Volume 12, Issue 5 , Pages 541-551, May 2006
Effect of Body Mass Index on Mortality of Patients with Lymphoma Undergoing Autologous Hematopoietic Cell Transplantation
Article Outline
Abstract
High-dose therapy with autologous hematopoietic cell transplantation (auto-HCT) is frequently used to improve outcomes in lymphoma. However, small studies suggest a survival disadvantage among obese patients. Using a retrospective cohort analysis, we studied the outcomes of 4681 patients undergoing auto-HCT for Hodgkin or non-Hodgkin lymphoma between 1990 and 2000 according to body mass index (BMI). Four groups categorized by BMI were compared by using Cox proportional hazards regression to adjust for other prognostic factors. A total of 1909 patients were categorized as normal weight (BMI 18-25 kg/m2), 121 as underweight (BMI <18 kg/m2), 1725 as overweight (BMI >25-30 kg/m2), and 926 as obese (BMI >30 kg/m2) at the time of HCT. Outcomes evaluated included overall survival, relapse, transplantation-related mortality (TRM), and lymphoma-free survival. TRM was similar among the normal, overweight, and obese groups; the underweight group had a higher risk of TRM (relative risk [RR], 2.46; 95% confidence interval [CI], 1.59-3.82; P < 0.0001) compared with the normal-BMI group. No differences in relapse were noted. Overall mortality was higher in the underweight group (RR, 1.48; 95% CI, 1.17-1.88; P = .001) and lower in the overweight (RR, 0.87; 95% CI, 0.79-0.96; P = .004) and obese (RR, 0.76; 95% CI, 0.67-0.86; P < .0001) groups compared with the normal-BMI group. In light of our inability to find differences in survival among overweight, obese, and normal-weight patients, obesity alone should not be viewed as a contraindication to proceeding with auto-HCT for lymphoma when it is otherwise indicated.
Key words: Body mass index , Lymphoma , Autologous HCT , Mortality
Introduction
Obesity is an increasing global health issue [1, 2, 3]. From 1991 to 1998 in the United States, the incidence of obesity, defined as a body mass index (BMI) of >30 kg/m2, escalated by 49% [4]. Estimates for 2001 to 2002 indicate that 28% of men and 33% of women are obese [5]. Obesity is known to increase the risk of a variety of common medical conditions, such as cardiovascular disease [6, 7, 8], diabetes mellitus [9], and cancer [10, 11], and contributes to premature death [12]. Additionally, because of the perception that obese patients experience poorer outcomes, obese patients are sometimes denied medical procedures that otherwise would be considered appropriate [13, 14]. Some data suggest that physicians’ judgments are affected by negative attitudes toward obese individuals [15, 16, 17, 18, 19, 20]. Recently, however, several studies examining the effect of obesity on surgical outcomes have indicated no excessive morbidity attributable to increased BMI alone after cardiac [21, 22, 23], general [14], and colorectal [24] surgery.
Concurrent with an epidemic of obesity is a continual increase in the incidence of non-Hodgkin lymphoma (NHL). It is estimated that approximately 61 000 new cases of NHL in the United States occurred in 2003 [25]. Interestingly, recent evidence suggests that obesity is associated with the development of NHL [10, 11]. High-dose therapy with autologous hematopoietic cell transplantation (auto-HCT) improves long-term disease-free survival in patients with refractory or relapsed lymphoma compared with conventional-dose chemotherapy [26, 27, 28, 29, 30, 31]. The effect of obesity on outcomes and toxicity after auto-HCT for lymphoma is not known. As early as 1970, Wiernik and Serpick [32] identified obesity as a risk factor for chemotherapy induction failure and mortality in patients with acute myelogenous leukemia. Studies of HCT show conflicting data about outcomes for obese patients; some report no difference in overall survival, whereas others indicate poorer survival (see reviews [33, 34]). In contrast, underweight patients are more consistently shown to have poorer outcomes than normal-weight patients [35, 36].
On the basis of the increasing frequency of obesity and lymphoma, it is clear that increasing numbers of obese individuals with lymphoma will be considered for auto-HCT. Therefore, we performed a retrospective study of individuals undergoing auto-HCT for lymphoma by using the database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to understand the effect of BMI on survival, relapse, and toxicity.
Methods
Database
The CIBMTR is a voluntary working group of more than 373 transplant centers worldwide that contribute detailed data on consecutive auto-HCTs to a Statistical Center at the Health Policy Institute of the Medical College of Wisconsin in Milwaukee or the National Marrow Donor Program Coordinating Center in Minneapolis. Participating centers are required to register all consecutive cases. The CIBMTR collects data at 2 levels: registration and research. Registration data include disease type, age, sex, pretransplantation performance status, disease stage and chemotherapy responsiveness, date of diagnosis, donor and graft type (bone marrow–derived and/or blood-derived stem cells), high-dose conditioning regimen, posttransplantation engraftment, disease recurrence and survival, development of a new malignancy, and cause of death. Requests for data on disease or death for registered patients are at 6-month intervals. All CIBMTR teams contribute registration data on all patients. Research data are collected on subsets of registered patients selected by using a weighted randomization scheme, including comprehensive pretransplantation and posttransplantation clinical information. Compliance is assessed by periodic audits, and accuracy of data is ensured by computerized record checks, physician review of submitted data, and on-site audits. Observational studies conducted by the CIBMTR are performed with a waiver of informed consent and in compliance with Health Insurance Portability and Accountability Act regulations as determined by the Institutional Review Board and the Privacy Officer of the Medical College of Wisconsin.
