ALBERT

Description: As previously reported (Colombat, Blood2001;97:101), rituximab (4 weekly doses of 375mg/m²) can lead to high response rates (RR) and prolonged remissions with minimal toxicity as 1st line therapy for low tumor burden FL. We report the final analysis of a trial evaluating long term efficacy and safety of rituximab in untreated low tumor burden FL (GELF criteria). 49 patients (pts) were included in the initial trial (median age 52 yrs), 2 refused consent for the extended F/Up period, and 1 pt died at M12. Molecular bcl2-JH rearrangement was assessed throughout the study. The median F/up was 83.8 mths. Overall best RR, complete/unconfirmed RR and partial RR at D78 were 74%, 50% and 24% respectively. Median PFS was 23.5 mths for the study population. Median duration of response (34 responders at D78, i.e 6 weeks after the last rituximab dose) was 28.6 mths, but response was still maintained without any further treatment in 11 pts after 5 years (24%) and in 7 pts after 7 years (15%). 31/46 pts were bcl2 positive in blood and/or marrow samples before rituximab: 11 (35%) became negative at D50, and 20 remained positive (65%). Median PFS was 37 mths for bcl2-negative pts at D50, and 12 mths for patients remaining positive (p=0.018 Log-rank). Of the 7 pts with sustained response after 7 years, 5 were bcl2 positive at D0, 2/5 became negative at D50, and 5/5 were still negative at M84. At year 7, 4/46 pts have died (1 from myelodysplasia, 3 from NHL), 35/42 have progressed, and 7 have never progressed without any other treatment than the initial rituximab therapy. Time to progression was significantly longer in the bcl2-negative population at D50 (p= 0.018, Log-rank). Duration of response was not correlated with bcl2 status at D50, but was associated with ‘Best response CR/Cru’ (p=0.007 Log-rank). Long-term tolerance was good, with only 13 SAE observed in 13 pts during the additional 4 years of F/Up (4 surgeries for non NHL-related pathologies, 1 node biopsy, 1 sleep apnea syndrome, 1 ischemic cardiopathy, 2 deaths from NHL, 1 depression, 1 pneumonia, 1 erysipela, 1 bronchitis). This long-term update confirms that a single 4-dose rituximab treatment yields durable benefits without the toxicity of chemotherapy for pts with low burden FL : Median PFS of 23.5 mths for the cohort, 28.6 mths for responders and 37 mths for pts turning bcl2-negative at D50, 15% of pts have maintained their response after 7 years, (2bis) the quality (CR/Cru) of the initial response was associated with a longer response duration high overall survival is observed with 4 deaths/46 pts (8.6%).

Description: The FL2000 study was undertaken to evaluate the combination of the anti-CD20 monoclonal antibody rituximab with chemotherapy plus interferon in the first-line treatment of follicular lymphoma patients with a high tumor burden. Patients were randomly assigned to receive either 12 courses of the chemotherapy regimen CHVP (cyclophosphamide, adriamycin, etoposide, and prednisolone) plus interferon-α2a (CHVP+I arm) over 18 months or 6 courses of the same chemotherapy regimen combined with 6 infusions of 375 mg/m2 rituximab and interferon for the same time period (R-CHVP+I arm). After a median follow-up of 5 years, event-free survival estimates were, respectively, 37% (95% confidence interval [CI], 29%-44%) and 53% (95% CI, 45%-60%) in the CHVP+I and R-CHVP+I arm (P = .001). Five-year overall survival estimates were not statistically different in the CHVP+I (79%; 95% CI, 72%-84%) and R-CHVP+I (84%; 95% CI, 78%-84%) arms. In a multivariate regression analysis, event-free survival was significantly influenced by both the Follicular Lymphoma International Prognostic Index score (hazard ratio = 2.08; 95% CI, 1.6%-2.8%) and the treatment arm (hazard ratio = 0.59; 95% CI, 0.44%-0.78%). With a 5-year follow-up, the combination of rituximab with CHVP+I provides superior disease control in follicular lymphoma patients despite a shorter duration of chemotherapy. This study's clinical trial was registered at the National Institutes of Health website as no. NCT00136552.

