<h2>What molecular pathways are implicated in cGVHD?</h2>
Several pathways have been shown to be key mediators of disease progression in chronic graft-versus-host disease.1

The rho-associated coiled-coil–containing protein kinase (ROCK) molecular pathway plays a key role in immune and fibrotic disease.2,3&nbsp;Additionally, ROCK is downstream of major profibrotic mediators and regulates multiple fibrotic processes, such as myofibroblast activation and profibrotic gene transcription.3 ROCK2, specifically, is involved in both the inflammatory and fibrotic components of cGVHD and has been shown to play an important role in modulating immune homeostasis.2 
 Selective ROCK2 inhibition has been shown to help resolve immune dysregulation by downregulating pro-inflammatory T helper (Th) 17 cells and increasing regulatory T (Treg) cells.2&nbsp;Furthermore, selective ROCK2 inhibition has been shown to downregulate key fibrotic processes, such as TGF-β and LPA, leading to a decrease in fibrosis and collagen deposition.3-5

ROCK

black

Following HCT, B-cell homeostasis and tolerance mechanisms are disrupted, resulting in reduced memory B-cell formation.6&nbsp;These host-reactive B cells are associated with the development of cGVHD.7 
 BTK is a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways,8&nbsp;which is expressed mainly in B cells and other hematopoietic tissues.9&nbsp;Signaling via BTK results in the activation of pathways necessary for B-cell trafficking, chemotaxis and adhesion.8

JAK1 and JAK2 are signal mediators of several cytokines and growth factors that are necessary for hematopoiesis and immune function. STATs are recruited to cytokine receptors during JAK signaling, leading to modulation of gene expression.10 In cGVHD pathogenesis, JAK-STAT molecular pathways regulate the development, proliferation and activation of various immune cell types.10

IL-2, a cytokine signaling molecule, is essential for normal Treg cell development, expansion, activity and survival. CD4+&nbsp;Treg cells play a role in immune tolerance and controlling immune responses.&nbsp;Impaired Treg cell function is characteristic of cGVHD and is associated with loss of tolerance and autoimmunity.11

IL-2

Research continues to uncover the role of these pathways.

Learn more about inflammation and fibrosis

What manifestations are caused by the activation of these pathways?

Abbreviations

References

Molecular Pathway

CHRONIC-GRAFT-VERSUS-HOST-DISEASE-CGVHD

TRANSPLANT

<h2>HOW CAN THE TREATMENT PARADIGM OF cGVHD BE OPTIMIZED?</h2>
The lack of standardized treatment and response biomarkers, as well as the variability of the disease from person to person, impedes the goals of extending survival and improving QOL.1

with systemic corticosteroids, with or without CNIs, is well established in patients with chronic graft-versus-host disease.2-4

First-line therapy

Second-line therapy 
 may be required for approximately 70% 
 of patients with cGVHD.5

Second-line therapy

may be required for approximately 50% 
 of those patients, with many progressing to later lines of therapy.5

Third-line therapy

Both corticosteroids and CNIs may provide effective initial therapy for cGVHD. However, prolonged systemic use of either can cause significant toxicities.2
Toxicities associated with prolonged corticosteroid use include2

<ul>
 <li>Weight gain</li>
 <li>Bone loss&nbsp;</li>
</ul>

<ul>
 <li>Myopathy</li>
 <li>Diabetes&nbsp;</li>
</ul>

<ul>
 <li>Hypertension</li>
 <li>Mood swings</li>
</ul>

<ul>
 <li>Cataract formation</li>
 <li>Increased risk of infection</li>
</ul>

Toxicities associated with prolonged CNI use include6

<ul>
 <li>Metabolic abnormalities</li>
</ul>

Corticosteroids should be tapered to allow for the lowest dose that adequately controls cGVHD. Once cGVHD is controlled, corticosteroids should be withdrawn, followed by withdrawal of CNIs.2&nbsp;For these patients who are unable to tolerate prolonged exposure, a more targeted approach may be required.3,4,6,7
As patients progress to later lines of therapy, the focus of treatment becomes stabilizing the condition while limiting AEs and maintaining QOL.6,8

<div>
 A treatment paradigm that allows for the right treatment for the right patient at the right time may better address the manifestations of cGVHD.
</div>

Learn more about other treatment options

If initial therapy is not enough, what is the next step?

Optimizing Treatment

<h2>What is the Pathogenesis of cGVHD?</h2>
Chronic graft-versus-host disease is a complex multisystem disorder caused by an immune imbalance following an allogeneic HCT, which leads to serious and potentially life-threatening complications from both inflammatory and fibrotic processes. cGVHD is mediated by multiple immune pathways and is characterized by1

Early inflammation due to tissue injury

Chronic inflammation and a dysregulated adaptive immune system

Chronic graft-versus-host disease presents multiple challenges for both clinicians and patients, specifically through manifestations of inflammation and fibrosis.
Although advances have been made in the understanding of cGVHD, many questions still remain.

Understanding the manifestations of cGVHD

What roles do the inflammatory and fibrotic processes play in cGVHD?

cGVHD is a significant burden on patients, affecting them physically, mentally, emotionally and financial

What is the full impact of cGVHD on patients' lives?

How targeting alternative molecular pathways may offer a different treatment approach

What is under clinical development?

cGVHD,chronicgraft-versus-hostdisease.
Although the understanding of the pathophysiology of cGVHD is improving, there is still much to be uncovered about the nature of the inflammatory cascade and the complex dynamics of the inflammatory and fibrotic processes.
Improving comprehension of these manifestations could help in the development of more targeted treatments.

Learn more about ROCK, BTK, JAK and IL-2

What molecular pathways are implicated in cGVHD?

Reference

Understandig cGVHD

<h2>cGVHD has a significant impact on the overall well-being of patients</h2>
cGVHD impacts patients' QOL
The&nbsp;inflammation and fibrosis&nbsp;associated with chronic graft-versus-host disease lead to multiple physical ailments, some of which include

Skin thickening or tightening, as well as painful rashes and lesions on the skin1-3

Joint stiffness and loss of mobility and dexterity2

Lung function impairment, which leads to significant 
 morbidity3-6

Results from multiple studies show that patients with cGVHD reported significantly worse QOL,&nbsp;as measured by various tools, such as the Lee Symptom Scale, the SF-36 and the FACT-BMT.7,8 
 A multicenter, prospective, observational cohort study evaluated 298 patients with cGVHD. When compared with age- and sex-matched US population normative data, patients with cGVHD had significantly lower scores, as measured by the SF-36 and the FACT-BMT, for8

When comparing mean SF-36 scores of patients with moderate to severe cGVHD with those of other chronic health conditions, patients with cGVHD had PCS comparable with8
✓ Systemic sclerosis ✓ Systemic lupus erythematosus ✓ Multiple sclerosis
Patients with moderate to severe cGVHD also showed greater impairment when compared with other conditions, including8
✓ Chronic lung disease ✓ Hypertension ✓ Diabetes ✓ Arthritis
Fibrosis, in particular, has a negative effect on QOL, especially when affecting the joints or extensive areas of the skin.2,9 This can lead to chronic disability and, in cases where fibrosis spreads to organs such as the lungs, significant mortality.4-6

Impact on Patients

<h2>WHAT ARE OTHER TREATMENT OPTIONS?</h2>
There are several adjunctive options for the treatment of patients with chronic graft-versus-host disease, including targeted therapies and ECP. However, there is currently limited guidance regarding when each should be considered and for which patients these treatments will be most effective.1-4

ECP is a nonpharmacologic immunomodulatory therapy that involves leukapheresis of patient peripheral blood mononuclear cells, exposure of the cellular product to UV-A light in the presence of 8-methoxypsoralen and reinfusion of the ex vivo–treated cells.1 
 The mechanisms of ECP are not completely understood, although it is believed that ECP suppresses alloimmune responses by altering the maturation and function of dendritic cells, as well as through the induction of Treg cells.1&nbsp;The procedure has shown benefit in patients with steroid-refractory cGVHD,1&nbsp;as well as in those with skin, oral, and liver cGVHD.5 
 ECP requires venous or central access and involves a variety of treatment schedules to identify the appropriate dose intensity and length of treatment.6

BTK inhibitors form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. Nonclinical studies have shown that this class of drug inhibits the proliferation and survival of malignant B cells in vivo, as well as cell migration and substrate adhesion in vitro.3&nbsp;Some BTK inhibitors also inhibit IL-2–ITK, which is highly expressed in T cells and is closely related to BTK.1 
 Both B and T cells play important roles in the pathogenesis of cGVHD,7&nbsp;and the inhibition of BTK and ITK has shown clinical benefit.1,7 
 Warnings and precautions associated with BTK inhibitors include infections and cytopenias, which include thrombocytopenia, neutropenia and anemia.3

BTK inhibitors

JAK1 and JAK2 mediate receptor signaling for a variety of pro-inflammatory cytokines, which are elevated in cGVHD.1 
 Inhibitors of this pathway have been shown to decrease expression of inflammatory cytokines and reduce GVHD in murine models,1,2&nbsp;as well as suppress activation and differentiation of dendritic cells and T cells.1&nbsp;This approach has shown promising results in patients with steroid-refractory cGVHD.1,8 
 Safety considerations associated with JAK inhibitors include monitoring for pruritus, infections, thrombocytopenia and leukopenia.8

JAK inhibitors

A greater number of treatments that address both the inflammatory and fibrotic processes of cGVHD are needed.

Learn more about potential targeted options

Are there new approaches to the treatment of cGVHD under clinical development?

Other Treatment Options

<h2>WHAT ROLES DO THE INFLAMMATORY AND FIBROTIC PROCESSES PLAY IN cGVHD?</h2>
Chronic graft-versus-host disease is characterized by a combination of tissue inflammation and fibrosis, which manifest across multiple organ systems.1-4 
 The relationship between these 2 processes in cGVHD is complex and not fully understood.3&nbsp;Fibrosis may be viewed as a natural consequence of inflammation, as an independent process or as interrelated with inflammation in some ways but not completely dependent on it.5

Because of chronic inflammatory changes, cGVHD can present with collagen-producing fibroblasts,2 resulting in fibrotic lesions.2,4
Fibrotic lesions can develop across multiple organs4

SKIN

MOUTH

JOINTS

EYES

GI TRACT

ESOPHAGUS

LIVER

LUNGS

Fibrosis is a major contributor to life-threatening complications and significant morbidity.6

<h3>Patients develop multiorgan manifestations, including skin, mouth, joint/fascia, eye, upper and lower GI tract, esophagus, liver, genitourinary and/or lung manifestations.4,7,8</h3>

Skin manifestations are the most common, occurring in

Approximately half of patients have lung involvement,

which can manifest as bronchiolitis obliterans, a fibrotic manifestation that can be especially difficult to treat.

<div>
 Although the inflammation associated with cGVHD can be addressed, there is limited evidence regarding the impact of current treatments on fibrosis.10-15
</div>

Learn more about patient quality of life

How do inflammation and fibrosis affect patients’ lives?

Learn more about current treatment options

What treatments are currently available for cGVHD?

Inflammation and Fibrosis Role

<h2>WHAT TREATMENTS ARE UNDER CLINICAL DEVELOPMENT?</h2>
There are multiple novel therapies currently being investigated for the treatment of chronic graft-versus-host disease with the hopes of improving patient outcomes.

Selective rho-associated coiled-coil–containing protein kinase (ROCK) 2 inhibitors have been studied as a potential treatment option for cGVHD, given that this molecular pathway&nbsp;mediates both the inflammatory and fibrotic components&nbsp;of the disease.1,2 
 Selective ROCK2 inhibition has been shown to help resolve immune dysregulation by downregulating pro-inflammatory T helper (Th) 17 cells and increasing regulatory T (Treg) cells. Furthermore, selective ROCK2 inhibition has been shown to downregulate key fibrotic processes, such as TGF-β and LPA, leading to a decrease in fibrosis and collagen deposition.1-4 
 Clinical studies are currently ongoing to evaluate the potential benefifits of selective ROCK2 inhibition in cGVHD.

Selective ROCK2 inhibitors

The involvement of JAKs in the signaling of pro-inflammatory cytokines involved in cGVHD pathogenesis has been a large area of interest. The potential use of JAK1 selective inhibitors in the treatment of cGVHD is currently being explored.

Selective JAK1 inhibitors5

The important role that IL-2 plays in Treg cell development, expansion, activity and survival has led to interest in its use for the treatment of cGVHD. Clinical studies in patients with cGVHD have shown that low-dose subcutaneous IL-2 has increased Treg cells, with minimal effect on CD4+&nbsp;T cells. Clinical studies are currently ongoing to explore the potential benefits of IL-2 therapy.

IL-26

Combination therapy that is intended to disrupt each phase of the GVHD cascade is another area in which research is underway. This approach to therapy would ideally use synergistic agents with different mechanisms of action and nonoverlapping toxicities

Combination therapy7

As research continues, promising targets in cGVHD are being uncovered, with the possibility of offering patients more comprehensive and optimized treatments in the near future.

What are the manifestations of cGVHD that need to be addressed?

