Abstract
Background
B-lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Despite high overall cure rates, relapsed B-ALL remains a leading cause of cancer death among children. Adding the bispecific T-cell engager blinatumomab (CD19xCD3) to therapy for newly diagnosed NCI standard risk (SR) pediatric B-ALL may improve outcomes.
Methods
AALL1731 is a phase 3 trial that randomized children with newly diagnosed SR B-ALL of average (SR-Avg) and higher (SR-High) relapse risk to chemotherapy or chemotherapy plus two non-sequential 28-day blinatumomab cycles. The primary endpoint was disease-free survival.
Results
The data and safety monitoring committee reviewed results from the first efficacy interim analysis including 1440 randomized patients (chemotherapy alone N=722, blinatumomab N=718) and recommended randomization be terminated. At median follow-up of 2.5 years the 3-year disease-free survival (± standard error) was 96.0±1.2% for blinatumomab arms vs 87.9±2.1% for chemotherapy alone arms [restricted mean survival time difference 72 days, 95% CI 36–108 days, 1-sided stratified log-rank p=0.00004]. The 3-year disease-free survival for the blinatumomab arm compared to chemotherapy alone was 97.5±1.3% vs 90.2±2.3% for SR-Avg and 94.1±2.5% vs 84.8±3.8% for SR-High. Grade 3 cytokine release syndrome, seizures, and sepsis were rare during blinatumomab cycles, but overall rates of non-fatal sepsis and catheter-related infections were significantly higher in SR-Avg patients receiving blinatumomab compared to chemotherapy alone.
Conclusions
Adding blinatumomab to combination chemotherapy significantly improves disease-free survival in newly diagnosed childhood SR B-ALL of average or higher risk. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number NCT03914625.)
INTRODUCTION
Cure rates for acute lymphoblastic leukemia (ALL) have increased dramatically over the last five decades.1–4 However, progress has slowed as several recent attempts to intensify traditional chemotherapeutic agents have failed to increase cure rates.5–10
Blinatumomab is a novel bispecific single-chain molecule that targets the CD19 antigen on the surface of B-lineage cells and redirects CD3+ T-cells for CD19-selective lysis. Blinatumomab improves outcomes among children with relapsed B-ALL.11–13 Among adults, the E1910 study found that adding blinatumomab to standard chemotherapy increased relapse-free and overall survival among adults with newly diagnosed disease.14 Whether incorporating blinatumomab also improves outcomes among children with newly diagnosed B-ALL was unknown.
We conducted an international randomized, controlled, Children’s Oncology Group (COG) trial among children with National Cancer Institute (NCI) standard risk (SR) B-ALL. Our primary objective was to determine whether the addition of two non-sequential cycles of blinatumomab to standard chemotherapy would improve the outcomes of SR B-ALL patients with average and higher risk features.
METHODS
Patients
Patients with newly diagnosed SR [age ≥1 and <10 years at diagnosis and presenting white blood cell count (WBC) <50,000/µL] B-ALL, including those with Down syndrome, without testicular leukemia or significant central nervous system (CNS) disease were eligible. High Risk Down syndrome patients and those with localized B-lymphoblastic lymphoma were eligible but not randomized and not reported here. Detailed eligibility criteria are included in the trial protocol (available NEJM.org).
Trial Design and Oversight
AALL1731 is a phase 3 multicenter randomized controlled trial conducted at centers in the United States, Canada, Australia, and New Zealand. The protocol was approved by the pediatric Central Institutional Review Board (CIRB) of the NCI and local IRBs. Each patient’s legal guardian provided written informed consent; assent was obtained as necessary. The independent data and safety monitoring committee met biannually at pre-planned intervals to review trial data.
The study was funded by the NCI Cancer Therapy Evaluation Program (CTEP), designed by COG, and approved by CTEP and Amgen. Data collection was done by the COG Statistics and Data Center and analysis conducted by authors J.A.K. and C.W and was reviewed by all authors. The study chairs (co-first authors) wrote the manuscript with the approval of all the authors, without the assistance of non-authors. The authors vouch for the data, its analysis, and adherence to the protocol.
Cytogenetic and MRD Assessments
Cytogenetic and fluorescence-in-situ-hybridization analyses were conducted at COG-approved clinical labs and centrally reviewed. Measurable residual disease (MRD) in the peripheral blood at day 8 of Induction and in the bone marrow on Day 29 at the end of Induction and end of Consolidation were assessed by multiparameter flow cytometry using standardized methods.3 Day 8 peripheral blood MRD and end of induction marrow MRD were performed for all patients locally; end of consolidation marrow MRD was done centrally for those with detectable MRD at end of induction.
SR-Average (SR-Avg) patients [except those with double trisomies of chromosomes 4 and 10 and end of induction marrow MRD 0.01-<0.1%] also had end of induction marrow MRD measured by high-throughput sequencing of the immunoglobulin loci. Once a patient was risk stratified as SR-Avg, banked diagnostic marrow or peripheral blood and end of induction marrow samples were shipped to Adaptive Biotechnologies where sequencing MRD was measured using ClonoSEQ B-cell clonality/tracking assays.15 Sequencing MRD results were incorporated into post-Consolidation treatment assignment or randomization (Figure 1, CONSORT diagram).
Figure 1: CONSORT flow diagram.
Status of all National Cancer Institute (NCI) standard risk (SR) B-lymphoblastic leukemia (B-ALL) patients enrolled on AALL1731 (N=4264) throughout the course of the trial is shown. At the end of Induction therapy patients were risk stratified as Down syndromeS-High, SR-Favorable (SR-Fav), SR-Average (SR-Avg) and SR-High (N=916). Down Syndrome-High and SR-Fav were not eligible for randomization. Consent for randomization was obtained at EOI after risk stratification, while randomization did not occur until Consolidation therapy had been completed or was near completion. The number of and reasons for SR-Avg and SR-High patients not being randomized and for randomized patients not receiving randomized therapy are shown.
