Blinatumomab improves outcomes for pediatric patients with low-risk B-cell acute lymphoblastic leukemia in first marrow relapse
Editorial Commentary

Blinatumomab improves outcomes for pediatric patients with low-risk B-cell acute lymphoblastic leukemia in first marrow relapse

Lindsey Murphy1, Ibrahim Aldoss2

1Department of Pediatrics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA; 2Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, CA, USA

Correspondence to: Ibrahim Aldoss, MD. Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA. Email:

Comment on: 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.

Keywords: Acute lymphoblastic leukemia (ALL); first relapse; blinatumomab

Submitted Oct 21, 2023. Accepted for publication Dec 29, 2023. Published online Mar 06, 2024.

doi: 10.21037/tp-23-521

Over the last several decades, advances in treatment approaches have resulted in significant improvements in survival outcomes for children, adolescents, and young adults with newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL). Unfortunately, disease relapse remains the main reason for treatment failure in about 15% of pediatric patients and cure rates following relapse are suboptimal, with high rates of subsequent relapse and death (1-4). Generally, most patients that relapse after completion of primary treatment are able to achieve a second complete remission and cure rates for these patients are around 50%. However, for patients who relapse while on therapy, only 50% to 70% are able to achieve a second remission, with cure rates of only 20% to 30% (1).

Several prognostic factors for survival outcomes have been identified and have been incorporated into risk stratification approaches for first relapse including time from diagnosis to relapse, site of relapse, and minimal residual disease (MRD) after reinduction chemotherapy (2,5,6). While different collaborative groups employ different risk stratification criteria, patients treated on Children’s Oncology Group trials have historically been considered low-risk (LR) with more favorable outcomes if they experience bone marrow (BM) relapse [with or without extramedullary disease (BM ± EM)] ≥36 months from initial diagnosis or isolated extramedullary (IEM) relapse ≥18 months from initial diagnosis and have low MRD (<0.1%) at end of reinduction chemotherapy.

The current standard treatment approach for pediatric patients in first relapse includes a 4-week block of intensive reinduction chemotherapy followed by consolidation chemotherapy. For children who have early BM relapse (<36 months from diagnosis) or have late BM relapse (≥36 months after diagnosis) and MRD ≥0.1% after reinduction, consolidation chemotherapy followed by hematopoietic stem cell transplant (HSCT) serve as the best chance of cure for these patients (4). For LR patients with late first relapse and MRD <0.1% following reinduction, survival outcomes are favorable with an approach of chemotherapy alone without HSCT (7-9).

Blinatumomab is a genetically modified antibody and novel immunotherapy that serves as a T cell engager that effectively brings CD3-positive T cells into contact with CD19-expressing B-lineage leukemia cells, inducing T-cell mediated cell death. With its favorable response rate and tolerable safety profile, blinatumomab is approved by the Food and Drug Administration and the European Medicines Agency for the treatment of adult and pediatric relapsed/refractory B-ALL, as well as B-ALL with positive MRD (10). The multicenter, randomized, Phase III Children’s Oncology Group trial AALL1331 was a confirmatory trial to test whether the addition of blinatumomab to standard chemotherapy for the treatment of B-ALL in first relapse would improve disease-free survival (DFS) and reduce rates of subsequent relapse (9-11).

Hogan and colleagues recently reported the findings of LR patients with B-ALL from AALL1331 (11). One of the aims of this study was to compare survival of patients specifically with LR first relapse treated with chemotherapy alone or chemotherapy plus blinatumomab. All patients aged 1–30 years old with B-ALL in first relapse were eligible for AALL1331 and patients were stratified at end-induction to the LR group if they had BM relapse ≥36 months after diagnosis or IEM ≥18 months after diagnosis, and MRD <0.1%. End-induction MRD was chosen as the distinguishing feature to stratify between intermediate risk (≥0.1%) and LR patients (<0.1%). Patients with first marrow relapse ≥36 months after diagnosis and MRD <0.1% after reinduction have outstanding cure rates with chemotherapy alone without HSCT, while relapse ≥36 months after diagnosis and MRD ≥0.1% is associated with significantly worse survival outcomes (7,8). The results for the intermediate and high-risk patients, all of whom underwent HSCT, have previously been published (9).

All patients received 4 weeks of reinduction chemotherapy with dexamethasone, vincristine, pegaspargase, mitoxantrone, and risk-based intrathecal chemotherapy, according to the UKALL R3 regimen (12). Following reinduction, LR patients were randomized to standard chemotherapy versus three 4-week blinatumomab blocks intercalated with the standard chemotherapy blocks, followed by maintenance chemotherapy. Patients with CNS3 disease received intensified intrathecal chemotherapy and cranial radiotherapy. Patients with testicular involvement that persisted after reinduction received testicular radiation.