Abbreviation

Treatment under Clinical Development

<h2>cGVHD impacts patients’ psychological health</h2>
Approximately one-third of patients with moderate to severe cGVHD have clinically significant psychological distress, including depression or anxiety.10 
 In a prospective observational study evaluating 53 patients with moderate to severe cGVHD, the rates of clinically significant depression and anxiety symptoms were

Greater cGVHD symptom burden was associated with an increased rate of depression.10 
 In a multicenter, prospective, observational cohort study of 298 patients, when comparing mean SF-36 scores with those of other chronic health conditions, patients with severe cGVHD had MCS comparable with depression.8

cGVHD poses multiple economic challenges for patients
Patients who undergo an allogeneic HCT face financial hardship, which may be further amplified by a diagnosis of cGVHD.
 A multicenter, prospective, observational cohort study evaluated 298 patients wiA study that supplemented data from the multicenter, prospective, observational Chronic GVHD Consortium Response Measures Validation Study found that11

reported having difficulty paying medical bills

24%

did not have enough money at the end of the month

28%

reduced spending on utilities and other expenses

49%

used retirement savings

31%

borrowed money or sold assets&nbsp;&nbsp; &nbsp;

16%

Factors that contributed to this financial burden included multiple treatments, inability to return to work, frequent physician visits and losing/changing insurance.11

<table align="center" border="0" cellpadding="1" cellspacing="1" style="width: 1500px;">
 <tbody>
 <tr>
 <td style="text-align: center; background-color: rgb(136, 146, 153); border-color: rgb(136, 146, 153);">Sixty-six percent of patients with cGVHD face a financial challenge&nbsp;after transplant, regardless of insured status.11&nbsp;Twenty-five percent of patients will lose 20 years of&nbsp;earnings because of permanent disability.12&nbsp;Overall, patients with cGVHD are significantly&nbsp;less likely to return to the workforce, even 2 to 3 years after transplant,&nbsp;compared with those without cGVHD.13</td>
 </tr>
 </tbody>
</table>

Even in patients receiving treatment, cGVHD has a considerable impact on QOL, as well as psychological and financial well-being.

Learn more about treatment options

Could optimizing treatment help improve patient outcomes?

Psychological & Economical impact

<h3>KEY TAKEAWAY</h3>
This population-based real-world registry study analyzed clinical outcomes of cGvHD among patients who underwent allogeneic HSCT in Sweden.

<ul>
 <li>Among patients surviving ≥6 months post-HSCT, cGvHD incidence was 71.9%</li>
 <li>At 1-year post-HSCT, non-cGvHD patients had 4.72 times higher mortality risk compared to those with moderate-severe cGvHD (P &lt;0.0001)</li>
 <li>Patients with moderate-severe cGvHD had higher rates of morbidities (P &lt;0.05) and healthcare utilization (~1.6-fold) vs non- and mild cGvHD</li>
 <li>The study findings emphasize the need for novel treatments and real-time methods to monitor effective immunosuppression following HSCT</li>
</ul>

cGvHD is a serious immune-mediated complication of HSCT but is associated with superior survival in patients with hematological malignancies.
<ul>
 <li>Hence, a major challenge in managing cGvHD is to optimize prevention of severe disease while maximizing the graft-versus-leukemia effect</li>
</ul>

There is limited data on cGvHD burden from real-world studies
<ul>
 <li>cGvHD disease burden and associated clinical outcomes have not been adequately assessed in Sweden</li>
 <li>Hence, this study evaluated cGvHD disease burden (mortality and morbidities) and associated healthcare resource utilization in Sweden</li>
</ul>

<ul>
 <li>Retrospective, population-based longitudinal study using 4 national registers*</li>
 <li>All patients with a record of allogeneic HSCT from 2006 to 2015 were identified in the Patient Register</li>
 <li>Exclusion criteria: Absence of hematological malignancy prior HSCT; reused proxy identification numbers; age &lt;18 or &gt;75; death ≤6 months post-HSCT</li>
 <li>The 0–6-month follow-up period for patients who survived ≥6 months (index date) was 6–12 months post-HSCT</li>
 <li>Based on the timing and extent of commonly used cGvHD treatments, patients were classified as having non-, mild, or moderate-severe cGvHD†</li>
 <li>Statistical analysis‡: OS rates by Kaplan-Meier method and difference among groups by log-rank/Mantel–Haenszel test; time-dependent HRs by multi-variate Cox-regression model; adjusted morbidity incidence rate ratios (IRR) by multivariate negative binomial model 
 <ul>
 <li>For each follow-up year, rate of healthcare resource utilization was calculated as the total number of days in inpatient/outpatient care reported in the Patient Register for all causes divided by the total days contributed to follow-up time for that follow-up year</li>
 </ul></li>
</ul>

Patient characteristics
<ul>
 <li>Of 1,246 included patients, 28.1% were classified as non-cGvHD and 71.9% as cGvHD (mild cGvHD, 27.7%; moderate-severe cGvHD, 44.2%).</li>
 <li>Sex (58% men), age (median, 52 [40–61] years), year of HSCT (2011–2015, 65%; 2006–2010, 35%), and source for HSCT (peripheral blood stem cells, 76%; bone marrow/cord blood, 24%) were comparable across cohorts.</li>
 <li>Diagnosis of acute leukemia was more common in non-cGvHD patients (63%) vs those with moderate-severe cGvHD (51%) and mild cGvHD (52%).</li>
</ul>

Overall survival
<ul>
 <li>At 1-year post-HSCT: 
 <ul>
 <li>OS decreased with decreasing cGvHD severity status</li>
 <li>Best OS was in patients with moderate-severe cGvHD</li>
 <li>Lowest OS rate was in non-cGvHD patients, mainly due to relapse-related mortality (RRM)</li>
 </ul></li>
 <li>At 5-year follow-up: 
 <ul>
 <li>OS was similar among the 3 groups</li>
 <li>During the entire follow-up period, OS did not significantly differ among the groups (P = 0.73)</li>
 </ul></li>
 <li>More patients died from RRM than transplant-related mortality in all groups.</li>
</ul>

<table align="center" border="1" cellpadding="1" cellspacing="1">
 <tbody>
 <tr>
 <td style="text-align: center;">OS ratea</td>
 <td style="text-align: center;">Non-cGvHD 
 (n = 350)</td>
 <td style="text-align: center;">Mild cGvHD 
 (n = 345)</td>
 <td style="text-align: center;">Moderate-Severe 
 cGvHD (n = 551)</td>
 <td style="text-align: center;">P-valueb</td>
 </tr>
 <tr>
 <td style="text-align: center;">1-year OS rate, %</td>
 <td style="text-align: center;">74.3</td>
 <td style="text-align: center;">82.0</td>
 <td style="text-align: center;">87.5</td>
 <td style="text-align: center;">&lt;0.0001</td>
 </tr>
 <tr>
 <td style="text-align: center;">5-year OS rate, %</td>
 <td style="text-align: center;">67.7</td>
 <td style="text-align: center;">63.3</td>
 <td style="text-align: center;">65.3</td>
 <td style="text-align: center;">0.5</td>
 </tr>
 <tr>
 <td colspan="5">
 aOS rate by Kaplan-Meier method;&nbsp;bDifference among groups by log-rank/Mantel–Haenszel test.</td>
 </tr>
 </tbody>
</table>

