Search

Background Current NCCN guidelines recommend 1 of 3 first-line (1L) regimens for stage III or IV classical Hodgkin lymphoma (cHL): ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), A+AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine), or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone); preferred regimens vary by region (e.g., North America vs Europe). The NCCN recommends positron emission tomography/computerized tomography (PET/CT) imaging after cycle 2 (interim PET2) to guide ABVD escalation or de-escalation. We surveyed physicians on their cHL treatment decision-making process and how PET/CT scan access, reimbursement, and comprehension influence their choices as part of CONNECT, the first real-world survey of physicians, patients, and caregivers in cHL. Methods Medical oncologists, hematologist/oncologists, or hematologists who treat cHL were invited to participate in an Institutional Review Board-approved, 30-minute online anonymous survey. Eligible participants had ≥2 years of practice experience in the United States (US) and treated ≥1 adult (aged ≥18 years) with stage III or IV cHL and ≥1 adult with cHL in the 1L setting within the prior 12 months. Surveys were completed from October 19, 2020-November 16, 2020. Results Of 301 participating physicians, 80% were hematologist/oncologists with a median practice duration of 15 years; 62% practiced in community and 38% in academic settings. Participants were located in the US (South, 34%; Northeast, 26%; West, 21%; Midwest, 20%) and spent 90% of their professional time in direct patient care. In the preceding 12 months, participants treated a median (interquartile range) of 16 (7-40) patients with active cHL (stage III [median], 4; stage IV, 5) and 15 (8-40) cHL survivors. When treating cHL, 88% of participants reported giving NCCN guidelines somewhat/significant consideration. Overall, 94% of participants (n=284) reported using a PET/CT combined scan to diagnose/stage cHL, in line with current guideline recommendations. Of these participants, 97% reported typically getting an interim PET/CT scan for stage III or IV cHL with 65% typically getting the scan after cycle 2 (Figure A). Participants reported both escalating and de-escalating treatment based on interim PET/CT results (Figure B) with 61% making decisions after cycle 2. Of participants using a PET/CT scan, 42% reported receiving both a Deauville score and a standardized uptake value (SUV; Figure C) with 62% of participants noting that the Deauville score was the primary system used for reviewing PET/CT results (Figure D). However, 19% of participants reported challenges interpreting PET/CT results. Among participants using a Deauville score (n=209), consensus was limited on what defined a positive scan (≥3, 44%; ≥4, 37%). Challenges obtaining PET/CT scans were reported by 16% of participants using PET/CT scans. However, despite not reporting challenges 55% of participants on average were unable to obtain a PET/CT scan 20% of the time. Of participants using PET/CT scans, 86% reported typically receiving results within 2 business days and 14% within 3-5 business days. Twenty-one percent of participants reported that delays in PET/CT results affected their ability to use a PET-adaptive approach. Forty-nine percent of those using PET/CT scans reported increased difficulty in PET/CT access for stage III or IV cHL due to lack of insurance coverage. In absence of a PET/CT scan, 36% of participants reported using an interim biopsy and 63% an interim CT scan to inform treatment choices. Among all participants, 36% reported increased difficulty in getting patients with cHL access to PET/CT scans due to COVID-19. Conclusions Although participants consider NCCN guidelines when treating cHL, interim PET scans are not universally obtained after cycle 2 for stage III or IV cHL, with 65% of participants who use PET/CT scans obtaining an interim PET scan after cycle 2 for stage III or IV cHL. When PET/CT scans are obtained, Deauville scores are commonly provided; however, there is variability in what is termed a positive or negative Deauville score. Challenges in obtaining PET/CT scans, with increased difficulty during COVID-19, were reported. Also, there are other barriers, such as lack of insurance, that may prohibit the optimal adherence to guidelines on interim PET/CT utilization. Figure 1 Figure 1. Disclosures Parsons: SeaGen: Consultancy. Yu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Liu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Kumar: Seagen, Inc: Consultancy. Fanale: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Flora: Seagen, Inc: Research Funding.

