ALBERT

Description: Key Points DS4 is recommended as the cutoff value for PET-2 positivity after 2 cycles eBEACOPP for advanced-stage HL.

Description: Background: Patients with MYC rearrangement positive large B cell lymphoma other than Burkitt lymphoma (MYC+ LBCL), have a dismal prognosis following standard first line therapy with R-CHOP. Retrospective studies report complete remission rates 〈 50% and 2-year overall survival (OS) of approximately 35%. Lenalidomide is an immunomodulatory drug and is able to down-regulate MYC and its target genes and proteins in B cells that harbor a MYC rearrangement. We report data of a prospective phase II study evaluating the efficacy of lenalidomide in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients. Methods: A national screening program for MYC rearrangement by fluorescence in situ hybridization (FISH) was performed in newly diagnosed LBCL patients. Patients with a proven MYC rearrangement, ≥ 18 year, Ann Arbor stage II-IV, were offered participation in a single arm phase II study. Treatment consisted of 6 cycles R-CHOP21 plus lenalidomide 15 mg on day 1-14, followed by two additional rituximab administrations. Use of G-CSF was mandatory. All patients received intrathecal methotrexate prophylaxis. 18F-FDG PET-CT (PET-CT) scans were performed at baseline, midterm (after 3 cycles) and end-of-treatment (EOT). Diagnostic lymphoma samples were centrally reviewed including immunohistochemical (IHC) work-up and complementary BCL2 and BCL6 FISH analysis. Cell of origin classification was determined by IHC (Hans) and by gene expression profiling (Lymph2Cx). The primary endpoint was complete metabolic response rate (CMR) on EOT PET-CT scan, according to the Deauville criteria and assessed by 2 independent nuclear medicine physicians performing central review. In case of discordance, a third adjudicator reviewed. Confirmation of bone marrow (BM) negativity at EOT for patients with positive BM at diagnosis was not required for CMR. Secondary endpoints included disease free survival (DFS), progression free survival (PFS), OS and predictive value of midterm PET-CT for EOT PET-CT scan. Data cut-off was July 4th 2018. Results: From April 2015 to February 2018, 85 patients were included at 20 hospitals. Planned interim analysis (after 26 consecutive patients completed treatment) revealed no safety concerns. At data cut-off, central data management, pathology and imaging review processes were completed for the first 60 patients. The remaining patients (60 to 85) are still on treatment or have recently finished treatment. Among the first 60 patients, 2 were declared ineligible, leaving 58 patients for this analysis (demographics and disease characteristics in table 1). Central pathology review confirmed diagnosis of MYC+ LBCL in all patients. Additional FISH analysis revealed that 41/58 patients (71%) had MYC and BCL2 and/or BCL6 rearrangements (double hit or triple hit), 11/58 (19%) had a single MYC rearrangement, 6/58 (10%) had a MYC rearrangement but no information on BCL2 and BCL6. At EOT PET-CT scan (primary endpoint), 36/58 patients (62%) were in CMR (95% confidence interval (CI) 50%-71%). 2/58 patients (3%) reached a partial metabolic response (PMR), and 20/58 patients (34%) had progressive disease (PD). At midterm PET-CT, 39/58 patients (67%) were in CMR; of these 29 were still in CMR and 10 showed PD at EOT PET-CT. 18/58 patients (31%) were in PMR at midterm; 7 of them converted to CMR, 2 remained in PMR, 9 showed PD at EOT. One patient went off protocol after two cycles due to progression. With a median follow-up of 17.2 months, 1-year estimates for OS were 79% (CI 66%-88%), for DFS 74% (CI 59%-85%), and for PFS 60% (CI 47%-72%). Grade 3 and 4 adverse events (AE) were seen in 26 (43%) respectively 9 patients (15%). Most common grade 3-4 AEs were gastrointestinal disorders, infections, and neutropenia. 55 serious AEs were reported in 27 patients (all hospitalization). 