PET2 Response Research Articles

High IL1-RA Plasma Levels at Baseline Allow to Identify Hodgkin Lymphoma Patients with High Risk of Treatment Failure

Introduction: About 10% of localized stages and 20-30% of advanced stages patients (pts) with classical Hodgkin lymphoma (cHL) progress or relapse after the first line of treatment. Therapeutic failures prediction at diagnosis is a major challenge to modulate treatments to minimize acute and long-term toxicities, while having optimal efficacy. The development of prognostic tools is crucial to help therapeutic decision. In 2007, Casasnovas et al. JCO 2007, demonstrated that a plasma cytokine signature composed of IL1-RA, IL-6 and sCD30 could predict pts outcomes and identify pts with high risk of treatment failure. However, it was unusable in routine practice as the ELISA technique used had extensive delay. Since interim PET during induction chemotherapy became the standard approach to guide the therapeutic strategy, and therefore the use of new pre-therapeutic biomarkers deserves to be investigated in the context of PET-guided treatment. As PD-L1, and thymus and activation-related chemokine (TARC) have an important role in cHL physiopathology we analyzed the prognostic impact on progression-free, and overall survival (PFS and OS) of pretherapeutic plasma levels of PD-L1 and TARC in addition to IL1-RA, IL-6, sCD30, in pts treated with a PET-guided strategy. Method: The dosage of IL1-RA, IL-6, PD-L1 and TARC was performed using the ELLA automated immunoassay system (Biotechne) while sCD30 was performed in triplicate using ELISA assay. Samples were prospectively collected (period 2016-2020) within the biocollection BIO-LYMPH (NCT04417803) in the pts treated in the department of Hematology at Dijon Hospital. X tile analysis was used to define the optimal cutoff for survival prediction for each cytokine. Survival functions of pts' subgroups defined by the cytokine circulating levels were estimated using the Kaplan-Meier product limit method and compared using the log rank test. The Cox proportional hazard regression model was used to estimate HRs and associated 95% CI in univariate and multivariate analyses. Results: Among the 105 pts enrolled in this study (Median age: 36 years, range: 17 - 85), 60% were under 45 years, 61% had advanced stage disease, 58% B symptoms, and 39% an IPS >2. 63% of pts had nodular sclerosis HL subtype and 22% had EBV associated HL. Response was assessed at the end of treatment: 89 pts (84 %) achieved a complete response, 4 pts (4%) a partial response, and 9 pts (9%) had progressive disease. With a median follow-up time of 40 months (1-78 months), 13 pts (12 %) relapsed with a median time to relapse of 16 months (range, 4 to 65 months), 14 pts (13 %) died (11 due to cHL progression; 1 due to septic shock; 1 from SARS covid infection; and 1 after a traumatism). While pretherapeutic plasmatic levels of IL-6, sCD30, TARC and PD-L1 did not impact pts survival, IL1-RA was an independent predictor of both PFS and OS. Indeed, 31% of pts harbored high IL1-RA plasma level (≥ 740 pg/ml) and had an unfavorable PFS (5y-PFS: 50.2% vs 86.7%; HR=4.2, CI=2.1-10.3, p=0.0001, figure 1A) and OS (5y-OS 71.4% vs 95%, HR=4.49, CI=1.3-14.2, p=0.006). PET2 positivity (17% of pts) had an unfavorable prognosis value on PFS (5y-PFS 58% vs 86.6%, HR 4.3, CI= 1.4-12.8, p=0.014) but not on OS (5y-OS 91.8% vs 74.1%; HR=3.2 CI=0.7-14.4, p=0.15) independent from pretherapeutic IL1-RA plasma level (PFS multivariate analysis: PET2 positivity HR=2.43, CI=1-6, p= 0.05; High level IL1-RA HR= 3.4, CI=1.5-8.3, p= 0.005). The combination of both PET2 results and pretherapeutic IL1-RA plasma levels allow to stratify pts' outcome into 3 groups (figure 1B): - Pts (57%) with low levels of IL1-RA and negative PET2 had a 5y-PFS of 89.3% and 5y-OS of 95.8%, - Pts with high levels of IL1-RA or positive PET2 (35%) had a 5y-PFS of 57% and 5y-OS of 74.8% whereas - Pts with both (8%) had a 5y-PFS of 42.9% and 5y-OS of 71.4%. The groups with one or 2 prognostic factors (PET2+ or high IL1RA and PET2+ & high IL1RA) had a significantly different PFS compared to the double negative group (1 factor: HR=4.7, CI=1.8-12.2, p=0.0011 and 2 factors: HR= 8.57, CI=2.5-28.3, p=0.0004 respectively). The group with 1 prognosis factor had a significantly different OS (HR=4.1, CI=1.1-15.3, p=0.03) compared to double negative group but not the 2 factors group (HR= 4.9, CI=0.8-30, p=0.08). Conclusion: Pretherapeutic IL1-RA plasma levels allow to stratify the prognosis of pts with cHL treated with first line PET-guided strategies and add prognosis information to PET2 response.

