With up to 75% of patients allografted for AML poised for relapse, and fewer than 10% surviving long-term, only patients who achieve a second complete remission (CR) with salvaged chemotherapy after allogenic stem cell transplantation (allo-SCT) have encouraging long-term survival. Remission and relapse after allo-SCT currently seen in the context of dynamic competition between the graft-versus-leukemia (GVL) effect and progression of residual disease. Novel strategies are needed to further exploit the GVL effect.
On 25 March 2019, at the 45th Annual Meeting of the European Society for Blood and Marrow Transplantation, in Frankfurt, Germany, Charlie Craddock, from the Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, University of Birmingham, presented an educational session on strategies to optimize the GVL effect in AML patients.
Mounting a sufficient GVL effect after allo-SCT is still seen as the most effective mechanism to prevent relapse in patients with AML. Various mechanisms have been described for how leukemic cells evade immune surveillance post-transplant.
Mechanisms of immune evasion in patients relapsing post-transplant1
- Production of immunosuppressive enzymes (IDO, CD73, CD39, arginase)
- Reduced secretion of pro-inflammatory cytokines and growth factors (IL-15, G-CSF)
- Increased secretion of anti-inflammatory cytokines (IL-10, TGF-β)
- Altered expression of immune checkpoint ligands (PD-L1, CD155, VISTA, B7-H3, B7-H4)
- Impaired expression of leukemia cell recognition (loss of HLA, impaired Ag/HLA presentation machinery)
Prof Craddock outlined four strategies2 to enhance the GVL effect:
- Optimization of cytoreductive conditioning regimen
- Selection of correct stem cell source
- Maintenance therapy: Targeting leukemia-specific antigens post-transplant
- Development of effective salvage regimens
Optimization of cyto-reductive conditioning therapy3 (EBMT RICMAC study, NCT01203228)
- Myeloablative conditioning (MAC):
- Low relapse rates but high non-relapse mortality (NRM)
- Standard of care (SOC) for patients with high-risk AML
- Reduced intensity conditioning (RIC):
- Leads to lower NRM
- good results achieved with FLAMSA based regimens
- Higher relapse rates have been observed and linked to the requirement for high immunosuppressive treatment (e.g. cyclosporine)
Selection of the correct source of stem cells
- Allo-SCT with cells from unrelated donors give lower relapse rates compared with sibling donors
Targeting leukemia-specific antigens post-transplant – Maintenance therapy4
- Azacitidine upregulates putative GVL targets
> Encouraging results have been obtained using azacitidine as a preemptive/prophylactic treatment after allo-SCT (RELAZA2 study, NCT01462578)
- Targeted therapies, such as imatinib and sorafenib:
> Delay kinetics of relapse
> Augment antitumor activity of graft
> Change the need of donor lymphocyte infusion (DLI)
- DLI alone, or in combination with one of the above
Effective salvage regimens
- Achieving a CR after salvage is a requirement for long-term survival in patients with AML relapsing after allo-SCT5
- Good results with salvage therapy obtained by:
- Withdrawal of immunosuppression6
- Azacitidine +/- lenalidomide7
- Azacitidine + DLI
- Enhancing GVL requires a personalized approach and monitoring MRD before and after SCT is imperative for optimal treatment decisions.
- Conditioning regimens are still central to maximize the GVL effect post-transplant, due to their cytoreductive properties.
- Maintenance therapy allows the manipulation of the GVL effect post allo-SCT
- Novel and more effective options for salvage therapy are being developed and need to be tested in randomized trials
Prof Craddock concluded the session by stating that the biology of the disease post-relapse needs to be better understood to develop more effective therapies.
- Zeiser, R. and Vago, L., Mechanisms of immune escape after allogeneic hematopoietic cell transplantation. Blood, 2019 Mar 21; 133(12):1290—1297. DOI: 1182/blood-2018-10-846824
- Craddock C. Educational Session: Strategies to optimize the GVL effect. 2019 Mar 25. 45th Annual Meeting of the European Society for Blood and Marrow Transplantation, Frankfurt, Germany
- Kröger, N., et al. Dose-reduced versus standard conditioning followed by allogeneic stem-cell transplantation for patients with myelodysplastic syndrome: a prospective randomized phase III study of the EBMT (RICMAC Trial). Journal of Clinical Oncology, 2017; 35(19):2157—2164.
- Platzbecker, U., et al. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): An open-label, multicentre, phase 2 trial. The Lancet Oncology, 2018 Dec; 19(12):1668—1679.
- Schmid, C., et al. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood, 2012 Feb 9; 119(6):1599-1606.
- Kekre, N., et al. Efficacy of immune suppression tapering in treating relapse after reduced intensity allogeneic stem cell transplantation. Haematologica, 2015 Jun 16; 100(9):1222—1227.
- Craddock, C., et al. Combination Lenalidomide and Azacitidine: A Novel Salvage Therapy in Patients Who Relapse After Allogeneic Stem-Cell Transplantation for Acute Myeloid Leukemia.Journal of Clinical Oncology, 2019 Mar 1; 37(7):580—588.
- Lancet, J.E., et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. Journal of Clinical Oncology, 2018 Jul 19; 36(26):2684.