Treatments and Randomization
All patients received a 3-drug Induction (Supplemental Figures 1-2). At end of induction, patients were stratified into three risk groups: SR-Favorable (SR-Fav), SR-Avg, and SR-High, based on blast cytogenetics [categorized as favorable (ETV6::RUNX1 fusion or double trisomies of chromosomes 4 and 10), unfavorable (iAMP21, KMT2A rearranged, hypodiploidy (<44 chromosomes or t(17;19)(q21-q22;p13.3), or neutral (lacking favorable and unfavorable genetic features)), CNS status,16 and flow cytometry MRD on day 8 in blood and in end of induction marrow (Supplemental Figure S3).
Following Induction, SR-Fav patients were non-randomly assigned to receive standard chemotherapy (Arm A).4 SR-Avg patients were further stratified based on end of induction sequencing MRD. Those with undetectable MRD were non-randomly assigned to Arm A; all others were randomized to Arm A or chemotherapy plus two non-sequential cycles of blinatumomab (Arm B). Post Induction, SR-High patients were treated with an augmented Berlin-Frankfurt-Münster (BFM) chemotherapy backbone.17 SR-High patients with end of consolidation marrow MRD <0.1% were randomized to chemotherapy alone (Arm C) or chemotherapy plus two cycles of blinatumomab (Arm D). SR-High patients with higher end of consolidation MRD were either non-randomly assigned to Arm D or, if ≥1%, removed from protocol therapy. Patients assigned to experimental arms received two cycles of continuous intravenous infusion blinatumomab 15µg/m2/day (max 28µg/day) for 28 days, before and after the first Interim Maintenance phase of therapy, one dose of intrathecal methotrexate was given on day 1 of each cycle of blinatumomab (Supplemental Material). The total number of intrathecal treatments was equal between randomized arms.
The 1:1 randomization was conducted centrally and stratified by SR-Avg non-Down syndrome, SR-Avg Down syndrome, and SR-High. Neither providers nor patients were blinded.
Endpoints
Disease-free survival was defined as time from randomization to first event (relapse, second malignant neoplasm, or death) or censoring at date of last contact. Post-hoc disease-free survival analyses were performed in subgroups defined by patient- and disease-related factors but were not formally powered. Though not formal endpoints specified in the protocol, other endpoints were also examined as exploratory. Overall survival was defined as the time from randomization to death or censoring at date of last contact. Relapses were also examined as an exploratory endpoint, both overall and by site of relapse. Toxicities were reported using CTCAE v.5 criteria.18 Infection-related adverse event detailed case report forms were reviewed in real- time.19
Statistical Analysis
Study data as of June 30, 2024 are presented. Targeted trial accrual was 6,420–6,720 patients with SR B-ALL, an estimated 2,245 of whom would be eligible for the primary randomization. Using a two-sided α of 5%, the trial would have 81% power to detect a 34.5% improvement [hazard ratio (HR)=0.655] in disease-free survival, with 194 events at final analysis.
Disease-free and overall survival estimates were determined using the Kaplan-Meier method, with standard errors and confidence intervals (CI) estimated by Peto’s method.20,21 The primary analysis was intent-to-treat and thus included all eligible randomized patients. Among these randomized patients, disease-free survival was compared between the chemotherapy and the chemotherapy plus blinatumomab groups using a log-rank test stratified by non-Down syndrome SR-Avg vs. Down syndrome SR-Avg vs. SR-High. Cox proportional hazard models were used to determine the effect of adding blinatumomab on disease-free and overall survival adjusting for patient- and disease-related factors. Based on similar prior Children’s Oncology Group ALL trials, we did not anticipate or plan for substantial or informative missingness. Indeed, no data were missing for the primary analysis; the only missing values were from five patients missing one variable (Day 8 blood MRD), with values categorized as ‘Unknown’ in the exploratory multivariable Cox model. Interim disease-free survival analyses were planned at 20 (non-binding futility only),22 40, 60, and 80% of expected information, using alpha-t square spending functions. Efficacy interim analyses of disease-free survival used a 1-sided p-value (α=0.025); all other analyses are presented with 2-sided p-values. The statistical analysis plan did not include a provision for correction for multiplicity when tests for secondary or other outcomes were conducted. Corresponding confidence intervals should thus not be used in place of a hypothesis test.
We planned to use proportional-hazards modeling to test the primary and secondary outcomes, unless strong evidence of nonproportionality of the Kaplan–Meier survival curves was seen, in which case we would use a restricted mean survival time (RMST) analysis, truncating follow-up at the time of the last follow-up visit. As time-dependent analysis showed some evidence of nonproportionality for the primary outcome (Supplemental Material), only RMSTs (truncated at the maximum 1,652 days of follow-up) are reported. Full statistical analysis plans are detailed in the protocol, available at NEJM.org.
RESULTS
Enrollment and patient characteristics
We enrolled 4,264 SR-ALL patients between June 2019 and June 2024 (Figure 1). Of 4,018 patients risk stratified at end of induction, 1,635 SR-Fav and 49 DS-High will be reported separately. Of the remaining, 1,418 were SR-Avg and 916 were SR-High. Among SR-Avg patients, 150 had undetectable end of induction MRD by sequencing and were non-randomly assigned to Arm A; their results will also be reported separately. Among patients eligible for randomization, demographic and clinical features were overall balanced between those randomized and those not randomized (Supplemental Table S1).