Comprehensive Analysis of Treatment Related Morbidity and Progression -Free Survival in the GHSG Phase III HD21 Trial

INTRODUCTION The GHSG-HD21 trial for newly diagnosed adult patients with advanced-stage classical Hodgkin lymphoma (AS-cHL) compares the BrECADD regimen (Brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) to eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in a PET adapted approach. Separate analyses of the co-primary endpoints for tolerability and efficacy demonstrated a significant and relevant reduction in treatment-related morbidity (TRMB) and non-inferiority of PFS, respectively. Here, we report the first combined comprehensive analysis of the primary endpoints of the HD21 trial. METHODS This international open-label phase III trial included adult patients aged ≤ 60 yrs with AS-cHL. Patients were randomized in a 1:1 ratio to PET2-guided 4-6 21-day cycles of either eBEACOPP or BrECADD. PET2 and PFS events were assessed by blinded panel review. At a planned interim analysis at 36 months follow-up, the efficacy endpoint PFS was determined in the ITT cohort comprising 1,482 patients (eBEACOPP n=740, and BrECADD n=742) while the safety endpoint TRMB was determined in 1,470 patients (BEACOPP n=732, and BrECADD n=738). Subgroup analyses were calculated with 95% confidence intervals (Cis). The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. RESULTS Between July 2016 and August 2020, we enrolled 1,500 patients from 9 countries across 233 trial sites. Actual median follow-up for this analysis was 40 months. Baseline characteristics were well balanced between treatment arms, median age was 34 yrs (range 18-61), and 47% were high-risk (international prognostic index IPS ≥ 3). Overall, the relative risk for a TRMB event was 0.72 (95% CI, 0.65-0.79) in favor of BrECADD. Subgroup analyses confirmed a consistent, highly significant TRMB benefit in all relevant subgroups. Dose reductions were required less frequently with BrECADD than with eBEACOPP (figure 1); full dose treatment at cycle 4 was administered in 58.5% of patients in the eBEACOPP group compared to 77.8% in the BrECADD group. In PET2-positive patients at cycle 6, full dose treatment was received by 42.5% in the eBEACOPP group versus 67.3% in the BrECADD group. Most frequent reasons for dose reductions were leukopenia for eBEACOPP (in 33.7% of patients) and thrombocytopenia for BrECADD (in 23.1 % of patients). 59% of patients achieved a PET2-negative response and were treated with a total of 4 cycles in each group; conversely, 41% of patients were PET2-positive and received 6 cycles. At the end of treatment with either 4 or 6 cycles, a complete metabolic response was seen in 80% and 82% of patients in the eBEACOPP and BrECADD cohorts, respectively. The 3-yr PFS was 94.9% for BrECADD (95% CI 93.5% - 96.7%), and 92.3% for eBEACOPP (95% CI 90.3% - 94.3%), with a corresponding HR of 0.63 (95% CI 0.42-0.94). A HR favoring BrECADD was consistently observed across all relevant subgroups (figure 2). Notably, HRs favoring BrECADD were generally lower in lower-risk cohorts including IPS (0, 1; 2, 3; 4-7: HR 0.45, 0.59, 0.87, respectively), stage (Ann-Arbor stage II, III, IV: HR 0.35, 0.6, 0.78, respectively), or PET-2 response (negative versus positive, HR 0.4, 95% CI 0.21-0.76 vs 0.78, 95% CI 0.44-1.38). Corresponding 3-yr PFS rates for BrECADD versus eBEACOPP were 97.1% (95% CI 95.5% - 98.7%) versus 93.6% (95% CI 91.3% - 95.9%) for PET2-negative patients and 93.5% (95% CI 90.6% - 96.5%) versus 90.6% (95% CI 87.1% - 94.1%) for PET2-positive patients, respectively. CONCLUSION With the novel BrECADD regimen, we observed the highest 3-yr PFS rates reported to date in a randomized clinical trial in advanced-stage cHL. Our analyses suggest that the unexpectedly high and improved efficacy of the new BrECADD regimen compared to eBEACOPP is a direct consequence of its improved tolerability and deliverability. Importantly, while the larger patient cohort of PET2-negative patients achieves a very high 3-yr PFS of 97% with a very short and safe 12-week treatment, this benefit was also observed for PET2-positive patients. In conclusion, the optimized risk-benefit ratio of the BrECADD regimen combined with the individualized PET2-guided treatment duration sets a new benchmark for the treatment of adult patients with newly diagnosed advanced stage cHL

Combined modality therapy for early-stage Hodgkin lymphoma in the PET era: A real-world study.

e19532 Background: The traditional approach to the treatment of early-stage classical Hodgkin lymphoma (cHL) has been combined modality therapy (CMT) with both chemotherapy and radiotherapy (RT). CMT has shown improved disease control, but RT can lead to long-term adverse effects, including secondary malignancies and cardiac toxicity. Multiple clinical trials have assessed treatment de-escalation strategies to chemotherapy-alone regimens, but results are conflicting. We aimed to assess the real-world implications of these trials by comparing patient outcomes based upon treatment with CMT or chemotherapy-alone. Furthermore, we proposed to assess differences in treatment outcomes stratified by disease bulk, favorable/unfavorable disease, and PET2 response. Methods: We conducted a retrospective, multi-center cohort study of consecutive adult patients with early-stage (stage IA-IIB) cHL treated between January 2010-December 2020. Baseline characteristics, treatment modality, and outcomes were abstracted by chart review. Available PET2 scans (n=110) were independently reviewed by a blinded nuclear radiologist. Deauville score (DS) ≥4 was characterized as positive (+), and DS≤3 negative (-). All analysis was conducted using intention-to-treat principles based upon the initial treatment plan (CMT or chemotherapy-alone). Results: In 125 patients [58% male, median age 34 (range, 18-78)] with early-stage cHL, CMT was intended in 63 (50%) patients, with chemotherapy-alone in 62 (50%). Bulky disease was observed in 43 (34%), unfavorable disease in 81 (65%), and 15 (14%) were found to be PET2+. With median follow-up of 59.8 months (95%CI, 48.6 to 71.0), 5 (4%) deaths occurred, and 17 (14%) patients had relapsed/refractory disease. No significant differences in overall survival (OS) were seen based upon treatment intention. However, there was substantially reduced progression-free survival (PFS) (Table) with chemotherapy-alone in the whole cohort, and also in those with bulky, unfavorable, and PET2+ disease. No significant PFS differences were seen based upon treatment intention for patients with non-bulky, favorable, or PET2- disease. Conclusions: Based on our real-world experience, CMT appears particularly beneficial for patients with bulky disease, unfavorable prognostic factors, and PET2+ disease. However, while recent trials showed a benefit of CMT in non-bulky, favorable and PET2- patients, chemotherapy-alone may be comparable for these patients in actual clinical practice.[Table: see text]

