Skip to main content


Log in

Comparing the efficacy of salvage regimens for relapsed/refractory B-cell acute lymphoblastic leukaemia: a systematic review and network meta-analysis

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript


The complete remission (CR) rate and overall survival (OS) of relapsed/refractory (R/R) B-cell acute lymphoblastic leukaemia (B-ALL) are not satisfactory. The available salvage regimens include standard chemotherapy, inotuzumab ozogamicin, blinatumomab and cluster of differentiation (CD)19 chimeric antigen receptor T cells (CAR T), and the NCCN guidelines recommend all of these therapies with no preference. Dual CD19/CD22 CAR T-cells have emerged as new treatments and have shown some efficacy, with high CR rates and preventing CD19-negative relapse. However, direct comparisons of the CR rate and long-term survival among the different salvage therapies are lacking. Databases including PubMed, Embase, Web of Science and Cochrane were searched from inception to January 31, 2022, for relevant studies. The outcomes of interest were complete remission/complete remission with incomplete haematologic recovery (CR/CRi) rates and 1-year overall survival (OS) rates. Odds ratios (ORs) were generated for binary outcomes, and the mean difference (MD) was generated for consecutive outcomes by network meta-analysis. CD19 CAR T-cells demonstrated a significantly better effect in improving the CR/CRi rate than blinatumomab (OR = 8.32, 95% CI: 1.18 to 58.44) and chemotherapy (OR = 16.4, 95% CI: 2.76 to 97.45). In terms of OS, CD19 CAR T-cells and dual CD19/CD22 CAR T-cells both had a higher 1-year OS rate than blinatumomab, inotuzumab ozogamicin and chemotherapy. There was no significant difference between CD19 CAR T-cells and dual CD19/CD22 CAR T-cells in terms of 1-year OS and CR/CRi rates. CD19 CAR T-cells are effective in inducing CR, and CD19 CAR T-cells and dual CD19/CD22 CAR T-cells show benefits for overall survival. More high-quality randomized controlled trials and longer follow-ups are needed to confirm and update the results of this analysis in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

This study did not produce any new data.


  1. Huang FL, Liao EC, Li CL et al (2020) Pathogenesis of pediatric B-cell acute lymphoblastic leukemia: molecular pathways and disease treatments. Oncol Lett 20:448–454.

    Article  CAS  Google Scholar 

  2. Portell CA, Wenzell CM, Advani AS (2013) Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia. Clin Pharmacol 5:5–11.

    Article  CAS  Google Scholar 

  3. O’Brien S, Thomas D, Ravandi F et al (2008) Outcome of adults with acute lymphocytic leukemia after second salvage therapy. Cancer 113:3186–3191.

    Article  Google Scholar 

  4. Tavernier E, Boiron JM, Huguet F et al (2007) Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia 21:1907–1914.

    Article  CAS  Google Scholar 

  5. Gökbuget N, Stanze D, Beck J et al (2012) Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood 120:2032–2041.

    Article  CAS  Google Scholar 

  6. Kantarjian H, Stein A, Gökbuget N et al (2017) Blinatumomab versus Chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 376:836–847.

    Article  CAS  Google Scholar 

  7. Fielding AK, Richards SM, Chopra R et al (2007) Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 109:944–950.

    Article  CAS  Google Scholar 

  8. Przepiorka D, Ko CW, Deisseroth A et al (2015) FDA approval: blinatumomab. Clin Cancer Res 21:4035–4039.

    Article  CAS  Google Scholar 

  9. Topp MS, Gökbuget N, Stein AS et al (2015) Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol 16:57–66.

    Article  CAS  Google Scholar 

  10. Raponi S, De Propris MS, Intoppa S et al (2011) Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibody-based immunotherapy in acute lymphoblastic leukemia: analysis of 552 cases. Leuk Lymphoma 52:1098–1107.

    Article  CAS  Google Scholar 

  11. DiJoseph JF, Armellino DC, Boghaert ER et al (2004) Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood 103:1807–1814.

    Article  CAS  Google Scholar 

  12. Kantarjian H, Thomas D, Jorgensen J et al (2013) Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer 119:2728–2736.

    Article  CAS  Google Scholar 

  13. Kantarjian HM, DeAngelo DJ, Stelljes M et al (2019) Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer 125:2474–2487.

    Article  CAS  Google Scholar 

  14. Jiang H, Li C, Yin P et al (2019) Anti-CD19 chimeric antigen receptor-modified T-cell therapy bridging to allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia: an open-label pragmatic clinical trial. Am J Hematol 94:1113–1122.

    Article  CAS  Google Scholar 

  15. Sotillo E, Barrett DM, Black KL et al (2015) Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov 5:1282–1295.

    Article  CAS  Google Scholar 

  16. Orlando EJ, Han X, Tribouley C et al (2018) Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat Med 24:1504–1506.

    Article  CAS  Google Scholar 

  17. Hu Y, Zhou Y, Zhang M et al (2021) CRISPR/Cas9-engineered universal CD19/CD22 dual-targeted CAR-T cell therapy for relapsed/refractory B-cell acute lymphoblastic leukemia. Clin Cancer Res 27:2764–2772.

    Article  CAS  Google Scholar 

  18. Frey NV, Shaw PA, Hexner EO et al (2020) Optimizing chimeric antigen receptor T-cell therapy for adults with acute lymphoblastic leukemia. J Clin Oncol 38:415–422.

    Article  CAS  Google Scholar 

  19. Jadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12.

    Article  CAS  Google Scholar 

  20. Faderl S, Jain N, O'Brien SM et al (2013) Inotuzumab ozogamicin (CMC-544) compared to chemotherapy in patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL): A retrospective comparison. J Clin Oncol 31:15

  21. Rambaldi A, Ribera JM, Kantarjian HM et al (2020) Blinatumomab compared with standard of care for the treatment of adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia. Cancer 126:304–310.

    Article  CAS  Google Scholar 

  22. Stelmach P, Wethmar K, Groth C et al (2020) Blinatumomab or inotuzumab ozogamicin as bridge to allogeneic stem cell transplantation for relapsed or refractory B-lineage acute lymphoblastic leukemia: a retrospective single-center analysis. Clin Lymphoma Myeloma Leuk 20:e724–e733.

    Article  Google Scholar 

  23. Badar T, Szabo A, Dinner S et al (2021) Sequencing of novel agents in relapsed/refractory B-cell acute lymphoblastic leukemia: blinatumomab and inotuzumab ozogamicin may have comparable efficacy as first or second novel agent therapy in relapsed/refractory acute lymphoblastic leukemia. Cancer 127:1039–1048.

    Article  CAS  Google Scholar 

  24. Wei G, Hu Y, Pu C et al (2018) CD19 targeted CAR-T therapy versus chemotherapy in re-induction treatment of refractory/relapsed acute lymphoblastic leukemia: results of a case-controlled study. Ann Hematol 97:781–789.

    Article  CAS  Google Scholar 

  25. Wang Y, Yang Y, Hong R et al (2020) A retrospective comparison of CD19 single and CD19/CD22 bispecific targeted chimeric antigen receptor T cell therapy in patients with relapsed/refractory acute lymphoblastic leukemia. Blood Cancer J 10:105.

    Article  CAS  Google Scholar 

  26. Liu S, Zhang X, Dai H et al (2021) Tandem CD19/CD22 dual targets CAR-T cells therapy obtains superior CR rate than single CD19 CAR-T cells infusion as well as sequential CD19 and CD22 CAR-T cells infusion for relapsed/refractory B-cell acute lymphoblastic leukemia patients. Blood 138:1755.

    Article  Google Scholar 

  27. Zhao YL, Liu DY, Sun RJ et al (2021) Integrating CAR T-Cell therapy and transplantation: comparisons of safety and long-term efficacy of allogeneic hematopoietic stem cell transplantation after CAR T-cell or chemotherapy-based complete remission in B-cell acute lymphoblastic leukemia. Front Immunol 12:605766.

    Article  CAS  Google Scholar 

  28. Salhotra A, Yang D, Mokhtari S et al (2020) Outcomes of allogeneic hematopoietic cell transplantation after salvage therapy with blinatumomab in patients with relapsed/refractory acute lymphoblastic leukemia. Biol Blood Marrow Transplant 26:1084–1090.

    Article  CAS  Google Scholar 

  29. Martinelli G, Boissel N, Chevallier P et al (2021) Long-term follow-up of blinatumomab in patients with relapsed/refractory Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukaemia: Final analysis of ALCANTARA study. Eur J Cancer 146:107–114.

    Article  CAS  Google Scholar 

  30. Aldoss I, Song J, Stiller T et al (2017) Correlates of resistance and relapse during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. Am J Hematol 92:858–865.

    Article  CAS  Google Scholar 

  31. Haso W, Lee DW, Shah NN et al (2013) Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 121:1165–1174.

    Article  CAS  Google Scholar 

  32. Shah NN, Stevenson MS, Yuan CM et al (2015) Characterization of CD22 expression in acute lymphoblastic leukemia. Pediatr Blood Cancer 62:964–969.

    Article  CAS  Google Scholar 

  33. Kantarjian HM, DeAngelo DJ, Stelljes M et al (2016) Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 375:740–753.

    Article  CAS  Google Scholar 

  34. Jabbour E, Ravandi F, Kebriaei P et al (2018) Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: a phase 2 clinical trial. JAMA Oncol 4:230–234.

    Article  Google Scholar 

  35. Aamir S, Anwar MY, Khalid F et al (2021) Systematic review and meta-analysis of CD19-specific CAR-T cell therapy in relapsed/refractory acute lymphoblastic leukemia in the pediatric and young adult population: safety and efficacy outcomes. Clin Lymphoma Myeloma Leuk 21:e334–e347.

    Article  Google Scholar 

  36. Hu L, Charwudzi A, Li Q et al (2021) Anti-CD19 CAR-T cell therapy bridge to HSCT decreases the relapse rate and improves the long-term survival of R/R B-ALL patients: a systematic review and meta-analysis. Ann Hematol 100:1003–1012.

    Article  Google Scholar 

  37. Zhang X, Lu XA, Yang J et al (2020) Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell acute lymphoblastic leukemia with high-risk features. Blood Adv 4:2325–2338.

    Article  CAS  Google Scholar 

  38. Zhang Y, Li S, Wang Y et al (2022) A novel and efficient CD22 CAR-T therapy induced a robust antitumor effect in relapsed/refractory leukemia patients when combined with CD19 CAR-T treatment as a sequential therapy. Exp Hematol Oncol 11:15.

    Article  CAS  Google Scholar 

Download references


This work was supported by the grants from the National Natural Science Foundation of China (Grant No. 81970138, 82270165), Jiangsu Province Natural Science Foundation of China (Grant No. 20221235). Translational Research Grant of NCRCH (Grant No. 2020ZKMB05), Jiangsu Province ‘333’ Project, Social Development Project of the Science and Technology Department of Jiangsu (Grant No. BE2021649) and Gusu Key Medical Talent Program (Grant No. GSWS2019007), Jiangsu Province Natural Science Foundation of China (Grant No. BK20221235).

Author information

Authors and Affiliations



Han-Yu Cao was responsible for protocol writing, data analysis and manuscript writing. Chao-Ling Wan was responsible for data extraction. Sheng-Li Xue helped perform the analysis with constructive discussions.

Corresponding author

Correspondence to Sheng-Li Xue.

Ethics declarations

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cao, HY., Wan, CL. & Xue, SL. Comparing the efficacy of salvage regimens for relapsed/refractory B-cell acute lymphoblastic leukaemia: a systematic review and network meta-analysis. Ann Hematol 102, 155–165 (2023).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: