SpringerLink
Log in

CLAG combined with total body irradiation as intensive conditioning chemotherapy prior to allogeneic hematopoietic stem cell transplantation in patients with refractory or relapsed acute myeloid leukemia

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

Abstract

Refractory or relapsed acute myeloid leukemia (R/R AML) remains the major challenge of AML treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only valid option to achieve cure, but the prognosis is still dismal. We conducted a retrospective analysis for the feasibility of CLAG regimens (cladribine, cytarabine, and granulocyte colony-stimulating factor) combined with total body irradiation (TBI) as new intensive conditioning chemotherapy prior to HSCT in R/R AML. A total of 70 patients, including 21 primary refractory and 49 relapsed AML, were analyzed. Forty-nine (70%) patients had extramedullary diseases, and 54 (77%) patients received haploidentical transplantation. Except for one who died before white blood cell engraftment, all of the 69 evaluable patients achieved measurable residual disease (MRD) negative complete remission. The 3-year overall survival (OS) and relapse-free survival (RFS) rates were 46.0% (95% confidence interval [CI], 33.5–57.7%) and 38.5% (95%CI, 26.8–50.0%). The 1-year cumulative incidences of relapse and non-relapse mortality (NRM) were 38.6% (95%CI, 27.3–49.3%) and 11.6% (95%CI: 5.4–20.3%), respectively. The presence of chronic graft-versus-host disease (cGVHD) showed a trend to be associated with a lower risk of relapse (P = 0.054) and extramedullary diseases with a higher risk of NRM (P = 0.074). Multivariate analyses identified low leukemia burden pre-HSCT (defined as bone marrow blasts ≤ 50%) and cGVHD as independent factors associated with favorable OS and RFS. In conclusion, intensive conditioning with CLAG regimens plus TBI may be an effective and well-tolerated choice for R/R AML patients undergoing allo-HSCT.

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

Access this article

Log in via an institution

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 includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

The data that support the findings of this study are available on request from the corresponding author.

References

  1. Juliusson G, Hough R (2016) Leukemia. Prog. Tumor Res 43:87–100

    Article  Google Scholar 

  2. Thol F, Ganser A (2020) Treatment of relapsed acute myeloid leukemia. Curr Treat Options Oncol 21(8):66

    Article  PubMed  PubMed Central  Google Scholar 

  3. Thol F, Schlenk RF, Heuser M et al (2015) How I treat refractory and early relapsed acute myeloid leukemia. Blood 126(3):319–327

    Article  PubMed  CAS  Google Scholar 

  4. Schlenk RF, Dohner K, Mack S et al (2010) Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German-Austrian trial AMLHD98A. J Clin Oncol 28(30):4642–4648

    Article  PubMed  Google Scholar 

  5. Duval M, Klein JP, He W et al (2010) Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol 28(23):3730–3738

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mohamed Jiffry MZ, Kloss R, Ahmed-Khan M et al (2023) A review of treatment options employed in relapsed/refractory AML. Hematology 28(1):2196482

    Article  PubMed  Google Scholar 

  7. Robak T (2003) Purine nucleoside analogues in the treatment of myleoid leukemias. Leuk Lymphoma 44(3):391–409

    Article  PubMed  CAS  Google Scholar 

  8. Martin MG, Welch JS, Augustin K et al (2009) Cladribine in the treatment of acute myeloid leukemia: a single-institution experience. Clin Lymphoma Myeloma 9(4):298–301

    Article  PubMed  CAS  Google Scholar 

  9. Wang L, Xu J, Tian X et al (2019) Analysis of efficacy and prognostic factors of CLAG treatment in Chinese patients with refractory or relapsed acute myeloid leukemia. Acta Haematol 141(1):43–53

    Article  PubMed  CAS  Google Scholar 

  10. Bao Y, Zhao J, Li ZZ (2018) Comparison of clinical remission and survival between CLAG and FLAG induction chemotherapy in patients with refractory or relapsed acute myeloid leukemia: a prospective cohort study. Clin Transl Oncol 20(7):870–880

    Article  PubMed  CAS  Google Scholar 

  11. Xu J, Lv TT, Zhou XF et al (2018) Efficacy of common salvage chemotherapy regimens in patients with refractory or relapsed acute myeloid leukemia: a retrospective cohort study. Medicine (Baltimore) 97(39):e12102

    Article  PubMed  CAS  Google Scholar 

  12. Luger SM, Ringden O, Zhang MJ et al (2012) Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant 47(2):203–211

    Article  PubMed  CAS  Google Scholar 

  13. Ringden O, Labopin M, Ehninger G et al (2009) Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol 27(27):4570–4577

    Article  PubMed  Google Scholar 

  14. Leukemia & Lymphoma Group, Chinese Society of Hematology, Chinese Medical Association (2021) Chinese guidelines for the diagnosis and treatment of relapsed/refractory acute myelogenous leukemia. Zhonghua Xue Ye Xue Za Zhi 42(8):624–627

    Google Scholar 

  15. Huang XJ, Liu DH, Liu KY et al (2006) Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 38(4):291–297

    Article  PubMed  Google Scholar 

  16. Schuurhuis GJ, Heuser M, Freeman S et al (2018) Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood 131(12):1275–1291

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Austin PC, Fine JP (2017) Practical recommendations for reporting Fine-Gray model analyses for competing risk data. Stat Med 36:4391–4400

