The international perspective | Professor Mark A. Schroeder analyzes the three major research advances in GVHD

Allogeneic hematopoietic stem cell transplantation (alloSCT) is widely used in the treatment of blood system diseases, and even the only cure for certain diseases.

Graft versus host disease (GVHD) is the most important complication after transplantation and the main cause of death after transplantation.
Therefore, prevention and treatment of GVHD is extremely important to ensure the success of transplantation and long-term survival after transplantation.

Recently, Dr.
Mark A.
Schroeder, Associate Professor of Oncology, Washington University School of Medicine in St.
Louis, selected 3 GVHD-related research progress reported at the 2020 American Society of Hematology Annual Meeting (ASH 2020), and analyzed the research results.

Progress in the treatment of chronic GVHD Chronic graft-versus-host disease (cGVHD) is the main cause of long-term death of recipients after alloSCT, and its first-line treatment is glucocorticoids.

After alloSCT, up to 70% of patients will develop cGVHD, and about 50% of them respond to standard treatment with glucocorticoids.

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 the second-line treatment of glucocorticoid-resistant cGVHD.

However, due to the lack of large randomized phase III studies, there is no standard second-line treatment for glucocorticoid-resistant cGVHD.

Therefore, cGVHD patients who have failed glucocorticoid therapy lack effective treatment options.

The REACH3 study Zeiser and colleagues reported the results of the randomized phase III REACH3 study of the JAK inhibitor Rucotinib vs.
Best Available Treatment (BAT) at the ASH 2020 meeting.
The study included 329 patients with severe glucose ≥12 years old.
Patients with corticosteroid resistance or glucocorticoid-dependent cGVHD, and myeloid and platelet implantation after hematopoietic stem cell transplantation.

The patients were randomly divided into two groups and received rucotinib/BAT+glucocorticoid ± calcineurin inhibitor (CNI) treatment.

The primary endpoint is the overall response rate (ORR) at 6 months, and the secondary endpoints include the failure-free survival rate (FFS) at 6 months and the modified Lee symptom score (mLSS).

The 6-month ORR of the Rucotinib group was 49.
7%, while the BAT group was 25.
6% (odds ratio [OR]: 2.
99; P<0.
001), and most of the patients had partial remission (PR; 43.
0% vs 22.
6%) .

The median duration of response (DOR) in the BAT group was 6.
24 months, while the median DOR in the rucotinib group was not reached.

The best ORRs of the Rucotinib group and the BAT group were 76.
4% and 60.
4% (OR: 2.
15), respectively.

The median FFS of the rucotinib group was significantly longer than that of the BAT group (less than 5.
7 months; HR, 0.
370 [95% CI, 0.
268-0.
510]; P<0.
0001), and the remission rate of mLSS was significantly higher than that of the BAT group (24.
2%) vs 11.
0%; OR, 2.
62; P=0.
0011).

The safety of rucotinib is similar to previous reports in acute GVHD.

In the REACH3 study, 37.
6% and 16.
5% of the rucotinib group and 16.
5% of the patients in the BAT group adjusted their dosage due to AE, and 16.
4% and 7.
0% of the patients discontinued the drug due to AE.

In the rucotinib group and the BAT group, the most common hematological adverse events (≥15%) were anemia (29.
1% vs 12.
7%) and thrombocytopenia (21.
2% vs 14.
6%). Dr.
Schroeder pointed out that compared with the BAT group, the incidence of fungal infections in the rucotinib group was higher (11.
5% vs.
5.
7%).
Therefore, patients receiving rucotinib treatment should be closely monitored for fungal infections, and Consider preventing fungal infections before starting treatment.

Dr.
Schroeder said that the REACH3 study is the first randomized controlled study to successfully treat patients with cGVHD who have failed glucocorticoid therapy.
The results of the study show that rucotinib is better than the best available in patients with cGVHD who have failed glucocorticoid therapy.
The treatment achieved higher ORR, longer FFS and better symptom improvement, and the safety was in line with expectations.

The results of ROCKstar's pivotal clinical trial (ROCKstar study) for the treatment of cGVHD with an oral selective ROCK2 inhibitor belumosudil (KD025) was also announced at ASH 2020.
The study is an ongoing randomized, multicenter, open-label phase II study , Included 132 patients ≥12 years old who were diagnosed with cGVHD after alloSCT and had received 2-5 treatments in the past.

The median age of the enrolled patients was 56 years, the median number of previous treatment lines was 3, and 67% of patients had severe cGVHD.

About 50% of patients have at least 4 organs involved, and most of them are resistant to the last-line treatment.

The enrolled patients were randomly assigned to receive belumosudil 200 mg once a day (200 mg QD) or 200 mg twice a day (200 mg BID).

The primary endpoint is ORR at 6 months; secondary endpoints include safety, DOR, Lee symptom score, and survival rate.

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 time to remission was 4 weeks, and the median DOR was 50 weeks.

78% (n=74) of patients who had previously failed ibrutinib treatment, and 68% (n=38) of patients who had previously received rucotinib treatment responded to belumosudil treatment.

The safety of belumosudil is acceptable and in line with expectations.

Adverse events with an incidence of ≥20% included fatigue (38%), diarrhea (33%), nausea (31%), cough (28%), and upper respiratory tract infection (27%).

Grade ≥3 adverse events with an incidence of ≥5% include pneumonia (n=10), hypertension (n=8), and hyperglycemia (n=6).

