Immunotherapy with blinatumomab in B-cell acute lymphoblastic leukemia: a narrative review of efficacy, toxicity, and patient management in relapse and consolidation

Introduction

Acute lymphoblastic leukemia (ALL) is a neoplastic disorder affecting B or T lymphoblasts and is marked by the accumulation of blasts (immature blood cells) in the bone marrow, peripheral blood, or lymphoid organs (1). A global increase in ALL from 66,810 cases in 1990 to 153,320 cases in 2019 was reported in a study that incorporated data obtained from approximately 204 countries (2). In addition, the incidence of new ALL cases has increased by 1.29% worldwide, and the age-standardized incidence rate has increased by 1.61% annually. The incidence of ALL in children aged 1–4 years is twice as high in Caucasian populations as in Black populations (3). B-cell ALL (B-ALL) is the most common subtype of ALL, accounting for 85% of ALL cases (4,5), and is reported to be most prevalent in children; however, it accounts for approximately 20% of acute leukemia cases in adults (6,7).

Blinatumomab (BLINCYTO; Amgen Inc., USA) is a targeted immunotherapy primarily used for the treatment of B-ALL (8). It is a unique type of drug classified as a bispecific T-cell engager (BiTE^®) and represents a major advancement in cancer immunotherapy by harnessing the patient’s own immune system to target and destroy cancer cells (8-10).

Blinatumomab is a non-immunogenic, single-chain protein consisting of an anti-CD19 variable fragment (Fv) and an anti-CD3 Fv joined by a flexible 5-amino acid glycine-serine linker (11). Its primary mechanism involves targeting two key antigens: CD19, which is expressed on the majority of B-cell leukemia and lymphoma cells; and the CD3 complex, a co-receptor for the T-cell receptor involved in activating both cytotoxic T cells (CD8⁺ naive T cells) and T helper cells (CD4⁺ naive T cells) (8,10,12). The immunological synapse between CD19 on leukemia cells and CD3 on the patient’s T cells allows T cells to recognize and destroy CD19-expressing malignant B cells.

Blinatumomab is indicated for the treatment of relapsed or refractory (R/R) B-ALL, measurable residual disease (MRD)-positive ALL, and MRD-negative B-ALL in consolidation as an add-on to multiphase chemotherapy (13). Blinatumomab is administered as a continuous intravenous (IV) infusion, typically over 28 days per cycle, followed by a 1- or 2-week treatment-free interval (13). Subcutaneous (SC) administration of blinatumomab is an alternative and convenient mode of administration that has recently gained interest (14). An ongoing phase Ib dose-escalation study (NCT04521231) reported an acceptable safety profile and promising antileukemia activity of SC blinatumomab in patients with R/R B-ALL (15).

This review article provides an overview of the efficacy and safety of blinatumomab in adult and pediatric patients with B-ALL, as well as the patient management for blinatumomab therapy. To the best of our knowledge, this is the first comprehensive assessment of all key trials conducted over the past 15 years since the development of blinatumomab in B-ALL. We present this article in accordance with the Narrative Review reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-25-5/rc).

Methods

The articles were searched using PubMed database using search terms like “blinatumomab”, “acute lymphoblastic leukemia”, “clinical trial” or “clinical study” published from 2010 to 2024 (Table 1). Peer-reviewed literature published in English, adult and pediatric patient population, clinical studies and review articles were included.

Efficacy

Key clinical trials and study results

Numerous studies have demonstrated the efficacy of blinatumomab in both adult and pediatric patients with B-ALL. The results from key clinical trials are presented below and summarized in Table 2.

Adults

Data from multiple phase II and phase III clinical trials have shown the clinical benefits of blinatumomab in the treatment of R/R B-ALL. An open-label, phase II, single-arm, multicenter study (MT103-211; NCT01466179) evaluated blinatumomab in adult patients with Philadelphia chromosome-negative (Ph−) R/R B-ALL (16). Overall, 43% of patients achieved complete remission (CR) or CR with partial hematologic recovery (CRh) within the first two cycles of treatment. In addition, 73 patients who achieved CR or CRh within the first two cycles were evaluable for MRD; of these, 60 achieved an MRD response. In patients with <50% bone marrow blasts, the rate of CR or CRh was 73%, whereas in patients with ≥50% blasts, the rate was 29% (16).

