Additional Doses Of Rituximab Research Articles

Results from a Phase 1 Study of ACTR707 in Combination with Rituximab in Patients with Relapsed or Refractory CD20+ B Cell Lymphoma

The antibody-coupled T cell receptor (ACTR) platform is an autologous engineered T cell therapy combining the cell-killing ability of T cells and the tumor-targeting ability of coadministered antibodies. Activation of the T cell product ACTR707 is dependent on the engagement of antibody bound to target cells via the CD16 domain of the chimeric receptor (CD16V-CD28-CD3ζ). ACTR707 in combination with the anti-CD20 monoclonal antibody rituximab was evaluated in the ATTCK-20-03 study, a multisite, single-arm, open-label phase I trial in B cell non-Hodgkin lymphoma (NHL). The primary objectives of this study were to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Secondary objectives included evaluation of antitumor activity and ACTR T cell persistence. The study design included an ACTR707 cell dose escalation phase and an expansion phase at the RP2D. Escalating dose levels of ACTR707 in combination with rituximab were explored in 5 dose cohorts, with 25 subjects receiving study treatment. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m2/day and fludarabine 30 mg/m2/day) for 3 days, followed by rituximab 375 mg/m2 and, 24 to 48 hours later, a single dose of ACTR707. Additional doses of rituximab were administered every 3 weeks until disease progression, unacceptable toxicity, or investigator decision. Blood samples were collected at various time points to assess levels of rituximab, cytokines, inflammatory markers, and ACTR707 T cells. The overall response rate of ACTR707 plus rituximab was 56% (14 of 25) across all dose levels. Ten subjects (40.0%) achieved a complete response, with the longest duration of 586 days (range, 85 to 586 days), and 4 subjects (16.0%) experienced a partial response, with the longest duration of 130 days (range, 44 to 130 days). Only 1 case of cytokine release syndrome (grade 2) and no events of neurotoxicity were reported. There were no dose-limiting toxicities or events leading to death. ACTR707 plus rituximab resulted in only 1 adverse event (neutropenia), leading to study discontinuation of rituximab. The ATTCK-20-03 trial serves as proof of principle regarding the ACTR approach that potentially could be used with other antibodies targeting other markers in other malignancies. Although the ACTR707 program has been discontinued, these results may support other programs in the use of similar novel approaches of antibody-coupled T cell activation.

T cell responses to SARS-CoV-2 vaccination differ by disease-modifying therapy for multiple sclerosis.

Immune responses in people with multiple sclerosis (pwMS) receiving disease-modifying therapies (DMTs) have been of significant interest throughout the COVID-19 pandemic. Lymphocyte-targeting immunotherapies, including anti-CD20 treatments and sphingosine-1-phosphate receptor (S1PR) modulators, attenuate Ab responses after vaccination. Evaluation of cellular responses after vaccination, therefore, is of particular importance in these populations. In this study, we used flow cytometry to analyze CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy control study participants and pwMS receiving 5 different DMTs. Although pwMS receiving rituximab and fingolimod therapies had low Ab responses after both 2 and 3 vaccine doses, T cell responses in pwMS taking rituximab were preserved after a third vaccination, even when an additional dose of rituximab was administered between vaccine doses 2 and 3. PwMS taking fingolimod had low detectable T cell responses in peripheral blood. CD4 and CD8 T cell responses to SARS-CoV-2 variants of concern Delta and Omicron were lower than to the ancestral Wuhan-Hu-1 variant. Our results indicate the importance of assessing both cellular and humoral responses after vaccination and suggest that, even in the absence of robust Ab responses, vaccination can generate immune responses in pwMS.

Rituximab Use for the Treatment of Childhood Nephrotic Syndrome by Canadian Pediatric Nephrologists: A National Survey.

Background:There is known practice variation in the treatment of frequently relapsing, steroid-dependent, and steroid-resistant nephrotic syndrome in children. Rituximab is an emerging therapy for difficult-to-treat nephrotic syndrome; however, there are no clear treatment guidelines. We therefore hypothesized that a wide variety of approaches to this therapy exist.Objective:To evaluate when and how rituximab is used for the treatment of childhood nephrotic syndrome in Canada.Design and setting:An online survey was used.Participants:Canadian pediatric nephrologists.Methods:A cross-sectional survey was distributed across Canada through the Canadian Association of Pediatric Nephrologists (CAPN) to evaluate rituximab treatment practices.Results:Of a total of 20 responses, 19 (95%) use rituximab in the treatment of nephrotic syndrome, usually as a third or fourth agent. For the number of rituximab doses, the majority (68%) uses 2 doses each time they use it. Eighteen respondents (90%) measure B cells when using this medication, mostly monthly (50%) or every 3 months (39%). Respondents were administered additional doses of rituximab prophylactically (74%) or at first relapse (47%). Long-term drug safety and drug funding were identified as the main barriers to rituximab use.Limitations:This survey represents the practice styles of physicians in a single country, and there is a nonresponse bias of 63%. Also, associations were not calculated.Conclusions:Among Canadian pediatric nephrologists, rituximab use for nephrotic syndrome appears to be increasing, but significant practice variations remain, including approaches to B-cell monitoring. It is reserved mostly for second-line and third-line use due to cost, funding issues, and residual uncertainty regarding long-term safety. Understanding these critical areas of practice uncertainty is a first step to optimize treatment of nephrotic syndrome in children.

