Effect of initial body mass index on survival outcome of patients with myelodysplastic syndrome: a single-center retrospective study

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1 Leukemia & Lymphoma ISSN: (Print) (Online) Journal homepage: Effect of initial body mass index on survival outcome of patients with myelodysplastic syndrome: a single-center retrospective study Xi Xu, Qianying Zhang, Gang Hu, Qiang Zhuang, Chongyun Xing, Yifen Shi, Bin Liang, Zhijian Shen, Songfu Jiang, Kang Yu & Jianhua Feng To cite this article: Xi Xu, Qianying Zhang, Gang Hu, Qiang Zhuang, Chongyun Xing, Yifen Shi, Bin Liang, Zhijian Shen, Songfu Jiang, Kang Yu & Jianhua Feng (2017): Effect of initial body mass index on survival outcome of patients with myelodysplastic syndrome: a single-center retrospective study, Leukemia & Lymphoma, DOI: / To link to this article: View supplementary material Published online: 02 Jun Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at Download by: [ ] Date: 02 June 2017, At: 14:07

2 LEUKEMIA & LYMPHOMA, ORIGINAL ARTICLE: CLINICAL Effect of initial body mass index on survival outcome of patients with myelodysplastic syndrome: a single-center retrospective study Xi Xu a, Qianying Zhang a, Gang Hu a, Qiang Zhuang a, Chongyun Xing a, Yifen Shi a, Bin Liang a, Zhijian Shen a, Songfu Jiang a, Kang Yu a and Jianhua Feng a,b a Division of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, PR China; b Division of Pediatric Hematology-Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, PR China ABSTRACT Multiple studies have associated elevated body mass index (BMI) and increased incidence of hematologic malignancies, including myelodysplastic syndrome (MDS). The purpose of the present study was to evaluate the association between BMI at diagnosis and overall survival (OS) in a retrospective cohort of 92 patients with MDS. The median age at diagnosis was 63 (14 84) years. The median BMI was ( ) kg/m 2. Eleven (12.0%) patients were underweight, 64 (69.6%) were normal weight, 17 (18.5%) were overweight or obese. Three-year OS rates differed significantly when the three BMI groups were compared (p ¼.0449). Multivariate Cox regression analysis indicated that normal weight (versus underweight) had a marginally significant effect on OS (hazard ratio ¼ 0.456, p ¼.127), and overweight/obese (versus underweight) had a significant effect on OS (hazard ratio ¼ 0.171, p ¼.015). Further investigations are required to elucidate the mechanisms responsible for this association. ARTICLE HISTORY Received 29 January 2017 Accepted 6 May 2017 KEYWORDS Body mass index; myelodysplastic syndrome; prognosis; survival Introduction Body mass index (BMI), a simple anthropometric tool, is commonly used to evaluate the degree of obesity that may lead to health problems. Multiple studies have associated elevated BMI and increased incidence of several types of cancer, including hematologic malignancies [1 6]. However, mixed results have been reported investigating the impact of BMI on survival in hematologic malignancies. In multiple myeloma, elevated BMI did not confer a negative impact on the survival of obese patients [7]. In lymphoma, several studies reported that increased BMI was associated with improved survival in patients with Hodgkin lymphoma (HL) [8], intermediate-grade B-cell non- Hodgkin lymphoma (NHL) [9], diffuse large B-Cell Lymphoma (DLBCL) [10] and extranodal natural killer/ T-cell lymphoma, nasal type (ENKTL) [11,12]. However, some studies reported that increased BMI was associated with a poorer prognosis in patients with NHL [13,14], and others could not conclude on BMI prognostic value, with no impact of BMI on clinical outcomes among patients with DLBCL, follicular lymphoma (FL) or HL [15]. Similar mixed results have also been found in patients with acute leukemia. In acute myeloid leukemia (AML), indeed several studies found that increased BMI was associated with better outcome [16], others did not found any relationship between BMI and survival [17 20]. Additionally, for acute lymphoblastic leukemia (ALL), Butturini et al. [21] found that obesity at diagnosis was significantly associated with high risk of relapse in preteenagers and adolescents with ALL, while other authors did not show any effect of BMI on outcome [22]. Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic malignancies and characterized by peripheral cytopenias due to ineffective hematopoiesis and the risk of transformation into AML [23]. Although several studies have linked obesity to increasing risk of developing MDS [24 26], to the best of our knowledge, no studies regarding the prognostic value of BMI at diagnosis in MDS are available, with the exception of one report describing the poor prognostic effect of obesity in lower risk MDS [27]. Therefore, we carried out this retrospective study to evaluate the prognostic significance of BMI CONTACT Jianhua Feng wzfjh@126.com; Kang Yu yukang62@126.com Division of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Ouhai Zone, Wenzhou , Zhejiang, PR China These authors contributed equally to this work. Supplemental data for this article can be accessed here. ß 2017 Informa UK Limited, trading as Taylor & Francis Group

3 2 X. XU ET AL. at the time of diagnosis in a cohort of 92 newly diagnosed MDS patients. Methods Patients In this retrospective study, we evaluated a total of 92 patients diagnosed with de novo MDS (after excluding therapy-related MDS) from November 2011 to January 2016 at the First Affiliated Hospital of Wenzhou Medical University. The diagnosis and classification of MDS were established according to the 2008 World Health Organization (WHO) classification of MDS [28]. All patients were 14 years of age or older. This retrospective study was approved by the Institutional Review Board (IRB) at the First Affiliated Hospital of Wenzhou Medical University. The requirement for patient informed consent was waived by the IRB due to the retrospective nature of this study, but patient confidentiality was protected. Patient characteristics including age, sex, weight, height, initial peripheral blood data (absolute neutrophil count, hemoglobin, platelet count), initial percentage of bone marrow (BM) blasts, karyotype and survival status were collected. Besides, comorbidity data were obtained from detailed review of the patients medical charts. Comorbidities were classified according to the MDS-specific comorbidity index (MDS-CI) [29], which identifies three risk groups: low (score 0), intermediate (scores 1 2), and high risk (score 3). Prognosis risk classifications were based on international prognosis scoring system (IPSS) and the revised IPSS (IPSS-R) for MDS [30,31]. BMI calculation The BMI at diagnosis for each patient was calculated as weight measured in kilograms divided by the square of height measured in meters (kg/m 2 ). Height data recorded consistently from any time in the clinical history were considered accurate. Patients were stratified into four BMI groups according to the WHO classification [32] as follows: underweight, BMI <18.5 kg/m 2 ; normal weight, BMI 18.5 to <25 kg/m 2 ; overweight, BMI 25 to <30 kg/m 2 ; obese, BMI 30 kg/m 2. Response evaluation Response assessment was performed following the guidelines of the 2006 International Working Group [33]. Depending on the response to treatment, the patients were then classified into response, stable, and primary failure groups. The response group included complete remission (CR), partial remission, marrow CR with or without hematologic improvement. The stable group was defined as failure to achieve a response, but no evidence of progression for >8 weeks. The primary failure group was defined as progression to higher-risk MDS or to AML. Statistical analysis Overall survival (OS) was defined as the interval from the date of diagnosis until either the date of death from any cause or the last date on which patients were censored. Comparisons between patient clinical and laboratory characteristics were done by Kruskal Wallis test or Wilcoxon rank-sum test for continuous variables and Chi-square test or Fisher s exact test for categorical variables. Pearson s correlation analysis was used to test the linear relationship between parameters. The probability of OS was estimated through