A total of 255 eligible LR patients after reinduction were randomized with 128 receiving standard chemotherapy alone and 127 receiving chemotherapy plus blinatumomab. Median follow-up was 3.5 years (range, 25 days–6.6 years; interquartile range, 2.5–4.7 years). There was no statistical difference in DFS and overall survival (OS) rates between the blinatumomab and chemotherapy arms with the 4-year DFS (P=0.089) and OS (P=0.11) rates, respectively, 61.2% and 90.4% for blinatumomab versus 49.5% and 79.6% for chemotherapy.

However, DFS and OS differed significantly based on the site of first relapse. Of the two-thirds of patients who had a BM ± EM relapse (n=174), the 4-year DFS (P=0.015) and OS (P=0.02) were 72.7% and 97.1% for blinatumomab versus 53.7% and 84.8% for chemotherapy. For isolated BM relapse (n=142), the 4-year DFS (P=0.031) and OS (P=0.044) were 72.9% and 96.3% for blinatumomab (n=70) versus 57.1% and 84.0% for chemotherapy (n=72). However, for BM + EM relapse (n=32), the 4-year DFS (P=0.30) and OS (P=0.14) were not statistically significantly different at 69.5% and 100% for blinatumomab (n=17) versus 36.1% and 85.7% for chemotherapy (n=15). Nonetheless, while DFS and OS were numerically superior with blinatumomab use in patients with BM + EM relapse, the small number of patients in this subgroup has likely impacted the power to derive a statistically significant difference. One-third of patients (n=81) had a late IEM relapse [25% central nervous system (CNS) and 6.7% testicular] and the 4-year DFS (P=0.62) and OS (P=0.53) were 36.6% and 76.5% for blinatumomab (n=40) versus 38.8% and 68.8% for chemotherapy (n=41). Those with isolated CNS (ICNS) relapse were more likely to have second relapses (66.7%), in which the majority occurred in the CNS (71%).

Importantly, blinatumomab was well tolerated by LR patients with significantly lower toxicities, especially when evaluating hematologic and infectious toxicities, compared with the intensive chemotherapy blocks alone. Additionally, there were overall low rates of cytokine release syndrome and neurotoxicity from blinatumomab, and most were low grade. All adverse events that were attributed to be blinatumomab-related were fully reversible.

The combination of blinatumomab and chemotherapy for LR first relapse B-ALL patients did not improve outcomes for the group as a whole; however, the addition of blinatumomab did significantly improve both DFS and OS for the two thirds of patients who had BM ± EM relapse. Multivariable analysis of DFS for BM ± EM relapse highlighted those younger patients who relapsed later and who had MRD <0.01% had improved outcomes. Of particular interest is that patients with IEM relapse had poor outcomes with both arms. Unfortunately, those with ICNS relapse did the worst with high rates of second relapse and inferior DFS in both arms compared to previous studies. The authors attributed the lower DFS rate for ICNS relapses to reduced intensity of CNS-directed therapy compared to prior trials with fewer intrathecal doses of chemotherapy as well as fewer systemic doses of high-dose cytarabine and methotrexate given on AALL1331, along with different overall approaches to cranial radiation doses and HSCT for these patients. Additionally, given that the majority of second relapses in the ICNS relapse cohort were in the CNS, this emphasizes that blinatumomab is not particularly effective in treating CNS disease.

Similar experiences and results have been reported in studies of adult relapsed patients with B-ALL. Generally, adult patients with relapsed/refractory (R/R) B-ALL have a dismal prognosis and intensive chemotherapy leads to complete remission in less than 40% of patients (13,14). For these patients, 5-year OS is less than 20%, with some improvement and prolonged OS in patients proceeding to HSCT (14). In the pivotal phase III TOWER study, blinatumomab was found to be superior to conventional chemotherapy for adult patients with R/R B-ALL and a viable bridge to HSCT (15). Dombret et al. performed a retrospective analysis on adult patients treated with blinatumomab as first versus later relapse therapy on the pivotal phase III TOWER study (15,16). A total of 104 adult patients in first relapse were compared to 167 patients treated with blinatumomab in second or greater relapse. Median OS was 11.1 months [95% confidence interval (CI): 8.2–not reached] for first salvage versus 5.1 months (95% CI: 3.2–7.1) for those patients treated with blinatumomab in second/later salvage (16). A similar trend was found in a retrospective analysis performed by Topp et al. with patients who received blinatumomab as first salvage therapy having longer median OS compared to second/later salvage therapy [10.4 versus 5.7 months; hazard ratio (HR), 1.58; P<0.001] (17). These results confirmed the benefit of blinatumomab is more evident when administered in first relapse compared to second or greater relapse.