Mortality
<ul>
 <li>During the follow-up period, the risk of mortality was significantly higher in non- and mild cGvHD patients than in those with moderate-severe cGvHD.</li>
 <li>Factors such as HSCT treatment period, sex, or donor relationship did not have an impact on the risk of mortality (P &gt;0.05).</li>
 <li>Patients aged 60–75 years who underwent HSCT had increased risk of mortality vs those aged 18–39 years.</li>
 <li>Patients who received peripheral blood stem cells had reduced risk of mortality vs those who received bone marrow or cord blood as donor source.</li>
</ul>

<table align="center" border="1" cellpadding="1" cellspacing="1">
 <tbody>
 <tr>
 <td style="text-align: center;">&nbsp;</td>
 <td style="text-align: center;">Multivariate analysis 
 HR (95% CI)</td>
 <td style="text-align: center;">P-valuea 
 (multivariate)</td>
 </tr>
 <tr>
 <td>cGvHD</td>
 <td>&nbsp;</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td style="text-align: center;">Non-cGvHD vs moderate-severe cGvHD</td>
 <td style="text-align: center;">4.72 (3.07–7.24)</td>
 <td style="text-align: center;">&lt;0.0001</td>
 </tr>
 <tr>
 <td style="text-align: center;">Mild cGvHD vs moderate-severe cGvHD</td>
 <td style="text-align: center;">2.21 (1.37–3.56)</td>
 <td style="text-align: center;">0.001</td>
 </tr>
 <tr>
 <td>Age at follow-up, years</td>
 <td>&nbsp;</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td style="text-align: center;">60–75 vs 18–39</td>
 <td style="text-align: center;">1.47 (1.14–1.91)</td>
 <td style="text-align: center;">0.004</td>
 </tr>
 <tr>
 <td>Source for HSCT</td>
 <td>&nbsp;</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td style="text-align: center;">PBSC vs bone marrow/cord blood</td>
 <td style="text-align: center;">0.77 (0.63–0.95)</td>
 <td style="text-align: center;">0.016</td>
 </tr>
 <tr>
 <td colspan="3">
 aP-value produced using a univariate and multivariate Cox-regression model, respectively.</td>
 </tr>
 </tbody>
</table>

Morbidities
<ul>
 <li>During the follow-up period, the risk of mortality was significantly hIncidence of most morbidities was significantly higher (P &lt;0.05) among patients with moderate-severe cGvHD vs those with non- (21–83% higher IRRs) and mild cGvHD (10–77% higher IRRs).</li>
</ul>

Healthcare resource utilization‡ 
 &nbsp;
<ul>
 <li>During the 10-year study period, number of transplants more than doubled, but the proportion of patients with cGvHD remained approximately constant.</li>
 <li>In the follow-up period, more moderate-severe cGvHD patients received inpatient or outpatient healthcare after HSCT vs non- or mild cGvHD patients.</li>
 <li>At 1-year follow-up, the proportion of patients with moderate-severe cGvHD using healthcare was ~1.6-fold higher vs those with non- or mild cGvHD.</li>
 <li>Compared to non- and mild cGvHD patients, those with moderate-severe cGvHD spent larger proportion of follow-up time in: 
 <ul>
 <li>Inpatient healthcare (59% and 31% more, respectively)</li>
 <li>Outpatient healthcare (54% and 36% more, respectively)</li>
 </ul></li>
</ul>

*Four national population-based registers held by the National Board of Health and Welfare were linked: The Patient Register, the Cancer Register, the Cause of Death Register, and the Prescribed Drug Register. †non-cGvHD, patients who received neither systemic corticosteroids nor systemic immunosuppressive treatment during the entire observation period after tapering of post-HSCT GvHD prophylaxis immuno-suppression; mild cG- vHD, patients receiving either corticosteroids or immunosuppressants alone; moderate-severe cGvHD, patients re- quiring more intensive treatment than those with mild cGvHD. ‡Patients who did not survive ≥6 months post-HSCT (n = 193) were excluded.
Please refer to the source publication&nbsp;<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC9997892/">Novitzky-Basso I, et al.</a>&nbsp;for additional details.

Clinical outcomes of cGvHD following allogeneic HSCT: A Swedish population-based real-world registry study

<h3>KEY TAKEAWAY</h3>
The ERS/EBMT task force developed evidence-based recommendations for the treatment of pulmonary cGvHD-BOS in adults. This clinical guideline aimed to assist HCPs in optimizing pulmonary cGvHD care to promote safe and effective treatment and to improve quality of care for patients.

The guideline addresses common therapeutic options (inhalation therapy, fluticasone, azithromycin and/or montelukast, imatinib, ibrutinib, ruxolitinib, belumosudil, extracorporeal photopheresis, and lung transplantation) and aspects of general management (lung functional and radiological follow-up, and pulmonary rehabilitation)

Recommendations include key advancements for incorporation in managing adults with pulmonary cGvHD-BOS and are aimed at improving and standardizing treatment and improving outcomes; however,
<ul>
 <li>Individual values, preferences, perceptions, and clinical circumstances should be considered while interpreting all recommendations</li>
</ul>

Importantly, it is crucial that these drugs be prescribed by physicians who have expertise in their use and potential AEs

cGvHD frequently causes late-onset noninfectious complications in the lung after alloHSCT, which develops in ~20% of patients, usually within the first two years after transplant

The most common late pulmonary complication is the obstructive phenotype BOS, which is presently the only entity formally recognized as a pulmonary cGvHD manifestation

No standardized or harmonized approach is available for the optimal management of patients with pulmonary cGvHD
<ul>
 <li>Additionally, little is known about the impact of newer, recently approved agents for cGvHD treatment, particularly on BOS</li>
</ul>

Hence, the ERS/EBMT task force developed evidence-based recommendations for the treatment of pulmonary cGvHD-BOS in adults targeting treatment, lung functional and radiological follow-up, and supportive treatment

A multidisciplinary group including specialists in hematology, respiratory medicine and methodology, and patient advocates, formulated eight patient, intervention, comparison, outcome (PICO), and two narrative questions

Systematic reviews were conducted to address these questions and the Grading of Recommendations Assessment, Development and Evaluation approach was used to develop recommendations following the ERS standardized methodology

