Bronchiolitis obliterans after allo-SCT: clinical criteria and ... - Nature

Bone Marrow Transplantation (2012) 47, 1020–1029 & 2012 Macmillan Publishers Limited All rights reserved 0268-3369/12

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Bronchiolitis obliterans after allo-SCT: clinical criteria and treatment options HH Uhlving1,2, F Buchvald1,3, CJ Heilmann1, KG Nielsen1,3, M Gormsen4 and KG Mu¨ller1,2 1

Paediatric Clinic, National University Hospital Rigshospitalet, Copenhagen, Denmark; 2Department of Rheumatology, Institute of Inflammation Research, National University Hospital Rigshospitalet, Copenhagen, Denmark; 3Paediatric Pulmonary Service, National University Hospital Rigshospitalet, Copenhagen, Denmark and 4Department of Radiology, National University Hospital Rigshospitalet, Copenhagen, Denmark

Bronchiolitis obliterans (BO) following allogeneic haematopoietic SCT (HSCT) is a serious complication affecting 1.7–26% of the patients, with a reported mortality rate of 21–100%. It is considered a manifestation of chronic graftversus-host disease, but our knowledge of aetiology and pathogenesis is still limited. Diagnostic criteria are being developed, and will allow more uniform and comparable research activities between centres. At present, no randomised controlled trials have been completed that could demonstrate an effective treatment. Steroids in combination with other immunosuppressive drugs still constitute the backbone of the treatment strategy, and results from our and other centres suggest that monthly infusions of high-dose pulse i.v. methylprednisolone (HDPM) might stabilise the disease and hinder progression. This article provides an overview of the current evidence regarding treatment options for BO and presents the treatment results with HDPM in a paediatric national HSCT-cohort. Bone Marrow Transplantation (2012) 47, 1020– 1029; doi:10.1038/bmt.2011.161; published online 29 August 2011 Keywords: bronchiolitis obliterans; allogeneic haematopoietic SCT; chronic graft-versus-host disease; treatment outcome; methylprednisolone

Introduction Bronchiolitis obliterans (BO) is an obstructive lung disease seen after allogeneic haematopoietic SCT (HSCT).1 Respiratory symptoms include cough, dyspnoea and wheeze, but patients may remain relatively asymptomatic despite moderate-to-severe obstruction. The pronounced variability in reported incidences (1.7–26%) and mortality rates (21–100%)2–11 of BO may be because of the lack of consistent definitions.11–16 No validated treatment protocol has been established.

Correspondence: Dr HH Uhlving, Paediatric Clinic 4072, National University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Oe, Denmark. E-mail: [email protected] All authors have approved the final version. Received 4 February 2011; revised 4 July 2011; accepted 6 July 2011; published online 29 August 2011

This article reviews our current knowledge of the pathogenesis of BO and outlines the current practice in the treatment of this serious complication. Finally, we present our experience of high-dose i.v. pulse methylprednisolone treatment (HDPM) in children with BO after allogeneic HSCT.

Pathogenesis Because BO resembles allograft-rejection in lung-transplant recipients (BO syndrome (BOS)) at a pathological, immunological and physiological level,17 studies of BO in HSCT patients are discussed along with studies of BOS in lung transplant patients in the following. Increasing evidence suggests that T-cell-mediated recognition of alloantigens expressed in the lung tissue constitutes a central event in the pathogenesis of BO. Thus, in lung transplanted patients HLA mismatch confers an increased risk,18 and signs of BO after HSCT is often accompanied by alloreactivity in other organs (for example, skin, liver and eyes).1,3–8,19–22 The essential role of T-cellmediated allorecognition was further indicated by a study showing reduced frequency of BO in HSCT patients receiving a T-cell-depleted graft.23 Other reported risk factors are BU-based conditioning regimens,9,24–26 the intensity of conditioning,27 time from leukaemia diagnosis to HSCT, peripheral blood-derived stem cell source, grade II–IV acute GvHD (aGvHD),9 pre-transplant airflow obstruction and viral respiratory tract infection within the first 100 days after HSCT.10 The findings are however, not consistent between studies. Histopathologically, the BO process begins with lymphocyte infiltration around the small vessels and beneath the respiratory epithelial lining in the small airways, followed by epithelial cell necrosis and denudation of mucosa.28 A secondary cascade of non-specific inflammatory mediators attracts other cells, including neutrophils, and leads to migration of fibroblasts, proliferation of smooth muscle cells, and eventually collagen deposition and fibrous obliteration of the lumen.29,30 Interestingly, studies of BOS in lung transplant recipients have suggested a central role of T-cell-mediated reactivity towards collagen. Thus, infiltrating monocytes as well as collagen type V (col(V))-specific Th17 cells are seen in the

Bronchiolitis obliterans in clinical practice HH Uhlving et al

1021

inflammatory focus.31 Col(V), which is essential for lungtissue elasticity and compliance, is in healthy individuals not exposed to immune cells. It is conceivable, although not yet shown, that T-cell-mediated recognition of col(V) may also play a pathogenetic role in BO after HSCT, where col(V) may be exposed as a result of epithelial damage by chemotherapy and/or irradiation. T-cell activation is initiated by APCs—usually DCs and differentiation of T-cells into T helper 1 (Th1), Th2, Th17 and/or regulatory T-cells (Treg) is determined by the cytokine profiles in the microenvironment during T-cell differentiation.32 Animal studies have suggested a mutually exclusive differentiation of CD4 þ cells into either Th17 or Treg, depending on the presence (Th17) or absence (Treg) of IL-6.33 The Th17 subset is important in the development of inflammation and autoimmunity, while Tregs may downregulate inflammatory activity in autoimmune diseases and inhibit graft rejection in organ transplantation.32 Lung transplant patients affected with BOS have a lower level of circulating CD4 þ CD25 þ Treg than patients in a stable clinical condition.34 In line with this, an animal model of BOS has shown increased local IL-17 production, with decreased peripheral blood levels of Tregs.35 IL-17 has been shown to induce IL-8 secretion,36,37 which in turn is related to airway neutrophilia.38,39 This may be of potential clinical interest because the number of neutrophils in the airways has been associated with clinically defined BOS phenotypes following lung transplantation.40 Increasing interest is rewarded the role of B cells in chronic GvHD.41 Elevated blood levels of B-cell activating factor, essential for survival and differentiation of B cells, have been demonstrated in cGvHD-42,43 and BO-patients.44 A study in lung transplant recipients has suggested a temporal relationship between development of anti-HLA antibodies and BOS.45 Murine studies have demonstrated that specific antibodies towards HLA class I activate parenchymal cells in a tracheal allograft, resulting in proliferation, growth factor production and apoptosis. This process leads to the activation of fibroblasts, tissue remodelling and proliferation of fibrous tissue observed during BOS development.46 Taken together, these data suggest a model in which respiratory insults and extensive inflammation during the transplantation constitute a ‘primary hit’ that results in upregulation of MHC molecules and exposure of ‘neoantigens’ including col(V). This leads to Th17-biased differentiation of T-cells, and subsequently IL-8-driven neutrophilia. B-cell activation, Ag presentation and production of anti-HLA Abs may result in aggravation and maintenance of the inflammatory response and ultimately epithelial destruction and pulmonary fibrosis. Efforts to prevent and treat BO have been directed towards various steps of this cascade, but the limited clinical success underlines that our knowledge of this condition is still sparse.

