Extranodal Sites Research Articles

Final Results of a Phase I/II Trial of Carfilzomib + R-CHOP for Frontline Treatment of Patients with Non-Germinal Center Diffuse Large B-Cell Lymphoma (DLBCL)

INTRODUCTION: Recent data from the REMoDL-B trial show that addition of the proteasome inhibitor bortezomib to R-CHOP improves progression free survival (PFS) of patients (Pts) with activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) compared to R-CHOP, but peripheral neuropathy limited dose intensity. Relative to bortezomib, carfilzomib (K) displays comparable clinical activity in plasma cell neoplasms but does not cause neurotoxicity. K has preferential clinical activity in relapsed non-germinal center (non-GC) DLBCL treated with chemotherapy (Torka, et al. Blood Adv. 2023). To explore the safety and efficacy of K in combination with R-CHOP (KR-CHOP), we performed a phase I trial to identify the recommended phase 2 dose (RP2D) in all DLBCL Pts followed by a phase II extension exclusively in non-GC DLBCL. METHODS: Between 2015-2020, Pts with untreated de novo or transformed DLBCL, adequate organ function and ECOG PS ≤ 3 were enrolled at 3 US academic medical centers. As previously reported [Hill, et al, Blood (2018), 132 (Supl.1):1692], during phase I dose escalation, the RP2D of K was 20 mg/m 2 on days (D) 1 & 2 of cycle 1 and 56 mg/m 2 on D1 & 2 of cycles 2-6. Rituximab was given on D2 and CHOP was given on D3. All Pts received pegfilgrastim and zoster prophylaxis. To assess the cardiac safety of combining K with anthracycline, we compared echocardiogram data at baseline and conclusion of therapy from study Pts and control NHL Pts treated with CHOP. To gauge for differential clinical activity of KR-CHOP vs R-CHOP, we compared PFS and overall survival (OS) rates for study Pts with non-GC DLBCL vs. Pts with non-GC DLBCL receiving standard of-care (SOC) R-CHOP at the Cleveland Clinic during the same period. The outcomes were also compared between propensity score (PS)-matched pairs, to account for differences in baseline demographics and clinical risk. RESULTS: 48 Pts were enrolled, and 47 treated; 18 in dose levels < RP2D and 29 at RP2D.Baseline demographics and treatment outcomes are shown in the Table. All-grade (G) hematologic adverse events (AEs) were: anemia, 35% (22% ≤ G2, 13% G3); thrombocytopenia, 24% (15% ≤ G2, 2% G3, 7% G4); febrile neutropenia, 9% (all G3/G4). Non-hematologic AEs included: nausea, 49% (47% ≤ G2, 2% G3); vomiting, 23% (21% ≤ G2, 2% G3), peripheral sensory neuropathy, 27% (all ≤ G2); dyspnea, 24% (all ≤G2). There was one case of G3 congestive heart failure. Echocardiograms from 42 study Pts who completed 6 cycles of KR-CHOP showed no statistically significant difference in change in ejection fraction from baseline compared to 39 control Pts [95% vs. 94%, respectively (P = 0.59)]. The overall response rate was 89% (70% CR, 19% PR). At a median follow-up of 31 months, 3-year Kaplan-Meier estimates of PFS and OS for the study population were 79% and 87%, respectively. There were 8 deaths in the study: 4 due to lymphoma; 2 due to infection; 2 due to other causes. Comparing outcomes of the 36 study Pts with non-GC DLBCL to 172 control Pts receiving R-CHOP as SOC, more control Pts had stage IV disease (54% vs 34%, p=0.03) and older age (median 67 vs 66 years old, p=0.03), but less frequently >1 extranodal site of disease (23% vs. 42%, P = 0.02). PS matching using logistic regression identified 25 case-control pairs of Pts with non-GC DLBCL according to gender, age, and other International Prognostic Index (IPI) elements (see Table). In analysis of PS-matched pairs of Pts with non-GC DLBCL, Pts treated with KR-CHOP had better 3-year PFS and OS relative to Pts treated with R-CHOP as SOC [96% vs. 50% (p=0.002) (see Figure) and 67% vs. 96% (p = 0.02), respectively]. In Cox univariate analysis, treatment with R-CHOP vs. KR-CHOP was associated with an increased risk of PFS and OS with hazard ratios (HR) of 6.15 [95% confidence interval (CI) 1.71 - 22.05, P = 0.002] and 3.19 [(95% CI, 1.01 -10.11), P = 0.02], respectively. CONCLUSION: KR-CHOP can be delivered safely, without excess cardiac toxicity or peripheral neuropathy. The superior PFS and OS rates for Pts with non-GC DLBCL vs. controls receiving R-CHOP are encouraging but should be interpreted with caution due to inherent selection bias in clinical trial populations. These data suggest that, like bortezomib, carfilzomib (K) may have preferential clinical activity in ABC DLBCL. Future randomized trials are justified using advanced molecular profiling to further investigate which Pts with DLBCL may benefit from addition of a proteasome inhibitor as part of frontline treatment.

PIM1 Point Mutations Increase Migration of Diffuse Large B-Cell Lymphoma (DLBCL) Cells

PIM1 serine-threonine kinase is known proto-oncogene, highly expressed in lymphoid malignancies. It regulates crucial processes for the cancer cell, like proliferation, apoptosis, metabolism or migration. In DLBCLs, PIM1 gene is a target of somatic hypermutation and one of the most frequently mutated genes in DLBCL patients. PIM1 mutations are more frequent in ABC-type tumors, which have worse survival prognosis than GCB-type, and often co-occur with mutations in MYD88 and CD79B. Analyses of the available clinical data show that the most significant differences between the groups of DLBCL patients with or without PIM1 mutations are tumor mutational burden, age at diagnosis and extranodal (testicular) involvement. In line with this finding, PIM1, MYD88 and CD79B mutations have also been reported to be highly prevalent in extranodal B cell lymphomas, localized in central nervous system (PCNSL), testicles (PTL) or intravascular space (IVLBCL). Our goal was to assess the role of the most common PIM1 point mutations in the biology and pathogenesis of DLBCL cells. The HBL-1 cell line was chosen as a model of MYD88 L265P-positive ABC-DLBCL subtype. PIM1 knock-out was performed using CRISPR/Cas9 method. Sequences of wild type PIM1, kinase-dead PIM1K67M, serving as a an inactive kinase control, and 7 most frequent mutants (PIM1G28D, PIM1E70K, PIM1P81L, PIM1S97N, PIM1P125A, PIM1L164F, PIM1L184F) were reintroduced to the HBL-1 PIM1 KO cells using lentiviral vectors. PIM1 mutations did not affect the proliferation of DLBCL cells and did not increase resistance to doxorubicin, excluding the proliferation rate or treatment resistance as a cause of the poor prognosis associated with PIM1 mutations. We performed RNA-seq analysis of the HBL-1-PIM1-WT and HBL-1-PIM1-mutants. The most upregulated pathways in PIM1 mutants (including PIM1K67M) were those related to Interferon gamma, IL-15, STAT3, cMET and semaphorin-plexin signaling (involved in proliferation, actin dynamics and migration of cancer cells). We also found that PIM1 mutants universally overexpress cMET oncogene. Moreover, gene set and pathway enrichment analyses indicated that the PIM1-mutant cells exhibit features associated with altered actin polymerization, RHO GTPases and cell membrane dynamics, suggesting the increased migratory potential of the cells and their propensity to spread to extranodal sites. Higher surface level of cMET in PIM1 mutant cells was confirmed using FACS analysis. Since cMET and CXCR4 cooperate in signaling and trigger AKT/mTOR, which is required for CXCR4-mediated cell motility, we evaluated whether PIM1 mutant cells would exhibit increased phosphorylation of AKT. In line with this hypothesis, we noted higher pAKT and pERK1/2 in PIM1 mutant cells than in PIM1 WT cells. Finally, in transwell assays, PIM1 mutant cells exhibited markedly increased migratory potential. Taken together, these studies indicate that PIM1 mutants are not likely associated with differential drug responses, but rather facilitate tumor dissemination and are thus associated with inferior prognosis in DLBCL patients harboring PIM1 mutations.