High-risk stage IIB Hodgkin lymphoma treated in the H10 and AHL2011 trials: total metabolic tumor volume is a useful risk factor to stratify patients at baseline.

Stage IIB Hodgkin lymphoma (HL) patients, with a mediastinum-to-thorax (M/T) ratio of ≥0.33 or extranodal localization have a poor prognosis and are treated either as limited or advanced stage. We compared these two approaches in patients included in two randomized phase III trials enrolling previously untreated early (H10) or advanced stage HL (AHL2011). We included HL patients with Ann-Arbor stage IIB with M/T ≥0.33 or extranodal involvement enrolled in the H10 or AHL2011 trials with available positron emission tomography at baseline (PET0) and after two cycles of chemotherapy (PET2). Baseline total metabolic tumor volume (TMTV) was calculated using the 41% SUVmax method. PET2 response assessment used the Deauville score. One hundred and fourty-eight patients were eligible, including 83 enrolled in the AHL2011 trial and 65 in the H10 trial. The median TMTV value was 155.5 mL (range, 8.3-782.9 mL), 165.6 mL in AHL2011 and 147 mL in H10. PET2 positivity rates were 16.9% (n=14) and 9.2% (n=6) in AHL2011 and H10 patients, respectively. With a median follow-up of 4.1 years (95% confidence interval [CI]: 3.9-4.4), overall 4-year PFS was 88.0%, 87.0% in AHL2011 and 89.2% in H10. In univariate and mutivariate analyses, baseline TMTV and PET2 response influenced significantly progression-free survival (hazard ratio [HR]=4.94, HR=3.49 respectively). Notably, among the 16 patients who relapsed, 13 (81%) had a baseline TMTV baseline ≥155 mL. Upfront ABVD plus radiation therapy or upfront escBEACOPP without radiotherapy provide similar patient's outcome in high-risk stage IIB HL. TMTV is useful to stratify these patients at baseline.

PET2 response associated with survival in newly diagnosed diffuse large B-cell lymphoma: results of two independent prospective cohorts

Studies evaluating Positron Emission Tomography scan after 2 cycles of chemotherapy (PET2) in newly diagnosed diffuse large B cell lymphoma (DLBCL) are heterogeneous in patient characteristics, treatments and have conflicting results. Here we report association of PET2 with outcomes in two large independent prospective cohorts of newly diagnosed DLBCL pts treated with two RCHOP-based regimens. The discovery cohort consisted of pts enrolled in single arm phase 2 MC078E study of lenalidomide with RCHOP (R2CHOP). The validation cohort consisted of RCHOP-treated pts from the Molecular Epidemiology Resource (MER) cohort. Pts who received 3-6 cycles of therapy and had PET2 were included in the study. Patients who progressed on PET2 were excluded. Revised response criteria 2007 were used to define PET2 response PET2 positive (PET2 + ) pts had inferior EFS [24-month EFS 45.5% vs 87.9%, HR 4.0, CI95 (2.1–7.9), p < 0.0001) with a trend towards lower OS [24-months OS 77% vs 94.8%, HR 2.0, CI95 (0.9–4.8), P = 0.1] than PET2 negative (PET2−) pts in MC078E cohort. PET2 + pts had an inferior EFS (24 month EFS 48.7% vs 81.6%, HR 2.9, CI95 2.0–4.2, p < 0.0001) and OS (24-month OS 68.6% vs 88.1%, HR 2.3, CI95: 1.5–3.5, p < 0.0001) in the MER cohort. These results were consistent regardless of age, sex and in the subgroup of advanced stage and high-risk international prognostic index (IPI). For MER, PET2 + pts also had higher odds of positive end of treatment PET (OR: 17.3 (CI95 7.9–37.7), p < 0.001). PET2 is an early predictor DLBCL pts at high risk of progression and death in two independent prospective cohorts. PET2-guided risk-adapted strategies may improve outcomes, and should be explored in clinical trials.

