Single Rituximab Research Articles

Combined Modality Low-Dose Radiation Therapy (2 Gy x 2) and Single-Agent Rituximab Immunotherapy in the Treatment of Indolent Non-Hodgkin Lymphoma

Introduction Low-dose involved site radiation therapy (ISRT) of 2 Gy x 2 is effective in terms of palliation and local control for indolent Non-Hodgkin Lymphoma (NHL), with >80% response rate (Hoskin et al., Lancet 2014). It is commonly used in patients for whom radiation-related toxicity is of concern due to location, volume of disease, or poor performance status, and because of the ease of re-treatment if necessary. An alternative treatment for these patients is rituximab monotherapy, which is well-tolerated and has a good initial response rate but poor long-term response rate (Ardeshna et al., Lancet 2014). To date, no study has examined the efficacy of low-dose ISRT with single-agent rituximab in patients for whom treatment-related toxicity is a concern. We hypothesize that this combination is an effective treatment modality for indolent NHL that may result in the optimal balance of local and systemic disease control with minimal toxicity. Methods From a prospectively maintained clinical database of patients treated with radiation therapy (RT) at UT-Southwestern Medical Center, we performed an IRB-approved, retrospective review of 40 treated sites from 34 patients with indolent B-cell lymphoma (predominantly follicular, marginal zone, and mucosal associated lymphoid tissue) treated with low-dose ISRT (2 Gy x 2) between 2013-2019. Of primary interest, 7 patients received single-agent rituximab (median 4 cycles) either concurrently or within a short interval (median 18 days) of their ISRT, with a median follow-up of 13 months. Of the remaining patients, 14 received RT alone and 13 received combination therapy (predominantly bendamustine-rituximab or R-CHOP). Of the patients who received a combination of low-dose ISRT and single-agent rituximab, treated sites included parotid (3), brain (2), orbit (1), and pre-sacral space (1). The median ECOGperformance status was 1 (range, 1-2), the median age was 75 (range, 21-87), and 4/7 patients were female. The majority of patients were stage I (5), and remaining were stage II (1) and stage III (1). Nopatients had prior RT or systemic therapies. The primary outcome was response rate, categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).Secondary outcomes included progression free survival (PFS), overall survival (OS), symptom relief, and acute and long-term toxicities. Treatment response and disease control were determined by radiographic studies and/or physical examinations. SPSS Statistics software was used for statistical analysis. Results In all patients who received low-dose ISRT, the progression-free survival and overall survival at 1-year was 58% and 82%, respectively. In the patients who received combined low-dose ISRT and single-agent rituximab, the response rate was 100% (7/7), of which 5 had CR, 1 had PR and 1 had SD at the time of latest follow-up. For patients with multiple lesions (stage II-III), there was a 100% CR rate of un-irradiated lesions as well. There were no distal failures or deaths. Of note, 1 patient had progression of disease locally and a second had progression of disease distally initially after ISRT, both of which resolved as SD and CR, respectively, after the administration of rituximab. Also, 1 patient had progression of disease locally while receiving rituximab maintenance therapy, which resolved as CR after treatment with ISRT. Two patients experienced acute toxicities, 1 with mild diarrhea from presacral RT that resolved within days and 1 with dysgeusia from parotid RT that resolved within 2 months. Only 1 patient noted long-term toxicity from RT, in the form of dry mouth from about 50% reduction in saliva post-RT to the left parotid gland. All 7 patients presented with symptoms, of which 6 noted improvement. The remaining 1 patient had stable symptoms, as well as SD, with significant improvement in her initial condition confounded by a lower presenting ECOG and C2 fracture from a symptomatic fall prior to RT. Conclusion In patients with indolent lymphoma, combined low-dose ISRT of 2 Gy x 2 with single-agent rituximab appears to provide effective palliation and disease control with minimal toxicity. This combination is a promising new treatment paradigm, particularly for patients in whom radiation or chemotherapy related toxicities are of concern, and warrants evaluation in a larger prospective series. Disclosures No relevant conflicts of interest to declare.

Splenic Marginal Zone Lymphoma: A U.S Population-Based Survival Analysis (1997-2016)

