ALBERT

Description: Abstract 877 Introduction: Patients with follicular lymphoma (FL) usually respond well to immuno-chemotherapy as initial treatment and can have long survival times. However, a small proportion of patients are refractory or have early relapses. Early identification of this subgroup of patients could lead to early therapeutic changes and, potentially, to a better prognosis. [18F]Fluorodeoxyglucose-Positron Emission Tomography (FDG-TEP) is widely used for the staging and restaging of aggressive lymphoma patients but little is known about the use of FDG-PET in patients with FL, except that FL is almost uniformly FDG-avid. FDG-PET is not recommended today as a routine procedure in FL patients (Cheson et al. J Clin Oncol 2007). In this first prospective, multicentric study, we evaluated the prognostic value of FDG-PET performed at mid-treatment and at the end of treatment in patients with high-tumor mass FL treated with immuno-chemotherapy in first line. Patients & methods: Patients with previously untreated FL (grades 1–3A) presenting with a high tumor burden as defined by the GELF criteria, were treated with 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus 2 cycles of rituximab, given every 21 days. Patients did not receive rituximab maintenance. A FDG-PET was performed before treatment, after 4 cycles of R-CHOP (interim FDG-PET: I-PET), and at the end of treatment (final PET: F-PET). FDG-PET scans were first interpreted in each centre, then centrally reviewed by 3 investigators blinded to clinical data. Positivity or negativity was rated according to the Deauville visual semi-quantitative criteria (Meignan M: Leuk Lymphoma 2009), positivity being defined as a fixation at level 4 (FDG uptake superior to that of the liver) or 5 (uptake clearly superior to liver and/or new sites of disease). Results: 121 patients were included. The median age was 57 years and the male-to-female ratio was 1.12. Ninety-three percent had Ann Arbor stage III–IV. Ninety-seven percent had a good performance status (ECOG score 0–1). The repartition according to the FLIPI was: 0–1 factors: 15%; 2 factors: 43%; 3–5 factors: 42%. The Kappa coefficient indicated a good degree of concordance between the 3 PET reviewers. The initial FDG-TEP was positive in all except 1 case out of 118 centrally reviewed cases. After central review, I-PET (n=111) was negative in 76% of patients and F-PET (n=106) was negative in 78%. With a median follow-up of 23 months, 2-year-progression-free survival rates for I-PET negative versus positive and for F-PET negative versus positive were I-PET 86% versus 61% (p=0.0046); F-PET 87% versus 51% (p

Description: Abstract 1598 Tumor bulk assessed by maximum tumor diameter was previously found to influence the outcome of young patients with low risk (aaIPI 0–1) DLBCL (Pfreundschuh et al Lancet Oncol, 2011; 12: 1013), but the prognostic impact of bulk and more generally tumor volume in high-risk DLBCL remains to be explored. Conversely, maximum SUV reduction calculated between baseline PET and PET performed after 4 cycles of immunochemotherapy (ΔSUVmax0–4) was recently shown to predict outcome in this population (Casasnovas et al Blood 2011; 118: 37). In this study, we assessed the metabolic tumor volume (MTV) and the tumor bulk at baseline in 121 patients 10 cm assessed on CT scan was considered as bulky. Median follow-up was 28 months. Median baseline MTV was 303 cc (17–1488). Baseline MTV (≥625 cc vs 10 cm was not predictive of outcome. As previously published ΔSUVmax0–4 (〉 70% vs ≤70%) found to predict 2y-PFS (88% vs 40%; p

