Unfavorable Hodgkin Lymphoma Research Articles

PET-Based Response after 2 Cycles of Brentuximab Vedotin in Combination with AVD for First-Line Treatment of Unfavorable Early-Stage Hodgkin Lymphoma: First Analysis of the Primary Endpoint of Breach, a Randomized Phase II Trial of Lysa-FIL-EORTC Intergroup

Background: About 15-20% of patients with early-stage unfavorable Hodgkin lymphoma (HL) relapse or are refractory to first-line treatment with combined modality therapies. Early assessment of metabolic response after 2 cycles of ABVD has been shown to be an accurate predictor of progression-free survival and overall survival. Brentuximab vedotin (BV) in combination with AVD chemotherapy (BV-AVD) has demonstrated a promising efficacy with a favorable safety profile in a phase I trial for treatment-naive patients (Younes A. et al, Lancet Oncol 2013). Based on these results, we conducted a randomized, multicentric, phase II trial in order to improve the PET response rate after 2 cycles with BV-AVD regimen for previously untreated, early-stage unfavorable Hodgkin lymphoma.Methods: Patients with previously untreated, stage I/II, HL and unfavorable EORTC/LYSA criteria (defined with at least one of the following: age ≥ 50 y, bulky mediastinal mass with mediastinum / thorax ratio ≥ 0.35, number of involved nodal areas ≥ 4, ESR ≥ 50mm/h or ≥ 30mm/h with B symptoms) were enrolled at the time of diagnosis. Patients were randomly assigned in a 2:1 ratio to receive 4 cycles of BV-AVD (experimental arm) or ABVD (standard arm), followed by 30Gy involved node radiation therapy (INRT). The primary objective was to evaluate the efficacy of the BV-AVD regimen, as measured by negative-PET rate after 2 cycles based on central review. PET was interpreted according to the Deauville 5-point scale with negative PET defined as Deauville 1-3. Patients with missing PET evaluation, whatever the reason, were considered as non-responders. The statistical hypothesis was based on an increase of 10% (from 75% to 85%) of the PET negativity rate after 2 cycles in the experimental arm. The standard arm was added in order to ensure that the hypothesis taken in the sample size evaluation (negative-PET rate after 2 cycles of ABVD ≤ 75%) was verified. If ≥ 93 patients out of 113 evaluable patients had negative-PET, the hypothesis that the negative-PET rate ≤ 75% in the experimental arm would be rejected. This planned analysis of the primary endpoint was performed by intention to treat (ClinicalTrials.gov registration: NCT02292979).Results: From March 2015 to October 2016, 170 patients were included, 113 were randomized in the BV-AVD arm and 57 in the ABVD arm. Median age at randomization was 29 y (range 18-60) and 51% were female. The median number of involved nodal areas was 3 and 92% of the patients were Ann Arbor stage II, 57% had a bulky disease and 40% had B symptoms. After 2 cycles of treatment, 93/113 patients (82.3%, 95% CI 75.3-88.0) and 43/57 (75.4%, 95% CI 64.3-84.5) achieved a negative-PET based on central review in the experimental and standard arms, respectively. With the lower bound of the 95% confidence interval superior to 75% in the experimental arm, the primary objective can be considered to be met. During the first 2 cycles, grade 3-4 adverse events (AEs) were documented in 74% of the patients in the BV-AVD arm and 56% in the ABVD arm. The most frequent grade 3-4 AEs in the experimental arm were neutropenia (64%), leucopenia (31%), gastro-intestinal disorders (8%), febrile neutropenia (7%), transaminases increased (4%) and infections (4%). Only 2 patients (2%) have developed a grade 3-4 peripheral neuropathy after the first 2 cycles of BV-AVD. No pulmonary toxicity has been observed. Grade 3-4 serious AEs (SAEs) were documented in 19% of the patients in the experimental arm (treatment-related SAEs in 17%) and 7% in the standard arm. SAEs have led to permanent BV discontinuation in 7/113 (6%) patients during the first 2 cycles. Reasons for permanent BV discontinuation were loss of weight, hyponatremia, febrile neutropenia, epileptic seizure, peripheral neuropathy, hepatitis and cutaneous rash.Conclusion: This randomized, multicentric, open-label phase II trial aimed to evaluate the efficacy of BV in combination with AVD chemotherapy based on PET response after 2 cycles for previously untreated, unfavorable early-stage HL. The primary objective was met with an improvement of the negative-PET rate with BV-AVD regimen. This first analysis highlighted an increased toxicity with BV-AVD regimen compared to ABVD, with a higher rate of grade 3-4 AEs and SAEs during the first 2 cycles of treatment. DisclosuresFornecker:BMS: Honoraria; Servier: Honoraria; Gilead: Honoraria; Roche: Honoraria; Takeda: Honoraria. Aurer:takeda: Honoraria, Research Funding. Bonnet:Takeda: Other: advisory board. Perrot:Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Amgen: Honoraria. Specht:Takeda: Other: advisory board. Touati:Takeda: Honoraria. Stamatoullas:Takeda: Consultancy; Celgene Corporation: Honoraria. Lugtenburg:Takeda: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Servier: Honoraria; Celgene: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Federico:takeda: Honoraria, Research Funding. Andre:Takeda: Honoraria, Other: Advisory board, Research Funding.

