Blinatumomab use in pediatric B-ALL: where are we now? Open Access

B-cell acute lymphoblastic leukemia (B-ALL) is the most common cancer of childhood. Through risk stratification and refinements of multiagent chemotherapy regimens, remarkable progress has been made with survival rates for children with B-ALL of ∼90% on recent cooperative group trials.^1,2 Despite improvements in survival, patients with B-ALL remain at risk for late effects secondary to cytotoxic chemotherapy, including secondary malignancies, cardiotoxicity, obesity, metabolic syndrome, and neurocognitive changes.³ Additionally, with chemotherapy alone, relapses occur in ∼15% of patients, and outcomes after relapse remain poor.^1,4 

Immunotherapy has shifted the treatment paradigm of B-ALL, allowing for more precise targeting of the leukemic blasts with a more favorable toxicity profile compared with cytotoxic chemotherapy. Of the investigated immunotherapies, blinatumomab has arguably made the greatest impact on the therapeutic approach in B-ALL. Blinatumomab is a bispecific T-cell–engaging antibody construct that links CD3⁺ cytotoxic T cells and CD19⁺ B cells, allowing a patient’s own T cells to recognize and lyse CD19⁺ leukemia cells. Blinatumomab received its first approval from the US Food and Drug Administration in December 2014 and as of June 2024 is approved for the treatment of patients aged ≥1 month with relapsed or refractory (R/R) and newly diagnosed BCR::ABL-negative, CD19⁺ B-ALL (Figure 1). This remarkable progress made in the last decade means that most patients with B-ALL will now receive blinatumomab. The purpose of this review is to provide a comprehensive review of the studies that culminated in these regulatory approvals, with a focus on its use in pediatric patients (Table 1). We will also address the use of blinatumomab in special populations, explore lingering questions related to the use of blinatumomab in B-ALL, and discuss key considerations for future use.

Outcomes for children and adolescents/young adults (AYAs) with relapsed B-ALL are generally poor, with 5-year overall survival (OS) rates ranging from 25% to 65%, with the most dismal outcomes among those with early relapses.⁴ Risk stratification of relapsed disease is generally based on site(s) of relapse, time from diagnosis, and minimal residual disease (MRD) response to reinduction, with high-risk patients proceeding to allogeneic hematopoietic stem cell transplant (HSCT) and lower-risk patients potentially treated with chemotherapy alone. After a number of studies in adult patients demonstrating acceptable tolerability and promising efficacy,^14-16 a phase 1/2 study of blinatumomab in pediatric patients with R/R B-ALL with an M3 (≥25% blasts) marrow established the maximum tolerated dosage as 5 μg/m² per day for 1 week followed by 15 μg/m² per day for the remainder of the 28-day cycle.⁵ Among 70 patients who received the recommended dosage, 27 (39%) achieved a complete remission (CR; defined as no circulating blasts or extramedullary disease and <5% marrow blasts) within the first 2 cycles of blinatumomab, and 52% of those in CR achieved an MRD-negative response (MRD at <10⁻⁴). This study established the safety of single-agent blinatumomab in children with R/R B-ALL and demonstrated a promising efficacy signal in this heavily pretreated population. The RIALTO study was an open-label, single-arm, expanded access study that included 110 patients aged <18 years with R/R B-ALL. Patients received up to 5 cycles of blinatumomab as induction and/or consolidation. The results of this study further supported the safety of blinatumomab in children with R/R B-ALL, with grade ≥3 cytokine release syndrome (CRS) and neurotoxicity reported in only 1.8% and 3.6% of patients, respectively.^6,7 Within the first 2 cycles, 63% of patients achieved a CR; 83% of these responders achieved an MRD response, defined as conversion of MRD ≥10⁻³ to MRD <10⁻⁴. The higher response rates observed in this study compared with the pediatric phase 1/2 trial may be partly attributed to the lower baseline tumor burden in RIALTO patients, with 38% having bone marrow blasts of ≥50% compared with 74% in the phase 1/2 trial. Together, these trials laid the groundwork for subsequent randomized trials investigating optimal use of blinatumomab in children with R/R B-ALL.

