Deauville 5-point Scale Research Articles

Association between textural and morphological tumor indices on baseline PET-CT and early metabolic response on interim PET-CT in bulky malignant lymphomas.

We investigated whether metabolic, textural, and morphological tumoral indices evaluated on baseline PET-CT were predictive of early metabolic response on interim PET-CT in a cohort of patients with bulky Hodgkin and non-Hodgkin malignant lymphomas. This retrospective study included 57 patients referred for initial PET-CT examination. In-house dedicated software was used to delineate tumor contours using a fixed 30% threshold of SUV max and then to compute tumoral metabolic parameters (SUV max, mean, peak, standard deviation, skewness and kurtosis, metabolic tumoral volume (MTV), total lesion glycolysis, and area under the curve of the cumulative histogram), textural parameters (Moran's and Geary's indices, energy, entropy, contrast, correlation derived from the gray-level co-occurrence matrix, area under the curve of the power spectral density, auto-correlation distance, and granularity), and shape parameters (surface, asphericity, convexity, surfacic extension, and 2D and 3D fractal dimensions). Early metabolic response was assessed on interim PET-CT using the Deauville 5-point scale and patients were ranked according to the Lugano classification as complete or not complete metabolic responders. The impact of the segmentation method (alternate threshold at 41%) and image resolution (Gaussian postsmoothing of 3, 5, and 7mm) was investigated. The association of the proposed parameters with early response was assessed in univariate and multivariate analyses. Their added predictive value was explored using supervised classification by support vector machines (SVM). We evaluated in leave-one-out cross-validation three SVMs admitting as input features (a) MTV, (b) MTV+histological type, and (c) MTV+histology+relevant texture/shape indices. Features associated with complete metabolic response were low MTV (P=0.01), low TLG (P=0.003), high power spectral density AUC (P=0.007), high surfacic extension (P=0.006), low 2D fractal dimension (P=0.007), and low 3D fractal dimension (P=0.003). The prognostic value of these metrics was optimal with the 30% segmentation threshold and overall was progressively altered with decreasing image resolution. In cross-validation, the SVM accounting for texture and shape achieved the highest predictive value with ROC AUC of 0.82 and 80% accuracy (compared with 0.68 and 61% for MTV, and 0.65 and 68% for MTV+histology). The combination of usual prognostic factors with appropriately chosen textural and shape parameters evaluated on baseline PET-CT improves the prediction of early metabolic response in bulky lymphoma.

Prediction of outcome in pediatric Hodgkin lymphoma based on interpretation of 18FDG-PET/CT according to ΔSUVmax, Deauville 5-point scale and IHP criteria.

Minimizing side effects by using response-adopted therapy strategies plays an important role in the management of pediatric Hodgkin lymphoma (HL); however, the criteria for the definition of adequate or inadequate response are controversial. The aim of this study is to compare different methods of interpretation of 18F-FDG-PET/CT (PET) in the prediction of disease outcome in order to determine the optimum method in this regard. Baseline, interim and post-treatment PET scans of 72 children were interpreted according to revised International Harmonization Project criteria (IHP) and Deauville criteria. Cut-off values for changes in interim and post-treatment FDG uptake (ΔSUVmax) in the prediction of progression-free survival (PFS) were measured using ROC analysis. Quantitative and visual data were compared with each other in the prediction of PFS. Mean interim and post-treatment ΔSUVmax of the primary lesions were 77.4±19.5 and 68.8±30.4% and respective cut-off values were 82 and 73%. However, only post-treatment ΔSUVmax yielded statistically significant results in the prediction of 3-year PFS (p=0.043). Interim ΔSUVmax was further analyzed according to the values reported in the literature (66 and 77%) yet statistically significant results were not reached (p=0.604 and 0.431). For interim evaluation, IHP criteria was correlated to Deauville criteria (p=0.002 and p=0.001) and ΔSUVmax (p=0.03), whereas for post-treatment evaluation, significant correlation with ΔSUVmax (p=0.04) but marginally significant (p=0.055 and p=0.058) correlation with Deauville criteria were achieved. Overall, 1, 3 and 5-year PFS were 95.7±0.2, 89.6±0.4 and 80.8±0.7%, respectively. All methods demonstrated comparable performance in the prediction of 3-year PFS; however, interim PET using Deauville criteria and post-treatment PET using IHP criteria were statistically significant. All methods demonstrated high negative-predictive value but substantially low positive-predictive value. Deauville criteria are superior to other methods in the prediction of pediatric HL outcome using interim PET data. On the other hand, quantitative evaluation and visual evaluation by IHP can be used reliably at the end of the treatment. In this regard, we report the optimal cut-off value of SUVmax reduction as 73%.

A PILOT STUDY OF BRENTUXIMAB VEDOTIN AND AVD CHEMOTHERAPY FOLLOWED BY 20 GY INVOLVED‐SITE RADIOTHERAPY IN EARLY STAGE, UNFAVORABLE RISK HODGKIN LYMPHOMA

