Abstract: Abstract. The science guiding the EUREC4A campaign and its measurements is presented. EUREC4A comprised roughly 5 weeks of measurements in the downstream winter trades of the North Atlantic – eastward and southeastward of Barbados. Through its ability to characterize processes operating across a wide range of scales, EUREC4A marked a turning point in our ability to observationally study factors influencing clouds in the trades, how they will respond to warming, and their link to other components of the earth system, such as upper-ocean processes or the life cycle of particulate matter. This characterization was made possible by thousands (2500) of sondes distributed to measure circulations on meso- (200 km) and larger (500 km) scales, roughly 400 h of flight time by four heavily instrumented research aircraft; four global-class research vessels; an advanced ground-based cloud observatory; scores of autonomous observing platforms operating in the upper ocean (nearly 10 000 profiles), lower atmosphere (continuous profiling), and along the air–sea interface; a network of water stable isotopologue measurements; targeted tasking of satellite remote sensing; and modeling with a new generation of weather and climate models. In addition to providing an outline of the novel measurements and their composition into a unified and coordinated campaign, the six distinct scientific facets that EUREC4A explored – from North Brazil Current rings to turbulence-induced clustering of cloud droplets and its influence on warm-rain formation – are presented along with an overview of EUREC4A's outreach activities, environmental impact, and guidelines for scientific practice. Track data for all platforms are standardized and accessible at https://doi.org/10.25326/165 (Stevens, 2021), and a film documenting the campaign is provided as a video supplement.

Abstract: Interim positron emission tomography (PET) using the tracer, [ 18 F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP—plus rituximab (R-CHOP) in CD20-positive lymphomas—followed by a PET scan that was evaluated using the ΔSUV max method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt’s lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606] ; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.

Abstract: Introduction: The predictive value of 18-fluorodeoxyglucose PET performed after a few cycles of chemotherapy has been questioned in aggressive lymphomas. Inconsistent study results, however, may be due to procedural differences rather than an inability of the method to predict outcome. Whether changing treatment in pts. with an unfavorable interim PET (iPET) improves outcome, has not been determined in a randomized study. The PETAL trial (EudraCT 2006-001641-33, NCT00554164) was initiated to resolve these issues. Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O) and prednisone (CHOP) followed by iPET. The conditions of iPET were strictly defined: 3-week interval between the 2nd R-CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd R-CHOP cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve objectivity of evaluation (favorable iPET response: reduction of maximum SUV by 〉 66 % compared to baseline; J Nucl Med 48:1626, 2007). Pts. with CD20-positive lymphomas and a favorable iPET were randomized to receive 4 additional cycles of R-CHOP or the same treatment plus 2 extra doses of R (Part A of the trial). Pts. with an unfavorable iPET were randomized to continue standard R-CHOP for 6 additional cycles or receive 6 blocks of a more complex and more intensive protocol yielding excellent results in Burkitt and other aggressive lymphomas (Part B). Its main components were hyperfractionated alkylating agents (C, ifosfamide) and high doses of methotrexate and cytarabine, with dose reductions in pts. 