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]

A Polymorphism in the C1qA Component of Complement Correlates with Prolonged Complete Remission Following Rituximab Therapy of Follicular Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 778-778 ◽  
Author(s):  
Emilian Racila ◽  
Wen-Kai Weng ◽  
James E. Wooldridge ◽  
Brian K. Link ◽  
Ronald Levy ◽  
...  
Keyword(s):  
Complete Remission ◽  
Follicular Lymphoma ◽  
Single Agent ◽  
Progression Free Survival ◽  
Time To Progression ◽  
Free Survival ◽  
Relative Risks ◽  
Complete Clinical Remission ◽  
Duration Of Response ◽  
Anti Cd20

Abstract There is indirect but intriguing evidence that complement plays a role in the clinical response to rituximab and other mAb-based therapies of cancer. We identified a non-coding polymorphism in the C1qA component of complement that appears to result in a post-translational splice variant of the C1qA protein. We examined this polymorphism in 90 patients with follicular lymphoma who were treated with single agent rituximab to assess whether a correlation exists with clinical efficacy. The presence of an A versus a G allele at the C1qA[276] locus was determined using restriction fragment length polymorphism analysis by investigators blinded to the clinical outcome of the patients. The molecular and clinical data was then analyzed according to C1qA polymorphism, including measurement of radiographic response and duration of response, using methods similar to those used to evaluate the correlation between polymorphisms in CD16/CD32 genes and clinical outcome. No statistically significant difference in response rate was found based on C1qA polymorphism. However, prolonged remission was noted among those subjects that achieved remission (either PR or CR) for individuals who were carriers of the A allele at the C1qA[276] locus (AA or AG) compared to homozygous GG subjects. The strongest correlation was found among those subjects that achieved a complete remission to single agent rituximab. In this group, GG subjects had a time to progression of 250 days, while AA /AG subjects had time to progression of 830 days (HR=4.1, 95% CI=2.1–96.9). Multivariate Cox regression analysis of the joint effects of the C1qA, CD32 and CD16 polymorphisms showed that C1q[276] A allele was an independent factor for good prognosis, while FcgRIIIa 158 phenylalanine carrier and FcgRIIa 131 arginine carrier indicated poor survival. Thus, the relative risk was 0.2 for C1qA[276] AA/AG versus GG after controlling for CD32 and CD16 polymorphisms. The relative risks were 4.8 for CD32 HR versus HH and 6.16 for CD32 RR versus HH after controlling for complement and CD16 polymorphisms. The relative risks were 4.57 for CD16 VF against VV and 3.69 for CD16 FF versus VV after controlling for complement and CD32 polymorphisms. These data suggest polymorphisms in C1qA may impact on duration of response to rituximab therapy of follicular lymphoma. Ongoing studies are expanding this cohort, assessing whether this polymorphism correlates clinically with outcome in other malignancies or with other therapeutic approaches in lymphoma patients, and exploring the functional significance of this C1qA polymorphism. If further studies confirm that C1qA genetic polymorphisms correlate with duration of response to rituximab, it will have major implications on our understanding of the role of complement in the immune response to lymphoma, and on development of the next generation of mAb-based cancer treatments. Total AA+AG GG p (log-rank test) TTP=Median time to progression (days) All Subjects 90 70 20 Responders 59 46 13 CR 27 22 5 TTP Overall 177 173 191 0.64 TTP Responders 352 456 334 0.12 TTP CR 798 830 250 0.007 Complement C1qA polymorphism associates with freedom from progression in follicular lymphoma patients who achieve a CR after anti-CD20 therapy. Progression-free survival logrank curves were plotted by C1qA[276] AA and AG vs GG genotype. Cheson criteria were used to estimate complete clinical remission after one round of anti-CD20 therapy. Complement C1qA polymorphism associates with freedom from progression in follicular lymphoma patients who achieve a CR after anti-CD20 therapy. Progression-free survival logrank curves were plotted by C1qA[276] AA and AG vs GG genotype. Cheson criteria were used to estimate complete clinical remission after one round of anti-CD20 therapy.

