2022CSH| Professor Jiang Erlie: Advances in the prevention and treatment of acute graft-versus-host disease

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 this conference, Professor Jiang Erlie of the Blood Disease Hospital of the Chinese Academy of Medical Sciences introduced the development and current situation
of acute graft-versus-host disease under the title of "Progress in the Prevention and Treatment of Acute Graft-versus-Host Disease".

Graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HSCT) and a leading cause
of transplant-related death.
The onset of acute GVHD (aGVHD) involves the activation of the innate immune system and the
acquired immune system.
The activation of the immune system leads to the release of a large number of inflammatory factors, which in turn causes damage to the patient's organs, but this also provides some clues for the diagnosis of aGVHD, and there are currently relevant studies to predict or differentiate the diagnosis of aGVHD
by detecting cytokines 。 Since 2021, Professor Jiang Erlie's team has also carried out relevant research, through artificial intelligence means to combine about 200 clinical indicators (including inflammatory factors, leukocyte subsets, T cell subsets, patient signs and biochemical indicators, etc.
) to predict the risk of aGVHD, and has achieved preliminary results in adult and pediatric patients, especially in adult patients, the high risk of 23 days after transplantation can well predict the occurrence
of aGVHD 。 Professor Jiang Erlie said that in the future, prospective clinical research will be carried out in this direction, using the system to predict the risk of aGVHD in patients, and intervening in high-risk patients before the emergence of aGVHD to better prevent aGVHD
.

The TCR pathway is a classic pathway in the preventive treatment of aGVHD, and the classic therapeutic drugs based on this pathway are calcineurin inhibitors, mTOR inhibitors, methotrexate and the like
.
ATG is also an important drug in the preventive treatment of aGVHD
.
A multicenter, open-label Phase III clinical study in China showed that ATG at a dose of 4.
5 mg/kg prevented the occurrence of II-IV degrees aGVHD, chronic GVHD (cGVHD) and widespread cGVHD after sibling fully concorporated HSCT (MSD-HSCT) and improved the patient's recurrence without GVHD (GRFS
).
The results of a prospective study in South Korea showed that a dose of 2.
5 mg/kg of ATG could prevent the occurrence of cGVHD after MSD-HSCT, but had little
effect on the prevention of aGVHD.
These two studies have found that relatively high doses of ATG have a better preventive effect
on aGVHD.

So while enhancing aGVHD prevention, does ATG lead to an increase in recurrence rates after MSD-HSCT? The above two studies also explore
this.
The results of the Chinese study suggest that ATG does not increase the recurrence rate of MSD-HSCT, but this result may be related
to the fact that all enrolled patients are standard-critical acute leukemia.
In the Korean study, enrolled patients included high-risk patients, and the results showed that ATG increased the recurrence rate
after MSD-HSCT in high-risk patients.
The above results suggest that ATG is a "double-edged sword" in MSD-HSCT, and ATG should be used with caution in high-risk patients; Older MSD-HSCT patients with a low risk of recurrence can be prevented
with relatively low doses of ATG.
In addition, ATG combined with PTCy has also shown good efficacy
in the preventive treatment of aGVHD.
A U.
S.
study showed that ATG+PTCy was more effective at reducing the incidence
of aGVHD compared with ATG monotherapy applications.
Professor Jiang Erlie said that this is also one of
the exploration directions for the prevention and treatment of aGVHD in the future.

In addition, some new drugs have emerged in the exploration of aGVHD preventive treatment, such as the JAK1 inhibitor Itacitinib
.
The results of a preliminary study on Itacitinib showed that there were no transplant failures for HSCT after Itacitinib prophylaxis and no patients developed degree III-IV aGVHD
.
Professor Jiang said that domestic JAK1 inhibitors are mostly used in the treatment of autoimmune diseases, and the treatment of aGVHD is found in clinical work, with good safety but poor results, so it may have more research value
in the prevention of aGVHD and cGVHD.