A Pilot Study of Brentuximab Vedotin and AVD Chemotherapy Followed By 20 Gy Involved-Site Radiotherapy in Early Stage, Unfavorable Risk Hodgkin Lymphoma

A Pilot Study of Brentuximab Vedotin and AVD Chemotherapy Followed By 20 Gy Involved-Site Radiotherapy in Early Stage, Unfavorable Risk Hodgkin Lymphoma

How does escalated BEACOPP chemotherapy compare with ABVD in people with early unfavorable or advanced-stage Hodgkin lymphoma?

How does escalated BEACOPP chemotherapy compare with ABVD in people with early unfavorable or advanced-stage Hodgkin lymphoma?

A PILOT STUDY OF BRENTUXIMAB VEDOTIN AND AVD CHEMOTHERAPY FOLLOWED BY 20 GY INVOLVED‐SITE RADIOTHERAPY IN EARLY STAGE, UNFAVORABLE RISK HODGKIN LYMPHOMA

Introduction: The combination of brentuximab vedotin (BV) with AVD chemotherapy followed by 30 Gy involved-site radiotherapy (ISRT) for the treatment of early stage, unfavorable risk Hodgkin lymphoma (HL) has demonstrated promising efficacy and an acceptable safety profile in the first cohort of this pilot study (Kumar et al., Blood, 2016). In cohort 2, we evaluated whether the reduced dose of ISRT to 20 Gy decreased RT-related toxicity while maintaining efficacy. Methods: Patients received 4 cycles of BV 1.2 mg/kg with AVD chemotherapy every 2 weeks followed by 30 Gy ISRT in cohort 1 and 20 Gy ISRT in cohort 2. Eligible patients had untreated stage I/II classical HL with any of the following unfavorable risk factors: bulky disease (maximal transverse or coronal diameter > 7 cm on CT), elevated ESR, extranodal involvement, >2 lymph node sites, or infradiaphragmatic disease. Patients with stage IIB disease with disease bulk or extranodal involvement were eligible. PET/CT after 2 and 4 cycles and ISRT were interpreted with the Deauville 5-point scale (negative = 1-3). The primary endpoint of cohort 2 was to evaluate preliminary efficacy by complete response (CR) rate. Results: In cohort 2, 29 patients were enrolled from May 2015 to October 2016 with median age of 33 (range, 19-55), 100% stage II, 69% with disease bulk (>7 cm), 38% elevated ESR, 38% B-symptoms, 21% extranodal involvement, 69% >2 involved lymph node sites, and 3% infradiaphragmatic disease. Twenty patients (69%) had bulky anterior mediastinal masses, ranging from 7 to 17.3 cm. Nine patients (31%) had advanced stage disease by the GHSG criteria: IIBX (n = 7) and IIBXE (n = 2). In cohort 2, 90% and 93% of patients achieved a negative PET scan after 2 and 4 cycles of therapy, respectively. Of the 2 patients with positive PET-4 scans, one underwent a biopsy that was negative for HL, and the other had residual FDG-uptake in a location not amenable to biopsy. Both patients received ISRT. The 25 patients who completed combined modality therapy (CMT) have achieved CRs. To date, the duration of remission ranges from 2 to 13 months, and no relapses have occurred. The efficacy is similar across cohorts 1 and 2 with interim PET negative rates of ≥90%, and all patients who completed CMT have achieved a CR (Figure 1). In cohort 1, 2 patients had biopsy-proven primary refractory HL after 4 cycles of chemotherapy, and in cohort 2, there have been no treatment failures. Conclusion: BV + AVD x 4 cycles followed by 20 Gy ISRT has promising preliminary efficacy for the treatment of early stage, unfavorable risk HL, including a high proportion of patients with bulky disease. As with 4 cycles of escalated BEACOPP tested in the GHSG HD11 clinical trial, 20 Gy ISRT may be adequate consolidation after BV + AVD x 4 cycles. We recommend that BV + AVD x 4 + 20 Gy ISRT is studied in a larger, randomized prospective study for early stage, bulky HL. Updated response data for all patients will be presented at the meeting. Keywords: brentuximab vedotin; Hodgkin lymphoma (HL)

Comparison of first-line chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for people with early unfavourable or advanced stage Hodgkin lymphoma.

