2022 CSH Prof. Linghui Xia: Advances in the prevention and treatment of allogeneic hematopoietic stem cell transplantation in high-risk AML/MDS patients

The 17th National Hematology Academic Conference of the Chinese Medical Association was grandly opened in Shanghai on September 23-25, 2022, with the theme of "respect, inheritance, collaboration and innovation", and invited well-known experts at home and abroad to talk about the latest progress
in the field of blood diseases.
At the conference, Professor Xia Linghui, Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, introduced the current situation and prevention strategies
of recurrence after allogeneic hematopoietic stem cell transplantation (allo-HSCT) under the topic of "Progress in the Prevention and Control of Recurrence after Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk AML/MDS Patients".

In 2019, 60% of hematopoietic stem cell transplants in China were derived from semi-conjunctive donors (HIDs), while in the United States, bone marrow unrelated donors (MUD) were the mainstay
.
The analysis of 12,744 allogeneic transplant patients in China in 2021 showed that 47% of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) accounted for 47%.

In the latest CIBMTR data, statistical results from the 2018-2019 three-year survival information after allogeneic transplantation show that relapse remains the leading cause
of death for patients after 100 days of allo-HSCT.
The 2020 European Society for Blood and Bone Marrow Transplantation (EBMT) Congress published survival data on 8,160 adult patients with AML who received transplantation during the first complete remission and relapsed between 2000 and 2018, showing that the total 2-year survival (OS) rate of these patients was only 17%, and primary disease was the cause of death in 77% of
patients.
In addition, one retrospective study showed that the earlier the recurrence after transplantation, the shorter
the survival time of AML patients.
Professor Xia Linghui said that post-transplant recurrence seriously affects the long-term survival of patients with hematological tumors, so there are also many studies exploring the mechanism of post-transplantation recurrence, such as mutations and deletions of HLA, overexpression of PD-L1 and CD155 molecules, etc.
, hoping that these mechanism studies can provide new treatment ideas
for post-transplantation recurrence in the future.

Professor Xia Linghui introduced that the prevention and control points of recurrence after allo-HSCT mainly include pre-transplant treatment, pretreatment protocol, post-transplant recurrence prevention and post-recurrence treatment, therefore, Professor Xia Linghui introduced
the prevention and treatment strategy of post-transplant recurrence from the above four aspects.

For pre-transplant treatment, the 2021 EBMT Conference published the results of a retrospective study that showed that Venecra combined with demethylation drugs was effective in treating patients with either initial AML or relapsed/refractory (R/R) AML (n=24), of which 9 patients were able to receive bridging transplants, and the median OS of transplanted patients was significantly better than that of non-transplanted patients (9.
7 vs 3.
0 months, P=0.
001).

In addition, CAR-T therapy has also made progress
in R/R AML.
A 2021 study published in the journal Blood showed that three patients with R/R AML achieved remission and bridging grafting
after receiving a generic CAR-T product targeting CD123 。 In addition, clinical trials targeting CLL1 CAR-T therapy for R/R AML patients have also been carried out in China, and the 2022 data results were published in the Journal of Hematology & Oncology, which included 10 patients with R/R AML, 4 patients without bridging grafts after CAR-T treatment, and 3 of them had early deaths; Six patients received CAR-T treatment bridging transplantation, of which 5 were still alive at data cut-off
.
Professor Xia Linghui said that there are fewer clinical trials related to CAR-T therapy in R/R AML, and fewer cases after CAR-T treatment bridging transplantation, and it is hoped that the results of future exploration of CAR-T products will provide more transplantation opportunities
for R/R AML patients.

For pretreatment protocols, the 2020 EBMT conference published data from a study of 2936 AML adult patients with pretreatment protocols, which showed that patients with AML with a KPS score of 80% had lower recurrence rates (RI) and higher recurrence rates (GRFS) in the myeloinated pretreatment (MAC) group compared with the reduced dose pretreatment (RIC) group; However, in patients with KPS scores < 80 percent, non-recurrence mortality (NRM) was lower in the RIC group and higher<b10> OS rates.
The results of a clinical trial published at the EBMT conference in 2021 to explore the efficacy of the FLAMSA+Bu (fludarabine, cytarabine, daplazididine + busulfan) regimen in AML patients showed that patients with FLAMSA+Bu protocol had lower RI and higher survival rates without leukemia (LFS), but higher incidence
of grade 2-4 acute graft-versus-host disease (GVHD).
。 In addition, the 2021 EBMT Conference announced the efficacy of the application of thiatipid + busulfan + fludarabine (TBF) as a pretreatment protocol in AML patients, which showed that patients with TBF regimens had better survival outcomes, higher disease-free survival (DFS) rates, and lower
RI compared with systemic radiotherapy (TBI) and non-TBI-non-TBF regimens 。 Professor Linghui Xia's team published a 2022 study comparing
the pretreatment regimen of BUCY2 (hydroxyurea + cytarabine + cytarabine + busulamide + semustine) and the intensive pretreatment protocol of decitabine + BUCY2 in high-risk MDS patients 。 The study showed that the decitabine + BUCY2 intensive pretreatment protocol significantly improved the survival prognosis of high-risk MDS patients, and the cumulative recurrence rate (20.
2% vs 39.
0%, P=0.
034), 3-year OS rate (70.
2% vs 51.
1%, P=0.
031), and 3-year DFS rate (64.
9% vs 43.
9%, P=0.
027) were all better than those in the BUCY2 group
。 Professor Xia Linghui said that there are relatively many trials of pre-transplant pretreatment regimens for high-risk AML/MDS patients, and significant progress has been made, and the combination of decitabine and modified BUCY intensive pretreatment regimens has achieved the same good efficacy
in high-risk AML patients.

