Advanced-stage Hodgkin Lymphoma Research Articles

Assessment of Residual Bulky Tumor Using FDG-PET In Patients with Advanced-Stage Hodgkin Lymphoma After Completion of Chemotherapy: Final Report of the GHSG HD15 Trial

AbstractAbstract 764 IntroductionThe role of additional radiotherapy after chemotherapy for advanced-stage Hodgkin lymphoma is unclear. The German Hodgkin Study Group (GHSG) thus performed the HD15 trial in which advanced-stage Hodgkin lymphoma patients having residual disease after 6–8 cycles of BEACOPP were evaluated by 18F-fluorodesoxyglucose positron emission tomography (PET) following chemotherapy. MethodsEntry criteria for the PET question in HD15 were partial remission (PR) after the end of chemotherapy with at least one involved nodal site measuring more than 2.5 cm in diameter by computed tomography (CT). Exclusion criteria included diabetes, elevated blood sugar levels and skeletal involvement with risk of instability. Calculations were restricted to those cases with either progressive disease (PD) or relapse within 12 months after PET or at least 12 months of follow-up. A total of 2,137 patients with de novo HL were included in HD15 of whom 728 had a tumor bulk ≥ 2.5 cm after BEACOPP chemotherapy and were qualified for the PET question. An expert panel performed the assessment of response and PET. Only PET-positive patients were scheduled for radiotherapy of residual disease. The negative prognostic value (NPV) of PET was defined as the proportion of PET-negative patients without progression, relapse or radiotherapy despite being PET-negative within 12 months. ResultsThe full analysis set included 728 patients of whom 699 had at least 12 months of follow-up. Median age was 30 years, 57% were males and 66% had NS histology. Of the 728 qualified patients with residual disease ≥ 2.5 cm after BEACOPP, 74.2% were PET-negative and 25.8% PET-positive. In the PET-negative group, a total of 28 patients relapsed or had radiotherapy despite being PET-negative (8 patients including 1 relapsing patient) resulting in a negative prognostic value of 94.6% (95% CI 92.7% to 96.6%). With a median follow-up of 38 months, the time-to-progression after PET at 3 years was 92.1% for PET-negative patients counting radiotherapy as failure and 86.1% for PET-positive patients (95%-CI for difference -11.9% to -0.1%). Overall, only 11% of patients had additional radiotherapy as compared to 71% after BEACOPPescalated in our prior HD9 trial. In addition, there was no difference in PFS or overall survival as compared to our earlier trials in advanced-stage HL. DiscussionThe NPV of PET of 0.95 suggests that indeed only patients with residual disease after chemotherapy who are PET-positive need additional radiotherapy. PET-negative patients at least after BEACOPP can be spared from additional radiotherapy. Disclosures:No relevant conflicts of interest to declare.

A Randomized Phase III Trial of ABVD Vs. Stanford V +/− Radiation Therapy In Locally Extensive and Advanced Stage Hodgkin's Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperatve Oncology Group (E2496)

