Relapsed Diffuse Large B-cell Lymphoma Research Articles

Prevalence of Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma: A Comprehensive Review

Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is a rare but serious complication associated with poor outcomes. The prevalence of CNS relapse in DLBCL varies widely in the literature, ranging from 1% to 30%, depending on several risk factors and diagnostic methods. This article provides a comprehensive review of the current literature on the prevalence of CNS relapse in DLBCL, focusing on risk factors, diagnostic approaches, and treatment strategies. Understanding the epidemiology and clinical characteristics of CNS relapse in DLBCL is crucial for the development of effective preventive and therapeutic strategies.

Phase II single-arm study of a combination of obinutuzumab and venetoclax in early relapsed or refractory diffuse large B-cell lymphoma—final results of the AGMT NHL15B study

BackgroundPatients with diffuse large B-cell lymphoma (DLBCL) relapsing early (within 12 months) or primary refractory to induction therapy with rituximab (R) and CHOP have a poor prognosis. We therefore initiated a study with obinutuzumab and venetoclax.Study design and methodsTwenty-one patients with DLBCL (relapsed within 12 months or primary refractory), detectable Bcl-2 protein expression, and CD20 positivity were included in this prospective single-arm study between 2016 and 2021. Obinutuzumab was administered i.v. at a dose of 1,000 mg on days 1, 8, and 15 in cycle 1 and on day 1 of each of the following 21-day cycles. Venetoclax was given at 800 mg daily p.o. continuously. Treatment was repeated for up to three cycles. Eligible patients were planned to either proceed to cellular therapies or receive up to nine cycles of maintenance. The primary endpoint was objective response rate (ORR) after three cycles (Eudract Nr. 2016-001760-10 and NCT02987400).ResultsTwenty-one patients (median age, 64 years) with refractory or early relapsed DLBCL after one (N = 11) to four previous lines of therapy were included. The majority of patients received three cycles of obinutuzumab/venetoclax (range, 1–8). The regimen was well tolerated with manageable cytopenias and infections. Severe adverse events related to treatment were observed in 9.5%. The ORR was 38.1% (8/21 patients) with a best response of five complete remissions (CRs; 23.8%) and three partial remissions (PRs; 14.2%). The primary endpoint (45% ORR) was not met. Response duration was 83.3% at 84 days, with a progression-free survival of 38.8% at 84 days and 25.9% at 168 days and a median overall survival of 169.1 weeks. All deaths were due to underlying disease. Seven patients became eligible for autologous transplant. Overall, nine patients (42.8%) received 11 cellular therapies (5 ASCT and 6 CAR-T). Three patients went directly from obinutuzumab/venetoclax to CAR-T therapy. All patients had successful peripheral stem cell or T-cell harvests. Characteristics of responders include relapsed disease (response rate, 6 of 11 = 54%), very good or good R-IPI (7 of 8), and low number of previous therapies (median = 1).ConclusionObinutuzumab/venetoclax represents an effective chemo-free relapse regimen with low toxicity that can be followed by cellular therapies, particularly CAR-T cells.

STAT6 mutations enriched at diffuse large B-cell lymphoma relapse reshape the tumor microenvironment

Diffuse large B-cell lymphoma (DLBCL) relapses in approximately 40% of patients following frontline therapy. We reported that STAT6D419 mutations are enriched in relapsed/refractory DLBCL (rrDLBCL) samples, suggesting that JAK/STAT signaling plays a role in therapeutic resistance. We hypothesized that STAT6D419 mutations can improve DLBCL cell survival by reprogramming the microenvironment to sustain STAT6 activation. Thus, we investigated the role of STAT6D419 mutations on DLBCL cell growth and its microenvironment. We found that phospho-STAT6D419N was retained in the nucleus longer than phospho-STAT6WT following IL-4 stimulation, and STAT6D419N recognized a more restricted DNA-consensus sequence than STAT6WT. Upon IL-4 induction, STAT6D419N expression led to a higher magnitude of gene expression changes, but in a more selective list of gene targets compared with STATWT. The most significantly expressed genes induced by STAT6D419N were those implicated in survival, proliferation, migration, and chemotaxis, in particular CCL17. This chemokine, also known as TARC, attracts helper T-cells to the tumor microenvironment, especially in Hodgkin’s lymphoma. To this end, in DLBCL, phospho-STAT6+ rrDLBCL cells had a greater proportion of infiltrating CD4+ T-cells than phospho-STAT6− tumors. Our findings suggest that STAT6D419 mutations in DLBCL lead to cell autonomous changes, enhanced signaling, and altered composition of the tumor microenvironment.

Autologous stem cell transplant in fit patients with refractory or early relapsed diffuse large B-cell lymphoma that responded to salvage chemotherapy.

Chimeric antigen receptor T-cell (CAR-T) therapy is the new standard of care in fit patients with refractory or early relapsed diffuse large B-cell lymphoma (DLBCL). However, there may still be a role for salvage chemotherapy (ST) and autologous stem cell transplant (ASCT) in certain circumstances (eg, lack of CAR-T resources, chemosensitive relapses, etc). We retrospectively studied 230 patients with refractory or early relapsed DLBCL who underwent ST and ASCT. Median line of ST was 1 (range 1-3). Best response before ASCT was complete response (CR) in 106 (46%) and partial response (PR) in 124 (54%) patients. Median follow-up after ASCT was 89.4 months. The median progression-free (PFS) and overall survival (OS) were 16.1 and 43.3 months, respectively. Patients relapsing between 6 to 12 months after frontline therapy had numerically better median PFS (29.6 months) and OS (88.5 months). Patients who required 1 line of ST, compared to those requiring >1 line, had better median PFS (37.9 vs 3.9 months; P = 0.0005) and OS (68.3 vs 12.0 months; P = 0.0005). Patients who achieved CR had better median PFS (71.1 vs 6.3 months; P.

Current development of chimeric antigen receptor T-cell therapy for diffuse large B-cell lymphoma and high-grade B-cell lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy has become a commercially available treatment option for relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) with two or more lines of prior therapies, and recently for high-risk r/r DLBCL with one prior line of therapy. The successful development of CAR T-cell therapy for multiple relapsed DLBCL has led to a boom in subsequent trials that investigated its utility in patients with other r/r B-cell lymphoma subtypes. However, CAR T-cell therapy is a multistep process that includes leukapheresis and manipulation which take several weeks. Therefore, patients with rapidly progressing or bulky disease may not be able to complete the therapeutic regimen involving CAR T-cell products. This raises the question of the generalizability of the results of pivotal studies to the entire population. In this review, we summarize the development of CAR-T cell therapy for B-cell lymphoma and discuss strategies to further improve the clinical outcomes of this treatment.

Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma: New Approved Options.