Impact of Immunochemotherapy with R-Bendamustine or R-CHOP in the Post-Induction Management of Treatment Naïve Advanced Stage Follicular Lymphoma Patients: A Subset Analysis of the FOLL12 Trial By the Fondazione Italiana Linfomi (FIL)

Impact of Immunochemotherapy with R-Bendamustine or R-CHOP in the Post-Induction Management of Treatment Naïve Advanced Stage Follicular Lymphoma Patients: A Subset Analysis of the FOLL12 Trial By the Fondazione Italiana Linfomi (FIL)

Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly × 4 schedule

AbstractThe potential benefits of extended rituximab treatment have been investigated in a randomized trial comparing the standard schedule with prolonged treatment in 202 patients with newly diagnosed or refractory/relapsed follicular lymphoma (FL). All patients received standard treatment (rituximab 375 mg/m2 weekly × 4). In 185 evaluable patients, the overall response rate was 67% in chemotherapy-naive patients and 46% in pretreated cases (P < .01). Patients responding or with stable disease at week 12 (n = 151) were randomized to no further treatment or prolonged rituximab administration (375 mg/m2 every 2 months for 4 times). At a median follow-up of 35 months, the median event-free survival (EFS) was 12 months in the no further treatment versus 23 months in the prolonged treatment arm (P = .02), the difference being particularly notable in chemotherapy-naive patients (19 vs 36 months; P = .009) and in patients responding to induction treatment (16 vs 36 months; P = .004). The number of t(14;18)-positive cells in peripheral blood (P = .0035) and in bone marrow (P = .0052) at baseline was predictive for clinical response. Circulating normal B lymphocytes and immunoglobulin M (IgM) plasma levels decreased for a significantly longer time after prolonged treatment, but the incidence of adverse events was not increased. In patients with FL, the administration of 4 additional doses of rituximab at 8-week intervals significantly improves the EFS.

Unfavorable impact of anti-rituximab antibodies on clinical outcomes in children with complicated steroid-dependent nephrotic syndrome.

Anti-rituximab antibodies (ARA) are associated not only with adverse events, such as infusion reactions (IR) and serum sickness, but also with rituximab efficacy. However, the clinical relevance of ARA in children with steroid-dependent nephrotic syndrome (SDNS) remains unknown. We retrospectively reviewed clinical outcomes of 13 children with complicated SDNS receiving repeated single-dose rituximab treatments at 375 mg/m2 to assess whether ARA formation could impact toxicity and efficacy of additional rituximab. Pre-rituximab 22 samples collected from patients who developed IR during the second or subsequent rituximab doses were measured by electrochemiluminescence analysis. ARA were identified in 5 of 13 patients (9 of 22 samples). Median time to recovery of CD19+ B cells to > 1% of total lymphocytes and median relapse-free time after rituximab treatment were significantly shorter in the 9 ARA-positive samples than the 13 ARA-negative samples (41 vs. 100 days, p < 0.01 and 119 vs. 308 days, p < 0.05, respectively). Kaplan-Meier analysis showed that time to CD19+ B cell recovery after rituximab was significantly shorter in ARA-positive samples than in ARA-negative samples (p < 0.005). Severe IR developed in two ARA-positive patients and serum sickness in one ARA-positive patient. The incidence of ARA formation was high in the pre-rituximab samples of patients with complicated SDNS who developed IR during the second or subsequent rituximab doses, suggesting that ARA formation might have an unfavorable impact on the toxicity and efficacy of additional rituximab doses in these patients.

Preliminary Clinical Results from a Phase 1 Study of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ non-Hodgkin Lymphoma

Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR707 comprises the extracellular domain of CD16 linked to a CD3ζ signaling domain and a CD28 co-stimulatory domain. ACTR707 is in clinical development in combination with rituximab (NCT03189836) or trastuzumab (NCT03680560). Here we present clinical findings from the dose escalation phase of Study ATTCK-20-03, an ongoing, multicenter, phase 1 study of ACTR707+rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The primary objectives of this first-in-human study are to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Other objectives include evaluating antitumor activity and ACTR T-cell persistence. Subjects must have CD20+ NHL that is R/R after prior treatments, which must include anti-CD20 antibody-containing chemotherapy. Subjects receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR707. Additional doses of rituximab are administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study includes a dose escalation phase (increasing doses of ACTR707 with fixed dose of rituximab at 375 mg/m2 q3w) and an expansion phase at the RP2D. Results: Six subjects received ACTR707 at Dose Level 1 (DL1; 23-38×106 ACTR+ T cells), 3 subjects at DL2 (30-50×106 ACTR+ T cells), and 5 subjects at DL3 (45-55×106 ACTR+ T cells). The majority of the subjects were diagnosed with DLBCL (93%) and had refractory disease (71%), defined as progressive disease as the best response to any prior treatment or relapse &amp;lt;1 year post autologous stem cell transplant. In DL1 through DL3, as of 27 May 2019, there were no dose-limiting toxicities, AEs of cytokine release syndrome (CRS), serious or severe neurologic AEs, or AEs leading to deaths on treatment. TEAEs reported in &amp;gt;2 subjects, regardless of causality or grade, included neutropenia, thrombocytopenia, anemia, febrile neutropenia, pyrexia, cough, constipation, diarrhea, nausea, and vomiting. SAEs considered possibly related to ACTR707 were febrile neutropenia (n=2) and cytopenia (n=1). ACTR707 expansion generally reached peak levels within 1 to 2 weeks after administration. All subjects with complete response (CR) up to 1 year had detectable ACTR at the last timepoint evaluated. Higher ACTR707 CD8:CD4 T-cell ratios were associated with clinical responses. Clinical activity was reported across DL1 through DL3, with an overall response rate of 64% including durable complete responses (CRs), with one subject in CR for 387+ days (Table 1). Conclusions: Data available from DL1 through DL3 of ACTR707+rituximab suggest that clinical responses can be achieved without severe T cell-mediated toxicities (eg, CRS and neurotoxicity) that have been reported with other autologous T-cell products. Dose escalation continues at a target dose of 80×106 ACTR+ T cells; enrollment in DL4 (n=6) was recently completed. Updated data, including identified correlates of clinical outcomes, will be presented for DL1 through DL4. Disclosures Flinn: TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Westin:Genentech: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; 47 Inc: Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding. Cohen:Genentech, Inc.: Consultancy, Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Bristol-Meyers Squibb Company: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy. Akard:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau. Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Bachanova:Celgene: Research Funding; Gamida Cell: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Novartis: Research Funding.