A phase 3 trial conducted in Europe enrolled children with high-risk (relapse at <18 months after diagnosis or marrow relapse at ≥18 months from diagnosis but <6 months after completion of therapy), first relapse of B-ALL.⁸ Those achieving an M1 (<5% blasts) or M2 (≥5 but <25% blasts) marrow after reinduction therapy were treated with 2 cycles of standard consolidation chemotherapy and were then randomized to receive either blinatumomab or consolidation chemotherapy before planned allogeneic HSCT. In total, 108 patients were randomized before early termination of enrollment because of meeting prespecified criteria finding benefit of blinatumomab. With a median follow-up of 22.4 months, the incidence of events in the blinatumomab arm was 31% vs 57% in the chemotherapy arm (log-rank P < .001; hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.18-0.61); this event-free survival (EFS) benefit was seen across all specified subgroups, including very early relapses (<18 months from initial diagnosis to relapse) and in patients with extramedullary disease at relapse. Patients who received blinatumomab had fewer deaths (14.8% vs 29.6% with chemotherapy), a higher chance of MRD-negative remission (90% vs 54% with chemotherapy), and lower rates of grade ≥3 adverse events (57.4% vs 82.4% with chemotherapy). A higher proportion of patients who received blinatumomab also successfully proceeded to allogeneic HSCT while in second CR (89% vs 70% of patients receiving chemotherapy). Relapses occurred in 24.1% of patients randomized to the blinatumomab arm and 53.7% of those in the chemotherapy arm (HR, 0.24; 95% CI, 0.13-0.46). In a subsequent report with a median follow-up of 44 months, blinatumomab demonstrated persistent benefit on EFS across subgroups and improved OS (HR, 0.34; 95% CI, 0.17-0.69).⁹ 

In parallel, the Children’s Oncology Group (COG) AALL1331 trial randomized children and AYAs with high-risk (marrow relapse at <36 months after diagnosis or isolated extramedullary [IEM] relapse at <18 months after diagnosis) and intermediate-risk (marrow relapse at ≥36 months after diagnosis or IEM relapse at ≥18 months after diagnosis; and MRD after reinduction at ≥0.1%) first relapse of B-ALL to receive 2 cycles of blinatumomab or 2 courses of consolidation chemotherapy after a standard UKALLR3 reinduction block (vincristine, asparaginase, dexamethasone, and mitoxantrone), with subsequent planned allogeneic HSCT.¹⁰ As in the European trial, randomization was terminated early because of the combination of findings of higher disease-free survival (DFS), OS, and MRD clearance, as well as lower toxicity in the blinatumomab arm compared with the chemotherapy arm. With a median follow-up of 2.9 years, 2-year DFS in the blinatumomab arm was 54.4% vs 39.0% in the chemotherpay arm (HR, 0.7; 95% CI, 0.47-1.03) and OS in the blinatumomab arm was 71.3% vs 58.4% in the chemotherarpy arm (HR, 0.62; 95% CI, 0.39-0.98). Of patients who received blinatumomab, 70% successfully proceeded to HSCT, compared with 43% of patients randomized to the chemotherapy arm. In a post hoc subgroup analysis of these AYA (aged 18-30 years) patients, 2-year DFS and OS were 66.7% and 66%, respectively, for those randomized to receive blinatumomab (vs 41% [HR, 0.62; 95% CI, 0.17-2.2] and 47.1% [HR, 0.78; 95% CI, 0.20-3.0], respectively, for chemotherapy).¹⁰ Overall, both randomized trials clearly demonstrated that blinatumomab is superior to standard consolidative chemotherapy in terms of its capacity to induce MRD-negative remissions with less toxicity. The striking results of these seminal studies led to blinatumomab becoming a standard-of-care component in the setting of higher-risk relapsed B-ALL.

