Obesity and lymphoma therapy: not a bad combination after all

In this issue of Leukemia and Lymphoma, Jones and colleagues present a retrospective analysis on a relatively large single institution experience examining the impact of adiposity on outcomes for intermediate-grade B-cell lymphoma (IGBCL) [1]. As the authors point out, obesity remains highly prevalent in the developed world [2,3], and IGBCL is one of the most common and curable hematologic malignancies. Thus, even a modest impact on outcomes has the potential to have significant impact from a public health perspective.

Examining the outcomes of 712 patients treated with a CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like regimen, with more than 60% of patients either overweight or obese, the authors found that obese patients fared no worse, and overweight patients actually enjoyed improved progression-free and overall survival compared to normal weight patients. The patients for this analysis had been enrolled on clinical trials in which chemotherapy dosing was not adjusted for obesity, save for vincristine, and the vast majority of patients are known to have received the planned doses of therapy.

Combined with toxicity data, this study contributes to insight about actual dosing for overweight and obese patients and shows that the incidence of all grade 3–4 adverse events was higher in the overweight and obese groups, though only documented infection incidence reached statistical significance. Thus, it does appear that dosing by actual weight results in modestly higher toxicity rates, though with minimal clinical consequence in this study. Still, this finding points out that it is not yet clear what the optimal dosing schema should be for obese patients; even less is known about optimal dosing for the morbidly obese, who, as is typical, represented less than 3% of the study population here.

Similar treatment outcomes for overweight and obese compared to normal weight patients have been reported for hematologic malignancies in both the non-transplant [4] and hematopoietic cell transplant setting [5–7]. However, outcomes for overweight and obese patients with hematologic malignancies have not been consistent. Meloni and colleagues reported that obese patients with acute myeloid leukemia (AML) undergoing autologous transplant without dose adjustment for adiposity fared worse than normal weight patients, primarily as a result of increased treatment-related complications [8]. It appears from that work that conditioning regimens probably should be adjusted for adiposity, though there is no standard compensatory formula and, as a result, surprising variability in the formulas used [9]. Likewise, Lange et al. showed worse outcomes for obese children with AML, again with increased treatment-related mortality as the primary driver of poorer outcomes [10]. In acute lymphoblastic leukemia, the obese also fared worse than normal weight patients [11]. It may be that obesity adversely impacted maintenance therapy, since induction rates were similar to those for normal weight patients, whether by altered pharmacokinetics or by decreased tolerance leading to dose reductions.

Mortality outcomes from a very large epidemiologic study published by Calle and co-workers [12] of the American Cancer Society also raise concern for overweight and obese patients with cancer. In that article, the authors report that the relative risk of death for the obese in the setting of all cancers and for hematologic malignancies was significantly higher than for the normal weight population, with the exception of leukemia in women. One must wonder whether the higher risk of death among the overweight and obese with hematologic malignancies resulted less from biologic differences and more from widespread undertreatment.

So, how should we apply these results? The authors convincingly demonstrate that patients with IGBCL, irrespective of weight, should receive full dose anti-lymphoma therapy. The study population tended toward lower risk disease, but this does not alter the idea that dose intensity should be maintained. Adiposity alone should not, at least up to a body mass index (BMI) of 40, influence treatment. It must be kept in mind, though, that the patients studied by Jones and colleagues were all on clinical trials, and therefore represent a selected population. Co-morbidities were minimized as a result, and the treating physician must still account for them in deciding on risk/benefit and on a treatment plan.

Prospective investigations with pharmacokinetic data could help address dosing issues, though with clear evidence now that dosing of standard therapy for lymphoma is safe, such studies may be of lower priority; what is more, increasing availability and use of agents with broader therapeutic-toxic windows may make such studies less relevant.

More challenging are the patients with hematologic malignancies who are underweight; this group has been shown to fare worse [6,10]. Several issues may be at play. First, these patients may have less ‘biologic reserve’ to tolerate the nutritional disturbances that occur during intensive chemotherapy. Second, they may have underlying co-morbidities that affect their tolerance of therapy. Lastly, their disease is likely to be biologically distinct when associated with weight loss. This last issue could be addressed in prospective trials that capture when weight loss occurred: at baseline, which may be less problematic, or with disease onset, which may define more aggressive, poorer prognosis disease.

With the increasing rates of obesity in the United States, treatment of the overweight and obese with hematologic malignancies will remain an issue. Similarly, we must also focus on how to treat underweight patients differently, to shift inferior outcomes toward comparability with the rest of the population.