Introduction: Interim PET identifies patients with early stage classical HL (cHL) suitable for risk-adapted treatment escalation or de-escalation, but relapse-free survival remains inferior for patients with a negative interim PET who omit radiotherapy. Genetic risk predictors have demonstrated potential to enhance the negative predictive value of interim PET. In the BioPET study reported here, we evaluated the association between a priori selected candidate genes with interim PET and cHL-specific event free survival (cHL-EFS) for patients enrolled on the UK NCRI RAPID trial (NCT00943423). Methods: Patients with stage 1A or 2A cHL treated with 3 cycles of ABVD followed by interim PET assessment using a 5-point scale, full clinical data and available diagnostic biopsy material were included. Patients with a score of 1-2 (PET 'negative') were randomised (1:1) to involved field radiotherapy (IFRT) or no further treatment (NFT); those with a score of 3-5 (PET 'positive') received a further cycle of ABVD plus IFRT. Pre-treatment diagnostic FFPE material was obtained for 227 patients (21 with cHL events). Tissue homogenates were prepared and analysed using Quantigene 2.0 (QG_2.0) Plex for expression of 57 candidate genes known to be associated with treatment response and survival in cHL. QG_2.0 data were generated for experimental samples (n=227), RNA controls (n=15) and FFPE controls (n=12). Data were capped at both upper and lower limits of detection. Four housekeeper genes with the lowest variance (GUSB, TBP, HMBS, ABL1) were used for normalisation using the geometric mean. Candidate genes were ranked according to variability of expression. The association between gene expression, PET outcomes and cHL-EFS (disease progression or death) in the three treatment groups was evaluated in a series of regression analyses (Cox and binary logistic), both in univariable and multivariable settings using stepwise procedures, taking baseline EORTC and GHSG risk stratification into account. Analyses were run on the full dataset as there were insufficient cases for a training:validation split. Results: In total, cHL events were observed in 10/121 (8.3%) PET score 1, 4/53 (7.5%) PET score 2, 2/33 (6.1%) PET score 3, 1/10 (10.0%) PET score 4 and 4/10 (40.0%) PET score 5 respectively. Several genes were found to be associated with PET response after ABVD, and two genes remained in the multivariable model: PRF1 increased the risk of PET score 3-5 (OR=1.49, 95% CI: 1.05-2.13, p=0.03); BCL2L1 decreased risk (OR=0.65, 95% CI: 0.44-0.96, p=0.03). BCL2L1 was also strongly associated with a lower PET score (OR=0.62, 95% CI: 0.46-0.83, p Conclusions: A combined multivariable model using interim PET and selected pre-treatment genes shows promising utility for enhanced prediction of cHL-EFS in early stage cHL that is independent of EORTC and GHSG pre-treatment clinical risk scores. These findings warrant further evaluation in an independent cohort with a view to more precisely individualising treatment, improving disease control and minimising late toxicity for patients with early stage cHL. Figure 1. Kaplan-Meier survival plot of cHL-EFS based on expression of CD22, BID and IL15RA Figure Disclosures Linton: Roche: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel, accommodations, expenses ; Celgene: Other: Travel, accommodations, expenses; Beigene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Burton:Leeds Teaching Hospitals NHS Trust: Current Employment; Takeda: Honoraria, Other: Travel Support; BMS: Honoraria; Celgene: Honoraria; Roche: Honoraria, Other: Travel Support. Illidge:Takeda: Honoraria; Merck: Research Funding; Roche: Consultancy; Takeda: Consultancy; Roche: Speakers Bureau; Takeda: Speakers Bureau; Roche: Honoraria. Radford:Pfizer: Research Funding; AstraZeneca: Current equity holder in publicly-traded company, Other: Spouse; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Current equity holder in publicly-traded company, Other: Spouse.

