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Allogeneic haematopoietic cell transplantation for myelofibrosis: proposed definitions and management strategies for graft failure, poor graft function and relapse: best practice recommendations of the EBMT Chronic Malignancies Working Party

Abstract

Allogeneic haematopoietic cell transplantation (allo-HCT) remains the only curative approach in myelofibrosis (MF). Despite advances over recent decades, relapse and non-relapse mortality rates remain significant. Relapse rates vary between 15 and 25% across retrospective studies and management strategies vary widely, ranging from palliation to adoptive immunotherapy and, in some cases, a second allo-HCT. Moreover, in allo-HCT, there is a higher incidence of poor graft function and graft failure due to splenomegaly and a hostile “pro-inflammatory” marrow niche. The Practice Harmonisation and Guidelines subcommittee of the Chronic Malignancies Working Party (CMWP) of EBMT convened an international panel consisting of transplant haematologists, histopathologists and molecular biologists to propose practical, clinically relevant definitions of graft failure, poor graft function and relapse as well as management strategies following allo-HCT. A systematic approach to molecular monitoring, histopathological assessment and chimerism testing is proposed. These proposed recommendations aim to increase the accuracy and uniformity of reporting and to thereby facilitate the development of more consistent approaches to these challenging issues. In addition, we propose management strategies for these complications.

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Fig. 1: Differential diagnosis in MF patients with post transplant cytopaenias.

References

  1. 1.

    McLornan DP, Yakoub-Agha I, Robin M, Chalandon Y, Harrison CN, Kroger N. State-of-the-art review: allogeneic stem cell transplantation for myelofibrosis in 2019. Haematologica. 2019;104:659–68.

  2. 2.

    Kröger NM, Deeg JH, Olavarria E, Niederwieser D, Bacigalupo A, Barbui T, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia 2015;29:2126–33.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  3. 3.

    McLornan DP, Szydlo R, Robin M, van Biezen A, Koster L, Blok HJP, et al. Outcome of patients with Myelofibrosis relapsing after allogeneic stem cell transplant: a retrospective study by the Chronic Malignancies Working Party of EBMT. Br J Haematol. 2018;182:418–22.

    PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    McLornan DP, Sirait T, Hernández-Boluda JC, Czerw T, Hayden P, Yakoub-Agha I. European wide survey on allogeneic haematopoietic cell transplantation practice for myelofibrosis on behalf of the EBMT chronic malignancies working party. Curr Res Transl Med. 2020;69:103267.

  5. 5.

    McLornan D, Szydlo R, Koster L, Chalandon Y, Robin M, Wolschke C, et al. Myeloablative and reduced-intensity conditioned allogeneic hematopoietic stem cell transplantation in myelofibrosis: a retrospective study by the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2019;25:2167–71.

    PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Wolff S. Second hematopoietic stem cell transplantation for the treatment of graft failure, graft rejection or relapse after allogeneic transplantation. Bone Marrow Transplant. 2002;29:545–52.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Valcárcel D, Sureda A. Graft failure. In: Carreras E, Dufour C, Mohty M, Kröger N, editors. The EBMT Handbook. Cham: Springer International Publishing; 2019. p. 307–13. http://link.springer.com/10.1007/978-3-030-02278-5_41.

  8. 8.

    Olsson R, Remberger M, Schaffer M, Berggren DM, Svahn B-M, Mattsson J, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013;48:537–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Hernández-Boluda JC, Pereira A, Kröger N, Beelen D, Robin M, Bornhäuser M, et al. Determinants of survival in myelofibrosis patients undergoing allogeneic hematopoietic cell transplantation. Leukemia. 2021;35:215–24.

    PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Carreras E, Dufour C, Mohty M, Kröger N, editors. The EBMT Handbook: hematopoietic stem cell transplantation and cellular therapies. Cham: Springer International Publishing; 2019. http://link.springer.com/10.1007/978-3-030-02278-5.

  11. 11.