ALCANTARA (NCT02000427), an open-label, single-arm, multicenter phase II study, examined the CR rate in patients with R/R Philadelphia chromosome-positive precursor (Ph+) B-ALL who received at least one infusion of blinatumomab. The study demonstrated improved outcomes in patients treated with blinatumomab. Overall, 36% of patients achieved CR or CRh, and 88% achieved a complete MRD response (17). Another open-label, single-arm, phase II study (BLAST study; NCT01207388) evaluated blinatumomab in adults with B-ALL in hematologic remission with detectable MRD. This study enrolled adults with B-ALL in remission but MRD-positive. Overall, 78% of patients achieved MRD negativity after one cycle of blinatumomab (18).

TOWER (NCT02013167), a phase III study, further explored the efficacy of blinatumomab in patients with R/R B-ALL. This study compared blinatumomab with standard chemotherapy in adult patients with Ph− R/R B-ALL. A significant improvement in overall survival (OS) was reported with blinatumomab vs. chemotherapy [hazard ratio (HR), 0.71; P=0.01]. After 12 weeks of treatment, CR/CRh ratio was 44% in the blinatumomab group and 25% in the chemotherapy group. In addition, the median duration of remission was 7.3 months in the blinatumomab group and 4.6 months in the chemotherapy group (19).

Another phase III study (E1910; NCT02003222), conducted by the ECOG-ACRIN Cancer Research Group, assessed the efficacy of the addition of blinatumomab to chemotherapy as a frontline therapy for adult patients with newly diagnosed B-ALL (20). Patients with MRD negativity (<0.01% leukemic cells in the bone marrow) at the time of randomization were allocated to receive standard chemotherapy alone (four cycles of consolidation chemotherapy) or blinatumomab (two cycles) plus chemotherapy (four cycles of consolidation chemotherapy). Blinatumomab was added after MRD-negative CR was achieved with chemotherapy, with the goal of eliminating residual leukemia cells (although not detectable with the currently available MRD techniques) and improving survival outcomes. Blinatumomab treatment significantly improved the 3-year OS compared with chemotherapy alone [HR for death, 0.41; 95% confidence interval (CI), 0.23–0.73; P=0.002]. Relapse-free survival was 80% in the blinatumomab arm vs. 64% in the chemotherapy alone arm (HR for relapse or death 0.53; 95% CI, 0.32–0.87). The effect was more pronounced in patients aged <55 years; blinatumomab improved both OS (70% vs. 65% with chemotherapy alone; HR for death, 0.66; 95% CI, 0.33–1.35) and relapse-free survival (69% vs. 57%; HR for relapse or death, 0.74; 95% CI, 0.39–1.43) at 3 years (20).

Children

An open-label, single-arm, multicenter, phase I/II study (MT103-205; NCT01471782) in pediatric patients evaluated the safety, pharmacokinetics, dosage, and efficacy of blinatumomab and determined the recommended/maximum tolerated dose (MTD) in patients with R/R B-ALL (>25% blasts in the bone marrow at the time of enrollment in the study). In this study, patients received continuous IV infusion of blinatumomab over 4 weeks, followed by a 2-week treatment-free interval. CR was achieved in 39% of pediatric patients after the first two cycles of blinatumomab treatment. Among patients who achieved CR/CRh, 52% showed a complete MRD response. This study established blinatumomab as an effective salvage therapy in pediatric patients with R/R B-ALL, demonstrating meaningful remission rates and MRD clearance, which are associated with better long-term outcomes. In addition, an MTD of 15 µg/m²/d was identified in children with overt B-ALL relapse (21).

Results from a recent phase III, multicenter randomized study (AALL1731; NCT03914625) in pediatric patients with B-ALL showed improved disease-free survival (DFS) with blinatumomab. The 3-year DFS in patients with B-ALL with an average and higher relapse risk was 98% and 94%, respectively, for patients receiving blinatumomab plus chemotherapy compared with 90% and 85%, respectively, in the chemotherapy-only group. The 3-year OS with and without blinatumomab was 98% and 97%, respectively (22).