Response-Adapted Therapy with Infusional EPOCH Chemotherapy Plus Rituximab in HIV-Associated, B-Cell Non-Hodgkin's Lymphoma

Introduction: Six cycles of rituximab plus infusional EPOCH is considered a preferred regimen for first-line treatment of HIV-associated diffuse large B-cell lymphoma (DLBCL), HHV8-positive DLBCL, and primary effusion lymphoma, and is among the preferred regimens for HIV-associated Burkitt's lymphoma in the 2019 NCCN guidelines. A phase III trial demonstrated non-inferiority of 4 cycles of R-CHOP (followed by 2 additional doses of rituximab) compared with 6 cycles of R-CHOP in immunocompetent patients with low-risk DLBCL (stage I-II, age 18-60 years, and an age-adjusted International Prognostic Index score of 0), indicating that de-escalation of treatment duration may be safely achieved without compromising curability in an appropriately selected patient population. Here we report the outcomes for patients with HIV-associated DLBCL and high-grade non-Hodgkin lymphoma (NHL) treated with 4-6 cycles of EPOCH plus rituximab based a response-adapted treatment strategy under a completed prospective clinical trial (AMC-034). Methods: One hundred-six patients with HIV-associated DLBCL or high-grade CD20-positive NHL enrolled at multiple centers across the U.S. were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of dose-adjusted EPOCH regimen tailored for HIV+ patients. EPOCH consisted of a 96-hour IV infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by IV bolus cyclophosphamide every 21 days for 4 to 6 cycles. Patients received 2 additional cycles of therapy after documentation of a complete response (CR) by computerized tomography after cycles 2 and 4. Results: Sixty-four of 106 patients (60%, 95% CI 50%, 70%) had a CR in both treatment arms; characteristics of entire population and CR proportions stratified by number of EPOCH treatment cycles were similar (Table 1).The 2-year event-free survival (EFS) rates were similar in the 24 patients with CR who received 4 or fewer EPOCH cycles (78%, 95% confidence intervals [55%, 90%]) due to achieving a CR after 2 cycles, compared with those who received 5-6 cycles of EPOCH (85%, 95% CI 70%, 93%) due to failure to achieve a CR after 2 cycles (Table 2 and Figure 1). Time to disease progression and overall survival wer also similar for those treated with 4 or fewer cycles compared with 5-6 cycles (91% vs. 87%, and 78% vs. 90%, respectively) (Table 2 and Figure 1). Conclusion: A response-adapted strategy may permit a shorter treatment duration without compromising therapeutic efficacy in an appropriately selected population of patients with HIV-associated NHL, which merits further evaluation in additional prospective trials. Disclosures Noy: Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding.

A Phase 1 Study of ACTR087 in Combination with Rituximab, in Subjects with Relapsed or Refractory CD20-Positive B-Cell Lymphoma

Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR087 comprises the extracellular domain of CD16 linked to a CD3ζ-signaling domain and a 4-1BB co-stimulatory domain. Here we present the clinical experience from Study ATTCK-20-2 (NCT02776813), a multicenter, phase 1 study of ACTR087 in combination with rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The main objectives of this first-in-human study were to evaluate the safety and antitumor activity of ACTR087+rituximab. Other objectives included evaluating ACTR T-cell persistence and other correlative biomarkers. Subjects must have had CD20+ NHL that was R/R after prior treatments, which must have included anti-CD20 antibody-containing chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR087. Additional doses of rituximab were administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study included a dose escalation phase (increasing doses of ACTR087) and an expansion phase (ACTR087 at the preliminary recommended phase 2 dose [RP2D]); all subjects received rituximab at a fixed dose of 375 mg/m2 q3w. Results: Two dose levels (DL) of ACTR087 were evaluated during dose escalation (n=17). The MTD was exceeded at DL2, with severe cases of cytokine release syndrome (CRS) and neurotoxicity. Statistical analysis of the relationship between non-hematologic toxicity and ACTR+ T-cell doses was retrospectively performed (two-parameter Bayesian logistic regression model) to estimate an RP2D of 35×106 ACTR+ T cells. Nine subjects enrolled in an expansion cohort and received ACTR087 at this RP2D in combination with rituximab. Among all subjects treated (n=26), the majority (69%) were diagnosed with DLBCL. Subjects had received a median of 3 (range 1-9) prior lines of therapy, with 77% having received ≥3 prior lines. ACTR087 showed dose-dependent expansion with peak levels generally observed 7 to 14 days post administration. In subjects with ongoing clinical response (CR), ACTR remained detectable through the last timepoint evaluated. Across all cohorts, Grade ≥3 TEAEs reported in &amp;gt;3 subjects regardless of causality were limited to hematologic events. Potential T cell-mediated toxicities were observed, including 4 serious cases of CRS (Gr 4 in 2 subjects, both with fatal sepsis) and 2 serious cases of neurotoxicity (1 Gr 5, 1 Gr 4 in a subject with fatal septic shock). Elevated baseline inflammatory markers (eg, ferritin, CRP) were observed in patients who developed Gr ≥3 CRS and neurotoxicity post ACTR087. Of note, severe CRS presented without fever and events occurred &amp;gt;7 days post ACTR087. Clinical activity was reported with an ORR of 50% in all dose levels tested, including durable complete responses, with one subject in CR for 869+ days (Table 1). Conclusions: ACTR087+rituximab demonstrated antitumor activity, with observed safety events that are expected with other autologous T-cell products. The time to onset and clinical presentation of severe CRS and neurotoxicity events in this study informed the safety monitoring and adverse reaction management guidance across clinical studies of ACTR T-cell products. Data from this first-in-human study of ACTR087+rituximab confirm the proof of concept and will be used to guide further development for the ACTR platform. Updated clinical data, as well as expanded biomarker correlations to efficacy and safety, will be presented. Disclosures Munoz: Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Portola: Research Funding; Incyte: Research Funding; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Juno: Consultancy, Other: advisory board. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Stiff:Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Akard:Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau.