1 patient went off protocol due to grade 3 diarrhea. Univariate regression analyses revealed no significant prognostic factors for achieving CMR or prolonged survival yet. Conclusion: These data represent the first prospective trial worldwide for newly diagnosed MYC rearrangement positive LBCL patients. Treatment with R2CHOP demonstrates acceptable toxicity and promising efficacy with 62% CMR on centrally reviewed PET-CT scan and a 1-year OS rate of 79%. In December 2018, all 85 registered patients will have finished treatment and complete analysis of the primary endpoint and additional biological studies will be available. Disclosures Chamuleau: Gilead: Research Funding; celgene: Research Funding; Genmab: Research Funding; BMS: Research Funding. Mous:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; JANSSEN CILAG: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; sandoz: Membership on an entity's Board of Directors or advisory committees. Lugtenburg:takeda: Consultancy, Research Funding; servier: Consultancy, Research Funding; roche: Consultancy; BMS: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; GenMab: Research Funding. Kersten:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; roche: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Introduction Baseline metabolic tumor volume (bMTV) is increasingly studied as a prognostic factor for classical Hodgkin lymphoma (cHL). Before implementation as a clinical prognostic marker, it is important to investigate different methods for deriving bMTV since not all methods are suitable for each type of malignancy. Semi-automatic segmentation is influenced less by observer bias and variability compared to manual segmentation and might therefore be more reliable for assessing bMTV. However, not much is known about the use of different semi-automatic segmentation methods and how this influences the prognostic value of bMTV in cHL. Here we present a comparison of bMTV derived with 6 semi-automatic segmentation methods. In addition, a visual quality scoring of all segmentations is performed to gain insight into which segmentation methods could be used to determine bMTV in cHL. Methods We selected 61 baseline 18FDG-PET-CT scans that met specific quality criteria (http://EARL.EANM.org) from patients treated in the Transplant BRaVE study for relapsed/refractory cHL [Blood 2018 132:2923]. Six semi-automatic segmentation methods were applied using the Accurate tool, an in-house developed software application which has already been validated in other types of cancer, including diffuse large B-cell lymphoma [Eur Radiol 2019 06178:9, J Nucl Med. 2018;59(suppl 1):1753]. We compared two fixed thresholds (SUV4.0 and SUV2.5), two relative thresholds (A50P: a contrast corrected 50% of standard uptake value (SUV) peak, and 41max: 41% of SUVmax), and 2 majority vote methods, MV2 and MV3 selecting delineations of ≥2 and ≥3 of previously mentioned methods, respectively. Quality of the segmentation was scored using visual quality scores (QS) by two reviewers (JD, GZ): QS-1 for complete selections containing all visible tumor localizations; QS-2 when segmentations 'flood' into regions with physiological FDG uptake; QS-3 when segmentations do not select all visible lesions; or QS-4: a combination of QS-2 and QS-3. In addition, the quality of the delineation was rated: QS-A for good visual delineation of lesions; QS-B for too small delineation; and QS-C for too large delineation. All segmentations that had score QS-2 or QS-4 were manually adapted by erasing regions that flooded into areas with high physiological uptake. Figure 1 shows examples of the quality scores. We used Spearman's correlations to compare the bMTV of all semi-automatic methods. Comparison of quality scores was performed using chi-square tests. Results The median bMTV differed substantially among the segmentation methods, ranging from 24 mL for SUV4.0 to 88 mL for 41max (Table 1). However, there was a high significant correlation (p

