Outcome and Treatment of Late-Onset Noninfectious Pulmonary Complications After Allogeneic Haematopoietic SCT

Home , Obstructive lung disease

ORIGINAL ARTICLE Outcome and treatment of late-onset noninfectious pulmonary complications after allogeneic haematopoietic SCT

K Ueda1, T Watadani2, E Maeda2, S Ota3, K Kataoka1, S Seo1, K Kumano4, A Hangaishi1, T Takahashi1, Y Imai1, K Ohtomo2, M Fukayama3, Y Nannya1 and M Kurokawa1,4

1Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 2Department of Radiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 3Department of Pathology and Diagnostic Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan and 4Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan

Late-onset noninfectious pulmonary complications (LO- Introduction NIPCs) are life threatening for allogeneic hematopoietic SCT (allo-HSCT) recipients. However, the impact of Allogeneic hematopoietic SCT (allo-HSCT) is a curative LONIPCs on survival has not been properly evaluated treatment option for a variety of hematological disorders. and little is known about treatment efficacy. We retro- However, pulmonary complications develop in 25–60% of spectively investigated 290 allo-HSCT recipients in our the recipients, and account for B50% of transplant-related institute and reviewed the clinical aspects of 44 patients deaths.1–6 Recently, the outcomes of infectious pulmonary who had been diagnosed with LONIPCs. LONIPCs complications improved as a result of advances in anti- were significantly associated with higher rates of chronic microbial therapy, for example, against invasive fungal GVHD (Po0001) and nonrelapse mortality (P ¼ 0.013), infection.7 However, late-onset noninfectious pulmonary and lower rates of relapse (P ¼ 0.009). As a result of these complications (LONIPCs) after allo-HSCT still remain effects, OS was significantly worse in those with potentially life threatening.8,9 LONIPCs (P ¼ 0.003). This result differs from a previous After the first case report of fatal bronchiolitis in an allo- report. We then assessed short-term treatment response HSCT recipient with chronic GVHD (cGVHD) in 1982,10 and final outcome. These results were defined by radio- a series of LONIPCs were described in 1987 as small- logical findings, subjective symptoms, oxygen requirement airway disease in recipients of allo-HSCT.11 In 1998, and survival. Use of inhaled and systemic steroids did Palmas et al.12 classified LONIPCs after allo-HSCT into not affect either short-term response or final outcomes. five groups: bronchiolitis obliterans (BO), bronchiolitis However, administration of systemic corticosteroids obliterans with organizing pneumonia (BOOP), diffuse earlier than at 21 days (median interval of time from alveolar damage, lymphocytic interstitial pneumonia and onset of symptoms to systemic corticosteroids adminis- nonclassifiable pneumonia. According to this classification, tration) was associated with a better outcome (P ¼ 0.054 BO was diagnosed based on the obstructive pattern in for short-term response, and 0.016 for final outcome). Our pulmonary function tests (PFTs) and the other LONIPCs study indicates that LONIPCs reduce OS, and early on histological findings.12 It is thus impractical to apply this intervention with systemic corticosteroids may be effective. classification to clinical settings because this criterion relies Bone Marrow Transplantation (2010) 45, 1719–1727; heavily on histology and lung specimens are not always doi:10.1038/bmt.2010.48; published online 8 March 2010 available. These facts limited the standardization of Keywords: SCT; pulmonary complication; survival Palmas’s criteria and individual reports of LONIPCs use analysis; GVHD; corticosteroids different classification criteria.8,9,12 Recently, several studies have revealed many risk factors that are associated with the onset of LONIPCs, including cGVHD,9,12–19 donor and recipient age,13 baseline pulmonary function,13 use of TBI,20 and so on. There is a general agreement that cGVHD is the most strongly associated risk factor.9,12–19 Although patients with LO- NIPCs have high nonrelapse mortality (NRM) rates,9,12 they experience low relapse rates of the underlying Correspondence: Dr M Kurokawa, Departments of Hematology and disease presumably because high concomitant rates of Oncology, Cell Therapy and Transplantation Medicine, University of cGVHD exert a graft-vs-tumor effect.9 Thus, it remains Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: [email protected] unknown whether the onset of LONIPCs has an impact on Received 3 September 2009; revised 29 December 2009; accepted 30 OS or relapse-free survival as a consequence of these December 2009; published online 8 March 2010 contradictory factors. Only one study reported that Outcome and treatment of LONIPCs K Ueda et al 1720 survival of patients with and without LONIPCs was not gical typing for HLA-A and -B Ags, and molecular typing significantly different.9 for HLA-DRB1 Ag. Disease morphology was determined Standard therapies for LONIPCs have not been estab- according to the French–American–British classification. lished. Inhaled steroids and bronchodilators are supposed Standard risk diseases were defined as acute leukemia in to be effective for BO.21 High-dose corticosteroid therapy first or second CR, CML in first or second chronic phase, was suggested to be a valuable treatment option in pediatric chemosensitive lymphoma, myelodysplastic syndrome with patients with BO.22 However, the role of systemic admini- refractory anemia or refractory anemia with ringed side- stration of corticosteroids for adults with LONIPCs has roblasts, and aplastic anemia. All other conditions were not been clarified. classified as high-risk diseases. Prophylaxis against bacter- To better understand the pathophysiology of LONIPCs, ial infection was principally performed with quinolones, we investigated computed tomography (CT) images, fungal infection with fluconazole or itraconazole, herpes pathological specimens and medical records of all adult simplex virus infection with acyclovir and Pneumocystis patients who had received allo-HSCT for a hematological jiroveci infection with sulfamethoxazole/trimethoprim. disorder in our institute and identified patients who had LONIPCs, as a result of which we examined the effect of PFTs LONIPCs on survival. Furthermore, we investigated Routine PFTs were performed before transplantation diagnostic criteria, risk factors and treatment outcome of (except for four patients). After allo-HSCT, most patients LONIPCs. Especially, we analyzed whether time to with cGVHD received PFTs every 3–6 months. The administration of systemic corticosteroids from appearance restrictive pattern was assumed to have reduced the vital of symptoms affects outcomes, to explore the relevance of capacity (VC) to 80% of the expected values. The early intervention. o obstructive pattern was assumed to have a forced expiratory volume in 1 s (FEV1) of o70% of forced VC (FVC). When these two criteria are fulfilled concurrently, Patients and methods a diagnosis of mixed pattern was made.

