2022 EBMT Research progress of ruxolitinib in the treatment of graft-versus-host disease

Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective method for the treatment of various hematological diseases, and its efficacy has been continuously improved in recent years.
However, graft-versus-host disease (GVHD) is still an important cause of transplantation failure and death.
One of the reasons [1]
.

Hormones have reached a consensus as the first-line treatment for acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD) after transplantation [1,2].
However, there is currently no standard preferred treatment for second-line treatment [1] ,2]
.

Ruxolitinib, a Janus kinase inhibitor, is currently approved by the U.
S.
Food and Drug Administration for the treatment of hormone-refractory aGVHD and cGVHD in adults and children (≥12 years of age) who have failed first- or second-line systemic therapy [3] ]
.

At the upcoming 48th European Society for Blood and Marrow Transplantation (EBMT) annual meeting, a number of research progresses on ruxolitinib in the treatment of post-transplant GVHD will be announced.
Yimaitong will now organize the main content as follows for readers reference
.

Abstract No.
OS10-03 Title: Comparison of the efficacy of ruxolitinib and best available therapy in the treatment of hormone-refractory aGVHD: a post hoc analysis of remission in different involved organs in the REACH2 study Background of the multicenter, randomized phase 3 clinical trial REACH2 ( NCT02913261) showed that in patients with hormone-refractory aGVHD, ruxolitinib improved overall response rate (ORR) at day 28 and durable ORR at day 56 compared with best available therapy (BAT) (key secondary end point; 39.
6% vs 21.
9%)
.

Furthermore, ruxolitinib-treated patients had better ORR at day 28 regardless of aGVHD severity (Figure 1)
.

Figure 1 ORR of ruxolitinib versus BAT in patients with aGVHD in REACH2 Study Methods Patients aged ≥12 years with grade II-IV hormone-refractory aGVHD were randomized to receive ruxolitinib or the investigator's choice of BAT
.

Patients were allowed to cross from the BAT group to the ruxolitinib group on or after day 28
.

Results of the analysis included (1) ORR (complete remission [CR] + partial remission [PR]) at day 28 in patients with different organ involvement, (2) improvement in aGVHD ≥ from baseline to day 28 and day 56 in patients with different organ involvement The proportion of patients with degree 1
.

Odds ratios (ORs), 95% CIs and P values ​​were calculated using the Cochran-Mantel-Haenszel test
.

Results The baseline characteristics of the patients are shown in Table 1
.

Table 1 Baseline characteristics assessing response to treatment for aGVHD involving 4 organs
.

In all affected organ subgroups, ORR at day 28 was improved with ruxolitinib compared with BAT (Figure 2)
.

Figure 2 ORR in patients with aGVHD involving different organs.
Analysis of disease improvement in patients with different organ involvement showed that the proportion of patients with ≥1 degree improvement was higher in the ruxolitinib group (Table 2)
.

Table 2 Proportion of patients with a ≥1 degree improvement from baseline Study Conclusions REACH2 post hoc analysis showed that regardless of the severity of aGVHD, patients with aGVHD receiving ruxolitinib The remission rate obtained with the second-line treatment of Nitrogen is higher than that of BAT
.

Abstract #: OS14-02 Title: Biomarker analysis of efficacy of ruxolitinib or best available therapy in patients with hormone-refractory/dependent cGVHD - an exploratory analysis of the randomized phase 3 REACH3 study background inhibition of Janus kinase 1 The (JAK1)/JAK2 pathway regulates various biomarkers associated with cGVHD
.

Ruxolitinib, a JAK1/JAK2 inhibitor, demonstrated superior efficacy over BAT in REACH3, a randomized phase 3 clinical trial in patients with hormone-refractory/dependent cGVHD
.

This exploratory analysis of the REACH3 study assessed the predictive role of baseline levels of proinflammatory cytokines, cGVHD biomarkers, and immune cell subsets in response to treatment
.

Methods Patients aged ≥12 years with moderate or severe hormone-refractory/dependent cGVHD were randomized 1:1 to ruxolitinib 10 mg twice daily (n=165) or to investigator-selected BAT (n=164)
.

A total of 316 patients had valid biomarkers at baseline
.

Blood samples were collected at baseline, cycle 1 day 1 (C1D1), C1D8, C1D15, C2D1, and C7D1
.

The biomarkers assessed are shown in Table 3
.

