Indolent Lymphoma Research Articles

Pre-Treatment Pulmonary Assessment Have Limited Utility in B-Cell Lymphoma Patients Treated with Autologous Anti-CD19 CAR T-Cell Therapy

Introduction Pulmonary function tests (PFT) play a pivotal role in hematopoietic cell transplantation (HCT), with routine evaluation in HCT candidates. However, their predictive value in chimeric antigen receptor T-cell (CAR-T) therapy outcomes remains uncertain. To address this gap, we conducted a retrospective analysis of PFT metrics and pulmonary comorbidity definitions, following the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), in B-cell lymphoma patients treated with autologous CD19-CAR-T cell therapy. Patients and Methods In this retrospective analysis, we included adult patients (age ≥ 18 years) with B-cell lymphoma who received treatment at a tertiary medical center with commercially available or point-of-care (POC) anti-CD19 CAR T-cell therapy (Kedmi et al., Transplant Cell Ther. 2022) as their 3rd line of treatment or above, between 2017 and 2022. Patients underwent routine PFT assessment before CAR-T cell therapy, as part of institutional practice, including spirometry, body plethysmography, and single-breath diffusing capacity for carbon monoxide (DLCO). Patients were categorized into three pre-treatment pulmonary comorbidity groups (normal, moderate, severe) based on HCT-CI definitions for forced expiratory volume in 1 second (FEV1) and DLCO expressed as precent of predicted value (>80%, 66-80%, <66%, respectively). Results A total of 192 patients (median age, 60 [range 46-69]) were included. Aggressive B-cell lymphoma was the predominant diagnosis (n=166, 86%) followed by indolent B-cell lymphoma (n=18, 9.4%), and Mantle cell lymphoma (n=8, 4.2%). Most patients had a good performance status (KPS ≥ 90, 78%), although with high-risk disease features (pre-lymphodepletion LDH was elevated in 108 [56%]). Seventy-eight (41%) patients received bridging therapy. POC CAR-T were used in 56%, while 44% received commercial CAR-T (26% axi-cel, 18% tisa-cel). Pre-CAR-T smoking history was documented in 25% of patients. The median pre-treatment measured-to-predicted DLCO and FEV1 were 96% and 92%, respectively. Seventy-four percent of patients had normal DLCO, and 77% had a normal FEV1. The calculated normal, moderate, and severe pulmonary comorbidity levels, per the HCT-CI, were 64%, 23%, and 13%, respectively. With a median follow-up of 17.6 months (IQR 8.5-29.7), the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 7.6 months. There was no correlation between pulmonary comorbidity level and the best overall response rate. Categorical PFT results (FEV1 and DLCO) and pulmonary comorbidity (per-HCT-CI) were not associated with reduced OS (p=0.3, p=0.4, p=0.6, respectively) or reduced PFS (p=0.058, p>0.9, p=0.2, respectively) in a univariable Cox regression analysis. However, FEV1 as continuous measure and FEV1 categorized into 2 levels (normal vs. moderate-severe) were associated with reduced PFS ( Figure 1). FEV1 (as a continuous metric) association with PFS remained consistent (HR 0.99 [95% CI 0.98-1], p=0.007) in a multivariable Cox regression adjusted for pre CAR T KPS score, elevated LDH level, and co-stimulatory CAR-T domain. Nevertheless, this association is minor, with unclear clinical significance. No association was observed between pulmonary function measures and immune-toxicities, including cytokine release syndrome grade >2 or immune effector cell-associated neurotoxicity grade > 2. Conclusions To the best of our knowledge, this is the first study evaluating the relationship between PFTs and the outcomes of CAR T-cell treatment. Our results indicate that among standard measures of pulmonary assessment, only FEV1 was predictive of poor PFS, though with minor association, with unclear clinical significance. We did not observe any association with overall survival. These findings suggest that pre-CAR-T pulmonary assessment may have limited utility in evaluating CAR-T candidates. Nevertheless, further validation in a multicenter setting is required.

Real-World Patterns of Care and Financial Burden of Patients with Follicular Lymphoma in the United States

Introduction: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma and accounts for nearly a quarter of cases. As a heterogenous disease with an estimated 20% having progression of disease within 24 months of first FL therapy, FL often quickly becomes relapsed or refractory (R/R) to current therapy. The objective of this study was to evaluate the real-world treatment patterns, time to next treatment, and associated costs and healthcare resource utilization (HCRU) in patients with FL in the United States. Methods: A retrospective observational study was conducted using an integrated real-world database including linked data from the Symphony Integrated Dataverse (IDV ®), electronic medical records, specialty pharmacy, and in-office dispensing datasets. Patients were included in the study if they were ≥ 18 years old and initiated a first-line (1L), second-line (2L), third-line (3L), or fourth-line (4L) of therapy for FL between 1/1/2019 and 12/31/2022. Patients were categorized by line of therapy into non-mutually exclusive cohorts based on the date of initiation of their treatment regimen. Each line of therapy cohort was followed for a minimum of 90 days through lost to follow-up or end of the study period (3/31/2023). Patients were also required to have continuous pre-index enrollment of 365 days to record baseline comorbidities. Demographics, clinical characteristics, and treatment regimens were examined for each line of therapy cohort. Within each line of therapy, patients were categorized into 6 mutually exclusive subgroups based on their treatment regimens: bendamustine + rituximab (BR), rituximab monotherapy (R-mono), cyclophosphamide, doxorubicin, prednisone, rituximab + vincristine (R-CHOP), bendamustine + obinutuzumab (BO), lenalidomide + rituximab (R2), and other treatments for all other regimens. Advancement to the next line of therapy, treatment regimen distribution, and switching for each cohort and subgroup were evaluated during the follow-up period. Treatment duration, time to next treatment (TTNT), HCRU and pharmacy costs were measured for each cohort and treatment regimen during the follow-up period. HCRU included outpatient visits and hospital claims, reported as per patient per month (PPPM) over the time on each treatment regimen. Results: The study population included 9,579 patients initiating 1L, and then 3,061, 952 and 263 patients who received 2L, 3L, and 4L, respectively. The median follow-up was 719 days (1L), 652 days (2L), 578 days (3L), and 468 (4L). Mean age at index was similar across treatment lines, ranging from 66.7 years (1L) to 67.9 years (4L). Males represented a little under half (47.3%) in 1L cohort but increased slightly with subsequent lines (49.3%, 2L; 54.9%, 3L; 70% 4L). The most common baseline comorbidities across treatment lines were hypertension (1L=35.2%; 2L=32.3%; 3L=29.8%; and 4L=28.1%) and gastrointestinal disease (1L=23.9%; 2L=22.2%; 3L=22.2%; and 4L=22.1%). Across all treatment lines, R-mono was the most common regimen (1L=34.1%; 2L=29.0%; 3L=23.8%; and 4L=18.6%) followed by BR (1L=32.8%; 2L=17.3%; 3L=12.0%; and 4L=11.4%), and R-CHOP (1L=14.5%; 2L=12.8%; 3L=10.1%; and 4L=9.5%). Median TTNT across all regimens was 417 days (159, 691) in 1L, 444.5 days (225, 661) in 2L, 414 days (174, 784) in 3L, and 382.5 days (200.5, 599.5) in 4L (Figure 1). Mean (standard deviation; SD) of all-cause outpatient visits PPPM were 5.99 (4.86) in 1L, 6.06 (5.42) in 2L, 6.27 (6.04) in 3L, and 6.25 (5.95) in 4L. Mean (SD) of FL-specific outpatient visits PPPM were 4.59 (4.00) in 1L, 4.49 (4.31) in 2L, 4.57 (4.93) in 3L, and 4.42 (4.65) in 4L. The mean all-cause hospitalizations PPPM were 0.35 (1.72) in 1L, 0.79 (3.36) in 2L, 1.94 (6.29) in 3L, and 1.85 (5.00) in 4L. The mean FL-related hospitalizations PPPM were 0.13 (0.76) in 1L, 0.18 (1.02) in 2L, 0.36 (1.56) in 3L, and 0.45 (2.12) in 4L (Figure 2). Average pharmacy costs PPPM increased from $1,033 ($3,963.8) in 1L to $2,166.6 ($6,001.1) in 2L, and $2,943.7 ($6,413.1) to $3,374.1 ($7,361.3) in 3L and 4L, respectively. Conclusions: Real-world treatment patterns for patients with FL were shown to be mostly consistent with clinical guidelines. This study highlighted that TTNT decreased while hospitalizations and pharmacy costs increased as line of therapy progressed, suggesting high financial burden and unmet need for better treatment options for R/R FL patients.

