Impact of body mass index on pulmonary ...

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Impact of body mass index on pulmonary complications in patients with non-Hodgkin lymphoma treated with hematopoietic stem cell transplant a

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c

a

d

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Chi Lin , Jeffmin Lin , Mark Stavas , Sicong Li , Kerry J. Canady , Debra J. Romberger & e

Fausto R. Loberiza Jr a

Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA

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Princeton University, Princeton, NJ, USA

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College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA

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Pulmonary, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA e

Hematology Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA Published online: 15 May 2015.

To cite this article: Chi Lin, Jeffmin Lin, Mark Stavas, Sicong Li, Kerry J. Canady, Debra J. Romberger & Fausto R. Loberiza Jr (2015): Impact of body mass index on pulmonary complications in patients with non-Hodgkin lymphoma treated with hematopoietic stem cell transplant, Leukemia & Lymphoma To link to this article: http://dx.doi.org/10.3109/10428194.2015.1025393

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Leukemia & Lymphoma, 2015; Early Online: 1–7 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2015.1025393

original article: clinical

Impact of body mass index on pulmonary complications in patients with non-Hodgkin lymphoma treated with hematopoietic stem cell transplant Chi Lin1, Jeffmin Lin2, Mark Stavas3, Sicong Li1, Kerry J. Canady4, Debra J. Romberger4 & Fausto R. Loberiza Jr5 1Department of Radiation Oncology, 3College of Medicine, 4Pulmonary, Department of Internal Medicine and 5Hematology

Downloaded by [Chi Lin] at 09:24 15 May 2015

Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA and 2Princeton University, Princeton, NJ, USA

Abstract The objective of this study was to examine the association between body mass index (BMI) and the incidence of pulmonary complications (PCs) after hematopoietic stem cell transplant (HCT). We reviewed 398 adult patients with non-Hodgkin lymphoma (NHL) who received autologous or allogeneic HCT between 1993 and 1997. BMI was classified as normal (18.5  BMI  24.9), overweight (24.9  BMI  30) and obese (BMI  30). Multivariate logistic regression was used to analyze the relationship between BMI and presence of PCs within 100 days post-HCT while adjusting for patient-, disease- and transplantrelated variables. The incidence of PCs within 100 days post-HCT was 32% (n  129). Median BMI was 25.4 (range: 18.6–52.2). Median age was 48.8 years (range: 19.5–73.6 years). Multivariate analysis failed to show significant association between BMI and PCs. However, a total body irradiation (TBI)-based conditioning regimen was associated with lower rate of PCs.

infections; and treatment-related factors such as prior localized chest irradiation, chemotherapeutic agents and the use of TBI. There are also factors that have remained provocative. One of them is the role of weight at the time of treatment on clinical outcomes. Studies suggest that being underweight is a contributing factor toward inferior outcomes after HCT [8–10], and being overweight has protective effects from inferior outcomes [8,11,12]. It is assumed that underweight individuals are less tolerant to chemotherapy and radiation therapy than normal weight individuals of the same age, gender and height and have increased treatment-related complications. On the contrary, some studies have demonstrated that being underweight is not associated with the outcome of HCT, and being overweight is associated with inferior outcomes [13–15]. We therefore retrospectively analyzed the University of Nebraska Medical Center (UNMC) Oncology Transplant Database (ONCOBASE) to evaluate the impact of body mass index (BMI) on post-transplant pulmonary complications, using a homogeneous group of patients with non-Hodgkin lymphoma receiving similar preparative regimens with or without TBI before autologous or allogeneic HCT, thus excluding the influence of primary tumor type and type of chemotherapy.