At present, the first-line treatment drugs for aGVHD recommended by the domestic and foreign guidelines are all glucocorticoids, but the efficacy of the first-line treatment of aGVHD with glucocorticoids is limited, so scholars at home and abroad are actively exploring new drug combinations aimed at improving the efficacy of first-line treatment of
aGVHD.
The results of the GRAVITAS-301 study showed that Itacitinib combined with glucocorticoids did not improve the overall response rate (ORR) in patients with aGVHD compared with placebo + glucocorticoids, but postmortem analysis showed that this combination protocol improved the 28-day complete response (CR) rate
.

In addition, CD6 monoclonal antibody Itolizumab showed good efficacy in aGVHD treatment, and the results of the EQUATE study showed that Itolizumab treated aGVHD patients with aGVHD for 15 days with ORR up to 71%, 1.
6mg/kg dose for 15 days and ORR for 29 days up to 78%-80%.

It is worth noting that clinical trials on Itolizumab will soon be launched
in China.

At present, there is no standard treatment plan for the second-line treatment of aGVHD, and effective second-line treatment options are still being explored
.
Baliximab is a drug with a high remission rate in second-line treatment of aGVHD
.
The results of a multicenter real-world study in China showed that the treatment of valliximab can reach 81% in patients with degree II aGVHD for 28 days, and the ORR for patients with degree III-IV aGVHD can reach 61%
in 28 days.

In addition, rucotinib is also a popular drug in the treatment of aGVHD
.
The results of the REACH2 study showed that reglucotinib (10 mg BID) could reach 62%, 76% II, 56%, and 53% IV in 28 days after treating patients with aGVHD; The results of post-mortem analysis showed that the ORR of aGVHD patients with skin and upper gastrointestinal tract was about 70%, the ORR of patients with aGVHD in the lower gastrointestinal tract could reach more than 50%, and the ORR of patients with aGVHD in the liver was 44%.

Clinically believe that intestinal aGVHD is the most dangerous, the highest mortality, Professor Jiang Erlie mentioned that in terms of personal experience, liver aGVHD, especially the liver aGVHD characterized by elevated bilirubin is the most difficult to treat, and the current treatment needs for liver aGVHD have not been met, and more energy
should be invested in this direction in the future.

In addition, there are some small samples of new drugs to explore
in hormone-resistant aGVHD (SR-aGVHD).
For example, the glucagon-like peptide-2 analogue Teduglutide (commonly used in the field of digestion), Teduglutide regulates the growth, proliferation and repair of cells in the small intestine, increases the number of Paneth cells, and improves intestinal SR-aGVHD symptoms
.
There is also the serine protease inhibitor α1 antitrypsin (AAT1), which also shows good efficacy in SR-aGVHD, and the ORR of AAT1 post-line treatment of SR-aGVHD can reach 57%.

Professor Jiang Erlie said that related new drugs, especially those related to the field of digestion, may be helpful
for the treatment and research of aGVHD, especially intestinal aGVHD.

Professor Jiang Erlie

• Chief physician, doctoral supervisor

• Director of Stem Cell Transplantation Center of Hematology Hospital of Chinese Academy of Medical Sciences

• Deputy Leader of the Hematopoietic Stem Cell Application Group of the Hematology Branch of the Chinese Medical Association

• Deputy Leader of the Hematopoietic Stem Cell Transplantation and Cell Therapy Group of the Hematology and Oncology Professional Committee of the Chinese Anti-Cancer Association

• He is a member of the Hematology Branch of the China Association for the Promotion of International Healthcare Exchange

• He is a member of the Academic Working Committee on Transplant Infection of the Hematology Branch of the Chinese Geriatrics Association

• Vice President of Tianjin Society of Hematology and Regenerative Medicine

• Standing Committee Member of Hematology Professional Committee of Tianjin Anti-aging Society

• He is a member of Tianjin Medical Association and Hematology Branch of Integrative Chinese and Western Medicine Society

• He is a member of the Organ Transplantation Branch of Tianjin Medical Association

• He is a member of the Hematology Physicians Branch of Tianjin Medical Doctor Association

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