Patients
This study includes 4681 patients who underwent auto-HCT from 1990 to 2000 for NHL or Hodgkin lymphoma in 192 transplant centers. Patients were divided into groups by weight based on BMI. Weight groups were defined according to consensus weight designations by the World Health Organization [3] and the National Heart Lung and Blood Institute Expert Panel [37] as follows: underweight, BMI <18 kg/m2 (n = 121); normal, BMI 18 to 25 kg/m2 (n = 1909); overweight, BMI >25 to 30 kg/m2 (n = 1725); and obese, BMI >30 kg/m2 (n = 926). A total of 12
221 patients with NHL were registered with the CIBMTR during the study period, of which 4681 patients had research data (see above for distinction) and were included in the study. To ensure that the research patients were representative of all registered patients, demographics and relapse and survival rates between research and registered patients were compared; no differences were noted. Median follow-up was not statistically different across the weight groups, with a combined median follow-up of 44 months (range, 2-147 months) and a completeness of follow-up index [38] of 88%.
Study End Points
Primary end points were transplantation-related mortality (TRM), relapse, lymphoma-free survival (LFS), and overall survival. TRM was defined as death within the first 28 days of transplantation from any cause or death in continuous complete remission at any subsequent time point. Relapse was defined as the time to onset of clinical recurrence, disease progression, or persistent disease. For relapse, patients with persistent disease were considered events at day 28. LFS was defined as survival in continuous complete remission of primary disease; disease relapse, persistence, or death were events. Overall survival was defined as time to death from any cause.
Secondary end points studied were the incidence of infection, organ toxicity, secondary malignancies, and median days of hospitalization. Infections were divided into bacterial, viral, fungal, mixed, and other. Lung toxicity was divided into interstitial pneumonitis, adult respiratory distress syndrome, bronchiolitis obliterans, pulmonary hemorrhage, and other. Hepatic toxicity was assessed from patient’s maximum total bilirubin level and the presence or absence of veno-occlusive disease. Other types of organ dysfunction included were renal failure requiring dialysis, thrombotic thrombocytopenia purpura/hemolytic uremic syndrome, hemorrhagic cystitis, avascular necrosis, and other. New malignancies were categorized as clonal cytogenetic abnormalities without leukemia, acute myelogenous leukemia, other leukemias, myelodysplasia, lymphoma other than original histology, and other.
Statistical Analysis
Patient-, disease-, and transplant-related factors were compared among the 4 weight groups by using the χ2 test for categorical variables and the Kruskal-Wallis test for continuous variables. Univariate probabilities of LFS and overall survival were estimated by using the Kaplan-Meier method, whereas TRM and relapse were estimated by using cumulative incidence to allow for competing risks. Multivariate analyses used Cox proportional hazards regression models. Models were constructed to compare the outcomes among the 4 weight groups, with normal BMI used as the baseline group, while adjusting for all covariates listed in Table 1. Information on the patient’s International Prognostic Index (IPI) at the time of diagnosis was not available. However, with 27% of data missing, limited information is available regarding IPI at transplantation (Table 2). A model was built for each primary outcome of interest as a dependent variable and all the relevant exposure variables as explanatory variables. A main effect term for the 4 weight groups was forced into the model. The proportional hazards assumption for all the variables was examined by using time-varying covariates. Construction of stratified proportional hazards models or time-dependent covariates was performed whenever nonproportional hazards were identified. Interactions between weight groups and other significant explanatory variables were explored. Bonferroni corrections were applied to allow adjustment for multiple pairwise comparisons among weight groups. A P value ≤.02 was therefore considered statistically significant, whereas the P values for inclusion in the final models of all other potentially confounding covariates was set at ≤.05. Comparisons of all secondary outcomes were limited to univariate comparisons.
