Juweid, Malik E.

Abstract Antibody-dependent cellular cytotoxicity (ADCC) mediated by PBMC’s is believed to play an important role in the anti-tumor effects of rituximab in patients (pts) with NHL but little is known about the trafficking of PBMC’s into the involved nodes. The primary objective of this pilot study is to demonstrate the feasibility of imaging PBMC trafficking in pts with NHL prior to and following various forms of therapy, including rituximab. To date, autologous PBMC’s were harvested in 9 pts (7M, 2F, age 49–83 y) using 100 ml of peripheral blood and Ficoll-Paque density gradient for cell separation and then radiolabeled with 400–450 mCi of 111In-oxine. Total number of leukocytes in the final product ranged from 1.5–12x107 (mean=5.5x107) with %PBMC’s ranging from 40–98 (mean= 75). The radiolabeling efficiency ranged from 53 to 87% (mean = 71) Viability of PBMC’s by trypan blue exclusion was 99–100%. Eight patients were imaged at baseline and six of these also following 2 cycles of rituximab (n=5) or one cycle of R-CHOP (n=1). Imaging was performed at approximately 4, 24, and 48 h after injection of 165–300 mCi of 111In-PBMCs. No significant adverse events were observed. All 8 pts showed the expected biodistribution of PBMC’s in normal organs, such as lung (primarily at 4h) and liver and spleen (at all timepoints). There was no evidence of PBMC localization in normal lymph nodes prior to or posttherapy. In contrast, PBMC localization was seen prior to therapy in ≥ 1 known tumor lesion per pt in all 8 pts and in the 6 pts imaged posttherapy, similar or greater PBMC tumor accumulation was observed. In conclusion, our initial results demonstrate the feasibility of imaging PBMC trafficking in pts with NHL prior to and following therapy with promising initial imaging findings. Our studies could eventually help better understand the role that PBMC play in the anti-tumor effect of rituximab and prove useful in the development of combination treatments such as the use of moAbs and cytokines.

Abstract Background: Positive interim PET scans have been associated with inferior outcomes in DLBCL treated with chemotherapy, alone or with rituximab. In the ECOG 3404 study for bulky and advanced DLBCL, PET scans at baseline and after 3 R-CHOP are centrally reviewed by a single reader; those with positive scans cross-over to R-ICE after 4 R-CHOP, whereas those with negative scans continue on R-CHOP. The primary endpoint of E3404 is progression-free survival. To determine the reproducibility of interim PET scan interpretation, we convened an expert panel. Methods: Three external nuclear medicine physicians visually scored baseline and interim PET scans independently and blinded to other clinical information or outcome. ECOG study criteria were binary (0,1) based on residual disease in initially involved sites with uptake greater than the liver. London criteria were on a scale of 0–5, where 4–5 was positive, based on increased uptake relative to the liver. Overall scores and agreement among experts were evaluated for both criteria, with application of the kappa statistic to correct for chance. Results: Using the ECOG criteria, external reviewers were in complete agreement in 68% of 38 interim scans and completely agreed with the central review in the same 68% cases. Agreement among the experts was 71% employing the London criteria in these cases. The range of PET+ interim scans by reviewer was 16.8% to 34.2% (p=NS) by both ECOG and London criteria. The kappa statistic for overall pairwise correlation between readers was 0.445 (0.396–0.533) using ECOG and 0.502 (0.396–0.630) using London criteria – indicating moderate consistency. Areas of disagreement often, but not exclusively, related to bone disease, the shape and focality of residual uptake, splenic disease, and rare scans without CT-fusion. Conclusions: These data show that visual criteria, either ECOG or London in this series, for interim PET results are moderately reproducible among individual nuclear medicine experts. Our finding of variability among experts indicates the need for caution in interpreting interim PET results in studies and in practice. Review of all E3404 cases is planned after accrual is completed (projected 12/08). Other ongoing studies evaluating interim PET after 1–3 cycles of therapy, the application of quantitative criteria, and consensus panels may provide further valuable information.

