CD20-positive B-cell non-Hodgkin Lymphoma Research Articles

Abstract CT173: Preliminary results from a phase I study of IMM0306 in patients with relapsed or refractory CD20-positive B-cell non-Hodgkin's lymphoma

Abstract Background: IMM0306 is a fusion protein of CD20 monoclonal antibody with the CD47 binding domain of SIRPα on both heavy chains. It exerts excellent cancer killing efficacy by activating both macrophages and NK cells via blockade of CD47-SIRPα interaction and FcɣR engagement. Here, we report the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy results of phase I in patients (pts) with relapsed or refractory (R/R) CD20-positive B-cell non-Hodgkin's lymphoma (B-NHL). Methods: Eligible pts with R/R CD20-positive B-NHL were enrolled in this open-label, multicenter phase I/II study (NCT05805943). IMM0306 was administered as monotherapy at escalating doses of 0.04, 0.1, 0.25, 0.5, 0.8, 1.2, 1.6, 2.0 mg/kg intravenously once a week after a 2-week single-dose observation period, until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated in the first 28 days. Safety was evaluated per CTCAE 5.0, PK and PD analysis were also assessed, tumor assessments performed once every 8 weeks by Lugano 2014. Results: As of Nov 21, 2023, 48 pts were enrolled. The median age was 56 years with 30 (62.5%) males. The median prior lines of therapy was 2. All pts received previous anti-CD20 therapy. No DLTs were observed. Recommended phase II dose (RP2D) was determined as 2.0 mg/kg. The most frequent treatment related adverse events (TRAEs) were WBC decreased (66.7%), anemia (64.6%), lymphocyte decreased (58.3%), ANC decreased (47.9%), PLT decreased (45.8%), infusion-related reactions (35.4%). Grade ≥3 TRAEs occurred in 33 (68.8%) pts, the most frequent grade ≥ 3 TRAEs were lymphocyte decreased (56.3%), WBC decreased (18.8%), ANC decreased (18.8%). Eight (16.7%) pts experienced treatment related serious adverse event, including PLT decreased, chest pain and pneumonia. Drug discontinuation due to AEs occurred in 1 pt (G4 PLT decreased occurred at 1.6mg/kg without any bleeding). No AE led to death. IMM0306 exhibited approximate dose-proportional increase in PK exposure from 0.5 to 2.0 mg/kg and no obvious accumulation was observed after repeated dosing. At 1.2 mg/kg, CD47 receptor occupancy on peripheral lymphocytes was saturated, suggesting IMM0306 is well tolerated from perspective of CD47 engagement in high dose cohorts. B-cell counts depleted rapidly at doses ≥ 0.8 mg/kg. Elevated cytokines levels were observed after first dosing of IMM0306, but multiple dosing did not stimulate further cytokine activation. Among 33 pts who received active doses ≥ 0.8 mg/kg, 5 CR (4 follicular lymphoma [FL], 1 marginal zone lymphoma [MZL]), 5 PR (3 FL, 1 MZL, 1 diffuse large B cell lymphoma) and 11 SD were seen. Among 17 FL pts, 7 (41%) responded including 4 CR and 3 PR; among 6 MZL pts, 2 (33.3%) responded including 1 CR and 1 PR. Conclusions: IMM0306 was well-tolerated and with a robust preliminary anti-tumor activity especially in pts with R/R FL and MZL. The phase II study is ongoing. Citation Format: Yuankai Shi, Jianliang Yang, Yongping Song, Keshu Zhou, Zhiming Li, Mingzhi Zhang, Hongmei Jing, Zhen Wang, Li Yu, Qiying Lu, Frank Gan, Wenzhi Tian. Preliminary results from a phase I study of IMM0306 in patients with relapsed or refractory CD20-positive B-cell non-Hodgkin's lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT173.

Bone Marrow Infiltration Is a Distinctive Risk Factor for Rituximab Infusion-Related Reactions in CD20-Positive B-Cell Non-Hodgkin Lymphoma.

Background Bone marrow infiltration of lymphoma cells is a candidate risk factor for infusion-related reactions (IRRs) in patients with CD20-positive B-cell non-Hodgkin lymphoma (B-NHL). However, despite with the lack of sufficient data, the effect of bone marrow infiltration of B-NHL cells on the incidence rate of grade 2 or higher IRRs with the administration of rituximab has been retrospectively studied in this paper. Methods Patients with CD20-positive B-NHL who received the rituximab induction therapy for the first time were enrolled in this study. To evaluate the bone marrow infiltration of B-NHL cells, May–Giemsa stain of bone marrow films and flow cytometry examination of bone marrow aspiration samples were performed. IRR grade was determined using the IRR criteria in the Common Terminology Criteria for Adverse Events version 4.0. Results A total of 127 patients were eligible for this study. Grade 2 or higher IRRs were observed in 43 (34%) patients. In univariate analysis, use of glucocorticoid before rituximab infusion was a strong risk-avoiding factor for grade 2 or higher IRRs. Advanced stage of disease (Ann Arbor: stages III and IV) or bone marrow infiltration of B-NHL cells revealed the risk factors, regardless of glucocorticoid premedication. Using multivariate analysis, bone marrow infiltration was found to be an independent risk factor for patients without prior glucocorticoid use. Conclusion Bone marrow infiltration of B-NHL cells is a risk factor for grade 2 or higher IRRs at the first rituximab induction therapy without glucocorticoid premedication.

A multi-center, open-label, randomized, parallel-controlled phase II study comparing pharmacokinetic, pharmacodynamics and safety of ripertamab (SCT400) to rituximab (MabThera®) in patients with CD20-positive B-cell non-Hodgkin lymphoma.

