Sami Boussetta

Baseline Metabolic Tumor Volume Predicts Outcome in High–Tumor-Burden Follicular Lymphoma: A Pooled Analysis of Three Multicenter Studies

PURPOSE Identifying patients at high risk of progression and early death among those with high-tumor-burden follicular lymphoma (FL) is unsatisfactory with current prognostic models. This study aimed to determine the prognostic impact of the total metabolic tumor volume (TMTV) measured at baseline with [18F]fluorodeoxyglucose/positron emission tomography-computed tomography ([18F]FDG/PET-CT) scans and its added value to these models. PATIENTS AND METHODS A pooled analysis was performed by using patient data and centrally reviewed baseline PET-CT scans for 185 patients with FL who were receiving immunochemotherapy within three prospective trials. TMTV was computed by using the 41% maximum standardized uptake value thresholding method, and the optimal cutoff for survival prediction was determined. RESULTS Median age was 55 years, 92% of patients had stage III to IV disease, 37% had a Follicular Lymphoma International Prognostic Index (FLIPI) score of 3 to 5, and 31% had a FLIPI2 score of 3 to 5. With a median follow-up of 64 months, overall 5-year progression-free survival (PFS) was 55% and overall survival (OS) was 92%. Median TMTV was 297 cm3 (quartile 1 through quartile 3, 135 to 567 cm3). The optimal cutoff identified was 510 cm3, with a markedly inferior survival in the 29% of patients with TMTV > 510 cm3. Five-year PFS was 33% versus 65% (hazard ratio [HR], 2.90; P < .001), and 5-year OS was 85% versus 95% (HR, 3.45; P = .010). On multivariable analysis, TMTV (HR, 2.3; P = .002) and FLIPI2 score (HR, 2.2; P = .002) were independent predictors of PFS. In combination, they identify three risk groups: high TMTV and intermediate-to-high FLIPI2 score with 5-year PFS of 20% (HR, 5.0; P < .001), high TMTV or intermediate-to-high FLIPI2 score with 5-year PFS of 46% (HR, 2.1; P = .007), and low TMTV and low FLIP2 with 5-year PFS of 69%. CONCLUSION Baseline TMTV is a strong independent predictor of outcome in FL. In combination with FLIPI2 score, it identifies patients at high risk of early progression. It warrants further validation as a biomarker for development of first-line PET-adapted approaches in FL.

The Prognostic Impact of CD163-Positive Macrophages in Follicular Lymphoma: A Study from the BC Cancer Agency and the Lymphoma Study Association

Purpose: We aimed to assess the prognostic significance of follicular lymphoma–associated macrophages in the era of rituximab treatment and maintenance. Experimental Design: We applied immunohistochemistry for CD68 and CD163 to two large tissue microarrays (TMA). The first TMA included samples from 186 patients from the BC Cancer Agency (BCCA) who had been treated with first-line systemic treatment including rituximab, cyclophosphamide, vincristine, and prednisone. The second contained 395 samples from PRIMA trial patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, and randomized to rituximab maintenance or observation. Macrophage infiltration was assessed using Aperio image analysis. Each of the two cohorts was randomly split into training/validation sets. Results: An increased CD163-positive pixel count was predictive of adverse outcome in the BCCA dataset [5-year progression-free survival (PFS) 38% vs. 72%, respectively, P = 0.004 in the training cohort and 5-year PFS 29% vs. 61%, respectively, P = 0.004 in the validation cohort]. In the PRIMA trial, an increased CD163 pixel count was associated with favorable outcome (5-year PFS 60% vs. 44%, respectively, P = 0.011 in the training cohort and 5-year PFS 55% vs. 37%, respectively, P = 0.030 in the validation cohort). Conclusions: CD163-positive macrophages predict outcome in follicular lymphoma, but their prognostic impact is highly dependent on treatment received. Clin Cancer Res; 21(15); 3428–35. ©2015 AACR.

Rituximab exposure is influenced by baseline metabolic tumor volume and predicts outcome of DLBCL patients: a Lymphoma Study.

High variability in patient outcome after rituximab-based treatment is partly explained by rituximab concentrations, and pharmacokinetic (PK) variability could be influenced by tumor burden. We aimed at quantifying the influence of baseline total metabolic tumor volume (TMTV0) on rituximab PK and of TMTV0 and rituximab exposure on outcome in patients with diffuse large B-cell lymphoma (DLBCL). TMTV0 was measured by 18F-fluorodeoxyglucose-positron emission tomography-computed tomography in 108 previously untreated DLBCL patients who received four 375 mg/m2 rituximab infusions every 2 weeks in combination with chemotherapy in 2 prospective trials. A 2-compartment population model allowed describing rituximab PK and calculating rituximab exposure (area under the concentration-time curve; AUC). The association of TMTV0 and AUC with metabolic response after 4 cycles, as well as progression-free survival (PFS) and overall survival (OS), was assessed using logistic regression and Cox models, respectively. Cutoff values for patient outcome were determined using receiver operating characteristic curve analysis. Exposure to rituximab decreased as TMTV0 increased (R2 = 0.41, P < .0001). A high AUC in cycle 1 (≥9400 mg × h per liter) was associated with better response (odds ratio, 5.56; P = .0006) and longer PFS (hazard ratio [HR], 0.38; P = .011) and OS (HR, 0.17; P = .001). A nomogram for rituximab dose needed to obtain optimal AUC according to TMTV0 was constructed, and the 375 mg/m2 classical dose would be suitable for patients with TMTV0 <281 cm3 In summary, rituximab exposure is influenced by TMTV0 and correlates with response and outcome of DLBCL patients. Dose individualization according to TMTV0 should be evaluated in prospective studies. These studies were registered at www.clinicaltrials.gov as #NCT00498043 and #NCT00841945.

Impact of doxorubicin dose capping on the outcome of DLBCL patients with elevated Body Surface Area

To the editor: In 2012, the American Society of Clinical Oncology (ASCO) published guidelines regarding the dosing of chemotherapy for obese patients with cancer.[1][1] In these patients, empiric dose reductions are often performed, usually by capping body surface area (BSA) at 2 m2 because of