Description: Impact of 18 F-fluoro-deoxyglucose positron emission tomography (PET) imaging has become increasingly important in recent years in the management of patients with malignant lymphomas and is recommended for the staging and response to treatment assessment of both diffuse large B-cell and Hodgkin's lymphoma. Few data on the relevance of PET in the management of patients with mantle cell lymphoma (MCL) are available so far. Then, we retrospectively investigated the PET value for initial staging, interim response and predicting outcome in patients with MCL treated in two French institutions (Dijon University Hospital and the Centre Leon Berard, Lyon). From 2004 to 2013, a total of 61 de novo MCL patients assessed by PET were included. For each patient, were collected at baseline, the whole body SUVmax site, the presence of a bone marrow (BM) uptake, total metabolic tumour volume (TMTV) and total tumour glycolysis (TLG). The interim PET response after 3 or 4 cycles of induction treatment was assessed using the Deauville score and the quantitative variation of SUV between the baseline PET and the PET performed after 4 cycles of immunochemotherapy (ΔSUV). Patient's median age was 64 years [38 - 84]. At diagnosis, 92% presented a disseminated disease (stage III-IV). Mean MCL International Prognostic Index (MIPI) was 6.09 [5.89 - 6.29]. All patients received a first-line induction treatment. Twenty-eight (46%) received an autologous stem cell transplantation as consolidation treatment and 10 (16%) a rituximab maintenance. The baseline FDG uptake intensity was low (median SUVmax: 6.93 [2.5 - 25]) leading to consider that baseline PET was informative and suitable for a further PET reassessment in 40 (93%) patients. 72% of the patients with an informative baseline PET, had a SUVmax 〈 10 making the metabolic quantitative analyses (TMTV, TLG, ΔSUV) uninformative. Among the 46 (75%) patients with histologically proven BM involvement, only 14% of them had BM FDG uptake. After 3 to 4 cycles of induction treatment, 27 (75%) patients achieved a negative PET. With a median follow up of 27 months, a shorter PFS was related to a disseminated disease (stage III-IV) on the basis of baseline PET (2y-PFS: 47% vs 80% p = 0.03) and an insufficient interim metabolic response according to the Deauville score (score ≥ 4) (16% vs 64% p=6 (p = 0.04, HR = 7.1 IC 95% [1.1 - 46]) retained an independent negative impact on PFS. FDG avidity of LCM is usually low. PET underestimates BM involvement at diagnosis in 86 % of patients, compared with cytological and histological techniques, and has no independent prognostic value. The interim metabolic response assessed using the Deauville criteria is a prognosis factor independent from MIPI in patients with MCL. Disclosures Salles: Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau. Casasnovas:Gilead: Consultancy; Takeda: Consultancy; Roche: Consultancy, Research Funding.

Description: The prognostic value of interim positron emission tomography (PET) interpreted according to visual criteria is a matter of debate in diffuse large B-cell lymphoma (DLBCL). Maximal standardized uptake value reduction (ΔSUVmax) may better predict outcome. To compare the prognostic value of both methods, we analyzed PET done at baseline (PET0) and after 2 (PET2) and 4 (PET4) cycles in 85 patients with high-risk DLBCL enrolled on a prospective multicenter trial. All images were centrally reviewed and interpreted visually according to the International Harmonization Project criteria and by computing ΔSUVmax between PET0 and PET2 (ΔSUVmaxPET0-2) or PET4 (ΔSUVmaxPET0-4). Optimal cutoff to predict progression or death was 66% for ΔSUVmaxPET0-2 and 70% for ΔSUVmaxPET0-4. Outcomes did not differ significantly whether PET2 and PET4 were visually positive or negative. Inversely, ΔSUVmaxPET0-2 analysis (〉 66% vs ≤ 66%) identified patients with significantly different 2-year progression-free survival (77% vs 57%; P = .0282) and overall survival (93% vs 60%; P 〈 .0001). ΔSUVmaxPET0-4 analysis (〉 70% vs ≤ 70%) seemed even more predictive for 2-year progression-free survival (83 vs 40%; P 〈 .0001) and overall survival (94% vs 50%; P 〈 .0001). ΔSUVmax analysis of sequential interim PET is feasible for high-risk DLBCL and better predicts outcome than visual analysis. The trial was registered at http://clinicaltrials.gov as NCT00498043.

