Rituximab Era Research Articles

Response Duration and Relapse Free Survival Shorten after Each Episode of Immune Thrombotic Thrombocytopenic Purpura (iTTP) Treated in the Rituximab Era

INTRODUCTION: Immune thrombotic thrombocytopenic purpura (iTTP) is caused by an autoantibody mediated deficiency of ADAMTS13 and characterized by recurrent episodes of life-threatening thrombotic microangiopathy. Rituximab (anti-CD20 monoclonal antibody) reduces relapse rates in many cases. This multicenter observational aimed at comparing durability of rituximab response (measured as relapse free survival, RFS) in first versus subsequent episodes of iTTP based on the clinical observation that patients with multiply relapsing disease may have attenuated responses to rituximab. METHODS: We first evaluated clinical RFS (time from rituximab treatment to clinical relapse) in the United States Thrombotic Microangiopathy Consortium retrospective iTTP registry that includes data from 15 high volume academic centers. We performed a subsequent analysis from the well-phenotyped Johns Hopkins University (JHU) and University of Minnesota (UM) prospective iTTP cohorts, that additionally include serial assessments of ADAMTS13 activity in remission, to confirm our findings and to evaluate overall RFS [a composite of clinical relapse, ADAMTS13 relapse including ADAMTS13 relapse treated with preemptive rituximab) which is a clinically relevant endpoint in the era of ADAMTS13 monitoring and receiving preemptive rituximab. ADAMTS13 relapse was defined as ADAMTS13 <20% without thrombocytopenia or symptoms. In both analyses, we included only patients with > 1 year follow up after treatment with rituximab (either during iTTP episodes or preemptive) and excluded those who received immunosuppression other than rituximab or steroids. Patients who started maintenance rituximab (every 3 or 6 months) were censored at that point). We used Cox regression to examine factors associated with clinical RFS and overall RFS including first versus subsequent rituximab treatment episodes as a covariate, and Kaplan-Meier survival curves to visualize these relationships. RESULTS: In the USTMA registry, 310 unique patients had a total of 384 iTTP episodes treated with rituximab (310 first, 53 second, and 21 were 3rd to 5th courses of rituximab) between 2003-2019. Presenting in relapsed iTTP [HR 2.10 (95% CI 1.24 - 3.58)], Black race [HR 3.12 (95% CI 1.68-5.80)] and second or subsequent rituximab course [HR 2.80 (95% CI 1.53-5.10)] were associated with clinical relapse in a Cox regression model that also included age, sex, and exacerbations. Median RFS was higher after the first compared with subsequent (2nd-5th) rituximab courses (6.0 vs 2.1 years, P = 0.04). Since race was significantly associated with clinical RFS in the Cox regression model, we evaluated clinical RFS after first and subsequent rituximab courses separately for Black and White participants. Among White patients, clinical RFS after the second or subsequent rituximab courses was not significantly different compared to the first course [HR=1.86 (95% CI 0.22-15.80), P=0.57]. However, in Black patients, clinical RFS was shorter after the second and subsequent rituximab courses [HR=2.82 (95% CI 1.52-5.24), P=0.001]. The JHU and UM cohort included 97 patients with 266 episodes of rituximab treatment. Similar to the USTMA cohort, median clinical RFS was shortened with reach subsequent rituximab course. Median overall RFS (time to clinical or ADAMTS13 relapse) was also longest after the first rituximab course [2.8 (IQR 2.0-6.0) years] followed by the second course [2.0 (IQR 1.2-3.6) years], and third and subsequent episodes courses [1.0 (IQR 0.5-2.5) years] (P< 0.001). Overall RFS was shorter in White patients and the loss of response durability with later courses was most prominent in Black versus patients. For examples, median overall RFS from the first to the third or later courses reduced from 3.6 years to 1.5 years for White patients, and from 2.7 years and 0.9 years in Black patients (Figure 1). CONCLUSIONS: Despite's rituximab's known effect of prolonging RFS in iTTP, the time to clinical relapse or ADAMTS13 relapse (often a precursor of clinical relapse) shortens with multiple episodes/treatment courses with an earlier ‘wearing off’ effect in Black patients especially those being treated in relapse. Patients who have had ≥ 2 rituximab courses may need closer monitoring and and consideration of maintenance rituximab or other immunomodulators.