〉 60 yrs. Other constituents were R, H, O, vindesine, etoposide and dexamethasone (Blood 120: abstr 667, 2012). R was omitted in pts. with CD20-negative lymphomas. Sample size was based on the empirically derived assumption that treatment failure after 2 yrs. (TF: progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 80 % to 90 % in Part A and from 30 % to 45 % in Part B (alpha=0.05, power=0.8). Complete remission (CR), overall survival (OS) and toxicity were secondary endpoints. Results: From 2007 to 2012 926 pts. were recruited by 57 participating oncological centers and analyzed by PET in 23 nuclear medicine institutions. With a median follow-up of 33 months 853 pts. are currently evaluable in the intent-to-treat population. 757 pts. had CD20-positive B cell lymphomas (80 % diffuse large B cell [DLBCL], 3 % primary mediastinal B cell, 8 % follicular lymphoma grade 3), 13 had CD20-negative B cell lymphomas and 83 had peripheral T cell lymphomas. Interim PET was favorable in 746 pts. (87 %) and unfavorable in 107 (13 %). It was highly predictive of outcome, time to TF being significantly higher in Part A than Part B (2-year probability: 79 % vs. 47 %; hazard ratio (HR) for B 3.4, 95 % confidence interval (CI) 2.6 – 4.6, p 〈 0.0001; Figure). On multivariate analysis iPET response, International Prognostic Index and B vs. T cell lineage independently predicted TF. Interim PET was also predictive of OS (HR 3.9, CI 2.7 – 5.7, p 〈 0.0001). In pts. with CD20-positive lymphomas and a favorable iPET, addition of 2 extra doses of R failed to improve TF (HR for 2 extra doses 1.2, CI 0.8 – 2.1) and all secondary endpoints. Likewise, in pts. with an unfavorable iPET response, a switch from R-CHOP to the Burkitt-type regimen showed no beneficial effect on TF (HR for Burkitt 1.6, CI 0.9 – 2.7), CR rate (50 % vs. 31 %, p=0.10) or OS (HR 1.0, CI 0.5 – 2.1). Similar results were obtained, when the analysis was restricted to DLBCL, and for covariate adjusted Cox regression of all survival endpoints. Although treatment related deaths (3 vs. 2 pts.) were comparable in both treatment arms, the Burkitt protocol was associated with more severe grade 3/4 leukopenia (84 % vs. 67 %, p=0.043), thrombocytopenia (63 % vs. 35 %, p=0.007) and mucositis (41 % vs. 12 %, p=0.002). Conclusion: Applying strict rules to the procedure and its interpretation iPET proved highly predictive of outcome in pts. with aggressive lymphomas in this large multicenter trial. Because switching to a more aggressive protocol failed to improve outcome, our results do not support a change in cytotoxic regimen in poor iPET responders. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Duehrsen: Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Klapper:Roche: Research Funding. Hoelzer:Amgen: Speakers Bureau; Medac: Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: The PETAL trial is a multicenter randomized controlled study for patients with aggressive lymphomas of diverse histologies (EudraCT 2006-001641-33, NCT00554164). In the study population as a whole interim PET (iPET) reliably predicted time to treatment failure (TTTF) and overall survival (OS). Interim PET-based treatment changes, however, had no impact on outcome (ASH 2014, abstract 391). Here we report the exploratory analysis for aggressive B cell lymphomas. Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) followed by iPET. The conditions of iPET were strictly defined: 3-week interval between the 2nd R-CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve reproducibility (favorable iPET response: reduction of maximum SUV by 〉 66 % compared to baseline; J Nucl Med 48:1626, 2007). Pts. with CD20+ lymphomas and a favorable iPET were randomized to receive 4 more cycles of R-CHOP or the same treatment plus 2 extra doses of R (part A of the trial). Pts. with an unfavorable iPET were randomized to continue R-CHOP for 6 additional cycles or receive 6 blocks of a more complex methotrexate-, cytarabine- and etoposide-based regimen originally designed for Burkitt lymphoma (Blood 124: 3870, 2014; part B). R was omitted in pts. with CD20- lymphomas. Sample size of the entire study population was based on the empirically derived assumption that treatment failure after 2 yrs. (TF: progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 80 % to 90 % in part A and from 30 % to 45 % in part B (alpha=0.05, power=0.8). Secondary