Transplantation/Zelltherapie bei Akuter Myeloischer Leukämie

Die allogene hämatopoetische Stammzelltransplantation ist der bisher effektivste immuntherapeutische Ansatz zur Behandlung der Akuten Myeloischen Leukämie (AML). Bei AML-Patient*innen mit rezidivierter oder chemotherapierefraktärer sowie mit genetischer Hochrisikoerkrankung stellt die allo-HSZT die einzige kurative Option dar. Welche Parameter, Risikofaktoren und aktuellen Entwicklungen in der Therapie eine Rolle spielen, erläutert der Beitrag.

Abstract

To date allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective immunotherapeutic approach for the treatment of acute myeloid leukemia (AML). It involves the transplantation of blood stem cells from a healthy donor into a patient, with the goal of using the donor’s immune system to recognize and attack cancer cells (Graft-versus-leukemia effect). Thereby, allo-HSCT is more efficient than chemotherapy alone, as it combines high dose chemotherapy +/- irradiation with immunotherapy establishing a long-term control of leukemic cells while allowing reconstitution of a healthy donor hematopoiesis and a new immune system. However, the procedure carries significant risks, including the possibility of graft-versus-host disease (GvHD), and requires careful patient selection to ensure the best possible outcome. In AML patients with high-risk, relapsed or chemo-refractory disease allo-HSCT provides the only curative option.

While allo-HSCT is currently the most established form of immunotherapy in the treatment of AML, other approaches that use the immune system to fight cancer are being researched. These may include immunomodulatory drugs or cell therapies such as CAR-T cells, which stimulate the immune system to attack cancer cells. Even if this does not yet play a role in current standard therapy, as our understanding of the immune system and its role in cancer grows, it is likely that targeted immunotherapies will become increasingly important in the treatment of AML The following article gives you an overview of allo-HSCT in AML patients and the current developments.

Kernaussagen

• Die kurative Wirkung der allo-HSZT beruht neben der antineoplastischen Wirkung der Konditionierungstherapie auch auf der immuntherapeutischen Wirkung des applizierten allogenen Blutstammzelltransplantats („Graft“) → Graft-versus-Leukämie-Effekt.

• Patientenspezifische Faktoren (wie Alter und Performance-Status), krankheits- sowie transplantationsspezifische Faktoren (wie der Grad des HLA-Matchings, die Intensität der Konditionierungsbehandlung und die Art der GvHD-Prophylaxe) sind zu berücksichtigen, um den kurativen Ansatz der allo-HSZT für alle AML-Patient*innen erfolgreich realisieren zu können.

• Die Grundvoraussetzung für eine allo-HSZT ist, dass ein geeigneter Blutstammzellspender zur Verfügung steht. Die „Histokompatibilität“ (HLA-Typisierung!) definiert dabei die immunologische Verträglichkeit zwischen Patient und Spender. HLA-haploidentische Familienspender kommen bei vergleichbaren Transplantationsergebnissen zunehmend als Alternative zum Einsatz.

• Die besten Transplantationsergebnisse werden bei AML-Patient*innen in CR1 erreicht.

• Adaptationen in der Induktionschemotherapie vor der allo-HSCT sowie Modifikationen in der Intensität und dem Konzept der Konditionierungsbehandlung zur allo-HSZT (z.B. sequenzielle Therapie), als auch zielgerichtete Behandlungen (Sorafenib als FLT3-Target) und adaptive immuntherapeutische Verfahren (z.B. DLI) nach der allo-HSZT haben dazu beigetragen, die Ergebnisse der allogenen Blutstammzell-Transplantation bei AML-Patient*innen in der Hochrisikosituation wie auch in der rezidivierten/refraktären Situation zu verbessern.