INTRODUCTION: Splenic marginal zone lymphoma (SMZL) is a rare and indolent form of NHL with no standard treatment due to scarcity of clinical trials. Watch and wait approach, single agent rituximab or with chemotherapy and splenectomy are valid treatment approaches. No population-based studies examining the impact of chemotherapy and splenectomy on survival of SMZL patients are available. Thus, we decided to compare survival outcomes by clinical factors in SMZL patients deposited in the SEER database, emphasizing in the role of splenectomy on survival outcomes. METHODS: Retrospective analysis of SMZL cases in the SEER database from 1997 to 2016.SEER collects cancer incidence and survival data from population-based cancer registries covering 34% of the U.S. population. PATIENTS: SEER database was queried for SMZL patients at all ages from 1997 to 2016. Cases without histologic confirmation or no survival data were excluded. Demographic and clinical variables (age, sex, race, ethnicity, B-symptoms, Ann-Arbor stage, DLBCL transformation, first malignancy, chemotherapy with or without rituximab, splenectomy and radiotherapy) were summarized by descriptive statistics. Logistic regression used to determine variables associated with splenectomy. Overall survival (OS) and Cancer-specific survival (CSS) were the major end-points, estimated by Kaplan-Meier method. Cox regression used to calculate Hazard Ratios. RESULTS: 2212 patients met inclusion criteria, with a median age of 68yo (25-96). Patient characteristics were a follows: males (n=1152, 52.1%); whites (n=1991, 90.0%), blacks (112, 5.1%); Non-Hispanics (n=2049, 92.6%); B-symptoms (n=461, 20.8%); first malignancy (n=1754, 79.3%); Ann-Arbor Stage I (429, 19.4%), Stage IV (n=1351, 61.1%); DLBCL transformation (n=84, 3.8%). Adjusted Odds ratio (aOR) were used to compare splenectomy versus non-splenectomy treated patients: ≥60yo (aOR 0.49;0.40-0.62), males (aOR 0.77;0.64-0.93). Median survival of all the patients was 120 months (95%CI:111-132); On univariate analysis: shorter OS was significantly associated with age ≥60(HR 3.55;2.87-4.38) and non-first malignancy(HR 1.6;1.36-1.88), while shorter CSS was significantly associated with age ≥60(HR 1.76;1.33-2.34), B-symptoms (HR 1.93;1.44-2.60), Stage IV (HR 1.62;1.15-2.28), DLBCL transformation (HR 2.27;1.55-3.33) and treatment with chemotherapy (HR 1.54;1.22-1.94). On multivariate analysis, shorter OS was significantly associated with age ≥60(HR 3.52;2.83-4.37), male sex (HR 1.15;1.00-1.33), B-symptoms (HR 1.23;1.01-1.51) and non-first malignancy (HR 1.42;1.20-1.67). Shorter CSS was significantly associated with age ≥60(HR 2.15;1.61-2.87), Hispanic ethnicity (HR 1.44;1.00-2.07), B-symptoms (HR 1.77;1.30-2.39), DLBCL transformation (HR 2.03;1.38-2.99) and treatment with chemotherapy (HR 1.38;1.07-1.77). Ann Arbor staging and splenectomy were not associated with OS or CSS. CONCLUSIONS: Older age, Hispanic ethnicity, B-symptoms, DLBCL transformation, and treatment with chemotherapy were associated with poor lymphoma-specific survival. Although, age<60 and female gender were associated higher odds to undergo splenectomy, splenectomy had no impact on the risk of lymphoma-related death or OS. This retrospective study demonstrates that chemotherapy treatment (excluding rituximab) was associated with inferior outcomes in SMZL, while advanced Ann-Arbor stage was not associated with shorter survival as is observed in other indolent lymphomas that commonly present at advanced stage. Table Disclosures Alderuccio: Targeted Oncology: Honoraria; Foundation Medicine: Other: Immediate family member; Agios: Other: Immediate family member; Puma Biotechnology: Other: Immediate family member; OncLive: Consultancy; Inovio Pharmaceuticals: Other: Immediate family member. Lossos:NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees.

Maintenance Rituximab in Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) in the First Line Setting or at Relapse

Introduction: Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) is a CD20 positive subtype of Hodgkin lymphoma and can frequently present an indolent behavior. Indeed, NLPHL patients relapse more commonly than patients with classic Hodgkin Lymphoma, but relapses can usually be responsive to lower intensity therapy such as rituximab. The choice of frontline and relapse therapies depends on different factors, including staging and burden of disease, thus therapy can range from observation, to radiotherapy (XRT) alone, to systemic therapy such as R-CHOP, R-ABVD or single agent Rituximab (R) or to combined modality (systemic therapy and XRT). However, it is unclear whether maintenance rituximab (MR) would be of clinical benefit if administered after induction therapy. Methods: We retrospectively reviewed the characteristics and outcomes of 17 consecutive patients treated at our center between 12/1972 and 7/2019, with proven diagnosis of NLPHL and who received MR after having achieved complete response (CR) or partial response (PR) after any line of therapy. MR consisted of rituximab 375 mg/m2 once every 2 or 3 months for 2 years or rituximab 375 mg/m2 weekly 4 times every 6 months for 2 years, for a total maximum of 12 doses over 2 years. Progression free survival (PFS) time was calculated from start date of MR to progression date, transformation date or death date, whichever happened first. Patient with no progression, transformation or death were censored at the last follow-up date. Results: At time of initial diagnosis, median age was 37 (range, 15-50 years), 13 patients (76.5%) were male, and 4 patients (24%) had Ann Arbor stage III-IV disease. At completion of the line of induction therapy followed by MR, 75.0% of patients presented CR and 25% presented PR. However 18.7% of patients were restaged with computer tomography (CT) and 81.3% with Positron emission tomography-computed tomography (PET/CT), making the treatment response evaluation uneven. Nine patients received MR after frontline therapy, including R-CHOP in 5 patients (55.6%), rituximab monotherapy in 2 patients (22.2%), R-CVP in 1 patient (11.1%) and rituximab induction with XRT in 1 patient (11.1%). The median number of rituximab maintenance doses was 8 (range 3-12) and the median duration of MR was over 25 months (range 10-32 months). Among these patients, only one (11.1%), treated with frontline R-CHOP, progressed 97.6 months after initiation of MR. No salvage treatment was needed at time of progression, and this patient was still alive at last follow-up, 7 months after progression. No transformation and no death occurred in this patient cohort. Seven patients received MR after second line therapy, including induction R and MR (R+MR) in 5 patients (71.4%), R-CHOP in 1 patient (14.3%) and R with lenalidomide in 1 patient (14.3%). The median number of rituximab maintenance doses was 10 (range 6-12) and the median duration of MR was over 18 months (range 14-20 months). Among these patients who received MR after second line, 1 patient (14.3%) presented with transformation into diffuse large B-cell lymphoma, 7 years after start of MR. This patient received R-EPOCH chemotherapy and frontline autologous stem cell transplant (ASCT) and died of ASCT related infection 1 month after ASCT. One patient received third line R+MR with 12 doses of MR and was in complete remission at last follow-up, 93 months after start of 3rd line therapy. Globally, after a median follow-up from start of any line of MR of 54 months (range: 15-119 months), 1 patient (5.9%) progressed and did not require salvage therapy and 1 patient (5.9%) presented a transformation and died of ASCT-related infection; 5-year PFS and 5-year OS were100% (median PFS and OS were not reached). Conclusions: Patients with NLPHL receiving MR, either after frontline or subsequent lines of therapy, rarely experience relapse and have a very favorable prognosis. However, larger randomized prospective trials are essential to confirm the eventual clinical benefit of maintenance rituximab. Figure Disclosures Pinnix: Merck: Research Funding. Lee:Seattle Genetics, Inc.: Research Funding.