Another phase III study (NCT02393859) compared blinatumomab with standard-of-care chemotherapy in pediatric patients with high-risk first-relapse B-ALL. After induction therapy and two courses of consolidation chemotherapy, patients received either one cycle of blinatumomab or standard chemotherapy as post-relapse therapy. In this randomized clinical trial, blinatumomab treatment compared with chemotherapy as consolidation treatment significantly improved event-free survival (EFS; HR 0.33) after a median of 22.4 months of follow-up. The HR for OS was 0.43. The MRD remission rate was 93% in the blinatumomab arm and 24% in the chemotherapy arm (23,24). At a later median follow-up of 44 months, a major improvement in OS was observed, with an HR of 0.34 (25). This trial demonstrated that blinatumomab can improve EFS and OS when used during consolidation in pediatric patients with first high-risk relapse of B-ALL, reducing the risk of relapse by achieving deeper remissions compared with conventional chemotherapy (24).

A study by Children’s Oncology Group (AALL1331) evaluated blinatumomab in pediatric and adolescent patients with high- (early relapse), intermediate-risk (residual disease after induction chemotherapy) or low risk (LR)-first relapse. This randomized study assessed blinatumomab as a post-relapse therapy after reinduction chemotherapy.

Two cycles of blinatumomab were added to conventional chemotherapy consolidation after induction therapy (26). The median follow-up was 2.9 years. The 2-year DFS was 54.4% in the blinatumomab arm and 39% in the chemotherapy arm. The 2-year OS was 71.3% in the blinatumomab arm and 58.4% in the chemotherapy arm.

Another aim of the Children’s Oncology Group AALL1331 study was to compare DFS in patients with LR first relapse of B-ALL treated with chemotherapy alone vs. chemotherapy plus blinatumomab (26). After block 1 reinduction, patients aged 1–30 years with LR first relapse of B-ALL were randomly assigned to either two cycles of chemotherapy alone or two cycles of chemotherapy intercalated with three cycles of blinatumomab treatment. The 4-year DFS (P=0.09) and OS (P=0.11) rates for the 255 LR patients enrolled between December 2014 and September 2019 were 61.2% and 90.4%, respectively, in the blinatumomab arm vs. 49.5% and 79.6%, respectively, in the chemotherapy arm. A significant difference in DFS (P=0.02) and OS (P=0.02) was demonstrated between blinatumomab and chemotherapy arms in patients experiencing bone marrow relapse with or without extramedullary disease (EM), but not in patients with isolated EM relapse. This study indicates that pediatric patients with high-risk, intermediate-risk, and LR first relapse of B-ALL benefit from blinatumomab treatment if the disease recurrence involves the bone marrow. These findings reinforce results from other trials by showing that blinatumomab improves EFS and OS after treatment in the consolidation setting (26).

Toxicity

Cytokine release syndrome (CRS)

CRS is a common toxicity associated with blinatumomab, resulting from rapid activation and proliferation of T cells, which leads to a massive release of inflammatory cytokines such as interleukins, tumor necrosis factor, and interferons (27). This immune response induces a systemic inflammatory response. The incidence of grade 3 or higher CRS was low in clinical studies of blinatumomab, with CRS reported in 5% of patients in the TOWER study (relapse) (19), <1% of pediatric patients (22) and 2–6% of patients across several other trials (16). The incidence was higher in patients receiving blinatumomab in the presence of a high leukemia burden.

Neurological toxicities

Neurological adverse events are well-recognized complications of blinatumomab therapy, possibly stemming from cytokine release from T cells within the central nervous system. However, the exact pathological mechanism remains incompletely understood (28).

Symptoms can include seizures, confusion and disorientation, difficulty in speaking or slurred speech, loss of balance, loss of consciousness, headache, and trouble sleeping. Neurological toxicities typically occur within the first 2 weeks of treatment initiation, with symptoms gradually resolving after the drug is paused or discontinued (29).

Grade 3 or higher neurological toxicities following the initiation of blinatumomab administration occurred in 9–23% of patients (17-21) and included encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Most neurologic toxicities resolved following the interruption of blinatumomab treatment, but some resulted in treatment discontinuation. The incidence of severe neurological events (grade 3 or higher) in pediatric patients ranged from 4–5% (23-26).

Infections

Blinatumomab treatment is associated with an increased risk of infections. In clinical studies, serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in approximately 25% of patients, some of which were life-threatening or even fatal (29). In adult patients, severe infections were observed in 8% of patients treated for MRD-positive disease and in 15% of those treated for R/R disease compared with 32% in patients treated with chemotherapy (13).