Schlüsselwörter

akute myeloische Leukämie - allogene Blutstammzell-Transplantation - Graft-versus-Leukämie-Effekt

Keywords

acute myeloid leukemia - allogeneic hematopoietic stem cell transplantation - graft-versus-leukemia effect

Publication History

Article published online:
29 March 2023

• Literatur

• 1 Cornelissen JJ, Breems D, Putten van WLJ. et al. Comparative analysis of the value of allogeneic hematopoietic stem-cell transplantation in acute myeloid leukemia with monosomal karyotype versus other cytogenetic risk categories. J Clin Oncol 2012; 30: 2140-2146
• 2 Thomas ED, Lochte Jr HL, Lu WC. et al. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med 1957; 257: 491-496 DOI: 10.1056/NEJM195709122571102. (PMID: 13464965)
• 3 Passweg JR, Baldomero H, Chabannon C. et al. Hematopoietic cell transplantation and cellular therapy survey of the EBMT: monitoring of activities and trends over 30 years. Bone Marrow Transplant 2021; 56: 1651-1664 DOI: 10.1038/s41409-021-01227-8. (PMID: 33623153)
• 4 McCurdy SR, Kasamon YL, Kanakry CG. et al. Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide. Haematologica 2017; 102: 391-400
• 5 Doppelhammer M, Fraccaroli A, Prevalsek D. et al. Comparable outcome after haploidentical and HLA-matched allogeneic stem cell transplantation for high-risk acute myeloid leukemia following sequential conditioning-a matched pair analysis. Ann Hematol 2019; 98: 753-762 DOI: 10.1007/s00277-019-03593-2. (PMID: 30617644)
• 6 Finke J, Bethge WA, Schmoor C. et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol 2009; 10: 855-864 DOI: 10.1016/S1470-2045(09)70225-6. (PMID: 19695955)
• 7 Döhner H, Wei AH, Appelbaum FR. et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022; 140: 1345-1377
• 8 Innes AJ, Woolley P, Szydlo RM. et al. Complete remission with incomplete count recovery (CRi) prior to allogeneic HCT for acute myeloid leukaemia is associated with a high non-relapse mortality. Leukemia 2020; 34: 667-670
• 9 Gilleece MH, Labopin M, Savani BN. et al. Allogeneic haemopoietic transplantation for acute myeloid leukaemia in second complete remission: a registry report by the Acute Leukaemia Working Party of the EBMT. Leukemia 2020; 34: 87-99 DOI: 10.1038/s41375-019-0527-4. (PMID: 31363160)
• 10 Craddock C, Labopin M, Pillai S. et al. Factors predicting outcome after unrelated donor stem cell transplantation in primary refractory acute myeloid leukaemia. Leukemia 2011; 25: 808-813 DOI: 10.1038/leu.2011.13. (PMID: 21339758)
• 11 Tallman MS, Rowlings PA, Milone G. et al. Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission. Blood 2000; 96: 1254-1258
• 12 Frick M, Chan W, Arends CM. et al. Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation. J Clin Oncol 2019; 37: 375-385 DOI: 10.1200/JCO.2018.79.2184. (PMID: 30403573)
• 13 Luznik L, O'Donnell PV, Symons HJ. et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14: 641-650 DOI: 10.1016/j.bbmt.2008.03.005. (PMID: 18489989)
• 14 Fraccaroli A, Prevalsek D, Fritsch S. et al. Sequential HLA-haploidentical transplantation utilizing post-transplantation cyclophosphamide for GvHD prophylaxis in high-risk and relapsed/refractory AML/MDS. Am J Hematol 2018; 93: 1524-1531 DOI: 10.1002/ajh.25281. (PMID: 30194866)
• 15 Schmid C, Schleuning M, Ledderose G. et al. 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 DOI: 10.1200/JCO.2005.07.061. (PMID: 16110027)
• 16 Schmid C, Labopin M, Nagler 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: 4938-4945
• 17 Röllig C, Serve H, Noppeney R. et al. Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial. Leukemia 2021; 35: 2517-2525 DOI: 10.1038/s41375-021-01148-x. (PMID: 33603142)
• 18 Dominietto A, Pozzi S, Miglino M. et al. Donor lymphocyte infusions for the treatment of minimal residual disease in acute leukemia. Blood 2007; 109: 5063-5064 DOI: 10.1182/blood-2007-02-072470. (PMID: 17522340)
• 19 Krishnamurthy P, Potter VT, Barberet LD 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 Transplant 2013; 19: 562-568
• 20 Schuler E, Wagner-Drouet EM, Ajib S. et al. Treatment of myeloid malignancies relapsing after allogeneic hematopoietic stem cell transplantation with venetoclax and hypomethylating agents-a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group. Ann Hematol 2021; 100: 959-968