Influence of body mass index on survival in indolent and mantle cell lymphomas: analysis of the StiL NHL1 trial

Obesity is not only a well-known risk factor for the development of cardiovascular disease and diabetes [1], but also for the development of several types of cancer [2], including lymphomas [3]. Despite this known negative general impact of obesity on morbidity as well as mortality, we [4] and others [5] have described the somehow unexpected improved survival of overweight and obese patients with diffuse large B cell lymphoma, although others could not reproduce this finding [6].

Considering the present prevalence of excess body weight in the western hemisphere and its continuing global increase [7], medical oncologists are frequently confronted with overweight and obese patients, including their specific set of comorbidities [1] and differential pharmacokinetics [8]. More and more scientific effort is put into deciphering the effects of obesity once a cancer diagnosis has been established.

For hematological malignancies, several studies could not demonstrate a negative impact of overweight and obesity on survival: a retrospective analysis of 712 patients with B cell non-Hodgkin’s lymphoma (NHL) treated with chemotherapy showed no negative impact of higher BMI on OS or PFS [9].

Underdosing of chemotherapy is frequently seen in patients with a calculated body surface area (BSA) of more than 2 m² [10]. Furthermore, a possible influence of B-symptoms on BMI has been unknown so far, but is highly probable, since unexplained weight loss of more than 10% of body weight within the last 6 months constitutes one of its defining criteria [11].

The StiL (Study Group Indolent Lymphomas) NHL 1 trial was a prospective, muticenter, randomized, controlled phase III trial to compare the efficacy and tolerability of chemo-immunotherapy with bendamustine and rituximab (BR) versus R-CHOP in patients with previously untreated indolent non-Hodgkin’s lymphoma or mantle cell lymphoma [12]. This trial was conducted by the StiL and could demonstrate a significantly longer median progression-free survival (PFS) for BR with 69.5 months compared to 31 months in the R-CHOP arm (p < 0.0001; HR 0.58). Since BR was also associated with significantly lower toxicity than R-CHOP, it has since then been widely adopted as new standard first-line regimen for patients with indolent NHL, as well as patients with mantle cell lymphoma who are not eligible for intensive therapy [13].

We performed an unplanned subgroup analysis of 502 patients of the StiL NHL1 trial, intended to investigate the influence of BMI on the OS in a well-defined study cohort of patients with indolent NHL and mantle cell lymphoma.

As required by the StiL NHL1 protocol, patients aged 18 years or older with a WHO performance status of 2 or less were eligible for inclusion if they had a histologically confirmed diagnosis of mantle cell lymphoma or indolent non-Hodgkin’s lymphoma (follicular (grades 1 and 2), lymphoplasmacytic (Waldenstrom’s macroglobulinemia), small lymphocytic, and marginal-zone lymphoma). All patients had to have a previously untreated stage III or IV disease with indication for therapy. For detailed inclusion and exclusion criteria, see Rummel et al. [12]. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration. Of the 549 patients initially included in the study, 35 were excluded due to protocol violations and for another 12 patients, no biometric data was available, leading to 502 patients eligible for this unplanned subgroup analysis. The BMI was calculated as weight (kg) divided by the square of height (m). The patients were stratified into BMI groups according to the WHO guidelines: underweight (BMI <18.5 kg/m²), normal weight (BMI 18.5 to <25 kg/m²), overweight (BMI 25 to <30 kg/m²), obesity class I (BMI 30 to <35 kg/m²), obesity class II (BMI 35 to <40 kg/m²), and obesity class III (≥40 kg/m²) [14]. The optimal BMI cut-off for discerning the life and death status of patients at the end of the follow-up time was calculated based on the receiver operating characteristics (ROC) analyses and the Youden Index J, which represents the maximum of sensitivity_c + specitivity_c-1 for all cut points in the ROC curve [15]. The robustness of the BMI cut-off was tested by 1000 bootstrap iterations, and a 95% confidence interval was provided. The height and weight were consistently recorded at screening. Mann-Whitney U test and Pearson’s χ2 test were used for univariate analyses of baseline characteristics, where appropriate. An association of the different parameters with BMI groups was also tested with a multivariate logistic regression analysis. The survival was estimated using Kaplan-Meier curve analysis, with statistical comparison using the log-rank statistic. A two-tailed significance level of 0.05 was considered statistically significant. Only statistically significant factors were included into multivariate Cox regression analysis. The BMI was also considered as continuous variable and the association with OS or PFS was tested with a Cox regression analysis. In either case, the Cox proportional hazard assumption was tested and time-varying effects on the hazard were analyzed using Schoenfeld residuals. All statistical analyses were carried out using the IBM® SPSS® statistics software (version 20) and the statistal environment R (including packages survival, OptimalCutpoints, boot, and ROCR).