Patient handling and toxicity management

Given its unique mechanism of action, blinatumomab requires careful handling and management of potential toxicities to ensure patient safety and optimize treatment outcomes according to the respective local label and treatment standards.

Patient selection and pretreatment recommendations

It is important to assess the baseline health of patients by evaluating the overall health status, including cardiac, hepatic, and renal function. This helps in predicting how well the patient may tolerate blinatumomab, particularly because the drug is associated with potentially serious toxicities such as CRS and neurological complications.

Patients with ongoing infections or poorly controlled medical conditions should receive appropriate treatment and stabilization before initiating blinatumomab therapy because they are at a higher risk of complications.

Debulking prior treatment with steroids and/or chemotherapy

To reduce the risk of early toxicities such as CRS, reduction of tumor load with corticosteroids (such as dexamethasone or equivalent), biological therapy (such as tocilizumab), and/or chemotherapy is recommended. A pooled analysis of five clinical trials reported that dexamethasone (10–24 mg/m²/day for up to 5 days) lowered baseline bone marrow blast percentage (bBMB) to <50% in approximately 20% of patients, and most of these patients with <50% bBMBs achieved CR with blinatumomab treatment (30).

A real-world multicenter study reported that among debulking regimens, the highest CR rates after blinatumomab treatment were observed in patients receiving polychemotherapy and low-intensity chemotherapy with or without steroids (31).

In the phase II Australasian Leukemia and Lymphoma Group study, patients with Ph− B-ALL received debulking low-intensity chemotherapy comprising cyclophosphamide 150 mg/m², vincristine 2 mg, and dexamethasone 10 mg/m², followed by 7 days of blinatumomab treatment at 9 µg/day on days 1–7 and 28 µg/day on days 8–28. All patients achieved CR, with estimated 24-month EFS and OS rates of 62% and 69%, respectively (32). In adolescent and adult patients with R/R B-ALL, Jabbour et al. reported favorable outcomes using a lower-intensity regimen comprising cyclophosphamide, vincristine, and dacarbazine, followed by blinatumomab, achieving a 3-year RFS of 73%. Only one patient experienced grade 3 CRS (33).

Monitoring for neurological events

As discussed earlier in the manuscript, the major toxicities of blinatumomab that clinicians should be aware of are neurological adverse events and CRS. Prompt management should be initiated to minimize the potential risks of these conditions. In addition, a baseline neurological evaluation should be performed to identify any pre-existing conditions that might exacerbate treatment-related neurological toxicity. Additional methods, including imaging studies (computed tomography, magnetic resonance imaging), electroencephalography, or cerebrospinal fluid analysis, should be performed to rule out other potential neurological disorders (29).

CRS management

Monitoring and early intervention

Vital signs should be monitored regularly, especially during the first 48 h of each treatment cycle, as CRS typically presents early in life. Regular monitoring of temperature, blood pressure monitoring, diuresis, and laboratory assessments for inflammatory markers (e.g., C-reactive protein and ferritin) can help identify early signs of CRS. In mild cases, supportive care such as with antipyretics (e.g., acetaminophen for fever) and IV fluids for hypotension may be sufficient (29).

For the management of severe CRS (grades 3–4), high-dose corticosteroids (e.g., dexamethasone 20 mg IV) are often used to suppress excessive immune responses. Tocilizumab, an IL-6 receptor antagonist, can be administered in severe or lifethreatening cases of CRS (29). Patients with severe hypotension may require vasopressors, whereas those with respiratory distress might require supplemental oxygen or, in extreme cases, mechanical ventilation.

Neurological toxicity management

Neurological toxicities are common in patients receiving blinatumomab, with symptoms ranging from mild confusion to severe seizures or encephalopathy.

