Early View
Task force report
ERS/EBMT clinical practice guideline on
treatment of pulmonary chronic graft-versus-host
disease in adults
Saskia Bos, John Murray, Monia Marchetti, Guang-Shing Cheng, Anne Bergeron, Daniel Wolff, Clare
Sander, Akshay Sharma, Sherif M. Badawy, Zinaida Peric, Agnieszka Piekarska, Joseph Pidala, Kavita
Raj, Olaf Penack, Samar Kulkarni, Molly Beestrum, Andrea Linke, Matthew Rutter, Courtney Coleman,
Thomy Tonia, Hélène Schoemans, Daiana Stolz, Robin Vos
Please cite this article as: Bos S, Murray J, Marchetti M, et al. ERS/EBMT clinical practice
guideline on treatment of pulmonary chronic graft-versus-host disease in adults. Eur Respir J
2024; in press (https://doi.org/10.1183/13993003.01727-2023).
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is
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,ERS/EBMT clinical practice guideline on treatment of pulmonary chronic graft-versus-host
disease in adults
Saskia Bos1,2, John Murray3, Monia Marchetti4, Guang-Shing Cheng 5, Anne Bergeron6, Daniel Wolff 7,
Clare Sander8, Akshay Sharma9, Sherif M. Badawy10, Zinaida Peric 11, Agnieszka Piekarska 12, Joseph
Pidala13, Kavita Raj14, Olaf Penack15,16, Samar Kulkarni3, Molly Beestrum17, Andrea Linke18, Matthew
Rutter19,20, Courtney Coleman21, Thomy Tonia 22, Hélène Schoemans23,24, Daiana Stolz25**, Robin Vos1**
** Contributed equally as senior author
1. Dept. of Respiratory diseases, University Hospitals Leuven, Leuven, Belgium
2. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
3. Dept. of Haematology and Transplant Unit, Christie Hospital NHS Foundation Trust, Manchester, UK
4. Dept. of Haematology, Azienda Ospedaliera Nazionale SS Antonio e Biagio e Cesare Arrigo,
Alessandria, Italy
5. Division of Clinical Research, Fred Hutchinson Cancer Research Center and Div. of Pulmonary, Critical
Care and Sleep Medicine, Department of Internal Medicine, University of Washington, USA
6. Dept. of Pulmonology, Hôpitaux Universitaires de Genève, Switserland
7. Dept. of Medicine III, Haematology and Oncology, University Hospital Regensburg, Germany
8. Dept. of Respiratory Medicine, Addenbrooke's Hospital, Cambridge, UK
9. Dept. of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children’s Research Hospital,
Memphis, USA
10. Dept. of Pediatrics, Division of Haematology, Oncology and Stem Cell Transplant, Ann & Robert H.
Lurie Children’s Hospital, Northwestern University Feinberg School of Medicine, Chicago, USA
11. Dept. of Haematology, University Hospital Zagreb, Croatia
12. Dept. of Haematology and Transplantology, Medical University of Gdansk, Poland
13. Dept. of Medical Oncology, Moffitt Cancer Center, Tampa, USA
14. Dept. of Haematology, University College London Hospital NHS Foundation trust, London, UK
15. Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-
Universität zu Berlin, Dept. of Hematology, Oncology and Tumorimmunology, Berlin, Germany
16. Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
17. Northwestern University Feinberg School of Medicine, Chicago, USA
18. EBMT Patient Advocacy Committee
19. ERS Patient Advocacy Committee
20. Dept. of Respiratory Physiology, Addenbrooke's Hospital, Cambridge, UK
21. European Lung Foundation, Sheffield, UK
22. Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
23. Dept. of Haematology, University Hospitals Leuven, Leuven, Belgium
24. Dept. of Public Health and Primary Care, ACCENT VV, KU Leuven – University of Leuven, Leuven,
Belgium
25. Clinic of Respiratory Medicine, Medical Center – University of Freiburg, Faculty of Medicine,
University of Freiburg, Germany
Address for correspondence: Prof. Dr. Robin Vos
Univ. Hospitals Leuven, Dept. of Respiratory Diseases
Herestraat 49, B-3000, Leuven, Belgium
Tel.: +32 16/34 15 48 Fax.: +32 16/34 68 03
robin.vos@uzleuven.be
ORCID iD: 0000-0002-3468-9251
,MANUSCRIPT SUMMARY
Journal: Eur. Respir. J.