    Keyzner A, Han S, Shapiro S, Moshier E, Schorr E, Petersen B, et al. Outcome of allogeneic hematopoietic stem cell transplantation for patients with chronic and advanced phase myelofibrosis. Biol Blood Marrow Transplant. 2016;22:2180–6.

    PubMed  Article  Google Scholar 

  12. 12.

    Stasia A, Ghiso A, Galaverna F, Raiola AM, Gualandi F, Luchetti S, et al. CD34 selected cells for the treatment of poor graft function after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20:1440–3.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Klyuchnikov E, El-Cheikh J, Sputtek A, Lioznov M, Calmels B, Furst S, et al. CD34+-selected stem cell boost without further conditioning for poor graft function after allogeneic stem cell transplantation in patients with hematological malignancies. Biol Blood Marrow Transplant. 2014;20:382–6.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Alchalby H, Yunus D-R, Zabelina T, Ayuk F, Kröger N. Incidence and risk factors of poor graft function after allogeneic stem cell transplantation for myelofibrosis. Bone Marrow Transplant. 2016;51:1223–7.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Zhao Y, Gao F, Shi J, Luo Y, Tan Y, Lai X, et al. Incidence, risk factors, and outcomes of primary poor graft function after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019;25:1898–907.

    PubMed  Article  Google Scholar 

  16. 16.

    Cuadrado M, Richard M, Szydlo M, Watts M, Patel N, Renshaw H, et al. Predictors of recovery following allogeneic CD34+-selected cell infusion without conditioning to correct poor graft function. Haematologica. 2019;105:2639–46.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  17. 17.

    Tefferi A, Cervantes F, Mesa R, Passamonti F, Verstovsek S, Vannucchi AM, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013;122:1395–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90:1128–32.

    PubMed  Google Scholar 

  19. 19.

    Tefferi A, Nicolosi M, Mudireddy M, Lasho TL, Gangat N, Begna KH, et al. Revised cytogenetic risk stratification in primary myelofibrosis: analysis based on 1002 informative patients. Leukemia. 2018;32:1189–99.

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Jain T, Kunze KL, Mountjoy L, Partain DK, Kosiorek H, Khera N, et al. Early post-transplantation factors predict survival outcomes in patients undergoing allogeneic hematopoietic cell transplantation for myelofibrosis. Blood Cancer J. 2020;10:36.

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Srour SA, Olson A, Ciurea SO, Desai P, Bashir Q, Oran B, et al. Mixed myeloid chimerism and relapse of myelofibrosis after allogeneic stem cell transplantation. Haematologica. 2019. https://doi.org/10.3324/haematol.2019.223503.

  22. 22.

    Deeg HJ, Salit RB, Monahan T, Schoch G, McFarland C, Scott BL, et al. Early mixed lymphoid donor/host chimerism is associated with improved transplant outcome in patients with primary or secondary myelofibrosis. Biol Blood Marrow Transplant. 2020;26:2197–203.

    PubMed  Article  Google Scholar 

  23. 23.

    Sale GE, Deeg HJ, Porter BA. Regression of myelofibrosis and osteosclerosis following hematopoietic cell transplantation assessed by magnetic resonance imaging and histologic grading. Biol Blood Marrow Transplant. 2006;12:1285–94.

    PubMed  Article  Google Scholar 

  24. 24.

    Tamari R, Mughal TI, Rondelli D, Hasserjian R, Gupta V, Odenike O, et al. Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era? Bone Marrow Transplant. 2015;50:628–36.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Thiele J, Kvasnicka HM, Dietrich H, Stein G, Hann M, Kaminski A, et al. Dynamics of bone marrow changes in patients with chronic idiopathic myelofibrosis following allogeneic stem cell transplantation. Histol Histopathol. 2005;20:879–89.

    CAS  PubMed  Google Scholar 

  26. 26.

    Kröger N, Zabelina T, Alchalby H, Stübig T, Wolschke C, Ayuk F, et al. Dynamic of bone marrow fibrosis regression predicts survival after allogeneic stem cell transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2014;20:812–5.

    PubMed  Article  Google Scholar 

  27. 27.