Comparison of first-line chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for people with early unfavourable or advanced stage Hodgkin lymphoma.

Prognostic Value of Bone Marrow Tracer Uptake Pattern in Baseline PET Scans in Hodgkin Lymphoma: Results from an International Collaborative Study.

PET/CT-ascertained bone marrow involvement (BMI) constitutes the single most important reason for upstaging by PET/CT in Hodgkin lymphoma (HL). However, BMI assessment in PET/CT can be challenging. This study analyzed the clinicopathologic correlations and prognostic meaning of different patterns of bone marrow (BM) 18F-FDG uptake in HL. Methods: One hundred eighty newly diagnosed early unfavorable and advanced-stage HL patients, all scanned at baseline and after 2 adriamycin-bleomycin-vinblastine-dacarbazine (ABVD) courses with 18F-FDG PET, enrolled in 2 international studies aimed at assessing the role of interim PET scanning in HL, were retrospectively included. Patients were treated with ABVD × 4-6 cycles and involved-field radiation when needed, and no treatment adaptation on interim PET scanning was allowed. Two masked reviewers independently reported the scans. Results: Thirty-eight patients (21.1%) had focal lesions (fPET+), 10 of them with a single (unifocal) and 28 with multiple (multifocal) BM lesions. Fifty-three patients (29.4%) had pure strong (>liver) diffuse uptake (dPET+) and 89 (48.4%) showed no or faint (≤liver) BM uptake (nPET+). BM biopsy was positive in 6 of 38 patients (15.7%) for fPET+, in 1 of 53 (1.9%) for dPET+, and in 5 of 89 (5.6%) for nPET+ dPET+ was correlated with younger age, higher frequency of bulky disease, lower hemoglobin levels, higher leukocyte counts, and similar diffuse uptake in the spleen. Patients with pure dPET+ had a 3-y progression-free survival identical to patients without any 18F-FDG uptake (82.9% and 82.2%, respectively, P = 0.918). However, patients with fPET+ (either unifocal or multifocal) had a 3-y progression-free survival significantly inferior to patients with dPET+ and nPET+ (66.7% and 82.5%, respectively, P = 0.03). The κ values for interobserver agreement were 0.84 for focal uptake and 0.78 for diffuse uptake. Conclusion: We confirmed that 18F-FDG PET scanning is a reliable tool for BMI assessment in HL, and BM biopsy is no longer needed for routine staging. Moreover, the interobserver agreement for BMI in this study proved excellent and only focal 18F-FDG BM uptake should be considered as a harbinger of HL.

Modeling Long-Term Survival in Chemotherapy-Only Versus Combined Modality Therapy in Patients with Early Stage Unfavorable Hodgkin Lymphoma Involving the Mediastinum