Type: Clinical Practice Guideline
Support statement: This work was supported by the European Respiratory Society and the European
Society for Blood and Marrow Transplantation.
Funding: The Task Force was funded by the European Respiratory Society.
Conflict of interest:
SB is funded by the Paul Corris International Clinical Research Training Scholarship and reports lecture
fees from Mallinckrodt and Jazz, travel support from Takeda. JM reports lecture fees from Therakos
and Sanofi. MM reports consultancy fees from Gilead and lecture fees from Novartis. GSC reports
being site PI of an ongoing multicentre phase II trial for ruxolitinib in BOS after HCT (clinicaltrials.gov
NCT03674047). AB reports a scientific committee fee to the institution from Astra Zeneca, travel grant
from Boehringer, adjudication board fee from ENANTA, lecture fee to the institution from Novartis,
outside the submitted work. DW received honoraria from Sanofi, Incyte, Mallinckrodt and Novartis
and a research grant from Novartis. AS reports grants from CRISPR Therapeutics, personal fees from
Vertex Pharmaceuticals, Editas Medicine, Sangamo Therapeutics, Spotlight Therapeutics, Medexus
Inc. and RCI BMT / NMDP, outside the submitted work; AS is the St. Jude Children’s Research Hospital
site principal investigator of clinical trials for genome editing of sickle cell disease sponsored by Vertex
Pharmaceuticals/CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907) and
Beam Therapeutics (NCT05456880). The industry sponsors provide funding for the clinical trial, which
includes salary support paid to the institution. AS has no direct financial interest in these therapies.
AP reports lecture fees from Novartis, outside the submitted work. KR reports lecture fees from
Celgene, Pfizer, Mallinckrodt, Jazz, BMS and Astellas; travel support from Celgene, BMS and
Mallinckrodt. OP received honoraria or travel support from Gilead, Jazz, MSD, Novartis, Pfizer and
Therakos. He has received research support from Incyte and Priothera. He is a member of advisory
boards to Equillium Bio, Jazz, Gilead, Novartis, MSD, Omeros, Priothera, Sanofi, Shionogi and SOBI. OP
acknowledges the support of José Carreras Leukämie-Stiftung (3R/2019, 23R/2021), Deutsche
Krebshilfe (70113519), Deutsche Forschungsgemeinschaft (PE 1450/7-1, PE 1450/9-1, PE 1450/10-1)
and Stiftung Charité BIH (BIH_PRO_549, Focus Group Vascular Biomedicine). TT acts as a senior ERS
methodologist. HS reports grants from Novartis and BHS, personal fees from Novartis, Janssen and
Sanofi, travel grants from Gilead, Pfizer, EBMT, CIBMTR and BHS. DS reports grants from Curetis and
AstraZeneca to the institution, personal fees from CSL Behring, Berlin-Chemie Menarini, Novartis,
GlaxoSmithKline, AstraZeneca, Vifor, Merck, Chiesi, Grifols, MSD, Merck, Sanofi, and Pfizer;
participation on advisory boards for CSL Behring, Berlin-Chemie Menarini, Novartis, GlaxoSmithKline,
AstraZeneca, Vifor, Merck, Chiesi, Grifols, MSD, Merck and Sanofi. RV reports a research grant from
Research Foundation-Flanders (FWO), advisory board fees to the institution from AstraZeneca, GSK,
Takeda and Zambon, outside the submitted work. CS, SMB, ZP, JP, SK, MB, AL, MR and CC have nothing
to disclose.