Background AHL2011 study (NCT01358747) demonstrated that PET negativity after 2 cycles of upfront BEACOPPescalated (BEA) allows to switch to 4 cycles of ABVD 84% of patients (pts) with advanced Hodgkin lymphoma (HL) leading to reduce immediate treatment toxicity without loss of tumor control (Casasnovas RO, Lancet Oncol 2019). We report an updated follow-up of the study with a focus on the late treatment-related adverse events including secondary primary malignancies (SPM) and unfertility. Methods In AHL2011 823 patients aged 18-60 with a newly diagnosed advanced HL defined by an Ann Arbor stage III, IV or IIB with M/T>0.33 or extranodal involvement were prospectively randomized between a standard arm (n=413) delivering 6 x BEA and a PET-driven arm (n=410) after 2 x BEA delivering 4 x ABVD in PET2- pts and 4 x BEA in PET2+ pts. In both arms PET performed after 4 cycles of chemotherapy had to be negative to complete the planned treatment. We aimed at excluding inferiority of the PET-driven arm of at least 10% compared to the standard arm which was achieved with the analysis on 10/2017. The data cutoff for the present analysis was 29 April 2019. A prospective fertility substudy for patients 24 IU/L twice during 5y follow-up when available, with estradiol < 50pg/ml, and low ovarian reserve (OR) by AMH < 0.16ng/ml. - In males, FSH serum levels and sperm analysis. Results With a 5.6 year median follow-up, 5y PFS and OS were similar in both randomization arms (PFS: 87.5% vs 86.7% ;HR 1.07, 95%CI 0.74-1.57; p=0.67; OS: 97.7% in both arms; HR=1.012, 95%CI 0.50-2.10; p=0.53). In the whole cohort full interim PET assessment predicted patients PFS (5y PFS = 92.3% in PET2-/PET4-, 75.4% [HR= 3.26 ;95%CI 18.3-5.77] in PET2+/PET4- and 46.5% [HR= 12.4 ;95%CI :7.31-19.51] in PET4+ pts respectively; p 5g (HR=0.36, 95%CI 0.14-0.96; p=0.04) but not to arms. In males, median baseline FSH levels were similar in both arms but 19 and 23% experienced severe oligospermia at baseline in standard (n=214) and PET-driven arms (n=210), respectively. Chemotherapy dramatically reduced sperm numeration in both arms but recovery occured more frequently in the PET-driven arm (severe oligospermia at 4-5 year: 50% vs 93%). A total of 84 patients (14.7%) reported pregnancies including 49 (17.2%) in the PET driven arm vs 35 (12.3%) in the standard arm (p=0.12) and required assisted reproductive technology treatment more frequently in the standard arm (23% vs 14%). Conclusions The prolonged follow-up confirms that the PET-driven strategy delivering 4 cycles of ABVD in PET negative patients after 2 cycles of BEA is non inferior compared to standard 6 cycles of BEA. PET4 provides additionnal prognostic information to PET2 and identifies patients with particularly poor prognosis. The PET-driven treatment allows to reduce significantly the risk of infertility in both men (recovery of oligospermia) and women (decreasing by 5 the risk of POI) and improves the chances of spontaneous pregnancy after completion of HL treatment. With the current follow-up the risk of SPM was low (2.7%) and similar in both arms. Disclosures Casasnovas: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; abbvie: Consultancy, Honoraria. Brice:Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; BMS: Honoraria; MSD: Honoraria; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Ghesquieres:Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; CELGENE: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria. Stamatoulas Bastard:Takeda: Consultancy; Celgene: Honoraria; Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Dupuis:Henri Mondor University Hospital Creteil France: Current Employment. Gac:Roche: Consultancy; Takeda: Consultancy. Bouabdallah:Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Morschhauser:Genentech, Inc. Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. André:Johnson & Johnson: Research Funding; Celgene: Other, Research Funding; Takeda: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Seattle Genetics: Consultancy; Novartis: Consultancy, Research Funding; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; Abbvie: Consultancy; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Meignan:ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Demeestere:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; THERAMEX FERRING: Other: TRAVEL, ACCOMMODATIONS, EXPENSES., info:eu-repo/semantics/published

