Evidence for Fcγ Receptor IIIA-Independent Rituximab Effector Mechanisms in Patients with Follicular Lymphoma Treated with Combined Immuno-Chemotherapy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 590-590 ◽  
Author(s):  
Sebastian Boettcher ◽  
Christiane Pott ◽  
Matthias Ritgen ◽  
Wolfgang Hiddemann ◽  
Michael Unterhalt ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Single Agent ◽  
Observation Time ◽  
Taqman Assay ◽  
High Dose ◽  
Low Grade ◽  
Fcγ Receptor ◽  
Large Patient ◽  
Lymphoma Study Group ◽  
Anti Cd20

Abstract The response to the anti-CD20 antibody Rituximab used as a single agent in follicular lymphoma (FL) patients can be predicted by the valine/phenylalanine (V/F) dimorphism of amino acid 158 of Fcγ Receptor IIIA (Fcγ RIIIA) (Cartron et al., Blood99: 754, 2002; Weng and Levy, JCO21: 3940, 2003). This suggested important contributions for Fcγ RIIIA mediated mechanisms like antibody dependent cellular cytotoxicity to the efficacy of the antibody. Recently, the German Low Grade Lymphoma Study Group (GLSG) demonstrated a significant shorter time to treatment failure (TTF) in patients who received standard CHOP (cyclophosphamide d1, doxorubicin d1, vincristin d1, prednisone d1-5) chemotherapy only compared to patients who received Rituximab (d1) plus CHOP (R-CHOP). Estimated median TTF was 2.6 years in FL patients treated with CHOP and was not reached after 3 years observation time in R-CHOP treated FL patients (p<0.0007) (Blood 102, Abstract # 352, 2003). We examined the Fcγ RIIIA dimorphism in 75 FL patients from this GLSG trial who were treated with 6 to 8 cycles R-CHOP followed by interferon maintenance or high dose chemo-radiotherapy and autologous stem cell transplantation. Using a TaqMan assay with allele specific fluorochrome labelled probes we detected a V/V genotype in 8 patients (10.7%), a V/F genotype in 38 patients (50.6%), and an F/F genotype in 29 patients (38.7%). Patients with different Fcγ RIIIA status responded similarly to R-CHOP (CR rate: V/V 37.5%, V/F 36.8%, F/F 24.1%; overall response rate: V/V 100.0 %, V/F 97.4%, F/F 96.6%; ns). Moreover, TTF was not significantly different between the groups with V/V, V/F, and F/F Fcγ RIIIA(log rank p = 0.48) after a median observation time of 24 months. A correlation between the Fcγ RIIIA status and the efficacy of R-CHOP could not be demonstrated in this large patient cohort. On the other hand it is evident that R-CHOP treated patients significantly benefited from the addition of Rituximab to CHOP chemotherapy in comparison to the standard arm of this randomized trial. This observation supports the hypothesis that the anti-lymphoma effects of Rituximab when used in combination with chemotherapy might be mediated by Fcγ RIIIA-independent mechanisms such as complement dependent cytotoxicity or direct apoptosis induction.

Unique Toxicities and Resistance Mechanisms Associated with Monoclonal Antibody Therapy

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 329-334 ◽  
Author(s):  
Jonathan W. Friedberg
Keyword(s):  
Follicular Lymphoma ◽  
Single Agent ◽  
Antibody Therapy ◽  
Resistance Mechanisms ◽  
Complement Dependent Cytotoxicity ◽  
Dependent Cell ◽  
Impact On Treatment ◽  
Anti Cd20 ◽  
In Vivo Cytotoxicity

Abstract Anti-CD20 therapy has had a truly dramatic impact on treatment and outcome of patients with follicular lymphoma. Unfortunately, the majority of responses to single-agent rituximab are incomplete, and all patients with follicular lymphoma will experience disease progression at some point following rituximab therapy. Rituximab has multiple mechanisms of inducing in vivo cytotoxicity, including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptotic signaling, and possible vaccinal effects. The cellular microenvironment within follicular lymphoma has a profound impact on which mechanism is dominant, and confers resistance in many situations. Both tumor-associated and host-associated factors also contribute to rituximab resistance. There are multiple potential approaches to overcoming rituximab resistance, including rational biologic combination immunotherapy, engineered antibodies, and radioimmunoconjugates. Improved ability to overcome resistance will require further elucidation of critical signaling pathways involved in rituximab induced cytotoxicity and a comprehensive understanding of interactions between its multiple mechanisms of action.