PET2 Response Associated with Survival in Newly Diagnosed Diffuse Large B-Cell Lymphoma: Results of Two Independent Prospective Cohorts

PET2 Response Associated with Survival in Newly Diagnosed Diffuse Large B-Cell Lymphoma: Results of Two Independent Prospective Cohorts

Concurrent Pembrolizumab with AVD for Untreated Classical Hodgkin Lymphoma

Concurrent Pembrolizumab with AVD for Untreated Classical Hodgkin Lymphoma

The neutrophil to lymphocyte ratio (NLR) and the presence of large nodal mass are independent predictors of early response: A subanalysis of the prospective phase II PET‐2‐adapted HD0607 trial

BackgroundThe neutrophil to lymphocyte ratio (NLR) and the lymphocyte to monocyte ratio (LMR) can reflect both the myeloid dysfunction and T‐cell immune suppression and have prognostic significance.MethodsIn 771 newly diagnosed advanced‐stage Hodgkin Lymphoma (HL) patients we evaluated the baseline values of NLR and LMR as predictors of clinical outcome. According to the multicenter prospective phase II GITIL‐HD0607 trial, all patients received two ABVD courses and if PET‐2 negative received four additional ABVD cycles while if PET‐2‐positive patients were randomized to either BEACOPP escalated (Be) plus BEACOPP baseline (Bb) (4 + 4 courses) or Be + Bb (4 + 4) and Rituximab. PET scans were centrally reviewed by an expert panel by Blinded Independent Central Review.ResultsHigher NLR and lower LMR were associated with a PET‐2 positivity and failure to achieve long‐term disease control, respectively. By univariate and multivariate analysis, large nodal mass (>7 cm), IPS ≥ 3, NLR > 6 were strong independent predictors of early PET‐2 response after ABVD. Only NLR > 6 and IPS ≥ 3 were strong independent predictors of outcome at diagnosis; however, when PET‐2 status was added, only PET‐2‐positive status and IPS ≥ 3 were independent predictors of PFS. Focusing on PET‐2‐negative patients, those with NLR > 6 had an inferior 3‐year PFS compared to patients with NLR ≤ 6 (84% vs 89% months, P = .03).ConclusionIn advanced‐stage HL patients treated with a PET‐2‐driven strategy, IPS ≥ 3 and NLR > 6 are independent predictors of outcome at diagnosis while the presence of large nodal mass, IPS ≥ 3, and NLR > 6 at diagnosis are independent predictors of early ABVD response.

Stage IIb High Risk Hodgkin Lymphoma Treated in the H10 and AHL2011 Trials: Similar Efficacy of Both Strategies and Prognostic Impact of Baseline Tmtv and PET2 Response

Stage IIb High Risk Hodgkin Lymphoma Treated in the H10 and AHL2011 Trials: Similar Efficacy of Both Strategies and Prognostic Impact of Baseline Tmtv and PET2 Response

A Pilot Trial of Adriamycin, Pembrolizumab, Vinblastine and Dacarbazine (APVD) for Patients with Untreated Classical Hodgkin Lymphoma

Background: ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) forms the backbone of frontline management of classical Hodgkin lymphoma (CHL) in North America regardless of stage. Expected cure rates with upfront therapy approach 75% in advanced stage, and 85-90% in early stage. A novel regimen incorporating brentuximab vedotin sought to improve upon ABVD in untreated advanced stage CHL patients (brentuximab vedotin + AVD). While it demonstrated a modest modified PFS benefit, it was associated with notable toxicities including higher rates of neuropathy and infection. PD-1 inhibition is highly effective in relapsed/refractory CHL, leading to the FDA approval of nivolumab and pembrolizumab in this setting. The first-line setting may represent the ideal time for a PD-1 inhibitor, with relatively intact host immunity and coexistence of malignant cells and T-cells in the microenvironment. Using a proven chemotherapy backbone, we designed a trial adding pembrolizumab to AVD chemotherapy (APVD) without a PD-1 inhibitor lead-in for untreated CHL (NCT03331341). Methods: This is a single arm pilot study combining pembrolizumab with AVD in untreated CHL of any stage. Eligibility requires ECOG 0-1, adequate organ function, and measurable disease. The trial intends to enroll 30 patients. AVD is given at standard doses on days 1 and 15 of a 28-day cycle. Pembrolizumab (200 mg IV) is given starting cycle 1 day 1 and every 21 days thereafter (cycle 1 day 22, cycle 2 day 15 etc.). The primary objective is to estimate the safety of delivering 2 cycles of APVD. The study will be determined a success if &gt; 85% of subjects are able to complete 2 cycles of therapy without a dose delay &gt; 3 weeks. Operationally, the stopping rule will be activated if the lower limit of the 95% confidence interval of toxicity crosses 15%. Thus, the trial would stop if 4/10, 7/20, 8/25, or 9/30 had a dose delay of &gt;3 weeks due to toxicity. The secondary objective is to estimate the FDG-PET2 negative (Deauville score 1-3) after 2 cycles of APVD. Exploratory objectives include overall and progression free survival, predictive capacity of PET2 after APVD, peripheral blood flow cytometry of T-cell subsets, and analysis of ctDNA. After PET2 response assessment, subjects may continue APVD for up to 6 total cycles, or pursue treatment deemed appropriate for their stage/risk factors (including alternate systemic therapy or radiotherapy) at investigator discretion. Results: Six subjects have enrolled and received 2 cycles of therapy. Median age of these subjects was 28 years (range 18-69). Most subjects have advanced stage (stage II n=1 (17%), stage III n=3 (50%), stage IV n=2, (33%)). 3/6 (50%) of subjects had B symptoms at diagnosis, while 1/6 (17%) had bulky disease. Among the 6 subjects enrolled thus far, all have completed the first 2 cycles of therapy without any treatment delays. 3/6 subjects achieved a complete metabolic response (Deauville 1-3) on PET2, and 3/6 had a partial response (PR) with Deauville 4. The only subject who has completed all 6 cycle of therapy had a PET2 with Deauville 4 which converted to Deauville 2 upon completion of all therapy. There were no grade 2+ AEs attributable to pembrolizumab. No serious AEs have been reported. Non-hematologic grade 1 AEs of note include fatigue (50%), AST/ALT increase (33%), nausea (33%), arthralgia (17%), diarrhea (17%), maculopapular rash (17%), fever (17%), and alkaline phosphatase increased (17%). Conclusion: The concurrent combination of pembrolizumab with AVD chemotherapy for untreated CHL has been safe to date without any dose delays, serious adverse events, or immune-related adverse events of grade 2 or higher. All patients treated thus far achieved an objective response by PET2, with 3/6 achieving a complete metabolic response by interim scan. One subject has completed all therapy with a complete metabolic response (Deauville 2) after PET2 showed Deauville 4. Trial enrollment is ongoing. Disclosures Lynch: Incyte Corporation: Research Funding; T.G. Therapeutics: Research Funding; Johnson Graffe Keay Moniz &amp; Wick LLP: Consultancy; Juno Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding. Ujjani:Atara: Consultancy; Astrazeneca: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Consultancy; PCYC: Research Funding; Pharmacyclics: Honoraria. Kurtz:Roche: Consultancy. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria.