AbstractAbstract 415 Background:The ability to cure patients (pts) with advanced Hodgkin's Lymphoma (HL) with combination chemotherapy (CC) (MOPP and variants, ABVD and variants) represented a major milestone in oncology research, and CC became a paradigm for other malignancies. Further, the rationale for combined modality therapy (CMT) (radiation (RT) and CC) in HL evolved based on the high frequency of relapse in initially involved sites. As response rates and survival improved, newer treatments such as the combined modality Stanford V regimen were developed to shorten the duration of chemotherapy, add RT to sites of disease and reduce toxicity while maintaining or improving the cure rate. Indeed, the Stanford V regimen was tested and validated in a Phase II co-operative group trial (E1492) (J Clin Oncol 2000; 18:972). In order to investigate this approach against “standard” therapy, we conducted a randomized Phase III Intergroup trial of ABVD vs. the Stanford V regimen for patients with locally extensive or advanced HL. Objectives:The trial was designed to detect a 33% reduction in the failure free survival (FFS) hazard rate with Stanford V compared with ABVD, which corresponds to a difference in five-year FFS of 64% vs. 74%. Method:Patients with locally extensive (defined as clinical Ann Arbor Stage I-IIA/B and bulky mediastinal disease (BMD) (mass > 1/3 maximum intrathoracic diameter on standing postero-anterior chest x-ray or >/−10 cm on computerized tomography) or advanced (Ann Arbor Stage III or IV) HL were randomized to receive either ABVD × 6–8 cycles (C) (51% had 6 C, 35% had 8 C, 14% had <6 C) + 36 Gy (only in pts with BMD) or Stanford V × 12 weeks (95% had 12 weeks) + 36 Gy (for sites >5cm or for macroscopic splenic disease). The log-rank test was used to compare FFS for all eligible patients stratified on extent of disease (locally extensive vs. advanced), and number of International Prognostic Factor Project (IPFP) risk factors (0–2 vs. 3–7). An extended Cox model was also used to address non-proportional hazard between the two arms. Results:854 pts enrolled from April, 1999 to June, 2006 and 812 were eligible for analysis. 404 pts were randomized to ABVD and 408 to Stanford V. Median age was 33 yrs in both arms (range 16–83). 53% were men and 47% women; 4% had Stage I, 31% had Stage II, 39% had Stage III and 25% had Stage IV disease by Ann Arbor criteria. 35% of pts on ABVD and 35% on Stanford V had BMD. Three % of pts had nodular lymphocyte predominant HL, 77% of pts had nodular sclerosis HL, 14% had mixed cell HL. Age, stage, pathology and risk factors (0–2 vs. 3–7) were similar in both arms. In total, 65% were IPFP score 0–2 and 33% were 3–6. Response rate. There was no difference in response rates (RR) between the two arms (ABVD=72% CR+ CCR, 7.7% PR, 7.9% SD; Stanford V= 69 % CR +CCR, 7% PR and 10 % SD. 8% were not evaluable for response on ABVD and 9% on Stanford V. Toxicity was similar in both groups. The most frequent Grade 3 + 4 toxicity was neutropenia, and was similar between the 2 groups (76% Grade 3 + 4 in ABVD and 70% Grade 3+ 4 in Stanford V). Grade 5 toxicity was <1% in both groups. There was, however, more Grade 3 lymphopenia in Stanford V (78% vs. 42%, p< 0.0001) and more Grade 3 +4 sensory neuropathy in Stanford V (10%) than in ABVD (3%) (p< 0.0001). A total of 26 second primary cancers developed, 12 after ABVD and 14 after Stanford V (p=NS). FFS and OS. For 812 eligible patients, with a median follow up of 5.25 years, 5-year FFS was 73% for ABVD and 71% for Stanford V (p=0.29 by log rank) (Figure left); 5-year OS was 88% for ABVD and 87% for Stanford V (p=0.87 by log-rank, HR=0.97, 95% CI: 0.65 to 1.44) (Figure right) indicating no significant difference in either FFS or OS between the 2 arms. Conclusion:In the largest Phase III intergroup trial of HL in North America, there was no significant difference in RR, FFS, OS, and 5-year toxicity when ABVD (+ RT for BMD) is compared with Stanford V (+RT for nodal sites >5 cm and macroscopic splenic disease). There was more Grade 3 lymphopenia (p< 0.0001) and more Grade 3 + 4 sensory neuropathy (p< 0.0001) on Stanford V. Thus ABVD (plus RT for BMD) remains the standard of care because Stanford V did not meet the objective of 33% improvement in FFS. For some patients, Stanford V, when given as described with RT, remains an acceptable alternative. [Display omitted] [Display omitted] Disclosures:Friedberg:Genentech: Honoraria. Blum:Seattle Genetics: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Horning:Genentech: Employment.

PVAG (Prednisone, Vinblastine, Doxorubicin and Gemcitabine) In Elderly Patients with Intermediate or Advanced Stage Hodgkin Lymphoma: Final Results of a Phase II Study of the German Hodgkin Study Group (GHSG).

AbstractAbstract 2827About 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.

Randomized Phase III Trial Comparing ABVD + Radiotherapy and the Stanford V Regimen In Patients with Stage I/II Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the US Intergroup Trial E2496

AbstractAbstract 416 Background:Standard therapy for locally extensive Hodgkin Lymphoma (HL) defined as stage I/II with bulky mediastinal disease [mediastinal mass ratio (MMR) > than 1/3 of the chest diameter on standing postero-anterior chest x-ray or 10 cm on computerized tomography] is combined modality therapy (CMT). E2496 was a North American intergroup, randomized phase III study comparing ABVD versus the Stanford V regimen for patients with locally extensive and advanced stage HL. In this subgroup analysis we compare two CMT approaches, ABVD + radiotherapy (RT) and the Stanford V regimen, in patients with stage I/II bulky mediastinal HL. Methods:Patients with stage I/II HL bulky mediastinal disease were randomized to receive chemotherapy (CT) on either Arm A (ABVD × 6–8 cycles administered q 28 days) or Arm B (12 weeks of Stanford V, administered weekly). Two-3 weeks after completion of chemotherapy, modified involved field RT was delivered at 36 Gy to the mediastinum to patients on ABVD as well as Stanford V. Patients on Stanford V also received involved field RT to any other sites >5 cm at diagnosis. The primary endpoint was failure free survival (FFS) defined as the time to either progression/relapse or death. The log-rank test was used to compare FFS and OS (overall survival) for all eligible patients. Results:Of the 812 eligible patients with advanced HL enrolled on the study 267 had locally advanced bulky mediastinal disease: 136 on ABVD and 131 on Stanford V. Patient characteristics between the two randomized groups were well matched with a median age of 30 years and 86% had stage II disease. On ABVD 61% of patients received 6 cycles, 29% 8 cycles of CT and 77% required some dose modification. In Stanford V 97% completed the assigned 12 weeks of CT and 76% required some dose modification. 82% received RT per protocol in ABVD versus 88% in Stanford V. The overall response (CR+PR) was 82% in ABVD and 86% in Stanford V. At a median follow-up of 5.47 years, there are 19 failures and 6 deaths in the ABVD group and 25 failures with 9 deaths in the Stanford V group. We failed to detect statistically significant differences between ABVD +RT and Stanford V for FFS (5y 85% versus 77% p=0.13, HR=1.56 95% CI (0.87, 2.88) and OS (5y 95% versus 92% p=0.31, HR=1.69 95% CI (0.60, 4.75). No difference in hematologic toxicity was observed between the two arms. Evaluation of pulmonary function and patterns of failure are pending. Conclusions:For stage I/II patients with bulky mediastinal disease, CMT with either ABVD +RT or the Stanford V regimen results in high cure rates and is highly effective. ABVD for 6–8 cycles plus 36 Gy RT remains the US standard of care. Longer follow up is required to assess RT related late effects. Future research efforts should focus on risk stratification to identify; a) the 15–20% of patients destined to relapse after standard therapy and evaluate treatment intensification strategies and b) the 80–85% of patients who are cured with standard therapy and determine whether a subset can achieve the same excellent outcomes with a reduction or elimination of radiation. Planned US cooperative group trials will address these questions, using ABVD as the chemotherapy backbone in conjunction with interim PET imaging for risk stratification. Disclosures: Blum:Seattle Genetics: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Horning:Genentech: Employment.