Background: Anti-CD19 chimeric antigen receptor (CAR19) T-cells have significant activity in patients with relapsed/refractory DLBCL (rrDLBCL). While the majority of rrDLBCL patients receiving axicabtagene ciloleucel (Axi-cel)achieve complete responses, a significant subset of patients experience disease progression (Locke FL, et al. Lancet Oncol. 2019). Circulating tumor DNA (ctDNA) analysis has demonstrated utility for predicting therapeutic benefit in DLBCL, as well as for detecting emergent resistance mechanisms to targeted therapies. Here we apply cell-free DNA (cfDNA) analysis to patients receiving Axi-cel, to characterize molecular responses, resistance mechanisms, and to track CAR19 cells. Methods: We performed Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) on DNA from germline and plasma samples collected prior to CAR T-cell infusion, multiple time-points post infusion, and, where available, at the time of relapse from 30 patients receiving Axi-cel for rrDLBCL at Stanford University. We designed a novel hybrid-capture panel and analysis pipeline designed to detect both tumor variants, as well as Axi-cel specific recombinant retroviral sequences to quantify CAR19 levels in cfDNA. Tumor variants were identified prior to and following Axi-cel therapy to assess for emergent variants, and Axi-cel specific sequences were quantified. Results: The median follow-up for the 30 patients after Axi-cel infusion was 10 months, with 47% (14/30) of patients experiencing disease progression after Axi-cel therapy. We identified an average of 164.3 SNVs per case (range:1-685) before Axi-cel therapy; the most common coding variants identified at baseline were in MLL2 (29.2%), BCL2 (22.5%), and TP53 (19.3%). When treated as a continuous variable, pretreatment ctDNA levels were prognostic of PFS (HR 2.16, 95% CI 1.11-4.21, P=0.02). Using a previously established ctDNA threshold to stratify disease burden (2.5 log10(hGE/mL); Kurtz et al. JCO 2018), we observed significantly superior PFS in patients with low pretreatment ctDNA levels treated with Axi-cel (Fig. 1A). In the majority of Axi-cel treated patients (62.9%), ctDNA was detectable at day 28, and PFS was significantly longer in patients with undetectable ctDNA at this time-point (Fig. 1B). Multiple putative resistance mechanisms were identified at relapse after Axi-cel, including emergent variants in CD19, HVEM, and TP53, as well as copy number gains in PD-L1 (Fig. 1C). For example, in one patient, a CD19 stop-gain mutation, which was not detected prior to treatment or at the time of the first interim PET scan, emerged at the time of relapse (Fig. 1D). Finally, we found cfDNA evidence for Axi-cel DNA in 74% of patients 28 days after therapy, including in patients without evidence of circulating CAR T-cells in PBMCs. Axi-cel levels in cfDNA as measured by CAPP-Seq were significantly correlated with CAR19 flow cytometry (Pearson r=0.55, P=.015; Fig. 1E). Conclusions: Baseline and interim ctDNA measurements have prognostic significance in DLBCL patients being treated with CAR19 T-cells, and potential emergent resistance mutations, including in CD19, can be identified in patients via cfDNA analysis. Quantification of CAR19 T-cells using cfDNA is significantly correlated with flow cytometric quantification, indicating that these cells can be quantified via cfDNA. Taken together, these data indicate that cfDNA analysis is a powerful tool for predicting response to CAR19 therapy, identifying genomic determinants of resistance and quantifying CAR19 cells, which may in turn inform the next therapeutic steps. Figure 1: A) Kaplan Meier analysis of PFS, with patients stratified based on pre-Axi-cel therapy ctDNA level, above and below a previously established threshold (2.5 log10[haploid Genome Equivalents/mL]). B) A Kaplan Meier plot depicting PFS stratification for patients with detectable versus undetectable ctDNA at day 28 after Axi-cel infusion. C) Oncoprint depicting selected emergent and baseline tumor variants in progressors and non-progressors after Axi-cel therapy. D) Change in mean ctDNA variant allele frequency (VAF) and emergence of a CD19 stop-gain mutation (CD19 pTrpX) at the time of relapse in a patient who initially achieved a CR at day 28 after CAR19 infusion. E) Relationship between CAR19 T-cell quantification by cfDNA and flow cytometry. (ND: Not detected) Disclosures Kurtz: Roche: Consultancy. Chabon:Lexent Bio Inc: Consultancy. Khodadoust:Corvus Pharmaceuticals: Research Funding. Majzner:Xyphos Inc.: Consultancy; Lyell Immunopharma: Consultancy. Mackall:Obsidian: Research Funding; Lyell: Consultancy, Equity Ownership, Other: Founder, Research Funding; Nektar: Other: Scientific Advisory Board; PACT: Other: Scientific Advisory Board; Bryologyx: Other: Scientific Advisory Board; Vor: Other: Scientific Advisory Board; Roche: Other: Scientific Advisory Board; Adaptimmune LLC: Other: Scientific Advisory Board; Glaxo-Smith-Kline: Other: Scientific Advisory Board; Allogene: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Diehn:Roche: Consultancy; Quanticell: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy; BioNTech: Consultancy. Miklos:Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees. Alizadeh:Genentech: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Chugai: Consultancy; Roche: Consultancy; Pfizer: Research Funding.