Cumulatively, 1,440 SR-Avg/SR-High patients were randomized and included in the intent-to-treat efficacy analysis (Figure 1). Of randomized patients, 835 were SR-Avg (Arm A=418, Arm B=417) and 605 SR-High (Arm C=304, Arm D=301). The small subset of randomized patients not receiving any post-randomization protocol therapy are included in efficacy analyses, but not toxicity analyses.
The median age of randomized patients was 4.3 years [interquartile range (IQR) 2.8–6.4]; 52.6% were male, 26% were Hispanic and 5% were non-Hispanic Black. Patients with Down syndrome made up 3.8% of randomized SR-Avg patients, equally distributed to Arms A and B. Clinical, demographic, and disease features were overall balanced between randomized arms (Table 1). Although numbers in each group were small, Day 8 blood flow MRD <1% was numerically more common among patients randomized to the chemotherapy arms. Among SR-Avg patients, Day 29 marrow MRD by sequencing unavailability was numerically more common among patients randomized to receive chemotherapy only.
Table 1.
Characteristics of the Patients who Underwent Randomization
| SR-Average | SR-High | |||||
|---|---|---|---|---|---|---|
| Characteristic | Chemotherapy only (N=418) | Blinatumomab and Chemotherapy (N=417) | Total (N=835) | Chemotherapy only (N=304) | Blinatumomab and Chemotherapy (N=301) | Total (N=605) |
| Median age (range) – yr | 4.3 (1.0–10.0) | 4.0 (1.0–9.9) | 4.2 (1.0–10.0) | 4.2 (1.1–9.9) | 4.6 (1.0–10.0) | 4.4 (1.0–10.0) |
| Sex – N (%) | ||||||
| Female | 195 (46.7%) | 207 (49.6%) | 402 (48.1%) | 137 (45.1%) | 143 (47.5%) | 280 (46.3%) |
| Male | 223 (53.3%) | 210 (50.4%) | 433 (51.9%) | 167 (54.9%) | 158 (52.5%) | 325 (53.7%) |
| Race/ethnicity – N (%) | ||||||
| Hispanic | 104 (24.9%) | 100 (24.0%) | 204 (24.4%) | 84 (27.6%) | 84 (27.9%) | 168 (27.8%) |
| Non-Hispanic Asian | 19 (4.5%) | 20 (4.8%) | 39 (4.7%) | 10 (3.3%) | 13 (4.3%) | 23 (3.8%) |
| Non-Hispanic Black | 20 (4.8%) | 26 (6.2%) | 46 (5.5%) | 18 (5.9%) | 16 (5.3%) | 34 (5.6%) |
| Non-Hispanic White | 213 (51.0%) | 217 (52.0%) | 430 (51.5%) | 140 (46.1%) | 156 (51.8%) | 296 (48.9%) |
| Other/Unknown | 62 (14.8%) | 54 (12.9%) | 116 (13.9%) | 52 (17.1%) | 32 (10.6%) | 84 (13.9%) |
| Down Syndrome – N (%) | ||||||
| Yes | 16 (3.8%) | 16 (3.8%) | 32 (3.8%) | - | - | - |
| No | 402 (96.2%) | 401 (96.2%) | 803 (96.2%) | 304 (100.0%) | 301(100.0%) | 605 (100.0%) |
| Median white blood cell count – x109/liter | 7.5 (0.0–49.7) | 7.7 (0.3–49.7) | 7.6 (0.0–49.7) | 7.4 (0.6–49.8) | 8.8 (0.4–47.8) | 8.0 (0.4–49.8) |
| CNS status – N (%) | ||||||
| CNS1 | 407 (97.4%) | 399 (95.7%) | 806 (96.5%) | 245 (80.6%) | 242 (80.4%) | 487 (80.5%) |
| CNS2 | 11 (2.6%) | 18 (4.3%) | 29 (3.5%) | 59 (19.4%) | 59 (19.6%) | 118 (19.5%) |
| Cytogenetics – N (%) | ||||||
| Favorable | 114 (27.3%) | 127 (30.5%) | 241 (28.9%) | 96 (31.6%) | 72 (23.9%) | 168 (27.8%) |
| Neutral | 304 (72.7%) | 290 (69.5%) | 594 (71.1%) | 148 (48.7%) | 165 (54.8%) | 313 (51.7%) |
| Unfavorable | - | - | - | 60 (19.7%) | 64 (21.3%) | 124 (20.5%) |
| Day 8 peripheral blood flow MRD – N (%) | ||||||
| <1% | 271 (64.8%) | 242 (58.0%) | 513 (61.4%) | 196 (64.5%) | 177 (58.8%) | 373 (61.7%) |
| ≥1% | 147 (35.2%) | 173 (41.5%) | 320 (38.3%) | 107 (35.2%) | 122 (40.5%) | 229 (37.9%) |
| Unknown | 0 (0.0%) | 2 (0.5%) | 2 (0.2%) | 1 (0.3%) | 2 (0.7%) | 3 (0.5%) |
| Day 29 bone marrow mpFC MRD – N (%) | ||||||
| <0.01% | 374 (89.5%) | 375 (89.9%) | 749 (89.7%) | 78 (25.7%) | 75 (24.9%) | 153 (25.3%) |
| 0.01%-<1% | 44 (10.5%) | 42 (10.1%) | 86 (10.3%) | 192 (63.2%) | 195 (64.8%) | 387 (64.0%) |
| ≥1% | - | - | - | 34 (11.2%) | 31 (10.3%) | 65 (10.7%) |
| Day 29 bone marrow HTS MRD – N (%) | ||||||
| Detectable, ≥1x10−5 | 154 (41.2%) | 151 (40.3%) | 305 (40.7%) | - | - | - |
| Detectable, <1x10−5 | 196 (52.4%) | 201 (53.6%) | 397 (53.0%) | - | - | - |
| Indeterminate | 17 (4.5%) | 21 (5.6%) | 38 (5.1%) | - | - | -- |
| Unavailable | 7 (1.9%) | 2 (0.5%) | 9 (1.2%) | - | - | - |
| Country – N (%) | ||||||
| Australia | 24 (5.7%) | 25 (6.0%) | 49 (5.9%) | 15 (4.9%) | 10 (3.3%) | 25 (4.1%) |
| Canada | 27 (6.5%) | 20 (4.8%) | 47 (5.6%) | 23 (7.6%) | 18 (6.0%) | 41 (6.8%) |
| New Zealand | 5 (1.2%) | 4 (1.0%) | 9 (1.1%) | 6 (2.0%) | 4 (1.3%) | 10 (1.7%) |
| United States | 362 (86.6%) | 368 (88.2%) | 730 (87.4%) | 260 (85.5%) | 269 (89.4%) | 529 (87.4%) |
yr – years; CNS – Central nervous system; HTS – High-throughput sequencing; N – Number; mpFC – Multiparameter flow cytometry; MRD – Minimal residual disease
Efficacy outcomes