Diagnosis Early diagnosis of BO is difficult, because patients are often asymptomatic in the early stages of the disease7 and

inconsistency in applied diagnostic criteria have made it difficult to compare research results with respect to aetiology, treatment and outcome. The National Institute of Health (NIH) Consensus Development Project published in 2006 the first comprehensive attempt to define clinical criteria for the diagnosis.12 Accordingly, the diagnosis of BO requires fulfillment of all of the following criteria: (1) Absence of active infection. (2) Forced expiratory volume in 1 second (FEV1) o75% of predicted normal and FEV1/forced vital capacity ratio o0.7. (3) Evidence of air trapping or small airway thickening or bronchiectasis on high-resolution computed tomography, residual volume 4120% of predicted or pathological confirmation of constrictive bronchiolitis Chronic GvHD may be diagnosed when BO is proven by lung biopsy. BO diagnosed via clinical criteria requires at least one manifestation in a separate organ system to establish the diagnosis of cGvHD.12 The term idiopatic pneumonia syndrome is by the American Thoracic Society defined as widespread alveloar injury evidenced by radiology, signs and symptoms of pneumonia and either an increased alveolar to arterial oxygen gradient or a restrictive pulmonary function test not attributed to infection, cardiac dysfunction, renal failure or iatrogenic fluid overload.47 Although BO primarily is defined as an obstructive lung disease, cases of BO will often also fit the idiopatic pneumonia syndrome definition. Most cases of idiopatic pneumonia syndrome, however, occurs in the first 3 months after SCT.47–50 The need for further development of these criteria is, however, a matter of ongoing discussion. In a retrospective study by Williams et al.,11 only 18% of previously diagnosed BO patients with a FEV1 of o55%, met the NIH consensus criteria. As forced vital capacity and total lung capacity in HSCT patients can be falsely low because of restriction from scleroderma or myositis, these authors suggested a definition of obstruction confirmed by either FEV1/slow vital capacity or air trapping on high-resolution computed tomography with residual volume or residual volume/total lung capacity4120%.11

Treatment Although a number of first- or second-line treatment strategies have been described in the literature, no randomised controlled trials have described a long lasting effect of any treatment modality for BO.51–53 A Medline search on English literature, including prospective and retrospective studies, randomised or not randomised, with more than three participants published since 2000, revealed 18 studies54–72 and 10 treatment modalities (Table 1). Using the NIH grading system, no treatment modality reached an evidence level above III (evidence from opinions of respected authorities based on clinical experience, descriptive studies or reports from expert committees). The strength of recommendation was C (insufficient evidence to support recommendation or outweigh adverse effects or Bone Marrow Transplantation

SoR-EL

C-III

C-III

C-III

C-III

C-III

C-III

HDPM

Inhaled steroids

Bone Marrow Transplantation

Montelukast

Azithromycin

TNF-a inhibitor

Extracorporal photopheresis

Severe cGVHD with BO according to the NIH Consensus Criteria12

Prospective cohort study, no randomisation or control group

Observational study, Decline in FEV1 of 420%, and evidence Eight patients. Mean age 36 no randomisation or of air trapping on HRCT years (range 18–63) control group

Randomised double- FEV1o75%, FEV1/FVC ratio o0.7 and 12 patients in treatment group, No significant changes in respiratory scores blinded placeboreduction of FEV1 by 410% compared mean age 44.5 years (range 31– and FEV1 in the treatment and control with baseline values controlled study 56), 10 patients control group groups mean age 43 years (24–57)

10 mg 1. Median treatment period 16 months (range 2–29)

500 mg 1 for 3 days, followed by 250 mg three times/week for 3 months

250 mg 1 for 12 weeks

Etanercept subcutaneously 25 mg twice weekly for 4 weeks, followed by once weekly for 4 weeks

Etanercept 25 mg (0.4 mg/kg for children) twice weekly for 4 weeks, followed by once weekly for 4 weeks

Three cycles/week for 1 week Randomised, singlefollowed by twice weekly on blinded multicentre consecutive days during study weeks 2–12

Two to four treatments/week Retrospective, until partial response, non-randomised, subsequently tapered by 1/ single-centre study week. Maintenance regimen two treatments/2 weeks.

Khalid57

Lam58

Busca59

Chiang60

Flowers61

Couriel62

Prospective cohort study, no randomisation or control group

cGVHD with symptomatic BO and (1) decrease in FEV1 420% in 1 year, (2) air trapping or small-airway thickening or bronchiectasis on HRCT or pathologic confirmation of BO and (3)

Extensive cGVHD with lung involvement, as defined by Lee et al.:13 FEV1o80% and a decrease in FEV1/ FVC by 10% in o1 year not explained by infection, asthma or aspiration. Stable corticosteroid dose for at least 2 weeks before inclusion

Steroid dependent cGVHD involving lungs (not specified further)

Retrospective study, Steroid-refractory cGVHD with BO no randomisation or according to the NIH Consensus control group Criteria12

11 patients with lung involvement/71 with cGVHD. Median age all patients 39 years (range 5–70)

Nine patients with lung involvement/48 with cGVHD in ECP group. 7/47 in control group. Median age ECP group 41 years (range 16–67), controls 43 years (range 13–67)

Five patients with lung involvement/10 with cGVHD. Median age all patients 38 years (range 3–48)

Complete response in 1/11. Partial response in 5/11 (sustained improvement in FEV1 and/or the ability to taper corticosteroids by 50% without deterioration of pulmonary function). Follow-up 6 months

Improvement defined as investigators assessment of complete resolution or objective improvement: ECP group 11%, control group 29%; NS. Follow-up 12 weeks

Partial response in 2/5 (450% improvement in symptoms, reduction in steroid dose or immunosuppressive agents). One died of TTP. Median follow-up all patients 7 months (range 3–18)

Five patients with BO/8 with Partial response in 3/5 (450% response in cGVHD. Median age all one evaluable organ without deterioration patients 52 years (range 26–70) of other). Progressive disease in 2/5. 1/5 died of GVHD and septic shock. Median follow-up 13.5 months (range 10.1–22.5)

412% improvement in FEV1 in 7/8 patients. Mean increase in FEV1 20.58% (Po0.0067) and FVC 21.57% (Po0.0052). Follow-up 12 weeks