Background: Optimal therapy for patients with early stage Hodgkin lymphoma (HL) is controversial. Combined modality therapy (CMT) utilizes chemotherapy plus consolidative radiotherapy (RT). CMT produces higher initial cure rates, but also increases the long-term risk of radiation toxicity. The most important risks include higher rates of breast and lung cancer, and ischemic heart disease due to mediastinal radiation exposure. Chemotherapy-only (CT) treatment with ABVD produces lower initial cure rates versus CMT, but also yields less long-term toxicity. Furthermore, those CT patients that fail initial therapy can often be salvaged with autologous stem cell transplant (ASCT). To help guide patient-specific strategies, we developed a Markov decision-analytic model to estimate long-term mortality in patients with early stage unfavorable HL involving the mediastinum treated with CMT vs. CT.Methods: We builta decision tree with Markov modeling to compare long-term mortality due to relapse, ischemic heart disease, and breast or lung cancer in hypothetical patients treated with CT or CMT using TreeAge Pro 2016. The model follows a hypothetical cohort of patients from primary therapy through 20-year follow-up. Patients transition between health states (Figure 1) based on probabilities extracted from 13 published studies. Patients that fail therapy then move to survival curves based on early vs. late relapse. The probability of toxicity was based on relative risks found in studies that used ABVD alone or ABVD with involved field or larger RT volumes. Patients who develop a toxicity move to a survival curve specific to that adverse effect. The model estimated 20-year survival in cohorts based on sex, upper vs. lower mediastinal disease, and age (20 y/o vs. 40 y/o) in non-smokers.Results: In 20 y/o patients, CMT showed better long-term survival than CT alone with slightly larger difference in mortality (1.6%) in males with upper mediastinal disease than in females (1.4%) (Table 1). In the cohort of 20 year old males, the causes of death in CMT vs. CT 20 years from starting therapy, respectively, were as follows: HL (4.7% vs. 6.6%); breast cancer (0% vs. 0%); lung cancer (0.1% vs. 0.1%); ischemic heart disease (0.6% vs. 0.3%). In 40 y/o patients, CT showed better long-term survival. The largest difference in mortality was 7.6% in 40 y/o females with lower mediastinal disease (19.9% in CMT vs. 12.3% in CT-only). In this cohort, the causes of death in CMT vs. CT, respectively were: HL (4.6% vs. 6.6%); breast cancer (4.7% vs. 1.0%); lung cancer (2.9% vs. 2.1%); ischemic heart disease (7.8% vs. 2.6%). CT-only also showed a survival benefit of 4.9% in 40 y/o males with lower mediastinal disease. Causes of death in CMT vs. CT, respectively: HL (4.6% vs. 6.6%); lung cancer (3.3% vs. 2.2%); ischemic heart disease (8.5% vs. 2.7%). At 20 years post treatment, CT-only tends to favor older patients, while CMT tends to favor younger patients due to lower baseline risks of dying from second cancers and ischemic heart disease in 40 y/o compared to 60 y/o survivors.Conclusions: This model may help multidisciplinary decision making when determining the optimum strategy for different types of patients based on disease location and risk factors for relapse and toxicity. In this study the benefits of radiation were erased by the higher rates of toxicities in older patients. Of note, the published relative risks used in this model were from studies using outdated large radiation fields rather than modern approaches. The impact of using much smaller "involved site" volumes, intensity modulated RT, and/or proton therapy is unknown but would likely lower long-term mortality from CMT. Further work using probabilistic sensitivity analyses can test these initial conclusions. [Display omitted] [Display omitted] DisclosuresHwang:Novartis: Research Funding. Nasta:Millennium Pharmaceuticals: Research Funding. Mato:Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy; Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding. Schuster:Hoffman-LaRoche: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen Research & Development: Research Funding. Svoboda:Celgene: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding.

Brentuximab Vedotin and AVD Chemotherapy Followed by ISRT: A Safe Primary Treatment Regimen for Early-Stage, Unfavorable Hodgkin Lymphoma

Brentuximab Vedotin and AVD Chemotherapy Followed by ISRT: A Safe Primary Treatment Regimen for Early-Stage, Unfavorable Hodgkin Lymphoma

Treatment of Early-Stage Unfavorable Hodgkin Lymphoma: Efficacy and Toxicity of 4 Versus 6 Cycles of ABVD Chemotherapy With Radiation

The GHSG trial HD11 established 4 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy followed by involved field radiation therapy (IFRT) as the standard of care for patients with early unfavorable Hodgkin lymphoma (HL). Despite these results, practitioners often still recommend 6 cycles of chemotherapy followed by radiation therapy (RT), especially for patients with high risk features. We compared the outcomes of patients treated with 4 vs. 6 cycles of ABVD followed by RT, including patients with bulky disease. We also examined the relapse rates of patients treated with involved site radiation therapy (ISRT) compared with IFRT. One hundred twenty-eight patients diagnosed with early stage, unfavorable HL by GHSG criteria and treated between 2000 and 2013 were identified. Medical records were reviewed for clinical, pathologic, and treatment information as well as toxicities. Clinical outcomes including overall survival (OS) and freedom from relapse (FFR) were estimated for the entire cohort as well as a subset of bulky patients using the Kaplan-Meier method. One hundred twenty-eight patients were included in the study with a median follow-up of 5.0 years. Seventy patients (55%) received 4 cycles of chemotherapy and 58 patients (45%) received 6 cycles. Bulky disease was present in 22 patients (31%; 0 stage IA, 3 stage IB, 19 stage IIA) of the 4 cycle group and 42 patients (72%; 5 stage IA, 3 stage IB, 34 stage IIA) of the 6 cycle group. 68% of all patients received ISRT. Six year OS was 100% and 97% for patients receiving 4 and 6 cycles of chemotherapy, respectively (P = 0.35). Six year FFR was 100% and 98% for patients receiving 4 and 6 cycles of chemotherapy, respectively (P = 0.28). A greater proportion of patients received 6 cycles of chemotherapy if treated before 2010 (year of HD11 report) (P = 0.01) and if bulky disease was present (P < 0.01). A greater proportion of patients developed bleomycin pulmonary toxicity in the group receiving 6 cycles of chemotherapy (20% vs 31%, P = 0.16). Six year FFR was 99% and 100% for patients receiving ISRT and IFRT, respectively (P = 0.58). Patients with bulky disease had a median follow up of 4.7 years. Amongst these patients, there were no significant differences in 4 year FFR between the 4 (100%) and 6 (98%) cycle group (P = 0.48). Four year FFR was 100% and 98% for patients receiving IFRT and ISRT, respectively (P = 0.52). There were no deaths in the patient group with bulky disease. Patients diagnosed with early unfavorable HL have excellent outcomes with 4 cycles of ABVD chemotherapy followed by radiation therapy. Six cycles of chemotherapy does not appear superior in terms of disease control and may provide little added value in this population, even for patients with high risk features such as bulky disease. Increased relapse rates are not seen with ISRT compared to IFRT after 4 cycles of ABVD.

ACR Appropriateness Criteria® Hodgkin Lymphoma-Unfavorable Clinical Stage I and II.

These guidelines review the historical evolution of treatment for early-stage Hodgkin lymphoma (HL) with current standards that rely on prognostic factors to risk stratify and direct current treatment schemes that includes differentiation of favorable and unfavorable presentations. The major clinical trials for unfavorable early-stage HL are reviewed. Patients in this heterogenous subgroup of classic HL are best managed with sequential chemotherapy and radiotherapy. The role of imaging response assessment as a means to modify therapy is a strategy under investigation. Tailoring the radiation treatment volume and radiation dose prescription along with selective use of modern conformal techniques is expected to help reduce long-term toxicities. Many patients are well served receiving involved-site radiotherapy to 30 Gy after appropriate systemic therapy intensity; but, there are nuances for which some variations in the chemotherapy and radiotherapy specifics are appropriately individualized. Following a discussion of the current evidence-based treatment algorithms, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Treatment of Early-Stage Unfavorable Hodgkin Lymphoma: Efficacy and Toxicity of 4 Versus 6 Cycles of ABVD Chemotherapy With Radiation

The German Hodgkin Study GroupHD11 trial validated 4 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy followed by involved field radiation therapy (IFRT) for early unfavorable Hodgkin lymphoma (HL) patients. However, practitioners often recommend 6 cycles followed by RT, especially for bulky disease. We compared patient outcomes after treatment with 4 or 6 cycles of ABVD followed by RT (IFRT and involved site RT [ISRT]). We identified 128 patients treated for early unfavorable HL (GHSG criteria) between 2000 and 2013. Clinical outcomes (overall survival [OS] and freedom from relapse [FFR]) were estimated using Kaplan-Meier analysis. Toxicities were evaluated. The median follow-up time was 5.0years. Patients received 4 (70 patients, 55%) or 6 (58 patients, 45%) cycles of chemotherapy. Bulky disease was present in 22 patients (31%; 0 stage IA, 3 stage IB, 19 stage IIA) of the 4-cycle group and 42 patients (72%; 5 stage IA, 3 stage IB, 34 stage IIA) of the 6-cycle group. For patients receiving 4 and 6 cycles, the 6-year OS was 100% and 97% (P=.35), respectively, and the 6year FFR was 100% and 98% (P=.28), respectively. More patients received 6 cycles if they were treated before 2010 (HD11 report) (P=.01) and if they had bulky disease (P<.01). Sixty-eight percent of patients received ISRT. The 6-year FFR was 99% and 100% for patients receiving ISRT and IFRT, respectively (P=.58). More patients experienced bleomycin pulmonary toxicity in the 6-cycle group (20% vs 31%, P=.16). For patients with bulky disease, the 4-year FFR was similar with receipt of 4 (100%) or 6 (98%) cycles (P=.48) and IFRT (100%) or ISRT (98%) (P=.52). There were no deaths among patients with bulky disease. Patients with early unfavorable HL have excellent outcomes with 4 cycles of ABVD chemotherapy followed by ISRT. Six cycles of chemotherapy does not appear superior for disease control, even for bulky disease.

Primary Progressive Disease in Hodgkin Lymphoma Patients: A Retrospective Analysis from the German Hodgkin Study Group

Background: Primary progressive disease still remains an unmet medical need in Hodgkin Lymphoma (HL). Due to missing data on treatment effects and survival there is no established standard of care. We thus performed a retrospective analysis using the German Hodgkin Study Group (GHSG) database to improve the knowledge on the course of primary progressive HL patients.Methods: Patients aged between 18 and 60 years treated within the GHSG first-line trials HD13-HD15 were screened for primary progressive HL. Primary progression was defined as progressive disease during ongoing therapy, within 3 months after the end of treatment, or up to 6 months after the end of treatment in patients with partial response or stable disease in the final restaging. We investigated types and outcome of second-line treatment approaches and overall survival, which was calculated from first diagnosis of HL (OS) and from diagnosis of first progression or relapse (OSp).Results: We analyzed 5,126 patients, of whom 112 (2.2%) were identified with primary progressive disease. Of those, 62 (55%) patients had initially been treated for advanced-stage HL with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) variants, 30 (27%) for early-stage unfavorable HL with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)- or BEACOPP-like regimens (24 and 6 patients, respectively) and 20 (18%) for early-stage favorable HL with ABVD variants. The median age at the time of progression was 33 years.3 patients (3%) died before a salvage therapy was started. Second-line treatment strategies included reinduction with intensified salvage regimens (77%), conventional chemotherapy (14%), and radiotherapy (8%). Autologous stem cell transplantation (ASCT) was performed in 76% of the patients who had received intensified reinduction chemotherapy, and allogeneic stem cell transplantation in ten (9%) patients. After the first salvage therapy, 42% of all patients achieved a complete remission (CR) and did not require further treatment. In total, 66% of the patient cohort achieved a CR after one or more second-line approaches. Median duration of the first CR was 61 months.After a median observation time of 7 years, 55 of the patients with primary progressive disease (49%) had died, mostly from progressive or relapsed HL (n=36) or toxicity of salvage treatment (n=10). The majority of the 57 survivors was in CR at the time of analysis; 2 were under treatment for HL and there was no information available for one patient. Median OSp for the entire cohort was 83 months, 5-year OSp was 55.4% (95%-CI, 46% to 65%). Since OSp differed among patients of different initial stages and types of pre-treatment (early-stage favorable and unfavorable patients treated with ABVD variants, OSp 74.2% [61%-87%] vs. higher-stage patients treated with BEACOPP variants, OSp 42.9% [31% - 55%]), treatment groups were analyzed for survival separately. In both groups, patients responding to the first salvage therapy had a significantly better OSp compared to those not responding (each p<0.001). OS was significantly worse in patients with primary progressive disease when compared to the complementary study cohort in both treatment groups (each p<0.001). When comparing patients with primary progressive disease with those patients with a relapse of HL (n=272), there were significant advantages of the latter regarding OS and OSp within the BEACOPP-pre-treated subgroup (each p<0.001). In patients pre-treated with ABVD variants, there was also a significant difference in OS (p=0.007), but no detectable difference regarding OSp (5-year OSp 74% vs. 78%, p=0.3).Conclusion: Overall, the 5-year OSp in this unselected patient cohort of primary progressive HL patients is encouraging and supports the use of aggressive salvage regimens and consolidating high-dose chemotherapy in general. However, this approach is known to induce severe long-term toxicities and has limited efficacy in patients failing first-line treatment for advanced stage disease. We conclude that there is a need to develop different treatment approaches in primary progressive HL patients. Disclosuresvon Tresckow:Novartis: Consultancy, Other: Travel and accomodation, Research Funding; Amgen: Other: honoraria for preparation of scientific educational events; Celgene: Other: honoraria for preparation of scientific educational events; Takeda: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Engert:Takeda: Consultancy, Research Funding. Borchmann:Millennium: Research Funding.

Low-Dose Consolidation Radiation Therapy for Early Stage Unfavorable Hodgkin Lymphoma

The German Hodgkin Study Group (GHSG) trial HD11 established 4 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and 30 Gy of radiation therapy (RT) as a standard for early stage (I, II), unfavorable Hodgkin lymphoma (HL). Additional cycles of ABVD may allow for a reduction in RT dose and improved toxicity profile. Patients treated with combined modality therapy at the Duke Cancer Institute for early stage, unfavorable HL by GHSG criteria from 1994 to 2012 were included. Patients who did not undergo post-chemotherapy functional imaging (positron emission tomography or gallium imaging) or who failed to achieve a complete response were excluded. Clinical outcomes were estimated using the Kaplan-Meier method. Late effects were also evaluated. A total of 90 patients met inclusion criteria for analysis. Median follow-up was 5 years. Chemotherapy consisted primarily of ABVD (88%) with a median number of 6 cycles. The median dose of consolidation RT was 23.4 Gy. Four patients had relapses, 2 of which were in-field. Ten-year progression-free survival (PFS) and overall survival (OS) were 93% (95% confidence interval [CI]: 0.82-0.97) and 98% (95% CI: 0.92-0.99), respectively. For the subset of patients (n=46) who received 5 to 6 cycles of chemotherapy and ≤ 24 Gy, the 10-year PFS and OS values were 88% (95% CI: 70%-96%) and 98% (95% CI: 85% - 99%), respectively. The most common late effect was hypothyroidism (20%) with no cardiac complications. Seven secondary malignancies were diagnosed, with only 1 arising within the RT field. Lower doses of RT may be sufficient when combined with more than 4 cycles of ABVD for early stage, unfavorable HL and may result in a more favorable toxicity profile than 4 cycles of ABVD and 30 Gy of RT.

Combined Modality Approach for Early Stage Unfavorable Hodgkin Lymphoma- Can We Avoid Radiation Therapy Based on Interim PET Imaging?

Background: Prior studies have demonstrated the utility of involved field radiation therapy to reduce relapse rates and improve local control in Hodgkin Lymphoma (HL). The standard treatment for early stage unfavorable HL is combined modality approach with chemotherapy and radiation therapy (XRT). Despite reduction in the fields of XRT, long term adverse outcomes are associated with the combined modality approach. Recent clinical trials have focused on adapting therapy based on interim PET scans. There is, however, limited data evaluating patient outcomes with chemotherapy alone in unfavorable, bulky HL patients.Methods: Two hundred and fifteen patients diagnosed with HL at our institution were included in our retrospective analysis after obtaining IRB approval. Statistical analysis was performed by chi-square analysis, Wilcoxon signed rank sum test and Kaplan-Meier plots using SPSS.19 software.Results: Of the 215 patients, 48 had early stage unfavorable HL and were included in this analysis. Unfavorable HL was defined as bulky disease (>10cm or >1/3 thoracic diameter), ESR >50 or >3 extra nodal sites involvement at presentation. The median age at diagnosis was 31 years (range 17-58). Twenty-two patients (46%) were male. All patients had an Eastern Cooperative Oncology Group performance status of either 0 or 1. Nineteen patients (40%) presented with B symptoms. The majority (83%) of patients were treated with 4-6 cycles of ABVD as first line therapy, while the remainder were treated with COPP/ABV, Stanford V, ABV or MOPP/ABV. Approximately half of the patients received XRT (54%), which was determined by physician choice. Forty-six patients (96%) were alive at the time of analysis. Seven patients (15%) underwent autologous stem cell transplantation for either disease relapse or for an incomplete response. Interim PET data was missing in 8 patients, who were excluded from subsequent analysis. Interim PET was positive in 13 of the remaining 40 patients, 9 of whom received consolidative radiation therapy and 4 of whom received high dose therapy followed by autologous stem cell transplantation. Among the 27 patients with negative interim PET, 12 received XRT. The median overall survival (OS) of all patients was 38.8 months. In patients with negative interim PET scan, the PFS was 83% and 80% in patients who received chemotherapy with and without XRT, respectively. The OS was 83% and 100% in patients who received chemotherapy with and without XRT, respectively. The differences in PFS and OS were not statistically significant between the two groups. Two patients died in the group that received combined modality treatment after negative interim PET, one from pre-existing cardiomyopathy and one from progression of disease. No death was related to XRT. In a subgroup analysis, eleven of the 27 patients with negative interim PET had bulky disease, 8 of whom received XRT. The PFS in this subgroup was 75% and 100% in patients who received chemotherapy with and without XRT, respectively. The OS in this subgroup was 88% and 100% in patients who received chemotherapy with and without XRT, respectively.Conclusion: Our data suggests that radiation therapy can be avoided based on interim PET scan in early stage unfavorable HL without compromising OS. The high overall survival of these patients may be accounted for by the fact that many who fail initial treatment can be salvaged with high dose chemotherapy and autologous stem cell transplantation. Given the potential for reduction in radiation related adverse outcomes, we encourage participation in ongoing prospective, PET-adapted, clinical trials investigating the need for consolidative XRT following chemotherapy in patients with unfavorable, bulky disease. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Low-Dose Consolidation Radiation Therapy for Early-Stage Unfavorable Hodgkin Lymphoma

The German Hodgkin Study Group (GHSG) HD11 trial established 4 cycles of ABVD and 30 Gy of radiation therapy (RT) as a standard for early-stage, unfavorable Hodgkin lymphoma (UF HL). HD11 also demonstrated that with 4 cycles of baseline BEACOPP, 20 Gy is as efficacious as 30 Gy. Additional cycles of ABVD may also allow for a reduction in RT dose. At our institution, patients often receive more than 4 cycles of ABVD for UF HL. If a complete response (CR) by positron emission tomography (PET) is achieved, ∼20 Gy of consolidation RT is typically administered.

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.

