Lymphomatous Involvement Research Articles

Splenic Lymphoma: A Series of Seven Cases

Splenic Lymphoma (SL) is a lymphoproliferative disorder characterised by involvement of the spleen, with or without bone marrow involvement. However, advancements in imaging modalities have led to more frequent diagnosis of isolated splenic lesions. There is always a dilemma in diagnosis as to whether the pathology truly originates from the spleen or if it is part of systemic involvement in Non-Hodgkin Lymphoma (NHL). Clinical manifestations vary widely, and treatment outcomes for SL depend on accurate diagnosis. However, prognosis still remains poor in these cases compared to systemic NHL. The present case series provide a comprehensive overview of patients diagnosed with SL, focusing on their clinicopathological characteristics, therapeutic details, prognosis and outcomes. Previously isolated case reports have been published, and there is still a lack of consensus on the management of this entity. The present case series included seven cases over a two-year period, from January 2022 to December 2023. In the current case series, authors have highlighted the heterogeneity and variability in the presentation of SL and how the clinical behaviour ranges from indolent to highly aggressive. Nevertheless, the presenting clinical, laboratory and pathological features of these diseases often display significant overlaps and pose confusion in arriving at an exact diagnosis. The authors emphasise how flow cytometry helps facilitate the diagnosis and systemic therapy is the modality of choice for treatment decided based on the histology type; however, outcomes still remain dismal, highlighting the unmet need to improve accurate diagnosis and explore newer treatment options. The novelty in this series lies in the detailed analysis and comparison of different subtypes of SL, a rare group of lymphomas primarily originating in the spleen. The present case series discusses the latest World Health Organisation (WHO) classification, which redefines the Hairy Cell Leukaemia (HCL) variant as Splenic B-cell Leukaemia/ Lymphoma with Prominent Nucleoli (SBLPN). Detailed molecular and genetic characteristics of various SLs are highlighted, such as the presence of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) p.V600E mutation in HCL, Mitogen-activated Protein Kinase 1 (MAP2K1) and Immunoglobulin Heavy Variable 4-34 (IGHV4-34) mutations in the HCL-variant, and 7q distortion in Splenic Marginal Zone Lymphoma (SMZL). Emphasis is placed on the individualised treatment approach based on specific patient profiles, genetic markers and disease characteristics. The study underscores the need for further research and clinical trials to validate emerging therapies, such as the use of Rituximab plus Doxorubicin, Bleomycin, Vinblastine and Dacarbazine (R-ABVD) in Hodgkin lymphoma and combinations of novel agents in aggressive SLs like HCL-variant and CD20-negative B-cell NHL.

The value of cytology in diagnosis of body fluids with lymphoma involvement: a report of 29 cases

Abstract Introduction/Objective Lymphoma involving body fluids (pleural, abdominal or pericardial) can be secondary or primary (such as primary effusion lymphoma). The incident rate is variable depending on the hospital setting (general or specialty hospitals), and it is generally low. Due to the large specimen volume, relatively easy collecting sample and stable cellular preservation, body fluids are good sources for diagnosis and classification of lymphoproliferative diseases. Methods/Case Report A retrospective case search from a tertiary academic medical center during 2015 to 2023 were performed for body fluid cytology with diagnosis of lymphoma. The results of cytology, ancillary cellblock, immunohistochemistry and flow cytometry were collected, and the synchronous or follow-up surgical biopsies/resections were cross examined. Results (if a Case Study enter NA) Total 29 cases of body fluids with lymphoma involvement were identified in the study period. There were 22 patients including 9 males and 13 females and age ranged from 16 to 88 years (mean 64.5 years). Only 4 patients (4/22, 18.2%) had history of lymphoma when they presented with body fluids, and the remaining 18 patients (18/22, 81.8%) presented body fluids as the initial or synchronous sign of lymphoma. 26/29 cases had cellblock or flow cytometry done and 13/29 cases had both. All 22 cases had adequate lymphoma diagnosis and classification by combined cytology and ancillary tests and included 5 high grade B cell lymphoma, 3 diffuse large B cell lymphoma, 2 Burkitt, 2 CLL/SLL, 2 small mature B cell lymphoma, NOS, 1 mantel, 1 MYC and BCL-2 double hits lymphoma, 1 primary effusion lymphoma, 1 plasma cell myeloma, 2 T lymphoblastic lymphoma, 1 anaplastic large cell lymphoma, 1 angioimmunoblastic T cell lymphoma. 11 patients had synchronous or follow-up tissue biopsies, and cytology had 100% agreement with the histology diagnosis. Conclusion The majority (81.8%) cases of body fluid involvement with lymphomas presented as the initial or synchronous sign of lymphomas in our study series indicating that high pathologic suspicion and adequate cytomorphological skills for lymphoproliferative disorders are necessary for making the diagnosis. Body fluid samples are excellent sources for diagnosis and classification of lymphomas using the available ancillary tools including immunohistochemistry, flow cytometry and molecular testing.

The Potential Utility of Cerebral Fluid sLR11 and sIL-2R As a Marker for CNS Involvement of Malignant Lymphoma

Introduction: LR11 is a type I membrane protein that releases serum-soluble LR11 (sLR11) by proteolytic shedding. In the past, we reported that patients with acute leukemia and malignant lymphoma showed significantly increased serum sLR11 levels compared to those in normal controls. The diagnosis of central nervous system involvement of malignant lymphoma (CNS ML) is often difficult to diagnose by cytology. This study analyzed the potential utility of cerebral fluids (CFs) sLR11 and sIL-2R as diagnostic markers for CNS ML. Materials and Methods: We enrolled patients suspected of CNS ML and administrated intrathecal anticancer drugs from 2017 to 2023. We analyzed CFs levels of sLR11 and sIL-2R, and cytological malignant grades. Then, we analyzed the relationship between changes in these CFs markers and clinical outcomes. Results: We studied 26 patients (16 men and 10 women; mean age: 72 years old). The 20 patients were diagnosed as CNS ML in clinical conditions, and the other 6 patients were treated with prevention because of ML of the testis and adrenal glands. The sLR11 of CFs levels significantly and positively correlated with the sIL-2R of CFs levels (r = 0.6618, p = 0.0002) (Figure 1A). As shown in Figure 1B, in CNS invasion groups, only four patients showed class V in the cytology of CFs, the other patients showed negative results. There were no relations between the number of cell numbers and sLR11 and sIL-2R of CFs. As shown in Figure 2, the levels of sLR11 of CFs in diagnosis tended to be higher (p = 0.1831) in the CNS invasion group (36.5±30.0 ng/ml) than in the no-invasive group (23.9±5.8 ng/ml). The levels of sIL-2R of CFs in diagnosis were significantly higher (p = 0.0035) in the CNS invasion group (986.0±1274.3 U/ml) than in the no-invasive group (74.2±78.2 U/ml). The LR11 and sIL-2R of CFs post-treatment were lower in the remission group (n=9; 13.46±6.37 ng/ml, <50.0 U/ml) than non-remission group (n=5; 22.40±14.32 ng/ml, 78.4±41.1 U/ml), p = 0.2861, 0.0629 respectively. Conclusions: Patients diagnosed with CNS ML showed high levels of sLR11 and sIL-2R of CFs. These two may be good markers for evaluating diagnosis and treatment effects. Further examination of a large number of cases is required to elucidate these mechanisms.

Systematic Review and Meta-Analysis of Factors Associated with CNS Involvement in Mantle Cell Lymphoma

Background: Mantle cell lymphoma is a mature B -cell Non-Hodgkin's Lymphoma with a variable clinical course. CNS involvement in mantle cell lymphoma is usually associated with recurrent/refractory disease but can also complicate its initial presentation. CNS involvement carries a dismal prognosis. The Mantle Cell Lymphoma International Prognostication Index includes age, ECOG status, LDH, and WBC count to prognosticate the disease. This study aimed to systematically review existing real-world studies to find statistically significant factors associated with CNS metastasis in Mantle Cell Lymphoma. Evidence acquisition: we performed a comprehensive database search on four major databases (Pubmed, Embase, Google Scholar, and Cochrane Central). Then, a team of independent reviewers selected relevant studies and extracted the data. 54 studies were reviewed from the databases, and 14 were found eligible for the systematic review. Five of the studies were retrospective studies, which were included in the meta-analysis. Revman 5.4 statistical analysis software was used for the analysis. Results: A total of 857 patients with Mantle Cell Lymphoma were involved in the meta-analysis :( Chihara et al): 608, (Ferrer et al): 82, (Cheah et al): 105 and (Gill et al): 62. Of these, 107 patients had CNS involvement: (Chihara et al): 33, (Ferrer et al): 12, (Cheah et al): 57 and (Gill et al): 5. Mantle cell lymphoma patients with staging III/IV disease were found to be associated more with CNS metastasis (OR 4.51 (1.56- 8.23) compared to stages I/II. Serum LDH level more than the upper limit of normal was found to have a statistically significant association with CNS involvement (OR 4.27 {1.17-15.51}: Heterogeneity: Tau2= 0.89, df=2 (p=0.009), I2= 79%, Overall effect size Z=2.43 p= 0.02) among Mantle Cell lymphoma patients. Ki 67 expression > 50% had increased odds for CNS metastasis (OR 2.83 {1.67 -4.79}: Heterogeneity: Tau2=0.43, Chi2=0.34, df=2 p=0.84); I2=70%, Overall effect size Z=3.87 p=0.0003). Blastoid/ pleomorphic histologic subtypes had significant odds of leading to CNS metastasis compared to the classic MCL subtypes (OR 5.27 {3.07- 9.06}, Heterogeneity: Tau2=0.03, Chi2=3.2, df= 3 (p=0.35), I2= 9%, Overall effect size Z= 6.03 p=0.0001). Serum Beta 2 microglobulin levels and WBC count at initial presentation had no statistically significant association with CNS involvement. CONCLUSION: As per the current NCCN guidelines, CNS chemoprophylaxis is indicated for Diffuse Large B- Cell Lymphoma (DLBCL) with high-risk features (as per the CNS international prognostication index). CNS involvement in Mantle Cell Lymphoma has a dismal prognosis. The findings of this meta-analysis underscore a noteworthy correlation between certain risk factors and CNS involvement in Mantle Cell Lymphoma. Additional studies are needed to determine the impact of chemoprophylaxis in patients with these high-risk features.

Is Breast Involvement in Marginal Zone Lymphoma Associated with Worse Outcomes? a Nationwide Analysis

Background Marginal zone lymphoma (MZL) is the second most common indolent non-Hodgkin's lymphoma (NHL). It accounts for 6% of all B-cell lymphomas. Several MZL subtypes are recognized in the World Health Organization classification with the following rates :70% Extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue (MALT lymphoma), 10% splenic MZL and 20% nodal MZL. MZL involving the breast, is a rare occurrence, it constitutes 1.7-2.2% of all extranodal NHLs and 0.04-0.5% of all malignant neoplasms of the breast (P L Cohen, 1991) and (M Vasei, 1997). Involvement of the breast by a primary lymphoma like DLBCL portends a more aggressive behavior but data is lacking in indolent lymphomas like MZL. We assume that patients with EMZL involving the breast will require earlier treatment compared with nodal MZL. In this population-based analysis we intend to examine this theory and investigate predictors of breast involvement in MZL and its outcomes. Methods We conducted a retrospective cohort analysis using de-identified data accessed from NCDB. The NCDB provided records of 17,198 patients diagnosed with nodal MZL and 1250 patients diagnosed with EMZL involving the breast between 2004 and 2016. We excluded patients without histologic or cytologic confirmation of the diagnosis. We also excluded patients who received treatment outside the reporting facility and patients missing survival data. Exploratory analysis of the patient groups was performed. Summary statistics are presented as percentages for categorical data and median with interquartile range for quantitative data. Chi square test was used to compare categorical variables and t-test was used to compare means. Multivariate regression models were used to analyze the predictors of breast involvement and survival. Results We identified 11,130 patients with nodal MZL and 769 patients with EMZL involving the breast. The median age was 68 (IQR 58-77), there were 56.5% females. Majority of the patients were non-Hispanic whites (85.9%), had a government insurance (58.5%), had comorbidity score of 0 (78.6%), belonged to a metropolitan area (86.2%), and were treated at a comprehensive community cancer centers or academic programs (79.1% combined). Black race, receiving treatment in a comprehensive community cancer center, and having insurance were associated with more breast involvement of MZL. While younger age was associated with less breast involvement. Median follow up was 9.1 years (IQR 8.8-9.5). Black race was associated with worse survival (HR 1.1, 95CI 1.0-1.3, p 0.004). Receiving treatment in a comprehensive community cancer center (HR 0.84, 95CI 0.76-0.93, p ≤ 0.01), older age (HR 0.996, 95CI 0.993-0.999, p 0.003), and living in an urban area (HR 0.92, 95CI 0.84-0.99, p 0.03) were associated with better survival. Breast involvement did not affect survival (HR 1.02, 95CI 0.93-1.12, p 0.71). The average days to start treatment in patients with EMZL involving the breast was 48 compared with 37 in nodal MZL (p ≤0.01). Conclusion Our study highlights clinical and socioeconomic predictors of breast involvement in MZL. Breast involvement in the whole cohort was not associated with worse clinical outcomes and our data does not suggest a different treatment approach for this patient population. Although, African American patients tend to have more breast involvement in MZL and it was associated with decreased survival. Our study is limited by its retrospective nature and its inherent selection bias, adjustment for baseline characteristics using univariate and multivariate analyses was used to mitigate this bias.

CNS Involvement in Pediatric Hodgkin Lymphoma: A Comprehensive Retrospective Analysis from the Staging, Evaluation and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (CAYAHL) Group

Introduction Hodgkin lymphoma (HL) accounts for approximately 7% of childhood cancer, most frequent in adolescents and young adults. In contrast to non-Hodgkin lymphoma (NHL), central nervous system (CNS) involvement at the time of diagnosis with HL is rare and poorly understood. Information regarding the clinical presentation, management, response to treatment and outcome of patients who exhibit this finding is limited to case reports or small series. We sought to describe CNS involvement at the time of diagnosis with pediatric HL by performing a retrospective analysis of 3 large international clinical trials. Methods Patients with CNS involvement were identified from the imaging databases of the COG trial AHOD1331 (NCT02166463) and EuroNet trials PHL-C1 (NCT00433459, EudraCT 2006-000995-33) and PHL-C2 (NCT02684708, EudraCT 2012-004053-88). Imaging was reviewed collaboratively by COG and Euronet radiologists and nuclear medicine physicians with expertise in HL, with input from radiation oncologists and pediatric oncologists. All identified cases of CNS involvement had morphologic (CT) and metabolic (FDG-PET) imaging prior to initiation of therapy, as well as disease response assessment after 2 cycles of therapy. Variables evaluated included: age, sex, Ann Arbor stage, histology, symptoms at the time of presentation (pain, neurologic symptoms), corticosteroid administration prior to FDG-PET scan, number and location of CNS lesions, tissue of origin of the CNS lesion, anatomic description of the involvement of the CNS lesion, number and location of E-lesions, whether emergency irradiation or an operative procedure were performed at diagnosis, FDG tracer uptake at the time of initial staging, response of the CNS lesions after 2 cycles of chemotherapy, whether relapse occurred and in which location. CNS involvement was defined in 2 ways: (1) lesions originating within the CNS parenchyma and (2) lesions extending into the CNS. Results 45 patients with 55 CNS lesions were identified from a combined cohort of 5569 patients with a new diagnosis of HL. 9 patients presented with pain and 4 with neurologic symptoms, however information regarding clinical symptoms was not available for 34/45 patients. Symptoms corresponded to the location of the CNS lesion. All identified lesions extended into the CNS from surrounding tissue, none originated within the CNS parenchyma. 82.2% of patients had a single lesion extending into the CNS, most commonly through the neural foramina into the thoracic spine (45.5%), sacrum (23.6%) or lumbar spine (21.8%). Lesions originated from adjacent bone (45%) or soft tissue (40%). 89% of patients with CNS lesions had stage IV HL, and 68.8% had extranodal (non-CNS) disease. 54.8% of lesions displaced the spinal cord, but none infiltrated the spinal cord itself. After 2 cycles of chemotherapy, 67.3% of CNS lesions had a >75% reduction in size or complete resolution, and 32.7% of CNS lesions decreased in volume by 50-75%. A residual mass was present for 74% of lesions involving the neural foramina after 2 cycles of chemotherapy. 89.1% of lesions were PET negative at interim response assessment (IRA). 2 CNS lesions were associated with relapse at the CNS site, these were PET negative at IRA. 13 lesions received irradiation, none of these were sites of subsequent relapse. Conclusions This large, combined cohort of intermediate- and high-risk pediatric patients enrolled on clinical trials from 2007 to 2021 confirms the rarity of CNS involvement at the time of diagnosis with HL, with an overall incidence of 0.8%. Importantly, CNS lesions extended from adjacent tissue and did not originate within the CNS itself. These lesions never directly infiltrated the brain parenchyma or spinal cord. They were highly metabolically active at diagnosis, and demonstrated an excellent metabolic and morphologic response to the first 2 cycles of chemotherapy. Patients with CNS involvement had a 2-fold greater incidence of extranodal disease than previously reported cohorts. In summary, this retrospective study provides key information about CNS involvement in pediatric HL at the time of diagnosis, contributing to our understanding of this rare, yet important, clinical presentation.

Efficacy of CD19-Directed CAR T Cell Therapy in Patients with Primary or Secondary CNS Lymphoma - an Analysis of the EBMT Lymphoma WP and the Gocart Coalition

Introduction: The prognosis of patients (pts) with relapsed or refractory (r/r) large B cell lymphoma (LBCL) and central nervous system (CNS) involvement is dismal. Standard treatment for pts with r/r LBCL are anti-CD19 chimeric antigen receptor T-cells (CART). Several reports with limited numbers of patients suggest that CART might also be an effective treatment for pts with CNS lymphoma. This EBMT registry study aimed at compiling data to investigate the potential of CART in pts with primary (PCNSL) or secondary CNS lymphoma (SCNCL). Methods: Centers contributing to the EBMT database were asked for cases of PCNSL and SCNSL, treated with CART between 01/ 2018 and 07/ 2022. Reported pts were identified in the database, patient characteristics and pre-treatment retrieved, and major clinical endpoints analyzed. To calculate overall survival (OS) and progression-free survival (PFS) from date of CART infusion Kaplan Meier estimates were used, whereas cumulative incidence was used for relapse incidence (RI) and non-relapse mortality (NRM). Results: 88 pts with PCNSL (n=10) or SCNSL (n=78) with complete information on major endpoints were analyzed. Median follow-up was 20.3 months [95% CI: 16-27]. Median age was 63 years (range 31-80), 52 pts (59%) were male. ECOG was ≥ 2 in 19 of 86 pts (22%). 41 of 65 pts (63%) had undergone ≥3 prior treatment lines, 56 of 82 pts (68%) were refractory to at least one previous line of chemotherapy. 29 of 86 pts (34%) had received autologous stem-cell transplantation (ASCT). Of 84 patients 68% were not in remission at time of CART, 8% were in complete remission (CR) and 24% in partial remission (PR). Information on disease status was missing for four patients. 49 pts were treated with axicabtagene ciloleucel, 39 pts received tisagenlecleucel. OS- and PFS-rates at 24 months were 47% [95% CI: 37-61] and 32% [CI: 23-45] for the whole cohort (figure 1). RI at 24 months was 58% [CI: 47-68], NRM 10% [CI: 4-19]. OS and PFS for pts in CR/PR were 58% [CI 40-85] and 51% [CI: 33-77]. For 57 pts not in remission at CART infusion OS and PFS were 42% [CI: 30-59] and 24% [CI: 14-39], respectively. Conclusion: With a 47% OS rate at 24 months CART seem to be a very effective therapeutic option in heavily pre-treated r/r LBCL with CNS manifestation. These results compare favorably with those reported for conventional treatment including pts treated with ASCT. Indeed, these results are similar to those reported by real-world analyses of CART in LBCL without CNS manifestation (Bethge et al., 2021, Le Gouill et al., 2021). Based on these promising early results, we consider treatment with CART for pts with CNS involvement and r/r LBCL as the preferred treatment option.

Clofarabine and High-Dose Melphalan Reduced Intensity Conditioning Regimen with Methotrexate-Based GvHD Prophylaxis

Introduction: Reduced-intensity conditioning (RIC) allogeneic stem cell transplant (allo-SCT) remains a curative option for elderly and/or unfit patients with hematologic malignancies. Fludarabine-containing regimens make up the cornerstone of RIC regimens, however, during the nation-wide fludarabine shortage in 2022, many institutions used fludarabine-free RIC regimens out of necessity though data was extremely limited. Clofarabine is a second-generation purine analog with more potent anti-leukemic activity and a different adverse effect profile compared to fludarabine. We report our experience with clofarabine-based RIC conditioning for adult patients with non-Hodgkin's lymphoma (NHL) and myeloid malignancies. Methods: In this retrospective single-center matched cohort study at Stanford Health Care, we compared adult RIC allo-SCT patients receiving clofarabine and melphalan (CloMel) with a matched cohort receiving fludarabine and melphalan (FluMel) from January 1, 2022 to December 31, 2022. CloMel consisted of clofarabine 30 mg/m 2 on days -6 to -2 followed by melphalan 140 mg/m 2 on day -1, while FluMel consisted of fludarabine 30 mg/m 2 on days -5 to -2 followed by melphalan 140 mg/m 2 on day -1. Clofarabine dose adjustments were made in patients with renal dysfunction according to the following institutional guidelines based on creatinine clearance (CrCl): 22.5 mg/m 2 for CrCl 60 to 79 mL/min, 15 mg/m 2 for CrCl 30 to 59, and avoiding clofarabine for CrCl less than 30 mL/min. Dose modifications for fludarabine and melphalan due to renal dysfunction were at the discretion of the care team. Patients received graft versus host disease (GvHD) prophylaxis with tacrolimus and methotrexate. Efficacy and safety outcomes were assessed. Data were analyzed using Mann-Whitney U and chi-square tests. Results: We identified 9 matched pairs for a total of 18 patients. Most patients received an allo-SCT for a myeloid malignancy (8 patients with AML, 8 patients with MDS, and 2 patients with NHL). All patients received a peripheral blood stem cell transplant, with 89% receiving a matched unrelated donor and 11% receiving a matched related donor transplant. Baseline characteristics were balanced between groups. There was no difference in time to neutrophil engraftment (mean 14 vs 14 days; p=0.42), time to platelet engraftment (mean 16 vs 24 days; p=0.33), or 100% donor whole blood chimerism (71% vs 78%; p=0.32) at 6 months in the CloMel and FluMel groups, respectively. No statistically significant difference was observed for the number of patients who experienced acute (2 vs 0; p=0.13) and chronic GvHD (0 vs 4, p=0.09) at 6 months between groups. At 6 months, 2 patients in the CloMel group and no patients in the FluMel group experienced early non-relapse mortality (p=0.13). Both patients who died experienced acute renal failure secondary to conditioning chemotherapy with a median onset of renal dysfunction 6 days after initiation of clofarabine, followed by sepsis and multi-organ failure. Both patients required initiation of external renal replacement therapy and ultimately passed 12 days and 29 days post-transplant, prior to engraftment. Notably, both patients had a history of kidney dysfunction prior to transplant, one patient with chronic kidney disease (CKD) stage 3 and the other patient with lymphomatous involvement of the kidneys, and received appropriate clofarabine renal dose adjustments per institutional standards. Conclusion: CloMel demonstrated similar efficacy outcomes at 6 months and represents a feasible alternative to FluMel as a RIC regimen. However, given the notable occurrence of renal failure and early death in the CloMel arm, careful consideration and particular caution in administering to patients with a prior history of renal disease is recommended.

Lacutamab in Patients with Relapsed and Refractory Sèzary Syndrome: Results from the Tellomak Phase 2 Trial

Introduction Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Sézary syndrome (SS) is a rare, aggressive and advanced type of CTCL. It has a unique biology, with high expression of KIR3DL2, a killer immunoglobulin-like receptor, reported in more than 85% of patients. SS is characterized by erythroderma, significant blood involvement with malignant SS cells, and lymphadenopathy. These patients suffer from debilitating itching and recurrent skin infections, often affecting quality of life (QoL). SS is distinguished by its poor prognosis, as the median survival of patients is approximately 5 years. Lacutamab is a first-in-class monoclonal antibody designed to specifically deplete KIR3DL2-expressing cells via antibody-dependent cell-cytotoxicity and phagocytosis. Methods TELLOMAK is an international, open-label, Phase 2 trial with multiple cohorts (NCT03902184). We report here results from Cohort 1, designed to evaluate safety and efficacy of single agent lacutamab in patients with relapsed/refractory (R/R) SS after at least 2 prior systemic therapies including mogamulizumab. Patients had blood stage B2 (≥1000 circulating Sézary cells/mm 3) at screening based on central evaluation by flow cytometry. Patients with evidence of large cell transformation were excluded. Lacutamab 750 mg is administered as an intravenous infusion weekly × 5 weeks (w), every 2 w × 10, then every 4 w until progression or unacceptable toxicity. Primary endpoint was Objective Response Rate (ORR) by global response score based on the evaluation of 4 compartments: skin, blood, lymph nodes and viscera according to International Consensus criteria (Olsen 2011). Secondary endpoints included but not limited to additional efficacy endpoints, safety, QoL assessments. Results At the data cut-off of May 1, 2023, 56 SS patients were enrolled treated and evaluated in Cohort 1. Median age was 69 years (range: 42-86), the median prior lines of systemic therapies was 6.0 (range: 2-15), 60.7 % (n=34) had stage IVA1, 32.1 % (n=18) had stage IVA2 and 7.1% (n=4) had stage IVB disease at baseline, all patients (100%) had blood involvement (B2), 67.9% (n=38) had confluence of erythema covering ≥ 80% body surface area (T4), 35.7% (n=20) had lymph node lymphoma involvement (N3). Median follow-up was 14.4 months (95% CI 9.0-18.4). In the ITT population (n=56), Global confirmed ORR was 37.5% (n=21; 95% CI 26.0-50.6) including 2 CRs, with a median time to response of 2.8 months (range 1-9; Figure 1). Confirmed ORR in skin was 46.4% (n=26; 95% CI 34.0-59.3) including 5 CRs. Confirmed ORR in blood was 48.2% (n=27; 95% CI 35.7-61.0) including 15 CRs. Clinical Benefit Rate (CBR, defined as CR+PR+SD) was 87.5 % (n=49; 95% CI 76.4-93.8). Median PFS was 8.0 months (95% CI 4.7-21.2). Grade ≥ 3 Treatment-related (TR) Treatment-Emergent Adverse events (TEAEs) were observed in 10/56 (17.9%) pts, Serious TR TEAEs were observed in 4/56 (7.1%) and 3/56 (5.4%) pts discontinued study drug due to TR TEAE. Data from additional key endpoints will be presented. Conclusion In this SS cohort from the TELLOMAK study, our data confirm that lacutamab monotherapy shows promising clinical activity in a R/R population previously treated with 2 or more prior systemic therapies including mogamulizumab, and an overall favourable safety profile. Continued evaluation of this new targeted treatment option for patients with SS is warranted.

Association between Microenvironment-Related Genes and Prognosis of Primary Central Nervous System Lymphoma

Background: Comprehensive gene mutation profiling of primary central nervous system lymphoma (PCNSL) revealed genomic abnormalities associated with the NFκB signaling pathway and immune escape (Chapuy B, et al. Blood 2016). Although this has led to advances in targeted therapy, there are only a few candidate biomarkers for diagnosis and prediction of survival in PCNSL. Recurrence still occurs at high rate of over 60% and therapeutic resistance is a significant challenge in the management of recurrent PCNSL. Until now, the systemic profiling of tumor micro-environment (TME) was performed through gene expression analysis by whole transcriptome analysis (WTA) and single-cell RNA sequencing analysis (Heming M, et al. Genome medicine 2022), and stratification in PCNSL was attempted by using spatial transcriptome analysis (Xia Y, et al. Leukemia 2023). However, TME of PCNSL and their impact on prognosis remain uncertain. Objective: We performed this study to investigate the prognostic impact on survival and establish novel prognostic biomarkers in PCNSL. Methods: We analyzed the expression levels of 770 neuroinflammation-related (NFR) genes by the NanoString nCounter technology in tumor samples from 30 PNCSL patients. The clinical significance of genes and their association with prognosis were assessed. Genes related to “worse prognosis (WP)” or “better prognosis (BP)” were identified. We performed the univariable analysis using a cox proportional hazards model to evaluate the predictive value of expression of genes related to WP and clinical risk factors, such as age, sex, serum lactate dehydrogenase level, Karnofsky Performance Status (KPS), consciousness levels at diagnosis and lymphoma involvement of the deep brain structure. Gene expression data related to WP were subjected to multivariate analysis with clinical variables with p values less than 0.15 in the univariate analysis. The genes associated with WP were further validated using WTA of an independent PCNSL cohort (n=30, previously published by Fukumura K, et al. Acta neuropathologica 2016). Results: The median age at diagnosis was 69 years old (range, 32-83). The median follow-up period was 25 months (range, 1-110 months), with overall survival (OS) at 3 years of 39.7% and progression free survival at 3 years of 25.4%. Notably, 48 of 770 NFR genes were highly expressed in the WP group (3-year OS, 22.2%), compared with the BP group (3-year OS, 66.7%) (Figure 1). We found that oligodendrocyte and astrocyte-related signatures were enriched in the WP-associated gene set. Among clinical prognostic factors, KPS > 70 (p=0.0293), and consciousness levels at diagnosis (other than JCS 0-1) (p=0.104) were relatively associated with poor OS (p < 0.15) in univariate analysis. Multivariate analysis revealed that high expressions of TUBB4A (p=0.028, HR:3.88), S100B (p=0.046, HR:3.093) and SLC6A1 (p=0.034, HR:3.765) were significantly related to death independent from KPS and consciousness levels at diagnosis. Expression levels of these 3 genes were also significantly associated with poor OS in a validation cohort. Conclusion: Our observations suggest high expression of TUBB4A, S100B and SLC6A1 are the clinical indicators to predict poor prognosis in PCNSL patients. Furthermore, these data suggest that genes related to TME may play a crucial role in the pathogenesis of PCNSL, complementing the well-known involvement of the NF-kB signaling pathway. Therefore it is necessary to continue research focused on TME-targeted therapeutics to encounter drug resistance and refractoriness in PCNSL.

"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.

Anterior segment involvement in vitreoretinal lymphoma: clinical manifestations, molecular findings and in vivo confocal microscopy

BackgroundIntermediate and posterior manifestations of vitreoretinal lymphoma (VRL) are well characterised. However, there is limited information on anterior segment involvement in VRL. This study aimed to describe the anterior manifestations...

CNS Involvement of DLBCL Presenting with an Unusual Non-Enhancing Infiltrative Mass.

Central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL) is relatively uncommon, occurring in approximately 5% of cases, with the majority of instances manifesting during relapse and often associated with poor prognoses. The aim of this case report is to present a unique occurrence of non-enhancing relapse of CNS lymphoma. Significantly, the patient had recently encountered a disease involvement in the axilla region, and subsequent to scheduled chemotherapy, she developed persistent neurological symptoms, leading to the discovery of a relapse of the CNS lymphoma. Our focus will be on delineating the clinical presentation, elucidating the findings observed in clinical imaging, and detailing the therapeutic approaches employed in this specific case. By highlighting these aspects, we aim to provide valuable insights into the diagnosis of the atypical presentation of CNS lymphoma.

Clinical Features and Therapeutic Evaluation of Central Nervous System Involvement in Pediatric Anaplastic Large Cell Lymphoma

Objective：To analyze the clinical features of central nervous system involvement (CNS3) in pediatric anaplastic large cell lymphoma (ALCL) and evaluate the efficacy of CNCL-ALCL-2017 protocol for the treatment of CNS3. Methods：The clinical data of 215 pediatric ALCL patients ≤18 years old enrolled in the Chinese Children's Cancer Group (CNCL) between April 2017 and March 2023 were collected sequentially. All enrolled patients staging and CNS layering were according to the IPNHLSS staging system and treated with CNCL-ALCL-2017 protocol (modified BFM-ALCL99 protocol). The clinical features at diagnosis and treatment outcomes of CNS3 patients were analyzed. All patients were followed up until June 30, 2023. Data were collected using a unified information platform. Associations between patient characteristics were analyzed with Chi-squared or Fisher's exact tests. Eventfree survival (EFS) and overall survival (OS) curves were estimated according to the KaplanMeier method and compared by Logrank test. Furthermore, statistical analysis was performed using SPSS 22.0 software. P<0.05 was considered statistically significant. Results: Among the 215 ALCL pediatric patients, 17 (7.9%) had CNS3, including 13 males and 4 females with median age of 8.0 (range 1.0-14.0) years. In this patients, brain parenchyma and spinal cord involvement were found in 58.8% (10/17) patients on imaging, with space-occupying lesions in 7 cases and abnormal signals on MRI in 4 cases. Concurrent space-occupying lesions and abnormal signals on MRI was detected in 1 case. Cerebrospinal fluid (CSF) positivity was detected in 35.3% (6/17) patients, including 2 cases with positive ALK gene and 5 cases with positive flow cytometry, with 1 case positive for both. Cranial nerve deficits such as facial nerve palsy, visual or hearing impairment were observed in 23.5% (4/17) patients. Concurrent CSF, imaging and cranial nerve abnormalities were present in 5.9% (1/17), while two of this were present in 29.4% (5/17). Isolated CSF positivity without other abnormalities was detected in 23.5% (4/17). Pathological subtypes included common type (76.5%, 13/17), histiocyte-rich variant (5.9%, 1/17), small cell variant (5.9%, 1/17), others (11.8%, 2/17). Immunohistochemistry showed ALK + in 94.1% (16/17) and CD3 + in 76.5% (13/17). Concurrent ALK gene positivity in both peripheral blood and bone marrow was detected in 64.7% (11/17), with 58.8% (10/17) positive in both samples. The median follow-up of all patients was 35.4 months (range 0.5-74.9). All CNS3 patients had stage IV disease and were treated with regimen D (with 5 g/m 2 methotrexate). The 3-year OS was 94.3%, 98.2% and 93.3% for CNS1 (144, 67.0%), CNS2 (54, 25.1%) and CNS3 (17, 7.9%) patients, respectively; the 3-year EFS was 85.6%, 90.3% and 86.7%, respectively. No significant differences were found among the three groups. The 3-year OS and EFS for the whole cohort were 95.1% and 84.7%, respectively, also with no significant differences from the CNS3 group. Of the CNS3 patients, 1 was lost to follow-up after the first course, 1 died during treatment, and the interim CR rate was 75.0% (12/16). CSF conversion was achieved in 3/6 (50%) CSF-positive patients. 6.25% (1/16) patient had CSF ALK gene re-positivity during maintenance and persistent positivity despite additional ALK inhibitor alectinib and intrathecal therapy. In the CNS1 group, 2 cases were lost to follow-up and 4 cases died. The relapse rate was 11.4% (16/140), and the rate of central nervous system relapse was 2.1% (3/140). Additionally, the rate of CNS1 relapse was slightly higher but not statistically significantly different for CNS2. Conclusions: CNS involvement is relatively rare in pediatric ALCL. Detection rate of CNS3 can be improved by CSF flow cytometry and gene screening. The prognosis of CNS3 was significantly improved with CNCL-ALCL-2017 protocol, which may be related to the increased dose of methotrexate in the protocol. The short follow-up time and the small number of cases in this group may affect the results. Furthermore, CNS relapse rate of CNS2 was not markedly higher compared to CNS1. Keywords: Anaplastic large cell lymphoma; Pediatric; Central nervous system; Clinical features; Prognosis

18-FDG PET-CT Scan Is a Good Tool to Detect Bone Marrow Involvement in Patients with Diffuse Large B-Cell Lymphoma: A Retrospective Analysis of 602 Patients

Background: Bone marrow biopsy is considered a gold standard to detect the involvement in lymphomas. Multi-color flow cytometry improves the detection of low-volume disease and is expected to increase the sensitivity over a BM Biopsy. These procedures are painful, expensive and with the widespread use of 18FDG PET-CT scan as the preferred staging scan, their utility is being re-evaluated. We analyzed the utility of BM studies, including multi-color flow cytometry in DLBCL and developed an algorithm to identify patients where it would be useful. Methods: This is a retrospective study from a tertiary care center in India conducted on patients registered from 01/2018 till 12/2019. De-novo patients aged ≥15 years with DLBCL who underwent their staging workup including both a PET-CT scan and BM studies were included for this analysis. Bone marrow studies include assessment by morphology, flow cytometry (optional) and biopsy. A 13-16 color multi-parameter flow cytometry (BD Fortessa) was used and 500,000 to 1 million events were acquired for the analysis. We recorded the baseline characteristics, Lugano staging and findings from the PET-CT scan and Bone marrow studies. The primary objective was to study the value of BM studies in altering the stage and management compared to a PET-CT scan. Additionally, the positive and negative predictive value of PET-CT scan, reasons for discordant findings, value of flow cytometry studies and impact of BM studies on the final prognostic index were analyzed. Results: A total of 698 DLBCL patients were registered during the period, 602(86%) of whom underwent both a PET-CT scan and Bone marrow studies. Flow cytometry was performed in 572 patients (95%). The median age was 52 years (15-82 years), 425 (70%) were male patients. The stage-wise distribution was; stage I-64(11%), stage II-118(20%), stage III- 74(12%) and stage IV- 346(57%) patients. The utility of PET-CT scan and BM studies in classifying a patient as stage IV is summarized in Table 1. BM studies upstaged a patient to stage IV in only 18 (3%) cases. In the absence of BM studies, these patients would be classified as stage I (4), stage II (4) and stage III (10) (Table 2). A change in prognosis would happen in only 4 of these patients due to a change in stage in 3 (stage I-1, stage II-2) and a change in NCCN-IPI from low-intermediate to high-intermediate in one patient. A change in treatment would occur in only 1 patient. The PPV and NPV of PET-CT for BM involvement using BM studies as a gold standard were 44.2% and 92.3% respectively. While 23/29 (79%) diffuse uptake on PET scan was detected by BM studies, only 35/102 (34%) focal uptake was detected by BM studies. The histological involvement was concordant in 63 patients, while 32 patients had a discordant histological finding. Flow cytometry alone was positive in 32(5.6%) patients, of which 27 patients were already classified as advanced stage (Stage III-7, Stage IV-20). Conclusions: Bone marrow studies, including flow cytometry can be avoided in patients with DLBCL who undergo a PET-CT scan. The additional value of BM studies from a prognostic or therapeutic view is too low to justify a regular use of this painful and expensive test.

Limited Duration Loncastuximab Tesirine with Rituximab Induces High Complete Metabolic Response Rate in High-Risk Relapsed/Refractory Follicular Lymphoma - a Phase 2 Study

Introduction: There is no standard-of-care for treatment of relapsed/refractory (rel/ref) follicular lymphoma (FL) with worse prognosis in those demonstrating progression of disease within 24 months (POD24) from frontline immunochemotherapy. Loncastuximab tesirine (loncastuximab) is an antibody-drug conjugate comprising a monoclonal antibody directed against CD19 and a DNA cross-linking pyrrolobenzodiazepine. Preclinical data demonstrated synergistic activity between rituximab-induced cytotoxicity and loncastuximab. Here we report pre-specified initial results of a single-institution investigator-initiated study evaluating this combination for the first time in FL (NCT04998669). Methods: Adult patients with rel/ref FL previously treated with ≥1 line of systemic therapy presenting GELF criteria or POD24 at enrollment were eligible.Primary study endpoint was complete response (CR) by week 12 PET/CT based on Lugano 2014 criteria. Bone marrow biopsy was required at screening and repeated at week 12 if initial involvement. The initial 21 weeks of therapy consisted of 4 weekly doses of rituximab i.v. 375mg/m 2 followed by 1 dose every 8 weeks for a total of 5 doses in association with loncastuximab i.v. 0.15mg/kg every 3 weeks for 2 doses followed by 0.075mg/kg every 3 weeks for a total of 7 doses. Patients achieving CR by week 21 PET/CT discontinued loncastuximab and received two more doses of rituximab every 8 weeks. Premedication with dexamethasone 4 mg twice daily for 3 days was required with loncastuximab. No antibiotic or growth factor prophylaxis was mandated by study protocol. Enrollment occurred according to a Simon's minimax two-stage design with a total sample size of 39 patients based upon a projected CR rate ≥50% vs ≤30% (H0), type I error alpha 5%, power 80%. In stage 1, 19 patients enrolled and 7 or more CRs were required to proceed with stage II. In stage II, an additional 20 patients will be enrolled. Based on n=39, a total of ≥17 CRs are required for rejecting the H0. Results: Twenty-six patients have been enrolled from January 2022 to July 2023, 25 evaluable for toxicity (1 patient has not yet initiated treatment) and 21 for response. Median age was 68 years (range 47 to 89). Most were women (n=14; 54%), with advanced-stage (n=20; 77%), high-risk FLIPI score (n=13; 50%), and 12 (46%) demonstrating POD24 after immunochemotherapy. Median lines of prior therapy were 1 (range 1 to 6). R-CHOP was most common first-line therapy (n=14; 54%) followed by bendamustine with rituximab and single-agent rituximab (n=6; 23%; each). Most common grade 1 adverse events (AEs) included alkaline-phosphatase (48%), ALT (44%), AST (36%) elevation; maculo-papular rash (44%), fatigue (28%), thrombocytopenia (28%), photosensitivity (28%), leg edema (24%), and anasarca (20%). Grade 2 AEs were alkaline phosphatase elevation (12%), anasarca (8%) and leg edema (4%) Grade 3 AEs included neutropenia (n=2; 8%), and one case each (4%) of cellulitis and pleural effusion. Neutropenia was the only grade 4 AE in a patient post-CAR T-cell. All toxicities resolved with supportive management and dose delays (n= 4); no treatment-related deaths occurred during study period. CR was observed in 7 of the initial 10 patients meeting pre-specified criteria to proceed to stage II. Among 21 patients evaluable for response, the overall response rate at week 12 was 95.2% [CR rate of 66.7% (n=14), partial response (PR) rate of 28.6% (n=6)]. All CR were maintained and 4 of the 6 PR (2 patient have not yet re-evaluated) improved to CR at week 21 for a best CR rate of 86% (n= 18). Baseline bone marrow involvement by FL resolved in all patients (n=5) at week 12 reassessment. Two patients were removed from the study. One patient due to disease progression on week 12 PET/CT with biopsy-proven diffuse large B-cell lymphoma in a kidney mass and another with cholangiocarcinoma, who achieved CR with respect to known lymphoma involvement. Both lesions were present before study enrollment but radiologically considered FL. All seven patients who completed the study remained in CR after end of treatment for a median follow up of 4.8 months (range 3.2 to 6.7) ( Figure 1). Updated analysis will be presented at the meeting. Conclusion: A limited duration program combining loncastuximab with rituximab in patients with rel/ref FL is well tolerated and highly effective with a metabolic CR rate of 86% including high-risk patients with POD24 and/or high disease burden.

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.

Responses and Outcomes after Second-Line Therapy in Transplant-Eligible Patients with DLBCL Relapse over 1 Year after First-Line Therapy

Introduction Chimeric antigen receptor T-cell therapy (CAR T) is approved as second-line therapy in patients with large B cell lymphoma (LBCL) that is refractory to, or relapsed within 1 year of, initial therapy. In patients with LBCL that relapses more than 1 year after completion of initial therapy, salvage chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) remains the standard of care for transplant-eligible patients. However, data on the outcomes of salvage chemoimmunotherapy with intent for ASCT for this specific population are lacking. Methods We retrospectively reviewed patients with relapsed LBCL more than 1 year after 1 st line therapy who received salvage treatment. We included patients seen at our institution prior to the start of salvage therapy, who began therapy between 1/2008 and 1/2023, and were treated with stated intent to proceed to ASCT. We excluded patients with CNS involvement at relapse and those not evaluable for response. The primary outcome was progression-free survival (PFS), defined as the time from initiation of salvage therapy to LBCL progression or death. Event-free survival (EFS) was defined as time from salvage initiation to change in lymphoma therapy, disease progression, or death. Additional key outcomes included overall survival (OS), overall response rate (ORR) and complete response rate (CRR) to salvage therapy, and outcomes after subsequent CAR T. Outcomes for important subgroups using baseline characteristics were compared. ORR and CRR were compared using Fisher's exact test. PFS, EFS and OS were estimated using the Kaplan-Meier method, and differences were tested by the log-rank test. Results A total of 78 patients met inclusion criteria, with characteristics summarized in Table 1. Median time from completion of initial therapy to relapse was 31.2 months (range, 12.3 - 177 months). CRR to salvage therapy was 76%, with a 94% ORR. In 60 patients who completed ASCT, CRR was 85%. With a median of 45 months' follow-up from salvage initiation, median PFS was 50 months (95% confidence interval (CI) of 25 - NR), and median EFS was 29.2 months (95% CI, 19.6 - NR)( Figure 1). Median OS was 132 months (95% CI 108 - NR). On subgroup analysis, factors significantly associated with shorter PFS were time from last treatment to relapse < 36 months, Ann Arbor stage 3-4, LDH above normal, and increased international prognostic index at relapse. Other factors such as age, gender, salvage regimen, extranodal disease, cell of origin, transformation from indolent lymphoma, bulky disease, and marrow involvement at relapse, were not significantly associated with PFS. Comparing response to salvage in 60 ASCT recipients, patients in CR (n=52) had longer median PFS than those in PR (n=8) (108 vs 33 mo), but this was not statistically significant (p = 0.4). In 33 patients who received 3 rd line therapy or beyond, 16 (48%) received CAR T therapy; 7 proceeded directly to CAR T after inadequate response to salvage, and 9 had progression after completion of ASCT and received CAR T. Among all patients, CRR after CAR T was 81% and ORR 94%, with median PFS and OS not reached; PFS and OS at 24 months after CAR T were 63% and 81%, respectively. Discussion To our knowledge, this is the first study to specifically evaluate outcomes of ASCT-eligible patients with relapsed LBCL more than 1 year after initial therapy, who did not meet FDA criteria for CAR T-cell therapy. We observed highly favorable outcomes, with longer PFS and OS compared to studies that evaluated late LBCL relapses (Hilton LK., JCO 2023, Harrysson S., BJH 2022), possibly reflecting the exclusive use of modern salvage regimens with intent for ASCT, improvements in subsequent therapies, or bias related to the single-center design. In patients who received CAR T in 3 rd line or later, frequent and durable responses were seen. However, due to the small sample size, whether CAR T should be considered as an alternative to ASCT in patients with late LBCL relapse remains unknown. Our data represent a benchmark for patients with LBCL relapses >12 months after completion of frontline therapy and may help inform patient counseling and future clinical trial designs.

Smart Stop: Lenalidomide, Tafasitamab, Rituximab, and Acalabrutinib Alone and with Combination Chemotherapy for the Treatment of Newly Diagnosed Diffuse Large B-Cell Lymphoma

Background: Despite recent advances, first-line (1L) chemoimmunotherapy (CIT) for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades.In the Smart Start trial, we established the feasibility of targeted chemotherapy-free 1L therapy with rituximab (R), lenalidomide (L), and ibrutinib, prior to chemotherapy in patients with newly diagnosed DLBCL with an overall response rate (ORR) and complete response rate (CRR) of 86% and 36%, respectively, prior to chemotherapy, and a 2 year progression free survival rate of 91.3% following 6 cycles of standard CIT (Westin et al, JCO 2023, PMID: 35952327). One patient withdrew from the study after achieving CR and prior to receiving CIT and remains in remission without further therapy at >4 years. BTK inhibitors like acalabrutinib (A) and the immunomodulatory agent L result in synthetic lethality in non-GCB DLBCL models. Both the CD20 antibody R and CD19 antibody tafasitamab (T) demonstrate clinical activity when combined with L in patients with DLBCL. L, T, R, and A are immunomodulatory, driving an anti-tumor immune response. Based upon these data, we are conducting the Smart Stop trial (NCT04978584) to evaluate if the number of CIT cycles can be reduced or omitted after response to targeted therapy, and now report the preplanned interim results from cohort 1. Methods: Eligibility criteria include patients who are 18y+ with previously untreated DLBCL (initially the Hans algorithm was used to select non-GCB DLBCL, but this criteria was removed this criteria) with adequate organ and bone marrow function. Patients with known CNS involvement of lymphoma, recent thrombosis, or inability to tolerate prophylactic anticoagulation are ineligible. Patients receive lenalidomide 25mg on days (d) 1-10, tafasitamab 12mg/kg IV d1, 8, and 15, rituximab 375mg/m2 IV d1, and acalabrutinib 100mg PO twice/d in a 21 day cycle. All patients receive LTRA for 4 cycles, followed by PET/CT scan (CR defined as a 5PS of 1, 2, or 3). In cohort 1, patients receive an additional 6 cycles of LTRA combined with a response adapted number of cycles of CHOP therapy. After 4 cycles of LTRA, patients with CR receive 2 cycles of CHOP, and all other patients receive 6 cycles of CHOP. In the upcoming cohort 2, patients with CR after 4 cycles of LTRA are planned to receive no cycles of CHOP. The primary objectives are to determine the 1A: ORR after 4 cycles of uLTRA and 1B: CRR at of LTRA +/-CHOP at the end of therapy. Results: Cohort 1 enrolled 30 patients from May 2022 - July 2023, with all patients expected to be evaluable for 1A endpoint and 22 patients (73%) evaluable for endpoint 1B by the ASH meeting. The median age was 61 years (range: 32-85), 30% were >= 70 years, and 50% were female. 67% of patients have poor risk R-IPI, 77% had advanced stage, and 83% had an elevated LDH. 83% had the non-GCB subtype and 17% had the GCB subtype of DLBCL. After 4 cycles of LTRA, the ORR is 100% and the CRR is 64% (endpoint 1A, n = 14/22 evaluable at abstract submission, figure 1 schema and swimmer plot). After an additional 2 cycles of LTRA-CHOP, the ORR is 100% and the CRR is 95% (n = 18/19 evaluable at abstract submission). At end of all therapy, the CRR is 100% (endpoint 1B, n = 12 evaluable at abstract submission), including 7 patients who received LTRA for 10 cycles and CHOP for 2 cycles (early CR) and 5 patients who received LTRA for 10 cycles and CHOP for 6 cycles. To date, no patient has progressive lymphoma, including the first 6 patients who have 3 and 6 month follow up scans. 47% of patients experienced rash (13% grade 3), and 40% of patients required a dose reduction of lenalidomide. Conclusions: The Smart Stop trial demonstrates that combination of lenalidomide, tafasitamab, rituximab, and acalabrutinib is highly effective as an initial chemotherapy-free combination in patients with newly diagnosed DLBCL, and may allow for a response adapted reduction in chemotherapy. Response and time to event data will be updated for presentation at the meeting. We will soon open cohort 2 which will enroll an additional 30 patients where those with early CR after 4 cycles of LTRA will receive no cycles of CHOP.

Improved Visualization of Lymphomatous Cardiac Involvement with Retrospective PET/MRI Fusion.

Improved Visualization of Lymphomatous Cardiac Involvement with Retrospective PET/MRI Fusion.