Single-Cell RNA Sequencing Reveals Hypo-Responsiveness of T and NK Cells to Interferon Stimulation As an Immune Hallmark in Asymptomatic Waldenstrom's Macroglobulinemia

Introduction Waldenstrom macroglobulinemia (WM) is a rare, indolent non-Hodgkin lymphoplasmacytic lymphoma of the bone marrow (BM), characterized by monoclonal IgM protein production. WM is preceded by IgM monoclonal gammopathy of undetermined significance (IgM MGUS) and smoldering WM (SWM), which are clinically detectable but asymptomatic precursor phases (collectively referred to as asymptomatic WM; AWM). Recent work has revealed significant changes in the immune microenvironment of patients with overt WM, however, less is known about immune dysregulation in patients with early-stage disease. Methods We performed 5' single-cell RNA sequencing (scRNAseq) on BM immune cells from patients with AWM (n=28), healthy donors (HD, n=23), and patients with smoldering multiple myeloma (SMM) (n=27). We also performed an in vitro stimulation experiment using universal Type I interferon (IFN) and subsequent scRNAseq on bone marrow mononuclear cells (BMMCs) and peripheral blood mononuclear cells (PBMCs) from AWM (n=3) and HD (n=3). Results Overall, we annotated 210,019 immune cells, excluding normal B cells. Despite their early stage, AWM patients showed significantly altered BM immune cell composition, including increased proportions of CD56dim NK cells, CD8+ effector memory cells, and CD16 + Monocytes and decreased proportions of pro-inflammatory CD14 + monocytes and activated and interferon (IFN)-stimulated T and NK cells (q<0.2). Low-risk AWM presented similar changes in immune cell composition as intermediate- and high-risk AWM, implying that compositional alterations may be established early in the disease course. Notably, however, the proportion of Tregs was significantly increased in patients with SWM compared to IgM MGUS (p=0.04), suggesting that Tregs may play a role in disease progression. Next, we compared BM immune cell composition between patients with AWM and SMM. In both tumor types, patients showed significantly higher proportions of CD56dim NK cells and CD16 + monocytes compared to healthy donors. However, strikingly, a significant decrease in activated and IFN-stimulated T and NK cells was only observed in AWM, suggesting it may be a hallmark of disease. Comparison of BMMCs and PBMCs from patients with AWM following in vitro culture revealed that the lack of IFN-stimulated cells was systemic-in both BMMCs and PBMCs-although the effect was significantly more pronounced in BMMCs than PBMCs. Interestingly, while in vitro stimulation with Type I IFN resulted in the generation of IFN-stimulated T and NK cells in both HD and AWM, the levels of IFN stimulation did not entirely normalize, reproducing the gradient observed in the control samples without in vitro stimulation: AWM BM < AWM PB < HD BM. To test whether the observed defect was due to a lack of IFN in AWM, we next compared the gene expression profile of monocytes from AWM and HD, which revealed significantly higher activity of the IFN signature in monocytes from AWM compared to HD (p < 10 -5). This suggests that IFN levels in patients are at least not reduced. Collectively, these results indicate that T and NK cells from AWM are hypo-responsive to IFN stimulation, despite the presence of normal or possibly increased IFN in the BM microenvironment. Conclusion Our results indicate that despite the absence of symptoms, patients with AWM already have immune dysregulation in the BM, including the absence of IFN-stimulated T and NK cells, which may provide a rationale for therapeutic intervention. Previous studies have demonstrated clinical responses to therapeutic IFN administration, suggesting that novel formulations with improved therapeutic windows may have a role in treating patients with WM in the future.

Retrospective Analysis of the Impact of Bendamustine Dose Reduction and Chemotherapy on the Outcomes of Follicular Lymphoma

Introduction Follicular lymphoma (FL) is the most common indolent non-Hodgkin's lymphoma and primarily affects the elderly population. While bendamustine serves as a pivotal drug in standard therapy, it is often not administered as planned due to side effects, especially among the elderly. Clinical studies have shown that dose reduction and chemotherapy delays in the treatment of diffuse large B-cell lymphoma are associated with lower survival rates. However, few studies have analyzed the impact of bendamustine delays and dose reduction on the outcome of FL. Thus, the aim of our study was to clarify the effect of bendamustine dose reduction and chemotherapy course delay on treatment outcomes and to evaluate the effects of chemotherapy modification on FL. Patients and Methods This is a retrospective pooled analysis of previously untreated patients with FL who underwent consecutive bendamustine-based regimens at our institute. Patients receiving less than four courses of bendamustine-based regimens were excluded. Bendamustine dose reduction was defined as a cumulative dose reduction of at least 20% of the total prescribed dose. The total dose was defined as the sum of six cycles administered at 100% of the prescribed dose. Chemotherapy delays were defined as the total number of days of delay exceeding 21 days. The main goal of the study was to assess the impact of the chemotherapy scheme modification (dose reduction or delay) on progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method was used for single-variable survival data analysis. Differences in survival rate were determined using the log-rank test. Comparison among subgroups was performed using ANOVA for continuous covariates and Fisher's exact test for categorical variables. Results From January 2016 to June 2023, 43 untreated FL patients (23 females and 20 males) were started on rituximab-bendamustine (R-B) or obinutuzumab-bendamustine (G-B) at our institution. Median patient age was 69 years (range, 41-90 years) and the median follow-up time was 44 months (range, 5-74 months). Thirteen patients were treated with R-B, and 30 with G-B. Only one patient received obinutuzumab maintenance therapy due to the COVID-19 pandemic. Patients were divided into for three bendamustine delay/reduction groups. No bendamustine dose reduction or chemotherapy delays was observed in 27 patients (62.7%). The chemotherapy scheme was modified in 16 patients (37.2%): 10 patients (23.2%) experienced a bendamustine-only dose reduction and 6 patients (13.9%) experienced chemotherapy-only delays. None of the patients experienced both bendamustine dose reduction and delays. The main reasons for bendamustine dose reductions were the following: elderly/ frailty (60.0%), neutropenia (10.0%), thrombocytopenia (10.0%), and patient request (10.0%). The main reasons for chemotherapy delays were the following: patient request (33.3%), thrombocytopenia (33.3%), infection (16.6%), and skin rash (16.6%). Baseline characteristics were summarized in Table 1. The PFS of the three groups was comparable (Figure. 1a). The OS of the group with chemotherapy delays was comparable to the group with no dose reduction or delay, while that of the group with dose reduction was inferior (Figure. 1b). There were no differences in objective response rate (Table1). Conclusion Our study showed that chemotherapy delays or bendamustine dose reduction did not adversely affect PFS, and only chemotherapy delays adversely affected OS. No clinically significant differences in PFS were observed among patients with chemotherapy delays, which could be attributed to insufficient statistical power. Our cohorts comprised a heterogeneous population, including patients treated with R-B and G-B. However, considering the lack of evidence regarding the optimal dose intensity or chemotherapy interval for different populations, reducing the bendamustine dose may be a valid option for vulnerable patients.

Impact of Prior Bendamustine Exposure on Bispecific Antibody Treatment Outcomes for Patients with B-Cell Lymphoma

Introduction: Bispecific antibodies (BsAbs) were recently approved for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) and follicular lymphoma (FL) based on phase I-II clinical trials. These T-cell engaging agents achieve 40-50% of complete responses, but information regarding prognostic factors is scarce. Given the deleterious effect of previous bendamustine (benda) reported for patients receiving chimeric antigen receptor (CAR) T-cell therapy, we aimed to assess if prior benda exposure had an impact on BsAb outcomes. Methods: We conducted a retrospective, multicenter study including patients with LBCL or FL treated at 5 centers with BsAbs from November 2017 to March 2023. We analyzed baseline characteristics, response rates and survival outcomes according to prior benda exposure. Then, we carried out subgroup analyses according to histology (LBCL and FL) and treatment partner (monotherapy and combination regimens), assessing the impact of benda in each of these cohorts. Finally, we examined the impact of benda dose and washout before BsAb start on efficacy outcomes. Results: We included 143 patients (104 LBCL, 39 FL) who received BsAb therapy, 43 (30%) of which had been previously exposed to benda at a median of 653 days (range 31-2369 days). The BsAb targeted CD20/CD3, either in monotherapy (60%) or in combination with other agents (40%). Median follow-up for the full data set was 21.8 months (CI 95% 18.1 - 25.1 months). In terms of baseline characteristics (table) median age was 66 years and most patients had an advanced stage of disease (86%), increased LDH (65%) and at least 1 prior line of therapy (90%, median 2 [range 0-9]); CAR T-cell therapy was a prior line for 15% of patients. The benda-exposed cohort had an increased rate of transformed indolent lymphoma (47% vs 25%, p=0.01) and more prior lines of therapy (>2, 53% vs 26%, p<0.01) in comparison with benda-naïve patients. First, we analyzed the impact of previous benda on several parameters. Patients with prior exposure to benda had lower median CD3+ cells (543 vs 930/mm3, p=0.01) than benda-naïve patients. In terms of toxicity, there were no differences in the incidence or severity of cytokine release syndrome and neurotoxicity. Regarding efficacy, overall and complete response rates (ORR [CRR]) were comparable between benda-exposed and naïve patients (75% [60%] vs 72% [56%], respectively [p=0.73]). Median PFS and OS for the full cohort were 16.0 months and 43.4 months, respectively, without significant differences for the benda-exposed and naïve cohorts (16.8 vs 15.3 months [p=0.88] and NR vs 43.4 months [p=0.99]). In the univariate analysis for PFS, primary refractory and bulky disease, increased LDH and >2 previous lines were associated with a shorter survival. The same factors carried a negative impact for OS, with the addition of previous CAR T-cell therapy and ECOG >0. Then, we carried out subgroup analyses according to underlying histology. In the LBCL cohort (n=104), overall and complete response rates were similar between benda-exposed and naïve patients (74% [52%] vs 71% [55%], p=0.81), as were PFS (p=0.78) and OS (p=0.76). In the FL cohort (n=39), overall and complete response rates were also comparable (77% [71%] vs 78% [61%], p=0.94) as were PFS (p=0.96) and OS (p=0.96). We focused next on the presence of a treatment partner with the BsAb. Overall (complete) response rates were significantly increased in the combination cohort (mainly with immunotherapy [70%] or chemotherapy [30%]), compared to monotherapy (90% [75%] vs 62% [46%], p<0.01), as were 12-month PFS (77% vs 36%, p<0.01) and 12-month OS (88% vs 55%, p<0.01). Inside both of these cohorts, we did not identify any differences in response rate or survival between the benda-exposed and naïve patients. Given the wide range in washout from last benda dose, we analyzed the impact of this interval on efficacy outcomes. We did not identify any difference according to time between last benda dose and BsAb start. Noteworthy, only 7 patients had a washout shorter than 6 months. In terms of the benda dose, median number of cycles was 6 (range 1-10). We did not identify an impact of benda cycles on response rate or survival. Conclusions: Bendamustine-containing regimens do not seem to confer a negative prognostic impact before BsAb therapy, in contrast to what has been reported in the CAR T-cell setting. Longer follow-up and larger cohorts are warranted to confirm these results.

Real-World Treatment Patterns and Outcomes of Patients (Pts) with Follicular Lymphoma (FL) Who Experienced Progression of Disease within 24 Months (POD24)

Introduction: Follicular lymphoma (FL) accounts for about 35% of all non-Hodgkin lymphomas and 70% of indolent lymphomas in the United States. Despite relatively high 1L remission rates, a clinically high-risk subgroup experiences early disease progression within 24 months of 1L initiation (POD24). As the understanding of this population evolves, a treatment paradigm is yet to be established. This study aimed to describe the characteristics of patients who experienced POD24 to 1L therapy and their outcomes following receipt of select 2L treatment sequences using a contemporary real-world (rw) dataset. Methods: Pts meeting the study criteria were identified in the COTA rw database. Eligible pts were aged ≥ 18 years at diagnosis (dx) with grade I-IIIA FL and had no documented grade IIIB or transformation anytime from dx until index date. Pts were treated with 1L CD20+chemotherapy (CHOP/CVP or Benda) and initiated 2L therapy with one of the following treatment categories between January 1, 2010 and December 31, 2019: Benda-CD20, CHOP/CVP-CD20, chemosalvage (e.g., R-ICE), or other novel therapy (e.g., lenalidomide-CD20). Pts were excluded if they were not treated with the specified 1L or 2L therapies, had missing or imprecise key study dates, multiple concurrent primary malignancies at dx, evidence of histologic transformation prior to 2L,1L or 2L clinical trial participation, or documentation of 1L maintenance therapy that did not contain CD20. Characteristics, treatment patterns, and outcomes were analyzed among pts who experienced POD24, defined as documented progression/relapse event within 24 months of 1L initiation. The index date was the date of 2L therapy initiation, and the observation period was defined as the duration of time from index date to the date of death or last visit date (if date of death was not available). Characteristics and treatment patterns were summarized as appropriate using means, medians, and/or counts and percentages. The following rw time to event outcomes were evaluated using the Kaplan-Meier method: time to next treatment (rwTTNT), progression-free survival (rwPFS), and overall survival (rwOS). Rw complete response rate (rwCRR) was calculated as the proportion of pts who achieved a complete response (CR) as the best response to 2L among all POD24 pts. Results: The study included 149 pts who experienced POD24 and met the remaining study criteria. An additional 170 pts (53.3%) qualified for the study but did not experience POD24. The median age at dx for POD24 pts was 61 years. This population was mostly male (57.0%), White (87.9%), and treated in the community practice setting (86.6%). More than 85% of pts had low grade FL at their last assessment at index. Following 1L therapy, 47.0%, 1.3%, 39.6%, and 0.7% of pts had a documented CR, near CR, partial response, or stable disease, respectively. About 11% of pts had progression as their best documented response to 1L. The most common 2L treatment category was Benda+CD20 (47.0%), followed by CHOP/CVP-CD20 (25.5%), chemosalvage (17.4%), and other novel therapies (10.0%). The CD20 received most commonly in 2L was rituximab (87.2%). Of 68 pts who received 3L, 11 (16.2%) received stem cell transplant. Median rwOS from 2L initiation overall was 64.8 months (95% CI: 54.0, 99.6). For pts who received Benda-CD20, CHOP/CVP-CD20, chemosalvage, and other novel therapies in 2L, 5-year rwOS rate from 2L initiation was 49.9%, 52.3%, 57.2%, and 86.2%, respectively. (Table 1) Median rwPFS from 2L initiation overall was 11.3 months, and pts who received Benda-CD20 or other novel therapies in 2L experienced median rwPFS of 25.6 and 18.0 months, respectively, while pts who received CHOP/CVP-CD20 or chemosalvage in 2L experienced median rwPFS of 8.3 and 4.6 months, respectively. (Figure 1) A similar trend was seen in rwTTNT from 2L initiation (overall: 19.6, Benda-CD20: 38.0, CHOP/CVP-CD20: 12.0, chemosalvage: 5.4, and other novel therapies: 19.6 months) and rwCRR for pts who received 2L (overall: 47.7%, Benda-CD20: 57.1%, CHOP/CVP-CD20: 34.2%, chemosalvage: 34.6%, and other novel therapies: 60.0%). Conclusions: Among pts who experienced POD24 and received qualified therapies, 2L outcomes highlight continued unmet need despite recent improvements. Future research is required to identify this subset of high-risk pts at diagnosis and to investigate prospectively the effect of novel therapeutic approaches on their treatment outcomes.

Treatment Intensity and Outcomes in Elderly Patients with DLBCL Receiving First Line Therapy

Background: One-third of patients (pts) with newly diagnosed DLBCL are 70 and older. Although a standard of care for first-line (1L) DLBCL is anthracycline-based chemoimmunotherapy with R-CHOP, in elderly DLBCL pts treatment approaches vary and outcomes of these are poorly understood. In this study, we aimed to evaluate long-term outcomes among elderly pts with DLBCL across 1L regimens with a focus on those who received reduced dose (RD) R-CHOP, standard dose (SD) R-CHOP, and non-anthracycline alternative regimens (AR). Methods: We evaluated a cohort of pts from the Flatiron Health electronic health record (EHR)-derived, de-identified database with DLBCL diagnosis (dx) after 1/1/2011, age 70 or greater at dx, and with no evidence of prior indolent lymphoma or other malignancy within 2 years of 1L therapy. RD R-CHOP was defined as <80% SD doxorubicin or cyclophosphamide. Time-to-event analysis was performed with the Kaplan-Meier method and differences were evaluated using the log rank test. Real world overall survival (rwOS) was defined as the interval, in months (mos), from DLBCL dx to death or last follow-up. Real world progression free survival (rwPFS) was defined as the interval, in mos, from initiation of 1L therapy to progression, death, or last follow-up. Multiple imputation was performed (m = 50). Multivariate Cox regression analysis (MVA) was conducted within each imputed dataset and pooled. MVA was additionally performed across age strata. Results: There were 434 pts included in the complete cohort. Eighty-six percent (N=372) received 1L therapy and 62 pts (14%) had no therapy documented. Among treated pts, 47% were female, median age was 79 (IQR 75-82), and median CCI score 7 (IQR 6-9). Twenty-six percent and 47% had limited and advanced stage at dx, respectively; stage was unknown in 27%. Cell of origin was germinal center (GCB), non-GCB, and unknown in 34%, 24%, and 43%, respectively. Forty-eight percent of pts (N=212) received R-CHOP as 1L. Best real world response (rwR), defined as either complete response (CR) or partial response (PR) to 1L, was 89.0%, 89.5%, and 81.6% (p = 0.20) in pts who received SD R-CHOP, RD R-CHOP, and AR, respectively. CR rates were 78.0%, 58.1%, and 60.2% (p = 0.008) among these cohorts, respectively. Median rwOS and rwPFS among all treated pts was 39.0 mos (32.4-47.3) and 15.2 mos (12.3-23.4), respectively. Among patients who received SD R-CHOP, RD R-CHOP, and AR, median age (IQR) was 72 (71-77), 81 (79-83), and 80 (77-81), respectively (p<0.001). Median Charlson comorbidity index (CCI) score (IQR) was 6 (5-8), 8 (6-9), and 7 (6-9) across these groups, respectively (p<0.001). SD R-CHOP was associated with better rwPFS and rwOS in the entire treated cohort. Real world OS and rwPFS were 95.6 mos (67.0-NE) and 77.3 mos (40.3-NE) for SD R-CHOP, 37.6 mos (27.9-NE) and 15.8 mos (11.9-35.8) RD R-CHOP, and 25.7 mos (16.0-32.6) and 9.6 mos (8.1-12.0) for AR, respectively. When stratifying by age, pts 70-79 years had PFS of 77.3 mos (41.2-NE), 22.4 mos (9.86-NE), and 11.0 mos (8.6-23.4) with SD R-CHOP, RD R-CHOP, and AR, respectively (p <0.0001), whereas pts >=80 had PFS 6.14 mos (4.21-NE), 14.7 mos (8.87-NE), and 7.3 mos (4.47-12.0) with these regimens (p=0.03). In Cox regression MVA, CCI was associated with rwPFS in pts >=80 (HR 1.18, p=0.004). High-risk IPI score was associated with rwPFS (HR 2.13, p=0.05) and rwOS (HR 2.51, p=0.033), but only in pts age 70-79. When stratifying by age and adjusting for comorbidities, IPI, and MYC alteration, treatment with RD R-CHOP and AR were associated with inferior rwPFS and rwOS compared to SD R-CHOP among pts age 70-79, however, there was no association between treatment intensity and outcome among pts >=80 (Table). Conclusions: This study represents one of the largest real-world studies evaluating contemporary outcomes among elderly pts with DLBCL receiving 1L therapy. In MVA, SD R-CHOP is significantly associated with improved rwPFS and rwOS compared to RD-RCHOP and AR, but only among pts aged 70-79. There was no effect of treatment intensity or regimen on either rwPFS or rwOS among pts aged >=80. Other covariates significantly associated with outcome included CCI among pts >=80 and high-risk IPI in pts 70-79. These results suggest that pts aged 70-79 should receive SD R-CHOP whenever feasible, but that treatment intensity is not the primary determinant of outcomes among pts aged >=80. CCI should be part of routine evaluation in elderly DLBCL pts.

Obinutuzumab, Lenalidomide and Venetoclax in Patients with Treatment-Naïve Advanced-Stage Follicular Lymphoma: First Results of the Investigator-Initiated Phase Ib/II, Multicenter Leverage Study

Background Follicular lymphoma (FL) is the most common indolent lymphoma. The most widely used initial treatment is chemo-immunotherapy, however conventional cytotoxic agents may result in acute and late toxicities which can be problematic. There is a need for active novel treatment approaches with more favorable safety profiles. Methods We designed a phase Ib/II study of obinutuzumab, lenalidomide and venetoclax in patients with treatment-naïve follicular lymphoma. Key inclusion criteria included non-contiguous or bulky stage II-IV disease, meeting GELF criteria for treatment, adequate organ function and performance status. Treatment was divided into 2 phases, induction (6 x 28-day cycles) and maintenance (12 x 56-day cycles). During induction, patients received fixed doses of obinutuzumab (1000mg D1, 8, 15 cycle 1; D1 of C2-6) and lenalidomide 20mg days 1-21 from C2-6. Venetoclax was given from C1-6 and the dose was escalated, according to a 3+3 design with 4 dose levels (DL) tested: DL 1: 400mg daily D1-10, DL 2: 800mg D1-10, DL 3: 400mg D1-28 and DL 4: 800mg D1-28. After 6 cycles, patients who attained complete response (CR) received obinutuzumab maintenance (1000mg every 8 weeks for 2 years). Patients who attained partial response received a further 6 cycles of lenalidomide (10mg D1-28) and venetoclax (at the same dose given in induction) in addition to the obinutuzumab maintenance. Patients who experienced SD discontinued study in favour of alternate therapy. The primary endpoint of phase Ib was recommended phase II dose (RP2D). The primary endpoint of phase II was intention to treat CR rate by investigator assessment at end of induction by Lugano 2014. Key secondary endpoints included safety, objective response rate (ORR), progression free survival (PFS), overall survival and quality of life. This interim analysis focuses on the RP2D, safety and preliminary efficacy data. Results As of 13 Mar 2023, 36 patients have been enrolled of whom 26 completed end of induction phase and are included in this interim analysis. Eighteen patients were treated in dose escalation (3, 6, 3 and 6 at dose levels 1-4, respectively) and 18 in expansion phase. The baseline characteristics are summarized in Table 1. The median relative dose intensity was >90% for all 3 agents. One dose limiting toxicity (DLT) occurred (grade 3 ALT elevation possibly related to venetoclax on C1D1, which resolved within 48 hours) and no maximum tolerated dose was reached. Dose level 4 (venetoclax 800mg daily D1-28) was the RP2D. The only grade≥3 AEs to occur in more than two patients were neutropenia (65%), without febrile neutropenia. The most common any grade AEs were nausea (50%), diarrhea (46%), maculopapular rash (31%), thrombocytopenia (27%), fatigue (23%) and constipation (23%). One patient developed biochemical TLS. 7 patients prematurely discontinued study treatment due to progressive disease (PD) in 2, and 1 case of each DLT, COVID-19, grade≥3 cytopenias lasting >28 days, upper respiratory infection and development of a second malignancy requiring systemic therapy. At the end of induction, the CR and ORR were 81% and 92%, respectively. The 2 PD events were both found at the end of induction restaging, and biopsy revealed histologic transformation to diffuse large B-cell lymphoma. Updated data (including PFS) will be presented at the meeting. Conclusion The combination of obinutuzumab, lenalidomide and venetoclax is a highly active and safe combination in patients with treatment-naïve high tumor burden FL. No unexpected safety signals were identified. Enrolment to phase II is ongoing at 4 Australian sites. This trial is registered at clinicaltrials.gov (NCT03980171)

A Randomized, Open-Label, Phase 3 Study of Acalabrutinib in Combination with Rituximab and Reduced Dose CHOP (R-miniCHOP) in Older Adults with Untreated Diffuse Large B-Cell Lymphoma (ARCHED / GLA 2022-1)

Background Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, and its incidence increases with age. Approximately 40% of patients with DLBCL are older than 70 years. Since the addition of the anti-CD20 antibody rituximab to CHOP regime (cyclophosphamide, doxorubicin, vincristine, and prednisone) prognosis in elderly patients has improved but still remains worse compared to their younger counterparts. Adequate dosage of chemotherapy in older adults is limited by comorbidities/frailty, especially in patients >80 years of age. An attenuated chemotherapy regimen, R-miniCHOP, has been evaluated in prospective trials and seems to provide a good balance between safety and efficacy in this vulnerable patient population (Peyrade et al, 2011). However, even with this regime, outcomes remain modest with 2-year overall survival at 50-60%, underlining the need for more effective treatment in this population. Acalabrutinib is a selective, irreversible, second-generation small molecule inhibitor of Bruton Tyrosine Kinase (BTK) with a more favorable safety profile compared to first generation BTK inhibitors. Although, not yet approved for the treatment of DLBCL, acalabrutinib showed promising results both as a single agent (Strati et al, Haematologica 2021) and in combination with full dose R-CHOP (Davies et al, ASH 2022), in patients aged up to 80 years. Furthermore, acalabrutinib carries the potential of improved efficacy in specific subgroups. The activated B-cell like (ABC) DLBCL subtype has been shown to depend on chronic active B-cell receptor signaling involving many downstream kinases including BTK. Additionally, the genetically defined subgroups MCD/C5, N1, and BN2/C1 and also may serve as potential predictive biomarkers for acalabrutinib. Study design and endpoints ARCHED is an investigator initiated, randomized, multicenter, open-label, phase III trial of R-miniCHOP with or without acalabrutinib in older adults with untreated DLBCL. Patients in the standard arm will receive 6 cycles of R-miniCHOP every 21 days followed by 2 cycles of rituximab alone, while patients in the experimental arm will receive the same regimen and additionally acalabrutinib 100 mg p.o. twice daily from day 1 to day 21 for 8 cycles (Figure 1). The primary endpoint of the study is investigator assessed progression-free survival (PFS). Secondary endpoints include overall survival, PFS per blinded independent review, event-free survival, outcomes according to cell of origin and molecular genotype, response rates, duration of response, progression, relapse and central nervous system (CNS) relapse rates as well as toxicity. Key eligibility criteria Patients are eligible for enrolment if they are >80 years old or >60 years old and ineligible for full-dose R-CHOP according to investigator assessment after standardized simplified geriatric evaluation and are diagnosed with untreated CD20+ DLBCL according to the 2017 WHO classification. Primary mediastinal lymphoma, high grade B-cell lymphoma and follicular lymphoma 3B as well as concurrent diagnosis of indolent lymphoma is allowed, but Richter's transformation is an exclusion criterion. Ann Arbor stage I patients can be included only in the presence of concomitant bulky disease (≥ 7.5 cm). Further exclusion criteria are CNS involvement, stroke or intracranial hemorrhage in the past 6 months and relevant organ dysfunction. An ECOG performance status score of 0 - 2 is required for enrolment but an ECOG score of 3 is acceptable if lymphoma associated. Statistical analysis With an expected 5% drop out rate, we aim to recruit 330 patients (165 in each arm) to achieve 80 % power at a 5 % significance level (two-sided) to observe a PFS difference of 15 % in favor of the experimental arm. An interim analysis for efficacy comparing PFS between the two treatment arms will be performed with n=200 patients and 1 year follow-up for the last patient, with approximately 50% of events. Additionally, an interim analysis for safety regarding treatment completion rates and all-cause mortality will take place when 92nd patient in each group has completed the sixth R-mini-CHOP cycle or died. ARCHED is an academic study of the German Lymphoma Alliance and is coordinated by the Saarland University Clinical Trials Unit. This study is funded by AstraZeneca GmbH. The trial is approved in the EU and is open for recruitment in Germany. (EU-CTN: 2022-501187-18-00, NCT05820841).

Correlation between PFS and OS in FL: Implications for Clinical Trial Endpoint Selection

Introduction: Follicular lymphoma (FL) comprises 15% of all lymphoma cases and 70% of indolent lymphomas. Cytotoxic, targeted, and novel treatments lead to prolonged remission periods, with a median overall survival (OS) of greater than 10 years. For this reason, surrogate endpoints for OS are frequently used in clinical trials of FL to allow for quicker results and shorter time to drug approvals, as well as to offset the likely cost and difficulty in funding long term trials with OS as a primary endpoint. A frequently used surrogate endpoint is progression free survival (PFS); however, PFS has not been previously validated as a surrogate endpoint for OS in the treatment of FL. Previous systematic reviews of multiple trials did not have mature enough data to draw definitive conclusions (Zhu et al, AAPS J 2017). Methods: To evaluate the correlation between PFS and OS in FL trials, we conducted a comprehensive systematic review. We included all completed phase 2 or 3 clinical trials with posted results on ClinicalTrials.gov from the inception of the database until July 2023. Additionally, we manually added trials that were completed before the database inception in February 2000 culled from HemOnc.org. For inclusion, randomized controlled trials reporting a hazard ratio for both PFS and OS were considered. We performed statistical analyses, utilizing unadjusted linear regression weighted by sample size to evaluate the association between hazard ratios for PFS and OS. Results: A total of 169 randomized controlled trials for FL were initially identified. Upon screening, 74 randomized trials reported rates for both PFS and OS. 20 trials with 22 interventional arms that included hazard ratios were eligible for inclusion in final analysis. 21 (96%) phase 3 trials and 1 (4%) randomized phase 2 trial were included, encompassing 10,729 participants. Among the included interventional arms, 12 (55%) were in the first-line setting and 10 (45%) were in the refractory or relapsed setting. 14 (64%) arms demonstrated a PFS benefit, and 4 (18%) demonstrated both a PFS and OS benefit. Disease characteristics and treatment outcomes are included in Table 1. The correlation coefficient between PFS and OS was 0.558 (95% CI 0.545-0.571), indicating a weak association. The coefficient of determination was 0.311 (95% CI: 0.08-0.52) suggesting 31.1% of OS variance could be explained by changes in PFS (Figure 1). Discussion: PFS showed a weak correlation with OS in FL trials, challenging its role as a surrogate endpoint. Factors such as patient heterogeneity, treatment regimens, subsequent therapies, and treatment-related complications may contribute to the discrepancy. While PFS aids regulatory approval and drug development, our study suggests that PFS may not be an appropriate surrogate endpoint for OS in the treatment of FL, and alternative surrogate endpoints should be pursued. Possible alternative endpoints though will need to be validated using similar systematic methods given often contradictory findings between individual studies. For example, progression within 24 months of initial treatment (POD 24) was a valid surrogate endpoint for OS in the PRIMA study, however this was not the case in the GALLIUM study (Bachi et al., Blood Adv 2021). Other surrogate endpoints such as complete response rate at 30 months (CR30) have demonstrated strong correlation with PFS however their association with OS has yet to be established (Shi el, JCO 2016).

Spectrum and Clinical Features of Gene Mutations in Chinese Follicular Lymphoma

Background: Follicular lymphoma (FL) is the most common indolent lymphoma with variable biologic presentation and heterogeneous clinical outcomes, and some of patients experiences early progression and have inferior survival outcomes. Next-generation sequencing (NGS) identified recurrently mutated genes in FL. While few studies on gene mutations in Chinese FL patients have been identified in the real world, this present study aimed to characterize the genomic landscape and provide insights into the biomarkers of high-risk FL populations. Methods: 590 FL patients were reviewed, and 100 patients with sufficient samples were enrolled in our cohort. We performed targeted sequencing of 521 lymphoma-related genes based on NGS in this study. Results: A total of 207 genetic alterations were detected in 99/100 patients. T NFRSF14, CARD11, and NOTCH3 mutations were common in FL1-2 patients compared to FL3a patients (p = 0.025, 0.0036, and 0.0047, respectively). SOCS1 mutations were more common in patients with Ki-67 index > 30% (p =0.324), and PRDM1 mutations were more common in patients who experienced progression of disease within 24 months (POD24) (33.3% vs. 0%, p =0.008). We observed a trend that patients with a high mutation load (with ≥ 6 mutated genes) showed decreased PFS compared with patients with < 6 mutated genes (p=0.068). For patients who received R-CHOP-like regimens, the multivariate COX proportional hazard modeling identified TP53, TNFAIP3, and SOCS1 mutations as independent risk factors of PFS (HR 6.76, 95% CI 1.81 to 25.18, p =0.004; HR 3.68, 95% CI 1.06 to 12.82, p =0.041; HR 5.07, 95% CI 1.81 to 21.73, p =0.029). TP53 and TNFAIP3 were significant independent predictors of PFS when testing with either FLIPI (p=0.029) or FLIPI2 (p=0.023) in multivariable analysis. Conclusion: Our study depicted genomic characterization of real-world Chinses FL patients and demonstrated TP53, TNFAIP3 and SOCS1 mutations can help identify high-risk patients.

DLBCL arising from indolent lymphomas: How are they different?

Transformation to diffuse large B-cell lymphoma (DLBCL) is a recognized, but unpredictable, clinical inflection point in the natural history of indolent lymphomas. Large retrospective studies highlight a wide variability in the incidence of transformation across the indolent lymphomas and the adverse outcomes associated with transformed lymphomas. Opportunities to dissect the biology of transformed indolent lymphomas have arisen with evolving technologies and unique tissue collections enabling a growing appreciation, particularly, of their genetic basis, how they relate to the preceding indolent lymphomas and the comparative biology with de novo DLBCL. This review summarizes our current understanding of both the clinical and biological aspects of transformed lymphomas and the outstanding questions that remain.

SIOG2023-5-P-330 - Age differences in quality of life and distress in adult patients with indolent lymphoma

SIOG2023-5-P-330 - Age differences in quality of life and distress in adult patients with indolent lymphoma

Analysis of vaccine responses after anti-CD20 maintenance in B-cell lymphoma in the Balearic Islands. A single reference center experience.

The use of maintenance approaches with anti-CD20 monoclonal antibodies has improved the outcomes of B-cell indolent lymphomas but may lead to significant peripheral B-cell depletion. This depletion can potentially hinder the serological response to neoantigens. Our objective was to analyze the effect of anti-CD20 maintenance therapy in a reliable model of response to neoantigens: SARS-CoV-2 vaccine responses and the incidence/severity ofCOVID-19 in a reference hospital. In our series (n=118), the rate of vaccination failures was 31%. Through ROC curve analysis, we determined a cutoff for SARS-CoV-2 vaccine serologic response at 24 months from the last anti-CD20 dose. The risk of severe COVID-19 was notably higher within the first 24months following the last anti-CD20 dose (52%) compared to after this period (just 18%) (p=0.007). In our survival analysis, neither vaccine response nor hypogammaglobulinemia significantly affected OS. While COVID-19 led to a modest mortality rate of 2.5%, this figure was comparable to the OS reported in the general immunocompetent population. However, most patients with hypogammaglobulinemia received intravenous immunoglobulin therapy and all were vaccinated. In conclusion, anti-CD20 maintenance therapy impairs serological responses to SARS-CoV-2 vaccines. We report for the first time that patients during maintenance therapy and up to 24 months after the last anti-CD20 dose are at a higher risk of vaccine failure and more severe cases of COVID-19. Nevertheless, with close monitoring, intravenous immunoglobulin supplementation or proper vaccination, the impact on survival due to the lack of serological response in this high-risk population can be mitigated, allowing for the benefits of anti-CD20 maintenance therapy, even in the presence of hypogammaglobulinemia.

In the skin lesions of patients with mycosis fungoides, the number of MRGPRX2-expressing cells is increased and correlates with mast cell numbers.

Mycosis fungoides (MF) is an indolent T-cell lymphoma that mainly affects the skin and presents with itch in more than half of the patients. Recently, the expression of Mas-related G protein-coupled receptor X2 (MRGPRX2), a receptor of mast cell (MC) responsible for the IgE-independent non-histaminergic itch, has been shown in lesional skin of patients with pruritic skin diseases, including chronic urticaria, prurigo, and mastocytosis. As of yet, limited knowledge exists regarding the MRGPRX2 expression in the skin of patients with MF. To investigate the number of MRGPRX2-expressing (MRGPRX2+) cells in the skin of patients with MF and its correlation with clinical and laboratory characteristics of the disease. MRGPRX2 was analyzed in lesional and non-lesional skin of MF patients and healthy skin tissues by immunohistochemistry. Co-localization of MRGPRX2 with the MC marker tryptase was assessed by immunofluorescence. Public single-cell RNAseq data was reanalyzed to identify the MRGPRX2 expression on the distinct cell types. In lesional skin of MF patients, MRGPRX2+ cell number was higher than in non-lesional skin and healthy control skin (mean:15.12 vs. 6.84 vs. 5.51 cells/mm2, p=0.04), and correlated with MC numbers (r=0.73, p=0.02). MC was the primary cell type expressing MRGPRX2 in MF patients. The ratio of MRGPRX2+ MCs to MRGPRX2+ cells in lesional and non-lesional skin correlated with the severity of disease (r=0.71, p=0.02 and r=0.67, p=0.03, respectively). Our findings point to the role of MRGPRX2 and MC in the pathogenesis of MF that should be investigated in further studies.

Three-year follow-up analysis of axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5)

AbstractAxicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel for patients with R/R indolent non-Hodgkin lymphoma (iNHL; N = 104), including FL and marginal zone lymphoma (MZL). In the primary analysis (median follow-up, 17.5 months), the overall response rate (ORR) was 92% (complete response rate, 74%). Here, we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after ≥2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2 × 106 CAR T cells per kg). The primary end point was ORR, assessed in this analysis by investigators in all enrolled patients (intent-to-treat). After median follow-up of 41.7 months in FL (n = 127) and 31.8 months in MZL (n = 31), ORR was comparable with that of the primary analysis (FL, 94%; MZL, 77%). Median progression-free survival was 40.2 months in FL and not reached in MZL. Medians of overall survival were not reached in either disease type. Grade ≥3 adverse events of interest that occurred after the prior analyses were largely in recently treated patients. Clinical and pharmacokinetic outcomes correlated negatively with recent exposure to bendamustine and high metabolic tumor volume. After 3 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable responses, with very few relapses beyond 2 years, and manageable safety in patients with R/R iNHL. The ZUMA-5 study was registered at www.clinicaltrials.gov as #NCT03105336.

Indolent lymphoma care delivery and outcomes during the COVID-19 pandemic in Ontario, Canada.

The treatment pattern and outcomes in patients with indolent B-cell lymphoma treated during the coronavirus disease 2019 (COVID-19) pandemic period compared to the prepandemic period are unclear. This was a retrospective population-based study using administrative databases in Ontario, Canada (follow-up to 31 March 2022). The primary outcome was treatment pattern; secondary outcomes were death, toxicities, healthcare utilization (emergency department [ED] visit, hospitalization) and SARS-CoV-2 outcomes. Adjusted hazard ratios (aHR) from Cox proportional hazards models were used to estimate associations. We identified 4143 patients (1079 pandemic, 3064 prepandemic), with a median age of 69 years. In both time periods, bendamustine (B) + rituximab (BR) was the most frequently prescribed regimen. During the pandemic, fewer patients received R maintenance or completed the full 2-year course (aHR 0.81, 95% CI 0.71-0.92, p = 0.001). Patients treated during the pandemic had less healthcare utilization (ED visit aHR 0.77, 95% CI 0.68, 0.88, p < 0.0001; hospitalization aHR 0.81, 95% CI 0.70-0.94, p = 0.0067) and complications (infection aHR 0.69, 95% CI 0.57-0.82, p < 0.0001; febrile neutropenia aHR 0.66, 95% CI 0.47-0.94, p = 0.020), with no difference in death. Independent of vaccination, active rituximab use was associated with a higher risk of COVID-19 complications. Despite similar front-line regimen use, healthcare utilization and admissions for infection were less in the pandemic cohort.

Proteomics identifies apoptotic markers as predictors of histological transformation in patients with follicular lymphoma

AbstractFollicular lymphoma (FL) is an indolent lymphoma with a generally favorable prognosis. However, histological transformation (HT) to a more aggressive disease leads to markedly inferior outcomes. This study aims to identify biological differences predictive of HT at the time of initial FL diagnosis. We show differential protein expression between diagnostic lymphoma samples from patients with subsequent HT (subsequently-transforming FL [st-FL]; n = 20) and patients without HT (nontransforming FL [nt-FL]; n = 34) by label-free quantification nano liquid chromatography-tandem mass spectrometry analysis. Protein profiles identified patients with high risk of HT. This was accompanied by disturbances in cellular pathways influencing apoptosis, the cytoskeleton, cell cycle, and immune processes. Comparisons between diagnostic st-FL samples and paired transformed FL (n = 20) samples demonstrated differential protein profiles and disrupted cellular pathways, indicating striking biological differences from the time of diagnosis up to HT. Immunohistochemical analysis of apoptotic proteins, CASP3, MCL1, BAX, BCL-xL, and BCL-rambo, confirmed higher expression levels in st-FL than in nt-FL samples (P < .001, P = .015, P = .003, P = .025, and P = .057, respectively). Moreover, all 5 markers were associated with shorter transformation-free survival (TFS; P < .001, P = .002, P < .001, P = .069, and P = .010, respectively). Notably, combining the expression of these proteins in a risk score revealed increasingly inferior TFS with an increasing number of positive markers. In conclusion, proteomics identified altered protein expression profiles (particularly apoptotic proteins) at the time of FL diagnosis, which predicted later transformation.

Characteristics and predictors of infusion-related reactions to rituximab in patients with B-cell non-Hodgkin lymphoma

This retrospective study aimed to assess the characteristics and predictors of infusion-related reactions (IRRs) to rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL). The medical records of adult patients with B-NHL who received their first cycle of rituximab from August 2020 to August 2022 were reviewed. IRRs were defined as any signs experienced by patients during rituximab infusion and graded according to the Common Terminology Criteria for Adverse Events. During the study period, 334 patients were included; among them, 100 patients (30%) developed IRRs (mean age 54.7 (SD 13.2) years). Of the reported IRRs, 90% were grade II reactions, and 10% were grade III reactions. The multivariate analysis identified indolent lymphoma [OR 1.90, p = 0.025], no hydrocortisone as premedication [OR 3.03, p = 0.029], thrombocytopenia [OR 2.55, p = 0.009], and absolute lymphocyte count ≥ 2000 lymphocytes/microL [OR 1.74, p = 0.045] as independent predictors for IRRs.

Local Control after Low-Dose Radiation for Two Rare Forms of Indolent Non-Hodgkin Lymphoma.

Small lymphocytic lymphoma (SLL) and lymphoplasmacytic lymphoma (LPL) are two rare subsets of indolent non-Hodgkin lymphoma (NHL). National guidelines recommend 24-30 Gy for localized SLL. However, based on data for follicular and marginal zone lymphoma, lower dose RT (4 Gy) has been increasingly utilized. We reviewed our experience with SLL and LPL and hypothesized that low dose RT would provide excellent local control. We retrospectively reviewed patients at three tertiary cancer centers who had been treated with RT for SLL or LPL. Response to RT was classified using the World Health Organization response criteria and by examining available PET and CT imaging. Radiographic response was assessed at first imaging follow-up and clinical response was recorded if no imaging was performed. Time to best response was noted, and Kaplan Meier estimates and cumulative incidence tests were performed to determine progression-free survival (PFS) and local progression (LP), respectively. From 2014-2022, 16 patients with 18 sites of SLL (n = 13) or LPL (n = 5) were treated with RT and available to review. Five sites of SLL represented diffuse large B-cell lymphoma transformation and were excluded from analysis. In total, eight sites of SLL (seven patients) and five sites of LPL (five patients) were treated with doses ranging from 4 to 30 Gy in 2 to 12 fractions (median 20 Gy). Four sites of disease received 4 Gy in 2 fractions, one of which (SLL) progressed approximately four months after RT. This site was successfully salvaged with 24 Gy in 12 fractions. There were no other LP. Toxicity overall was low: one patient experienced grade 2 mucositis after 25 Gy in 10 fractions to the maxillary sinus and palate and the remainder of patients experienced grade 1 or no toxicity. Of 10 symptomatic sites, seven (5/7 SLL and 2/3 LPL) attained at least partial relief after RT. A complete response (CR) was achieved in 14% of SLL disease sites and 60% of LPL sites. Partial response was achieved in 57% of SLL and 40% of LPL sites, and 29% of SLL sites were deemed to be stable. One patient with SLL died after their first RT treatment, but this was unrelated to RT. The median time to best response was 284 days (IQR 189-292 days) for SLL and 131 days (IQR 106-166 days) for LPL. 4 Gy in 2 fractions did not result in any CR, yet one patient from the LPL group exhibited a striking CR after 8 Gy in 2 fractions. PFS at one year was 51% for SLL and 100% for LPL - cumulative incidence of LP at two years was 15% and 0% respectively. In this cohort of patients with two types of indolent NHL, one patient progressed locally after 4 Gy, while none progressed after higher doses. LPL sites achieved more complete responses than SLL sites, and RT was tolerated extremely well. These results indicate that similar to other indolent lymphomas, clinical judgment should be used when deciding between 4 Gy or higher doses of RT. For SLL in particular, higher doses of RT are more likely to provide durable local control and CR.