<h3>SUMMARY OF PICO QUESTIONS AND RECOMMENDATIONS</h3>

<table border="1" cellpadding="1" cellspacing="1">
 <tbody>
 <tr>
 <td colspan="1" rowspan="1" style="background-color: rgb(35, 0, 76); border-color: rgb(35, 0, 76); text-align: center;">Title</td>
 <td style="background-color: rgb(35, 0, 76); border-color: rgb(35, 0, 76); text-align: center;">Recommendations</td>
 <td style="background-color: rgb(35, 0, 76); border-color: rgb(35, 0, 76); text-align: center;">Considerations</td>
 </tr>
 <tr>
 <td>Q1. In adults with lung cGvHD-BOS, should ICS ± LABA be used in addition to their conventional immunosuppressive regimen?</td>
 <td>Suggest using ICS ± LABA in addition to their conventional immunosuppressive regimena</td>
 <td>
 <ul>
 <li>It is critical to select the most appropriate device for a patient and train them in its use, ensuring optimal technique and considering patient preferences.</li>
 <li>In patients with a bronchiectasis phenotype, consider ICS use on a case-by-case basis</li>
 </ul></td>
 </tr>
 <tr>
 <td>Q2. In adults with lung cGvHD-BOS, should FAM be used in addition to conventional immunosuppressive regimen?</td>
 <td>Suggest using FAM in addition to their conventional immunosuppressive regimenb</td>
 <td>
 <ul>
 <li>In patients with a high risk of secondary malignancies or cancer predisposition syndromes (e.g., Fanconi anemia, Bloom syndrome, short telomere syndrome), azithromycin should be used with caution</li>
 </ul></td>
 </tr>
 <tr>
 <td>Q3. In adults with lung cGvHD-BOS, should imatinib be used in addition to their conventional immunosuppressive regimen?</td>
 <td>Suggest either imatinib in addition to their conventional immunosuppressive regimen or conventional immunosuppressionc</td>
 <td>
 <ul>
 <li>Consider GvHD manifestations in other organs. Imatinib can be an option in those with sicca symptoms (e.g., ocular cGvHD, due to its side effects, which includes peri-orbital edema), and in patients with CML, due to its potential impact on underlying disease</li>
 <li>It would be a less favorable option in patients with cGvHDrelated myalgia, GI symptoms and anorexia due to risk of drugrelated exacerbation of these symptoms</li>
 </ul></td>
 </tr>
 <tr>
 <td>Q4. In adults with lung cGvHD-BOS, should ibrutinib be used in addition to their conventional immunosuppressive regimen?</td>
 <td>Suggest not using ibrutinib in addition to their conventional immunosuppressive regimenb</td>
 <td>
 <ul>
 <li>In general, the panel suggests against using ibrutinib, although it might still be a valuable option in selected patients, where other options might not be possible</li>
 <li>Ibrutinib might be an option in patients with cytopenia, as it is not a frequent side-effect of ibrutinib, and in patients with CLL due to its impact on underlying disease</li>
 <li>Ibrutinib is a less favorable option in patients with a history of frequent infectious complications, bleeding, symptoms similar to ibrutinib side-effects, and patients taking CYP3A inhibitors due to drug interactions</li>
 </ul></td>
 </tr>
 <tr>
 <td>Q5. In adults with lung cGvHD-BOS, should ruxolitinib be used in addition to their conventional immunosuppressive regimen?</td>
 <td>Suggest either ruxolitinib in addition to their conventional immunosuppressive regimen or conventional immunosuppressionc</td>
 <td>
 <ul>
 <li>More data from BOS-specific trials are needed to fully evaluate Ruxolitinib efficacy</li>
 <li>Use Ruxolitinib with caution in patients with a history of (recurrent) infections and cytopenia</li>
 <li>Ruxolitinib might be an option in patients with extra-pulmonary GvHD, as it has been shown to be effective for this condition</li>
 </ul></td>
 </tr>
 <tr>
 <td>Q6. In adults with lung cGvHD-BOS, should belumosudil be used in addition to their conventional immunosuppressive regimen?</td>
 <td>Suggest either belumosudil in addition to their conventional immunosuppressive regimen or conventional immunosuppressionc</td>
 <td>
 <ul>
 <li>More data from BOS-specific trials are needed to fully evaluate belumosudil efficacy</li>
 </ul></td>
 </tr>
 <tr>
 <td>Q7. In adults with lung cGvHD-BOS, should ECP be used in addition to their conventional immunosuppressive regimen?</td>
 <td>In adults with progressive lung cGvHD-BOS, suggest using ECP in addition to their conventional immunosuppressive regimenb</td>
 <td>
 <ul>
 <li>Given the logistical challenges, it might be difficult to perform ECP in every patient or at every site. Consider the need for a central line and related low risk of line infection. Consider patientspecific details and preferences to determine if ECP is appropriate for a given patient</li>
 </ul></td>
 </tr>
 <tr>
 <td>Q8. In adults with endstage lung cGvHDBOS, should lung transplantation be performed?</td>
 <td>In highly selected adults with endstage lung cGvHDBOS, we suggest lung transplantation as a life-saving therapeutic optionb</td>
 <td>
 <ul>
 <li>Lung transplantation might be an option for highly selected adults, considering other comorbidities and general eligibility criteria for lung transplantation. Establish specific lung transplant criteria for patients with lung cGvHD-BOS</li>
 <li>Consider risk of hematological relapse based on patient profile</li>
 </ul></td>
 </tr>
 </tbody>
</table>

BOS, bronchiolitis obliterans syndrome; cGvHD, chronic graft-versus-host disease; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CYP3A, cytochrome P450 3A; ECP, extracorporeal photopheresis; FAM, fluticasone, azithromycin, and/or montelukast; GI, gastrointestinal; GvHD, graft-versus-host disease; ICS, inhaled corticosteroids; LABA, long-acting β-agonist; PICO, patient, intervention, comparison, outcome.
aConditional recommendation, low certainty of evidence. bConditional recommendation, very low certainty of evidence. cConditional recommendation for either intervention or comparison, very low certainty of evidence.

SUMMARY OF NARRATIVE QUESTIONS AND RECOMMENDATIONS

<ul>
 <li>BOS-specific studies are rare; most included studies were retrospective in nature and involved a small number of patients with BOS per study</li>
 <li>Timing of treatment administration for BOS was likely to be heterogeneous, e.g., treatment with early-phase vs established late-phase disease, which could have affected treatment efficacy</li>
 <li>Across studies, study protocols, treatment doses, conventional immunosuppression, transplant-related drugs, and lines of treatment differed</li>
 <li>Comparisons between studies were very challenging, as endpoints often varied and some studies used combined endpoints (i.e., ORR based on symptoms and PFT data)</li>
</ul>

Please refer to the source publication <a href="https://erj.ersjournals.com/content/63/3/2301727.long">Bos S, et al.</a> for additional details.
ABBREVIATIONS 
 AEs, adverse events; alloHSCT, allogeneic hematopoietic stem cell transplantation; BOS, bronchiolitis obliterans syndrome; cGvHD, chronic graft-versus-host disease; ERS, European Respiratory Society; EBMT, European Society for Blood and Marrow Transplantation; ORR, overall response rate; PICO, patient, intervention, comparison, outcome; PFT, pulmonary function test.

European Respiratory Society (ERS)/ European Society for Blood and Marrow Transplantation (EBMT) clinical practice guidelines on treatment of pulmonary cGvHD in adults

<h3>KEY TAKEAWAY</h3>
This article discussed 38 EBMT consensus recommendation*&nbsp;statements for use in the routine management of GVHD in allogeneic SCT in adult patients with hematological malignancies with the following key updates to the 2014 EBMT recommendations.

