Lung function 5 yrs after allogeneic bone marrow transplantation conditioned with busulphan and cyclophosphamide

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1 Eur Respir J 2004; 23: DOI: / Prited i UK all rights reserved Copyright #ERS Jourals Ltd 2004 Europea Respiratory Joural ISSN Lug fuctio 5 yrs after allogeeic boe marrow trasplatatio coditioed with busulpha ad cyclophosphamide M.B. Lud*, L. Brich #, J. Kogerud*, J. Boe* Lug fuctio 5 yrs after allogeeic boe marrow trasplatatio coditioed with busulpha ad cyclophosphamide. M.B. Lud, L. Brich, J. Kogerud, J. Boe. #ERS Jourals Ltd ABSTRACT: Log-term data o lug fuctio after boe marrow trasplatatio (BMT) are icoclusive. Previously, a persistet reductio i gas trasfer 1 yr after allogeeic BMT with busulpha ad cyclophosphamide coditioig was reported by the curret authors. I the preset study this reductio was examied to see if it was permaet, trasiet or progressive. Prospectively, 43 cosecutive adult patiets with maligat blood disorders udertook lug fuctio measuremets prior to BMT, at 3 moth itervals durig the 1st yr after BMT ad fially after 5 yrs. Mea baselie lug fuctio values were w90% predicted. Withi the 1st yr after BMT a trasiet declie i lug volumes ad a persistet reductio i gas trasfer were observed. After 5 yrs, baselie values were restored for all variables, except i four patiets who developed obliterative brochiolitis. Acute leukaemia ad smokig were idepedetly associated with gas trasfer reductios at baselie ad durig the 1st yr after BMT. Allogeeic boe marrow trasplatatio with busulpha ad cyclophosphamide coditioig was associated with a reductio i gas trasfer 1 yr after boe marrow trasplatatio but baselie values were usually restored after 5 yrs. Sice recovery may be gradual ad slow, a observatio periodw1 yr is required before drawig coclusios cocerig the developmet of a permaet reductio i lug fuctio after allogeeic boe marrow trasplatatio coditioed with busulpha ad cyclophosphamide. Eur Respir J 2004; 23: *Dept of Respiratory Medicie, Divisio of Heart ad Lug Diseases, ad # Sectio of Haematology, Medical Dept, The Natioal Hospital, Uiversity of Oslo, Norway. Correspodece: J. Boe Dept of Respiratory Medicie Divisio of Heart ad Lug Diseases The Natioal Hospital Uiversity of Oslo N-0027 Oslo Norway Fax: jacob.boe@klimed.uio.o Keywords: Allogeeic boe marrow trasplatatio busulpha cyclophosphamide log term pulmoary fuctio Received: July Accepted after revisio: February Sice therapeutic success has resulted i a growig umber of log-term survivors after allogeeic boe marrow trasplatatio (BMT), the risk of delayed adverse effects has become a matter of cocer [1, 2]. Lug disease, as a cause of early morbidity ad mortality followig BMT, has bee extesively described [3 6]. However, few studies have focused o log-term lug fuctio i adult BMT survivors [7 10]. Furthermore, such studies have ofte bee limited by heterogeeous patiet groups [7 9], ad short periods of observatio (v5 yrs) [7 10]. The term "late-oset oifectious pulmoary complicatios" has bee itroduced to describe a sydrome of lug ijury occurrig w3 6 moths after BMT [8, 11]. The pathogeesis of this sydrome is uclear but may be related to coditioig regimes give prior to BMT, immuosuppressive therapy followig BMT, or to the developmet of chroic graft versus host disease (GVHD) [8, 11, 12]. I maligat diseases, late toxicity due to previous covetioal treatmet (chemotherapy ad irradiatio) may also be of importace. Cytoreductive therapy with high-dose busulpha (BU) ad cyclophosphamide (CY) is a alterative to coditioig regimes that iclude total body irradiatio (TBI) [13, 14]. However, both BU ad CY are potetially toxic to the lug ad may iduce iterstitial peumoitis ad subsequet pulmoary fibrosis [15]. Methotrexate ad cyclosporie, which are commoly used as prophylactic agets agaist GVHD, have also bee associated with adverse pulmoary effects [15]. Furthermore, boe marrow recipiets are at risk of developig obliterative brochiolitis (OB) usually associated with GVHD [16]. I Norway, all allogeeic BMT operatios are performed i The Natioal Hospital, Uiversity of Oslo. The patiet populatio is recruited from the etire coutry, referred ad selected accordig to uiform criteria ad subjected to stadardised treatmet procedures. Coditioig with BU/ CY prior to BMT is the stadard cytoreductive treatmet for maligat blood disorders ad TBI is ot applied. I a previous, short-term lug fuctio study by the preset authors, allogeeic BMT with BU/CY was foud to be associated with a persistet reductio i gas trasfer 1 yr after therapy [17]. I the preset study, the authors aimed to assess log-term lug fuctio i the same oirradiated patiet populatio coditioed with BU/CY accordig to a stadard protocol. The preset study was specifically udertake to fid out whether the observed impairmet i gas trasfer, 1 yr after BMT would be permaet, trasiet or progressive after a exteded observatio period of 5 yrs. Study subjects ad desig Material ad methods A total of 65 adult patiets uderwet allogeeic BMT at the Natioal Uiversity Hospital, Oslo, Norway, durig , ad were cosecutively erolled ito a prospective

2 902 M.B. LUND ET AL. study. The patiets (37 males ad 28 females, aged media (rage) 33 (17 54) yrs) represeted a atioal cohort, which were referred ad selected accordig to uiform criteria, ad had bee subjected to stadardised treatmet prior to BMT. Each patiet was examied o six occasios: prior to BMT; at y3 moths itervals durig the 1st yr after BMT; ad fially, after 5 yrs. Five patiets, trasplated for omaligat blood disorders ad give coditioig regimes without BU, were excluded from the study. Altogether, 17 patiets were lost before the 5-yr follow-up examiatio. A total of 12 had died (five withi the first year), oe of them from pulmoary complicatios (10 maligat relapse, oe GVHD ad oe suicide). Five patiets who were followed-up at regioal hospitals for geographical reasos, were all reported to be healthy ad without pulmoary complaits. The remaiig 43 patiets, who all completed the 5-yr follow-up, were icluded i the study. Their characteristics at iclusio are outlied i table 1. Trasplatatio procedures Coditioig prior to BMT has previously bee described [14, 17]. Briefly, all patiets were treated with BU orally at a dose of 1 mg?kg -1 of body weight, four times daily for four cosecutive days followed by CY at a daily dose of 60 mg?kg -1 admiistered i.v. over a period of 30 mi for two cosecutive days [14]. Boe marrow was ifused 2 days after the fial dose of CY. No patiets received TBI. GVHD prophylaxis cosisted of methotrexate (i.v. o day 1, 3, 6 ad 11) ad cyclosporie. After stable egraftmet, Trimetoprimsulpha-methoxazol was give as prophylaxis agaist Peumocystis cariii ifectio. Chroic GVHD was diagosed accordig to defied criteria [18]. Table 1. Baselie cliical characteristics of 43 cosecutive patiets with maligat blood disorders treated with boe marrow trasplatatio ad busulpha/cyclophosphamide coditioig Sex M:F 25:18 Age yrs 34 (17 54) Diagosis CML 29 AML 9 ALL 3 MDS 2 Door Siblig 32 Urelated 11 Smokig Nosmoker 28 Exsmoker 2 Curret smoker 13 Lug fuctio FVC % pred FEV1 % pred FEV1/FVC % 81 7 TL,CO % pred TL,CO-Hb % pred Hb g?100 ml Data are preseted as, media (rage) or mea SD. M: male; F: female; CML: chroic myeloid leukaemia; AML: acute myeloid leukaemia; ALL: acute lymphocytic leukaemia; MDS: myelodysplastic sydrome; FVC: forced vital capacity; FEV1: forced expiratory volume i oe secod; % pred: per cet predicted; TL,CO: trasfer factor of the lug for carbo mooxide; TL,CO-Hb: trasfer factor of the lug for carbo mooxide corrected for haemoglobi level; Hb: haemoglobi. Cliical ad radiological evaluatio All patiets uderwet cliical examiatio ad had chest radiographs take before BMT ad at each of the six followup cosultatios. If acute respiratory ifectios coicided with the scheduled times of follow-up, lug fuctio testig was postpoed util the patiet was free from sigs ad symptoms of ifectio. All chest radiographs were evaluated by two radiologists ad a cosesus was obtaied. Lug fuctio measuremets Lug fuctio tests icluded dyamic spirometry ad gas diffusio capacity. Spirometry was performed with a watersealed spirometer. Gas trasfer was measured by the sigle breath techique. All measuremets were performed with the Gould automated system 2400 (Sesormedics BV, Bilthove, Netherlads) accordig to guidelies recommeded by the America Thoracic Society [19, 20]. Registered variables were forced vital capacity (FVC), forced expiratory volume i oe secod (FEV1), FEV1/FVC x 100 (FEV1/FVC ratio) ad the trasfer factor of the lug for carbo mooxide (TL,CO). All TL,CO values were adjusted for haemoglobi (Hb) cocetratio by usig the correctio formula recommeded by COTES et al. [21]. The Hb-levels were obtaied o the same day as the lug fuctio testig. Sice the correctio of TL,CO for alveolar volume (VA) did ot ifluece the results of the aalyses, the variable TL,CO/VA is ot reported. The lug fuctio variables were expressed i absolute values ad as percetage of predicted [22]. To assess logitudial chages i lug fuctio, values for FVC, FEV1 ad trasfer factor of the lug for carbo mooxide corrected for haemoglobi level (TL,CO-Hb) were expressed as a percetage of their baselie values. Complete recovery of lug fuctio was defied as a improvemet to w90% of baselie values. OB was defied as post-bmt developmet of irreversible airflow obstructio characterised by both FEV1 v70% pred ad FEV1/FVC v70% [16]. Statistics Categorical data were compared by the Chi-squared test. Group mea data were compared with the upaired t-test. The t-test for paired data was used to compare lug fuctio values pre-bmt with post-bmt at the time of maximum reductio (i.e. 3 moths), at 1-yr follow-up ad 5-yr followup. Boferroi9s correctio was applied whe multiple comparisos were carried out. I total four patiets with OB were excluded from the logitudial lug fuctio aalyses. Multiple liear regressio was used to detect relatioships betwee pulmoary fuctio ad relevat idepedet covariates. Variables with more tha two categories were trasformed ito biary variables. Chroic myeloid leukaemia (CML) ad myelodysplastic sydrome (MDS) were tested versus the acute leukaemias (i.e. CMLzMDS=1 ad otherwise =0). Smokers were tested versus osmokers, with the two exsmokers excluded from the aalyses. The idepedet variables etered ito the regressio models were those foud to be sigificat at the 20% level by previous uivariate aalysis. A p-value v0.05 was cosidered to be statistically sigificat. Results All patiets had ormal chest radiographs at the time of iclusio. Pulmoary fuctio for the etire study group was

3 LUNG FUNCTION AFTER BMT 903 withi the ormal rage. Baselie spirometric values were w100% ad gas trasfer (Hb-adjusted) w90% pred (table 1). Patiets with acute leukaemias had sigificatly lower baselie TL,CO-Hb (mea SD % pred) tha patiets with chroic leukaemia (84 13% versus 96 14%, p=0.02), ad smokers had lower baselie TL,CO-Hb tha osmokers (87 13% versus 96 15%, p=0.04). The effects of maligat disorder ad smokig o TL,CO-Hb i a multiple liear regressio model were aalysed cotrollig for sex ad age. The curret authors foud that the associatios betwee TL,CO-Hb ad acute leukaemia ad smokig persisted ( (b coefficiet SE), p=0.005, ad , p=0.05, respectively). Withi the 1st yr after BMT, eight patiets developed chroic GVHD. I total, four developed persistet airflow obstructio cosistet with OB (fig. 1). These four patiets were oasthmatic osmokers with ormal baselie lug fuctio. After 5 yrs, two of the patiets were cliically stable, while two had developed brochiectasis, recurret ifectios ad chroic respiratory failure. Oe patiet was o the waitig list for lug trasplatatio, while the other was still uder assessmet at the time of writig the curret article. I total, four patiets with OB were excluded from the aalyses. Table 2 shows lug fuctio before BMT, ad at 3 FEV1 % pred Patiet o. Fig. 1. Forced expiratory volume i oe secod (FEV1) predicted before boe marrow trasplatatio (BMT), ad 1 yr ad 5 yrs after BMT i four patiets who developed obliterative brochiolitis. u baselie; h 1 yr; q 5 yrs. Table 2. Lug volumes, gas trasfer ad haemoglobi before ad after boe marrow trasplatatio (BMT) i 39 cosecutive patiets with maligat blood disorders treated with BMT ad busulpha/cyclophosphamide coditioig (patiets with obliterative brochiolitis excluded) Pre-BMT 3 moths 12 moths 5 yrs FVC % pred *** FEV1 % pred * FEV1/FVC % * TL,CO % pred *** 70 14*** TL,CO-Hb % pred *** 76 15*** Hb g?100 ml *** Data are preseted as mea SD; Statistical comparisos: values at the time of maximum impairmet (i.e. 3 moths) ad values at 12 moths ad 5 yrs after BMT are compared with values pre-bmt. FVC: forced vital capacity; % pred: per cet predicted; FEV1: forced expiratory volume i oe secod; TL,CO: trasfer factor of the lug for carbo mooxide; TL,CO-Hb: trasfer factor of the lug for carbo mooxide corrected for haemoglobi level; Hb: haemoglobi. *: pv0.05; ***: pv0.001, Boferroi9s correctio for multiple comparisos. 3 4 moths (i.e. adir), 1 yr ad 5 yrs after BMT. FVC ad FEV1 were sigificatly reduced after 3 moths, but recovered after 1 yr. The correspodig icrease i FEV1 % pred at 3 moths reflects the restrictive patter of the vetilatory impairmet. Figure 2 shows the lug fuctio variables expressed as a percetage of their baselie values. TL,CO-Hb reached a adir of 79 19% (mea SD) of baselie after 3 moths, was still sigificatly reduced by 82 15% of baselie after 1 yr, but recovered to 94 15% of baselie after 5 yrs. I patiets with acute leukaemias, TL,CO-Hb was restored to 98 14% of baselie after 5 yrs, as compared with % of baselie i patiets with chroic leukaemia. I a multiple liear regressio model, the associatio betwee a reductio i TL,CO-Hb ad acute leukaemia persisted 3 moths after BMT ( (b coefficiet SE), p=0.01), but ot after 1 yr ad 5 yrs. Smokig was associated with a declie i TL,CO-Hb 3 moths ( , p=0.007) ad 1 yr (b coefficiet , p=0.04) after BMT, but o loger after 5 yrs. Sex, age ad door status were ot sigificatly associated with reductios i TL,CO-Hb at ay time of follow-up. All patiets (icludig the four with OB) had ormal chest radiographs at 1 yr ad 5 yr follow-up. There were o cases of chroic pulmoary complicatios, other tha OB. Discussio The authors of the curret study have previously show a sigificat reductio i gas trasfer throughout the 1st yr after allogeeic BMT, coditioed with BU/CY [17]. The major fidig of the preset study was that mea baselie lug fuctio was restored after 5 yrs. The authors of the preset study suggest that it may be premature to iterpret a reductio i lug fuctio 1 yr after cytotoxic therapy as a permaet reductio, sice it may be that the restoratio process is slow ad ot yet fully completed. For the etire study group, baselie lug fuctio was ormal, reflectig that the patiets were youg ad otherwise healthy subjects. I geeral, baselie lug fuctio was w80% pred i patiets both with acute ad chroic leukaemias. The curret authors suspected that prior chemotherapy would make the patiets with acute leukaemias more susceptible to a reductio i lug fuctio after BMT. The multivariate % predicted s s s s Moths Fig. 2. Chages i lug fuctio after boe marrow trasplatatio expressed as a percetage of baselie values. %: forced vital capacity; &: forced expiratory volume i oe secod; +: trasfer factor of the lug for carbo mooxide corrected for haemoglobi level. s