Bendamustine-Rituximab Does Not Improve Survival over Rituximab Monotherapy for Older Patients with Nodal or Splenic Marginal Zone Lymphoma

Background: Nodal and splenic marginal zone lymphomas (NMZL/SMZL) are rare, usually disseminated, and typically diagnosed in older patients (median age 69 years). They are increasingly treated with first-line bendamustine/rituximab (BR) based on phase 3 trials that pooled various B-cell indolent lymphomas (Rummel et al., Lancet 2013). However, NMZL and SMZL have unique biology and clinical course. In this context, without histology-specific evidence, the risk/benefit ratio of BR over single-agent rituximab (R) in SMZL/NMZL is uncertain. Our objective was to examine treatment patterns, and to compare survival and toxicity outcomes of BR versus (vs.) R, using population-based data. Methods: Using Medicare claims linked to cancer registry data covering ~34% of the US population (SEER-Medicare), we identified all SMZL/NMZL patients age ≥65 who received 1st line R or BR between 2009-2016 (after approval of bendamustine) and had complete Medicare records. We used a propensity score to generate "pseudo-randomized" cohorts (pooled, including NMZL and SMZL, and histology -specific for NMZL and SMZL), balancing patient and disease characteristics: age, sex, race, comorbidities (including kidney disease and heart failure), performance status, lymphoma stage, B symptoms, prior splenectomy, anemia (including autoimmune hemolytic), transfusions, hospitalizations, and time from diagnosis to therapy. In the balanced pseudo-randomized cohorts, we compared event-free survival (EFS, defined as 2nd line chemotherapy, splenectomy, hospice, or death) and overall survival (OS) from the start of therapy, risk of major toxicities (hospitalization, transfusions), and inflation-adjusted Medicare spending. Outcome models report hazard ratios (HR) or risk ratios (RR) with 95% confidence intervals (95%CI), and marginal means for costs. Results: Among 1,315 patients (901 with NMZL and 414 with SMZL), median age was 78 years [y], and there were 52% women. About half of patients received first-line R every year, but the proportion treated with BR increased from 4% in 2009 to 23% in 2016 (Fig. A). In the pooled NMZL/SMZL cohort of patients receiving BR or R (N=926), those treated with BR were on average younger, more likely to have NMZL, stage 2-4 lymphoma, and B symptoms. With median follow-up 3.8 y, median EFS was 4.3 y (95%CI, 3.5-5.1) for NMZL, and 4.5 y (95%CI, 3.8-6.5) for SMZL. Median OS was 5.7 y (95%CI, 4.9-6.7) in NMZL, and 5.2 y (95%CI, 4.4-6.7) in SMZL. After balancing the confounders, there was no significant difference in either EFS (HR for BR, 1.00; 95%CI, 0.76-1.30, P=.98) or OS (HR, 1.14; 95%CI, 0.85-1.53; P=.38). Toxicities were higher with BR, including hospitalizations (RR, 1.46; 95%CI, 1.14-1.87; P=.003) and transfusions (RR, 2.35; 95%CI, 1.55-3.56; P<.001). Mean Medicare spending within 1 year from diagnosis was higher after BR (mean $83,480) than R (mean $53,776; P<.001). A sensitivity analysis showed that >50% of BR patients would need to have an unobserved risk factor doubling their mortality to explain lack of OS benefit. We then fitted separate propensity score models in NMZL and SMZL. In the comparative NMZL cohort (N=609), 434 patients (71%) received R, and 175 (29%) received BR. We observed no significant difference in either EFS (HR for BR, 0.93; 95%CI, 0.68-1.29; P=.67; Fig. B) or OS (HR, 1.16; 95%CI, 0.82-1.63; P=.40), whereas toxicities and costs were consistently higher with BR. In the comparative SMZL cohort (N=317), 272 patients (86%) received R, and 45 (14%) received BR. Again, there was no significant difference in EFS (HR for BR, 0.84; 95%CI, 0.46-1.53; P=.56; Fig. C) or OS (HR, 0.92; 95%CI, 0.46-1.83; P=.80). Results for toxicities and costs were again consistent. Conclusions: Among older patients with SMZL and NMZL treated in the community, the use of first-line BR is increasing. However, in this large observational study, BR was not associated with any significant EFS or OS benefit over single-agent R, while it increased toxicities and costs. Without a formal randomized histology-specific study, single-agent R may offer a favorable risk/benefit ratio as a first-line therapy for older NMZL/SMZL patients at average risk, reserving BR for those with compelling clinical circumstances. Our results may however be affected by bias due to unobserved confounding, and may not be applicable to younger patients. Disclosures Olszewski: Adaptive Biotechnologies: Research Funding; Genentech: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding. OffLabel Disclosure: Rituximab with bendamustine is off-label for marginal zone lymphoma