Analyzing 502 patients treated in the StiL NHL1 trial, we could detect a significant association of higher BMI (>22.55 kg/m²) with longer OS. Although this finding is in line with reports in diffuse large B cell lymphoma, where overweight and obese patients showed longer OS [4, 5], it is somehow unexpected: obesity in general is associated with higher morbidity and mortality [1] and is known to promote a state of low-level chronic inflammation [16]. Adipokines play a role in inflammation [17] and are often increased in obese patients. As an example, leptin increases proliferation in hematopoietic cells [18], circulating monocytes [19] as well as T lymphocytes [20]. Polymorphisms in the genes encoding leptin and leptin receptors are associated with an increased risk of NHL [21]. Furthermore, insulin and the insulin-like growth factor 1—both being increased in the plasma of obese patients [2]—have been shown to induce cell proliferation and to inhibit apoptosis [22]. An important role of the IGF-1/IGF-1R for proliferation and survival of malignant cells was described in mulitple myeloma [23], mantle cell lymphoma [24] as well as Hodgkin’s lymphoma [25].

So, although there is mounting evidence that obesity is associated with an increased risk for the development of lymphoma [3], surprisingly, obesity does not seem to negatively impact on the further course of disease.

Several other factors may contribute to this observed BMI effect, one of them being B-symptoms: In most clinical trials for indolent NHL, around one third of patients are reported to have B-symptoms [12, 26]. Although B-symptoms per se represent an indication for treatment, it is very likely that many patients with yet undiagnosed lymphoma or those with established diagnosis but unrecognized or milder, “subclinical” B-symptoms, experience considerable weight loss until the initiation of first lymphoma-specific therapy. Here, a relevant difference in the biology of lymphomas has to be noted, with follicular lymphoma showing a mean time to first treatment of 3 years [27, 28], in contrast to aggressive lymphomas such as diffuse large B cell lymphoma, where the first diagnosis itself is equivalent to indication for treatment. Therefore we hypothesize that in indolent NHL, B-symptoms can significantly impact on BMI, which is supported by our observation of significantly lower BMI in B-symptomatic patients with indolent NHL, but not in patients with mantle cell lymphoma—a subtype known to generally exhibit a more aggressive clinical course than indolent NHL.

But also pharmakokinetics have to be taken into account when analyzing the effect of BMI: in aggressive lymphomas, higher body weight has been associated with an increased rituximab clearance leading to shorter rituximab exposure times when compared to lower body weight [29].

Dosing of chemotherapy is based on the patient’s BSA, and higher BSA frequently coincides with higher BMI. Despite existing literature confirming the safety and clinical necessity of full weight-based chemotherapy dosing, patients with excess body weight frequently receive limited chemotherapy doses in daily practice [10]. A substantial portion of overweight and obese patients in the StiL NHL1 trial have also experienced dose capping to a BSA of 2 m², although being treated in a randomized phase III trial. This practice clearly contradicts current treatment guidelines [30] and is explicitly addressed in the follow-up protocol of the NHL7 protocol of the StiL group.

In our opinion, the present study has an important strength: we evaluated a considerable cohort of 502 patients treated within a prospective, randomized phase III clinical trial, thereby ensuring uniform data collection of biometric, histological, and clinical parameters.

In conclusion, our study shows that excess body weight may affect the clinical course of lymphomas. To our minds, the most pressing open question remains to what extent B-symptoms might bias the interpretation of the individual contribution of BMI. Despite the breath-taking evolution of our understanding of the molecular basis of lymphomas, thanks to technologies such as next-generation sequencing, we should not neglect the clinical methodologies such as taking an accurate patient’s history or standardized assessment and documentation of biometric data. Only the collection of molecular as well as clinical data according to the highest standards of scientific quality will allow us to link a genotype to a certain phenotype and thereby possibly generate new insights into disease biology.