Clinical Characteristics and Outcomes of Elderly Patients with Stage I Diffuse Large B-Cell Lymphoma: A Study By Jiangsu Cooperative Lymphoma Group (JCLG)

Introduction Stage I diffuse large B-cell lymphoma (DLBCL) is defined as the involvement of a single lymph node or a group of adjacent nodes, or the presence of isolated extranodal lesions without nodal involvement. Generally, the prognosis of stage I DLBCL is excellent with 5-year overall survival (OS) over 90%. However, differences in disease characteristics and prognosis between elderly and younger patients with stage I DLBCL were not clear. Methods In this study, we conducted a retrospective data collection from 255 newly diagnosed patients with stage I DLBCL who were above 60 years old. The data was collected from 19 medical centers of of Jiangsu Cooperative Lymphoma Group (JCLG) located in Jiangsu Province, China. To enroll, patients had to undergo staging using either positron emission tomography/computed tomography (PET/CT) or contrast-enhanced CT scans of the chest, abdomen, and pelvis (C/A/P CT) with contrast, as well as bone marrow examination. Results The clinical characteristics of the 255 patients are presented in Table 1. The median age at presentation was 69 years, with a range of 61 to 92 years old. Among the 255 patients, 65.9% had at least one coexistent disease. A high Charlson Comorbidity Index (CCI), defined as ≥2, was found in 10.1% of patients. 63.9% had extranodal disease. The most common sites of extranodal involvement were the stomach (37.4%), intestine (19.0%), testes (11%), breast (7.4%), skin/soft tissue (5.5%), and sinus/nose (5.5%). According to the Hans algorithm, the non-GCB subtype accounted for 63.7% of patients and did not show a significant difference between the nodal and extranodal groups. None of the patients were diagnosed with double-hit lymphoma. Additionally, EBER was found to be positive in 3.7% of patients (5/134). The treatment approaches are outlined in Table 1. A total of 84.5% patients received the R-CHOP regimen as their primary treatment. The median number of R-CHOP courses administered was 6. Among the 204 patients with treatment evaluation records, 183 (89.7%) achieved complete remission (CR). With a median follow-up time of 30 months, 32 patients died during the follow-up period. Among them, 18 died from causes unrelated to lymphoma at a median age of 73 years. The 3-year progression-free survival (PFS) rate was 81.5% and the 3-year OS rate was 85.6%. In the univariate analysis, age ≥75 years (HR 3.30, P < 0·001) and CCI ≥2 (HR 2.92, P = 0·002) were significantly associated with worse PFS; age ≥75 years (HR 3·29, P = 0·001), CCI ≥2 (HR 2.57, P = 0·022) and non-GCB subtype (HR 1.79, P = 0·018) were significantly associated with worse OS. In multivariate analysis, age ≥75 years (HR 2.91, P = 0·001) and CCI ≥2 (HR 2.32, P = 0·02) remained independent risk indicators for worse PFS; age ≥75 years (HR 2.57, P = 0·015) and non-GCB subtype (HR 1.74, P = 0·025) were independent risk indicators for worse OS. None of the prognostic models including IPI, NCCN-IPI or stage-modified International Prognostic Index (sm-IPI) demonstrated statistical significance. However, by incorporating age≥75 and CCI≥2 into the sm-IPI, we could be able to provide a more accurate prediction of the prognosis for elderly patients with stage I DLBCL (Figure 1). Relapse occurred in 20 patients at a median time of 9 months. 91.7% (11/12) of patients with early relapse (defined as PFS less than 24 months) experienced recurrence in the same anatomical site as the primary disease. In contrast, only 25% (2/8) of patients with late relapse exhibited relapse in the initial site. Conclusion To the best of our knowledge, this is the largest retrospective study conducted specifically on stage I DLBCL in the Asian population during the rituximab era. Our findings suggest that elderly patients with stage I DLBCL have a higher non-lymphoma-related mortality rate and a higher likelihood of relapse in the same anatomical site for early relapses compared to late relapses. Integrating age ≥75 and CCI score into the sm-IPI will help to better assess prognosis.

Primary breast diffuse large B-cell lymphoma in the rituximab era: A retrospective study of the Chinese Southwest Oncology Group.

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare subtype of extranodal DLBCL, and the standard treatment remains controversial. In this study, we aimed to define the optimal treatment management in the rituximab era. A total of 5089 newly diagnosed DLBCL patients treated with rituximab-containing immunochemotherapy between 2008 and 2019 from the Chinese Southwest Oncology Group-affiliated institutes were identified, of whom 135 diagnosed with PB-DLBCL were eligible for this analysis. PB-DLBCL accounted for 2.7% of all DLBCLs. With a median follow-up of 4.2 years, the 5-year overall survival and progression-free survival rates were 84.8% and 71.6%, respectively. Breast and central nervous system (CNS) relapses were the main cause of treatment failure. We observed that consolidative breast radiotherapy (RT) significantly decreased breast relapse risk (5-year risk, 2.9% vs. 20.1%, p = 0.007). The CNS relapse risk was lower for patients who received high-dose methotrexate (HD-MTX) than for patients who did not (5-year risk, 0% vs. 15.2%, p = 0.015). We further screened the genetic mutation profile of 20 patients from two institutes, and found that MYD88 (25%) and CD79B mutations (25%) frequently occur in PB-DLBCL. In addition, four patients with MYD88 and/or CD79B mutations experienced CNS relapse, while three patients with MYD88 and/or CD79B mutations who received HD-MTX did not experience CNS relapse. Collectively, our results indicate combined modality therapy including rituximab-containing immunochemotherapy and consolidative breast RT is a promising approach for PB-DLBCL, while HD-MTX is useful for preventing CNS relapse.