Description: Abstract 2931 Poster Board II-907 Introduction: PET assessment of early response allows to predict outcome of patients with DLBCL, but the more accurate criteria for early PET interpretation remain to be define. So we evaluated the prognostic value of PET after two cycles of immuno-chemotherapy and compared a semiquantitative approach using FDG uptake reduction, with two methods of visual analysis. Patients and methods: Forty five consecutive patients with newly diagnosed DLBCL treated in a single institution with rituximab and CHOP or CHOP-like regimen underwent 18F-FDG PET at baseline (PET0) and after 2 cycles of induction treatment (PET2). Images were interpreted visually according to two separate methods: - Juweid criteria (JCO 2007; 25: 571) (visual analysis-1) – A visual comparison of the FDG uptake between the residual mass and the normal hepatic tissue, a PET being considered as positive when the uptake of at least one residual mass was found greater than the liver (visual analysis-2). The quantitative approach was based on the lymphoma FDG uptake estimated by the maximal standardized uptake value (SUVmax) corrected to body weight. The SUV reduction between PET0 and PET2 (ΔSUVmax) was calculated for each patient. The ΔSUVmax cut-off was estimated to 65% by ROC analysis. Results: Patient median age was 50 years (range, 24 – 79) and 37 patients (73%) were younger than 61 years. The age-adjusted IPI score was, 2 or 3, 1 and 0 in 26 (49%), 16 (36%) and 7 (16%) patients respectively. With a median follow-up of 25 months, 6 (13%) out of 45 patients progressed or relapsed after treatment and 4 died from progressive disease. According to the visual analysis-1, PET2 was interpreted as negative in 16 (36%) patients and positive in the 29 remaining patients. Using the visual analysis-2, PET2 was negative in 25 cases (56%) and positive in 20 cases. The quantitative analysis showed a ΔSUVmax 〈 65% in 9 patients and a ΔSUVmax 〉= 65% in 36 patients (80%). The estimated efficiency of the three methods to predict patient outcome is detailed below: The probability of 2-years progression-free survival (PFS) for patients with a negative PET2 according to the visual analysis was slightly higher than those with a positive PET2 when using as well the Juweid criteria (93% vs 83%; p = 0.3), as the visual analysis-2 (95% vs 75%: p = 0.04). However, the quantitative aproach allows to better identify and split up the population of patients with a good outcome from those with a poor outcome, since the 2-years PFS was 56% in patients with a ΔSUVmax reduction less than 65% compared to a 94% 2-years PFS probability in patients with a ΔSUVmax higher than 65% (p=0.0009). A multivariate analysis was performed including the IPI score and the ΔSUVmax reduction as explanatory variables for PFS, showing that the PET2 result assessed by the ΔSUVmax reduction remains the only independant prognosis factor for PFS (p = 0.008; RR = 10). Conclusion: SUV-based assessment of PET after two courses of immuno-chemotherapy is more reliable to patient outcome than visual analysis. The SUVmax reduction is an early prognostic factor for DLBCL patients that may help to reduce false positive interpretations, and provides a useful tool to guide risk-adapted treatment. Disclosures: No relevant conflicts of interest to declare.