endpoints included OS and toxicity. Results: Fifty-seven oncological centers and 23 nuclear medicine institutions participated in the trial. Between 2007 and 2012 1072 pts. were registered, and 862 (80.4 %) had a positive baseline PET, received 2 cycles R-CHOP, underwent iPET and were allocated to one of the post-iPET treatment arms detailed above. Reference pathology was available in 98 %, and median follow-up is 52 months. All in all, there were 779 patients with CD20+ aggressive B-cell lymphomas (90.4 % of all treated pts.) of whom 606 had diffuse large B-cell lymphoma (DLBCL), 42 primary mediastinal B-cell lymphoma (PMBCL) and 42 follicular lymphoma grade 3 (FL3). Interim PET was favorable in 691 pts. (88.7 %) and unfavorable in 88 pts. with CD20+ lymphomas (11.3 %). It was highly predictive of TTTF for CD20+ lymphomas in general and for each of the DLBCL, PMBCL and FL3 subgroups (Table). In CD20+ lymphomas and DLBCL, the iPET response predicted TF independently of the International Prognostic Index, and it was also predictive of OS. The groups of PMBCL and FL3 were too small for multivariate analyses. In part A, adding 2 extra doses of R failed to improve TTTF and OS in all histological entities. Separate analyses for subgroups defined by sex, age ( 〈 vs. 〉 60 yrs.) or a combination of the two showed no statistically significant benefit of extra doses of R in any of the subgroups. In pts. with an unfavorable iPET response, a switch from R-CHOP to the Burkitt regimen failed to improve TTTF or OS in CD20+ lymphomas in general (Figure) and in the DLBCL, PMBCL and FL3 subgroups. In part B, the Burkitt protocol was associated with more grade 3/4 leukopenia (82 % vs. 57 %, p=0.02), thrombocytopenia (59 % vs. 18 %, p=0.0001), infection (41 % vs. 16 %, p=0.017) and mucositis (39 % vs. 7 %, p=0.0007) than R-CHOP, but treatment-related mortality was similar in both arms (1 death each). Conclusion: In this large multicenter trial iPET proved highly predictive of outcome in pts. with CD20+ aggressive B-cell lymphomas, DLBCL, PMBCL or FL3 treated with R-CHOP. In pts. with a favorable iPET response, addition of 2 extra doses of R to 6 cycles R-CHOP failed to improve outcome in CD20+ lymphomas in general and in subgroups defined by histology, sex or age. In pts. with an unfavorable iPET response, switching to a more aggressive protocol also failed to improve outcome in any of the entities. Novel strategies are required for aggressive B-cell lymphomas failing to respond to the first 2 cycles of R-CHOP. Table Table. Figure Figure. Disclosures Duehrsen: Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Giagounidis:Celgene Corporation: Consultancy. Grube:BMS, Sanofi: Consultancy. Klapper:Roche, Novartis, Amgen, Takeda: Research Funding. Hüttmann:Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria; Gilead, Amgen: Other: Travel cost.

Abstract: Introduction For patients (pts) with aggressive B-cell lymphoma immunochemotherapy with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone) represents the standard of care with curative intention. For elderly pts a dose-reduced R-mini-CHOP protocol is feasible. No standard of care exists for frail or very old ( 〉 80 yrs) pts not eligible for CHOP-like treatment. Here we present the final results of the prospective DSHNHL-phase-2 trial for old or frail pts receiving Rituximab/Bendamustine (RB) for 1st-line treatment of aggressive B-cell lymphoma. Our goal was to determine feasibility, toxicity of the BR regimen in this pt cohort, and to determine which pts groups might potentially benefit from this reduced-intensity approach. Methods The open-label, multicenter, prospective, non-randomized phase-II trial "Subcutaneous Rituximab and Intravenous Bendamustine in very Elderly Patients or Elderly Medically Non Fit Patients ("Slow Go") with Aggressive CD20-positive B-cell Lymphoma" (B-R-ENDA, DSHNHL 2010-1, EudraCT 2010-024004-98) included all pts aged ≥81 yrs or 61-80 yrs and elevated CIRS 〉 6, not qualifying for R- CHOP, with histologically confirmed CD20+aggressive lymphoma of any Ann Arbor-stage and IPI