Keywords: Body mass index, pulmonary complications, transplant

Introduction Pulmonary complications are commonly reported in patients who have received a hematopoietic stem cell transplant (HCT), occurring at a high rate of 40–60% [1–4]. These complications can include: interstitial pneumonitis, idiopathic interstitial pneumonitis, bronchiolitis obliterans, alveolar hemorrhage, restrictive lung disease, impaired gas exchange and diffusing capacity, and decreased total lung capacity. Studies have also shown that some consolidative regimens administered prior to HCT, including those with total body irradiation (TBI), are risk factors for pulmonary complications after HCT [5–7]. Other known risk factors for pulmonary complications after HCT include patient-related factors such as pre-existing lung disease, abnormal pulmonary function, smoking history and concurrent pulmonary

Patients and methods Patient selection A total of 464 patients diagnosed with non-Hodgkin lymphoma (NHL) received either autologous or allogeneic HCT at UNMC between the years 1993 and 1997. The data were retrieved from the UNMC ONCOBASE. We included only patients up to 1997 because the use of TBI is one of the factors we were interested in evaluating, and its use in patients with NHL ended in 1997. Patients who were categorized as pediatric (18 years old or younger in the state of Nebraska) and those with missing height and weight data

Correspondence: Chi Lin, MD, PhD, 987521 Nebraska Medical Center, Department of Radiation Oncology, Omaha, NE 68198-7621, United States. Tel: 402-552-3844. Fax: 402-552-3013. E-mail: [email protected] Received 2 December 2014; revised 10 February 2015; accepted 25 February 2015

1

2 C. Lin et al. were excluded, leaving 406 evaluable for the study. We additionally excluded eight underweight patients (with BMI 18.5 or less) because they were too few to provide statistically useful information. Thus, a total of 398 patients were included for analysis in this study.


Variable categorization Body mass index was calculated using the formula [weight (kg)/height2 (m2)], and classified as underweight (BMI  18.5), normal (18.5  BMI  24.9), overweight (24.9  BMI  30) and obese (BMI  30). Age was stratified into three groups ( 40, 40–59,  60). Ethnicity was grouped into whites and non-whites. Patients were also grouped into non-smokers, past smokers and current smokers. Patients received one of three types of conditioning regimen: TBIbased, BEAM (BCNU, etoposide, cytosine arabinoside and melphalan) or BEAC (BCNU, etoposide, cytosine arabinoside and cyclophosphamide). Chest–waist width difference was defined as the difference in lateral width of the chest at the axillary level and the waist at the umbilical level. The following characteristics were retrieved: age, gender, ethnicity, smoking history, pre-existing pulmonary conditions, weight, height, type of NHL, Ann Arbor stage at transplant, the presence of B symptoms, bone marrow involvement, lactate dehydrogenase levels at transplant, disease stage at transplant, conditioning regimen and transplant type.

Study endpoint The primary endpoint in this study was the presence or absence of post-transplant pulmonary complications within the first 100 days post-HCT. Medical records were retrospectively reviewed for pulmonary complications by two pulmonary specialists. Complications were categorized into one of the following four entities: interstitial pneumonitis, diffuse alveolar hemorrhage, bronchiolitis obliterans/bronchiolitis obliterans with organizing pneumonia and other non-infectious pulmonary abnormalities. Data reviewed included clinical notes, radiographic reports and histology, if available. Diffuse alveolar hemorrhage was diagnosed via chest radiograph and confirmed via bronchoscopy with persistently hemorrhagic bronchoalveolar fluid. Interstitial pneumonitis most commonly included diagnoses of infection and acute respiratory distress syndrome, which were diagnosed by radiography, clinical factors and positive cultures. Bronchiolitis obliterans/bronchiolitis obliterans with organizing pneumonia required lung histology for diagnosis. The most frequent non-infectious pulmonary abnormality was pulmonary edema or pleural effusion, which was diagnosed by radiography.

Statistical methods Descriptive statistics, such as count, percentage, mean, standard deviation, median and range, were used to describe all study variables. Both univariate and multivariate logistic regression models were used to analyze the likelihood of post-HCT pulmonary complications at 100 days as related to BMI. Stepwise model building, forcing BMI into the model, led to a final adjusted model that included covariates at a

significance level of a  0.05, including patient’s age and conditioning regimen. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using SAS for Windows version 9.3.

