ALBERT

Description: Approximately 20% of all Hodgkin lymphoma (HL) patients are older than 60 years and have a poor prognosis, mainly because of increased treatment-related toxicity resulting in reduced overall dose intensity and more treatment-related mortality. To possibly improve the treatment of elderly HL patients, the German Hodgkin Study Group developed a new regimen, PVAG (prednisone, vinblastine, doxorubicin, and gemcitabine). In this multicenter phase 2 study, elderly HL patients in early unfavorable and advanced stages received 6 to 8 cycles of PVAG and additional radiotherapy if they were not in complete remission (CR) after chemotherapy. Endpoints included feasibility, acute toxicity, and response rate. Fifty-nine patients 60 to 75 years of age (median, 68 years) were eligible for analysis; 93% had advanced stage disease. WHO grade 3/4 toxicities were documented in 43 patients; 46 patients responded with CR/CR uncertain (78%). Within 37 months median observation time, 15 progressions or relapses and 17 deaths were observed, of which 8 were related to HL and 1 was the result of treatment-related toxicity. The 3-year estimates for overall survival and progression-free survival were 66% (95% CI, 50%-78%) and 58% (95% CI, 43%-71%), respectively. We conclude that PVAG is safe and feasible in elderly HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00147875.

Description: Abstract 2827 About 20% of all patients diagnosed with Hodgkin lymphoma (HL) are older than 60 years. These patients have a rather poor prognosis, particularly when presenting in intermediate or advanced stages. Besides a biologically more aggressive disease, the main reason is a drastically increased toxicity of chemo- and radiotherapy resulting in a higher treatment-related mortality and insufficient dosing of the applied treatment. In the GHSG-HD9 trial, elderly patients did not benefit from the BEACOPP regimen in terms of overall survival due to a high toxicity related death rate. In order to improve tolerability, the PVAG regimen (prednisone, vinblastine, doxorubicin, and gemcitabine) was developed. This is a modification of the ABVD regimen in which bleomycin and dacarbazine were replaced by prednisone and gemcitabine. Here we report for the first time on the final analysis of this multi-center phase II study for elderly HL patients. 61 patients were recruited between 2004 and 2007. 2 patients were excluded due to histology review not confirming HL, resulting in 59 patients with intermediate- or advanced-stage HL aged between 60 and 75 years. Treatment consisted of 6 cycles PVAG in patients achieving a complete remission (CR) after 4 cycles or 8 cycles PVAG in case of partial remission (PR) after 4 cycles. Patients who did not achieve CR after the end of chemotherapy received additional radiotherapy. Primary endpoints were administration of adequate dose without excessive delays, and response rate 3 months after end of treatment. Secondary endpoints included WHO grade III/IV toxicities, and occurrence of early progression. 59 patients with a median age of 68 years were evaluated, of which 59% were male and 93% had advanced stage disease. The relative dose intensity (relative dose divided by relative chemotherapy duration) was at least 80% in 44 patients (76%). Regarding the single cycles, of which 85% started without major delay (max. 1 day), the mean relative dose of all agents was slightly decreasing over time but always exceeded 90%. WHO grade III/IV toxicities were documented in 43 patients (75%). Only 3 patients terminated CT because of excessive toxicity. 10 Patients (17%) received consolidating radiotherapy. In total, 46 patients responded with CR/CRu (78%; 95% CI: 65% to 88%), 2 with PR (3%), 2 with no change (3%) and 4 with progressive disease (7%). 3 patients died before restaging with unknown response and in 2 patients treatment outcome is unknown. With a median observation time of 37 months, 6 patients (10%) had progressive disease and 9 patients (15%) relapsed. In total, 10 patients died from relapsing or progressing HL, 2 from second malignancies (one of lung cancer after 23 months, and one of AML after 25 months) and 5 patients due to other reasons. Overall 17 patients (29%, 95% CI: 18% to 42%) have died so far. In conclusion, PVAG is safe and feasible in Hodgkin patients older than 60. The PFS indicates activity of this regimen in this poor prognosis patient cohort. However, a controlled randomized trial to determine the best treatment in this patient population is warranted. This trial was registered at www.clinicaltrials.gov as #NCT00147875. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Whether adolescent (alc) patients with HL represent a distinct patient group, requiring a therapy strategy separated from adults, is currently focussed in international debates. Most study groups are treating adult (ad) patients (pts) (age 〉 18 years) apart from younger patients (age 〈 18 years), considering a difference in treatment related toxicity and therapy outcome in both patient groups. Between 1988 and 1998, the GHSG trial generations 2 (G2) and 3 (G3) included younger patients from the age of 15 (G2), and 16 (G3), in identically therapy regimen with adults up to 65, and 75 years. The trials for early stages HD were comparing radiation therapy (RX) arms only (HD4, recruited 1988–1993), and, RX vs 2 cycles polychemotherapy plus RX (HD7, 1993–1998). Intermediate stages HD received 2 cycles of different chemotherapy regimen plus identically RX (HD5, 1988–1993), and, 2 identically cycles of chemotherapy plus different RX (HD8, 1993–1998). Advanced stages HL were treated with either 4 cycles conventional polychemotherapy plus EF, or, 4 cycles of a hybrid regimen plus EF RX (HD6, 1988–1993); the following trial (HD9, 1993–1998) compared 3 arms of different polychemotherapy followed by RX on bulky disease. Methods: In G2 and G3, a total of 573 adolescents (15–21 yrs) in early, intermediate, and advanced stages HL were compared with 4917 pts (15–75 yrs) for complete remission rate (CR), 5 yrs survival rate (SV), 5 yrs freedom from treatment failure (FFTF), and, secondary neoplasias (2nd NPL). (table 1) Conclusion: Based on this large analysis of HL patients treated in prospectively randomized trials, the prognosis of patients aged 15–21 years is rather similar to the prognosis of adult patients. A more detailed evaluation including age-adapted prognosis will be presented. Results: Adolescents /Adults CR % 5 yrs FFTF % 5 yrs SV % Alc Ad Alc Ad Alc Ad Early stages HD4 97.7 97.3 81.6 80.5 97.6 95.1 HD7 93.3 94.3 82.0 83.3 100 94.1 Intermediate stages HD5 93.5 93.4 83.3 81.7 94.3 90.5 HD8 93.8 92.6 84.5 82.7 97.3 91.3 Advanced stages HD6 77.8 77.0 61.0 58.8 85.3 78.6 HD9 93.5 90.3 85.8 79.2 92.4 88.0

Description: Introduction: Lymphocyte predominant Hodgkin lymphoma (LPHL) differs in histological and clinical presentation from classical Hodgkin lymphoma (cHL). Treatment of LPHL patients using standard approaches leads to complete remission (CR) in more than 95% of patients. However, differences in terms of relapse rates, overall survival (OS) and freedom from treatment failure (FFTF) between LPHL and cHL patients were suggested by a recent intergroup analysis. To obtain a more comprehensive picture, we reviewed all LPHL-cases registered in the GHSG database comparing patient characteristics and treatment outcome with cHL patients. Patients and methods: We retrospectively analyzed 8298 HL patients treated within the GHSG trials (HD4 to HD12). 394 patients had LPHL and 7904 cHL. From 394 LPHL patients, 63% were in early favorable stage, 16% in early unfavorable and 21% in advanced stage of disease. Of the 7904 cHL patients analyzed, 22% were in early favorable, 39% in early unfavorable and 39% in advanced stages. 9% of LPHL patients had B symptoms compared to 40% in cHL patients. Results: 91% LPHL vs. 86% cHL patients in early favorable stages, 86% vs. 83% in early unfavorable and 79% vs. 75% in advanced stages reached CR/CRu. 0.3% LPHL patients developed progressive disease (PD) compared to 3.7% cHL patients. The relapse rate of LPHL patients was very similar to cHL (8.1% vs. 7.9%). There were 2.5% secondary malignancies in LPHL and 3.7% in cHL patients. 4.3% LPHL patients and 8.8% cHL patients died. The FFTF rates for LPHL and cHL patients at a median observation of 41 or 48 months were 88% and 82% (p=0.0093), respectively. The OS for LPHL and cHL patients was 96% and 92%, respectively (p=0.0166). The analysis between LPHL stages showed significant differences in FFTF (p=0.0239). According to a multiple Cox-regression analysis, advanced stage (p=0.0089) and lymphocytes 〈 8% of white cell count was shown as negative prognostic factors for FFTF and age ≥ 45 years (p=0.008) as negative factor for OS in LPHL patients. Hb value 〈 10.5 g/dl was shown as negative factor for both, FFTF and OS (p=0.0125, p=0.0002). Conclusion: This is the largest analysis comparing LPHL and cHL patients. We found differences in FFTF and OS rates between both groups and differences in FFTF between LPHL stages. New treatment protocols for LPHL patients with reduced intensity schedules are to be discussed.

