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.

  • Letter to the Editor
  • Published:

Allogeneic stem cell transplantation for non-de novo AML or advanced myelodysplastic syndromes: influence of GvHD and donor lymphocyte infusions on long-term outcome

Bone Marrow Transplantation volume 53, pages 101–103 (2018)Cite this article

Subjects

Allogeneic stem cell transplantation (alloSCT) is an essential treatment option for the various hematopoietic neoplasms. Its efficacy in maintaining long-lasting remissions and cure is mainly based on the graft-versus-leukemia (GvL) effect, which is mediated by the donor immune cells1, 2 and can be enhanced by donor lymphocyte infusions (DLI).3, 4 AML with myelodysplasia-related changes or therapy-related AML (tAML), two distinct subgroups in the current World Health Organization classification of myeloid neoplasms and leukemias frequently termed non-de novo AML in daily clinical routine, are commonly associated with inferior outcome. This is due to the presence of an unfavorable genetic risk profile, poor response to induction chemotherapy, advanced age and the presence of comorbidities.5

We retrospectively analyzed 204 patients with non-de novo AML or advanced myelodysplastic syndrome with excess of blasts-2 transplanted at our center between September 1995 and June 2015 (Table 1). Conditioning, GvHD prophylaxis and supportive care were carried out as described previously.6 Acute GvHD (aGvHD) and chronic GvHD (cGvHD) were graded according to standard criteria.7 Patients with aGvHD I received topical treatment only. Therapy of aGvHD II–IV consisted of prednisolone 2 mg/kg for 7 days, which was gradually tapered thereafter.8 DLI were derived either from the granulocyte-CSF-stimulated PBSC graft or collected separately without growth factor stimulation and aliquoted and cryopreserved by CD3+ cells count as follows: 1 × 106; 5 × 106; 10 × 106; and 50 × 106/kg recipient body weight. In patients transplanted from a matched unrelated donor, the starting dose was 1 × 106/kg CD3+ cells; in matched related donor recipients, first DLI contained 5 × 106/kg CD3+ cells. Indication for DLI was prophylactic in patients treated with Flamsa-reduced intensity conditioning, pre-emptive in patients with a persistent/recurrent molecular marker or progressive mixed chimerism with >5% recipient cells in the bone marrow in the absence of hematologic relapse, or hematologic relapse. DLI were paused in case GvHD occurred or when molecular remission or 100% donor chimerism was achieved. DLI were given at 4-week intervals. Remission status and chimerism were tested by bone marrow analysis in 3-month intervals. Statistical analyses were performed using NCSS 10 (NCSS; Kaysville, UT, USA) and SPSS 22 (SPSS; Chicago, IL, USA). Overall survival (OS) and disease-free survival (DFS) were determined by the Kaplan–Meier method. Relapse and non-relapse mortality (NRM) were calculated as cumulative incidences (CI-R and CI-NRM) with death from any cause and relapse as competing events. Statistical significance was tested univariately by log-rank test for OS and DFS, or Gray’s test for CI-R and CI-NRM (P<0.05, two-sided). For cGvHD and DLI Landmark analyses were performed. To this end, all patients with an event or censored before the corresponding landmark (GvHD: 3.0 months; DLI: 2.1 months) were excluded from the analysis. For univariate and multivariate analyses the Cox proportional hazard regression model was used. At first, a univariate model was calculated for age, disease subtype and status, cytogenetic risk group, Karnofsky performance status (KPS), comorbidities (hematopoietic cell transplantation-specific comorbidity index; HCT-CI), treatment before alloSCT, conditioning, donor type, aGvHD, cGvHD and DLI. Thereafter, variables showing statistical significance at a level of P<0.1 were entered into multivariate analyses (forward logistic regression, inclusion P=0.05, exclusion P=0.10; stepwise entry). Hazard ratios (HRs) are given with a 95% confidence interval (CI) and corresponding P-values. cGvHD und DLI were entered into the multivariate model as time-dependent covariates.

Table 1 Patients and transplant characteristics
Full size table

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

Figure 1

References

  1. Baron F, Labopin M, Niederwieser D, Vigouroux S, Cornelissen JJ, Malm C et al. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation. Leukemia 2012; 26: 2462–2468.

