Introduction Of Rituximab Research Articles

The Outcome of Mantle Cell Lymphoma patients after Treatment Failure and Prognostic value of Secondary Mantle Cell International Prognostic Index (sec MIPI)

▪Background: MCL is a distinct lymphoma entity with improved outcome achieved by the introduction of rituximab, high dose Ara-C and autologous stem cell transplantation (ASCT) into the first line therapy. The outcome of the relapsed patients (pts) remain however poor and there is little data on the outcome after subsequent relapses and there is no information on secondary MIPI prognostic value.Aim: To analyze the outcome of the MCL patients after first line treatment failure and to evaluate the prognostic role of the sec MIPI which is MIPI calculated at the time of relapse/progression.Methods: This analysis is a part of the Lymphoma project in which consecutive lymphoma patients are registered since the year 1999. Altogether 519 newly diagnosed MCL patients were registered in 5 university centers and 9 regional departments between 1999 and 2011. Patients who were treated with rituximab as part of the first line treatment (n=388) were included into the analysis. The diagnoses were confirmed according to WHO classification in the reference pathology centers. The median follow up is 4.5 years.Results: The whole cohort consists of 261 males and 127 females (2.1:1) with median age 65 y (28-87), the majority of pts had advanced disease (CS IV in 81.6% pts), PS ECOG ≥ 2 in 23.6% pts, elevated LDH in 52.5% of pts. The MIPI risk profile was as follows: low risk 21.7%, intermediate risk 27.2% and high risk in 51.1%. All pts received rituximab as part of the induction, 48.7% pts received CHOP, 5.7% alternation of CHOP and HD Ara-C, 26.2% intensive induction with HD Ara-C, 10.3% CVP, 6.4% FC. High dose therapy with ASCT was performed in 23.9% of pts. The ORR was 89.0% with 63.8 CR/CRu, 6.3% had stable disease and 4.9% were primary progressive. The PFS and OS were 2.9 y and 5.5 y with significant impact of MIPI risk (p<0.0001) for both PFS and OS. There were observed 179 relapses/progressions (R/P) and 70 deaths not related to subsequent progression. The cohort of patients with 1st R/P consisted out of 125 males and 54 females (2.3:1) with median age 68 years (38-89). The sed MIPI at the time of 1st R/P was low in 12.7% pts, intermediate in 32.1% and high 59.8% pts. Rituximab was used in 69.5% of patients, DHAP or ESHAP was used in 25.1% cases, FC in 22.8% of cases, CHOP like regimen in 9.4%, HD Ara-C in 11.8%, only 4.7% were treated with targeted therapy temsirolimus or lenalidomide. Altogether 77.2% pts were treated with the polychemotherapy and 22.8 with monotherapy. ASCT and AlloSCT were performed in 5.5% and 8.7% pts resp. During follow up there were observed 74 deaths not related to subsequent progression and 53 2nd R/Ps. The median of 2nd PFS and 2nd OS from the date of 1st R/P was 1.0 and 1.3 years resp. The sec MIPI low vs. intermediate vs. high risk had significant prognostic impact on 2nd PFS: 5.8 vs 1.7 vs 0.9 years (p<0.0001) (fig 1) as well as on OS : 5.8 vs 3.4 vs 1.1 years (p<0.0001) (fig 2). The cohort of 53 pts with 2nd R/P had median age 68 (38-85) yers, male/female ratio was 1.4. Rituximab was used in 45.9% of treated patients and 48.3% of pts were treated with single drug. During follow up 11 pts developed 3rd R/P and other 30 pts died due to current progression, toxicity or in remission. The median of 3rd PFS from the time of 2nd R/P was 6.8 m and OS 7.4 months. Pts who were treated for 3rd R/P recieved rituximab in 50% of cases and the majority (81.2%) were treated with other single drug. The median of 4th PFS from 3rdR/P was 4.9 m and OS 5.5 months .Conclusions: Our analysis of relapsed MCL patients shows that 1: Median PFS from the Dg was 2.9 y but each subsequent relapse resulted in significantly shorter PFS median 12.1, 6.8 and 4.9 months resp. 2: The median OS from Dg was 5.5y but after each relapse it became shorter - 15.7 m, 7.4 m and 5.5 months resp. 3: The sec MIPI at the time of relapse discriminates the groups with significantly different prognosis. DisclosuresNo relevant conflicts of interest to declare.

