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Introduction: Rituximab (R) is an integral component of therapy for B-cell lymphoid malignancies; bortezomib (Btz) has shown provocative single agent activity in Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL) and Waldenström’s Macroglobulinaemia (WM), providing the rationale for investigating the combination. Patients+Methods: Forty-five adult patients (pts.) (30 men, 15 women) with histologically confirmed recurrent CD20+ve FL, MCL or WM, median age 60 years (range 45-79), FL: 17, MCL: 18, WM: 10, stage III/IV 40 (93%), bone marrow (BM) infiltration 32 (73%), elevated LDH 22 (49%), performance status ≥1 22 (49%), were enrolled in a randomised trial comparing 2 schedules of Brz+R: Arm A (twice weekly) Btz: 1.3mg/m2 (on days 1, 4, 8, 11 of a 21-day cycle) and R: 375mg/m2 (on day 1) for 8 cycles, or Arm B (weekly) Btz: 1.6mg/m2 (on days 1, 8, 15, 22 of a 35-day cycle) and R: 375mg/m2 (on days 1, 8, 15, 22 of cycles 1 and 4) for 6 cycles (23 arm A, 22 arm B). The median number of previous treatments was 2 (range 1-7). Seventeen pts. had received a R-containing regimen, with response lasting >6 months, and 8 high-dose treatment. Response was evaluated using the IWR criteria (Cheson et al, JCO17: 1244, 1999) and the updated response criteria from the 3rd International Workshop on WM (Treon et al, Blood107: 3442, 2006) Results: Ability to deliver the therapy, toxicity and efficacy were equivalent in both arms. The median number of cycles given in arm A was 4 and 5 in arm B. Haematological toxicity (grade≥3: anaemia 0%, neutropenia 25%, thrombocytopenia 22%) was significantly influenced by the high percentage of pts. with BM infiltration and concomitant cytopenia on entry to the trial. The most common non-haematological adverse events were fatigue (76%), nausea (56%), diarrhoea (56%), lethargy (46%). Neurotoxicity occurred in 19 pts. (46%) (10 pts. grade 1, 7 pts. grade 2, 2 pts. grade 3). Btz dose was reduced in 7 pts.; 5 doses were omitted because of neuro or haematological toxicity. In 16 pts., treatment was delayed by 1-14 days and in 24 pts. treatment was stopped prematurely. The reasons for stopping treatment were: treatment-related toxicity 11 pts., progressive disease 9 pts., patient’s preference 3 pts., myocardial infarction 1 pt. One pt. was excluded having been found ineligible post randomisation. Thirty-nine pts. (21 arm A, 18 arm B) are evaluable for response so far, one having only received 1 cycle of therapy, which had to be discontinued because of excessive toxicity. 15/32 were in remission (CR, CRu, PR) at the completion of therapy, 7/7 at “mid-therapy” assessment, and 5 have yet to be evaluated. Thus the overall response rate (RR) presently is 22/39 (56%) (CR, CRu, PR), FL 44%, MCL 46%, WM 90%. Conclusions: The combination was active in pts. with recurrent NHL especially WM (RR 90%), despite multiple previous treatments, The weekly schedule is preferable being more convenient, as efficacious and no more toxic. Further investigation is warranted, despite not insignificant therapy compromising toxicity.

Background: FLIPI has been proposed as an accurate, simple, and validated prognostic index on the basis of routinely performed tests (age > 60 yrs, Ann Arbor stage III-IV, serum LDH level increased, Hg < 12g/dL, and more than four nodal areas involved (Solal-Celigny et al., Blood 2004; 104: 1258–1265). FLIPI has reliably predicted outcome for many follicular lymphoma (FL) patients (pts) treated with chemotherapy and rituximab. Currently, monoclonal antibody (Mab) therapy and a number of radioimmunoconjugates are considered important components of the treatment of FL; therefore, evaluating FLIPI in clinical trials of these modalities is of interest for optimizing therapy. Methods: A subset analysis was performed to assess the impact of FLIPI on the outcome of patients with relapsed/refractory FL enrolled in a larger, multi-center, open label, single-arm study of epratuzumab (humanized anti-CD22 Mab) in combination with rituximab (chimeric anti-CD20 Mab) (Strauss et al., ASCO 2004). Results: A total of 32 pts with FL were treated according to this protocol (4 weekly infusions at full dose of each agent), including 16 pts who had received > 2 prior chemotherapy regimens and 11 pts who had previously received rituximab. Twenty pts (62%) achieved an objective response (OR), including 8 pts (25%) with complete responses (CR, CRu) and 12 (37%) with partial responses, with a median response duration of 16.5 months (95% CI: 6.3 - 25.4) and median time-to-progression (TTP) of 11 months (95% CI: 9.9 - 19.2). Conclusion: Our data indicate that high OR rates and durable CR/CRu’s can be achieved with a combination of rituximab and epratuzumab in pts with low- (0–1) and intermediate-risk (2) FL, who failed multiple prior therapies. OR, CR rates and TTP are similar to rituximab front-line therapy for pts with low tumor burden FL (Solal-Celigny et al., Blood 104: 169a, 2004). The combination of rituximab and epratuzumab was significantly less efficacious for pts with high-risk (3–5) FLIPI ( P =.0.0023 for TTP). This small Phase-II study supports the prognostic value of FLIPI for pts with recurrent FL who are treated with MAbs. Prospective use of FLIPI may facilitate the optimal design of randomized trials using rituximab in combination with epratuzumab in pts with FL. | FLIPI score (No. of pts) | OR (%) | CR/CRu (%) | Median Duration in months (95% CI) | Median TTP in months (95% CI) | TTP P-value* | |:----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------:| ------ | ---------- | ---------------------------------- | ----------------------------- | ------------ | | N/A - Not available due to patients with long TTPs that are still censored (i.e. not reached progression of disease). * - Patients with high (3–5) FLIPI scores versus others, based on the log-rank test. | | 0–1 (11) | 9 (82) | 4 (36) | 15.7 (N/A) | 19.2 (10.3 – 21.3) | 0.0023 | | 2 (9) | 6 (67) | 3 (33) | 18.3 (17.2 – 25.4) | 18.8 (10 – 26.7) | | | 3–5 (12) | 5 (42) | 1 (8) | 6.3 (N/A) | 7.7 (7.1 – 10.2) | | Results stratified by FLIPI risk groups

The activity of the proteasome inhibitor bortezomib has been evaluated in follicular lymphoma (FL) and mantle cell lymphoma (MCL) patient samples using a modification of a primary lymphoma culture system based on the CD40-CD40L interaction (Johnson et al, Blood. 1993 5;82(6):1848). Methods: Single B-cell suspensions were isolated from lymph nodes, ascites or peripheral blood from 12 patients with histologically confirmed FL or MCL. After disaggregation and/or density gradient separation, cells were plated at a density of 5x105 cells/well into 96-well plates containing CHO cells transfected with the CDw32 Fc receptor to express the CD40 ligand, which, when irradiated to prevent further proliferation, provide a stromal layer supporting B-cell proliferation. Malignant or normal B-cells were cultured in IMDM medium supplemented with 10% human serum and 2ng/ml IL-4, and could be maintained for up to 8 days whilst retaining close phenotypic resemblance to the original sample, confirmed by flow cytometric quantitation of cell surface markers. After 24hrs drug was added at varying concentrations in triplicate and cell number and viability were assessed after a further 48hrs using the trypan blue exclusion assay. EC50 values for % viability were derived for each sample using Graphpad Prism. Results: MCL cells were significantly more sensitive to bortezomib than FL cells (median EC50 209nM range (122–989nM) n=5, vs 1311nM (153–2211nM) n=8 respectively, Mann-Whitney U-test P Conclusion: These data demonstrate a significant difference in bortezomib sensitivity between MCL and FL, which may be related to differences in CD40 signalling. The difference in in vitro sensitivity correlates with clinical response in 5 patients and suggests the possible use of this system as an in vitro predictor of response to bortezomib treatment.

Introduction: The 26S proteasome is an important regulator of proteins involved in cell cycle progression, cell survival, and transcription of anti-apoptotic proteins via activation of NF-κB. Bortezomib, (VELCADE®) is a potent, selective, reversible inhibitor of the 26S proteasome with demonstrated clinical activity in multiple myeloma for which it gained FDA and EMEA approval. On the basis of encouraging phase I data in lymphoma, a phase II clinical study was undertaken to examine the efficacy and toxicity of bortezomib in pts with relapsed, refractory NHL and HD. Methods: 1.3 mg/m2 bortezomib was administered twice weekly for 2 of 3 weeks to pts who had adequate ECOG performance status (PS) >2, and haematological function with an absolute neutrophil count >1.0 x109/l (0.5 x109/l if bone marrow involvement) and platelets >30 x109/l. Pts were assessed for toxicity at each cycle, re-staged after 4 cycles and received up to 8 cycles of treatment. Results: 32pts, 20 male and 12 female with a median age of 58 yrs (35–75) received a total of 119 cycles of treatment. 11 pts had mantle cell lymphoma (MCL), 10 follicular lymphoma (FL), 4 Waldenstrom’s macroglobulinaemia (WM), and 1 lymphoplasmacytic lymphoma. Other diagnoses included HD (n=3), diffuse large B-cell lymphoma (n=1), ATL (n=1), and diffuse follicle centre lymphoma (n=1). Pts were heavily pre-treated with a median of 3.5 previous therapies (range 1–8) and 12 pts (38%) had received prior HDT. Sixteen pts (50%) had bone marrow involvement and 13 (40%) a raised LDH. 13 pts (40%) had a ECOG PS of 1 and 7 pts (22%) a PS of 2. The most common grade III-IV toxicities observed in patients, who received a median of 4 cycles of treatment (range 1–8), were thrombocytopenia in 14 pts (45%); fatigue in 8 pts (26%), anaemia in 5 pts (16%) and peripheral neuropathy in 2 pts (6%). Four of 11 pts with MCL initially responded to treatment, 3PR, 1 CR (ORR of 36%); one pt progressed at the end of 8 cycles having required 2 dose reductions. No patients with FL had an objective response at the outcome assessment after a median of 4 cycles (range 1–8) and within a month of completing therapy; however 4 had stable disease and 2 achieved a ‘late response’ with reduction in tumour volumes of 76.7% and 56.1% when assessed 3 mths later. Two pts with WM achieved a PR on the basis of >50% reduction in paraprotein, but with no change in the bone marrow. No patients with HD or other diagnoses responded to treatment. The sensitivity of tumour biopsy samples to bortezomib was examined in vitro in a CD40 ligand primary culture system in 5 pts on the clinical trial, where sensitivity correlated with clinical response. In a larger group of patients the median EC50 for MCL (n=5) was 209nM, and FL (n=8) 1311nM (p Conclusion: The first European report of bortezomib in pts with relapsed/refractory NHL/HD demonstrates encouraging efficacy in MCL, evidence of activity in WM, and a suggestion of ‘late responses’ in FL. Clinical activity correlated with in vitro sensitivity to bortezomib and continues to be assessed as a potential predictor for response to treatment.