the Kaplan Meier method. Survival comparisons were performed through the log-rank test. Furthermore, a stepwise backward Cox regression analysis was performed to evaluate independent predictors of OS. A full model was created with variables with a p value of less than 0.1 in the univariate analysis. Variables with a p >.2 were removed from the full model. Variables with a p <.1 were then added back to the model individually. This iterative process continued until the final model was determined. Twotailed p <.05 were considered statistically significant. Statistical analyzes were performed using Stata version 12 (StataCorp LP, College Station, TX, USA) and SPSS version 24.0 (IBM Corp, Armonk, NY, USA). Results Patient characteristics The median age of the entire cohort was 63 (14 84) years, and 39 patients (42.4%) were younger than 60 years. Sixty patients were men (65.2%) and 32 women (34.8%). The median BMI was ( ) kg/m 2. According to the WHO classification, 11 (12.0%) patients were underweight, 64 (69.6%) were normal weight, 16 (17.4%) were overweight, and 1 (1.1%) were obese. Because there was relatively small number in the obese category, it was grouped into one BMI group with the overweight category, i.e. overweight/ obese group (17 patients, 18.5%). During the course of disease, a total of 52 (56.5%) patients received supportive care with transfusions

4 EFFECT OF BMI ON SURVIVAL IN MDS 3 and/or growth factors. The remaining 40 (43.5%) patients received disease-modifying therapy as follows: 18 patients received induction anthracycline-based chemotherapy (IC) with (n ¼ 12) or without (n ¼ 6) hypomethylating agent (HMA) decitabine, 11 patients received hypomethylating therapy (HMT) (including decitabine [n ¼ 7] and azacitidine [n ¼ 4]), four patients received immunosuppressive and/or immunomodulatory therapy (IST and/or IMT) (including shalidomide [n ¼ 1], cyclosporine [n ¼ 1] and both [n ¼ 2]), and seven patients received allogeneic hematopoietic stem cell transplantation (allo-hsct). Comparisons of clinical and laboratory characteristics among different BMI groups are listed in Table 1. No major differences in patient characteristics were observed between the different BMI groups. Underweight patients tended to more often have lower initial hemoglobin levels than normal weight patients, who in turn tended to more often have lower initial hemoglobin levels than overweight/obese patients (p ¼.0182). In addition, although the patient sample size was small, more patients with high BMI received anthracycline-based intensive chemotherapy, while more patients with low BMI received HMT. In fact, the formal introduction of HMA for the treatment of MDS was started in 2013 in our hospital. Due to that more patients with low BMI were diagnosed after 2013 (11 [100%] in the underweight group versus 56 Table 1. Clinical characteristics of patients in the three BMI groups. Characteristic Underweight (N ¼ 11) Normal weight (N ¼ 64) Overweight/Obese (N ¼ 17) p value Age (years) 59 (14 79) 63 (16 84) 60 (26 79).9270 Age groups 60 years 5 (45.45) 38 (59.38) 10 (58.82).685 <60 years 6 (54.55) 26 (40.62) 7 (41.18) Sex Male 8 (72.73) 43 (67.19) 9 (52.94).469 Female 3 (27.27) 21 (32.81) 8 (47.06) Hemoglobin (g/l) 64 (49 107) 76 (31 142) 96 (36 139).0182 ANC ( /L) 0.54 ( ) 1.36 ( ) 1.18 ( ).3779 Platelets ( /L) 43 (8 174) 89 (4 1264) 53 (2 215).1995 BM blasts (%) 4.4 (0 13.5) 3.55 (0 19) 3 (0 19).8611 WHO classification RCUD/RA(RS) 2 (18.18) 8 (12.50) 1 (5.88).775 RCMD 2 (18.18) 14 (21.88) 6 (35.29) RAEB-1 3 (27.27) 16 (25.00) 4 (23.53) RAEB-2 4 (36.36) 18 (28.13) 3 (17.65) MDS-U 0 8 (12.50) 3 (17.65) Karyotype risk group Good 7 (63.64) 49 (76.56) 15 (88.24).737 Intermediate 1 (9.09) 6 (9.38) 1 (5.88) Poor 3 (27.27) 8 (12.50) 1 (5.88) No data 0 1 (1.56) 0 IPSS Low 1 (9.09) 14 (21.88) 4 (23.53).750 Intermediate-1 5 (45.45) 30 (46.88) 10 (58.82) Intermediate-2 5 (45.45) 16 (25.00) 3 (17.65) High 0 3 (4.69) 0 No data 0 1 (1.56) 0 IPSS-R Very low 0 1 (1.56) 2 (11.76).195 Low 0 17 (26.56) 6 (35.29) Intermediate 4 (36.36) 23 (35.94) 4 (23.53) High 3 (27.27) 11 (17.19) 4 (23.53) Very high 4 (36.36) 11 (17.19) 1 (5.88) No data 0 1 (1.56) 0 MDS-CI Low (score 0) 8 (72.73) 46 (71.88) 11 (64.71).708 Intermediate (scores 1 2) 3 (27.27) 15 (23.44) 6 (35.29) High (score 3) 0 3 (4.69) 0 Treatment type received IC with/without HMA 1 (9.09) 11 (17.19) 6 (35.29).475 HMT 2 (18.18) 9 (14.06) 0 IST and/or IMT 0 4 (6.25) 0 allo-hsct 1 (9.09) 5 (7.81) 1 (5.88) Supportive care 7 (63.64) 35 (54.69) 10 (58.82) Data are presented as medians (range) or numbers (%). ANC: absolute neutrophil count; BM: bone marrow; WHO: World Health Organization; RCUD: refractory cytopenia of unilineage dysplasia; RA: refractory anemia; RARS: RA with ringed sideroblasts; RCMD: refractory cytopenia with multilineage dysplasia; RAEB: refractory anemia with excess of blasts; MDS-U: myelodysplastic syndromeunclassifiable; IPSS: international prognostic scoring system; IPSS-R: revised IPSS; MDS-CI: myelodysplastic syndrome-specific comorbidity index; IC: induction chemotherapy; HMA: hypomethylating agent; HMT: hypomethylating therapy; IST and/or IMT: immunosuppressive and/or immunomodulatory therapy; allo-hsct: allogeneic hematopoietic stem cell transplantation.

5 4 X. XU ET AL. [87.5%] in the normal weight group versus 12 [70.6%] in the overweight/obese group), thus more patients with low BMI had the chance to choose HMT instead of intensive chemotherapy. Associations between BMI and patient characteristics Table 2 showed the correlation between BMI and other patient characteristics in patients with MDS. The results in Table 2, it is clear that there is a positive correlation between BMI with initial hemoglobin levels (Pearson correlation coefficient [r] ¼ , p ¼.0001), while there is a negative correlation with IPSS-R (r ¼ , p ¼.0268). Table 2. Correlation between BMI with other patient characteristics in patients with MDS. BMI (kg/m 2 ) Characteristic Pearson correlation p value Age (years) Sex (male/female) Hemoglobin (g/l) ANC ( /L) Platelets ( /L) BM blasts (%) WHO classification (others/raeb-1/raeb-2) Karyotype risk (good/int/poor) IPSS (low/int-1/int-2/high) IPSS-R (very low/low/int/high/very high) MDS-CI (low/int/high) Therapy regimen (supportive care/others) BMI: body mass index; MDS: myelodysplastic syndrome; ANC: absolute neutrophil count; BM: bone marrow; WHO: World Health Organization; RAEB: refractory anemia with excess of blasts; IPSS: international prognostic scoring system; IPSS-R: revised IPSS; MDS-CI: MDS-specific comorbidity index. Values in bold are statistically significant (p <.05). Associations between BMI and treatment response Response to IC with/without HMA was evaluable in 18 patients. According to the treatment response, the patients were classified into three groups: response group (n ¼ 10, 55.6%), stable group (n ¼ 1, 5.5%), and primary failure group (n ¼ 7, 38.9%). Response to IC with/without HMA was not significantly different in MDS patients with different BMI groups. (p ¼ 1.000, Table S1) In addition, response to HMT was evaluable in 11 patients. According to the treatment response, the patients were classified into three groups: response group (n ¼ 6, 54.5%), stable group (n ¼ 0), and primary failure group (n ¼ 5, 45.5%). Response to HMT was also not significantly different in MDS patients with different BMI groups. (p ¼ 1.000, Table S2) Associations between BMI and survival A total of 39 deaths (42.4%) occurred during a median follow-up period of ( ) months. The estimated three-year OS rate for all 92 patients was ± 6.56%. Three-year OS rates differed significantly when the three BMI groups were compared (p ¼.0449, Figure 1). In comparisons between underweight and either normal weight or overweight/obese groups, normal weight patients had a trend to higher threeyear OS rate than that of patients with underweight (50.05 ± 7.44% versus ± 14.31%, p ¼.1510); while overweight/obese patients had a significantly higher three-year OS rate (62.75 ± 16.07%, p ¼.0127); Besides, the univariate log-rank analysis showed the following variables were also significantly associated with OS: Figure 1. Overall survival of patients with myelodysplastic syndrome (MDS) according to different body mass index (BMI) classification.