Analysis of an Online Treatment Decision Tool Reveals Variances in Practice between Experts and Oncology Healthcare Providers for Newly Diagnosed Follicular Lymphoma

Analysis of an Online Treatment Decision Tool Reveals Variances in Practice between Experts and Oncology Healthcare Providers for Newly Diagnosed Follicular Lymphoma

BI-1206, a Monoclonal Antibody Against Fcγriib, Showed Superior Anti-Tumor Activity in an Ibrutinib-Venetoclax Dual Resistant PDX Model in Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) is a rare but aggressive non-Hodgkin lymphoma (NHL). CD20 antibodies (e.g. rituximab), BTK inhibitors (e.g. ibrutinib and acalabrutinib), and BCL-2 inhibitors (e.g. venetoclax) alone or in combination have shown great anti-MCL efficacy. However, primary and acquired resistance to one or multiple therapies commonly occurs, resulting in poor clinical outcome. Overcoming such mechanisms of resistance holds promise to significantly improve survival, meeting a significant medical need for patients with refractory/relapsed MCL. Recent studies showed Fc gamma receptors (FcγRs) play important roles in controlling therapeutic efficacy. FcgRIIB (CD32B), the inhibitory FcγR, negatively controls antibody efficacy through distinct inhibitory mechanisms in immune effector cells and lymphoma cells, respectively. When expressed on leukemic or lymphoma cells, FcgRIIB promotes rituximab internalization and removal from the tumor cell surface, resulting in reduced immune effector cell activation and ultimately decreased in vivo therapeutic efficacy. We recently developed antagonistic antibodies to FcgRIIB and demonstrated that these antibodies blocked rituximab internalization and helped prevent and overcome rituximab resistance in a PDX model of CLL. In this study, we investigated the expression of FcgRIIB in MCL cell lines and primary patient MCL samples, and we assessed the in vivo efficacy of BI-1206, a monoclonal antibody against FcgRIIB, in MCL PDX models. Methods: Flow cytometry analysis was performed to examine the cell surface expression of FcgRIIB in MCL cell lines (n=8) and primary patient MCL samples (n=27). An orthotopic patient-derived xenograft (PDX) model was established from a MCL patient with dual resistance to ibrutinib-venetoclax. In the first mouse cohort, single-agent ibrutinib, venetoclax, or vehicle control were administrated in mice carrying the orthotopic PDX model to assess their in vivo efficacies. In the second mouse cohort, mice were treated with vehicle, single agent BI1206, rituximab plus lenalidomide, or a combination of BI-1206, rituximab, and lenalidomide (triple combination) to assess their in vivo efficacies in the same PDX model. Results: Flow cytometry analysis showed that all 8 MCL cell lines and all 27 primary patient MCL samples expressed high levels of FcgRIIB, highlighting the potential importance of FcgRIIB on the control of therapeutic efficacy in MCL. In the first mouse cohort, we validated the ibrutinib and venetoclax resistance in the PDX model established from a MCL patient with resistance to both therapies. In the second mouse cohort, single agent BI-1206 (10 mg/kg, twice a week) potently diminished PDX growth in spleen, liver, bone marrow, and peripheral blood (Figure 1). Treatment with rituximab (10 mg/kg, twice per week) plus lenalidomide (50mg/kg, daily) or the triple combination showed similar potency (Figure 1). To investigate whether BI-1206 mediates boosting of rituximab-based targeted drug therapies, and/or overcoming of resistance to such therapies, a follow-up experiment with revised treatment setting using the same PDX model or an alternative CD20/FcγRIIb co-expressing PDX model is currently under investigation. Conclusions: All MCL cell lines and all primary MCL cells tested highly express FcγRIIb on the tumor cell surface. Single agent BI-1206 has potent anti-MCL activity in the FcγRIIb-expressing MCL PDX model to overcome ibrutinib-venetoclax dual resistance. Our data suggests FcγRIIb may be an important target for anti-MCL therapies. Disclosures Wang: Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BioInvent: Consultancy, Research Funding; Aviara: Research Funding; Juno Therapeutics: Research Funding; Celgene: Honoraria, Research Funding; Loxo Oncology: Research Funding; VelosBio: Research Funding; Dava Oncology: Honoraria.

New developments in the treatment of follicular lymphoma.

The treatment of follicular lymphoma (FL) continues to evolve. Those patients who present with minimal symptoms often are observed without therapy until significant progression occurs. When treatment is needed, initial options include single agent rituximab (R, anti-CD20), or various forms of chemoimmunotherapy including either R or the newer anti-CD20 monoclonal antibody obinutuzumab (O), with or without maintenance administration. Recent data suggest that the immunomodulatory agent lenalidomide can also be effective in combination with rituximab in both the upfront and relapsed setting. Patients with recurrent disease are frequently treated with chemoimmunotherapy or phosphoinositol-3-kinase (PI3K) inhibitors. Current information suggests that the most important prognostic feature of FL is the presence or absence of early progression (within 2 years of initial treatment/diagnosis). Ongoing efforts are focused on biomarkers to optimally match treatment to patient populations and further improve clinical outcomes.