AALL1331 also included patients with “low-risk” relapse of B-ALL (marrow relapse at ≥36 months after diagnosis or IEM relapse at ≥18 months after diagnosis; and MRD after reinduction at <0.1%).¹¹ After induction, patients were randomized to receive either blinatumomab or chemotherapy as block 3 of consolidation, with 2 additional intercalated blocks of blinatumomab in continuation for those randomized to the blinatumomab arm. Among 255 patients randomized, 4-year DFS and OS in patients who received blinatumomab were 61.2% and 90.4%, vs 49.5% and 79.6%, respectively, among patients in the chemotherapy arm (P = .089 and P = .11, respectively). Although in the overall randomized cohort, the improvement in DFS and OS did not reach statistical significance, blinatumomab was associated with significantly improved outcomes among patients with marrow involvement, with 4-year DFS and OS 72.7% and 97.1%, respectively, for patients receiving blinatumomab (vs 53.7% and 84.8% in patients receiving chemotherapy [P = .15 and P = .02 respectively]). Importantly, there was no difference in outcomes among randomized patients with isolated central nervous system (CNS) disease. This group did quite poorly on both arms, with DFS rates inferior to those in previous COG studies with more intense CNS-directed therapy and with most second relapses occurring in the CNS. Blinatumomab is known to have limited activity in the CNS, but importantly, AALL1331 also decreased CNS-directed therapy, which likely contributed to these poorer outcomes.

Efforts are now underway to understand how to further reduce chemotherapy in children with R/R B-ALL, to lessen both short- and long-term toxicities. The United Kingdom relapse treatment pathway transitions patients who achieve <5% marrow blasts after 15 days of reinduction chemotherapy to blinatumomab. High-risk patients proceed to transplant after 1 to 2 cycles of blinatumomab whereas standard-risk patients proceed to chemotherapy. Among 111 patients treated on this pathway, there were no induction deaths, and among those with marrow involvement, 52.2% were able to receive blinatumomab after day 15 of induction, and 87% of patients who received blinatumomab achieved a complete MRD response.¹⁷ These outcomes are encouraging given the high rates of toxicity associated with the UKALLR3 reinduction, especially in AYA patients.

The efficacy of blinatumomab has more recently been established in patients with newly diagnosed B-ALL. After results demonstrating the ability of blinatumomab to improve outcomes in newly diagnosed adults with MRD-level disease,^18,19 the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network E1910 trial randomized patients aged 30 to 70 years with BCR::ABL-negative B-ALL who were MRD negative (<0.01% by flow cytometry) after initial therapy to receive a standard consolidative chemotherapy with or without 4 cycles of blinatumomab followed by maintenance therapy. With a median follow-up of 43 months, blinatumomab significantly improved OS and relapse-free survival (RFS) compared with chemotherapy alone (3-year OS, 85% vs 68%; 3-year RFS, 80% vs 64%).²⁰ The results of this pivotal trial led to expansion of the US Food and Drug Administration label to include blinatumomab in the consolidation phase of therapy for all patients with newly diagnosed, BCR::ABL-negative B-ALL.

An international, phase 2, single-arm study evaluated whether 1 course of blinatumomab added to the Interfant-06 backbone regimen would improve outcomes for KMT2A-rearranged (KMT2Ar) infant B-ALL. Thirty infants (aged <1 year) with newly diagnosed KMT2Ar, CD19⁺, B-ALL with <25% disease at the end of induction received a single cycle of blinatumomab after induction followed by the remainder of Interfant-06 therapy.¹² Twenty-eight patients (93%) were either MRD negative or had low levels of MRD (detectable but <5 × 10⁻⁴) after blinatumomab. All high-risk (age <6 months with white blood cell count of ≥300 × 10⁹/L at diagnosis or a prednisone poor response) and medium-risk (all others with KMT2Ar ALL) patients with MRD of ≥5 × 10⁻⁴ before OCTADAD (vincristine, dexamethasone, asparaginase, daunorubicin, thioguanine, cytarabine, and cyclophosphamide) chemotherapy were eligible to proceed to HSCT in first CR. Of 9 high-risk patients, 8 underwent HSCT in first CR. None of the medium-risk patients met MRD level criteria for HSCT in first CR although 2 underwent HSCT at investigator discretion. Two-year DFS and OS were 81.6% and 93.3%, compared with historical controls of 49.4% and 65.8%, respectively, on Interfant-06.²¹ The incidence of relapse was 13%, with all relapsing patients having CNS involvement at relapse. All relapses were CD19⁺ and no lineage switches occurred.

The recently completed COG AALL1731 trial was a randomized phase 3 trial evaluating the benefit of the addition of blinatumomab to standard chemotherapy in patients with National Cancer Institute (NCI) standard-risk B-ALL (age of <10 years and presenting white blood cell count of <50 × 10³/μL at diagnosis).¹³ Patients who had an average risk (n = 835) and a higher risk (n = 605) of relapse were randomized after induction and consolidation chemotherapy to receive either risk-adapted chemotherapy alone or with 2 nonconsecutive cycles of blinatumomab. At the first planned interim efficacy analysis, the study’s data and safety monitoring committee recommended early termination of randomization because of the remarkable benefit demonstrated with blinatumomab. With a median follow-up of 2.5 years, 3-year DFS was 96.0% ± 1.2% among patients randomized to receive blinatumomab with chemotherapy, compared with 87.9% ± 2.1% in the chemotherapy-alone group. Blinatumomab improved DFS in patients with both average (3-year 97.5% ± 1.3% vs 90.2% ± 2.3% in chemotherapy alone) and higher (94.1% ± 2.5% vs 84.8% ± 3.8% in chemotherapy alone) risk of relapse. The 3-year cumulative incidence of relapse was 3.3% ± 0.8% with blinatumomab and chemotherapy, compared with 11.8% ± 1.6% with chemotherapy alone. Notably, blinatumomab reduced the incidence of marrow relapses but not isolated CNS relapses, which is unsurprising given the limited activity of blinatumomab in the CNS. All patients (10/10) who relapsed after blinatumomab with available CD19 expression data were CD19⁺.¹³ 

Blinatumomab is associated with a distinct toxicity profile, which uniquely includes CRS and neurotoxicity. Fever is the hallmark of CRS and can be accompanied by myalgias; fatigue; hypotension; and, in more severe cases, capillary leak syndrome and organ dysfunction. In the initial pediatric dose-determining trial, 11% of patients had any CRS, with 6% being grade 3 or 4 and requiring either interruption or discontinuation of the cycle (Table 2).⁵ However, rates of grade ≥3 CRS on subsequent trials were lower, ranging from 0.2% to 2%, likely because of the lower baseline disease burden of patients on these studies, as high disease burden is a known risk factor for CRS.^6,8,10-13 Factors associated with CRS in this low disease burden setting are not well defined and is an area that requires additional research.

Neurotoxicity secondary to blinatumomab may present with tremor, confusion, ataxia, dizziness, altered mental status, or seizure. The incidence of grade ≥3 neurotoxicity in children is relatively low, reported at 0% to 5% across studies.^6,8,10,11 In contrast, higher rates have been reported among adult patients, including a notable 23% of adult patients treated on E1910 reporting grade ≥3 neuropsychiatric events.²⁰ Patients with Down syndrome appear to be at increased risk of blinatumomab-associated seizures, warranting consideration of antiseizure prophylaxis for this population.²² 

Overall, compared with standard cytotoxic chemotherapies, blinatumomab is associated with lower rates of profound cytopenias, nausea, vomiting, and fatigue.^5,6,8,10-13 In the relapse setting, when compared with standard intensified blocks of chemotherapy, blinatumomab is also associated with significantly reduced rates of severe infectious complications.^8,10,11 Of note, patients with newly diagnosed NCI standard-risk disease with average risk of relapse randomized to blinatumomab on the COG AALL1731 trial more frequently had grade ≥3 sepsis and catheter-related infections (14.8% vs 5.1% with chemotherapy alone; P < .001).¹³ Although some of these infectious events occurred during blinatumomab cycles, many occurred in subsequent chemotherapy cycles. B-cell aplasia, a known side effect of CD19-targeting therapies, may contribute to infectious risk in these patients and is an area that warrants further exploration.

It is notable that several of the aforementioned studies were terminated early after the dramatic positive effect of blinatumomab was noted in interim analyses. Despite these strong positive findings of the effects of blinatumomab, there remain several unknowns as the use of blinatumomab rises.

Although the trials in newly diagnosed patients conducted to date evaluated the addition of blinatumomab to standard therapy, it is plausible that blinatumomab may be able to replace components of therapy while maintaining equivalent outcomes. Hodder et al²³ published a report of children and young adults with B-ALL deemed to have chemotherapy intolerance who were eligible to receive first-line treatment with blinatumomab, in accordance with United Kingdom ALL consensus guidelines. Blinatumomab was well tolerated and 97% of patients who were MRD positive before blinatumomab achieved MRD negativity after, with impressive 2-year EFS and OS among patients who went on to receive additional chemotherapy (95% and 97%, respectively). In a similar vein, because of the high treatment-related mortality in infant ALL, the United Kingdom ALL guidelines for KMT2Ar infant ALL were modified such that infants deemed medium risk after induction and 1 cycle of blinatumomab received a second cycle of blinatumomab while deescalating the intensive chemotherapy backbone by removing protocol 1b (cyclophosphamide, cytarabine, and mercaptopurine) and MARMA (high-dose cytarabine, high-dose methotrexate, and pegylated asparaginase).¹⁷ Among 27 infants with medium risk KMT2Ar B-ALL, 93% achieved an MRD-negative (MRD < 0.01%) remission. There were no treatment-related deaths and the 2-year OS and EFS were 93% and 78%, respectively, suggesting that it may be possible to deescalate the chemotherapy backbone for infant B-ALL.

In adult patients with BCR::ABL-positive B-ALL, using blinatumomab with a tyrosine kinase inhibitor (TKI) and corticosteroids without other chemotherapy has been shown to be effective. Among 63 adults with newly diagnosed BCR::ABL-positive B-ALL enrolled on a phase 2 trial who received dexamethasone and dasatinib then 2 to 4 cycles of blinatumomab with dasatinib, 98% achieved a CR and 60% achieved a molecular response.²⁴ With a median follow-up of 18 months, DFS/OS was 88%/95%. Many enrolled patients proceeded to HSCT as is largely considered standard of care for adult BCR::ABL-positive B-ALL; however, it is notable that 28 patients with a molecular response to initial therapy received only dasatinib as postprotocol therapy without HSCT, and of those, 27 remain in continuous CR at a median follow-up of 4 years.²⁵ This chemotherapy-free strategy has also been successfully replicated with other TKIs in adults.²⁶ Although this strategy may be effective in children, there remains a lack of data for pediatric BCR::ABL-positive B-ALL; a clinical trial evaluating blinatumomab in combination with TKI and chemotherapy in newly diagnosed pediatric BCR::ABL-positive B-ALL is planned (ClinicalTrials.gov identifier: NCT06124157).

With the addition of blinatumomab, historically used prognostic factors may no longer hold the same significance, because results from many of the noted trials suggest that blinatumomab may be able to level the playing field for high-risk features. In both the COG AALL1731 and E1910 trials, all genomically defined subsets appear to derive benefit from blinatumomab, although numbers are limiting in some rare subsets.^13,20 For instance, among children on COG AALL1731, 3-year DFS in patients with the unfavorable cytogenetic lesion, iAmp21, receiving blinatumomab and chemotherapy was 96.7%, compared with 77.6% in those receiving chemotherapy alone. Although 3-year DFS in children with hypodiploid ALL and KMT2Ar ALL still lags compared with other subgroups, DFS among those who received blinatumomab was improved compared with those who received chemotherapy alone (hypodiploid ALL 84.9% vs 68.2%; KMT2Ar ALL 84.9% vs 74.1%). Additionally, patients with CNS2 disease and with any MRD level at the end of induction also benefited significantly from the addition of blinatumomab to therapy. Importantly, a striking and significant benefit with blinatumomab was also noted in patients of Hispanic ethnicity, a subgroup of patients who have historically have inferior outcomes in B-ALL.¹³ The ability of blinatumomab to, at least partially, negate these historically high-risk features is noteworthy and suggests all prognostic features will have to be reevaluated in the context of blinatumomab-containing therapy regimens. There are some data indicating that patients with TP53 mutations may be at higher risk of CD19⁻ relapses after blinatumomab therapy, but, thus far, this evaluation has been restricted to adults with R/R disease.²⁷ Thus, study in pediatric populations and more detailed exploration in the upfront setting are needed.

Although blinatumomab has demonstrated benefit in patients with marrow involvement, patients with isolated CNS disease may not fare as well and are a group that warrant further study. The CNS is a well-established sanctuary site for B-ALL, and blinatumomab’s efficacy is limited in preventing¹³ and treating¹¹ isolated CNS relapses. Among newly diagnosed children with B-ALL on COG AALL1731, rates of isolated CNS relapse were unchanged by the addition of blinatumomab (3-year cumulative incidence of relapse of isolated CNS relapse: 1.5% for blinatumomab vs 1.8% for chemotherapy alone).¹³ On COG AALL1331, patients with low-risk, isolated CNS-relapsed B-ALL randomized to blinatumomab had no improvement in outcomes compared with the control arm, with 4-year DFS of 24.7% vs 24.0%,¹¹ highlighting the need for better treatment strategies for this subset of patients. This lack of CNS activity must be taken into consideration as approaches attempting to replace standard therapy with blinatumomab are pursued (eg, preferentially maintaining systemic therapies with CNS activity). Alternatively, or in addition, intensification of intrathecal therapy (IT) to address CNS disease is worth consideration. For example, instead of single-agent IT methotrexate, perhaps the combination of IT hydrocortisone/methotrexate/cytarabine (triple IT) address CNS disease more effectively. On the Children’s Cancer Group study, CCG1952, patients with standard-risk B-ALL randomized to receive triple IT therapy had reduced CNS-involving relapses compared with those receiving IT methotrexate alone, although this was accompanied by higher rates of marrow relapses.²⁸ Perhaps in a therapy backbone that includes blinatumomab, which is more effective at preventing marrow relapses compared with the chemotherapy used in this historical trial, the addition of triple ITs could lessen the risk of CNS relapse without concomitant increase in marrow relapses.

The optimal number and sequence of blinatumomab cycles has yet to be established. Variable numbers of cycles have been used across several trials, each demonstrating beneficial effect of blinatumomab. Although additional cycles could potentially deepen response and improve efficacy, there are also reports of patients with R/R MRD-negative disease converting to MRD-positive disease after receiving a subsequent consecutive cycle, highlighting the need for more robust data.¹⁰ In addition, the optimal timing of introducing blinatumomab into therapy remains to be determined, with some studies inserting it right after induction,^7,10,12some after later cycles of therapy,^8,13,20 and some ongoing studies testing it during induction (ClinicalTrials.gov identifier: NCT06533748). Thus, determining the optimal number and timing of courses will require additional well-designed trials in the future.

Although the lower rates of relapse seen with blinatumomab treatment are encouraging, longer follow-up is needed to ensure these excellent outcomes are maintained over time. Additionally, with blinatumomab now a routine component of upfront therapy for most children with B-ALL, future relapses could be enriched for antigen escape or lineage switch. Although the Interfant infant trial,¹² COG AALL1731,¹³ and other reports indicate this is likely quite rare in patients treated with blinatumomab patients, particularly when used in the upfront setting,²⁹ CD19 antigen escape after blinatumomab would complicate subsequent therapeutic options such as CD19-directed chimeric antigen receptor (CAR) T cells. Even in the absence of antigen escape, previous blinatumomab exposure could affect the likelihood of CAR response. A single-center study of 166 patients found that previous therapy with blinatumomab was associated with inferior CAR response,³⁰ whereas another 2-center analysis of 51 patients found that previous blinatumomab was associated with early CAR failure.³¹ In contrast, a multicenter retrospective cohort of >400 CD19 CAR recipients found that although blinatumomab nonresponse was correlated with inferior RFS after CAR, there was no significant difference in outcomes in patients who were blinatumomab naïve and blinatumomab responders, suggesting that previous blinatumomab exposure was not the main driver of inferior outcomes in these patients. Thus, the impact of previous blinatumomab therapy on the efficacy of subsequent CAR therapy is unresolved.

Although decades of experience have highlighted the late effects of cytotoxic chemotherapy, longer follow-up will be needed to understand the late effects of blinatumomab. Prolonged B-cell aplasia has been reported among adult blinatumomab recipients, with patients experiencing delayed recovery of immunoglobulin G and immunoglobulin A levels and thus potential delay in recovery of memory B cells and plasma cells.³² However, to date, there are no published data in pediatric patients who have received blinatumomab; thus, efforts are needed to understand the long-term impact of blinatumomab on immune function in children.

With the advent of new immunotherapies in B-ALL, ensuring equitable access to such agents including blinatumomab is critical. Blinatumomab is administered via a continuous intravenous infusion, often initiated in the inpatient setting followed by frequent outpatient follow-up to safely change out medication bags.^33,34 Given the overall favorable toxicity profile and ability to be administered at home, albeit with high-level of health care coordination needed, incorporation of blinatumomab could ideally improve patient and family quality of life during treatment. However, administration of blinatumomab may also pose disproportionate burdens for some caregivers, for example, those with low resources, those from geographically rural areas, or those with low health literacy. Access to blinatumomab outside of the United States and Europe is also a complex issue. In partnership with St. Jude Children’s Research Hospital, Amgen offers a humanitarian access program to provide blinatumomab to pediatric patients with B-ALL living in low- to middle-income countries.³⁵ However, even through this program, blinatumomab is only available to patients in an inpatient setting and likely unable to be accessed by all children who could benefit. Future efforts to improve access to blinatumomab may involve the use of subcutaneous (SQ) formulations, which can be intermittently dosed. An early phase trial of SQ blinatumomab in adults with R/R B-ALL demonstrated efficacy with high MRD-negativity rates and an acceptable toxicity profile with all CRS and neurotoxicity events responsive to typical management.³⁶ Clinical trials of SQ blinatumomab in children are in development. A longer-acting CD3-CD19 bispecific T-cell engager, AZD0486, has also shown durable responses in follicular lymphoma and is being evaluated in patients with R/R B-ALL (ClinicalTrials.gov identifier: NCT06137118).³⁷ 

Blinatumomab has dramatically changed the treatment landscape of pediatric B-ALL. Since the first published early-phase clinical pediatric data in 2016, blinatumomab is now largely considered a standard-of-care component of therapy for all patients with R/R B-ALL and most newly diagnosed patients. This remarkable trajectory occurred secondary to striking efficacy data from several large studies conducted worldwide, including data so clearly demonstrating blinatumomab’s positive effects on outcome that multiple randomized trials closed early to offer it to all patients.^8,10,13 In addition to its efficacy, blinatumomab has a toxicity profile that is largely viewed as acceptable by physicians, patients, and caregivers. Although this combination of efficacy and tolerability are cause for excitement and optimism, challenges remain. Blinatumomab must be given via continuous IV infusion, a mode of administration that is cumbersome for all and, for some, completely prohibitive. Thus, ensuring all patients who would benefit from it have equal access to blinatumomab is imperative and will require the concerted efforts and advocacy of oncologists, insurers, home health companies, pharmaceutical partners, and government and regulatory agencies. Furthermore, although the traditional toxicities associated with cytotoxic chemotherapy may be lessened, blinatumomab-specific toxicities such as CRS and neurotoxicity can be life threatening, thus efforts to predict, prevent, and treat such events are still needed. Lastly, because it is now a nearly ubiquitous standard-of-care agent, we will ultimately have many adult survivors who have received blinatumomab. Its long-term toxicity profile is undefined, thus dedicated long-term follow-up studies are of critical importance. Overall, although work remains to optimize its use, blinatumomab can now be considered a cornerstone of pediatric B-ALL therapy.

Contribution: A.G.H. and R.E.R. wrote and edited the manuscript and approved the final version.

Conflict-of-interest disclosure: R.E.R. received an honorarium from Amgen Pharmaceuticals for participating in an educational session. A.G.H. declares no competing financial interests.

Correspondence: Rachel E. Rau, Department of Pediatric Hematology/Oncology, University of Washington/Seattle Children’s Hospital, 4800 Sand Point Way NE, Seattle, WA 98105; email: rachel.rau@seattlechildrens.org.