Prognostic Impact of Gender in Diffuse Large B Cell Lymphoma Patients Treated with R-CHOP Therapy

Background: Since the introduction of rituximab, an anti-CD20 monoclonal antibody, the prognosis of patients with CD20-positive non-Hodgkin lymphoma has significantly improved. Recent reports have shown a gender-associated difference in rituximab clearance and clinical response, suggesting that rituximab may be more effective in female patients. However, the prognostic impact of gender with regard to rituximab clearance in diffuse large B-cell lymphoma (DLBCL) patients has not been elucidated thus far.Methods: We retrospectively analyzed data from 576 consecutive DLBCL patients, uniformly treated with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-21) therapy in 9 institutions in Japan, between 2001 and 2012. Patients with a dose reduction greater than 20%, mainly elderly patients with low performance status, were excluded from this study. The median age of the cohort was 63 years (range, 18–89 years), and 331 (57%) of the patients were male.Results: With respect to the International Prognostic Index (IPI) factors, a significantly higher proportion of female patients had elevated serum lactate dehydrogenase (sLDH) levels than male patients (57% vs. 48%, P = 0.03). A difference was also observed in the frequency of bone marrow (BM) involvement, which was primarily observed in male patients (8% in female vs. 15% in male, P= 0.006).No difference was observed between sexes in other baseline factors (other IPI factors, bulky mass over 10 cm, B symptoms). Complete remission rate for R-CHOP-21 was 86% in female patients and 85% in male patients (P = NS). After a median follow-up of 48 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 73.7% and 84.3%, respectively. The IPI on diagnosis was low for 238 (41.3%) patients, low-intermediate for 152 (26.4%) patients, high-intermediate for 94 (16.3%) patients, and high for 92 16.0%) patients, with significant differences in survival among the 4 groups (3-year OS: 93.2%, 85.1%, 81.1%, and 63.6%, respectively, P < 0.001). Univariate analysis revealed that advanced clinical stage, poor performance status (PS 2-4), elevated sLDH, more than 1 extranodal involvement, BM involvement, bulky mass over 10 cm, and B symptoms had prognostic impact for both PFS and OS (all P <0.001). However, there was no significant difference in the survival rate between female and male patients (3-year PFS; 73.9% vs. 73.5%, P = 0.58; 3-year OS; 84.9% vs. 84.0%, P = 0.47). Moreover, gender did not have an impact on prognosis among younger (<60 years)/elderly (>60 years), normal/elevated sLDH, and positive/negative BM involvement patients’ cohort. Multivariate analysis revealed that clinical stage (P = 0.002 for PFS, 0.009 for OS), bulky mass (0.009, 0.03), B symptom (0.05, 0.02), and sLDH (P = 0.08 for PFS) had a prognostic impact, whereas gender was not identified as a prognostic factor.Conclusion: Although a difference in the rate of rituximab clearance has been previously reported (Pfreundschuh et. al., Blood 2014), gender was not found to be a prognostic factor among DLBCL patients receiving uniform R-CHOP therapy in this study with Japanese patients’ cohort. DisclosuresNo relevant conflicts of interest to declare.

Extended Use of Rituximab in Older Adults with Non-Hodgkin Lymphoma

Background: The introduction of rituximab has improved outcomes in B-cell non-Hodgkin lymphoma (BCL) across all histologies. Extended use of rituximab, or maintenance rituximab, improves progression-free survival in follicular lymphoma (FL) patients who achieve a response to induction rituximab with or without chemotherapy, but there is no evidence of an overall survival benefit. There is currently little evidence to support extended use of rituximab in other histologic subgroups, and older patients in particular may be at risk of adverse events. Our objective was to characterize patterns and predictors of extended rituximab therapy in a population-based cohort of older BCL patients in the United States.Methods: In the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset,we identified patients 66 years and older diagnosed with BCL in 2000-2010. Histology was classified as diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), FL, mantle cell lymphoma (MCL), other indolent BCL, and BCL not otherwise specified (NOS). We identified Medicare claims for rituximab starting at any point following diagnosis. Extended rituximab therapy was defined as a duration of greater than 7 months with no gap in rituximab claims greater than 6 months. Demographic and clinical characteristics associated with extended rituximab were evaluated in multivariable logistic regression.Results: There were 24,232 BCL patients who received rituximab during the study period. The cohort was predominantly white (91%), half were men, 15% had a Charlson comorbidity score ≥2, and 12% were 85 years or older. DLBCL was the most common histology (44%), followed by FL (21%), other indolent BCL (17%), BCL-NOS (13%), MCL (6%), and BL (1%). Overall, most patients (85%) received rituximab for ≤7 months, but duration varied by histology (Table 1). More than a quarter of FL patients had extended therapy, including 7% who had rituximab for more than 24 months. Among patients with other histologies, receipt of extended therapy varied from 20% (other indolent BCL) to 8% (BL). Compared with FL patients and controlling for demographic and disease characteristics, patients with other histologies were less likely to receive extended rituximab therapy (p<0.0001). Adjusted odds ratios were 0.91 (95% CI 0.78-1.05) for MCL, 0.83 (0.75-0.91) for other indolent BCL, 0.67 (0.60-0.75) for BCL-NOS, 0.32 (0.29-0.36) for DLBCL, and 0.28 (0.15-0.53) for BL. However, 75% of patients who had extended rituximab, and 63% of those who had rituximab >24 months, were of non-FL histology. Controlling for histology and other characteristics, extended rituximab therapy was more likely among women (adjusted OR 1.09, 95% CI 1.01-1.18), and less likely among unmarried patients (0.92, 0.85-0.99) and those in rural areas (0.84, 0.75-0.94). There was significant regional variation (p<0.0001), with patients in the West (adjusted OR 0.86, 95% CI 0.79-0.95), and Midwest (0.75, 0.66-0.86) less likely to receive extended rituximab than those in the Northeast. There was no significant relationship between extended therapy and age, race, or comorbidity.Conclusions: While FL patients were more likely than others to receive extended rituximab, the majority of patients receiving extended rituximab had other diagnoses across the entire spectrum of B-cell lymphoma, for which extended rituximab is neither indicated nor supported by guidelines or prospective data. After controlling for histology, several demographic characteristics significantly influenced the duration of therapy. Extended use of rituximab – particularly in patients for whom it is not clearly indicated – may have important implications for clinical outcomes, toxicity, and costs.Table 1Duration of rituximab use across B-cell lymphoma histologic subgroupsHistologyDuration of RituximabN≤7 mos>7-24 mos>24 mosDLBCL10,56791%7%2%FL5,00176%17%7%BL12792%6%2%MCL1,33979%16%5%Other indolent4,09580%15%5%BCL NOS3,10383%13%4%Total24,23280%15%5% DisclosuresMatasar:Merck: Research Funding; GlaxoSmithKline: Research Funding; Genentech: Honoraria; Spectrum: Honoraria. Nabhan:Celgene: Honoraria, Research Funding.