Results Patient characteristics The rate of pulmonary complications within 100 days in this study group was 128/398, 32.4% (58/183, 15%; 48/136, 12%; and 22/79, 6% from patients with normal, overweight and obese BMI, respectively, p  0.5). Among 128 cases with pulmonary complications, there were 59 (26 normal, 24 overweight, nine obese) interstitial pneumonitis, 45 (21 normal, 16 overweight, eight obese) other non-infectious, seven (four normal, two overweight, one obese) pulmonary hemorrhage, one (normal) organizing pneumonia and 16 unknown (Table I). The median age for each BMI class was 46.6 (19.6–73.6), 49.4 (22.1–69.0) and 47.9 (19.5–68.2) for patients with normal, overweight and obese BMI, respectively (p  0.09). Among patients with normal BMI, approximately half were males. Patients with overweight and obese BMI were approximately 70% males (p  0.003). Most patients were of white, non-Hispanic ethnicity (n  386, 97%). Most patients did not have pre-existing pulmonary complications at the time of transplant (n  372, 93%, one missing). Only 25 patients had pre-transplant pulmonary complications that included a history of asthma, emphysema, asbestosis, opportunistic infections (Klebsiella pneumoniae sepsis, Pneumocystis pneumonia, aspergillosis), pulmonary embolism, respiratory syncytial virus, cytomegalovirus and spontaneous pneumothorax. Other patient characteristics did not have significantly varied proportions across BMI groups (Table II).

Regression analysis All potential predictor variables such as age, gender, ethnicity, smoking history, pre-existing pulmonary conditions, weight, height, type of NHL, Ann Arbor stage at transplant, the presence of B symptoms, bone marrow involvement, lactate dehydrogenase levels at transplant, disease stage at transplant, conditioning regimen and transplant type were analyzed in the univariate logistic regression model. All but age and conditioning regimen were not significantly correlated with post-transplant pulmonary complications. Therefore, only age and conditioning regimen were included in multivariate logistic regression analysis. Stepwise multivariate logistic regression showed that age group (OR 1.48, 95% CI 1.05–2.08) and conditioning regimen with and without TBI (OR 0.5, 95% CI 0.29–0.87) were significantly correlated with post-transplant pulmonary complications. Forcing BMI into the model showed that BMI was not significantly correlated with the risk of having pulmonary complications within 100 days post-transplant (Table III). Given that no patients aged 60 or older received a TBIbased conditioning regimen, a subset analysis was done excluding patients aged 60 and older. Univariate analysis showed that conditioning regimen with and without TBI (OR 0.5, 95% CI 0.31–0.96) continued to be significantly correlated with post-HCT pulmonary complications. All other factors

9 (11.4) 8 (10.1) 1 (1.3) 0 4 (5.1) 22 (28) BMI, body mass index; TBI, total body irradiation; BEAM, BCNU, etoposide, cytosine arabinoside and melphalan; BEAC, BCNU, etoposide, cytosine arabinoside and cyclophosphamide.

24 (17.6) 16 (11.7) 2 (1.4) 0 6 (4.4) 48 (35) 26 (14.2) 21 (11.5) 4 (2.2) 1 (0.5) 6 (3.3) 58 (32) 45 (17.5) 32 (12.5) 4 (1.6) 0 9 (3.5) 90 (35) 6 (10.2) 7 (16.3) 2 (4.1) 0 3 (6.1) 18 (37) 8 (8.7) 6 (6.5) 1 (1.1) 1 (1.1) 4 (4.3) 20 (22) 7 (18.4) 1 (2.6) 1 (2.6) 1 (2.6) 2 (5.3) 12 (32) 52 (14.4) 44 (12.2) 6 (1.6) 0 14 (3.9) 116 (32) Interstitial pneumonitis Other non-infectious Pulmonary hemorrhage Organizing pneumonia Unknown Total

BMI

BEAC (n  257), n (%) BEAM (n  49), n (%)

Conditioning regimen

Chemotherapy with TBI (n  92), n (%) Allogeneic (n  38), n (%)

Type of transplant

failed to be associated with post-HCT pulmonary complications. In the multivariate analysis model, BMI again was not associated with pulmonary complications after adjusting for conditioning regimen.