Description: Introduction Diffuse large B-Cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL). Up to one third of patients relapse or fail to achieve complete remission, with poor prognosis. and low response rates to salvage treatments. Early identification of patients unlikely to be cured with R-CHOP might improve their chance of cure and quality of life. Interim [18F]FDG PET (I-PET) measures the pattern of response during treatment, which might add important prognostic value. These measures could be used for I-PET guided treatment for both patients with a good response and patients with a poor response. At this moment it is unclear what the influence of timing and PET positivity criteria is on the prognostic value of I-PET. Therefore, the aim of this individual patient data (IPD) meta-analysis was to determine the optimal timing and optimal PET positivity criteria for I-PET to predict response in DLBCL patients. Methods Individual patient data from 1977 de novo DLBCL patients were obtained from the PETRA database (www.petralymphoma.org). These patients had been enrolled in 9 clinical studies and treated with R-CHOP14, R-CHOP21 or DA-EPOCH-R. All patients had an I-PET following one to four cycles of therapy. Progression free survival (PFS) was the primary endpoint. We used the Deauville score (DS) as a visual assessment of the I-PET with two different cut-offs for PET-positivity: DS 4-5 positive and DS 5 positive. Relative reductions (Δ) of Standardized Uptake Values (SUV) were used for semi-quantitative scoring of I-PET. A cut-off of 66% reduction was used for I-PET scans after 1,2 or 3 cycles and a cut-off of 70% was used for I-PET after 4 cycles. DS were available for 1828 patients and ΔSUV data for 1632 patients. Multilevel Cox proportional hazards models were used to study the effects of timing and PET positivity criteria on 2-year PFS, with I-PET after 2 cycles as reference. Results After correction for Ann Arbor stage and age, there were no significant differences in PFS between the 9 studies. I-PET1 was not able to significantly discriminate between responders and non-responders. I-PET2 and I-PET4 were able to significantly discriminate responders and non-responders, with higher hazard ratios (HR) for I-PET4. HR were 1.65 and 2.36 for DS4-5 positive, 3.69 and 5.28 for DS5 positive and 2.36 and 3.67 for ΔSUV criteria for I-PET2 and I-PET4 respectively. I-PET3 was able to significantly discriminate responders and non-responders only for DS5 positive criteria (HR: 7.92) (Table 1). However, there were few patients with I-PET1 and I-PET3 scans. Regarding I-PET negative patients, there were no significant differences in PFS using any of the response criteria at the 4 timepoints assessed. Regarding I-PET positive patients, there was a significantly lower PFS at I-PET4 than at I-PET2 , using the DS4-5 positive criteria (p = 0.009, HR = 1.52 (95% BI 1.11 - 2.09)) and ΔSUV criteria (p = 0.05, HR = 1.68 (95%BI 1.00-2.82)) but no other significant differences using other criteria or timepoints (Table 2). Conclusions I-PET is able to significantly discriminate between responding and non-responding patients after 2, 3 or 4 cycles of chemotherapy. The optimal timing to identify responders is after 2 cycles, as there is no significant increase in survival at later times, regardless of PET criteria. As the PFS of I-PET4 positive patients is significantly lower than that of I-PET2 patients, I-PET4 might be the optimal timing to identify non-responders. We suggest to perform an I-PET4 scan to identify poor-responding patients. The worst prognostic subgroup is best identified using the DS 5 positive or ΔSUV criteria. Based on these data, I-PET could be used to design response adapted trials for patients with good and poor responses respectively. Disclosures Barrington: Roche: Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding; Amgen: Research Funding; Bristol Myers Squibb: Research Funding; Takeda: Honoraria, Speakers Bureau. Dührsen:Alexion: Honoraria; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria; Teva: Honoraria; CPT: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Research Funding. Hüttmann:University Hospital Essen: Employment; Takeda: Honoraria; Gilead: Honoraria. Zucca:Janssen: Research Funding; AstraZenaca: Research Funding; Kite, A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celltrion Helathcare: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Abbvie: Other: Travel Grant. Higley:FNIH: Research Funding; CCS associates: Employment; NCIS/Leidos: Research Funding. Hutchings:Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Lugtenburg:Celgene: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Janssen Cilag: Honoraria; Servier: Consultancy, Honoraria, Research Funding; BMS: Consultancy; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding. Zijlstra:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria.