Prognostic Role of Serum Albumin Level in DLBCL before and during the Rituximab Era. Retrospective GISL Study over 738 Cases

Introduction.Serum albumin (SA) has been shown to be a prognostic marker in many hematological malignancies, and in diffuse large B-cell lymphoma (DLBCL) before the introduction of rituximab. SA may be a surrogate for age, comorbid status, and disease severity. Here, we aimed to assess the role of SA as prognostic marker for overall survival (OS) in patients with newly diagnosed DLBCL treated with and without rituximab (R) containing regimens (CHOP and CHOP-like).Patients and methodWe collected 738 patients complete for IPI factors [age, LDH, extra nodal sites, stage and performance status (PS)] and SA recorded in the GISL database from 1998 to 2012. OS was estimated using the Kaplan-Meier method, with Cox proportional hazard model used to identify potential risk factors for time-to-event data. Optimal cut-off for SA was calculated by means of ROC curve at 5 years of follow-up. Stability of the cut-point was analyzed using bootstrap techniques. The role of SA was explored interacting SA with R and adjusting by IPI. The strength of SA as prognostic factor was evaluated counting the bootstrap frequency of inclusion (BIF, 1000 re-samples) of SA, adjusted by the IPI factors, in Cox PH regression.ResultsOf the 738 patients included in the study 322 (44%) were treated with R-CHOP and 416 (56%) were treated without regimens containing R. The median age at diagnosis was 60 years (range 21-89) and 45%, 25% and 30% were categorized in IPI 0-1, 2 and 3/5 respectively; and the median SA was 3.8 g/dL (range 1.0-6.4). Patients treated with R showed a greater % of high IPI 3/5 (43%) compared to those not treated with R (20%, P<0.001) and a lower SA level (3.7 vs 3.9 g/dL, P=0.001). SA showed correlation with IPI (4.0, 3.8 and 3.5 g/dL in IPI 0-1, 2 and 3/5, respectively, P=0.0001).Overall, the median follow-up was 64 months (range 1-157) with 241 dead. The 5-ys OS was 66% (95 CI 62-70) and the best cut-off for SA was 3.7 g/dL with ROC=68.5%. OS at 5-yrs in patients not treated with R was 74% and 52% for SA ≥3.7 and <3.7 g/dL, respectively (P<0.001). In patients treated with R the 5-yrs OS was 78% and 50% for SA ≥3.7 and <3.7 g/dL (P<0.001). The SA <3.7 g/dL, interacted by R and adjusted by IPI, had HR = 1.71 (95 CI 1.22-2.40, P=0.002) and HR = 1.99 (95 CI 1.31-3.01, P=0.001) in cases not treated and treated with R, and the HRs did not vary between treatments (P=0.582). The BIF of SA<3.7 g/dL adjusted by IPI factors was 88% and 79% in patients without and with R chemotherapy.ConclusionThe SA is a simple variable collected from the clinical-chemistry, that showed a good prognostic property in DLBCL. Although correlated with the IPI, SA has maintained a strong prognostic value both before or during the rituximab era. The biologic role of SA over the survival is unclear. It has been hypothesized that low level of SA may be associated with 1) increased inflammatory response to the tumor, 2) increased cytokine release and 3) poor nutritional status, and due to this condition the patients would not be able to receive the full cycles of chemotherapy. DisclosuresNo relevant conflicts of interest to declare.

Hypermethylation of DAPK1 is an independent prognostic factor predicting survival in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. Improvements in overall survival have been observed with the introduction of rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), however, prognostic markers are still needed. Methylation of the death associated protein kinase (DAPK or DAPK1) gene and TP53 mutations are likely to have prognostic value in DLBCL. We have assessed TP53 mutations and allelic DAPK1 methylation patterns in a cohort of 119 DLBCL patients uniformly treated with R-CHOP-like regimens. We found that DAPK1 promoter methylation was associated with shorter overall survival (p=0.017) and disease-specific survival (p=0.023). In multivariate analyses DAPK1 methylation remained as an independent prognostic factor predicting disease-specific survival (p=0.038). When only considering individuals heterozygous for the rs13300553 SNP monoallelic methylation of the A-allele was associated with shorter overall- and disease-specific survival (p<0.001). Patients carrying both DAPK1 methylation and a TP53 mutation had an inferior survival compared to patients carrying only one of these molecular alterations, however, this was borderline statistically significant. Allele-specific DAPK1 methylation patterns were also studied in a cohort of 67 multiple myeloma patients, and all of the methylated multiple myeloma samples heterozygous for the rs13300553 SNP were methylated on both alleles.

ANTI-B-CELL THERAPY AT IMMUNE INFLAMMATORY RHEUMATIC DISEASES: EFFICACY AND TOLERABILITY IN 229 PATIENTS

Objective: to assess the efficacy and tolerability of Rituximab treatment in patients with serious immune inflammatory rheumatic diseases (IRD) like systemic lupus erythematosus (SLE), systemic sclerosis (SS), systemic vasculitis (SV), Sjogren syndrome (SjS), dermatomyositis/polymyositis (DM/PM). Subjects and methods. The clinical efficacy has been analyzed in 229 patients with IRD: SLE (n=97), SV (n=50), SS (n=40), SjS (n=23) and DM/PM (n=19). Rituximab treatment was accompanied by administration of glucocorticoids and/or immunosuppressive drugs. Most patients demonstrated resistance to or low tolerability of standard therapy. Efficacy of treatment was analyzed in each group with the criteria relevant for each disease. To compare clinical response to the treatment between the groups we used gradations accepted by international registries: complete (good) response, partial response, no response. Average duration of monitoring comprised 72 (1–288) weeks after the first introduction of Rituximab. Average Rituximab dose administered to patients over the period of monitoring was low and varied from 1.6±0.84 in DM/PM to 3.1±1.75 in SV. About 80% of patients received one or two courses of Rituximab except for patients with SS (half of them received three and more courses). Results. «Complete response» was observed in 50.6%, «partial response» – in 35% of patients. Rituximab courses provided positive dynamics in clinical scores and allowed to reduce supportive dose of glucocorticoids and to lower the dose or withdraw of immune-stimulating drugs. Multiple Rituximab courses provided stable and longlasting effect. Recurrences were observed less frequently, whereas efficacy of the therapy increased during a year and longer. Occurrence of adverse events and mortality rate were comparable to data of other national Rituximab registries. Conclusion. The results of the study may prove administration of Rituximab in patients with resistance to standard therapy

Long-term survey of survival time, histological transformation, and secondary malignancies in Japanese patients with advanced-stage follicular lymphoma in the rituximab era: Hokkaido Hematology Study Group.

Following the introduction of rituximab, the long-term overall survival (OS) rate of advanced-stage follicular lymphoma (FL) cases was expected to improve after the introduction of rituximab: however, there is a lack of large-scale survey data in Asia due to the relatively low incidence of FL. We conducted a retrospective survey to assess the treatment outcomes in patients with newly diagnosed advanced-stage FL in 29 institutions in Hokkaido from January 2001 to December 2010. The total number of patients was 443 (men 47.6%, women 52.4%), with a median age of 55 years (range 20-80 years). Of the cases examined, 42.2% had stage III and 57.8% had stage IV disease. Furthermore, 62.5, 19.7, 9.2, 5.2, and 3.4% had performance statuses of 0, 1, 2, 3, and 4, respectively. The 5-year OS was 91.2%, and no survival plateau was observed. Seventeen patients experienced secondary malignancies (six hematological diseases and 11 solid cancers; 5-year probability, 4.2%). Eighteen patients experienced transformation (5-year probability, 4.5%). The overall survival at 5 years after therapy for transformation was 50%. Before the introduction of rituximab, the 5- to 10-year OS of advanced-stage FL patients in Japan was reported to be about 30-60%. Although these data are limited, improvement in OS has been observed in Japan during the rituximab era.

Socioeconomic disparities in mortality after diffuse large B-cell lymphoma in the modern treatment era

AbstractDespite advances in treatment, including the introduction of rituximab, survival after diffuse large B-cell lymphoma (DLBCL) remains heterogeneous. However, no studies have considered the association between neighborhood socioeconomic status (SES) and race/ethnicity on DLBCL mortality before (1988-2000) and after (2001-2009) the introduction of rituximab. We studied all 33 032 DLBCL patients diagnosed between 1988-2009 in California for vital status through December 31, 2010. Patients diagnosed from 2001 to 2009 vs 1988 to 2000 had significantly decreased overall and DLBCL-specific mortality. However, those living in lower SES neighborhoods had 34% (95% confidence interval [CI], 27%-40%) and 24% (95% CI, 16%-32%) higher mortality rate from all causes and lymphoma, respectively, than patients in higher SES neighborhoods. The magnitude of mortality disparities by neighborhood SES was more marked in younger (<65 years) than in older patients (≥65 years), in married than nonmarried patients, and after 2000. We concluded that patients living in low SES neighborhoods had substantially worse survival after DLBCL, and this disparity was striking in younger (ie, not eligible for Medicare-aged) patients, married patients, and after the introduction of rituximab. These disparities suggest there are barriers, including inadequate insurance coverage with additional financial burden, to effective treatment among socioeconomically disadvantaged patients.

Ki-67 is a valuable prognostic predictor of lymphoma but its utility varies in lymphoma subtypes: evidence from a systematic meta-analysis

BackgroundKi-67 is a nuclear protein involved in cell proliferation regulation, and its expression has been widely used as an index to evaluate the proliferative activity of lymphoma. However, its prognostic value for lymphoma is still contradictory and inconclusive.MethodsPubMed and Web of Science databases were searched with identical strategies. The impact of Ki-67 expression on survival with lymphoma and various subtypes of lymphoma was evaluated. The relationship between Ki-67 expression and Diffuse Large B Cell Lymphoma (DLBCL) and Mantle Cell Lymphoma (MCL) was also investigated after the introduction of a CD-20 monoclonal antibody rituximab. Furthermore, we evaluated the association between Ki-67 expression and the clinical-pathological features of lymphoma.ResultsA total of 27 studies met the inclusion criteria, which comprised 3902 patients. Meta-analysis suggested that high Ki-67 expression was negatively associated with disease free survival (DFS) (HR = 1.727, 95% CI: 1.159-2.571) and overall survival (OS) (HR = 1.7, 95% CI: 1.44-2) for lymphoma patients. Subgroup analysis on the different subtypes of lymphoma suggested that the association between high Ki-67 expression and OS in Hodgkin Lymphoma (HR = 1.511, 95% CI: 0.524-4.358) was absent, while high Ki-67 expression was highly associated with worse OS for Non-Hodgkin Lymphoma (HR = 1.777, 95% CI: 1.463-2.159) and its various subtypes, including NK/T lymphoma (HR = 4.766, 95% CI: 1.917-11.849), DLBCL (HR = 1.457, 95% CI: 1.123-1.891) and MCL (HR = 2.48, 95% CI: 1.61-3.81). Furthermore, the pooled HRs for MCL was 1.981 (95% CI: 1.099-3.569) with rituximab and 3.123 (95% CI: 2.049-4.76) without rituximab, while for DLBCL, the combined HRs for DLBCL with and without rituximab was 1.459 (95% CI: 1.084-2.062) and 1.456 (95% CI: 0.951-2.23) respectively. In addition, there was no correlation between high Ki-67 expression and the clinical-pathological features of lymphoma including the LDH level, B symptoms, tumor stage, extranodal site, performance status and IPI score.ConclusionsThis study showed that the prognostic significance of Ki-67 expression varied in different subtypes of lymphoma and in DLBCL and MCL after the introduction of rituximab, which was valuable for clinical decision-making and individual prognostic evaluation.

Rituximab in recurrent idiopathic giant cell myocarditis after heart transplantation: a potential therapeutic approach

Giant cell myocarditis (GCM) is a very aggressive form of myocardial inflammation. While immunosuppressive therapy is usually able to keep under control the disease and prolong the average transplant-free survival in many patients, effective therapeutic strategies to prevent or treat the recurrence of GCM in transplanted organs are still to be defined. We report the case of a young woman with idiopathic GCM who, despite immediate aggressive immunosuppressive therapy, rapidly progressed to irreversible heart failure and required urgent heart transplantation. Yet, 2 months later, the disease recurred in the transplanted heart, despite an intensive four-drug antirejection regimen. The introduction of rituximab, an anti-CD20 monoclonal antibody, 375 mg/m(2) /week i.v. for four consecutive weeks and then every 4 months as maintenance therapy, determined a complete and steady clinical remission of the disease. After nineteen months since rituximab administration, the patient is doing well and repeated follow-up endo-myocardial biopsies confirmed the complete resolution of myocardial inflammation. Our experience seems to suggest that rituximab can be a reasonably effective and safe therapeutic option in GCM recurring in transplanted organs.