Overall, around 40% of patients with diffuse large B-cell lymphoma (DLBCL) have refractory disease or relapse after the first line of treatment. Until relatively recently, the prognosis of patients with relapsed or refractory DLBCL was very poor and treatment options were very limited. In recent years, several novel therapies have been approved that provide more effective options than conventional chemotherapy and that have manageable toxicity profiles. CAR-T cell therapy has become the new standard treatment for patients with refractory or early relapsed DLBCL, based on the positive results of the phase 3 ZUMA-7 and TRANSFORM clinical trials. This review addresses the role of CAR-T therapy and autologous stem cell transplantation in the treatment of these patients and other approved options for patients who are not candidates for transplant, such as the combinations of polatuzumab vedotin with bendamustine and rituximab, and tafasitamab with lenalidomide.

Diffuse Large B-Cell Lymphoma CNS Relapse Prophylaxis with Intrathecal or High-Dose Intravenous Methotrexate

Introduction: Central nervous system (CNS) relapse is a relatively infrequent but often fatal complication of the most common subtype of non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL). Median overall survival (OS) after DLBCL relapse in the CNS is about 4 months. Despite identifying patients at high risk of developing CNS relapse using the CNS international prognostic index (CNS-IPI) score, it has been difficult to validate any specific strategy. Various chemotherapies and administration methods have been tested. Thus far, only the addition of rituximab to chemotherapy has yielded significant results. Our objective is to determine if administering prophylactic chemotherapy is efficacious in preventing DLBCL relapse in the CNS. Methodology: We collected retrospective data for patients with newly diagnosed DLBCL treated with rituximab and anthracycline-based chemotherapy from 2010 to 2020 in the Northwell Health system to determine the efficacy of CNS prophylaxis. Patients with CNS disease at diagnosis, primary testicular lymphoma, primary mediastinal large B-cell lymphoma, and HIV-associated lymphoma were excluded from this study. CNS prophylaxis was defined as receiving at least two doses of prophylactic chemotherapy, whether intravenous or intrathecal. Follow up for at least one year after diagnosis was required for inclusion. Overall survival (OS) was defined as the time difference between the date of definitive diagnosis to death or last date of contact. Other potential prognostic factors including double hit status and cell of origin, germinal center B-cell (GCB) vs. non-germinal center B-cell (non-GCB), were also evaluated. Pearson's chi-square analysis was used to compare the rate of DLBCL relapse in the CNS based on whether patients received CNS prophylaxis. Low risk was defined as CNS-IPI score 0 to 3 and high risk as CNS-IPI score 4 to 6. Kaplan-Meier analysis with log-rank (Mantel-Cox) testing was used to determine if any significant OS benefit was observed for the low and high-risk groups based on CNS-IPI score. Results: Of the 437 charts reviewed, 127 were eligible for inclusion. Most patients were male (56.7%). Median age was 69 years and median Eastern Cooperative Oncology Group (ECOG) performance status was 1. Most cases were non-GCB (44.9%, as 25% of cases were missing data) and not double hit (85%). Of the 35 patients at high risk for CNS relapse, 27 (77%) received prophylaxis. Intrathecal methotrexate (IT MTX) was given to 26 patients (96%) and high dose intravenous methotrexate (HD MTX) was given to 1 patient. CNS relapse occurred in 6 patients, of which 5 had a low-risk CNS-IPI score. One of the five patients in the low-risk group and the one patient in the high-risk group that had CNS relapse received prophylaxis. No significant difference in overall relapse rates were observed based on whether prophylaxis was given, X 2 (1, N = 127) = 0.30, p = .59. Kaplan-Meier analysis showed no difference in OS after stratification of patients by CNS-IPI score into the high-risk ( p = .50) and low-risk ( p = .24) groups. HD MTX was not administered frequently enough to determine its efficacy. Neither cell of origin (X 2 (1, N = 95) = 2.95, p = .086) nor double hit status (X 2 (1, N = 127) = 1.512, p = .22) had any significant effect on OS. Conclusions: We did not observe any clear benefit for administering IT MTX to prevent DLBCL relapse in the CNS. Most of the CNS relapse events occurred in the low-risk group, even though 8 patients in the high-risk group did not receive any CNS prophylaxis. This study did not have sufficient power to make a definitive conclusion. As CNS relapse is a rare event, a much larger sample size is required to determine the true efficacy of CNS prophylaxis. Non-GCB cell origin and positive double hit status are not included in the CNS-IPI score but their potential association with risk of DLBCL relapse in the CNS is understudied. Future studies should build upon these findings.

A Phase II Study of Chidamide Plus R-GDP Salvage Chemotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Ineligible for Autologous Transplantation: Efficacy and Safety Analysis

Background: A significant subset of Diffuse large B-cell lymphoma (DLBCL) patients (30%-40%) face treatment failure, necessitating effective salvage chemotherapy. We conducted a phase II study evaluating the efficacy and safety of chidamide plus R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin) in relapsed/refractory (r/r) DLBCL patients. Methods: This open-label, single-arm study included 27 patients with r/r DLBCL who were ineligible for autologous stem cell transplantation. Prior to the induction monotherapy phase, chidamide was administered orally at a dose of 30 mg twice a week for one week. The combination therapy phase consisted of oral chidamide at a dose of 20 mg twice a week for two weeks, with a one-week discontinuation period, along with intravenous administration of rituximab, gemcitabine, dexamethasone, and cisplatin on a 21-day cycle. Results: A total of 27 patients received at least one dose of Chidamide plus R-GDP and were evaluated for safety. The median follow-up period was 17.0 months (range: 3.5 to 55 months). Radiological response assessment was available for 24 patients, who constituted the efficacy population. Fourteen patients completed six cycles of chidamide plus R-GDP (per-protocol population), while 10 patients discontinued treatment at the data cutoff. The baseline characteristics of enrolled patients included a median age of 67 years, predominantly older than 65 years. Approximately half of the patients exhibited elevated lactate dehydrogenase levels. All patients had received prior therapy with R-CHOP or equivalent chemoimmunotherapy. The majority of cases were classified as stage III/IV and non-germinal center B-cell-like (non-GCB) type by immunohistochemistry. Refractory or relapsed DLBCL within 1 year since the last treatment was observed in 74.0% of patients. Efficacy Outcomes: The investigator-assessed best objective response rate (ORR) was 79.2% (95% CI: 75.1% to 83.3%), with a complete response (CR) rate of 45.8% (95% CI: 41.6% to 49.9%) and a partial response (PR) rate of 33.3% (95% CI: 29.3% to 37.4%). The median time to response was 1.2 months, and the median time to CR or CRu (unconfirmed complete response) was 3.9 months. The best disease control rate was 87.5%. Among the patients who completed six cycles of chidamide plus R-GDP, the best ORR was 100%, with 71.4% achieving CR and 28.6% PR. Kaplan-Meier plots reveal that the median investigator-assessed progression-free survival (PFS) for the efficacy population was 5.9 (95% CI, 3.1 to 12.4) months. The median overall survival was 48.3 (95% CI, 13.1 to not reach (NR)) months. Safety Outcomes: A total of 13 patients (48.1%) required treatment interruption, primarily due to adverse events (22.2%) and disease progression (18.5%). Among patients who completed six cycles of chidamide plus R-GDP, 57.1% required a chidamide dose reduction. The most frequent treatment-emergent adverse event was anemia, occurring in all patients. Thrombocytopenia was the most common grade ≥3 adverse event leading to treatment interruption or dose reduction, affecting 48.1% of patients. Non-hematologic events included hypocalcemia (59.3%), hyponatremia (55.6%), and hypokalemia (44.4%). Three patients experienced grade 3 pneumonitis, and one patient had grade 3 skin rash. Conclusion: Chidamide plus R-GDP salvage chemotherapy demonstrated promising efficacy (ORR: 79.2%; CR rate: 45.8%) in r/r DLBCL patients. Adverse events were manageable but necessitated monitoring. Larger trials are needed to validate these findings and establish chidamide plus R-GDP as a potential treatment option for this challenging population. Keywords: relapsed/refractory DLBCL, salvage chemotherapy, chidamide, R-GDP, efficacy, safety