In July 2024, the Data and Safety Monitoring Committee reviewed the first planned interim efficacy analysis when 81/194 (41.8%) anticipated events occurred (data cutoff June 30, 2024). At this time, 1,440 eligible and evaluable patients had been randomized (63% planned accrual). Median follow up was 2.5 years (IQR=1.6–3.2). The 3-year post-randomization disease-free survival (± standard error) was 96.0±1.2% for patients randomized to blinatumomab arms vs 87.9±2.1% for those randomized to control arms (Figure 2). Adding blinatumomab significantly improved disease-free survival [RMST difference 72 days, 95% CI 36–108 days, 1-sided stratified log-rank p=0.00004], exceeding pre-specified stopping criteria of p<0.0044. The data safety and monitoring committee recommended early termination of randomization. Three-year post-randomization overall survival estimates with and without blinatumomab were 98.4±0.9% vs 97.1±1.1%, respectively. Adjusting for age, sex, presenting WBC count, cytogenetic risk group (favorable vs. neutral vs. unfavorable), CNS status, Induction day 8 MRD, end of induction MRD measured by flow, and race/ethnicity, the addition of blinatumomab significantly improved disease-free survival (adjusted RMST difference 74 days, 95% CI 38–110 days (Figure 3). The 3-year cumulative incidence of relapse with and without blinatumomab were 3.3±0.8% versus 11.8±1.6%, respectively. A post-hoc per-protocol sensitivity analysis including only randomized patients who started post-Consolidation therapy (N=1,325) revealed similar improved disease-free survival among patients randomized to receive blinatumomab and chemotherapy (RMST difference 67 days, 95% CI 31–104 days).
Figure 2: Outcomes according to randomization.
Panel A shows the comparison of 3-year disease-free survival (DFS) (top row), overall survival (OS) (middle row) and cumulative incidence of relapse (CIR) (bottom row) for the overall randomized cohort (left column), randomized SR-Avg patients (middle column) and randomized SR-High patients (right column). Panel B shows the comparison of the 3-year DFS, OS, total CIR and CIR by relapse site among the overall randomized cohort, SR-Avg group, and SR-High group. Note that OS and CIR were not protocol-specified formal endpoints. Widths of intervals were not adjusted for multiplicity and thus for non-primary analyses should not be used in place of hypothesis testing.
Figure 3: Disease-free survival among various patient subgroups using restricted mean survival time estimates.
Risk Group was a stratification factor, all other subgroup analyses were post-hoc. The lines indicate the 95% confidence intervals, and arrows represent confidence intervals that exceed the graph parameters. Widths of intervals were not adjusted for multiplicity and thus for non-primary analyses should not be used in place of hypothesis testing.
HTS, High-throughput sequencing; MRD, Minimal residual disease; N, Number; SR, Standard risk.
*Day 29 HTS MRD subgroup analysis includes only SR-Average patients with detectable HTS measured MRD. Patients with undetectable HTS MRD were not eligible for randomization. Patients with unavailable HTS MRD or indeterminate HTS MRD were eligible for randomization and are included in the overall outcomes.
Among SR-Avg patients, 3-year disease-free survival for Arm B (blinatumomab) was 97.5±1.3% vs 90.2±2.3% for Arm A (control) (RMST difference 67 days, 95% CI 24–110 days). The 3-year overall survival was 100% for SR-Avg Arm B and 98.4±1.0% for Arm A. For Arm B the 3-year cumulative incidence of relapse was 2.5±0.9% versus 9.8±2.0% for Arm A. No deaths in remission were observed among SR-Avg patients.
For SR-High patients, 3-year disease-free survival was 94.1±2.5% for Arm D (blinatumomab) vs 84.8±3.8% for Arm C (control) (RMST difference 79 days, 95% CI 17–140 days). 3-year overall survival was 96.1±2.0% for Arm D versus 95.3±2.2% on Arm C. The 3-year cumulative incidence of relapse was 4.3±1.4% on Arm D compared to 14.4±2.7% on Arm C. Among randomized SR-High patients, there were 5 deaths in remission, 2 on Arm C and 3 on Arm D.
Though caution in interpretation is warranted given the post-hoc nature of these subgroup analyses, patients of all race/ethnicities benefited from blinatumomab, with a notable RMST difference of 150 days, 95% CI 64–235 days) among patients of self-reported Hispanic ethnicity. The benefit of blinatumomab was also apparent among patients of all cytogenetic risk groups (Supplemental Table S2), CNS status, and EOI MRD levels (Figure 3). Among SR-Avg Down Syndrome patients, 2/16 on Arm A and 0/16 on Arm B had events.