Background:The role of radiation therapy (XRT) for advanced stage Hodgkin lymphoma (HL) is controversial. In the HD15 trial, the German Hodgkin Study Group (GHSG) administered XRT for PET-positive residual disease ≥2.5 cm at least 2 weeks after completion of chemotherapy and showed 91.5 % in-field control rate with a median follow-up of 102 months (Engert, A; personal communication). However, there is no comparison arm where patients with PET-positive residual disease ≥2.5 cm did not receive XRT. SWOG S0816 was a US intergroup trial utilizing ABVD-based therapy with response adaptation based on interim PET imaging; XRT was not allowed per protocol, and counted as an event. In this analysis, we identified patients in S0816 who would have met HD15 criteria for XRT, but did not receive XRT per design. We then modeled the potential impact of XRT on disease control. Patients and Methods:Of 336 eligible and evaluable HIV-negative patients enrolled in S0816, 49 had an end-of-treatment PET (termed "PET3," to be done 6-8 weeks after completion of chemotherapy) that was positive (i.e. Deauville 4-5) upon central review. We simulated the progression free survival (PFS) if XRT had been delivered per HD15 criteria (PET positive disease and ≥2.5 cm), evaluating by assumptions of 50, 80 and 90% control of the disease within the XRT fields. Receiver operating characteristics (ROC) analyses were performed with additional size cut-off points of 2.0 and 1.5 cm. Results:The median follow-up for the 49 PET3 positive patients was 71 months (range 9.7-92.6). For these 49 patients, the observed landmark PFS at 2 years after the date of PET3 was 30.6%. Twenty-four (49%), 33(67%), and 40 (82%) of the 49 patients had at least one site of disease that met the HD15 criteria for XRT with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm size cut-offs respectively. Sixteen, 19, and 25 patients had disease progression respectively from each group at median of 1.4-1.5 months. Twelve, 12, and 15 patients had relapses limited to the sites that would have been radiated following HD15 criteria with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm respectively. Estimated landmark PFS at 2 years for the 49 PET3 positive patients assuming 50, 80, and 90 % control of the disease within the radiated sites following HD15 guideline with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm cut-off are summarized in columns A, B, and C of the table respectively. For the entire group of 336 patients, the observed PFS at 2 years was 79%. Estimated 2-year PFS for the entire group of 336 patients assuming 50, 80, and 90 % control of the disease within the radiated sites following HD15 guideline with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm cut-off are in columns D, E, and F of the table respectively. Conclusion: Among the PET3 positive patients, consolidation XRT per HD15 criteria with cut-off points of 2.5, 2.0, and 1.5 cm could have raised the 2-year PFS by 12-28 % assuming 50-90% local control within radiated sites. However, the improvement in PFS is more moderate at 1.6-3.9 % if we consider the entire cohort of 336 patients. Although there may be some gain in PFS as the cut-off point is lowered by our ROC analysis, one needs to consider the trade-off against potentially increasing normal tissue toxicity as more sites are irradiated. Table. Table. Disclosures Brem: Pharamcyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees. Bartlett:Merck & Co: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Immune Design: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImaginAB: Research Funding; Janssen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Millennium: Research Funding; Genentech: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Evens:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Janssen: Consultancy; Tesaro: Research Funding; Bayer: Consultancy; Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Leonard:Novartis: Consultancy; Celgene: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; United Therapeutics: Consultancy; BMS: Consultancy; Biotest: Consultancy; Sutro: Consultancy; Karyopharm: Consultancy; Juno: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Bayer: Consultancy. Kahl:Seattle Genetics: Consultancy; Genentech: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy; Juno: Consultancy; Celgene: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.

Introduction:The combination of brentuximab vedotin (BV) with AVD chemotherapy followed by 30Gy 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 tested whether the ISRT dose could be reduced to 20Gy to minimize 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 20Gy ISRT in cohort 2. Eligible patients were 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 after ISRT were interpreted with the 5-point Deauville scale (negative=1-3). The primary endpoint of cohort 2 was to evaluate preliminary efficacy with the rate of complete responses (CRs). Results: In cohort 2, 29 patients were enrolled with median age of 33 (range 19-55), 100% stage II, 69% with disease bulk (>7cm), 41% elevated ESR, 38% B-symptoms, 21% extranodal involvement, 72% >2 involved lymph node sites, and 3% infradiaphragmatic disease. Twenty patients (69%) had bulky anterior mediastinal masses, ranging from 7 to 17.3cm. Nine patients (31%) had advanced stage disease by the GHSG criteria: IIBX (n=7) and IIBXE (n=2) disease. In cohort 2, 90% and 93% of patients achieved a negative PET scan after 2 and 4 cycles of therapy, respectively (Figure 1). Of the 2 patients with positive PET-4 scans, one underwent a biopsy that was negative for HL and the other was not biopsied due to the inaccessible location of residual FDG-uptake. Both patients received ISRT. The 28 patients who have completed combined modality therapy (CMT) all have achieved CRs. One additional patient chose to forego ISRT, received 2 additional cycles of ABVD off study, and achieved a CR. To date, the median duration of remission is 8.5 months, with a range of less than 1 month to 17 months. 