Treatment of follicular lymphoma.

Follicular lymphoma (FL) is the most common subtype of indolent lymphomas. Several lines of evidence suggest that the prognosis of patients with FL has improved since the introduction of rituximab, although cure cannot be achieved. Although the treatment paradigm for FL has changed over the past decade with the introduction of rituximab and other agents, there is still no standard therapy to fit all patients. Instead, treatment decisions are made taking into consideration disease status (stage, tumor burden, and presence of symptoms) and patient factors including patient preferences. Rituximab-containing chemotherapy such as R-CHOP, R-CVP, and bendamustine plus rituximab is usually recommended for symptomatic patients. However, optimal rituximab-containing chemotherapy has not been established. Rituximab maintenance is one of the post-induction options for patients responding to first-line chemoimmunotherapy. For patients without symptoms and low-tumor burden, both expectant management (watchful waiting) and rituximab monotherapy are reasonable options. A very limited proportion of patients with FL are diagnosed at stage I with rigorous staging using bone marrow biopsy and whole-body imaging with computed tomography (CT) and/or positron emission tomography/CT. Although local radiotherapy has been the standard approach for these patients, its role is being questioned. Patients with FL who achieve remission eventually relapse and require salvage therapy. The salvage regimen should be chosen taking into account previous treatment and its response duration. Moreover, the presence of histological transformation should be assessed.

Rituximab in patients with rheumatoid arthritis in routine practice (GERINIS): six-year results from a prospective, multicentre, non-interventional study in 2,484 patients

IntroductionThe aim of this study was to evaluate the safety and efficacy of rituximab (RTX) in a large cohort of patients with rheumatoid arthritis in routine care, and to monitor changes in daily practice since the introduction of RTX therapy.MethodsThis was a multicentre, prospective, non-interventional study conducted under routine practice conditions in Germany. Efficacy was evaluated using Disease Activity Score in 28 joints (DAS28) and Health Assessment Questionnaire-Disability Index (HAQ-DI). Safety was assessed by recording adverse drug reactions (ADRs). Physician and patient global efficacy and tolerability assessments were also evaluated.ResultsOverall, 2,484 patients (76.7% female, mean age 56.4 years, mean disease duration 11.7 years) received RTX treatment (22.7% monotherapy). The total observation period was approximately six-years (median follow-up 14.7 months). RTX treatment led to improvements in DAS28 and HAQ-DI that were sustained over multiple courses. DAS28 improvements positively correlated with higher rheumatoid factor levels up to 50 IU/ml. Response and tolerability were rated good/very good by the majority of physicians and patients. Mean treatment intervals were 10.5 and 6.8 months for the first and last 400 enrolled patients, respectively. Infections were the most frequently reported ADRs (9.1%; 11.39/100 patient-years); approximately 1% of patients per course discontinued therapy due to ADRs.ConclusionsProlonged RTX treatment in routine care is associated with good efficacy and tolerability, as measured by conventional parameters and by physicians’ and patients’ global assessments. Rheumatoid factor status served as a distinct and quantitative biomarker of RTX responsiveness. With growing experience, physicians repeated treatments earlier in patients with less severe disease activity.

Impact of Rituximab Desensitization on Blood-Type-Incompatible Adult Living Donor Liver Transplantation: A Japanese Multicenter Study

We evaluated the effects of rituximab prophylaxis on outcomes of ABO-blood-type-incompatible living donor liver transplantation (ABO-I LDLT) in 381 adult patients in the Japanese registry of ABO-I LDLT. Patients underwent dual or triple immunosuppression with or without B cell desensitization therapies such as plasmapheresis, splenectomy, local infusion, intravenous immunoglobulin and rituximab. Era before 2005, intensive care unit-bound status, high Model for End-Stage Liver Disease score and absence of rituximab prophylaxis were significant risk factors for overall survival and antibody-mediated rejection (AMR) in the univariate analysis. After adjustment for era effects in the multivariate analysis, only absence of rituximab prophylaxis was a significant risk factor for AMR, and there were no significant risk factors for survival. Rituximab prophylaxis significantly decreased the incidence of AMR, especially hepatic necrosis (p < 0.001). In the rituximab group, other B cell desensitization therapies had no add-on effects. Multiple or large rituximab doses significantly increased the incidence of infection, and early administration had no advantage. In conclusion, outcomes in adult ABO-I LDLT have significantly improved in the latest era coincident with the introduction of rituximab.

Rituximab-Based Treatments Followed By Adoptive Cellular Therapies For EBV-Associated Post-Transplant Lymphoproliferative Disease In Recipients Of Allogeneic Hematopoietic Stem Cell Transplantation

Background The introduction of rituximab has improved the complete remission(CR) rate of EBV-associated posttransplant lymphoproliferative disease(PTLD), thus the recurrence of PTLD becomes the main cause affecting long-term survival, which is closely related with the reestablishment of immune functions. Unfortunately, PTLD happens generally at the early stage of transplants and the reconstitution of immunocompetence needs for 3-5 years in the recipients of allo-HSCT. In this study, a sequential therapeutic strategy that based on rituximab followed by adoptive cellular therapies (G-CSF mobilized donor lymphocyte infusion (DLI) or EBV-specific cytotoxic T lymphocyte infusion (EBV-CTL)) was evaluated for decreasing relapse of PTLD. Methods Fifty-two patients with EBV-PTLD were enrolled in this prospective study. Once PTLD was diagnosed,immunosuppressants would be withdrawn in a stepwise fashion (ie, total dose reduced by 20%/week)if the condition of the patient was acceptable. The rituximab-based treatments (rituximab alone or combined with chemotherapy) were administrated based on PTLD histopathology and the blood cells counts. After CR or 2 cycles of rithuximab-based treatments, DLI or EBV-CTL therapy would be performed in this cohort. The rituximab-based treatments would be discontinued once patient obtained CR, and DLI would be performed once Monthly till GVHD occurred or for a total of 4 doses and EBV-CTL infusion would be performed every two weeks till GVHD occurred or for a total of 8 doses . Results After 2 cycles of the rituximab-based treatments, 37 patients obtained complete remission (CR), 8 obtained partial remission (PR), and 7 no remission (NR), including 4 died of PTLD progression. The CR rate of 2 cycles of rituximab-based treatments was 71.2%. After rituximab-based treatments combined with the adoptive cellular therapies, 9 obtained CR and 2 died of PTLD progression in 11 patients who did not achieve CR within 2cycles of rituximab-based treatments. The CR rate of 2 cycles of rituximab-based treatments combined with cellular therapies was 88.5%. Seven patients experience acute GVHD (aGVHD) (grade I in 1 and grade II in 6) and 8 chronic (cGVHD) (limited cGVHD in 5 and extensive cGVHD in 3) in 39 patients underwent a median 4 doses of DLI. One patient experienced grade II aGVHD and 2 limited cGVHD in 8 patients underwent a median of 7 doses of EBV-CTL. There were no differences in incidence of aGVHD(P=1.000) and cGVHD(P=1.000) between the patients received DLI and CTL. Within a median follow-up of 632 (range, 21 to 1651) days, one patient experienced PTLD relapse, and the 4 year cumulative incidence of PTLD relapse and primary malignancy relapse was 5.3%±5.1% and 6.2±4.3%, respectively. The 4 year cumulative overall survival (OS) after PTLD and disease(PTLD)-free survival were 66.2%±7.1% and 65.9±7.3%, respectively. Conclusions Rituximab-based treatments combined with the adoptive cellular therapies might elevate PTLD CR rate, and decrease the relapse in the recipients of allo-HSCT. Disclosures: Liu: It was supported by 863 Program (No. 2011AA020105), National Public Health Grand Research Foundation (Grant No. 201202017): Research Funding; It was supported by National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China(11A72121174): Research Funding.

Secondary central nervous system involvement in 599 patients with diffuse large B-cell lymphoma: are there any changes in the rituximab era?

The introduction of rituximab has improved the overall prognosis of diffuse large B-cell lymphoma (DLBCL). However, the impact of rituximab on central nervous system (CNS) involvement in DLBCL remains a matter of debate. Patients with DLBCL and no CNS involvement at initial diagnosis were eligible for this analysis. Patients must have received treatment either with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP plus rituximab (R-CHOP). We analyzed the incidence, clinical features and outcomes of CNS involvement that developed during or after completion of therapy. A cohort of 599 patients was eligible for this analysis. With a median follow-up of 26 and 21 months, respectively, 19 of 294 (6.5 %) in the CHOP group and 13 of 305 (4.3 %) in the R-CHOP group developed CNS involvement. Rituximab did not significantly reduce the risk of CNS involvement either in the univariate (P = 0.354) or in the multivariate analysis (RR 0.632, 95 % CI 0.301–1.327, P = 0.225). No patient developed CNS disease after 19 months in the R-CHOP group whereas four patients (21.1 %) in the CHOP group developed CNS disease 2 years after initial diagnosis (range 34–83 months). Systemic disease prior to or coincident with CNS occurrence was more common in the CHOP group than in the R-CHOP group (73.7 versus 38.5 %, P = 0.046). Isolated CNS events were more common in the R-CHOP group than those in the CHOP group (53.8 versus 10.5 %, P = 0.015). This study indicates that isolated CNS events are more common in DLBCL patients treated with R-CHOP than those treated with CHOP alone. Our data also suggest that the time and pattern of CNS events and systemic disease status differ with the addition of rituximab. Better methods for earlier detection and prophylaxis of CNS involvement are needed in the rituximab era.

One Size Does Not Fit All in Follicular Lymphoma

One Size Does Not Fit All in Follicular Lymphoma

Clinical outcome of elderly patients with Epstein–Barr virus positive diffuse large B‐cell lymphoma treated with a combination of rituximab and CHOP chemotherapy

Several studies have suggested the possibility of a prognostic relationship between Epstein-Barr virus (EBV) and diffuse large B-cell lymphoma (DLBCL). The clinical outcome of EBV-associated DLBCL is not clear, especially since the introduction of rituximab. We retrospectively analyzed 222 elderly patients (≥50 years) with DLBCL who received R-CHOP chemotherapy and evaluated the state of EBV-encoded RNA-1 (EBER). Eighteen cases (8.1%) were EBER-positive (+). After a median of six cycles of R-CHOP chemotherapy, the response rate (≥partial response) was 72.2% (13/18) in the EBV (+) patients and 90.2% (184/204) in the EBV (-) DLBCL patients (P = 0.021). Four of 18 (22.2%) EBV (+) DLBCL patients received two or fewer cycles of R-CHOP chemotherapy. R-CHOP chemotherapy was also interrupted early more frequently compared with the EBV (-) group (2.5%) (P = 0.00). At a median follow-up of 32.8 months, there was no significant difference in the overall survival between the groups (P = 0.627). The EBV (+) DLBCL patients with early interruption of R-CHOP chemotherapy showed a trend toward a high EBV-DNA titer (≥1,000 copies/mL) (P = 0.091). The results suggest that the EBV (+) tumoral status of elderly DLBCL patients who undergo R-CHOP chemotherapy does not predict their survival but that their EBV status may contribute to the early interruption of R-CHOP chemotherapy.

Comparison of prognostic models for patients with diffuse large B-cell lymphoma in the rituximab era

Several revisions of International Prognostic Index (IPI) have been proposed for patients with diffuse large B-cell lymphoma (DLBCL) after the introduction of rituximab. Expanding evidence suggests that baseline absolute lymphocyte count (ALC) is also an independent factor for outcome prediction. We investigated the optimal prognostic model for these patients in the rituximab era. The study enrolled 274 consecutive patients with DLBCL receiving first-line cyclophosphamide, doxorubicin, vincristine, and prednisone based chemotherapy with rituximab between 2003 and 2009. Five factors within IPI and ALC were entered for Cox regression analysis. Overall survival (OS) and progression-free survival were calculated for different risk groups of models. Efficacy of models was compared by the value of Akaike information criterion (AIC). Revised IPI (R-IPI) and ALC/R-IPI, but not IPI, were informative to discriminate between different risk groups. In multivariate analysis for individual factors of the prognostic models, performance status >1 [odds ratio (OR) 3.59], Ann Arbor stage III or IV (OR 2.24), and ALC <1 × 10⁹/L (OR, 2.75) remained significant. Another modified score based on the three factors divided patients into four risk groups and the 3-year OS rate was 93, 77, 39, and 13 %, respectively. By comparing AIC values in the Cox proportional hazards model, the modified three-factor model was the superior prognostic model followed by established ALC/R-IPI, R-IPI, and standard IPI. In conclusion, the addition of the novel factor, ALC, interacts with other established factors in outcome prediction for DLBCL. Development of a new score is needed for a better risk stratification in the rituximab era and would be helpful in the design of future clinical trials. The proposed three-factor model should be validated in large-scale studies.

SP0028 Adults with lupus nephritis

Lupus nephritis is the most common severe manifestation of SLE and is associated with increased mortality, chronic kidney disease and end stage renal failure. Outcomes are improved by early diagnosis...

Latest advances in connective tissue disorders.

The connective tissue disorders comprise a number of related conditions that include systemic lupus erythematosus (SLE) and the antiphospholipid (Hughes) syndrome, scleroderma, myositis and Sjögren's syndrome. They are characterized by autoantibody production and other immune-mediated dysfunction. There are common clinical and serological features with some patients having multiple overlapping connective tissue disorders. The latest advances include new approaches to therapy, including more focused utilization of existing therapies and the introduction of biological therapies in SLE, more precise protocols for assessment of severe disease manifestations such as in interstitial lung disease and pulmonary artery hypertension in scleroderma, new antibodies for disease characterization in myositis and new approaches to patient assessment in Sjögren's syndrome. B cells have a critical role in most, if not all of these disorders such that B-cell depletion or suppression of B-cell activating cytokines improves disease in many patients. In particular, the introduction of rituximab, a monoclonal antibody targeting the CD20 molecule on B cells, into clinical practice for rheumatoid arthritis and B-cell lymphoma has been a key driver of experimental approaches to therapy in connective tissue disorders. Genetic studies also suggest a role for the innate immune system in disease pathogenesis, suggesting further future targets for biological therapies over the next few years.