Five patients with BO/19 with 430% increase in FEV1 in 3/5 patients. 2/5 cGVHD. Median age 33 years patients died of end-stage BO. Follow-up (range 17–54) time not reported

410% increase in FEV1 in 13/13 patients. Mean increase in FEV1 36±27% (P ¼ 0.018). Decreased dyspnea in 11/13 pt. Median follow-up 12.8 months (range 5– 29)

Significant improvement in FEV1 at 2 months (Po0.02). 7/9 remained clinically stable. One died from respiratory failure. Mean follow-up 42±20 months (range 19–67)

Or56

13 patients. Median age 44 years (range 16–57)

Nine patients, of whom five were able to perform spirometry. Median age 8 years (range 1–17)

Retrospective study, FEV1/VCo5th percentile of normal no randomisation or value without reversibility OR HRCT control group with air-trapping score 45 (maximum score 18,73). No extrathoracic signs of cGVHD

4/5 of criteria fulfilled: (1) airway obstruction without reversibility; (2) no pulmonary infiltrates; (3) no signs of infection in blood or BAL; (4) reduced FEV1 without airway restriction; (5) bronchial dilatation and mosaic pattern on HRCT

Budenosid/formoterol 400/ 12 mg 2/daily

Retrospective paediatric study, no randomisation or control group

Bergeron55

No. and age of patients enrolled Results

i.v. Methylprednisolone 10 mg/kg for 3 consecutive days every 4–6 weeks. Median 4 treatment cycles (range 1–6)

cGVHD and BO definitions

Ratjen54

Type of publication

Dosage

Author

Clinical studies on treatment strategies for BO and chronic lung GvHD after HSCT

Treatment regimens

Table 1


1022

Continued

SoR-EL

C-III

C-III

C-III

Table 1

Treatment regimens

Rituximab

Pentostatin

Imatinib

Two treatments per week for Retrospective singlecentre study 3–4 weeks, decreased to every 2–3 weeks. Maintenance regimen two treatments/4 weeks. Median treatment period not reported Retrospective multicentre study

Open-label, multicentre, prospective phase II study

375 mg/m2 i.v. every week. Median 4 treatments (range 4–20)

375 mg/m2 i.v. weekly for 4 weeks, then monthly for 4 months

Lucid65

Zaja66

Kim67

Olivieri69

Initially 100 mg/day, increased over 4 months to maximum 400 mg/day, depending on the response. Median treatment period 5 months (range 6–15)

Five patients with lung involvement/32 with cGVHD. Median age 35 years (range 25–56)

14 patients with lung involvement/44 with cGVHD (12 patients with moderate to severe obstruction). Median age all patients 8.2 years (range 0.3–20.5)

Biopsy proven active cGVHD (increase in symptoms during, or when tapering, immunosuppressive medicine) and PFT o50% of normal values (PFT not formally included endpoint). Failure of one or more immunosuppressive in at least 4 months

Steroid refractory moderate to severe cGVHD according to the NIH consensus criteria (Filipovich12)

Extensive cGVHD (Revised Seattle Classification, Lee13) with lung involvement (FEV1o80%, decreased FEV1/FVC by 10% in o1 year, no infection, asthma or aspiration and if no cGVHD in other organ: air trapping on HRCT, negative BAL or BO in biopsy)

11 patients with lung involvement/19 with cGVHD. Median age all patients 29 years (range 10–62)

Six patients with lung involvement/58 with cGVHD. Median age all patients 33 (range 5–64)

11 patients with lung involvment/37 with cGVHD. Median age all patients 29 years (range 8–57)

Nine patients with lung involvement/38 with cGVHD. Median age all patients 48 years (range 22–61)

Complete remission after 6 months in 3/11. Partial remission in 4/11 (sustained improvement in PFT or ability to taper corticosteroids by at least 50% without deterioration). 9/11 alive at follow-up. Median follow-up 17 months (range 8–22)

Immunosuppression tapered/discontinued in 4/6. Median follow-up of responding patients 175 days (range 1–701)

Partial response in 1/11 (clinical score reduction in at least one affected organ, without deterioration in other organ). No response in 10/11. Follow-up 1 year

Partial response (450% regression of cGVHD) and dose reduction of immunosuppressives in 3/9. Follow-up 15 months (range 12–22)

Stabilized lung function in 6/9 patients. Symptomatic improvement in 2/3 ‘nonresponders’. Median follow-up 25 days (range 20–958)

Partial response in 2/5. Stabilisation in 1/5. Disease progression in 2/5 (no further specification). Follow-up time not reported

Complete response in 4/12 with moderate/ severe lung disease. Partial response in 2/7 with severe disease (450% response in organ involvement). Follow-up time not reported


BO according to amended NIH criteria Nine patients. Median age 38 (Williams11). Refractory to prior therapy years (range 21–54) with median five different drugs (range 2–7)

Steroid refractory cGVHD with lung involvement assessed by pulmonologist based on FEV1, FVC, DLCO and HRCT (criteria not further specified)

cGVHD (Sullivan15) failing to respond to X2 lines of therapy. Obstructive lung disease characterised as mild (FEV1 70–100%), moderate (FEV1 60–70%), moderate severe (FEV1 50–60%), severe (FEV1 34–40%) (American Thoracic Society74)

no evidence of active infection. Refractory to immunosuppressives


Prospective nonActive cGVHD with fibrotic randomised single scleroderma-like features, resistant to centre phase 1–2 trial 42 immunosuppressives. BO and/or extensive lung fibrosis confirmed by biopsy and/or spirometry, DLCO and HRCT. Median FEV1 at baseline 70%(range 32–78%). Median DLCO 68% (48–74%)

Jacobsohn68 4 mg/m2 i.v. every 2 weeks Prospective, nonfor at least 12 doses. Median randomised, double12 doses (range 1–32) centre study. No control group

Prospective nonrandomised singlecentre study. No control group

Two treatments on consecutive days every 2 weeks for 4 months, then once monthly for at least 2 months. Median treatment period not reported

Rubegni64

Retrospective paediatric, multicentre nonrandomised study

Type of publication

Two treatments on consecutive days per week for 1 month, every 2 weeks for 2 months, then monthly for at least 3 months. Median treatment period not reported

Median 32 ECP procedures (range 1–259)

Dosage

Messina63

Author


1023


Complete response 3/14. Partial response in 2/14 (improved performance status, 450% resolution of signs and symptoms). Median follow-up 53 months (range 5–159) 14 patients with lung involvement/59 with cGVHD. Median age all patients 31.5 years (range 2–52) Retrospective, nonrandomised study Initially 50–100 mg 3, increased gradually depending on tolerance and clinical response Median daily dose 400 mg (range 50–1200). Median treatment period 61 days (range 1–1210) Kulkarni71

