenia incidence was comparable, with an overall incidence of 28.36%, with 23.48% experiencing ≥ grade 3 toxicity (Tables 1, 2; Figure 2B). In young pediatric patients, the incidence lymphopenia was 3.13% (Table 3). The majority of ALL patients (58.54%) experienced lymphopenia. When ALL patients were excluded, 15.05% of pediatric patients and 3.45% young pediatric patients experienced lymphopenia (Tables 1, 3).

Infection is a known BTZ AE in both adult and pediatric populations. Infectious complications including bacterial, viral, and fungal infections in BTZ-treated adults. Of these, only the incidence of pneumonia (8%) and herpes zoster (11%) were reported (Takeda Pharmaceuticals, 2022). Infection of any kind occurred in 42.81% of pediatric patients during BTZ treatment (Table 1; Figure 2C), with 16.96% experiencing ≥ grade 3 toxicity (Table 2). Reported infection types ranged from mild sinusitis to severe life-threatening pulmonary aspergillosis, bacteremia or sepsis (Supplementary Tables S4–S6). In young pediatric patients, the incidence of any grade infection was 44.26% (Table 3). The majority of ALL and AML patients (55.87%) experienced lymphopenia. When these patients with ALL and AML were excluded, 5.03% of pediatric patients and 13.79% of young pediatric patients experienced infection (Tables 1, 3; Figure 2C).

Respiratory toxicity is a rare but potentially serious complication of BTZ in adults, ranging in severity from asthma-like symptoms or dyspnea to rapidly progressive pulmonary fibrosis (Saglam et al., 2020), though the incidence of milder respiratory toxicity in BTZ-treated adults treated is unknown. Respiratory events reported in pediatric studies included hypoxia, respiratory failure, and ARDS, which were pooled into a single category because of differences in reporting across studies. The overall incidence of respiratory toxicity was 10.62%, with 1.46% experiencing ≥ grade 3 toxicity (Tables 1, 2; Figure 2D). In young pediatric patients, the incidence was 12.39% (Table 3). ALL and AML patients had a 12.50% incidence of respiratory AEs. When patients with AML and ALL were excluded, 2.20% of pediatric patients and 3.45% of young pediatric patients experienced respiratory toxicity (Tables 1, 3; Figure 2D).

Gastrointestinal (GI) toxicities are known AEs of BTZ treatment owing to its effect on rapidly dividing GI epithelial cells. In BTZ-treated adults, 20% had anorexia, 28% had vomiting, and 46% experienced diarrhea; 7%, 2%, and 4% experienced these ≥ grade 3 toxicities, respectively (Takeda Pharmaceuticals, 2022). GI toxicities for pediatrics were categorized differently than in adults (Takeda Pharmaceuticals, 2022) and thus direct comparison was not possible. Nevertheless, pediatric incidence of GI AE appeared lower. Reported GI toxicities in pediatric patients included abdominal pain, typhlitis/colitis, nausea, vomiting, anorexia, diarrhea, mucositis, enterocolitis, ileus, and pancreatitis. When multiple GI toxicities occurred in a single patient, they are reported as a single GI AE. The overall incidence of GI AEs was 18.18%, with 5.91% experiencing ≥ grade 3 toxcity (Tables 1, 2; Figure 2D). In young pediatric patients, the rate of any grade GI toxicity was 12.20% (Table 3). ALL and AML patients had a 8.13% incidence of GI toxicities. When patients with ALL and AML were excluded, 28.30% of pediatric patients and 10.34% of young pediatric patients experienced GI toxicity (Tables 1, 3; Figure 2D).

Cardiac toxicity has been described in the drug insert as a potential BTZ AE. The adult incidence of treatment-related cardiac conditions is at 8% and includes new or worsening heart failure, decreased left ventricular ejection fraction, ischemic symptoms/myocardial infarction, arrhythmias, pericarditis, and pericardial effusion (Takeda Pharmaceuticals, 2022). Pediatric incidence of cardiac AEs was 5.51%, with 2.06% experiencing ≥ grade 3 toxicity (Tables 1, 2; Figure 2D). Toxicities reported in pediatric patients included heart failure, left ventricular systolic dysfunction, and hypotension. In young pediatric patients, the overall incidence was 0.91% (Table 3). ALL and AML patients had a 6.82% incidence of cardiac toxicities. When ALL and AML were excluded, 1.1% of pediatric patients and no young pediatric patients experienced cardiac AEs (Tables 1, 3; Figure 2D). In summary, pediatric patients experienced a lower incidence of cardiac AEs than adults.

DLT occurred in 13% of adults treated with BTZ, with the most common reasons for discontinuation being PN (5%) and diarrhea (3%) (Takeda Pharmaceuticals, 2022). Pediatric incidence of DLT was comparable at 13.78% (Table 1; Figure 2E). Reasons for discontinuation, reduction, or delay in dose were often not reported. The most frequently specified DLT was GI toxicity (0.65%), thrombocytopenia (0.65%), or PN (0.65%). In young pediatric patients, the incidence of DLT was lower than adults at 10.66% (Table 3). ALL and AML patients had a 16.09% incidence of dose-limiting toxicities. When patients with ALL and AML were excluded, the incidence of DLT was even lower at 7.01% of all pediatric patients and 3.45% of young pediatric patients (Tables 1, 3; Figure 2E).

Deaths while on BTZ therapy were rare. Adult mortality rate during BTZ treatment (with or without other concurrent treatment) ranged from 0.17% to 4% (Takeda Pharmaceuticals, 2022; Bringhen et al., 2018). Pediatric mortality rate was 1.92% (Table 1; Figure 2E), with an incidence for young pediatric patients of 0.82% (Table 3). The most common cause of on-therapy mortality was infection. Infections were predominantly fungal (5/8) and occurred in the context of broad immunosuppression with co-therapy of combinations of vincristine, dexamethasone, pegylated L-asparaginase, doxorubicin, intrathecal methotrexate, and/or intrathecal triple chemotherapy (methotrexate, cytarabine, methylprednisolone or hydrocortisone) (Supplementary Table S4). Of the 12 pediatric deaths reported to be possibly related to BTZ therapy, 11 occurred in patients with ALL (Table 3; Figure 2E). One death (0.60%) occured after heart transplantation due to renal and pulmonary complications (Morrow et al., 2012).

Of the 64 articles used in this systematic review, 4 articles (2 clinical trials and 2 case series/reports) described the use of BTZ as a single agent (Supplementary Tables S1–S3). This cohort of patients had higher neurological toxicities (4.55%) and GI toxicities (31.82%) (Figure 2; Supplementary Table S7). Interestingly, they had similar incidence of toxicities relative to non-ALL or AML patients receiving multi-therapy.

A significant limitation of this systematic review is a paucity of blinded pediatric studies of BTZ. The majority of studies (48/64) included in this analysis were case reports or case series ≤10 patients and did not have a systematic framework for evaluating AEs. The risk of researcher influence or selection bias in cases chosen for publication was also possible.