Disease Control Affects Outcomes of Patients with Relapsed Diffuse Large B Cell Lymphoma Treated with CD19 Directed CAR T-Cell Therapy

Introduction: CAR T-cell therapy against CD19 (CART-19) has become the standard of care for pts with primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL) in the second and third line settings. The use of CART-19 therapy improves clinical outcomes compared to standard chemotherapy-based salvage regimens. However, DLBCL pts with disease progression following CART-19 therapy have poor overall survival (OS). Identifying biomarkers associated with improved outcomes can inform the optimal timing for CART-19 implementation. We report the impact of disease control at the time of CART-19 therapy on clinical outcomes. Methods: We conducted a retrospective study of relapsed/refractory (r/r) DLBCL treated at our institution with commercial CART-19 products between 4/2018 and 2/2023. Clinical, pathologic, and pharmacologic (type of bridging, lymphodepletion) characteristics were collected. PET/CT imaging prior to CART-19 therapy was used to determine pretreatment disease status (CR, PR or chemo-resistant disease). Treatment outcomes included best response to CART-19 therapy, frequency and severity of adverse events (CRS or ICANS), PFS and OS. Associations with clinical outcomes were evaluated using logistic regression models by Firth's method. Odds ratios [OR] and 95% CI were obtained. OS and PFS were summarized via Kaplan-Meier method; estimates of median 6- and 12-m rates were obtained with 95% CI. Associations with OS and PFS were evaluated using Cox regression models. Analyses were conducted in SAS v9.4; significance level 0.05. Results: 94 pts were included in this study. Median age was 64 yrs [range 22-81]; 66% were male; 90% Caucasian. Comorbidity index [assessed by HCT-CI] was 2+ in 51.7% pts. Median time from CART-19 discussion to re-infusion was 3.1 m [range 0.2-80 m]. Based on PET/CT scan assessment prior to CART-19 therapy, 9.6% pts achieved CR to bridging, 19% had PR, 64% were resistant (SD or PD). High risk IPI score was present in 23.4%. 14.9% pts had prior ASCT. FluCy lymphodepletion was given in 83% pts. Best response to CART-19 therapy: CR 45.7%, PR 12.8%. PD and SD observed in 28.7% and 3.2% of pts respectively. At median follow up of 36.5 m, median PFS was 6.7 m [95% CI 3.8-18.4]; median OS was 16.0 m [95% CI 9.8-30.6]. Any grade CRS occurred in 61.7%; Grade 3+ CRS 8.5%. Any grade ICANS occurred in 45.7%; Grade 3+ ICANS 16%. Second cancers occurred in 9.6%; 4 pts developed MDS. Adequate disease control at the time of CART-19 therapy was associated with improved ORR (P=0.028). Lack of disease control determined by PET/CT at the time of CART-19 infusion correlated unfavorably with OS and PFS. Pts with chemoresistant disease at the time of CART-19 therapy had a median survival of 7.2 m [HR 2.07 (0.74-5.79)] compared to pts in CR or PR at the time of CART-19 (median survival 27.9 m and 26.8 m respectively, p=0.023). Any grade ICANS [HR 2.46 (1.43-4.23) p=0.001], and ICANS grade 3+ [HR 3.38 (1.82-6.26) p=<0.001] were associated with an increased risk of death. On analysis of associations with PFS, lack of response to CART-19 therapy [SD/NR HR 15.05 (3.92-57.74) p=<0.001], any grade ICANS [HR 1.74 (1.06-2.87) p=0.029], and ICANS grade 3+ [HR 2.52 (1.38-4.59) p=0.003] were associated with increased risk for progression. Grade 3+ ICANS was adversely correlated with PFS in CR pts [HR 3.81 (1.22-11.90) p=0.021] and CR + PR pts. Several factors were associated with increased risk for toxicities. Lack of disease control at the time of CART-19 therapy, [OR 3.30 (0.79-13.79) p=0.003], development of ICANS, any grade [OR 4.08 (1.64-10.14) P=0.003] or grade 3+ ICANS [OR 7.71 (1.28-46.27) p=0.025] correlated with the development of any grade CRS. ICANS of any grade [OR 6.92 (1.12-42.79) p=0.037] and ICANS grade 3+ [OR 6.57 (1.50-28.77) p=0.013] correlated with Grade 3+ CRS. Lack of disease control status [OR 4.18 (0.85-20.55) p=0.011], any grade CRS [OR 4.08 (1.64-10.15) p=0.003], and grade 3+ CRS [OR 6.92 (1.03-46.64) p=0.047] were associated with an increased incidence and severity of ICANS. Conclusions: Disease control assessed by functional imaging at the time of CART-19 therapy for r/r DLBCL may be an independent predictor of CART-19 therapy outcomes. In this cohort, adequate disease control prior to CART-19 therapy was associated with improved ORR, PFS and OS. Optimizing disease control prior to cellular therapy may ultimately improve clinical outcomes while mitigating cellular therapy related toxicity.

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.

Deciphering Transcriptomic and (Epi)Genetic Signatures of Central Nervous System Infiltration in Patients Diagnosed with Diffuse Large B-Cell Lymphoma

