Effects of Obesity on the Efficacy and Toxicity of Induction Chemotherapy in Adult Acute Lymphoblastic Leukemia (ALL)

Background

The efficacy and toxicity of induction regimens for acute lymphoblastic leukemia (ALL) are affected by numerous patient and regimen specific variables including age, performance status, cytogenetics, comorbidities, and the selection and dosing of chemotherapeutic agents. Notably, the incidence of leukemia and the ability to achieve remission have been shown to be affected by obesity.^1,2 Although there is a lack of data in obese adults with ALL, previous studies have confirmed the poor prognostic implications of obesity in pediatric patients.³ Current practice with regard to chemotherapy dosing in obese patients is dependent on the American Society of Clinical Oncology (ASCO) guidelines, which recommend that chemotherapy should be dosed on actual body weight, regardless of obesity status.⁴ With the lack of data in obese adults with ALL, it has been postulated that empirically reducing chemotherapy doses may  worsen their prognosis. This provided the rationale for this investigation into the effect of obesity on the efficacy and toxicity of induction chemotherapy in adults with ALL.

Methods

The primary objective of this study was to evaluate complete remission (CR) rate to initial induction chemotherapy of obese patients (defined as actual body weight (ABW) > 130% of ideal body weight (IBW)), compared to that of non-obese patients. Secondary objectives included overall survival (OS), relapse free survival (RFS), time to platelet and absolute neutrophil count (ANC) recovery, and grade 3/4 non-hematologic toxicities as graded by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). OS and RFS were estimated by the Kaplan-Meier method, with differences across groups accessed via the logrank test.  The incidence of CR was estimated by the cumulative incidence method for competing risks, with differences across groups accessed via Gray’s test. Death was considered a competing risk for CR. This retrospective chart review included patients with ALL who received initial induction chemotherapy between January 1, 2003, and December 31, 2013, at Memorial Sloan Kettering Cancer Center (MSKCC). Patients included were > 18 years old, newly diagnosed with ALL who were chemotherapy-naïve for treatment of ALL.

Results

Seventy-two patients were identified during the specified period with a median age at diagnosis for all patients of 46 years (18-86). Patients were primarily excluded as chemotherapy was initiated prior to establishing care with MSKCC. A majority of patients received multi-agent chemotherapy with ALL2, L-20, NY-II, ECOG2993, and CALGB 10403 with a smaller subset of patients of older age or poor performance status treated with vincristine and steroids. Twenty-three patients were identified as being obese with a median of 154% of their IBW. The median % of IBW among the non-obese patients (49 patients) was 115%. All patients received chemotherapy based on body surface area (BSA) calculated on total body weight.

All patients in the obese group and 96% of non-obese patients experienced at least one grade 3 or 4 non-hematologic toxicity. Time to ANC recovery (26 days vs. 31 days, for obese and non-obese patients respectively) and platelet recovery (29 days vs. 35 days, respectively) were not different between groups. 

There was no difference in the cumulative incidence of CR among obese and non-obese patients (p=0.477), with a 1 year incidence of 96% in both groups. RFS was similar among obese and non-obese patients (p=0.203, 36.4% and 52.9% respectively at 3 years). Similarly, there was no significant difference in OS between obese and non-obese patients (p=0.161, 45.5% and 57.1% respectively at 3 years). Univariate analyses demonstrated that there was no significant effect of intensity of regimen utilized or baseline cytogenetics on relapse free survival or overall survival.

Conclusion

The findings of this retrospective chart review are consistent with current ASCO guidelines for dosing in obese patients. As there were no differences noted in efficacy or safety between obese and non-obese patients in our study, it remains appropriate to continue dosing obese patients based on actual body weight. Further prospective evaluations are necessary to confirm these findings.

References

1. Pulte et al. PloS ONE 2014; 9: e85554.
2. Castillo JJ et al. Leuk Res 2012; 36:868-875.
3. Butturini AM et al. Journ      Clin Onc 2007; 25(15):2063-2069.
4. Griggs JJ et al. J Clin Oncol 2012; 30(13): 1553-61.