Table 3 Biomarkers assessed Patients stratified for response (CR, PR, no response [NR]) to ruxolitinib or BAT at C7D1; biomarker levels assessed by disease severity and key patient characteristics , including organ involvement and aGVHD history at enrollment
.

Changes in biomarker levels over time were analyzed using the ANOVA method
.

RESULTS: In patients with hormone-refractory/dependent cGVHD, baseline levels of proinflammatory cytokines, cGVHD biomarkers, and immune cell markers did not predict overall and organ-specific response, regardless of disease severity
.

Considering the heterogeneity of cGVHD, the predictive value of these biomarkers was assessed while analyzing the impact of patient baseline characteristics on biomarker expression
.

Most findings were consistent with previous analyses; however, among patients with baseline GI involvement, those with lower baseline levels of Reg3A (a marker of GI involvement in aGVHD) after ruxolitinib treatment had lower baseline levels of Reg3A than those with baseline GI involvement.
High patients were more likely to achieve remission (Figure 3)
.

No substantial changes in the levels of most biomarkers were observed in either treatment group over time
.

Figure 3.
Correlation study between baseline Reg3A levels and treatment remission in patients with gastrointestinal cGVHD Conclusions The baseline levels of proinflammatory cytokines, chemokines, and immune cells in patients with hormone-refractory/dependent cGVHD in REACH3 did not predict patient outcomes Treatment remission
.

However, a positive result was found in patients with baseline gastrointestinal involvement that predicted response to ruxolitinib treatment by lower baseline Reg3A levels
.

Overall, this analysis highlights the heterogeneity and complexity of cGVHD and shows that despite the limited value of known blood biomarkers in predicting response to treatment, patients regardless of their baseline inflammatory biomarker levels Potential benefit from ruxolitinib treatment
.

Abstract No.
: P202 Title: Real-world data of ruxolitinib in the treatment of hormone-refractory gastrointestinal aGVHD BackgroundAGVHD involving the lower gastrointestinal tract is a major life-threatening complication in allo-HSCT patients, and is often resistant to glucocorticoids medicine
.

Recently, a phase III study demonstrated higher overall response and failure-free survival rates with ruxolitinib compared with the best available second-line therapy
.

However, these promising results lack real-world data support and external validation
.

METHODS: To determine the outcome of ruxolitinib in patients with gastrointestinal aGVHD, we retrospectively analyzed data from patients with gastrointestinal aGVHD over a 6-year period to determine treatment response and survival outcomes
.

Results: A total of 144 patients with gastrointestinal aGVHD were analyzed, of whom 83 (58%) were steroid-resistant
.

The most commonly used second-line therapy was ruxolitinib (74.
3%)
.

The ORR and CR of patients in the ruxolitinib arm at day 28 in the analysis were 60.
0% and 27.
3%, respectively (Figure 4A), similar to those reported in the REACH2 study
.

At day 56, 31.
6% of patients in the ruxolitinib group achieved durable CR, compared with 16.
7% in the other single-agent groups (Figure 4B)
.

Even after third-line (25.
8%) and fourth-line therapy (25.
0%), approximately one-quarter of patients achieved CR
.

In addition, steroid-resistant GVHD patients had a lower 5-year overall survival (OS) than steroid-sensitive patients (34.
8% vs 53.
3%, p=0.
0014) and a higher cumulative incidence of 12-month recurrence-free mortality (NRM).
high (39.
2% vs 14.
3%, p=0.
016)
.

Interestingly, among patients with hormone-resistant aGVHD, those who achieved a CR at day 28 had a higher 5-year OS compared with those without a response (56.
3% vs 14.
9%, p<0.
0001; Figure 4C), 12-month NRM was lower (13.
8% vs 77.
4%, p<0.
0001), which was comparable to the clinical outcome of hormone-sensitive patients (Fig.
4C)
.

Figure 4 Response rate and overall survival study results of ruxolitinib and other regimens in the treatment of aGVHD This real-world data further confirms the response rate results of ruxolitinib in the REACH2 study as a second-line treatment for hormone-resistant gastrointestinal aGVHD and the results of these patients poor prognosis
.

In addition, data showed improved OS in patients who achieved durable CR with ruxolitinib, suggesting that patients who have failed first-line therapy may still achieve CR with preferred second-line therapy
.