Take Home Message (256/256c):
Optimal management of patients with pulmonary chronic graft-vs-host disease is challenging. This
ERS/EBMT evidence-based guideline, developed by a multidisciplinary team along with patient
advocates, aims to support clinicians in treating pulmonary cGvHD.
Running title: Treatment of pulmonary chronic GvHD
,Keywords: pulmonary graft-versus-host disease, haematopoietic stem cell transplantation,
bronchiolitis obliterans syndrome, azithromycin, FAM, ICS/LABA, imatinib, ibrutinib, extracorporeal
photopheresis, ruxolitinib, belumosudil, lung transplantation, vaccination, pulmonary rehabilitation
Word Count: Abstract: 222/250 Main body: 9188/8000
References: 134 Figures: 1 Tables: 4 (/15 total)
Online Supplementary materials: 3 Reprint request: no reprints are requested
ABBREVIATIONS
BOS bronchiolitis obliterans syndrome
cGvHD chronic graft-versus-host disease
EBMT European Society for Blood and Marrow Transplantation
ELF European Lung Foundation
ERS European Respiratory Society
EtD evidence to decision
FAM fluticasone, azithromycin, montelukast
FEV1 forced expiratory volume in one second
FVC forced vital capacity
GRADE Grading of Recommendations Assessment, Development and Evaluation
AlloHSCT allogeneic haematopoietic stem cell transplantation
ICS inhaled corticosteroid
LABA long-acting beta agonist
NIH National Institutes of Health
PFT pulmonary function test(ing)
PICO Patient, Intervention, Comparison, Outcomes
PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses
RCT randomised controlled trial
,Abstract
Chronic graft-versus-host disease (cGvHD) is a common complication after allogeneic haematopoietic
stem cell transplantation, characterised by a broad disease spectrum that can affect virtually any
organ. Although pulmonary cGvHD is a less common manifestation, it is of great concern due to its
severity and poor prognosis. Optimal management of patients with pulmonary cGvHD is complicated
and no standardised approach is available.
The purpose of this joint European Respiratory Society and European Society for Blood and Marrow
Transplantation Task Force was to develop evidence-based recommendations regarding the
treatment of pulmonary cGvHD phenotype bronchiolitis obliterans syndrome in adults. A
multidisciplinary group representing specialists in haematology, respiratory medicine, methodology
as well as patient advocates formulated eight PICO (Patient, Intervention, Comparison, Outcome) and
two narrative questions. Following the ERS standardised methodology, we conducted systematic
reviews to address these questions and used the GRADE (Grading of Recommendations Assessment,
Development and Evaluation) approach to develop recommendations.
The resulting guideline addresses common therapeutic options (inhalation therapy, fluticasone-
azithromycin-montelukast, imatinib, ibrutinib, ruxolitinib, belumosudil, extracorporeal photopheresis
and lung transplantation), as well as other aspects of general management, such as lung functional
and radiological follow-up and pulmonary rehabilitation, for adults with pulmonary cGvHD phenotype
bronchiolitis obliterans syndrome. These recommendations include important advancements that
could be incorporated in the management of adults with pulmonary cGvHD, primarily aimed at
improving and standardising treatment and improving outcomes.
,Scope and objectives
This European Respiratory Society (ERS) – European Society for Blood and Marrow Transplantation
(EBMT) guideline provides evidence-based recommendations for the management of adult patients
with pulmonary chronic graft-versus-host disease (cGvHD) after allogeneic haematopoietic stem cell
transplantation (alloHSCT). It specifically focuses on patients with bronchiolitis obliterans syndrome
(BOS), as defined in the National Institutes of Health (NIH) consensus document.[1] Other clinical
phenotypes of pulmonary cGvHD, such as the restrictive phenotype, are not addressed in this
guideline.[2] For the sake of making more homogeneous recommendations, children with pulmonary
cGvHD were excluded, as were patients with BOS after lung transplantation.