Patient selection We retrospectively studied 314 consecutive adult patients Definition and classification of LONIPCs (age 16–67 years old, median 40 years old) with hemato- A diagnosis of LONIPCs was made when a patient fulfilled logical disorders who underwent allo-HSCT at the Uni- all the following criteria: (1) respiratory symptoms devel- versity of Tokyo Hospital, Japan, between June 1995 and oping after 60 days from allo-HSCT, (2) no evidence of December 2007, of whom 290 patients were included in this infection detected despite extensive examinations, (3) at study; 24 patients were excluded due to death within 60 least one of the following abnormalities observed: days after allo-HSCT. Clinical information was obtained (a) abnormal interstitial shadow on chest CT, (b) patho- from detailed review of medical charts, institute database logical diagnosis of interstitial pneumonia or BO, c) PFT and computer ordering system. revealing an obstructive or mixed pattern and a decline of FEV1 to o75% of the predicted value, or a decline of at least 20% FEV1 from baseline. Protocols for allo-HSCT The CT images were reviewed by two expert chest Myeloablative conditioning regimens included either TBI- radiologists and pathological specimens were reviewed by based regimens or non-TBI-based regimens. TBI-based an expert pathologist. To exclude infection, standard regimens mainly consisted of CY (60 mg/kg/day for 2 days) culture and staining methods for bacterial, fungal and viral plus fractionated TBI (12 Gy), whereas non-TBI-based pathogens were used. Bronchoalveolar lavage was collected regimens included BU (1 mg/kg orally or 0.8 mg/kg i.v. whenever possible, and subjected to bacterial and fungal every 6 h for 4 days) plus CY (60 mg/kg/day for 2 days). culture, aspergillus galactomannan and multiplex PCR Patients were offered nonmyeloablative conditioning regi- tests for herpes group viruses. mens when they were ineligible for myeloablative prepara- We then classified subtypes of LONIPCs. BO was tive regimens because of (1) age X56 years (n ¼ 28); (2) defined according to the National Institutes of Health preexisting significant comorbidities (n ¼ 5, severe cardiac consensus development project on criteria for clinical trials dysfunction (n ¼ 3), invasive pulmonary aspergillosis in chronic graft-versus-host disease criteria.24 Briefly, BO is (n ¼ 1), interstitial pneumonia caused by granulocyte diagnosed clinically when both the following criteria in colony stimulating factor (n ¼ 1)); (3) a history of high- addition to that of LONIPCs are met: (1) LONIPCs criteria dose HSCT (n ¼ 8; two patients were also over age); and 3 (c), and (2) evidence of air trapping or small-airway (4) allo-HSCT for Hodgkin’s lymphoma (n ¼ 1). Non- thickening or bronchiectasis on high-resolution chest CT myeloablative conditioning consisted of fludarabine-based (with inspiratory and expiratory cuts), residual volume regimens with or without low-dose TBI (4 Gy). Prophylaxis X120% or pathological confirmation of constrictive for GVHD was performed with calcineurin inhibitors (CsA bronchiolitis.24,25 LONIPCs other than BO were classified or tacrolimus) with or without short-term MTX (sMTX) in based on either radiological or pathological findings, most patients. In vivo T-cell depletion using alemtuzumab according to the American Thoracic Society/European was performed in 26 patients for HLA 1 haplotype- Respiratory Society International Multidisciplinary mismatched patients, concomitant with CsA and sMTX.23 Consensus Classification of the Idiopathic Interstitial HLA matching for donor selection was based on serolo- Pneumonias.26 CT findings at the onset of respiratory

Bone Marrow Transplantation Outcome and treatment of LONIPCs K Ueda et al 1721 symptoms, after 2–8 weeks from the start of treatment and method.28 For NRM, relapse was the competing event; for at the last follow-up were reviewed and evaluated by two relapse, NRM was the competing event; and for GVHD, radiologists. Patients having air space consolidation death without GVHD was the competing event. Patients (especially in the lower lobes), peribronchial small nodules who were alive without an event were censored at last and multiple solid nodules are classified as cryptogenic follow-up. Comparisons of short-term response and final organizing pneumonia, whereas those with bilaterally outcome between two groups were performed with the symmetric, peripheral ground glass shadowing are classified Fisher’s exact test. Results of PFTs were compared with as nonspecific interstitial pneumonia. No patient con- one-sided t-tests. All P-values except for PFTs (Figure 3) formed radiologically to idiopathic pulmonary fibrosis, were two-sided, with a type I error rate fixed at 0.05. acute interstitial pneumonia, desquamative interstitial Statistical analyses were performed with R 2.6.2 software pneumonia, respiratory bronchiolitis-associated interstitial (The R Foundation for Statistical Computing, 2007). lung disease or lymphocytic interstitial pneumonia. Lung histology of transbronchial lung biopsy, necropsy and Ethical problems autopsy were reviewed by a pathologist. Pathological 12 We obtained written informed consent from allo-HSCT classification was ascribed to Palmas et al. recipients to use their clinical data. This study was conducted in accordance with the Declaration of Helsinki Evaluation of treatment outcomes and approved by the Institutional Review Board of Tokyo Short-term response was defined as those who received University Hospital. either or both inhalant or systemic corticosteroid therapy, and start of therapy was defined as the administration of either form, whichever came first. Short-term response was Results assumed to be responsive when patients fulfilled at least two out of the following three criteria in 2–4 weeks after the Patient characteristics start of therapy: (1) at least 50% decrease of supplemental Of the 290 patients who survived more than 60 days after oxygen requirement or ventilator weaning; (2) improve- allo-HSCT, 44 (15.2%) developed LONIPCs. Comparisons ment in subjective respiratory symptoms; and (3) improve- of patient characteristics between patients with and without ment in radiological findings. The same criteria were LONIPCs are shown in Table 1. Male sex (P ¼ 0.041) and applied at the last follow-up and defined as the final donor–recipient sex mismatch (P ¼ 0.021) were associated outcome. Those who received neither inhaled nor systemic with a higher incidence of LONIPCs. Multivariate analysis corticosteroid were included. Dead patients were consid- revealed that male sex (P ¼ 0.006), donor–recipient sex ered nonresponders. mismatch (P ¼ 0.001) and existence of cGVHD (Po0.001) were independent risk factor of LONIPCs. Statistical methods Duration of follow-up was the time from transplantation to Clinical, radiological and pathological presentation the last assessment for survivors. Variables regarding of LONIPCs patients, underlying diseases and transplantation proce- Before allo-HSCT, only five patients had shown abnormal dures were compared between patients with and without PFTs (hemoglobin-corrected diffusing capacity of carbon LONIPCs using the Fisher’s exact test for categorical monoxide o80% in four patients, obstructive pattern in variables and the Mann–Whitney U-test for continuous one patient) and three patients had been smokers. Of 44 variables. A multivariate analysis using a logistic regression patients who were diagnosed with LONIPCs, 21 were model was conducted including the following factors as classified as BO, 28 as LONIPCs other than BO and 5 potentially significant: sex, age (o55 vs X55 years old), patients fulfilled the criteria of both BO and other disease risk, number of previous HSCT, graft source LONIPCs. The median time to diagnosis of LONIPCs (peripheral blood vs others), HLA compatibility (matched was 292 days after allo-HSCT (range 61–2169 days). In all, related donor vs matched unrelated donor vs mismatched 19 patients complained of dry cough as an initial symptom, donor), donor–recipient sex mismatch, intensity of con- whereas 7 patients complained of productive cough, and 27 ditioning (myeloablative vs reduced intensity), GVHD patients complained of dyspnea. Only six patients had fever prophylaxis (with alemtuzumab vs without) and existence and four had sputum. Out of 21 patients diagnosed with of acute and chronic GVHD. Probabilities of OS were BO, 12 had CT findings compatible with BO, and the other calculated with the Kaplan–Meier method, treating the nine were shown to have increased residual volume in onset of LONIPCs as a time-dependent covariate, and were PFT.24 Of the 28 patients diagnosed with LONIPCs other compared using the log-rank test. In the time-dependent than BO, a pathological diagnosis was available in 10 analysis, a covariate indicates whether a patient has patients (TBLB for three patients, autopsy for six patients LONIPCs before time t. Note that this covariate is initially and both TBLB and autopsy for one patient, four patients zero in all cases and changes to 1 at the time when the diagnosed with BOOP, three with diffuse alveolar damage patient develops LONIPCs.27 For analysis of OS, death and three with nonspecific alveolitis or pneumonia). from any cause was considered an event, and data on Bronchoalveolar lavage was collected to exclude infectious patients who were alive at the last follow-up were censored. lung complications in 18 patients. Nine patients required Probabilities of NRM, relapse, acute and chronic GVHD ventilator support, and only one was successfully extu- were calculated with the cumulative incidence function bated. Altogether, 32 patients were discharged at least once

Bone Marrow Transplantation Outcome and treatment of LONIPCs K Ueda et al 1722 Table 1 Clinical features of 290 patients surviving 42 months 1.0 after allo-HSCT P=0.003 Clinical feature Non-LONIPCs LONIPCs P-valuea 0.8

n % n % 0.6 No. of patients 246 44

Sex 0.041 0.4 Male 148 81.3 34 18.7

Female 98 90.7 10 9.3 Overall survival 0.2 Age (years) 0.270b Non-LONIPCs Median 39 — 42 — Range 16–66 — 17–61 — 0.0 LONIPCs

Diagnosis 0.751 0 2 4 6 8 10 Aplastic anemia 11 91.7 1 8.3 Years from HSCT ALL 57 86.4 9 13.6 AML 69 84.1 13 15.9 Figure 1 OS of patients with or without LONIPCs. OS was calculated Acute undifferentiated 4 100 0 0 using the Kaplan–Meier method, treating LONIPCs as a time-dependent leukemia covariate. P-value shows the statistical significance of the difference in CML 42 84 8 16 outcome between LONIPCs and non-LONIPCs arms using the log-rank Chronic myelomonocytic 3 100 0 0 test. LONIPCs, late-onset noninfectious pulmonary complications; HSCT, leukemia hematopoietic SCT. MDS (RA/RARS) 8 100 0 0 MDS (RAEB/RAEBT) 17 70.8 7 29.2 Non-Hodgkin’s lymphoma 29 82.9 6 17.1 Others 6 100 0 0 after the onset of LONIPCs, and home oxygen therapy was Disease risk 0.618 High 102 86.4 16 13.6 started in 14 patients. Eight patients developed a pneu- Standard 144 83.7 28 16.3 mothorax and/or mediastinal emphysema during the course of disease. Frequency of HSCT 0.326 First HSCT 228 84.1 43 15.9 Second HSCT 18 94.7 1 5.3 Survival and relationship between LONIPCs and GVHD, relapse and NRM Transplantation source 0.642 The OS of patients with LONIPCs was significantly worse BM 167 85.2 29 14.8 BM+peripheral blood 5 100 0 0 compared with those without LONIPCs when the onset of Cord blood 6 100 0 0 LONIPCs was treated as a time-dependent covariant as Peripheral blood 68 81.9 15 18.1 shown in Figure 1 (P ¼ 0.003). Although the incidence of grades II–IV acute GVHD was not different in LONIPCs HLA compatibility 0.978 Mismatch donor 71 84.5 13 15.5 ( þ ) and LONIPCs (À) groups (P ¼ 0.942, Figure 2a), Matched related donor 94 85.5 16 14.5 extensive cGVHD was significantly more common in the Matched unrelated donor 81 84.4 15 15.6 LONIPCs ( þ ) group (Po0.001, Figure 2b). A cumulative incidence of relapse was lower in LONIPCs ( þ ) group Sex compatibility 0.021 (P 0.009, Figure 2c). However, NRM rates were higher in Match 143 89.4 17 10.6 ¼ Mismatch 103 79.2 27 20.8 the LONIPCs ( þ ) arm (P ¼ 0.013, Figure 2d).

Conditioning regimen 1 Myeloablative 212 84.8 38 15.2 Treatment and outcomes Non-myeloablative 34 85 6 15 We administered inhaled steroid and a b-stimulator to 12 patients, 9 of whom had BO. As shown in Table 2a, TBI 0.850 administration of inhalant steroid did not affect outcomes. TBI regimen 184 84.4 34 15.6 Non-TBI regimen 62 86.1 10 13.9 Seventeen patients received reinitiation or dose escalation of calcineurin inhibitors. Systemic corticosteroids were GVHD prophylaxis 0.484 administered to 31 patients who received high-dose methyl- Alemtuzumab 23 88.5 3 11.5 prednisolone; 1000 mg for 3 days, whereas others received CsA 13 100 0 0 0.5–1.0 mg prednisolone orally or i.v.), and this also CsA+MTX 192 83.5 38 16.5 Tacrolimus+MTX 18 85.7 3 14.3 failed to inﬂuence outcome as shown in Table 2a. Next, we divided the patients into three groups: those who Abbreviations: HSCT ¼ hematopoietic SCT; LONIPCs ¼ late-onset non- received systemic corticosteroids before 21 days (median of infectious pulmonary complications; MDS ¼ myelodysplastic syndrome; all corticosteroid recipients) from appearance of respiratory RA ¼ refractory anemia; RAEBT ¼ refractory anemia with excess of blasts symptoms (early steroid); those who received them after 22 in transformation; RARS ¼ refractory anemia with ringed sideroblasts. aFisher’s exact test except for age. days from the onset (late steroid); and those who did not bMann–Whitney U-test. receive (steroid–). The early steroid group had a trend of showing a better short-term response and had signiﬁcantly

Bone Marrow Transplantation Outcome and treatment of LONIPCs K Ueda et al 1723 1.0 1.0 Non-LONIPCs Non-LONIPCs LONIPCs 0.8 LONIPCs 0.8

0.6 0.6

0.4 0.4

0.2 0.2 P=0.942 P < 0.001 Probability of cGVHD Probability of aGVHD 0.0 0.0 020 40 60 80 100 0255 10 15 20 Days from HSCT Months from HSCT

1.0 Non-LONIPCs 1.0 Non-LONIPCs 0.8 LONIPCs 0.8 LONIPCs 0.6 0.6 P=0.009 0.4 0.4 P=0.013 0.2 0.2 Probability of NRM

Probability of relapse 0.0 0.0 0 2 4 6 8 10 0 2 4 6 8 10 Years from HSCT Years from HSCT Figure 2 Cumulative incidence of acute GVHD, cGVHD, relapse and NRM. Cumulative incidence of grades II–IV acute GVHD (a), extensive cGVHD (b), relapse (c) and NRM (d) after allo-HSCT in patients divided by the occurrence of LONIPCs. NRM, nonrelapse mortality; HSCT, hematopoietic SCT; LONIPCs, late-onset noninfectious pulmonary complications.

Table 2a Treatment outcome of LONIPCs by inhaled or systemic Table 2b The treatment outcome of LONIPCs by systemic administration of corticosteroids administration of corticosteroids within 21 days from onset of LONIPCs Inhaled steroid (+) Inhaled steroid (À) P-value Early steroid Late steroid and steroid- P-value Short-term response No 5 13 Short-term response Yes 5 17 0.731 No 4 14 Yes 12 10 0.054 Final outcome Not improved 9 23 Final outcome Improved 1 11 0.241 Not improved 8 24 Improved 8 4 0.016 Systemic steroid (+) Systemic steroid (À) P-value Abbreviation: LONIPCs ¼ late-onset noninfectious pulmonary complications. Short-term response P-value indicates the statistical significance of difference between steroid No 13 5 within 21 days (+) and steroid within 21 days (À) groups using Fisher’s Yes 18 4 0.705 exact test. Final outcome Not improved 21 11 statistically significant (P ¼ 0.282). Next, we compared Improved 10 2 0.459 FEV1/FEV1 predicted in the three groups, early steroid, late steroid and steroid–. As shown in Figure 3, FEV1/ Abbreviation: LONIPCs ¼ late-onset noninfectious pulmonary complications. FEV1-predicted values in the early steroid group at last P-value indicates the statistical significance of difference between steroid follow-up was significantly higher than those of the steroid– (+) and steroid (À) groups using Fisher’s exact test. group (P ¼ 0.039) or the late steroid group (P ¼ 0.033). At last follow-up, 20 patients out of 44 had died and the better final outcomes compared with the late steroid and median from onset of LONIPCs to death of these 20 the steroid– groups, as shown in Table 2b (P ¼ 0.054 patients was 278 days (range: 31–2315). The cause of death for short-term response, P ¼ 0.016 for final outcome, was respiratory failure in 17 patients, and respiratory respectively). When we evaluated early response and infection was involved in the cause of death in only two final outcome of BO and LONIPCs other than BO patients. separately, only final outcome of BO was significantly improved by early administration of corticosteroids (P ¼ 0.546 for early response of BO, P ¼ 0.041 for final Discussion outcome of BO, P ¼ 0.411 for early response of LONIPCs other than BO, P ¼ 0.228 for final outcome of LONIPCs Previous reports of LONIPCs included patients with other than BO). As for patients who received high-dose respiratory syndromes that developed after the first 2 or 3 methylprednisolone, any advantage of early steroid was not months from allo-HSCT without any evidence of infec-

Bone Marrow Transplantation Outcome and treatment of LONIPCs K Ueda et al 1724 FEV1/FEV1-predicted without lung pathology, and we applied both radiological % and pathological classifications to the cases with lung 140 * * pathology. In support of this is the recommendation that 120 * histopathological, clinical and radiological classification 100 should be considered comprehensively in the field of idiopathic pneumonia or small-airway diseases.26,33,34 In 80 Steroid - these previous reports, the authors claimed that initial 60 Late steroid classification of interstitial pneumonia should be made with Early steroid 40 available information such as CT or clinical presentation, 20 and the initial diagnosis should be revised in the light of 0 new information such as histology. They also mentioned ABCDE that when histology is incompatible with clinical and Figure 3 Results of PFTs. Box pots of FEV1/FEV1 predicted before radiological appearances, pathological diagnosis should HSCT (A; n ¼ 40), the period after HSCT and before onset of respiratory not be finalized.33,34 symptoms (B; n ¼ 22), at the diagnosis of LONIPCs (C; n ¼ 33), during the In this study, male patients and patients with donor– first 2 months of treatment (D; n ¼ 18) and at the last follow-up (E; n ¼ 30). Late steroid means that corticosteroids are administered systemically after recipient sex mismatch were associated with a higher 22 days from onset of symptoms and early steroid means that incidence of LONIPCs. Furthermore, a cumulative inci- corticosteroids are administered before 21 days from onset. FEV1/FEV1 dence of cGVHD and NRM was more frequent in patients predicted at last follow-up was significantly high in the early steroid group with LONIPCs than those without. These findings are compared with the other two groups (*P ¼ 0.033, **P ¼ 0.039). FEV1, compatible with previous reports.9,12,17–19 On the other forced expiratory volume in 1 s; HSCT, hematopoietic SCT; LONIPCs, 35 late-onset noninfectious pulmonary complications. hand, reduced-intensity conditioning and use of alemtuzumab did not reduce LONIPCs in our study, which was not compatible with previous reports. tion.8,9,12 The time after HSCT for patients with non- Relapse of hematological disorders was less frequent in infectious pulmonary complications to be diagnosed with patients with LONIPCs, as previously reported.9 This LONIPCs differed from study to study.9,12 Although some supports the hypothesis that the presence of LONIPCs is studies set the threshold at 90 days,9 we set it at 60 days associated with a strong graft-versus-tumor effect. On the based on the observation that, in our cohort, five patients other hand, LONIPCs significantly increased NRM rates; developed respiratory symptoms without any evidence of 20 patients out of 44 with LONIPCs had died at last follow- infection between 60 and 90 days after allo-HSCT. Because up, including 11 who died within 1 year after onset of their clinical courses were typical for LONIPCs in that they LONIPCs. This negative effect of LONIPCs on mortality did not fulfill criteria of other lung complications and was strong enough to outweigh the favorable impact on a responded to corticosteroids, we considered it reasonable to decrease in relapse rate, which clearly worsens OS in include them in the study. On the other hand, although four cohorts with LONIPCs. The OS of patients with or without patients who received allo-HSCT in our institution devel- LONIPCs has not been reported to be significantly oped respiratory symptoms within 60 days (days 19, 32, 40 different,9 and we suppose that employment of time- and 48) after allo-HSCT, we excluded them from our study dependent analysis or not might account for the different because we had difficulty in distinguishing them from outcome. It is of note that time-dependent analysis is idiopathic pneumonia syndrome29 or engraftment syndrome.30 required for validating the effect of LONIPCs on survival In our study, those patients whose FEV1 decreased at because onset of LONIPCs cannot be predicted on day 0 of least 20% from the baseline were diagnosed with BO even if HSCT.27 FEV1/FVC ratio was over 0.7. This condition was not Routine PFTs are recommended before transplantation, included in the previous criteria for BO.9,12 However, we and are also recommended after transplantation for used this criterion because it is recommended to be one of patients with cGVHD every 3–6 months. Pretransplanta- the diagnostic criteria for BO25 in the disease category tion abnormalities in PFTs are reported to predict poor derived from obliterative bronchiolitis after lung transplan- pulmonary outcomes in survivors after allo-HSCT.36,37 tation as BO syndrome (BOS).31,32 The criteria of BOS are In our cohort, however, only two patients who developed based on the idea that recognition of small air way BO had abnormal PFTs before transplantation. Therefore, obstruction is more sensitive than that of decline of we cannot evaluate the usefulness of pretransplant PFTs. FEV1/FVC.31 Otherwise, reduction of FVC would mask Although abnormal post-transplant PFTs are also reported obstructive change, thus we considered that these criteria to predict LONIPCs,38 only four patients had abnormal are reasonable. Four patients were actually diagnosed PFTs between allo-HSCT and onset of BO in our cohort. according to these criteria. These results indicate that it is difficult to detect airway Because the classification of LONIPCs other than BO obstruction before the appearance of respiratory symptoms still remains unsettled, we reviewed previous reports and unless PFTs are more frequent. Telemetric monitoring of classified them by both radiological and pathological PFTs is one of the effective ways of detecting BO earlier,39 findings. Although Palmas’s classification has been widely which may be considered for outpatients with cGVHD who used for LONIPCs,12 we found it impractical to apply this are at high risk of LONIPCs. classification because this system requires lung specimens, As for treatment of LONIPCs, no promising therapy has which are not always available. We therefore used been reported. Although inhaled steroids and bronchodi- radiological criteria of interstitial pneumonia26 for cases lators are reported to improve respiratory function of

Bone Marrow Transplantation Outcome and treatment of LONIPCs K Ueda et al 1725 patients with BO,21,40 use of these agents did not affect excluded, 0.5–1.0 mg/kg corticosteroids should be adminis- outcome in our cohort. Although 0.5–1.0 mg/kg cortico- tered systemically as soon as possible. steroids are recommended to treat BOOP41–43 and high- This study has several limitations. This study was a dose corticosteroids are reported to be effective for retrospective, single-institute study including various pa- pediatric cases with BO,22 the effect of corticosteroids for tients’ backgrounds. In addition, the relatively small adult patients with LONIPCs including BO is still number of patients made it difficult to conduct multivariate unknown. Using the composite evaluation system of analyses. Although prospective study is difficult in treating outcomes that includes symptoms, supplemental oxygen rare complications after HSCT, multicenter, large-scale necessity and radiological change, we found that early studies are necessary to confirm our findings. administration of systemic corticosteroids leads to good outcomes in patients with LONIPCs. As for patients with BO, two out of three in the early steroid group has Conflict of interest improved, whereas only two out of seven patients in the late steroid group improved, Although seven patients in the The authors declare no conflict of interest. early steroid group had already received calcineurin inhibitors at the start of corticosteroids, five patients responded to corticosteroids. We cannot evaluate whether Acknowledgements high-dose methylprednisolone is effective for patients with LONIPCs in this study because we tended to administer We thank the members of the Department of Emergency and high-dose methylprednisolone for patients with severe and Critical Care Medicine, the Department of Respiratory Medi- progressive diffuse alveolar damage or cryptogenic orga- cine and the Department of Cardiothoracic Surgery, Graduate nizing pneumonia/BOOP, and for these patients, advantage School of Medicine, University of Tokyo, for providing excellent of early steroid was not significant, as stated above. care of the patients with lung complications after allo-HSCT. Early steroid administration was significantly associated Authorship: KU conceived and designed the study, with a better final outcome of LONIPCs. It is difficult to collected the data and wrote the paper; TW and EM associate this result with PFTs because analysis of the PFT reviewed CT; SO reviewed pathology; K Kataoka collected profile shows that systemic steroid therapy serves only to the data; SS, K Kumano, AH, TT and YI provided clinical stop further deterioration of PFTs, and the difference in care; KO and MF supervised the study; YN designed the PFT results in final assessment between early and late study and wrote the paper; MK supervised the study and steroid group could be attributed to the differences in these approved the paper. at the time of LONIPCs diagnosis (Figure 3). This underscores the significance of diagnosing LONIPCs before PFTs deteriorate. Although PFT recovery after steroid References therapy was limited in early and late steroid groups as a whole, detailed analysis of individual patients suggests that 1 Krowka MJ, Rosenow 3rd EC, Hoagland HC. Pulmonary Chest PFT recovery is associated with a better outcome (three out complications of bone marrow transplantation. 1985; 87: 237–246. of five patients who had improved outcome according to 2 Weiner RS, Bortin MM, Gale RP, Gluckman E, Kay HE, our criteria had PFT recovery, although none of the 19 Kolb HJ et al. Interstitial pneumonitis after bone marrow nonimproved patients had) and we consider this represents transplantation. Assessment of risk factors. Ann Intern Med one aspect of lung function. These results suggest that early 1986; 104: 168–175. administration of corticosteroids prevents pulmonary 3 Chan CK, Hyland RH, Hutcheon MA. Pulmonary complica- fibrosis and leads to better outcomes. This hypothesis is tions following bone marrow transplantation. Clin Chest Med supported by the fact that delayed administration of 1990; 11: 323–332. corticosteroids increases relapse of cryptogenic organizing 4 Crawford SW, Hackman RC. Clinical course of idiopathic pneumonia,42 and early administration of corticosteroids pneumonia after bone marrow transplantation. Am Rev Respir Dis leads to a good outcome in preterm infants by inhibiting 1993; 147(6 Pt 1): 1393–1400. 44 5 Quabeck K. The lung as a critical organ in marrow trans- fibrogenic mediators. We presume that any positive effect plantation. Bone Marrow Transplant 1994; 14 (Suppl) 4: of early administration of corticosteroids could be adapted S19–S28. to other specific cytokine inhibitors such as etanercept. 6 Kantrow SP, Hackman RC, Boeckh M, Myerson D, Crawford Further study is required on this point. SW. Idiopathic pneumonia syndrome: changing spectrum of In conclusion, this study demonstrates that patients lung injury after marrow transplantation. Transplantation developing LONIPCs have a poor prognosis despite a 1997; 63: 1079–1086. lower incidence of relapse. Furthermore, detection of 7 Upton A, Kirby KA, Carpenter P, Boeckh M, Marr KA. LONIPCs before the appearance of respiratory symptoms Invasive aspergillosis following hematopoietic cell trans- is difficult unless PFTs are performed more frequently. plantation: outcomes and prognostic factors associated with Clin Infect Dis Once patients have developed LONIPCs, early administra- mortality. 2007; 44: 531–540. 8 Afessa B, Litzow MR, Tefferi A. Bronchiolitis obliterans and tion of corticosteroids might be effective and lead to a other late onset non-infectious pulmonary complications in better outcome. Our recommendations for patients with hematopoietic stem cell transplantation. Bone Marrow Trans- respiratory symptoms are therefore as follows: (1) Exclu- plant 2001; 28: 425–434. sion of infection should be done as soon as possible, even 9 Sakaida E, Nakaseko C, Harima A, Yokota A, Cho R, Saito Y for outpatients. (2) After an infectious etiology has been et al. Late-onset noninfectious pulmonary complications after

Bone Marrow Transplantation Outcome and treatment of LONIPCs K Ueda et al 1726 allogeneic stem cell transplantation are significantly associated 25 Yoshihara S, Yanik G, Cooke KR, Mineishi S. Bronchiolitis with chronic graft-versus-host disease and with the graft- obliterans syndrome (BOS), bronchiolitis obliterans organizing versus-leukemia effect. Blood 2003; 102: 4236–4242. pneumonia (BOOP), and other late-onset noninfectious 10 Roca J, Granena A, Rodriguez-Roisin R, Alvarez P, Agusti- pulmonary complications following allogeneic hematopoietic Vidal A, Rozman C. Fatal airway disease in an adult with stem cell transplantation. Biol Blood Marrow Transplant 2007; chronic graft-versus-host disease. Thorax 1982; 37: 77–78. 13: 749–759. 11 Chan CK, Hyland RH, Hutcheon MA, Minden MD, 26 American Thoracic Society/European Respiratory Society Alexander MA, Kossakowska AE et al. Small-airways disease International Multidisciplinary Consensus Classification of in recipients of allogeneic bone marrow transplants. An the Idiopathic Interstitial Pneumonias. This joint statement of analysis of 11 cases and a review of the literature. Medicine the American Thoracic Society (ATS), and the European (Baltimore) 1987; 66: 327–340. Respiratory Society (ERS) was adopted by the ATS board of 12 Palmas A, Tefferi A, Myers JL, Scott JP, Swensen SJ, Chen directors, June 2001 and by the ERS Executive Committee, MG et al. Late-onset noninfectious pulmonary complications June 2001. Am J Respir Crit Care Med 2002; 165: 277–304. after allogeneic bone marrow transplantation. Br J Haematol 27 Klein JP, Rizzo JD, Zhang MJ, Keiding N. Statistical methods 1998; 100: 680–687. for the analysis and presentation of the results of bone marrow 13 Clark JG, Schwartz DA, Flournoy N, Sullivan KM, Crawford transplants. Part 2: Regression modeling. Bone Marrow SW, Thomas ED. Risk factors for airflow obstruction in Transplant 2001; 28: 1001–1011. recipients of bone marrow transplants. Ann Intern Med 1987; 28 Klein JP, Rizzo JD, Zhang MJ, Keiding N. Statistical methods 107: 648–656. for the analysis and presentation of the results of bone marrow 14 Holland HK, Wingard JR, Beschorner WE, Saral R, Santos transplants. Part I: unadjusted analysis. Bone Marrow Trans- GW. Bronchiolitis obliterans in bone marrow transplantation plant 2001; 28: 909–915. and its relationship to chronic graft-vs-host disease and low 29 Clark JG, Hansen JA, Hertz MI, Parkman R, Jensen L, Peavy serum IgG. Blood 1988; 72: 621–627. HH. NHLBI workshop summary. Idiopathic pneumonia 15 Clark JG, Crawford SW, Madtes DK, Sullivan KM. syndrome after bone marrow transplantation. Am Rev Respir Obstructive lung disease after allogeneic marrow transplanta- Dis 1993; 147(6 Pt 1): 1601–1606. tion. Clinical presentation and course. Ann Intern Med 1989; 30 Spitzer TR. Engraftment syndrome following hematopoietic 111: 368–376. stem cell transplantation. Bone Marrow Transplant 2001; 27: 16 Curtis DJ, Smale A, Thien F, Schwarer AP, Szer J. Chronic 893–898. airflow obstruction in long-term survivors of allogeneic bone 31 Reynaud-Gaubert M, Thomas P, Badier M, Cau P, Giudicelli marrow transplantation. Bone Marrow Transplant 1995; 16: R, Fuentes P. Early detection of airway involvement in 169–173. obliterative bronchiolitis after lung transplantation. Func- 17 Sanchez J, Torres A, Serrano J, Roman J, Martin C, Perula L tional and bronchoalveolar lavage cell findings. Am J Respir et al. Long-term follow-up of immunosuppressive treatment Crit Care Med 2000; 161: 1924–1929. for obstructive airways disease after allogeneic bone marrow 32 Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz M transplantation. Bone Marrow Transplant 1997; 20: 403–408. et al. Bronchiolitis obliterans syndrome 2001: an update of 18 Chien JW, Martin PJ, Gooley TA, Flowers ME, Heckbert SR, the diagnostic criteria. J Heart Lung Transplant 2002; 21: Nichols WG et al. Airflow obstruction after myeloablative 297–310. allogeneic hematopoietic stem cell transplantation. Am J 33 Myers JL, Katzenstein AL. Beyond a consensus classification Respir Crit Care Med 2003; 168: 208–214. for idiopathic interstitial pneumonias: progress and contro- 19 Santo Tomas LH, Loberiza Jr FR, Klein JP, Layde PM, versies. Histopathology 2009; 54: 90–103. Lipchik RJ, Rizzo JD et al. Risk factors for bronchiolitis 34 Rice A, Nicholson AG. The pathologist’s approach to small obliterans in allogeneic hematopoietic stem-cell transplanta- airways disease. Histopathology 2009; 54: 117–133. tion for leukemia. Chest 2005; 128: 153–161. 35 Yoshihara S, Tateishi U, Ando T, Kunitoh H, Suyama H, 20 Wyatt SE, Nunn P, Hows JM, Yin J, Hayes MC, Catovsky D Onishi Y et al. Lower incidence of Bronchiolitis obliterans et al. Airways obstruction associated with graft versus host in allogeneic hematopoietic stem cell transplantation with disease after bone marrow transplantation. Thorax 1984; 39: reduced-intensity conditioning compared with myeloablative 887–894. conditioning. Bone Marrow Transplant 2005; 35: 1195–1200. 21 Bergeron A, Belle A, Chevret S, Ribaud P, Devergie A, 36 Savani BN, Montero A, Srinivasan R, Singh A, Shenoy A, Esperou H et al. Combined inhaled steroids and broncho- Mielke S et al. Chronic GVHD and pretransplantation dilatators in obstructive airway disease after allogeneic stem abnormalities in pulmonary function are the main determi- cell transplantation. Bone Marrow Transplant 2007; 39: nants predicting worsening pulmonary function in long-term 547–553. survivors after stem cell transplantation. Biol Blood Marrow 22 Ratjen F, Rjabko O, Kremens B. High-dose corticosteroid Transplant 2006; 12: 1261–1269. therapy for bronchiolitis obliterans after bone marrow 37 Singh AK, Karimpour SE, Savani BN, Guion P, Hope AJ, transplantation in children. Bone Marrow Transplant 2005; Mansueti JR et al. Pretransplant pulmonary function tests 36: 135–138. predict risk of mortality following fractionated total body 23 Kanda Y, Oshima K, Asano-Mori Y, Kandabashi K, irradiation and allogeneic peripheral blood stem cell trans- Nakagawa M, Sakata-Yanagimoto M et al. In vivo alemtuzu- plant. Int J Radiat Oncol Biol Phys 2006; 66: 520–527. mab enables haploidentical human leukocyte antigen-mis- 38 Patriarca F, Skert C, Sperotto A, Damiani D, Cerno M, matched hematopoietic stem-cell transplantation without ex Geromin A et al. Incidence, outcome, and risk factors of vivo graft manipulation. Transplantation 2005; 79: 1351–1357. late-onset noninfectious pulmonary complications after un- 24 Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, related donor stem cell transplantation. Bone Marrow Trans- Lee SJ et al. National Institutes of Health consensus plant 2004; 33: 751–758. development project on criteria for clinical trials in chronic 39 Guihot A, Becquemin MH, Couderc LJ, Randrianarivelo O, graft-versus-host disease: I Diagnosis and staging working Rivaud E, Philippe B et al. Telemetric monitoring of group report. Biol Blood Marrow Transplant 2005; 11: pulmonary function after allogeneic hematopoietic stem cell 945–956. transplantation. Transplantation 2007; 83: 554–560.

Bone Marrow Transplantation Outcome and treatment of LONIPCs K Ueda et al 1727 40 Bashoura L, Gupta S, Jain A, Couriel DR, Komanduri KV, Recherche sur les Maladles ‘Orphelines’ Pulmonaires (GER- Eapen GA et al. Inhaled corticosteroids stabilize constrictive M’O’P). Am J Respir Crit Care Med 2000; 162(2 Pt 1): 571–577. bronchiolitis after hematopoietic stem cell transplantation. 43 Wells AU. Cryptogenic organizing pneumonia. Semin Respir Bone Marrow Transplant 2008; 41: 63–67. Crit Care Med 2001; 22: 449–460. 41 Epler GR. Bronchiolitis obliterans organizing pneumonia. 44 Vento G, Matassa PG, Ameglio F, Capoluongo E, Semin Respir Infect 1995; 10: 65–77. Tortorolo L, Romagnoli C. Effects of early dexamethasone 42 Lazor R, Vandevenne A, Pelletier A, Leclerc P, Court-Fortune I, therapy on pulmonary ﬁbrogenic mediators and respiratory Cordier JF. Cryptogenic organizing pneumonia. Characteristics of mechanics in preterm infants. Eur Cytokine Netw 2002; 13: relapses in a series of 48 patients. The Groupe d’Etudes et de 207–214.

Bone Marrow Transplantation