Patients who received TBI-based conditioning: subgroup analysis

Autologous (n  360), n (%) Pulmonary complications

Table I. Pulmonary complications stratified by type of transplant, conditioning regimen and BMI.


Normal (n  183), n (%)

Overweight (n  136), n (%)

Obese (n  79), n (%)

BMI on pulmonary complications after HCT 3

All patients who received TBI received 12 Gy at 2 Gy per fraction, two fractions per day, for a total of 3 days. Photon energy used in total body irradiation was 10 MV. Radiation was administered to the left and right lateral fields. The dose was prescribed to the middle plane of the body at the waist (umbilical level) (Table IV). The median measurement for patients’ chest width at the axillary level in each BMI group was 31.75 cm (range: 25–37.5), 35 cm (range: 29–41) and 38.5 cm (range: 30–46) for patients with normal, overweight and obese BMI, respectively (p  0.0001). At the umbilical level, the median waist width in each BMI group was 28.125 cm (range: 21–36), 32.25 cm (25–39.5) and 35.5 cm (26–41) for patients with normal, overweight and obese BMI, respectively (p  0.0001). Because TBI was prescribed to the middle plane of the body at the waist, the difference between lateral width at the axillary level and the umbilical level was potentially correlated to post-transplant pulmonary complications. However, logistic regression analysis showed that chest–waist difference was not associated with post-transplant pulmonary complications. There were no further detailed dosimetric data to be analyzed in this group of patients because twodimensional radiation treatment planning was used for TBI. We also evaluated the impact of all potential factors listed in Table II on pulmonary complications in this subset of patients. No association with pulmonary complications was found for all factors.

Discussion Although we failed to find a significant correlation between BMI and post-transplant pulmonary complications, we believe that this is an important negative finding. It suggests that physicians should not discriminate against overweight or obese patients in administering HCT. The second important finding of this study is that the use of a TBI-based conditioning regimen was associated with lower post-transplant pulmonary complications. This finding supports the current clinical practice of using a TBI-based preparation regimen for HCT. Among the subgroup of patients who received TBI as part of their preparative regimen, a chest–waist width difference was not correlated with the risk of post-transplant pulmonary complications.

BMI Several studies have revealed that higher BMI (overweight or obese) is linked to inferior survival [16,17] and higher risk of infection [18]. Fuji et al. conducted a study in 3935 patients who received a bone marrow transplant, showing that obese BMI was linked with an increased risk of post-transplant infections compared to normal BMI [18]. In a study done in pediatric patients receiving allogeneic stem cell transplant,

4 C. Lin et al.


Table II. Patient characteristics. n Age (median, range)  40 40 to  60  60 Sex Female Male Race White Non-White Smoking Non-smoker Past smoker Current smoker Missing Past pulmonary medical problems No Yes Missing Diagnosis NHL CL NHL DL NHL DM NHL DSC NHL FL NHL FM NHL FSC NHL IB NHL LB NHL mantle cell/DSI NHL MF NHL peripheral T-cell NHL SL NHL SNC Burkitt NHL SNC non-Burkitt NHL anaplastic NHL-DSI/blastic NHL-MALT NHL-MCL-MZL NHL-nodal MZ B cell Ann Arbor stage at transplant CR/CRU Stage I/II Stage III/IV Missing Presence of B symptoms No Yes Missing Bone marrow involvement at transplant No Yes Missing Lactate dehydrogenase at transplant Normal Elevated Missing Stage at transplant CR1 CR2 PIF Rel 1 Rel 2 Type of transplant Autologous Allogeneic Conditioning regimen TBI-based BEAM BEAC

n

Normal (%)

Overweight (%)

Obese (%)

p-Value

97 241 60

183 46.6 (19.6–73.6) 52 (28) 102 (56) 29 (16)

136 49.4 (22.1–69.0) 24 (18) 91 (67) 21 (15)

79 47.9 (19.5–68.2) 21 (27) 48 (61) 10 (13)

NA 0.0931 0.2060

153 245

87 (48) 96 (52)

41 (30) 95 (70)

25 (32) 54 (68)

0.0026

386 12

180 (98) 3 (2)

131 (96) 5 (4)

75 (95) 4 (5)

0.2835

213 114 62 9

107 (59) 49 (27) 24 (13)

69 (53) 35 (27) 27 (21)

37 (47) 30 (38) 11 (14)

0.1301

372 25 1

166 (91) 16 (9)

132 (97) 4 (3)

74 (94) 5 (6)

0.1046

33 103 16 3 32 44 22 37 10 28 2 2 13 3 8 23 8 4 4 3

16 (9) 47 (26) 7 (4) 1 (1) 11 (6) 20 (11) 11 (6) 23 (13) 6 (3) 11 (6) 2 (1) 1 (1) 6 (3) 3 (2) 3 (2) 7 (4) 3 (2) 2 (1) 2 (1) 1 (1)

11 (8) 37 (27) 5 (4) 1 (1) 13 (10) 14 (10) 7 (5) 8 (6) 3 (2) 10 (7) 0 (0) 0 (0) 6 (4) 0 (0) 2 (1) 9 (6) 5 (4) 2 (1) 1 (1) 2 (1)

6 (8) 19 (24) 4 (5) 1 (1) 8 (10) 10 (13) 4 (5) 6 (8) 1 (1) 7 (9) 0 (0) 1 (1) 1 (1) 0 (0) 3 (4) 7 (9) 0 (0) 0 (0) 1 (1) 0 (0)

0.8594

97 110 164 27

42 (23) 52 (28) 77 (42) 12 (7)

30 (22) 36 (26) 57 (42) 13 (10)

25 (32) 22 (28) 30 (38) 2 (3)

0.4026

248 96 54

111 (61) 44 (24) 28 (15)

85 (63) 34 (25) 17 (13)

52 (66) 18 (23) 9 (11)

0.8887

286 97 15

129 (70) 49 (27) 5 (3)

94 (69) 35 (26) 7 (5)

63 (80) 13 (16) 3 (4)

0.3251

321 73 4

149 (81) 31 (17) 3 (2)

111 (82) 24 (18) 1 (1)

61 (77) 18 (23) 0 (0)

0.5829

54 33 172 125 14

26 (14) 15 (8) 82 (45) 50 (27) 10 (5)

16 (12) 11 (8) 64 (47) 43 (32) 2 (1)

12 (15) 7 (9) 26 (33) 32 (41) 2 (3)

0.2683

360 38

164 (90) 19 (10)

123 (90) 13 (10)

73 (92) 6 (8)

0.7802

92 49 257

45 (25) 27 (15) 111 (61)

35 (26) 11 (8) 90 (66)

12 (15) 11 (14) 56 (71)

0.1015

HL, non-Hodgkin lymphoma; CL, composite; DL, diffuse large cell; DM, diffuse mixed cell; DSC, diffuse small cleaved; FL, follicular large cell; FM, follicular mixed; N FSC, follicular small cleaved; IB, large cell immunoblastic; LB, lymphoblastic; DSI, diffuse intermediate; MF, mycosis fungoides; peripheral T-cell, peripheral T-cell lymphoma unspecified; SL, small cell lymphocytic; SNC, small non-cleaved; anaplastic, anaplastic large-cell lymphoma; MALT, mucosal associated lymphoid tissue type (extranodal marginal zone B-cell); MCL-MZL, mantle cell-marginal zone lymphoma; CR/CRU, complete remission/CR status uncertain; CR1, first CR; CR2, second chronic phase; PIF, primary induction failure; Rel 1, first relapse; Rel 2, second relapse; BEAM, BCNU, etoposide, cytosine arabinoside and melphalan; BEAC, BCNU, etoposide, cytosine arabinoside and cyclophosphamide.

BMI on pulmonary complications after HCT 5 Table III. Effect of BMI status on likelihood of pulmonary complications. Adjusted model*

Unadjusted model

BMI Normal Overweight Obese BMI Overweight Obese

Pulmonary complications, OR (95% CI)

p-Value

Pulmonary complications, OR (95% CI)

p-Value

1.00 1.15 (0.72–1.83) 0.81 (0.45–1.45)

— 0.5679 0.4806

1.00 1.13 (0.70–1.81) 0.77 (0.43–1.39)

— 0.6238 0.3858

1.00 0.71 (0.39–1.30)

— 0.2623

1.00 0.68 (0.37–1.27)

— 0.2262


BMI, body mass index; OR, odds ratio; CI, confidence interval. *Factors included in the adjusted model: age group and conditioning regimen.

Bulley et al. demonstrated that overweight status was linked to inferior survival [16]. Tarella et al. showed that in patients with high-risk NHL undergoing high-dose sequential chemotherapy including peripheral blood progenitor cell autografting, overweight BMI was associated with a higher risk of death [17]. Furthermore, a few studies have shown that underweight BMI is also associated with increased transplantrelated mortality [8,19]. Navarro et al., in a study involving 4681 patients with lymphoma undergoing autologous HCT, found that transplant-related mortality was similar among normal, overweight and obese patients, and higher among underweight patients [8,12]. In a study involving 544 adults who received allogeneic stem cell transplant and myeloablative conditioning, Le Blanc et al. showed that a low BMI ( 20) was correlated to increased transplant-related mortality, decreased survival and decreased relapse-free survival [19]. Interestingly, a small study including 144 patients found that BMI was not associated with an increased risk for documented infection or microbiologically documented infection [20]. Although various studies have been performed regarding the relationship between BMI and survival, very little investigation has been initiated on the relationship between BMI and post-transplant pulmonary complications, despite the fact that pulmonary complications are a major component of post-transplant morbidity and mortality. This study, however, showed that BMI is not linked to post-transplant pulmonary complications in patients with NHL, after adjusting for age and conditioning regimen.

Age Studies have shown that older age is associated with various post-transplant pulmonary complications [21–23] and decreased lung capacity [24]. Majhail et al. performed a study in 1919 patients who received HCT; the study found that older age was predictive of an increased risk Table IV. TBI technique. Dose Fractions Treatment days Energy Radiation fields Prescription point Separation at waist/umbilicus Separation at chest/axilla

12 Gy 6 3 10 MV (two patients had 4 MV) Right and left lateral Middle plain of body at waist/umbilicus Mean  SD: 34  4 Mean  SD: 31  4

TBI, total body irradiation; SD, standard deviation.

of post-transplant alveolar hemorrhage [21]. Analysis of 932 patients who received a bone marrow transplant by Weiner et al. found that older age was associated with an increased risk of interstitial pneumonitis [22]. Fukuda et al., in a study in 1100 patients who underwent allogeneic HCT, found that older age was associated with significantly increased risk for idiopathic pneumonia syndrome [23]. In a study done to compare TBI regimens with respect to pulmonary toxicity, Gopal et al. found that patients aged 45 years or older had lower post-transplant values, on average, of forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) than younger patients [24]. Interestingly, a few studies have found that age is not predictive of post-transplant interstitial pneumonitis [25] or pulmonary complications in general [26]. Chen et al. performed a study in 94 patients with myeloma undergoing autologous stem cell transplant, and found that age was not predictive of post-transplant interstitial pneumonitis [25]. A study by Thomas et al. including 478 patients who received TBI-based conditioning before bone marrow transplant found that age was not correlated to long-term pulmonary complications [26]. In this study, older age was associated with a higher risk of post-transplant pulmonary complications (p  0.03). Further analysis revealed that no patients aged 60 or older received TBI-based conditioning, which could be due to the safety consideration, and they all received autologous transplant. In fact, when both age (with or without excluding age 60 and older) and conditioning regimen were placed in the logistic model, age lost significant association with post-transplant pulmonary complications, suggesting that age was not necessarily predictive of post-transplant pulmonary complications.

Conditioning regimen Several studies have found that TBI and TBI-based conditioning constituted a significant risk factor contributing to various pulmonary complications. In a study in 158 adults receiving autologous bone marrow transplant, Carlson et al. [27] found that TBI was a significant risk factor for developing pulmonary complications. Chen et al. [25] found that TBI was the predominant factor contributing to lung toxicity in 94 patients with myeloma receiving autologous stem cell transplant. Fukuda et al. [23] found that high dose TBI-based regimens were associated with an increased


6 C. Lin et al. risk of idiopathic pneumonia syndrome compared to non-TBI-based regimens. Lee et al. [28] reviewed 295 adult patients who received HCT and found that a TBI-based conditioning regimen increased the risk of tuberculosis infection. Other studies have found that TBI-based conditioning was not associated with a higher risk of pulmonary toxicity; in fact, Diaconescu et al. [29] found in a study of 146 patients receiving HCT that patients who received non-myeloablative conditioning experienced significantly less toxicity in pulmonary function. Gutierrez-Delgado et al. [30] found no difference in toxicity between a TBI, cyclophosphamide and etoposide regimen and a busulfan, melphalan and thiotepa regimen. Thomas et al. [26] found that neither conditioning regimen nor total dose of TBI was associated with pulmonary complications. This study found that those who received TBI-based conditioning were less likely to have incident pulmonary complications. When age was placed in the model, conditioning regimen continued to have significant association, showing that the conditioning regimen is predictive of post-HCT pulmonary complications. Our data are consistent with the results reported by Ringdén et al. In their study, they found that obstructive bronchiolitis occurred in 26% of the patients receiving busulfan but in only 5% of the patients receiving TBI (p  0.01) [31]. Among patients who received a nonTBI-based conditioning regimen, there was no difference between those who received BEAM and BEAC in the pulmonary complication rate (37% vs. 35%, respectively) (Table I).

Limitations This study is limited by its retrospective study design. Also, all subjects reviewed were treated in a single center. This study was also not able to include patients who were underweight due to small numbers, but this is probably a reflection of real practice in patient selection. The exact number of patients with post-HCT pulmonary complications may also have been underestimated, because patients with mild clinical manifestation of their illnesses may have been missed or some patients may have been too ill to receive the diagnostic procedure. In addition, there were no pre-HCT pulmonary function tests (PFTs) available; therefore, the impact of pre-HCT PFTs on post-HCT pulmonary complications was not evaluated. Although HCT following preparation chemotherapy with or without TBI has become uncommon for patients with NHL, using this homogeneous group of patients with NHL receiving similar preparative regimens with or without TBI before HCT will exclude the influence of primary tumor type on post-transplant pulmonary complications. In addition, the method of HCT and the dose of TBI (12 Gy in six fractions in 3 days) have remained the same for the past 20 years. Therefore, findings from this study may still be useful to predict pulmonary toxicity in patients with different diseases such as acute lymphoblastic leukemia who require a pre-HCT regimen with or without TBI followed by HCT. We are aware that the supportive care for patients with HCT may be better now, which may have a positive impact on post-HCT pulmonary complications.

Finally, patients with allogeneic transplant have cellular interactions between graft and host cells, and have been reported to have more frequent pneumonia [32] than those with autologous transplant. However, our data show no difference between autologous and allogeneic transplants in the rate of post-transplant pulmonary complications (32% for both groups) (Table I) in this particular group of patients. Therefore, we decided to include not only patients who received autologous transplant but also patients with allogeneic transplant to increase the sample size.

Conclusion BMI did not correlate with post-transplant pulmonary complications. Patients who received a TBI-based conditioning regimen were less likely to develop post-HCT pulmonary complications. Further dosimetric studies examining the association of integrated radiation lung dose and pulmonary complications will be conducted. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

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