Introduction Central Nervous System (CNS) involvement in Diffuse Large B Cell Lymphoma (DLBCL) is a rare complication with bad prognosis. The CNS Prognostic Index is employed to categorize patients at a high risk of CNS relapse; however, its effectiveness is not accurate. The discovery of precise biomarkers for predicting CNS involvement in DLBCL patients remains unmet. Our objective was to characterize the immune, transcriptomic, genomic and epigenomic hallmarks of systemic tumors at diagnosis of patients who later experienced relapse in the CNS. By exploring these biological profiles, we sought to gain valuable insights into the underlying mechanisms and potential biomarkers associated with CNS relapse in DLBCL. Methods We conducted a retrospective study including 38 patients diagnosed with nodal DLBCL who experienced relapse within the first two years after diagnosis. Among these patients, 12 individuals relapsed specifically in the CNS, while 26 relapsed in systemic sites. As a control group, we included 21 patients who did not relapse. DNA and RNA were extracted from FFPE tumor samples collected at diagnosis. To evaluate immune cell infiltration, we utilized the nCounter PanCancer Immune Profiling Panel (Nanostring); cell-of-origin (COO) was determined using the Lymph2Cx assay. Transcriptomic profiles were generated by bulk RNA sequencing and mutational analysis was performed using a custom targeted NGS panel, which included the most frequently mutated genes observed in lymphoid neoplasms. Methylation profiles were obtained using the Illumina Infinium MethylationEPIC Array 850K. Results Immune profiling analysis showed cell composition was not significantly different between groups; however, we observed distinct immune gene expression patterns at diagnosis in patients who experienced CNS relapse. Multiple genes were overexpressed in the CNS-relapsed group compared to non-relapsed group, which encompassed various functional categories including chemokine signaling such as IL7R (FC=2; P=0.05) and CCR6 (FC=3.4; P=0.01); adhesion like VCAM1 (FC=1.6; P=0.03) and ITGA4 (FC=2.2; P=0.006); and immune regulation such as CD1A (FC=4.8; P=0.001), LTB (FC=3.3; P=0.009) and BTLA (FC=2.3; P=0.02) (Fig.1A). The ITGA4 gene also presented higher expression levels in the CNS-relapsed group when compared to both systemic-relapsed and non-relapsed groups combined (FC=1.7; P=0.03). No significant differences were observed in the COO classification between groups. Whole-genome transcriptomic data revealed enrichment in gene sets associated with proliferation and survival in the CNS-relapsed group (Fig.1B). Analysis of genetic alterations indicated that patients with CNS relapse exhibited an increased mutation load and frequency in PIM1, IGLL5, and KMT2D genes. Finally, analysis of the CNS relapse-related epigenome showed 343 differentially hypomethylated CpG sites compared to both systemic and non-relapsed groups together, affecting a total of 211 genes. Pathway enrichment analysis of these genes revealed a link between CNS infiltration and cell migration and locomotion. Conclusions Tumors from DLBCL patients that will relapse in the CNS present a higher chemokine, adhesion and proliferation signatures at diagnosis. Of notice, BTLA, CCR6 and IL7R proteins have been previously reported to be implicated in B cell entry into the CNS in B-cell malignancies. Interestingly, patients with CNS relapse demonstrated significant overexpression of the ITGA4 gene, which encodes the integrin α4 subunit (CD49d) of the Very Late Antigen-4. Engagement between CD49d on B cells and its endothelial ligand VCAM-1 is required for migration of these cells across the blood-brain barrier. In fact, Natalizumab (anti-CD49d mAb) is administered in multiple sclerosis to impede entrance and accumulation of B cells in the brain. Initial experiments in mice have shown increased expression of CD49d in lymphoma B cells that have infiltrated the brain, compared to those in the spleen. Herein, we have demonstrated that DLBCL cells at diagnosis already own specific transcriptomic and (epi)genetic hallmarks that could confer a higher capacity to infiltrate the CNS. Validation of these findings in larger cohorts of patients could improve selection of patients with an increased risk of CNS involvement in need of prophylactic CNS-directed therapies at diagnosis.

Long Term Durable Responses in Relapsed/Refractory (r/r) ALL, DLBCL, and FL Patients Treated with Tisagenlecleucel and Its Association with Persistence of CAR T-Cells

Introduction: Monitoring of chimeric antigen receptor (CAR) transgene levels in peripheral blood post tisagenlecleucel (tisa-cel) infusion provides information on expansion and persistence of CAR T-cells. In adult diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) patients (pts), the expansion of CAR T-cells was similar between responding and non-responding pts, while in pediatric and young adult acute lymphoblastic leukemia (ALL) pts, higher expansion in responding pts was observed. Based on long term follow up data from tisa-cel treated pts, analyses were performed to delineate the impact of CAR persistence and B cell aplasia on duration of remission (DOR). Methods: Transgene levels in blood measured by quantitative polymerase chain reaction were available from pivotal phase II studies in pts with r/r ALL (ELIANA [N=79], ENSIGN [N=64], NCT03123939 [N=69], NCT01626495 [N=60]), r/r DLBCL (JULIET [N=115]), and r/r FL (ELARA [N=97]), along with the long term follow up study (NCT02445222). The time related to loss of persistence of CAR T-cells (T loss) was defined as the time at which transgene levels first dropped below 50 transgene copies/µg DNA (approximates to lower limit of quantification (LLOQ) of the assay) after maximal expansion. Kaplan Meier analysis was performed to investigate the impact of duration of T loss and time corresponding to last quantifiable level (T last) on DOR/relapse. The impact of time to B cell recovery (>1% CD19+ B cells/WBCs or >3% CD19+ B cells/lymphocytes for ALL, and 80-616 cells/µL for DLBCL and FL), on DOR/relapse was also investigated. Results: Long term CAR persistence in tisa-cel treated pts has been observed for up to 9, 6, and 2.5 years for ALL, DLBCL, and FL pts, respectively, reflecting differing length of follow up based on initiation of trials in respective indications. Across indications, pts who lost transgene within 6 months or between 6-12 months had shorter DOR relative to pts with persistent transgene (Fig 1, ALL pts). In ALL, the median T loss was 27.4, 18.2, 9.7, and 18.0 months for ongoing complete response (CR) > 12 months, CR pts between 6-12 months, relapsed pts < 12 months, and relapsed pts > 12 months, respectively. However, of the pts who lost transgene within first 6 months, some pts maintained durable responses for ≥12 months (29%, 15%, and 50% in ALL, DLBCL, and FL, respectively). Among ALL relapsed pts, majority (17/26, 65%) of the pts with T loss < 6 months showed B cell recovery, however 6 pts had T loss at < 6 months as well as B-cell recovery but maintained response for ≥ 12 months. In ALL, Pulsipher et al.,(Blood Cancer Discov. 2022)have shown that NGS MRD within the first 6 months to 1 year post infusion may be a more reliable predictor of potential relapse than B cell recovery. The median time to B-cell recovery was 266 days in pts who relapsed/censored within 12 months but was not reached for pts with ongoing response at 12 months. On the contrary, B cell recovery seems to have no association with relapse in DLBCL or FL pts. Of the ALL pts with CAR persistence, pts with <50% morphologic blasts at any time prior to infusion of tisa-cel had longer DOR compared to pts with ≥50% blasts. This may also reflect a more resistant high risk ALL at the time of study entry or greater potential for stochastic loss of CD19 in pts with the higher disease burden. Conclusions: Long term sustained remission/response was observed in tisa-cel treated pts in the pivotal trials. The analyses demonstrate a positive association between CAR persistence and durable clinical responses across indications, however, some pts maintained durable responses despite early loss of transgene and/or early B cell recovery (< 6 months post infusion; Myers et al., J Clin Oncol. 2021). To note, in DLBCL and FL, the transgene levels in blood may not represent the levels at target sites including lymph nodes, moreover, T last and T loss are dependent on the duration of follow up, LLOQ etc. Of note, these analyses represent data from pivotal tisa-cel clinical studies with a heavily treated pt population post multiple lines of therapy including prior HSCT, and may not represent pts treated with commercial product, at earlier times post diagnosis in current studies with fewer lines of prior treatment, lower pre-infusion disease burden, and/or other CAR product. In pts with early loss of transgene, further research is needed to identify potential factors or patient characteristics resulting in durable responses.