3229 Helicobacter pylori-Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphomas: A Challenge in Treatment Options

INTRODUCTION: Primary gastric lymphoma is a rare entity of which the specific variant, mucosa-associated lymphoid tissue (MALT) lymphomas may be the best recognized given its association with Helicobacter pylori (H. pylori) infection. It has been thought that repetitive immune stimulation from underlying infection is influential in the pathogenesis of this tumor. However up to 10% of gastric MALT lymphomas are diagnosed without a concomitant H. pylori infection. The pathogenesis and management of H. pylori-negative gastric MALT lymphomas remains uncertain. CASE DESCRIPTION/METHODS: 65 year old woman with Celiac disease and GERD presented with worsening severe reflux and epigastric pain. She underwent EGD which revealed multiple superficial ulcers in the cardia with notable nodularity, ulceration, and friability. Cold forceps biopsies of the abnormal mucosa demonstrated diffuse atypical small B-Cell lymphoid infiltrate with features compatible with low grade MALT lymphoma. Of note, immunostain for H. Pylori was negative. Subsequent H. pylori stool antigen assay as well H. pylori IgG, IgM, and IgA were all negative. Given her negative antibodies indicating she truly had no exposure to H. Pylori, the patient has been referred to oncology for multidisciplinary management. DISCUSSION: This case of early stage gastric MALT lymphoma without evidence of active H. pylori infection elucidates that there is limited literature for the management for these patients. Studies have suggested that H. pylori eradication therapy can be efficacious for a proportion of H. pylori-negative gastric MALT lymphomas, possibly due to a false negative detection by biopsy. Local radiation therapy with curative intent and single agent rituximab therapy rather than H. pylori eradication have also been explored as alternate options. The data stems from retrospective studies and single agent prospective trials. Thus, there may be a role for future research directly comparing treatment strategies for optimal management of this clinical entity.

Follicular lymphomas in vulnerable/older patients.

Unlike for diffuse large-cell lymphoma, both the management of elderly patients with follicular lymphoma and the role of comprehensive geriatric evaluation to optimize treatment choices have been rarely addressed. This review analyses available evidence on follicular lymphoma occurring in aged persons. Most retrospective studies and expert recommendations agree that the diagnostic approach and the treatment algorithm in elderly follicular lymphoma should not differ from younger patients up to the age of 80. However, slowly progressing follicular lymphoma low-tumor burden should start treatment even though asymptomatic. Prospective identification of those unfit patients is needed where a treatment deintensification may not be detrimental. Octogenarians have more aggressive disease and do not benefit from chemoimmunotherapy more than from single-agent rituximab. An activity of daily living loss significantly impact on their outcome and specific prognostic scores may help in the better manage these oldest patients. Given the lack of prospective studies there is an urgent need to investigate if geriatric assessment including comorbidities, geriatric parameters, patient's reported outcomes and quality of life issues, may help selecting those frail elderly follicular lymphoma patients less suitable for full-dose treatments. In addition, the potential usefulness of the new noncytotoxic agents of proven efficacy in follicular lymphoma warrants specific investigations in older patients.

Rituximab as Maintenance Treatment for Systemic Lupus Erythematosus: A Multicenter Observational Study of 147 Patients.

The efficacy of rituximab (RTX) in systemic lupus erythematosus (SLE) is a subject of debate. This study was undertaken to investigate the outcomes of RTX treatment in a European SLE cohort, with an emphasis on the role of RTX as a maintenance agent. All patients with SLE who were receiving RTX as induction therapy in 4 centers were included. Patients who received a single course of RTX and those who received RTX maintenance treatment (RMT) were followed up after treatment. Disease flares during the follow-up period were defined as an increase in disease activity and the number or dose of immunosuppressive drugs. Of 147 patients, 27% experienced treatment failure at 6 months. In a multivariate analysis, a low number of previous immunosuppressive therapies (P = 0.034) and low C4 levels (P = 0.008) reduced the risk of treatment failure. Eighty patients received RMT over a median of 24.5 months during which 85 relapses, mainly musculoskeletal, were recorded (1.06 per patient). At the time of the last RTX course, 84% of the patients were in remission. Twenty-eight (35%) of 80 patients never experienced a flare during RMT and had low damage accrual. Active articular disease at the time of the first RTX administration was associated with a risk of flare during RMT (P = 0.011). After RMT, relapse-free survival was similar to that in patients receiving a single RTX course (P = 0.72). RMT is a potential treatment option for patients with difficult-to-treat disease. Relapses occur during RMT and are more likely in those with active articular disease at the time of the first RTX administration. Relapse risk after RMT remains high and apparently comparable to that seen after a single RTX course.

M7-FLIPI is not prognostic in follicular lymphoma patients with first-line rituximab chemo-free therapy.

The clinical course of follicular lymphoma (FL) is highly variable. Recently the m7-FL international prognostic index (FLIPI) integrating performance status, FLIPI score and the mutational status of seven genes, was shown to stratify patients into "low-risk" and "high-risk" with respect to 5-year failure-free survival after first-line immunochemotherapy. Our aim was to evaluate the model after rituximab without chemotherapy. The Nordic Lymphoma Group performed two randomized clinical trials on indolent lymphoma patients receiving single rituximab and rituximab with interferon-α2a. In total, 95 FL patients had sufficient fresh-frozen diagnostic material for sequencing. A targeted panel for the genes EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11 was utilized for m7-FLIPI score calculation. With a median follow-up of 10·6years, 76% of patients were alive. No difference in time to treatment failure (TTF), defined as the interval between start of trial therapy and initiation of new therapy or death, nor overall survival (OS) was found between the m7-FLIPI risk groups (log-rank P=0·94 and 0·99, respectively). EZH2 mutations were associated with longer TTF (log-rank P=0·04) and in EP300 mutations were associated with shorter TTF (log-rank P=0·01). We conclude that the prognostic value of the m7-FLIPI clinicogenetic model seems dependent on therapeutic regimen.

