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

KEY TAKEAWAY

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,

Individual values, preferences, perceptions, and clinical circumstances should be considered while interpreting all recommendations

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

WHY THIS MATTERS

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

Additionally, little is known about the impact of newer, recently approved agents for cGvHD treatment, particularly on BOS

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

KEY HIGHLIGHTS

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

SUMMARY OF PICO QUESTIONS AND RECOMMENDATIONS

Title		Recommendations	Considerations
	Q1. In adults with lung cGvHD-BOS, should ICS ± LABA be used in addition to their conventional immunosuppressive regimen?	Suggest using ICS ± LABA in addition to their conventional immunosuppressive regimen^a	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. In patients with a bronchiectasis phenotype, consider ICS use on a case-by-case basis
	Q2. In adults with lung cGvHD-BOS, should FAM be used in addition to conventional immunosuppressive regimen?	Suggest using FAM in addition to their conventional immunosuppressive regimen^b	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
	Q3. In adults with lung cGvHD-BOS, should imatinib be used in addition to their conventional immunosuppressive regimen?	Suggest either imatinib in addition to their conventional immunosuppressive regimen or conventional immunosuppression^c	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 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
	Q4. In adults with lung cGvHD-BOS, should ibrutinib be used in addition to their conventional immunosuppressive regimen?	Suggest not using ibrutinib in addition to their conventional immunosuppressive regimen^b	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 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 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
	Q5. In adults with lung cGvHD-BOS, should ruxolitinib be used in addition to their conventional immunosuppressive regimen?	Suggest either ruxolitinib in addition to their conventional immunosuppressive regimen or conventional immunosuppression^c	More data from BOS-specific trials are needed to fully evaluate Ruxolitinib efficacy Use Ruxolitinib with caution in patients with a history of (recurrent) infections and cytopenia Ruxolitinib might be an option in patients with extra-pulmonary GvHD, as it has been shown to be effective for this condition
	Q6. In adults with lung cGvHD-BOS, should belumosudil be used in addition to their conventional immunosuppressive regimen?	Suggest either belumosudil in addition to their conventional immunosuppressive regimen or conventional immunosuppression^c	More data from BOS-specific trials are needed to fully evaluate belumosudil efficacy
	Q7. In adults with lung cGvHD-BOS, should ECP be used in addition to their conventional immunosuppressive regimen?	In adults with progressive lung cGvHD-BOS, suggest using ECP in addition to their conventional immunosuppressive regimen^b	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
	Q8. In adults with endstage lung cGvHDBOS, should lung transplantation be performed?	In highly selected adults with endstage lung cGvHDBOS, we suggest lung transplantation as a life-saving therapeutic option^b	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 Consider risk of hematological relapse based on patient profile

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

Title

Recommendations

Considerations

Q1. How and how frequently should adults with lung cGvHD -BOS be re-evaluated?

How often should PFT evaluation be conducted?
How often should imaging/ chest CT evaluation be conducted?

Spirometry at least every 3 months for follow-up;
Full PFT at time of BOS diagnosis, annually thereafter, and at time of disease progression;
High-resolution chest CT scan at time of diagnosis and upon indication, for e.g., in cases of PFT decline or respiratory symptoms, to exclude other causes

After BOS diagnosis, more frequent spirometry testing is suggested, as some patients may have rapid decline in FEV1 (e.g.,every month for first 3 months),in patients who are clinically unstable, after onset of new symptoms or GvHD in another organ, respiratory infection, or change in therapy.
In patients who stabilize after treatment initiation, gradually reducing frequency of spirometry testing to every 6–12 months may be considered based on time after transplantation and BOS diagnosis.

Q2. Should attention be paid to other interventions in adults with lung cGvHD-BOS: flu,pneumococcal and COVID -19 vaccination, infection prophylaxis, including Ig, pulmonary rehabilitation, smoking cessation, longterm oxygen treatment?

Annual influenza immunization with an inactivated vaccine as per existing recommendations for alloHSCT patients;
Pneumococcal vaccination with four doses of pneumococcal conjugate vaccine as per existing recommendations for cGvHD patients;
COVID-19 vaccination with repeated booster vaccinations as per existing recommendations for alloHSCT patients and local policies;
Consider antimicrobial prophylaxis, targeting encapsulated organisms and Pneumocystis pneumonia, antiviral and antifungal prophylaxis for duration of immunosuppressive therapy based on individual risk factors, as per existing advice for cGvHD patients;
Consider immunoglobulins in patients with severe infections and IgG levels <400 mg/dL as per existing advice for cGvHD patients;
Physical activity, including formal pulmonary rehabilitation programs, is encouraged in patients with functional impairment;
Use long-term oxygen therapy in case of severe chronic resting hypoxemia, as per existing recommendations for patients with COPD

There is no clear evidence of the benefit of a booster influenza vaccine, although a second dose might be benefical in cGvHD patients as they tend to respond less.
Policies regarding COVID-19 vaccination may change over time due to changes in the pandemic.
Consider ambulatory oxygen use in patients with severe exertional hypoxemia.

alloHSCT, allogeneic hematopoietic stem cell transplantation; BOS, bronchiolitis obliterans syndrome; cGvHD, chronic graft-versus-host disease; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CT, computed tomography; FEV1, forced expiratory volume in 1 s; GvHD, graft-versus-host disease; Ig, immunoglobulins; IgG, immunoglobulin G; PFT, pulmonary function test.

Conditional recommendation, very low quality of evidence stemming from narrative review of evidence.

KEY LIMITATIONS

BOS-specific studies are rare; most included studies were retrospective in nature and involved a small number of patients with BOS per study
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
Across studies, study protocols, treatment doses, conventional immunosuppression, transplant-related drugs, and lines of treatment differed
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)

Please refer to the source publication Bos S, et al. 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.

Reference

Bos S, Murray J, Marchetti M, Cheng GS, Bergeron A, Wolff D, et al. ERS/EBMT clinical practice guidelines on treatment of pulmonary chronic graft-versus-host disease in adults. Eur Respir J. 2024;63(3):2301727. doi: 10.1183/13993003.01727- 2023. PMID: 38485149.

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MAT-KW-2400454/V1/Dec2024