Updates in chronic graft‐versus‐host disease management

Chronic graft‐versus‐host disease (cGvHD) remains the most important long‐term complication of allogeneic hematopoietic cell transplantation (allo‐HCT), but the field has seen significant changes in the last decade. Remarkable advances in the understanding of the biological pathways of cGvHD, lead to the development of targeted therapy with novel drugs thereby minimizing the exposure to harmful corticosteroids, preserving function and mobility, preventing disability, and improving quality of life (QoL) and overall survival (OS). Steroid‐refractory cGvHD management has recently experienced significant improvement since ibrutinib and ruxolitinib were approved for patients that failed at least one line of treatment and belumosudil for patients that failed two lines. These recently approved drugs will be discussed in this review, along with perspectives regarding cGVHD management and additional promising drug in development.

12 years. Centers reported that cGvHD was the most common (37.8%) cause of NRM and was associated with organ failure, infection, or additional causes not otherwise specified. Severe skin and lung cGvHD manifestations were associated with increased NRM which increased without plateau. 1

| PATHOGENESIS OF CHRONIC GVHD INVOLVES INFLAMMATORY AND FIBROTIC PATHWAYS
Chronic GvHD is a result of complex mechanism and often involves inflammatory and fibrotic pathways. The initial biologic phase is characterized by early inflammation due to injury of the host tissue; the release of inflammatory cytokines stimulates the activation of donor alloreactive T cells causing further cytotoxicity to host target cells. In the second phase, it is characterized by injury to the thymus and downstream loss of central and peripheral tolerance. There is a loss of regulatory T and B cells and emergence of auto and alloreactive T cell populations. This can lead to chronic inflammation by active T-helper 17 (Th17) cells as they may escape immune regulation. The third phase is heralded by abnormal tissue repair. Activated macrophages stimulate the production of transforming growth factor beta and platelet-derived growth factor alpha which can lead to fibroblast activation resulting in fibrotic phenotypes of cGvHD such as scleroderma or bronchiolitis obliterans syndrome. 2

| STANDARDIZING DIAGNOSIS AND GRADING OF CGVHD
The National Institutes of Health (NIH) Chronic GvHD projects of 2005

| CHRONIC GVHD TREATMENT CONSIDERATIONS
The ideal treatment for cGvHD remains elusive and clear guidelines for treatment and management are lacking but goals of therapy should focus on clinical efficacy including symptom burden reduction and prevention of progression to organ involvement by cGvHD. Prevention of fibrosis and disability increase the ability to withdraw immunosuppression while maintaining a response and improving QoL and survival. Other important treatment considerations include an acceptable drug safety profile, a mode of delivery (central line access, IV infusion, injection, pill) that is convenient for patients, and healthcare providers, patient compliance, and of course cost to both patient and healthcare system. The response rate is about 50% over 2-3 years, with greater than half of the patients requiring second-line therapy within 2 years. At 6 months, <40% of patients are alive, without malignancy, on lower doses of steroids, and without additional treatment for cGvHD.