While the 3-year cumulative incidence of relapse for isolated CNS (iCNS) and for combined BM/CNS relapses were not affected by the addition of blinatumomab, the 3-year cumulative incidence of relapse of isolated BM relapses was reduced in the overall cohort (1.5%±0.5% on blinatumomab arms versus 7.7±1.3% on control arms), among SR-Avg patients (1.0%±0.6% Arm B versus 6.7%±1.7% Arm A) and SR-High patients (2.3%±1.0% arm D versus 9.1%±2.1% Arm C) (Figure 2, Supplemental Table S3). Across randomized arms, CD19 expression was reported for 69/75 (92%) relapses; all (100%) were CD19+. All 6 relapses with unknown CD19 status were iCNS.
Toxicity
Treatment-related adverse events were reported on 1,277 randomized patients who initiated post-randomization protocol therapy and submitted data. Table 2 summarizes rates of select CTCAE version 5.0 grade 3+ adverse events by arm. SR-Avg children who received blinatumomab were more likely to experience grade 3+ sepsis and catheter-related infections (Grade 3, blood culture positive with signs or symptoms and treatment indicated; Grade 4, life-threatening consequences and urgent intervention indicated) during overall protocol therapy than those who did not [52/351 (14.8%) vs. 19/376 (5.1%); p<0.001]; no increase was seen among SR-High patients [57/273 (20.9%) vs. 47/277 (17.0%); p=0.28]. Supplemental Figures S4-S5 illustrate rates by treatment phase. Rates of Grade 4 infectious toxicity were low and not different between randomized arms (Supplemental Table S4). Conversely, SR-Avg patients receiving blinatumomab were less likely to experience Grade 3+ allergic reactions [10/351 (2.8%) vs. 27/376 (7.2%); p=0.01].
Table 2.
Proportion of patients with select Grade 3 or greater toxicities by randomized arm
| SR-Average | SR-High | |||||
|---|---|---|---|---|---|---|
| Chemotherapy only (N=376) | Blinatumomab and Chemotherapy (N=351) | p-value | Chemotherapy only (N=277) | Blinatumomab and Chemotherapy (N=273) | p-value | |
| Neurotoxicities | ||||||
| Seizure | 7 (1.9%) | 4 (1.1%) | 0.55 | 7 (2.5%) | 10 (3.7%) | 0.47 |
| All other CNS* | 3 (0.8%) | 2 (0.6%) | 1.00 | 4 (1.4%) | 3 (1.1%) | 1.00 |
| Peripheral neuropathy | 9 (2.4%) | 2 (0.6%) | 0.07 | 2 (0.7%) | 6 (2.2%) | 0.17 |
| Infectious toxicities | ||||||
| Febrile neutropenia | 149 (39.6%) | 165 (47.0%) | 0.05 | 140 (50.5%) | 156 (57.1%) | 0.12 |
| Sepsis and catheter related infection# | 19 (5.1%) | 52 (14.8%) | <0.001 | 47 (17.0%) | 57 (20.9%) | 0.28 |
| Other infection^ | 99 (26.3%) | 115 (32.8%) | 0.06 | 105 (37.9%) | 96 (35.2%) | 0.54 |
| Other toxicities | ||||||
| Pancreatitis | 4 (1.1%) | 3 (0.9%) | 1.00 | 8 (2.9%) | 11 (4.0%) | 0.49 |
| Thrombosis | 2 (0.5%) | 0 (0.0%) | 0.50 | 0 (0.0%) | 0 (0.0%) | - |
| Allergic reaction | 27 (7.2%) | 10 (2.8%) | 0.01 | 15 (5.4%) | 11 (4.0%) | 0.55 |
| Mucositis | 58 (15.4%) | 46 (13.1%) | 0.40 | 49 (17.7%) | 41 (15.0%) | 0.42 |
| CRS | 0 (0.0%) | 1 (0.3%) | 0.48 | 0 (0.0%) | 1 (0.4%) | 0.50 |
| Bilirubin increased | 29 (7.7%) | 27 (7.7%) | 1.00 | 14 (5.1%) | 21 (7.7%) | 0.22 |
CNS – Central nervous system; CRS – Cytokine release syndrome; SR – Standard risk
CTCAE Grade 3 Sepsis: “Blood culture positive with signs or symptoms; treatment indicated”. Grade 4 – “Life-threatening consequences; urgent intervention indicated”
Includes all other infection-related CTCAE v.5 terms
Includes the CTCAE v.5 terms encephalopathy, leukoencephalopathy, posterior-reversible encephalopathy syndrome, stroke, and intracranial hemorrhage
There were five deaths in remission among randomized patients receiving any post-Consolidation therapy, all among SR-High patients. Two occurred among patients receiving chemotherapy only (both sepsis-related, one in Delayed Intensification and one in Maintenance). Three occurred among patients receiving blinatumomab and chemotherapy (one sepsis in Delayed Intensification, one multi-organ failure in Delayed Intensification following sepsis, and one hypoxic ischemic encephalopathy in Maintenance following a seizure)
Only randomized patients with reported post Consolidation therapy were included in this table.
P-values were calculated using 2-sided Fisher’s exact test
Five deaths in remission occurred (Table 2), none during blinatumomab cycles. During blinatumomab cycles, blinatumomab-associated toxicities (Grade 3+ cytokine release syndrome (CRS), sepsis or catheter-related infections, seizures) were rare (Supplemental Table S5). Among the overall cohort, the cumulative incidence of treatment-related mortality at 2 years was 0.4%±0.3% among patients randomized to receive blinatumomab and chemotherapy vs. 0.3%±0.2% among those receiving chemotherapy alone. Treatement-related mortality events were noted among SR-Avg patients. Among SR-High patients, the 2-year cumulative incidence was 0.8%±0.6% in both randomized arms.