Introduction: The combination of brentuximab vedotin (BV) with AVD chemotherapy followed by 30 Gy involved-site radiotherapy (ISRT) for the treatment of early stage, unfavorable risk Hodgkin lymphoma (HL) has demonstrated promising efficacy and an acceptable safety profile in the first cohort of this pilot study (Kumar et al., Blood, 2016). In cohort 2, we evaluated whether the reduced dose of ISRT to 20 Gy decreased RT-related toxicity while maintaining efficacy. Methods: Patients received 4 cycles of BV 1.2 mg/kg with AVD chemotherapy every 2 weeks followed by 30 Gy ISRT in cohort 1 and 20 Gy ISRT in cohort 2. Eligible patients had untreated stage I/II classical HL with any of the following unfavorable risk factors: bulky disease (maximal transverse or coronal diameter > 7 cm on CT), elevated ESR, extranodal involvement, >2 lymph node sites, or infradiaphragmatic disease. Patients with stage IIB disease with disease bulk or extranodal involvement were eligible. PET/CT after 2 and 4 cycles and ISRT were interpreted with the Deauville 5-point scale (negative = 1-3). The primary endpoint of cohort 2 was to evaluate preliminary efficacy by complete response (CR) rate. Results: In cohort 2, 29 patients were enrolled from May 2015 to October 2016 with median age of 33 (range, 19-55), 100% stage II, 69% with disease bulk (>7 cm), 38% elevated ESR, 38% B-symptoms, 21% extranodal involvement, 69% >2 involved lymph node sites, and 3% infradiaphragmatic disease. Twenty patients (69%) had bulky anterior mediastinal masses, ranging from 7 to 17.3 cm. Nine patients (31%) had advanced stage disease by the GHSG criteria: IIBX (n = 7) and IIBXE (n = 2). In cohort 2, 90% and 93% of patients achieved a negative PET scan after 2 and 4 cycles of therapy, respectively. Of the 2 patients with positive PET-4 scans, one underwent a biopsy that was negative for HL, and the other had residual FDG-uptake in a location not amenable to biopsy. Both patients received ISRT. The 25 patients who completed combined modality therapy (CMT) have achieved CRs. To date, the duration of remission ranges from 2 to 13 months, and no relapses have occurred. The efficacy is similar across cohorts 1 and 2 with interim PET negative rates of ≥90%, and all patients who completed CMT have achieved a CR (Figure 1). In cohort 1, 2 patients had biopsy-proven primary refractory HL after 4 cycles of chemotherapy, and in cohort 2, there have been no treatment failures. Conclusion: BV + AVD x 4 cycles followed by 20 Gy ISRT has promising preliminary efficacy for the treatment of early stage, unfavorable risk HL, including a high proportion of patients with bulky disease. As with 4 cycles of escalated BEACOPP tested in the GHSG HD11 clinical trial, 20 Gy ISRT may be adequate consolidation after BV + AVD x 4 cycles. We recommend that BV + AVD x 4 + 20 Gy ISRT is studied in a larger, randomized prospective study for early stage, bulky HL. Updated response data for all patients will be presented at the meeting. Keywords: brentuximab vedotin; Hodgkin lymphoma (HL)

Imaging of Early Response to Predict Prognosis in the First-Line Management of Follicular Non-Hodgkin Lymphoma with Iodine-131-Rituximab Radioimmunotherapy.

The purpose of this study was to evaluate prediction of prognosis after first-line radioimmunotherapy (RIT) of advanced follicular non-Hodgkin lymphoma (FL), by imaging with fluorine-18-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG-PET/CT) three months after induction treatment by Iodine-131-rituximab (131I-rituximab). Objective response was determined using the Deauville 5-point scale in 68 prospective clinical trial patients. Baseline 18F-FDG-PET/CT studies were used to calculate total-metabolic-tumor-volume (TMTV). Non-imaging studies included the Follicular lymphoma international prognostic index (FLIPI) and absolute baseline monocyte and lymphocyte counts. Patients were monitored for over ten years (median follow-up 59 months), and no patient was lost to follow-up. Complete response (CR) of 88% predicted excellent prognosis with median time-to-next-treatment (TTNT) not yet reached. Those patients (12%) who failed to achieve CR (Deauville ≤ 3) on 18F-FDG-PET/CT at three months had significantly poorer outcomes (p < 0.0001) with a median TTNT of 41 months. Requirement for re-treatment was predicted by FLIPI and absolute baseline monocyte count but not lymphocyte count. The TTNT was accurately predicted by 18F-FDG-PET/CT Deauville response at three months following first-line therapy of FL with RIT. Early response demonstrated by imaging does, therefore, foretell prognosis in the individual FL patients.

FDG PET/CT Findings in Abdominal Fat Necrosis After Treatment for Lymphoma

FDG PET/CT is now validated in non-Hodgkin lymphoma for response assessment in interim and posttreatment lymphoma. We report the case of a 62-year-old man followed by FDG PET/CT for a diffuse large B-cell lymphoma, with initial stage III. The interim FDG PET/CT examination concluded in complete metabolic and morphological response of subdiaphragmatic lymphadenopathy but a persistent abnormal subdiaphragmatic uptake (SUVmax at 9 and Deauville 5-point scale at 5). Therefore, an abdominal biopsy of the corresponding nodules was conducted with a final diagnosis of diffuse fat necrosis.

Prognostic Role of Pre–Radiation Therapy 18F-Fluorodeoxyglucose Positron Emission Tomography for Primary Mediastinal B-Cell Lymphomas Treated with R-CHOP or R-CHOP-Like Chemotherapy Plus Radiation

Tovalidate, in a monoinstitutional cohort with extended follow-up, that post-rituximab chemotherapy (R-CT) (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) is a prognostic factor allowing discrimination of primary mediastinal B-cell lymphoma (PMBCL) patients at higher risk for progression after radiation therapy. We analyzed 51 patients, and (18)FDG-PET scans were re-examined evaluating both the Deauville 5-point scale (D5PS) score and the standardized uptake value (SUV) of residual activity, if present. These parameters were then tested by univariate analysis for a potential correlation with progression-free survival (PFS) as the primary study endpoint. Median follow-up time was 51months (range, 9-153months). After R-CT, D5PS score was 1 in 10 (19.6%), 2 in 11 (21.6%), 3 in 7 (13.8%), 4 in 17 (33.3%), and 5 in 6 patients (11.7%). Forty-three out of 51 patients (84.3%) had an SUVmax ≤5, and 8 out of 51 (15.7%) had an SUVmax ≥5. Overall, 6 patients experienced progression or relapse: 1 had a D5PS score 2 (with SUVmax ≤5), and 5 had a D5PS score 5 (and SUVmax ≥5). Patients with a D5PS score 5 showed significantly lower PFS rates versus all other scores (log-rank P<.001), as did patients with SUVmax ≥5 when compared with those with SUVmax ≤5 (log-rank P<.001). The present study confirmed the prognostic role of (18)FDG-PET after R-CT, with patients with a D5PS score of 5 and/or an SUVmax ≥5 being at high risk of progression/relapse after RT.