Radioimmunotherapy versus autologous hematopoietic stem cell transplantation in relapsed/refractory follicular lymphoma: a Fondazione Italiana Linfomi multicenter, randomized, phase III trial

Optimal consolidation for young patilents with relapsed/refractory (R/R) follicular lymphoma (FL) remains uncertain in the rituximab era, with an unclear benefit of autologous stem cell transplantation (ASCT). The multicenter, randomized, phase III FLAZ12 (NCT01827605) trial compared anti-CD20 radioimmunotherapy (RIT) with ASCT as consolidation after chemoimmunotherapy, both followed by rituximab maintenance. Patients (age 18-65 years) with R/R FL and without significant comorbidities were enrolled and treated with three courses of conventional, investigator-chosen chemoimmunotherapies. Those experiencing at least a partial response were randomized 1 : 1 to ASCT or RIT before CD34+ collection, and all received postconsolidation rituximab maintenance. Progression-free survival (PFS) was the primary endpoint. The target sample size was 210 (105/group). Between August 2012 and September 2019, of 164 screened patients, 159 were enrolled [median age 57 (interquartile range 49-62) years, 55% male, 57% stage IV, 20% bulky disease]. The study was closed prematurely because of low accrual. Data were analyzed on 8 June 2023, on an intention-to-treat basis, with a 77-month median follow-up from enrollment. Of the 141 patients (89%), 70 were randomized to ASCT and 71 to RIT. The estimated 3-year PFS in both groups was 62% (hazard ratio 1.11, 95% confidence interval 0.69-1.80, P= 0.6662). The 3-year overall survival also was similar between the two groups. Rates of grade ≥3 hematological toxicity were 94% with ASCT versus 46% with RIT (P < 0.001), and grade ≥3 neutropenia occurred in 94% versus 41%, respectively (P < 0.001). Second cancers occurred in nine patients after ASCT and three after radioimmunotherapy (P= 0.189). Even if prematurely discontinued, our study did not demonstrate the superiority of ASCT versus RIT. ASCT was more toxic and demanding for patients and health services. Both strategies yielded similar, favorable long-term outcomes, suggesting that consolidation programs milder than ASCT require further investigation in R/R FL.

Metabolic Tumor Volume from Baseline PET/CT Improves Stratification in the High IPI Risk Patients with Diffuse Large B‐Cell Lymphoma

Background: In the rituximab era, the international prognostic index (IPI) risk stratification was not enough to predict outcome in patients with diffuse large B cell lymphoma (DLBCL). Previous studies showed the Metabolic tumor volume（MTV） from baseline [ 18F]FDG PET/CT could be used to predict outcome. In this study, we evaluated the prognostic value of IPI and MTV in DLBCL patients. Patients and methods: A total of 262 de novo DLBCL patients who were treated with the R-like chemotherapy were retrospectively analyzed in this study. The IPI and MTV were compared to the Overall Survival (OS) and Progression Free Survival (PFS). Results: The MTV is better than TLG and SUVmax for predicting disease progression. The cutoff value of MTV was 444 cm 3. Patients with high MTV showed inferior OS and PFS ( p &amp;lt; 0.001, respectively). Although the IPI remains predictive it distinguishes only 2 risk groups, rather than the 4 groups originally described. Further analysis showed high MTV could identify a subgroup of patients with extremely inferior OS and PFS in high IPI risk patients ( p = 0.0089 and p= 0.024, respectively). Multivariate analysis revealed that high MTV is a significant poor prognostic factor for both OS (HR 3.168[1.81-5.56], p &amp;lt;0.001) and PFS (HR 2.637 [1.51-3.71], p &amp;lt;0.001). Conclusions: Our study suggests that MTV from baseline PET/CT is an important prognostic factor in DLBCL patients, allowing the identification of an inferior outcome subgroup in high-risk patients, which may help to guide treatment in clinical trial.