DISCUSSION
This randomized phase 3 trial of children with SR B-ALL showed that the addition of blinatumomab to standard chemotherapy resulted in a substantial and significant improvement in Disease-free survival. This improvement was consistent across subgroups defined by patient- or disease-related characteristics, due mainly to a decrease in relapses involving the BM.
Over recent decades, progress in pediatric ALL has been achieved through refinements in risk stratification and selective treatment intensification.3,23–29 Patients with the most favorable risk characteristics have outstanding outcomes, with 5-year disease-free survival now exceeding 95%.4 However, the remaining children with higher risk features have seen a plateau in outcomes for the past two decades. Recent attempts to improve cure rates for these subpopulations through further chemotherapy intensification have failed due to an inability to decrease relapse rates or excessive toxicity.6–10,17,30
After showing efficacy in adults with refractory and MRD-positive B-ALL,31,32 several recent randomized clinical trials have examined the impact of adding blinatumomab to chemotherapy regimens. Litzow et al. recently reported that adding four cycles of blinatumomab to four cycles of consolidation chemotherapy improved relapse-free survival among adult patients with MRD-negative B-ALL from 64% to 80% (HR 0.53, 95% CI 032–0.87).14 To date, most pediatric data have come from studies of children in first relapse. A European study of children with high-risk relapsed B-ALL substituted one block of intensive chemotherapy with one cycle of blinatumomab, improving event-free survival from 31% to 57% (HR 0.33, 95% CI 0.18–0.61).13 COG trial AALL1331 found that incorporating blinatumomab improved outcomes for children with both high- and low-risk relapse.11,12 Whether blinatumomab is equally effective in populations who already have baseline outcomes superior to adults was unknown.
We show that even among subgroups with baseline disease-free survival of 85–90%, adding blinatumomab shows notable efficacy, preventing two-thirds of relapses. Indeed, both SR-Avg and SR-High patients who received blinatumomab and chemotherapy experienced 3-year disease-free survival exceeding 94%, similar to what was previously seen in the most favorable risk group.4 Remarkably, this improvement seems to hold across subpopulations. Though post-hoc, subgroup analyses show consistency in the magnitude of effect across leukemia cytogenetic risk group and regardless of end of induction BM mpFC MRD or, among SR-Avg patients, amount of high throughput sequencing MRD positivity. Race- and ethnicity-defined groups previously shown to experience inferior outcomes, even when treated with modern therapy,33 also benefited. Hispanic children receiving blinatumomab showed a significant and substantial improvement in disease-free survival. While small numbers of enrolled non-Hispanic Black children preclude definitive conclusions, none of those 42 children who received blinatumomab and chemotherapy have relapsed to date. Finally, our results showed an encouraging increase in overall survival among patients with SR-Avg disease, though this requires confirmation with longer follow-up.
Adding blinatumomab improved outcomes predominantly through decreasing marrow relapses. In contrast, the cumulative incidence of iCNS relapse remained the same. The most likely explanation for this finding is the known limited CNS activity of blinatumomab.34 Indeed, the COG relapsed B-ALL trial AALL1331 showed that the addition of blinatumomab did not improve the outcomes of patients with late iCNS relapse.12 Of note, our study did not include patients with CNS3 disease. Preventing the remaining relapses will require an increased focus on identifying patients at highest risk of CNS relapse, and novel methods of targeting the CNS without adversely impacting neurocognitive outcomes.
SR-Avg children who received blinatumomab and chemotherapy were more likely to experience Grade 3+ sepsis or catheter-related infections. Importantly, this was not attributable to infectious events occurring during blinatumomab cycles but occurred instead in subsequent treatment cycles like Delayed Intensification. B-cell aplasia is a known consequence of CD19-directed therapies, but duration and impact on infection risk is unknown. Though serious Grade 4+ infectious events were rare, future studies should examine whether patients receiving blinatumomab benefit from enhanced supportive care (e.g., intravenous immunoglobulin, antimicrobial prophylaxis).
Both our study and the adult E1910 trial added blinatumomab to chemotherapy backbones without additional modifications. Trials in the relapsed setting have demonstrated the efficacy of replacing blocks of traditional chemotherapy with blinatumomab.11–13 Even without blinatumomab, several cooperative groups have successfully removed some chemotherapy from the treatment of NCI SR B-ALL.28,35 Whether the demonstrated efficacy of blinatumomab allows for removal of even more elements of traditional chemotherapy without compromising cure rates is presently unknown among newly diagnosed patients. De-intensification may decrease the acute and long-term burden of ALL treatment but requires studies that balance potential decreases in morbidity and improvements in quality of life with the risk tolerance of patients, caregivers, and providers. Given the above noted lack of CNS activity of blinatumomab, particular care when considering removing elements of traditional chemotherapy with significant CNS activity is warranted.
