Enlarged spleen is associated with low neutrophil and platelet engraftment rates and poor survival after allogeneic stem cell transplantation in patients with acute myeloid leukemia and myelodysplastic syndrome

Abstract

Primary graft failure can be a cause of early morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), as it leads to a high risk of severe infections and bleeding. Splenomegaly is associated with primary graft failure in patients of myelofibrosis, but the association between splenomegaly and outcomes after HSCT in patients with myeloid malignancies has not been previously evaluated. The aim of this study was to investigate the effect of spleen volume on engraftment kinetics in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We enrolled 85 patients. The median spleen volume was 146 cm3 (quartile 88–201 cm3). The adjusted hazard ratios for neutrophil and platelet engraftments were 0.17 (0.07–0.40, p < 0.001) and 0.19 (0.05–0.69, p = 0.011), respectively, for the high-risk group, at a cutoff splenic volume of 320 cm3. Overall survival at 3 years after HSCT was significantly poor in the high-risk group with an adjusted hazard ratio of 13.8 (2.61–72.4, p = 0.002). Enlarged spleen was associated with low neutrophil and platelet engraftment rates and poor survival after allogeneic HSCT in patients of AML and MDS.

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

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Remberger M, Mattsson J, Olsson R, Ringdén O (2011) Second allogeneic hematopoietic stem cell transplantation: a treatment for graft failure. Clin Transpl 25:E68–E76. https://doi.org/10.1111/j.1399-0012.2010.01324.x

    Article  Google Scholar 

  2. 2.

    Olsson RF, Logan BR, Chaudhury S, Zhu X, Akpek G, Bolwell BJ, Bredeson CN, Dvorak CC, Gupta V, Ho VT, Lazarus HM, Marks DI, Ringdén OTH, Pasquini MC, Schriber JR, Cooke KR (2015) Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies. Leukemia 29:1754–1762. https://doi.org/10.1038/leu.2015.75

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Schriber J, Agovi M-A, Ho V, Ballen KK, Bacigalupo A, Lazarus HM, Bredeson CN, Gupta V, Maziarz RT, Hale GA, Litzow MR, Logan B, Bornhauser M, Giller RH, Isola L, Marks DI, Rizzo JD, Pasquini MC (2010) Second unrelated donor hematopoietic cell transplantation for primary graft failure. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant 16:1099–1106. https://doi.org/10.1016/j.bbmt.2010.02.013

    Article  Google Scholar 

  4. 4.

    Helenglass G, Treleaven J, Parikh P, Aboud H, Smith C, Powles R (1990) Delayed engraftment associated with splenomegaly in patients undergoing bone marrow transplantation for chronic myeloid leukaemia. Bone Marrow Transplant 5:247–251

    CAS  PubMed  Google Scholar 

  5. 5.

    Bacigalupo A, Soraru M, Dominietto A, Pozzi S, Geroldi S, van Lint MT, Ibatici A, Raiola AM, Frassoni F, de Stefano F, Verdiani S, Casarino L, Barosi G (2010) Allogeneic hemopoietic SCT for patients with primary myelofibrosis: a predictive transplant score based on transfusion requirement, spleen size and donor type. Bone Marrow Transplant 45:458–463. https://doi.org/10.1038/bmt.2009.188

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Gergis U, Kuriakose E, Shore T, Mayer S, Mark T, Pearse R, Schuster M, Feldman E, Roboz G, Ritchie E, Scandura J, Wang H, Zhou XK, Silver RT, van Besien K (2016) Allogeneic transplantation for patients with advanced myelofibrosis: splenomegaly and high serum LDH are adverse risk factors for successful engraftment. Clin Lymphoma Myeloma Leuk 16:297–303. https://doi.org/10.1016/j.clml.2016.02.004

    Article  PubMed  Google Scholar 

  7. 7.

    Song M-K, Chung J-S, Lim S-N, Lee GW, Lee SM, Lee NK, Choi JC, Oh SY (2016) Usefulness of spleen volume measured by computed tomography for predicting clinical outcome in primary myelofibrosis. Int J Hematol 104:476–484. https://doi.org/10.1007/s12185-016-2050-y

    Article  PubMed  Google Scholar 

  8. 8.

    Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, Sandmaier B (2009) Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant 15:367–369. https://doi.org/10.1016/j.bbmt.2008.12.497

    Article  Google Scholar 

  9. 9.

    Hamadani M, Mohty M, Kharfan-Dabaja MA (2011) Reduced-intensity conditioning allogeneic hematopoietic cell transplantation in adults with acute myeloid leukemia. Cancer Control J Moffitt Cancer Cent 18:237–245

    Article  Google Scholar 

  10. 10.

    Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, Apperley J, Slavin S, Pasquini M, Sandmaier BM, Barrett J, Blaise D, Lowski R, Horowitz M (2009) Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant 15:1628–1633. https://doi.org/10.1016/j.bbmt.2009.07.004

    Article  Google Scholar 

  11. 11.

    Hart C, Klatt S, Barop J, Müller G, Schelker R, Holler E, Huber E, Herr W, Grassinger J (2016) Splenic pooling and loss of VCAM-1 causes an engraftment defect in patients with myelofibrosis after allogeneic hematopoietic stem cell transplantation. Haematologica 101:1407–1416. https://doi.org/10.3324/haematol.2016.146811

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Ruggeri A, Labopin M, Sormani MP, Sanz G, Sanz J, Volt F, Michel G, Locatelli F, Diaz de Heredia C, O'Brien T, Arcese W, Iori AP, Querol S, Kogler G, Lecchi L, Pouthier F, Garnier F, Navarrete C, Baudoux E, Fernandes J, Kenzey C, Eapen M, Gluckman E, Rocha V, Saccardi R, Eurocord, Cord Blood Committee EBMT, Netcord (2014) Engraftment kinetics and graft failure after single umbilical cord blood transplantation using a myeloablative conditioning regimen. Haematologica 99:1509–1515. https://doi.org/10.3324/haematol.2014.109280

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Davies SM, Kollman C, Anasetti C, Antin JH, Gajewski J, Casper JT, Nademanee A, Noreen H, King R, Confer D, Kernan NA (2000) Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the national marrow donor program. Blood 96:4096–4102

    CAS  PubMed  Google Scholar 

  14. 14.

    Bensinger WI, Martin PJ, Storer B, Clift R, Forman SJ, Negrin R, Kashyap A, Flowers MED, Lilleby K, Chauncey TR, Storb R, Blume K, Heimfeld S, Rowley S, Appelbaum FR (2001) Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 344:175–181. https://doi.org/10.1056/NEJM200101183440303

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Akpek G, Pasquini MC, Logan B et al (2013) Effects of spleen status on early outcomes after hematopoietic cell transplantation. Bone Marrow Transplant 48:825–831. https://doi.org/10.1038/bmt.2012.249

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Hara M, Sakata Y, Nakatani D, Suna S, Nishino M, Sato H, Kitamura T, Nanto S, Hamasaki T, Hori M, Komuro I, OACIS Investigators (2016) Subclinical elevation of high-sensitive troponin T levels at the convalescent stage is associated with increased 5-year mortality after ST-elevation myocardial infarction. J Cardiol 67:314–320. https://doi.org/10.1016/j.jjcc.2015.08.021

    Article  PubMed  Google Scholar 

  17. 17.

    Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, Jacobsen N, Ruutu T, de Lima M, Finke J, Frassoni F, Gluckman E, Acute Leukemia Working Party of European Blood and Marrow Transplant Group, Eurocord-Netcord Registry (2004) Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 351:2276–2285. https://doi.org/10.1056/NEJMoa041469

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Blaise D, Kuentz M, Fortanier C, Bourhis JH, Milpied N, Sutton L, Jouet JP, Attal M, Bordigoni P, Cahn JY, Boiron JM, Schuller MP, Moatti JP, Michallet M (2000) Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: a report from the Société Française de Greffe de Moelle. J Clin Oncol Off J Am Soc Clin Oncol 18:537–546. https://doi.org/10.1200/jco.2000.18.3.537

    CAS  Article  Google Scholar 

  19. 19.