Extensive cGVHD (present in 41 organ) with lung involvement (Sullivan,14 Akpek16). No, or insufficient, response to prednisolone and cyclosporine and/or azathioprine

Recovery of lung function (from severe to moderate reduction) in 1/9. Ability to taper steroids in 2/9. No change in 5/9. 2/9 died of BO and/or relapse. Follow-up time not reported Nine patients. Median age 45 years (range 24–50) Severe pulmonary cGVHD, resistant to extensive immunosuppressive therapy. Median FEV1 29% (range 18–41) Prospective, single centre, open-label non-randomised study 100–400 mg/day. Median treatment period 4 months (range 1–17) Stadler70

Continued

SoR-EL

C-III

Table 1

Treatment regimens

Thalidomide

Type of publication Dosage Author



1024


Abbreviations: BAL ¼ bronchoalveolar lavage; BO ¼ bronchiolitis obliterans; cGVHD ¼ chronic GVHD; DLCO ¼ carbon monoxide diffusing capacity; EL ¼ evidence level; ECP ¼ extracorporeal photopheresis; FEV1 ¼ forced expiratory volume in 1 second; FVC ¼ forced vital capacity; HDPM ¼ high-dose pulse i.v. methylprednisolone; HRCT ¼ high-resolution computed tomography; HSCT ¼ haematopoietic SCT; NS ¼ non significant; NIH ¼ National Institute of Health; PFT ¼ pulmonary function test; SoR ¼ strength of recommendation; TTP ¼ thrombotic thrombocytopenic purpura.


costs of the approach) for all treatment modalities apart from treatment with corticosteroids (A-III), which is discussed in the following.

Corticosteroids In 2005, Ratjen et al.54 reported their experience with HDPM treatment in a small cohort of nine children. To our knowledge, no other published study has described this treatment regimen for BO after HSCT. HDPM treatment is recommended in other inflammatory lung diseases in children.75,76 Reported side effects include transient flushing, headache, mood changes77 and sinus bradycardia,78 but no serious long-term events have been described in children. HDPM has been the standard treatment of BO since 1999 at our centre, and we here summarise the results. HDPM treatment in the Danish paediatric BO cohort. Within the recent 12 years BO has been diagnosed in 13 children following HSCT (median age 9.3 years, range 0.6–13.4) at the national paediatric HSCT centre in Denmark. This corresponds to 7.3% of Danish SCT patients below 16 years of age in this period. Nine of the patients were able to perform a reliable spirometry and had significantly reduced levels of function (Table 2). In five cases BO was confirmed by open lung biopsy. The final diagnosis of BO was based on a combination of decreased lung function parameters, highresolution computed tomography findings, lung biopsy and/or clinical symptoms, but none of the nine patients fully met the NIH clinical criteria for BO. Our patient cohort was treated with a combination of conventional immunosuppressive agents (Table 3) and i.v. HDPM 15 mg/kg for 2–3 consecutive days every 4–6 weeks. Median time from HSCT to first BO symptoms was 141 days (range 53–254) and from symptoms to first course of HDPM 35 days (3–244). Spirometry was performed before HSCT, before initiating HDPM therapy, and then monthly. Patients with FEV1 o35% and patients who were unable to taper oral prednisolone within 6 months of HDPM initiation were given additional treatment with monthly infusions of infliximab. One patient (no. 8) died of respiratory insufficiency because of CMV-pneumonia 1 month after initiation of therapy, whereas one patient (no. 6) died of leukaemic relapse. In the patients tested, a significant increase in FEV1 was seen 3 months (P ¼ 0.010) and 1 year (P ¼ 0.011) after initiation of HDPM (the Wilcoxon rank sum test), with median increase in FEV1 from 48.1% at treatment initiation to 71.4% and 83.0%, respectively (Figure 1). During further follow-up lung function generally stabilised at a moderately reduced level. This small population-based study of a rather heterogeneous group of patients has obvious limitations, shared by the majority of the previous studies presented in Table 1, and does not allow firm conclusions. Our data suggests that stabilisation of lung function in BO patients may be achieved by early commencement on high-dose pulse corticosteroids in combination with other immunosuppressive treatment. The effect of HDPM on relapse rate and infectious complications cannot be properly assessed in a study of this size. Further studies, preferebly a multicenter


1025 The Danish paediatric BO cohort accordance with NIH clinical criteria at time of diagnosis

Table 2 BO on biopsy

FEV1%

FEV1/ FVC%

1 2 3 4 5 6 7 8

Yes Yes No No No No Yes Yes

42.8 39 53.5 29.3 62.0 61 53.5 40.4

106.8 89.4 77.4 91.0 95 85 65.8 109.3

9

No

39.8

69.3

HRCT Bronchiectasis, air trapping Air trapping Bronchiectasis, bronchial thickening, small nodular opacities Air trapping, bronchiectasis, bronchial thickening Bronchiectasis, bronchial thickening, air trapping — Centrilobular opacities and reduced transparency Air trapping, bronchiectasis, bronchial thickening, ground glass opacities, consolidation of peripheral lung segments Normal

RV%

Infection

RV/TLC%

cGVHD in other organ

Unknown Unknown 111.40 Unknown 127 131 Unknown Unknown

No No No No No No No No

Unknown Unknown 137.70 Unknown 142 132 Unknown Unknown

Skin No No No No Skin No No

Unknown

No

Unknown

No

Abbreviations: BO ¼ bronchiolitis obliterans; cGVHD ¼ chronic GVHD; FEV1 ¼ forced expiratory volume in 1 second; FVC ¼ forced vital capacity; HRCT ¼ high-resolution computed tomography; NIH ¼ National Institute of Health; RV ¼ residual volume; TLC ¼ total lung capacity.

Patient characteristics

Table 3 Diagnosis

Age at SCT HSCT conditioning

1 JMML

11

2 SAA

Bu, Cy, Me, ATG

4

3 MDS secondary to ALL 4 Pre-B-ALL

10

5 HLH 6 Pre-B ALL

13 13

MTX, Cic/MPA

Bu, Cy, ATG MTX, Cic Bu, Cy, Me, ATG Bu, Cy, Et, ATG Bu, Cy, ATG Cy, ATG, TBI Bu, Cy, ATG

7

7 MLD

GVHD Days between Days from BO treatment Outcome prophylaxis SCT and onset symptoms to HDPM

9

MTX, Cic/MPA MTX, Cic MTX, Cic MTX, Cic/MPA MTX, Cic/MPA MTX, Cic

8 T-ALL

10

Cy, ATG, TBI

9 SAA

11

Bu, Cy, ATG MTX, Cic/MPA

159

16

HDPM, Po, In, Ra/Ta

Stable for 3 y. Deterioration after widened HDPM-intervals. Dead from end-stage BO 5 years after BO-diagnosis. Alive, stable

57

244

254

35

HDPM, Cic/Ta, In HDPM, Po

Alive, stable

212

111

HDPM, In

Lost to follow-up after 6 months

231 72

16 21

HDPM, Po HDPM, Po

141

86

HDPM, Po

Paraplegia after car-accident Relapse 8 months after BO diagnosis. Dead Alive, stable

99

3

HDPM, Po

53

106

HDPM, Po, In, Ra

Dead from respiratory insufficiency (CMV pneumonia) 1 month after HDPM initiation. Alive, stable

120 110 100 90 80 70 60 50 40 30 20 10 0

*P =0.011 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7

>1 2

on

th s m on th s

s th m

on m

m

on +3

+6

s si +1

di

ag

no

SC e BO

fo r Be

th

*P =0.010

T

FEV1% pred

Abbreviations: ATG ¼ anti-thymocyte globulin; BO ¼ bronchiolitis obliterans; Bu ¼ busulfex; Cic ¼ ciclosporine; Et ¼ etophos; HDPM ¼ high-dose pulse i.v. methylprednisolone; HLH ¼ haemophagocytic lymphohistiocytosis; HSCT ¼ haematopoietic SCT; In ¼ infliximab; JMML ¼ juvenile myelomonocytic leukaemia; Me ¼ melphalan; MDS ¼ myelodysplastic syndrome; MLD ¼ metachromatic leucodystrophy; MPA ¼ mycophenolate mofetil; Po ¼ oral prednisolone; Ra ¼ rapamune; SAA ¼ severe aplastic anemia; Ta ¼ tacrolimus.

Figure 1 A significant increase in FEV1 is seen from time of BO diagnosis and initiation of HDPM compared with 3 months and 1 year after initiation of therapy.

randomised study would be needed to properly adress both treatment response and possible adverse effects of HDPM therapy. Corticosteroids have been the backbone of cGvHD therapy, since Sullivan et al.14 in 1981 demonstrated improved outcome in cGvHD patients receiving corticosteroids in combination with other immunosuppressors.14 The role of prednisolone was further established in two randomised studies,79,80 where the addition of azathioprine79 and cyclosporine80 did not seem to further improve outcome in standard risk cGvHD patients. However, the effect of orally administrated prednisolone on lung involvement was not reported in those studies. First-line treatment of cGVHD mainly consists of prednisolone with a starting dose of 1 mg/kg/day orally.52 Inhaled corticosteroids in combination with long-acting bronchodilators are now being tested in BO patients in a Bone Marrow Transplantation


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prospective multicentre, randomised double-blinded trial.81 A pilot study of 13 patients with respiratory symptoms, but no extrapulmonary signs of cGvHD, showed some effect on lung function parameters55 (Table 1).

TNF-a inhibitors Insights into the role of proinflammatory cytokines in disease pathogenesis, has led to the use of TNF-a inhibitors as second-line BO treatment. The three patients in the Danish cohort, who received infliximab due to a decrease in lung function during the standard HDPM regimen, experienced stabilisation after commencement of infliximab. A case study from Texas described complete resolution of symptoms in a patient with steroid refractory BO on etanercept treatment.82 The two studies on the effect of infliximab described in Table 1(refs 59,60) suggests some improvement. An ongoing study of etanercept therapy at the Ann Arbor Cancer Center (NCT00141726) may provide further insights. Azithromycin The ability of azithromycin to inhibit airway neutrophilia and IL-8 production39,40 may explain the improvement after treatment in a subgroup of lung transplant recipients with BOS.83,84 Similar positive results have been reported in a preliminary study on 8 patients with BO after HSCT57 (Table 1). However, a randomised placebo-controlled clinical trial from Hong Kong58 failed to prove superiority of azithromycin to placebo when initiated (mean) 4.3 and 5.8 years, respectively, after BO diagnosis. A recently published case-series indicates a steroid sparing effect of azithromycin in combination with inhaled corticosteroids and montelukast in patients with newly diagnosed BO.85 Further studies are needed to establish an eventual effect of azythromycin on incipient BO. Extracorporeal photopheresis Selective downregulation of T-cell-mediated immunity is thought to explain the effect of extracorporeal photopheresis in the treatment of GvHD.86 Though several studies have been performed in patients with BO after HSCT61– 65,87–91 and lung transplantation,92–94 the studies are difficult to interpret because of the heterogeneity in the treatment schedules, diagnostic criteria and response assessment criteria (Table 1). A prospective randomised study of extracorporeal photopheresis treatment performed by Flowers et al.61 revealed a significant improvement of cGVHD in the skin, and indicated a steroid sparing effect on cGvHD in general. No effect on lung function parameters was noted. Rituximab An attempt to attack the B-cell response suspected to be a part of cGvHD aetiology has led to the application of the monoclonal CD20-Ab Rituximab. Although several studies have suggested an effect on cGvHD in the skin,66,95–98 no convincing effect on BO has been established.66,67 Bone Marrow Transplantation

Conclusion Solid evidence regarding the efficacy of the various available treatment modalities in BO is still sparse. Ongoing clinical trials together with new insights into the pathogenesis will hopefully contribute to fill this gap. Though established clinical criteria are important as a research tool, the experience with the NIH Consensus Criteria may indicate a need for further development of clinical criteria and simplification of these. Our experience emphasises the need for improved diagnostic criteria, in particular for the young children who are unable to perform spirometry. The preliminary experiences with HDPM treatment from our and other centres suggest that the efficacy of this treatment regimen, including the long-term effects deserves further validation in clinical trials. Though alternative treatment options may seem promising, corticosteroids are still likely to remain a mainstay in GvHD treatment in the coming years. However, with improved insights into the pathogenesis of BO new treatment modalities, including cytokine antagonists and cellular therapy, may change treatment strategies fundamentally.

Conflict of interest The authors declare no conflict of interest.

Acknowledgements This work was supported by grants from the Danish Children’s Cancer Association and the Research Council at the National University Hospital Rigshospitalet.

References 1 Chien JW, Duncan S, Williams KM, Pavletic SZ. Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2010; 16(Suppl 1): S106–S114. 2 Dudek AZ, Mahaseth H, DeFor TE, Weisdorf DJ. Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes. Biol Blood Marrow Transplant 2003; 9: 657–666. 3 Nakaseko C, Ozawa S, Sakaida E, Sakai M, Kanda Y, Oshima K et al. Incidence, risk factors and outcomes of bronchiolitis obliterans after allogeneic stem cell transplantation. Int J Hematol 2011; 93: 375–382. 4 Nishio N, Yagasaki H, Takahashi Y, Muramatsu H, Hama A, Tanaka M et al. Late-onset non-infectious pulmonary complications following allogeneic hematopoietic stem cell transplantation in children. Bone Marrow Transplant 2009; 44: 303–308. 5 Sakaida E, Nakaseko C, Harima A, Yokota A, Cho R, Saito Y et al. Late-onset noninfectious pulmonary complications after allogeneic stem cell transplantation are significantly associated with chronic graft-versus-host disease and with the graftversus-leukemia effect. Blood 2003; 102: 4236–4242. 6 Holland HK, Wingard JR, Beschorner WE, Saral R, Santos GW. Bronchiolitis obliterans in bone marrow transplantation


1027

7

8

9

10

11

12

13 14

15

16

17

18

19

20

21

22

and its relationship to chronic graft-v-host disease and low serum IgG. Blood 1988; 72: 621–627. Clark JG, Crawford SW, Madtes DK, Sullivan KM. Obstructive lung disease after allogeneic marrow transplantation. Clinical presentation and course. Ann Intern Med 1989; 111: 368–376. Schultz KR, Green GJ, Wensley D, Sargent MA, Magee JF, Spinelli JJ et al. Obstructive lung disease in children after allogeneic bone marrow transplantation. Blood 1994; 84: 3212–3220. Santo Tomas LH, Loberiza Jr FR, Klein JP, Layde PM, Lipchik RJ, Rizzo JD et al. Risk factors for bronchiolitis obliterans in allogeneic hematopoietic stem-cell transplantation for leukemia. Chest 2005; 128: 153–161. Chien JW, Martin PJ, Gooley TA, Flowers ME, Heckbert SR, Nichols WG et al. Airflow obstruction after myeloablative allogeneic hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2003; 168: 208–214. Williams KM, Chien JW, Gladwin MT, Pavletic SZ. Bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation. JAMA 2009; 302: 306–314. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant 2003; 9: 215–233. Sullivan KM, Shulman HM, Storb R, Weiden PL, Witherspoon RP, McDonald GB et al. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood 1981; 57: 267–276. Sullivan KM, Agura E, Anasetti C, Appelbaum F, Badger C, Bearman S et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: 250–259. Akpek G, Zahurak ML, Piantadosi S, Margolis J, Doherty J, Davidson R et al. Development of a prognostic model for grading chronic graft-versus-host disease. Blood 2001; 97: 1219–1226. Philit F, Wiesendanger T, Archimbaud E, Mornex JF, Brune J, Cordier JF. Post-transplant obstructive lung disease (‘bronchiolitis obliterans’): a clinical comparative study of bone marrow and lung transplant patients. Eur Respir J 1995; 8: 551–558. Schulman LL, Weinberg AD, McGregor CC, Suciu-Foca NM, Itescu S. Influence of donor and recipient HLA locus mismatching on development of obliterative bronchiolitis after lung transplantation. Am J Respir Crit Care Med 2001; 163: 437–442. Schwarer AP, Hughes JM, Trotman-Dickenson B, Krausz T, Goldman JM. A chronic pulmonary syndrome associated with graft-versus-host disease after allogeneic marrow transplantation. Transplantation 1992; 54: 1002–1008. Clark JG, Schwartz DA, Flournoy N, Sullivan KM, Crawford SW, Thomas ED. Risk factors for airflow obstruction in recipients of bone marrow transplants. Ann Intern Med 1987; 107: 648–656. Palmas A, Tefferi A, Myers JL, Scott JP, Swensen SJ, Chen MG et al. Late-onset noninfectious pulmonary complications after allogeneic bone marrow transplantation. Br J Haematol 1998; 100: 680–687. Duncan CN, Buonanno MR, Barry EV, Myers K, Peritz D, Lehmann L. Bronchiolitis obliterans following pediatric allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2008; 41: 971–975.

23 Ditschkowski M, Elmaagacli AH, Trenschel R, Peceny R, Koldehoff M, Schulte C et al. T-cell depletion prevents from bronchiolitis obliterans and bronchiolitis obliterans with organizing pneumonia after allogeneic hematopoietic stem cell transplantation with related donors. Haematologica 2007; 92: 558–561. 24 Ringden O, Remberger M, Ruutu T, Nikoskelainen J, Volin L, Vindelov L et al. Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group. Blood 1999; 93: 2196–2201. 25 Bruno B, Souillet G, Bertrand Y, Werck-Gallois MC, So SA, Bellon G. Effects of allogeneic bone marrow transplantation on pulmonary function in 80 children in a single paediatric centre. Bone Marrow Transplant 2004; 34: 143–147. 26 Marras TK, Chan CK, Lipton JH, Messner HA, Szalai JP, Laupacis A. Long-term pulmonary function abnormalities and survival after allogeneic marrow transplantation. Bone Marrow Transplant 2004; 33: 509–517. 27 Yoshihara S, Tateishi U, Ando T, Kunitoh H, Suyama H, Onishi Y et al. Lower incidence of bronchiolitis obliterans in allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning compared with myeloablative conditioning. Bone Marrow Transplant 2005; 35: 1195–1200. 28 Yousem SA. The histological spectrum of pulmonary graftversus-host disease in bone marrow transplant recipients. Hum Pathol 1995; 26: 668–675. 29 Shulman HM, Kleiner D, Lee SJ, Morton T, Pavletic SZ, Farmer E et al. Histopathologic diagnosis of chronic graftversus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant 2006; 12: 31–47. 30 Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz M et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002; 21: 297–310. 31 Burlingham WJ, Love RB, Jankowska-Gan E, Haynes LD, Xu Q, Bobadilla JL et al. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest 2007; 117: 3498–3506. 32 Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol 2007; 148: 32–46. 33 Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441: 235–238. 34 Meloni F, Vitulo P, Bianco AM, Paschetto E, Morosini M, Cascina A et al. Regulatory CD4+CD25+ T cells in the peripheral blood of lung transplant recipients: correlation with transplant outcome. Transplantation 2004; 77: 762–766. 35 Nakagiri T, Inoue M, Morii E, Minami M, Sawabata N, Utsumi T et al. Local IL-17 production and a decrease in peripheral blood regulatory T cells in an animal model of bronchiolitis obliterans. Transplantation 2010; 89: 1312–1319. 36 Laan M, Linden. IL-17 as a potential target for modulating airway neutrophilia. Curr Pharm Des 2002; 8: 1855–1861. 37 Vanaudenaerde BM, Wuyts WA, Dupont LJ, Van Raemdonck DE, Demedts MM, Verleden GM. Interleukin-17 stimulates release of interleukin-8 by human airway smooth muscle cells in vitro: a potential role for interleukin-17 and airway smooth muscle cells in bronchiolitis obliterans syndrome. J Heart Lung Transplant 2003; 22: 1280–1283. Bone Marrow Transplantation


1028 38 Zheng L, Whitford HM, Orsida B, Levvey BJ, Bailey M, Walters EH et al. The dynamics and associations of airway neutrophilia post lung transplantation. Am J Transplant 2006; 6: 599–608. 39 Verleden GM, Vanaudenaerde BM, Dupont LJ, Van Raemdonck DE. Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2006; 174: 566–570. 40 Verleden GM, Vos R, De Vleeschauwer SI, Willems-Widyastuti A, Verleden SE, Dupont LJ et al. Obliterative bronchiolitis following lung transplantation: from old to new concepts? Transpl Int 2009; 22: 771–779. 41 Alousi AM, Uberti J, Ratanatharathorn V. The role of B cell depleting therapy in graft versus host disease after allogeneic hematopoietic cell transplant. Leuk Lymphoma 2010; 51: 376–389. 42 Sarantopoulos S, Stevenson KE, Kim HT, Cutler CS, Bhuiya NS, Schowalter M et al. Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. Blood 2009; 113: 3865–3874. 43 Sarantopoulos S, Stevenson KE, Kim HT, Bhuiya NS, Cutler CS, Soiffer RJ et al. High levels of B-cell activating factor in patients with active chronic graft-versus-host disease. Clin Cancer Res 2007; 13: 6107–6114. 44 Kuzmina Z, Weigl R, Krenn K, Petkov V, Koermoeczi U, Rottal A et al. Excess of BAFF and distortion of B-cell homeostasis in patients with newly diagnosed bronchiolitis obliterans syndrome associated with chronic graft-versus-host disease. Bone Marrow Transplantation 2011; 46(Suppl 1): S7. Ref Type: Abstract. 45 Jaramillo A, Smith MA, Phelan D, Sundaresan S, Trulock E, Lynch J et al. Temporal relationship between the development of anti-HLA antibodies and the development of bronchiolitis obliterans syndrome after lung transplantation. Transplant Proc 1999; 31: 185–186. 46 Maruyama T, Jaramillo A, Narayanan K, Higuchi T, Mohanakumar T. Induction of obliterative airway disease by anti-HLA class I antibodies. Am J Transplant 2005; 5: 2126– 2134. 47 Panoskaltsis-Mortari A, Griese M, Madtes DK, Belperio JA, Haddad IY, Folz RJ et al. An official American thoracic society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome. Am J Respir Crit Care Med 2011; 183: 1262–1279. 48 Zhu KE, Hu JY, Zhang T, Chen J, Zhong J, Lu YH. Incidence, risks, and outcome of idiopathic pneumonia syndrome early after allogeneic hematopoietic stem cell transplantation. Eur J Haematol 2008; 81: 461–466. 49 Gower WA, Collaco JM, Mogayzel Jr PJ. Lung function and late pulmonary complications among survivors of hematopoietic stem cell transplantation during childhood. Paediatr Respir Rev 2010; 11: 115–122. 50 Fukuda T, Hackman RC, Guthrie KA, Sandmaier BM, Boeckh M, Maris MB et al. Risks and outcomes of idiopathic pneumonia syndrome after nonmyeloablative and conventional conditioning regimens for allogeneic hematopoietic stem cell transplantation. Blood 2003; 102: 2777–2785. 51 Hildebrandt GC, Fazekas T, Lawitschka A, Bertz H, Greinix H, Halter J et al. Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant 2011; 46: 1283–1295. 52 Wolff D, Gerbitz A, Ayuk F, Kiani A, Hildebrandt GC, Vogelsang GB et al. Consensus conference on clinical practice in chronic graft-versus-host disease (GVHD): first-line and topical treatment of chronic GVHD. Biol Blood Marrow Transplant 2010; 16: 1611–1628. Bone Marrow Transplantation

53 Wolff D, Schleuning M, von HS, Bacher U, Gerbitz A, Stadler M et al. Consensus conference on clinical practice in chronic GVHD: second-line treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2011; 17: 1–17. 54 Ratjen F, Rjabko O, Kremens B. High-dose corticosteroid therapy for bronchiolitis obliterans after bone marrow transplantation in children. Bone Marrow Transplant 2005; 36: 135–138. 55 Bergeron A, Belle A, Chevret S, Ribaud P, Devergie A, Esperou H et al. Combined inhaled steroids and bronchodilatators in obstructive airway disease after allogeneic stem cell transplantation. Bone Marrow Transplant 2007; 39: 547–553. 56 Or R, Gesundheit B, Resnick I, Bitan M, Avraham A, Avgil M et al. Sparing effect by montelukast treatment for chronic graft versus host disease: a pilot study. Transplantation 2007; 83: 577–581. 57 Khalid M, Al SA, Saleemi S, Al DS, Zeitouni M, Al MA et al. Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study. Eur Respir J 2005; 25: 490–493. 58 Lam DCL, Lam B, Wong MKY, Lu C, Au WY, Tse EWC et al. Effects of Azithromycin in bronchiolitis obliterans syndrome after hematopoietic SCT—a randomized doubleblinded placebo-controlled study. Bone Marrow Transplant 2011; 46: 1551–1556. 59 Busca A, Locatelli F, Marmont F, Ceretto C, Falda M. Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versushost disease following allogeneic hematopoietic stem cell transplantation. Am J Hematol 2007; 82: 45–52. 60 Chiang KY, Abhyankar S, Bridges K, Godder K, HensleeDowney JP. Recombinant human tumor necrosis factor receptor fusion protein as complementary treatment for chronic graft-versus-host disease. Transplantation 2002; 73: 665–667. 61 Flowers ME, Apperley JF, van BK, Elmaagacli A, Grigg A, Reddy V et al. A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood 2008; 112: 2667–2674. 62 Couriel DR, Hosing C, Saliba R, Shpall EJ, Anderlini P, Rhodes B et al. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood 2006; 107: 3074–3080. 63 Messina C, Locatelli F, Lanino E, Uderzo C, Zacchello G, Cesaro S et al. Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell transplantation. Br J Haematol 2003; 122: 118–127. 64 Rubegni P, Cuccia A, Sbano P, Cevenini G, Carcagni MR, D’Ascenzo G et al. Role of extracorporeal photochemotherapy in patients with refractory chronic graft-versus-host disease. Br J Haematol 2005; 130: 271–275. 65 Lucid CE, Savani BN, Engelhardt BG, Shah P, Clifton C, Greenhut SL et al. Extracorporeal photopheresis in patients with refractory bronchiolitis obliterans developing after alloSCT. Bone Marrow Transplant 2011; 46: 426–429. 66 Zaja F, Bacigalupo A, Patriarca F, Stanzani M, Van Lint MT, Fili C et al. Treatment of refractory chronic GVHD with rituximab: a GITMO study. Bone Marrow Transplant 2007; 40: 273–277. 67 Kim SJ, Lee JW, Jung CW, Min CK, Cho B, Shin HJ et al. Weekly rituximab followed by monthly rituximab treatment for steroid-refractory chronic graft-versus-host disease: results from a prospective, multicenter, phase II study. Haematologica 2010; 95: 1935–1942. 68 Jacobsohn DA, Chen AR, Zahurak M, Piantadosi S, Anders V, Bolanos-Meade J et al. Phase II study of pentostatin in


1029

69

70

71

72

73

74

75 76

77

78

79

80

81

82

83

84

patients with corticosteroid-refractory chronic graft-versushost disease. J Clin Oncol 2007; 25: 4255–4261. Olivieri A, Locatelli F, Zecca M, Sanna A, Cimminiello M, Raimondi R et al. Imatinib for refractory chronic graft-versushost disease with fibrotic features. Blood 2009; 114: 709–718. Stadler M, Ahlborn R, Kamal H, Diedrich H, Buchholz S, Eder M et al. Limited efficacy of imatinib in severe pulmonary chronic graft-versus-host disease. Blood 2009; 114: 3718–3719. Kulkarni S, Powles R, Sirohi B, Treleaven J, Saso R, Horton C et al. Thalidomide after allogeneic haematopoietic stem cell transplantation: activity in chronic but not in acute graft-versushost disease. Bone Marrow Transplant 2003; 32: 165–170. Couriel D, Carpenter PA, Cutler C, Bolanõs-Meade J, Treister NS, Gea-Banacloche J et al. Ancillary therapy and supportive care of chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 2006; 12: 375–396. De Jong PA, Dodd JD, Coxson HO, Storness-Bliss C, Pare´ PD, Mayo JR et al. Bronchiolitis obliterans following lung transplantation: early detection using computed tomographic scanning. Thorax 2006; 61: 799–804. American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1992; 146(5 Part 1): 1368–1369. Clement A. Task force on chronic interstitial lung disease in immunocompetent children. Eur Respir J 2004; 24: 686–697. Desmarquest P, Tamalet A, Fauroux B, Boule M, BocconGibod L, Tournier G et al. Chronic interstitial lung disease in children: response to high-dose intravenous methylprednisolone pulses. Pediatr Pulmonol 1998; 26: 332–338. Buchvald F, Petersen BL, Damgaard K, Deterding R, Langston C, Fan LL et al. Frequency, treatment, and functional outcome in children with hypersensitivity pneumonitis. Pediatr Pulmonol (e-pub ahead of print 26 May 2011). Akikusa JD, Feldman BM, Gross GJ, Silverman ED, Schneider R. Sinus bradycardia after intravenous pulse methylprednisolone. Pediatrics 2007; 119: e778–e782. Sullivan KM, Witherspoon RP, Storb R, Weiden P, Flournoy N, Dahlberg S et al. Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-vhost disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation. Blood 1988; 72: 546–554. Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA et al. Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood 2002; 100: 48–51. Bergeron A, Chagnon K, Feuillet S, Chevret S, Tazi A. Prospective evaluation of the efficacy of the combination of budesonide/formoterol in obstructive airway disease after allogeneic hematopoietic stem cell transplantation]. Rev Mal Respir 2009; 26: 794–800. Fullmer JJ, Fan LL, Dishop MK, Rodgers C, Krance R. Successful treatment of bronchiolitis obliterans in a bone marrow transplant patient with tumor necrosis factor-alpha blockade. Pediatrics 2005; 116: 767–770. Gottlieb J, Szangolies J, Koehnlein T, Golpon H, Simon A, Welte T. Long-term azithromycin for bronchiolitis obliterans syndrome after lung transplantation. Transplantation 2008; 85: 36–41. Vanaudenaerde BM, Meyts I, Vos R, Geudens N, De WW, Verbeken EK et al. A dichotomy in bronchiolitis obliterans

85

86

87

88

89

90

91

92

93

94

95

96

97

98

syndrome after lung transplantation revealed by azithromycin therapy. Eur Respir J 2008; 32: 832–843. Norman BC, Jacobsohn DA, Williams KM, Au BKC, Au MA, Lee SJ et al. Fluticasone, azithromycin and montelukast therapy in reducing corticosteroid exposure in bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: a case series of eight patients. Bone Marrow Transplant 2011; 46: 1369–1373. Kanold J, Merlin E, Halle P, Paillard C, Marabelle A, Rapatel C et al. Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines based on field experience and review of the literature. Transfusion 2007; 47: 2276–2289. Ilhan O, Arat M, Arslan O, Ayyildiz E, Sanli H, Beksac M et al. Extracorporeal photoimmunotherapy for the treatment of steroid refractory progressive chronic graft-versus-host disease. Transfus Apher Sci 2004; 30: 185–187. Garban F, Drillat P, Makowski C, Jacob MC, Richard MJ, Favrot M et al. Extracorporeal chemophototherapy for the treatment of graft-versus-host disease: hematologic consequences of short-term, intensive courses. Haematologica 2005; 90: 1096–1101. Foss FM, DiVenuti GM, Chin K, Sprague K, Grodman H, Klein A et al. Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors. Bone Marrow Transplant 2005; 35: 1187–1193. Berger M, Pessolano R, Albiani R, Asaftei S, Barat V, Carraro F et al. Extracorporeal photopheresis for steroid resistant graft versus host disease in pediatric patients: a pilot single institution report. J Pediatr Hematol Oncol 2007; 29: 678–687. Bisaccia E, Palangio M, Gonzalez J, Adler KR, Scarborough R, Goldberg SL et al. Treatment of extensive chronic graftversus-host disease with extracorporeal photochemotherapy. J Clin Apher 2006; 21: 181–187. O’Hagan AR, Stillwell PC, Arroliga A, Koo A. Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation. Chest 1999; 115: 1459–1462. Benden C, Speich R, Hofbauer GF, Irani S, Eich-Wanger C, Russi EW et al. Extracorporeal photopheresis after lung transplantation: a 10-year single-center experience. Transplantation 2008; 86: 1625–1627. Morrell MR, Despotis GJ, Lublin DM, Patterson GA, Trulock EP, Hachem RR. The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant 2010; 29: 424–431. Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, Cutler C, Mohty M, Kumar A. Efficacy of rituximab in the setting of steroid-refractory chronic graft-versus-host disease: a systematic review and meta-analysis. Biol Blood Marrow Transplant 2009; 15: 1005–1013. Teshima T, Nagafuji K, Henzan H, Miyamura K, Takase K, Hidaka M et al. Rituximab for the treatment of corticosteroidrefractory chronic graft-versus-host disease. Int J Hematol 2009; 90: 253–260. Cutler C, Miklos D, Kim HT, Treister N, Woo SB, Bienfang D et al. Rituximab for steroid-refractory chronic graft-versushost disease. Blood 2006; 108: 756–762. von BM, Oelschlagel U, Radke J, Stewart M, Ehninger G, Bornhauser M et al. Treatment of chronic steroid-refractory graft-versus-host disease with low-dose rituximab. Transplantation 2008; 86: 875–879.
