Schöder, Heiko

PURPOSE Patients with bulky stage I/II classic Hodgkin lymphoma (cHL) are typically treated with chemotherapy followed by radiation. Late effects associated with radiotherapy include increased risk of second cancer and cardiovascular disease. We tested a positron emission tomography (PET)–adapted approach in patients with bulky, early-stage cHL, omitting radiotherapy in patients with interim PET-negative (PET−) disease and intensifying treatment in patients with PET-positive (PET+) disease. METHODS Eligible patients with bulky disease (mass > 10 cm or 1/3 the maximum intrathoracic diameter on chest x-ray) received two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by interim fluorodeoxyglucose PET (PET2). Patients with PET2–, defined as 1-3 on the 5-point scale, received four additional cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Patients with PET2+ received four cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone followed by 30.6 Gy involved-field radiation. RESULTS Of 94 evaluable patients, 53% were female with median age 30 years (range, 18-58 years). Eight-five (90%) had stage II disease, including 48 (51%) with stage IIB/IIBE. Seventy-eight (78%) were PET2– and 21 (22%) were PET2+. The predominant toxicity was neutropenia, with 9% of patients developing febrile neutropenia and one developing sepsis. The primary end point of 3-year progression-free survival (PFS) was 93.1% in PET2– and 89.7% in PET2+ patients. Three-year overall survival was 98.6% and 94.4%, respectively. The estimated hazard ratio comparing PFS of patients with PET2+ and patients with PET2− was 1.03 (85% upper bound 2.38) and was significantly less than the null hypothesis of 4.1 (one-sided P = .04). CONCLUSION Our study of PET-adapted therapy in bulky stage I/II cHL met its primary goal and was associated with an excellent 3-year PFS rate of 92.3% in all patients, with the majority being spared radiotherapy and exposure to intensified chemotherapy.

Abstract Advanced molecular and pathophysiologic characterization of primary central nervous system lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: (1) critically review the use of advanced positron emission tomography (PET) and magnetic resonance imaging (MRI) in the setting of PCNSL; (2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and (3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both “ideal” and “minimum standard” protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.

Abstract Background Patients with human papillomavirus–related oropharyngeal cancers have excellent outcomes but experience clinically significant toxicities when treated with standard chemoradiotherapy (70 Gy). We hypothesized that functional imaging could identify patients who could be safely deescalated to 30 Gy of radiotherapy. Methods In 19 patients, pre- and intratreatment dynamic fluorine-18-labeled fluoromisonidazole positron emission tomography (PET) was used to assess tumor hypoxia. Patients without hypoxia at baseline or intratreatment received 30 Gy; patients with persistent hypoxia received 70 Gy. Neck dissection was performed at 4 months in deescalated patients to assess pathologic response. Magnetic resonance imaging (weekly), circulating plasma cell-free DNA, RNA-sequencing, and whole-genome sequencing (WGS) were performed to identify potential molecular determinants of response. Samples from an independent prospective study were obtained to reproduce molecular findings. All statistical tests were 2-sided. Results Fifteen of 19 patients had no hypoxia on baseline PET or resolution on intratreatment PET and were deescalated to 30 Gy. Of these 15 patients, 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4% (95% confidence interval = 84.4% to 100%) and 94.7% (95% confidence interval = 85.2% to 100%), respectively. No acute grade 3 radiation–related toxicities were observed. Microenvironmental features on serial imaging correlated better with pathologic response than tumor burden metrics or circulating plasma cell-free DNA. A WGS-based DNA repair defect was associated with response (P = .02) and was reproduced in an independent cohort (P = .03). Conclusions Deescalation of radiotherapy to 30 Gy on the basis of intratreatment hypoxia imaging was feasible, safe, and associated with minimal toxicity. A DNA repair defect identified by WGS was predictive of response. Intratherapy personalization of chemoradiotherapy may facilitate marked deescalation of radiotherapy.