    Arber DA, Orazi A, Hasserjian R, Borowitz MJ, Beau MM, Bloomfield CD, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–406.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Kvasnicka HM, Beham-Schmid C, Bob R, Dirnhofer S, Hussein K, Kreipe H, et al. Problems and pitfalls in grading of bone marrow fibrosis, collagen deposition and osteosclerosis—a consensus-based study. Histopathology. 2016;68:905–15.

    PubMed  Article  Google Scholar 

  29. 29.

    Bench AJ, White HE, Foroni L, Godfrey AL, Gerrard G, Akiki S, et al. Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the detection of JAK2 V617F and other relevant mutations. Br J Haematol. 2013;160:25–34.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Gagelmann N, Ditschkowski M, Bogdanov R, Bredin S, Robin M, Cassinat B, et al. Comprehensive clinical-molecular transplant scoring system for myelofibrosis undergoing stem cell transplantation. Blood. 2019;133:2233–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Kröger N, Panagiota V, Badbaran A, Zabelina T, Triviai I, Araujo Cruz MM, et al. Impact of molecular genetics on outcome in myelofibrosis patients after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2017;23:1095–101.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  32. 32.

    Ali H, Aldoss I, Yang D, Mokhtari S, Khaled S, Aribi A, et al. MIPSS70+ v2.0 predicts long-term survival in myelofibrosis after allogeneic HCT with the Flu/Mel conditioning regimen. Blood Adv. 2019;3:83–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Tamari R, Rapaport F, Zhang N, McNamara C, Kuykendall A, Sallman DA, et al. Impact of high-molecular-risk mutations on transplantation outcomes in patients with myelofibrosis. Biol Blood Marrow Transplant. 2019;25:1142–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Stevens EA, Jenkins IC, Beppu LW, Zhang Q, Salit R, Loeb KR, et al. Targeted sequencing improves DIPSS-Plus prognostic scoring in myelofibrosis patients undergoing allogeneic transplantation. Biol Blood Marrow Transplant. 2020;26:1371–4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Grinfeld J, Nangalia J, Baxter EJ, Wedge DC, Angelopoulos N, Cantrill R, et al. Classification and personalized prognosis in myeloproliferative neoplasms. N Engl J Med. 2018;379:1416–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Luque Paz D, Riou J, Verger E, Cassinat B, Chauveau A, Ianotto J-C, et al. Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of ASXL1 mutations: a FIM study. Blood Adv. 2021;5:1442–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Lange T, Edelmann A, Siebolts U, Krahl R, Nehring C, Jäkel N, et al. JAK2 p.V617F allele burden in myeloproliferative neoplasms one month after allogeneic stem cell transplantation significantly predicts outcome and risk of relapse. Haematologica. 2013;98:722–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Shah MV, Patel KP, Luthra R, Shamanna RK, Mehrotra M, Champlin RE, et al. Real time PCR detects relapse of JAK2 V617F myelofibrosis earlier than pyrosequencing after allogeneic transplantation. Biol Blood Marrow Transplant. 2017;23:S298–9.

    Article  Google Scholar 

  39. 39.

    Wolschke C, Badbaran A, Zabelina T, Christopeit M, Ayuk F, Triviai I, et al. Impact of molecular residual disease post allografting in myelofibrosis patients. Bone Marrow Transplant. 2017;52:1526–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Guardiola P, Anderson JE, Bandini G, Cervantes F, Runde V, Arcese W, et al. Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Société Française de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study. Blood. 1999;93:2831–8.

    CAS  PubMed  Google Scholar 

  41. 41.

    Byrne JL, Beshti H, Clark D, Ellis I, Haynes AP, Das-Gupta E, et al. Induction of remission after donor leucocyte infusion for the treatment of relapsed chronic idiopathic myelofibrosis following allogeneic transplantation: evidence for a ‘graft vs. myelofibrosis’ effect. Br J Haematol. 2000;108:430–3.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Cervantes F, Rovira M, Urbano-Ispizua A, Rozman M, Carreras E, Montserrat E. Complete remission of idiopathic myelofibrosis following donor lymphocyte infusion after failure of allogeneic transplantation: demonstration of a graft-versus-myelofibrosis effect. Bone Marrow Transplant. 2000;26:697–9.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Klyuchnikov E, Holler E, Bornhäuser M, Kobbe G, Nagler A, Shimoni A, et al. Donor lymphocyte infusions and second transplantation as salvage treatment for relapsed myelofibrosis after reduced-intensity allografting. Br J Haematol. 2012;159:172–81.

    PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Kröger N, Alchalby H, Klyuchnikov E, Badbaran A, Hildebrandt Y, Ayuk F, et al. JAK2-V617F–triggered preemptive and salvage adoptive immunotherapy with donor-lymphocyte infusion in patients with myelofibrosis after allogeneic stem cell transplantation. Blood. 2009;113:1866–8.

    PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Peggs KS, Thomson K, Hart DP, Geary J, Morris EC, Yong K, et al. Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses. Blood. 2004;103:1548–56.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Dholaria B, Savani BN, Labopin M, Luznik L, Ruggeri A, Mielke S, et al. Clinical applications of donor lymphocyte infusion from an HLA-haploidentical donor: consensus recommendations from the Acute Leukemia Working Party of the EBMT. Haematologica. 2020;105:47–58.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Janson D, Ayuk FA, Wolschke C, Christopeit M, Badbaran A, von Pein U-M, et al. Ruxolitinib for myelofibrosis patients relapsing after allogeneic hematopoietic transplantation. Blood. 2016;128:1948.

    Article  Google Scholar 

  48. 48.

    Nabergoj M, Wang J, Robin M, Kröger N, Angelucci E, Poire X, et al. Outcomes following second allogenic haematopoietic Cell transplantation in patients with myelofibrosis: a retrospective study on behalf of the Chronic Malignancies Working Party of EBMT. Blood. 2019;134:698.

    Article  Google Scholar 

  49. 49.

    Atagunduz IK, Klyuchnikov E, Wolschke C, Janson D, Heidenreich S, Christopeit M, et al. Treosulfan-based conditioning regimen for second allograft in patients with myelofibrosis. Cancers. 2020;12:3098.

    CAS  PubMed Central  Article  Google Scholar 

  50. 50.

    Atagunduz IK, Christopeit M, Ayuk F, Zeck G, Wolschke C, Kröger N. Incidence and outcome of late relapse after allogeneic stem cell transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2020;26:2279–84.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Polverelli N, Mauff K, Kröger N, Robin M, Beelen D, Beauvais D, et al. Impact of spleen size and splenectomy on outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis: a retrospective analysis by the chronic malignancies working party on behalf of European society for blood and marrow transplantation (EBMT). Am J Hematol. 2021;96:69–79.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Petrovic A, Hale G. Clinical options after failure of allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies. Expert Rev Clin Immunol. 2011;7:515–27.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Robin M, Espérou H, De Latour RP, Petropoulou AD, Xhaard A, Ribaud P, et al. correspondence: splenectomy after allogeneic haematopoietic stem cell transplantation in patients with primary myelofibrosis: correspondence. Br J Haematol. 2010;150:721–4.

    PubMed  Article  Google Scholar 

  54. 54.

    For the Nordic MPD Study Group, Abelsson J, Merup M, Birgegård G, WeisBjerrum O, Brinch L, et al. The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries. Bone Marrow Transplant 2012;47(Mar):380–6.

    Google Scholar 

  55. 55.

    De Vos J, Baudoux E, Bay J-O, Calmels B, Cras A, El Cheikh J, et al. Injections de lymphocytes du donneur (DLI): recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC). Bull du Cancer. 2019;106:S35–9.

    Article  Google Scholar 

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McLornan, D.P., Boluda, J.C.H., Czerw, T. et al. Allogeneic haematopoietic cell transplantation for myelofibrosis: proposed definitions and management strategies for graft failure, poor graft function and relapse: best practice recommendations of the EBMT Chronic Malignancies Working Party. Leukemia (2021). https://doi.org/10.1038/s41375-021-01294-2

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