Table 1. Variables Tested in the Multivariate Models
| Patient related |
| Age: <40 vs. ≥40 yr |
| Sex: male vs. female |
| Karnofsky status at transplantation: <90% vs. ≥90%-100% |
| Ethnicity: white vs. other |
| Disease related |
| Lymphoma histology: low-grade NHL vs. intermediate NHL vs. high-grade NHL vs. Hodgkin disease |
| Disease stage at diagnosis: stage I-II vs. stage III-IV |
| Presence of B symptoms at diagnosis: yes vs. no |
| Increased lactate dehydrogenase: yes vs. no |
| Disease stage and chemosensitivity: first complete remission vs. second complete remission vs. sensitive relapse/primary induction failure vs. resistant relapse/primary induction failure vs. untreated/unknown |
| Bone marrow involvement at diagnosis/transplantation: yes vs. no |
| Interval from diagnosis to transplantation: <12 vs. ≥12 mo |
| Transplant related |
| Conditioning regimen: TBI-containing vs. no TBI |
| Use of growth factors within 7 d after transplantation: yes vs. no |
| Graft type: marrow vs. peripheral blood stem cells or both |
| Purging: yes vs. no |
| Year of transplantation: 1990-1992 vs. 1993-1995 vs. 1996-1998 vs. 1999-2000 |
| Prior involved-field radiation: yes vs. no |
Table 2. Patient Characteristics
| Variables | Normal Weight | Underweight | Overweight | Obese | P Value |
|---|---|---|---|---|---|
| n | 1909 | 121 | 1725 | 926 | |
| Median age, y (range) | 42(18-73) | 34(18-67) | 47(18-75) | 46(18-76) | <.0001 |
| <40 y, n (%) | 898(47) | 73(60) | 564(33) | 312(34) | <.0001 |
| ≥40 y, n (%) | 1011(53) | 48(40) | 1161(67) | 614(66) | |
| Males | 970(51) | 44(36) | 1199(70) | 578(62) | <.0001 |
| International Prognostic Index at transplantation⁎ | .01† | ||||
| Low | 1038(75) | 57(63) | 957(76) | 511(77) | |
| Low-intermediate | 236(17) | 20(22) | 214(17) | 110(17) | |
| High-intermediate | 88(6) | 9(10) | 83(6) | 31(5) | |
| High | 22(2) | 5(5) | 13(1) | 6(1) | |
| Missing | 525 | 30 | 458 | 268 | |
| Karnofsky performance status at transplantation ≥90% | 1226(64) | 60(50) | 1162(67) | 667(72) | <.0001 |
| Race | |||||
| White | 1633(86) | 91(75) | 1505(87) | 786(85) | .002 |
| Others | 276(14) | 30(25) | 220(13) | 140(15) | |
| Histology‡ | |||||
| Low-grade NHL | 273(14) | 7(6) | 330(19) | 188(20) | <.0001 |
| Intermediate-grade NHL | 794(42) | 46(38) | 763(44) | 417(45) | |
| High-grade NHL | 224(12) | 20(17) | 196(11) | 97(11) | |
| Hodgkin disease | 618(32) | 48(39) | 436(26) | 224(24) | |
| Presence of B symptoms | 844(44) | 65(54) | 698(40) | 349(38) | .0002 |
| Increased LDH | 545(29) | 38(31) | 508(29) | 320(35) | .01 |
| Stage III-IV | 1244(65) | 68(56) | 1149(67) | 610(66) | .13 |
| Bone marrow involvement at diagnosis | 379(20) | 16(13) | 418(24) | 198(21) | .001 |
| Bone marrow involvement at transplantation | 161(8) | 8(7) | 161(9) | 60(7) | .08 |
| Interval from diagnosis to transplantation, n (%) | |||||
| <12 mo | 607(32) | 30(25) | 497(29) | 261(28) | .07 |
| ≥12 mo | 1302(68) | 91(75) | 1228(71) | 665(72) | |
| Disease stage and chemosensitivity | |||||
| CR1 | 248(13) | 17(14) | 209(12) | 115(12) | .46 |
| CR2+ | 343(18) | 19(16) | 321(19) | 174(19) | |
| Relapse/PIF sensitive | 822(43) | 46(38) | 781(45) | 425(46) | |
| Relapse/PIF resistant | 226(12) | 16(13) | 172(10) | 98(11) | |
| Untreated/unknown | 270(14) | 23(19) | 242(14) | 114(12) | |
| Use of TBI for conditioning | 408(21) | 16(13) | 393(23) | 243(26) | .002 |
| Use of other field radiation | 90(5) | 6(5) | 62(4) | 42(5) | .37 |
| Type of graft | |||||
| Bone marrow | 573(30) | 37(30) | 477(28) | 251(27) | .28 |
| Peripheral blood | 1126(59) | 72(60) | 1080(63) | 566(61) | |
| Both | 210(11) | 12(10) | 168(9) | 109(12) | |
| Use of growth factors within 7 d after transplantation | 1288(67) | 81(67) | 1216(70) | 678(73) | .01 |
| Purged | 155(8) | 4(3) | 176(10) | 95(10) | .01 |
| Year of transplantation | |||||
| 1990-1992 | 378(20) | 31(25) | 290(17) | 136(15) | .001 |
| 1993-1995 | 670(35) | 42(35) | 587(34) | 319(34) | |
| 1996-1997 | 467(24) | 24(20) | 438(25) | 224(24) | |
| 1998-2000 | 394(21) | 24(20) | 410(24) | 247(27) | |
| Median follow-up of survivors, mo (range) | 44(2-147) | 48(2-126) | 44(2-146) | 44(2-135) | .52 |
⁎ Five adverse prognostic factors were considered: Age >60 years, Eastern Cooperative Oncology Group ≥2 (equivalent to Karnofsky score before transplantation of ≤70), extranodal involvement of >1 site, stage III/IV, and LDH concentrations above normal. One point was given for each of the above characteristics present in the patient:
| ||||||||||
† Other significant χ2 comparisons: P12 = .01; P23 = .001; P24 < .001. | ||||||||||
‡ Low-grade NHL = small cell lymphocytic, follicular predominantly small cleaved, follicular mixed, small cleaved and large cell, and small lymphocytic plasmacytoid; intermediate grade NHL = follicular predominantly large cell, diffuse small cleaved, diffuse mixed, small and large cell, diffuse large cell, and large cell immunoblastic; high-grade NHL = lymphoblastic, small noncleaved unclassified, Burkitt, non-Burkitt, primary mediastinal large B-cell, and precursor T-lymphoblastic. |
Results
Patient Characteristics
Comparisons of patient-, disease-, and transplant-related characteristics among the weight groups are listed in Table 2. No differences among the groups were observed with respect to disease stage at diagnosis, marrow involvement at transplantation, the interval from diagnosis to transplantation, remission status and chemosensitivity at transplantation, the use of field irradiation, the type of graft source, or median follow-up of survivors. The underweight group differed from the other groups in that they were younger and were more likely to be female and nonwhite and to have poor performance status and a higher IPI score at transplantation. They were less likely to have stage III/IV disease at diagnosis but more likely to have “B” symptoms. They were less likely to have received total body irradiation or a purged cell product. The overweight and obese groups tended to be somewhat older, were more likely to be male, and were more likely to have low-grade histologic characteristics.