Prognostic Relevance of Neutrophil to Lymphocyte Ratio (NLR) and Lymphocyte to Monocyte Ratio (LMR) in Newly Diagnosed Advanced-Stage Hodgkin Lymphoma Patients Treated up-Front with a PET-2 Risk Adapted Protocol

Background: Hodgkin Lymphoma (HL) is characterized by an inflammatory background and it has been demonstratedthat the reactive myeloid cells may exert an immune suppressive effect that favors progression of disease. The easily measurable NLR, the ratio between absolute neutrophils counts (ANC) and absolute lymphocyte count (ALC) and LMR, the ratio between ALC and absolute monocyte count (AMC) have been reported to reflect both the systemic inflammation and the myeloid associated immune suppression. We previously identified NLR, and to a lesser extend LMR, at baseline, as predictor of progression free survival (PFS) in HL patients.Objectives: To validate NLR>6 and LMR≤2 as predictor of clinical outcome at diagnosis in the context of a prospective clinical trial of newly diagnosed advanced stage (aa) HL patients treated upfront with a PET-2 risk-adapted strategy.Methods: According to HD 0607 trial (Gallamini, JCO 2018), 782 advanced-stage HL patients were treated with 2 ABVD courses and a PET-2 performed afterwards. PET-2 positive (PET-2+) patients (N=149) were randomized to either BEACOPP escalated (Be) plus BEACOPP baseline (Bb) (4+4 courses) or Be+Bb (4+4) and Rituximab. PET-2 negative (PET-2-) patients were treated with 4 additional ABVD and, upon CR achievement, randomized to either consolidation radiotherapy on the sites of initial bulky disease or no further treatment. PET scans were centrally reviewed by an expert panel by Blinded Independent Central Review.Results:Median NLR at baseline was 5.7 (IQ range 3.8-8.3). NLR was higher in younger patients (<45 years, p=0.0005), in females (p=0.0027) and in patients with B symptoms (p<0.0001), bulky disease (>7 cm, p<0.0001) and high IPS (p<0.0001). LMR was lower in males (p=0.01) and in patients with B symptoms (p<0.0001), bulky disease (p<0.0001) and high IPS (≥3, p<0.0001). Neither NLR nor LMR values were associated with Ann Arbor stage. Higher NLR (p=0.0001 and p=0.0003) and lower LMR (p=0.01, and p=0.02) were respectively associated with a PET-2+ (DS score 4 and 5) and failure to achieve long-term disease control. Receiving operator curve (ROC) confirmed 6 as the cut-off of NLR to predict clinical outcome with 59% (95% C.I. 51-68) sensitivity and 57% (95% C.I. 53-61) specificity (AUC 0.59). Negative predictive value of LMR, with cutoff of 2, was 79% with 40% (95% C.I. 31-48) sensitivity and 50% (95% C.I. 46-54) specificity (AUC 0.56). NLR was >6 in 88/149 (59%) PET-2+ and in 269/628 (43%) PET-2- patients. By univariate and multivariate analysis, bulky disease, IPS≥3, NLR>6 were strong independent predictors of early PET-2 response after ABVD (table I). Only PET-2 positivity (p<0.0001) and IPS≥3 (p=0.0001) were independent predictors of PFS by multivariate analysis.Focusing on PET-2 negative patients, we found that patients with NLR>6 had an inferior 3-years PFS compared to patients with NLR ≤6 (84% versus 89%, p=0.003), while there was no stastical difference based on LMR status.Conclusion: At diagnosis, the presence of bulky disease, IPS score ≥3 and NLR>6 are independent predictors of early ABVD response (PET-2 positivity) and this information should be considered when selecting the initial treatment for aaHL patients. [Display omitted] DisclosuresDi Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Trentin:Janssen: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Gilead: Research Funding. Gallamini:Takeda: Consultancy, Speakers Bureau. Rambaldi:Amgen Inc.: Consultancy; Celgene: Consultancy; Roche: Consultancy; Italfarmaco: Consultancy; Omeros: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.

Metabolic Tumour Volume for Response Prediction in Advanced-Stage Hodgkin Lymphoma.

Rationale: (18F)fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) for staging Hodgkin lymphoma may allow for accurate and reliable assessment of the metabolic tumour volume (MTV) as baseline risk factor. Our aim was to analyse the prognostic impact of MTV measurements, obtained by different means in advanced-stage Hodgkin lymphoma patients treated within the German Hodgkin Study Group HD18 trial. Methods: Within the German Hodgkin Study Group trial HD18, 310 patients underwent 18F-FDG PET/CT scanning for staging which was available to the central review panel for quantitative analysis. We calculated the MTV by four different thresholding methods and performed receiver operating characteristic (ROC) analysis to evaluate the potential for prediction of early response determined by PET after two cycles (PET-2) dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP). Logistic regression was used to evaluate its prognostic value concerning progression-free survival (PFS) and overall survival (OS). Results: All different MTV calculations used predicted PET-2 response to a moderate and comparable degree (area under the curve = 0.62-0.63, P = 0.01-0.06). With none of the measuring methods did the ROC curves point to any unique cut-off values, but indicated a wide range of possible cut-offs. However, none of the MTV measurements was prognostic for PFS (Hazard ratio 1.2-1.5, P = 0.15-0.52) or OS (Hazard ratio 1.0-1.5, P = 0.95 - 0.27). Conclusion: Baseline MTV as determined by different means, is a predictive factor for early response to eBEACOPP after two cycles. However, value as a prognostic factor after highly effective PET-2 adapted treatment strategy could not be observed.

18F-FDG PET Response of Skeletal (Bone Marrow and Bone) Involvement After Induction Chemotherapy in Pediatric Hodgkin Lymphoma: Are Specific Response Criteria Required?

To determine whether the current 18F-FDG PET response criterion for skeletal involvement in Hodgkin lymphoma (HL) is suitable, we performed a systematic evaluation of the different types of skeletal involvement and their response on PET after 2 cycles of chemotherapy (PET-2). A secondary objective was to observe the influence of the initial uptake intensity (measured as qPET) and initial metabolic tumor volume (MTV) of skeletal lesions on the PET-2 response. Methods: The initial PET scans of 1,068 pediatric HL patients from the EuroNet-PHL-C1 trial were evaluated for skeletal involvement by central review. Three types of skeletal lesions were distinguished: PET-only lesions (those detected on PET only), bone marrow (BM) lesions (as confirmed by MRI or BM biopsy), and bone lesions. qPET and MTV were calculated for each skeletal lesion. All PET-2 scans were assessed for residual tumor activity. The rates of complete metabolic response for skeletal and nodal involvement on PET-2 were compared. Results: Of the 1,068 patients, 139 (13%) showed skeletal involvement (44 PET-only, 32 BM, and 63 bone). Of the 139 patients with skeletal involvement, 101 (73%) became PET-2-negative in the skeleton and 94 (68%) became PET-2-negative in the lymph nodes. The highest number of PET-2-negative scans in the skeleton was 42 (95%) in the 44 PET-only patients, followed by 22 skeletal lesions (69%) in the 32 BM patients and 37 (59%) in the 63 bone patients. Lesions that became PET-2-negative showed a lower initial median qPET (2.74) and MTV (2 cm3) than lesions that remained PET-2-positive (3.84 and 7 cm3, respectively). Conclusion: In this study with pediatric HL patients, the complete response rate for skeletal involvement on PET-2 was similar to that for nodal involvement. Bone flare seemed to be irrelevant. Overall, the current skeletal PET response criterion-comparison with the local skeletal background-is well suited. The initial qPET and MTV of skeletal lesions were predictive of the PET-2 result. Higher values for both parameters were associated with a worse PET-2 response.

Association of Gene Expression Profiling, Interim PET, EBV Status and PD-L1 Expression in Classical Hodgkin Lymphoma