Predictive Significance of a New Prognostic Score for Patients With Diffuse Large B-Cell Lymphoma in the Interim-Positron Emission Tomography Findings.

We hypothesized that the objective treatment response of patients with diffuse large B-cell lymphoma (DLBCL) was affected by many factors such as pathophysiological, biological, and pharmaceutical mechanisms. This retrospective study aimed to evaluate the predictive significance of clinical prognostic factors and interim fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), and to find a new prognostic predictor significantly associated with DLBCL patients’ outcome. A total of 105 adult patients with DLBCL were reviewed. Each patient underwent an interim 18F-FDG PET/CT scan after the second chemotherapy cycle. The visual method based on the Deauville 5-point scale was used to evaluate the interim-PET/CT scans. The relationships among the prognostic factors, the 3-year progression-free survival (PFS) rate and overall survival (OS) rate were analyzed with Kaplan–Meier plots. The predictive value of the newly constructed prognostic score was analyzed with multivariate analysis (Cox proportional hazard regression model). The visual analysis showed statistically significant differences in both PFS and OS between the patients with a negative interim-PET/CT and those with a positive interim-PET/CT. Advanced age, advanced stage, and DLBCL subtype were also significantly associated with outcome. A new prognostic score that composed of the above 4 factors was obtained. New prognostic score stratified patients into 4 risk groups with 3-year PFS of 98.5%, 73.9%, 11.1%, and 0%, and 3-year OS of 100%, 91.3%, 55.6%, and 0% (P < 0.001 for PFS and OS). Multivariate analysis showed that the new prognostic score had the greatest ability to predict relapse (P < 0.001) and death (P < 0.001). In DLBCL patients, interim 18F-FDG PET/CT can provide significant independent prognostic information. Our work illustrates that the new prognostic score has the strongest potential for accurately prognostication, for stratification in clinical trials, and for design of novel strategies for DLBCL patients in the high-risk group.

Favorable Outcome of Primary Mediastinal Large B-Cell Lymphoma Patients Treated with Sequential R-CHOP/R- ICE Regimen Omitting Radiation

Introduction: Progression-free (PFS) and overall survival (OS) rates for Primary mediastinal large B-cell lymphoma (PMBL) have risen to 84% and 92%, respectively, with the addition of rituximab to standard CHOP. Despite general acceptance of RCHOP as standard of care for Diffuse Large B-Cell lymphoma (DLBCL), many centers recommended alternative regimens for PMBL such as RMACOPB, RVACOPB, RCHOP-RICE and DA-EPOCH-R. The latter was adopted with great worldwide enthusiasm, despite its lack of proven superiority in randomized controlled trials (RCT). The benefits of DA-EPOCH-R include the omission of consolidation radiotherapy (RT), an attractive option in PMBL patients (pts), given their demographic profile-mainly females in their 3rd decade. We aimed to evaluate the PFS, the OS, the number of hospitalization days for treatment, and complications and the need for consolidation RT in a single center in the Rituximab era; where since 2007 over 80% of our pts were treated with the RCHOP-RICE regimen consisting of 4 courses of RCHOP followed by 3 courses of RICE.Methods: We reviewed the files of all PMBL pts who received 1st-line treatment in Hadassah Medical Center between 8/2002-10/2014, extracting clinical, laboratory and imaging data.Results: Of the 47 pts, 24 were treated with RCHOP-RICE (80% since 2007), 12 with RMACOPB, 3 with RVACOPB, 6 with RCHOP and 2 with DA-EPOCH-R. Pts were mainly female, with Stage I-II disease, and a high LDH level. Pt characteristics were comparable between the protocols (Table). In total, 21 (45%) of our pts received RT; only 3 pts (12%) treated with RCHOP-RICE compared to 18 pts (78%) treated with other protocols (p<0.01). A mean of 11+8 hospitalization days/pt were needed to administer the RCHOP-RICE regimen, significantly more than required for other treatments combined (p<0.01), except DA-EPOCH-R where the mean hospitalization days to administer 6 courses-=37+2 /pt (2 patients). Treatment-related toxicities did not differ between the groups. Late toxicity included advanced breast cancer in one pt who received RMACOPB and radiotherapy. The Deauville 5-point scale at interim was available for 39 pts, of whom 43% had an uptake </= to mediastinal blood pool, 33% had an uptake greater than the mediastinum and </= liver uptake and 23% had >liver uptake. At the end of therapy the numbers were 68%, 23% and 9% respectively, for 35 pts who were evaluated. The median 5-year PFS and OS were 93% and 98% respectively, with no difference between treatment regimens.Conclusion: The RCHOP-RICE regimen does not appear inferior to other regimens, allows to omit RT in PMBL and demonstrated no significant late toxicities. Published phase 2 data on DA-EPOCH-R (93% EFS and 95% OS) do not demonstrate an advantage compared to the simpler regimens described here. RCTs are required to establish the standard for efficacy, efficiency and safety of care in PMBL.Table 1CharacteristicsRCHOP-RICEOthersAll patientsNumber of patients242347Median age343434Female n(%)16 (67)15 (65)31 (66)Stage 1-2 n(%)17 (71)21 (91)38 (81)Median tumor size (cm)10.210.510.2High LDH n(%)21 (87)17 (81)38 (84)Effusion n(%)10 (42)9 (39)19 (40)Median 5 year PFS90%95%93%Median 5 year OS100%95%98% DisclosuresLavie:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Predictive Value of Interim 18 f-FDG PET-CT Scans on Diffuse Large B-Cell Lymphoma Treated with R-CHOP: A Prospective Study

