International Perspective | On the Present and Future of GVHD Prevention and Control at Home and Abroad

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective method to treat a variety of blood system diseases.
The success of haplotype hematopoietic stem cell transplantation (haplo-HSCT) has led to a rapid increase in the number of hematopoietic stem cell transplantation cases.

Although the prevention and treatment of graft-versus-host disease (GVHD) has made great progress in the past ten years, GVHD is still the main comorbidity and cause of death of allo-HSCT.

Dr.
Corey S.
Cutler, associate professor of medicine at Harvard Medical School, said that the prevention and treatment of GVHD is entering a new stage.
In addition to the progress made in the prevention of acute GVHD (aGVHD) and chronic GVHD (cGVHD), there are currently several Drugs can be used for the treatment of glucocorticoid resistance or advanced GVHD, and more importantly, researchers are trying to push these new therapies to the first-line treatment, rather than waiting for patients to develop glucocorticoid resistance or refractory.

Exploration of GVHD prevention strategies.
In terms of GVHD prevention, based on the latest randomized research results, pan-T cell depletion may not be an effective prevention strategy.
Researchers are trying to selectively deplete T cell subsets, which may lead to better curative effects.
.

In addition, in terms of the application of antithymocyte globulin (ATG), China and North America still use it mainly for GVHD prevention, while most parts of Europe use ATG as a standard treatment.

It has to be mentioned that in recent years, some scholars believe that ATG may not be used in cord blood stem cell transplantation.

Professor Sun Zimin’s team at Anhui Provincial Hospital used myeloablative pretreatment regimen cyclosporin A (CsA) + mycophenolate mofetil (MMF) to prevent GVHD for non-blood cord blood stem cell transplantation, and the control group was myeloablative pretreatment regimen CsA+ MMF+MTX or ATG-FreseniusS (7.
5 mg/kg/d × 3 d) prevent GVHD for non-blood cord blood stem cell transplantation.
There was no statistically significant difference in the incidence of aGVHD between the two groups.
, And the implantation rate, disease-free survival rate and overall survival rate of the ATG group were significantly better than those of the ATG group, and the difference was statistically significant.

Current status and research progress of aGVHD treatment Glucocorticoids are the standard first-line treatment for aGVHD.

There are currently a number of clinical trials exploring strategies to minimize glucocorticoid exposure, and the multicenter randomized phase II BMT CTN 1501 study is one of them.

The study recruited 127 patients with aGVHD initially treated with a standard risk and compared the efficacy of sirolimus and prednisone.

The primary endpoints were complete remission (CR) and partial remission (PR) rates on day 28.
The sirolimus group was similar to the prednisone group (64.
8% vs 73.
0%, p=0.
68).

The secondary endpoint was the CR/PR rate with prednisone ≤ 0.
25 mg/kg/d treatment on day 28.
The sirolimus group was better than the prednisone group (66.
7% vs 31.
7%, p<0.
001).

This study introduces a new strategy for the treatment of aGVHD without glucocorticoid therapy.

In the United States, the JAK1/2 inhibitor rucotinib is currently the standard treatment for first-line glucocorticoid-resistant aGVHD.

In China, the anti-interleukin 2 receptor antibody (IL-2RA) monoclonal antibody (basiliximab) is by far the most used second-line aGVHD drug in China.

Currently, new JAK inhibitors and drugs that prevent T cells from being transported to disease targets or T cell activation targets are under development.
If these drugs have therapeutic activity, they may also be used for aGVHD prevention or first-line treatment in the future.

At the same time, researchers are also trying to develop new GVHD prevention or first-line treatment strategies, such as blockade of co-stimulatory signals.

Current status and research progress of cGVHD treatment cGVHD is the main cause of long-term death of recipients after alloSCT, and its first-line treatment is glucocorticoids.