For the prevention of post-transplant recurrence, the team of Professor Liu Qiqi of Southern Medical University Southern Hospital published a trial data
on the prevention of recurrence after transplantation in patients with FLT3-ITD⁺ AML in the journal Lancet Oncology in 2020.
The results of the study showed that the cumulative recurrence rate of 1 year in the sorafenib group was 7%, which was significantly lower than that in the control group (24.
5%) (P=0.
001), the 2-year OS rate and LFS rate were significantly benefited, and the patients with AML after transplantation had good
tolerance to long-term sorafenib maintenance therapy.
In addition, the team of Professor Xi Zhang of Xinqiao Hospital of the Army Military Medical University published data
from a trial of recombinant human granulocyte stimulating factor (rhG-CSF) combined with a small dose of decitabine in high-risk AML transplantation patients in the Journal of Clinical Oncology in 2020 。 The study included 202 high-risk AML patients who received transplantation, and at the time of data cut-off, the recurrence rate of patients receiving rhG-CSF plus low-dose decitabine was 15% (15/100 cases), the recurrence rate in the control group was 38.
2% (39/102 cases), and the estimated cumulative recurrence rate was 15% and 38.
3% respectively at 2 years, both with statistical differences
.
Professor Xia Linghui said that whether it is sorafenib or rhG-CSF combined with a small dose of decitabine, it can reduce the recurrence rate after transplantation in high-risk AML patients and greatly improve survival, which shows that recurrence prevention is also an important intervention
.

For post-relapse treatment, at the 2022 EBMT conference, researchers in the German RELAZA2 trial published trial data
on 270 high-risk AML/MDS patients receiving preemptive treatment after transplantation based on MRD monitoring results.
The results of the study showed that 52 patients with positive MRD received preemptive treatment with 6-cycle azacitidine, and the CR rate was 67% after 6 cycles, and finally 11 cases had hematological recurrence
.
In addition, at the 2022 EBMT conference, the data results reported by Peking University People's Hospital showed that IFNα-2b combined with rucotinib had a good effect in patients with recurrent or MRD-positive AML/ALL/MDS after transplantation, with an ORR of 100% in relapsed patients and 95.
2%
in MRD-positive patients.
Donor lymphocyte infusion (DLI) is also an important tool for post-transplant recurrence therapy, with Greek researchers evaluating the efficacy and safety of DLI in patients with high-risk AML/ALL recurrence after transplantation, with data published at the 2021 EBMT conference
.
The results of the study were optimistic, with an OS rate of 76%, NRM of 14%, a 20% incidence of grade III acute GVHD, and an 8%
incidence of moderate to severe chronic GVHD in 39 patients.
Professor Xia Linghui said that secondary transplantation is also a hot spot in recent years, and a number of studies have confirmed that secondary transplantation can bring certain benefits to high-risk AML/MDS patients, but the disease status before secondary transplantation, patient economic conditions and other conditions need to be carefully considered by clinicians
.

Professor Xia Linghui concluded that disease recurrence after allogeneic transplantation is the leading cause
of death in high-risk AML/MDS patients.
Post-transplant recurrence prevention is better than preemptive treatment, and preemptive treatment is better than post-relapse treatment, but clinicians should also be alert to the possibility of overtreatment, of which MDS monitoring is a good means
to prevent overtreatment.
It is hoped that future research advances will bring better solutions to the problem of post-transplant recurrence
.

Professor Xia Linghui

• Doctor of Medicine, Professor, Chief Physician, Doctoral Supervisor

• Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology

• He is a member of the Hematopoietic Stem Cell Application Group of the Hematology Branch of the Chinese Medical Association

• Member of the Expert Committee of the Chinese Hematopoietic Stem Cell Donor Database

• He is a member of the Standing Committee of the Hematology Branch of the Chinese Geriatrics Association and the Deputy Secretary-General of the Transplant Infection Group

• He is a member of the Hematology Professional Committee of the Cross-Strait Medical and Health Exchange Association

• Standing Committee Member and Secretary of Hubei Hematology Society

• Vice Chairman of the Blood Branch of Hubei Association of Integrative Traditional Chinese and Western Medicine

• Vice Chairman of the Academic Committee of Hubei Medical Bioimmunology Society

• Member of the Standing Committee of Hubei Organ Transplantation Society

• Member of the editorial boards of the journals Clinical Hematology and Thrombosis and Hemostasis

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