Abstract Background: CT imaging has routinely been used for assessing therapy response in most malignancies including Non-Hodgkins Lymphoma (NHL). The presence of residual tumor is generally categorized using the International Workshop Criteria from CT imaging and bone marrow biopsies for assessing response after treatment. CT imaging has limitations in assessment of response to therapy in NHL with false positive results due to residual masses having viable tumor cells in less than 20% and the remainder being fibrosis or necrosis. In addition false negative CT results are seen due to viable tumor cells in nodes measuring less than 1.5 cm in size. F-18 FDG PET scans provide metabolic imaging of viable tumor cells due to uptake and retention of F-18 fluorodeoxyglucose preferentially in malignant cells. Method: Forty-eight patients with aggressive NHL having completed anthracycline-based chemotherapy had the post therapy FDG PET scans and CT scans reviewed by experienced readers blinded from the comparison scan and from the clinical history. PET scans were read as positive or negative for abnormal FDG consistent with residual viable tumor and the CT was read as positive or negative for nodes greater than 1.5 cm in diameter. Records were reviewed for tumor histology and evidence of tumor relapse with a median follow-up of 35 months. Results: The FDG PET and CT imaging prediction of PFS at 2 years had positive predictive values of 67% and 38%, negative predictive values of 88% and 78%, and accuracy of 81% and 50% respectively. The sensitivity and specificity of the FDG PET scan was 71% and 82% for predicting disease progression within 2 years from beginning treatment. Conclusion: FDG PET imaging was compared with CT imaging done after completing initial chemotherapy for aggressive NHL and demonstrated superior prediction of tumor response status at 2 years. These results indicate that FDG PET imaging should be combined with bone marrow biopsy for restaging aggressive NHL after completion of chemotherapy. The use of FDG PET is more accurate and should replace response assessment by CT imaging in most pateints with aggressive NHL following treatment.

Abstract Positive interim positron emission tomography (PET) scans are thought to be associated with inferior outcomes in diffuse large B-cell lymphoma. In the E3404 diffuse large B-cell lymphoma study, PET scans at baseline and after 3 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone were centrally reviewed by a single reader. To determine the reproducibility of interim PET interpretation, an expert panel of 3 external nuclear medicine physicians visually scored baseline and interim PET scans independently and were blinded to clinical information. The binary Eastern Cooperative Oncology Group (ECOG) study criteria were based on modifications of the Harmonization Criteria; the London criteria were also applied. Of 38 interim scans, agreement was complete in 68% and 71% by ECOG and London criteria, respectively. The range of PET+ interim scans was 16% to 34% (P = not significant) by reviewer. Moderate consistency of reviews was observed: κ statistic = 0.445 using ECOG criteria, and κ statistic = 0.502 using London criteria. These data, showing only moderate reproducibility among nuclear medicine experts, indicate the need to standardize PET interpretation in research and practice. This trial was registered at www.clinicaltrials.gov as #NCT00274924.

Purpose To determine whether a response classification based on integration of fluorine-18–fluorodeoxyglucose positron emission tomography (FDG-PET) into the International Workshop Criteria (IWC) provides a more accurate response assessment than IWC alone in patients with non-Hodgkin's lymphoma (NHL). Patients and Methods Fifty-four patients with aggressive NHL who underwent FDG-PET and computed tomography 1 to 16 weeks after four to eight cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone were assessed for complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD), and progressive disease (PD) by the IWC and by integrated IWC and FDG-PET (IWC+PET). Progression-free survival (PFS) was also compared between IWC- and IWC+PET-assigned response designations. Results By IWC, 17 patients had a CR, seven had a CRu, 19 had a PR, nine had SD, and two had PD. In comparison, by IWC+PET, 35 patients had a CR, 12 had a PR, six had SD, one had PD, and zero had a CRu. In separate multivariate models, PFS was significantly shorter in patients with PR than in those with a CR using IWC (hazard ratio [HR], 8.9; P = .021) or IWC+PET (HR, 29.7; P = .0003). However, when the two classifications were included in the same multivariate model, only IWC+PET was a statistically significant independent predictor for PFS (P = .008 v P = .72 for IWC). In addition, when patients with a PR by IWC and a CR by IWC+PET were compared with those with a CR by IWC and a CR by IWC+PET, there was no significant difference in PFS (HR, 1.6; P = .72), indicating that IWC+PET identified a subset of IWC-PR patients with a more favorable prognosis. Conclusion Compared with IWC, the IWC+PET-based assessment provides a more accurate response classification in patients with aggressive NHL.