score, and ECOG 〈 4 as determined during or after a prephase treatment. During run-in-phase, 20 pts received a prephase treatment of Prednisolone 100mg p.o. d-7 to -1, followed by Rituximab 375mg/m² i.v. on d-3, again followed by 7 cycles of Rituximab 375mg/m² i.v. on d1,q21 and 6 cycles of Bendamustine 90mg/m² i.v. on d1 and 2,q21. After a safety analysis, subsequent pts received prephase treatment with Rituximab 375mg/m² i.v. followed by 7 cycles of subcutaneous (s.c.) Rituximab 1400mg on d1,q21 and bendamustine as above. Primary endpoints were 2-year-progression-free survival (PFS) for efficacy (expected at 30-50% in the 〉 80 yr cohort), and treatment-associated deaths, frequency of grade 3/4 adverse events and SAEs, adherence to the protocol, complete and partial remission rate, rate of primary progression and relapse, and quality of life assessed by geriatric assessment and EORTC-QLQ-C30 for feasibility. Results: From 2012 to 2016, 68 pts (22 male, 46 female) were recruited in 24 centers into the trial and included into this intent-to-treat analysis (ITT). The median age was 81 yrs with 21% of pts older than 85 yrs. The median CIRS score was 8 and 72% had a CIRS 〉 6. The IPI was 〉 2 in 59% of pts. The patient population was per protocol divided into two subgroups: pts 61 to 80 yrs old and medically non-fit (29 pts) and pts older than 80 yrs (39 pts). For the 61 to 80 yrs old medically non-fit patients median age was 77 yrs (64-80), median CIRS score was 10 (2-22), IPI was 〉 2 in 76% of pts, 66% of pts had stage 3 or 4 disease, and ECOG was 〉 1 in 52% of pts. For the subgroup of pts 〉 80 yrs, median age was 84 yrs (81-95), median CIRS score was 7 (1-17), IPI was 〉 2 in 46% of pts, 51% of pts had stage 3 or 4 disease, and ECOG was 〉 1 in 23% of pts. 49% of pts received the complete treatment as planned (61-80 yrs: 38%; 〉 80 yrs: 56%). Reasons for early termination of treatment were PD in 15% (17%; 13%) and toxicity in 24% (24%; 23%) of pts. 29% 95% Confidence interval 19-42% of pts (38%; 23%) had grade 3-5 infections. Treatment related mortality was 15% (17%; 13%). Overall response rate (ORR) was 41% (28%; 51%) with 31% CR (10%; 46%). Median observation time was 29 months for EFS, PFS and OS. 2-yrs EFS was 23% (10%; 37%), PFS was 40% (32%; 45%), OS was 42% (37%; 46%). In a multivariate analysis adjusted for IPI factors elevated LDH and ECOG 〉 1 constituted the most significant risk factors for poor outcome. Conclusions: We describe a frail patient cohort with a median CIRS score of 8, with 72% pts with a CIRS 〉 6, considerable comorbidities and a high percentage of high-risk IPI. The primary efficacy endpoint (2 yr PFS 〉 80 yrs 45%) was met; for R-mini-CHOP, this was reported at 47% (Peyrade et al., Lancet Haemat, 2011). The IPI predicts outcome in the 〉 80 yrs cohort reliably. The RB regimen is active even in very elderly and frail pts up to 90 yrs of age. Therefore, in pts not eligible for full- or reduced dose R-CHOP treatment, it represents a tolerable and efficient alternative, albeit with a limited curative potential preferably in IPI low/intermediate-risk pts. Biomarker, comorbidity and QoL data will be analysed subsequently. Disclosures Zettl: Roche: Other: travel grants, Research Funding; Mundipharma: Research Funding. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Korfel:Mundipharma: Consultancy, Research Funding. Dreyling:Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Novartis: Other: scientific advisory board; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Sandoz: Other: scientific advisory board; Acerta: Other: scientific advisory board; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau. Illmer:Roche: Other: travel support. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Poeschel:Hexal: Speakers Bureau; Roche: Other: Travel support; Amgen: Other: Travel support; Abbvie: Other: Travel support; Astra Zeneca: Other: Travel support. Truemper:Takeda: Consultancy, Research Funding; Roche: Research Funding; Seattle Genetics, Inc.: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Nordic Nanovector: Consultancy.