Notably, blinatumomab has a more favorable safety profile and superior efficacy when it is administered to patients in remission as opposed to fully relapsed disease, either in the setting of persistent MRD similar to what was done in the AALL1331 study following reinduction chemotherapy or cytoreduction regimen, or in the R/R MRD+ setting as it was applied in the BLAST study (18). Furthermore, survival benefit for even earlier use of blinatumomab as part of the consolidation program was also established among adult patients enrolled in the ECOG 1910 study after achieving MRD-negative CR1 with chemotherapy, and this approach will likely become the new standard of care in adults with newly diagnosed B-ALL (19). Several other studies have demonstrated safety and efficacy of utilizing blinatumomab in combination with chemotherapy early in the course of therapy, with the benefit of blinatumomab extending beyond those in MRD+ CR1 and establishing survival advantage for blinatumomab even in MRD-negative patients (20-23). Therefore, investigating the benefit of integrating blinatumomab during frontline therapy in children with B-ALL may further improve overall outcomes and reduce the risk of relapse.

Given that EM relapse in the CNS is associated with a dismal prognosis and is extremely challenging to treat due to many therapies having decreased permeability and access to the CNS, we sought to better understand extramedullary failure of blinatumomab therapy (24). In this retrospective study, the outcomes of 132 adult patients with either R/R (n=103) or MRD+ (n=29) B-ALL who were treated with blinatumomab were analyzed. Patients with no history of extramedullary disease prior to receiving blinatumomab had improved response to blinatumomab (P=0.019) compared to patients with EM disease. Blinatumomab failure was defined as primary refractory disease to blinatumomab or relapse after an initial response. Of the 89 patients who failed blinatumomab, 38 relapsed with EM disease, including 15 with CNS relapses. This study demonstrated that any prior history of extramedullary disease predicts an inferior response to blinatumomab and is associated with increased risk of subsequent relapse at EM sites, with the CNS as the most common site of extramedullary failure (24). These findings, together with the recent results from AALL1331, confirm decreased efficacy of blinatumomab for the treatment of relapsed EM+ B-ALL when compared to isolated BM involvement. Especially in the setting of CNS involvement prior to blinatumomab, the data suggest limited access of blinatumomab to the CNS with particularly poor responses and increased CNS relapses for patients.

This is contrary to what has been observed for CD19-directed chimeric antigen receptor (CAR) T cell therapy. Many publications report favorable responses to CD19 CAR T cell therapy for patients with EM and CNS disease that are similar to those seen in patients without CNS disease (25-29). Jacoby et al. conducted a retrospective analysis of 55 pediatric patients who received CD19-targeted CAR T cell therapy for the treatment of relapsed B-ALL with CNS involvement with 94% of patients achieving a complete remission as a result of this treatment (27). The Pediatric Real World CAR Consortium reported on the outcomes of 184 patients who were treated with CAR therapy and found there was no difference in 12-month relapse-free survival (P=0.92) and 24-month OS (P=0.41) between patients with CNS involvement at time of relapse (n=40), non-CNS extramedullary disease (n=15), and those with BM only relapse (25). In patients with CNS disease, 88% are able to achieve a complete remission in response to CAR T cell therapy compared to 66% of patients with non-CNS EM relapse (25). Ultimately, CAR T cells are effective at clearing CNS disease and can result in durable remissions for relapsed B-ALL patients with CNS involvement (28).

The recently published results from AALL1331 for children, adolescents, and young adult patients with LR B-ALL with first BM ± EM relapse demonstrated significant improvements in DFS and OS for this cohort. As a result, blinatumomab in combination with chemotherapy for these patients should be considered the new standard of care. Alternatively, those LR patients with IEM relapse, and specifically ICNS relapse, had poor rates of DFS and OS despite the addition of blinatumomab. There is a critical need to improve upon the significantly inferior outcomes of these patients with particular focus on optimizing CNS-directed therapy. Given the promising data on CAR T cell therapy in patients with leukemia with CNS involvement, further clinical trials investigating this treatment approach are of the utmost importance.


Funding: None.


Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article has undergone external peer review.