Monitoring, early detection, and management of neurological toxicity

Patients should undergo frequent assessments for neurological symptoms, particularly during the first 2 weeks of therapy. Regular monitoring includes checking for changes in mental status, motor skills (writing test and/or finger-nose test), speech, and sensory function. Occasionally, neurological events start with intention tremors, which can be monitored using a regular writing test and/or a finger-nose test. In such cases, early initiation of dexamethasone may be beneficial. At the onset of any grade 2 or higher neurological event, blinatumomab should be paused temporarily (29). Symptoms, such as seizures or encephalopathy, require immediate interruption of blinatumomab treatment. In cases of severe (grade 4) neurological toxicity, the drug may need to be permanently discontinued (29). Blinatumomab infusion may be continued; however, the patient should be closely monitored for any progression of symptoms. Corticosteroids (e.g., dexamethasone) may be required for neurological events to reduce inflammation of the central nervous system (29). Steroids can manage blinatumomab-related toxicities but may impair immunity, raising the risk of infection in patients with B-ALL. Therefore, steroid doses should be carefully optimized. Antiepileptic medications should be administered to patients experiencing seizures, and further neurological consultation is often warranted.

Infection risk management

Since blinatumomab is administered to patients who are at risk of infections, possible aggravation of immunosuppression should be closely monitored.

Monitoring and prevention

Routine monitoring of complete blood counts is necessary to assess for neutropenia and other cytopenias (29). Prophylaxis against viral (e.g., herpes simplex or varicella zoster) and fungal infections should be considered, especially in high-risk patients (34). Any sign of infection, such as fever, should be promptly evaluated, and empiric antibiotics should be started without delay if febrile neutropenia is suspected. Patients with severe and persistent neutropenia may benefit from administration of granulocyte-colony stimulating factor and, possibly, antibiotic prophylaxis. Replacement therapy with IV immunoglobulin is recommended for patients with hypogammaglobulinemia (35).

SC blinatumomab administration

Blinatumomab is traditionally administered as a continuous IV infusion, primarily because of its short half-life (36). However, there has been an interest in developing an SC formulation of blinatumomab, as this route could offer several benefits (15).

Potential benefits of SC administration

SC administration could make treatment less invasive than continuous IV infusion, enhancing patient comfort. Further, IV administration over long periods can carry risks, such as catheter-related infections or thrombosis. These infusion-related complications can be minimized with SC delivery.

A recent study demonstrated that SC blinatumomab displayed efficacy as observed in studies involving IV blinatumomab administration (14). Additionally, SC administration of blinatumomab demonstrated a favorable pharmacokinetic profile, with a gradual increase in exposure compared with IV administration (14). This approach allows for higher doses, earlier exposure, and an apparent increase in the half-life of SC blinatumomab (approximately 8–12 h versus approximately 2 h for continuous IV infusion) (36). Patients could potentially receive SC injections in an outpatient setting or even self-administer the drug, allowing more freedom in daily life.

Preliminary data demonstrated the convenience of application and high efficacy of SC blinatumomab. Patients with various prior treatment lines for B-ALL received SC blinatumomab at the following two doses: (I) 250 µg once daily (QD) for week 1 and 500 µg thrice weekly (TIW) thereafter (250 µg/500 µg) or (II) 500 µg QD for week 1 and 1,000 µg TIW thereafter (500 µg/1,000 µg). After two cycles, 12 of 14 patients (85.7%) from the 250 µg/500 µg dose had gone into remission, and nine of which patients (75.0%) were negative for MRD. At the 500 µg/1,000 µg dose, 12 of the 13 patients (92.3%) achieved CR, and all of which (100.0%) were MRD–negative. SC injections were well tolerated (37).

Patient education and support

Patient education is critical for ensuring successful blinatumomab treatment. Patients and caregivers should be informed of the potential side effects and symptoms that require immediate medical attention. Additionally, they should understand the importance of adhering to the treatment schedule, monitoring adverse events, and maintaining close communication with healthcare teams.

Key educational points for patients

Fever, hypotension, shortness of breath, and flu-like symptoms should be reported immediately. Any neurological symptoms, such as confusion, headaches, speech difficulties, or seizures, should be promptly reported. Prevention of infection should be encouraged by practicing good hygiene, avoiding crowded places, and by early reporting of fever or signs of infection. Patients should also be taught about the process of administration and schedule of continuous infusions and the importance of maintaining infusion pump function at all times (13).

In summary, blinatumomab toxicity management is critical to achieving successful outcomes while minimizing risks. Careful patient selection, pretreatment evaluation, proactive prevention, and management of CRS, neurological toxicity, infections, and hematologic complications are essential to maximize the therapeutic benefit of blinatumomab. Early intervention and comprehensive patient monitoring, particularly during the first cycle, can mitigate many serious adverse events associated with this therapy, ensuring safer treatment courses for patients with ALL.