Comparison of dose-dense ABVD and standard ABVD in the treatment of early unfavorable and advanced Hodgkin’s lymphoma: A retrospective analysis

This retrospective analysis compared standard regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with the dose-dense ABVD regimen (ABVD-21) in terms of efficacy and toxicity. Patients who had early-stage unfavorable or advanced Hodgkin's lymphoma (HL) according to German Hodgkin Study Group criteria from March 1999 to February 2011 were analyzed for treatment response, long-term survival and hematological toxicity. There were 85 patients in the ABVD-21 group and 118 patients in the ABVD group respectively. The complete remission rates after completion of treatment were 92.9% and 90.7% for ABVD-21 and ABVD, respectively. During a median follow-up period of 62 months, no significant difference was found in projected 10-year progression-free survival (PFS) and overall survival (OS) rates (84.7% and 94.1% respectively for ABVD-21; 81.4% and 91.5% for ABVD). Subgroup analyses showed that ABVD-21 was significantly better than ABVD for patients with IPS≥3 in terms of PFS and OS rates. Grade 3 to 4 leukopenia (51.8% vs. 28.8%, P=0.001) and neutropenia (57.6% vs. 39.0%, P=0.009) were more common with ABVD-21. We were led to conclude that dose-dense ABVD did not result in better tumor control and overall survival than did ABVD for early-stage unfavorable HL. However, patients at high risk, for example, with IPS≥3, may benefit from dose-dense ABVD.

XVII. Radiotherapy in early stage Hodgkin lymphoma

The treatment of patients with Hodgkin lymphoma (HL) is one of the major success stories in oncology and 60–90% of patients are cured of their malignancy depending on clinical stage and risk factors. Radiotherapy was used to cure patients with HL as early as the 1940s, but more widespread successes came in the 1960s for early stage diseases I A and II A with the use of extended field radiotherapy (RT) techniques to include all nodal stations above the diaphragm such as the ‘mantle’ field [1]. Recurrence of disease outside the radiation field in some patients led to studies of adjuvant chemotherapy as part of a combined modality approach. These studies led to improved progression free survival (PFS) but no overall survival (OS) advantage was seen over RT alone because patients developing recurrent disease after RT were very efficiently salvaged by chemotherapy [2]. A sequential and thorough approach in large randomized trials exemplified by the German Hodgkin Study Group (GHSG) has led to substantial treatment reduction and established a standard of care based on minimal highly effective combined modality treatment (CMT). With a median follow-up of 7.5 years, 8-year results of the GHSG HD10 trial involving 1370 patients with early stage favourable HL showed that two cycles of chemotherapy regimen consisting of Adriamycin, Cyclophosphamide, Oncovin, Procarbazine, Prednisolone (ABVD) and 20Gy of involved field radiotherapy (IFRT) were as effective as four cycles ABVD and 30 Gy, produced less immediate toxicity and resulted in an OS of 95% and freedom from treatment failure and event-free survival of 86% [3]. For early stage unfavourable HL, moderate dose escalation using a chemotherapy regimen consisting of Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Oncovin, Procarbazine and Prednisone (BEACOPP) did not significantly improve outcome over four cycles of ABVD and 30 Gy IFRT, which the GHSG HD11 concluded remains the standard of care [4] Whilst efforts to improve a 5-year Failure From Treatment Failure (FFTF) of 85% and OS of 94.5% are ongoing in unfavourable disease, it will be difficult to improve the results of two cycles of ABVD and 20 Gy for the favourable

Limited-Stage Hodgkin Lymphoma: Optimal Chemotherapy and the Role of Radiotherapy

Approximately 90% of patients with early-stage Hodgkin lymphoma (HL) will be cured with first-line therapy. Chemotherapy alone or combined-modality therapy are both acceptable standard treatment options for nonbulky early-stage HL. Combined-modality therapy is associated with more serious late effects and, in at least one study, showed inferior survival rates compared with chemotherapy alone. Modern radiotherapy fields and doses are likely to result in fewer complications, but given the common involvement of the mediastinum in HL, complete avoidance of the heart, lungs, and breasts in the radiotherapy field is unlikely. In patients receiving chemotherapy alone, four to six cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), with fewer cycles being given to those with an early complete remission, is recommended. Three cycles of ABVD may be adequate in those with an early negative PET, but these results have been published only in abstract form. Current standards for combined-modality therapy include two cycles of ABVD and 20 Gy of involved field radiotherapy in those with a favorable risk profile and four cycles of ABVD plus 30 Gy for unfavorable HL in early-stage patients. Standard of care for bulky early-stage HL remains combined-modality therapy. Whether an interim PET will allow selection of patients with nonbulky HL who will benefit most from consolidative radiotherapy is still under investigation.

PD-0472: Early stage unfavourable Hodgkin's Lymphoma in children: Treatment outcomes and patterns of failure

PD-0472: Early stage unfavourable Hodgkin's Lymphoma in children: Treatment outcomes and patterns of failure