Description: We report 28 patients (pts) who experienced late onset severe neutropenia (NCI/CTC grade III/IV) after rituximab. Rituximab had been given for the treatment of DLCL(N=15), follicular lymphoma (N=9), mantle cell lymphoma (N=2), CLL (N=2). Rituximab was administered as a front line treatment (N=11), for recurrent disease (N=17), before ASCT (N=1) or after ASCT (N=5). Rituximab was given as a single agent (N=14), with CHOP (N=9) or with other regimen (N=5). Rituximab was given at a dose of 375mg/m2 at weekly intervals over a period of 4 weeks when used as a single agent, or as a single dose of 375mg/m2 with chemotherapy. Characteriscs of neutropenia are summarized in Table. At the time of the neutropenia, all the pts were in CR or VGPR. In 3 pts, the neutropenia had relapsed. All 3 pts were still in CR, and had not been retreated with rituximab. 3 patients were retreated with rituximab for a recurrence of their NHL after the outbreak of neutropenia and 1 pt experienced a further episode of neutropenia after the reintroduction of rituximab. Tests for anti PMN antibodies were performed in 6 pts. In 4 pts, antibodies bound to the surface of neutrophils were detected by the direct neutrophil immunofluorescence test. No antibody could be detected in the serum. A direct toxic effect of rituximab can be ruled out as granulocytes and uncommitted hematopoietic precursor stem cells do not express CD 20. We propose the following hypothesis. The rituximab-induced depletion of the normal B-lymphocyte population was followed by the acquisition of a new immune repertoire under non physiological condition which could promote the transient production of autoantibodies. Some of these antibodies might target either neutrophils or hematopoietic precursors. Some of these antibodies might also be directed against other cells since other delayed-onset cytopenia have been reported after the administration of rituximab, pure red aplasia in particular. An other possible mechanism can be proposed. Rituximab administration could lead to the production of antibodies directed against the complex formed when rituximab is bound to the FcγRIIIb receptor on the PMN. This hypothesis does not account for the delay between the administration of rituximab and the onset of the neutropenia. Characteristics of neutropenic episodes. Characteristics N *: interval between the last infusion of rituximab and the nadir of neutropenia. **: 1 pt was lost to follow-up for 4.5 months but had a normal blood count subsequently. Median time to neutropenia (range) (weeks)* 15 (4–33) Nadir PMN 10x9/L median (range) 0.135 (0–0.760) Bone marrow aspiration 14 Hypocellular marrow 7 Normocellular marrow with severe reduction in mature neutrophils 6 Normal 1 Fever/sepsis 6/1 Patients treated with G-CSF/duration (range) (days) 12/6 (3–21) Duration of neutropenia (range) (days) Patients treated with G-CSF N=12 4 (2-53) Patients not treated with G-CSF N=16 12 (4–105)** Follow-up from the nadir of neutropenia (range) (month) 6 (0.5–36) NHL/CLL status at follow-up CR or CRu 22 VGPR 1 Progression 5 Status of PMN count at follow-up Normal 26 Neutropenia 2

Description: Autologous stem cell transplantation (ASCT) as first-line therapy for follicular lymphoma (FL) remains controversial. The multicenter study randomized 172 patients with untreated FL for either immunochemotherapy or high-dose therapy (HDT) followed by purged ASCT. Conditioning was performed with total body irradiation (TBI) and cyclophosphamide. The 9-year overall survival (OS) was similar in the HDT and conventional chemotherapy groups (76% and 80%, respectively). The 9-year progression-free survival (PFS) was higher in the ASCT than the chemotherapy group (64% vs 39%; P = .004). A PFS plateau was observed in the HDT group after 7 years. On multivariate analysis, OS and PFS were independently affected by the per-formance status score, the number of nodal areas involved, and the treatment group. Secondary malignancies were more frequent in the HDT than in the chemotherapy group (6 secondary myelodysplastic syndrome/acute myeloid leukemia and 6 second solid tumor cancers vs 1 acute myeloid leukemia, P = .01). The occurrence of a PFS plateau suggests that a subgroup of patients might have their FL cured by ASCT. However, the increased rate of secondary malignancies may discourage the use of purged ASCT in combination with TBI as first-line treatment for FL. This trial has been registered with ClinicalTrials.gov under identifier NCT00696735.

Description: High amounts of intra-tumoral reactive macrophages have been reported to be associated with a poor prognosis in patients with follicular lymphoma (FL) (Blood2005;106:2169). However, this study has been retrospectively performed in a patients’ population selected before the monoclonal antibody therapeutic area, and has not been confirmed on independent series. To establish whether the intra-tumoral macrophages count (MC) is definitely able to predict the outcome of FL patients, we analysed both immunohistochemical CD68 expression and clinical outcome in patients included in the GELA-GOELAMS FL-2000 trial (ASH-2004; ASCO-2006). Patients between 18 and 75 years of age with high tumor burden FL were randomized to receive either CHVP-I or R-CHVP-I. Among the 358 patients included on the basis of histologically proven FL after reviewing by 3 hematopathologists, 194 had available biopsy specimen. Clinical characteristics of those 194 patients were not different of those of the whole population and median time to event was 43.1 months in 92 pts receiving CHVP-I arm and 54.5 months in the 102 pts receiving R-CHVP-I. Slides were stained with the anti-CD68 KP1 antibody using a standard IHC procedure, then scored on high power field (hpf) (× 400 magnification) by 3 different pathologists. Analysis of the relative risk of event according to the intra-follicular MC (IF-MC) led us to determine a single cut-off point to categorize the covariate, the best cut-off point being estimated to be 10 macrophages/hpf. The IF-MC was equal or less than 10 intra-follicular KP1+ macrophages/hpf in 53 patients, and more than 10 in 141 patients. With this cut-off of 10, a low MC was significantly associated with a better EFS for all patients (p=0.011). However, this effect was predominantly observed in patients that received CHVP-I (p=0,012, OR) but not in those receiving R-CHVP-I (p=0.15).Multivariate analysis adjusting for 10 IF-MC cut-off (p

Description: The role of high dose chemotherapy with autologous stem cell support in first line therapy in patients with B-CLL remains to be defined. The aim of the prospective randomized GOELAMS LLC 98 (Groupe Ouest Est d’etude des Leucemies et Autres Maladies du Sang) trial was to compare two therapeutic strategies in previously untreated B-CLL patients younger than 60 years with B and C Binet stages. Conventional chemotherapy (Arm A) consisted of six monthly courses of CHOP, (i.e. vincristin IV 1 mg/m2 on day 1, doxorubicin IV 25 mg/m2 on day 1, cyclophosphamide (Cy) 300 mg/m2 and prednisone 40 mg/m2 both given orally from day 1 to day 5, followed by 6 CHOP courses every other 3 month in case of response. Fludarabine (25 mg/m2 /d IV for 5 consecutive days) was used in case of progression after 3 CHOP or non response after 6 CHOP. Conventional therapy was compared to high dose therapy with autologous CD34+ purified stem cell support (Arm B), using as consolidation of Complete Remission (CR) (NCI criteria) or Very Good Partial Response (VGPR, defined by 〉50 % tumoral response and 〈 30 % bone marrow lymphocyte count) obtained after 3 monthly courses of CHOP. In case of absence of CR or VGPR, 3 to 6 monthly-courses of fludarabine were realized before mobilization with Cy 4 g/m2 + G-CSF administration. Conditioning regimen included TBI 12 Gy and Cy 60 mg /kg /d for 2 days. Study end points included Event Free Survival (EFS), toxicity, feasibility. Between March 1999 and December 2004, 86 patients were randomized of which 79 were evaluable. A number of 38 patients were randomized to CHOP regimen and 41 to high dose therapy. The groups were well-balanced; 29% females, mean age 53 years (35 to 61), 67 % B and 25 % C Binet stages, 2 patients with A stage were included, 1 stage was not mentioned. In Arm B, 13 out of 41 patients were not transplanted because of disease progression (n=7), sepsis shock and death during the first CHOP course (n=1), patient’s refusal (n=1), graft contamination (n=1), mobilization failure (n=2) and violation criteria (n=1). CD34+ cells purification was performed in 69% of the grafts. Post transplant grade 3–4 non-hematological toxicity was mainly infectious (2 CMV and 1 aspergillus infections). Second cancers occurred in 3 patients in Arm A; skin cancer (n=1), breast cancer (n=1), Acute Myeloid Leukemia (AML) + skin cancer (n=1). One pretransplant case of skin cancer was reported in Arm B. Six patients died in Arm A from disease progression (n=5), AML (n=1) and 3 in Arm B from toxic death during the first course of CHOP (n=1), disease progression (n=2). As an intent-to-treat analysis and with a median follow-up time of 30 months (range 1–74), median EFS was 23.6 months in Arm A and 63.1 months in Arm B (p

Description: Abstract 2875 Background: Radioimmunotherapy (RIT) is under study as a consolidation treatment after chemotherapy induction in follicular lymphoma patients. This approach also appears interesting in diffuse large B-cell lymphoma (DLBCL) patients 〉60 years, who are not candidates for bone marrow transplantation. 90Y-epratuzumab tetraxetan (Immunomedics, Inc.) is a radiolabeled humanized anti-CD22 antibody that has been used for a fractionated RIT, showing high rates of durable complete responses with manageable hematologic toxicity in previously-treated indolent and aggressive non-Hodgkin lymphoma (NHL) patients (Morschhauser et al., J Clin Oncol. 2010;28(23);3709-16). A French phase II trial sponsored by the GOELAMS group is ongoing, assessing fractionated RIT using 90Y-epratuzumab tetraxetan as a consolidation therapy after first-line chemotherapy in disseminated DLBCL patients 〉60 years. The protocol has been designed to include 75 patients; 64 patients have been already enrolled. We report the initial results, in particular safety data, on the first 29 available patients. Design and Method: From October 2008 to November 2009, 29 untreated DLCBL patients 〉60 years were studied in several French institutions with an initial course of six cycles of R-CHOP14 followed 8 weeks later by two weekly infusions of 90Y-epratuzumab tetraxetan (15 mCi/m2 [555 MBq/m2]) 7 days apart. Hematologic and non-hematologic toxicities were evaluated using NCI-CTC v.3.0. Treatment responses were classified according to the 1999 International Workshop for Response Criteria for NHL. Results: Twenty-six patients underwent the entire course of R-CHOP and 23 received the 2 weekly RIT injections. Following R-CHOP, grade 3–4 neutropenia was observed in 20 patients (68.9%) and grade 3–4 thrombocytopenia in 4 (13.7%). During RIT infusions, 4 patients showed transient change of pulse or blood pressure, with 2 attributed to vasovagal reactions. RIT toxicity included grade 3–4 hematologic toxicity in 18 of 23 patients (78.3%); the most common grade 〉 3 toxicities were neutropenia (N=18, 78.3%) and thrombocytopenia (N=17, 73.9%). Serious febrile neutropenia was observed in 4 cases (13.8%) after R-CHOP and in 2 patients (8.7%) following RIT. Compared to R-CHOP, RIT non-hematologic toxicity was uncommon; moderate or severe gastrointestinal toxicity was observed in 10 patients (34.5%) after R-CHOP and in 2 (8.7%) following RIT; moderate or severe infection in 9 patients (31.0%) after R-CHOP and in 1 (4.3%) after RIT; and moderate or severe mucositis in 10 (34.4%) patients following R-CHOP, while no patient had mucositis after RIT. Following RIT, red cells and/or platelets transfusions were given to 12 patients (52,2%). Following R-CHOP, 10 of the 25 patients (40.0%) achieved a complete response (CR) or unconfirmed CR (CRu), 13 patients (52.0%) had a partial response (PR) and 2 patients (8.0%) had a stable disease. Six weeks after RIT, 13 patients (56.5%) achieved a CR or CRu, 9 patients (39.1%) had PRs, and 1 patient (4.3%) had progressive disease. Four of 13 patients (30.7%) who achieved less than a CR or CRu with R-CHOP improved their remission status 6 weeks after RIT. Conclusion: These preliminary results indicate the feasibility and safety of fractionated RIT with 90Y-epratuzumab as a consolidation therapy for elderly DLBCL patients. Additional data will be presented at the time of the communication. Disclosures: Off Label Use: monoclonal antibody epratuzumab labeled with yttrium 90 in phase II clinical trial. Wegener:Immunomedics, Inc.: Employment, shareholders. Goldenberg:Immunomedics, Inc.: Employment, shareholders.

Description: Abstract 2796 Background: Diffuse large B-cell lymphoma (DLBCL) relapse prognosis is poor, and the optimal salvage treatment is not known. In a previous pilot study, vinorelbine, ifosfamide, mitoxantrone, and prednisone (NIMP) without rituximab has shown a promising efficacy in the setting of relapsed DLBCL. Aims: To evaluate the efficacy and tolerability of the combination of rituximab and NIMP in the treatment of DLBCL in first relapse. Methods: This multicentric, single-arm phase II study included patients 18 to 75 years old, with CD20-positive DLBCL in first relapse (defined as having obtained at least a PR of more than 50% to an anthracycline-based front-line regimen) occurring more than 30 days after the last chemotherapy cycle or more than one year after an autologous stem cell transplantation (ASCT) in first line. Other inclusion criteria were a performance status ≤ 2, absence of CNS involvement, and having signed an informed consent form. Patients with evidence of transformation from indolent lymphoma, primary refractory disease, or positive HIV tests were excluded. Initial and relapse biopsies were centrally reviewed. Patients received intravenous (IV) rituximab 375 mg/m2 D1, ifosfamide 1000 mg/m2 as a continuous infusion from D1 to D5, IV vinorelbine 25 mg/m2 D1 and D15, IV mitoxantrone 10 mg/m2 D1, and oral prednisone 1 mg/kg D1 to D5, repeated every 28 days for three cycles. Pegfilgrastim support (6 mg at D7) was recommended. The primary endpoint was CR/CRu after 3 cycles, and was assessed by computed tomography according to the IWG criteria. Mobilization, consolidation or subsequent salvage therapy was decided at the discretion of the investigator. All the monitoring and data management were performed by the GOELAMS clinical research assistants, with a database lock on July 27, 2010. Results: Fifty patients (21[42%] women and 29[58%] men) were included in 18 centers between December 2004 and accrual closure in April 2010. All patients received at least 1 cycle of R-NIMP. Forty-five patients were available for central pathology review, toxicity and response. The central review of all patient samples confirmed DLBCL histology. Median age at study entry was 62.9 years (range: 34.8–75.6). Median time between first diagnosis of DLBCL and relapse was 18.0 months (range: 2.4–208). The following tumor responses were observed: 67.9 % overall response rate with 20 CR/CRu (43.5%), 11 PR (24.4%), 2 SD (4.4%), and 12 (26.7%) progressed under therapy. Toxicity information was available for 109/120 (91 %) of the first 3 cycles of R-NIMP administered. The following toxicities were observed (all grades, ≥ grade 3 for all cycles): anemia (87%, 8%), neutropenia (66%; 46%), thrombopenia (65%, 14%), elevated liver tests (39%, 0%), constipation (25%, 0%), kidney failure (7%, 0%), nausea (14%, 0%), vomiting (6%, 0%), allergic reactions (5%, 0%), and mucositis (5%, 0%). Twenty-nine infectious events (27%) were observed needing hospitalization in 9 cases. Twenty-nine patients received consolidation therapy at the discretion of the investigator. Of the 11 patients who received 3 additional cycles of R-NIMP, 3 remained in CR/CRu, 1 remained in PR, 4 converted from PR to CR/CRu, and 3 progressed. Among the 11 patients who underwent ASCT, 9 were in CR at the end of the procedure, one patient died of toxicity and 1 progressed. For the 12 patients mobilized after a R-NIMP cycle, a median of 1 apheresis (range 1–4) was necessary to harvest a median of 3.85 × 106 CD34+ cells/kg. The median time to second progression or relapse (TTP2) was 11.4 months, and the median survival of 55.5 months. On multivariate analysis, the variable associated with a longer TTP2 was the achievement of CR/Cru (RR: 0,12; CI95%: 0.03–0,39; p=0.0006). Within the subgroup of patients having received a consolidation treatment, having received an ASCT was associated with a longer TTP2 (RR: 0.20; CI95%: 0.04–0.98; p=0.047). Time to first relapse or previous rituximab exposure did not affect TTP2 nor OS, whereas relapse-IPI (as a continuous variable, by 1 additional risk factor) was associated with a poor survival (RR: 2.59; CI95%: 1.25–4.45; p=0.008). Conclusions: R-NIMP is a well-tolerated regimen, yields a high complete response rate, and allows for successful mobilization of CD34+ cells. This regimen is a suitable salvage treatment for relapsed DLBCL prior to appropriate consolidation. Further investigation is warranted. ClinicalTrials.gov number: NCT00842595 Disclosures: Off Label Use: Vinorelbine in Non-Hodgkin's Lymphoma (Off-label in France).

Description: Background: The prognostic value of COO classification by immunohistochemistry (IHC) for de novo untreated advanced DLBCL remains controversial after Rituximab-based frontline therapy. Other biomarkers such as BCL2 or MYC protein expression have been proposed to predict survival. IHC characteristics were investigated in a large multicenter randomized study. Methods: Three hundred twenty-three patients (pts) younger than 60 years with de novo untreated advanced DLBCL were randomized in the french prospective multicenter trial GOELAMS-075 to receive either 8 courses of RCHOP14 (n=161) or 2 courses of RCEEP (Rituximab, Cyclophosphamide, Eldisine, Epirubicine, Prednisone) and 1 course of Rituximab-Methotrexate-Cytarabine (RMC) followed by intensive BEAM conditionning with autologous transplant (ASCT) (n=162) upon negative interim PET-CT (visual analysis). In case of positivity, salvage regimen followed by ASCT was applied. Three years Event-free-survival (3y-EFS) was the primary endpoint. Event was defined by interim PET-CT positivity, progression or relapse, or death from any cause. Central pathology review confirmed de novo DLBCL diagnosis for 300 pts (93%). COO determination using Hans algorithm, BCL2 protein expression (clone 124, Dako) and MYC protein expression (clone Y69, Abcam) were recorded. Cut-off values were 70% for BCL2, and 40% for MYC. Results: COO analysis could be performed for 125/161 pts in RCHOP arm and 134/162 pts in intensive regimen arm including 36 and 34 Primary-Mediastinal-B-Cell subtype (PMBL) respectively. Repartition of non-PMBL was: 33/89 (37%) Germinal-Center subtype (GC), 56/89 (63%) Non-Germinal-Center subtype (NGC) in R-CHOP arm; 48/100 (48%) GC, 52/100 (52%) NGC in intensive regimen arm. Of 70 PMBL there were 50 NGC, 4 GC and 16 NE equally distributed in both arms. Clinical characteristics were similar in both GC and NGC subtypes, whereas PMBL presented with more frequent bulky disease and predominantly female gender. BCL2 ≥70% and MYC ≥40% were found in 147/285 (55%) and 85/185 (46%) of available samples, without difference between two arms. No correlation was found between BCL2 or MYC protein expression and GC or NGC subtype, however there were seen in a significantly lower proportion of PMBL (34% and 17% respectively). Coexpression of BCL2≥70% and MYC≥40% (MYC+/BCL2+) occurred in 52/184 (28%) cases, without difference between two arms or COO subtypes. By contrast, PMBL subtype displayed an extremely low rate of MYC+/BCL2+ cases (1/49, 2%). 3y-EFS rates were 52% ± 6% for GC, 58% ± 5% for NGC and 49% ± 6% for PMBL (p= 0,42) with no significant difference according to treatment arm. Of note, in PMBL, the majority of events was positive interim PET-CT. Worse EFS was seen in BCL2≥70% cases (3y-EFS: 47% ± 4% vs 60% ± 4%, p= 0,05) but this difference was erased in RCHOP arm (3y-EFS: 52% ± 6% vs 58% ± 6%). 3y-Progression Free Survival (PFS) rates were 73% ± 6% for GC, 76% ± 6% for NGC and 94% ± 4% for PMBL (p=0,03) with no difference between the two arms (Fig 1). There was no PFS difference in BCL2≥70% vs