    Ringdén O, Barrett AJ, Zhang M-J et al (2003) Decreased treatment failure in recipients of HLA-identical bone marrow or peripheral blood stem cell transplants with high CD34 cell doses. Br J Haematol 121:874–885

    Article  PubMed  Google Scholar 

  20. 20.

    Barker JN, Scaradavou A, Stevens CE (2010) Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies. Blood 115:1843–1849. https://doi.org/10.1182/blood-2009-07-231068

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Delgado J, Thomson K, Russell N, Ewing J, Stewart W, Cook G, Devereux S, Lovell R, Chopra R, Marks DI, Mackinnon S, Milligan DW, British Society of Blood and Marrow Transplantation (2006) Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study. Blood 107:1724–1730. https://doi.org/10.1182/blood-2005-08-3372

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Rohrer C, Arni U, Deubelbeiss KA (1983) Influence of the spleen on the distribution of blood neutrophils. Quantitative studies in the rat. Scand J Haematol 30:103–109

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Ito T, Akagi K, Kondo T, Kawabata H, Ichinohe T, Takaori-Kondo A (2012) Splenic irradiation as a component of a reduced-intensity conditioning regimen for hematopoietic stem cell transplantation in myelofibrosis with massive splenomegaly. Tohoku J Exp Med 228:295–299

    Article  PubMed  Google Scholar 

  24. 24.

    Matsubara E, Yamanouchi J, Kitazawa R, Azuma T, Fujiwara H, Hato T, Yasukawa M (2016) Usefulness of low-dose splenic irradiation prior to reduced-intensity conditioning regimen for hematopoietic stem cell transplantation in elderly patients with myelofibrosis. Case Rep Hematol 2016:8751329–8751326. https://doi.org/10.1155/2016/8751329

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Gratwohl A, Iacobelli S, Bootsman N et al (2016) Splenic irradiation before hematopoietic stem cell transplantation for chronic myeloid leukemia: long-term follow-up of a prospective randomized study. Ann Hematol 95:967–972. https://doi.org/10.1007/s00277-016-2638-6

    Article  PubMed  Google Scholar 

  26. 26.

    Robin M, Tabrizi R, Mohty M, Furst S, Michallet M, Bay JO, Cahn JY, de Coninck E, Dhedin N, Bernard M, Rio B, Buzyn A, Huynh A, Bilger K, Bordigoni P, Contentin N, Porcher R, Socié G, Milpied N (2011) Allogeneic haematopoietic stem cell transplantation for myelofibrosis: a report of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Br J Haematol 152:331–339. https://doi.org/10.1111/j.1365-2141.2010.08417.x

    Article  PubMed  Google Scholar 

  27. 27.

    Robin M, Zine M, Chevret S, Meignin V, Munoz-Bongrand N, Moatti H, Xhaard A, Sicre de Fontbrune F, Peffault de Latour R, Sarfati E, Socié G (2017) The impact of splenectomy in myelofibrosis patients prior to allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant 23:958–964. https://doi.org/10.1016/j.bbmt.2017.03.002

    Article  Google Scholar 

  28. 28

    Elliott MA, Chen MG, Silverstein MN, Tefferi A (1998) Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia. Br J Haematol 103(2):505–511

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the medical and nursing staff working at our institution and would like to express our gratitude to the Japan Society of Clinical Research (http://www.japanscr.org/) for their dedicated supports.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yoshimitsu Shimomura.

Ethics declarations

The study protocol complied with the Helsinki Declaration standards and was approved by the Ethical Committee of our institutions (Approval No. zn161209 at Kobe City Hospital Organization, Kobe City Medical Center General Hospital and No. 16–22 at Foundation for Biomedical Research and Innovation).

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shimomura, Y., Hara, M., Katoh, D. et al. Enlarged spleen is associated with low neutrophil and platelet engraftment rates and poor survival after allogeneic stem cell transplantation in patients with acute myeloid leukemia and myelodysplastic syndrome. Ann Hematol 97, 1049–1056 (2018). https://doi.org/10.1007/s00277-018-3278-9

Download citation

Keywords

  • Allogeneic stem cell transplantation
  • Acute myeloid leukemia
  • Myelodysplastic syndrome
  • Splenomegaly
  • Engraftment