Rabbit anti-thymocyte globulin (rATG) is recommended for preventing GVHD in patients undergoing matched unrelated donor (MUD) allogeneic SCT (Category 1†; 100% consensus)

Grade 2 acute GVHD (aGVHD) with isolated skin or upper gastrointestinal tract (GIT) manifestations can be treated with lower steroid doses, such as 1 mg/kg per day methylprednisolone or prednisone (Category 1; 100% consensus)

As an initial treatment of bronchiolitis obliterans syndrome, the fluticasone montelukast regimen is recommended in combination with systemic steroids; however, prolonged use of azithromycin after resolution of bronchiolitis obliterans syndrome in chronic GVHD (cGVHD) is not recommended because of the possibility of increased risk of relapse (Category 2A‡; 100% consensus)

Addition of novel drugs in the available treatment options is recommended for steroid-refractory aGVHD (Category 2A; 100% consensus) and cGVHD (Category 2B§; 95% consensus)

In 2014, EBMT and European Leukemia Net (ELN) working group published recommendations on management of GVHD to harmonize clinical practice 
 and address unmet medical need

Several important studies, impacting GVHD prophylaxis and therapy were published following the 2014 recommendations

A&nbsp;<a href="https://www.nature.com/articles/bmt2016298">follow up study</a>&nbsp;by EBMT-ELN working group highlighted several 
 shortcomings in the 2014 recommendations

Thus, these guidelines were updated, and the present article discussed recommendations from the updated EBMT guidelines

EBMT task force developed 38 statements (29: 100% consensus; 9: 95% consensus), to update the 2014 GVHD recommendations related to GVHD prophylaxis, drug management during GVHD prophylaxis, and treatment of aGVHD and cGVHD.

<h3 style="text-align: center;">Prophylaxis of GVHD</h3>

<table border="1" cellpadding="1" cellspacing="1">
 <tbody>
 <tr>
 <td colspan="1" rowspan="1" style="text-align: center; background-color: rgb(35, 0, 76); border-color: rgb(35, 0, 76);">Category of evidence, 
 Consensus (100%)</td>
 <td style="text-align: center; background-color: rgb(35, 0, 76); border-color: rgb(35, 0, 76);">Recommendations</td>
 </tr>
 <tr>
 <td style="text-align: center; background-color: rgb(244, 242, 246); border-color: rgb(244, 242, 246);">Category 1</td>
 <td style="background-color: rgb(244, 242, 246); border-color: rgb(244, 242, 246);">Patients undergoing MRD or MUD allogeneic transplant should receive GVHD prophylaxis with a calcineurin inhibitor plus an antimetabolitea</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 1</td>
 <td>Tacrolimus or ciclosporin can be used in the setting of sibling or MUD transplants. The choice should be made based on experience at the center (e.g., ciclosporin is the standard calcineurin inhibitor adopted in most European centres)</td>
 </tr>
 <tr>
 <td style="text-align: center; background-color: rgb(244, 242, 246); border-color: rgb(244, 242, 246);">Category 1</td>
 <td style="background-color: rgb(244, 242, 246); border-color: rgb(244, 242, 246);">Methotrexate is the recommended antimetabolite for patients receiving MAC</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 2A</td>
 <td>Mycophenolate mofetil can be used instead of methotrexate for patients receiving MAC in case of contraindications to methotrexate or for those patients who need rapid engraftment (e.g., those with aspergillosis)</td>
 </tr>
 <tr>
 <td style="text-align: center; background-color: rgb(244, 242, 246); border-color: rgb(244, 242, 246);">Category 2A</td>
 <td style="background-color: rgb(244, 242, 246); border-color: rgb(244, 242, 246);">Mycophenolate mofetil is the recommended antimetabolite for patients receiving non-MAC and RIC</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 1</td>
 <td>rATG should is recommended for preventing GVHD in patients undergoing MUD allogeneic SCTb</td>
 </tr>
 <tr>
 <td colspan="2">
 aIn children (&lt;18 years) many centres use calcineurin inhibitor as a single agent;&nbsp;bIn children (&lt;18 years) many centres use rATG in MUD allogeneic SCT. MAC, myeloablative conditioning; MRD, matched related donor; MUD, matched unrelated donor; RIC, reduced intensity conditioning.</td>
 </tr>
 </tbody>
</table>

<h3 style="text-align: center;">Drug management during prophylaxis of GVHD</h3>

<table border="1" cellpadding="1" cellspacing="1">
 <tbody>
 <tr>
 <td colspan="1" rowspan="1" style="text-align: center; background-color: rgb(35, 0, 76); border-color: rgb(35, 0, 76);">Category of evidence, 
 Consensus (100%)</td>
 <td style="text-align: center; background-color: rgb(35, 0, 76); border-color: rgb(35, 0, 76);">Recommendations</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 2A</td>
 <td>Ciclosporin concentration should be carefully monitored. When using the two daily doses regimen, the target concentration in the first-week post-transplant should be 200–300 μg/L to efficiently prevent aGVHD</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 2A</td>
 <td>Ciclosporin concentrations should be monitored with whole blood sampling for 12 h after a dose; sampling from the lines used for ciclosporin infusion should be avoided</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 2A</td>
 <td>The standard duration of ciclosporin prophylaxis is 6 months; however, it needs to be adjusted to the risk of relapse, chimerism, and presence or absence of GVHD. If no GVHD is reported, ciclosporin dose is tapered from 4 months until the regimen is stopped. Faster tapering is recommended if the risk of relapse is high and a bone marrow graft is provided, especially if complete chimerism is reported. The dose is not tapered, if there are signs of aGVHD or cGVHD with the exception of mild cutaneous aGVHD. In cases of persistent disease or relapse and no GVHD, ciclosporin dose can be carefully tapereda</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 2A</td>
 <td>Methotrexate is given as a bolus intravenous injection. In MAC transplants, initial methotrexate dose is 15 mg/m2 given on the first day after the transplant; however, lower doses of methotrexate have also been reported in RIC transplants. In MAC transplants, two additional doses of 10 mg/m2 are given on day three and six after the transplant, an additional dose at 11 days after transplant can be administered. Lower doses are usually administered in RIC transplants on 3 and 6 days after the transplant</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 2A</td>
 <td>On the basis of expert opinion, we recommend leucovorin rescue after prophylactically given methotrexate; however, no definite evidence supports leucovorin rescue for preventing methotrexate toxicity or enhancing methotrexate efficacy</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 2A</td>
 <td>The leucovorin regimen is usually started 24 h after each dose of methotrexate; on the first day after the transplant the leucovorin should be three 15 mg doses every 6 h, the dose should then increase to four 15 mg doses every six hr after methotrexate doses 3-, 6-, and 11-days after the transplant; leucovorin should be administered by intravenous injection</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 2A</td>
 <td>Mycophenolate mofetil should be administered intravenously or orally in three 10–15 mg/kg daily doses; the dose should be adapted according to toxicity</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 2A</td>
 <td>The recommended total dose of rATG ranges from 2.5–5.0 mg/kg in MRD and 4.5–6.0 mg/kg in MUD transplants; higher doses are associated with a higher risk of infectious complications</td>
 </tr>
 <tr>
 <td colspan="2">
 aIn children (&lt;18 years) with allogeneic SCT for non-malignant diseases, a longer duration of calcineurin inhibitor is often applied. MAC, myeloablative conditioning; RIC, reduced intensity conditioning.</td>
 </tr>
 </tbody>
</table>

<h3 style="text-align: center;">Treatment of aGVHD¶</h3>

<table border="1" cellpadding="1" cellspacing="1">
 <tbody>
 <tr>
 <td colspan="1" rowspan="1" style="text-align: center; background-color: rgb(35, 0, 76); border-color: rgb(35, 0, 76);">Category of evidence, 
 Consensus (100%)</td>
 <td style="text-align: center; background-color: rgb(35, 0, 76); border-color: rgb(35, 0, 76);">Recommendations</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 1</td>
 <td>Systemic treatment is initiated for grade 2 or higher aGVHD</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 1</td>
 <td>First-line treatment of aGVHD is methylprednisolone with an initial dose of 2 mg/kg per day; prednisone in a dose of 2.0–2.5 mg/kg per day is regarded as equivalent to methylprednisolone 2.0 mg/kg per day dose</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 1</td>
 <td>Grade 2 aGVHD with isolated skin or upper GIT manifestations can be treated with lower steroid doses, such as 1 mg/kg per day methylprednisolone or prednisone</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 1</td>
 <td>No reduction in the prednisolone dose is recommended during the first 7 days after transplant, but parenteral steroids can be stopped, and oral steroids can be used until all signs of aGVHD have disappeared. Tapering of the dose is a slow, response dependent process: In cases of complete response, steroid dose should be gradually reduced to 10% of the initial dose over a period of approximately four weeks. In cases of steroid-resistant GVHD, long-term use of steroids might cause major complications; therefore, second-line therapy is recommended</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 1</td>
 <td>Non-absorbable oral steroids, such as budesonide (9 mg per day) or oral beclomethasone (1.3–2.0 mg four times a day), can be given in addition to systemic corticosteroids as treatment of gastrointestinal aGVHD</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 2A</td>
 <td>There is no standard second-line treatment for aGVHD. Current practice is to prescribe one of the following drugs: Alemtuzumab, α1-antitripsin, basiliximab, cellular therapies (eg, mesenchymal cells and regulatory T-cells) daclizumab, extracorporeal photopheresis, faecal microbiota transplantation, JAK inhibitors (eg, ruxulotinib which is FDA approved), mycophenolate mofetil, methotrexate, pentostatin, rATG, sirolimus, or vedolizumab; for second-line treatment of aGVHD, centres should follow their institutional guidelines, and patients should be treated in clinical trials when possible</td>
 </tr>
 <tr>
 <td colspan="2">
 FDA, US Food and Drug administration; JAK, Janus kinase</td>
 </tr>
 </tbody>
</table>

<h3 style="text-align: center;">Treatment of cGVHD#</h3>

<table border="1" cellpadding="1" cellspacing="1">
 <tbody>
 <tr>
 <td colspan="1" rowspan="1" style="background-color: rgb(35, 0, 76); border-color: rgb(35, 0, 76); text-align: center;">Category of evidence, 
 Consensus (100%)</td>
 <td style="background-color: rgb(35, 0, 76); border-color: rgb(35, 0, 76); text-align: center;">Recommendations</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 2A</td>
 <td>The first-line treatment of newly diagnosed cGVHD is steroids</td>
 </tr>
 <tr>
 <td style="text-align: center;">Category 2A</td>
 <td>As an initial treatment of bronchiolitis obliterans syndrome, the fluticasone montelukast regimen is recommended in combination with systemic steroids; however, prolonged use of azithromycin after resolution of bronchiolitis obliterans syndrome is not recommended because of the possibility of increased risk of relapse</td>
 </tr>
 </tbody>
</table>

*Please refer to the source publication <a href="https://www.sciencedirect.com/science/article/pii/S235230261930256X?via%3Dihub">Penack O, et al. </a> for additional details.
The National Comprehensive Cancer Network classification of evidence and consensus was used to define consensus recommendations; †Category 1: High-level evidence (randomized trials or meta-analyses) and 100% consensus; ‡Category 2A: Lower-level evidence (small, randomized trials) and 100% consensus; §Category 2B: Lower-level evidence (small, randomized trials) and 80–100% consensus; ¶aGVHD was defined using the Mount Sinai Acute GvHD International Consortium group criteria; #cGVHD was defined using the National Institutes of Health 2014 criteria

Updated European Society of Blood and Marrow Transplantation consensus recommendations for GVHD prophylaxis and management in hematological malignancies after stem-cell transplantation

<h3>KEY TAKEAWAY</h3>
Dr. Mohty discussed the pathophysiology, therapeutic targets, and diagnostic biomarkers for the management of cGVHD, based on published evidence and highlighted that:

The pathophysiological continuum of cGVHD involves early thymic damage leading to dysfunctional selection of T and B cells with subsequent production of autoantibodies and tissue fibrosis

Understanding pathways allows more diverse and more specific therapeutic approaches for cGVHD
<ul>
 <li>Therapeutic targets (e.g., ROCK2) and microbiome-derived protection from cGVHD may be explored</li>
</ul>

There exists a lack of clarity regarding organ specificity for organ-specific damage, the role of microbiota, and tissue-specific antigens and antibodies

Various studies have demonstrated diagnostic biomarkers for cGVHD, but prospective validation is needed

In this presentation, Dr. Mohty provided insights into the biology and pathophysiology of cGVHD and suggested diagnostic biomarkers and therapeutic targets for its management, based on published scientific evidence.

<h3>KEY HIGHLIGHTS</h3>
Definition of cGVHD (<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC6786777/">Schoemans HM, et al. 2018</a>)

<ul>
 <li>While the historical perception was that acute GVHD (aGVHD) occurs in the first three months after transplant and cGVHD thereafter, a consensus was provided to capture various cGVHD entities including an overlap cGVHD</li>
</ul>

<ul>
 <li>Manifestations of aGVHD are limited to skin, liver, and GI tract, while manifestations of cGVHD (meeting NIH 2014 diagnostic criteria) cover a wider list*</li>
</ul>

<ul>
 <li>Undefined other cGVHD includes atypical signs and symptoms of alloreactivity falling outside the NIH 2014 diagnostic criteria</li>
</ul>