Abstract: Introduction Based on improvement of overall survival (OS), lenalidomide (R) maintenance after up-front autologous stem cell transplantation has recently been approved for multiple myeloma (MM) patients (pts). Conversely, in transplant non-eligible (TNE) pts R maintenance after R-based induction improved progression free survival (PFS) but had no impact on OS. First-line treatment with VMP is considered a standard of care for newly diagnosed (ND) TNE pts, but whether maintenance therapy with R after VMP induction can further improve PFS and OS is currently unknown. Aims The prospective phase IIb GERMAIN trial (EudraCT-No: 2012-003023-38) aimed to evaluate the role of R maintenance after VMP induction in ND TNE MM pts. The trial, which planned to include 286 ND TNE MM pts, closed early in December 2017 due to insufficient accrual and high discontinuation rate. The present analysis focuses on the reasons for the high drop out rate. Methods After induction with 6 courses of VMP (Mateos et al., Lancet Oncology 2010), pts achieving at least a partial response (PR) were randomized 1:1 to R 10 mg or placebo (PCB) daily until progression (PD) or unacceptable toxicity. Pts with 〈 PR could receive second line therapy with R 25 mg/day (three weeks on, one week off) and low dose dexamethasone until PD in the observational arm of the study. Pts with poor performance status (ECOG ≥3), creatinine clearance 〈 15 ml/min, or other concomitant serious medical conditions were excluded, but no upper age limit was applied. Results From May 2014 to December 2017 85 pts were enrolled. Median age was 75 years (range 63-87). A significant proportion of pts presented with at least one concomitant illness: 75% were hypertensive, 29% had a cardiac disorder, 37% a metabolic disorder and 19% a chronic kidney disease. Induction was completed by 53 pts and 40 pts entered maintenance randomization (Figure 1). Of patients completing induction therapy 77% achieved at least a PR, including 11% of sCR/CR and 26% of VGPR. Overall 70% of pts discontinued the study; main reasons for trial discontinuation were PD (24%), unacceptable toxicity (17%), investigator decision (16%) and withdrawal of informed consent (12%). Of pts discontinuing treatment, 27 pts (47%) stopped during induction, and in 71% of these cases discontinuation was due to unacceptable toxicities (26%) or investigator (26%) and patients (19%) decision. Only one pt discontinued due to insufficient response during induction. In total 745 adverse events (AE) and 71 serious AEs (SAE) were reported; of these 814 had complete data and were analyzed. During induction 571 AE occurred, of which 110 (19%) were of grade ≥3. Seventy-one pts (86%) reported at least one AE, and 49 (59%) at least one grade ≥3 AE. The most common grade ≥3 AE were: leukopenia (25%), thrombocytopenia (20%), cardiac toxicity (10%), infections (8%), peripheral neuropathy (6%), anemia and gastrointestinal toxicity (5% each). The cumulative probability of development of a grade ≥3 AE at 6 months was 59% (95% CI: 47 to 69%). SAEs during VMP were 54; 39% of pts experienced at least one SAE during induction. The cumulative probability for an SAE at 6 months was 41% (95% CI: 30 to 51%). During induction 4 deaths were recorded, all within the first month of treatment. Of the pts randomized to maintenance treatment 37 received at least one dose of R/PCB and were considered evaluable. Twenty-one pts (36%) discontinued the study during maintenance. Main reason for discontinuation was PD (11 pts, 4 in R and 9 in PCB arm); only 2 pts (both in R arm) discontinued due to AE 2 and 21 months after start of maintenance, respectively. Of the AE recorded during maintenance (n=157, 92 in the R and 65 in the PCB group) 17% were grade ≥3 and 12 were considered SAE. At least one AE and at least one SAE were reported in 29 (78%) and 8 pts (22%), respectively. Four secondary malignancies (1 basal cell carcinoma, 1 AML, 1 bladder cancer and 1 lung cancer) were reported, 1 during VMP induction and 3 during maintenance. Conclusions In comparison to other studies focusing on ND TNE MM pts, our study investigated a remarkably elderly and frail population. In the cohort investigated, treatment with VMP resulted in increased toxicity and higher rate of discontinuation. Nevertheless, in those pts able to complete induction a promising ORR was observed. In elderly and frail MM pts, regimens other than VMP should be considered for induction. Disclosures Brioli: Celgene: Honoraria, Other: Travel support, Research Funding; Janssen: Honoraria. Hänel:Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Pfirrmann:Novartis: Research Funding. von Lilienfeld-Toal:Janssen: Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding. Fabisch:Novartis: Research Funding. Knop:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hochhaus:Incyte: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria.

Abstract: Abstract 2695 Poster Board II-671 Introduction: Positron emission tomography (PET) performed after a few cycles of chemotherapy (interim-PET) in aggressive lymphomas correlates with long-term outcome: While the majority of patients with a negative interim-PET scan enjoy long-lasting remissions, patients with persistent pathological glucose uptake almost invariably relapse. The multicenter PETAL trial was initiated in Germany in 2008 to resolve the question whether a change in treatment protocol may improve the outcome of patients with a positive interim-PET scan (ClinicalTrials.gov Identifier: NCT00554164). Patients and Methods: The PETAL trial is open for patients with newly diagnosed aggressive B cell or T cell non-Hodgkin's lymphomas between 18 and 80 years of age with a performance status of 0 to 3 according to the Eastern Cooperative Oncology Group scale and a positive PET scan before starting any lymphoma-directed therapy. Interim-PET is done after 2 cycles of the CHOP protocol (cyclophosphamide, doxorubicine, vincristine, prednisone; plus rituximab (R) in CD20-positive lymphomas) administered at a 14-day interval. Precautions were taken to minimize the risk of false-positive interim-PET results. First, the interval between the second (R-)CHOP cycle and the interim-PET scan is three weeks. Second, hematopoietic growth factors accelerating blood cell recovery are not allowed after the second cycle of chemotherapy. Third, quantitative standard uptake value (SUV)-based assessment rather than exclusive visual interpretation is used for interim-PET evaluation as described by Lin et al (J Nucl Med 48: 1626, 2007). Results: So far, a total of 266 patients have been recruited into the trial. A negative pre-treatment scan was observed in 18 patients, the majority of whom had complete lymphoma resection. 196 patients have reached interim-PET scanning, 168 with diffuse large B cell lymphoma (86%), 11 with grade 3a/b follicular lymphoma (6%), and 17 with peripheral T cell lymphoma (8%). Median SUVmax at staging did not differ across these three lymphoma subgroups. However, the SUVmax reduction at interim-PET was significantly lower in T-cell lymphomas as compared to B-cell lymphomas. Six patients (3%) with a low SUV at staging ( 〈 10) were rated as non-responders by quantitative, but as responders by visual assessment. Maximum SUV at staging and SUV reduction after two cycles of (R-)CHOP were independent of the International Prognostic Index (IPI). In contrast to lymphoma patients with baseline SUV values below 30, patients with higher SUV values almost invariably met the predefined criteria for therapy response (p = 0,033, Fisher's exact test). With a median follow up of less than six months, lymphoma relapses across all IPI risk groups have occurred more frequently in patients with a positive interim-PET scan than in patients with a negative scan. Neither absolute baseline SUVmax levels nor magnitude of SUVmax reduction at interim-PET were predictive of relapse. Conclusion: A combined strategy of SUV-based quantitative and visual qualitative interim-PET assessment is feasible in a multicenter randomized trial designed to guide treatment in lymphoma patients. In this largest series of interim-PET scanning in aggressive lymphoma reported so far, interim-PET response and the IPI risk score proved to be independent. With an as yet short follow-up period relapses were unevenly distributed between PET responders and non-responders. The PETAL trial will help define criteria for interim-PET scanning and response prediction. Recruitment into the trial continues. Disclosures: Hüttmann: Roche: Research Funding; Amgen: Research Funding. Duehrsen:Amgen: Research Funding; Roche: Research Funding.

