Skip to main content
SpringerLink
Log in

Successful treatment of acute myeloid leukemia co-expressing NUP98/NSD1 and FLT3/ITD with preemptive donor lymphocyte infusions

  • Case Report
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Patients with acute myeloid leukemia (AML) co-expressing NUP98/NSD1 and FLT3/ITD have a dismal prognosis despite undergoing hematopoietic stem cell transplantation (HSCT). There are a few studies on successful treatment of relapsed AML co-expressing NUP98/NSD1 and FLT3/ITD. We report a refractory case of molecular relapse of AML co-expressing NUP98/NSD1 and FLT3/ITD post-matched sibling HSCT. Donor lymphocyte infusion (DLI) at an early stage of post-transplantation resulted in complete molecular remission for 29 months with durable chronic graft-versus-host disease. Our case suggests the clinical efficacy of preemptive DLI following minimal residual disease analysis for the treatment of refractory AML.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

allo-HSCT:

Allogeneic hematopoietic stem cell transplantation

allo-PBSCT:

Allogeneic peripheral blood stem cell transplantation

AML:

Acute myeloid leukemia

cGVHD:

Chronic graft-versus-host disease

CR:

Complete remission

DLI:

Donor lymphocyte infusion

FAB:

French–American–British

GVHD:

Graft-versus-host disease

GVL:

Graft-versus-leukemia

HSCT:

Hematopoietic stem cell transplantation

JCCG:

Japan Children’s Cancer Group

JPLSG:

Japanese Pediatric Leukemia/Lymphoma Study Group

MRD:

Minimal residual disease

References

  1. Ostronoff F, Othus M, Gerbing BR, Loken RM, Raimondi CS, Hirsh AB, et al. NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: a COG and SWOG report. Blood. 2014;124:2400–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Shimada A, Iijima-Yamashita Y, Tawa A, Tomizawa D, Yamada M, Shiba N, et al. Risk-stratified therapy for children with FLT3-ITD-positive acute myeloid leukemia: results from the JPLSG AML-05 study. Int J Hematol. 2018;107:586–95.

    Article  PubMed  Google Scholar 

  3. Tomizawa D, Tanaka S, Hasegawa D, Iwamoto S, Hiramatsu H, Kiyokawa N, et al. Evaluation of high-dose cytarabine in induction therapy for children with de novo acute myeloid leukemia: a study protocol of the Japan Children’s Cancer Group Multi-Center Seamless Phase II-III Randomized Trial (JPLSG AML-12). Jpn J Clin Oncol. 2018;48:587–93.

    Article  PubMed  Google Scholar 

  4. Roux C, Tifratene K, Socié G, Galambrun C, Bertrand Y, Rialland F, et al. Outcome after failure of allogeneic hematopoietic stem cell transplantation in children with acute leukemia: a study by the société Francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC). Bone Marrow Transpl. 2017;52:678–82.

    Article  CAS  Google Scholar 

  5. Tarlock K, Chang B, Cooper T, Gross T, Gupta S, Neudorf S, et al. Sorafenib treatment following hematopoietic stem cell transplant in pediatric FLT3/ITD acute myeloid leukemia. Pediatr Blood Cancer. 2015;62:1048–54.

    Article  CAS  PubMed  Google Scholar 

  6. Brunner AM, Li S, Fathi AT, Wadleigh M, Ho VT, Collier K, et al. Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission. Br J Haematol. 2016;175:496–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mathew NR, Baumgartner F, Braun L, O’Sullivan D, Thomas S, Waterhouse M, et al. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD mutant leukemia cells. Nat Med. 2018;24:282–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995;86:2041–50.

    Article  CAS  Google Scholar 

  9. Schmid C, Labopin M, Nagler A, Bornhäuser M, Finke J, Fassas A, et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT acute leukemia working party. J Clin Oncol. 2007;25:4938–45.

    Article  CAS  PubMed  Google Scholar 

  10. Krishnamurthy P, Potter VT, Barber LD, Kulasekararaj AG, Lim ZY, Pearce RM, et al. Outcome of donor lymphocyte infusion after T cell-depleted allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndromes. Biol Blood Marrow Transpl. 2013;19:562–8.

    Article  Google Scholar 

  11. Bar M, Sandmaier BM, Inamoto Y, Bruno B, Hari P, Chauncey T, et al. Donor lymphocyte infusion for relapsed hematological malignancies after allogeneic hematopoietic cell transplantation: prognostic relevance of the initial CD3+ T cell dose. Biol Blood Marrow Transpl. 2013;19:949–57.

    Article  Google Scholar 

  12. Dominietto A, Pozzi S, Miglino M, Albarracin F, Piaggio G, Bertolotti F, Grasso R, et al. Donor lymphocyte infusions for the treatment of minimal residual disease in acute leukemia. Blood. 2011;109:5063–4.