18 F-PET-CT is clinically recommended for monitoring therapeutic response in DLBCL patients. But the role of interim PET-CT remains controversial, and most of the previous researches were retrospective. We designed this study to prospectively evaluate whether interim PET-CT was a valid prognostic tool for patients with DLBCL treated with R-CHOP regimen and if yes, try to determine the more appropriate time and interpretation method for interim PET-CT.This study was a sub-study of the parental study "A prospective, multicenter randomized phase III clinical trial of intensified chemotherapy in improving the treatment efficacy of patient with diffuse large B-cell lymphoma" (NCT01793844). The sub-study included patients that have already been enrolled in the parent study at Sun Yat-Sen University Cancer Center prospectively. Patients were evaluated with PET-CT scans before treatment and after every 2 cycles of R-CHOP and after the completion of first-line treatment. Regular follow-up starts from the enrollment.Between Jan. 2008 and Aug. 2014, 221 patients in Sun Yat-Sen University Cancer Center were enrolled in this sub-study, among whom 203 patients were included in the analysis and the other 18 were excluded for lacking the necessary raw data of PET-CT scan. PET evaluation would be applying the visual criteria of International Harmonization Project(IHP) and the Deauville 5-point scale(5-PS). The results showed PET positive in 103 patients and negative in 100 patients after 2 cycles of R-CHOP chemotherapy with IHP criteria. Among the 103 patients with positive PET-2, 53 patients turned negative after 4 cycles of chemotherapy and still 50 patients remain positive. At the evaluation of end-of-first-line-treatment, 165 patients achieved CR, while 30 achieved PR and 8 PD . According to 5-PS criteria, 146 patients were PET negative with 57 were positive after 2 cycles of chemotherapy. And 173 patients were negative in PET-4 evaluation, while 30 patients remained positive. With a median follow-up of 25.46 months (range 3.60~77.33 months) and according to IHP criteria, patients with negative PET-2 had superior 3-year PFS (84.7% vs. 63.8%, p < 0.001) and OS (89.8% vs. 80.4%, p = 0.045) than those with positive results. Patients with negative PET-4 also had a better clinical outcome compared with the positive group with 3-year PFS (84.1% vs. 43.8%, p < 0.001) and OS (90.7% vs. 67.8%, p < 0.001). A further analysis showed that patients who achieved PET negative just after 2 cycles of chemotherapy (Early responder, ER) had a similar prognosis comparing with those who achieved PET negative after 4 cycles (Later responder, LR). There were no significant differences in the persistent CR rates (87.00% vs. 86.79%, p = 0.971), 3-year PFS (84.7% vs. 82.2%, p = 0.867) and 3-year OS (89.8% vs. 92.9%, p = 0.638) between the ER group and the LR group. Patients who remained PET positive after 4 cycles of chemotherapy (Interim non-responder, I-NR) had the worst prognosis. Their persistent CR rate (42.00% vs. 87.00%, p < 0.001; 42.00% vs. 86.79%, p < 0.001), 3-year PFS (43.8% vs. 84.7%, p < 0.001; 43.8% vs. 82.2%, p < 0.001) and 3-year OS (67.8% vs. 89.8%, p < 0.001; 67.8% vs. 92.9%, p = 0.002) were significantly lower, comparing with the ER and LR group. And according to 5-PS criteria, the results were similar. Patients with negative PET-2 had superior 3-year PFS (82.9% vs. 51.6%, p < 0.001) and OS (89.7% vs. 72.9%, p = 0.001) than those with positive results. Patients with negative PET-4 also had a better clinical outcome compared with the positive group with 3-year PFS (81.8% vs. 30.0%, p < 0.001) and OS (90.1% vs. 54.2%, p < 0.001). In the multivariate analysis, PET-4 with IHP criteria, PET-4 with 5-PS criteria and IPI score were independent predictive factors for PFS of patients with DLBCL. A further analysis of positive predictive value (NPV) and negative predictive value (PPV) showed PET-4 was superior than PET-2, especially interpretated with 5-PS. The PPV and NPV of PET-4 with 5-PS criteria were 70.00% and 83.82% respectively.These data indicates that Interim 18 F-FDG PET-CT scan could predict the prognosis of DLBCL patients treated with R-CHOP regimen. And it was recommended that interim 18 F-FDG PET-CT scan be done after 4 cycles of chemotherapy, and that 5-PS criteria be applied in the interpretation of interim PET-CT scan rather than IHP criteria. DisclosuresNo relevant conflicts of interest to declare.