CD19-Targeting CAR T-Cell Therapy in Transformed Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma: A Descar-T and US Collaborative Study

Introduction: Patients with histological transformation (HT) of Waldenström macroglobulinemia (WM) who relapse or are refractory (R/R) have a poor prognosis with standard chemoimmunotherapy, notably patients who are unable to undergo high dose chemotherapy (HCT) and autologous stem cell transplantation (ASCT) or who relapse after HCT/ASCT. CD19-targeted chimeric antigen receptor (CAR) T-cell therapies can lead to durable responses in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and thus may represent a promising therapeutic option in R/R transformed WM (tWM); however, data from pivotal trials is lacking. This study aimed to evaluate the efficacy and safety of anti-CD19 CAR T-cells in real-word patients with R/R tWM. Methods: We retrospectively identified patients with biopsy-proven transformed WM/lymphoplasmacytic lymphoma treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in the French DESCAR-T registry (NCT04328298) and 2 US centers. The primary endpoint was best complete response rate (CRR). Secondary outcomes were best overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. Responses were assessed according to the Lugano 2014 criteria at 1 month, 3 months and 6 months. Subsequent assessments were per institutional pratice. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT 2019 consensus criteria. Hematological toxicity and infections were graded according to the NCI CTCAE (version 5.0). Results: Between June 2017 and May 2023, 22 patients (18 from DECAR-T centers and 4 from US centers) with R/R tWM were treated with anti-CD19 CAR T-cells (13 axi-cel and 9 tisa-cel). Median age at WM diagnosis was 58 years (range 35-72). MYD88 L265P and CXCR4 mutations were present in 85% (11/13) and 29% (2/7) of patients with available data, respectively. Patients received a median of 1 prior line of treatment (range, 0-4) for WM and 2 prior lines (range, 1-4) for HT. Eight patients had received prior ASCT (2 for WM and 6 for HT) and 1 patient allogeneic SCT. The median time from WM to HT diagnosis was 4.5 years (range, 0-32) and 26 months (range, 3-90) from HT diagnosis to CAR T infusion. Of note, CNS involvement was present in 3 patients at DLBCL relapse before CAR T-cell therapy. At time of infusion, the median age was 66 years (range, 41-82) and 8 patients (36%) were older than 70 years. Median Eastern Cooperative Oncology Group (ECOG) was 1 (range, 0-2). Bridging therapy was administered to 16 patients (73%). Following bridging therapy, 6 patients had progressive disease (PD), 4 stable disease (SD) and 6 were responders (2 complete responses (CR) and 4 partial responses (PR)). After CAR T-cell infusion, best CRR was 82% and best ORR was 95%. The ORR/CRR was 95%/77% at 1 month, 76%/71% at 3 months and 68%/68% at 6 months. Seventeen patients (78%) experienced CRS, including 2 grade 3 (all after axi-cel), and 9 ICANS occurred (41%), including 1 grade 3 and 1 grade 4 (all after axi-cel). Eight patients (36%) presented infections, including 3 grade 3 and 1 grade 4. Neutropenia was reported in 78% (grade 3-4 = 68%), thrombocytopenia in 86% (grade 3-4 = 45%) and anemia in 86% (grade 3-4 = 32%) of patients. After a median follow-up of 17 months (range, 1-47), the 1-year PFS and OS were 70% and 84% respectively (figure). Five deaths were reported, 4 due to progressive disease and 1 from SARS-CoV-2 infection. Conclusion: This study shows a high efficacy of anti-CD19 CAR T-cell therapy in R/R tWM with no unexpected toxicity. Longer follow-up is needed to confirm the long-term efficacy of CAR T-cells in tWM.

Phase II, Single-Center, Prospective Study of Intrathecal Thiotepa for the Prophylaxis of Secondary Central Nervous System Involvement in Highly Aggressive B-Cell Lymphoma

Background Central nervous system (CNS) recurrence of systemic diffuse large B cell lymphoma (DLBCL) is a well-recognized and almost uniformly fatal complication that tends to occur within 2 years of initiating treatment. The probability of CNS relapse in DLBCL ranges from 4 to 7% overall but is increased to 20% in certain subgroups. Evidence supporting the use of intravenous methotrexate (MTX) or arabinoside (AraC) in high-risk patients is growing, however, the use of other agents remains to be defined. Thiotepa (TT) is a polyfunctional alkylating agent first developed in the 1950s. Both thiotepa and its metabolite tepa demonstrate good CNS bioavailability, making thiotepa a useful adjunctive chemotherapy for primary and secondary CNS lymphoma, particularly in the context of hematopoietic stem cell transplant (HSCT). Herein, we conduct this prospective trial to evaluate the efficacy and safety of prophylactic intrathecal thiotepa for the prevention of secondary CNS involvement in patients with DLBCL. Methods Patients The primary end point is 2-year cumulative incidence of CNS. The secondary end points are 2-year progression free survival (PFS), 2-year overall survival (OS), and safety. The main inclusion criteria include: adults patients ≥18 years old; histopathological confirmed DLBCL without previous antitumor therapy; high-risk CNS involvement (one of the following): primary breast or testicular lymphoma, involvement of any of the following organs: testis, breast, kidney, adrenal gland, paranasal sinus, epidural space or uterus; CNS International Prognostic Index (CNS-IPI)≥4; dual protein expression (DE) or double/triple hit (DH/TH) lymphoma. The main exclusion criteria include: Burkitt lymphoma, primary CNS lymphoma, or large B cell lymphoma transformed from indolent lymphoma; the presence of parenchymal or meningeal lymphoma; history of whole brain radiotherapy or craniospinal cord irradiation; obstructive hydrocephalus patients requiring neurosurgical intervention. Treatment protocol The systemic chemotherapy regimen is determined by investigator. All patients are need to receive IT thiotepa 10 mg and dexamethasone 5 mg on day 1 of each cycle of chemotherapy for at least 4 cycles. All patients are asked to lie flat for 4 to 6 hours after the lumbar puncture. Follow-up Routine biochemical and cytological analysis of cerebrospinal fluid is performed for each cycle. Imaging examination, such as brain magnetic resonance imaging (MRI) and body computed tomography (CT), is repeated every 2 cycles of chemotherapy, then every 3 months during follow-up. Results From February 2022 to June, 2023, 27 patients (female 14, male 13) received IT thiotepa. The clinical characteristics are shown in Table 1. The median age was 66 years old (range: 46-74). As first-line chemotherapy, 15 (55.6%) patients received rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (RCHOP), 5 (18.5%) patients received RCHOP+BTK inhibitor, 3 (11.1%) patients received BTK inhibitor, lenalidomide with rituximab (ZR2) followed by RCHOP, and 4 (14.8%) patients received RCHOP with intravenous MTX. Thirteen (48.1%) patients had IPI score 4-6 and 17 (63%) patients had DE of c-myc and bcl-2. All patients received fluorescence in situ hybridization (FISH) cytogenetic testing for C-MYC, BCL-2, BCL-6 and TP53. Four (14.8%) patients had TP53 deletion, and 11 (40.7%) patients had sole rearrangement of C-MYC or BCL-2 or BCL-6, but no one were diagnosed with DH/TH lymphoma. All patient have received IT thiotepa for at least once, and 12 (44.4%) patients completed 4-6 cycles of IT, 84 cycles totally. IT thiotepa was a safe measure, for no one experienced post-LP headache, local infection, bleeding, or cerebral herniation. But there were 4 patients had five times of inability to identify direction and slow speech response. They could recover normally the next day without any treatment. Although the follow-up period was short, no patient developed CNS involvement. Conclusion Prophylactic intrathecal thiotepa is an effective and side-effects manageable measure for preventing secondary central nervous system involvement in high-risk DLBCL. Longer follow-up and larger-scale prospective trial is needed to testify this measure.