This guideline does not address the clinical diagnosis of BOS, but outlines key management questions
ranging from inhalation therapy to evidence on pulmonary effects of treatments used for cGvHD to
lung transplantation for end-stage pulmonary cGvHD. Other aspects of general management, such as
lung functional and radiological follow-up and supportive treatment, are also discussed. Table 1
provides a framework to understand the recommendations made in this document.[4,5]
The target audience for this guideline are professionals involved in adult pulmonary cGvHD care,
including specialists in haematology, respiratory medicine, primary care physicians, pharmacists,
specialist nurses, regulatory authorities, pharmaceutical companies, and policy makers. This guideline
also aims to inform patients with lung cGvHD-BOS and their carers to assist them in discussing
therapeutic options with their healthcare teams and to facilitate access to appropriate care. However,
a guideline document cannot address the full complexity of a disease such as lung cGvHD-BOS, and all
recommendations should therefore be interpreted by considering individual clinical circumstances
and perceptions, preferences and values.
Introduction
AlloHSCT is a potentially curative treatment for well-selected patients with various haematological
malignancies and non-malignant diseases.[6] Despite advances in donor and recipient selection,
conditioning regimens and immunosuppressive agents, cGvHD remains a major cause of late post-
transplant morbidity and mortality, occurring in 30-70% of patients.[7] It is characterised by
heterogeneous disease manifestations in which virtually any organ can be affected, and in which tissue
inflammation and fibrosis can result in permanent organ dysfunction.[7]
Late-onset non-infectious pulmonary complications – of which pulmonary cGvHD is a frequent cause
– are common after alloHSCT and develop in up to 20% of patients, mostly within the first two years
post-transplant.[8] Pulmonary cGvHD can present with obstructive or restrictive changes, or a
combination of both.[9] The obstructive phenotype BOS is the most common and best-defined late
pulmonary complication and currently the only entity formally recognised as a manifestation of
pulmonary cGvHD.[9] It is thought to affect 5% of patients after alloHSCT and up to 14% of patients
with established cGvHD, although these numbers are most likely underestimated due to suboptimal
diagnosis.[10] Similar to chronic lung allograft dysfunction after lung transplantation[3], other clinical
phenotypes have been identified in recent years, including a restrictive phenotype, characterised by
interstitial lung disease resulting in restrictive lung function decline.[2] Clear definitions of this entity
are still lacking, making its recognition in daily practice challenging. In this guideline, we will focus on
BOS as this is the most common and best-described clinical phenotype.
BOS is characterised by progressive small airways disease, which often responds poorly to treatment
and has a natural course of leading to respiratory insufficiency and lung failure.[9] Diagnosis is
primarily based on pulmonary function testing (PFT), according to NIH criteria.[1,11] Since PFT is often
,not implemented in routine clinical follow-up after alloHSCT, and respiratory symptoms only appear
at an advanced disease stage and may be non-specific, early diagnosis of BOS is often missed,
precluding timely intervention.[9] The NIH consensus therefore advocates the use of serial PFT after
alloHSCT, also in asymptomatic patients.[11]
Management of pulmonary cGvHD is challenging, both in terms of diagnosis and treatment. Only few
therapeutic options are available, some of which have been adopted from BOS after lung
transplantation. There is no standard of care and conventional immunosuppression for BOS varies
between centres and often consists of corticosteroids (inhaled and/or systemic), sometimes in
combination with azithromycin and/or montelukast. In addition, drugs for cGvHD are regularly used.
While the treatment landscape has expanded in recent years with the US Food and Drug
Administration’s approval of multiple agents for the treatment of cGvHD, little is currently known
about the impact of these newer agents on BOS.[12,13] As such, the use of these drugs often remains
empirical and some are associated with significant toxicities and high failure rates, primarily because
the exact underlying immunopathological mechanisms of pulmonary cGvHD are incompletely
understood.[7] It is important to emphasise that pulmonary cGvHD is usually part of a broader disease
spectrum, with patients already receiving immunosuppressants for other cGvHD manifestations.
Thus, there is currently no harmonised approach to manage pulmonary manifestations of cGvHD and
the aim of this guideline is to provide a state-of-the-art update on available evidence and to deliver a
practical guideline regarding the treatment of adults with lung cGvHD-BOS targeting 1) treatment, 2)
lung functional and radiological follow-up, and 3) supportive treatment.
Methods
This guideline was developed by a joint ERS/EBMT Task Force chaired by R. Vos (Belgium), D. Stolz
(Germany) and S. Bos (Belgium/UK) and included specialists in haematology and respiratory medicine,
with recognised expertise in the management of pulmonary cGvHD and/or BOS after lung
transplantation, as well as a specialist nurse, ERS methodologist, European Lung Foundation (ELF)
representative, and two patient representatives. The specific expertise of the panel is outlined in
Supplement 1. The patient representatives were actively involved in all discussions as full members of
the panel, provided input into the final recommendations, and will be involved in developing a lay
version of the guideline. Between September 2021 and July 2023, the panel met 20 times (all
videoconferences) and a smaller methodology subgroup met a further six times. In addition, regular
discussions on individual topics were held via email.
PICO and narrative questions
Key clinical questions for both clinicians and patients about treatment of pulmonary cGvHD were
discussed. Following the ERS methodology, we formulated eight questions in accordance with the
PICO format (Patient, Intervention, Comparison, Outcomes) alongside two narrative questions.[5] In
order to develop a meaningful and focused guideline, the panel restricted the PICO questions to
agents studied specifically for lung GvHD-BOS or used for cGvHD. Since there is currently no standard
of care and conventional immunosuppression used for lung cGvHD-BOS varies widely around the
world, no specific comparator was chosen, also to allow inclusion of all studies available. The panel
assumed conventional immunosuppression would encompass but not be restricted to routinely used
pharmacological treatments for cGvHD, including inhaled and/or systemic corticosteroids (PICO 1-7),
possibly in combination with azithromycin and/or montelukast (PICO 3-7), and sometimes other
immunosuppressants (e.g., calcineurin inhibitors, mycophenolate mofetil) or no immunosuppression.
,Often certain immunosuppressants (e.g., systemic corticosteroids, calcineurin inhibitors) are tapered
or discontinued during the new treatment course.
The panel, including patient representatives, decided on the outcomes of interest for each PICO
question, based on their relative importance to adults with lung cGvHD-BOS and clinical decision-
making.[14] (Supplement 1) Systematic reviews were performed to answer PICO questions. For
narrative questions, systematic searches were conducted, and the evidence was reviewed in a
narrative manner.
Disclosure of potential conflicts of interest
Panel members disclosed all potential conflicts of interest as per ERS policy. (Supplement 1) Members
with potential conflicts were asked to abstain from voting on recommendations in which there was
potential conflict. The ERS methodologist, ELF representative and librarian were non-voting members
of the panel.
Systematic review
The systematic review was performed according to ERS methodology.[15] An experienced librarian
designed and ran the search strategies on the electronic databases of PubMED, EMBASE and Cochrane
Library using MeSH terms and keywords for each clinical question. The initial searches undertaken in
March 2022 were updated in March 2023. Results of the searches were sent to panel member pairs
and independently screened using predefined inclusion and exclusion criteria. A detailed description
of the methods and PRISMA flow diagrams for all PICO and narrative questions can be found in
Supplement 1. For selective narrative questions, we conducted additional searches to seek supportive
evidence from alloHSCT, general cGvHD and respiratory literature, due to a lack of data specifically
addressing our questions.
Articles were summarised using the ERS framework for guideline development, including both
systematic (for PICO questions) and narrative (for additional sources and narrative questions) reviews
of the evidence.[5]
Assessment of the level of evidence and degree of recommendations
The GRADE approach was used to assess the certainty of the evidence and the degree of
recommendations.[4] Recommendations were graded as strong or conditional after considering the
certainty of the evidence, balance between desirable and undesirable outcomes, assumptions about
the relative importance of outcomes, implications for resource use, and acceptability and feasibility
of implementation. Key considerations correlated with these gradings are summarised in Table 1.
Evidence profiles and evidence to decision (EtD) frameworks were generated for each PICO question,
and EtD frameworks were generated for narrative questions.[16] (Supplement 2 and 3) Based on these
formats, the panel formulated clinical recommendations and decided on their strength by consensus
or voting, if required. Following the GRADE approach, strong recommendations are phrased as “we
recommend”, while conditional recommendations are phrased as “we suggest”.
Results
The number of studies identified and selected for each PICO and narrative question are displayed in
the PRISMA flow diagrams (Supplement 1). The EtD frameworks are summarised here, with complete
versions in Supplement 3, and grouped into treatment, lung functional and radiological follow-up, and
supportive treatment.
,Treatment
PICO question 1
In adults with lung cGvHD phenotype BOS, should inhaled corticosteroids with or without long-acting
beta agonists be used in addition to their conventional immunosuppressive regimen?
Recommendation
• In adults with lung cGvHD phenotype BOS, we suggest using inhaled corticosteroids with or
without long-acting beta agonists in addition to their conventional immunosuppress ive
regimen. (Conditional recommendation, low certainty of evidence)
Remarks
It is important to select the most appropriate device for a patient and train them in its use, ensuring
optimal technique and taking into account patient preferences. Some patients, for example, will not
have enough inspiratory flow to use dry powder inhalers. Consideration should also be given to
environmental factors, trying to avoid pressurised metered dose inhalers (MDIs) where possible.
The use of inhaled corticosteroids should be considered on a case-by-case basis in patients with a
bronchiectasis phenotype.
Summary of evidence
There is one multicentre randomised controlled trial (RCT) that investigated the efficacy of inhaled
corticosteroids and long-acting beta agonists (ICS/LABA) in 32 mild to moderate BOS patients.[17]
They demonstrated that forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)
were statistically significantly higher at 1 month compared with baseline in the
budesonide/formoterol arm than in the placebo arm and remained stable at 6 months. There were no
statistically significant changes in quality of life between baseline and 1 month evaluated using the St
George's Respiratory Questionnaire score. Regarding undesirable effects, there was no difference in
bronchial infections between both groups.[17]
Certainty of the evidence was low due to downgrading for imprecision.
Other supportive evidence
Weaker supportive evidence comes from three observational studies (13-77 patients per study, 107
in total).[18-20] One study found a mean increase in FEV1 of 534 mL (±286 mL), with all 13 patients
having an improved FEV1 of > 10% of predicted value or ≥ 200 mL.[18] Bashoura et al. found a
statistically non-significant increase in median FEV1 of +8% (p=0.057) using high-dose ICS.[20] The
third study found no difference in FEV1, but an improvement in FVC and quality of life, assessed by
chronic obstructive pulmonary disease assessment test, in 68% of patients. They also found no
difference in incidence of pneumonia or bronchitis symptoms requiring antibiotics 3 months before
compared with 3 months after treatment.[19] Unfortunately, none of these studies provided
information on the impact on oral corticosteroid dose.
This recommendation is based on four small studies, which did not compare specific types of ICS±LABA
inhalers. However, in much larger RCTs of patients with chronic obstructive pulmonary disease,
another obstructive airway disease, ICS/LABA therapy has been shown to reduce death and
exacerbations and improve health status and FEV1 compared with either component alone or
placebo.[21,22] Long-term safety data in this population suggest some increase in skin bruising and
oral candidiasis and a small increase in non-fatal pneumonia.[23] The benefit of combination inhalers
is largely cited as being secondary to improved adherence and cost-effectiveness.
Justification of recommendation
Although the number of studies and patients included was low, one RCT showed efficacy in BOS
patients with a low risk of adverse events, which was also seen in some of the observational studies.
Clinicians and patient advisory group conclude that ICS±LABA offers good value as a therapeutic
modality in terms of positive outcomes, especially FEV1, without evidence of increased infection risk.
, Implementation considerations
ICS±LABA inhalers are relatively widely available in countries in which alloHSCT is taking place. It is
important to have personnel available with experience in selecting and training how to use an inhaler.
There is benefit from having a close collaboration with local respiratory department and personnel. It
is also useful to have resources available on inhaler techniques (e.g., leaflets, online tutorials).
Monitoring/evaluation
It is important that inhaler technique and adherence are monitored and that the benefit of ICS±LABA
is objectively evaluated to make decisions on continuation. The optimal duration of therapy remains
unclear. Ideally, spirometry should be monitored one month after initiation of therapy and addition
of other therapies needs consideration in case of further disease progression.
Future research
Larger studies are needed and should include RCTs of ICS/LABA for patients with severe BOS as well
as combination therapy with long-acting muscarinic agonists. Given the irreversibility of BOS in most
cases, the duration of inhaled therapy and need for long-term bronchodilators should also be studied.
PICO question 2
In adults with lung cGvHD phenotype BOS, should fluticasone, azithromycin and/or montelukast be
used in addition to their conventional immunosuppressive regimen?
Recommendation
• In adults with lung cGvHD phenotype BOS, we suggest using fluticasone, azithromycin and/or
montelukast in addition to their conventional immunosuppressive regimen. (Conditional
recommendation, very low certainty of evidence)
Remarks
Azithromycin should be used with caution in patients with a high risk of secondary malignancies or
cancer predisposition syndromes (e.g., short telomere syndrome, bloom syndrome, Fanconi anaemia).
Summary of evidence
Two observational studies evaluated the combination of fluticasone, azithromycin and/or
montelukast (FAM) in adults with lung cGvHD-BOS.[24, 25] One prospective study, with 36 patients
within 6 months of BOS diagnosis, demonstrated a statistically significant decrease in treatment
failure, defined as ≥ 10% FEV1 decline at 3 months, from 40% in historical controls to 6%.[25] In
contrast, a retrospective case-control study showed no significant difference in FEV1 change at 6
months between eight patients treated with FAM and rapid steroid taper and 14 historical controls
on high-dose steroids with standard taper.[24] With respect to quality of life outcomes, SF-36 social
functioning, mental component score, and FACT emotional well-being scores improved statistically
significantly, as did the Lee symptom score and exercise capacity.[25]
The prospective study showed that prednisone dose could be reduced by ≥ 50% in 48% of patients at
3 months and 71% at 6 months, although new systemic treatments were added in 31% of patients.[25]
Similarly, prednisone exposure was statistically significantly lower in FAM-treated patients in the
retrospective study.[24] Regarding adverse events, there was no difference in disease relapse[24] and
a low incidence of respiratory tract infections (17%) and pneumonitis (3%)[25].
The certainty of the evidence was very low due to downgrading for risk of bias, inconsistency and/or
imprecision.
Other supportive evidence
Two studies examined the effect of azithromycin alone[26,27], with one RCT showing no statistically
significant changes in lung function or respiratory symptoms[27], and a case series showing a 21%
increase in FEV1 and a 22% increase in FVC, as well as improvements in dyspnoea and exercise
tolerance[26]. In a study examining montelukast alone, FEV1 stabilised in all 23 patients and improved
in 22%, with 17% achieving > 50% reduction in steroid dose.[28]