Abstract A003: Safety and preliminary efficacy of ACTR707, autologous T lymphocytes expressing an antibody-coupled T-cell receptor, in combination with rituximab in subjects with relapsed or refractory CD20-positive B-cell lymphoma

Abstract Background: Autologous T cells engineered to express a universal ACTR chimeric receptor kill tumors through interactions with tumor-targeting antibodies [Kudo, Cancer Res 2014]. ACTR707 was identified through rigorous preclinical screening of more than 100 different ACTR variants. It is composed of the extracellular domain of CD16, the cytoplasmic signaling domain of CD3ζ, and the costimulatory domain of CD28. Study ATTCK-20-03 (NCT03189836) is the first clinical trial of ACTR707. ACTR707 in combination with rituximab is being studied in subjects with relapsed or refractory CD20+ B-cell lymphoma previously treated with anti-CD20 monoclonal antibody (mAb) therapy. Herein we report data from the first dose level of ACTR707, where 6 subjects have been enrolled and treated.Methods: ATTCK-20-03 is a first-in-human, multicenter phase 1 dose escalation study of ACTR707 in combination with rituximab. The primary objective is to evaluate the safety of ACTR707 in combination with rituximab, and secondary objectives include evaluation of antitumor activity, assessment of T-cell expansion and persistence, cytokine levels, and rituximab pharmacokinetics. Eligible subjects must have histologically confirmed relapsed or refractory aggressive CD20+ B-cell lymphoma of DLBCL, MCL, PMBCL, Gr3b FL, or transformed FL subtype and have received prior anti-CD20 mAb therapy in combination with chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m2 and fludarabine 30 mg/m2) for 3 days, followed by rituximab (375 mg/m2) and a single infusion of ACTR707. Additional doses of rituximab are administered, one dose every 3 weeks in the absence of disease progression. The study is separated into two sequential phases, a dose escalation and a safety expansion phase. During dose escalation, ACTR707 will be tested at increasing doses in combination with rituximab. Results: Six subjects received ACTR707 in combination with rituximab at the first dose level: 5 diagnosed with DLBCL (83%) and 1 with Gr3b FL (17%). Median age was 61 years (range: 57-76), 83% were male, 50% were treated with ≥ 3 lines of prior therapy, and 67% had no response to or progression within 6 months of immediate prior therapy. ACTR707 was successfully manufactured for all subjects. ACTR+ T cells demonstrated expansion and were detectable at D28 post-ACTR707 infusion for all subjects tested. There were no dose-limiting toxicities observed in the 4 subjects evaluable for DLTs (2 subjects were not DLT-evaluable due to early disease progression). There were no serious adverse events of cytokine release syndrome, neurotoxicity, or autoimmune events and no deaths on study. Grade 3 or higher AEs included neutropenia (n=2), febrile neutropenia (n=2), and thrombocytopenia (n=1). Antitumor activity was assessed in all 6 subjects. Three subjects experienced disease progression and 3 subjects demonstrated investigator-reported complete responses at the first disease response assessment (D42). Responses are ongoing at the time of the data cut-off. Conclusions: In the first dose level studied in subjects with relapsed or refractory aggressive CD20+ B-cell lymphoma, ACTR707 in combination with rituximab induced complete responses in 3 out of 6 treated subjects, with no serious events of cytokine release syndrome or neurotoxicity. ACTR+ T-cells were detectable in all subjects and ACTR+ T-cells persisted in the presence of continued rituximab administration. These results support the continued dose escalation of ACTR707 in combination with rituximab. Citation Format: Veronika Bachanova, Jonathon Cohen, Luke Akard, Samantha Jaglowski, Jessica Sachs, Ann Ranger, Patricia Harris, Kathleen McGinness, Greg Motz, Ian Flinn. Safety and preliminary efficacy of ACTR707, autologous T lymphocytes expressing an antibody-coupled T-cell receptor, in combination with rituximab in subjects with relapsed or refractory CD20-positive B-cell lymphoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A003.

Preliminary Clinical Results of a Phase 1 Study Evaluating the Safety and Anti-Tumor Activity of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ B-Cell Lymphoma

Preliminary Clinical Results of a Phase 1 Study Evaluating the Safety and Anti-Tumor Activity of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ B-Cell Lymphoma

ACTR087, Autologous T Lymphocytes Expressing Antibody Coupled T-Cell Receptors (ACTR), Induces Complete Responses in Patients with Relapsed or Refractory CD20-Positive B-Cell Lymphoma, in Combination with Rituximab

Background: Autologous T cells engineered to express the universal ACTR chimeric receptor kill tumors through interactions with tumor-targeting antibodies [Kudo, Cancer Res. 2014]. Preclinical findings with ACTR+ T cells, which bind immunoglobulin Fc via CD16V158 and signal via CD3ζ and 4-1BB (ACTR087), demonstrate markedly enhanced target- and antibody-specific tumor cell cytotoxicity, as evidenced by CD20+ B cell lymphoma killing in combination with rituximab, compared with rituximab alone. Preclinical data also demonstrate rituximab dose-dependent effects in combination with ACTR087, suggesting that the therapeutic index of ACTR087 in combination with rituximab may be affected by rituximab dose or schedule and present an advantage over chimeric antigen receptor (CAR) T cell therapies [Huet H, Blood 2016]. Study UT-201501 (ATTCK-20-2) is the first clinical trial of ACTR087 in combination with rituximab in patients with relapsed or refractory CD20+ B cell lymphoma previously treated with rituximab (NCT02776813). We report data from the 7 patients treated with ACTR087 in the first dose level of the ATTCK-20-2 study.Methods: This is a multicenter Phase 1 dose escalation study. The primary objective is to evaluate the safety of the combination of ACTR087 and rituximab, and the key secondary objective is to evaluate antitumor efficacy. Exploratory objectives include measurement of ACTR T cell persistence, cytokines, and rituximab pharmacokinetics. Eligible patients must have histologically confirmed relapsed/refractory aggressive CD20+ B cell lymphoma of DLBCL, MCL, PBMCL, Gr3b FL, or transformed FL subtype and have received prior anti-CD20 mAb in combination with anthracycline-containing chemotherapy. In the first dose level, patients received lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2 and fludarabine 30 mg/m2) for 3 days, followed by rituximab (375 mg/m2) and ACTR087 (0.5x106 ACTR+ T cells/kg). Up to 7 additional doses of rituximab are then administered, one dose every 3 weeks in the absence of disease progression.Results: Seven patients received ACTR087 in combination with rituximab at the first dose level. Median age was 64 years (range: 36-71), 57.1% were male, all had ECOG PS 1, 86% were treated with ≥ 3 lines of prior therapy, and 86% were refractory to the immediate prior therapy. ACTR087 was successfully manufactured for all subjects. ACTR+ T cells were detectable in the peripheral blood and demonstrated expansion post-infusion. One patient had a dose-limiting toxicity of grade 4 thrombocytopenia for > 14 days that later resolved. At the first dose level, there were no SAEs or deaths related to ACTR087 and no AEs of special interest, including cytokine-release syndrome, neurotoxicity, or autoimmune events. Cytopenias were the most common ≥ grade 3 AEs (neutropenia n=7, leukopenia n=5). Rituximab pharmacokinetics were not affected by ACTR087 administration. Independently-confirmed objective responses were observed in patients evaluable for response (n=6), including 2 ongoing complete responses (CR) and 1 partial response (PR). One of the CRs continues 6+ months after a single dose of ACTR087.Conclusions:In the first dose level studied in patients with relapsed/refractory aggressive CD20+ B cell lymphoma, ACTR087 in combination with rituximab induced complete responses with no serious AEs, AEs leading to treatment discontinuation, cytokine-release syndrome, or neurotoxicity. ACTR+ T cells were detectable in all patients and ACTR+ T cells persisted in the presence of continued rituximab administration. These results support the continued dose escalation of ACTR087 in combination with rituximab; dose level 2 enrollment is ongoing and updated data, including correlative biomarkers, will be presented. DisclosuresJaglowski:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Unum Therapeutics: Research Funding; Pharmacyclics Inc: Research Funding. McKinney:Kite Pharma: Other: advisory comittee. Vasconcelles:Unum Therapeutics Inc: Employment. Huet:Unum Therapeutics Inc: Employment. Ettenberg:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc: Employment. Abramson:Seattle Genetics: Consultancy; Genentech: Consultancy; Gilead: Consultancy; Kite Pharma: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; LAM Therapeutics: Research Funding; Novartis: Consultancy.

Low-dose rituximab as an adjuvant therapy in pemphigus.

Pemphigus is a chronic autoimmune blistering disease where systemic steroids and immunosuppressants are the mainstay of therapy, but long-term treatment with these agents is associated with many side effects. Rituximab, a chimeric monoclonal anti-CD20 antibody, in low doses has shown efficacy as an adjuvant to reduce the dose of steroids. To study the clinical efficacy and safety of low-dose rituximab as an adjuvant therapy in pemphigus. Fifty patients with extensive pemphigus were selected, who either had recalcitrant pemphigus, were steroid dependent, had relapsed after pulse therapy, had anti-desmoglein levels >20, had contraindications to conventional treatment or wanted to avoid conventional treatment and its side effects. Two doses of rituximab (500 mg) were given 2 weeks apart and patients were regularly followed up every 2 weeks for 3 months and then monthly upto 2 years. Complete blood counts, liver function tests, renal function tests, skin biopsy, direct immunofluorescence and desmoglein levels were checked before and after rituximab administration. Pre-rituximab chest X-ray and electrocardiograph were also obtained. At 3 months, 41 (82%) patients showed complete remission. Nine (18%) patients had partial remission. After 6-12 months, 20 (40% of enrolled patients) continued to be in remission and were off all systemic therapy and the remaining 19 (38%) were continuing to take low doses of steroids with or without other adjuvant immunosuppressants and 2 (4%) had to be given another 2 doses of rituximab and subsequently could be managed with low-dose steroids. Of the 9 patients in partial remission at 3 months, after 6-12 months 5 (10% of the total) were completely off treatment and went into complete remission and 4 (8%) were on additional treatment out of which 2 (4%) had to be given 2 additional doses of rituximab and were in partial remission with low-dose therapy at the end of 12 months. One patient developed urticaria as a side effect. Another developed herpes zoster. Our results show that low-dose rituximab is a well-tolerated and beneficial adjuvant therapy in recalcitrant pemphigus which helps reduce both the severity of disease as well as the dose of steroids and immunosuppressants.

Predictors of relapse and long-term outcome in children with steroid-dependent nephrotic syndrome after rituximab treatment

In patients with complicated steroid-dependent nephrotic syndrome (SDNS), rituximab (RTX) followed by immunosuppressive agent (IS) can maintain remission without the use of prednisolone (PSL). However, available data on the predictive factors for relapse and the long-term outcome after this protocol are few. We retrospectively analyzed 43 SDNS patients who were followed-up for a long time (>2years, mean 5.4years) after a single dose of RTX (375mg/m2) from September 2007. After RTX, PSL was tapered off within 6months; monotherapy with IS, such as cyclosporine or mycophenolate mofetil, was continued to prevent post-RTX relapse. For patients who achieved >12months of PSL-free remission, IS was also tapered off. Thirty-nine patients (91%) could discontinue PSL without relapses at a median of 154days after the initial RTX. The first relapse of NS occurred in 39 patients (91%) at a median of 586days; additional RTX doses were administered in 28 patients (65%). Kaplan-Meier analysis showed that shorter CD19 cell depletion (<150days) and younger age at RTX initiation (<12.5years) were significantly associated with high risk for first relapse after RTX (log rank p<0.05). In multivariate analysis, mycophenolate mofetil therapy as maintenance IS after RTX was the only predicted risk factor for first relapse (hazard ratio 2.75; p=0.027). At the last follow-up, IS was still used in 33 patients (77%); treatment-free remission (>12months) was achieved in only five patients (12%). The introduction of RTX may not be necessarily associated with improved long-term outcome.

Follicular lymphoma: first-line treatment without chemotherapy for follicular lymphoma.

Opinion statement: The optimal initial treatment of follicular lymphoma (FL) is not known, and initial management of patients varies considerably between providers and institutions. The assertion that patients with low tumor burden can be observed for a period of time is being challenged owing to the safety and tolerability of novel therapeutics and the movement of the field away from traditional chemotherapy agents. Single agent rituximab has become increasingly popular as initial management of patients with low tumor burden disease, and there is evidence that prolonged treatment with rituximab can improve progression-free survival (PFS) when compared to induction with rituximab or observation. Radioimmunotherapy (RIT) has similarly shown efficacy in low tumor burden disease. Novel agents such as lenalidomide, idelalisib, and ibrutinib are being studied in the first-line setting. Importantly, none of these strategies have demonstrated an improved overall survival in a randomized study versus observation. It is the opinion of the authors that endpoints such as PFS alone, while important, should not drive changes in management with limited resources. Composite endpoints including quality of life are more informative on the true impact of treatments on patients with follicular lymphoma. Providers should encourage all patients to be treated in the context of an appropriate clinical trial when possible. If a patient is not a clinical trial candidate, we typically treat patients with advanced stage and high tumor burden with chemoimmunotherapy. The decision to give maintenance rituximab is individualized to the patient, as there is no overall survival benefit. In patients with early stage disease, we favor consideration of radiation therapy if the patient is a candidate. Our initial recommendation to patients with advanced stage, low tumor burden disease, is close observation or "watch and wait." We have observed that most patients become comfortable over time with an observation approach. If a patient is not comfortable with this recommendation, we will use single agent rituximab. If the patient responds to therapy, we do not recommend maintenance rituximab in low tumor burden disease but rather prefer a retreatment strategy or an extended schedule of four additional doses of rituximab.

Rituximab With or Without Bevacizumab for the Treatment of Patients With Relapsed Follicular Lymphoma

Inhibition of tumor angiogenesis by the interruption of VEGF pathway signaling is of therapeutic value in several solid tumors. Preclinical evidence supports similar importance of the pathway in non-Hodgkin lymphoma. In this randomized phase II trial, we compared the efficacy and toxicity of rituximab with bevacizumab versus single-agent rituximab, in patients with previously-treated follicular lymphoma. Patients (n = 60) were randomized (1:1) to receive rituximab (375 mg/m(2) intravenously [I.V.] weekly for 4 weeks) either as a single agent or with bevacizumab (10 mg/kg I.V. on days 3 and 15). Patients with an objective response or stable disease at week 12 received 4 additional doses of rituximab (at months 3, 5, 7, and 9); patients who received rituximab/bevacizumab also received bevacizumab 10 mg/kg I.V. every 2 weeks for 16 doses. After a median follow-up of 34 months, PFS was improved in patients who received rituximab/bevacizumab compared with patients who received rituximab alone (median 20.7 vs. 10.4 months respectively; HR, 0.40 (95% confidence interval [CI], 0.20-0.80); P = .007). Overall survival was also improved numerically (73% vs. 53% at 4 years), but did not reach statistical significance (HR, 0.40 (95% CI, 0.15-1.05); P = .055). The addition of bevacizumab increased the toxicity of therapy, but both regimens were well tolerated (no grade 4 toxicity). The addition of bevacizumab to rituximab significantly improved PFS. The role of angiogenesis inhibition in the treatment of follicular lymphoma requires further definition in larger clinical trials.

Intensive Immunochemotherapy In Patients With B-Cell Lymphoma, Unclassifiable (B-UCL), With Features Intermediate Between Diffuse Large B-Cell Lymphoma (DLBCL) and Burkitt Lymphoma (BL): A Comparison With BL Patients Treated With The Same Protocol In The Pethema-Burkimab-04 Trial

▪B-UCL is a new category of lymphomas that comprises a heterogeneous group of tumors from a morphological, phenotypic and genetic perspective with features intermediate between DLBCL and BL. This entity has been included as a new category in the 2008 World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues. The outcome of patients with B-UCL is generally considered very poor. However, the number of series analyzing the prognosis of B-UCL is scarce and they include small number of patients not homogeneously treated. Against this background, herein we present a series of patients diagnosed with B-UCL (WHO 2008) or Burkitt-like variant (WHO 2001) homogeneously treated according to the PETHEMA-Burkimab-04 trial. This trial was designed for the treatment of BL, including both HIV positive and negative patients. Patients with B-UCL were allowed to be treated following the same protocol and were considered separately. The main clinical characteristics and outcome were compared to those obtained from classical BL patients in the same trial (Ribera et al. Cancer 2013).Diagnosis of B-UCL was made in each center based on morphological, phenotypic and genetic characteristics and centrally reviewed by two pathologists. Patients received 6 courses of chemotherapy including continuous methotrexate infusion, cytarabine, vincristine and dexametasone among other drugs. A single dose of rituximab (375mg/m2) before each cycle was administered. Patients with non-bulky stage I-II disease received only 4 courses of treatment, whereas patients with advanced stage (II bulky-IV) received 2 additional doses of rituximab at the end of the chemotherapy.A total of 30 patients with B-UCL were included and were compared with the 118 patients with BL. Median follow-up for survivors was 24 months (range 3-93). Considering B-UCL, 8 (27%) patients were HIV positive and 10 (33%) had an ECOG performance status ≥ 2. Four (13%) and 6 (20%) patients had CNS involvement and bulky (>10 cm) disease, respectively. Serum LDH level was > UNL in 25 (83%) patients. These and other clinical characteristics were similar between patients with B-UCL and BL, except for the median age at diagnosis (57 years in B-UCL vs. 44 years in BL, p=0.001). In B-UCL patients, death during induction occurred in 5 patients (17%) and 2 patients experienced treatment failure. Twenty-three (77%) patients achieved complete remission. Relapse after CR and death in remission were observed in one patient, each. All these outcomes were comparable with BL patients except for a trend to a higher risk of death during induction in patients with B-UCL (17% in B-UCL, vs. 8% in BL, p= 0.1). A total of 104 consolidation cycles were evaluable for patients with B-UCL. Most frequent grade 3-4 toxicities were neutropenia (n=57, 54%), thrombocytopenia (n=44, 42%) and infection (n=21, 20%). Grade 3-4 gastrointestinal, renal and hepatic toxicities were seen in <5% of the cycles.Overall survival at 2 years for patients with B-UCL and BL was 68% (95% CI 59-77) vs. 78% (95% CI 74-82), p=0.2, respectively. Probability of disease-free survival from CR1 for B-UCL and BL patients was 84% (95% CI 76-92) vs. 80% (95% CI 69-91), p=0.6. In conclusion, the Burkitt-type chemotherapy included in the PETHEMA-Burkimab-04 trial was able to achieve an important number of complete and durable responses in patients with B-UCL with an acceptable toxicity. As a consequence, the outcome of patients with B-UCL treated with this intensive immunochemotherapy seems similar to that obtained in the treatment of classical BL. [Display omitted] Table 1Baseline characteristics of all patients according to definitive diagnosis.CharacteristicsBurkitt (n = 118)LDCG-B/Burkitt (n=30)pGender, male n (%)85 (72)21 (70)0.8Age, median [min -max]44 [15 - 83]57 [16-77]0.001Stage, n (%)Non bulky I – II26 (22)10 (33)0.8II (bulky), III - IV92 (78)20 (67)ECOG ≥2, n (%)55 (47)10 (33)0.3HIV infection39 (33)8 (27)0.4Extranodal involvement (≥2 sites), n (%)55 (47)11 (37)0.5CNS involvement, n (%)14 (12)4 (13)0.6Bulky disease, n (%)31 (26)6 (20)0.3LDH level above normal, n (%)106 (90)25 (83)0.5Age-adjusted IPI, n (%)Low6/116 (5)2 (7)1Low-intermediate17/116 (15)6 (20)Intermediate-high46/116 (40)11 (37)High47/116 (40)11 (37)Follow-up [all patients] (months)19 (0-92)16 (0-93)0.9 Disclosures:No relevant conflicts of interest to declare.

Rapid clearance of rituximab may contribute to the continued high incidence of autoimmune hematologic complications of chemoimmunotherapy for chronic lymphocytic leukemia

Rituximab is an effective treatment for autoimmune cytopenias associated with chronic lymphocytic leukemia. Despite the incorporation of rituximab into fludarabine-based chemotherapy regimens, the incidence of autoimmune cytopenias has remained high. Inadequate rituximab exposure due to rapid antibody clearance may be a contributing factor. To test this hypothesis, we measured serum rituximab levels in patients treated with fludarabine and rituximab (375 mg/m(2)). All patients had undetectable rituximab trough levels by the end of cycle 1, and one-third had undetectable levels already on Day 6 of cycle 1. Although rituximab trough levels increased progressively with each cycle, only by cycle 4 did the median trough level exceed 10 ug/mL. The median half-life of rituximab during cycle 1 was 27 hours, compared to 199 hours during cycle 4 (P<0.0001). There was a significant inverse correlation between the rituximab half-life in cycle 1 and the degree of tumor burden (P=0.02). Two patients who were identified as having subclinical autoimmune hemolysis prior to therapy were given additional doses of rituximab during the initial cycles of therapy and did not develop clinically significant hemolysis. One patient who developed clinically significant hemolysis during therapy was given additional rituximab doses during cycles 3-5 and was able to successfully complete his treatment. In conclusion, rituximab is cleared so rapidly during the initial cycles of therapy for chronic lymphocytic leukemia that most patients have only transient serum levels. More frequent dosing of rituximab may be required to prevent autoimmune complications in at-risk patients (clinicaltrials.gov identifier:00001586).

Outcomes Continue to Be Favorable for De Novo Philadelphia Chromosome Negative B-Lymphoblastic Leukemia (ALL) After Therapy with Hyper-CVAD (with or without Rituximab) Regimen

AbstractAbstract ▪3572▪This icon denotes a clinically relevant abstractThe hyper-CVAD regimen [Kantarjian, JCO 18: 547, 2000; Kantarjian, Cancer 101: 2788, 2004] includes intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternating with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted by early and late intensifications. The regimen was modified in 1999 to include use of laminar air flow rooms during the induction phase for patients (pts) aged 60 years or older. Therapeutic modifications included rituximab 375 mg/m2 (Days 1 & 11 of hyper-CVAD, Days 1 & 8 of MTX-cytarabine for 8 total doses) for CD20 expression > 20% to counteract increased propensity for relapse [Thomas D, Blood 113: 6330, 2009], early anthracycline intensification with liposomal daunorubicin-cytarabine from 1999–2000 only [omitted thereafter owing to lack of benefit, Thomas D, Cancer 116: 4580, 2010], augmentation of CNS prophylaxis, and extension of maintenance POMP therapy from 24 to 30 months with additional early and late intensifications [details in Thomas D, JCO 28: 3830, 2010]. Overall, 216 pts with Ph negative B-lymphoblastic leukemia have been treated with the modified hyper-CVAD regimens. Median age was 46 years (range, 16–84). For the CD20 positive B-lymphoblastic subset treated with hyper-CVAD and rituximab 3-yr rates of CR duration (CRD) and survival (OS) were 66% and 57%. In the younger (age < 60 years) CD20-positive subset, rates of CRD and OS were superior compared with standard hyper-CVAD (69% v 38%; P <.001% and 71% v 47%, P =.003). Historical experience in 37 adolescent and young adult (AYA) subset aged 15 – 30 yrs with CD20 positive B-lymphoblastic leukemia (prior to shift to augmented BFM regimen as first line therapy) showed that the addition of rituximab improved 3-yr CRD rates from 26% to 60% (P =.001) and 3-yr OS rates from 47% to 70% (P =.05) compared with standard hyper-CVAD without rituximab. There were no significant differences in outcome for this AYA subset by regimen (standard or modified) for the CD20 negative groups (all 3-yr rates > 70%). Elderly pts aged 60 year or older with CD20 positive B-lymphoblastic leukemia treated with hyper-CVAD and rituximab, in contrast to the Burkitt experience, had outcomes which were similar to the historical experience with standard hyper-CVAD (rates of CRD 59% v 50%, P = NS and OS 23% v 32%, P = NS, respectively), despite high rates of negativity for minimal residual disease (MRD) by multiparameter flow cytometry (MFC) at CR, related mainly to deaths in CR during consolidation. MRD positivity by MFC after induction therapy with hyper-CVAD and rituximab was associated with a higher relapse rate and lower 3-yr CR duration rates compared with MRD negative status at the time of CR. Additional doses of rituximab were added to consolidation (Day 1 of cycles 5 – 8) and maintenance chemotherapy in order to potentially improve outcomes for the MRD positive subset. Upfront dose reductions of cyclophosphamide, doxorubicin, vincristine, dexamethasone and methotrexate have been implemented for all cycles of induction-consolidation phase for older age and/or poor performance status with reduction in rate of deaths in CR noted. Incorporation of pegylated asparginase (one dose of 2000 Units/m2 with capping per cycle, 1000 Units/m2 if older or poor performance status) during the induction-consolidation phase (“augmented hyper-CVAD”) was piloted as first line therapy in 19 pts aged 30 – 59 years of age, then omitted owing to excessive toxicity. Incorporation of rituximab into first line intensive chemotherapy such as the hyper-CVAD regimen appears beneficial for younger pts, prompting investigation of second generation anti-CD20 monoclonal antibodies such as ofatumumab and hyper-CVAD (regardless of CD20 expression owing to data showing upregulation of CD20 expression) for the younger subsets and inotuzumab (with or without rituximab) and “mini-hyper-CVAD” for the elderly group. Multivariate analysis of outcomes by risk groups (age/MRD status/CD20 expression) and the impact of the early/late intensifications during maintenance chemotherapy will be presented. Disclosures:O'Brien:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Rituximab +/− Bevacizumab for Patients with Previously Treated Follicular Non-Hodgkins Lymphoma: A Randomized Phase II Trial of the Sarah Cannon Research Institute.