Strengths and limitations

This review article summarizes the efficacy and safety of blinatumomab using findings from key clinical trials of blinatumomab. Specifically, outcomes from the clinical trials in both adult and pediatric patients with R/R B-ALL were included. Further, this review article also summarizes aspects of patient management, particularly while tackling medically relevant AEs such as CRS and neurological toxicity. Blinatumomab has a short half-life and is administered to patients as a continuous IV infusion. The short half-life is a major asset in mitigation of adverse events, which in most cases resolves after treatment interruption. Furthermore, the infusion pumps present challenges. To circumvent this, an SC formulation of blinatumomab has been developed recently. This review article also summarizes the benefits of SC blinatumomab, including the ease of administration, by providing outcomes of an important clinical trial evaluating the safety and efficacy of SC blinatumomab.

The review article did not present original findings, thereby limiting its contribution to advancing scientific knowledge. Although this narrative review summarizes all the key blinatumomab trials, there is a potential for confirmation bias and a skewed representation of the literature. Notwithstanding these limitations, to the best of our knowledge, this is the first comprehensive assessment of all key trials conducted over the past 15 years since the development of blinatumomab in B-ALL.

Conclusions

Blinatumomab is a groundbreaking therapy for patients with B-ALL, offering significant benefits for those with R/R disease or consolidation after the achievement of CR. When administered in consolidation therapy, blinatumomab has been demonstrated to offer major improvements in survival independent of age, genetic aberrations, and/or disease phase. The elimination of residual disease by blinatumomab after debulking of the tumor load with chemotherapy and/or corticosteroids shows promising efficacy. This may be the paradigm for a new approach to cancer management through the eradication of residual disease. The next goal was to reduce chemotherapy by administering blinatumomab. The mechanism by which blinatumomab harnesses the body’s immune system to attack cancer cells represents a paradigm shift in cancer treatment. Although blinatumomab, an off‑the‑shelf product, is highly effective in achieving remission and improving survival outcomes, its use is associated with toxicities that require careful management. CRS and neurological toxicity are the most frequent toxicities associated with blinatumomab. Studies have shown that a high disease burden is associated with an increased risk of CRS. Therefore, debulking therapy before initiating treatment with blinatumomab may reduce its toxicity. The administration of blinatumomab as a continuous infusion can be challenging. There has been an interest in using the SC route as an alternative delivery method. The early experience with the SC formulation of blinatumomab shows potential and warrants further investigation. Ongoing research continues to explore its potential as a combination therapy and frontline treatment, further expanding its role in the treatment strategy for both adult and pediatric patients with B-ALL.

Acknowledgments

We thank Divyaanka Iyer, PhD, and Vibhuti Singh, PhD, from Cactus Life Sciences Pvt. Ltd. (part of Cactus Communications) for their medical writing support and/or editorial support.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-25-5/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-25-5/prf