PS1324 GENETIC SIMILARITY BETWEEN WALDENSTRÖM MACROGLOBULINEMIA AND IGG-TYPE LYMPHOPLASMACYTIC LYMPHOMA. TARGETED NEXT-GENERATION SEQUENCING RESULTS OF FORMALIN-FIXED PARAFFIN EMBEDDED SAMPLES

Background: Follicular lymphoma (FL), the most frequent type of indolent non Hodgkin lymphoma, exhibits a heterogeneous clinical behavior. Predictive biological variables are eagerly sought, in an effort to better anticipate outcomes for each individual patient. Cytokines are small proteins involved in cell signaling and immune regulation. The levels of soluble interleukin 2 receptor (sIL-2R), interleukin 6 (IL-6), and tumor necrosis factor (TNF) have been correlated with tumor burden and prognosis in solid tumors and some lymphomas. High sIL-2R has been associated with shorter progression-free survival (PFS) in FL, but the impact of the levels of IL-6 and TNF is not known in this disease specifically. Aims: To determine the prognostic significance of the serum levels of sIL-2R, IL-6 and TNF in patients with newly diagnosed FL. Methods: We identified 300 patients (132 males/168 females; median age: 60 years) diagnosed with FL at our institution between January 2002 and December 2017 who had available information about serum cytokine levels (sIL-2R, IL-6 and TNF), determined by ELISA, before the initiation of frontline treatment. Baseline patient and disease characteristics, type of frontline treatment, PFS and overall survival (OS) were assessed retrospectively and compared between patients with normal vs. elevated levels (above the upper normal limit) of each one of the three evaluated cytokines. Results: Baseline characteristics, treatment, response, PFS and OS data are detailed in the table. Patients with elevated IL-6 or TNF levels were older and those with elevated IL-6 had a worse performance status and higher rate of B symptoms. An advanced stage was more frequently seen in patients with any elevated cytokine, while secondary extranodal involvement, and specifically, bone marrow involvement, was more frequent if either sIL-2R or TNF were raised. Patients with any elevated cytokine were more likely to have elevated LDH or β2-microglobulin (β2m) levels or a high-risk FLIPI score. A Ki67 index >30% was more frequently seen among patients with high TNF levels. Patients requiring frontline treatment with R-CHOP showed higher levels of any one of the 3 evaluated cytokines, while those who were not treated or received single-agent rituximab were more likely to have normal levels. The complete response (CR) rate was higher for patients with normal levels of sIL-2R and TNF. Median PFS was 10 years for treated patients in the entire series. 10-year PFS was significantly lower for patients with high levels of either sIL-2R, IL-6 or TNF. Similarly, patients who had elevated levels of any one of the 3 evaluated cytokines had a lower 10-year OS. However, in a multivariate analysis including FLIPI score, β2m and cytokine levels, only FLIPI and β2m retained statistical significance for PFS and OS.Summary/Conclusion: FL patients with elevated levels of cytokines are more symptomatic and have a higher tumor burden. Despite being treated more aggressively, they are less likely to achieve a CR after treatment or to maintain it after 2 years. PFS and OS are also significantly shorter in patients with elevated cytokine levels compared to those with normal levels. Determination of serum cytokine levels is simple and could become an additional factor informing about response to treatment, early progression, and survival.

Cardiac Transplantation across Preformed HLA-Antibody Barriers: Results of a Peritransplant Desensitization Protocol

Purpose A growing number of patients awaiting heart transplantation presents with preformed anti-HLA antibodies. This allosensitization prolongs waiting times and increases morbidity and mortality. In 2017, we designed aprotocol for peritransplant desensitization of heart-transplanted patients showing preformed anti-HLA donor specific antibodies (pfDSA), i.e. a positive virtual crossmatch. The protocol included: an intraoperative single dose of the IL-6 receptor antibody Tocilizumab (10mg/kg) just before releasing the aortic clamp; 5 sessions of plasmapheresis (PE, 1 before transplantation, 1 during transplantation and 3 thereafter); an infusion (2g/kg) of IgA and IgM-enriched human immunoglobulins G (IgGAM) after the last PE; and a single Rituximab dose (375mg/m2) after IgGAM. IgGAM are repeated every 4 weeks (0.5g/kg) for a maximum of 6 months, if DSA are still positive. Aim of this study was to present the preliminary results of this peritransplant desensitization protocol. Methods Records of heart-transplanted patients at our institution between 01/2017 and 10/2018 were reviewed. Patients with pfDSA (positive virtual crossmatch) formed the case group, remaining patients the control group. Median (IQR) follow-up amounted to 9 (5, 16) months. Results During the study period, among the 42 transplanted patients, 9 (21%) patients formed the case group and the remaining 33 (79%) the control group. All 9 case patients showed pfDSA with >50% pre-transplant panel reactive antibodies (PRA). Pretransplant recipient and donor characteristics did not differ between groups. Post-transplant, no case patients showed severe primary graft dysfunction, but 6 (19%) control patients did (p=0.19). At treatment end, pfDSA were cleared in 4 (44%) patients. At 1-year follow-up, survival was 100% vs. 75% in case and control patients (p=0.18); freedom from biopsy-confirmed rejection (Grade >1R) was 89% vs. 92% in case (n=1) and control (n=2) patients (p=0.78); and from steroid-pulsed therapy 89% vs. 82% in case (n=1) and control (n=5) patients (p=0.76), respectively. One case patient showed minimal AMR (pAMR 1+). Conclusion The present study showed that heart transplantation across positive crossmatch barriers can be feasible and safe. The present peritransplant desensitization protocol yielded good survival and rejection-free survival.

Rituximab as a Preemptive Treatment to Prevent Recurrence of Primary Focal Segmental Glomerulosclerosis: A Novel Approach.

Primary idiopathic focal segmental glomerulo-sclerosis is a serious disease, frequently progressing to end-stage kidney failure. Management of recurrence after kidney transplant is challenging despite multiple proposed therapeutic approaches. Available treatment for focal segmental glomeru-losclerosis recurrence is plasma exchange, intravenous cyclosporine, and rituximab. In this study, we investigated kidney transplant recipients with focal segmental glomerulosclerosis who were at high risk for recurrence. Patients were given preemptive rituximab at day 0 posttransplant. Between January 2013 and June 2017, our center had 8 patients with primary focal segmental glomerulosclerosis at high risk for recurrence who were scheduled for kidney transplant. These patients received a single rituximab infusion of 375 mg/m2 on day 0 posttransplant. Recurrence of focal segmental glomerulosclerosis posttransplant was defined as repeated proteinuria > 2 g/day, without evidence of clinical or biopsy-proven rejection. Follow-up showed that none of our patients had immediate posttransplant proteinuria. Only 1 patient developed proteinuria at almost 4 months posttransplant. Mean follow-up duration was 8 months. With regard to complications, 2 patients had serious bacterial infections and 1 patient had cytomegalovirus infection. Rituximab at day 0 posttransplant may be used safely to prevent focal segmental glomeru-losclerosis recurrence in the graft in the early posttransplant period. However, longer follow-up studies with larger series are needed.

Combination lenalidomide-rituximab immunotherapy activates anti-tumour immunity and induces tumour cell death by complementary mechanisms of action in follicular lymphoma.

SummaryChemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma (FL) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R2) has shown clinical synergy in front‐line and relapsed/refractory FL. Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer (NK) cells ex vivo from FL patients by enhancing proliferative capacity and T‐helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody‐dependent cellular cytotoxicity in sensitive and chemo‐resistant FL cells, via a cereblon‐dependent mechanism. While single‐agent lenalidomide and rituximab increased formation of lytic NK cell immunological synapses with primary FL tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of FL patient samples from a phase 3 trial revealed that R2 treatment increased circulating T‐ and NK‐cell counts, while R‐chemotherapy was associated with reduced cell numbers. Finally, using an in vitro model of myeloid differentiation, we demonstrated that lenalidomide caused a reversible arrest in neutrophil maturation that was distinct from a cytotoxic chemotherapeutic agent, which may help explain the lower rates of neutropenia observed with R2 versus R‐chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of FL – moving from combination immunochemotherapy to chemotherapy‐free immunotherapy.

Emerging Treatment Strategies for Primary Breast Extranodal Marginal Zone Lymphoma of Mucosa-associated Lymphoid Tissue

IntroductionWe report our experience in treating patients with primary breast extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) to better elucidate the natural history and optimal treatment approach for these patients. Patients and MethodsPatients with localized primary breast MALT lymphoma treated between 1995 and 2016 were included. Disease-related endpoints including progression-free survival (PFS) were analyzed. ResultsEleven patients met inclusion criteria; all patients were women with a median age of 62 years (range, 42-75 years). Most (73%) patients presented with stage I disease, and most (73%) patients were treated initially treated with radiation therapy (RT). Local control following RT was 100%; all patients with progression following RT experienced distant relapse. Additionally, none of the 3 patients treated with ultra-low-dose RT (4 Gy) experienced subsequent progression (local or distant). Six (55%) patients progressed after initial therapy, of whom 5 received initial RT; the 5-year PFS after initial therapy was 60%. Salvage systemic therapy was utilized in all patients with progression, with 5 of 6 patients receiving single-agent rituximab. Of the patients treated with salvage therapy, only 1 experienced second relapse, with a 5-year PFS of 100% after salvage systemic therapy. With a median follow-up of 8 years, there were no deaths in the cohort. ConclusionsPatients with primary breast MALT lymphoma achieve excellent outcomes. Initial RT affords local control, and although subsequent distant progression is common, salvage rituximab yields high rates of PFS.

Epidermotropic CXCR3 positive marginal zone lymphoma: a distinctive clinical histopathological entity potentially originating in the skin; it does not always indicate splenic marginal zone lymphoma

Epidermotropic B cell lymphoma represents a rare form of marginal zone lymphoma presenting as a disseminated skin rash resembling pityriasis rosea. To date there are 8 reported cases. In addition to the widespread nature of the skin rash, there is a proclivity for spleen and bone marrow involvement raising consideration regarding its categorization as a systemic lymphoma. We present an 89-year-old man with epidermotropic B cell lymphoma, who presented with a pityriasis rosea-like skin rash. An initial diagnosis of diffuse large cell B cell lymphoma was made based on the extent of dermal-based large cell infiltration. However, after recognizing the epidermotropic component and the distinctive clinical presentation, a diagnosis of epidermotropic B cell lymphoma was rendered. There was minimal bone marrow involvement based only on flow cytometric analysis, but there was no apparent bone marrow or splenic involvement on routine light microscopic assessment. Remission was = achieved with single agent rituximab chemotherapy and the patient remained symptom free. The neoplastic CD20 positive epidermotropic B lymphocytes expressed CXCR3. Similar to the prior reported cases by the authors, the neoplastic cells expressed CXCR3, a chemokine whose organ and tissue specific ligands could contribute to its relatively indolent clinicalcourse.

Where to start? Upfront therapy for follicular lymphoma in 2018.

