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Pediatric chemotherapy versus allo-HSCT for adolescent and adult Philadelphia chromosome-negative ALL in first complete remission: a meta-analysis

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Abstract

Pediatric-inspired chemotherapy significantly improves survival for adolescent and adult patients with acute lymphoblastic leukemia (ALL). However, the benefits over allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unclear. To compare clinical outcomes between pediatric-inspired chemotherapy and allo-HSCT in consolidation therapy of adolescent and adult Philadelphia chromosome-negative (Ph-neg) ALL in first complete remission (CR1), related studies from MEDLINE, Embase, and Cochrane Controlled Register of Trials updated to July 2022 were searched. A total of 13 relevant trials including 3161 patients were included in the meta-analysis. Compared with allo-HSCT, pediatric-inspired chemotherapy achieved better OS (hazard risk (HR), 0.53; 95% confidence interval (CI), 0.41 to 0.68) and DFS (HR, 0.64; 95% CI, 0.48 to 0.86), with a significant reduction in NRM (risk ratio (RR), 0.30; 95% CI, 0.18 to 0.51), but no difference in the relapse rate (RR, 1.13; 95% CI, 0.93 to 1.39). When only studies based on intention-to-treat analysis were included, pediatric-inspired chemotherapy consistently conferred a survival advantage. In subgroup analyses, patients with baseline high-risk features demonstrated similar OS and DFS between pediatric-style chemotherapy and allo-HSCT, while pediatric-style chemotherapy had an OS and DFS advantage in standard-risk subgroup. Particularly, patients with positive minimal residual disease (MRD) achieved better OS and DFS if proceeded to allo-HSCT.

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For data sharing, contact the corresponding author: hu_xiaoxia@126.com.

References

  1. Nishiwaki S, Akahoshi Y, Morita-Fujita M, et al (2022) Improvements in allogeneic hematopoietic cell transplantation outcomes for adults with ALL over the past 3 decades. Blood Adv

  2. Kantarjian H, Thomas D, O’Brien S et al (2004) Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer 101(12):2788–2801

    Article  CAS  PubMed  Google Scholar 

  3. Rowe JM, Buck G, Burnett AK et al (2005) Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 106(12):3760–3767

    Article  CAS  PubMed  Google Scholar 

  4. Jabbour E, Haddad FG, Short NJ, Kantarjian H (2022) Treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia-from intensive chemotherapy combinations to chemotherapy-free regimens: a review. JAMA Oncol

  5. Brown PA, Shah B, Advani A et al (2021) Acute lymphoblastic leukemia, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Network: JNCCN 19(9):1079–1109

    Article  CAS  PubMed  Google Scholar 

  6. Hoelzer D, Bassan R, Dombret H, Fielding A, Ribera JM, Buske C (2016) Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol : Off J Eur Soc Medical Oncol 27(suppl 5):v69–v82

    Article  CAS  Google Scholar 

  7. Moorman AV, Barretta E, Butler ER, et al. Prognostic impact of chromosomal abnormalities and copy number alterations in adult B-cell precursor acute lymphoblastic leukaemia: a UKALL14 study

  8. Gupta V, Richards S, Rowe J (2013) Acute leukemia stem cell transplantation trialists’ collaborative G. allogeneic, but not autologous, hematopoietic cell transplantation improves survival only among younger adults with acute lymphoblastic leukemia in first remission: an individual patient data meta-analysis. Blood 121(2):339–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ram R, Gafter-Gvili A, Vidal L et al (2010) Management of adult patients with acute lymphoblastic leukemia in first complete remission: systematic review and meta-analysis. Cancer 116(14):3447–3457

    Article  PubMed  Google Scholar 

  10. Goldstone AH, Richards SM, Lazarus HM et al (2008) In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 111(4):1827–1833

    Article  CAS  PubMed  Google Scholar 

  11. Cornelissen JJ, van der Holt B, Verhoef GE et al (2009) Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison. Blood 113(6):1375–1382

    Article  CAS  PubMed  Google Scholar 

  12. Fielding AK, Rowe JM, Richards SM et al (2009) Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood 113(19):4489–4496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kako S, Hayakawa F, Imai K et al (2021) Optimal treatment for Philadelphia-negative acute lymphoblastic leukemia in first remission in the era of high-intensity chemotherapy. Int J Hematol 114(5):608–619

    Article  CAS  PubMed  Google Scholar 

  14. Seftel MD, Neuberg D, Zhang MJ et al (2016) Pediatric-inspired therapy compared to allografting for Philadelphia chromosome-negative adult ALL in first complete remission. Am J Hematol 91(3):322–329

    Article  PubMed  PubMed Central  Google Scholar 

  15. Greenwood M, Trahair T, Sutton R et al (2021) An MRD-stratified pediatric protocol is as deliverable in adolescents and young adults as in children with ALL. Blood Adv 5(24):5574–5583

    Article  PubMed  PubMed Central  Google Scholar 

  16. Rajendra A, Jain H, Bonda VNA et al (2021) Outcomes and prognostic factors in adolescents and young adults with ALL treated with a modified BFM-90 protocol. Blood Adv 5(5):1178–1193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Moorman AV, Antony G, Wade R, et al (2022) Time to cure for childhood and young adult acute lymphoblastic leukemia is independent of early risk factors: long-term follow-up of the UKALL2003 trial. J Clin Oncol JCO2200245

  18. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097

    Article  PubMed  PubMed Central  Google Scholar 

  19. Pidala J, Djulbegovic B, Anasetti C, Kharfan-Dabaja M, Kumar A (2011) Allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia (ALL) in first complete remission. Cochrane Database Syst Rev (10):CD008818

  20. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605

    Article  PubMed  Google Scholar 

  21. Schwarzer G (2014) meta: meta-analysis with R. R package version 4.0–2. https://www.cranR-projectorg/package=meta

  22. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  CAS  PubMed  Google Scholar 

  23. Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17(24):2815–2834

    Article  CAS  PubMed  Google Scholar 

  24. Williamson PR, Smith CT, Hutton JL, Marson AG (2002) Aggregate data meta-analysis with time-to-event outcomes. Stat Med 21(22):3337–3351

    Article  PubMed  Google Scholar 

  25. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101

    Article  CAS  PubMed  Google Scholar 

  26. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF (1999) Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses Lancet 354(9193):1896–1900

    CAS  PubMed  Google Scholar 

  27. Stroup DF, Berlin JA, Morton SC et al (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283(15):2008–2012

    Article  CAS  PubMed  Google Scholar 

  28. Hasselblad V, Eddy DM, Kotchmar DJ (1992) Synthesis of environmental evidence: nitrogen dioxide epidemiology studies. J Air Waste Manage Assoc 42(5):662–671

    Article  CAS  PubMed  Google Scholar 

  29. Hedges LV, Olkin I (1985) Statistical methods for meta-analysis. In: Academic Press

  30. Lipsey M, Wilson D (2001) Practical meta-analysis. In: Vol 49. Sage publications

  31. Wieduwilt MJ, Stock W, Advani A et al (2021) Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic cell transplantation in older adolescents and young adults with Ph-negative acute lymphoblastic leukemia in first complete remission: analysis from CALGB 10403 and the CIBMTR. Leukemia 35(7):2076–2085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Storring JM, Minden MD, Kao S et al (2009) Treatment of adults with BCR-ABL negative acute lymphoblastic leukaemia with a modified paediatric regimen. Br J Haematol 146(1):76–85

    Article  PubMed  Google Scholar 

  33. Huguet F, Leguay T, Raffoux E et al (2009) Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 27(6):911–918

    Article  CAS  PubMed  Google Scholar 

  34. Ribera JM, Oriol A, Morgades M et al (2014) Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial. J Clin Oncol 32(15):1595–1604

    Article  CAS  PubMed  Google Scholar 

  35. Huguet F, Chevret S, Leguay T et al (2018) Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 clinical trial. J Clin Oncol 36(24):2514–2523

    Article  CAS  PubMed  Google Scholar 

  36. Bassan R, Pavoni C, Intermesoli T et al (2020) Updated risk-oriented strategy for acute lymphoblastic leukemia in adult patients 18–65 years: NILG ALL 10/07. Blood Cancer J 10(11):119

    Article  PubMed  PubMed Central  Google Scholar 

  37. Ribera JM, Morgades M, Ciudad J et al (2021) Chemotherapy or allogeneic transplantation in high-risk Philadelphia chromosome-negative adult lymphoblastic leukemia. Blood 137(14):1879–1894

    Article  CAS  PubMed  Google Scholar 

  38. Isshiki Y, Ohwada C, Sakaida E et al (2017) CD20 positivity and white blood cell count predict treatment outcomes in Philadelphia chromosome-negative acute lymphoblastic leukemia patients ineligible for pediatric-inspired chemotherapy. Jpn J Clin Oncol 47(11):1047–1054

    Article  PubMed  Google Scholar 

  39. Dhedin N, Huynh A, Maury S et al (2015) Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia. Blood 125(16):2486–2496 (quiz 2586)

    Article  CAS  PubMed  Google Scholar 

  40. Feng J, Zhang L, Cao XX et al (2020) A pediatric-inspired regimen for adolescents and young adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: results from a single center. Zhonghua Xue Ye Xue Za Zhi 41(5):399–404

    CAS  PubMed  Google Scholar 

  41. Haroon A, Alfraih F, Hanbali A et al (2022) Allogeneic transplant compared to pediatric-inspired therapy for Philadelphia chromosome-negative adolescent and adult ALL in first complete remission. Bone Marrow Transplant 57(4):593–597

    Article  CAS  PubMed  Google Scholar 

  42. Hoelzer D, Bassan R, Dombret H et al (2016) Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 27(suppl 5):v69–v82

    Article  CAS  PubMed  Google Scholar 

  43. Swoboda R, Labopin M, Giebel S et al (2022) Total body irradiation plus fludarabine versus thiotepa, busulfan plus fludarabine as a myeloablative conditioning for adults with acute lymphoblastic leukemia treated with haploidentical hematopoietic cell transplantation. A study by the Acute Leukemia Working Party of the EBMT. Bone marrow transplantation. 57(3):399–406

    Article  CAS  PubMed  Google Scholar 

  44. Eder S, Canaani J, Beohou E et al (2017) Thiotepa-based conditioning versus total body irradiation as myeloablative conditioning prior to allogeneic stem cell transplantation for acute lymphoblastic leukemia: a matched-pair analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Am J Hematol 92(10):997–1003

    Article  CAS  PubMed  Google Scholar 

  45. Pidala J, Djulbegovic B, Anasetti C, Kharfan-Dabaja M (2011) Kumar A (2011) Allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia (ALL) in first complete remission. Cochrane Database Syst Rev 10:Cd008818

    Google Scholar 

  46. Schultz KR, Pullen DJ, Sather HN et al (2007) Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG). Blood 109(3):926–935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Short NJ, Kantarjian H, Jabbour E (2021) Optimizing the treatment of acute lymphoblastic leukemia in younger and older adults: new drugs and evolving paradigms. Leukemia 35(11):3044–3058

    Article  PubMed  Google Scholar 

  48. Wolach O, Stevenson KE, Wadleigh M et al (2016) Allogeneic transplantation is not superior to chemotherapy in most patients over 40 years of age with Philadelphia-negative acute lymphoblastic leukemia in first remission. Am J Hematol 91(8):793–799

    Article  PubMed  Google Scholar 

  49. Lv M, Jiang Q, Zhou DB et al (2020) Comparison of haplo-SCT and chemotherapy for young adults with standard-risk Ph-negative acute lymphoblastic leukemia in CR1. J Hematol Oncol 13(1):52

    Article  PubMed  PubMed Central  Google Scholar 

  50. Locatelli F, Zugmaier G, Rizzari C et al (2021) 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 325(9):843–854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jabbour E, Sasaki K, Ravandi F et al (2018) Chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD, with or without blinatumomab, is highly effective in patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in first salvage. Cancer 124(20):4044–4055

    Article  CAS  PubMed  Google Scholar 

  52. Brown PA, Shah B (2018) Emerging treatment options for acute lymphoblastic leukemia: focus on CAR T-Cell therapy. J Natl Compr Canc Netw 16(5S):651–655

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank all authors of the studies included in this meta-analysis sincerely.

Funding

This work was supported by grants from the National Natural Science Foundation of China (81770106 and 82170206 to Hu) and Natural Science Foundation of Shanghai (20ZR1457100 to Libing Wang).

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Author notes

  1. Zengkai Pan and Luxiang Wang contribute equally.

Authors and Affiliations

  1. State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Shanghai Institute of Hematology, Shanghai RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Ruijin Er Road 197, Shanghai, 200025, China

    Zengkai Pan, Luxiang Wang, Chuanhe Jiang, Zilu Zhang & Xiaoxia Hu

  2. Department of Hematology, Institute of Hematology, Changhai Hospital, Changhai Road 168, Shanghai, 200433, China

    Weijia Fu & Libing Wang

  3. Department of Health Statistics, Naval Medical University, Xiangyin Road 800, Shanghai, 200433, China

    Qi Chen

  4. Collaborative Innovation Center of Hematology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Xiaoxia Hu

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Contributions

Pan and Luxiang Wang reviewed the literature, analyzed the data, and wrote the paper. Fu and Jiang reviewed the literature and performed statistical analysis. Zhang and Chen performed statistical analysis. Chen, Libing Wang, and Hu proposed and designed the study, interpreted the results, wrote the manuscript, and oversaw the project. All authors reviewed, edited, and approved the final version of the manuscript.

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Correspondence to Qi Chen, Libing Wang or Xiaoxia Hu.

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Qi Chen, Libing Wang, and Xiaoxia Hu are co-senior authors.

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Pan, Z., Wang, L., Fu, W. et al. Pediatric chemotherapy versus allo-HSCT for adolescent and adult Philadelphia chromosome-negative ALL in first complete remission: a meta-analysis. Ann Hematol 102, 1131–1140 (2023). https://doi.org/10.1007/s00277-023-05160-2

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