Outcome of Patients with Advanced Hodgkin Lymphoma Who Are Either Refractory to or Relapsed After Primary Therapy with the Stanford V Regimen

AbstractAbstract 4828 Purpose:Stanford V is an abbreviated combined modality approach for the treatment of advanced stage Hodgkin lymphoma (HL). This regimen was developed with the aim of shortening the duration of chemotherapy, limiting the radiotherapy (RT) to a modified involved field and thereby potentially reducing short and long term toxicity while maintaining or improving cure rates. Specifically the chemotherapy regimen has significantly lower cumulative doses of adriamycin, bleomycin and alkylating agents compared to other standard regimens such as ABVD or escalated BEACOPP. We have previously reported excellent outcomes with this regimen with a freedom from progression (FFP) of 89% and overall survival (OS) of 96% (Horning, S.J., et al., J Clin Oncol 2002, 20:630-7). The purpose of this study was to determine the outcome of patients (pts) treated with secondary therapy after failing Stanford V. Methods:Pts with advanced stage HL who had either refractory disease or had relapsed after primary therapy with Stanford V, were retrospectively identified from the HL database. We analyzed this group of patients for risk factors, salvage therapy, and treatment outcome. Results:Between May 1989 and March 2003, 167 pts were treated on protocol. At a median follow-up of 12.8 years the outcomes are excellent with a 10-year FFP and OS of 87% and 93%, respectively. Therapy failed in 19 pts (11%) of which 16 relapsed and 3 did not complete the intended treatment (disease progression n=2, and muscle pain and hyponatremia n=1). The median age of pts who failed therapy was 31 years (range 21 – 58) with a median time to progression of 5.1 months (range 0.2 – 41.4). 11 pts relapsed at 0 to 12 months from completion of therapy and 8 pts relapsed at > 12 months. At initial diagnosis 5 had stage I/II disease with bulky mediastinum, 5 stage III and 9 stage IV disease. The International Prognostic Score (IPS) at initial diagnosis was 0–1 (n=4), 2–3 (n=10) and 4–7 (n=5). 13/19 (68%) pts relapsed outside the RT field, 2 infield, 3 both infield and outside and 1 unknown. 7/19 pts in whom therapy failed had bulky disease and of these 5 failed outside the RT field. Relapse was detected clinically in 12 pts, and on surveillance positron emission tomography scan performed every 3 to 6 months in 5 pts who were asymptomatic (2 pts unknown). 14/19 (74%) pts received secondary therapy with a platinum-containing regimen (ICE or DHAP) with an overall response rate (ORR) of 91% (complete response [CR] n=1, partial response [PR] n=9, progressive disease [PD] n=1, unknown response n=3), followed by an autologous hematopoietic stem cell transplant. 5 pts were treated with non-transplant regimens consisting of chemotherapy with MOPP/ABV + RT (n=2), ChlVPP (n=1), oral cyclophosphamide (n=1) and procarbazine/alkeran/adriamycin/etoposide (n=1), with an ORR of 80% (CR n=4). Reasons for non-transplant therapy were neuropathy (n=1), pt preference (n=1), liver disease (n=1), and unknown (n=2). 11 of the 19 pts in whom Stanford V failed died (disease progression n=3, second malignancy n=2, graft failure n=1, infection n=1, liver failure n=1, cardiac arrest n=1, suicide n=1 and unknown n=1). At a median follow-up of 8 years, the disease-specific survival (DSS), FFP and OS for pts with refractory or relapsed disease after Stanford V was 84%, 63% and 42%, respectively. Outcome of pts who relapsed within a year was worse than pts who relapsed > 1 year with an OS of 36% versus 50%, respectively. There was no difference in FFP for these groups, 64% versus 63%, respectively. Conclusions:The outcome of pts with advanced HL is excellent with the Stanford V regimen. For the 11% of pts in whom front line therapy fails, secondary therapy is effective with a DSS of > 80%. The majority of pts (84%) failed at distant sites suggesting that more aggressive upfront chemotherapy may have been beneficial in these pts. Future efforts will aim at identifying this subset upfront. Pts who relapse within a year have a worse outcome despite salvage and for this subgroup, newer therapies are warranted. Disclosures:Horning: Genentech: Employment.

G-CSF as Secondary Prophylaxis of Febrile Neutropenia In the Management of Advanced-Stage Hodgkin Lymphoma Treated with ABVD Chemotherapy: A Decision Analysis.

AbstractAbstract 3831 Background:ABVD is the standard treatment for advanced stage Hodgkin Lymphoma (HL) with rates of complete remission achieved in the majority of patients treated. Current practice guidelines (American Society of Clinical Oncology, Smith TJ et al. JCO 2008) recommend the use of granulocyte colony stimulating factor (G-CSF) in secondary prophylaxis despite lack of a survival benefit and potential toxicities, including bleomycin pulmonary toxicity (BPT). Recently, small retrospective series and expert opinion (Horning S, ASH Education Program Book 2007) advocate for the omission of G-CSF, although this approach has not been prospectively studied. The purpose of this study was to perform a decision analysis that compared the life expectancy and quality-adjusted life expectancy of advanced-stage HL managed with and without secondary prophylactic G-CSF. Methods:We constructed a decision-analytic model to compare the strategy of secondary prophylaxis with G-CSF to a strategy of no G-CSF with severe neutropenia for a hypothetical cohort of 40 year-old patients with clinical stage IIB to IV Hodgkin Lymphoma treated with 8 cycles of ABVD chemotherapy. Markov models were used to simulate a 2-year clinical course of patients. Baseline probability estimates were derived from a systematic review of relevant published studies. Utilities for various health states were derived from expert opinion. One-way sensitivity analysis was performed on key variables such as severe neutropenia, febrile neutropenia and bleomycin pulmonary toxicity, as well as the utilites associated with these health states. Results:The life expectancy was 1.858 years for the G-CSF strategy and 1.875 years for no G-CSF, yielding a net expected benefit of 0.017 years for no G-CSF use in severe neutropenia. The quality-adjusted life expectancy was 1.371 years for the G-CSF strategy and 1.408 years for no G-CSF with a net expected benefit for no G-CSF of 0.037 QALYs. On microsimulation (10,000 trials), 96% of the simulations showed that the no G-CSF strategy is preferred to the use of G-CSF. This analysis was not sensitive to the odds ratio of lung toxicity with G-CSF, the hazard ratios of febrile neutropenia and severe neutropenia, the probability of death from febrile neutropenia, or the utilities associated with bleomycin pulmonary toxicity, hospitalization for febrile neutropenia and musculoskeletal pain from G-CSF. Conclusions:While the difference between the two strategies is small, our model predicted that for a 40 year-old patient with advanced-stage Hodgkin Lymphoma treated with ABVD chemotherapy, the strategy of avoiding use of G-CSF with severe neutropenia is preferred. This finding is robust across a wide range of sensitivity analyses. Disclosures:No relevant conflicts of interest to declare.

Early Interim 18f-FDG PET In Hodgkin's Lymphoma: Evaluation on 304 Patients

AbstractAbstract 3879 Purpose.The use of early (interim) positron emission tomography (PET) restaging during front-line therapy in Hodgkin's lymphoma (HL) has considerably increased in clinical practice as an early recognition of treatment failure allows patients to be addressed to more intensive treatment regimens. Patients and Methods.Between June 1997 and June 2009, 304 newly-diagnosed Hodgkin's lymphoma patients (147 early-stage and 157 advanced-stage) were treated with the ABVD regimen at two Italian institutions. Patients underwent to a PET staging and restaging at baseline, after 2 cycles of therapy and at the end of the treatment. Results.53 patients showed a positive interim PET and only 13/53 (24.5%) achieved a complete response (CR), whereas 251 patients showed a negative PET and 231/251 (92%) remained in CR. Comparison between interim PET-positive and interim PET-negative patients indicated a significant association between PET findings and 9-year progression-free survival (p=0.0000) and 9-year overall survival (p=0.0000), with a median follow-up of 31 months.Among the early-stage patients, 19 had a positive interim PET and only 4 (21%) achieved a CR; among the 128 negative interim PET patients, 122 (97.6%) obtained a CR. In the advanced-stage subset, 34 patients showed a persistently positive PET (with only 9/34, 26.4% in CR), whereas 123 showed a negative interim PET, with 109 (88.6%) remaining in CR. Conclusions.Our results confirm the role of early PET as a significant step forward for the management of both early and advanced-stage HL patients, offering the potential for an immediate switch to high-dose treatments, if required. Disclosures:No relevant conflicts of interest to declare.

Phase II study of ABVd therapy for newly diagnosed clinical stage II–IV Hodgkin lymphoma: Japan Clinical Oncology Group study (JCOG 9305)

Although ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) therapy has been regarded as a standard of care for advanced-stage Hodgkin lymphoma (HL) since 1992, there has been no prospective data of ABVD therapy in Japan. To investigate the efficacy and safety of ABVd therapy with the lower dose of dacarbazine (250 mg/m(2)) in patients with newly diagnosed stage II-IV HL, Lymphoma Study Group of Japan Clinical Oncology Group conducted a phase II study. The primary endpoints were complete response rate (%CR) and progression-free survival (PFS). A total of 128 patients with age less than 70 years were enrolled and received 6-8 cycles of ABVd followed by radiation to initial bulky mass. The %CR in 118 eligible patients was 81.4% [95% confidence interval (CI) 73.1-87.9%]. Major toxicity was grade 4 neutropenia (45.3%). Grade 3 nausea/vomiting was the most frequent non-hematological toxicity (10.9%). Transient grade 4 constipation, infection (abscess), hypoxemia and hyperbilirubinemia were observed in 4 patients. No treatment-related death was observed. PFS and overall survival at 5 years were 78.4% (95% CI 70.9-85.9%) and 91.3% (95% CI 86.1-96.5%), respectively. In conclusion, ABVd is effective in Japanese patients with stage II-IV HL with acceptable toxicities (UMIN-CTR Number: C000000092).

Allogeneic haematopoietic stem-cell transplantation with reduced intensity conditioning for advanced stage Hodgkin's lymphoma in Sweden: high incidence of post transplant lymphoproliferative disorder

Allogeneic transplantation after reduced intensity conditioning (allo-RIC) is a treatment option for patients with Hodgkin's lymphoma (HL) relapsing after autologous transplantation. In all, 23 adult patients with HL underwent allo-RIC in Sweden between 2000 and 2007. The median number of previous treatment lines was five and 20 patients (87%) were previously autografted. TRM at 100 days and at 1 year was 13 and 22% respectively. Acute GVHD grades II-IV developed in 7 out of 23 patients (30%) and chronic GVHD in 10 out of 20 patients at risk (50%). The OS and EFS at three years was 59 and 27%, respectively. Four patients (17%) developed post transplant lymphoproliferative disease (PTLD) after a median time of 55 days (range 38-95); two of these patients later died. The study confirmed that allo-RIC is feasible, but associated with a substantial relapse rate: only 20% of the patients were still alive 7 years after the transplant. A finding of high incidence of PTLD needs to be confirmed in a larger trial that includes patients with non-HL and CLL.

No protection of the ovarian follicle pool with the use of GnRH-analogues or oral contraceptives in young women treated with escalated BEACOPP for advanced-stage Hodgkin lymphoma. Final results of a phase II trial from the German Hodgkin Study Group

Background: The reduction of treatment-related toxic effects is the main goal in the current trials of the German Hodgkin Study Group (GHSG). In this regard, the protection of the ovarian reserve in young women is very important. Therefore, the GHSG investigated the use of gonadotropin-releasing hormone-analogues (GnRH-a) and oral contraceptives (OC) in young women with advanced-stage Hodgkin lymphoma (HL).Patients and methods: Women (18–40 years) were randomly assigned either to receive daily OC or monthly GnRH-a during escalated combination therapy with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). Hormonal levels were determined at baseline, during therapy, and at follow-up.Results: The study was closed prematurely after an interim analysis of 12 patients in arm A (OC) and 11 in arm B (GnRH-a), 9 and 10 are assessable for the primary end point. Women’s median age was 25 years in both arms. The anti-Mullerian hormone level after at least 12 months was reduced in all patients. For the entire study cohort, the respective ovarian follicle preservation rate was 0% (95% confidence interval 0% to 12%).Conclusion: We observed no protection of the ovarian reserve with hormonal co-treatment during BEACOPPesc. This result supports efforts of ongoing trials to reduce chemotherapy intensity and toxicity. Alternative strategies for the protection of fertility must be offered to young female HL patients before the start of BEACOPPesc therapy.

Combination of gonadotropin-releasing hormone (GnRH) agonists with GnRH antagonists before chemotherapy reduce but does not completely prevent a follicle-stimulating hormone flare-up

Increasing evidence supports GnRH agonists to be an effective treatment to preserve ovarian function during chemotherapy, but the initial flare-up of FSH during the first week after GnRH agonist application still limits its use. The combination of GnRH agonists with GnRH antagonists might solve this problem to some extent as the addition of GnRH antagonists at least significantly reduces the FSH flare-up.

Phase 2 study of BACOPP (bleomycin, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) in older patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group (GHSG)

AbstractFor older patients with early unfavorable or advanced stage Hodgkin lymphoma (HL) the prognosis is much worse than for younger HL patients. We thus developed a new regimen, BACOPP (bleomycin, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone), to improve both tolerability and efficacy of treatment for older HL patients. Between 2004 and 2005, 65 patients with early unfavorable or advanced stage HL aged between 60 and 75 years were enrolled in this phase 2 trial. Treatment consisted of 6 to 8 cycles of BACOPP. Residual tumor masses were irradiated. Primary endpoints were feasibility as determined by adherence to protocol and overall response rate. Secondary endpoints included toxicity, freedom from treatment failure, and progression free and overall survival. For the final analysis 60 patients (92%) were eligible; 75% of treatment courses were administered according to protocol. World Health Organization grade 3/4 toxicities occurred in 52 patients. Fifty-one patients (85%) achieved complete remission, 2 (3%) partial remission, and 4 (7%) developed progressive disease. With a median observation time of 33 months, 18 patients died (30%), including 7 treatment-associated deaths. Three patients died before response assessment. Thus, the BACOPP regimen is active in older HL patients but is compromised by a high rate of toxic deaths. This trial was registered at www.clinicaltrials.gov as #NCT00284271.

Interim PET in lymphoma: a step towards standardization

In this issue, Barrington et al. propose well-defined criteriafor interim PET/CT reporting in lymphoma [1]. Thesecriteria, based on a five-point scale, introduce two mainconcepts which are highly relevant for interim PETanalysis: (1) the intensity of the residual uptake frequentlyobserved at interim is graded relative to various levels ofreference background (RB)—mediastinal blood pool(MBP) and liver—and (2) this grading process is indepen-dent of the size of the residual tumour. Furthermore, theauthors reported that this five-point scale assessed on asample of 50 patients with advanced stage Hodgkin’slymphoma (HL) by 4 pairs of experts from 4 Europeancentres: (1) seems a reproducible tool for guiding thera-peutic strategy after 2 cycles of ABVD (Adriamycin,bleomycin, vinblastine, dacarbazine) when liver is chosenas an RB and (2) is robust enough to be used in multicentretrials for interim PET reporting.The authors have decided to use this scale in theResponse Adapted Treatment in Hodgkin Lymphoma(RATHL) trial, an interim PET-driven therapeutic strategyin patients with advanced stage HL. Although manytrials are ongoing worldwide in HL and non-Hodgkin’slymphoma (NHL) to test whether the results of an interimPET performed after one to four cycles of chemotherapycan tailor a response-adapted therapy, standardized interimPET criteria are still missing. Interim PET requires indeedspecific criteria which should be different from thosedefined for end treatment by the International Harmoniza-tion Project (IHP) in Lymphoma [2]. In the context of drugdevelopment and survival improvement observed inlymphoma, the rationale of interim PET is to define ana posteriori prognostic index reflecting tumour chemo-sensitivity during first-line therapy, allowing earlychanges of therapy (escalation or de-escalation) adaptedto specific situations. In many trials the strategy can bemodified according to the results of two interim PETexams performed at different times during inductiontreatment. As a matter of fact, depending on thecharacteristics of tumour growth and histological typethe evolution of PET under treatment is different. Indiffuse large B-cell lymphoma (DLBCL) neoplastic cellsconstitute more than 90% of the total cell population.The metabolic activity during therapy decreases in acontinuous mode, with cell killing. Interim PET after oneor two cycles of chemotherapy evaluates the response ofthe cells with the highest mitotic index, thereby providingan early evaluation of chemosensitivity and identifyingresponders and non-responders [3, 4]. On the other hand,after three or four cycles of therapy, FDG uptake is moredependent on the tumour regrowth [5]. In HL, the Reed-Sternberg (RS) cells account for less than 1% of the tumour.Bystander, lymphomononuclear cells work, throughcytokines, as an amplifier of the PET detection power. Thesecells are switched off very early (one to two cycles) bychemotherapy [6]. Therefore, the amount of residual activityat interim varies with the kinetics of tumoral destruction, thehistology of lymphoma, the tumoral microenvironment, thetreatment and the time point (two cycles or more) at whichPET is performed. These variations are better described by aquantitative analysis by reference to the baseline PET thanby using a visual dichotomous analysis (positive or negative)which results in a loss of information [3, 5]. In this regard thefive-point scale proposed by Barrington et al. is goingtowards the right direction by giving the possibility to grade

Procarbazine-Free OEPA-COPDAC Chemotherapy in Boys and Standard OPPA-COPP in Girls Have Comparable Effectiveness in Pediatric Hodgkin's Lymphoma: The GPOH-HD-2002 Study

Vincristine, etoposide, prednisone, and doxorubicin (OEPA)-cyclophosphamide, vincristine, prednisone, and dacarbazine (COPDAC) is derived from standard vincristine, procarbazine, prednisone, and doxorubicin (OPPA)-cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) chemotherapy by replacing procarbazine with etoposide and dacarbazine for a potentially less gonadotoxic regimen for boys with Hodgkin's lymphoma (HL). Five hundred seventy-three pediatric patients with classical HL were enrolled onto the German Society of Pediatric Oncology and Hematology-Hodgkin's Disease (GPOH-HD) -2002 study between November 2002 and December 2005. Boys received two courses of OEPA and girls received two courses of OPPA for induction. Treatment group (TG) -2 (intermediate stages) and TG-3 (advanced stages) patients received further two or four cycles COPP (girls) or COPDAC (boys), respectively. After chemotherapy all patients received involved-field irradiation with 19.8 Gy, except for patients with early-stage disease (TG-1) in complete remission. Five hundred seventy-three patients (287 males and 286 females) were less than 18 years old and fulfilled all inclusion criteria; 195 patients (34.0%) were allocated to TG-1, 139 (24.3%) were allocated to TG-2, and 239 (41.7%) were allocated to TG-3. Toxicity of OEPA-COPDAC was tolerable overall. Hematotoxicity was more pronounced with OEPA than OPPA, whereas it was less pronounced with COPDAC compared with COPP. The median observation time was 58.6 months. Overall survival and event-free survival (EFS) rates (+/- SE) at 5 years were 97.4% +/- 0.7% and 89.0% +/- 1.4%, respectively. In TG-1, overall EFS was 92.0% +/- 2.0%. EFS of patients without irradiation (93.2% +/- 3.3%) was similar to that of irradiated patients (91.7% +/- 2.5%), confirming results of the previous GPOH-HD-95 study. In TG-2+3, EFS did not significantly differ between boys and girls (90.2% +/- 2.3 v 84.7% +/- 2.7, respectively; P = .12). In TG-2+3, results in boys and girls are superimposable. OPPA-COPP and OEPA-COPDAC seem to be exchangeable regimens in intermediate- and advanced-stage classical HL in pediatric patients.

Effect of early chemotherapy intensification with BEACOPP in high-risk, interim-PET positive, advanced-stage Hodgkin lymphoma on overall treatment outcome of ABVD.

8006 Background: Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) performed after two ABVD courses (PET2) is the most reliable prognosticator in advanced-stage Hodgkin lymphoma (AS-HL) patients (pt.). We evaluated retrospectively the results of a therapeutic strategy based on early chemotherapy (CT) intensification with BEACOPP in PET2 positive (PET2+) in AS-HL. Methods: Between January 2006 and December 2007 164 newly diagnosed HL pt. consecutively admitted to 8 Italian and 1 American centers sharing this PET response adapted strategy were enrolled. Results: Prognostic factors were well-balanced between PET2+ and PET2- pt. (p= 0.14-0.89). In 97/164 pt. (59%) PET2 scans underwent central review (CREw) according to a 5-point semiquantitative score with the liver as reference organ for FDG uptake. (Meignan 2009). In 90/97 pt. CREw confirmed the PET2 interpretation of the local PET center (LOPc). Four pt. with a PET2- by LOPc, reclassified as PET2+, showed CT failure after a median of 1.7 months after ABVD CT end. In 3 pt. a PET2+ by LOPc was redefined as PET2- by CREw: 2 were treated with BEACOPP, 1 with ABVD for medical decision: they are all in CCR 22.6 months (20-22.9) after diagnosis. After a median follow up of 26 (10-44) months the 2-year failure free survival (FFS) and overall survival (OS) for the entire cohort (164 pt.) were 88% and 97.5%; 61% and 96% for PET2+, 92.5% and 98% for PET2- pt. (p<0.0001 and p<0.05, respectively). In the 97 pt. with a reviewed PET2 scan the 2-y FFS was 86.5%, 95% for PET2-, 43.8% for PET2+ pt. HR 14.26; p<0.00001. Conclusions: PET response-adapted treatment outcome in this 164 pt. cohort is comparable with that obtained with front-line BEACOPP chemotherapy for all AS- HL pt., however toxicity from over-treatment was spared on most of them. No significant financial relationships to disclose.

Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Epoetin Alfa in Patients With Advanced-Stage Hodgkin's Lymphoma: Results of the Randomized Placebo-Controlled GHSG HD15EPO Trial

To determine whether epoetin alfa reduces anemia-related fatigue, improves other aspects of health-related patient-recorded outcomes (PROs), reduces the number of RBC transfusions, and has an impact on freedom from treatment failure (FFTF) and overall survival (OS) in patients with advanced-stage Hodgkin's lymphoma (HL). The prospectively randomized HD15EPO study performed by the German Hodgkin Study Group investigated epoetin alfa administered at doses of 40,000 U weekly during and after chemotherapy (six to eight cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP]) in a double-blind, placebo-controlled setting. The study accrued 1,379 patients, of whom 1,328 were assessable for safety, 1,303 were assessable for clinical outcome, and 930 were assessable for PROs. PROs were not different in patients receiving placebo or epoetin alfa, both after the end of chemotherapy and 6 months thereafter. There was no difference between patients treated with epoetin alfa or placebo with respect to FFTF and OS. There were also no differences in the numbers of deaths, progressions, relapses, and thromboembolic events. The median number of RBC transfusions was reduced from four per patient in the placebo group to two per patient in the epoetin alfa group (P < .001), with 27.4% of patients needing no RBC transfusion in the placebo group compared with 36.7% of patients in the epoetin alfa group (P < .001). Epoetin alfa administered at 40,000 U weekly parallel to BEACOPP chemotherapy was safe in patients with advanced-stage HL and reduced the number of RBC transfusions but had no impact on fatigue and other PRO domains.