Characterization of Hemophagocytic Lymphohistio(HLH）in Relapsed Diffuse Large B-Cell Lymphoma Patients after CAR-T Therapy

Background: Patients with chemotherapy-refractory diffuse large B-cell lymphoma (DLBCL) have poor prognoses. The objective response rate of patients with standard salvage regimens is 26%, while CART therapy have complete remission (CR) rates of 40%- 54% against DLBCL. Half of DLBCL patients relapsed or progressed after chimeric CAR-T cell therapy, but only a few of them were accompanied by HLH. Its clinical characteristics are unclear. This study aimed to investigate the clinical characteristics of these patients. Methods: We retrospectively analyzed the clinical data of 8 patients with relapsed DLBCL lymphoma accompany by HLH after CAR-T therapy between May 2019 and July 2023(NCT02537977 and NCT04036019). We investigate the clinical characteristics of these patients, compare the survival between patients with and without CR after CAR-T therapy, compare the survival between patients with and without CRS after CAR-T therapy. Results: 8 R/R DLBCL patients were enrolled. Median age was 59.5 years (range, 37-69), and 6(75%) patients had non-germinal center B-cell-like (non-GCB) DLBCL, one had GCB DLBCL, one had transformed DLBCL. 2 patients (25.0%) had HLH before CAR-T treatment previously. Among them, 3 patients (37.5%) achieved CR after CART therapy, while 3 patients (37.5%) achieved partial remission. ALL of the patients (100%) relapsed or progressed, and all of them died because of disease progression. With a median follow-up of 7 months, the median overall survival (OS) was 206.0 days (95%CI 106.2-305.8) and progress-free survival (PFS) was 125.0 days (95%CI 40.5-210.0). Particularly，the median time from HLH to death was only 45.0 days (95%CI: 22.8-67.2). 6 patients (75.0%) occurred grade 1-2 CRS, no patient occurred ≥grade 3 CRS, and 2 patients (25.0%) did not occurred any CRS. The median OS was 328.0 days and 142.0 days (95%CI 60.4-223.6) for patients without CRS and with CRS1-2, respectively. There is significantly different in OS for patients with and without CRS ( P=0.03). The median OS was 328.0 days (95%CI 217.6-438.4) and 142.0 days (95%CI 133.4-150.6) for patients with CR and without CR, respectively. The median PFS was 257.0 days (95%CI 103.4-410.6) and 77.0 days (95%CI 8.3-145.7) for patients with CR and without CR. There is significantly different in OS and PFS for patients with CR and other patients ( P=0.01 and P=0.01). Conclusion: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life threatening disorder. The prognosis of patients with relapsed DLBCL lymphoma accompany by HLH after CAR-T therapy is very poor. Patients with CRS during CART therapy may more likely have HLH when DLBCL relapse. The patients without CRS have better survival time than those with CRS during CART therapy. We hypothesis that because both HLH and CRS is inflammatory syndrome resulting from T-cell activation.

A Personalized Whole Genome-Informed Assay Targeting Single Mutant in Circulating Tumor DNA Can Identify MRD and Predict Relapse in DLBCL

Introduction: Minimal residual disease (MRD) detected by circulating tumor DNA (ctDNA) has emerged as a promising biomarker in diffuse large B-cell lymphoma (DLBCL). MAESTRO (minor-allele-enriched sequencing through recognition oligonucleotides) was recently developed to aid the detection of low-frequency mutations by enriching for mutant alleles using probes preferentially capturing single-nucleotide variants. We have extended this application - termed MAESTRO-Pool - to analyze personalized MRD variant detection within a cohort-level single assay. We demonstrate high sensitivity to detect MRD using MAESTRO-Pool and the detection of emergent mutations using targeted sequencing of the same samples. Methods: Fifty-nine plasma specimens from 9 patients with relapsed/refractory (R/R) DLBCL treated on a phase II trial (NCT02362997) of post-autologous stem cell transplant (ASCT) pembrolizumab maintenance were tested. Cases were selected based on the availability of genomic DNA from tumor tissue, patient-matched germline DNA, and serial post-ASCT plasma samples (≥ 3 time points). MAESTRO probes were designed to target patient tumor-specific somatic variants using results of baseline tumor-normal whole genome sequencing. Probes were then pooled into an integrated, cohort-level assay (MAESTRO-Pool). Serial samples were compared with an orthogonal, whole-genome, tumor-informed MRD test which does not use mutation enrichment (MRD Tracker; Parsons, HA et al. Clin Cancer Res26, 2556-2564 (2020)) for sensitivity and specificity of variant detection. In addition, sensitivity to detect MRD and predict relapse was compared to that observed with immunoglobulin locus high-throughput sequencing (IgHTS). Additional baits were designed to capture single nucleotide variants (SNVs) previously reported in R/R DLBCL (63 loci in 12 genes), enabling detection of treatment-emergent mutations not identified in baseline tumor specimens. Results: Tumor-normal WGS revealed a median of 433 somatic SNVs per tumor (range 81-1653). The pooled assay comprised 6044 SNV-specific probes. MRD identification was similar for MAESTRO-Pool and MRD Tracker. Among 59 samples, a discrepant MRD call was observed for a single sample where ctDNA was detected at 4 ppm using MRD Tracker, but not detected using MAESTRO-Pool (limit of detection [LoD] 16 ppm). Estimated tumor fractions using MRD Tracker and MAESTRO-Pool were concordant. Even with reduced sequencing requirements of MAESTRO-Pool, we observed a similar median limit of detection (LoD) for MAESTRO-Pool (median 30 ppm, range 1-18,243) and MRD Tracker (median 40 ppm, range 1-4,727 ppm). MAESTRO-Pool identified ctDNA prior to recurrence for all 5 patients who relapsed, including at the earliest available post-ASCT timepoint for 4 of 5 relapsing patients. The time from ctDNA detection to clinical relapse (lead time) was the same or longer for each patient using MAESTRO-Pool (median 178 days, range 69-518) compared to IgHTS (median 44 days, range not detected to 518 days) (p=0.37) (Fig.1a). MAESTRO-POOL was associated with improved sensitivity compared to IgHTS (MAESTRO-Pool sensitivity of 90.5% for samples with matched IgHTS results versus IgHTS sensitivity of 61.9%, p=0.006). Superior sensitivity was primarily driven by MAESTRO-Pool's improved detection of low-frequency (<1000 ppm) mutant alleles. In addition to tracking molecular tumor burden, we identified several de novo mutations in relapsing patients using targeted sequencing of the same samples. Notably, plasma from a patient who progressed at 18.5 months post-ASCT (DL-015) manifested an emergent CREBBP R1446H mutation not detected in the baseline tumor whose allele frequency steadily increased from 0.048% one week after ASCT to 30.533% at relapse (Fig 1b). Conclusion: In this pilot study, MAESTRO-Pool enabled ultrasensitive detection and quantification of MRD with superior sensitivity compared to IgHTS. Complementary targeted sequencing also characterized genetic evolution, including detection of treatment-emergent mutations. Our results support the incorporation of ctDNA testing using MAESTRO-Pool in future prospective trials in DLBCL.