I131-tositumomab monotherapy as frontline treatment for follicular lymphoma: Updated results after a median follow-up of 8 years

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8033-8033 ◽  
Author(s):  
M. S. Kaminski ◽  
J. Estes ◽  
M. Tuck ◽  
C. W. Ross ◽  
R. L. Wahl
Keyword(s):  
Follicular Lymphoma ◽  
Single Agent ◽  
Progression Free Survival ◽  
Single Institution ◽  
Free Survival ◽  
Frontline Treatment ◽  
Anti Cd20 ◽  
High Degree ◽  
The Impact

8033 Background: Monoclonal antibody-based therapies are improving the outcome for patients (pts) with follicular lymphoma (FL). Radioimmunotherapy has been found to be effective for pts with relapsed/refractory disease, but even more so when used as frontline treatment. Methods and Results. We previously reported the results of a phase II, single-institution, study of anti-CD20 I-131- Tositumomab (Bexxar) given as a single agent and as a single one-week treatment for 76 pts with Stage 3 or 4 FL (NEJM 352:441, 2005). An overall response (OR) rate and complete remission (CR) rate of 95% and 75%, respectively, were observed. With a median follow-up of 5.1 yrs, 5-yr overall survival (OS) and progression-free survival (PFS) were 89% and 59%, respectively, with a median PFS reached at 6.1 yrs. We now report on this pt cohort after a median follow-up of 7.93 yrs. The 8-year and 10-yr OS is estimated (by KM) now at 86% and 8-yr PFS is 50% (95% CI: 38.8 - 61.7%). Only 3 additional relapses have occurred in the additional follow-up period (at 8.0, 8.3, and 9.2 years) in those with CRs. The 8-yr PFS for the 57 pts who achieved CR is now 64%. The median for PFS has now being reached for CRs at 9.2 yrs. When the impact of baseline FLIPI scores were analyzed, only 8-yr OS was significantly affected when low-risk (LR) and intermediate-risk (IR) categories were combined and compared to the high-risk (HR) category (92% vs. 75%; p = 0.029). The 8-yr PFS for LR + IR pts was 56% vs. 35% for HR pts (p = 0.317). 27 of the 76 total pts (35%) had HR scores. Of additional importance, no cases of MDS or AML have yet been observed. Other longterm toxicities including thyroid status and second non-hematologic cancers will be updated at the meeting. Conclusions. These data underscore the high degree of effectiveness and durability of remissions achieved with a single, one-week course of frontline Bexxar and should serve as a benchmark for comparison to other studies using more prolonged and toxic treatments, including those combining unlabeled or radiolabeled antibodies with chemotherapy. No significant financial relationships to disclose.

Clinical outcome of patients with follicular lymphoma receiving chemoimmunotherapy in the PRIMA study is not affected by FCGR3A and FCGR2A polymorphisms

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2650-2657 ◽  
Author(s):  
Hervé Ghesquières ◽  
Guillaume Cartron ◽  
John Francis Seymour ◽  
Marie-Hélène Delfau-Larue ◽  
Fritz Offner ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Follicular Lymphoma ◽  
Response Rate ◽  
Single Agent ◽  
Progression Free Survival ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Free Survival ◽  
Rituximab Maintenance

Abstract In patients with follicular lymphoma treated with single-agent rituximab, single nucleotide polymorphisms in the FCGR3A gene are known to influence response and progression-free survival. The prognostic role of FCGR3A and FCGR2A polymorphisms in patients with follicular lymphoma treated with rituximab and chemotherapy combination remains controversial and has not been evaluated in the context of rituximab maintenance. FCGR3A and FCGR2A single nucleotide polymorphisms were evaluated in, respectively, 460 and 455 patients treated in the PRIMA study to investigate whether these were associated with response rate and patient outcome after rituximab chemotherapy induction and 2-year rituximab maintenance. In this representative patient cohort, complete and unconfirmed complete responses after rituximab chemotherapy were observed in 65%, 67%, 66% (P = .86) and 60%, 72%, 66% (P = .21) of FCGR3A VV, VF, FF and FCGR2A HH, HR, RR carriers, respectively. After 2 years of rituximab maintenance (or observation), response rates did not differ among the different genotypes. Progression-free survival measured from either treatment initiation or randomization to observation or maintenance was not influenced by these polymorphisms. These data indicate that FCGR3A and FCGR2A polymorphisms do not influence response rate and outcome when rituximab is combined with chemotherapy or used as maintenance treatment. The PRIMA study is registered at www.clinicaltrials.gov as NCT00140582.

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.

The role of obinutuzumab in the management of follicular lymphoma

2019 ◽  
Vol 15 (31) ◽  
pp. 3565-3578 ◽  
Author(s):  
Jenny O’Nions ◽  
William Townsend
Keyword(s):  
Clinical Trials ◽  
Follicular Lymphoma ◽  
Progression Free Survival ◽  
Free Survival ◽  
Cd20 Antibody ◽  
Anti Cd20 ◽  
Almost All ◽  
Cd20 Antibodies

The outcomes for follicular lymphoma (FL) have improved significantly in recent years. This has been driven by an improved understanding of the pathobiology of FL and the development of therapeutic anti-CD20 antibodies. Combining rituximab with chemotherapy, coupled with its use as maintenance therapy, has contributed to significant improvements in disease control and progression-free survival. However, FL remains incurable and almost all patients invariably relapse. Therefore, there remains a need to develop novel therapeutic options and optimize existing regimens. Obinutuzumab (a first-in-class, glycoengineered, humanized type 2 anti-CD20 antibody) has been evaluated in a number of clinical trials. In this review, we will summarize the evaluable results of clinical trials investigating the efficacy of obinutuzumab in the treatment of FL.

Phase I/II Study of Galiximab, an Anti-CD80 Antibody, for Relapsed or Refractory Follicular Lymphoma

2005 ◽  
Vol 23 (19) ◽  
pp. 4390-4398 ◽  
Author(s):  
Myron S. Czuczman ◽  
Aron Thall ◽  
Thomas E. Witzig ◽  
Julie M. Vose ◽  
Anas Younes ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Primary Therapy ◽  
Dose Escalation Study ◽  
Best Response ◽  
The Mean ◽  
Favorable Safety ◽  
Dose Dependent

Purpose This multicenter, dose-escalation study evaluates the safety, pharmacokinetics, and efficacy of galiximab (anti-CD80 monoclonal antibody) in patients with relapsed or refractory follicular lymphoma. Patients and Methods Patients had follicular lymphoma that had relapsed or failed to respond to primary therapy; the majority (90%) presented with stage III or IV disease. Four weekly intravenous infusions of galiximab were administered at doses of 125, 250, 375, or 500 mg/m2. Results Thirty-seven patients received galiximab treatment and were evaluated for safety; 35 were assessable for response. Antibody infusions were safe and well tolerated with no dose-limiting toxicities. A total of 22 (60%) of 37 patients experienced adverse events related to galiximab. All but one of the events were grade 1 or 2; the most common were fatigue, nausea, and headache. Cytopenias were rare; only one patient experienced anemia and febrile neutropenia, which were unrelated to galiximab and resolved after treatment. No patient developed antigaliximab antibody formation. The mean serum half-life ranged from 13 to 24 days. The overall response rate was 11% (two complete responses and two partial responses). Time to best response was delayed (months 3, 6, 9, and 12). Twelve patients (34%) maintained stable disease. Nearly half of all patients (49%) had a decrease in indicator lesions. Two responders remain on study without progression (22 and 24.4 months). Conclusion The favorable safety profile of galiximab and evidence of single-agent biologic activity and dose-dependent pharmacokinetics support further evaluation of galiximab as a treatment for follicular lymphoma, possibly in combination with other lymphoma therapies.

Phase II Study of Rituximab in Newly Diagnosed Stage IA Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL): A Report From the German Hodgkin Study Group (GHSG)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2711-2711
Author(s):  
Dennis A. Eichenauer ◽  
Michael Fuchs ◽  
Annette Pluetschow ◽  
Beate Klimm ◽  
Teresa Halbsguth ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Free Survival ◽  
Stage Ia ◽  
Cd20 Antibody ◽  
Anti Cd20

Abstract Abstract 2711 Background: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma (HL) accounting for about 5% of cases. The clinical course is usually more indolent than in classical HL (cHL) resulting in an excellent long-term prognosis. This is particularly true for patients diagnosed with early-stage NLPHL representing the majority of cases. However, current standard treatment consisting of chemotherapy and/or radiotherapy (RT) is associated with an increased risk of late toxicity. Thus, there is a need for novel treatment strategies. Since CD20 is consistently expressed on the malignant lymphocyte-predominant (LP) cells, anti-CD20 antibody treatment appears to be a promising option. After impressive response rates were reported in relapsed NLPHL patients, the German Hodgkin Study Group (GHSG) initiated a trial to evaluate the anti-CD20 antibody rituximab in newly diagnosed stage IA NLPHL without clinical risk factors. Methods: Between June 2006 and October 2007, 29 patients from 23 sites were enrolled in this multicenter phase II trial. Study entry was restricted to adult patients (age 18 to 75) with biopsy-proven stage IA NLPHL without clinical risk factors. Treatment consisted of four weekly infusions of the anti-CD20 antibody rituximab at a dose of 375 mg/m2. Efficacy endpoints included remission status as assessed by computed tomography (CT) four weeks after completion of treatment, overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) at two years; feasibility endpoints were acute treatment-related toxicities, adverse events, dose reductions and therapy delays. Results: Twenty-eight patients were eligible for the final analysis of this phase II trial; 71.4% of patients were male, 72% had supradiaphragmatic disease and the median age was 40 years. Treatment was conducted in the outpatient setting in the majority of cases. Rituximab was well tolerated; no grade III/IV toxicities were observed. Transfusions of erythrocytes or platelets were not required. At final restaging four weeks after the last rituximab application, 24 patients (85.7%) were in CR/CRu and four patients (14.3%) had partial remission (PR). Thus, overall response rate (ORR) was 100%. After a median follow-up of 43 months, all patients were still alive. Progression-free survival rate estimates at two, three and four years were 85.3%, 81.4% and 77.1%, respectively. Seven patients (25%) have relapsed and two patients developed secondary solid tumors. All patients with NLPHL relapse were successfully salvaged. Conclusions: The results of the present trial confirm the previously reported excellent response of NLPHL patients to rituximab. However, with a relapse rate of 25% at a median observation time of 43 months, rituximab does not seem to be as effective as RT alone or combined-modality strategies in stage IA NLPHL patients. Nonetheless, anti-CD20 antibodies have a favorable toxicity profile and may be offered to selected patients who are at particular risk for long-term side effects such as secondary malignancies. In addition, the combination of anti-CD20 antibodies and chemotherapy may also improve efficacy and decrease toxicity of NLPHL treatment in early unfavorable, advanced or relapsed disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Changing role of stem cell transplantation in follicular lymphoma

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 417-425 ◽  
Author(s):  
Ginna G. Laport
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Follicular Lymphoma ◽  
Cell Transplantation ◽  
Single Agent ◽  
Progression Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Conditioning Regimens ◽  
First Remission

Abstract Patients with advanced follicular lymphoma (FL) have numerous treatment options, including observation, radiotherapy, single-agent or combination chemotherapy, mAbs, and radioimmunoconjugates. These therapies can extend progression-free survival but none can provide a cure. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curable therapy for FL, with the field shifting more toward the use of reduced-intensity conditioning regimens because of the lower associated nonrelapse mortality compared with myeloablative regimens. However, GVHD and infection are still problematic in the allo-HSCT population. Autologous HSCT (auto-HSCT) confers high response rates and prolongs progression-free survival in relapsed patients who are chemosensitive, and an increasing amount of data suggest that auto-HSCT may be curative if offered to relapsed patients who are not heavily pretreated. Auto-HSCT has no role as consolidation therapy for patients in first remission based on the results from 3 large randomized trials. Novel conditioning regimens with radioimmunoconjugates have been used in both auto-HSCT and allo-HSCT regimens and results have shown efficacy even in chemorefractory patients. Therefore, with the exception of patients in first remission, the optimal timing for HSCT remains controversial. However, the outcomes seen after auto-HSCT and allo-HSCT continue to improve, and HSCT represents a treatment modality that should be considered in all FL patients, especially while their disease remains chemoresponsive.

scholarly journals Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study

Blood ◽  
2012 ◽  
Vol 119 (16) ◽  
pp. 3698-3704 ◽  
Author(s):  
Myron S. Czuczman ◽  
Luis Fayad ◽  
Vincent Delwail ◽  
Guillaume Cartron ◽  
Eric Jacobsen ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
Free Survival ◽  
Overall Response ◽  
Median Progression Free Survival ◽  
Grade 3

Abstract New treatments are required for rituximab-refractory follicular lymphoma (FL). In the present study, patients with rituximab-refractory FL received 8 weekly infusions of ofatumumab (CD20 mAb; dose 1, 300 mg and doses 2-8, 500 or 1000 mg; N = 116). The median age of these patients was 61 years, 47% had high-risk Follicular Lymphoma International Prognostic Index scores, 65% were chemotherapy-refractory, and the median number of prior therapies was 4. The overall response rate was 13% and 10% for the 500-mg and 1000-mg arms, respectively. Among 27 patients refractory to rituximab monotherapy, the overall response rate was 22%. The median progression-free survival was 5.8 months. Forty-six percent of patients demonstrated tumor reduction 3 months after therapy initiation, and the median progression-free survival for these patients was 9.1 months. The most common adverse events included infections, rash, urticaria, fatigue, and pruritus. Three patients experienced grade 3 infusion-related reactions, none of which were considered serious events. Grade 3-4 neutropenia, leukopenia, anemia, and thrombocytopenia occurred in a subset of patients. Ofatumumab was well tolerated and modestly active in this heavily pretreated, rituximab-refractory population and is therefore now being studied in less refractory FL and in combination with other agents in various B-cell neoplasms. The present study was registered at www.clinicaltrials.gov as NCT00394836.

