2022CSH Professor Xia Linghui: Progress in the prevention and treatment of recurrence after allogeneic hematopoietic stem cell transplantation in high-risk AML/MDS patients

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The 17th National Hematology 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 famous experts at home and abroad to discuss the latest progress
in the field of blood diseases.
At this conference, Professor Xia Linghui from the Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, introduced the current status and prevention strategies of recurrence after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with the topic of "Progress in the prevention and control of recurrence after allogeneic hematopoietic stem cell transplantation in high-risk AML/MDS patients
".

Current status of relapse after allo-HSCT

In 2019, 60% of hematopoietic stem cell transplants in China were derived from hemi-zygous donors (HIDs), while in the United States, bone marrow unrelated donors (MUDs) 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) were included.
In the latest CIBMTR data, statistical results of three-year survival information after allogeneic transplantation in 2018-2019 show that relapse remains the leading cause
of death after 100 days of allo-HSCT.
The 2020 European Society of Blood and Marrow Transplantation (EBMT) Congress published the survival data of 8160 adult patients with AML who received transplantation at the first complete response and relapsed between 2000 and 2018, which showed that the 2-year overall survival (OS) rate of these patients was only 17%, and the primary disease was the cause of
death in 77% of patients.
In addition, one retrospective study showed that earlier recurrence after transplantation was associated with shorter
survival in AML patients.
Professor Xia Linghui said that recurrence after transplantation seriously affects the long-term survival of patients with hematological tumors, so there are also many studies exploring the mechanism of recurrence after transplantation, such as mutation and deletion of HLA, overexpression of PD-L1 and CD155 molecules, etc.
, hoping that these mechanism studies can provide new treatment ideas
for recurrence after transplantation in the future.

Prevention and treatment strategies for recurrence after allo-HSCT

Professor Xia Linghui introduced that the key points of prevention and treatment of recurrence after allo-HSCT mainly include pre-transplant treatment, pretreatment plan, post-transplant recurrence prevention and post-relapse treatment, therefore, Professor Xia Linghui introduced
the prevention and treatment strategies of post-transplantation recurrence from the above four aspects.

For pre-transplant treatment, the 2021 EBMT Conference presented data from a retrospective study showing that veneclax in combination with demethylation was effective in treating patients with treatment-naïve AML or relapsed/refractory (R/R) AML (n=24), 9 of whom were able to receive bridging transplantation, 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 advanced
in R/R AML.
A 2021 study published in the journal Blood showed that 3 patients with R/R AML achieved remission and bridging transplantation
after receiving generic CAR-T products targeting CD123 。 In addition, clinical trials targeting CLL1 CAR-T therapy for patients with R/R AML have also been carried out in China, and the data results in 2022 were published in the Journal of Hematology & Oncology, which included 10 patients with R/R AML, 4 cases did not bridge transplantation after CAR-T treatment, and 3 of them died early; Six patients underwent CAR-T therapy bridging transplantation, of which five were alive
at the end of the data.
Professor Xia Linghui said that there are fewer clinical trials related to CAR-T THERAPY for R/R AML, and fewer cases of CAR-T therapy after bridging transplantation, and hopes that the results of future exploration of CAR-T products will provide more transplant opportunities
for patients with R/R AML.

For the pretreatment regimen, the 2020 EBMT Conference presented data from a study of 2936 adult patients with AML pretreatment regimen, which showed that patients with AML with KPS score = 80% had a lower recurrence rate (RI) and a higher GVHD-no-recurrence-free survival (GRFS) rate in the myeloablative pretreatment (MAC) group compared with the reduced-dose pretreatment (RIC) group; However, patients with a KPS score < 80% had lower non-recurrence mortality (NRM) and higher OS rates in the RIC group<b10>.
The results of a clinical trial published at the EBMT conference in 2021 to explore the efficacy of FLAMSA+Bu (fludarabine, cytarabine, triamteridine + busulfan) in AML patients showed that patients with FLAMSA+Bu regimen after sequential transplantation had lower RI and higher leukemia-free survival (LFS) rates, but grade 2-4 acute graft-versus-host disease (GVHD) has a high
incidence.
In addition, the 2021 EBMT Conference announced the efficacy of titipai + busulfan + fludarabine (TBF) as a pretreatment regimen in AML patients, which showed that patients after sequential transplantation of TBF regimens had better survival, higher disease-free survival (DFS) rates, and lower
RI compared with systemic radiotherapy (TBI) and non-TBI-non-TBF regimens.
Professor Xia Linghui's team published a trial
comparing BUCY2 (hydroxyurea + cytarabine + busulfan + cyclophosphamide + smostolastine) pretreatment regimen in high-risk MDS patients in patients with high-risk MDS in the journal Bone Marrow Transplantation 。 The results showed that the decitabine + BUCY2 intensive pretreatment regimen significantly improved the survival prognosis of patients with high-risk MDS, and the cumulative recurrence rate at 3 years after transplantation (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 better than those in
BUCY2 。 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 combined with modified BUCY-intensive pretreatment regimens has achieved the same good efficacy
in high-risk AML patients.

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

For post-relapse treatment, at the 2022 EBMT conference, the researchers of the German RELAZA2 trial announced the trial data
of 270 high-risk AML/MDS patients who received preemptive treatment based on MRD monitoring results after transplantation.
The results of this study showed that 52 patients with MRD conversion received 6 cycles of azacitidine preemptive treatment, and the CR rate was 67% after 6 cycles, and finally 11 patients had hematologic relapse
.
In addition, at the 2022 EBMT conference, the data results reported by Peking University People's Hospital showed that IFNα-2b combined with ruxolitinib had a good efficacy in patients with relapsed 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 transfusion (DLI) is also an important tool for the treatment of post-transplant relapse, and Greek researchers evaluated the efficacy and safety of DLI in patients with high-risk AML/ALL who relapse after transplantation, data published at the EBMT 2021 conference
.
The results of this study were optimistic, with 39 patients with OS rate of 76%, NRM rate of 14%, grade III acute GVHD incidence of 20%, and moderate to severe chronic GVHD incidence of 8%.

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 state and economic conditions of patients before secondary transplantation need to be carefully considered
by clinicians.

summary

Professor Xia Linghui concluded that disease recurrence after allogeneic transplantation is the leading cause
of death in high-risk AML/MDS patients.
Relapse prevention after transplantation 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, and MDS monitoring is a good means
to prevent overtreatment.
It is hoped that future research progress will bring better solutions to the problem of recurrence after transplantation
.

Professor Xia Linghui

Doctor of Medicine, Professor, Chief Physician, Doctoral Supervisor

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

Member of Hematopoietic Stem Cell Application Group, Hematology Branch of Chinese Medical Association

Member of the Expert Committee of China Hematopoietic Stem Cell Donor Database

Member of the Standing Committee of the Hematology Branch of the Chinese Geriatric Society and Deputy Secretary-General of the Transplant Infection Group

Member of the Hematology Professional Committee of the Cross-Strait Medical and Health Exchange Association

Member of the Standing Committee and Secretary of Hubei Hematology Society

Vice Chairman of Hematology Branch of Hubei Association of Integrative Medicine

Vice Chairman of the Academic Committee of Hubei Medical Bioimmunology Society

Member of the Standing Committee of Hubei Organ Transplantation Society

Editorial Board Member of the journals Clinical Hematology and Thrombosis and Haemostasis