Primary Follicular Lymphoma of the Duodenum Is a Distinct Mucosal/Submucosal Variant of Follicular Lymphoma: A Retrospective Study of 63 Cases

2011 ◽  
Vol 29 (11) ◽  
pp. 1445-1451 ◽  
Author(s):  
Ana-Iris Schmatz ◽  
Berthold Streubel ◽  
Elisabeth Kretschmer-Chott ◽  
Andreas Püspök ◽  
Ulrich Jäger ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Stable Disease ◽  
Cell Transformation ◽  
Large Cell ◽  
Low Grade ◽  
Complete Regression ◽  
Watch And Wait ◽  
Small Series ◽  
Anti Cd20

Purpose Small series with limited follow-up have suggested primary follicular lymphoma of the duodenum (FL-D) to be an indolent disease. We report our experience on a large series of patients followed for a median time period of longer than 6 years. Patients and Methods The study comprised 63 patients with primary FL-D defined as stage I disease. Endoscopy and detailed pathologic work-up was performed at diagnosis and at restaging to monitor the behavior of the neoplastic process. Results Histologically, all 63 patients had FL, low grade (1 to 2). Duodenal endosonography demonstrated lesions confined to mucosa/submucosa in 19 of 20 patients. At an overall median follow-up of 77 months (range, 12 to 177 months), only two untreated patients had developed nodal disease, the remaining 61 patients never experienced extrasmall intestinal disease and large cell transformation did not occur at all. Among 24 patients followed by watch and wait strategy, seven showed spontaneous complete regression and 17 had stable disease; radiotherapy resulted in complete regression in all 19 patients; anti-CD20 antibody monotherapy achieved complete regression in four patients and stable disease in one patient. Various chemotherapy protocols in eight patients caused complete regression in all of them, but local relapses occurred in three. No patients required surgery or died of disease. Conclusion These findings characterize primary FL-D as a remarkably indolent FL variant, which, even left untreated, does not develop tumorous growth, very rarely disseminates (two of 63 patients) and does not transform to high grade disease. A watch and wait approach appears to be the most sensible strategy.

Rituximab Overcomes Sex as a Strong Adverse Prognostic Factor for Treatment Outcome in Patients with Follicular Lymphoma: Analysis of Patients Treated with Rituximab/CHOP or CHOP in Randomized Trials of the German Low Grade Lymphoma Study Group (GLSG).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3706-3706 ◽  
Author(s):  
Christian Buske ◽  
Eva Hoster ◽  
Martin H. Dreyling ◽  
Roswitha Forstpointner ◽  
Michael Kneba ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Prognostic Factor ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Low Grade ◽  
Study Group ◽  
Female Patients ◽  
Male Patients ◽  
Male Sex ◽  
Lymphoma Study Group

Abstract Abstract 3706 Poster Board III-642 Sex has been recognized as an important prognostic factor for the treatment outcome of patients with lymphoma. Thus, several retrospective analyses have shown that male sex is associated with an inferior outcome in advanced stage follicular lymphoma. This was confirmed in a retrospective analyses of 1795 patients with follicular lymphoma using Cox regression analysis, in which male sex was independently associated with inferior survival (Solal-Celigny et al., Blood 2004). We now analyzed the prognostic impact of sex on treatment outcome of 1172 patients with follicular lymphoma treated first line with CHOP or R-CHOP in prospectively randomized clinical trials of the German Low-Grade Lymphoma Study Group (GLSG). From these, 616 pts were treated with CHOP, 556 pts with R-CHOP. FLIPI was equally distributed between the two treatment arms (low risk 14% vs. 14%, intermediate risk 42% vs. 41% and high risk 44% vs. 45 %, respectively). 48% of the patients were male (50% in the CHOP and 46% in the R-CHOP arm). For all patients there was a significantly inferior time to treatment failure (TTF) for male patients with a median of 43 months compared to 61 months for female patients (p=0.0035). In the patient group treated with CHOP alone the median TTF was 30 months for male vs. 40 months for female patients (p=0.0041). The observation that male sex was associated with inferior treatment outcome was seen both in the elderly (above 60 yrs of age) as well as the younger patient group (below 60 yrs of age). However, after treatment with R-CHOP sex did not affect treatment outcome anymore with virtually the same results in male vs. female patients (for the total group and for patients < 60yrs TTF median not reached in both arms, p = n.s.; for pts > 60 yrs TTF 81 vs. 84 months, respectively, p=n.s.). In multivariate analysis, also adjusting for FLIPI risk factors, male sex showed up as an independent prognostic factor for patients treated with CHOP alone (HR 1.82; 1.32 – 2.5; p=0.0002), but not for patients treated with R-CHOP (HR 1.06; 0.68 - 1.66, p = 0.79; p=0.0476 for the interaction term of sex with Rituximab). Based on this, male patients had the highest benefit when rituximab was added to CHOP (R-CHOP vs. CHOP: male pts HR 0.31,0.21 - 0.46, p<0.0001 and female pts. HR 0.53, 0.37 - 0.76, p = 0.0005). These data demonstrate that Rituximab functions as an equalizer with regard to sex as a prognostic factor and underlines that well established prognostic factors may lose their predictive power with the emergence of novel effective treatment approaches. Disclosures: Buske: Roche: Honoraria. Hoster:Roche: travel support. Dreyling:Roche: Honoraria, Research Funding. Hallek:BayerScheringAG: Honoraria, Research Funding. Hiddemann:Roche: Honoraria, Research Funding. Unterhalt:Roche: .

Combination Biologic Therapy as Initial Treatment for Follicular Lymphoma: Initial Results From CALGB 50701 - a Phase II Trial of Extended Induction Epratuzumab (anti-CD22) and Rituximab (anti-CD20)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 427-427 ◽  
Author(s):  
Barbara Grant ◽  
John P. Leonard ◽  
Jeffrey L Johnson ◽  
Lale Kostakoglu ◽  
Eric Hsi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Follicular Lymphoma ◽  
Phase Ii ◽  
Stable Disease ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Good Tolerability ◽  
Grade 3 ◽  
Anti Cd20

Abstract Abstract 427 Rituximab is effective as single agent therapy in the treatment of follicular lymphoma (FL), and when combined with chemotherapy has extended remissions and survival. Epratuzumab (Immunomedics), a humanized anti-CD22 monoclonal antibody, also has single agent activity in FL, and in combination with rituximab led to durable complete responses in the treatment of patients (pts) with relapsed and refractory indolent NHL. To evaluate the hypothesis that combining a second biological agent with rituximab might improve efficacy with good tolerability, the CALGB treated 60 previously untreated pts with epratuzumab and rituximab in a multicenter phase II trial and we report here the preliminary response and toxicity findings. Rituximab was administered at 375 mg/m2 iv weekly for four weeks, then every 8 weeks for four additional doses for a total of 8 doses over 9 months. Epratuzumab, was given at 360 mg/m2 two days before the first rituximab dose to assess toxicity. From week 2 on, epratuzumab was given before the rituximab on the same day for a total of 8 doses over 9 months. Fifty-seven evaluable pts were enrolled between May 2008 and September 2009. FLIPI scores at study entry were 13 (22%) low; 28 (47.5%) intermediate; and 18 (30.5%) high. Fifty-three pts completed all therapy through month 9. One pt was taken off therapy due to progression after month 5. One pt died during induction from line sepsis. Two pts were taken off study due to adverse events, 1 during induction (grade 4 thrombosis and MI), 1 following month 5 (dyspnea, hypoxia and pulmonary NOS). All other toxicities were grade 3 or lower, including fatigue (grade 3 3%, grade 2 17%), nodal pain (grade 3 5%, grade 2 8%), and cytokine release and pruritis (grade 2, 5% each). To date, there have been 19 CRs (33.3%), 29 PRs (50.9%)(ORR 84.2%); 9 (15.8%) had stable disease. All 19 CR patients completed all treatment. The mean time to CR was 9 months. Two patients progressed after a period of stable disease, and 25 of the 29 patients who achieved PR remain in response. All 19 CRs also remain in remission at this point with a median follow-up of 0.82 years (range 0.52 to 2.0). FLIPI score was not predictive of response. The CR rate in low risk pts was 31%, 44% in intermediate risk and 18% in high risk pts. There was a trend toward higher CR rate among patients with FcgR2A His (n=10, CR 60%) and to a lower CR rate among those with FcgR2A Arg (n=14, CR 14.3%). Correlations with PET scan at week 3, with tissue biomarkers and to statin use are being analyzed. Rituximab and epratuzumab is an effective and very well tolerated regimen with an ORR of 84% in previously untreated patients with follicular lymphoma. Disclosures: Off Label Use: Use of Epratuzumab, a humanized antiCD22 monoclonal antibody in treatment of follicular lymphoma. Leonard:BiogenIDEC: Consultancy; Genentech: Consultancy; Immunomedics: Consultancy. Jones:Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Cheson:Genentech: Consultancy.

Efficacy of ocaratuzumab (AME-133v) in relapsed follicular lymphoma patients refractory to prior rituximab.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8081-8081 ◽  
Author(s):  
Jennifer L. Wayne ◽  
Kristen N. Ganjoo ◽  
Brad L. Pohlman ◽  
Sven De Vos ◽  
Ian W. Flinn ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Binding Affinity ◽  
Overall Response Rate ◽  
Single Agent ◽  
Progression Free Survival ◽  
Fold Increase ◽  
Dose Escalation Study ◽  
Free Survival ◽  
Dependent Cell ◽  
Anti Cd20

8081 Background: Ocaratzumab, previously known as AME-133v, is a humanized next-generation anti-CD20 monoclonal antibody. It has been optimized with a 13 to 20-fold increase in binding affinity to CD20 and improved binding to the low-affinity (F/F and F/V) polymorphisms of FcγRIIIa (CD16), which are thought to predict lower response rates and shorter duration of responses to rituximab. Methods: In a phase I dose escalation study in relapsed follicular lymphoma (FL) patients, ocaratuzumab was well-tolerated at doses up to 375 mg/m2 (Forero-Torres et al. CCR 2012). In a follow-on phase II trial, 44 patients with relapsed FL following prior rituximab and the low-affinity FcγRIIIa polymorphism (F-carriers) received 375 mg/m2 of ocaratuzumab weekly for 4 doses. In this study, overall response rate (ORR) was 36% and median progression free survival (PFS) was 91 weeks (Ganjoo et al. Haematologica 2011). Results: Amongst the 56 patients receiving 100 and 375 mg/m2 of ocaratuzumab, 8 patients had a previous time to progression of ≤ 180 days following their last rituximab treatment. These patients had a median of 2 prior rituximab treatments, (range 1-6 treatments), and median PFS following last treatment of 159 days. Five of the 8 patients showed a longer PFS after ocaratuzumab administration, compared with last rituximab treatment. All 5 patients expressed the homozygous low-affinity genotype of FcγRIIIa (F/F). At the time of study closure, 3 of the patients were still in remission (indicated by * in the table). Conclusions: This retrospective analysis suggests that ocaratuzumab may be non-cross-resistant to rituximab in patients with the low-affinity FcγRIIIa polymorphism. Prolonged PFS in selected patients following ocaratuzumab suggests that the increased binding affinity to CD16 and improved antibody-dependent cell-mediated cytotoxicity (ADCC) of this antibody is clinically relevant. As a single agent, ocaratuzumab may provide prolonged clinical benefit in relapsed FL patients and a clinical trial comparing ocaratuzumab to rituximab is in preparation. [Table: see text]

CHOP Improves Response Rates but Not Overall Survival in Follicular and Mantle Cell Lymphoma (MCL)- Results of a Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 611-611 ◽  
Author(s):  
Christina Nickenig ◽  
Martin H. Dreyling ◽  
Eva Schiegnitz ◽  
Michael Pfreundschuh ◽  
Lorenz H. Truemper ◽  
...  
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Low Grade ◽  
Study Group ◽  
Advanced Stage ◽  
Conventional Chemotherapy ◽  
Mantle Cell ◽  
Lymphoma Study Group

Abstract In advanced stage follicular lymphoma conventional chemotherapy is non-curative and no major improvement in overall survival has been achieved by different regimens. Similarly, MCL, a lymphoma subtype with an especially poor clinical outcome, cannot be cured by conventional chemotherapy. In 1996, the German Low Grade Lymphoma Study Group (GLSG) started a randomized trial to evaluate the efficacy of two different anthracycline/anthrachinon containing regimens comparing CHOP (cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 2, adriamycine 50 mg/m2 day 1, prednisone 100 mg/m2 days 1–5) and MCP (mitoxantrone 8 mg/m2 days 1–2, chlorambucil 3x3 mg/m2 days 1–5; prednisone 25 mg/m2 days 1–5). 415 previously untreated patients with advanced stage indolent lymphoma were prospectively randomized to receive either 6–8 cycles of CHOP or MCP and are evaluable for induction therapy. 277 patients (67%) had a follicular lymphoma, 86 (21%) had a mantle cell lymphoma and 52 (13%) patients had another indolent histology. Responders up to 60 years were subsequently assigned to either myeloablative radiochemotherapy and autologous stem cell transplantation or to interferon-a maintenance (IFNa ), all other patients received IFNa. As stem cell mobilization was hampered in the MCP arm (only 44% sucessful mobilisations after MCP, 93% after CHOP; p=0.0003), from July 1998 all younger patients were asssigned to the CHOP arm. 86% complete and partial remissions (18% CR) were observed in the CHOP arm, whereas after MCP an overall response rate of 77% was obtained (14% CR, p=0.0094). In subgroup analysis similar improvement of remission rates were detected in follicular lymphoma (91% vs 82%, p=0.026) and mantle cell lymphomas (87% vs 73%, p=0.080). No differences, were observed, however, between both regimens for progression-free survival in both lymphoma subtypes. Overall survival was comparable for FL in both study arms (74% vs 69% at five years, p=0.29). In MCL, overall survival was slightly higher in the CHOP arm (5y OS: 57% vs. 31%; p=0.0578), but this difference was mostly due to unbalanced patient characteristics (IPI). In conclusion, CHOP appears superior to MCP in achieving a higher initial response rate but has no long term impact on response duration or overall survival.

High Anti-Lymphoma Activity of Bendamustine/Mitoxantrone/Rituximab (BMR) in Rituximab Pretreated Relapsed or Refractory Indolent Lymphomas. A Multicentre Phase II Study of the German Low Grade Lymphoma Study Group (GLSG).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2480-2480
Author(s):  
Rudolf Weide ◽  
Georg Hess ◽  
Hubert Koeppler ◽  
Jochen Heymanns ◽  
Joerg Thomalla ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Observation Time ◽  
Low Grade ◽  
Multicentre Phase ◽  
Not Otherwise Specified ◽  
Mantle Cell ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Lymphoma Study Group ◽  
Indolent Lymphomas

Abstract Purpose: Bendamustine is a new anti-lymphoma agent with promising activity. Based on a preceeding phase I study the current trial explored Bendamustine in combination with Mitoxantrone and Rituximab (BMR) in patients with relapsed or refractory indolent lymphomas. Patients and Methods: Patients with relapsed or refractory symptomatic stage III/IV indolent lymphomas with or without prior treatment with Rituximab were eligible. Therapy consisted of Bendamustine 90 mg/m2 days 1+2, Mitoxantrone 10 mg/m2 day 1, Rituximab 375 mg/m2 day 8. Treatment was repeated on day 29 for a total of 4 cycles. Results: Between 04/03 and 07/04 62 patients were recruited from 24 participating institutions, 40% of whom had received prior Rituximab therapy. Median age was 67 years (40–83). Lymphoma subtypes were 30 follicular (FL), 18 mantle cell (MCL), 4 B-CLL with plasmacytic differentiation, 3 lymphoplasmacytic (LPL), 3 marginal zone (MZL), 2 diffuse large B-cell (DLBCL), 1 high grade lymphoma not otherwise specified and 1 hairy cell leukemia. The overall response rate (ORR) was 88% with 36% CR and 53% PR. ORR in Rituximab pretreated patients was 75% (38% CR, 38% PR). After a median observation time of 17 months (1 – 33), the estimated median progression free survival is 19 months. Treatment related toxicities of grade 3/4 comprized a reversible myelosuppression (10 % anemia, 78 % leukocytopenia, 46 % granulocytopenia, 16 % thrombocytopenia). However, unexpected hospitalisations were necessary after 10 of 231 cycles (4%) only. Conclusion: BMR is a very effective new outpatient immuno-chemotherapy with low toxicity for patients with relapsed/refractory indolent lymphoma. Response rates All patients FL MCL pretreated with Rituximab n 62 30 18 25 end of therapy without staging 3 3 0 1 evaluable patients 59 27 18 24 CR 21 (36%) 13 (48%) 6 (33%) 9 (38%) PR 31 (53%) 12 (44%) 8 (44%) 9 (38%) MR 1 (2%) 0 (0%) 1 (6%) 1 (4%) SD 0 (0%) 0 (0%) 0 (0%) 0 (0%) PD 6 (10%) 2 (7%) 3 (17%) 5 (21%) EX 0 (0%) 0 (0%) 0 (0%) 0 (0%) CR+PR 52 (88%) 25 (93%) 14 (78%) 18 (75%) Figure Figure

Sign in / Sign up

Export Citation Format

Share Document