Two cycles of escalated BEACOPP followed by four cycles of ABVD utilizing early-interim PET/CT scan is an effective regimen for advanced high-risk Hodgkin's lymphoma

BackgroundEscalated combination therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (escBEACOPP) regimen is superior to cyclophosphamide, vincristine, procarbazine and prednisone alternating with doxorubicin, bleomycin, vinblastine and dacarbazine (COPP–ABVD) for advanced-stage Hodgkin's lymphoma (HL) patients. However, the original schedule of eight cycles of escBEACOPP was associated with significant toxicity. This study was conducted in an attempt to reduce the toxicity of the original schedule, while attempting to preserve improved initial tumor control. Patients and methodsForty-five newly diagnosed patients with advanced-stage HL and International Prognostic Score ≥3 received two initial cycles of escBEACOPP and then were evaluated by positron emission tomography (PET)/computed tomography scan. If a good imaging response was obtained, they were treated by four cycles of ABVD. ResultsFollowing the first two cycles of escBEACOPP, the overall response was 100% and at the end of all therapy, 40 (89%) patients were in complete response (disappearance of all clinical evidence of disease and PET negativity), three (7%) in partial response (PET-positive residual lesions and a size reduction of the majority of large masses by >50%), while two (4%) had progressive disease. After a median follow-up of 48 months, progression-free survival (PFS) and overall survival at 4 years were 78% and 95%, respectively. The 4-year PFS for early PET-negative patients (n=31) and early PET-positive patients (n=13) were 87% and 53%, respectively (P=0.01). ConclusionsThese data indicate that combined escBEACOPP–ABVD may improve the outcome in patients with high-risk advanced HL. The potential benefit of early-interim PET activity as a guide to continuing therapy in these patients merits further study in the future.

Brazilian Experience Using High-Dose Sequential Chemotherapy Followed by Autologous Hematopoietic Stem Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma

PurposeWe evaluate the effectiveness and toxicity of high-dose sequential chemotherapy (HDS) as salvage therapy in patients with advanced-stage Hodgkin lymphoma. Patients and MethodsWe performed a retrospective analysis on 77 patients receiving HDS between 1998 and 2006. Patients enrolled were in disease progression or relapsed disease, or did not achieve a complete remission after first-line treatment. HDS consisted of the sequential administration of cyclophosphamide and granulocyte colony-stimulating factor with stem cell harvesting, followed by methotrexate plus vincristine and etoposide. ResultsThe majority of patients had stage III/IV (64%) and B symptoms (71.4%). Disease status improvement after HDS was observed in 24 of 57 patients (42%) previously in disease progression or relapse. HDS-related deaths occurred in 8 of 77 patients (10.4%). Four patients (5.2%) developed acute myeloid leukemia/myelodysplastic syndrome. Overall, disease-free and progression-free survival was 27%, 57%, and 25%, respectively. ConclusionDespite the treatment-related mortality, HDS is feasible, with satisfactory response rates, even in patients with poor prognosis.

Escalated BEACOPP Versus ABVD-Like Chemotherapy for Hodgkin Lymphoma Patients: a Cochrane Review.

Abstract 3705Poster Board III-641 IntroductionThe main challenge in treating Hodgkin lymphoma (HL) is to find the optimal treatment with the best efficacy and least toxicity. So far there are two different international standards for the treatment of intermediate and advanced stage HL: chemotherapy with ABVD regime and chemotherapy with escalated BEACOPP regime. This review aims to clarify advantages and disadvantages of both treatments. MethodsMEDLINE, CENTRAL and EMBASE were systematically searched for randomised controlled trials from 1985 to 2008. Trials comparing treatment with at least 2 cycles escalated BEACOPP versus chemotherapy with at least 4 cycles of ABVD within patients in intermediate or advanced stages HL were included. Trials without any published results will be excluded from the meta-analysis. Trial selection, quality assessment and data extraction were done independently by two review authors. Time-to-event outcome were analyzed with hazard ratios (HR) and 95% confidence interval (CI) in a fixed effects model. ResultsA total of 683 references were screened. Four eligible trials with 1970 patients were identified and included in the main analysis: the HD9 and HD14 trials from Germany, the HD2000 and GSM-HD trials from Italy. The escalated BEACOPP regime was more toxic during treatment than ABVD. Progression free survival (PFS) was statistically significantly longer for escalated BEACOPP: HR was 0.53 (95% CI [0.42, 0.67], I2=0%). In the main analysis of overall survival (OS), escalated BEACOPP was statistically significantly better than ABVD: HR was 0.70 (95% CI [0.50, 0.98], I2=0%). However, this result is not robust. In the OS-analysis restricted to advanced stage trials, the HR was 0.93 (95% CI [0.52, 1.04], I2=0%). Due to the high weight of the HD9 trial (57%), the OS-results are strongly influenced by this trial. In a sensitivity OS analysis without the HD9 trial the HR was 0.83 (95% CI [0.50, 1.38]). Only one trial (HD9) had a follow-up of over 5 years; the median of the other trials was approx. 3 years. ConclusionsThis meta-analysis showed a better PFS and suggests a benefit in OS for escalated BEACOPP in comparison to ABVD-like regimen. However, many trials had a short follow-up. Longer follow-up and the inclusion of the ongoing EORTC 20012 trial should allow a more definitive answer concerning OS. Disclosures:No relevant conflicts of interest to declare.