Background FDG-PET is used in staging and response assessments in patients (pts) with DLBCL. An analysis of 158 pts with DLBCL receiving R-CHOP or DA-EPOCH-R on CALGB/Alliance 50303 failed to show an association between the interim PET (iPET, after cycle 2 of therapy) visual 5-point scale score (5-PS) by central review and progression-free survival (PFS) or overall survival (OS), but did show a significant association between percent change in FDG uptake from baseline to after cycle 2 (∆SUV) and PFS/OS (Schoder et al. 2020). As central review of FDG-PET is not feasible in routine practice, we retrospectively compared local vs central readings, and determined associations from local imaging data with PFS/OS. Methods 126 pts at baseline and 109 at iPET had local imaging data submitted across 21 institutions. Visual scores 1-3 defined PET- and scores 4-5 defined PET+ disease. ∆SUV was defined as the percent change in the maximum SUV at any site (maxSUV) from baseline to iPET. Continuous ∆SUV and categorized ∆SUV (<66% vs >66%) were analyzed. Differences in quantitative measures were calculated as the local minus central result. The Kappa statistic estimated agreement in PET and ∆SUV groups between local and central review. PFS and OS distributions for local PET and ∆SUV groups were landmarked at iPET, estimated with the Kaplan-Meier method, and compared using the log-rank test. Results At baseline, maxSUV was reported locally and centrally in 118 pts. Median maxSUV was 24.3 (range: 5.9-77.3) by local review and 24.3 (range: 5.9-77.0) by central review. The median difference in maxSUV was 0 (range: -12.9 to 21.9), with 50% of differences between -1.1 and 0.1, and 90% of differences between -7.8 and 4.1. In 106 pts with visual iPET 5-PS results, 52 (49.1%) were PET+ by local review and 37 (34.9%) by central review. Agreement in local and central review was moderate (kappa=0.53), occurring in 81 pts (76.4%; 32 PET+ and 49 PET-). Disagreement occurred in 25 patients, 20 with local PET+ but central PET- and 5 with local PET- but central PET+. iPET maxSUV was reported locally and centrally in 90 pts. Median maxSUV was 3.4 (range: 0-18.3) by local review and 3.3 (range: 1.2-18.2) by central review. The median difference in maxSUV was 0 (range: -8.6 to 2.4), with 50% of differences between -0.3 and 0.4, and 90% of differences between -4.4 and 1.8. ∆SUV was calculated in 87 pts. Median ∆SUV was 84.6% (range: -3.0% to 95.9%) by local review and 85.1% (range: -34.9% to 95.8%) by central review. The median difference in ∆SUV was -0.3 (range: -19.6 to 31.9), with 50% of differences between -2.1 and 1.1, and 90% of differences between -7.1 and 12.3. ∆SUV was <66% in 12 (13.8%) pts by local review and 12 pts by central review. Agreement in local and central review was high (kappa=0.81), occurring in 83 pts (95.4%; 10 with ∆SUV <66%, 73 with ∆SUV >66%). Disagreement occurred in 4 pts, 2 in each direction. Using local data, PFS and OS estimates were numerically lower in pts with iPET+ vs iPET- disease, but did not reach statistical significance (p=0.12 and p=0.15). Two-year estimates for PFS were 79% (95% CI 68-91%) and 89% (95% CI 81-98%), and 2-year estimates for OS were 84% (95% CI 75-95%) and 96% (95% CI 91-100%) in pts with iPET+ and iPET-, respectively. In contrast, ∆SUV groups were significantly associated with PFS and OS (p=0.03 and p=0.002). Two-year estimates for PFS were 56% (95% CI 34-94%) and 87% (95% CI 79-95%) and 2-year estimates for OS were 56% (95% CI 34-94%) and 93% (95% CI 88-99%) in pts with ∆SUV <66% and ∆SUV >66%, respectively. Conclusion Agreement in visual 5-PS at iPET was moderate; most discrepancies arose from a local PET+ result when central review called PET-. Differences in maxSUV and ∆SUV tended to be small. Grouping ∆SUV resulted in only 4 discrepancies (4.6%). Similar to the previous analysis using central data, the separation in PFS and OS curves using local data for ∆SUV was greater than by visual 5-PS. Encouragingly, the agreement in ∆SUV of <66% vs ≥66% was high between local and central review. Overall agreement however may be unduly influenced by the large proportion of pts with ∆SUV ≥66%, with less certainty in agreement for pts with ∆SUV <66%. Larger prospective studies comparing local and central imaging data are warranted to best determine the utility of local imaging in clinical trials. Support: P30 CA008748, U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT00118209 (CALGB 50303) Disclosures Kahl: Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Friedberg:Astellas: Consultancy; Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Portola Pharmaceuticals: Consultancy; Seattle Genetics: Research Funding; Roche: Other: Travel expenses; Kite Pharmaceuticals: Research Funding; Bayer: Consultancy. Leonard:MEI Pharma: Consultancy; Sutro: Consultancy; Bayer: Consultancy; BMS/Celgene: Consultancy; GenMab: Consultancy; Roche/Genentech: Consultancy; Gilead/Kite: Consultancy; ADC Therapeutics: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; Miltenyi: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy. Bartlett:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Forty Seven: Research Funding; BMS/Celgene: Research Funding; BTG: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding.

Abstract 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.

Abstract As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.

Abstract Introduction For patients with Stage III/IV Hodgkin lymphoma (HL), lack of response as assessed by PET scan following cycle 2 (PET2) of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is predictive of poor clinical outcomes. SWOG Study S0816 utilized response-adapted therapy, where patients achieving a complete remission (CR) on PET2 (Deauville Score ≤ 3) continued 4 additional cycles of ABVD and those patients unable to achieve a complete remission (CR) on PET2 (Deauville Score > 3) were switched to therapy with escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. This study demonstrated a 2-year PFS of 64% in the PET2+ patients after switching to eBEACOPP, which was much higher than expected (Press 2016). Herein, we report the 5-year follow-up of survival and toxicities of the patients treated on S0816. Methods Patients with Stage III/IV HL were enrolled to S0816 from 7/1/09-12/2/12 (n=358). Eligible patients were age 18-60 years, had measurable disease, no prior lymphoma therapy, a Zubrod performance status of 0-2, and no serious medical comorbidities. Patients were treated with response-adapted therapy as above. A subset of 336 eligible and HIV-negative patients were analyzed. Of 336, 331 had central review of PET2. PFS and OS estimates were calculated using the Kaplan-Meier method. The two-sided Fisher's exact test was used to compare the rate of second cancer between patients switched to treatment eBEACOPP and those treated with continued ABVD after 2 initial cycles of ABVD. Results The median age of patients was 32 years (range, 18-60). All were Stage III/IV and 51% had an International Prognostic Score of ≥ 3. PET2 was negative in 271 patients (82%) and positive in 60 patients (18%). Of PET2+ patients, 49 (82%) switched to eBEACOPP as planned and 11 (18%) declined. Median follow-up is now 5.9 years (range, 0.2-8.3 years). Eighty-five (25%) patients have either progressed or died, for an estimated 5-year PFS of 74% (95% CI: 69%-79%; Figure 1). There were 64 (24%) events in those patients who were PET2- for a 5-year PFS of 76% (95% CI: 71-81%; Figure 2). There were 20 (33%) events in those patients who were PET2+ for a 5-year PFS of 65% (95% CI: 51-76%; Figure 2). One event occurred in a patient without central review of PET2. Nineteen patients have died for an estimated 5-year overall survival of 94% (95% CI: 91%-96%; Figure 1). Eleven (3%) patients died of HL including 6 (2%) that had PET2- and 5 (8%) that had PET2+. Other causes of death included: treatment-related toxicity [sepsis (eBEACOPP n=1), bleomycin lung injury (eBEACOPP n=1; ABVD n=1), and graft versus host disease (ABVD n=1)]; second primary cancers [(eBEACOPP n=2; cervical cancer and non-Hodgkin lymphoma (NHL)]; and unknown causes (ABVD n=2). Post-therapy grade 3 adverse events were uncommon but included 1 case each of heart failure, peripheral neuropathy, prolonged neutropenia, diarrhea, DVT (catheter-related) in patients who received continued ABVD and osteonecrosis of hips/shoulders in patients who received eBEACOPP. There were 13 (4%) cases of reported second cancers, including 7 (14%) in patients treated with eBEACOPP [1 each of myelodysplastic syndrome, kidney, melanoma, NHL, cervical, medullary thyroid, and basal cell carcinoma] and 6 (2%) in patients treated with ABVD (1 each of kidney, melanoma, NHL, bladder, prostate, and squamous cell carcinoma; 2-sided Fisher's exact P value = 0.001). Conclusions The long-term overall survival of the patients treated on S0816 remains high (94%) at 5 years. Despite historical data suggesting favorable clinical outcomes in patients with a negative PET2, nearly 25% of these patients experienced relapse events, demonstrating limitations of a PET-adapted approach and of standard frontline therapy with ABVD. In patients who were PET2+, PFS was favorable relative to historical series, but was associated with a high rate of secondary malignancies. Our results emphasize the importance of long-term follow-up in this disease, and the need for better biomarkers at diagnosis of HL and less toxic approaches for patients with a positive PET2. Acknowledgment In memory of Oliver W. Press, principal investigator of this trial, who died in 2017. Disclosures Straus: DAVA Oncology: Consultancy, Honoraria; Medical Crossfire: Speakers Bureau; Millenium (Takeda): Consultancy, Research Funding; JUNO: Consultancy; Bayer: Consultancy; Onco Tracker: Consultancy; Seattle Genetics: Consultancy; Roch China: Speakers Bureau; InPractice Elselvier: Consultancy; Memorial Sloan Kettering Cancer Center: Employment. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Bartlett:ImaginAB: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Evens:Janssen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Acerta: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria. Barr:AbbVie, Gilead: Consultancy. Leonard:Gilead: Consultancy; Sutro: Consultancy; BMS: Consultancy; Juno: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Biotest: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Genentech/Roche: Consultancy; ADC Therapeutics: Consultancy; United Therapeutics: Consultancy. Kahl:Genentech: Consultancy; Celgene: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Juno: Consultancy; CTI: Consultancy; ADC Therapeutics: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.

Abstract 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.