Description: BACKGROUND Escalated BEACOPP (BEAesc) demonstrated a better disease control than ABVD but no overall survival (OS) improvement in patients with advanced Hodgkin Lymphoma (HL) (Federico et al , J Clin Oncol 2009, Viviani et al, N Engl J Med 2011, Mounier et al, Ann Oncol 2014). The superior efficiency of BEAesc is associated to a substantially higher immediate hematological toxicity, and an increased risk of secondary myelodysplasia/leukemia and infertility. So, to better manage HL treatment there is a need to identify early responding patients able to benefit from a strategy of dose intensity de-escalation after upfront BEAesc, without impairing the disease control. PET performed after 2 cycles of chemotherapy (PET2) might identify such a population suitable for receiving ABVD after 2 cycles of upfront BEAesc, and was implemented in the present study. METHODS The AHL 2011 trial (NCT01358747) was designed to evaluate in 16 to 60 years old HL patients with Ann Arbor stage III, IV or high risk IIB, a treatment strategy driven by PET after 2 BEAesc cycles (PET2), delivering 4 cycles of ABVD for PET2 negative patients and 4 cycles of BEAesc for PET2 positive patients. This PET-driven strategy was randomly compared to a standard treatment not monitored by PET and delivering 6 cycles of BEAesc. A baseline PET was mandatory before treatment and PET2 were centrally reviewed and interpreted according to Deauville criteria within 48 hours. The allocation of treatment in the experimental arm was based on the PET2 central review results. PFS was the primary endpoint of the study with a hypothesis of non-inferiority of the PET driven arm compared to the standard arm with a margin of 10% (85% 5y-PFS in the standard arm vs 〉75% in the PET driven arm). An interim analysis of the primary endpoint was planned after 50% (n = 49) of the 97 scheduled events needed for the final analysis. RESULTS From May 2011 to May 2014, 823 patients were registered and 782 were eligible for the interim analysis including 401 patients in the arm A, and 381 in arm B. Patients characteristics were well balanced in both arms: median age was 30 years (16 - 60), 64% were male, 81% had nodular sclerosis and 12% mixed cellularity HL, 12% had stage IIB, 28% stage III, 60% stage IV, and 58% had an international prognosis score ≥3. After 2 cycles of BEAesc PET was positive in 97 (12%) patients and PET2 positivity was similar in the standard and experimental arms (n = 48, 12% and n = 49, 13% respectively). Based on PET2 results, 319 (84%) patients received 4 cycles of ABVD and 49 (13%) 4 additional cycles of BEAesc in the experimental arm. Grade ≥3 toxicity was significantly higher in patients receiving 6 cycles of BEAesc compared to those who received 2 cycles of BEAesc + 4 cycles of ABVD with more frequent anemia (11% vs 2%), leukopenia (85% vs 72%), thrombocytopenia (44% vs 13%), febrile neutropenia (6% vs 3%), and sepsis (7% vs 4%). 182 serious adverse events (SAE) related to treatment occurred in 108 (24%) patients treated with 6 cycles of BEAesc (leading to death in 4 cases), compared to 72 SAE (leading to death in 1 case) in 50 (15%) patients treated with 2 x BEAesc + 4 x ABVD (p

Description: Abstract 3630 Positron emission tomography with [18F]fluorodeoxyglucose (PET) performed after two cycles of chemotherapy could predict treatment outcome in Hodgkin lymphoma (HL) (Gallamini et al J.Clin.Oncol. 2007; 25: 3746), but suitable criteria to interpret interim PET remain to be established. A standardized visual analysis using a 5-point scale (5PS) was proposed to assess interim PET response and an international validation study is currently on going. However, standardized uptake value (SUV) may improve interim PET accuracy, and maximum SUV reduction (ΔSUVmax) between baseline and interim PET was shown to be superior to visual analysis in patients with diffuse large B cell lymphoma (Casasnovas et al, Blood 2011; 118: 37). To compare the clinical usefulness of both methods in patients with HL, we analysed interim PET according to visual and SUV criteria in a retrospective single centre study. From January 2007 to January 2010, 59 consecutive patients with a first diagnosis ofHL were treated in our institution. All patients received 4 to 8 cycles of chemotherapy including ABVD in 50 cases (85%) and BEACOPP in 9 cases. Radiotherapy was performed in 14 responding patients with localized disease. PET was done at baseline (PET0) and after 2 cycles of chemotherapy (PET2) and therapeutic strategy was not modified according to PET2 result. All PET scans were reviewed by SK, ABR and IDC, and interpreted using the 5PS criteria, PET being considered positive when the 5PS score was 4 or 5. SUVmax reduction values between PET0 and PET2 (ΔSUVmaxPET0–2) were available for all patients, and after using the receiver operating characteristics approach, patients with a ΔSUVmaxPET0–2 〉71% were considered as good responders after 2 cycles. Progression-free survival (PFS) and freedom from treatment failure (FFTF) were analyzed according to PET results based on 5PS and ΔSUVmaxcriteria. Median follow-up was 39 months (range: 6–62). Using visual analysis,46 (78%) patients achieved a negative PET2. Seven of them experienced a treatment failure, leading to a PET2 negative predictive value (NPV) of 85%. Fourty nine (83%) patients had a ΔSUVmaxPET0–2 〉71% and 6 of them failed to treatment (NPV = 88%). By contrast PET2 positive predictive value (PPV) was significantly better for ΔSUVmax analysis (70%) compared to visual analysis (46%). Using ΔSUVmax analysis, 6 (46%) of the 13 PET2 positive patients could be reclassified as good responder after 2 cycles of chemotherapy. While visual PET2 positivity was associated to a lower 3-year PFS (45%) or FFTF (51%) compared to PET2 negativity (3-year PFS=80%, p=0.001 and 3-year FFTF= 82%, p71% vs≤71%) was more accurate to identify patients with significantly different 3-year PFS (81% vs 30%; p

Description: Although progression free survival and overall survival of patients with Hodgkin lymphoma (HL) has improved with modern treatment in the past 10 years, 10 % of patients will fail to conventional therapy and die of their lymphoma. The search of new prognostic factors for identifying these high risk patients at diagnosis of HL remains challenging in daily practice. The evaluation of the tumor microenvironnement was shown to help identifying a subset of patients treated with ABVD having a high risk of treatment failure (Tan KL et al, Blood 2012). PET positivity after 2 cycles of chemotherapy allows also identifying a subset of patients with poor outcome (Gallamini, JCO 2007) and PET-guided strategy were developed to improve the management of HL patients in order to either intensify treatment for high risk patients or deescalate treatment for sparing the others from toxicities. The aim of this study was therefore to evaluate the impact of baseline tumor microenvironnement in a large cohort of HL patients prospectively treated with upfront escalated BEACOPP in a randomized phase III clinical trial evaluating a PET-driven strategy (AHL 2011, NCT01358747) and to compare its prognostic value with other clinicopathological markers. Material and Methods Tumoral material was collected from May 2011 to May 2014 from HL patients prospectively enrolled in the AHL 2011 study. The AHL 2011 trial was designed to evaluate in 16-60 years old HL patients with Ann Arbor stage III, IV or high risk IIB, a de-escalade PET-driven strategy after 2 cycles of BEACOPPesc randomly compared to a standard treatment not driven by PET and delivering 6 cycles of BEACOPPesc. PET were centrally reviewed and interpreted according to Deauville criteria. As recently reported (Casasnovas, ASH 2015 Abs 577), the 2y-PFS was similar in the PET-driven (88%) and the standard arm (91%; p =0.79). The tumor microenvironnement was analyzed on formalin fixed paraffin embedded lymph node biopsy obtained for the diagnosis before treatment by morphological evaluation on standard staining (% polynuclear eosinophils, % lymphocytes, % plasmocytes, % histiocytes), and immunohistochemistry (IHC) scoring (score 0-1-2-3) for CD20, CD3, CD68-TAMs (tumor-associated macrophages) and CD163 and were centrally reviewed. Percentage of tumoral cells and EBV status were also analysed. In this analysis, the prognosis value of tissue markers expressions were compared to those of clinical and biological patient's characteristics, and PET results after 2 cycles of escalated BEACOPP. Results Six hundred fifty eight patients with available IHC data out of 823 enrolled in AHL2011 study were included in the analysis. With a median follow-up of 16.1 months, 2-year PFS was 89.4% (95% CI [86.2% ; 91.9%]) and 2-year OS 98.7% (95% CI [96.4% ; 99.5%]). In univariate analysis male gender, at least one extra-nodal involvement, B symptoms, Hemoglobin

Description: Abstract 320 Purpose: Positron emision tomography with [18F]fluorodeoxyglucose (PET) performed after one to four cycles of chemotherapy could predict treatment outcome in diffuse large B cell lymphoma (DLBCL). However, suitable criteria to interpret interim PET remain to be established. Visual analysis was related to reproducibility concerns and false positive results in previous reports, and standardized uptake value (SUV) was proposed to improve interim PET accuracy. To compare the clinical usefulness of both methods, we analysed sequential interim PET according to visual and SUV criteria in a prospective multicenter phase II trial. Patients and method: From 2007 to April 2009, 113 patients with aaIPI 2–3 factors DLBCL were randomly assigned to receive an induction treatment with four cycles of either R-ACVBP or R-CHOP14 in the LNH2007-3B GELA trial. PET was done at baseline (PET0) and after 2 (PET2) and 4 cycles (PET4) of immuno-chemotherapy. All PET scans were centrally reviewed and interpreted using visual criteria. SUVmax reduction values between PET0 and PET2 (DSUVmaxPET0-2) or PET4 (DSUVmaxPET0-4) were available for 85 out of 113 patients. After using the receiver operating characteristics approach, patients with a DSUVmaxPET0-2 〉66% were considered as good responders after 2 cycles and those with a DSUVmaxPET0-4 〉70% were considered as good responder at end of induction treatment. Progression-free survival (PFS) was analyzed according to PET results based on visual criteria and DSUVmax. Results: Using visual analysis, respectively 34% and 49% of patients achieved a negative PET2 and PET4. An agreement between on-site and review panel was observed in 89% and 92% of cases for PET2 and PET4 leading to a kappa coefficient of 0.769 and 0.836 respectively. Seventy (82%) patients had a DSUVmaxPET0-2 〉 66% and 74 (88%) had a DSUVmaxPET0-4 〉 70%. Using DSUVmax analysis, 45 (78%) of the 58 PET2 positive patients and 33 (80%) of the 41 PET4 positive patients could be reclassified as good responder after 2 and 4 cycles of immuno-chemotherapy, respectively. PET2 and PET4 results based on visual criteria had no impact on PFS (p=0.99 and p=.077, respectively). By constrast, PET results based on DSUVmax better predicted PFS: patients with a DSUVmaxPET0-2 〉66% had a better 1-year PFS than patients with a lower DSUVmaxPET0-2 (89% v 56%; p=0.0031). Similarly, patients with a DSUVmaxPET0-4 〉70% reached a 90% 1-year PFS, while patients with a lower DSUVmaxPET0-4 only had 23% 1-year PFS (p

Description: Purpose International Prognostic Index (IPS) is the most widely used risk stratification index for advanced stage Hodgkin's lymphoma (HL). The use of (18F)-fluorodeoxyglucose PET/CT at diagnosis allows a better characterization of extra-nodal involvement (ENI). We investigated if the type of ENI could affect the prognosis of stage IV HL patients diagnosed with PET/CT and if a specific prognostic index could be defined for these patients (pts). Patients and methods We retrospectively analyzed 220 stage IV HL patients treated from 2005 to 2015 in three LYSA centers. We considered the local investigator interpretation based on the nuclear medicine physician PET/CT report. Regarding ENI, six subgroups were identified: involvement of lung and/or pericard and/or pleural, liver, diffuse and/or focal bone involvement, digestive system, and other involvements; we also considered bone marrow involvement based on the results of bone marrow biopsy. The main outcome was event free survival (EFS) defined by relapse, progression, death from any cause and initiation of a new therapy. For prognostication, we first evaluated the six variables of IPS-6 (corresponding to IPS without "stage IV" item) in this population. ENI was tested adjusted on the retained IPS variables. Univariate and multivariate Cox models were used to assess their prognostic ability for EFS. Cross-validation (10-fold) was used to select the more robust variables avoiding optimism. The finally selected variables constituted a score that was tested on overall survival (OS). Results Among the 220 stage IV patients, 135 (61%) were male. Median age was 33 years (range, 16-86) and 72 pts (33%) were ≥45 years. 130 pts (59%) presented constitutional symptoms. Nodular sclerosis subtype was observed in 163 pts (74%), mixed cellularity subtype in 25 pts (11%) and 47/157 pts (30%) presented EBV-positive HL. For biological parameters of IPS, 158 pts (80%) had low albumin level