At present, many drugs have significant effects on cGVHD.
In 2017, based on the results of a phase II study of PCYC-1129-CA (NCT02195869) in patients with severe oral and skin cGVHD, Ibrutinib was approved by the FDA for use For the second-line treatment of glucocorticoid-resistant cGVHD.

Dr.
Corey S.
Cutler said that it is expected that before the end of 2021, rucotinib and belumosudil (KD025) will also be approved for the treatment of glucocorticoid-resistant cGVHD.

The multi-center, open-label, randomized phase III REACH3 study included 329 patients with severe glucocorticoid resistance or glucocorticoid-dependent cGVHD who were ≥12 years old and had myeloid lineage after hematopoietic stem cell transplantation (absolute neutrophil count>1000/mm3).
) And platelet (PLT>25000/mm3) implanted patients, compared the efficacy of JAK inhibitor Rucotinib and Best Available Therapy (BAT).

The 6-month ORR of the Rucotinib group was 49.
7% (CR: 6.
7%; PR: 43%), while the BAT group was 25.
6% (CR: 3%; PR: 22.
6%) (P<0.
001).

The median failure-free survival (FFS) of the rucotinib group was significantly longer than that of the BAT group (less than 5.
7 months; P<0.
0001), and the improved Lee symptom score (mLSS) remission rate was significantly higher than that of the BAT group (24.
2% vs.
11.
0%; P=0.
0011).

The pivotal phase II clinical trial (ROCKstar study) of the oral selective ROCK2 inhibitor belumosudil (KD025) for the treatment of cGVHD included 132 patients ≥12 years old who were diagnosed with cGVHD after alloSCT and had previously received 2-5 line therapy.
200mg (200mg QD) once a day or 200mg (200mg BID) twice a day.

At 6 months, the ORRs of the two dose groups were equivalent: 73% (QD) and 77% (BID), respectively, and the Lee symptom score remission rate was 42% and 36%, respectively.

The median duration of remission was 4 weeks, the median duration of remission was 50 weeks, and 60% of patients lasted more than 20 weeks.

The overall survival rate at 12 months was 90% (95% CI: 82%-93%), and the FFS rate was about 58%.

The most common adverse events were fatigue (38%), diarrhea (33%) and nausea (28%).

In addition to rucotinib and belumosudil, a phase I clinical trial of the CSF1R antagonist axatilimab for the treatment of ≥ 2 line cGVHD is also underway.

In addition to the drugs used to treat glucocorticoid-resistant cGVHD, researchers have also used some newer drugs as first-line treatments to reduce the use of glucocorticoids and minimize their toxicity.

Researchers have also developed strategies to prevent cGVHD after transplantation, such as the cyclophosphamide regimen after transplantation, or the preventive use of new drugs before the emergence of cGVHD after transplantation.

Conclusion In the whole course of management of GVHD, in addition to systemic treatment, it is also particularly important to provide supportive treatment to individual organs through local immunosuppression and support measures.

With the continuous improvement of the transplantation technology system, patients have higher and higher demands for the quality of life after transplantation.
Standardizing and optimizing the prevention and treatment of GVHD is very important to increase the success rate of transplantation and improve the survival of patients.
It is hoped that new prevention and treatment strategies can be adopted in the future.
Realize individual precision prevention and treatment of GVHD.

References: [1] Expert consensus on the treatment of hematological diseases in China with allogeneic hematopoietic stem cell transplantation (Ⅲ)—Acute graft versus host disease (2020 edition).
[2] Corey S.
Cutler.
My Thoughts on Current and Future Prophylactic and Therapeutic Strategies for GVHD.
[3] Chronic graft versus host disease (cGVHD) diagnosis and treatment Chinese experts Consensus (2021 edition).
[4] Joseph Pidala, Mehdi Hamadani, Peter Dawson, et al.
Randomized multicenter trial of sirolimus vs prednisone as initial therapy for standard-risk acute GVHD: the BMT CTN 1501 trial.
Blood (2020) 135 ( 2): 97–107.
Written by: Mia J stamped "read the original text", we make progress together