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, two 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 20Gy ISRT is an effective treatment program for 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, 20Gy ISRT appears to be adequate consolidation after BV+AVD x 4 cycles. A third cohort of this pilot study is currently accruing in which patients receive BV+AVD x 4 cycles followed by 30Gy consolidation volume radiation. There is also a planned 4th cohort with no radiotherapy for PET-negative patients after 4 cycles of BV+AVD. After completion of the 4 cohorts, we plan to recommend the therapeutic strategy with the greatest efficacy and least toxicity to be further studied in a larger, randomized prospective study for early stage, bulky HL. Updated response data for all patients will be presented at the meeting. Disclosures Kumar: Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Casulo: Gilead: Honoraria, Other: travel support; Celgene: Research Funding; Infinity: Consultancy. Advani: Sutro: Consultancy; Nanostring: Consultancy; Celgene: Research Funding; Agensys: Research Funding; Spectrum: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Juno Therapeutics: Consultancy; Gilead: Consultancy; Regeneron: Research Funding; Millennium: Research Funding; Bayer Healthcare Pharmaceuticals: Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Merck: Research Funding; Infinity: Research Funding; Kura: Research Funding; Cell Medica: Research Funding; Pharmacyclics: Consultancy. Barr: Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Infinity: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Celgene: Consultancy; AbbVie: Consultancy, Research Funding. Chen: Affimed: Research Funding; Pfizer: Consultancy; Merck: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Drullinsky: Seattle Genetics: Honoraria, Other: Ad Board. Friedberg: Bayer HealthCare Pharmaceuticals.: Other: Data and Safety Monitoring Board: Bayer HealthCare Pharmaceuticals.. Gerecitano: Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aratana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Royal Bank of Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Arcus Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Orexo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mass Medical International: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hamlin: Gilead: Consultancy, Honoraria; Seattle Geneitcs: Other: research support; Incyte: Other: research support; Novartis: Other: research support; Celgene: Consultancy, Honoraria; Portola: Consultancy, Honoraria, Other: research support. Horwitz: Kyowa Hakko Kirin: Consultancy, Research Funding; BMS: Consultancy; Mundipharma: Consultancy; Aileron Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; HUYA: Consultancy; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Spectrum Pharmaceuticals: Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy; ADCT Therapeutics: Research Funding; Celgene: Consultancy, Research Funding. Moskowitz: ADC Therapeutics: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Incyte: Research Funding; Takeda: Honoraria; Seattle Genetics: Honoraria, Research Funding. Noy: Pharmacyclics LLC, an AbbVie Company: Honoraria, Other: Travel, Accommodation, Expenses, Research Funding, Speakers Bureau. Palomba: Merck: Consultancy. Straus: Received consulting fee from Seattle Genetics for involvement in the research: Consultancy. Younes: Takeda Millenium: Honoraria; Johnson & Johnson: Research Funding; Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Curis: Research Funding; Seattle Genetics: Honoraria; Sanofi: Honoraria; Merck: Honoraria; Janssen: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Bayer: Honoraria; Novartis: Research Funding. Zelenetz: Celgene: Consultancy; Amgen: Consultancy. Moskowitz: Genentech BioOncology: Consultancy; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Other: Ad Board, Research Funding; Celgene: Consultancy.

Introduction: Baseline (PETb) and end of therapy (PETe) FDG PET is standard of care in the management of hodgkin's lymphoma (HL) and diffuse large B cell lymphoma (DLBCL). The role of interim PET (PETi) in HL is well established while its role in DLBCL is not well defined. We evaluated the utility of triPET (PETb, PETi and PETe ) in management of these two lymphomas. Methods: Retrospective review of PET archives revealed a total of 37 pts (HL=22, DLBCL=15). TriPET were acquired per accepted protocol. SUVmax and Deauville scores (DSc) were obtained from five target lesions, the average i.e. composite SUVmax & DSc were computed for each pt. Statistical analyses were performed with the composite maxSUV (cSUV) and Deauville scores (cDSc) (using EXCEL). Following statistics were performed (separately and combined in HL and DLBCL); mean+SD, PPV and NPV for complete response (CR) Vs. progressive disease (PD) on PETi using the following variables 1. cSUV and 2. cDSc and 3. delta change (DELT). Median progression free survival (PFS) was the clinical endpoint for response. Results: The mean PFS in our group was 17 and 15 months in HL and DLBCL respectively. Using cut off thresholds for intP to predict CR at cSUV=80%,. In HL: for cSUV- PPV 67%, NPV 95%; for DELT of cSUV PPV 100%, NPV 95%; for cDSC-PPV 30%, NPV 100%. In DLBCL: for cSUV- PPV 25%, NPV 100%; for DELT of cSUV PPV 33%, NPV 100%; for cDSC- PPV 50%, NPV 100%. Conclusion: The results from our series suggest that PETi has a role not only in HL but in DLBCL as well. Our modest cohort suggests that a negative PETi in DLBCL had a NPV of 100% across cSUV, cDSc and DELT, with regards to CR. Our data also suggests that PETe is not needed if PETi is -ve. While in HL subset, our results concur with results from other groups, this needs to be validated in a larger series. Disclosures No relevant conflicts of interest to declare.