Reactivation of Epstein-Barr virus and cytomegalovirus occurred in 2 patients.

67% (n=89) of patients had drug-related adverse events, and 5% (n=7) had serious adverse events.

There were 8 deaths in the study (4 for each of the two dosing regimens).

The death in the QD group was attributed to aspiration pneumonia, hemoptysis, multiple organ dysfunction syndrome/septic shock, or recurrence of acute myeloid leukemia (1 case each).

Death in the BID group was attributed to cardiac arrest (n=2), infection (n=1), or respiratory failure (n=1).

Dr.
Schroeder pointed out that in the ROCKstar study, belumosudil has shown clinically significant efficacy in cGVHD patients treated with 2-5 lines, and its safety is consistent with previous reports.

In all key subgroups and all affected organ systems (including fibrotic diseases), more than 70% of patients achieved remission (see figure below).

Moreover, belumosudil is also effective for patients who have previously failed ibrutinib treatment and for patients who have previously received rucotinib treatment.

In addition, the results of the survival analysis are also very encouraging, with a 12-month FFS of 58% and a median DOR of 50 weeks.

Research progress in GVHD prevention Acute GVHD (aGVHD) is a common complication after alloSCT, and the JAK inhibitor ruginib has been approved by the US FDA for the treatment of glucocorticoid-resistant aGVHD.

However, whether JAK inhibitors can be used for the prevention of GVHD is not yet known.

Although early use of JAK inhibitors is feasible, the main problem is the off-target effect of stem cell regeneration after alloSCT.

There are two studies on ASH 2020 that discussed this issue.
Dr.
Schroeder mainly introduced the larger of the two studies-GRAVITAS‑119 study: it evaluated the efficacy of itacitinib (a new selective JAK1 inhibitor) for the prevention of aGVHD .

GRAVITAS-119 Study The GRAVITAS-119 study is a single-arm, open-label Phase I clinical trial that recruited 65 patients with hematological malignancies ≥18 years of age who are suitable for reduced-intensity pretreatment and/or alloSCT.

Enrolled patients received Itacitinib (200 mg, QD) + tacrolimus (Tac) / methotrexate (MTX) or cyclosporin A (CsA) / mycophenolate mofetil (MMF) ± antithymocyte globulin ( ATG) treatment.
On the 90th day after transplantation, the dose of Itacitinib was reduced to 100 mg for 90 days, and then the dose was gradually reduced (as shown below).

The patients’ GVHD and OS were followed up for 6 months.

The primary endpoint is the patient's hematological recovery rate on day 28, defined as 3 consecutive absolute neutrophil count (ANC) ≥500/mm3, platelet count ≥20,000/mm3 and no platelet transfusion in the first 3 days.

Secondary endpoints include GVHD-free recurrence survival (GRFS), transplant-related mortality, OS, aGVHD and cGVHD, and safety.

On the 28th day, about 98.
5% of the patients achieved ANC and platelet recovery, and all patients achieved hematological recovery on the 31st day.

The median time for ANC recovery was 17 days, and the median time for platelet recovery was 14 days.

As shown in the table below, the incidence of grade III/IV aGVHD is lower in patients with reduced intensity pretreatment, which is about 5% in the ATG group and the non-ATG group.

At 12 months, the incidence of moderate to severe cGVHD in the ATG group and the non-ATG group were 10.
4% and 31.
3%, respectively, and the GRFS rates were 60.
9% and 23.
1%, respectively.
The 12-month OS estimates of the two groups were similar (82.
6% vs.
74.
3%).

Dr.
Schroeder pointed out that due to the small number of study samples, it is necessary to carefully interpret the results of the study, but the 12-month recurrence or progression rate does not seem to be affected.

In terms of safety, the most common hematological adverse events of grade ≥3 included thrombocytopenia (49.
3%), anemia (29.
2%), and decreased blood cell count (29.
2%).
Eight patients (12.
3%) developed ≥3 Grade febrile neutropenia.

The most common non-hematological adverse events of grade ≥3 included diarrhea (15.
4%), hypertension (13.
8%), and hypertriglyceridemia (12.
3%).

23.
1% of patients had dose adjustment or discontinuation due to adverse events.

Dr.
Schroeder mentioned that the use of JAK inhibitors after alloSCT in the REACH3 study resulted in an increased risk of infection, but in this small study, the risk of viral, bacterial or fungal infections did not seem to increase after Itacitinib treatment.

Nevertheless, all grades of cytomegalovirus infection were observed in both the ATG group and the non-ATG group.

In this study, 2 patients had secondary transplantation failure and had to undergo a second transplant: 1 patient with myelodysplastic syndrome received an 8/8-matched unrelated donor transplant, and 1 patient with acute lymphoma Patients with cell lymphoma received 8/8 matched related donor transplants.

The results of the GRAVITAS-119 study showed that after reducing the intensity of pretreatment with alloSCT, the JAK1 inhibitor Itacitinib can be safely used in combination with a calcineurin inhibitor-based regimen for the prevention of GVHD.

Although the number of patients is small, the preliminary data of the study suggests that the incidence of severe aGVHD (approximately 5%) on the 180th day after transplantation may be reduced.

Dr.
Schroeder pointed out that although the intensity of pretreatment for transplantation from unrelated donors was reduced, it is worrying that there are still 2 patients with secondary transplantation failure, which requires further follow-up evaluation.

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