    Article  Google Scholar 

  13. Tan Y, Du K, Luo Y, Shi J, Cao L, Zheng Y, et al. Superiority of preemptive donor lymphocyte infusion based on minimal residual disease in acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Transfusion. 2014;54:1493–500.

    Article  CAS  PubMed  Google Scholar 

  14. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for the classification of the acute leukaemias. French–American–British (FAB) co-operative group. Br J Haematol. 1976;33:451–8.

    Article  CAS  PubMed  Google Scholar 

  15. Taketani T, Taki T, Nakamura T, Kobayashi Y, Ito E, Fukuda S, et al. High frequencies of simultaneous FLT3-ITD, WT1 and KIT mutations in hematological malignancies with NUP98-fusion genes. Leukemia. 2010;24:1975–7.

    Article  CAS  PubMed  Google Scholar 

  16. Nakayama H, Tomizawa D, Tanaka S, Iwamoto S, Shimada A, Saito AM, et al. Fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin for relapsed childhood acute myeloid leukemia. Pediatr Int. 2017;59:1046–52.

    Article  CAS  PubMed  Google Scholar 

  17. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21:4642–9.

    Article  PubMed  Google Scholar 

  18. Bejanyan N, Weisdorf DJ, Logan BR, Wang HL, Devine SM, de Lima M, et al. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a center for international blood and marrow transplant research study. Biol Blood Marrow Transpl. 2015;21:454–9.

    Article  Google Scholar 

  19. Tamura A, Ishida T, Saito A, Yamamoto N, Yokoi T, Uemura S, et al. Low-dose azacitidine maintenance therapy after allogeneic stem cell transplantation for high-risk pediatric acute myeloid leukemia. Pediatr Blood Cancer. 2018;65:e27284.

    Article  PubMed  Google Scholar 

  20. Schroeder T, Rautenberg C, Haas R, Germing U, Kobbe G. Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation. Int J Hematol. 2018;107:138–50.

    Article  CAS  PubMed  Google Scholar 

  21. Guglielmi C, Arcese W, Dazzi F, Brand R, Bunjes D, Verdonck LF, et al. Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. Blood. 2002;100:397–405.

    Article  CAS  PubMed  Google Scholar 

  22. Mackinnon S, Papadopoulos EB, Carabasi MH, Reich L, Collins NH, Boulad F, et al. Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. Blood. 1995;86:1261–8.

    Article  CAS  Google Scholar 

  23. Dazzi F, Szydlo RM, Craddock C, Cross NC, Kaeda J, Chase A, et al. Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood. 2000;95:67–71.

    Article  CAS  Google Scholar 

  24. Rettinger E, Willasch AM, Kreyenberg H, Borkhardt A, Holter W, Kremens B, et al. Preemptive immunotherapy in childhood acute myeloid leukemia for patients showing evidence of mixed chimerism after allogeneic stem cell transplantation. Blood. 2011;118:5681–8.

    Article  CAS  PubMed  Google Scholar 

  25. Mo XD, Zhang XH, Xu LP, Wang Y, Yan CH, Chen H, et al. Comparison of outcomes after donor lymphocyte infusion with or without prior chemotherapy for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation. Ann Hematol. 2017;96:829–38.

    Article  PubMed  Google Scholar 

  26. Yan CH, Liu DH, Liu KY, Xu LP, Liu YR, Chen H, et al. Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Blood. 2012;119:3256–62.

    Article  CAS  PubMed  Google Scholar 

  27. Shiobara S, Nakao S, Ueda M, Yamazaki H, Takahashi S, Asano S, et al. Donor leukocyte infusion for Japanese patients with relapsed leukemia after allogeneic bone marrow transplantation: lower incidence of acute graft-versus-host disease and improved outcome. Bone Marrow Tranplant. 2000;26:769–74.

    Article  CAS  Google Scholar 

  28. Marks DI, Lush R, Cavenagh J, Milligan DW, Schey S, Parker A, et al. The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood. 2002;100:3108–14.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are indebted to Dr. Kozue Nakamura (Teikyo University Hospital, Tokyo, Japan) for referring this patient to us.

Author information

Authors and Affiliations

  1. Department of Pediatrics, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Yuichi Mitani, Mitsuteru Hiwatari, Masafumi Seki, Mayumi Hangai & Junko Takita

  2. Department of Pediatrics, Kyoto University, Kyoto, Japan

    Junko Takita

Authors
  1. Yuichi Mitani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mitsuteru Hiwatari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masafumi Seki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mayumi Hangai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Junko Takita
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mitsuteru Hiwatari.

Ethics declarations

Conflict of interest

Authors have no relevant financial conflict of interest to declare.

Additional information

Publisher's Note

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

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mitani, Y., Hiwatari, M., Seki, M. et al. Successful treatment of acute myeloid leukemia co-expressing NUP98/NSD1 and FLT3/ITD with preemptive donor lymphocyte infusions. Int J Hematol 110, 512–516 (2019). https://doi.org/10.1007/s12185-019-02665-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-019-02665-3

Keywords

Search

Navigation