Funding: This study was supported by Amgen Inc.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-25-5/coif). All authors report support for this study from Amgen Inc. G.Z. reports the following patents: Dosage Regimen for Administering a CD19XCD3 Bispecific Antibody (WO2011/051307), Stratification of ALL patients (WO2015181683), Treatment of Pediatric Acute Lymphoblastic Leukemia (WO2010/052013), Anti-leukocyte Adhesion for the Mitigation of Potential Adverse Events (WO2014/122251), Means and Methods of Treating DLBCL (WO2012055961), Adaptive Subcutaneous Dosing of Blinatumomab in B Precursor Lymphoblastic Leukemia (WO2023062188), Prevention Of Adverse Effects Caused By CD3 Specific Binding Domains (WO2012/062596), Novel treatment of acute lymphoblastic leukemia (WO2010/052014), Dosage Regimen for Administering a CD19XCD3 Bispecific Antibody to Patients at Risk (WO2012146394), and Novel Dosing Regimen of Blinatumomab for Treatment of Aggressive Non-Hodgkin-Lymphoma with Onset of Response within 2 weeks and Novel Medication for Prevention of Neurological Adverse Events (WO2020/221792). G.Z. also reports stocks and employment in Amgen Inc. M.S. reports research support from Amgen, BMS/Celgene, Gilead/Kite, Janssen, Miltenyi Biotec, Molecular Partners, Novartis, Roche, Seagen, Takeda, participation in speakers’ bureau for AstraZeneca, BMS, Gilead/Kite, GSK, Janssen, LAWG, Novartis, Pfizer, Roche, Springer Healthcare. M.S. also performed a consultancy or advisory board role for AbbVie, Amgen, Autolus, AvenCell, BMS, CanCell Therapeutics, Genmab US, Gilead, Ichnos Sciences, Incyte Biosciences, Interius BioTherapeutics, Janssen, Miltenyi Biomedicine, Molecular Partners, Nektar Therapeutics, Novartis, Orbital Therapeutics, Pfizer, Roche, Sanofi, Scare, Takeda, and received travel support from Gilead, Pfizer, and Roche. F.L. reports personal fees from Amgen Inc., Novartis, Miltenyi, Medac, Jazz Pharmaceuticals, and Takeda, and other financial or non-financial interests from Bellicum Pharmaceuticals and Neovi. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Puckett Y, Chan O. Acute Lymphocytic Leukemia. Treasure Island (FL): StatPearls Publishing; 2025.
2. Hu Y, Zhang X, Zhang A, et al. Global burden and attributable risk factors of acute lymphoblastic leukemia in 204 countries and territories in 1990-2019: Estimation based on Global Burden of Disease Study 2019. Hematol Oncol 2022;40:92-104. [Crossref] [PubMed]
3. Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version. National Cancer Institute (US).
4. Zhang L, Habeebu SSM, Li W. Prognostic and Predictive Biomarkers in Precursor B-cell Acute Lymphoblastic Leukemia. In: Li W, editor. Leukemia. Brisbane (AU): Exon Publications; 2022 Oct 16 Chapter 10.
5. Chiaretti S, Zini G, Bassan R. Diagnosis and subclassification of acute lymphoblastic leukemia. Mediterr J Hematol Infect Dis 2014;6:e2014073. [Crossref] [PubMed]
6. Jerez J, Goldschmidt V, Guerra MC, et al. Epidemiological and clinical characteristics of adult acute lymphoblastic leukemia patients in Chile: A single-center analysis. Leuk Res Rep 2023;21:100405. [Crossref] [PubMed]
7. Chennamadhavuni A, Iyengar V, Mukkamalla SKR, et al. Leukemia. Treasure Island (FL): StatPearls Publishing; 2025.
8. Oak E, Bartlett NL. Blinatumomab for the treatment of B-cell lymphoma. Expert Opin Investig Drugs 2015;24:715-24. [Crossref] [PubMed]
9. Withoff S, Helfrich W, de Leij LF, et al. Bi-specific antibody therapy for the treatment of cancer. Curr Opin Mol Ther 2001;3:53-62. [PubMed]
10. Wolf E, Hofmeister R, Kufer P, et al. BiTEs: bispecific antibody constructs with unique anti-tumor activity. Drug Discov Today 2005;10:1237-44. [Crossref] [PubMed]
11. Rogala B, Freyer CW, Ontiveros EP, et al. Blinatumomab: enlisting serial killer T-cells in the war against hematologic malignancies. Expert Opin Biol Ther 2015;15:895-908. [Crossref] [PubMed]
12. Bargou R, Leo E, Zugmaier G, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 2008;321:974-7. [Crossref] [PubMed]
13. BLINCYTO® (blinatumomab) for injection, for intravenous use [prescribing information]. Thousand Oaks (CA): Amgen Inc.; February 2024. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125557s029lbl.pdf. Accessed on May 28, 2025.
14. Pourhassan H, Agrawal V, Pullarkat V, et al. Positioning blinatumomab in the frontline of adult B-cell acute lymphoblastic leukemia treatment. Front Oncol 2023;13:1237031. [Crossref] [PubMed]