A Simplified IPI Including BCL2 Identifies IPI 3 Patients with Poor Prognosis - a GLA/ Dshnhl and Lysa Collaboration

Introduction: The original IPI remains valid to identify prognostic groups of DLBCL patients (pts) treated with R-CHOP (Ruppert et al. Blood 2020) and has been used to define eligibility for more than 20 studies randomizing pts between R-CHOP and R-CHOP + X, none of which except the Polarix study met its endpoint. One reason why some studies failed was the inclusion of IPI 2/3 pts equalizing the difference between standard and experimental arm although significant survival differences in pts with higher IPI were detected. Following the WHO-HAEM5 classification, determination of BCL2 and MYC rearrangements is mandatory to diagnose DLBCL, NOS and HGBL- MYC/ BCL2. As surrogate markers, we included immunohistochemistry (IHC) for MYC and BCL2 into the IPI model hoping for a wider spread of survival curves and better selection of pts suitable for future clinical trials. Methods: We analyzed 2765 pts treated on DSHNHL (German high-grade lymphoma study group) phase 2/3 studies, calculated the IPI, and added results for BCL2 and MYC expressionto individual IPI factors using published thresholds (50%; 70%) (Ziepert et al. Haematologica 2020). In univariate analyses, log-rank tests were used. Proportional hazard models for each of the biologic markers were separately adjusted for IPI factors. Using a variable selection algorithm the final model was built. Hazard ratios (HR) with p-values are presented. Results: 2765 DLBCL pts by reference pathology treated on 12 DSHNHL phase 2/ 3 studies were eligible. Median age at diagnosis was 57 years (range: 18-80 years), 43% of pts were female. Median observation time was 5 years. All pts had been treated with R-CHOP or variations. At diagnosis, 610 pts (22%) scored an IPI of 0, IPI was 1, 2, 3, 4, or 5 in 895 (32%), 546 (20%), 436 (16%), 212 (8%) and 64 (2%) pts with 3-year PFS- and OS-rates of 95%,87%,77%,66%,66%,47% and 98%,92%,83%,71%,73% and 54%, respectively. Multivariate analyses confirmed the significance of IPI factors (age, stage, performance status, and LDH) except the number of extranodal sites (EN) which did not significantly contribute to the model in this cohort (HR EFS,PFS,OS=1.0). Accordingly, EN>1 was deleted also resulting in better distinction of IPI groups (3-year PFS- and OS-rates: 95%,87%,74%,63%,51% and 98%,92%,80%,70%,57%%). In the final model, adjusted for all IPI factors except EN>1, BCL2 and MYC expression remained significant (HR PFS=2.3 and 2.0, p<0.001 and p=0.003). These results were validated and confirmed in 1176 DLBCL patients from 5 French (LYSA) studies. EN>1 but also MYC expression did not significantly contribute the final model in the validation set. Thus, MYC expression was deleted from the final model. Using the IPI deleting EN>1 but including BCL2 expression we observed 3-year PFS-rates of 74% vs. 83% in BCL2-positive vs. BCL2-negative patients with IPI 2 (p=0.136). In pts with IPI 3 the 3-year PFS rates were 53% vs. 80% (p=0.011) (see figure 1); in pts with IPI 4 the respective 3-year PFS rates were 49%% vs. 71%. This latter difference was not significant due to small pt numbers (p=0.381). Conclusions: Deletingthe number of extranodal sites and adding BCL2expression tothe original IPI factors as the only readily available biologic marker allows building an IPI model which effectively separates IPI 3 pts in 2 groups with significantly different prognosis. Restricting eligibility for future clinical trials to DLBCL pts with IPI 3 (and IPI 4) who are BCL2-pos. may help to avoid overtreatment of pts well treated with R-CHOP and at the same time better select pts representing a group with truly unmet medical need who are most likely to benefit from experimental therapies.

First Report of Asymptomatic Solitary High-Grade B-Cell Lymphoma NOS: An Enigmatic Entity

Background High-grade B cell lymphoma (HGBL) is a new disease entity introduced by WHO in 2016, including two types: HGBL with a double hit (DH) or triple hit (TH) and HGBL, not otherwise specified (NOS). HGBL DH/TH are defined by genetic rearrangements of specific oncogenes MYC, BCL2 and/or BCL6, while HGBL NOS is defined purely base on morphology in the absence of these genes. HGBL DH/TH is known for its poor prognostication given its propensity to rapidly progress and disseminate, however HGBL NOS remains ill-defined and poorly understood with no tangible literature describing its clinical nature and therapeutic susceptibility. Case presentation A 76-year-old post-menopausal woman with no significant PMH presented for evaluation of painless hematuria during a routine office visit. Evaluation with imaging showed a suspicious incidental liver mass concerning for possible metastatic or primary liver cancer. Obtained labs were unremarkable, including serum LDH, serological testing for hepatitis B/C and HIV1/2, and typical tumor markers. PET scan showed focal uptake of tracer in liver with no nodal involvement. Liver biopsy revealed diffuse infiltration by atypical lymphocytes. Immunohistochemical analysis showed CD20 and CD10 positivity, negative CD30, and high Ki-67 proliferation rate of 100%, however the absence of MYC, BCL6, BCL2, and t(8;14) rearrangements on FISH ruled out Burkitt and DH/TH lymphoma, consistent with HGBL-NOS. Following discussions with Henry Ford Lymphoma Tumor Board, patient was treated with six cycles of R-CHOP, where follow-up imaging indicated remission of her lymphoma. Conclusion This represents an extraordinary first report of HGBL NOS manifesting as an isolated primary hepatic lymphoma in the complete absence of clinical symptoms. The significance of this case lies in its atypical extra-nodal site of involvement and total absence of clinical symptoms and serological markers, underscoring the unfulfilled need to further describe this enigmatic entity.

Clinical Characteristics Analysis of Gastrointestinal Peripheral T-Cell Lymphoma:Impact of Non-Emergency Surgery on Overall Survival

Introduction The gastrointestinal tract is the most common extranodal site involved in non-Hodgkin lymphoma (NHL) and most NHL cases are of B-cell origin. Peripheral T-cell lymphoma (PTCLs) involving the gastrointestinal is less commont, comprising only about 4-6% of gastrointestinal lymphomas. This study retrospectively analyzed the clinical characteristics and potential clinical factors influencing survival outcomes in patients diagnosed with PTCLs through gastrointestinal tissue biopsy at our center. Methods Based on the clinical data, patients were reevaluated for clinical staging and risk stratification, including Ann Arbor staging, IPI scoring, and gastrointestinal lymphoma Lugano staging. Patient's follow-up was conducted through outpatient medical records and telephone communication. For the analysis of categorical data, the chi-square test or Fisher's exact test was used. Survival time was estimated using the Kaplan-Meier method. The Cox proportional hazards model was employed to calculate hazard ratios (HR) and their 95% confidence intervals (CI) to analyze prognostic factors. Data analysis was performed using SPSS 23 for Windows software. Results A total of 622 gastrointestinal tissue biopsy samples from October 2014 to September 2022 were retrieved from the medical records system. Among them, 67 cases (10.8%) were diagnosed as PTCLs. Among them, 5 cases had no available clinical data and were excluded. Detailed information regarding patient clinical characteristics can be found in the table. Treatment and Efficacy: Among the 62 patients with available clinical data, 43 received gastrointestinal surgical resection treatment, including 21 cases (33.9%) of elective non-emergency surgery and 22 cases (35.5%) of emergency surgery due to acute abdomen. The median courses of chemotheray was 5 (1~8). 15 patients (31.3%) achieved complete response (CR)/CRu; 10 patients (20.8%) achieved partial response (PR). Among the 59 patients who received chemotherapy and/or surgical treatment, progression-free survival (PFS) was evaluated with a median follow-up time of 48.4 months, and the median PFS was 4.4 months (95% CI: 2.5-6.3) (Figure). Multivariate analysis identified advanced Ann Arbor stage (stage 3/4) (HR=3.53, 95% CI: 1.53-8.17, P=0.003) as independent adverse prognostic factors for PFS. Receiving chemotherapy (HR=0.24, 95% CI: 0.09-0.66, P=0.005) and elective surgery (HR=0.45, 95% CI: 0.22-0.92, P=0.029) were identified as independent favorable prognostic factors for PFS. As of the last follow-up, a total of 49 patients (79.0%) had died and the median overall survival (OS) was 6.4 months (95% CI: 3.8-8.9) (Figure). Multivariate analysis identified Ann Arbor stages 3-4 (HR=3.01, 95% CI: 1.34-6.74, P=0.007) as an independent adverse prognostic factor for OS, and receiving chemotherapy (HR=0.13, 95% CI: 0.05-0.31, P<0.001), elective surgery (HR=0.36, 95% CI: 0.16-0.74, P=0.006) were identified as independent favorable prognostic factors for OS. Conclusion Data from four hematological disease treatment centers located in Zhejiang Province, southeastern China, showed that PTCLs involving the gastrointestinal tract accounted for approximately 10.8% (67/622) of all gastrointestinal lymphoma patients. These patients had a relatively high incidence of gastrointestinal perforation (35.5%). The overall treatment efficacy for patients was poor, with a majority of them succumbing to disease progression. The median PFS and OS were approximately six months. Elective surgery and chemotherapy appeared to improve the patients' outcomes.