Abstract No.
: P212 Title: Ruxolitinib as an effective and hormone-saving first-line treatment for newly diagnosed BOS patients after HSCT Background Bronchiolitis obliterans syndrome (BOS) is a common cause of cGVHD in patients with cGVHD after allo-HSCT Life-threatening pulmonary complications
.

The standard first-line treatment for BOS is systemic corticosteroids; however, patients with corticosteroid-refractory BOS do not experience significant improvement in lung function
.

In addition, long-term systemic use of hormones can lead to serious complications, such as infections
.

This study retrospectively analyzed the efficacy of ruxolitinib in the first-line treatment of BOS patients
.

Methods: Patients who underwent allo-HSCT for hematological malignancies at the Chinese Institute of Hematology, Chinese Academy of Medical Sciences, and Peking Union Medical College Medical Center from January 2019 to June 2021 were retrospectively analyzed
.

BOS was diagnosed using the National Institutes of Health (NIH) consensus criteria
.

The initial dose of ruxolitinib was 5 mg twice daily followed by a maintenance dose of 10 mg
.

The dose of ruxolitinib can be reduced if serious adverse events occur
.

Hormones or other immunosuppressive agents are added according to the clinical situation
.

In addition to ruxolitinib treatment, all patients received FAM regimen and antifungal prophylaxis
.

Efficacy assessments included symptom relief and disease relief
.

Symptom relief was assessed in the first two weeks after ruxolitinib administration, and was defined as relief of respiratory symptoms, increased peripheral oxygen saturation (SpO2 ≥ 96%), and significant disease improvement on CT scan
.

Disease response to ruxolitinib was assessed at month 3
.

In the assessment of disease response to ruxolitinib, CR was defined when clinical symptoms were significantly relieved and FEV1% predicted value increased by more than 75%; CR was defined when FEV1% predicted value level increased or symptoms improved with stable FEV1% predicted value.
for PR
.

NR was defined as clinical worsening and PFTs, or FEV1% predicted decline to less than 5% with stable symptoms
.

A total of 7 patients with BOS were included in the analysis
.

The median time from HSCT to diagnosis of BOS was 300 days (range, 103 to 489 days)
.

Five patients received hormone therapy concurrently with ruxolitinib
.

The mean initial daily dose of methylprednisolone was 48.
4 mg (range 6-80 mg)
.

Encouragingly, all patients achieved symptom relief within two weeks of ruxolitinib treatment
.

For disease remission, 6 patients (85.
7%) achieved CR and 1 (14.
3%) achieved PR (Figure 5)
.

Figure 5 Symptom remission and disease remission in patients with BOS treated with ruxolitinib as first-line treatment The average predicted value of FEV1% at the time of diagnosis of BOS was 58.
05%, and the predicted value of FEV1% increased to 79.
47% after 3 months of ruxolitinib treatment, indicating that ruxolitinib Cantinib treatment is effective
.

Meanwhile, the hormone dose was reduced to 50% of the initial dose within approximately two weeks (7 to 16 days) and discontinued within two months (23 to 58 days) of ruxolitinib treatment
.

The study concluded that in patients with BOS, first-line treatment with ruxolitinib can achieve significant disease remission, with a CR rate of 85.
7%
.

Notably, first-line ruxolitinib treatment for BOS also significantly shortened the duration of hormone therapy and reduced total hormone doses
.

In addition, ruxolitinib was well tolerated, and no serious infections or recurrences were reported
.

Abstract No.
: P245 Title: Myeloid-derived suppressor cells predict remission of aGVHD after first-line treatment with ruxolitinib and hormones Background aGVHD is still one of the main causes of recurrence-free death after HSCT
.

Systemic corticosteroids are often used as first-line therapy for aGVHD, but nearly 50% of patients with aGVHD become corticosteroid-resistant
.

The combination of ruxolitinib and corticosteroids has been reported to be tolerable in patients with newly diagnosed aGVHD and to improve ORR; however, the best predictors of response to patients are uncertain
.

Myeloid-derived suppressor cells (MDSCs) are a group of myeloid cells with immunosuppressive activity, including myeloid MDSCs (G-MDSCs), monocytic MDSCs (M-MDSCs) and early MDSCs (e-MDSCs)
.

This study focused on the kinetics of MDSC during ruxolitinib combined with hormone therapy in aGVHD and explored the relationship between MDSC and treatment remission
.

Methods Peripheral blood samples from patients undergoing HSCT were prospectively collected for periodic evaluation of post-transplantation MDSC reconstitution
.

Flow cytometry was used to monitor MDSCs at different time points
.

For patients with aGVHD, MDSC rates were also monitored before and after aGVHD treatment (days +3, +7, +14 and +28)
.

The MDSC inhibition assay was performed by co-culturing purified CD8+ T cells and MDSCs isolated from peripheral blood of patients to verify the inhibitory effect of MDSCs on T cell proliferation
.

Results: Significant changes in the kinetics of G-MDSCs were observed during ruxolitinib combined with hormone therapy, and G-MDSCs showed an upward trend after initiation of treatment (P=0.
012)
.

The ratio of G-MDSCs to peripheral blood CD45+ cells was significantly higher on day 3 after aGVHD treatment than before 3 days after aGVHD treatment
.

Compared with G-MDSC, M-MDSC showed a decreasing trend after aGVHD treatment (P=0.
004)
.

The E-MDSC ratio also changed significantly at different time points of aGVHD treatment (P=0.
010, Fig.
6)
.

Figure 6 Kinetic changes of MDSCs In addition, patients who were sensitive to ruxolitinib combined with hormone therapy had significantly higher G-MDSCs after treatment than baseline, while G-MDSCs of patients resistant to combination therapy had no significant changes (Figure 6)
.

In the MDSC inhibition assay, MDSC significantly inhibited T cell proliferation (proliferation index: no MDSC, 9.
24±8.
10 vs with MDSC, 5.
45±4.
05; P=0.
037)
.

Conclusions: For newly diagnosed aGVHD patients, the recovery of MDSC is closely related to the remission of first-line treatment with ruxolitinib combined with hormones
.

Compared with controls, aGVHD patients with lower G-MDSC levels at baseline and 7-21 days after HSCT were more likely to develop resistance to ruxolitinib in combination with corticosteroids
.

The kinetics of MDSC subsets can be used to predict the duration of response in patients to this novel first-line therapy
.

Abstract number: P244 Title: A prospective analysis of the incidence and outcomes of late-onset aGVHD and cGVHD from multiple transplant centers.
Background cGVHD is the most serious late-onset complication of allo-HSCT
.

This study is a multicenter analysis of transplant centers in Regensburg, Mannheim, Dresden, Vienna, Zagreb and Gdansk to analyze cGVHD and late-onset aGVHD (according to 2014 Annual NIH Consensus Criteria) and its impact on transplant-related mortality (TRM), recurrence (R), and OS
.

Methods: Data from 317 patients (296 adults and 21 children) who received allo-HSCT for the first time in participating centers in 2017 were retrospectively analyzed
.

Study endpoints were OS, TRM, and R at last follow-up and second transplant, the latter censored
.

Patients who developed TRM or R before day 100 after allo-HSCT were excluded from the cumulative incidence analysis of cGVHD
.

RESULTS: With a median observation time of 397 days, the cumulative incidence of late-onset aGVHD was 9.
5% and 4.
8% in adult and pediatric patients, respectively (median onset days, 137, range 100-415), whereas at-risk adult patients had a higher incidence of cGVHD.
The cumulative incidence rate was 43.
6% (median days onset, 198, range 68-1051)
.

The onset types of cGVHD could be divided into 45 (41.
3%) new onset, 54 (49.
5%) quiescent and 10 (9.
2%) progressive
.

In adults, the use of ATG (n=137) or post-transplant cyclophosphamide prophylaxis (n=62) compared with standard prophylaxis (n=116) significantly reduced the incidence of cGVHD (33.
3% vs 31.
9% vs 61.
5%, p< 0.
01) (Table 4)
.

Table 4 Incidence of cGVHD and late-onset aGVHD Excluding early mortality (day 100: TRM 7.
6%, R 6.
3%, OS 91.
2%), the remaining 269 patients at risk for cGVHD or late-onset aGVHD started TRM from day 100 The cumulative incidence of patients with aGVHD and cGVHD was significantly higher than those without cGVHD (19.
3% vs 9.
0% vs 5.
4%; p=0.
0036)
.

OS was higher in patients with cGVHD compared with patients without cGVHD (77.
7% vs 61.
1%; log-rank test p=0.
0006; HR 0.
3396, 95% CI 0.
1939-0.
5945); patients with cGVHD had recurrence compared with patients without cGVHD The rate was significantly lower (17.
9% vs 32.
6%; log-rank test p<0.
0001, HR 0.
216, 95% CI 0.
115-0.
405)
.

No significant effect of cGVHD onset type or maximum severity on TRM and R was found
.

The analysis also found that OS was significantly improved in patients with mild and moderate cGVHD compared with patients without cGVHD (mild 94.
3%; moderate 70.
7%; severe 55.
6% vs no cGVHD 61.
1%; p=0.
001; p=0.
0426 ; p=0.
9645)
.

Figure 7 Conclusions analysis of OS studies in adult patients after cGVHD diagnosis shows improved survival with mild and moderate GVHD compared with patients without cGVHD due to reduced recurrence rates
.

In contrast, severe cGVHD has a negative impact on OS, and future goals should focus on preventing severe cGVHD to improve OS and quality of life
.

Interestingly, the prognosis of patients with cGVHD appears to be better compared with data from past cohort studies
.

Abstract No.
: P658 Title: HSCT in Brazil - An Analysis of the Brazilian Public Health Care Database Background The purpose of this study was to analyze the characteristics of patients with HSCT performed in the Brazilian public health system from January 2015 to December 2019
.

The research methods were retrospectively analyzed based on the Brazilian national secondary database DATASUS
.

Data were collected through the "Hospital Information System" (SIH/SUS), and patients were enrolled based on HSCT patients' surgical authorization codes (505010011, 505010020, 505010038, 505010046, 505010054, and 505010062)
.

The management of HSCT-induced complications was analyzed concurrently
.

All procedures were analyzed by year, taking into account parameters such as ICD-10 data, country, and patient characteristics
.

RESULTS: 638, 690, 749, 857, and 929 patients hospitalized for HSCT were registered in 2015, 2016, 2017, 2018, and 2019, respectively, with a mean increase in HSCT procedures of 8.
9%
.

During the same period, 3922, 4479, 4796, 5306, and 5768 patients hospitalized due to complications after HSCT were reported, respectively, with an average annual growth rate of 9.
16%
.

Acute myeloid leukemia (27%) and acute lymphoblastic leukemia (24%) (ICD-10 C29.
0 and C91.
0, respectively) were the most common ICD-10 disease names that led to patients undergoing HSCT
.

The most common type of HSCT was related allo-HSCT (44%)
.

Most patients were male (59%), and the most common age group was 0-19 years (34%)
.

The states with the highest numbers of HSCT surgeries and hospitalizations in Brazil are São Paulo (51% and 54%, respectively), Paraná (14% and 11%), and Pernambuco (9% and 14%)
.

GVHD (12%) and unidentified pain (10%) were the main causes of hospitalization for HSCT-related complications, and the majority of patients were male (58%), and the predominantly affected age group was patients aged 10 to 29 years (39%)
.

CONCLUSIONS This analysis shows that in the Brazilian public health system, with the increase in HSCT procedures for the treatment of blood disorders, the number of hospitalizations to manage HSCT complications also increases
.

In addition, obtaining more precise data on HSCT-related events may allow for a more complete understanding of local conditions; this may have direct implications for the planning and implementation of more effective actions to improve patient outcomes
.

The DATASUS database is an important open source source of publicly available HSCT data, and wherever specific indicators and other variables are missing, the Brazilian Society for Bone Marrow Transplantation (SBTMO) registry study is a powerful option for addressing all aspects of HSCT
.

References: [1] Stem Cell Application Group, Hematology Branch of Chinese Medical Association.
Expert Consensus of Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Diseases in China (Ⅲ) - Acute Graft Versus Host Disease (2020 Edition) [J].
Zhonghua Blood Journal of Science, 2020, 41(07):529-536.
[2] Hematopoietic Stem Cell Application Group of Hematology Branch of Chinese Medical Association, Hematology Transformation Committee of China Anti-Cancer Association.
Diagnosis and treatment of chronic graft-versus-host disease (cGVHD) Chinese expert consensus (2021 edition)[J].
Chinese Journal of Hematology, 2021, 42(4): 265-275.
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The 48th Annual Meeting of the EBMT.
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The 48th Annual Meeting of the EBMT.
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The 48th Annual Meeting of the EBMT.
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