The initial approach to the management of follicular lymphoma (FL) is challenging for patients and physicians. Most FL patients present with minimal symptoms; given the lack of a survival benefit to early treatment in this population, a period of observation without therapy is often appropriate. Once there is disease progression beyond low-tumor-burden criteria or symptoms prompting intervention, patients may be considered for an array of potential treatment options. These range from single-agent rituximab (anti-CD20) to various forms of chemoimmunotherapy, including rituximab or the newer anti-CD20 monoclonal antibody obinutuzumab. Unfortunately, prognostic and other clinical factors are of limited value in guiding optimal selection of therapy. Once patients complete initial treatment and achieve a complete or a partial remission, the next decision relates to the pros and cons of maintenance anti-CD20 therapy. Maintenance antibody administration can improve progression-free, but not overall, survival; hence, patient preferences typically drive this decision. Monitoring after remission is achieved should generally be guided by symptoms, physical examination, and laboratory findings, with routine surveillance imaging discouraged in the absence of new clinical issues. Given the wide range of options available and the importance of optimizing quality of life in this chronic health condition, education and shared decision making are pillars in the upfront management of FL to help patients achieve the best possible outcomes.

Factors Associated with Overall Survival in Follicular Lymphoma Patients Who Are Eligible for Maintenance Therapy

Background: Follicular lymphoma (FL) is the most common indolent Non-Hodgkin lymphoma. Diagnosed with advanced disease, most patients have an excellent prognosis, but treatment options are not curative and can have significant morbidity. To date, there is no standard of care for first-line (1L) treatment for FL. In fact, current National Comprehensive Care Network (NCCN) guidelines list 11 (including three category 1) 1L treatment options for FL. Following the successful completion of 1L treatment, patients may also receive consolidation or maintenance rituximab (MR) therapy, with the intent of prolonging remission. Although MR has been shown to improve progression free survival, its impact on overall survival (OS) remains controversial. Leveraging electronic healthcare records, we identify and describe the demographics, treatment practices, and associated outcomes of FL patients diagnosed and treated in the nation's largest integrated healthcare system, the Veterans Health Administration (VHA),Methods: FL patients diagnosed and treated in the VHA between 2006-2014 were identified by linking information from the VA Clinical Cancer Registry (VACCR) and the Corporate Data Warehouse (CDW). Patients were excluded if they had evidence of a prior cancer, documented grade 3b, or stage I disease. Patient demographics, disease characteristics, and treatment history and associated outcomes were extracted. Patients were grouped by 1L treatment(s) which included rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP); rituximab, cyclophosphamide, vincristine, and prednisone (RCVP); bendamustine rituximab (BR), single-agent rituximab; and whether or not they received MR. Descriptive statistics were used to describe patient demographics, disease characteristics, and treatment practice patterns. Proportions were used for discrete variables; means and/or medians (with standard deviation or interquartile range, respectively) were used to describe continuous variables. Overall survival (OS) was compared between patients who received MR and those who did not, using an adjusted Cox proportional hazards model.Results: From 2006-2014, 2290 FL patients were diagnosed at VHA, from all regions of the United States. Median age was 65 years, 95% were male, 81% were non-Hispanic white, 7% were black, 2% were Hispanic, and 8% were other/unknown. At diagnosis, 25% of patients were grade 1, 27% grade 2, and 12% grade 3, and 4% were documented as grade 1-2. More than half (58%) of these patients had disease at stage III or IV at diagnosis, with 13% at stage II, and 21% at stage I. The most common comorbidity was diabetes, present in 27% of patients, followed by pulmonary disease (18%), peripheral vascular disease (8%), and renal disease (8%). Overall, 793 (85%) patients were treated with chemoimmunotherapy, with 341 (15%) patients receiving RCHOP, 253 (11%) receiving RCVP, and 199 (9%) receiving BR; while 132 (6%) patients were treated with single-agent rituximab. Compared to patients treated with chemoimmunotherapy, patients treated with single-agent rituximab were significantly older (77% ≥ 60 vs 67%, p=0.022) and less likely to have elevated LDH (14% vs 24%, p=0.03) or grade 3 disease (9% vs 21%, p= 0.002). Of the 905 patients who were treated with chemoimmunotherapy or single-agent rituximab and showed no evidence of progressive disease (i.e., MR-eligible patients), 319 patients (35%) received MR. On multivariable analysis, the following were independently associated with decreased OS: age at treatment ≥ 60 (HR=2.1, p=0. 0.0003), hemoglobin < 12 g/L (HR=1.5, p=0.041), LDH > ULN (HR=1.6, p=0.013), and Charlson comorbidity index (CCI) ≥ 2 (HR=1.1, p=0.05). Accounting for immortal time bias, MR was associated with a significant improvement in OS (HR = 0.7, p = 0.04).Conclusions: This nationwide real-world study yields detailed information and new insights into current FL patient characteristics, treatment practices, and associated outcomes. Rituximab maintenance was independently associated with an improvement in overall survival in patients with FL. DisclosuresHalwani:Takeda: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Miragen: Research Funding; Kyowa Hakko Kirin: Research Funding; Immune Design: Research Funding; Genentech, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Abbvie: Research Funding. Masaquel:Genentech: Employment, Equity Ownership; Roche: Equity Ownership. Henderson:Genentech/Roche: Employment, Equity Ownership. Delong-Sieg:Roche: Equity Ownership; Genentech, Inc.: Employment. Sauer:Amgen: Research Funding; COHRDATA: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding.

AUGMENT: A Phase III Randomized Study of Lenalidomide Plus Rituximab (R2) Vs Rituximab/Placebo in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

AUGMENT: A Phase III Randomized Study of Lenalidomide Plus Rituximab (R2) Vs Rituximab/Placebo in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma