The blastic variant (BV) form of mantle cell lymphoma (MCL) is considered to be a very aggressive subtype of non-Hodgkin's lymphoma (NHL). In order to determine its clinico-biological features and response to therapy we studied 33 patients (17%) out of 187 suffering from MCL who were diagnosed with a BV of MCL. Blastic variant was diagnosed according to histopathological patterns, immunophenotyping, and bcl1 gene rearrangement and/or cyclin D1 overexpression. Three patients initially diagnosed with large cell NHL were classified as BV. Patients received front-line therapy including CHOP-like regimen or CVP (n = 29), or chlorambucil (n = 4) and CHOP or ESAP as second-line therapy. High-dose intensification with stem cell transplantation (SCT) was performed in 11 cases (autoSCT, n = 8; alloSCT, n = 3). All but two patients were in complete remission (CR) at the time of transplant (CR1, n = 5; CR2, n = 4). Clinical and biological characteristics did not differ from those of the common form of MCL. The median age was 62 years (29-80), with a sex ratio (M/F) of 2.6:1. Of the 33 patients, 66% had extranodal site involvement, 85% had an Ann Arbor stage IV, and 82% had peripheral lymphadenopathy. Circulating lymphomatous cells were seen in 48% of cases. Twelve patients (36%) entered a CR1 with a median duration of 11 months. Fifteen patients (46%) failed to respond and rapidly died of progressive disease. Second-line therapy led to a 26% (6/23) CR2 rate. Nine patients relapsed after high-dose therapy. Twenty-two of the 33 patients (66%) died of refractory or progressive disease. Median overall survival (OS) time was 14.5 months for the 33 BV patients as compared to 53 months for the 154 patients with a common form of MCL, P Ͻ0.0001. In the univariate analysis, OS was influenced by age, extranodal site involvement, circulating lymphomatous cells, and international prognosis index (IPI). In the multivariate analysis, only IPI affected OS: patients with IPI у2 had 8 months median OS as compared to 36 months median OS for patients with IPI Ͻ2, P = 0.003. Blastic variant is one of the worst forms of NHL. An improved recognition of BV of MCL is required, particularly in high-grade CD5 + NHL using immunophenotyping and bcl1 molecular study. Standard therapy using anthracycline or even high-dose intensification produce poor results and an alternative treatment should be proposed to such patients. Leukemia (2001) 15, 1785-1791.
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%).
884 Background: RO5072759 (GA101) is the first humanized and glycoengineered type II monoclonal anti-CD20 antibody to enter clinical trials. In vitro, GA101 exhibits increased antibody-dependent cytotoxicity (ADCC) and strongly enhanced direct cell death compared to rituximab. Methods: A Phase I study was initiated to determine the safety, tolerability, dose-limiting toxicity (DLT), and pharmacokinetics of GA101 given as a single agent to patients with CD20+ B-CLL for whom no therapy of higher priority was available. A flat, intravenous dose ranging from 400 mg to 2000 mg was given in a safety-driven, dose escalating, 3 × 3 design on days 1, 8 and 22 and subsequently every 3 weeks for a total of 9 infusions. Here, we present the phase I data on 13 B-CLL patients, 33% [9/13 evaluable] with high risk cytogenetics (17p or 11q) and 70% [7/10 evaluable] displaying unmutated IgVH status, who received a median of 3 [1-8] prior regimens, including fludarabine (13/13) and rituximab-containing therapy, (8/13). Baseline median hematology parameters included hemoglobin 12.6 g/dL [9.4 -14.9], WBC 51.8 × 109/L [10-124], platelets 191 × 109/L [48-404], lymphocytes 47.4 × 109/L [7.0-119.3]. Results: GA101 was well tolerated with no DLTs and no dose reductions. The most common adverse events were Grade 1 or 2 infusion related reactions essentially limited to the first infusion. GA101-related Grade 3/4 hematological toxicities included transient neutropenia (n=9), febrile neutropenia (n=1) and transient thrombocytopenia (n=1). Neutropenia recovered spontaneously or with G-CSF. SAEs were reported in 3 patients (febrile neutropenia, thrombocytopenia, bronchitis, gingivitis, neutropenia and tumor lysis syndrome). Ten patients had infections (17 episodes with only three being Grade 3). No significant changes to baseline immunoglobulin levels were observed. Measurement of plasma cytokines during and immediately after the 1st infusion showed a transient increase in IL6 and IL8 with smaller increases in IL10, IFN-γ and TNFa. Activation of complement was not observed (C3a, C4a, C5a). Concurrent to cytokine increase was a decrease in T-cell subsets and NK cell counts (peripheral blood) after the first infusion. At the end of treatment, CD3 and CD8 counts had recovered while median CD4 and CD16/56 counts remained just below the normal range, with no clinical sequelae observed. Immunologic monitoring is ongoing. B-cell (CD19+) depletion was almost complete for all 13 patients and sustained following the first infusion. Best overall response rate according to IWCLL criteria was 62% (8/13) with 1 CRi, 7 PR and 5 SD observed across all FcγIIIRA [158F/V polymorphism] genotypes with no clear dose relationship established. Responses are ongoing with durations ranging from 3.5+ to 8+ months. End of treatment minimal residual disease (MRD) from 7/11 evaluable patients was detectable for 6 patients (median reduction of 2 log, range 2-4) and negative for one (despite a stable disease, as assessed by CT-scan). GA101 pharmacokinetics were characterized by one linear and one time-dependent saturable clearance components, consistent with target-mediated disposition, which is also observed with rituximab. Whilst the plasma concentrations demonstrate a dose-dependent increase, there was significant inter and intra-patient variability. Time-dependent clearance is consistent with a reduction in target-mediated antibody clearance with increasing duration of treatment. With the same doses of GA101, clearance is faster in B-CLL patients than NHL patients (Salles et al ASH 2008, 2009). Conclusion: These phase I results indicate that GA101 has promising activity when given as single agent to heavily pre-treated B-CLL patients and has a similar safety profile to that observed in NHL patients (Salles et al, ASH 2008, 2009) with an increased incidence of transient neutropenia in B-CLL. GA101 is currently being explored as a single agent in phase II in relapsed/refractory B-CLL and indolent/aggressive NHL and in combination with chemotherapy in a phase Ib study. Disclosures: Morschhauser: Roche Products Limited : Honoraria. Cartron:Roche Products Limited : Consultancy, Honoraria. Milpied:Roche Products Limited : Honoraria. Weisser:Roche Diagnostics : Employment. Birkett:Roche Products Limited : Employment. Salles:Roche Products Limited : Honoraria.
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