6 EFFECT OF BMI ON SURVIVAL IN MDS 5 Table 3. Univariate analysis for overall survival in MDS patients. Parameter p value BMI (<18.5/18.5 to <25/25 kg/m 2 ).0449 Age (<60/60 years).3389 Sex (male/female).1305 Hemoglobin (<100/100 g/l).0168 ANC (<1.8/ /L).2403 Platelets (<100/ /L).8551 BM blasts (<5%/5 10%/>10%).2478 WHO classification (others/raeb-1/raeb-2).0019 Karyotype risk (good/int/poor).0785 IPSS (low/int-1/int-2/high).0042 IPSS-R (very low/low/int/high/very high).0688 MDS-CI (low/int/high).3481 Therapy regimen (supportive care/others).5264 MDS: myelodysplastic syndrome; BMI: body mass index; ANC: absolute neutrophil count; BM: bone marrow; WHO: World Health Organization; RAEB: refractory anemia with excess of blasts; IPSS: international prognostic scoring system; IPSS-R: revised IPSS; MDS-CI: MDS-specific comorbidity index. Values in bold are statistically significant (p <.05). hemoglobin (<100/ 100 g/l) (p ¼.0168), WHO classification (Others/RAEB-1/RAEB-2) (p ¼.0019) and IPSS (low/int-1/int-2/high) (p ¼.0042). Additionally, karyotype risk (good/int/poor) (p ¼.0785) and IPSS-R (very low/low/int/high/very high) (p ¼.0688) were marginally significantly associated with OS (Table 3). After adjusting for the above parameters having a p <.1 in the univariate analysis, backward stepwise multivariate Cox regression analysis revealed that normal weight (versus underweight) had a marginally significant effect on OS (hazard ratio [HR] ¼ 0.456, 95% confidence interval [95% CI] , p ¼.127), and overweight/obese (versus underweight) had a significant effect on OS (HR ¼ 0.171, 95% CI , p ¼.015; Table 4). Because of a recent report describing the poor prognostic effect of obesity in lower risk MDS [27], we further analyzed the prognostic significance of BMI in 64 patients with IPSS low/int-1 risk MDS. Three-year OS rates differed significantly when the three BMI groups were compared (p ¼.0233, Figure 2). In comparisons between underweight and either normal weight or overweight/obese groups, normal weight patients had a significantly higher three-year OS rate than that of patients with underweight (57.58 ± 9.11% versus 0%, p ¼.0314); overweight/obese patients also had a significantly higher three-year OS rate (70.93 ± 15.28%, p ¼.0126). Besides, the univariate logrank analysis showed that WHO classification (others/ RAEB-1/RAEB-2) was also significantly associated with OS (p ¼.0098), while sex (male/female) was marginally significantly associated with OS (p ¼.0905, Table 5). After adjusting for the above parameters having a p <.1 in the univariate analysis, backward stepwise multivariate Cox regression analysis revealed that normal weight (versus underweight) had a marginally Table 4. Multivariate analysis for overall survival in MDS patients. Parameter HR 95% CI p value BMI <18.5 kg/m Reference 18.5 to <25 kg/m kg/m Hemoglobin <100 g/l Reference 100 g/l WHO classification Others Reference RAEB RAEB Karyotype risk Good Reference Int Poor IPSS-R Very low Reference Low Int High Very high MDS: myelodysplastic syndrome; BMI: body mass index; WHO: World Health Organization; RAEB: refractory anemia with excess of blasts; IPSS: international prognostic scoring system; IPSS-R: revised IPSS; HR: hazard ratio; 95% CI: 95% confidence interval. significant effect on OS (HR ¼ 0.384, 95% CI , p ¼.097), and overweight/obese (versus underweight) had a significant effect on OS (HR ¼ 0.203, 95% CI , p ¼.041; Table 6). However, there were too few patients with IPSS int-2/ high risk MDS (N ¼ 27) to make a similar analysis. Discussion While the association between elevated BMI and increased incidence of hematologic malignancies is well described [1 6], the prognostic implication of BMI remains a matter of discussion. There have been several studies investigating the prognostic significance of BMI in patients with hematologic malignancies, some of which demonstrated the negative prognostic effect of increased BMI [13,14,21], some found no association between higher BMI and worse outcomes [7,17 20,22], while others found that higher BMI was associated with better outcomes [8 12,16]. The aim of the present study was at clarifying the prognostic significance of BMI in MDS patients. Consistent with the findings of several previous studies [8 12,16], we found that increased BMI at diagnosis is an favorable prognostic factor in patients with MDS as well as in patients with IPSS low/int-1 risk MDS, after being adjusted for other confounding factors. This result seems to be inconsistent with a previous study which found obesity to be an independent poor prognostic factor for OS in patients with lower risk MDS [27]. The authors suggest that the adverse prognostic effect of obesity on MDS