Efficacy and Safety of Zanubrutinib-Containing Regimens in Patients with Secondary CNS Relapse in Diffuse Large B-Cell Lymphoma

Background: In the era of immune-targeted therapy represented by rituximab, despite improved remission and survival rates in patients with diffuse large B-cell lymphoma (DLBCL), central nervous system (CNS) relapse, occurring in some DLBCL patients after achieving remission, remains a clinical challenge. Zanubrutinib is one of a new generation of BTK inhibitors that have higher blood-brain barrier permeability compared to other BTK inhibitors. Research Design and Methods: We performed a multicenter retrospective study to evaluate the efficacy and safety of Zanubrutinib-containing regimens for salvage treatment in 28 relapsed DLBCL patients with CNS involvement treated in 6 centers from January 2020 to December 2021. Results: The IPI score and CNS-IPI score did not have good enough predictive significance for lack of consistency of the median time from the initial diagnosis to CNS recurrence. Of the 28 patients, 16 had targeted next-generation sequencing (NGS) data. NGS test was performed on their tissue samples that were obtained at initial diagnosis and/or at the timepoint of CNS relapse in DLBCL. 8 at the time of initial diagnosis and 10 at the time of recurrence, with 2 of them having undergone NGS sequencing at both initial diagnosis and recurrence. Median study follow-up from CNS relapse was 8.55 months, all patients were evaluated for response with 20/28 (71.4 %) showing a response: 11 CR, 9 PR, and 4 SD, 4 PD. The median PFS is 6.6 months, and the median OS has not yet been reached. Notably, MYD88, CD79B, or TP53 mutations tested at diagnosis in these patients were associated with significantly more favorable treatment response, while patients with a dual rearrangement of MYC and BCL2 and/or BCL6 genes did not get a treatment response to Zanubrutinib-containing regimens. It has well-tolerated toxicity with few adverse events requiring treatment discontinuation or dose reduction. Conclusion: Zanubrutinib-containing regimens extended PFS and OS in relapsed DLBCL patients with CNS involvement.

Differences in Characteristics and Outcomes of Central Nervous System Versus Systemic Relapse after First Line Therapy in DLBCL Patients: A Veterans Health Administration (VHA) Study

Introduction Around 30%-40% of patients with diffuse large B-cell lymphoma (DLBCL) will experience disease progression or relapse after first line (1L) chemoimmunotherapy with most patients relapsing within the first 12 months. Relapse may be systemic, isolated to the central nervous system (CNS), or both with CNS relapse occurring in 2-5% of patients. The purpose of this study is to evaluate the characteristics and outcome differences of Veterans diagnosed with DLBCL within the VHA who experienced systemic relapse, isolated CNS relapse or both. Methods A retrospective chart review of 6,266 lymphoma patients seen in the VHA nationwide between 01/01/2011 and 12/31/2021 was performed by trained abstractors. Patients diagnosed with DLBCL were included. Patients were excluded if they had a diagnosis other than DLBCL, had incomplete records or were diagnosed and treated outside the VHA, had baseline CNS involvement, did not receive treatment, or died before receiving a scan to assess response to 1L therapy. Outcomes including response to 1L treatment, time to relapse and overall survival (OS) defined as time from diagnosis to death were evaluated. Early relapse was defined as having primary refractory disease (stable or progressive disease (SD or PD) as best response to 1L therapy) or disease progression in ≤12 months in patients achieving a complete response (CR) or partial response (PR). Late relapse was defined as disease progression >12 months. Results A total of 2,658 patients met inclusion criteria for analysis with 97% of the population being male, 65% with stage III-IV disease, and 90% with an ECOG performance status of 0-2. Of the total cohort, 74% of patients received a CHOP-based regimen, 74% had an intermediate- or high-risk CNS International Prognostic Index (CNS-IPI) score, 81% did not receive a baseline diagnostic lumbar puncture (LP) and 86% did not receive any CNS prophylaxis. The median follow-up time for subjects in this study was 54 months. Relapse occurred in 29% of the total cohort with systemic only relapse occurring in 27% of patients, isolated CNS in 1%, and CNS + systemic in 1%. Of the 761 patients who experienced relapse, 77% had an early relapse with a median time to relapse of 4.4 months (IQR 2.8-6.7). For the 23% of patients with late relapse, the median time to relapse was 25 months (IQR 18-41). The characteristics of patients who experienced relapse were similar regardless of type of relapse or time to relapse (table 1). A higher percentage of patients with early relapse had a high-risk CNS-IPI score, bone marrow involvement, and renal or adrenal involvement. Autologous stem cell transplant was performed in 11% of patients, predominately in those with systemic only relapse. The median OS (mOS) was similar between relapse types with systemic, isolated CNS, and CNS + systemic having a mOS of 23.5 months (95% CI: 21-27), 30.6 months (95% CI: 15-71), and 29.6 months (95% CI: 20-45), respectively (p=0.75). Figure 1 describes mOS by relapse type and time to relapse. Overall, patients with early relapse had a poorer prognosis regardless of relapse type with a mOS of 17 months (95% CI: 15-18) compared to a mOS of 68 months (95% CI: 59-88) in patients with late relapse (p<0.001). The 24-month survival rate of those with early versus late relapse was 37% and 78%, respectively. Patients with a late systemic relapse had the longest mOS of 74 months (95% CI: 60-90). Conclusion This is the largest study reporting outcomes of Veterans who experienced relapsed DLBCL within the VHA. Although earlier data suggests specific features may correlate with early versus late relapse, all characteristics were similar in our population across relapse types regardless of time to relapse. The rate of relapse in the total cohort and the rates of CNS relapse were lower than previously reported, adding to recent data suggesting the use of CNS prophylaxis may have limited benefit. Patients with early relapse performed poorly and may benefit from novel therapies including chimeric antigen receptor T-cell therapy, which could not be evaluated with this study. The retrospective nature of this analysis, and a predominately male veteran population may limit external application.

