Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Venetoclax-based therapy as a bridge to allogeneic hematopoietic cell transplantation in children with relapsed/refractory AML

Bone Marrow Transplantation volume 58, pages 328–331 (2023)Cite this article

Subjects

Pediatric patients with relapsed/refractory acute myeloid leukemia (rAML) have a poor prognosis. Novel treatment options are needed to safely and effectively reduce disease burden and allow patients to undergo consolidative allogeneic hematopoietic cell transplantation (allo-HCT). The Bcl-2 inhibitor venetoclax in combination with cytarabine, with or without idarubicin, induces high rates of complete remission (CR) or CR with incomplete count recovery (-CRi) in pediatric patients with rAML [1]. Since 2017, the majority of rAML patients who achieved a CR/CRi after a venetoclax-based salvage regimen at our center underwent an allo-HCT. While venetoclax is well tolerated and lacks significant organ toxicity aside from myelosuppression [2], the inhibition of Bcl-2 may have unforeseen consequences related to key transplant variables. The literature on the use of venetoclax in the context of allo-HCT is scarce, particularly in the pediatric population. Here, we report our center’s clinical experience.

We performed an IRB-approved retrospective review of 28 patients who received venetoclax-based salvage therapy immediately prior to allo-HCT between October 2017 and April 2021 at our center. Venetoclax doses ranged from 240 mg/m2 to 360 mg/m2 (400–600 mg adult equivalent) in all but one patient (dose: 560 mg/m2) and were adjusted if a CYP3A4 inhibitor was used concurrently. Disease status in the bone marrow prior to transplant was defined as follows: minimal residual disease (MRD)–CR (MRD < 0.1% blasts), MRD+CR (≥0.1%–<5% blasts) and active disease (≥5% blasts or marrow aplasia). Neutrophil and platelet recovery were defined according to established standards [3]. Acute graft versus host disease (aGVHD) was graded according to Glucksberg et al. [4]. The Kaplan–Meier method was used to estimate overall survival (OS) and relapse-free survival (RFS), and the log-rank test was used to compare groups. The method of Kalbfleisch and Prentice was used to estimate the cumulative incidence of aGVHD grade 2–4 and non-relapse mortality (NRM), and the Gray’s test was used to compare groups. Relapse and death were considered competing risks when assessing the cumulative incidence of NRM and relapse, respectively. All analyses were performed using SAS 9.4 (Cary, NC).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Key transplant outcomes.

Data availability

For data sharing, contact the corresponding authors at pthomas@wustl.edu or swati.naik@stjude.org.

References

  1. Karol SE, Alexander TB, Budhraja A, Pounds SB, Canavera K, Wang L, et al. Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study. Lancet Oncol. 2020;21:551–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133:7–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kharfan-Dabaja MA, Kumar A, Ayala E, Aljurf M, Nishihori T, Marsh R, et al. Standardizing definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism in allogeneic hematopoietic cell transplantation: a report on Behalf of the American Society for Transplantation and Cellular Therapy. Transpl Cell Ther. 2021;27:642–9.

    Article  CAS  Google Scholar 

  4. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295–304.

    Article  CAS  PubMed  Google Scholar 

  5. DiNardo CD, Rausch CR, Benton C, Kadia T, Jain N, Pemmaraju N, et al. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol. 2018;93:401–7.

    Article  CAS  PubMed  Google Scholar 

  6. Wei AH, Strickland SA, Hou JZ, Fiedler W, Lin TL, Walter RB, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019;37:1277–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Naik S, Talleur AC, Li Y, Madden RM, Mamcarz E, Qudeimat A, et al. CD45RA-depleted haploidentical transplantation combined with NK cell addback results in promising long-term outcomes in pediatric patients with high-risk hematologic malignancies. Blood. 2021;138(Suppl 1):172.

    Article  Google Scholar 

  8. Gabriel SS, Bon N, Chen J, Wekerle T, Bushell A, Fehr T, et al. Distinctive expression of Bcl-2 factors in regulatory T cells determines a pharmacological target to induce immunological tolerance. Front Immunol. 2016;7:73.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Strobl J, Pandey RV, Krausgruber T, Kleissl L, Reininger B, Herac M, et al. Anti-apoptotic molecule BCL2 is a therapeutic target in steroid-refractory graft-versus-host disease. J Invest Dermatol. 2020;140:2188–98.

    Article  CAS  PubMed  Google Scholar 

  10. Davis JE, Du K, Ludford-Menting MJ, Prabahran A, Wong E, Huntington ND, et al. Venetoclax or ruxolitinib in pre-transplant conditioning lowers the engraftment barrier by different mechanisms in allogeneic stem cell transplant recipients. Front Immunol. 2021;12:749094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Thomas Pfeiffer, Ying Li, Rebecca Epperly, Renee Madden, Ewelina Mamcarz, Esther Obeng, Amr Qudeimat, Akshay Sharma, Ashok Srinivasan, Ali Suliman, Aimee C. Talleur, M. Paulina Velasquez, Stephen Gottschalk, Brandon M. Triplett & Swati Naik

  2. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Emily Ashcraft

  3. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Seth E. Karol & Jeffrey E. Rubnitz

Authors
  1. Thomas Pfeiffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emily Ashcraft
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seth E. Karol
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey E. Rubnitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rebecca Epperly
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Renee Madden
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ewelina Mamcarz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Esther Obeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Amr Qudeimat
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Akshay Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ashok Srinivasan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ali Suliman
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Aimee C. Talleur
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M. Paulina Velasquez
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Stephen Gottschalk
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Brandon M. Triplett
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Swati Naik
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TP and SN conceived and designed the retrospective study. Patient enrollment and management: SEK, JER, RE, RM, EM, EO, AQ, A Sharma, A Srinivasan, A Suliman, ACT, MPV, and BMT. Analysis and interpretation of data: TP, SN, YL, and EA. Writing of the manuscript: TP, SN, BMT, and SG. Review/revision of the manuscript: all authors.

Corresponding authors

Correspondence to Thomas Pfeiffer or Swati Naik.

Ethics declarations

Competing interests

SG and MPV are a co-inventors on patent applications in the fields of cell or gene therapy for cancer. SG is a consultant of TESSA Therapeutics, a member of the Data and Safety Monitoring Board (DSMB) of Immatics, and has received honoraria from Tidal, Catamaran Bio, Sanofi, and Novartis within the last 2 years. Author A Sharma has received consultant fees from Spotlight Therapeutics, Medexus Inc. and Vertex Pharmaceuticals, has received research finding from CRISPR Therapeutics and honoraria from Vindico Medical Education. All other authors have no conflict of interest to disclose.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pfeiffer, T., Li, Y., Ashcraft, E. et al. Venetoclax-based therapy as a bridge to allogeneic hematopoietic cell transplantation in children with relapsed/refractory AML. Bone Marrow Transplant 58, 328–331 (2023). https://doi.org/10.1038/s41409-022-01877-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-022-01877-2

Search

Advanced search

Quick links