    Article  CAS  Google Scholar 

  2. Martino R, Caballero MD, Perez-Simon JA, Canals C, Solano C, Urbano-Ispizua A et al. Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes. Blood 2002; 100: 2243–2245.

    Article  CAS  Google Scholar 

  3. Chang X, Zang X, Xia CQ . New strategies of DLI in the management of relapse of hematological malignancies after allogeneic hematopoietic SCT. Bone Marrow Transplant 2016; 51: 324–332.

    Article  CAS  Google Scholar 

  4. Kolb HJ . Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 2008; 112: 4371–4383.

    Article  CAS  Google Scholar 

  5. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129: 424–447.

    Article  Google Scholar 

  6. Hemmati PG, Terwey TH, Massenkeil G, le Coutre P, Vuong LG, Neuburger S et al. Reduced intensity conditioning prior to allogeneic stem cell transplantation in first complete remission is effective in patients with acute myeloid leukemia and an intermediate-risk karyotype. Int J Hematol 2010; 91: 436–445.

    Article  Google Scholar 

  7. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.

    Article  Google Scholar 

  8. Hemmati PG, Terwey TH, Na IK, Jehn CF, le Coutre P, Vuong LG et al. Allogeneic stem cell transplantation for refractory acute myeloid leukemia: a single center analysis of long-term outcome. Eur J Haematol 2015; 95: 498–506.

    Article  Google Scholar 

  9. Valcarcel D, Martino R, Caballero D, Martin J, Ferra C, Nieto JB et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol 2008; 26: 577–584.

    Article  CAS  Google Scholar 

  10. Terwey TH, Vega-Ruiz A, Hemmati PG, Martus P, Dietz E, le Coutre P et al. NIH-defined graft-versus-host disease after reduced intensity or myeloablative conditioning in patients with acute myeloid leukemia. Leukemia 2012; 26: 536–542.

    Article  CAS  Google Scholar 

  11. Hasskarl J, Zerweck A, Wasch R, Ihorst G, Bertz H, Finke J . Induction of graft versus malignancy effect after unrelated allogeneic PBSCT using donor lymphocyte infusions derived from frozen aliquots of the original graft. Bone Marrow Transplant 2012; 47: 277–282.

    Article  CAS  Google Scholar 

  12. Lutz C, Massenkeil G, Nagy M, Neuburger S, Tamm I, Rosen O et al. A pilot study of prophylactic donor lymphocyte infusions to prevent relapse in adult acute lymphoblastic leukemias after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2008; 41: 805–812.

    Article  CAS  Google Scholar 

  13. Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ . Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 2005; 23: 5675–5687.

    Article  Google Scholar 

  14. Finke J, Schmoor C, Bertz H, Marks R, Wäsch R, Zeiser R et al. Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2016; 51: 771–777.

    Article  CAS  Google Scholar 

  15. Kröger N, Brand R, van Biezen A, Zander A, Dierlamm J, Niederwieser D et al. Risk factors for therapy-related myelodysplastic syndrome and acute myeloid leukemia treated with allogeneic stem cell transplantation. Haematologica 2009; 94: 542–549.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Sabine Diehl and Doreen Uhlenbroch for excellent data management and nursing team for superb patient care.

Author information

Authors and Affiliations

  1. Department of Hematology, Oncology and Tumor Immunology, Charité—Universitätsmedizin Berlin, Berlin, Germany

    P G Hemmati, K Pfeifer, L G Vuong, C F Jehn, T H Terwey, P le Coutre, B Dörken & R Arnold

Authors
  1. P G Hemmati
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Pfeifer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L G Vuong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C F Jehn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T H Terwey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P le Coutre
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B Dörken
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R Arnold
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P G Hemmati.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Bone Marrow Transplantation website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hemmati, P., Pfeifer, K., Vuong, L. et al. Allogeneic stem cell transplantation for non-de novo AML or advanced myelodysplastic syndromes: influence of GvHD and donor lymphocyte infusions on long-term outcome. Bone Marrow Transplant 53, 101–103 (2018). https://doi.org/10.1038/bmt.2017.215

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2017.215

This article is cited by

Search

Advanced search

Quick links