A Multicenter, Open-Label, Phase 1b/2 Study to Evaluate the Effects of Maplirpacept in Combination with Tafasitamab and Lenalidomide in People with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Background Maplirpacept (PF-07901801) is an anti-CD47 molecule designed to enhance phagocytosis and antitumor activity by preventing CD47-mediated inhibitory signaling. Maplirpacept currently is being evaluated in an ongoing, multi-center, two-part, Phase 1a/1b study in participants with advanced hematologic malignancies (NCT03530683). Early safety and efficacy results for maplirpacept monotherapy have previously been reported in patients with refractory or relapsed lymphomas (Patel et al. Blood 2021;138:3560). Study Design This trial is a multicenter, open-label, Phase 1b/2 study (NCT05626322), to evaluate the effects of maplirpacept, in combination with tafasitamab and lenalidomide in participants with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The estimated enrollment is 70 patients, and the study will be split into two parts (Figure 1). Phase 1b will determine the maximum tolerated dose or recommended Phase 2 dose (2 dose levels) of maplirpacept, in combination with approved doses of tafasitamab and lenalidomide. In Phase 2, participants will be randomized to high or low doses of maplirpacept, in combination with approved doses of tafasitamab and lenalidomide, as per the Oncology Center of Excellence ‘Project Optimus’ initiative for dose optimization and selection in oncology drug development. Study interventions will be administered in 28-day cycles. Maplirpacept will be given weekly, by intravenous (IV) infusion, for the first three cycles and subsequently every two weeks. Tafasitamab will be administered, by IV infusion, on Days 1, 4, 8, 15 and 22 in cycle 1, weekly in cycles 2 and 3, then every 2 weeks in cycle 4 and beyond. Lenalidomide will be taken orally, daily for Days 1 to 21 of each 28-day cycle, for the first 12 cycles. In Phase 1b, approximately 20 participants will be allocated to sequential doses of maplirpacept, co-administered with approved doses of tafasitamab and lenalidomide, to select doses for further assessment in Phase 2. The primary endpoint for Phase 1b is to assess dose limiting toxicities up to 28 days following the first dose. In Phase 2, approximately 50 participants will be randomized to 1 of 2 different doses of maplirpacept, co-administered with tafasitamab and lenalidomide. The primary endpoint for Phase 2 is objective response as per the Lugano Response Classification Criteria 2014. Secondary endpoints are frequency of adverse events, frequency of clinical laboratory abnormalities, objective response (Phase 1b only), complete response, duration of response, duration of complete response, progression free survival, maplirpacept, tafasitamab and lenalidomide PKs, and immunogenicity of maplirpacept and tafasitamab. Inclusion criteria (Table 1) are adults with histologically confirmed, measurable relapsed and/or refractory DLBCL not otherwise specified, T cell/histiocyte rich large B-cell lymphoma, or Epstein-Barr virus positive DLBCL according to the 5th edition of the WHO classification of lymphoid neoplasms. Additionally, participants with follicular lymphoma grade 3b, or composite lymphoma with a DLBCL component with a subsequent DLBCL relapse are also eligible. Participants with evidence of histological transformation to DLBCL from an earlier diagnosis of low-grade lymphoma are eligible if relapsed or refractory to at least one line of therapy for DLBCL. Further inclusion criteria are participants who are not a candidates for, or are unwilling to receive, high-dose chemotherapy and subsequent stem cell transplant and/or are unable to undergo chimeric antigen receptor T-cell (CAR-T) therapy (e.g. due to logistical limitations), treatment with at ≥1 prior line of systemic therapy (for Phase 2, at least 1, and no more than 2, prior lines of systemic therapy) and prior therapy must include an anti-CD20 antibody. Participants must have adequate bone marrow, renal and hepatic function and an Eastern Cooperative Oncology Group performance status ≤2. Participants must provide a baseline tumor tissue sample (fresh or archival), for biomarker analysis. Exclusion criteria include previous treatment with anti-CD47, anti-CD19 (other than CAR-T) or immunomodulatory agents, prior allogeneic stem cell transplantation or autologous stem cell transplantation within 12 weeks prior to enrolment, and participants with active, uncontrolled viral, bacterial or fungal infections.

Prognosis of Patients with Diffuse Large B Cell Lymphoma with Central Nervous System Relapse: USC Experience

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma and a potentially curable disease with systemic immunochemotherapy regimens. Involvement of the central nervous system (CNS) in patients with DLBCL is a relatively rare event which occurs in approximately 2-5% of patients overall, but the CNS relapse rate can be as high as 10-12% in high-risk patients. Unfortunately, CNS relapse confers poor prognosis with some studies estimating median survival of 2.5 months from relapse. Our study evaluates prognostic factors and outcomes in this patient population. Methods: This study is a retrospective review of patients diagnosed with DLBCL who then developed CNS relapse and were treated at Los Angeles General Medical Center (LAGMC) and Norris Comprehensive Cancer Center (NCCC) from 2016-2023. Information regarding patient demographics, prognostic factors to calculate NCCN-IPI scores, pathologic characterization, therapy, clinical course, and survival were collected. CNS relapse was defined as pathologic or imaging diagnosis of CNS involvement after initial treatment was received. Results: A total of 29 patients with CNS relapse of DLBCL were identified with a median age of 60 (range 43-86). The median time from initial diagnosis to CNS relapse was 9 months. The patients were 72.4% male (N=21), 79.3% Hispanic (N=23), and 17.2% (N=5) HIV positive. NCCN-IPI scores were calculated for all patients and divided into NCCN-IPI risk groups. The low-risk group (NCCN-IPI 0-1) made up 10.3% (N=3), low-intermediate risk group (NCCN-IPI 2-3) 48.3% (N=14), high-intermediate risk group (NCCN-IPI 4-5) 34.5% (N=10), and high-risk group (6-8) 6.90% (N=2). Pathologic analysis revealed 41.4% (N=12) of patients had germinal center type lymphoma, 44.8% (N=13) were BCL-2/c-myc double expressors, 13.8% (N=4) were BCL-2/c-myc double hit, and 13.8% (N=4) were BCL-6/c-myc double hit (Table 1). Overall survival (OS) for the entire cohort was 18.5% at five years after CNS relapse of DLBCL with a median survival of 12 months. Patients with a low or low-intermediate NCCN-IPI score (0-3) had an OS of 57.4% at 12 months and 29.1% at five years. Patients with a high-intermediate or high NCCN-IPI score had an OS of 35.7% at 12 months and 0% by 33 months. OS at 12 months for the HIV negative group was 70.4% compared to 40.0% in the HIV positive group, but OS at 5 years was similar in both groups at 19.4% and 20.0%, respectively (Figure 1). Conclusions: CNS relapse in patients with DLBCL is a rare but devastating complication. In our largely male and Hispanic patient population, prognosis at five years was very poor for those with CNS relapse, but higher NCCN-IPI scores demonstrated a trend that conferred a higher likelihood of death at both the one year and five year time points compared to those with lower scores. Survival after CNS relapse in our cohort is longer compared to prior studies, indicating possible improvements in the prognosis of patients with CNS relapse of DLBCL. Given the overall poor prognosis of CNS relapse of DLBCL, improved prognostic stratification is of the utmost importance in this highly curable disease.