| STANDARD FIRST-LINE THERAPY
Despite these modest response rates, randomized trials that have evaluated the addition of other conventional agents (ciclosporin, azathioprine, or thalidomide) to standard corticosteroids, did not show improved patients' outcomes. [5][6][7] Furthermore, corticosteroids are associated with significant toxicities including infection, muscle weakness, bone loss, avascular necrosis, cataracts, mood changes, hyperglycemia, and other short-and long-term side effects. Most patients will require therapy beyond steroids.
In addition, for patients with bronchiolitis obliterans syndrome, use of the fluticasone, azithromycin and montelukast regimen, combining fluticasone (440 μg twice daily), azithromycin (250 mg three times weekly), and montelukast (10 mg daily) is recommended. Of note azithromycin has been associated with an increased risk of relapse of the underlying malignancy, therefore its continuation must be reassessed on a regular basis and it must be discontinued as soon as the bronchiolitis obliterans syndrome is resolved.  Once-daily oral ibrutinib was tested in a phase Ib/II trial (NCT 02195869) at a dose of 420 mg (recommended dose based on phase I) in 42 patients with steroid-dependent/refractory cGvHD consisting mainly of inflammatory features of cGvHD (Table 1). Patients had either >25% BSA erythematous rash or an NIH mouth score >4. The primary efficacy endpoint was cGvHD response based on 2005 NIH criteria. The overall response rate (ORR) was 67% with a complete response (CR) rate of 21% and a partial response (PR) rate of 45% and approximately 71% of responders continued to show a sustained response for at least 20 weeks. The results of this trial led in August T A B L E 1 Outcomes of the main studies evaluating ibrutinib, ruxolitinb and belumosudil in chronic graft-versus-host disease (cGVHD).     In this pivotal randomized trial, belumosudil was well tolerated, with no new safety signals. The most common grade 3 or higher AEs were pneumonia (8%), hypertension (6%), and hyperglycemia (5%).
Responses were seen in patients who had previously received ruxolitinib and ibrutinib. 17 Furthermore, 59 patients with cGVHD of the lung or bronchiolitis obliterans syndrome (BOS), 24 a particularly high-risk disease manifestation associated with poor outcomes, were identified among the two prospective clinical trials of belumosudil. 16,17 According to NIH response criteria, the best ORR for lung cGVHD was 32% (PR: 17%; CR: 15%). Response rates were inversely proportional to baseline NIH GVHD lung score at enrollment (lung score 1: ORR 50%; lung score 2: ORR 17%, lung score 3: ORR 0%) ( p = .006).

| Extracorporeal photopheresis
ECP is a cell-based immunotherapy that involved the reinfusion of autologous mononuclear cells after exposure to 8-methoxypsoralen and ultraviolet A (UVA) light irradiation. ECP was compared to conventional immunosuppressive treatment in a multicenter randomized study that included 95 patients with steroid-refractory or steroiddependent cGVHD. 25 At week 12, the median targeted symptom assessment scores improved in the ECP arm by 19% compared with 2.5% in the control arm ( p = .01). The ORR at week 12 in skin was 40% in the ECP arm compared to 10% in the control arm ( p = .002).
Best ORRs were observed in oral mucosal involvement with 53% in the ECP arm and 27% in the control arm, respectively ( p = .06), while for joint symptoms, improvement was noted in 22% versus 12% (ECP vs. control; p = .66). Of note, by week 12 at least a 50% reduction in steroid dose and a daily steroid dose below 10 mg were achieved in 21% of patients in the ECP cohort and 6% of the control (p = .04).
The incidence of infection was 53.1% in the ECP arm versus 44% in the control arm ( p = .42). Overall, this randomized study highlights the safety and efficacy of ECP in particular in skin and oral mucosal involvement.

| Anti-CD20 monoclonal antibodies
Anti-CD20 monoclonal antibodies, that target CD20+ B cells were also investigated in steroid-refractory cGVHD. In a prospective phase I/II study that included 21 patients with steroid-refractory cGVHD treated with rituximab, the clinical response rate was 70%, including 2 patients with CRs. 26 Of note, responses were limited to patients with cutaneous and musculoskeletal manifestations of chronic GVHD and were durable through 1 year after therapy.
Another study phase II study compares rituximab (n = 37) to imatinib (n = 35) for cGVHD with cutaneous sclerosis. 27 At 6 months, a significant clinical response was reported in 27% of patients treated with rituximab versus 26% of patients treated with imatinib.
Overall, rituximab may be a valuable option in patients with manifestations of cGVHD limited to the skin and the musculoskeletal system. Corticosteroid-free first-line treatment with rituximab was also investigated in a phase II study (n = 25). 28 The best ORR was 88% and cGVHD recurrence rate was 37% at a median of 166 days (range, 21-393 days). We also investigated in a phase II clinical trial (n = 24), rituximab combined with steroids for first-line treatment of cGVHD. 29 The ORR at one year was 83%, and among 19 evaluable patients, 14 (74%) were off steroids. Similarly, another anti-CD20 monoclonal antibody, ofatumumab, was investigated for first-line treatment of cGvHD in association with steroids (n = 38). 30 The ORR at 6 months was 62.5%, and FFS was 64.2% (95% CI 46.5%-77.4%) at 6 months and 53.1% (95% CI 35.8%-67.7%) at 12 months.

| Axatilimab
Axatilimab is a novel drug currently under study. It targets a different pathway than other cGvHD treatments. It is an IgG4 humanized monoclonal antibody. Colony stimulating factor-1 (CSF-1) has been shown to promote the growth and differentiation of donor-derived monocytes into macrophages (via signaling through its receptor [CSF-1R]), which in turn, promotes fibroblast activation and collagen production resulting in various manifestations observed in patients with cGvHD. Axatilimab has a high affinity to bind with CSF-1R which may reduce the number of these pro-inflammatory macrophages and play a meaningful role in the treatment of cGvHD. Axatilimab administered by IV infusion has shown clinical activity and was well-tolerated in a phase I study. 15

| FUTURES PERSPECTIVES
In November 2020, the 3rd NIH Chronic GvHD Consensus Conference sent a forward-thinking agenda to address gaps and needs and future cGvHD research over the next 3-7 years. 35

| Preemptive therapy (Working Group 2b)
This group was tasked with identifying knowledge gaps in how best to assess risk and prevent or preempt cGvHD. "Preemption" is defined as intervention planned after transplant in a patient who is found to be at increased risk, most likely by biomarkers, for the development of moderate or severe cGvHD. For such strategies to become a reality in clinical practice, they concluded that it is necessary to develop methods for timely and reliable prediction of who will develop moderate or severe cGvHD and that highly predictive, risk assignment biomarkers were necessary to identify patients who need preemptive treatment. They observed the need to develop therapeutics that target multiple pathways in cGvHD and that it is necessary to ascertain new endpoints in clinical trial design for preemptive therapy of cGvHD. 16

| Treatment of cGvHD (Working Group 3)
The aims of this Working Group were to foster and support the need to develop frontline treatment regimens that involve minimal or no use of corticosteroids. They emphasized the importance of developing individualized therapeutic approaches to determine which agent would be effective in a given patient, and of avoiding cumulative toxic treatments as occurs in the current "trial and error" paradigm. The importance of biological correlates to study the disease, the mechanism of action of the drug and the response of the disease to the drug were also part of this Group's remit.

| Highly morbid forms (Working Group 4)
Working Group 4 reviewed highly morbid forms of cGvHD, such as lung, skin sclerosis, and ocular disease, that pose a special challenge due to their rare and recalcitrant nature. They focused on better phenotyping of these forms of cGvHD in cohort studies and recommended new treatment approaches with a focus on a better understanding of fibrosis in cGvHD biology which has identified several promising new targets and combination approaches to be tested. Realistic endpoints were deemed necessary in clinical trials of these highly morbid forms including patient-reported outcomes, function, or disability.

| SUMMARY
Chronic GvHD remains the most important long-term complication of allo-HCT, but the field has seen significant changes in the last decade.
There are uniform diagnostic, grading, and response criteria; novel clinical trial designs and endpoints that have allowed investigators to successfully study the effects of new cGvHD therapeutics, and improved supportive care. There have been remarkable advances in the understanding of the biological pathways of cGvHD, leading to the development of targeted therapy with novel drugs approved for steroid-refractory cGvHD. Ibrutinib and ruxolitinib can thus be given as second-line treatment, nevertheless, the high incidence of invasive fungal infection and poor real-life outcomes with ibrutinib make ruxolitinb the favored treatment. Belumosudil is then approved for patients that failed ≥2 lines of systemic therapy.
Furthermore, in order to minimize the exposure to harmful corticosteroids, addition of ibrutinib to steroids was evaluated in the front-line setting with a negative result. Nevertheless, ruxolitinib and belumosudil remain alternative promising agents to be evaluated in the front-line to minimize the exposure to harmful corticosteroids, preserve function and mobility, prevent disability, and improve QoL and OS.

SEARCH STRATEGY AND SELECTION CRITERIA SECTION
We searched PubMed, Embase, and the Cochrane Library for articles and reviews in the English language published between January 1, 2018, and February 21, 2023, although older references were also used when appropriate. We used the search terms "chronic graft-versus-host disease", and "hematologic malignancies" and "allogeneic hematopoietic cell transplantation". We reviewed the abstracts and retrieved the full texts of articles, which were published in English and deemed relevant. We also searched the reference lists from articles and reviews identified by the search. The final reference list was generated on the basis of originality and relevance to the scope of this Review.