Peer Review File: Available at

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at I.A. reports serving on Advisory Boards for Amgen and KiTE Pharm. I.A. served as a consultant for Amgen, and received consulting fees and payment from them. The other author has no 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:


  1. Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in Children. N Engl J Med 2015;373:1541-52. [Crossref] [PubMed]
  2. Hunger SP, Raetz EA. How I treat relapsed acute lymphoblastic leukemia in the pediatric population. Blood 2020;136:1803-12. [Crossref] [PubMed]
  3. Pui CH, Yang JJ, Hunger SP, et al. Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration. J Clin Oncol 2015;33:2938-48. [Crossref] [PubMed]
  4. Nguyen K, Devidas M, Cheng SC, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia 2008;22:2142-50. [Crossref] [PubMed]
  5. Coustan-Smith E, Gajjar A, Hijiya N, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse. Leukemia 2004;18:499-504. [Crossref] [PubMed]
  6. Paganin M, Zecca M, Fabbri G, et al. Minimal residual disease is an important predictive factor of outcome in children with relapsed 'high-risk' acute lymphoblastic leukemia. Leukemia 2008;22:2193-200. [Crossref] [PubMed]
  7. Lew G, Chen Y, Lu X, et al. Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433. Haematologica 2021;106:46-55. [Crossref] [PubMed]
  8. Eckert C, Groeneveld-Krentz S, Kirschner-Schwabe R, et al. Improving Stratification for Children With Late Bone Marrow B-Cell Acute Lymphoblastic Leukemia Relapses With Refined Response Classification and Integration of Genetics. J Clin Oncol 2019;37:3493-506. [Crossref] [PubMed]
  9. 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. [Crossref] [PubMed]
  10. BLINCYTO® (blinatumomab) Prescribing Information. V13 2023. Available online:
  11. 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]
  12. Parker C, Waters R, Leighton C, et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet 2010;376:2009-17. [Crossref] [PubMed]
  13. Gökbuget N, Dombret H, Ribera JM, et al. International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia. Haematologica 2016;101:1524-33. [Crossref] [PubMed]
  14. Gökbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood 2012;120:2032-41. [Crossref] [PubMed]
  15. 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]
  16. Dombret H, Topp MS, Schuh AC, et al. Blinatumomab versus chemotherapy in first salvage or in later salvage for B-cell precursor acute lymphoblastic leukemia. Leuk Lymphoma 2019;60:2214-22. [Crossref] [PubMed]
  17. Topp MS, Stein AS, Gökbuget N, et al. Blinatumomab as first salvage versus second or later salvage in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia: Results of a pooled analysis. Cancer Med 2021;10:2601-10. [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. Erratum in: Blood 2019;133:2625. [Crossref] [PubMed]
  19. Litzow MR, Sun Z, Paietta E, et al. Consolidation Therapy with Blinatumomab Improves Overall Survival in Newly Diagnosed Adult Patients with B-Lineage Acute Lymphoblastic Leukemia in Measurable Residual Disease Negative Remission: Results from the ECOG-ACRIN E1910 Randomized Phase III National Cooperative Clinical Trials Network Trial. Blood 2022;140:LBA-1.
  20. Boissel N, Huguet F, Graux C, et al. Frontline Consolidation with Blinatumomab for High-Risk Philadelphia-Negative Acute Lymphoblastic Adult Patients. Early Results from the Graall-2014-QUEST Phase 2. Blood. 2021;138:1232.
  21. 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.
  22. 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]
  23. 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]
  24. Aldoss I, Otoukesh S, Zhang J, et al. Extramedullary disease relapse and progression after blinatumomab therapy for treatment of acute lymphoblastic leukemia. Cancer 2022;128:529-35. [Crossref] [PubMed]
  25. Fabrizio VA, Phillips CL, Lane A, et al. Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report. Blood Adv 2022;6:600-10. [Crossref] [PubMed]
  26. Jacoby E, Bielorai B, Avigdor A, et al. Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia. Am J Hematol 2018;93:1485-92. [Crossref] [PubMed]
  27. Jacoby E, Ghorashian S, Vormoor B, et al. CD19 CAR T-cells for pediatric relapsed acute lymphoblastic leukemia with active CNS involvement: a retrospective international study. Leukemia 2022;36:1525-32. [Crossref] [PubMed]
  28. Leahy AB, Newman H, Li Y, et al. CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials. Lancet Haematol 2021;8:e711-22. [Crossref] [PubMed]
  29. Aldoss I, Khaled SK, Wang X, et al. Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk Relapsed/Refractory ALL. Clin Cancer Res 2023;29:742-53. [Crossref] [PubMed]
Cite this article as: Murphy L, Aldoss I. Blinatumomab improves outcomes for pediatric patients with low-risk B-cell acute lymphoblastic leukemia in first marrow relapse. Transl Pediatr 2024;13(3):530-534. doi: 10.21037/tp-23-521

Download Citation