Abstract: Introduction: The PETAL trial is a multicenter randomized controlled study for patients with aggressive lymphomas of diverse histologies (EudraCT 2006-001641-33, NCT00554164). In the study population as a whole interim PET (iPET) reliably predicted time to treatment failure (TTTF) and overall survival (OS). Interim PET-based treatment changes, however, had no impact on outcome (ASH 2014, abstract 391). Here we report the exploratory analysis for peripheral T cell lymphomas (PTCL). Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) followed by iPET. R was omitted in pts. with CD20-negative lymphomas. The conditions of iPET were strictly defined: 3-week interval between the 2nd (R-)CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve reproducibility (favorable iPET response: reduction of maximum SUV by 〉 66 % compared to baseline; J Nucl Med 48:1626, 2007). PTCL pts. with CD20-negative lymphomas and a favorable iPET uniformly received 4 additional cycles of CHOP (part A of the trial). Pts. with an unfavorable iPET were randomized to continue CHOP for 6 additional cycles or receive 6 blocks of a more complex methotrexate-, cytarabine- and etoposide-based regimen originally designed for Burkitt lymphoma (Blood 124: 3870, 2014; part B). Sample size of the entire study population was based on the empirically derived assumption that treatment failure after 2 yrs. (progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 30 % to 45 % in part B (alpha=0.05, power=0.8). Secondary endpoints included OS and toxicity. Results: Fifty-seven oncological centers and 23 nuclear medicine institutions participated in the trial. Between 2007 and 2012 1072 pts. were registered, and 862 (80.4 %) had a positive baseline PET, received 2 cycles (R-)CHOP, underwent iPET and were allocated to one of the post-iPET treatment arms detailed above. Reference pathology was available in 98 %, and median follow-up is 52 months. All in all, there were 76 pts. (8.8 % of all treated pts.) with T-cell lymphomas of whom 21 had ALK+ anaplastic large cell lymphoma (ALCL), 13 ALK- ALCL, 18 angioimmunoblastic T-cell lymphoma (AITL) and 20 PTCL not otherwise specified (NOS). Interim PET was favorable in 57 pts. (75 %) and unfavorable in 19 pts. with T-cell lymphomas (25 %). It was highly predictive of outcome, TTTF and OS being significantly higher in part A than B (2-year probability for TTTF: 63 % vs. 21 %; univariate hazard ratio (HR) for B 3.4, 95 % confidence interval (CI) 1.8 - 6.4, p 〈 0.0001; OS: 79 % vs. 25 %; univariate hazard ratio (HR) for B 5.0, 95 % CI 2.4 - 10.3, p 〈 0.0001; Figure). Interestingly, the proportion of T-cell lymphoma pts. with an unfavorable iPET response was more than twice as high as the corresponding proportion of B-cell lymphoma pts., and the difference in survival between pts. with a favorable vs. unfavorable iPET response was more pronounced in T-cell lymphomas than in B-cell lymphomas. TTTF (2-year probability: 81 % vs. 46 % vs. 49 % vs. 35 %; p=0.0110) and OS (90 % vs. 69 % vs. 52 % vs. 50 %; p=0.0026) were better in ALK+ ALCL than in ALK- ALCL, AITL or PTCL NOS. In pts. with an unfavorable iPET response, a switch from CHOP to the alternative regimen failed to improve TTTF or OS. The latter was associated with more frequent grade 3/4 neutropenia (40 % vs. 0 % vs. 11 %, p=0.0279), thrombocytopenia (70 % vs. 33 % vs. 23 %; p=0.0106), infection (60 % vs. 44 % vs. 18 %, p=0.0057) and mucositis (40 % vs. 33 % vs. 4 %, p=0.0025) as compared to 6 or 4 post-iPET cycles of CHOP, respectively, but treatment-related mortality was similar in all treatment arms (2 vs. 1 vs. 2 deaths). Conclusion: In this large multicenter trial iPET proved highly predictive of outcome in PTCL. A favorable iPET was found in 75 % of pts., and this was associated with long-term survival in about 70 %. In pts. with an unfavorable iPET response, outcome was dismal and could not be improved by switching to a more aggressive regimen. Novel strategies are required for PTCL pts. failing to respond to the first 2 cycles of CHOP. Disclosures Hüttmann: Gilead, Amgen: Other: Travel cost; Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria. Giagounidis:Celgene Corporation: Consultancy. Klapper:Roche, Novartis, Amgen, Takeda: Research Funding. Duehrsen:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding.