H10 Trial Research Articles

Long-Term Follow-Up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 Trial for Localized Hodgkin Lymphoma.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary analysis of the Early positron emission tomography (ePET) Response-Adapted Treatment in localized Hodgkin Lymphoma H10 Trial demonstrated that in ePET-negative patients, the risk of relapse increased when involved-node radiotherapy (INRT) was omitted and that in ePET-positive patients, switching from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) significantly improved 5-year progression-free survival (PFS). Here, we report the final results of a preplanned analysis at a 10-year follow-up. In the favorable (F) ePET-negative group, the 10-year PFS rates were 98.8% versus 85.4% (hazard ratio [HR], 13.2; 95% CI, 3.1 to 55.8; P value for noninferiority = .9735; difference test P < .0001) in favor of ABVD + INRT; in the unfavorable (U) ePET-negative group, the 10-year PFS rates were 91.4% and 86.5% (HR, 1.52; 95% CI, 0.84 to 2.75; P value for noninferiority = .8577; difference test P = .1628). In ePET-positive patients, the difference in terms of PFS between standard ABVD and intensified BEACOPPesc was no longer statistically significant (HR, 0.67; 95% CI, 0.37 to 1.20; P = .1777). In conclusion, the present long-term analysis confirms that in ePET-negative patients, the omission of INRT is associated with lower 10-year PFS. Instead, in ePET-positive patients, no significant difference between standard and experimental arms emerged although intensification with BEACOPPesc was safe, with no increase in late adverse events, namely, second malignancies.

A Quality Control Study on Involved Node Radiation Therapy in the European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfomi H10 Trial on Stages I and II Hodgkin Lymphoma: Lessons Learned

Involved node radiation therapy (INRT) was introduced in the European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfomi H10 trial, a large multicenter trial in early-stage Hodgkin Lymphoma. The present study aimed to evaluate the quality of INRT in this trial. A retrospective, descriptive study was initiated to evaluate INRT in a representative sample encompassing approximately 10% of all irradiated patients in the H10 trial. Sampling was stratified by academic group, year of treatment, size of the treatment center, and treatment arm, and it was done proportional to the size of the strata. The sample was completed for all patients with known recurrences to enable future research on relapse patterns. Radiation therapy principle, target volume delineation and coverage, and applied technique and dose were evaluated using the EORTC Radiation Therapy Quality Assurance platform. Each case was reviewed by 2 reviewers and, in case of disagreement also by an adjudicator for a consensus evaluation. Data were retrieved for 66 of 1294 irradiated patients (5.1%). Data collection and analysis were hampered more than anticipated by changes in archiving of diagnostic imaging and treatment planning systems during the running period of the trial. A review could be performed on 61 patients. The INRT principle was applied in 86.6%. Overall, 88.5% of cases were treated according to protocol. Unacceptable variations were predominately due to geographic misses of the target volume delineations. The rate of unacceptable variations decreased during trial recruitment. The principle of INRT was applied in most of the reviewed patients. Almost 90% of the evaluated patients were treated according to the protocol. The present results should, however, be interpreted with caution because the number of patients evaluated was limited. Individual case reviews should be done in a prospective fashion in future trials. Radiation therapy Quality Assurance tailored to the clinical trial objectives is strongly recommended.

Relapse patterns in early-PET negative, limited-stage Hodgkin lymphoma (HL) after ABVD with or without radiotherapy-a joint analysis of EORTC/LYSA/FIL H10 and NCRI RAPID trials.

In the H10 and RAPID randomised trials, chemotherapy+radiotherapy (combined modalities treatment, CMT) was compared with chemotherapy (C) in limited-stage Hodgkin lymphoma (HL), with negative early positron emission tomography (ePETneg). We analysed patterns of relapses in the H10 trial, validated findings in the RAPID trial and performed a combined analysis stratified by trial. The impact of radiotherapy (RT) on risk of relapse was studied using adjusted Cox models, with time-varying effects. In H10, 1,059 ePETneg patients were included (465 European Organisation for Research and Treatment of Cancer (EORTC) favourable [F], 594 unfavourable [U]). Among the F patients, 2/227 (1%) relapsed after CMT, 30/238 (13%) after C: of these relapses, 21/30 (70%) occurred in less than 2 years and 25/30 (83%) affected originally involved areas. Among the U group, 16/292 (5%) relapsed after CMT: 8/16 (50%) in less than 2 years, 11/16 (69%) in originally involved areas. After C 30/302 (10%) relapsed: 27/30 (90%) in less than 2 years, and 26/30 (87%) in originally involved areas. Similar results were observed in 419 ePETneg RAPID patients (241 F, 128 U, 50 unclassified): among F patients, 6/118 (5%) relapsed after CMT; 13/123 (11%) after C: 11/13 (85%) in less than 2 years and 11/13 (85%) affecting originally involved areas. In U patients, 3/65 (5%) relapsed after CMT and 5/63 (8%) after C. In both trials, omitting RT in ePETneg HL resulted in more early relapses, mainly affecting originally involved areas. RT significantly reduced risk of early relapses in the combined stratified analysis.

P023: PET2-adapted approach after 2 cycles of ABVD is comparable to 2 cycles of BEACOPP escalated and 2 cycles of ABVD and irradiation in early unfavorable Hodgkin lymphoma

Background: PET2-adapted approach after 2 cycles of ABVD reduced treatment intensity in the majority of patients with early stages of classical Hodgkin lymphoma (cHL) according to EORTC H10 trial. GHSG HD17 enabled omission of radiotherapy in PET4-negative early unfavorable HL treated with 2 cycles of BEACOPP escalated and 2 cycles of ABVD (2 + 2 chemotherapy). We compared PET2-adapted approach with 2 + 2 chemotherapy followed by 30 Gy of involved-node radiotherapy (INRT) regardless of interim PET in patients with early unfavorable cHL assessed according to the GHSG risk factors. Methods: Overall, 224 patients with early unfavorable cHL (aged 18–60 years) prospectively observed in the Czech Hodgkin Lymphoma Study Group Registry between 2003–2021 were analyzed. Patients in clinical stage IIB with massive mediastinal tumor and/or with extranodal disease were excluded. Overall, 194 patients received 2 + 2+INRT chemotherapy and 30 patients were treated with PET2-adapted approach: 29 PET2-negative patients received 4 cycles of ABVD and 30 Gy of INRT and one PET2-positive patient was treated with 2 cycles of ABVD plus 2 cycles of BEACOPP escalated and 30 Gy INRT. Results: Median age at the time of cHL diagnosis was 32 (range 18–59) years. Median follow-up was longer in the 2 + 2+INRT group (98.9, range 6.2–211.7) months compared to the PET2-adapted approach (30.8, range 9.8–90.4) months. The 2-year progression-free survival and 2-year overall survival did not differ between two groups (99.5% [95% CI 98.5%–100%]) and 100% [95% CI 100%–100%]), respectively. The rate of patients with neutropenia grade 3 and anemia grade 3 did not differ significantly between both groups (p=0.09 and p=0.60, respectively). Thrombocytopenia was more frequent in the 2 + 2+INRT group (p0.001). Grade 3 non-hematological toxicity occurred in 3 patients in the 2 + 2+INRT group (2 infections, 1 deep vein thrombosis). Conclusion: This retrospective analysis indicates that there is no superiority in progression-free survival and overall survival when comparing 2 + 2 chemotherapy and INRT to PET2-adapted approach. The toxicity is higher in the 2 + 2+INRT group. This work was supported by the following grants AZV NU22-03–00182 from the Ministry of Health of the Czech Republic and Cooperatio Program awarded by the Charles University in Prague in the Czech Republic.

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.

Is It Better to Start Treatment with ABVD and Continue with PET2-Adapted Approach or Should We Use 2 Cycles of Beacopp Escalated and 2 Cycles of ABVD and Irradiation in Early Unfavorable Hodgkin Lymphoma?

Introduction. EORTC H10 trial confirmed better selection of patients who needed reduced or more intensive treatment using PET response after 2 cycles of ABVD in early stages of classical Hodgkin lymphoma (cHL). GHSG HD17 showed that radiotherapy can be safely omitted in PET4-negative early unfavorable HL treated with 2 cycles of BEACOPP escalated plus 2 cycles of ABVD (2+2 chemotherapy). We compared PET2-adapted approach including 30Gy involved-node radiotherapy (INRT) with 2+2 chemotherapy followed by 30 Gy INRT (or involved-field radiotherapy, IFRT) regardless of interim PET in patients with early unfavorable cHL assessed according to the GHSG risk factors.Methods. Overall 243 patients with early unfavorable cHL (aged 18-60 years) prospectively observed in the Czech Hodgkin lymphoma study group registry between 2003-2020 were analyzed. Patients in clinical stage IIB with massive mediastinal tumor and/or with extranodal disease were not included into this analysis as they were treated with BEACOPP escalated only. Chemotherapy 2+2+30 Gy INRT/IFRT received 213 patients. Overall 30 patients were treated with PET2-adapted approach: 29 PET2-negative patients received 4 cycles of ABVD and 30 Gy INRT and one PET2-positive patient was treated with 2 cycles of ABVD plus 2 cycles of BEACOPP escalated and 30 Gy INRT.Results. Median age at the time of cHL diagnosis was 32 (range 18-59) years. Median follow-up was longer in the 2+2+INRT/IFRT group (91.3, range 6.2-211.2) months when compared to the PET2-adapted approach (19.4, range 6.4-90.4) months. The estimated 2-year progression-free survival (PFS) did not differ in both groups (100% [95% CI 100-100] both), however, the estimated 5-year PFS was significantly better in the 2+2+INRT/IFRT group (99.5% [95% CI 98.5-100]) in comparison to PET2-adapted treatment (75.0% [95% CI 32.5-100]), p<0.001. The estimated 5-year overall survival was comparable in both groups (2+2+INRT/IFRT: 99.5% [95% CI 98.5-100]; PET2-guided treatment: 100% [95% CI 100-100]). Hematological toxicity was reported in most of the patients in both groups. Grade 3 non-hematological toxicity occured in 3 patients in the 2+2+INRT/IFRT approach (2 infections, 1 deep vein thrombosis).Conclusion. This retrospective analysis indicates that 2+2+INRT/IFRT is more effective in the long-term disease control, but there is no difference in overall survival in both groups. The current approach includes 2+2 chemotherapy and INRT is added in PET4-positive patients.This work was supported by the Research project Q 28 Progres awarded by the Third Faculty of Medicine of Charles University in Prague in the Czech Republic. DisclosuresBelada: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding.

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

Prognostic value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the standard arm of the H10 trial

AbstractWe tested baseline positron emission tomography (PET)/computed tomography (CT) as a measure of total tumor burden to better identify high-risk patients with early-stage Hodgkin lymphoma (HL). Patients with stage I-II HL enrolled in the standard arm (combined modality treatment) of the H10 trial (NCT00433433) with available baseline PET and interim PET (iPET2) after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine were included. Total metabolic tumor volume (TMTV) was measured on baseline PET. iPET2 findings were reported negative (DS1-3) or positive (DS4-5) with the Deauville scale (DS). The prognostic value of TMTV was evaluated and compared with baseline characteristics, staging classifications, and iPET2. A total of 258 patients were eligible: 101 favorable and 157 unfavorable. The median follow-up was 55 months, with 27 progression-free survival (PFS) and 12 overall survival (OS) events. TMTV was a prognosticator of PFS (P < .0001) and OS (P = .0001), with 86% and 84% specificity, respectively. Five-year PFS and OS were 71% and 83% in the high-TMTV (>147 cm3) group (n = 46), respectively, vs 92% and 98% in the low-TMTV group (≤147 cm3). In multivariable analysis including iPET2, TMTV was the only baseline prognosticator compared with the current staging systems proposed by the European Organization for Research and Treatment of Cancer/Groupe d'Etude des Lymphomes de l'Adulte, German Hodgkin Study Group, or National Comprehensive Cancer Network. TMTV and iPET2 were independently prognostic and, combined, identified 4 risk groups: low (TMTV≤147+DS1-3; 5-year PFS, 95%), low-intermediate (TMTV>147+DS1-3; 5-year PFS, 81.6%), high-intermediate (TMTV≤147+DS4-5; 5-year PFS, 50%), and high (TMTV>147+DS4-5; 5-year PFS, 25%). TMTV improves baseline risk stratification of patients with early-stage HL compared with current staging systems and the predictive value of early PET response as well.

Interobserver delineation uncertainty in involved-node radiation therapy (INRT) for early-stage Hodgkin lymphoma: on behalf of the Radiotherapy Committee of the EORTC lymphoma group

Background and purpose: In early-stage classical Hodgkin lymphoma (HL) the target volume nowadays consists of the volume of the originally involved nodes. Delineation of this volume on a post-chemotherapy CT-scan is challenging. We report on the interobserver variability in target volume definition and its impact on resulting treatment plans.Materials and methods: Two representative cases were selected (1: male, stage IB, localization: left axilla; 2: female, stage IIB, localizations: mediastinum and bilateral neck). Eight experienced observers individually defined the clinical target volume (CTV) using involved-node radiotherapy (INRT) as defined by the EORTC-GELA guidelines for the H10 trial. A consensus contour was generated and the standard deviation computed. We investigated the overlap between observer and consensus contour [Sørensen-Dice coefficient (DSC)] and the magnitude of gross deviations between the surfaces of the observer and consensus contour (Hausdorff distance). 3D-conformal (3D-CRT) and intensity-modulated radiotherapy (IMRT) plans were calculated for each contour in order to investigate the impact of interobserver variability on each treatment modality. Similar target coverage was enforced for all plans.Results: The median CTV was 120 cm3 (IQR: 95–173 cm3) for Case 1, and 255 cm3 (IQR: 183–293 cm3) for Case 2. DSC values were generally high (>0.7), and Hausdorff distances were about 30 mm. The SDs between all observer contours, providing an estimate of the systematic error associated with delineation uncertainty, ranged from 1.9 to 3.8 mm (median: 3.2 mm). Variations in mean dose resulting from different observer contours were small and were not higher in IMRT plans than in 3D-CRT plans.Conclusions: We observed considerable differences in target volume delineation, but the systematic delineation uncertainty of around 3 mm is comparable to that reported in other tumour sites.This report is a first step towards calculating an evidence-based planning target volume margin for INRT in HL.

Prognostic Value of Baseline Quantitative PET Metrics for Patients with Unfavourable Early Stage Hodgkin Lymphoma Enrolled in the Standard Arm of the EORTC/Lysa/FIL H10 Trial

Objective: Baseline quantitative PET parameters measuring tumour burden and metabolism are proposed as early prognosticators of outcome in different lymphoma subtypes. It has been shown that in advanced stage Hodgkin lymphoma (HL) and Primary mediastinal B cell lymphoma, total metabolic tumor volume (TMTV) or total lesion glycolysis (TLG) predicted outcome better than the bulk. From the H10 EORTC/LYSA/FIL randomized intergroup trial (NCT00433433) including patients with supradiaphragmatic stage I/II, histologically proven classical HL, we investigated the prognostic value of quantitative PET metrics measured on baseline FDG PET/CT in the unfavorable group of the standard arm.Methods: One hundred and fifty patients were randomly selected from the 352 patients recruited by the LYSA centers, in the unfavorable group (≥ 4 nodal areas or age ≥ 50 yrs or mediastinal thoracic (MT) ratio ≥ 0.35 or erythrocyte sedimentation rate (ESR) ≥ 50 (without B-symptoms) or ESR ≥ 30 (with B-symptoms)) of the standard arm of the H10 trial. Only patients who had baseline PET/CT with fused images available were analyzed. Standard treatment was 4 cycles of ABVD completed by involved-node radiotherapy. All patients had an interim PET performed after 2 ABVD cycles (PET2). Baseline TMTV was computed using the 41% and 25% SUVmax thresholding methods; SUVmax, TLG41%, TLG25% were calculated. PET2 was centrally reviewed reported. Optimal quantitative parameters cut-off to predict PFS and OS were determined by ROC curves, and Kaplan Meier (KM) curves were obtained. Multivariate analyses were performed using a Cox model.Results: 128 patients with a median age of 32 years were analyzed: 54 (42%) had B symptoms, 74 (58%) had ESR>40 (ROC optimal cut off), 48 (37%) mediastinal bulk as defined above. Median TMTV41%, TMTV25%, SUVmax and TLG41%, TLG25%were 81 cm3 (25th-75thpercentiles 44-145 cm3), 194 cm3 (112-323), 11 (8-14), 407 cm3 (221-475) and 731 cm3 430-1321) respectively. After a median follow-up of 5 years, the 5y-PFS was 84% and the 5y-OS was 92%.The strongest PET quantitative parameter to predict outcome was the TLG41% (p=0.0006 HR=6.5 for PFS with a cut off of 420 cm3, p=0.025 HR=7.7 for OS with a cut off of 584 cm3). Patients with a high TLG41% had a 5y-PFS of 76% vs 92% (95%CI 71-81; 88-96) and a 5y-OS of 88% vs 96% (95%CI 83-92; 92-100) for those with the lower TLG41% respectively. Similar results were found using 25% SUVmax threshold (p=0.0005 HR=4.7 for PFS, p=0.0032 HR=7.9 for OS).TMTV41% higher than 149 cm3 cut off was associated with a worse PFS (p=0.0099, HR=3.26) and OS (p=0.022, HR=4.8) but with a lower significance level. A SUVmax greater than 14 was also associated with a worse PFS (p=0.018 HR=3.0) with a 5y-PFS of 74% vs 86% but not with OS. In multivariate analysis testing TLG41% and SUVmax or TLG41%and TMTV41%, only TLG41% remained significant (p=0.0096 and p=0.015 for PFS and OS respectively).B symptoms and ESR>40 were predictive of PFS (p=0.0077 HR=3.7 and p=0.0062 HR=6.07 respectively) but not of OS. MT ratio was predictive of neither PFS nor OS (p=0.49, p=0.20). In multivariate analysis, B symptoms, ESR>40 and TLG41% remained significant independent predictors of PFS (p=0.038; p=0.034; p=0.014 respectively).For the 124 patients with a centralized reading available, a positive PET after two cycles (PET2 +) using IHP criteria (n=29) was associated with a worse PFS (p=0.0006). In multivariate analysis testing TLG41% and interim PET, they both remained independent prognosticators (p=0.014 and p=0.025 respectively).Interestingly combining TLG41% and interim PET brings out 3 distinctive prognostic categories (p<0.0001): negative PET2 and low TLG41% with good outcome (5y-PFS=92%, n=60); positive PET2 and high TLG41% with bad outcome (5y-PFS=57%, n=21) and an intermediate category (5y-PFS=88%, n=43) cf. KM curve. No progression was observed in the 8 patients with a positive interim PET but a low baseline TLG41%, suggesting that TLG41% results may reduce the numbers of false positive PET2 patients.Conclusion: Quantitative PET parameters improve patient risk stratification at staging. The study data suggest that TLG is an independent prognosticator of outcome and seems particularly interesting in early stage HL patients, to identify in conjunction with the early PET response, those patients who require treatment intensification. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Role of FDG-PET in the Implementation of Involved-Node Radiation Therapy for Hodgkin Lymphoma Patients

This study examines the role of (18)F-labeled fluorodeoxyglucose positron emission tomography (FDG-PET) in the implementation of involved-node radiation therapy (INRT) in patients treated for clinical stages (CS) I/II supradiaphragmatic Hodgkin lymphoma (HL). Patients with untreated CS I/II HL enrolled in the randomized EORTC/LYSA/FIL Intergroup H10 trial and participating in a real-time prospective quality assurance program were prospectively included in this study. Data were electronically obtained from 18 French cancer centers. All patients underwent APET-computed tomography (PET-CT) and a post-chemotherapy planning CT scanning. The pre-chemotherapy gross tumor volume (GTV) and the postchemotherapy clinical target volume (CTV) were first delineated on CT only by the radiation oncologist. The planning PET was then co-registered, and the delineated volumes were jointly analyzed by the radiation oncologist and the nuclear medicine physician. Lymph nodes undetected on CT but FDG-avid were recorded, and the previously determined GTV and CTV were modified according to FDG-PET results. From March 2007 to February 2010, 135 patients were included in the study. PET-CT identified at least 1 additional FDG-avid lymph node in 95 of 135 patients (70.4%; 95% confidence interval [CI]: 61.9%-77.9%) and 1 additional lymph node area in 55 of 135 patients (40.7%; 95% CI: 32.4%-49.5%). The mean increases in the GTV and CTV were 8.8% and 7.1%, respectively. The systematic addition of PET to CT led to a CTV increase in 60% of the patients. Pre-chemotherapy FDG-PET leads to significantly better INRT delineation without necessarily increasing radiation volumes.

Guidelines for the first line management of classical Hodgkin lymphoma

The guideline group was selected to be representative of UK-based medical experts and patients’ representatives. MEDLINE and EMBASE were searched systematically for publications in English from January 1990 to June 2013 using the key words Hodgkin, Lymphoma, Treatment, Chemotherapy and Radiotherapy. References from relevant publications were also searched. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato-Oncology Task Force of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of approximately 50 UK haematologists and the BCSH and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found in Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with classical Hodgkin Lymphoma (HL). The guidance may not be appropriate for all patients with HL and in all cases individual patient circumstances may dictate an alternative approach.

Omitting Radiotherapy in Early Positron Emission Tomography–Negative Stage I/II Hodgkin Lymphoma Is Associated With an Increased Risk of Early Relapse: Clinical Results of the Preplanned Interim Analysis of the Randomized EORTC/LYSA/FIL H10 Trial

Combined-modality treatment is standard treatment for patients with clinical stage I/II Hodgkin lymphoma (HL). We hypothesized that an early positron emission tomography (PET) scan could be used to adapt treatment. Therefore, we started the randomized EORTC/LYSA/FIL Intergroup H10 trial evaluating whether involved-node radiotherapy (IN-RT) could be omitted without compromising progression-free survival in patients attaining a negative early PET scan after two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) as compared with standard combined-modality treatment. Patients age 15 to 70 years with untreated clinical stage I/II HL were eligible. Here we report the clinical outcome of the preplanned interim futility analysis scheduled to occur after documentation of 34 events in the early PET-negative group. Because testing for futility in this noninferiority trial corresponds to testing the hypothesis of no difference, a one-sided superiority test was conducted. The analysis included 1,137 patients. In the favorable subgroup, 85.8% had a negative early PET scan (standard arm, one event v experimental arm, nine events). In the unfavorable subgroup, 74.8% had a negative early PET scan (standard arm, seven events v experimental arm, 16 events). The independent data monitoring committee concluded it was unlikely that we would show noninferiority in the final results for the experimental arm and advised stopping random assignment for early PET-negative patients. On the basis of this analysis, combined-modality treatment resulted in fewer early progressions in clinical stage I/II HL, although early outcome was excellent in both arms. The final analysis will reveal whether this finding is maintained over time.

Interim Analysis of the Randomized Eortc/Lysa/Fil Intergroup H10 Trial On Early PET-Scan Driven Treatment Adaptation in Stage I/II Hodgkin Lymphoma

AbstractAbstract 549 IntroductionEarly stage classical Hodgkin lymphoma (cHL) is highly curable with a combination of chemotherapy and radiotherapy (RT). Late toxicities due to RT are altering the outcome. FDG-PET (PET) has emerged as a potential new tool to early select good prognosis patients after a few cycles of chemotherapy. In the current trial, PET is used to guide early response-adapted therapy. Main objective is to evaluate whether chemotherapy alone is as effective as standard combined modality treatment in patients with an early PET negative status. In addition we evaluate whether intensification of chemotherapy is more effective than standard chemotherapy in early PET positive patients. This abstract concerns the results of the pre-planned interim safety analysis. Patients and methodsAll patients with a stage I and II supra-diaphragmatic cHL, between 15 and 70 years old are eligible for the study and stratified according to LYSA/EORTC criteria. Unfavorable (U) prognostic factors included patients with: CSII ≥ 4 nodal areas or age ≥ 50 yrs or MT ratio ≥ 0.35 or ESR ≥ 50 (without B-symptoms) or ESR ≥ 30 (with B-symptoms). All others are considered favorable (F). In the F group, the standard treatment is ABVDx3 and 30Gy involved-node RT (IN-RT); the early PET scan after 2 cycles is made solely for sake of comparison with the experimental arm but will not affect treatment. The experimental arm consisted of ABVDx2 followed by a PET: if the PET is negative, patients receive 2 additional cycles of ABVD and no RT. If the PET is positive, patients received BEACOPPesc x2 and 30 Gy IN-RT. In the U group, the same principles were used, the standard treatment is ABVDx4 and 30Gy IN-RT; a PET is performed for all patients after cycle 2 with no modification of treatment. The experimental arm is ABVDx2 followed by a PET: if the PET is negative, patients receive 4 additional cycles of ABVD and no RT. If the PET is positive, patients receive BEACOPPesc x2 and 30 Gy IN-RT. This report discloses the IA performed on the early PET negative patients. ResultsThe trial opened in October 2006 and in July 2009, 1137 patients were included with a median follow-up of 1.1 years with sufficient events to allow for the planned IA. In the F early PET negative group, 188 patients were included in the standard arm, and 193 in the experimental arm. A total of 10 events occurred: one in the standard arm and nine in the experimental arm. All these events were progressions or relapses, no deaths occurred in this group. Based on the actual information fraction (10 out of the 26 events required for the final analysis) and the resulting one-sided significance level to perform the statistical test (0.102), futility was declared (p-value=0.017<0.102). The estimated hazard ratio was 9.36 (79.6% CI=[2.45–35.73]). PFS rates at one year were 100.0% and 94.9% in the standard and experimental arms respectively. In the U early PET negative group, 251 patients were included in the standard arm and 268 in the experimental arm. A total of 23 events occurred in this group: 7 in the standard arm and 16 in the experimental arm. One patient died due to toxicity without signs of progression, all remaining events were progressions or relapses. Based on the actual information fraction (23 out of the 63 events required for the final analysis) and the resulting one-sided significance level to perform the statistical test (0.098), futility was declared (p-value=0.026<0.098). The estimated hazard ratio was 2.42 (80.4% CI=[1.35–4.36]). PFS rates at one year were 97.3% and 94.7% in the standard and experimental arms respectively. The IA for the early PET positive group gave no reason for stopping this part of the trial. Final accrual was reached in June 2011 with 1950 included patients.To exclude bias caused by differences in interpretation of the early PET scans by the various central reviewers, a new blind PET review was performed on all patients with an event and an equal number of randomly selected patients without event. Six patients from this group considered negative in the first review turned positive in the new review. This did no significantly alter the outcome of the IA. ConclusionThe planned futility IA of the H10 trial shows that the risk of early relapse in non-irradiated patients with stage I-II cHL was significantly higher than in standard combined modality treated patients, even in this selected group of patients with an early negative PET. Consequently, accrual was stopped for this part of the trial. Disclosures:No relevant conflicts of interest to declare.

Contribution of PET/CT In the Design of the Involved Node Radiotherapy (INRT) Concept for Patients with Localized Hodgkin Lymphoma: Preliminary Results on 117 Patients.

AbstractAbstract 2817 Background:The INRT concept, that limit delineates irradiated volume to lymphoma-infiltrated node, requires an extremely precise determination of the number and volume of initially involved nodes. In the study, we tried to assess the additional value of a PET/CT performed before treatment. Patients and methods:Early-stage lymphoma patients entered in the EORTC-GELA-IIL.Data imaging comprising PET/CT prior to treatment and CT simulation prior to radiotherapy were retrieved using the DICOM/DICOM-RT imaging network connecting all French cancer centers participating in the H10 trial. A lymph node was considered to be involved if it fulfilled 3 requirements: FDG uptake was greater than the background, was clearly identifiable on CT, and either decreased or disappeared after chemotherapy. Involved lymph nodes were delineated on CT first before adding the information provided by PET. Differences between the number of involved lymph nodes and areas were compared before and after PET/CT assessment. Results:From March 2007 to February 2010, 117 patients from 18 French Cancer Centers and hospitals were included in the study. PET/CT identified at least one additional FDG-avid lymph node in 82/117 patients (70%; CI 95%: 61–78%). Additional lymph nodes were observed significantly (p = 0.008) more frequently when PET/CT was performed without IV contrast (in 79% of the patients versus 56%). At least one additional lymph node area was detected by PET in 49/117 patients (42%; CI 95%: 33–51%). There was a 15% (CI 95%: 9–22%) increase in the gross target volume (GTV) due to the additional information provided by PET (a 20% increase in 10% of the patients). On the other hand, after chemotherapy, there was a 10% (CI 95%: 5–18%) increase in the clinical target volume (CTV) in the 96 assessable patients (a 20% increase in 10% of the patients). Conclusions:PET/CT with IV contrast may be an important imaging procedure for implementing the INRT concept. Disclosures:Ribrag:LFB: Honoraria, Research Funding; servier: Research Funding; celgene: Research Funding; pfizer: Honoraria; novartis: Honoraria.

Mid-Treatment Plasma Levels of Thymus Activated and Regulated Chemokine (TARC) Predict Treatment Outcome In Classical Hodgkin Lymphoma Patients

AbstractAbstract 748 Purpose:Thymus and Activation Regulated Chemokine (TARC) is highly expressed by the Hodgkin Reed Sternberg (HRS) tumor cells of classical Hodgkin lymphoma (cHL) in the vast majority of patients. This chemokine is released in the circulation and may serve as a cHL specific biomarker. We and others showed high serum levels of TARC before start of treatment and a significant decrease in serum TARC levels after treatment. The aim of the current study is to relate plasma TARC levels during treatment with response as observed by FDG-PET imaging in cHL patients. Patients and Methods:Sixty-three newly diagnosed cHL patients from the University Medical Center Groningen were included from 2005 until 2009. Patients were treated according to clinical trial (EORTC) or hospital protocols: 1st line treatment consisted of ABVD chemotherapy with or without involved node radiotherapy for stage I/II and ABVD or EscBEACOPP/BEACOPP chemotherapy for other stages. Plasma was collected before treatment and ideally also before start of every chemotherapy cycle, with at least a sample concurrent with mid-treatment FDG-PET evaluation and at completion of treatment. Plasma TARC levels were evaluated by ELISA. TARC expression in HRS cells was determined by immunohistochemistry (IHC) on tissue samples. Results:TARC staining was observed in the HRS cells in 95% of patients. Patients with negative TARC staining did not have elevated pre-treatment plasma TARC levels and were excluded from further analysis. Pre-treatment plasma TARC levels in stage II-IV disease were significantly higher compared to stage I disease (p < .001). Patients with bulky disease had significantly higher TARC values compared to patients without bulky disease (p = .04). Mid-treatment TARC was significantly elevated in 2 out of 54 patients with an available plasma sample (Figure 1). Mid-treatment FDG-PET was positive in 13/53 patients. Two patients had persistent mid-treatment FDG-PET activity in >2 nodes and these 2 patients were the only two patients with persistent high mid-treatment TARC. The other 11 mid-treatment FDG-PET positive patients only had residual FDG-PET positivity in 1 or 2 nodes and TARC was normalized in all 11 patients. Two of these 11 patients switched to EscBEACOPP dictated by the mid-treatment FDG-PET result since they were treated in the experimental arm of the EORTC H10 trial, while the 2 patients with >2 mid-treatment FDG-PET positive nodes and high TARC did not switch since they were treated in the standard arm of this trial. End-treatment TARC was significantly elevated in 2 out of 58 patients. 4/13 mid-treatment FDG-PET positive patients remained FDG-PET positive at end-treatment evaluation. The two patients with persistent activity in >2 nodes and high TARC at mid-treatment evaluation had progressive disease at end-treatment evaluation and TARC levels remained high. Of the 11 patients with mid-treatment FDG-PET positivity and low mid-treatment TARC, 9 became FDG-PET negative. Two patients (one of those who switched to EscBEACOPP) still had residual FDG-PET activity in the same spots at end-treatment evaluation while TARC remained low. The other patient proceeded to second line treatment but remained FDG-PET positive. However, both patients did not progress during 6 months follow-up without further treatment. Of note: after one cycle of first line chemotherapy we could already observe the same plasma TARC dynamics as observed at mid- and end-treatment evaluation (n=42, Figure 1). [Display omitted] Conclusion:Mid-treatment plasma TARC levels outperformed mid-treatment FDG-PET imaging in predicting response to therapy in primary cHL patients. Moreover, TARC levels after one chemotherapy cycle could already predict final response to treatment. Evaluation of TARC dynamics before and during treatment in future clinical trials is needed to confirm the prognostic value of plasma TARC in cHL patients. Disclosures:No relevant conflicts of interest to declare.

EARLY Interim FDG-PET Scan in Localised Hodgkin Lymphoma: Evaluation of Practice in 5 French Centers

Background: Long-term survival from Hodgkin lymphoma (HL) in early-stage (I–II) patients is more than 85%. However, certain patients have a primary refractory disease with a worse evolution. Early interim FDG-PET scan performed after 2 courses of chemotherapy (PET-2) provides an early and accurate assessment of response and a correlation has been demonstrated between normalization of PET-2 and patient outcome.Aim: To evaluate the percentage of negative PET-2 in early-stage patients, and to seek clinical or biological factors predictive of positive PET-2.Methods: Sixty-five patients from five French centers with early-stage Hodgkin lymphoma received ABVD as firstline chemotherapy. PET-2 was performed 3 weeks after the second course of ABVD. Radiotherapy and changes in management according to FDG-PET scan result could be decided by the clinician. Evaluation was retrospective.Results: The median age was 36 years (range17–77). Thirty-nine patients were male. Seventy-three percent of patients were in unfavorable group according to EORTC criteria (one or more of the following criteria: age > 50, systemic symptoms, elevated ESR >50 mm, bulk disease and more than three lymph node areas involved). Fifty-seven patients had a pre-treatment FDGPET scan with a modification of staging in 6 cases. Initial staging according to CT scan or FDG-PET scan was as follows: IA: 5 patients, IB: no patient, IIA: 35 patients and IIB: 25 patients. Fifty-three patients (82%) had a negative PET-2 whereas 12 patients (18%) had a clearly positive PET-2. Among the 53 patients with negative PET-2, 47 patients underwent radiation therapy after completion of four courses of ABVD. Among the 12 patients with positive PET-2, treatment intensification (BEACOPP) occurred for 7 patients with a negative FDG-PET scan for 6 of them after two courses. For the 5 PET+ patients pursuing with ABVD: three had a negative FDG-PET scan and two had a positive FDGPET scan after four cycles of ABVD. At a median follow-up of 30 months, 6 patients relapsed early after the end of the treatment (2 in the negative PET-2 group and 4 in the positive PET-2 group). Out of the 7 patients of the positive PET-2 group receiving an increase dose intensity of chemotherapy (BEACOPP), 3 of them relapsed. The 59 other patients did not presented any failure or relapse at the present time.Conclusion: We showed in this series that negative PET-2 is obtained in 82% of patients with early stage disease. These results are similar to those expected in the EORTC H10 trial which evaluates PET-2 guided treatment adaptation and expect about 85–90% of negative PET-2. This retrospective study augurs that positive TEP2 is a pejorative prognostic factor and the utilisation of the BEACOPP treatment in these population remains to define. Prospective studies, like H10 EORTC trial are warranted to confirm these results and find predictive factors for a positive PET-2.