IntroductionA challenge in the management of classical Hodgkin lymphoma (CHL) is selecting treatment which will maximise success while minimising treatment side effects. The international Response Adapted Therapy in Hodgkin Lymphoma (RATHL) trial (NCT00678327) demonstrated that treatment may be successfully adapted based on positron emission tomography (PET-CT) scan results after 2 cycles (PET2) of ABVD chemotherapy in advanced CHL. This approach however delays risk stratification meaning some patients may be over or under treated and therefore a baseline predictor is highly desirable. A gene expression-based model performed on RNA from formalin-fixed paraffin-embedded tissue (FFPET) biopsies on the Nanostring platform (Scott et al, J Clin Oncol 2013; 31:692-700) has been published. In addition Steidl et al used gene expression profiling (GEP) to correlate tumour-associated macrophages with survival in CHL (Steidl et al, NEJM 2010; 10:875-885). In order to explore whether GEP at baseline could be used in combination with PET2 results to predict outcome, these published gene signatures were explored on the DASL platform in a series of CHL cases and correlated with PET2 response. Recently, PD-1 ligand (PD-L1) on the cell surface of Reed-Sternberg cells (the hallmark cells of CHL) has been demonstrated to co-opt the PD-1 pathway allowing immune evasion (Green et al, Blood 2010;116:3268-77). Therefore this was also performed by immunohistochemistry (IHC) and GEP as well as assessment of EBV status.Methods50 patients with CHL were identified, with at least 2 years of follow up, diagnosed between 2008 and 2013. Deauville scores at PET2 were determined. IHC consistent with CHL, including: CD3, CD19, CD20, CD30, CD79, BOB-1, OCT-2, MUM1 and TARC was performed on 3mm FFPET lymph node sections, and reported by two independent observers. Latent Epstein-Barr virus (EBV) infection was determined by IHC for LMP-1 expression and in-situ hybridisation using fluorescein-labelled peptide nucleic acid probes (Dako, K5201). PD-L1 expression was determined by IHC using a rabbit monoclonal antibody (Cell Signaling Technology, E1L3N, #13684). Three to five 5mm sections of FFPET were used for RNA extraction using the Ambion RecoverAll™ kit standard protocol. GEP was quantified using Illumina's whole genome cDNA-mediated annealing, selection, extension, and ligation Assay (WG-DASL). 61 genes of interest were analysed for significance in the difference in gene expression between groups and included genes from the two recently reported GEP predictor tools in CHL (Steidl et al, 2010, Scott et al 2013) as well as PD-1 and PD-L1. The Mann-Whitney test was used to assess the significance in the difference between means (significant if p<0.05).ResultsA statistically significant difference in EBV status was found between PET negative (Deauville scores 1-3) and PET positive (Deauville scores 4-5) groups (Fisher's exact test: P-Value = 0.028). All patients who were EBV positive had a negative PET2 scan. GEP using WG-DASL revealed that only 2 genes of those reported in recent predictor models (Steidl et al 2010, Scott et al 2013) were expressed at significantly different levels between PET negative and PET positive patients (GLUL, RNF144B), both with increased expression in the PET2 positive group. There was no significant difference between PD-L1 expression and PET scores, CD274 gene expression and outcome. Assessment as to whether samples would cluster into groups according to PET positivity or PD-L1 expression status by unsupervised cluster analysis using four recently reported B cell lymphoma gene signatures (Monti et al, Blood 2005; 5:1851-61, Care et al, PloS one 2013; 2: e55895) was performed, but no significant grouping was found.ConclusionGEP on the DASL platform was not able to predict PET response. The original models were trained on outcome and therefore retraining of the GEP model based on PET response is likely to be required. EBV status was found to be predictive of PET response but this could not be correlated with other biomarkers to predict outcome. Although PD-1 and PD-L1 targeted therapy has shown exciting results in patients with CHL, PD-L1 IHC expression and CD274 gene expression, did not correlate with PET2 response or outcome. Baseline biomarkers capable of identifying patients likely to benefit from targeted treatment needs to be further investigated in proposed clinical trials. DisclosuresNo relevant conflicts of interest to declare.

Interim 18F-Fluorodeoxyglucose Positron Emission Tomography for Early Metabolic Assessment of Response to Cisplatin, Etoposide, and Bleomycin Chemotherapy for Metastatic Seminoma: Clinical Value and Future Directions

BackgroundIn patients with metastatic seminoma, designing a risk-adapted strategy that may help personalize the burden of treatment and follow-up is required. Patients and MethodsPatients who were administered cisplatin, etoposide, and bleomycin (PEB) were staged at baseline with computed tomography (CT), positron emission tomography (PET), and serum tumor markers. Restaging was then performed with PET after 2 cycles of PEB (PET2) and with CT after 3 to 4 cycles of treatment. The 20% cutoff of maximal standardized uptake value (SUVmax) changes and Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) criteria were applied to define the response. The Wilcoxon rank sum test was used to analyze the association between metabolic response and the shrinkage of target lesions. ResultsBetween February 2009 and November 2013, 37 patients were enrolled. After 2 cycles of PEB, 27 patients (72.9%; 95% confidence interval [CI], 55.8-86.2) had a metabolic complete response (CR) and 10 patients had a partial response (PR; 27%; 95% CI, 13.8-44.1). A significant association was found between PET2 response and baseline (P = .003), final diameter (P < .001), and percentage of tumor shrinkage (P = .014) of target lesions. After 18 months' (interquartile range [IQR], 13-23) median follow-up, 2 patients with PET2 PR had relapsed disease; none of those with a CR had relapsed disease. ConclusionsA significant association was found between early metabolic response and tumor shrinkage in patients with advanced seminoma. Patients achieving a PET2 CR could be predicted not to need additional treatment after PEB, and simplifying their follow-up should be an end point. PET2 might also identify difficult to treat cases at an early stage.

Interim [18f] fluorodeoxyglucose positron emission tomography (PET) for early metabolic assessment of response to PEB chemotherapy for metastatic seminoma: Preliminary findings.

381 Background: A risk-adapted strategy for metastatic seminoma may further refine the necessary burden of chemotherapy while sparing futile treatment. The objective of this study was to evaluate the association of the early metabolic response to cisplatin, etoposide, and bleomycin (PEB) and dimensional response. Methods: Patients (pts) with newly-diagnosed seminoma and who were candidate to PEB were staged at baseline by computed tomography (CT), PET and serum tumor markers (STM). Then, restaging with PET after 2 cycles of PEB (PET2), and with CT after treatment (3-4 cycles [CT3-4]) were provided. One (greatest) target lesion was chosen to evaluate metabolic/dimensional changes. Wilcoxon rank sum test was used to analyze the association between PET response and either the shrinkage of target lesion (primary endpoint) or baseline, or final dimensions. Results: In the time-frame 02/2009-11/2013, 37 pts have been enrolled. Two pts had CSIIA, 13 CSIIB, 13 CSIIC, and 9 CSIII. 3 had an intermediate prognosis because of liver (n=1) and bone (n=2) disease. The latter were recognized by PET while having a bone-negative CT scan. 4 had a retroperitoneal and 1 a mediastinal primary. All pts had a PET-positive target disease. After 2 cycles of PEB, 27 pts (72.9%) had a metabolic complete response (CR), 10 a partial response (PR). 12 pts had a CR at CT3-4. Median follow up was 18 months (IQR: 13-23). A significant association was found between PET2 response and baseline (p=0.003), final diameter (p&lt;0.001), and % of tumor shrinkage (p=0.014). Pts with PET2 CR had a median residual diameter of 1.2 cm (IQR: 1-1.9) while pts with PET2 PR 3.75 cm (IQR: 2.6-6.1, p=0.002). 6 Pts received RT after PEB. 2/10 pts with PET2 PR had a relapse (0/27 CR). Conclusions: A significant association was found between PET2 response and tumor shrinkage in pts with metastatic seminoma. PET2 CR pts could be predicted not to need additional re-imaging or treatment after PEB, and simplifying the follow up should be an endpoint. PET2 PR category includes pts yielding a difficult-to-treat disease. A detailed cost-efficacy analysis of the strategy will be required further.

Interim Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography for Early Metabolic Assessment of Therapeutic Response to Chemotherapy for Metastatic Transitional Cell Carcinoma

BackgroundThe prognostic impact of early metabolic response by fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) after 2 cycles of first-line chemotherapy is still unrecognized in metastatic transitional cell carcinoma (TCC). Patients and MethodsPatients with metastatic TCC receiving the modified combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), according to institutional protocol, underwent computed tomography (CT) and FDG-PET imaging at baseline, a restaging with PET imaging after 2 cycles only (PET2), and a CT (± FDG-PET) scan at the end of treatment and during follow-up. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan–Meier method; univariate (UVA) and multivariate (MVA) Cox models were fitted. Prespecified variables were the presence of visceral metastases, nodal or soft tissue disease, and early PET response. ResultsIn the period from May 2010 to October 2012, 31 patients with Eastern Cooperative Oncology Group performance status 0 received the modified MVAC regimen every 3 weeks. In all, 6 patients (19.3%) had a complete response (CR) and 17 (54.8%) a partial metabolic response (PR), 4 had stable disease (SD), and 4 progressed. PET2 responders had a median PFS of 8 months (95 % CI, 7-11 mo) compared with 3 months (95 % CI, 2-5 mo) of patients without response (P = .024). They also had a significant benefit in 8-month PFS (P < .001 via Klein test) and 15-month OS (P = .016). PET2 response was significant for PFS in both UVA and MVA Cox models (P = .027 and P = .023, respectively). ConclusionPET response after 2 cycles of first-line chemotherapy, compared with detection by early CT, was associated with longer PFS and OS in advanced TCC and warrants further investigation in the field.

Predictive and prognostic significance of early positron emission tomography/computed tomography (PET/CT) in advanced transitional cell carcinoma.

341 Background: A risk-adapted treatment for TCC may guide new trial designs for early-recognized unresponsive patients (pts). We aimed to prospectively identify early fluorodeoxyglucose (FDG)-PET/CT as a predictor of response and outcome. Methods: Pts with newly-diagnosed advanced/metastatic TCC receiving first-line chemotherapy underwent CT and FDG-PET/CT at baseline, a restaging with PET/CT after 2 cycles only (PET2), and a CT (± FDG-PET/CT) at the end of treatment and during follow up. The endpoints were PET2 metabolic response, RECIST response, progression-free (PFS) and overall survival (OS). Univariable (UVA) and multivariable (MVA) Cox models were fitted. Prespecified variables were presence of visceral metastases, nodal or soft tissue disease, and PET2 response. Results: In the time-frame 05/2010-10/2012, 31 pts with ECOG-PS 0 received a modified MVAC regimen according to Institutional protocol, every 3 weeks. After 2 cycles of MVAC, 6 patients (19.3%) had a complete (CR) and 17 (54.8%) a partial metabolic response (PR) (74% total responders; 95% CI, 55.4-88.1%), 4 had stable disease (SD), 4 progressed. Metabolic response (CR + PR) was associated with final CT response (p=0.007 at Fisher exact test). Metabolic CR was followed by a RECIST CR in all but one cases and metabolic progression at PET2 corresponded to a RECIST PD in all four patients and they all switched to second line chemotherapy. Median follow up was 18 months (IQR: 10-47). Those with metabolic response had a median (95% CI) PFS of 8 (7-11) months compared to 3 (2-5) months of patients without response (p=0.024). PET2 responders had a significant benefit in 8-month PFS (p&lt;0.001) and 15-month OS (p=0.016 at Klein test). A significant association was observed between PET2 response and longer PFS in both UVA and MVA (p=0.027 and p=0.023, respectively). Results are limited by small numbers. Conclusions: PET2 response might confer an independent prognostic impact on PFS and OS. Results warrant a validation series, a comparison with the impact of early RECIST response as well as a detailed cost-efficacy analysis prior to devise a new strategy of first-line treatment.