Time to Lymphoma Treatment within 24 Months in Watchful Waiting Follicular Lymphoma Defines Patients at High Risk for Progression: A Multicenter Analysis

Purpose Follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease, watch and wait (W&amp;W) remains a management therapeutic option in patients with advanced-stage, low-tumor-burden and asymptomatic FL in the rituximab era. We continue to use Groupe d'Etudes des Lymphomes Folliculaires criteria for active disease to initiate therapy. We sought to understand whether time to lymphoma treatment (TLT) after diagnosis in patients who managed by W&amp;W was a factor affecting survival outcomes in FL. Patients and Methods Between 2008 and 2022, 411 FL patients from 16 institutions in China were managed by W&amp;W strategy, and their TLT was retrospectively evaluated. Patients were further divided into training and validation Cohorts. Logistic regression was used to identify and incorporate independent predictors of early TLT into a model with variable scoring. Model performance was evaluated through the area under the receiver operating characteristic curve (AUC) and goodness-of-fit statistics. Results After a median follow-up of 46 months, 35 percent of W&amp;W patients experience TLT within 24 months (TLT24) after diagnosis, and the 5-year progression free survival (PFS) rate was significantly lower than that of patients who were treatment-free at 24 months (62.3% vs. 89.5%). In multivariable analysis, five clinical factors were identified as independent predictors of TLT24: stage III-IV, β 2 microglobulin ≥ 3mg/L, lymphocyte-to-monocyte ratio＜3.8, bone marrow involved and spleen enlargement. We calculated risk scores (TLT24PI) for each patient and defined three risk groups: low (0-1 points), intermediate (2 points), or high (3-5 points). Its AUC for TLT24 was 0.761 (95% CI, 0.698 - 0.823) in the development cohort and 0.761 (95% CI, 0.698 - 0.823) in the validation cohort. Risk groups were also associated with PFS ( P&amp;lt;0.001). Conclusion In patients with FL who initially managed by W&amp;W, TLT within 24 months after diagnosis was associated with poor outcomes. We developed a multivariable model that incorporates clinical and laboratory factors to identify patients at high risk for TLT24, which may be useful to identify candidates for early interventional treatment.

Outcomes of limited stage primary bone diffuse large B-cell lymphoma in the rituximab era: a multicenter, retrospective study.

Primary bone diffuse large B-cell lymphoma is a rare variant of extranodal non-Hodgkin lymphoma historically treated with induction chemotherapy followed by consolidative radiation therapy (RT). It remains unknown whether RT confers additional benefit following rituximab-based chemoimmunotherapy (CIT) induction in patients with limited stage disease. We conducted a multicenter, retrospective analysis of patients treated between 2005 and 2019 using rituximab-based CIT regimens with or without consolidative RT to discern whether consolidative RT adds benefit in patients with stage I-II disease that could be encompassed in one radiation field. A total of 112 patients were included: 78 received CIT and radiation (RT group), and 34 received CIT alone (no RT group). The overall survival at 10 years was 77.9% in the RT group and 89.0% in the no RT group (P=0.42). The relapse-free survival at 10 years was 73.5% in the RT group and 80.3% in the no RT group (P=0.88). Neither improved overall survival nor relapse-free survival was associated with the addition of consolidative RT. Subgroup analysis of patients only achieving a partial response after CIT suggests that these patients may benefit from consolidative RT.

Radiotherapy Effect on Long-Term Net Survival Benefit for Early-Stage Diffuse Large B-Cell Lymphoma in the Rituximab Era

It is controversial whether to add consolidative radiotherapy (RT) after chemoimmunotherapy in the first-line treatment for diffuse large B-cell lymphoma (DLBCL). This study aimed to investigate the long-term net survival benefit of RT for early-stage DLBCL in the rituximab era. The data of 10,841 adult patients with early-stage DLBCL from the Surveillance, Epidemiology, and End Results (SEER) database between 2002 and 2015 were extracted and analyzed. The patients had received combined modality treatment (CMT, chemotherapy plus RT) or chemotherapy alone. Linear regression analysis was performed for RT utilization by year of diagnosis. Competing risk analysis was used to evaluate the cumulative incidence of mortality according to the cause of death. Inverse probability of treatment weighting (IPTW) was used to balance the distribution of covariates between treatment arms. Relative survival (RS), standardized mortality ratio (SMR), and transformed Cox regression were performed to estimate the net survival benefit of RT by controlling for background mortality. Linear regression revealed that the slope of the best-fit line for RT utilization over time was negative between 2002 and 2015 (m = -0.006, P = 0.003). A total of 4,648 deaths were recorded among 10,841 patients; 55.6% were lymphoma-related death (LRD), and 44.4% were attributed to other causes. Patients initially treated with CMT had a lower cumulative incidence of LRD than chemotherapy alone (HR 0.63, 95% CI: 0.57-0.69; P < 0.001). The 10-year overall survival (OS) rate of 66.1%, RS rate of 85.0%, and SMR of 1.71 achieved with CMT were significantly better than chemotherapy alone (OS, 53.0%; RS, 69.8%; SMR, 2.62; P < 0.001). By IPTW and multivariable analysis, the addition of RT remained associated with better OS (HR 0.67, 95% CI: 0.62-0.71; P < 0.001) and RS (HR 0.69, 95% CI: 0.65-0.74; P < 0.001). RT was associated with better long-term net survival in patients with early-stage DLBCL in the rituximab era.

Decreased lymphoma-related deaths and improved long-term relative survival with radiotherapy for early-stage diffuse large B-cell lymphoma in the rituximab era

BackgroundWe aimed to investigate the incidence of lymphoma-related death (LRD) and the long-term net survival benefit of radiotherapy (RT) for early-stage diffuse large B-cell lymphoma (DLBCL) in the rituximab era. Methods10,841 adults diagnosed with early-stage DLBCL between 2002–2015 were retrospectively analyzed using data from the Surveillance, Epidemiology, and End Results database. Primary therapy was categorized into combined-modality treatment (CMT, n = 3,631) and chemotherapy alone (n = 7,210). Competing risk analysis was used to evaluate the cumulative incidence of mortality. Inverse probability of treatment weighting (IPTW) was used to balance groups. The net survival benefit of RT was estimated through relative survival (RS), standardized mortality ratio (SMR), and transformed Cox regression, while controlling for background mortality. ResultsPatients initially treated with CMT had a lower cumulative incidence of LRD compared to those who received chemotherapy alone (HR 0.63, 95%CI: 0.57–0.69; P < 0.001). The 10-year overall survival (OS), RS, and SMR for CMT were 66.1%, 85.0%, and 1.71 respectively, which were significantly better than those for chemotherapy alone (53.0%; 69.8%; 2.62; all P < 0.001). IPTW and multivariable analysis revealed that the addition of RT led to better OS (HR 0.67, 95%CI: 0.62–0.71; P < 0.001) and RS (HR 0.69, 95%CI: 0.65–0.74; P < 0.001). Moreover, compared with chemotherapy alone, the benefit of OS and RS for CMT increased over time within 10 years of diagnosis. ConclusionRT reduced LRD and improved the long-term net survival in early-stage DLBCL in the rituximab era. Further prospective studies are warranted to assess the specific patient population that would benefit the most from consolidative RT in early-stage DLBCL.

Outcomes of Patients Treated With RCHOP With a PET-Adapted Approach for Consolidative Radiotherapy: A Retrospective Single-Center Study at the Royal Marsden Hospital

BackgroundTreatment with CHOP-based chemotherapy with consolidative radiotherapy (CRT) for primary mediastinal B cell lymphoma (PMBCL) has been the standard approach in the pre-rituximab era. Overtreatment with CRT for patients who may have already been cured by primary immunochemotherapy in the rituximab era is a significant concern due to the long-term toxicity associated with radiotherapy. Positron emission tomography (PET) may help to identify patients who may not benefit from further CRT. MethodsWe conducted a retrospective review of patients treated at the Royal Marsden Hospital between 2003 and 2020 for PMBCL to assess CRT use and survival outcomes. ResultsForty-three patients were identified, with 95% of the patients receiving R-CHOP. CRT was given in 5 patients. Five-year event-free survival was 79% (95% confidence interval: 64%-89%) and 5-year overall survival was 88% (95% confidence interval: 73%-95%). Seven of 9 patients with DS4 did not receive CRT and instead monitored with serial PET scans. None of these 7 patients relapsed in the mediastinum. ConclusionCRT may be omitted in patients with a negative end of treatment PET scans; however, careful observation may also obviate the need for CRT in PET positive patients.

Consolidative Radiotherapy after Complete Remission following R-CHOP Immunochemotherapy in Stage III-IV Diffuse Large B-Cell Lymphoma Patients: A Systematic Review and Meta-Analysis.

Patients with diffuse large B-cell lymphoma (DLBCL) are treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The role of consolidative radiation therapy (RT) remains unclear among patients with advanced DLBCL who achieved complete remission (CR) after R-CHOP immunochemotherapy. The current systematic review and meta-analysis aimed to clarify the role of consolidative RT among these patients. The MEDLINE, Embase, and Cochrane Library databases were searched for studies comparing RT to no RT following CR after R-CHOP immunochemotherapy in Ann Arbor stage III-IV DLBCL patients. Overall survival (OS) was the primary endpoint, and disease-free survival (DFS) was the secondary endpoint. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the primary and secondary outcomes. Review Manager (version 5.4) was used to analyze the data. Six retrospective studies involving 813 patients who received R-CHOP ± consolidative RT were identified. OS was higher in the consolidative RT group, with an HR of 2.01 and a 95% CI of 1.30 to 3.12 (p = 0.002). DFS was also higher in the RT group, with an HR of 2.18 and a 95% CI of 1.47 to 3.24 (p < 0.0001). The results suggested that consolidative RT improved OS and DFS compared to no RT among advanced-stage DLBCL patients. Further research is needed to determine the optimal radiation fields and the appropriate indications for consolidative RT for advanced-stage DLBCL patients in the rituximab era.

Comparison of International Prognostic Indices and Validation Study for Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era

ABSTRACT In diffuse large B-cell lymphoma (DLBCL), patients needing new alternative regimens in first-line treatment should be selected with better risk classification. After International Prognostic Index (IPI), Revised-IPI (R-IPI), National Comprehensive Cancer Network (NCCN)-IPI, and Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea (GELTAMO)-IPI, have been developed to improve risk predictions. This study compared performances of four prognostic indices concerning differentiation of overall survival (OS), the most critical endpoint. The study was conducted on 116 patients diagnosed with DLBCL. Patients with primary nervous system and testicular DLBCL, and post-transplant lymphoproliferative disorders, were excluded. The fitting of prognostic indices for database and the prediction of patient discrimination were compared using Akaike’s information criterion and concordance index. Of the study cohort, 63.8% were male, the median age was 56 (18-88), and median follow-up term was 45.6 (0.3-75.2) months. All factors, constituting IPI and R-IPI scores, demonstrated a significant difference in OS. Involvements of the extranodal regions specified in NCCN-IPI and elevated serum beta-2 microglobulin levels in GELTAMO-IPI had prognostic significance (p= 0.005 and p= 0.040, respectively). Each of the four prognostic indices, resulted in risk groups with significantly different OS. R-IPI provided the best fit for database, while NCCN-IPI provided the best discrimination between patients with high and low OS. Although NCCN-IPI provides the best discrimination between patients with short and long OS, using original IPI still seems acceptable in the rituximab era. Integration of tumor molecular characteristics into NCCN-IPI may better characterize high-risk group in new treatment approaches. Keywords: International Prognostic Index, National Comprehensive Cancer Network, Validation, Diffuse Large B-Cell Lymphoma, Rituximab

Follicular Lymphoma Microenvironment Traits Associated with Event-Free Survival.

The majority of patients with Follicular Lymphoma (FL) experience subsequent phases of remission and relapse, making the disease "virtually" incurable. To predict the outcome of FL patients at diagnosis, various clinical-based prognostic scores have been proposed; nonetheless, they continue to fail for a subset of patients. Gene expression profiling has highlighted the pivotal role of the tumor microenvironment (TME) in the FL prognosis; nevertheless, there is still a need to standardize the assessment of immune-infiltrating cells for the prognostic classification of patients with early or late progressing disease. We studied a retrospective cohort of 49 FL lymph node biopsies at the time of the initial diagnosis using pathologist-guided analysis on whole slide images, and we characterized the immune repertoire for both quantity and distribution (intrafollicular, IF and extrafollicular, EF) of cell subsets in relation to clinical outcome. We looked for the natural killer (CD56), T lymphocyte (CD8, CD4, PD1) and macrophage (CD68, CD163, MA4A4A)-associated markers. High CD163/CD8 EF ratios and high CD56/MS4A4A EF ratios, according to Kaplan-Meier estimates were linked with shorter EFS (event-free survival), with the former being the only one associated with POD24. In contrast to IF CD68+ cells, which represent a more homogeneous population, higher in non-progressing patients, EF CD68+ macrophages did not stratify according to survival. We also identify distinctive MS4A4A+CD163-macrophage populations with different prognostic weights. Enlarging the macrophage characterization and combining it with a lymphoid marker in the rituximab era, in our opinion, may enable prognostic stratification for low-/high-grade FL patients beyond POD24. These findings warrant validation across larger FL cohorts.

Treatment strategies and survival outcomes of primary mediastinal large B-cell lymphoma

ABSTRACTObjectivesPrimary mediastinal large B-cel l lymphoma (PMBCL) is a rare subtype of B-cell lymphoma that is not yet fully understood. This population-based study aimed to assess the latest survival and treatment strategies for patients with PMBCL.MethodsThe study used the dataset from the Surveillance, Epidemiology, and End Results Program registry to retrospectively analyze adult patients diagnosed with PMBCL between 2001 and 2018. The primary outcome measures included overall survival (OS) and disease-specific survival (DSS).ResultsAmong the 814 identified cases, the study revealed a 5-year OS rate of 86.7% and a 5-year DSS rate of 88.2% after a median follow-up of 54 months. Cox regression analysis indicated that age over 60 years, pre-2010 diagnosis, non-White ethnicity, advanced stage, and absence of chemotherapy significantly reduced both OS and DSS. It also found that chemotherapy has remained the primary therapeutic protocol for PMBCL over the last 20 years, whereas the utilization of surgery and radiation declined significantly. Patients diagnosed with PMBCL between 2010 and 2018 had a significantly reduced mortality risk (∼50%) compared to those diagnosed between 2001 and 2009. Notably, in the era of rituximab’s widespread usage, recipients of radiotherapy exhibited a poorer OS rate than non-recipients.ConclusionSurvival outcomes for patients with PMBCL have significantly improved in the current era, possibly due to the evolving treatment paradigm. The value of radiotherapy in PMBCL is still debated and requires further prospective evaluation.

Risk Factors of Progression in Low-tumor Burden Follicular Lymphoma Initially Managed by Watch and Wait in the Era of PET and Rituximab

Patients (pts) with asymptomatic low-burden follicular lymphoma (FL) are usually observed at diagnosis. Time to lymphoma treatment (TLT) initiation can however be very heterogeneous and risk factors of progression are poorly studied. Our study evaluated 201 pts with grade 1-3a low-tumor burden FL diagnosed in four French centers between 2010 and 2020 and managed by a watch and wait strategy in real-life settings. After a median follow-up of 4.8 years, the median TLT was 4.2 years (95% confidence interval, 3.1-5.5). On multivariate analysis, elevated lactate dehydrogenase (hazard ratio [HR] = 2.2; P = 0.02), more than 4 nodal areas involved (HR = 1.7; P = 0.02) and more than 1 extranodal involvement (HR = 2.7; P = 0.01) were identified as independent predictors of TLT. The median TLT was 5.8 years for pts with no risk factor, 2.4 years for 1 risk factor, and 1.3 years for >1 risk factors (P < 0.01). In a subanalysis of 75 pts staged with positron emission tomography-computed tomography (PET-CT), total metabolic tumor volume (TMTV) ≥14 cm3 and standardized Dmax (reflecting tumor dissemination) >0.32 m-1 were also associated with shorter TLT (HR = 3.4; P = 0.004 and HR = 2.4; P = 0.007, respectively). In multivariate models combining PET-CT parameters and clinical variables, TMTV remained independent predictor of shorter TLT. These simple parameters could help to identify FL patients initially observed at higher risk of early progression. The role of PET-CT (extranodal sites and PET metrics) in low-burden FL appears promising and warrants further assessment in large cohorts.

The place of cyclical therapy for the treatment of membranous nephropathy in the era of rituximab.

Primary membranous nephropathy (MN) is the most frequent cause of nephrotic syndrome in adults, due to a variety of autoantibodies, most frequently against phospholipase A2 receptor (PLA2R). In severe cases or when spontaneous remission is not achieved, immunosuppression is required. Cyclical therapy, based on glucocorticoids and cyclophosphamide on alternate months for 6months, has proven effective to induce remission and reduce the risk of end-stage renal disease. Since the early 2000s, rituximab (RTX) has emerged as a key player in the management of MN, showing overall comparable effectiveness and likely better safety compared with the cyclical regimen, despite the lack of adequately powered trials comparing the two approaches head to head. For these reasons, RTX is now considered the agent of choice for most patients with MN. However, there are still uncertainties. Around 20-40% of patients are resistant to RTX, especially in the setting of high anti-PLA2R levels, and this drug remains relatively unexplored in patients with the most severe disease. In these scenarios, although the expanding therapeutic armamentarium is probably going to provide further options, the cyclical regimen still plays a key role as a safety net. The aim of this article is to illustrate the role of cyclical therapy in the RTX era.

Outcomes of human immunodeficiency virus-associated Burkitt lymphoma and diffuse large B-cell lymphoma treated in Australia: A report from the Australasian Lymphoma Alliance.

Antiretroviral therapy (ART) has improved outcomes for human immunodeficiency virus-associated non-Hodgkin lymphoma (HIV-NHL). This is an analysis of 44 patients with HIV with Burkitt lymphoma (HIV-BL) and diffuse large B-cell lymphoma (HIV-DLBCL) treated in Australia over a 10-year period (2009-2019) during the ART and rituximab era. At HIV-NHL diagnosis, the majority of presenting patients had adequate CD4 counts and undetectable HIV viral load <50 copies/mL. More than 80% of patients received chemotherapy with curative intent, rituximab, and concurrent ART with chemotherapy (immunotherapy). R-CODOX-M/IVAC or R-Hyper-CVAD (55%) were most commonly used in HIV-BL. CHOP (58%) was the most commonly used chemotherapy backbone for HIV-DLBCL, although 45% of patients received more intense chemotherapy regimens. Overall, 93% of patients who received curative therapy completed their intended course. The 2-year progression-free survival (PFS) and overall survival (OS) for the HIV-BL cohort was 67% and 67% respectively. The 2-year PFS and OS for the HIV-DLBCL cohort was 77% and 81% respectively. Treatment related mortality was 5%. In all, 83% of patients achieved a CD4 count of >0.2×109 /L 6 months after the end of treatment. Current Australian practice favours the treatment of HIV-BL and HIV-DLBCL similarly to the HIV-negative population with the use of concurrent ART, achieving outcomes comparable to the HIV-negative population.

Potential Prognostic and Predictive Role of Monocyte and Lymphocyte Counts on Presentation in Patients Diagnosed With Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma. Nearly 40% of patients will die of relapsed disease despite the use of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. Many prognostic markers established in the chemotherapy era are no longer valid in the rituximab era. We aim to identify whether we can add absolute lymphocyte count (ALC), absolute monocyte count (AMC), and lymphocyte-to-monocyte ratio (LMR) as new prognostic factors for DLBCL treated with R-CHOP. We also aim to find whether a correlation exists between these variables and the revised International Prognostic Index (R-IPI) score. This is an observational retrospective study done from 2005 to 2015 in Rafic Hariri University Hospital (RHUH), Lebanon, on 42 patients treated with R-CHOP. Patients' data were obtained from medical records. We used receiver operating characteristic (ROC) curve for establishing cutoff values. The chi-square test was used to analyze associations between variables. Patients were followed for a median of 42 months (24-96 months). Patients with LMR < 2.53 had a significantly worse outcome than those with LMR ≥ 2.53 (p< 0.0001). This was also true for patients with ALC < 1.47 × 109/L (p= 0.0163) and AMC > 0.603 × 109/L (p= 0.0053). LMR was also able to risk-stratify patients within each R-IPI category into high- and low-risk patients. ALC, AMC, and LMR, surrogate markers of the host immune system and tumor microenvironment, have prognostic significance in DLBCL patients treated with R-CHOP.

Risk factors for antibody-mediated rejection in ABO blood-type incompatible and donor-specific antibody-positive liver transplantation.

Antibody-mediated rejection (AMR) is a refractory rejection after ABO blood-type incompatible (ABOi) or donor-specific antibody (DSA)-positive liver transplantation (LT). Pretransplant rituximab desensitization dramatically reduced posttransplant AMR development; however, risk factors for AMR in the rituximab era remain unclear in both ABOi living-donor LT (ABOi-LDLT) and preformed DSA-positive LT (pDSA-LT). Of our 596 adult LDLTs (≥18y) after rituximab introduction (2004-2019), 136 were ABOi-LDLT (22.8%). After excluding retransplants (9), acute liver failure (7), and protocol deviations (16), 104 ABOi-LDLTs were finally enrolled. Of these, 19 recipients developed AMR, 18 of which occurred within 2 weeks after transplantation (95%). ABOi-AMR significantly worsened graft and recipient survival than those without ( p =0.02 and 0.04, respectively). Model for End-stage Liver Disease (MELD) ≤13 (OR: 5.15 [1.63-16.3], p =0.005) and pre-rituximab anti-ABO IgM-titer ≥128 (OR: 3.25 [1.05-10.0], p =0.03) were identified as independent risk factors for ABOi-AMR development. Recipients fulfilling both factors showed significantly worse survival rates than those who did not ( p =0.003). Of 352 adult LTs, after introducing the LABScreen Single Ag method (2009-2019), pDSA with mean fluorescence intensity (MFI) ≥500 was detected in 50 cases (14.2%). After excluding 10 ABOi-LDLTs, 40 pDSA-LTs were finally analyzed, of which 5 developed AMR. The combination of high-titer (sum-MFI ≥10,000) and multi-loci pDSAs was a significant risk factor for pDSA-AMR development ( p <0.001); however, it did not affect the 5-year recipient survival compared with those without ( p =0.56). In conclusion, preoperative MELD ≤13 and pre-rituximab anti-ABO IgM-titer ≥128 for ABOi-LDLT, and the combination of sum-MFI ≥10,000 and multi-loci pDSAs for pDSA-LT, are risk factors for AMR in the era of rituximab desensitization. Characteristically, ABOi-AMR significantly deteriorated graft and recipient survival, whereas pDSA-AMR did not.

Low T3 syndrome as a predictor of poor outcomes in patients with follicular lymphoma.

The aim of this study was to investigate the prognostic value of low T3 syndrome in follicular lymphoma (FL). A total of 221 FL patients with detailed serum thyroid hormone levels and other complete clinical data were enrolled. Baseline features associated with low T3 syndrome were analyzed and balanced by propensity score matching. Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). A receiver operating characteristic (ROC) curve was plotted, and the area under the curve (AUC) was calculated to assess the predictive accuracy of FL international prognostic index FLIPI-1/FLIPI-2 and low T3 syndrome. A total of 22 patients (10.0%) had low T3 syndrome at diagnosis, which was associated with poor PFS and OS in the rituximab era. It is an independent prognostic factor for PFS and OS. Low T3 syndrome and FLIPI-1/FLIPI-2 significantly increased the AUC of PFS and OS compared to FLIPI-1/FLIPI-2 alone. Low T3 is a risk factor for POD24. In conclusion, low T3 syndrome may be a good candidate for predicting the prognosis of CLL in future clinical practice. Our study demonstrates that low T3 syndrome is associated with poorer survival outcomes in FL patients.