Professor Nicolaus Kröger, Chairman of EBMT: GVHD prevention is very important, and ATG has a bright future in clinical application

The annual Lu Daupei Hematology Summit Forum has an important influence in the domestic academic field of hematology
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On June 25-26, 2021, the 9th Lu Daopei Hematology Summit Forum will be held in the form of online live broadcast.
The conference will invite many experts in the field of hematology at home and abroad, focusing on the latest progress in hematopoietic stem cell transplantation, CAR-T immune cell therapy, and lymph.
In-depth exchanges and discussions were carried out on the diagnosis and treatment of tumor/myeloma, clinical application of laboratory results, and special care for blood diseases
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At the meeting, Professor Nicolaus Kröger, the current chairman of the European Society for Blood and Bone Marrow Transplantation (EBMT), shared on the prevention of graft-versus-host disease (GVHD).
The editor compiled the highlights of the meeting as follows for readers
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Professor Nicolaus Kröger, Professor of Medicine and Director of the Department of Stem Cell Transplantation, Hamburg-Eppdorf University Medical Center, Germany Current Chairman of the European Society for Blood and Bone Marrow Transplantation (EBMT) Chairman of the German Stem Cell Working Group (DAG-KBT), Honorary Doctorate EHA, ESH, University of Belgrade, Serbia Members of ASH and many other scientific committees such as Blood, Haematologica, Bone Marrow Transplantation and other core journals.
Allogeneic hematopoietic stem cell transplantation (allo-SCT) is an effective and even the only cure for hematological malignancies
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GVHD is one of the main complications after transplantation and one of the main causes of transplant-related deaths
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In the process of allo-SCT, it is necessary to intervene in advance to prevent the occurrence of GVHD in order to reduce the risk of transplant-related death
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GVHD prevention strategies urgently need to be optimized.
Acute GVHD (aGVHD) and chronic GVHD (cGVHD) are still the main causes of morbidity and death after allo-SCT
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About 25%-55% of patients develop aGVHD within 100 days after transplantation, and about 20%-50% of patients develop cGVHD within 2 years after transplantation
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Factors related to the occurrence of GVHD include HLA matching, donor source, pretreatment plan, patient age, stem cell source, and GVHD prevention strategies
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Grade II-IV aGVHD is associated with higher non-relapse mortality (NRM)
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Data from the EBMT database shows that the incidence of II-IV degree aGVHD dropped from 40% to 28% from 1990 to 2015, but the incidence of II-IV degree aGVHD only decreased by 1% during the decade from 2006 to 2015; III The 5-year non-recurring mortality rate (NFR) of patients with grade aGVHD is as high as 40%, and the 5-year NFR of patients with grade IV aGVHD is as high as 70%-80%
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Therefore, the prevention strategy of GVHD after allo-SCT, especially aGVHD, needs to be optimized urgently in clinical practice
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The transplant contains the donor's T cells and CD34+ stem cells.
These cells can not only cause GVHD, but also induce the graft anti-leukemia (GVL) effect
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There is a strong correlation between the effects of GVHD and GVL.
Excessive reduction of GVHD will result in the loss of GVL effects, leading to an increased risk of disease recurrence
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Therefore, it is important to balance the risks between the effects of GVHD and GVL
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However, the correlation between the effects of GVHD and GVL may be different in different diseases
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Previous studies have found that there are differences in the effects of GVHD on recurrence in different diseases (as shown in the figure below).
No clear correlation has been found in acute myeloid leukemia (AML) and plasma cell disease (PCD), while in chronic myeloid leukemia (CML) ) And myeloproliferative tumors (MPN), the occurrence and severity of GVHD are significantly related to the risk of recurrence
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Clinical classification of GVHD The biological pathogenesis of GVHD is very complicated (as shown in the figure below)
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As for the clinical classification of GVHD, Professor Kröger said that aGVHD can be divided into classic aGVHD and late-onset aGVHD.
Classic aGVHD generally refers to the occurrence of within 100 days (+100 d) after transplantation, and the main manifestations are skin, gastrointestinal and liver.
Inflammatory reactions in three organs; late onset aGVHD refers to GVHD that has the clinical manifestations of classic acute GVHD, but occurs after +100 days
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Late aGVHD includes three situations: aGVHD that occurs newly after +100 d, a controlled classic aGVHD is reactivated after +100 d, and classic aGVHD continues after +100 d
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The mechanism of cGVHD is complex and the clinical manifestations are diverse.
Its diagnosis mainly relies on clinical signs, which are similar to autoimmune diseases and can affect any one or more organs of the body.
The most common ones are skin, hair, nails, mouth, liver, eyes, gastrointestinal, genital, fascia, or joint bone joints
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Professor Kröger emphasized that previously, cGVHD was defined only based on the time of GVHD after transplantation, but some patients with GVHD after +100 days do not meet the diagnostic criteria for cGVHD based on organ involvement
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At present, clinically, cGVHD can be divided into classic cGVHD and overlapping cGVHD.
Classic cGVHD can also occur within +100 days; when aGVHD and cGVHD are present at the same time, it is diagnosed as overlapping cGVHD
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ATG is included in the EBMT guidelines recommendation, and new drugs for the prevention of GVHD are being explored endlessly.