Transplantation-Related Mortality
There were no statistically significant differences in the cumulative incidence of TRM at 100 days after transplantation among the normal, overweight, and obese groups (normal: 4%; 95% confidence interval [CI], 3%-5%; overweight: 4%; 95% CI, 3%-5%; obese: 4%; 95% CI, 3%-6%). However, the cumulative incidence of TRM was significantly higher in the underweight group, at 12% (95% CI, 6%-17%), at 100 days. This difference persisted (Figure 1). At 60 months after transplantation, the cumulative incidence rates of TRM were 10% (95% CI, 8%-11%) in the normal-weight group, 9% (95% CI, 8%-11%) in the overweight group, 10% (95% CI, 8%-12%) in the obese group, and 20% (95% CI, 12%-28%) in the underweight group. In multivariate analysis of TRM (Table 3), by using normal-weight patients as the reference, the underweight group had a higher risk of TRM (relative risk [RR], 2.45; 95% CI, 1.58-3.81; P< .0001). Risks of TRM in the normal, overweight, and obese groups were similar. Other factors associated with an increased risk of TRM included age >40 years at transplantation, Karnofsky performance status (KPS) ≤80% at transplantation, lymphoma histology other than low grade, chemoresistant disease at transplantation, increased lactate dehydrogenase levels at transplantation, use of total body irradiation as part of the preparative regimen, treatment of the graft to reduce malignant cell contamination, and time interval >12 months from diagnosis to transplantation.
Figure 1.
Cumulative incidence of transplantation-related mortality (TRM) according to body mass index.
Table 3. Multivariate Analysis of Transplantation-Related Mortality (TRM)
| Variable | Relative Risk of TRM | P Value |
|---|---|---|
| Normal BMI⁎ | 1.00 | <.0001† |
| Underweight BMI | 2.45(1.58-3.81) | <.0001 |
| Overweight BMI | 0.88(0.70-1.09) | .24 |
| Obese BMI | 0.93(0.72-1.21) | .58 |
| Other significant covariates | ||
| Age | ||
| ≤40 y | 1.00 | |
| >40 y | 1.69(1.33-2.15) | <.0001 |
| Karnofsky performance status at transplantation | ||
| 90%-100% | 1.00 | |
| ≤80% | 1.50(1.23-1.84) | <.0001 |
| Histologic type | <.0001† | |
| Low-grade NHL | 1.00 | |
| Intermediate-grade NHL | 1.95(1.45-2.62) | <.0001 |
| High-grade NHL | 1.61(1.06-2.45) | .02 |
| Hodgkin disease | 2.15(1.51-3.06) | <.0001 |
| Disease stage and chemosensitivity at transplantation | .009‡ | |
| CR1 | 1.00 | |
| CR2+ | 1.17(0.80-1.70) | .42 |
| Relapse/PIF, sensitive | 1.06(0.75-1.49) | .75 |
| Relapse/PIF, resistant | 1.65(1.09-2.49) | .02 |
| Untreated/unknown | 1.52(1.04-2.23) | .03 |
| LDH levels at diagnosis | .01§ | |
| Normal | 1.00 | |
| Increased | 1.33(1.07-1.64) | .01 |
| Missing | 1.41(1.04-1.91) | .03 |
| Use of TBI | ||
| No | 1.00 | |
| Yes | 1.40(1.11-1.76) | .004 |
| Use of purging | ||
| No | 1.00 | |
| Yes | 1.89(1.42-2.53) | <.0001 |
| Interval from diagnosis to transplantation | ||
| <12 mo | 1.00 | |
| ≥12 mo | 1.81(1.39-2.35) | <.0001 |
⁎ Normal body mass index used as reference or baseline group. |
† Three degrees of freedom test. |
‡ Four degrees of freedom test. |
§ Two degrees of freedom test. |
Relapse
The cumulative incidence of relapse did not differ significantly among the 4 weight groups. The cumulative incidences of relapse at 1 year after transplantation were 44% (95% CI, 41%-46%) in the normal-weight group, 43% (95% CI, 34%-53%) in the underweight group, 40% (95% CI, 38%-43%) in the overweight group, and 38% (95% CI, 35%-42%) in the obese group (Figure 2). Similarly, in multivariate analysis, no differences of relapse risk were observed. Factors associated with higher risks of relapse were age >40 years at transplantation, KPS ≤80% at transplantation, disease stage other than first complete remission at transplantation, and marrow involvement at transplantation (data not shown).