A New Machine Learning-Based Prognostic Prediction Strategy for Patients with Diffuse-Large B-Cell Lymphoma

Introduction - Diffuse large B-cell lymphoma (DLBCL) is a frequent and aggressive lymphoma. First line of treatment associates an anti-CD20 immunotherapy with an anthracycline-based chemotherapy (R-CHOP). After this treatment, 30% of patients present primary refractory disease or early relapse within two years (R/R DLBCL). At date, CAR-T cells improve the prognosis of patients with R/R DLBCL compared with high-dose chemotherapy followed by autologous stem-cell transplant. However, predicting this failure remains a challenge at time of diagnosis. Current standard tools as the R-IPI score have many weaknesses, particularly for patients most at risk. A multitude of clinical, biological and PET data are available and could help to precise R/R DLBCL probability. In this study, we propose a new strategy based on machine learning and exploitation of a large dataset to early detect patients with high risk of R/R DLBCL at diagnosis. Material and methods - Between August 2012 and November 2021, we retrospectively collected a cohort of 218 patients with DLBCL receiving first-line treatment R-CHOP. Twenty-two parameters were evaluated for each patient, including well-known predictive factors such as R-IPI components, but also advanced metabolic parameters (SUVmax, total metabolic tumor volume (TMTV), total lesion glycolysis (TLG) and Dmax), as well as pathological and biological features. We used supervised machine learning (ML) to build a multidimensional model to predict POD24, which is defined by primary refractory disease or relapse within two years. Conventional binomial logistic regression was also performed to create a conventional predictive model. In parallel, a group of three hematologists was asked to generate a consensus about POD24 occurrence using Delphi method. Results - Median age was 70 years. With a median follow up of 46 months, complete response rate was 87% and overall response rate was 89%. Overall survival and progression-free survival were respectively 81.6 % (95%CI 76.6 - 86.9) and 70.6 % (95%CI 64.8 - 76.9) at 24 months. POD24 event occurred in 23,5 % of patients. Performance status, Ann-Arbor staging, number of extranodal sites, medullar infiltration, TMTV, TLG, Dmax, lymphocytes and LDH showed significant predictability of POD24 when considered in univariate analysis. We used forward selection of variables to build a conventional predictive model including LDH, lymphocytes and Dmax. Area under the ROC curve was 0,72. Secondly, a ML model was trained on 147 patients and was applied on a test cohort with 49 remaining patients. Prediction accuracy was 89.7% and area under the ROC curve was 0,91. Decision threshold was raised to 0.75 cut-off, allowing to predict 60% of POD24 with 100% specificity. The four predominant variables in the model were Dmax, hepatic SUV, LDH and monocytes. Additionally, experts were confronted to 55 patients randomly sampled from the cohort, 14 (25%) of whom showed POD24. Prediction accuracy was 71% and area under the ROC curve was 0,73. Seventy-nine percents of POD24 was predicted by experts, with 68% specificity. Conclusion - We present a ML model that was built to predict POD24 and then R/R situations in DLBCL patients. It showed great accuracy with high specificity rate. In new immunotherapies and CAR-T cells era, this proof-of-concept study highlights the fact that ML models could be a helpful to decide on first-line strategies for DLBCL patients. Larger multicentric study is necessary to confirm and validate this model for clinical use.

First Line Therapy Evaluation Using Propensity Score Approach in Newly Diagnosed Advanced Classical Hodgkin Lymphoma Patients from Prospective Real-World Realysa Cohort and Phase 3 AHL2011 Trial

Background: AHL2011, a randomized phase III trial demonstrated that PET-CT after two cycles of BEACOPP escalated chemotherapy safely guided treatment of patients aged 16-60 years with newly diagnosed advanced classical Hodgkin lymphoma (cHL) and allowed the use of ABVD in early responders with reduced toxicities and no impaired disease control. REALYSA study, a real-life multicentric cohort set up in France since 2018, included 6000 newly diagnosed lymphoma patients with over 1000 cHL patients. In the present study, we investigated whether real-world data could reproduce results issued from a randomized phase III clinical trial using the propensity score approach. Methods: After stringent propensity score matching (PSM) on 10 baseline parameters (gender, age, Ann Arbor stage, ECOG Performance Status, number of extranodal sites involved, B symptoms, albumin, hemoglobin, white blood cell count and lymphocytes), we performed a PSM testing ratios 1:1 (one patient from AHL2011 trial and one patient from REALYSA cohort). All patients from AHL2011 and REALYSA included in this study had PET-CT monitoring after two cycles of BEACOPP escalated. This approach allowed us to build well-balanced pairs as demonstrated by the absolute values of the standardize mean differences (SMDs) below 0.1 for all matching covariates except for ECOG (SMD=0.15). We also used the Inverse Probability of Treatment Weighting (IPTW, IPTW stabilized) to compare the experimental arm of the AHL2011 trial with a synthetic control arm established with real-world data from REALYSA cHL patients who respected the main inclusion criteria of AHL2011 trial and were treated following this PET-guided approach. The median follow-up was censored in the AHL2011 data in order to be comparable to the median follow-up observed in the REALYSA cohort. Results: Among the 823 patients of AHL2011 and 942 patients of REALYSA with newly diagnosed cHL, 390 and 100 patients respectively were eligible for propensity score calculation, corresponding to AHL2011 TEP-guided therapy, aged between 16 and 60 years, no missing data for the covariates included in the PSM and at least 12 months of follow-up in the REALYSA study. After 1:1 PSM (n=98 AHL2011 and n=98 REALYSA), the overall response rate at the end of induction was 91.8% vs 89.8% (p=0.81) for patients included in AHL2011 and REALYSA, respectively. The proportion of patients with positive PET-CT after 2 cycles was similar in AHL2011 (13%) and REALYSA (14%). After a median follow-up of 13 months, the 1-year progression free survival rates were 93.8% and 87.8% (HR=0.87; 95%CI 0.4-2.0; P=0.74) in AHL2011 and REALYSA, respectively (Figure 1A). Using IPTW model including covariates from the PSM, similar PFS were obtained between experimental arm of AHL2011 and patients included in REALYSA (Figure 1B). IPTW stabilized and other IPTW models also showed similar results for PFS. Conclusions: In this study, we demonstrated using a propensity score approach that patients with newly diagnosed advanced cHL treated according to the AHL2011 PET-guided frontline approach in routine care and included in REALYSA cohort reached similar outcomes as patients included in prospective phase III clinical trial. Beyond the relevant validation of the AHL2011 trial results in real-life, which will need longer follow up, these data could be used to design composite control arm for future clinical trials.

Autologous Stem Cell Transplant in Fit Patients with Late Relapsed Diffuse Large B-Cell Lymphoma That Responded to Salvage Chemotherapy

Background: The new standard of care for fit patients with refractory or early relapse of diffuse large B-cell lymphoma (DLBCL) is chimeric antigen receptor T-cell (CAR-T) therapy. However, for patients with a relapse ≥12 months after completing frontline therapy, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) remains the standard of care. There is a need to characterize such patients and their survival in view of the recent shift in treatment paradigm. Methods: Patients with DLBCL that relapsed ≥12 months after R-CHOP or R-CHOP-like frontline therapy who underwent salvage therapy and ASCT at Mayo Clinic or University of Iowa between 07/2000 and 4/2020 were identified from institutional lymphoma and transplant databases. Clinical characteristics, treatment information, and outcome data were abstracted. Progression-free survival (PFS) and overall survival (OS) from the time of ASCT were analyzed using Kaplan-Meier method and Cox proportional hazards models. Statistical analyses were performed in JMP v15. Results: A total of 158 patients with late relapsed DLBCL who underwent salvage chemotherapy and ASCT were identified. Baseline characteristics at relapse/ASCT are shown in Table 1. Median time from frontline therapy completion to 1st relapse was 26.4 months (range 12.0-152.4). Median age at relapse was 63 years (range 19-77), and 96 (61%) patients were male. A minority (3; 3%) had ECOG PS ≥2. 43 (52%) patients had an elevated serum LDH level, 70 (65%) had advanced stage disease, and 12 (11%) had >1 extranodal involvement. Median line of salvage therapy was 1 (range 1-3), and 17 (11%) patients required >1 line of salvage therapy. Best response before ASCT was complete response (CR) in 97 (61%) and partial response (PR) in 61 (39%). Median age at ASCT was 64 years (range 19-78). Median follow-up after ASCT was 91.5 months (95% CI 74.0-103.3). Median PFS and OS were 54.5 (95% CI 31.9-77.8) and 99.8 (95% CI 60.3-144.5) months, respectively. The 2-year PFS and OS rates were 64% (95% CI 56-71) and 81% (95% CI 74-87), respectively. No statistically significant difference in PFS was seen based on age at ASCT, sex, serum LDH, stage, or extranodal site involvement of >1 at relapse (Table 2). However, patients who required > 1 line of salvage therapy, compared to those requiring 1 line of salvage therapy, had significantly inferior PFS (median 6.1 vs 61.8 months, P <0.0001) and OS (17.8 vs 111.7 months, P <0.0004). There was no statistically significant difference in survival in patients who achieved CR vs PR prior to ASCT, with a median PFS of 61.8 vs 37.8 months( P=0.21) and a median OS of 111.7 vs 78.3 months ( P=0.62). Patients who achieved CR after 1 line of salvage therapy had the most favorable PFS and OS, with a median PFS of 65.6 vs 45.4 vs 6.1 vs 7.6 months ( P=0.0004) and a median OS of 133.0 vs 88.9 vs 24.2 vs 17.6 months ( P=0.004) in patients achieving CR after 1 line of salvage therapy vs PR after 1 line of salvage therapy vs CR after >1 line of salvage therapy vs PR after >1 line of salvage therapy, respectively (Table 2). In multivariate Cox regression models adjusted for age at ASCT and sex, patients requiring > 1 line of salvage therapy, compared to those who required 1 line of salvage therapy, had significantly inferior PFS with a hazard ratio (HR) of 3.25 (95% CI 1.82-5.78, P <0.0001) and OS with a HR of 3.50 (95% CI 1.86-6.60, P=0.0001). However, there remained no significant difference in survival based on response status (CR vs PR) with a HR for PFS 0.78 (95% CI 0.52-1.17, P=0.23) and OS 0.93 (95% CI 0.58-1.47, P=0.74). Conclusions: Survival after ASCT was excellent in patients with late relapsed DLBCL achieving CR after 1 line of salvage chemotherapy. Favorable survival outcomes were seen in patients who achieved PR after 1 line of salvage therapy. These data support the current clinical practice of ASCT consolidation in these patients. However, post-ASCT survival was poor in patients who required more than 1 line of salvage chemotherapy, despite achieving a satisfactory response to subsequent lines of salvage therapy. Alternative treatment strategies such as CAR-T therapy should be considered in such patients.

"Wandering Spleen" With Lymphomatous Involvement.

Wandering spleen is a rare condition caused by either lack or the laxity of ligaments, which results malposition in the lower abdomen or pelvis. FDG PET/CT is the cornerstone of the staging procedures in the management of lymphomas leading to upstaging and picking up occult lesions in the spleen and extranodal sites. Herein, we reported initial staging 18 F-FDG PET/CT findings of a woman with Hodgkin lymphoma whose spleen was absent in normal position and multiple intense heterogenous hypermetabolism in a pelvic mass raised a suspicion of wandering splenic involvement. The confirmation was made with selective spleen SPECT/CT images thereafter.

Plasmablastic lymphoma of the sphenoid bone in an immunocompetent patient: A diagnostic challenge.

Plasmablastic lymphoma is a rare type of highly aggressive B-cell non-Hodgkin lymphoma that usually occurs in immunocompromised patients and involves chiefly extra-nodal sites such as the oral cavity, jaw, gastrointestinal tract, soft tissue, bone, and skin. People above the age of 50 years are more commonly affected, with male predominance having a survival rate of 8 to 15 months. Here, we describe the case of a 48-year-old man who had an isolated plasmablastic lymphoma of the right sphenoid bone without any immunodeficiency. Plasmablastic lymphoma in immunocompetent patients at rare sites is a diagnostic challenge for both clinicians and pathologists because of vague clinical and histomorphology findings. This rare case report reemphasizes the utility of complete assimilation of clinical, histopathological, and immunohistochemical findings in such rare cases.

Cumulative Incidence, Predictors, and Outcomes of Transformation to Diffuse Large B-Cell Lymphoma in a Prospective Cohort of Patients with Marginal Zone Lymphoma

Background: Although marginal zone lymphoma (MZL) typically exhibits an indolent course, transformation to diffuse large B-cell lymphomas (DLBCL) is associated with a poorer outcome and remains a clinical challenge in managing patients with MZL. The limited existing literature reports various cumulative incidence rates, ranging from 2.5% and 4.7% (Finnish Cancer Registry, 1995-2018) to 6.6% and 8.4% (Florida Cancer Registry, 1995-2016) at 5 and 10-years, respectively, likely in part driven by varying study designs, ascertainment, and study population. Similarly, reported outcomes after transformed MZL (tMZL) have been variable. We evaluated the cumulative incidence of histological transformation (HT) to LBCL in a well-characterized prospective cohort of MZL patients from the upper Midwest, USA, and overall survival (OS) after transformation. Methods: Patients ≥ 18 years old with newly diagnosed MZL were prospectively enrolled in the University of Iowa/Mayo Clinic Molecular Epidemiology Resource (MER) cohort from 2002-2015. Clinical and treatment data were abstracted from medical records using a standard protocol. Patients were actively followed for retreatment, transformation, and death through 2022. Pathology was classified according to WHO 4/4R, including all transformations. The cumulative incidence of HT to LBCL was determined using death as a competing risk. Time to HT (TTHT) was defined as time from the date of MZL diagnosis to the date of transformation. We evaluated potential predictors of HT using a stepwise approach, and derived hazard ratios (HR) and 95% confidence intervals (CI) from Cox proportional hazards models. To assess predictors of OS after HT, patients ≥ 18 years old with newly diagnosed tMZL (into DLBCL) at Mayo Clinic between 1995 and 2002 (N=7) were combined with the MER cases. Results: We identified 524 patients with MZL in the MER cohort: 362 extranodal (EMZL; lung 18%, stomach 16%, orbit 13%, parotid 10%, skin 10%), 84 splenic (SMZL), and 78 nodal (NMZL). The median age at diagnosis was 63 years (range 18-92); 56% were female, and 83% were non-Hispanic white. During a median follow-up of 18.8 years (95% CI 16.7, NA), there were 25 HT (including 8 patients under observation) and 158 deaths. Eight Ten-year OS was 67% and 77% in the groups with and without HT, respectively. The overall cumulative incidence of HT was 1.5% at 2 years after diagnosis, 2.9% at 5 years, 4.5% at 10 years, and 5.7% at 15 years (Panel 1). The cumulative incidence of HT varied by subtype (e.g., at 5 years: 2%, 4% and 6%, in EMZL, NMZL and SMZL, respectively; Panel 2). The median time to HT also varied by subtype: 76 months (interquartile range (IQR) 43, 81) for EMZL, 30 months (IQR 16, 52) for SMZL, and 18 months (IQR 14, 23) for NMZL. In univariable analysis, predictors of HT were Stage III/IV (HR=3.4, 95% CI 1.36-8.53, p=0.009), elevated LDH (HR=2.98, 95% CI 1.25-7.12, p=0.014), and presence of ≥2 extranodal sites (HR=2.69, 95% CI 1.22-5.94, p=0.014). In multivariable analysis, elevated LDH was the only non-composite predictor of HT (HR=2.65, 95% CI 1.08-6.52, p=0.034). MALT-IPI score 2-3 (HR=3.61, 95% CI 1.06-12.25, p=0.040) and FLIPI score 3-5 (HR=2.19, 95% CI 1.22-8.22, p=0.018) also predicted HT. We analyzed OS after HT in 32 cases of tMZL (21 tEMZL, 7 tSMZL, 4 tNMZL). At HT, median age was 68 years (range 39-89); 24 (80%) patients presented with stage III/IV disease, 11 (58%) with elevated LDH, 12 (55%) with hemoglobin <12g/dL, 3 (14%) with platelet count <100x10 9/L and 9 (39%) with biopsy-proven bone marrow involvement. Twenty-six (81%) were treated with a systemic therapy, mainly CHOP-backbone therapy (R-CHOP n=13, CHOP n=4, R-EPOCH n=3, lenalidomide-R-CHOP n=1). Among these patients, the overall response rate was 85% (n=22/26). Three of the 4 non-responders died within 1 year. At last follow-up, 18/32 (56%) patients had died, and 6/13 (46%) alive patients had relapsed (MZL 3/6, DLBCL 3/6). After HT, 2-, 4- and 10-year OS were 76%, 55% and 55%, respectively. In univariable analysis, the only predictor of OS at HT was age ≥70 (HR 3.57 ,95% CI 1.34-9.48, p=0.011). Conclusion: In this North American prospective cohort of mainly non-Hispanic White patients, we found a low cumulative incidence of HT in MZL of 2.9% and 4.5% at 5- and 10-year, which was consistent with the Finnish findings (Kalashnikov et al., 2023). At HT, age was associated with OS and there was a high response rate to CHOP-backbone therapies.

Efficacy of Brentuximab Vedotin Maintenance Therapy Following Autologous Stem Cell Transplantation in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma with and without Pre-Transplant Exposure to Novel Agents

Background: Maintenance therapy with brentuximab vedotin (BV) after autologous stem cell transplantation (ASCT) improved progression-free survival (PFS) among high-risk patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) in the phase III AETHERA trial. However, cHL treatment has changed significantly since that trial with frequent incorporation of BV and PD-1 inhibitors into earlier lines of therapy. The efficacy of BV maintenance may be different among pts who receive novel agents before ASCT. Methods: Pts with a diagnosis of R/R cHL who underwent ASCT between 2010 and 2022 were identified at 5 US transplant centers. Pts receiving no systemic post-ASCT maintenance or BV maintenance were included, while pts receiving investigational maintenance treatments were excluded. Medical records were reviewed to identify clinical variables. Results: 921 pts were identified. Median age was 32 yrs (IQR 24-44). 641 pts (70%) had primary refractory disease or relapsed within 12 months of frontline therapy, 326 (35%) had extranodal disease at relapse, and 173 (19%) had B symptoms at relapse. Pts received a median of 2 (1-9) lines of therapy before ASCT, including 295 (32%) who received ≥3 lines. 425 (46%) pts received BV before ASCT (including 24 pts as part of frontline treatment). 70 pts (8%) were BV-refractory (defined as failure to achieve an objective response to any BV-based treatment). 169 (18%) received a PD-1 agent with salvage treatment. 638 pts (69%) had a complete response on pre-ASCT positron emission tomography (PET). BEAM (71%) or CBV (21%) conditioning were used for most pts and 236 pts (26%) received peri-ASCT radiation. 224 pts (24%) received post-ASCT BV maintenance (including 37% of pts undergoing ASCT from 2015-2022). Compared to pts receiving no maintenance, pts receiving BV maintenance were more likely to have primary refractory/early relapsed disease (79% vs 67%, p<0.001), have received only 1 salvage regimen (79% vs 65%, p=0.001), and received BEAM conditioning (83% vs 67%, p<0.001). BV maintenance pts were less likely to receive peri-ASCT radiation (20% vs 28%, p=0.022). The median number of BV maintenance cycles was 10 (1-18) and the most common reason for discontinuation was neuropathy. Median post-ASCT follow-up was 4.9 yrs. 5-yr PFS and OS after ASCT were 70% (95% CI 67-74%) and 85% (83-88%), respectively. Because BV-refractory pts were much less likely to receive BV maintenance (p=0.0044) and had inferior PFS (HR 2.2, p<0.001) (and therefore would serve as a confounder), we excluded BV-refractory pts from additional analyses. Use of BV maintenance was associated with improved PFS (5-yr 81% vs 67%, HR 0.47 [0.33-0.69], p<0.001) and OS (5-yr 92% vs 83%, HR 0.38 [0.20-0.73], p=0.004). The benefit of BV maintenance depended upon pre-ASCT therapy. BV maintenance was associated with a significant improvement in PFS for pts who received no novel agents before ASCT (HR 0.41 [0.25-0.65], p<0.001), but not for BV-treated (HR 0.69 [0.38-1.25], p=0.22) or PD-1-treated pts (HR 0.63 [0.13-3.03], p=0.56) ( Figure). Among pts with 0-1 modified AETHERA risk factors, BV maintenance was not associated with a significant PFS benefit in any treatment subgroup (no novel agents, HR 0.50, p=0.087; BV-treated, HR 1.28, p=0.67; PD-1-treated, HR 2.97, p=0.44). For pts with 2+ modified AETHERA risk factors, BV maintenance significantly improved PFS in the no novel agent group (HR 0.35, p<0.001) but not in the BV-treated (HR 0.55, p=0.099) or PD-1 treated groups (HR 0.24, p=0.19). In multivariable analyses that included key variables (age, year of ASCT, conditioning regimen, peri-ASCT radiation, early relapse/primary refractory disease, B symptoms, extranodal sites, pre-ASCT PET, lines of therapy), BV maintenance was associated with a significant PFS benefit among pts who received no novel agents before ASCT (HR 0.27 [0.12-0.65], p<0.001), but not for pts treated with BV (HR 0.56 [0.28-1.10], p=0.091) or PD-1 blockade (HR 1.10 [0.22-5.56], p=0.91) before ASCT. Conclusions: In this large cohort, BV maintenance was associated with the clearest benefit among pts who received only chemotherapy before ASCT. We were unable to identify a significant improvement in PFS for pts receiving novel agents before ASCT (which could be due to insufficient power to detect a small benefit in this population), suggesting that if these pts benefit from BV maintenance, its impact is likely more limited.

A Unique Case of Large Pelvic Non-Hodgkin Lymphoma

Introduction: Non-Hodgkin lymphoma (NHL) represents a diverse group of malignancies arising from lymphocytes and lymphoid tissues. It encompasses multiple subtypes, including the aggressive diffuse large B-cell lymphoma (DLBCL), which is the most common type of NHL in adults. DLBCL typically presents as a rapidly growing mass in the lymph nodes or extranodal sites. While DLBCL can affect various regions of the body, its occurrence in the pelvic region is infrequent and poses unique diagnostic and therapeutic challenges. Case Description: We present a rare and intriguing case of a 51-year-old female admitted for acute on chronic microcytic anemia, with accompanying symptoms of decreased oral intake due to nausea, and vomiting, significant weight loss, night sweats, and lower quadrant abdominal pain. Additionally, she reported decreased urinary frequency, urgency. CT imaging of the abdomen and pelvis revealed a large soft tissue mass measuring 7.6 x 4.6 x 5.7 cm in the posterior right pelvic region, resulting in severe hydroureteronephrosis, along with bilateral iliac chain adenopathy, retroperitoneal lymph node enlargement, and severe splenomegaly. CT chest revealed several small lung nodules indicating distant metastasis. Additionally, the patient exhibited elevated levels of LDH, CA 199, and CRP, and decreased hemoglobin levels, indicating the presence of systemic disease. A CT-guided biopsy of the right pelvic mass confirmed the diagnosis of non-Hodgkin malignant lymphoma, specifically of the diffuse large B-cell type. Immunohistochemistry and flow cytometry demonstrated CD20 positivity in the proliferating large cells, consistent with DLBCL, and revealed a kappa-restricted B-cell population expressing CD19, CD20, and kappa surface immunoglobulin light chains. The PET scan showed prominent splenomegaly, adenopathy, and retroperitoneal involvement, corroborating the lymphoma diagnosis. The patient was discharged for outpatient follow-up with oncology with a treatment plan of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) administered every 3 weeks, omitting rituximab during the first cycle. Discussion: This case stands out due to the unusual presentation of a large DLBCL in the pelvic region, which is a relatively rare occurrence. The localization of DLBCL in the pelvis poses a diagnostic challenge, as symptoms may overlap with various other conditions. Moreover, the extensive involvement of the retroperitoneal lymph nodes and splenomegaly added complexity to the management of the disease. The rarity of DLBCL in the pelvis highlights the importance of considering lymphoma in the differential diagnosis of patients presenting with non-specific pelvic symptoms and acute anemia. Early recognition of such cases is crucial for timely intervention and optimal treatment planning. Understanding the immunophenotypic characteristics of the tumor is essential for tailoring effective therapeutic strategies. This unique case sheds light on the need for further research and evidence-based guidelines for managing NHL in uncommon anatomical locations, promoting better patient outcomes and quality of life.

Phase Ib/II Study of Multi-Targeted Therapy with Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (ViPOR) in Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Background: Foundational studies have revealed essential oncogenic pathways in DLBCL, triggering the development of drugs targeting distinct survival pathways in this malignancy. While many of these agents are active in DLBCL as monotherapy, they rarely induce deep responses or cure. Based on our identification of drug synergy in DLBCL models, we hypothesized that targeting multiple survival pathways concurrently could be curative in DLBCL. We developed a 5-drug combination regimen (ViPOR) that targets DLBCL survival sustained by constitutive B-cell receptor (BCR) signaling (ibrutinib, lenalidomide, prednisone) and by BCL2 (venetoclax), and also enlists the innate immune system using obinutuzumab. To maximize drug exposure and minimize toxicity, we administered all agents in non-continuous cycles for fixed duration in R/R DLBCL. Methods: R/R DLBCL pts with adequate organ function were eligible. In Ph I, pts were treated at 4 doses of venetoclax (200-800 mg) PO D2-14 to identify the MTD. An initial 12d venetoclax ramp-up was given in combination with fixed-dose ibrutinib 560 mg PO D1-14, prednisone 100 mg PO D1-7, obinutuzumab 1000 mg IV D1-2, and lenalidomide 15 mg PO D1-14. Ph II expansion cohorts of R/R GCB and non-GCB DLBCL were included at the MTD. Max 6C of ViPOR q21d were given without maintenance. TLS, G-CSF, and PCP prophylaxis were given to all pts. Baseline CT, PET, BM, and tumor biopsies were performed with CT after C1, 2, 4, and 6 and PET after C6. CT was then performed q3m x 1y, q4m x 1y, q6m x 1y, then q12m x 2y. Tumor genomics and ctDNA (clonoSEQ) were studied. Results: 50 DLBCL pts were enrolled (25 DLBCL NOS, 17 HGBCL-DH-BCL2, 3 HGBCL-DH-BCL6, and 5 THRLBCL). 52% and 48% were GCB and non-GCB subtype by IHC, respectively, with transformed lymphoma in 34%. Median age was 61y (range 29-77), with stage 3-4 disease in 92%, elevated LDH in 86%, >2 extranodal sites in 56%, and IPI >3 in 68% of pts. Median prior txs were 3 (range 1-9), with 40% post-CAR-T pts and 58% refractory. A single DLT of G3 intracranial hemorrhage occurred, and venetoclax 800 mg was identified as the MTD. Heme AEs were most common, with G3-4 neutropenia in 24%, thrombocytopenia in 23%, and anemia in 7% of cycles. Febrile neutropenia occurred in 3 (1%) cycles. The only G3-4 non-heme AE in >10% pts was hypokalemia (28%). G3 A.fib occurred in 3 pts, and G4 TLS occurred in 1 pt, which resolved. Other common any grade non-heme AEs (% pts) included diarrhea (68%), hypokalemia (67%), nausea (45%), rash (35%), and fatigue (33%). Dose reductions occurred in 17% of pts, and 8% discontinued tx due to AE. Of 48 evaluable pts (2 came off tx prior to restaging), ORR was 54% (26/48), and CR was 38% (18/48). Responses were observed across all molecular DLBCL subtypes, including a CR rate of 62% (8/13) in non-GCB DLBCL, 53% (8/15) in HGBCL-DH-BCL2, 25% (2/8) in other DLBCL, and a PR rate of 33% (4/12) in GCB DLBCL (non-DH) (Fig. 1A). CR rate was 20% (4/20) and 19% (5/27) in post-CAR-T and refractory pts, respectively. With a median FU of 40m, 72% of CRs are ongoing, with a 2-year PFS and OS of 34% and 36%, respectively. By histology, 2-year PFS was 47%, 38%, 38%, and 8% in HGBCL-DH-BCL2, non-GCB DLBCL, other DLBCL, and GCB DLBCL (non-DH), respectively (Fig. 1B). 2-year PFS was 30% and 21% in post-CAR-T and refractory pts, respectively. MRD was undetectable in 38% (16/42) of pts at end of therapy (EoT), and in 93% (14/15) of pts in PET CR at EoT. Elevated baseline ctDNA or detectable ctDNA during or at EoT were associated with significantly inferior PFS and OS, as were quantitative PET parameters (elevated baseline TMTV and TLG). Two genetic subtypes known to rely on BCR-dependent NF-kB signaling - MCD and N1 - had a significantly higher CR rate (5/6, 83%) than all other genetic subtypes (4/22, 18%; p=0.0066). Conclusions: This is the first study to show the feasibility and curative potential of multi-targeted therapy in R/R DLBCL. ViPOR was well tolerated across all ages in R/R DLBCL with rare febrile neutropenia. ViPOR was most effective in non-GCB DLBCL, as expected from its reliance on BCR signaling and BCL2. ViPOR was also highly active in HGBCL-DH-BCL2, possibly due to inhibition of MYC-driven apoptosis by BCL2 in this subtype. Durable remissions and likely cure were observed in non-GCB DLBCL (38%) and HGBCL-DH-BCL2 (47%), including pts relapsed after or refractory to CAR-T (30%). Multicenter Ph II testing is in development to confirm the activity of ViPOR in R/R non-GCB DLBCL and HGBCL-DH-BCL2.

Comparing Clinical Characteristics and Outcomes of MYC and BCL6 Double Hit Lymphoma (DHL- BCL6) with Other Aggressive B-Cell Lymphomas: Understanding the Impact of New Who and International Consensus Classifications

Background: High Grade B cell Lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements(R) was introduced as an entity in 2016 by the WHO revised 4 th edition. In 2022, both the WHO 5 th edition (beta version) and the International Consensus Classification (ICC) separated DHL- BCL2 (+/- BCL6-R)from DHL- BCL6 given differences in biology . However, while the ICC has maintainedDHL- BCL6 as a provisional entity, the WHO has removed the category, thus removing the requirement to FISH for BCL6-R in this setting. Clinical data on DHL- BCL6 is much more limited, as these cases represent only 10-20% of DHL and have been combined with BCL2-R cases in prior studies. Outcomes are variable in retrospective studies with no consistent data on prognosis or optimal therapeutic strategies. By retaining the category of DHL-BCL6 as a provisional entity, the ICC emphasized the need for further, multicenter, prospective studies evaluating the clinical and biological features of this disease. We herein report a comprehensive comparison of clinical characteristics and outcomes in patients with DHL- BCL6 compared to diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS); DLBCL with MYC rearrangement only; DHL- BCL2; and HGBL, NOS in a large, multicenter, prospective cohort of patients from Lymphoma Epidemiology of Outcomes (LEO). Methods: Adult patients with newly diagnosed large B-cell or HGBL were enrolled within 6 months of diagnosis at one the 8 LEO cohort academic medical centers in the US between 2015 and 2020. Baseline characteristics were abstracted at the time of diagnosis per protocol. Based on FISH data patients were further sub mgrouped into DLBCL, NOS (without MYC rearrangement); MYC-R DLBCL, NOS; HGBL, NOS; DHL- BCL2 and DHL- BCL6. Event-free survival (EFS) was defined as the time from diagnosis until progression/relapse, retreatment, or death. Overall survival (OS) was defined as the time from diagnosis until death due to any cause. Results: A total of 1526 eligible patients were identified during this time period. All FISH data was available at the time of diagnosis and the choice of treatment was based on physician discretion. Median age at diagnosis was 63 years (IQR 53-72), with 148 (10%) patients in the AYA category, and 128 (8%) patients > 80 years. 58% (891) were male, 11% self identified as Hispanic or Latino, and 7% as Black/African American. The median diagnosis to treatment interval (DTI) was 20 days (IQR 12-32), and 33% had DTI < 14 days. The FISH-based subgroups were MYC-negative DLBCL, NOS (N=1146, 75%), MYC-R DLBCL,NOS 227 (N = 96, 6%), DHL- BCL2 (N=154, 10%), DHL- BCL6 (N=38, 3%), and HGBL, NOS (N=92, 6%). When available, COO by Hans algorithm was 92% GCB in DHL- BCL2 and 50% GCB in DHL- BCL6. Clinical characteristics can be found in the table. At a median follow-up of 49 months (IQR 36-67), 490 patients (32%) had an event and 356 patients (23%) died. EFS at 24 months (EFS24) was 75% (95% CI: 73-77). Patients with DHL- BCL6 were younger at diagnosis (median 60 years), had more extranodal site involvement (40%), more often stage III/IV disease (70%), and more often treated with a higher intensity regimen than R-CHOP (69%) compared to DLBCL,NOS and MYC-R DLBCL. DHL- BCL6 also had fewer patients that were males (47%), with DTI <=14 days (33%), NCCN IPI ≥ 4 (45%), elevated LDH (53%) than HGBL, NOS and DHL- BCL2. The 2-year EFS and OS rates were noted to be significantly better in the DHL- BCL6 (EFS 79%, 95% CI: 67-93; OS 92%, 95% CI: 84-100) as compared to DHL- BCL2 (EFS 58%, 95% CI: 50-66; OS 70%, 95% CI 63 - 78) and HGBL, NOS (EFS 74%, 95% CI: 65-84; OS 74%, 95% CI: 65-84 ), (Figure 1) but were comparable to that of DLBCL, NOS (EFS 78%, 95% CI: 76-81; OS 87%, 95% CI: 86-89). Conclusions: Our data support separating DHL- BCL6 from DHL -BCL2 as these patients form a unique subgroup with some clinical characteristics comparable to both DLBCL, NOS as well as HGBL, NOS and DHL- BCL2 subtypes. In this cohort, clinical outcomes are more comparable to DLBCL, NOS than DHL- BCL2 or HGBCL, NOS. More frequent use of intensive chemotherapy in DHL- BCL6 compared with DLBCL may account for this finding, although larger multicenter studies are needed. Our results support continued identification of DHL- BCL6 in the clinical setting to better understand optimal therapy and biology of this cohort.

DLBCL Patients' Journey: From Symptoms to Diagnosis

Background Symptoms of hematologic malignancies differ among the diagnoses with different proportion of patients (pts) who are diagnosed due to the incidental findings without symptoms reported by pts (e.g., 14% of MM and up to 80% of CLL cases are asymptomatic). Symptoms of lymphomas usually include peripheral lymphadenopathy, B-symptoms, gastrointestinal (GIT) and other symptoms in correlation with involved lymph node sites or affected organs. However, there is limited data on the incidence and types of initial lymphoma symptoms which lead to the diagnosis (Dg), their association with time to Dg and survival of the pts. The aim of this analysis was to describe a real-world pattern of symptoms of diffuse large B-cell lymphoma (DLBCL), which lead to the diagnostic process and ultimately to the DLBCL Dg and to correlate these findings with baseline characteristics and time to Dg. Methods Altogether 1576 pts with de novo DLBCL or high-grade B-cell lymphoma from Charles University, General Hospital, Prague, Czech Republic, were registered in the prospective lymphoma project (NiHiL; NCT03199066). A total of 929 pts were diagnosed between 2010-2021, including 602 (65%) pts treated by R-CHOP. Of them, 10 (2%) pts had no data on initial symptoms and were excluded from the analysis. Altogether 592 were analyzed; 574 pts (97%) had documented initial symptom or findings, which led the pts to contact the healthcare system. The remaining 18 (3%) pts had incidental findings described during examination due to the unrelated reasons which led to the diagnostic process and finally resulted to the DLBCL Dg . The type of symptoms of DLBCL and time to Dg were analyzed together with baseline characteristics and survival of the pts. Results The 592 pts with median age 64 years were diagnosed with advanced clinical stage in 65%, PS ECOG ≥ 2 in 26%, elevated LDH in 62%, ≥ 2 involved extranodal sites in 41%, bulky disease ≥ 7.5 cm in 41%, IPI 3-5 in 53%, and B-symptoms at the time of Dg in 42%. Median follow-up time from Dg was 7.5 years (range 0.1-13.2 years). Among the 574 symptomatic pts, altogether 672 initial symptoms were observed. The majority - 487 (85%) pts had a solitary initial symptom of DLBCL, 73 (13%) pts had two initial symptoms, and 13 (2%) pts presented with combination of three initial symptoms. The most common combination of symptoms were B-symptoms together with abdominal/gastrointestinal (GIT) symptoms in 51 (59%) pts out of pts with ≥ 2 symptoms. Out of the 672 initial symptoms, we have observed abdominal/GIT symptoms in 179 (27%) cases, followed by peripheral lymphadenopathy (132; 20%, most frequently head and neck in 68%), B-symptoms (76; 11%), craniofacial symptoms (71; 12%), back pain (50; 7%), limb pain/swelling (43; 6%) and respiratory symptoms (34; 5%), testicular tumor (31; 5%), chest symptoms (20; 3%), urological or gynecological (11; 2%), and skin symptoms (7; 1%; Figure 1). Although only 76 out of 592 pts (13%) presented initially with B-symptoms, additional pts developed them during the diagnostic work-up and 248 (42%) pts referred B symptoms at the time of the Dg. Median interval from the symptom occurrence to Dg was 10 weeks (interquartile range 5-19 weeks) with shorter interval observed in pts with testicular tumor (5 weeks, P= 0.009), and prolonged in pts with limb pain/swelling (17 weeks, P= 0.003; Figure 2). Higher IPI 3-5 was observed in 120 (74%) out of 163 pts who presented with initial B-symptoms or limb pain/swelling or and back pain ( P <0.001). Among the remaining 429 pts, higher IPI was observed in 194 (45%) pts. Conclusion In contrast to other hematologic malignancies, only minority (3%) of pts had incidental findings resulting in Dg of DLBCL. Out of 97% of symptomatic pts with DLBCL almost half of pts presented initially with abdominal/GIT symptoms or peripheral lymphadenopathy. Limb pain/swelling was associated with prolonged time to Dg of DLBCL, and higher IPI, while testicular tumors were associated with short time to Dg presumably due to their localization. It is important, that e.g. the proportion of pts with B symptoms increased more than 3x during diagnostic process (from initial 13% to 42% at the time of Dg). This analysis describes the unmet medical need to speed up the diagnostic process and to offer the curative therapy to the patients as soon as possible. This work was supported by the Charles University Hematology-Oncology Cooperatio Program and grant NU21-03-00411.

Identification and Clinical Characterization of CNS Relapse in DLBCL Patients across 19 Prospective Phase 2 and 3 Trials - a GLA/ DSHNHL and LYSA Collaboration

Introduction: Depending on clinical and molecular risk factors, CNS relapse occurs in 1-15% of DLBCL patients (pts) and is associated with dismal outcomes. Despite its important role in further improving DLBCL therapy, a comprehensive and large-scale characterization of secondary CNS relapse remains challenging. Methods: We conducteda retrospective analysis of 7775 pts treated within 19 prospective German and French phase 2/3 trials to identify and characterize DLBCL pts with progression or relapse in the CNS. Pts with histology different from DLBCL (subtypes), not treated with anti-CD20 antibody, or displaying CNS involvement at diagnosis were excluded from the analysis. Results: Among 5289 eligible pts, 159 (3%) experienced progression or relapse in the CNS. Median age at diagnosis was 62 years (range: 19-80 years), 47% of pts were female. In 91% of all cases, reference pathology confirmed the diagnosis of DLBCL. At diagnosis, 28 pts (18%), 62 pts (39%), and 69 pts (43%) had a low (0-1 point), intermediate, and high CNS IPI (4-6 points), respectively. 133 pts received front-line therapy with R/O-CHOP, 19 pts with R-(Mega)CHOEP, and 7 pts with R/O-ACVBP. Following first-line therapy, 54% of pts achieved a CR/CRu. For 131 pts (82%), CNS progress/ relapse represented the first PFS event. Prior to the CNS event, salvage therapy was administered to 30 pts, including 11 pts treated with HDT/ASCT and one pt receiving allogeneic SCT. For 70 out of 158 pts (44%), CNS involvement was classified as intracerebral, 31% showed meningeal, and 3% intraspinal lymphoma involvement. In 22% of pts, CNS involvement was classified as combined including 5 cases with eye involvement. The CNS event occurred as progression without prior CR/ CRu of disease in 61 out of 159 pts (38%). For 155 pts it could be specified that 25% had an isolated progress in the CNS while 12% showed both CNS and concomitant systemic progress. 35% of pts showed an isolated CNS relapse while 28% suffered from a combined relapse. 82% of all CNS events occurred within the first two years after randomization while 29 pts (18%) experienced a late CNS event after 24 months. Notably, 46% of pts with low CNS IPI developed a late CNS event compared to 9% with high CNS IPI at diagnosis (Fisher exact, p<0.001). During the course of disease, 138 pts (87%) showed extranodal lymphoma involvement outside the CNS. The most frequently involved extranodal sites were bone (34%), gastro-intestinal tract (21%), soft-tissue (21%), kidney/ adrenal gland (20%), lung (19%), and liver (18%). In general, pts with CNS event had poor outcomes with a median OS of 3.4 months (95% CI 2.9-4.2) and a 2-year OS of only 15% (10-22%). While sex and initial (CNS) IPI had no impact on OS, we observed significantly worse OS for pts older than 70 years at diagnosis (log rank, p<0.001). OS was poor regardless of the site of CNS manifestation. Pts with isolated CNS disease demonstrated significantly better OS than pts with concomitant systemic involvement (p=0.023). Pts with CNS events occurring later than 24 months from randomization did not show improved OS compared to pts with early relapse/ progression (p=0.19). Treatment categories were reported for 150 pts. 95 pts received immunochemotherapy (IC), 30 pts in combination with radiotherapy (RT). More precisely, 69 pts received salvage therapies containing systemic MTX and 22 pts underwent consolidation with HDT/ASCT (73% of which had thiotepa-based conditioning regimens). Three pts received allogeneic SCT for consolidation. 28 pts were treated with RT alone (+/- intrathecal therapy (IT)). 27 pts received only IT, corticosteroids, or no treatment. Pts consolidated with HDT/ ASCT or allogeneic SCT had superior outcomes with a 3-year OS of 36% (20%-66%) compared to 18% (7.5%-44%) for pts receiving IC and RT, and to 9.7% (3.9%-24%) and 9.5% (2.8-32%) for pts treated with IC or RT alone, respectively ( Fig. 1). Overall, pts achieving a CR after CNS event (38/159, 24%) showed a 3-year OS of 52% (37-73%). Conclusions: This large study including more than 5000 DLBCL pts all treated on prospective clinical trials highlights the unmet medical need to improve the outcome of DLBCL pts suffering from CNS relapse. About one third of pts who underwent transplantation showed long-term survival in contrast to all other pts displaying very dismal outcomes. Novel strategies including targeted therapies and CAR T cells will have to challenge the survival rates reported here.

Enhanced Computed Tomography and 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in the Uncommon Histiocytic Sarcoma of Small Intestine Arising after Gastric Large B-Cell Lymphoma.

Histiocytic sarcoma (HS) is an extremely rare and aggressive malignant neoplasm of hematopoietic origin that shows morphologic and immunophenotypic evidence of histiocytic differentiation. In approximately 25% of the cases, presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated. Various extranodal sites, particularly the gastrointestinal tract, soft tissue, skin, and spleen, can be involved. Enhanced CT and FDG PET/CT findings of extranodal histiocytic sarcoma have been barely reported. We present a case with extranodal HS originating in the small intestine after gastric large B-cell lymphoma, mistaken for prostate cancer metastasis in a 76-year-old man.

Survival Outcomes of Limited-Stage Diffuse Large B-Cell Lymphoma Treated With Radiation Therapy

BackgroundPatients with favorable risk limited-stage (LS) diffuse large b-cell lymphoma (DLBCL) have shown excellent outcomes without radiotherapy (RT). However, the role of RT for the remainder of LS-DLBCL patients is less well defined. We aimed to investigate whether the addition of RT provided an overall survival (OS) benefit in a real-world cohort of LS-DLBCL patients based on primary site at presentation. Materials and MethodsRetrospective data from 39,745 patients with stage I and II DLBCL treated with front-line combination chemotherapy alone or followed by RT were identified using the National Cancer Database from 2004 to 2015. ResultsThe addition of RT was associated with improved 5-year OS for all LS patients as compared to those treated with chemotherapy alone (85% vs. 80%, P < .001). RT was associated with improved 5-year OS in both the nodal and extranodal disease patients (nodal: 85% vs. 80%, P < .001; extranodal: 83% vs. 79%; P < .001). Extranodal sites with prolonged OS from the addition of RT include skin and soft tissue, head and neck, testicular, and thyroid sites (all P < .02). Breast, bone, lung and gastrointestinal extranodal primary sites had no OS benefit from the inclusion of RT. In multivariate analysis, the addition of RT was an independent factor for improved survival for all LS patients ([HR] 0.84, 95% [CI] 0.81-0.88; P < .001). ConclusionThough there is no consensus on optimal treatment indications for RT in LS-DLBCL, these data suggest certain subgroups may have benefit when RT is added to front-line chemotherapy.

Prevalence of Non-Hodgkin Lymphoma Patients at High Risk of Failure after CAR T-Cell Therapy Eligible for Bridging Radiation Therapy.

CD19-directed chimeric antigen receptor T-cell therapy (CART) has led to remarkable outcomes in patients with relapsed or refractory (R/R) non-Hodgkin's lymphomas (NHL), yet ∼50% of patients relapse. Predictive factors associated with high risk of relapse following CART have been identified in the literature. Studies have shown a potential improvement in outcomes with the use of bridging radiation (RT) prior to CART. The purpose of this study is to determine the incidence of patients meeting high risk criteria who have disease that could be encompassed in a standard radiation plan prior to CART. This was a single-center, retrospective study of patients with R/R NHL who received CART from 2018 to 2022. Data were obtained from the EHR and manual chart review was used to identify patients with disease encompassable in a standard radiation plan defined as <5 malignant lesions on pre-apheresis radiological studies. These patients were then screened for presence of ≥1 high risk criteria: bulky disease ≥10 cm, ≥1 extranodal (EN) sites, LDH ≥normal, or ≥1 lesion with SUVmax ≥10. Descriptive statistics were used to make inferences about the population. Eighty-one R/R NHL patients were evaluated with a median age of 65 years (range 23-84), 60% male, and received a median of 2 (range 1-7) prior lines of therapy. CART products included axi-cel (62%), brexu-cel (7%), liso-cel (16%), and tisa-cel (15%). Forty (49%) patients would have been eligible for bridging RT (<5 sites on pre-apheresis radiologic studies), including 29 patients who met high risk criteria: 19 had ≥1 lesion with SUVmax ≥10, 16 with bulky disease, 6 with ≥1 EN site, and 3 with elevated LDH. At 3 months post-CART, clinical response data were available for 19 high risk patients with ORR of 79% (11 CR, 4 PR, 1 SD, and 3 PD), compared to 8 patients with standard risk disease with ORR of 88% (7 CR and 1 PD). Of those with less than a CR, 8/9 met high risk criteria: 4 with bulky disease, 6 had ≥1 lesion with SUVmax ≥10, and 2 with ≥1 EN site. There were 9/40 patients who received bridging therapy, and only 2 high risk patients received bridging RT. One patient with transformed DLBCL had persistent disease in the nasopharynx following RCHOP x3C and R-HyperCVAD, and received 20 Gy/10 fx as a bridge to CART resulting in a continued CR at 23 months of follow-up. Another patient with non-DH, GCB-like DLBCL received R-CHOP x6C (achieved CR) but relapsed <1 year later and then received R-ICE x2C with PD in the left shoulder, which was radiated with 30 Gy/10 fx for pain as a bridge to CART, but experienced disease relapse 6 months after CART. Approximately 35% (28/81) of patients were classified as high risk of relapse after CART and had disease encompassable in a standard radiation plan. Of these patients, 44% (8/18) experienced either PR, SD or PD at 3 months post-CART. Future studies are needed to determine the role of bridging RT prior to CART as a strategy to improve outcomes and prevent relapse in high-risk NHL patients.