The Prognostic Role of Interim PET after First Chemotherapy Cycle and PET Sequential Evaluation of Response to ABVD in Hodgkin Lymphoma Patients - the Polish Lymphoma Research Group (PLRG) Observational Study

Background: Several studies confirmed the predictive role on treatment outcome of interim-PET after 2nd ABVD cycle (iPET2) in Hodgkin lymphoma (HL). We hypothesized that interim PET after 1st cycle (iPET1) might define chemosensitivity with a better accuracy than iPET-2. To test this hypothesis, PLRG launched in 2008 a prospective multicenter observational study aiming at assessing the prognostic role of iPET1 and the dynamic of sequential PET response to ABVD.Methods: Adult pts with newly diagnosed early (stage I-IIA) and advanced (stage IIB-IV) consecutively enrolled in 11 Polish centers were risk-stratified by the EORTC/GELA criteria and treated according to the ESMO guidelines: ABVD x 3-4 cycles + IFRT in early stage, ABVD x 6 ± consolidation RT in advanced stage disease. Patients were scanned with iPET1 and iPET2 and no treatment change was permitted based solely on iPET results, with the exception of clinical or radiological evidence of overt HL progression. After the first interim analysis (52 pts enrolled, 2010), which demonstrated that all the iPET1 negative patients had also a negative iPET2, the protocol was amended, limiting the iPET2 scans only to pts with iPET1 Deauville score 5,4,3. Quality control for PET-CT was supervised by the Italian-Polish core lab using a standard methodology. PET scans were interpreted locally according to the Deauville 5-point scale: Score 1 to 3, was considered a negative (-), score 4 to 5 a positive (+) scan. Subsequently all PET scans were uploaded to the web platform WIDEN® for central review and Italian-Polish expert panel (EP) scored them afresh. Discorcondant cases were discussed in a joint review session with all the five EP members. Binary and overall concordance rates were calculated using k Cohen's and alpha Krippendorf's coefficients, respectively. Negative (NPV) and positive predictive values (PPV) of iPET1 were calculated using time to progression free survival (PFS) event.Results: Between 2008 and 2014, 346 pts were registered. 35 pts were excluded from the analysis for absence/poor quality of images resulting in 108(35%) assessable pts with early and 203(65%) with advanced HL. Median age at diagnosis was 31(18-80) years. iPET1 was scored 1-3 in 87/108(81%), and 4-5 in 21/108(19%) of pts with early and in 133/203(65%), and 70/203(35%) with advanced stage, respectively. Out of 91pts with positive iPET1, 83 pts underwent iPET2, which remained (+) in 41/83(49,4%) pts. In 22 pts treatment was escalated. 11 of those pts, in whom the treatment escalation was decided solely on positive iPET were excluded from the analysis; the remaining had symptoms or CT evidence of progression. After a median follow-up of 40,2 (3,2-90,2) months 300 pts (103 "early" and 197 "advanced") were evaluable. 65(21,7%) of them (9 in early and 56 in advanced group) had a PFS event: in "early" group 9(9%) showed disease progression (4 with iPET1(-) and 5 with IPET1(+)) and 1 of them died. In advanced stage 49(25%) pts showed disease progression (16 with iPET1(-) and 33 withiPET1(+)) out of whom 13 died; 7 additional pts died without HL progression: 4 from toxicity and 3 from unrelated events. At 36 months NPV and PPV of iPET1 was 93% and 45% in "early" and 81% and 52% in "advanced" group, respectively. The dynamic of response to ABVD was assessed in 189 pts who underwent both iPETs. All 116 pts with iPET1(-) remained (-) in iPET2-(fast-responders). Out of 83pts with IPET1(+) 39 (47%) became iPET2(-)-(slow responders); the rest (34pts: 41%) remained iPET2(+)-(no responders). PFS for fast-responders @36 months was 85%, for slow-responders 80% (log rank p=0,36) and for no-responders 25% (log rank p=0,0000). The EP changed the local iPET1 score in 27 cases: in 14 from (+) to (-) in 13 from (-) to (+). The inter-observer-agreement among reviewers on evaluating a positive vs. negative interim PET scans was good, Fleiss' kappa = 0.73, comparable to that found in analogous studies (IVS, HD0607).Conclusion: iPET1 fails to better identify chemosensitivity in ABVD-treated HL compared to iPET2. PPV of iPET1 is substantially inferior to the published results for iPET2. However NPV of iPET1 is comparable to iPET2 and therefore might guide early treatment de-escalation strategies. DisclosuresZaucha:Roche: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Knopinska-Posluszny:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Teva: Other: travel, accommodation, Speakers Bureau. Walewski:Mundipharma; Roche; Takeda: Honoraria, Other: Travel expenses; Amgen; Boehringer Ingelheim; Celgene; Janssen-Cilag; Mundipharma; Roche; Takeda; Teva: Consultancy; Bayer (Inst); Bayer/Onyx (Inst); Boehringer Ingelheim (Inst); Celgene (Inst); Celltrion (Inst); Gilead Sciences (Inst); GlaxoSmithKline (Inst); GlaxoSmithKline (Inst); Mundipharma (Inst); Pfizer (Inst); Roche (Inst); Roche/Genentech (Inst); Seattle Geneti: Research Funding.

VI. FDG-PET as a biomarker in lymphoma: from qualitative to quantitative analysis.

VI. FDG-PET as a biomarker in lymphoma: from qualitative to quantitative analysis.

Prognostic value of FDG-PET prior to autologous stem cell transplantation for relapsed and refractory diffuse large B-cell lymphoma

AbstractHigh-dose chemotherapy (HDT) plus autologous stem cell transplantation (ASCT) is the standard of care for chemosensitive relapsed and refractory diffuse large B-cell lymphoma (rel/ref DLBCL). Interim restaging with functional imaging by positron emission tomography using 18F-deoxyglucose (FDG-PET) has not been established after salvage chemotherapy (ST) and before HDT-ASCT by modern criteria. Herein, we evaluated 129 patients with rel/ref DLBCL proceeding to HDT-ASCT, with ST response assessment by FDG-PET according to the contemporary Deauville 5-point scale. At 3 years, patients achieving a Deauville response of 1 to 3 to ST experienced superior progression-free survival (PFS) and overall survival (OS) rates of 77% and 86%, respectively, compared with patients achieving Deauville 4 (49% and 54%, respectively) (P < .001). No other pre-HDT-ASCT risk factors significantly impacted PFS or OS. Despite achieving remission to ST, patients with Deauville 4 should be the focus of risk-adapted investigational therapies.