Figure 2.
Cumulative incidence of relapse according to body mass index.
Lymphoma-Free Survival
Figure 3 shows Kaplan-Meier estimates of the probabilities of LFS. LFS was significantly lower in the underweight group. One-year LFS probabilities were 41% (95% CI, 32%-50%), 50% (95% CI, 47%-52%), 54% (95% CI, 52%-56%), and 54% (95% CI, 51%-57%) for the underweight, normal, overweight, and obese cohorts, respectively. Corresponding probabilities at 5 years were 24% (95% CI, 15%-32%), 32% (95% CI, 30%-35%), 33% (95% CI, 30%-36%), and 32% (95% CI, 29%-36%). In multivariate analysis (Table 4), with normal-weight patients as the reference, the underweight group had a higher risk of treatment failure (inverse of LFS; RR, 1.37; 95% CI, 1.11-1.71; P = .004), and the overweight group had a lower risk (RR, 0.91; 95% CI, 0.83-0.98; P = .02). The risks in the normal-weight and obese groups were similar (RR, 0.91; 95% CI, 0.83-1.01; P= .08). Other factors associated with treatment failure were age >40 years at transplantation, KPS ≤80% at transplantation, disease stage and chemosensitivity at transplantation, and the presence of B symptoms.
Figure 3.
Kaplan-Meier probability estimates of lymphoma-free survival (LFS) according to body mass index.
Table 4. Multivariate Analysis of Lymphoma-Free Survival⁎
| Variable | Relative Risk of Treatment Failure | P Value |
|---|---|---|
| Normal BMI† | 1.00 | <.001‡ |
| Underweight BMI | 1.37(1.11-1.71) | .004 |
| Overweight BMI | 0.91(0.83-0.98) | .02 |
| Obese BMI | 0.91(0.83-1.01) | .08 |
| Other significant covariates | ||
| Age | ||
| ≤40 y | 1.00 | |
| >40 y | 1.23(1.13-1.34) | <.0001 |
| Karnofsky performance status at transplantation | ||
| 90%-100% | 1.00 | |
| ≤80% | 1.27(1.18-1.38) | <.0001 |
| Disease stage and chemosensitivity at transplantation | <.0001§ | |
| CR1 | 1.00 | |
| CR2+ | 1.43(1.23-1.68) | <.0001 |
| Relapse/PIF, sensitive | 1.98(1.73-2.27) | <.0001 |
| Relapse/PIF, resistant | 3.15(2.68-3.70) | <.0001 |
| Untreated/unknown | 2.00(1.71-2.34) | <.0001 |
| Presence of B symptoms | .007∥ | |
| No | 1.00 | |
| Yes | 1.13(1.04-1.22) | .002 |
| Missing | 1.11(0.95-1.29) | .19 |
⁎ Model stratified by histology and lactate dehydrogenase levels due to nonproportional hazards. |
† Normal body mass index used as reference or baseline group. |
‡ Three degrees of freedom test. |
§ Four degrees of freedom test. |
∥ Two degrees of freedom test. |
Overall Survival
Figure 4 shows Kaplan-Meier estimates of overall survival by weight group. Probabilities of survival were higher in the overweight and obese groups and lower in the underweight group compared with the normal-weight cohort. One-year survival probabilities were 59% (95% CI, 50%-68%), 69% (95% CI, 67%-71%), 74% (95% CI, 72%-76%), and 75% (95% CI, 72%-78%) in the underweight, normal, overweight, and obese cohorts, respectively. Corresponding probabilities at 5 years were 34% (95% CI, 25%-44%), 46% (95% CI, 44%-49%), 49% (95% CI, 46%-52%), and 56% (95% CI, 52%-59%). In multivariate analysis (Table 5), with normal-weight patients as the reference, the underweight group had a higher risk of mortality (RR, 1.49; 95% CI, 1.17-1.89; P = .001), whereas both the overweight and obese groups had lower risks of mortality (RR, 0.87; 95% CI, 0.79-0.96; P = .004 for the overweight cohort; RR, 0.76; 95% CI, 0.67-0.86; P < .0001 for the obese cohort). Other factors associated with higher risks of mortality were age >40 years at transplantation, KPS ≤80% at transplantation, disease stage at transplantation other than first complete remission, presence of B symptoms, and transplantation in the early 1990s (compared with the later 1990s).
Figure 4.
Kaplan-Meier probability estimates of overall survival according to body mass index.