In the prevention and management of GVHD after hematopoietic stem cell transplantation for hematological malignancies, in the latest version of the EBMT consensus recommendation in 2020, calcineurin inhibitor (NCI) tacrolimus (TAC) ) And cyclosporine A (CsA) can be used for GVHD prevention in sibling/HLA unrelated donor (MUD) transplantation
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Four phase III randomized studies and several retrospective studies compared TAC and CsA, and the results of the study showed similar efficacy
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Clinically, drug selection should be based on the experience of each center.
Most centers in Europe use CsA as the standard NCI drug
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For patients receiving HLA-matched relatives (MRD)/MUD transplantation, it is recommended to use NCI combined with antimetabolites (preferably methotrexate [MTX], +1 d, +3 d, +6 d administration) for GVHD prevention
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In addition, for patients who are contraindicated with MTX or require rapid implantation (for example, with persistent aspergillosis) myeloablative pretreatment (MAC) patients, mycophenolate mofetil (MMF) can be used instead of MTX
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Meta-analysis and retrospective studies have shown that the incidence of grade II-IV GVHD and patient survival after MTX+NCI and MMF+NCI treatment are similar
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However, there are also some statistical data that show that the incidence of grade III-IV aGVHD slightly increased after MMF treatment
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EBMT recommends ATG for GVHD prevention.
In unrelated donor transplantation, there have been four randomized controlled studies comparing antithymocyte globulin/anti-T lymphocyte globulin (ATG/ATLG) with standard treatment.
The results of the studies all showed that ATG/ ATLG can reduce the incidence of cGVHD, especially widespread cGVHD
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In terms of aGVHD, the Bacigalupo study showed that higher doses of ATG can significantly reduce the incidence of grade III-IV aGVHD
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Although the NRMs of the two groups were similar, the Soiffer study data showed that the ATLG group had a higher recurrence rate and a lower 2-year overall survival rate (OS) (as shown in the figure below)
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In sibling transplantation, there have been two randomized controlled studies from Europe that have evaluated the efficacy of ATG
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The results of the study showed that the OS and NRM of the ATG group were similar to those of the non-ATG group.
The cGVHD-relapse-free survival rate (cGRFS) of the ATG group was significantly better (P=0.
005).
Therefore, Europe is active in the use of ATG in sibling transplantation.
Attitude
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A randomized study from China published on JCO in 2020 explored the efficacy of low-dose rabbit anti-human thymocyte globulin (rATG) in sibling transplantation, but its conclusions are exactly the opposite of European studies
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Research results show that rATG can not only significantly reduce the overall incidence of cGVHD (27.
9% vs 52.
5%, P＜0.
001) and the incidence of widespread cGVHD (8.
5% vs 23.
3%, P=0.
029), but also reduce II-IV The incidence of aGVHD (13.
7% vs 27.
0%, P=0.
007)
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At the same time, the use of rATG does not increase the cumulative recurrence rate (CIR) and NRM
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Although there was no difference in OS rate and disease-free survival (DFS) rate, the use of rATG significantly improved GVHD-relapse-free survival at 3 years after transplantation (GRFS: 40.
3% vs 26.
0%, p=0.
003)
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Based on the above research results, EBMT recommends rATG for MUD allo-SCT GVHD prevention, and MRD peripheral blood allo-SCT GVHD prevention; especially recommended for GVHD high-risk patients
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PTCy to prevent GVHD has not been included in the EBMT guidelines.
Since 2014, some studies have begun to use post-transplant cyclophosphamide alone (PTCy: +3 d, +4 d intravenous cyclophosphamide 50 mg/kg) as MRD/MUD post-transplant The GVHD prevention program, research shows that PTCy can reduce the incidence of cGVHD
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Judging from the EBMT registration data in the past ten years, the number of patients in Europe using PTCy as MRD/MUD or haploid transplantation GVHD prevention program is increasing year by year
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However, the latest version of the EBMT consensus recommendation does not formally recommend PTCy as a prevention plan for GVHD
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Exploration of new drugs in the prevention of GVHD In recent years, a large number of studies have been exploring the prevention and treatment of GVHD.
Many new drugs that act on new targets (as shown in the figure below), such as CTLA-4 globulin, anti-CD154 monoclonal antibody, anti-CD25 monoclonal antibody, and JAK inhibitors, etc.
, have good research and application prospects
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The JAK inhibitor Rucotinib has achieved good effects in GVHD that has failed glucocorticoid treatment.
Currently, Professor Kröger’s team is conducting clinical studies to explore the role of Rucotinib in preventing GVHD in patients with myelofibrosis.
12 Preliminary analysis of patients showed that the incidence of aGVHD of degree II-IV was 8%, and further research results are worth looking forward to
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Summary Although the mortality rate after the occurrence of GVHD has decreased in all patients with aGVHD scale, it is still high and has not improved since 2000.
Effective prevention strategies for aGVHD and cGVHD are still unmet clinical needs
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At present, calcineurin inhibitors combined with methotrexate or mycophenolate mofetil are still the standard preventive regimens for GVHD.
After transplantation, promising new drugs such as cyclophosphamide or JAK inhibitors are currently under clinical research.
It is looking forward to
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