7 6 X. XU ET AL. Figure 2. Overall survival of patients with international prognostic scoring system (IPSS) low/int-1 risk myelodysplastic syndrome (MDS) according to different body mass index (BMI) classification. Table 5. Univariate analysis for overall survival in patients with IPSS low/int-1 risk MDS. Parameter p value BMI (<18.5/18.5 to <25/25 kg/m 2 ).0233 Age (<60/60 years).9366 Sex (male/female).0905 Hemoglobin (<100/100 g/l).1679 ANC (<1.8/ /L).6523 Platelets (<100/ /L).6156 BM blasts (<5%/5 10%).1578 WHO classification (others/raeb-1/raeb-2).0098 Karyotype risk (good/int/poor).5361 IPSS (low/int-1).5472 IPSS-R (very low/low/int/high).2160 MDS-CI (low/int/high).4114 Therapy regimen (supportive care/others).5061 IPSS: international prognostic scoring system; MDS: myelodysplastic syndrome; BMI: body mass index; ANC: absolute neutrophil count; BM: bone marrow; WHO: World Health Organization; RAEB: refractory anemia with excess of blasts; IPSS-R: revised IPSS; MDS-CI: MDS-specific comorbidity index. Values in bold are statistically significant (p <.05). Table 6. Multivariate analysis for overall survival in patients with IPSS low/int-1 risk MDS. Parameter HR 95% CI p value BMI <18.5 kg/m Reference 18.5 to <25 kg/m kg/m WHO classification Others Reference RAEB RAEB IPSS: international prognostic scoring system; MDS: myelodysplastic syndrome; BMI: body mass index; WHO: World Health Organization; RAEB: refractory anemia with excess of blasts; HR: hazard ratio; 95% CI: 95% confidence interval. may be attributed to obesity-related comorbidities and metabolic dearrangements. Based on these inconsistent findings, we doubt whether the favorable prognostic effect of increased BMI on MDS is limited to a specific BMI range, such as <30 kg/m 2. However, we could not explore this possibility due to only one obese patient included in our study cohort. Further research is needed to confirm or disconfirm this speculation. Several possible explanations have been proposed for the relationship between increased BMI and improve survival in cancer, including the differences in chemotherapy elimination, which depends on the volume of distribution and the clearance. The differences in drug distribution, particularly in relation to anthracycline fat solubility [34,35], may contribute to survival differences due to an effective increased dose to patients with higher BMI who have more fat stores than those with lower BMI. In addition, previous studies have also reported that doxorubicin clearance was reduced in obese patients [35,36], implying that the differences in drug clearance between obese and nonobese patients may result in a higher physiologic level of chemotherapeutic drug in obese patients. Prospective pharmacokinetic and pharmacodynamic studies will be required to better understand the correlation between effective chemotherapy dose and outcomes in MDS patients with different BMI groups. It is noteworthy, however, that more efficient drug distribution of anthracyclines in obese patients would lead to potentially higher likelihood of toxicities such as cardiac adverse events. For instance, a recent study suggests beneficial effects of lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug) against late cardiotoxicity evoked by doxorubicin treatment [37]. However, we had no complete and detailed information on the anthracycline-induced early and delayed cardiotoxicity in our 18 patients treated with