Description: Abstract 719 Introduction: The standard of care for adolescent Hodgkin lymphoma (HL) patients is undefined, particularly the choice between adult and pediatric protocols. We thus analyzed and compared risk factors, outcome and incidence of secondary malignancies in adolescents and young adults treated within study protocols of the German Hodgkin Study Group (GHSG) to evaluate whether adolescents represent a distinct patient group. Patients and Methods: 3785 patients of all stages treated within the second (HD4-HD6, 1988-1993) and third (HD7-HD9, 1993-1998) trial generation of the GHSG were retrospectively analyzed. 557 patients were adolescents aged 15 to 20 and 3228 patients were young adults aged 21 to 45. Treatment consisted of chemo- and/or radiotherapy. Results: The risk factors large mediastinal mass (more than 1/3 of the maximum intrathoracic diameter) and involvement of three or more lymph node areas were more common in adolescents (30.2% vs. 20.9% and 67.7% vs. 58.7%, respectively, p

Description: Hodgkin’s disease can be cured by chemotherapy in the majority of cases. However a small proportion of patients show an aggressive course with multiple relapses after chemotherapy including autologous stem cell transplantation. Whether allogeneic stem cell transplantation constitutes a valid therapeutic option for these patients remains highly controversial. We report on our experience on 9 patients with Hodgkin’s disease receiving an allogeneic stem cell transplant from matched related (n=3), matched unrelated (n=1) or mismatched unrelated (2× 9/10, 2 ×8/10, 1× 7/10) donors. Median age was 28 years (range 18 – 35). All patients were extensively pre-treated including high-dose chemotherapy with autologous stem cell transplantation in 8 of 9 cases. The disease status before transplantation was CR (n=1), PR (n=5), SD (n=2) or progressive disease in 1 case. Conditioning treatment consisted of fludarabine 30 mg/m2 day -8 to -4, melphalan 70 mg/m2 day -3 to -2 and ATG 10–20 mg/kg day -4 to -2. Ciclosporin A and short course methotrexate was used for prophylactic immunosuppression. All patients showed prompt engraftment. Acute GvHD was found in 2 patients (Grade IV n=1, Grade I n=1), chronic GvHD did not occur after a median follow up of 471 days for the surviving patients. Two patients died from treatment-related causes, one from GvHD and one from septicemia. Estimated 2 year survival is 78%. Three patients have relapsed so far at day 128, 192 and 201 post transplant and received donor lymphocyte infusions or chemotherapy. The estimated 2 year disease free survival is 57%. Our results show a good feasibility of an allogeneic stem cell transplantation with reduced intensity conditioning for relapsed Hodgkin’s disease despite extensive pre-treatment and mostly partial remissions at transplant. The rate of acute and chronic GvHD was remarkably low in view of the fact, that 5 of 9 patients had mismatched unrelated donors. In summary allogeneic stem cell transplantation should be further exploited as treatment option for refractory and relapsed Hodgkin’s disease in younger patients.

Description: The German Hodgkin’s Lymphoma Study Group has previously demonstrated that dose-escalated BEACOPP chemotherapy administered every 21 days with filgrastim significantly improved failure-free and overall survival compared to COPP-ABVD in patients with advanced Hodgkin’s Lymphoma (Diehl et al, Annals of Oncology 1998). An alternative approach to dose escalation is reduction of cycle length to 14 days. BEACOPP given every 14 days (BEACOPP-14) with filgrastim has been demonstrated to be feasible and effective with moderate acute toxicity (Sieber et al, JCO 2003). The aim of this study was to explore the feasibility of pegfilgrastim to support full delivery of BEACOPP-14 in high-risk Hodgkin’s lymphoma. All patients received BEACOPP-14 for up to 8 cycles. Patients were randomised to receive a single, 6mg, subcutaneous dose of pegfilgrastim on day 4 (d4) or 8 (d8) of each cycle. Primary endpoints were proportion of chemotherapy cycles given at planned dose and on time and proportion of patients receiving all administered cycles of chemotherapy at planned dose and on time. A cycle was considered “on time” if it started ≤ 17 days after the start of the previous cycle, and at “planned dose” if a dose of 〉75% was administered for each myelosuppresive agent. Secondary endpoints included incidence of severe neutropenia (SN: absolute neutrophil count [ANC]