4 904 M.B. LUND ET AL. aalyses showed that the observed associatio betwee acute leukaemias ad reductio i TL,CO-Hb at baselie persisted 3 moths after BMT, but ot thereafter. At the 5 yr follow-up, mea TL,CO-Hb was restored i both groups. This implies that, although the patiets who had received chemotherapy prior to BMT had sigificatly lower TL,CO-Hb both at baselie ad 3 moths after BMT, they did ot suffer further declie ad they obtaied early the same level of recovery (compared with baselie) as the patiets with chroic leukaemias. The authors of the preset study foud that smokig was a sigificat predictor for a reductio i TL,CO-Hb at baselie ad 3 moths ad 1 yr after BMT, but the curret study failed to demostrate a similar associatio after 5 yrs. This may partly be explaied by chages i smokig habits over the 5 yrs. No patiets started to smoke after BMT, but some of the smokers had quit for shorter or loger periods, ad at 5 yrs follow-up, they described themselves as occasioal or periodic smokers rather tha daily (i.e. curret) smokers. Sice smokig habits were difficult to categorise i a stadardised maer at that time, the curret study also chose to use the iformatio obtaied at iclusio for the 5-yr aalysis. However, this implies a bias towards uderestimatig a effect of smokig, ad the results should, therefore, be iterpreted with due cautio. The preset study cosisted of a oirradiated patiet populatio, all coditioed with BU/CY. Sice 1989, BU/CY has bee the stadard myeloablative therapy for patiets udergoig allogeeic BMT for maligat blood disorders at the istitutio where the curret study was performed, ad the regime is still i curret use. Pretrasplat coditioig with high-dose BU/CY was itroduced i the early 1980s as a alterative to the established TBI/CY regime that had bee cosidered the treatmet of choice sice the 1970s [13, 14]. The developmet of the ew preparative BU/CY regime was motivated by a desire to reduce radiatio-related toxicity ad improve log-term survival. However, cotroversy still persists cocerig the optimal coditioig regime prior to allogeeic BMT. Some older studies idicated that iterstitial peumoitis occurred more frequetly amog patiets treated with TBI tha those treated with BU [23, 24], but more recet meta-aalysis [25] ad log-term follow-up of four radomised studies have cocluded that late pulmoary complicatios occur equally after both coditioig regimes [26]. The declie i TL,CO-Hb observed i the oirradiated patiets was comparable to that reported i patiets coditioed with TBI [9, 27]. However, the associated developmet of OB after allogeeic BMT remais to be prove. A radomised log-term study by the Nordic Boe Marrow Trasplatatio Group reported a sigificatly icreased risk of OB i patiets coditioed with BU/CY as compared with those coditioed with TBI/CY [28], but the subsequet report of four radomised studies did ot cofirm the fidig [26]. The prevalece of OB i subjects i the curret study was comparable to that observed i other studies, applyig coditioig regimes with ad without TBI [2]. I coclusio, allogeeic boe marrow trasplatatio with busulpha/cyclophosphamide coditioig is associated with a sigificat declie i gas trasfer throughout the first year after treatmet. However, after 5 yrs, recovery to baselie has geerally bee obtaied. Acute leukaemias ad smokig, prior to boe marrow trasplatatio, are idepedet risk factors for a reductio i gas trasfer at baselie ad durig the 1st yr after boe marrow trasplatatio, but after 5 yrs o risk factors ca be idetified. 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