Safety and Early Efficacy in an Ongoing Pilot Study of Brentuximab Vedotin and AVD Chemotherapy Followed By 30 Gray Involved-Site Radiotherapy for Newly Diagnosed, Early Stage, Unfavorable Risk Hodgkin Lymphoma

Background: Brentuximab vedotin has not been previously studied in combination with combined modality therapy for the frontline treatment of early stage Hodgkin lymphoma. We designed a pilot study to assess the safety and early efficacy of four cycles of brentuximab vedotin (BV) + AVD chemotherapy followed by 30 Gray involved-site radiotherapy (ISRT) for the treatment for early stage, unfavorable risk HL.Methods: Patients with newly diagnosed, stage I/II, classical HL with unfavorable risk profile (defined by the German Hodgkin Study Group (GHSG) with one of the following criteria: bulky mediastinal mass (≥1/3 maximum transverse thoracic diameter on PA-CXR or ≥10cm by CT imaging in transaxial plane), ESR≥50mm/h or ESR≥30mm/h in patients with “B” symptoms, extranodal involvement, or >2 involved lymph node sites) were eligible. Patients with stage IIB disease with disease bulk or extranodal involvement were included (conventionally classified as advanced stage per GHSG). Patients were treated with four cycles of brentuximab vedotin 1.2 mg/kg with AVD chemotherapy every 2 weeks followed by 30 Gray involved-site radiotherapy. The primary endpoint of the study was to evaluate the safety of this regimen, with particular attention to the development of pulmonary toxicity. A PET/CT was performed after 2 and 4 cycles of therapy. PET scans were interpreted using the Deauville 5-point scale and a negative scan was defined as Deauville 1-3.Results: Interim data for the first 19 of a planned 30 patients enrolled are presented here. Median age was 32 (range, 18-50), 47% female, 100% stage II disease, 53% with disease bulk by GHSG criteria, 53% elevated ESR, 34% B-symptoms, 37% extranodal involvement, 42% >2 involved lymph node sites. All patients with disease bulk had large anterior mediastinal masses measuring >10cm by CT in transverse plane (range, 10-16.9 cm). There were eight patients enrolled who would be considered to have advanced stage disease by the GHSG classification: 3 with IIBX, 3 with IIBE, and 2 with IIBXE disease. To date, 79% (15/19) and 63% (12/19) have completed interim PET-2 and PET-4 imaging studies, respectively. Ninety-three percent of patients (14/15) achieved a negative PET scan after 2 cycles (6, 8, and 1 patients achieved Deauville score of 2, 3, 4, respectively). All patients with disease bulk were PET-2 negative (10/10). Ninety-two percent of patients achieved a negative PET scan after 4 cycles of therapy (1, 8, 2, and 1 patients achieved Deauville score of 1,2,3,4, respectively). The patient with a positive PET-4 scan had a subsequent positive biopsy and will be treated off study for primary refractory HL. The study treatment has been well-tolerated. No pulmonary toxicity has been observed. Serious adverse events have been documented in two patients: febrile neutropenia and grade 3 hypertension. One patient discontinued protocol treatment due to the development of grade 3 peripheral neuropathy after one treatment with BV+AVD. The four patients who have completed combined modality therapy and an end-of-treatment imaging assessment achieved complete responses and no relapses have occurred to date.Conclusion: The combination of BV+AVD chemotherapy followed by ISRT appears well-tolerated with no early signal of increased pulmonary toxicity. In this interim analysis of 19 newly diagnosed patients with early stage, unfavorable risk HL, over ninety percent of the evaluable patients have achieved negative interim PET scans after 2 and 4 cycles of BV + AVD, suggesting this is a highly active treatment program even in patients with substantial disease bulk. Updated safety and response data will be presented at the meeting. DisclosuresHamlin:Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding; Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy. Horwitz:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Infinity: Research Funding; Kiowa Kirin: Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Research Funding; Amgen: Consultancy; Bristol Myers Squibb,: Consultancy; Jannsen: Consultancy. Matasar:Genentech: Consultancy; Spectrum: Consultancy. Younes:Novartis: Research Funding; J & J: Research Funding; Curis: Research Funding; Bayer; Bristol Meyer Squibb; Celgene; Incyte; Janssen R & D; Sanofi; Seattle Genetics; Takeda Millenium: Honoraria. Moskowitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Research Funding; Merck: Research Funding.

18F-fluorodeoxyglucose-positron emission tomography/computed tomography after one cycle of chemotherapy in patients with diffuse large B-cell lymphoma: results of a Nordic/US intergroup study

We evaluated the predictive value of interim positon emission tomography (I-PET) after one course of chemoimmunotherapy in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). One hundred and twelve patients with DLBCL were enrolled. All patients had PET/computed tomography (CT) scans performed after one course of chemotherapy (PET-1). I-PET scans were categorized according to International Harmonization Project criteria (IHP), Deauville 5-point scale (D 5PS) with scores 1–3 considered negative (D 5PS > 3) and D 5PS with scores 1–4 considered negative (D 5PS = 5). Ratios of tumor maximum standardized uptake value (SUVmax) to liver SUVmax were also analyzed. We found no difference in progression-free survival (PFS) between PET-negative and PET-positive patients according to IHP and D 5PS > 3. The 2-year PFS using D 5PS = 5 was 50.9% in the PET-positive group and 84.8% in the PET-negative group (p = 0.002). A tumor/liver SUVmax cut-off of 3.1 to distinguish D 5PS scores of 4 and 5 provided the best prognostic value. PET after one course of chemotherapy was not able to safely discriminate PET-positive and PET-negative patients in different prognostic groups.

PET/CT assessment in follicular lymphoma using standardized criteria: central review in the PRIMA study

We aimed to compare the standardized central review of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scans performed after induction therapy for follicular lymphoma (FL) in the PRIMA study (Salles et al., Lancet 377:42-51, 2011; Trotman et al., J Clin Oncol 29:3194-3200, 2011) to scan review at local centres. PET/CT scans were independently evaluated by two nuclear medicine physicians using the 2007 International Harmonization Project (IHP) criteria (Cheson et al., J Clin Oncol 25:579-586, 2007; Juweid et al., J Clin Oncol 25:571-578, 2007; Shankar et al., J Nucl Med 47:1059-1066, 2006) and Deauville 5-point scale (5PS) criteria (Meignan et al., Leuk Lymphoma 50:1257-1260, 2009; Meignan et al., Leuk Lymphoma 51:2171-2180, 2010; Barrington et al., Eur J Nucl Med Mol Imaging 37:1824-1833, 2010). PET/CT status was compared with prospectively recorded patient outcomes. Central evaluation was performed on 119 scans. At diagnosis, 58 of 59 were recorded as positive, with a mean maximum standardized uptake value (SUVmax) of 11.7 (range 4.6-35.6). There was no significant association between baseline SUVmax and progression-free survival (PFS). Sixty post-induction scans were interpreted using both the IHP criteria and 5PS. Post-induction PET-positive status failed to predict progression when applying the IHP criteria [p = 0.14; hazard ratio (HR) 1.9; 95 % confidence interval (CI) 0.8-4.6] or 5PS with a cut-off ≥3 (p = 0.12; HR 2.0; 95% CI 0.8-4.7). However, when applying the 5PS with a cut-off ≥4, there was a significantly inferior 42-month PFS in PET-positive patients of 25.0% (95% CI 3.7-55.8%) versus 61.4% (95% CI 45.4-74.1%) in PET-negative patients (p = 0.01; HR 3.1; 95% CI 1.2-7.8). The positive predictive value (PPV) of post-induction PET with this liver cut-off was 75%. The 42-month PFS for patients remaining PET-positive by local assessment was 31.1% (95% CI 10.2-55.0%) vs 64.6% (95% CI 47.0-77.6%) for PET-negative patients (p = 0.002; HR 3.3; 95% CI 1.5-7.4), with a PPV of 66.7%. We confirm that FDG PET/CT status when applying the 5PS with a cut-off ≥4 is strongly predictive of outcome after first-line immunochemotherapy for FL. Further efforts to refine the criteria for assessing minimal residual FDG uptake in FL should provide a reproducible platform for response assessment in future prospective studies of a PET-adapted approach.

The Role Of Qualitative FDG-PET Assessment Using The 5 Point Deauville Scale For Postinduction Response Assessment In Patients With Follicular Lymphoma. A Study From The Fondazione Italiana Linfomi (FIL)

BackgroundFDG PET/CT (PET) is commonly used in the management of patients with lymphomas and is recommended for both initial staging and response assessment after treatment in patients with diffuse large B-cell lymphoma and Hodgkin lymphoma. In follicular lymphoma (FL), PET proved to be more accurate than conventional imaging for initial staging and for restaging and a positive PET after induction treatment (piPET) has been recently confirmed as a negative prognostic factor for progression Free Survival (PFS). So far however a clear definition and standardization of how the assessment of piPET must be done is lacking. In this work we tested the 5 point Deauville scale (5PS), applied by an expert panel to piPET to determine if it could be a reliable and accurate tool to support the prognostic role of piPET in patients with FL. Patients and MethodsThis study was conducted on patients with advanced stage untreated FL enrolled in the FOLL05 randomized trial for whom pi- and baseline PET were available in DICOM format. Scans were then interpreted using visual assessment with the Deauville 5-point scale by an international expert panel (EP). Two EP readers scored piPET independently and a third one was asked to resolve the discrepancies. Binary (+ve vs –ve) and overall concordance rates were calculated using k Cohen's and Fleiss's kappa coefficients, respectively using the scores obtained on independent reading. Central review results were correlated with patients features, and with patients outcome using PFS as principal endpoint. ResultsAmong 534 patients randomized to the FOLL05 trial we could retrieve a digital PET-DICOM file in 121 patients; 31 patients were excluded for poor quality of the images with a total of 90 pts available for the central review. Median age was 54 (range 36 to 75), 80 (89%) had stage III-IV, 33.3% had high risk FLIPI (score 3-5). After review two different cutoffs were used to classify piPET as +ve or –ve. Using a cut off at 3, rate of +ve piPET was (18%) with a low Cohen's K index of 0.23. Using a cutoff at 4 +ve piPET rate was 11% but Cohen's K index improved to 0.62. Using the cut-off at 3 and at 4 concordance rate was 81%, and 94.5% respectively. When 5PS results were correlated with patients features no correlation was shown. Overall at time of current analysis and with a median follow-up of 25.9 months 56 pts (62%) were in continuous CR and 34 (38%) had progressed or relapsed. Overall Results of the 5PS were confirmed to be predictive of PFS (Log rank = 9, P<0.05). The 3-year PFS of piPET -ve and piPET +ve pts with score 3-5 as positive was 38% and 72%, respectively; PPV and NPV were 0.29 and 0.68, respectively. The 3-year PFS of piPET -ve and piPET +ve pts with score 4-5 as positive was 20% and 71%, respectively; PPV and NPV were 0.24 and 0.68, respectively. Looking at single 5PS scores the best discrimination for PFS was observed for scores 4 and 5. ConclusionsThe central review of FDG-PET scans using the 5PS confirmed that a qualitative assessment of response is feasible also for patients with FL. With the qualitative assessment of response the prognostic role of piPET had the best ratio between reproducibility and clinical informative power using a cut off at 4. These results confirm piPET-response as relevant prognostic factor for patients with FL, and warrants the adoption of the 5PS in future studies. Disclosures:No relevant conflicts of interest to declare.

Early Treatment Intensification in Advanced-Stage High-Risk Hodgkin Lymphoma (HL) Patients, with a Positive FDG-PET Scan After Two ABVD Courses – First Interim Analysis of the GITIL/FIL HD0607 Clinical Trial

AbstractAbstract 550 Background:Interim FDG-PET performed after 2 chemotherapy courses (PET-2) is the most powerful predictor of treatment outcome in advanced-stage, ABVD-treated HL (AAHL) patients (pts). Whether early therapy intensification in PET-2 positive HL pts improves overall treatment efficacy for all AAHL pts compared to standard ABVD is still unproven. Patients and study design:In the HD 0607 clinical trial (ClinicalTRial.gov identifier 00795613), AHL (stage IIB-IVB) pts prospectively enrolled by 26 Italian and one Israelian institution are treated with 2 ABVD courses and a PET-2 performed afterwards. PET-2+ pts are randomized to either BEACOPP escalated (Be) plus BEACOPP baseline (Bb) (4+4 courses) or Be+Bb (4+4) and Rituximab (R). PET-2 negative pts are treated with 4 additional ABVD and, upon CR achievement, randomized to either consolidation radiotherapy (Rxt) on the sites of initial bulky disease or no further treatment. Primary endpoint is the efficacy and feasibility of the overall therapeutic strategy. All the non-negative PET-2 (nnPET-2), defined as scans without any residual FDG uptake in any site outside the physiological areas of the tracer concentration, are uploaded in a website for blinded independent central review (BICR) by 6 nuclear medicine experts. Scans are interpreted by visual assessment according to the Deauville 5-point scale (5PS). Results:Starting from 07/2008 till 07/2012, 497 AHL pts were consecutively enrolled and 446 scanned with PET-2. 189/446 (42%) PET-2scans, judged as nnPET-2 by the local PET center, underwent review: 92 were adjudged as positive (62 score 4, 30 score 5) and 97 as negative (score 1–3). Altogether, of 446 pts scanned with a PET-2, 92 (20%) resulted positive and 354 (80%) negative. Age, sex, stage III-IV, bulky, extranodal sites or IPS class where equally distributed among PET-2 positive and negative pts.(p>.05). The median time from PET uploading in the website to review was 45.38 hours, (1–119). The BICR yielded a binary concordance rate among pair of reviewers “very good”, ranging from 0.77 to 0.83 (Cohen’s k coefficient) and a overall concordance rate of 0.77 (Krippendorf’s alpha). In 92 PET-2+ pts, 60 showed a single site of residual uptake in mediastinal (48), laterocervical (4), supraclavear (2), abdominal (3), axillary (1) nodes and in lung (2).In 32 there were ≥ 2 sites of persistent FDG uptake. In 38/40 pts with a positive PET-2 and bulky disease at baseline the residual FDG uptake (singe or multifocal) was seen within the bulky lesion. Overall response to treatment could be assessed in a cohort of 263 pts who had been fully restaged after lymphoma treatment. Forty-one (15%) had a positive and 222 (84%) a negative PET-2 scan. The relative dose intensity (RDI) for Be+Bb ± R and ABVD ± RxT treated pts. was 94.7% and 97.8%, respectively. Among 41 PET-2+ pts CR was achieved in 30 (73%), PR in 1 (2%) Progression or Relapse (Pro/Rel) in 8 (19%) and not evaluable (NE) in 2(5%). Among 222 PET-2- pts. CR was achieved in 212 (95.5%), PR in 2 (1%), Pro/Rel in 6 (3%), NE in 1 (0,5%). Treatment efficacy could be assessed in a cohort of 187 pts. with a complete treatment and a minimum follow-up of 12 months from treatment completion: 27 (15%) with a positive PET-2, treated with Be+Bb ± R and 160 (85%) with a negative PET-2, treated with ABVD ± RxT. The median follow-up from diagnosis was 845 days (101–1345). Among 27 PET-2+ pts, CCR (Continuous CR) was recorded in 22 (81%) Pro/Rel in 5 (18%). Three patients died in CR: 2 for septic shock and one for pneumonia. Among 160 PET-2- pts. CCR was recorded in 146 (91%), Pro/Rel in 9 (5%), Lost of FU (in CR) in 5 (3%). The 1-y PFS was 80.5%, 97.3% and 94.7% for PET-2+, PET-2- p, and for the entire population, respectively. Overall, treatment was well tolerated: 512 Adverse effects were reported: WHO grade 0+1: 453, grade 2: 45. Grade 3 were observed in 12 pts: anemia (2), neutropenia (6), pancytopenia (1), sepsis (1), diverticulitis (1), Vomiting (1). Grade 4 in 2 pts: pneumonia and neutropenia. Conclusions:These preliminary findings suggest that 1) an early switch from ABVD to escalated BEACOPP can be done safely in PET-2 positive pts, with CR achievement in the majority of cases; 2) a centralized online PET scan review system is feasible and allows a real time decision making process, without significant reduction in the RDI administered; 3) 5PS is a reliable interpretation criteria for interim PET scan, with a very good concordance rate among reviewers. Disclosures:No relevant conflicts of interest to declare.