This multi-center, open-label, randomized, parallel-controlled phase II study aimed to compare the pharmacokinetics (PK), pharmacodynamics (PD) and safety profile of ripertamab (SCT400), a recombinant anti-CD20 monoclonal antibody, to rituximab (MabThera®) in patients with CD20-positive B-cell non-Hodgkin lymphoma (NHL). Patients with CD20-positive B-cell NHL who achieved complete remission or unconfirmed complete remission after standard treatment were randomly assigned at a 1:1 ratio to receive a single dose of ripertamab (375 mg/m2) or rituximab (MabThera®, 375 mg/m2). PK was evaluated using area under the concentration-time curve (AUC) from time 0 to d 85 (AUC0-85 d), AUC from time 0 to week 1 (AUC0-1 w), AUC from time 0 to week 2 (AUC0-2 w), AUC from time 0 to week 3 (AUC0-3 w), AUC from time 0 to week 8 (AUC0-8 w), maximum serum concentration (Cmax), terminal half-life (T1/2), time to maximum serum concentration (Tmax) and clearance (CL). Bioequivalence was confirmed if the 90% confidence interval (90% CI) of the geometric mean ratio of ripertamab/rituximab was within the pre-defined bioequivalence range of 80.0%-125.0%. PD, immunogenicity, and safety were also evaluated. From December 30, 2014 to November 24, 2015, a total of 84 patients were randomized (ripertamab, n=42; rituximab, n=42) and the PK analysis was performed on 76 patients (ripertamab, n=38; rituximab, n=38). The geometric mean ratios of ripertamab/rituximab for AUC0-85 d, AUC0-inf, and Cmax were 96.1% (90% CI: 87.6%-105.5%), 95.9% (90% CI: 86.5%-106.4%) and 97.4% (90% CI: 91.6%-103.6%), respectively. All PK parameters met the pre-defined bioequivalence range of 80.0%-125.0%. For PD and safety evaluation, there was no statistical difference in peripheral CD19-positive B-cell counts and CD20-positive B-cell counts at each visit, and no difference in the incidence of anti-drug antibodies was observed between the two groups. The incidences of treatment-emergent adverse events and treatment-related adverse events were also comparable between the two groups. In this study, the PK, PD, immunogenicity, and safety profile of ripertamab (SCT400) were similar to rituximab (MabThera®) in Chinese patients with CD20-positive B-cell NHL.

A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Multiple Intravenous Doses of IGN002 Administered Weekly to Subjects with Refractory Non-Hodgkin Lymphoma

Background:Non-Hodgkin lymphoma (NHL) is the most common, adult hematologic malignancy. Despite available treatment, relapse rates are high and novel therapies are warranted. IGN002 consists of an anti-CD20 monoclonal antibody (mAb) fused to interferon-alpha (IFNα) via a short peptide linker. The mAb portion of IGN002 is a chimeric IgG1 antibody with the same amino acid sequence as rituximab. The interferon amino acid sequence is human IFNα2b (hIFNα2b). In nonclinical pharmacology studies using CD20-positive human NHL cells, IGN002 demonstrates compelling anti-tumor effects. When compared to rituximab, IGN002 demonstrated enhanced complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) effector functions against CD20-positive NHL cells. Moreover, compared to rituximab against normal human primary B-cells, IGN002 displayed higher maximal and more potent ADCC activity. Finally, in xenograft studies with immunodeficient mice using 3 different human NHL cell lines comparing IGN002 to rituximab, IGN002 demonstrated superior median and overall survival in all 3 NHL xenograft tumor lines. Study Design and Methods :This open-label, non-randomized, first-in-human, dose finding Phase 1 study comprises a Dose-Escalation Stage and an Expansion Stage (NCT02519270). In the Dose-Escalation Stage, ascending dose cohorts will be treated in 2 periods until the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) is identified. In Period 1, subjects will receive 2 doses of IGN002 administered weekly. Subjects with no anti-drug antibodies to IGN002 at Week 6 in Period 1 will proceed to Period 2 and receive up to 24 additional doses of IGN002 administered weekly in three 8-week cycles, with no treatment-free interval. In the Expansion Stage, subjects will receive up to 24 doses of IGN002 at the MTD or RP2D administered weekly in three 8-week cycles, with no treatment-free interval. Cohorts 1-5 at dose level 0.1, 0.3, 1, 3, and 10 ug/kg, respectively, have been completed without any dose limiting toxicity (DLT) and enrollment for Cohorts 6-8 is impending. Clinical Endpoints:The primary outcome measures are the evaluation of safety and tolerability of multiple doses of IGN002 administered weekly as an IV infusion to subjects with refractory NHL and the determination of MTD or RP2D of IGN002. The secondary outcome measures include characterizing the pharmacokinetic profile of ascending doses of IGN002, the incidence of anti-IGN002 antibody formation, and assessment of anti-tumor activity (e.g., response rate, duration) of IGN002 using the Lugano Classification criteria for NHL. Eligibility Criteria:This study is enrolling patients > 18 years with an ECOG <2 who have a documented history of immunohistochemistry-confirmed CD20-positive B-cell NHL, including diffuse large B-cell, mantle cell, marginal zone, lymphoplasmacytic, follicular, transformed follicular, or primary mediastinal B-cell lymphoma that is refractory to at least 1 documented regimen containing rituximab or a similar anti-CD20 therapy. Patients must also have measurable disease and adequate organ function. The exclusionary criteria encompass treatment with an approved or investigational chemotherapy or anti-CD20 drug within 28 days of Day 1, treatment with an approved or investigational biologic drug that does not target CD20 within 90 days of Day 1, or radiation therapy within 4 weeks of Day 1. Statistical Methods:The sample size was not predicated on formal statistical considerations. Descriptive statistics will be used to summarize continuous variables. Dichotomous endpoints will be summarized using frequencies, proportions, and exact binomial 95% CI. For subjects treated at the MTD or RP2D in Period 2 of the Dose-Escalation Stage and the Expansion Stage, time-to-event variables will be summarized using the Kaplan-Meier method. Target Accrual:In the Dose-Escalation Stage and Expansion Stage, approximately 9-18 (~3-6 subjects per cohort) and 14 subjects, respectively, will be accrued. Enrollment for Cohort 6 is expected to commence in September 2020. Disclosures Mataveli: Spectrum Pharmaceuticals:Current Employment, Current equity holder in publicly-traded company.

ALX148, a CD47 Blocker, in Combination with Rituximab in Patients with Non-Hodgkin Lymphoma

Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host's immune response. The high affinity CD47 blocker fusion protein, ALX148, is linked to an inactive immunoglobulin Fc region to minimize toxicity. ALX148 is half the size of an antibody, has been well tolerated, and enhances the innate and adaptive immune response against cancer in combination with anticancer therapeutics across solid and hematologic tumors (ASCO 2020 #3056, EHA 2020 #EP1247). Characterization of ALX148's tolerability profile and antitumor activity in combination with rituximab are reported in patients (pts) with non-Hodgkin Lymphoma (NHL). Methods: Patients with relapsed or refractory CD20-positive B-cell NHL for which no curative therapy was available received ALX148 (10 mg/kg QW or 15 mg/kg QW) in combination with rituximab (375 mg/m2 weekly for 4 doses followed by once monthly for 8 doses). The primary endpoint for the safety population was dose limiting toxicity (DLT). Tumor response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed in all pts. Data are reported as of 30Jun2020 in these fully enrolled cohorts with final data to be updated at the time of presentation. Results: A total of 33 patients with NHL were administered ALX148 in combination with rituximab. Twenty-two pts with median age of 66 years (range 32-80) were administered ALX148, 10 mg/kg QW (ALX10), in combination with rituximab [DLBCL, n=11; mantle cell lymphoma (MCL), n=4; follicular lymphoma (FL), n=5; and marginal zone lymphoma (MZL), n=2]. Eleven pts with median age of 64 years (range 53-78) were administered ALX148, 15 mg/kg QW (ALX15), in combination with rituximab (DLBCL, n=6; MCL, n=1; FL, n=3; and MZL, n=1). There have been no DLTs reported in the fully enrolled safety cohorts, and the MTD of ALX148 in combination with rituximab has not been reached. The maximum ALX148 administered dose is 15 mg/kg QW. Twenty-eight pts experienced any AE, while 16 pts reported mostly low grade treatment-related adverse events (TRAE). The most common TRAEs were rash (21%, n=7), fatigue (9%, n=3), anemia, nausea, neutropenia, and pruritus (6%, n=2 each). With a median follow up of 14 months, objective responses were observed across all histologies in response-evaluable ALX10 pts: 40.9% ORR (4CR,5PR, 6SD, n=22 total) and with a median follow up of 9 months in ALX15 pts: 63.6% ORR (3CR, 4PR, 1SD, n=11 total). Preliminary results indicate favorable ALX148 PK and near complete CD47 receptor occupancy across the dosing interval. Final results will be updated at time of presentation. Conclusions: ALX148 demonstrates excellent tolerability with durable responses in combination with rituximab in patients with relapsed/refractory NHL. The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity and favorable PK/PD characteristics in combination with rituximab were observed at all dose levels with greater objective response rates reported at the MAD of 15 mg/kg QW. Disclosures Kim: Boryung: Consultancy; Voronoi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Takeda: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding; AstraZeneca: Consultancy. Lakhani:incyte: Research Funding; merck: Research Funding; mersana: Research Funding; northern biologics: Research Funding; odonate: Research Funding; pfizer: Research Funding; ikena: Research Funding; symphogen: Research Funding; taiRx: Research Funding; tesaro: Research Funding; livzon: Research Funding; loxo: Research Funding; macrogenics: Research Funding; inhibRx: Research Funding; cytomx: Research Funding; formation biologics: Research Funding; forty seven inc: Research Funding; alexion Pharmaceuticals: Research Funding; Alpine Biosciences: Research Funding; ALX Oncology Inc.: Research Funding; Apexian: Research Funding; asana biosciences: Research Funding; ascentage pharma: Research Funding; beigene: Research Funding; celgene: Research Funding; cerulean pharma: Research Funding; constellation pharma: Research Funding; coordination therapeutics: Research Funding; regeneron: Research Funding; sapience therapeutics: Research Funding; shattuck labs: Research Funding; innovent bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; jounce therapeutics: Research Funding. Gainor:theravance: Consultancy; adaptimmune: Research Funding; ariad: Research Funding; astrazeneka: Research Funding; blueprint medicines: Research Funding; lily: Consultancy; gilead sciences: Consultancy; merck: Consultancy, Research Funding; moderna therapeutics: Consultancy, Research Funding; tesaro: Research Funding; blueprint medicines: Consultancy; novartis: Research Funding; oncorus: Consultancy; regeneron: Consultancy; bristol-myers Squibb: Consultancy, Research Funding; amgen: Consultancy; array biopharma: Consultancy, Research Funding; agios: Consultancy; ironwood pharmaceuticals: Consultancy; takeda: Consultancy; genentech: Consultancy, Research Funding; jounce therapeutics: Consultancy, Research Funding. Kamdar:Roche: Research Funding. Fanning:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Squifflet:ALX Oncology Inc.: Consultancy; IDDI: Current Employment. Jin:ALX Oncology Inc.: Current Employment. Forgie:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company; Pfizer Inc.: Ended employment in the past 24 months. Wan:Tallac Therapeutics: Current Employment, Current equity holder in private company; ALX Oncology Inc.: Consultancy, Current equity holder in publicly-traded company. Pons:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Randolph:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Kim:F. Hoffmann-La Roche: Research Funding; Pfizer: Research Funding; JJ: Research Funding; Celltrion: Research Funding; Kyowa Kirn: Research Funding; Donga: Research Funding; Mundipharma: Research Funding.

A Phase 1 Study of ALX148, a CD47 Blocker, in Combination with Rituximab in Patients with Non-Hodgkin Lymphoma

Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host's immune response. ALX148 is a fusion protein comprised of a high affinity CD47 blocker linked to an inactive human immunoglobulin Fc region. In combination with anti-tumor antibodies, ALX148 enhances the innate and adaptive immune response against cancer. ALX148 has previously been shown to be well tolerated both as a single agent and in combination with pembrolizumab or trastuzumab in a range of solid tumors with no maximum tolerated dose (MTD) identified (SITC 2018 #P335, ASCO 2019 #2514). Characterization of ALX148's safety profile and antitumor activity in combination with rituximab are reported in patients (pts) with both aggressive and indolent histologies of non-Hodgkin Lymphoma (NHL). Methods: Patients with relapsed or refractory CD20-positive B-cell NHL for which no curative therapy was available received ALX148 (10 mg/kg QW) in combination with rituximab (375 mg/m2 weekly for 4 doses followed by once monthly for 8 doses). The primary endpoint for the safety confirmation population was first cycle dose limiting toxicity (DLT). Tumor response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed in all pts. Preliminary clinical data from the fully enrolled cohort is reported as of July 15, 2019. Results: Twenty pts (15 males, 5 females) with NHL were administered ALX148 in combination with rituximab (DLBCL, n=11; mantle cell lymphoma, n=4; follicular lymphoma, n=3; and marginal zone lymphoma, n=2). The pts median age was 66 years (range 32-80) and ECOG PS 0/1 was 7/13. Patients had a median of 3 prior lines of therapy (range 1-7) with 50% having rituximab-refractory tumors. There were no dose limiting toxicities reported and the MTD of ALX148 in combination with rituximab was not reached. The maximum administered dose was 10 mg/kg QW. Sixteen pts experienced any AE, while 11 pts reported mostly low grade treatment-related adverse events (TRAE). The most common TRAEs were rash (20%, n=4); anemia, fatigue, nausea, neutropenia and decreased platelets (10%, n=2 each). One TRAE ≥ G3 of neutropenia occurred in more than 1 patient (1G3, 1G4). As of the data cut off with a median follow-up time of 3 (0.3-14) months, preliminary tumor response was assessed in 17 evaluable pts using the Lugano Classification, 2014. The ORR was 35% across all tumor histologies, with a 50% ORR reported in indolent (FL+MZL), and 31% ORR reported in aggressive (DLBCL+MCL) histologies. The overall DCR was 41%. Six pts achieved partial response [(2) follicular, (2) DLBCL, (2) mantle cell]. Four pts achieved SD [(1) each of follicular, marginal zone, DLBCL(>1yr), and mantle cell]. Preliminary results indicate favorable ALX148 PK and near complete CD47 receptor occupancy across the dosing interval. Results will be updated at time of presentation. Conclusions: ALX148 demonstrates excellent tolerability with favorable PK/PD characteristics in combination with rituximab in patients with relapsed/refractory NHL. The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity in combination with rituximab was observed with objective responses reported in heavily pretreated and rituximab-refractory patients. Clinical trial information: NCT03013218 Disclosures Kim: AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Bayer: Consultancy; Takeda: Consultancy. Lakhani:ALX Oncology Inc.: Research Funding; Ascentage Pharma: Research Funding; Asana Biosciences: Research Funding; BeiGene: Research Funding; Constellation Pharmaceuticals: Research Funding; Alexion Pharma: Research Funding; Cerulean Pharma: Research Funding; Forty Seven: Research Funding; Loxo: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; TaiRx: Research Funding; Apexian: Research Funding; Formation Biologics: Research Funding; Coordination Therapeutics: Research Funding; Symphogen: Research Funding; CytomX: Research Funding; InhbRx: Research Funding; Incyte: Research Funding; Jounce Therapeutics: Research Funding; Livzon: Research Funding; Northern Biologics: Research Funding; Tesaro: Research Funding; Innovent Biologics: Research Funding. Gainor:BMS: Research Funding; Genentech/Roche: Other: grant; Takeda: Other: grant, personal fees; Blueprint: Research Funding; Loxo: Research Funding; Oncorus: Other: grant , personal fees; Regeneron: Other: grant,personal fees; Pfizer: Other: grant personal fees; Incyte: Other: grant personal fees; Novartis: Other: grant, personal fees; Merck: Other: grant personal fees; Agios: Other: personal fees; Amgen: Other: personal fees; Array: Research Funding; Tesaro: Research Funding; Moderna: Other: grant; Adaptimmune: Other: grant; ALX Oncology: Other: grant; Ironwood Pharma: Equity Ownership. Kamdar:AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Seattle Genetics: Speakers Bureau. Fanning:ALX Oncology Inc: Employment, Equity Ownership. Squifflet:IDDI: Employment; ALX Oncology Inc: Consultancy. Jin:ALX Oncology Inc.: Consultancy. Wan:ALX Oncology Inc.: Employment, Equity Ownership. Pons:ALX Oncology Inc.: Employment, Equity Ownership; venBio: Employment, Membership on an entity's Board of Directors or advisory committees. Randolph:ALX Oncology Inc: Employment, Equity Ownership; venVio: Consultancy; Carrick: Equity Ownership. Kim:Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding.

Safety and Tolerability of Obinutuzumab (GA101) with Shorter Duration of Infusion in Japanese Patients with Previously Untreated CD20-Positive B-Cell Non-Hodgkin's Lymphoma (NHL)-Comparison with GAO4915g (GATHER) and BO21005 (GOYA) Studies

BackgroundObinutuzumab (GA101) is a novel humanized, glycoengineered Type II anti-CD20 monoclonal antibody. It has greater direct cell death induction and antibody-dependent cell-mediated cytotoxicity and lower complement-dependent cytotoxicity than Type I anti-CD20 antibody rituximab. Studies of obinutuzumab in patients (pts) with previously untreated or relapsed/refractory NHL demonstrated clinical activity with an acceptable safety profile. Infusion-related reactions (IRRs) were the most common adverse event, typically associated with the first infusion. Obinutuzumab 1000 mg is being administered over 4 hrs 15 min for the first infusion on Cycle 1 Day 1, and over 3 hrs 15 min for subsequent infusions. Shortening administration times can result in greater patient convenience and more efficient use of infusion facilities. To evaluate the tolerability of a Shorter Duration of Infusion (SDI), we conducted a Phase II study (JO29737, JapicCTI-152848, 'GATS') of G-CHOP (obinutuzumab in combination with CHOP [cyclophosphamide, doxorubicin, vincristine, prednisolone]) in Japanese pts with previously untreated CD20-positive B-cell NHL.MethodsThis study included adult pts with previously untreated CD20-positive B-cell NHL. Treatment consisted of 8 cycles of obinutuzumab (1000 mg intravenously on Day 1 of each 21-day cycle, with additional doses on Days 8 and 15 of Cycle 1) plus standard CHOP on Day 1 of Cycles 1-6. Obinutuzumab SDI is administered over 1 hr 30 min. Obinutuzumab was administered as an SDI from Cycle 2 to pts who met the following criteria: (1) No ≥ Gr 3 IRR related to obinutuzumab during regular infusions (RI) in Cycle 1, and (2) Lymphocyte count ≤ 5000/µL in peripheral blood prior to SDI. Primary endpoints were tolerability of SDI, pharmacokinetics (PK) of obinutuzumab. Tolerability of SDI was assessed by incidence of ≥ Gr 3 IRR in Cycle 2. Secondary endpoints were overall safety profile and efficacy. IRRs were defined as AEs related to obinutuzumab occurring during infusion or within 24 hrs from the end of infusion. Results were compared to the multicenter, open-label, randomized GOYA study (phase III, RI G-CHOP), and the multicenter, open-label, single-arm GATHER study (phase II, SDI G-CHOP). The GOYA study included 111 Japanese pts.ResultsAt database lock date, 35 pts were enrolled and treated, including 19 diffuse large B-cell lymphoma, 13 follicular lymphoma, and 3 other histologies; median age was 66 yrs (range, 35-78); 12/35 female; Ann Arbor stage I 11.4%, II 25.7%, III 20.0%, IV 42.9%; 7/35 positive bone marrow involvement. In 7 pts, treatment was prematurely discontinued due to AE (n=3; infected dermal cyst, bronchiolitis, and pneumonia aspiration, 1 pt each), progressive disease (n=2), or physician’s decision (n=2). Thirty-three pts received at least one SDI of obinutuzumab, given in Cycle 2 and subsequent cycles in 31 pts. Overall, 48.6% of pts (17/35) experienced IRRs. They were Gr 1/2 in all cases and occurred most commonly on Day 1 Cycle 1 (RI). No SDI-associated IRR was observed in Cycle 2, and very rare cases (2 pts) were noted in Cycles 6, 7, and 8. IRRs occurring in ≥5% pts were pyrexia (25.7%), chills (8.6%), and nausea, blood pressure increased, and headache (5.7%). Gr ≥3 AEs observed in ≥10% of pts were neutropenia (40.0%), neutrophil count decreased (25.7%), febrile neutropenia (17.1%), and leukopenia (14.3%). Obinutuzumab concentration just after Cycle 2 SDI was the same level as the concentration in Cycle 8. This shows PK reached a steady state at Cycle 2 and was not affected by shortening of administration. From PK analysis in the GATS study, AUC7day was 4170±885 µg·day/mL and t1/2 was 15.4±7.0 day, similar to the GATHER values (AUC7day, 3300±1130 µg·day/mL; t1/2, 23.0±15.9 day) after considering individual variability. No ethnic difference was observed. Overall response rate was 82.9% (29/35) (CR 62.9% [22/35], PR 20.0% [7/35]); 2 pts were not evaluable for response.ConclusionsObinutuzumab can be safely administered as SDI. No SDI-associated IRR was observed in Cycle 2. A few IRRs were observed with SDI in later cycles, but all were tolerable and manageable. RI and SDI have comparable safety, PK, and efficacy profiles in Japanese and non-Japanese. DisclosuresHatake:Meiji-Seika: Consultancy; Kyowa Kirin: Honoraria, Research Funding; Otsuka: Consultancy; Chugai: Research Funding. Izutsu:Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding. Kinoshita:Janssen: Honoraria; Solasia: Research Funding; Eisai: Honoraria, Research Funding; Ono: Research Funding; Gilead: Research Funding; Kyowa Kirin: Honoraria; Zenyaku: Honoraria, Research Funding; Takeda: Research Funding; Chugai: Honoraria, Research Funding. Tobinai:Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; HUYA Bioscience: Honoraria; Chugai Pharma: Research Funding; Eisai: Honoraria, Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy; Celgene: Research Funding; GlaxoSmithKline: Research Funding; Zenyaku Kogyo: Honoraria; SERVIER: Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Research Funding; Mundipharma KK: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding.

Risk of Reverse Seroconversion of Hepatitis B Virus Surface Antigen in Rituximab-Treated Non-Hodgkin Lymphoma Patients

Rituximab causes hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-seronegative patients with CD20-positive B-cell non-Hodgkin lymphoma (CD20+ NHL), especially for those seropositive to the antibody of core antigen (anti-HBc). Clinical hepatitis usually develops after reverse seroconversion of HBsAg (HBV-RS), indicated by the reappearance of HBsAg in serum. Because of the relatively high prevalence of anti-HBc seropositivity in unvaccinated HBsAg-seronegative adults in an HBV hyperendemic area, we aimed to investigate additional factors influencing the development of rituximab-associated HBV-RS.Between January 2000 and December 2010, unvaccinated HBsAg-seronegative adults with CD20+ NHL who had received rituximab-containing therapy but not anti-HBV agents were enrolled. Patients with and without HBV-RS were compared in terms of clinical factors and treatments including the number of cycles of rituximab therapy, and transplantation. Competing risk regression was used to identify the factors associated with HBV-RS.For the 482 patients enrolled, the serological status of anti-HBc was available in 75.9%, with a seropositivity rate of 86.6%. At the last follow-up, a total of 33 (6.85%) patients had HBV-RS, with 95.8% anti-HBc seropositive, 78.9% anti-HBs seropositive, and none anti-HCV seropositive. HBV-RS patients have received more cycles (≥6) and prolonged durations of rituximab therapy, and hematopoietic stem cell transplantation. The overall survival was not different between patients with and those without HBV-RS. At the time of HBV-RS, a total of 25 (78.1%) patients had hepatitis flare, especially when HBV-RS appeared during/after induction therapy (100%, 10 of 10). Three (9.1%) patients had fulminant hepatitis, resulting in death in 1 (3%) patient. A higher rituximab cycle intensity was associated with a higher rate of hepatitis flare at the time of HBV-RS. When death in the absence of HBV-RS was considered as the competing risk, the univariate and multivariate regression analyses showed that several factors were independently associated with the development of HBV-RS, including anti-HCV seronegativity, histological subtype of posttransplant lymphoproliferative disorders, ≥6 cycles of rituximab therapy, and succeeding hematopoietic stem cell transplantation.The findings of our study identify additional factors influencing the development of rituximab-associated HBV-RS in HBsAg-seronegative adults with CD20+ NHL.

Biomarker Analysis in a Phase Ib Study Combining Ibrutinib with R-CHOP in Patients with CD20-Positive B-Cell Non-Hodgkin Lymphoma (NHL)

IntroductionThe primary objective of the DBL1002 study was to determine the recommended phase 2 dose and assess dose limiting toxicities of ibrutinib in combination with R-CHOP in subjects with CD20-positive B-cell NHL (diffuse large B-cell lymphoma [DLBCL], mantle cell lymphoma [MCL], and follicular lymphoma [FL]). Secondary objectives included assessment of pharmacodynamic markers of ibrutinib in peripheral blood mononuclear cells, as well as identification of biomarkers predictive of response to the combination regimen.The clinical study is described in detail elsewhere (Younes, et al. 2013, 2014). Briefly, 33 subjects were enrolled in the study, of which 29 completed 6 cycles. The ibrutinib + R-CHOP combination demonstrated clinical activity across all dose cohorts in the all treated population (all subjects were treatment-naïve DLBCL, MCL, and FL) with an ORR of 90.9%. This abstract presents the results from evaluation of subject samples with SomaLogic SOMAscan proteomic analysis, flow cytometry (phospho-flow and immunotyping), Foundation Medicine (FM) sequencing, and gene expression profiling. Patients’ plasma samples were evaluated with SomaLogic SOMAscan to measure secreted levels of 1124 protein markers at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 (C4D1). As a part of pharmacodynamics biomarker assessment, PBMCs were evaluated at cycle 1 day 1 (C1D1), cycle 1 day 3 (C1D3), C2D1, C4D1, and end of treatment (EOT) time points by flow cytometry for cell surface markers and phosphorylated kinases in the BCR pathway. The primary tumor samples were evaluated by FM sequencing and gene expression profiling. Some subjects did not have sufficient tumor biopsies (bone marrow or lymph node) available, therefore a subset of PBMC samples enriched for CD19+ cells from time points C1D1 (N = 9) or C1D3 (N = 4) or C2D1 (N = 2) or EOT (N = 3) were used for sequencing.The overall response rate in evaluable DLBCL patients was 100%. In 13 patients whose lymphoma’s subtype for cell-of-origin was determined by the Hans method of immunohistochemistry at the central laboratory, 2 of the GCB sub-type were not evaluated for post baseline assessment (both subjects prematurely discontinued: 1 due to non-compliance and 1 due to rituximab infusion reaction prior to exposure of ibrutinib). Of the 11 evaluable subjects, 4/4 subjects with non-GCB DLBCL achieved CR (for CR rate of 100%), 5/7 subjects with GCB-DLBCL achieved CR (for CR rate of 71.4%), and 2/7 with GCB-DLBCL achieved PR for CR rate of 81.8% (9/11). Differential expression of proteins revealed that Aurora kinase B and HCK were overexpressed at baseline in GCB subjects, whereas peroxiredoxin-1 and interferon gamma were among those significantly overexpressed in the non-GCB subjects. After one cycle of therapy across all patients, matrilysin and WNT7A were decreased while IL-12 and macrophage colony stimulating factor-1 were increased. Phospho-flow analysis of BCR signaling pathways (p-BTK, p-PLCγ2, p-ZAP70/SYK, p-NFκB, p-AKT, and p-ERK1/2) in CD19+ B-cells revealed that these pathways were active in all treated DLBCL patients. No major changes were seen with treatment in the levels of cell surface proteins analyzed, including CD38 and CD79b. Baseline sequencing data showed that variants in MLL2, CREBBP, BCL2, TNFRSF14, and MYC were observed, consistent with recent reports in DLBCL. Mutational analyses correlating to response cannot be made at this time as the response rate among DLBCL patients was 100% and only one patient had progressive disease at the last data cutoff.In conclusion, ibrutinib once daily in combination with R-CHOP is active in treatment-naïve subjects with NHL, with an ORR of 100% in DLBCL patients at the recommended dose. Biomarker analyses showed that the BCR signaling pathway was active at baseline in these patients, and revealed differential protein expression patterns between GCB and non-GCB patients. Sequence variants were noted which are consistent with recent reports in DLBCL. DisclosuresChaturvedi:Janssen R&D: Employment. Schaffer:Janssen R & D: Employment. Davis:Janssen R & D: Employment. Aquino:Janssen R & D: Employment. Stepanchick:Janssen R & D: Employment. Oki:Janssen R & D: Research Funding. Fourneau:Janssen R & D: Employment. Younes:Novartis, Janssen, Curis: Research Funding; Bayer, Bristol Meyer Squibb, Celgene, Incyte, Janssen R&D, Sanofi, Seattle Genetics, Takeda Millenium: Honoraria. Balasubramanian:Janssen R & D: Employment; Janssen R & D: Equity Ownership.

Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study

Present first-line therapy for diffuse large B-cell lymphoma, a subtype of non-Hodgkin lymphoma, is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Ibrutinib, a novel oral Bruton's tyrosine kinase inhibitor, has shown single-drug activity in relapsed or refractory B-cell malignancies. We investigated the safety and efficacy of ibrutinib in combination with R-CHOP for patients with previously untreated CD20-positive B-cell non-Hodgkin lymphoma. In this phase 1b, open-label, non-randomised study, patients were recruited across six centres in the USA and France. Eligibility was age 18 years or older and treatment-naive histopathologically confirmed CD20-positive B-cell non-Hodgkin lymphoma. In the dose-escalation phase (part 1), patients with diffuse large B-cell lymphoma, mantle-cell lymphoma, or follicular lymphoma were enrolled. The primary objective was to determine a recommended phase 2 dose of ibrutinib with a standard R-CHOP regimen, by assessing safety in all patients who received treatment. Patients received ibrutinib 280 mg, 420 mg, or 560 mg per day in combination with a standard R-CHOP regimen every 21 days. Safety of the recommended phase 2 dose was then assessed in a dose-expansion population, which consisted of patients with newly diagnosed diffuse large B-cell lymphoma (part 2). Secondary objectives included assessments of the proportion of patients who had an overall response, pharmacokinetics, and pharmacodynamics. This trial is registered with ClinicalTrials.gov, number NCT01569750. From June 22, 2012, to March 25, 2013, 33 patients were enrolled (part 1: 17; part 2: 16) and 32 received ibrutinib plus R-CHOP treatment (one patient in the part 2 cohort withdrew). The maximum tolerated dose was not reached and the recommended phase 2 dose for ibrutinib was 560 mg per day. The most common grade 3 or greater adverse events included neutropenia (73% [24 of 33 patients]), thrombocytopenia (21% [seven patients]), and febrile neutropenia and anaemia (18% each [six patients]). The most frequently reported serious adverse events were febrile neutropenia (18% [six patients]) and hypotension (6% [two patients]). 30 (94%) of 32 patients who received one or more doses of combination treatment achieved an overall response. All 18 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose had an overall response. For those subtyped and treated at the recommended phase 2 dose, five (71%) of seven patients with the germinal centre B-cell-like subtype and two (100%) patients with the non-germinal centre B-cell-like subtype had a complete response. R-CHOP did not affect pharmacokinetics of ibrutinib, and ibrutinib did not alter the pharmacokinetics of vincristine. Pharmacodynamic data showed Bruton's tyrosine kinase was fully occupied (>90% occupancy) at the recommended phase 2 dose. Ibrutinib is well tolerated when added to R-CHOP, and could improve responses in patients with B-cell non-Hodgkin lymphoma, but our findings need confirmation in a phase 3 trial. Janssen.

The risk of infections in hematologic patients treated with rituximab is not influenced by cumulative rituximab dosage - a single center experience.

BackgroundRituximab, a monoclonal antibody directed against CD20, is approved for the treatment of CD20-positive B-cell Non-Hodgkin’s lymphoma and rheumatologic disorders. Due to its potent activity in depleting CD20-positive lymphocytes, the influence on opportunistic infections is still under discussion. Thus, we analyzed the impact of rituximab either as monotherapy or in combination with other chemotherapeutic regimens to elucidate its role in contributing to infectious complications.MethodsThe records of consecutive patients (n = 125, 141 treatment episodes) treated with rituximab alone or in combination with chemotherapy and corticosteroids were analyzed retrospectively for the incidence, spectrum and outcome of infections during treatment and 6 months after the last course of rituximab. Univariate analysis of cofactors such as steroid medication, antiinfective prophylaxis, underlying disease and remission status were performed.ResultsAltogether 80 therapy episodes were associated with infections, the median number of infections per patient being 1 (range 1–7). The number of infectious complications was significantly higher in patients receiving a combination of rituximab and chemotherapy compared to rituximab monotherapy (p < 0.001). There was no statistically significant difference regarding number of rituximab courses or cumulative rituximab dosage between episodes with and without infections, respectively.Mean cumulative prednisone dosage between the cohort with infections and the one without infections showed a trend towards higher dosage of prednisone in the patients with infections (mean difference 441 mg, p > 0.14).ConclusionsRituximab in induction treatment, either as monotherapy or combined with chemotherapy by itself does not increase the incidence or change the spectrum of infections in hematologic patients. However the possible influence of higher dosages of concomitant steroid medication on frequency of infections suggests that a heightened awareness of the potential for infectious complications should be applied to patients receiving higher doses of glucocorticoids in combination with other therapeutic regimens.

Phase Ib study combining ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with CD20-positive B-cell non-Hodgkin lymphoma (NHL).

8502 Background: Ibrutinib, a first-in-class oral Bruton’s tyrosine kinase inhibitor, has demonstrated single-agent activity in a variety of relapsed or refractory B-cell malignancies with limited toxicity, making it an appropriate drug to combine with standard R-CHOP chemotherapy in patients with previously untreated NHL. Methods: Patients received oral daily dose of ibrutinib (280, 420, or 560 mg) in combination with standard doses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, and vincristine on day 1, and prednisone on days 1 through 5 of each 21-day cycle for up to 6 cycles). The primary objective was to determine the recommended phase 2 dose (RP2D) of ibrutinib in combination with standard R-CHOP (IR-CHOP). The secondary objectives were to assess safety, overall response rate, pharmacokinetics, and pharmacodynamic biomarkers. Results: Seventeen patients (7, 4, and 6 in increasing ibrutinib doses) were enrolled: 59% male, median age 65 (range 46-81) years, diffuse large B-cell lymphoma 47%, mantle cell lymphoma 29% and follicular lymphoma 24%. In the 280 mg cohort, 2 patients had dose-limiting toxicity (DLT): 1 with transient syncope and 1 with periorbital cellulitis; at 560 mg, 1 patient had gastritis (grade 2). The RP2D was established at 560 mg ibrutinib. The most common (≥ 20% of patients) adverse events (AEs) were neutropenia (77%), thrombocytopenia (65%), vomiting (59%), anemia (53%), nausea (47%), fatigue (35%), headache (29%), constipation (24%), diarrhea (24%), and dizziness (24%). To date, 6 patients completed 6 cycles of treatment, and 2 patients discontinued treatment (1 due to noncompliance with the study drug and 1 due to non-DLT AE). At the time of this analysis, of the 10 patients had at least one post baseline tumor, the overall response rate was 100% (7 complete and 3 partial responses). Conclusions: The combination of IR-CHOP has an acceptable safety profile. No new toxicities were noted with adding ibrutinib to R-CHOP. An expansion cohort 560 mg ibrutinib (RP2D) is being opened to further explore the safety and efficacy of IR-CHOP in patients with newly diagnosed diffuse large B-cell lymphomas. Clinical trial information: NCT01569750.

Follow-up Data of 10 Patients With B-cell Non-Hodgkin Lymphoma With a CD20-negative Phenotypic Change After Rituximab-containing Therapy

Recently, a CD20-negative phenotypic change in CD20-positive B-cell non-Hodgkin lymphoma (B-NHL) after rituximab therapy was described. We report the follow-up data of 10 B-NHL patients showing this change after rituximab therapy. Ten patients (4 men and 6 women; median age, 57 y) with B-NHL who were initially CD20 positive and became CD20 negative after rituximab therapy were analyzed. Clinicopathologic features, including clinical course, CD20 expression, and histopathology, were examined. CD20 expression in lymphoma cells was evaluated using immunohistochemistry and/or flow cytometry. Histopathologically, diagnosis at initial presentation was follicular lymphoma (FL) in 7 patients; diffuse large B-cell lymphoma in 1; and chronic lymphocytic leukemia in 2. Six patients (60%, 3 FL, 1 diffuse large B-cell lymphoma, and 2 chronic lymphocytic leukemia patients) showed continuous CD20 negativity until 24 months after the phenotypic change. Three patients (30%) with FL regained CD20 expression within 1 to 7 months after detection of the CD20 change. Two patients (20%) with FL, including 1 who regained CD20 expression, showed heterogenous CD20 expression with a CD20-negative low-grade component and a CD20-positive large cell component. The overall response rate to therapy before the CD20-negative change was 70%. We reported the follow-up data of 10 B-NHL patients with a CD20-negative phenotypic change associated with rituximab-containing therapy. The most common histologic phenotypes were continuous CD20 negativity, recovery of CD20 expression within 7 months, and heterogenous CD20 expression. As the changes in morphology and CD20 expression after rituximab therapy vary widely, careful follow-up and rebiopsy are recommended.

O1-049 - Efficacy and Safety of Dose-Adjusted EPOCH for Relapsed and Refractory Non-Hodgkin Lymphoma (NHL)

ABSTRACT Introduction Since prognosis of patients with relapsed or refractory NHL is very poor, an effective salvage regimen is required to be investigated. We retrospectively evaluated the efficacy and safety of dose-adjusted EPOCH (DA-EPOCH) reported by Wilson et al. for relapsed or refractory NHL in our institute. Patients and methods Patients with relapsed or refractory NHL selected based on practical clinical situation were treated with DA-EPOCH. The starting dose was as follows: doxorubicin 10 mg/m2, etoposide 50 mg/m2 and vincristine 0.4 mg/m2 as a continuous infusion on days 1–4, cyclophosphamide 750 mg/m2 intravenously on day 5 and oral prednisone 60 mg/m2 twice a day on days 1–5. G-CSF was started on day 6 until neutrophil recovered to more than 5000/ml. The dose was adjusted according to hematologic toxic effects. Patients with CD20-positive B-cell NHL (B-NHL) received DA-EPOCH with rituximab (DA-EPOCH-R). Response was evaluated in patients who received three cycles or more, and toxicity was evaluated in all patients. Results A total of 22 patients (male/female = 13/9) were treated with DA-EPOCH (11 patients with T-cell NHL) or DA-EPOCH-R (11 patients with B-NHL). Median age was 61 years (range 44–81), and median number of prior therapy was 2 (range 1–4). The median dose level of DA-EPOCH was 100% (range 80–100%). The treatment was discontinued in nine patients, due to disease progression in four patients and prolonged toxic effects in five patients. Seven patients achieved CR and two patients achieved PR (40.9% of ORR). The most frequent toxicity was transient grade 4 neutropenia observed in 20 patients (91.0%). Grade 3 febrile neutropenia was observed in seven patients (31.8%). Dose reduction was required in 6 of 13 patients who received at least three cycles. No treatment-related death was observed. Conclusion DA-EPOCH(-R) regimen is effective and well tolerated, even in heavily pretreated patients with relapsed or refractory NHL. Further prospective large scaled study is warranted in Japan.

Rituximab: An innovative therapy for non-Hodgkin's lymphoma

The epidemiology, etiology, classification, and treatment of non-Hodgkin's lymphoma (NHL) are reviewed, and rituximab, a newly available therapy, is discussed. NHL comprises a group of lymphoproliferative disorders the frequency of which continues to rise. Although many classification systems exist for identifying specific histological subtypes, NHL is generally divided into indolent (low-grade) and aggressive (intermediate- and high-grade) forms. Low-grade NHL is characterized by a slowly progressive, continually relapsing course, with eventual transformation to a more rapidly progressive form that is usually fatal. Several options are available for the management of indolent NHL; none is curative. Rituximab, a human-mouse monoclonal antibody that targets the CD20 antigen expressed in over 90% of B-cell NHLs, provides an alternative to conventional chemotherapy that is relatively safe and effective. In a Phase III trial involving 166 patients with relapsed or refractory low-grade B-cell NHL, rituximab produced an overall response of 48%, with 20 of 80 responders still in remission more than 36 months after treatment. Study results in patients with bulky disease and those requiring retreatment have also been encouraging. Most adverse effects associated with rituximab are mild to moderate. Infusion-related reactions occur more commonly during initial infusions and in patients with evidence of increased tumor burden but can be effectively managed with premedication, supportive care, and adjusted infusion rates. Hematologic effects are generally mild and transient, and adverse immune responses are rare. Rituximab is an alternative to conventional chemotherapy for the treatment of relapsed or refractory low-grade or follicular CD20-positive B-cell NHL.