    Article  PubMed  PubMed Central  Google Scholar 

  18. Dohner H, Estey E, Grimwade D et al (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424–447

    Article  PubMed  PubMed Central  Google Scholar 

  19. Roboz GJ, Rosenblat T, Arellano M et al (2014) International randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia. J Clin Oncol 32(18):1919–1926

    Article  PubMed  CAS  Google Scholar 

  20. Kopinska A, Weglarz P, Koclega A et al (2023) Allogeneic hematopoietic stem cell transplantation for relapsed/refractory acute myeloid leukemia: a single-centre experience. Clin Lymphoma Myeloma Leuk 23(1):28–39

    Article  PubMed  Google Scholar 

  21. Todisco E, Ciceri F, Oldani E et al (2013) The CIBMTR score predicts survival of AML patients undergoing allogeneic transplantation with active disease after a myeloablative or reduced intensity conditioning: a retrospective analysis of the Gruppo Italiano Trapianto Di Midollo Osseo. Leukemia 27(10):2086–2091

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Steckel NK, Groth C, Mikesch JH et al (2018) High-dose melphalan-based sequential conditioning chemotherapy followed by allogeneic haematopoietic stem cell transplantation in adult patients with relapsed or refractory acute myeloid leukaemia. Br J Haematol 180(6):840–853

    Article  PubMed  CAS  Google Scholar 

  23. Bonifazi F, Pavoni C, Peccatori J et al (2022) Myeloablative conditioning with thiotepa-busulfan-fludarabine does not improve the outcome of patients transplanted with active leukemia: final results of the GITMO prospective trial GANDALF-01. Bone Marrow Transplant 57(6):949–958

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Spurgeon S, Yu M, Phillips JD et al (2009) Cladribine: not just another purine analogue? Expert Opin Investig Drugs 18(8):1169–1181

    Article  PubMed  CAS  Google Scholar 

  25. Freyer CW, Gupta N, Wetzler M et al (2015) Revisiting the role of cladribine in acute myeloid leukemia: an improvement on past accomplishments or more old news? Am J Hematol 90(1):62–72

    Article  PubMed  CAS  Google Scholar 

  26. Chow KU, Boehrer S, Napieralski S et al (2003) In AML cell lines Ara-C combined with purine analogues is able to exert synergistic as well as antagonistic effects on proliferation, apoptosis and disruption of mitochondrial membrane potential. Leuk Lymphoma 44(1):165–173

    Article  PubMed  CAS  Google Scholar 

  27. Sun Y, Zhang J, Long B et al (2021) A novel intensive conditioning regimen for allogeneic hematopoietic stem cell transplantation in the treatment of relapsed/refractory acute myeloid leukemia. Neoplasma 68(6):1351–1358

    Article  PubMed  CAS  Google Scholar 

  28. Wang J, Zhao J, Fei X et al (2018) A new intensive conditioning regimen for allogeneic hematopoietic stem cell transplantation in patients with refractory or relapsed acute myeloid leukemia. Medicine (Baltimore) 97(17):e0228

    Article  PubMed  Google Scholar 

  29. Oyekunle AA, Kroger N, Zabelina T et al (2006) Allogeneic stem-cell transplantation in patients with refractory acute leukemia: a long-term follow-up. Bone Marrow Transplant 37(1):45–50

    Article  PubMed  CAS  Google Scholar 

  30. Hosing C, Saliba RM, Shahjahan M et al (2005) Disease burden may identify patients more likely to benefit from second allogeneic hematopoietic stem cell transplantation to treat relapsed acute myelogenous leukemia. Bone Marrow Transplant 36(2):157–162

    Article  PubMed  CAS  Google Scholar 

  31. Michallet M, Thomas X, Vernant JP et al (2000) Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Societe Francaise de Greffe de Moelle (SFGM). Bone Marrow Transplant 26(11):1157–1163

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This work was supported by China Capital Characteristic Clinic Project (Grant No. Z211100002921037) to **gbo Wang.

Author information

Authors and Affiliations

  1. Department of Hematology, Aerospace Center Hospital, No.15, Yuquan Road, Haidian District, Bei**g, 100049, China

    **nhong Fei, Weijie Zhang, Jiangying Gu, Fan Yang, Tingting Li, Wen**g Wang & **gbo Wang

Authors
  1. **nhong Fei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weijie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiangying Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tingting Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wen**g Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. **gbo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

X.F. and J.W. conceived and designed the study. X.F. drafted the manuscript. X.F., W.Z., J.G., F.Y., T.L., W.W., and J.W. collected and analyzed the data, and revised the final version of the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to **gbo Wang.

Ethics declarations

Ethics approval

This study was approved by the Biomedical Ethics Committee of Aerospace Center Hospital and performed in accordance with the Helsinki Declaration.

Patient approval statement

Written informed consent was obtained from all patients in this study.

Conflicts of interest

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.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 18 KB)

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

Fei, X., Zhang, W., Gu, J. et al. CLAG combined with total body irradiation as intensive conditioning chemotherapy prior to allogeneic hematopoietic stem cell transplantation in patients with refractory or relapsed acute myeloid leukemia. Ann Hematol 103, 241–249 (2024). https://doi.org/10.1007/s00277-023-05502-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-023-05502-0

Keywords

Search

Navigation