Table 5. Multivariate Analysis of Mortality⁎
| Variable | Relative Risk of Mortality | P Value |
|---|---|---|
| Normal BMI† | 1.00 | <.0001‡ |
| Underweight BMI | 1.49(1.17-1.89) | .001 |
| Overweight BMI | 0.87(0.79-0.96) | .004 |
| Obese BMI | 0.76(0.67-0.86) | <.0001 |
| Other significant covariates | ||
| Age | ||
| ≤40 y | 1.00 | |
| >40 y | 1.39(1.25-2.54) | <.0001 |
| Karnofsky performance status at transplantation | ||
| 90%-100% | 1.00 | |
| ≤80% | 1.48(1.35-1.61) | <.0001 |
| Disease stage and chemosensitivity at transplantation | <.0001§ | |
| CR1 | 1.00 | |
| CR2+ | 1.60(1.32-1.93) | <.0001 |
| Relapse/PIF, sensitive | 1.81(1.53-2.14) | <.0001 |
| Relapse/PIF, resistant | 3.35(2.77-4.04) | <.0001 |
| Untreated/unknown | 2.12(1.75-2.56) | <.0001 |
| Presence of B symptoms | <.0001∥ | |
| No | 1.00 | |
| Yes | 1.22(1.12-1.33) | <.0001 |
| Missing | 1.10(0.92-1.32) | .28 |
| Year of transplantation | .0003‡ | |
| 1990-1992 | 1.00 | |
| 1993-1995 | 0.88(0.78-0.98) | .02 |
| 1996-1997 | 0.84(0.74-0.95) | .01 |
| 1998-2000 | 0.73(0.63-0.84) | <.0001 |
⁎ Model stratified by histology and lactate dehydrogenase levels due to nonproportional hazards. |
† Normal body mass index used as reference or baseline group. |
‡ Three degrees of freedom test. |
§ Four degrees of freedom test. |
∥ Two degrees of freedom test. |
Toxicity
Posttransplantation toxicities are summarized in Table 6. There were no differences in maximum bilirubin levels or in the incidence of infections, nonpulmonary/nonhepatic organ impairment, or new malignancies among the 4 weight groups. Pulmonary toxicity was more common in the underweight group (33% incidence versus 19%-22% in the other 3 groups; P = .002). Liver toxicity, including veno-occlusive disease, was marginally higher in the underweight group as well (18% versus 11%-13%; P = .03). The median hospitalization stays were slightly longer in the underweight group, at 23 days, versus 21 days for the other 3 groups (P = .03).
Table 6. Toxicities
| Variable | Underweight (n = 121) | Normal Weight (n = 1909) | Overweight (n = 1725) | Obese (n = 926) | P Value |
|---|---|---|---|---|---|
| Infection (%) | .311 | ||||
| No | 45(3) | 848(44) | 758(44) | 389(42) | |
| Yes | 76(63%) | 1061(56) | 967(56) | 537(58) | |
| Type of infection (%) | |||||
| Bacterial | 27(36) | 390(37) | 387(40) | 232(43) | |
| Fungal | 7(9) | 67(6) | 63(7) | 30(6) | |
| Viral | 11(14) | 88(8) | 100(10) | 38(7) | |
| Mixed | 23(30) | 349(33) | 260(27) | 171(32) | |
| Others | 8(11) | 167(16) | 157(16) | 66(12) | |
| Pulmonary (%) | .002 | ||||
| No | 81(67) | 1489(78) | 1391(81) | 741(80) | |
| Yes | 40(33) | 420(22) | 334(19) | 185(20) | |
| Type of pulmonary abnormality (%) | |||||
| Interstitial pneumonitis | 13(33) | 139(33) | 113(34) | 50(27) | |
| ARDS | 6(15) | 49(12) | 40(12) | 28(15) | |
| Bronchiolitis obliterans | 1(2) | 3(1) | 2(1) | 3(2) | |
| Pulmonary hemorrhage | 4(10) | 26(6) | 21(6) | 10(5) | |
| Others | 23(57) | 263(63) | 204(61) | 123(66) | |
| Maximum bilirubin level, mg/dL, median (range) | 1.10(0.4-26) | 1.05(0.4-36) | 1.10(0.4-36) | 1.10(0.4-32) | .717 |
| Liver toxicity (%) | 14 | 206 | 176 | 85 | .030 |
| No | 99(82) | 1653(87) | 1524(88) | 827(89) | |
| Yes | 22(18) | 256(13) | 201(12) | 99(11) | |
| VOD⁎ | 11(50) | 71(28) | 49(24) | 26(26) | |
| Organ impairment (%) | .433 | ||||
| No | 90(74) | 1454(76) | 1296(75) | 679(73) | |
| Yes | 31(26) | 455(24) | 429(25) | 247(27) | |
| Type of organ impairment (%) | |||||
| Renal failure requiring dialysis | 5(16) | 43(9) | 37(9) | 27(11) | |
| TTP/HUS | 1(3) | 10(2) | 5(1) | — | |
| Hemolytic cystitis | 6(19) | 26(6) | 43(10) | 22(9) | |
| Avascular necrosis | — | 6(1) | 3(1) | 3(1) | |
| Others | 20(65) | 378(83) | 344(80) | 200(81) | |
| New malignancies (%) | .655 | ||||
| No | 117(97) | 1837(96) | 1643(95) | 887(96) | |
| Yes | 4(3) | 72(4) | 82(5) | 39(4) | |
| Types (%) | |||||
| Clonal cytogenetic abnormality without leukemia or MDS | — | 2(3) | 2(2) | 2(5) | |
| AML | — | 4(6) | 6(7) | 3(8) | |
| Other leukemia | — | 2(3) | 5(6) | 1(2) | |
| Myelodysplasia | 1(25) | 22(30) | 22(27) | 9(23) | |
| Lymphoma | — | 1(1) | 3(4) | 1(2) | |
| Other cancer | 3(75) | 41(57) | 44(54) | 23(60) | |
| Median hospitalization, d, median (range) | 23(3-60) | 21(1-60) | 21(1-60) | 21(1-60) | .034 |
| 21 | 187 | 159 | 81 |
⁎ Represents the number of cases with liver toxicity manifesting as VOD. |
Discussion
With respect to TRM, relapse, LFS and, most importantly, overall survival, outcomes after auto-HCT for lymphoma are at least equivalent for overweight and obese patients compared with normal-weight individuals. The better overall survival experienced by the overweight and obese patients compared with normal-weight patients seems to reflect a combination of slightly decreased relapse and TRM rates.
