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To determine whether a high risk group could be identified within a group of patients with advanced stage Hodgkin's disease (HD), the authors applied several prognostic models to patients treated according to the H89 protocol. This study included 344 patients with Stage IIIB-IV HD who were treated with chemotherapy alone (8 cycles) or chemotherapy (6 cycles) plus radiation therapy. Four prognostic models were selected for this study: the numeric prognostic index of the Scotland and Newcastle Lymphoma Group, the Christie Hospital (Manchester)-St. Bartholomew's Hospital (London) model, the Memorial Sloan-Kettering Cancer Center (MSKCC) model, and the criteria used in the European Bone Marrow Transplant (EBMT)/Intergroup Trial. Univariate analysis of H89 protocol patients showed that 5 variables included in the models had prognostic significance: age > 45 years (P = 0.0001), anemia (hemoglobin < 12 g/dL for males and < 10 g/dL for females) (P = 0.0001), number of extranodal sites ≥2 (P = 0.0013), serum lactic acid dehydrogenase greater than the normal value (P = 0.0018), and lymphocyte count < 0.75 × 10⁹L^-1 (P = 0.0063). All four models divided patients into prognostic subgroups. Significant differences among the subgroups were found by log rank analysis (chi-square test = 11-48; P = 0.01-0.0001). The worst prognostic group defined by the MSKCC model (≥3 adverse factors) had an overall survival rate of 59% at 3 years and an estimated 3-year event free survival rate of 43%. Patients with at least three adverse factors according to the MSKCC model or the EBMT criteria had a higher risk of failure with conventional treatment; however, based on survival rate, no very high risk group could be identified. Nonetheless, these prognostic models may be useful to recognize patients with good prognosis who can be cured with conventional therapy and for whom treatment morbidity and mortality can be minimized. Cancer 1997; 80:1124-33. © 1997 American Cancer Society.

Serum interleukin-6 (IL-6) levels were measured in 58 adult patients with newly diagnosed acute myelogenous leukemia (AML) using an ELISA method in order to find potential clinical correlations. Detectable average levels were 57 ± 68 pg/ml and 52 patients (90%) had higher cytokine levels than normal donors. IL-6 levels (115 ± 102 pg/ml versus 36 ± 40 pg/ml, p = 0.0001) were higher in patients with fever of apparently non infectious origin, and higher levels were associated with higher percentage of blasts in the peripheral blood (R = 0.29, p = 0.04) and in the bone marrow (R = 0.39, p = 0.003), elevated serum LDH level (R = 0.36, p = 0.01), hyperbilirubinemia (R = 0.36, p = 0.008), elevated serum GGT level (R = 0.46, p = 0.003), and elevated serum GOT (R = 0.36, p = 0.008) and GPT levels (R = 0.44, p = 0.004). Highest IL-6 levels were observed in FAB M1 (86 ± 112 pg/ml), M3 (73 ± 69 pg/ml), and M6 (92 ± 60 pg/ml) AML subtypes. Serum IL-6 levels in AML might be related to both non specific inflammatory reactions and the specific biology of the disease.

Elderly mantle cell lymphoma (MCL) patients (pts) do not benefit from dose-intensive chemotherapy upfront.1 The GOELAMS group recently demonstrated that a regimen comprising Vincristine/Adriamycine/Dexamethasone plus Chlorambucil (VAD+C) was well tolerated, had a good efficacy/toxicity profile and induced similar PFS than R-CHOP (median PFS between 16 to 18 months2,3,4). Additionally, it has been shown that bortezomib (Velcade®), with or without Rituximab has efficacy in relapsed/refractory MCL patients5,6. These data prompted, our group to conducte a phase II prospective non randomized clinical trial evaluating the combination of Velcade plus Rituximab/Adriblastine/Dexamethasone/Chlorambucil (RiPAD+C) as a first line therapy for elderly MCL patients.To evaluate the overall response rate (ORR) and toxicity after 4 cycles of RiPAD+C regimen (main objective) and to evaluate prognostic factors for survival (secondary objective).RiPAD+C : Rituximab 375 mg/m2 on d1 (and d8 for cycle 1); PS 341, Velcade® 1.3 mg/m2 on d1, 4, 8 and 11; Adriblastine 9mg/m2/d as a continuous infusion for 4 days; Dexamethasone 20 mgx2/d from d1 to d4; Chlorambucil 12 mg/d, d20 to d29. Repeat cycles every 35d. After 4 cycles, responding pts (Cheson 1999 criteria) received 2 additional cycles for a maximum of 6.Inclusion criteria: All untreated elderly (65 to 80 years old) MCL patients (including blastoid forms) presenting with a stage II to IV disease with a good PS (ECOG<3) were eligible. Histologic samples were centrally reviewed and Ki67 expression was evaluated for each sample according to the European guidelines7.Population: from June 2007 to December 2009, 39 pts were enrolled in the study with a majority of males (n=30). Median age at diagnosis was 72 years [65-80]. All patients had stage III/IV disease and PS was ≥2 in 5 cases (15%). Elevated serum LDH were observed in 47% of cases. According to the MIPI, 28 patients (80%) had an intermediate or high score. Eleven (30%) patients presented with a blastoid variant and Ki67 staining was superior to 30% in 12 cases (37%). Toxicity: A total of 195 courses have been performed. Fourteen hospitalization (median duration = 7 days [1 and 55]) due to toxicity were necessary involving 12 pts (34%). Seven pts (18%) experienced grade 3 peripheral neuropathy. ten (25%) pts required blood transfusions for a total of 8 red blood cells and 14 platelets transfusions. Response after 4 cycles: ORR was 80% (n=31) including 51% of CRs. Eight pts discontinued the treatment before reaching cycle 4, two of them for toxicity reasons. Six patients (15%) were refractory or in progression. Response after 6 cycles (n=25; 64%): ORR was 74% including 20 pts in CRs (59%). Survival: With a median follow-up of 24 months, 27 pts are still alive. Two pts died of toxicity (severe sepsis) and 10 pts progressed. The median PFS is 26 months and the median OS has not been reached yet. According to the MIPI score, no differences in PFS were between pts with low and int/high scores. Conversely, the recently described Goelams index2 stratified pts with a low score (normal LDH, Ki67≤26%, PS≤1, and no B symptoms) from patients with an int/high score (p=.055).The results of the current phase II trial indicate that the RiPAD+C regimen, integrating bortezomib, is feasible and well tolerated as a first line therapy in elderly MCL pts. Historical comparisons suggest that this regimen compares favourably to the classical R-CHOP regimen in terms of response rates and duration.1 Romaguera JE et al, JCO 2005; 2 Gressin R et al., Haematological 2010; 3 Howard OM et al., JCO 2002; 4 Lenz G et al., Blood 2005; 5 Fisher RI et al., JCO 2006; 6 Goy A et al., JCO 2009; 7 Klapper W et al., Haematopathol 2009.Off Label Use: velcade is of label in France for the treatment of mantle cell lymphoma.