Description: In aggressive B-cell NHL, determination of early response to induction therapy by FDG-PET may improve risk stratification. In a multicenter prospective trial in patients with aggressive NHL (stage II–IV) treated with 2 or 3 weekly (R)CHOP chemotherapy, FDG-PET was performed after the third cycle of chemotherapy. Both clinicians and nuclear medicine physicians were blinded for PET and clinical outcome, respectively. Clinical decisions were based on conventional diagnostic methods (CDM) only. In total 114 patients were included of which 95 were evaluable. 19 patients were excluded because of patient refusal (n=7), early progression (n=7) or logistical reasons (n=5). Median age was 55 yrs (range 20–82), 72% had DLBC-NHL, 76% IPI

Description: Abstract 3658 Introduction Patients (pts) with transformed NHL have an extremely poor prognosis. However when diagnosed at an early stage outcome may be better, making early diagnosis crucial. Nowadays, transformation is diagnosed using biopsy of a lymph node when it starts growing rapidly or when the patient develops B symptoms or hypercalcemia. These pts often have advanced disease and diagnosis may be delayed because the lymph node biopsied is not representative. Positron emission tomography (PET) might be of value here: the commonly used tracer 18F-fluorodeoxyclucose (FDG)-PET can distinguish between indolent and aggressive lymphoma, but with considerable overlap in Standard Uptake Values (SUV). However, 18F-fluorothymidine (FLT) is thought to more directly reflect proliferation. We performed a head-to-head comparison of FDG and FLT PET in pts with indolent and transformed lymphoma to explore which tracer qualifies best for future research in timely diagnosis of transformation. Materials and methods Pts were selected based on histology: either follicular lymphoma or transformed lymphoma (defined as diffuse large B cell lymphoma diagnosed in a patient with former or simultaneous diagnosis of follicular lymphoma in a lymph node).In each patient two PET scans were made, one with FDG and one with FLT, maximum one week apart, before any treatment.Scans were made on the Philips Gemini TF PET-CT camera, 1 hour after injection of 185 MBq of FDG or FLT.Uptake (we present data as SUVmax normalized to body weight) was measured in all lymph nodes ≥ 2 cm (minimizing partial volume effects). Results 17 pts with indolent lymphoma and 10 with transformed lymphoma were included. Median age was 59 years (range 35–81) and a median of 9 lymph nodes were measured per patient (range 2–23). Between patients, SUVmax in the lymph node with the highest uptake for both FDG (p=0.01) as well as FLT (p=0.04) uptake was significantly higher in transformed lymphoma. For FDG values ranged from 4,9 to 19,6 in indolent and from 9,6 to 29,9 in transformed lymphoma, for FLT values were respectively 3,6 to 16,6 and 5,45 to 16,3. Accordingly, between patients, we found considerable overlap between highest values for indolent and transformed lymphoma with either tracer, making the determination of a cut off level for transformation difficult. The data suggest that, at least for FDG, the range between the lymph node with the highest and the lowest uptake within one patient was the best criterium to identify the transformed lymphomas, with significantly higher ranges for transformed lymphoma (p

Description: Despite the increasing number of publications concerning 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) for post-treatment evaluation of lymphoma and the increasing availability of this novel diagnostic modality, its exact role in response assessment after therapy is still unknown. The aim of this study was to systematically review the literature regarding the diagnostic performance of dedicated FDG-PET in evaluation of first line therapy of Hodgkin’s disease and (aggressive) non-Hodgkin’s lymphoma, and to calculate summary estimates of its sensitivity and specificity. The databases of PubMed and Embase were searched for relevant studies, up to January 2004. Criteria for inclusion of studies were 1) histologically proven Hodgkin’s disease (HD) or aggressive non-Hodgkin’s lymphoma (NHL), 2) evaluation of post-treatment patients following first line therapy, 3) the use of dedicated (ring) PET using 18FDG, and 4) study population of at least ten patients. Two reviewers independently assessed the methodological quality of each study. As a valid reference test, histology or follow-up of at least 12 months were accepted. A meta-analysis of the reported sensitivity, specificity, and positive Likelihood Ratio (LR+) and negative Likelihood Ratio (LR−) of each study were performed. Fifteen studies, involving 705 patients, met the inclusion criteria. The studies had several design deficiencies. The majority of studies did not describe whether the reference test was interpreted without knowledge of the FDG-PET findings. Furthermore, in only two studies, patients entered the study consecutively. In all studies, there was a description of the spectrum of patients included, i.e. all patients for post-treatment evaluation or only patients with substantial residual masses post-treatment. Pooled sensitivity, specificity, LR+ and LR- for detection of residual disease in Hodgkin’s lymphoma were 84% (95% CI 71–92%), 90% (95% CI 84–94%), 5.5 (95% CI 3.4–8.7) and 0.25 (95% CI 0.1–0.55), respectively. For non-Hodgkin’s lymphoma, pooled sensitivity, specificity, LR+ and LR− were 72% (95% CI 61–82%), 100% (95% CI 97–100%), 36 (95% CI 11–125) and 0.30 (95% CI 0.21–0.42), respectively. In conclusion, FDG-PET showed reasonable sensitivity and high specificity for evaluation of first line therapy in Hodgkin’s and in non-Hodgkin’s lymphoma.