Other unanswered questions merit consideration. First, longer-term follow-up is required to ensure that improved outcomes with blinatumomab are maintained over time. Second, pediatric patients with NCI high risk disease were not included. Nevertheless, SR-High patients were treated with the same chemotherapy backbone used for NCI high risk patients, which together with the E1910 results strongly suggest that these patients may also benefit from receiving blinatumomab. Other groups are currently studying the impact of blinatumomab in higher-risk pediatric patients (NCT03643276, NCT03117751) and will provide further data. Third, CD19-directed therapies like blinatumomab and chimeric antigen receptor T-cells (CARTs) have become standard components of relapse therapy,11–13,36 but may not be equally effective in patients previously exposed to blinatumomab.37,38 Importantly, none of the relapses seen on our study were known to be CD19-negative. Fourth, trials incorporating one to over four cycles of blinatumomab have now shown substantial efficacy.11–14,39,40 The optimal number and timing of blinatumomab cycles remain unclear, but AALL1731 and E1910 provide standard backbones against which alternative strategies can be evaluated. Fifth, the logistical burden of administering blinatumomab remains substantial; barriers may be significant for families with limited resources or living in remote/rural areas. Interventions targeting these barriers will be crucial to avoid disparities. Subcutaneous blinatumomab has shown efficacy in early studies,41 and may improve access in the future. Finally, the long-term effects of blinatumomab and other immunotherapies are poorly characterized.
This randomized clinical trial definitively establishes that adding blinatumomab to chemotherapy significantly improves disease-free survival in newly diagnosed childhood SR B-ALL of average or higher risk, resulting in outcomes similar to those previously achieved in only the most favorable risk subsets.
Supplementary Material
Funding
This study was supported by grants from the National Institutes of Health/National Cancer Institute (U10CA180899; U20CA180886) and from the St. Baldrick’s Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Contributor Information
Sumit Gupta, Faculty of Medicine, University of Toronto, Toronto, ON
Rachel E. Rau, Ben Towne Center for Childhood Cancer and Blood Disorders Research and the Department of Pediatrics, Fred Hutch Cancer Center, University of Washington, Seattle, WA
John A. Kairalla, Department of Biostatistics, Colleges of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL
Karen R. Rabin, Division of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX
Cindy Wang, Department of Biostatistics, Colleges of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL
Anne L. Angiolillo, Servier Pharmaceuticals, Boston, MA
Sarah Alexander, Faculty of Medicine, University of Toronto, Toronto, ON
Andrew J. Carroll, Department of Genetics, University of Alabama at Birmingham, Birmingham, AL
Susan Conway, Department of Biostatistics, Colleges of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL
Lia Gore, Children’s Hospital Colorado and the University of Colorado School of Medicine, Aurora, CO
Ilan Kirsch, Adaptive Biotechnologies, Inc., Seattle, WA
Holly R. Kubaney, Children’s Blood and Cancer Center, Dell Children’s Medical Center of Central Texas, Austin, TX
Amanda M. Li, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC
Jennifer L. McNeer, Division of Pediatric Hematology/Oncology, University of Utah, Primary Children's Hospital, Salt Lake City, UT
Olga Militano, Children’s Oncology Group, Monrovia, CA
Tamara P. Miller, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
Yvonne Moyer, Biopathology Center and Children’s Oncology Group Biospecimen Bank, Columbus, OH.
Maureen M. O’Brien, Children’s Hospital Colorado and the University of Colorado School of Medicine, Aurora, CO
Maki Okada, Pediatric Hematology/Oncology; Miller Children’s & Women’s Hospital Long Beach, Long Beach, CA
Shalini C. Reshmi, Nationwide Children’s Hospital and Institute for Genomic Medicine and Biopathology Center, Columbus, OH
Mary Shago, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON
Elizabeth Wagner, Biopathology Center and Children’s Oncology Group Biospecimen Bank, Columbus, OH.
Naomi Winick, Department of Pediatrics, Division of Pediatric Hematology/Oncology, UT Southwestern, Simmons Cancer Center, Dallas, TX, USA
Brent L. Wood, Children’s Hospital of Los Angeles, Pathology and Laboratory Medicine, Los Angeles, CA
Tara Haworth-Wright, Seattle Children’s Hospital, University of Washington, Seattle, WA
Faraz Zaman, Amgen, Thousand Oaks, CA
Gerhard Zugmaier, Amgen Research (Munich) München, Deutschland
Sue Zupanec, Hospital for Sick Children, Division of Haematology/Oncology, University of Toronto, Toronto, ON
Meenakshi Devidas, Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, TN
Stephen P. Hunger, Department of Pediatrics and The Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA
David T. Teachey, Department of Pediatrics and The Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA
Elizabeth A. Raetz, Department of Pediatrics and Perlmutter Cancer Center, NYU Langone Health, New York, NY
Mignon L. Loh, Ben Towne Center for Childhood Cancer and Blood Disorders Research and the Department of Pediatrics, Fred Hutch Cancer Center, University of Washington, Seattle, WA
REFERENCES
- 1.Mullighan CG. Genomic characterization of childhood acute lymphoblastic leukemia. Semin Hematol 2013;50:314–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. New Engl J Med 2015;373:1541–2. [DOI] [PubMed] [Google Scholar]
- 3.Borowitz MJ, Devidas M, Hunger SP, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood 2008;111:5477–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Schore RJ, Angiolillo AL, Kairalla JA, et al. Outstanding outcomes with two low intensity regimens with Low-Risk B-ALL: A report from COG AALL0932. Leukemia 2023;37:1375–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Mattano LA, Devidas M, Friedmann AM, et al. Outstanding Outcome for Children with Standard Risk-Low (SR-Low) Acute Lymphoblastic Leukemia (ALL) and No Benefit to Intensified Peg-Asparaginase (PEG-ASNase) Therapy: Results of Children’s Oncology Group (COG) Study AALL0331. Blood 2014;124:Abstract 793. [Google Scholar]