Promising Efficacy with the New Anti-CD20 Antibody GA101 In Heavily Pre-Treated NHL Patients – Updated Results with Encouraging Progression Free Survival (PFS) Data From a Phase II Study In Patients with Relapsed/Refractory Indolent NHL (iNHL)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2868-2868 ◽  
Author(s):  
Gilles Andre Salles ◽  
Franck Morschhauser ◽  
Catherine Thieblemont ◽  
Philippe Solal-Céligny ◽  
Thierry Lamy ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase Ii ◽  
Single Agent ◽  
Progression Free Survival ◽  
Survival Advantage ◽  
High Dose ◽  
Free Survival ◽  
Cd20 Antibody ◽  
Anti Cd20

Abstract Abstract 2868 Background: GA101 is the first type II, glycoengineered and humanized monoclonal anti-CD20 antibody with Phase I results (NHL/CLL) (Salles, ASH 2008, 2009; Cartron, EHA 2009; Morschhauser, ASH 2009; Sehn, ASH 2009) and phase II results (Indolent NHL) previously reported (EHA 2010). Based on an additional 1 year follow-up period, we report updated efficacy and safety results with single agent GA101, presenting new and encouraging progression free survival (PFS) data indicating a survival advantage of those patients randomized to the high dose cohort (1600/800mg). Methods: 40 eligible patients were randomized to receive GA101 in a low-dose (LD, n=18) or a high dose (HD, n=22) cohort. GA101 was given on d1, d8, d22 and q21 days for total of 9 infusions. In the LD cohort, GA101 was given 400mg all infusions; in the HD cohort, d1 and d8 at 1600mg and 800mg for subsequent infusions. Primary endpoint was end of treatment response (EOR), assessed 4 weeks after last infusion (44 weeks after treatment start). Secondary objectives were safety, pharmacokinetics and PFS. Results: Patients (Table 1) were heavily pre-treated (median 3 prior therapies) with 55% of patients not responding to or relapsing within six months after a previous rituximab-containing regimen (rituximab refractory). There were no significant differences in demographics and baseline tumour burden between the two cohorts and 75% of patients completed all scheduled 9 infusions. EOR was 17% (3 PR, 6 SD, 7 PD, 2 UNK) in the LD cohort, and 55% (2 CR, 10 PR, 6 SD, 4 PD) in the HD cohort. Of note, 6/22 rituximab-refractory patients (5 HD, 1 LD) responded, with a EOR response of 50% in rituximab-refractory patients in the HD cohort (5/10). Responses occurred across all FcγIIIR genotypes in both cohorts: of 3 responders in LD, 2 patients with F/F genotype, other unknown; of 12 responders in HD; 5 F/F, 7 F/V. Responding patients from both LD and HD groups appeared to have higher GA101 plasma concentrations compared to non-responding patients. Median PFS was 6 months [1.1-16.9+ months] and 11.3 months [1.8-14.2+ months] for the LD and HD cohorts respectively (Hazard ratio 0.55 [95% CI 0.24;1.27]). Of 15 responding patients at EOR, 9 have an ongoing response in follow-up (LD=2, HD=7), with 2 PRs converting to CR (LD=1, HD=1) and another PR to CRu (HD). In addition 2 patients (LD=1, HD=1) in follow-up converted from EOR SD to PR, one patient with an ongoing response and the other subsequently relapsing, therefore 10 patients currently have an ongoing response. GA101 was well tolerated in both cohorts with the most common AEs being infusion related reactions (LD 72%, HD 73% of patients), mostly of G1-2. During treatment, related G3-4 hematological AEs were transient neutropenia (n = 3 in HD), febrile neutropenia (n=1 in HD) and thrombocytopenia (n = 1 in HD), four patients experienced at least one G3-4 Infection (LD n=1, HD n=3). Nine patients experienced a total 12 SAEs during treatment period, with 4 related to GA101 (HD n=4; herpes zoster, febrile neutropenia, pancreatitis, neutropenia) and 2 patients in the additional follow-up period, with SAEs of pyrexia (LD) and bacteraemia (HD), both unrelated to GA101. In addition, no B-cell recovery has been observed to date. Conclusion: GA101 single agent is well tolerated, with promising efficacy and provides very encouraging PFS data, in this group of heavily pre-treated relapsed and refractory iNHL patients, indicating a survival advantage for those patients in the HD cohort (1600/800mg). Disclosure: Salles: Roche: Consultancy, Honoraria. Morschhauser:Roche: Consultancy, Honoraria. Wenger:Roche: Employment. Birkett:Roche: Employment. Cartron:Roche: Consultancy, Honoraria; GSK: Honoraria.

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