15. Sánchez PM, Zugmaier G, Gordon P, et al. Safety and Pharmacokinetics of Subcutaneous Blinatumomab (SC blinatumomab) for the Treatment of Adults with Relapsed or Refractory B Cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL); Results from a Phase 1b Study. Blood 2022;140:6122-4. [Crossref]
16. Topp MS, Gökbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol 2015;16:57-66. [Crossref] [PubMed]
17. Martinelli G, Boissel N, Chevallier P, et al. Long-term follow-up of blinatumomab in patients with relapsed/refractory Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukaemia: Final analysis of ALCANTARA study. Eur J Cancer 2021;146:107-14. [Crossref] [PubMed]
18. Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood 2018;131:1522-31. [Crossref] [PubMed]
19. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med 2017;376:836-47. [Crossref] [PubMed]
20. Litzow MR, Sun Z, Mattison RJ, et al. Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults. N Engl J Med 2024;391:320-33. [Crossref] [PubMed]
21. von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol 2016;34:4381-9. [Crossref] [PubMed]
22. Gupta S, Rau RE, Kairalla JA, et al. Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children. N Engl J Med 2025;392:875-91. [Crossref] [PubMed]
23. Locatelli F, Eckert C, Hrusak O, et al. Blinatumomab overcomes poor prognostic impact of measurable residual disease in pediatric high-risk first relapse B-cell precursor acute lymphoblastic leukemia. Pediatr Blood Cancer 2022;69:e29715. [Crossref] [PubMed]
24. Locatelli F, Zugmaier G, Rizzari C, et al. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA 2021;325:843-54. [Crossref] [PubMed]
25. Locatelli F, Zugmaier G, Rizzari C, et al. Improved survival and MRD remission with blinatumomab vs. chemotherapy in children with first high-risk relapse B-ALL. Leukemia 2023;37:222-5. [Crossref] [PubMed]
26. Hogan LE, Brown PA, Ji L, et al. Children’s Oncology Group AALL1331: Phase III Trial of Blinatumomab in Children, Adolescents, and Young Adults With Low-Risk B-Cell ALL in First Relapse. J Clin Oncol 2023;41:4118-29. [Crossref] [PubMed]
27. Stein A, Franklin JL, Chia VM, et al. Benefit-Risk Assessment of Blinatumomab in the Treatment of Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia. Drug Saf 2019;42:587-601. [Crossref] [PubMed]
28. Klinger M, Zugmaier G, Nägele V, et al. Adhesion of T Cells to Endothelial Cells Facilitates Blinatumomab-Associated Neurologic Adverse Events. Cancer Res 2020;80:91-101. [Crossref] [PubMed]
29. Conde-Royo D, Juárez-Salcedo LM, Dalia S. Management of adverse effects of new monoclonal antibody treatments in acute lymphoblastic leukemia. Drugs Context 2020;9: [Crossref] [PubMed]
30. Queudeville M, Stein AS, Locatelli F, et al. Low leukemia burden improves blinatumomab efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia. Cancer 2023;129:1384-93. [Crossref] [PubMed]
31. Bonifacio M, Papayannidis C, Lussana F, et al. Real-World Multicenter Experience in Tumor Debulking Prior to Blinatumomab Administration in Adult Patients With Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia. Front Oncol 2022;11:804714. [Crossref] [PubMed]
32. Fleming S, Reynolds J, Bajel A, et al. Sequential Blinatumomab with Reduced Intensity Chemotherapy in the Treatment of Older Adults with Newly Diagnosed Ph Negative B-Precursor Acute Lymphoblastic Leukemia - Interim Analysis of the Australasian Leukemia and Lymphoma Group ALL08 Study. Blood 2021;138:1234. [Crossref]
33. Jabbour E, Short NJ, Jain N, et al. Hyper-CVAD and sequential blinatumomab for newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: a single-arm, single-centre, phase 2 trial. Lancet Haematol 2022;9:e878-85. [Crossref] [PubMed]
34. Mikulska M, Lanini S, Gudiol C, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52). Clin Microbiol Infect 2018;24:S71-82. [Crossref] [PubMed]
35. Dale DC. Neutropenia. Available online: https://www.msdmanuals.com/professional/hematology-and-oncology/leukopenias/neutropenia. Accessed on May 28, 2025.
36. Burt R, Warcel D, Fielding AK. Blinatumomab, a bispecific B-cell and T-cell engaging antibody, in the treatment of B-cell malignancies. Hum Vaccin Immunother 2019;15:594-602. [Crossref] [PubMed]
37. Jabbour E, Zugmaier G, Agrawal V, et al. Single agent subcutaneous blinatumomab for advanced acute lymphoblastic leukemia. Am J Hematol 2024;99:586-95. [Crossref] [PubMed]