- 6.Maloney KW, Devidas M, Wang C, et al. Outcome in children with standard-risk B-cell acute lymphoblastic leukemia: Results of Children’s Oncology Group Trial AALL0331. J Clin Oncol 2020;38:602–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Angiolillo A, Schore RJ, Devidas M, et al. Intensification of oral methotrexate is not superior to standard methotrexate dosing during maintenance in children with National Cancer Institute (NCI) standard-risk B actue lymphoblastic leukemia (SR B-ALL): A report from the Children's Oncology Group (COG) study AALL0932. Blood 2017;130:140. [Google Scholar]
- 8.Attarbaschi A, Mann G, Zimmerman M, et al. Randomized post-induction and delayed intensification therapy in high-risk pediatric acute lymphoblastic leukemia: Long-term results of the international AIEOP-BFM ALL 2000 trial. Leukemia 2020;34. [DOI] [PubMed] [Google Scholar]
- 9.Conter V, Valsecchi MG, Cario G, et al. Four additional doses of PEG-L-Asparaginase during the Consolidation phase in the AIEOP-BFM ALL 2009 Protocol do not improve outcome and increase toxicity in high-risk ALL: Results of a randomized study. J Clin Oncol 2024;42:915–26. [DOI] [PubMed] [Google Scholar]
- 10.Kirkwood AA, Goulden N, Moppett J, et al. High dose methotrexate does not reduce the risk of CNS relapse in children and young adults with acute lymphoblastic leukaemia and lymphoblastic lymphoma. Results of the randomised phase III study UKALL 2011. Blood 2022;140:516–8.35613411 [Google Scholar]
- 11.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 2021;325:833–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Hogan LE, Brown PAB, Xu X, 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Litzow MR, Mattison RJ, Paietta EM, et al. Blinatumomab for MRD-negative acute lymphoblastic leukemia in adults. N Engl J Med 2024;391:320–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Logan AC, Vashi N, Faham M, et al. Immunoglobulin and T cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplantation relapse and survival. Biol Blood Marrow Transplant 2014;20:1307–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Frishman-Levy L, Izraeli S. Advances in understanding the pathogenesis of CNS acute lymphoblastic leukemia and potential for therapy. Br J Haematol 2016;176:157–67. [DOI] [PubMed] [Google Scholar]
- 17.Salzer WL, Burke MJ, Devidas M, et al. Impact of intrathecal triple therapy versus intrathecal methotrexate on disease-free survival for high-risk B-lymphoblastic leukemia: Children’s Oncology Group Study AALL1131. J Clin Oncol 2020;23:2628–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0. 2017. at https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R eference_5x7.pdf) [PubMed] [Google Scholar]
- 19.Elgarten CW, Thompson JC, Angiolillo A, et al. Improving infectious adverse event reporting for children and adolescents enrolled in clinical trials for acute lymphoblastic leukemia: A report from the Children’s Oncology Group. Pediatr Blood Cancer 2022;69:e29937. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–81. [Google Scholar]
- 21.Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer 1977;35:1–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Anderson JR, High R. Alternatives to the standard Fleming, Harrington, and O’Brien futility boundary. Clin Trials 2011;8:270–6. [DOI] [PubMed] [Google Scholar]
- 23.Matloub Y, Bostrom BC, Hunger SP, et al. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 2011;118:243–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Larsen EC, Devidas M, Chen S, et al. Dexamethasone and High-Dose Methotrexate Improve Outcome for Children and Young Adults With High-Risk B-Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group Study AALL0232. J Clin Oncol 2016;34:2380–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Vrooman LM, Sevenson KE, Supko JG, et al. Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00–01. J Clin Oncol 2013;31:1202–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Moricke A, Reiter A, Zimmerman M, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: Treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2008;111:4477–89. [DOI] [PubMed] [Google Scholar]
- 27.Moricke A, Zimmerman M, Valsecchi MG, et al. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood 2016;127:2101–12. [DOI] [PubMed] [Google Scholar]
- 28.Pieters R, de Groot-Kruseman HA, Van der Velden VH, et al. Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring: Study ALL10 from the Dutch Childhood Oncology Group. J Clin Oncol 2016;34:2591–601. [DOI] [PubMed] [Google Scholar]
- 29.Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. New Engl J Med 2009;360:2730–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Salzer WL, Burke MJ, Devidas M, et al. Toxicity associated with intensive postinduction therapy incorporating clofarabine in the very high-risk stratum of patients with newly diagnosed high-risk B-lymphoblastic leukemia: A report from the Children's Oncology Group study AALL1131. Cancer 2018;124:1150–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017;376:836–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Gokbuget 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Gupta S, Dai Y, Chen Z, et al. Racial and ethnic disparities in childhood and young adult acute lymphocytic leukaemia: Secondary analyses of eight Children’s Oncology Group cohort trials. Lancet Haematol 2023;10:e129–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Kopmar NE, Cassaday RD. How I prevent and treat central nervous system disease in adults with acute lymphpoblastic leukemia. Blood 2023;141:1379–88. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Vora A, Goulden N, Wade R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukemia defined by minimal residual disease (UKALL 2003): A randomised controlled trial. Lancet Oncol 2013;14:199–209. [DOI] [PubMed] [Google Scholar]
- 36.Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 2018;378:439–48. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Myers RM, Taraseviciute A, Steinberg SM, et al. Blinatumomab non-response and high-disease burden are associated with inferior outcomes after CD19-CAR for B-ALL. J Clin Oncol 2022;40:932–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Shah BD, Cassaday RD, Park JH, et al. Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3. J Immunother Cancer 2023;11:e007118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Clesham K, Rao V, Bartram J, et al. Blinatuomomab for infant acute lymphoblastic leukemia. Blood 2020;135:1501–4. [DOI] [PubMed] [Google Scholar]
- 40.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. [DOI] [PubMed] [Google Scholar]
- 41.Jabbour E, Zugmaier G, Agrawal V, et al. Single agent subcutaneous blinatumomab for advanced acute lymphoblastic leukemia. Am J Hematol 2024;99:586–95. [DOI] [PubMed] [Google Scholar]
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