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. Disclosures Zaucha: 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.

Background 18 F-FDG PET is currently used in diffuse large B-cell lymphoma (DLBCL) for staging and evaluation of therapeutic efficacy at various time points. Nevertheless, the predictive value of interim PET/CT (iPET/CT) has not been consistent throughout the studies. Since FDG is not a tumor-specific substance, it may accumulate to the point of being detected in a variety of benign conditions or infectious lesions, which may give rise to false positive interpretation. Particularly, iPET/CT assessment in patients with multifocal, non-contiguous involvement at extranodal (EN) sites may result in a false determination of prognosis due to tracer uptake of inflammatory or physiologic anatomic sites, which could contribute to the variability in outcomes and the poor reproducibility. Therefore, the purpose of this study is to investigate the predictive accuracy of iPET/CT response based on visual and quantitative SUV-based assessments in patients with DLBCL and EN involvements. Methods iPET/CT responses for 163 patients with newly diagnosed DLBCL and EN involvements were investigated retrospectively. iPET/CT responses were based on the visual and quantitative SUV-based assessments. Briefly, the assessment of PET/CT was performed at the time of diagnosis, at the third or fourth cycles and at the completion of R-CHOP. For visual assessment, the five-point scale (5-PS) based on the Deauville criteria was used and graded as negative or positive by comparison with initial PET/CT scan and grade 1-3 were considered as negative and grade 4-5 were considered the residual metabolic response. Second, we classified patients using the quantitative analysis of 18 F-FDG uptake changes based on the percentage of SUVmax reduction (DSUVmax) between initial and interim PET/CT scans. The cutoff points of DSUVmax were 65.7% based on previous reports. Results Median age was 61 years (range 18-83 years) and 88 patients (54.0%) in advanced disease (III/IV). Patients were classified according to the IPI risk with 95 patients (58.3%) being classified as low or low-intermediate and 68 patients (41.7%) as high-intermediate or high risk. Number of extranodal site(s) were 1 site in 102 patients (62.6%), 2 sites in 39 (23.9), 3 sites in 18 (11.0), and 4 sites in 4 (2.5%). iPET/CT responses based on visual analysis were classified into grade 1-3 of 5-PS in 99 patients (60.7%) and grade 4-5 in 64 (39.3%), and based on SUV-based, classified into higher the cutoff of DSUVmax (>65.7%) in 140 patients (85.9%) and lower (67.5%). The 5-year overall survival (OS) rates and progression free survival (PFS) rates were 75.6±3.8% vs 60.6±11.7% (p=0.056), and 77.9±3.7% vs 55.9±12.1% (p=0.007) depending on the cutoff of DSUVmax, respectively. Among the patients with 1 EN involvement, DSUVmax successfully predict the long-term outcomes in terms of 5yr-OS (83.2±4.3% vs 62.1±14.6%, p=0.012) and PFS (86.9±3.9% vs 41.3±16.6%, p Conclusion The quantitative SUV-based assessments in iPET/CT could have significant potential as a prognostic predictor of PFS and OS, especially in the patients with 1 EN site involvement. However, the visual assessments have the limitations to predict long-term outcomes with high false positive rates at EN involvements. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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

In this issue of Blood , Horning and colleagues report that there was disagreement by 3 nuclear medicine experts on interpretation of FDG-PET images obtained in the context of a clinical trial in aggressive non-Hodgkin lymphoma 32% of the time. 1 These results emphasize the need for standardized criteria to interpret interim PET scans in lymphoma and should cause physicians to question the practice of changing therapy based on PET imaging outside the context of a trial.