Our analysis is limited by the lack of data regarding weight-based dose adjustment of chemotherapy. Dosing schemes for preparative chemotherapy regimens are quite variable across transplant centers. Centers differ in their use of ideal body weight, actual body weight, or compensatory calculations that yield doses between actual and ideal weight [31]. Despite this variability in dosing, toxicity seems equivalent among the normal, overweight, and obese patients for the variables tested, as does the median length of hospitalization, thus implying that the overweight and obese patients do not experience increased transplantation-related complications. One possibility is that overweight and obese patients may be receiving a higher effective chemotherapy dose in the preparative regimen without concomitantly increased toxicity. Prospective pharmacokinetic studies to elucidate levels of chemotherapeutics will be required to better understand the correlation between effective dose and outcomes. Alternatively, obese and overweight patients may have had better-prognosis disease at the outset and were destined to fare better. We cannot assess the degree to which selection bias affects our findings. It is possible that sicker obese patients were excluded when comparably ill normal-weight patients were not. Also, there were modestly larger numbers of low-grade lymphomas in the obese and overweight groups and fewer Hodgkin lymphomas. Nevertheless, in multivariate analysis, these differences did not seem to explain the observed outcomes. Another, less likely, possibility is that the disease in obese or overweight patients is more sensitive to treatment; however, there are no data to suggest that this is true, and the reported pretransplantation chemosensitivity was not different across weight groups.
Previous single-institution studies have demonstrated a significant disadvantage for overweight and obese patients. Tarella et al. [35] reported outcomes for 121 patients receiving autografts for NHL, 28 of whom had a BMI >28 kg/m2. In that study, 5 of 28 overweight/obese patients never received an autograft; 6 of the remaining 23 patients had unspecified dose reductions that may have affected lymphoma-free and overall survival. As in this study, there was no difference in the TRM. In a retrospective study by Meloni et al. [39] that examined outcomes in 54 patients receiving autografts for acute myeloid leukemia, 9 of whom were obese, there was a significant difference in TRM. In that study, patients did not receive dose adjustments on the basis of overweight. Conversely, a study from the Fred Hutchinson Cancer Research Center retrospectively reviewed outcomes in their large series of allografts and autografts and found no significant survival disadvantage to overweight overall [36]. When Fred Hutchinson Cancer Research Center results only for allografts for chronic myeloid leukemia were reviewed by Hansen et al. [40], there was a slight survival disadvantage for the overweight/obese patients; this suggests that when disease factors such as relapse are less problematic, then mildly adverse effects of overweight can be discerned. Although there has been previous work showing conclusions opposite from this analysis, no prior study has been able to include such large patient numbers from multiple centers.
Adding credibility to these results is the dose-response relationship between BMI and overall survival. The underweight group had the worst survival, the normal-weight group had the third best, then the overweight group, and finally the obese group, which had the highest overall survival. This surprising result contradicts the conventional wisdom that as weight increases, outcomes worsen. Recent data published by Flegal et al. [41] examining the effects of overweight and obesity on mortality rates of the American population as a whole also suggested no increase in mortality for those who were overweight (BMI 25 to <30 kg/m2). This same phenomenon may be at least in part reflected in this study.
Another important finding of this study is the confirmation of prior investigations suggesting that underweight patients have higher transplantation-related mortality (TRM) and poorer lymphoma-free and overall survival than normal-weight, obese, or overweight patients. This observation has been made not only in HCT, but also in general population studies [42, 43] and in surgical [21, 44] and critical care [45] arenas. There are several possible explanations. The underweight group may have limited nutritional reserves and, therefore, lower tolerance to the stresses of auto-HCT, thus resulting in a higher rate of TRM. Unfortunately, no information is available regarding the patterns of use of parenteral nutritional support because the CIBMTR does not collect data regarding total parenteral nutrition use during transplantation. Lower BMI may reflect the presence of more aggressive disease causing a greater degree of physiologic derangement. However, although there seems to be a difference in disease severity (the underweight group manifested a higher IPI score at transplantation compared with the other groups), this did not result in a statistically higher rate of relapse. Finally, comorbid conditions may lead to both weight loss and an increased transplantation risk. It is not possible to easily ascertain which of these factors is playing a role, but the data suggest that disease-related factors are less likely to be the explanation, because relapse rates were not higher in the underweight patients.
As with any observational study, it is possible that patient selection bias may influence these findings. Data are not available for patient groups who did not undergo transplantation. It is conceivable that only patients believed by the transplant center to be sufficiently fit proceeded to transplantation, whereas more ill obese patients were excluded. However, there are substantial numbers of patients in the overweight or obese groups, thus suggesting that this is not a group of highly selected patients. Moreover, a review of comorbidities showed a statistically significantly increased incidence of coronary artery disease, hypertension, diabetes, and thyroid disease among the overweight and obese groups compared with normal-weight patients (data not shown). This finding suggests that the expected obesity-related illnesses were in fact observed, although whether the frequency of comorbidities observed reflects the expected incidence in the overweight and obese population as a whole is not known. The proportions of patients in the respective weight groups are as follows: normal, 40.7%; overweight, 36.9%; obese, 19.8%; and underweight, 2.6%. These proportions are reflective of weight distribution in the United States [46], although it cannot be known whether this proportion is reflective of the BMI distribution of lymphoma patients who are candidates for auto-HCT.
In conclusion, our study indicates that overweight and obese patients receiving auto-HCT for lymphoma do not experience inferior outcomes compared with normal-weight patients. Consideration of these patients for auto-HCT should not be adversely influenced by obesity alone. Conversely, for the underweight group, outcomes are significantly worse. Perhaps most notably, TRM seems to be markedly increased, thus suggesting that these patients may require more than standard levels of support. Studies of interventions to improve the nutritional status of low-BMI patients before and after transplantation may be warranted. These findings need to be confirmed in a well-designed prospective trial, perhaps in a cooperative group setting.
Previous studies documenting negative physician attitudes toward obese patients suggest that there may be prejudice in the decision-making and treatment processes. We hope that this study helps to dispel the belief that overweight or obese patients, when otherwise fit and qualified, cannot be treated as effectively or safely as normal-weight patients.
Acknowledgments
Supported by Public Health Service grant no. U24-CA76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute; Office of Naval Research; Health Resources Services Administration (Department of Health and Human Services); and grants from AABB, Aetna; AIG Medical Excess; American Red Cross; Amgen, Inc.; an anonymous donation to the Medical College of Wisconsin; AnorMED, Inc.; Berlex Laboratories, Inc.; Biogen IDEC, Inc.; Blue Cross and Blue Shield Association; BRT Laboratories, Inc.; Celgene Corp.; Cell Therapeutics, Inc.; CelMed Biosciences; Cubist Pharmaceuticals; Dynal Biotech, LLC; Edwards Lifesciences RMI; Endo Pharmaceuticals, Inc.; Enzon Pharmaceuticals, Inc.; ESP Pharma; Fujisawa Healthcare, Inc.; Gambro BCT, Inc.; Genzyme Corporation; GlaxoSmithKline, Inc.; Histogenetics, Inc.; Human Genome Sciences; ILEX Oncology, Inc.; Kirin Brewery Company; Ligand Pharmaceuticals, Inc.; Merck & Company; Millennium Pharmaceuticals; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec; National Center for Biotechnology Information; National Leukemia Research Association; National Marrow Donor Program; NeoRx Corporation; Novartis Pharmaceuticals, Inc.; Novo Nordisk Pharmaceuticals; Ortho Biotech, Inc.; Osiris Therapeutics, Inc.; Pall Medical; Pfizer, Inc.; Pharmion Corp.; QOL Medical; Roche Laboratories; StemCyte, Inc.; Stemco Biomedical; StemSoft Software, Inc.; SuperGen, Inc.; Sysmex; The Marrow Foundation; THERAKOS, a Johnson & Johnson Co.; University of Colorado Cord Blood Bank; Valeant Pharmaceuticals; ViaCell, Inc.; ViraCor Laboratories; WB Saunders Mosby Churchill; and Wellpoint Health Network. The contents of this article are the responsibility of the authors and do not represent the official views of the National Cancer Institute.
Appendix 1
Other authors in the study include James O. Armitage, MD, University of Nebraska Medical Center, Omaha, NE; Karen Ballen, MD, Massachusetts General Hospital, Boston, MA; Asad Bashey, MD, PhD, University of California, San Diego, CA; Jeanette Carreras, MPH, and Mary M. Horowitz, MD, MS, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI; Christopher N. Bredeson, MD, MSc, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada; César O. Freytes, MD, University of Texas Health Science Center, San Antonio, TX; John Gibson, MD, PhD, Royal Prince Alfred Hospital, Camperdown, Australia; Gregory A. Hale, MD, St. Jude Children’s Research Hospital, Memphis, TN; Charles F. LeMaistre, MD, Texas Transplant Institute, San Antonio, TX; John Lister, MD, Western Pennsylvania Cancer Institute, Pittsburgh, PA; David I. Marks, MD, PhD, Bristol Children’s Hospital, Bristol, UK; Rodrigo Martino, MD, Hospital Sant Creu I Sant Pau, Barcelona, Spain; Richard T. Maziarz, MD, Oregon Health & Science University, Portland, OR; Santiago Pavlovsky, MD, PhD, FUNDALEU, Buenos Aires, Argentina; Gary Schiller, MD, University of California, Los Angeles, CA; Harry C. Schouten, MD, PhD, University Hospital Maastricht, Maastricht, The Netherlands; and Edward Stadtmauer, MD, University of Pennsylvania Hospital, Pittsburgh, PA.
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PII: S1083-8791(05)01413-8
doi:10.1016/j.bbmt.2005.12.033
© 2006 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 12, Issue 5 , Pages 541-551, May 2006