8 EFFECT OF BMI ON SURVIVAL IN MDS 7 anthracycline-based chemotherapy, thus we could not adjust the association of BMI with risk of death for these influence factors. Another possibility is that low BMI may reflect the presence of more aggressive disease course, decreased immunity due to malnutrition and an increased incidence of comorbidities. Thus, BMI itself may have prognostic value through providing additional physiologic reserve to tolerate the treatment. Better treatment tolerance could result in higher treatment intensity in high BMI patients, resulting in improving survival. For instance, adjustment of the chemotherapy dose to the real weight (instead of the theoretical weight) in overweight/obese patients would lead to higher doses than recommended. However, there was no significant difference in the nadir count of leukocytes as well as blood transfusion requirements per therapy cycle among different BMI groups both in MDS patients receiving IC only (Table S3) and in those receiving IC with HMA (Table S4). Additionally, in our study, patients with lower BMI at presentation tended to more often have low initial hemoglobin levels than those with higher BMI. Although this difference did not seem to explain the observed outcomes in multivariate analysis, the difference regarding hemoglobin level implies one possibility that low BMI patients may have higher red blood cell transfusion rates and increased risk of developing an iron-replete state. It is noteworthy that transfusion dependency has been reported to worse the survival of MDS patients [38 40]. These may partly explain the relation between decreased BMI and poor prognosis in MDS. The mechanism by which increased BMI may contribute to patient survival in MDS may also involve metabolism-related cytokines and hormones, with a possible candidate being leptin. Experimental data reveal that leptin through its receptor, which is abundantly expressed in leukemic promyelocytes, may active various cellular signal transduction pathways leading to cell growth [41,42]. In particular, leptin has been shown to have proliferation effects on cytokinedependent myeloid leukemia cell lines in vitro [43]. Thus, it is possible that this endogenous stimulus may cause leukemic cells to be more susceptible to chemotherapy by promoting their proliferation. Further in vitro and in vivo studies are needed to elucidate the participation of metabolism-related cytokines and hormones in complex mechanisms that are involved in the prognostic effect of BMI on MDS. In conclusion, our results indicated that increased BMI was a favorable prognostic factor for patients with MDS. The limitations of the present study include the retrospective nature and the relatively small sample size, thus selection bias was difficult to be well balanced. Therefore, these findings need to be confirmed by well-designed prospective studies. Furthermore, our study design does not allow us to determine causation, thus we can only speculate about the underlying mechanisms of the clinical associations we found. Further investigations are required to elucidate the precise mechanisms responsible for the effect of BMI on survival in MDS and their relation to MDS treatment. Acknowledgements This work was supported by the Public Welfare Science and Technology Project of Wenzhou (Nos. Y , Y ), the Natural Science Foundation of Zhejiang Province (Nos. LQ14H080002, LY12H08002, LY16H080006), and the National Natural Science Foundation of China (No ). Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article online at Funding This work was supported by the Public Welfare Science and Technology Project of Wenzhou (Nos. Y , Y ), the Natural Science Foundation of Zhejiang Province (Nos. LQ14H080002, LY12H08002, LY16H080006), and the National Natural Science Foundation of China (No ). References [1] Soderberg KC, Kaprio J, Verkasalo PK, et al. Overweight, obesity and risk of haematological malignancies: a cohort study of Swedish and Finnish twins. Eur J Cancer. 2009;45: [2] Lichtman MA. Obesity and the risk for a hematological malignancy: leukemia, lymphoma, or myeloma. Oncologist. 2010;15: [3] MacInnis RJ, English DR, Hopper JL, et al. Body size and composition and the risk of lymphohematopoietic malignancies. J Natl Cancer Inst. 2005;97: [4] Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348: [5] Renehan AG, Tyson M, Egger M, et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371: [6] Bhaskaran K, Douglas I, Forbes H, et al. Body-mass index and risk of 22 specific cancers: a populationbased cohort study of 524 million UK adults. Lancet. 2014;384:

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