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 MTV was measured by FDG PET/CT with a semi automatic method using various volume shapes and systematic 41% SUVmax thresholding. Tumor mass with a maximum diameter > 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%; p70% after 4 cycles of immunochemotherapy (n=101, 88%) into 2 separated prognosis subsets (2y-PFS: 90% vs. 77%, p In our series baseline MTV was predictive of PFS and OS in high risk DLBCL patients while bulk was not. MTV identified different risk categories of DLBCL patients within DLBCL patients with a good interim response (ΔSUVmax0–4 >70%) and may improve the negative predictive value of interim PET. Disclosures: No relevant conflicts of interest to declare.

Abstract 2721 Role of interim- and final-PET in peripheral T-cell lymphoma (PTCL) is quite unknown. To determine predictive value of PET on overall survival (OS), we evaluated interim-PET (i-PET) and final-PET (f-PET) in PTCL patients treated in first-line with 6 CHOP-21 courses. From September 2003 to July 2010 we diagnosed and treated in our institution 34 advanced stage PTCL patients (15 females and 19 males). The median age at diagnosis was 46 years (range, 21–81 years); 9 patients were in stage III, and 25 in stage IV. According to the histologic subtype there were 11 PTCL-nos, 6 AILT, 9 ALCL Alk+, 6 ALCL Alk-, and 2 NK/T nasal type patients. Four patients had bulky disease; eight patients had bone marrow involvement, 15 patients had 1 extranodal involvement and 10 had more than 2 extranodal sites. All patients underwent initial staging PET/CT; i-PET was performed after 3 cycles of CHOP-21 and the median time from the end of third course to i-PET was 14 days (range, 7– 18 days). f-PET scans were performed 35 days (range, 30– 45 days) after the end of therapy. The table summarizes the correspondence between i-PET and f-PET results: N=34 f-PET negative, n (%) f-PET positive, n (%) i-PET negative 27 19 (70.4) 8 (29.6) i-PET positive 7 1 (14.2) 6 (85.8) With a median follow-up of 71 months (range, 5.8–120.9 months), 17/19 (89.5%) patients with i-PET negative are in continuous CR (CCR) and only 1/7 (14.2%) patient with i-PET positive is still in CCR. Figures show the overall survival (OS) according to response at i-PET and f-PET. In figure 1a we observe OS plotted according to i-PET results: 78.6% for negative patients (solid line) and 21.4% for positive patients (dashed line) at 88.7 months (p=0.02); in figure 1b we observe OS plotted according to f-PET results: 93.7% for negative patients (solid line) and 21.4% for positive patients (dashed line) (p In conclusion, our results demonstrate that positive i-PET is not predictive of a worse outcome in PTCL. On the contrary, the f-PET seems to represent a significant step forward in the prediction of survival for these patients. Larger and prospective studies and harmonization of PET reading criteria are needed. Disclosures: No relevant conflicts of interest to declare.

Abstract 3879 Purpose. The use of early (interim) positron emission tomography (PET) restaging during front-line therapy in Hodgkin's lymphoma (HL) has considerably increased in clinical practice as an early recognition of treatment failure allows patients to be addressed to more intensive treatment regimens. Patients and Methods. Between June 1997 and June 2009, 304 newly-diagnosed Hodgkin's lymphoma patients (147 early-stage and 157 advanced-stage) were treated with the ABVD regimen at two Italian institutions. Patients underwent to a PET staging and restaging at baseline, after 2 cycles of therapy and at the end of the treatment. Results. 53 patients showed a positive interim PET and only 13/53 (24.5%) achieved a complete response (CR), whereas 251 patients showed a negative PET and 231/251 (92%) remained in CR. Comparison between interim PET-positive and interim PET-negative patients indicated a significant association between PET findings and 9-year progression-free survival (p=0.0000) and 9-year overall survival (p=0.0000), with a median follow-up of 31 months. Among the early-stage patients, 19 had a positive interim PET and only 4 (21%) achieved a CR; among the 128 negative interim PET patients, 122 (97.6%) obtained a CR. In the advanced-stage subset, 34 patients showed a persistently positive PET (with only 9/34, 26.4% in CR), whereas 123 showed a negative interim PET, with 109 (88.6%) remaining in CR. Conclusions. Our results confirm the role of early PET as a significant step forward for the management of both early and advanced-stage HL patients, offering the potential for an immediate switch to high-dose treatments, if required. Disclosures: No relevant conflicts of interest to declare.

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