Pathophysiology of cGVHD and role of T and B cells 
 &nbsp;
<ul>
 <li><a href="https://www.sciencedirect.com/science/article/pii/S1470204509702256?via%3Dihub">Finke J, et al. 2009</a>&nbsp;reported that the addition of ATG-F to GVHD prophylaxis lowered the incidence of cGVHD (limited/extensive and extensive) vs control by depleting the T cells</li>
 <li><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC9642318/">Meyer E, et al. 2022</a>&nbsp;showed that Orca-T, an engineered allograft, resulted in high GVHD- free and relapse-free survival (at one year) following myeloablative conditioning for hematological malignancies vs CIBMTR control (71% vs 34%) 
 <ul>
 <li>Incidence of moderate to severe cGVHD (as per NIH Consensus Grading) through day +365 was reduced with Orca-T vs CIBMTR control (5% vs 38%)</li>
 </ul></li>
 <li>As per Dr Mohty, the risk factors† for cGVHD analyzed by&nbsp;<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062319/">Flowers M, et al. 2011</a>&nbsp;highlight its pathophysiology including HLA mismatching, minor HLA antigen, number of T cells, insult by the conditioning regimen and GVHD prophylaxis regimen, and thymic damage and immune reconstitution</li>
 <li>To avoid cGVHD, a normal immune reconstitution needs to be achieved. However, transplant patients can suffer from other complications highlighted by&nbsp;<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC6020045/">Cooke KR, et al. 2017</a>&nbsp;where the T cells can be impacted leading to immune dysregulation and abnormal proliferation of alloreactive T cells</li>
 <li>Injury to the thymus and the subsequent T cell recovery especially the naïve T helper cells plays an important role in T cell reconstitution (<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC7412601/">Gaballa A, et al. 2020</a>)</li>
 <li>An unbalanced reconstitution of donor-derived regulatory T cells (Tregs) as well as effector/ conventional T cells (Tcons) and CD8 T cells, observed after nine months of transplant, was associated with cGVHD (<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC4742552/">Alho AC, et al. 2016</a>) 
 <ul>
 <li>Thymic damage prevented recovery of naïve Tregs</li>
 </ul></li>
 <li>Findings from&nbsp;<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049519/">McManigle W, et al. 2019</a>&nbsp;highlighted that in cGVHD, after allogeneic HCT, B cell recovery occurs under constant exposure to chronic alloantigen and a high B-cell activating factor: B cells ratio, leading to altered peripheral B-cell with constitutive activation and survival signaling</li>
 <li>Also, as shown by&nbsp;<a href="https://rupress.org/jem/article-abstract/199/8/1133/40065/Minor-Histocompatibility-Antigen-DBY-Elicits-a?redirectedFrom=fulltext">Zorn E, et al. 2004</a>, after allogeneic SCT, T cell response, was blocked by anti-DRB1501; recognized endogenously processed peptide on female and male dendritic cells; and was followed by B cell response</li>
 <li><a href="https://ashpublications.org/blood/article/103/1/353/17591/Antibody-response-to-DBY-minor-histocompatibility">Mikios DB, et al. 2004</a>&nbsp;examined the magnitude of antibody responses to recombinant DBY and DBX and found anti-DBY response to be higher in male patients with female donors vs male patients with male donors</li>
 <li><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC5016705/">Sarvaria A, et al. 2016</a>demonstrated that IL-10+ regulatory B cells, enriched in cord blood, may protect against cGVHD after cord blood transplantation</li>
 <li>In general, the pathophysiology of cGVHD as per&nbsp;<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020045/">Cookee KR, et al. 2016</a>&nbsp;involves: 
 <ul>
 <li>Phase 1: Acute inflammation, tissue injury, and involves innate immunity</li>
 <li>Phase 2: Chronic inflammation and dysregulated immunity and involves adaptive immune system (including T cells, B cells, antigen-presenting cells, NK cells, and regulatory cells: Tregs, Bregs, and Tr1 cells)</li>
 <li>Phase 3: Marks aberrant tissue repair and fibrosis and involves innate and adaptive immunity</li>
 </ul></li>
</ul>

Therapeutic targets for cGVHD
<ul>
 <li>Dr. Mohty mentioned the therapeutic targets that could be considered while managing cGVHD</li>
 <li>He highlighted ROCK2‡, a critical regulator of immune modulation and fibrosis, and an emerging therapeutic target in cGVHD which can be effectively inhibited by drugs (<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC8456981/">Zannin-Zhorav A, et al. 2021</a>)</li>
 <li>Microbiota and dysbiosis in local organs after HCT can influence GVHD. Findings from&nbsp;<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC7332893/">Markey KE, et al. 2020</a>&nbsp;showed that microbe-derived short-chain fatty acids butyrate and propionate at day 100 were associated with protection from cGVHD</li>
</ul>

Diagnostic biomarkers for cGVHD
<ul>
 <li>The cGVHD biomarkers can aid in refining diagnosis, anticipating severity, and in guiding treatment</li>
 <li>Evaluation of diagnostic biomarker values (<a href="https://ashpublications.org/bloodadvances/article/7/14/3612/486749/A-diagnostic-classifier-for-pediatric-chronic">Cuvellier GDE, et al. 2023</a>) have shown that: 
 <ul>
 <li>At the onset of cGVHD, various populations of T cells§&nbsp;decreased, indicating thymic damage, whereas various cytokines and chemokines increased indicating effector T cell recruitment and cGVHD tissue damage</li>
 <li>Similar patterns of biomarkers were seen at the onset of moderate-severe GVHD except for a decrease in NKreg cells</li>
 </ul></li>
 <li>Assessment of cGVHD risk at three months after HCT identified cGVHD biomarkers including some key molecules including CXCL9, and fibrotic biomarkers like MMP3 and DKK3 (<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC10378149/">Logan BR, et al. 2023</a>)</li>
</ul>
*skin, nails, scalp, body hair, mouth, eyes, esophagus, lungs, muscles, joints, fascia, genitalia;&nbsp;†matched unrelated donor, mismatched related donor, mismatched unrelated donor, female donor/male recipient, mobilized blood cell graft, diagnosis of CML, total body irradiation, conditioning with rabbit ATG, patient age (per decade), donor age (per decade);&nbsp;‡Rho-associated coiled-coil–containing protein kinase;&nbsp;§&nbsp;naïve Th cells, naive Treg cells, NKreg cells, and cytolytic NK cells.
Disclaimer: Dr Ernst Holler is the author of this presentation. However, in his absence, it was presented by Dr Mohamad Mohty at the conference.
ABBREVIATIONS 
 ATG, anti-T-cell globulins; ATG-F, ATG-Fresenius; Breg, B regulatory cells; CD8, cluster of differentiation 8; CIBMTR, The Center for International Blood and Marrow Transplant Research; CML, chronic myeloid leukemia; CXCL9, chemokine (C-X-C motif) ligand 9; DBX, dead box RNAhelicase X; DBY, dead box RNAhelicase Y; DKK3, dickkopf-3; ELISA, enzyme-linked immunosorbent assay; GI, gastro-intestinal tract; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; HLA, human leukocyte antigen; HSCT, hematopoietic stemcell transplantation; IL-10, interleukin 10; MMP3, matrix- metalloproteinase 3; NIH, National Institutes of Health; NK, natural killer; NKreg, natural killer regulatory; SCT, stem cell transplantation; Tcons, conventional T cells; Th, T helper; Treg, T regulatory cells; Tr1, IL-10 producing regulatory T cells.

Advances in the biology of chronic GVHD

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