AbstractAbstract 2749 Background:Single-agent rituximab produces an overall response rate of approximately 50% and a median PFS of 9 months in patients with previously treated follicular NHL. Since resistance to rituximab eventually develops in nearly all patients, a number of novel agents are currently being evaluated in combination with rituximab to improve treatment efficacy. Vascular endothelial growth factor (VEGF) promotes angiogenesis and is increased in many tumor types. In NHL, high levels of VEGF are correlated with disease progression. Bevacizumab, a monoclonal antibody inhibiting VEGF, has extended PFS in several solid tumor types when added to combination chemotherapy. In this randomized phase II trial, we compared the efficacy and toxicity of bevacizumab + rituximab versus single-agent rituximab, in patients with previously treated follicular NHL. Methods:Eligible patients had follicular NHL (grade 1 or 2); NHL progression after either 1 or 2 prior chemotherapy regimens; measurable or evaluable disease; and ECOG PS 0–2. Prior rituximab treatment was allowed as long as progression occurred > 6 months following completion of treatment. Patients were randomized to receive single-agent rituximab (Regimen A) or rituximab plus bevacizumab (Regimen B). All patients received 375 mg/m2IV of rituximab weekly for 4 weeks. Regimen B patients also received bevacizumab 10 mg/kg IV on days 3 and 15 during the 4-week course of rituximab. Response evaluations were performed at weeks 6 and 12 as well as 4 weeks after the completion of all therapy. Patients with objective response or stable disease at week 12 received 4 additional doses of rituximab administered at months 3 (week 12), 5, 7, and 9; in addition, regimen B patients received bevacizumab 10 mg/kg IV every 2 weeks for a total of 16 doses (also beginning week 12). Addition of bevacizumab was hypothesized to improve the median PFS from 15 months to 20 months. Accrual of 90 patients (45/arm) was initially planned; the study was stopped early due to slow accrual. Results:Between 8/2005 and 3/2012, 60 patients were enrolled (Regimen A, 30; Regimen B, 29). Key clinical characteristics including age, performance status, FLIPI score, and previous treatment were comparable in the 2 treatment groups. 95% of patients had received 2 previous regimens, and 78% had received previous rituximab. After a median followup of 36 months, 92% of patients have either completed (40%) or discontinued treatment (lymphoma progression 30%, toxicity 12%, patient/physician decision 8%). The overall response rates were 42% in Regimen A (CR rate 10%) and 45% in Regimen B (CR rate 17%). The median progression-free survivals for Regimens A and B were 10.4 and 18.4 months, respectively (HR 0.33, p=0.0090). Median OS has not been reached for either group; at 3 years, the estimated OS rates are 54% (Regimen A) and 81% (Regimen B) (p=0.12). Grade 3/4 hematologic toxicity was uncommon, with no grade 4 neutropenia or thrombycytopenia, and 1 episode of febrile neutropenia (Regimen B). No grade 4 non-hematologic toxicity occurred; grade 3 non-hematologic toxicity occurred in 3 patients (10%) on Regimen A (infusion reaction 1, hyperglycemia 1, pneumonia 1) and 7 patients (24%) on Regimen B (hypertension 3, epistaxis 1, abdominal wall hematoma 1, wound dehiscence 1, confusion 1). All 7 patients who discontinued treatment due to toxicity (3 during the first 12 weeks) were on regimen B; 5 had bevacizumab-related toxicity. There were no treatment-related deaths. Conclusion:The addition of bevacizumab to rituximab was feasible with a modest increase in toxicity in this group of patients with previously-treated follicular NHL. The toxicities observed were consistent with the known profiles of each agent. While response rates were similar between regimens, the addition of bevacizumab lengthened the progression-free survival when compared to rituximab alone (median 18.4 vs. 10.4 months). Although results of this study must be interpreted with caution due to its small size, further study of VEGF- targeted therapies in NHL may be warranted. Disclosures:Off Label Use: Off-label bevacizumab use for treatment of follicular non-Hodgkin's lymphoma. Reeves:Celgene: Equity Ownership.