Abstract 2791

Elderly patients with mantle cell lymphoma (MCL) do not take benefit from dose-intensive chemotherapy such as HyperCVAD because of its high toxicity (Romaguera JCO 2005). Prior Goelams clinical trials using the VAD plus Chlorambucil regimen with or without Rituximab have demonstrated a good efficacy/toxicity ratio in front line therapy (EHA 2008, a0259). Proteasome inhibitors are among the most promising new agents for relapsing patients (Fisher, JCO 2006). Therefore, the GOELAMS conducted a phase II clinical trial including Velcade plus R-AD and Chlorambucil (RiPAD + Chlorambucil) for elderly MCL patients upfront. Aims: To evaluate toxicity and overall response rate after 4 cycles of RiPAD + Chlorambucil regimen. Protocol: RiPAD + C: Rituximab 375 mg/sqm, D1 (and D8 for cycle 1); PS 341, Velcade 1.3 mg/sqm D1, 4, 8 and 11; Adriblastine 9mg/sqm/D in a 4 days continuous infusion; Dexamethasone 20 mgx2/D for D1 to D4; Chlorambucil 12 mg/D, D20 to D29. One cycles every 35 D. The patients received a maximum of 6 cycles. Inclusion criteria: Untreated MCL patients (from 65 to 80 years) with a stage II to IV disease, and good PS (Ecog < 3). Response criteria is evaluated according to the 1999 Cheson’s criteria, all patients were also evaluated by FDG-PETscan. Results: since June 2007, 27 patients have been included. Thirteen have been evaluable after 4 cycles. Median age is 71 years (66–80 y). After 4 cycles, disease Status was: 10 patients in response (3 in CR with negative FDG-PETscan and 7 in PR including 3 with a negative PETscan) and 3 patients progressed on therapy. The 3 non responding patients had the highest Ki67 value over 30%. Toxicity evaluation has been evaluated based on 59 cycles. Grade 3–4 toxicities have been reported in 5 cases (2 neurologic, 1 hepatic, 1 cardiac and 1 pulmonary). Only 3 cycles were delayed because of toxic reasons. Conclusion: this intermediaire analysis shows an ORR of 77% (10/13) including 6 patients with a negative FDG-PET after only 4 cycles. Our study demonstrates that the RiPAD+C regimen has a good efficacy/toxicity ratio and is a promising therapeutic option for MCL elderly patients. The study is ongoing and additional results on response rate and toxicity will be updated for presentation in the ASH meeting.

Elderly patients with mantle cell lymphoma (MCL) do not take benefit from dose-intensive chemotherapy such as HyperCVAD because of its high toxicity (Romaguera JCO 2005). Prior Goelams clinical trials using the VAD plus Chlorambucil regimen with or without Rituximab have demonstrated a good efficacy/toxicity ratio in front line therapy (EHA 2008, a0259). Proteasome inhibitors are among the most promising new agents for relapsing patients (Fisher, JCO 2006). Therefore, the GOELAMS conducted a phase II clinical trial including Velcade plus R-AD and Chlorambucil (RiPAD + Chlorambucil) for elderly MCL patients upfront.