Center Diffuse Large B-cell Lymphoma Research Articles

A first-in-human study of the potent and highly selective BTK degrader ABBV-101 in patients with relapsed/refractory B-cell malignancies.

TPS7091 Background: Bruton tyrosine kinase (BTK) is a clinically validated target with an integral role in the proliferation and survival of neoplastic cells in several B-cell malignancies. Inhibitors of BTK, such as ibrutinib, have revolutionized the treatment landscape for B-cell malignancies. However, long-term use can lead to disease progression and clinical resistance associated with mutations in BTK. ABBV-101 is a reversible BTK degrader. By preclinical kinome profiling, ABBV-101 has demonstrated high selectivity with the potential for best-in-class AE profile. ABBV-101 has also shown potent activity against BTK wildtype and multiple therapy-resistant mutant forms. Degradation eliminates BTK scaffolding and enzymatic functions, which has led to deeper, more durable responses vs covalent and reversible BTKi in animal models (Pan C, et al. ASH 2023). Herein, we describe the first-in-human study of ABBV-101 monotherapy in patients with relapsed/refractory B-cell NHL. Methods: This international phase 1, open-label, multicenter study (NCT05753501) is evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of ABBV-101. Eligible patients(≥18 years) have measurable disease, received ≥2 prior systemic therapies, and have no available therapies known to provide clinical benefit.Primary objectives are to characterize safety and tolerability of ABBV-101; secondary objectives are to evaluate PK and preliminary efficacy. The study is conducted in 2 parts: dose escalation (part 1) and dose expansion (part 2). Part 1 aims to establish the maximum administered dose and maximum tolerated dose of ABBV-101 guided by a Bayesian optimal interval design; additional patients may be enrolled to a previous dose level to further explore safety, PK, and efficacy. Patients with WHO-defined chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma (including Waldenström macroglobulinemia), and transformed indolent NHL (including Richter’s transformation) are eligible. Part 2 will further characterize the safety and preliminary efficacy of ABBV-101; patients diagnosed with CLL/SLL (up to 3 dose cohorts) and non-germinal center DLBCL (1 cohort) are being enrolled. ABBV-101 is administered orally until disease progression, intolerable toxicity, or other study discontinuation criteria are met. Safety assessments include, but are not limited to, AEs, clinical laboratory parameters, vital signs, and ECG. Response evaluations are performed per disease-specific response criteria at screening and every 8 weeks (1st year), 3 months (2nd year), or 4 months (3rd year onward) until progressive disease. Enrollment is ongoing with active sites in the US and Japan. Clinical trial information: NCT05753501 .

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

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

Joint Analyses of Serum Proteins and Circulating Tumor DNA Improves Risk Assessment and Subtype Stratification in Large B-Cell Lymphomas

Introduction Inadequate dismantling of clinical and biological heterogeneity is an obstacle for improving outcome in large B-cell lymphoma (LBCL). Circulating tumor DNA (ctDNA)-based stratification holds great potential in resolving these challenges. However, the assessment is limited to genetic content, and excludes host response from the estimates. Previously, we have shown that an inflammatory signature identified from the pretreatment serum proteins translates to poor survival, and multiple serum proteins correlate with LBCL genetic subtypes. To further improve risk stratification and molecular characterization of LBCL from the liquid biopsy, we co-analyzed serum protein and ctDNA levels in LBCL patients treated in two Nordic Lymphoma Group (NLG) trials. Materials and methods Our discovery cohort consisted of 122 patients less than 65 years of age with clinically high-risk (age adjusted IPI ≥ 2) LBCL, who were treated in NLG-LBC-06 trial with immunochemotherapy. Plasma and serum samples were collected prior to treatment. Cell free DNA was extracted from plasma and sequenced with in-house adapted duplex sequencing platform using custom targeted panel of 347 lymphoma driver genes and immunoglobulin loci. An inflammation score was composed as log transformed mean of the most pertinent inflammatory serum proteins detected in the inflammatory signature (IL10, IL2RA, CXCL9, IL18, GZMB, PD-L1 and IFNG), and their levels were measured using antibody-based Luminex assay (pg/ml, R&D Systems). In addition, CCL17 and TNFRSF13B levels were analyzed to uncover their associations with genetic subtypes. An independent cohort of 91 patients treated in our previous NLG-LBC-05 trial was used for validation. Results Combined analysis of serum proteins and ctDNA identified a group of patients (n=12, 10%) with high serum inflammation scores and ctDNA burden (≥ 3.75 hGE/ml), which translated to poor survival compared to the patients with low concentrations of either inflammatory proteins or ctDNA, or both (progression free survival, PFS, hazard ratio 7.33, 95%-CI 2.59-20.79, P < 0.001, Figure 1A). This finding was confirmed in the independent validation cohort. In both cohorts, the combined analysis showed higher specificity in survival prediction as compared to the ctDNA-based assessment alone, indicating that inflammatory serum markers alongside with ctDNA can identify those patients who, despite of having high ctDNA burden, have excellent survival. Beyond inflammation, the levels of serum TNFRSF13B and CCL17 correlated with mutations associating with non-germinal center diffuse large B-cell lymphoma (non-GCB DLBCL)/MCD subtype and primary mediastinal B-cell lymphoma/grey-zone lymphoma (PMBCL/GZL), respectively. For example, serum TNFRSF13B levels correlated positively with mutations in MCD genes, such as CD79B, SETD1B, PIM2 and PRDM1, and negatively with mutations in EZB genes EZH2 and CREBBP in both cohorts (P < 0.05, Figure 1B). Supporting our earlier findings, high CCL17 levels revealed a group of patients diagnosed with DLBCL not otherwise specified or high-grade lymphoma but with a mutational landscape resembling PMBCL/GZL, including mutations in TNFAIP3, ITPKB, B2M, BTG1 and STAT6 (P < 0.05). Conclusion Our findings demonstrate that co-analysis of inflammatory serum markers along with the ctDNA improves ctDNA-based survival prediction. Moreover, analysis of serum proteins refines molecular classification. Altogether, joint analysis of serum proteins and ctDNA provides new tools to dismantle LBCL heterogeneity.

Circulating tumour DNA concentration and genetic classification improve risk stratification in newly diagnosed patients with Diffuse Large B‐Cell Lymphoma

Introduction: Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease with poor outcomes for the 40% of patients who relapse or are refractory to upfront therapy, and current prognostic tools are unable to identify many of those patients. Recently, novel prognostic biomarkers like genetic classification and circulating tumor DNA (ctDNA) have been developed. Here we explore the value these biomarkers to improve prognostic stratification in DLBCL. Methods: DNA was extracted from 2 to 5 ml of plasma and formalin-fixed paraffin-embedded (FFPE) tumor tissue obtained at diagnosis from patients with DLBCL treated with R-CHOP-like regimes. Samples were sequenced in an Illumia NovaSeq using a panel of 112 genes that are recurrently mutated in lymphoid neoplasms, and variants were called using a pipeline that follows GATK best practices. Genetic subtype (GS) was determined using LymphGen tool, excluding A53, as copy number variation data was unavailable. ST2, EZB MYC negative and BN2 subtypes were considered favorable, while N1, MCD, EZB MYC positive and other were considered unfavorable. ctDNA levels were reported as haploid genome equivalents per mL of plasma and expressed as a base 10 logarithm (log hGE/mL) Results: We included 46 patients with median age of 64.8 years, 58% advanced stage (III-IV) and 65% germinal center DLBCL by Hans’s algorithm. Somatic mutations were detected in FFPE in all patients and in ctDNA in 40 (87%) patients. Most frequently mutated genes were KMT2D, CREBBP, TP53, ARID1A, MYD88 and CARD11. The sensitivity of ctDNA to detect mutations present in paired FFPE samples was 66% (for all variants) and 74.5% (for variants with >5% allelic frequency in FFPE samples). 67.4% of patients were successfully classified by LymphGen, with a concordance between ctDNA and FFPE of 84.7%. Patients without detectable ctDNA presented localized disease (Ann Arbor stage I) and low DNA concentration in plasma (<15 ng/ml). In our cohort, 24 patients presented a poor R-IPI score with a 3-year progression-free survival (PFS) of 61.5% (Figure 1A). These patients were further stratified by ctDNA levels and GS, and those unfavorable GS or ctDNA concentration >4 log hGE/ml presented worse PFS and OS than without risk factors a 3-year PFS of 34.6% and 90.9%, respectively (Figure 1B). Patients were classified into three groups according IPI score modified by ctDNA levels (Figure 1C), with a 3-year PFS of 94.7%, 81.2% and 18.8%, and a 3-year overall survival (OS) of 100%, 87.5% and 37.5%, respectively (Figure 1D–E). Keywords: Diagnostic and Prognostic Biomarkers, Genomics, Epigenomics, and Other -Omics No conflicts of interests pertinent to the abstract.

High density of FOXP3 predicts better prognosis in germinal and non-germinal centre diffuse large B-cell lymphoma.

This study highlights the prognostic impact of FOXP3 and CD68 expression in DLBCL, NOS and in its GCB and non-GCB subtypes. This may help the development of individualized therapy, prognostic prediction and therapy stratification.

Hypercalcemia of malignancy with simultaneous production of parathyroid hormone-related peptide and 1,25-Dihydroxyvitamin D by non-Hodgkin lymphoma: Case report &amp; brief review

We report the case of a 63-year-old man with severe hypercalcemia, acute kidney injury, and concomitant diagnosis of germinal center diffuse large B-cell lymphoma (nHL). Hypercalcemia is a common finding in patients with cancer. Multiple mechanisms can lead to hypercalcemia of malignancy, and different malignancies are often associated with a specific mechanism of hypercalcemia. Parathyroid hormone-related protein (PTHrP) and excessive production of 1,25-dihydroxyvitamin D can independently (and rarely, concomitantly) lead to development of hypercalcemia in patients with a variety of malignancies. Literature review of hypercalcemia related with PTHrP and 1,25-dihydroxyvitamin D co-secretion shows that most reported cases are associated with solid tumors and responded to tumor directed therapy. Our case of nHL was associated with increased PTHrP and 1,25-dihydroxyvitamin D making this an unusual presentation.

Investigations of Redox Resistance in Aggressive Lymphomas with Cholesterol Modulating Lipid Nanoparticles

Introduction: High grade B cell lymphoma (HGBCL), characterized by C-MYC and BCL-2 rearrangements, are particularly aggressive with poor response to standard therapy and decreased overall survival (OS). We previously demonstrated that B-cell lymphomas, such as germinal center (GC) diffuse large B-cell lymphomas (DLBCL), are addicted to cholesterol uptake and that bioinspired gold core lipid nanoparticles (Au-LNPs) antagonize lipid uptake through the cell surface receptor called scavenger receptor type B-1 (SR-B1) and lead to cholesterol depletion in several lymphoma cell lines (Rink et al JBC 2020). Au-LNP treatment leads to lymphoma cell death by ferroptosis, through reduction of glutathione peroxidase (GPX4) and subsequent accumulation of oxidized lipids. The antioxidant Nrf2 pathway is known to resist oxidative stress and high levels of Nrf2 proteins predict poor response to chemotherapy in hematologic malignancies. We therefore hypothesized that 1) HGBCLs would be more resistant to Au-LNP and 2) antioxidant pathways might mediate that resistance. Methods: The GC DLBCL cell line (SUDHL-4) cells and HGBCL cell lines (RC, OCI-ly1, OCI-ly8 and OCI-ly18) were used. Cells were treated with PBS (control) or Au-LNPs for 72h. Au-LNPs were synthesized as previously described (Rink JBC 2022). Cell viability was measured by MTS assay. Total RNA in RC and SUDHL-4 cells were extracted and used to construct cDNA libraries for RNA sequencing (RNAseq) by HiSeq 4000 with single-end 50bp reads and 20-25 million reads per sample in the NUSeq Core of Northwestern University. Metascape was used for functional analysis of identified differentially expressed genes (DEGs) and DEGs related to Nrf2 survival signaling, NQO1, FTH1, FTL, G6PD, TXNRD, NFE2L2, TXN, P4HB, and MGAT3 were confirmed in control and Au-LNP treated SUDHL-4, RC, OCI-ly1, OCI-ly8 and OCI-ly18 cells by RT-qPCR and Western blot analysis. Results: HGBCL cells (RC, OCI-ly1, OCI-ly8 and OCI-ly18) were more resistant to treatment with Au-LNPs (IC50 = 31.42 nM, 27.22 nM, 58.24 nM, 26.06 nM, respectively) compared with SUDHL-4 (IC50 8.14 nM). RNAseq analysis identified 320 upregulated and 162 downregulated genes in SUDHL-4 cells and 346 upregulated and 182 downregulated genes in RC cells after treatment with Au-LNPs. Of these DEGs, 62 upregulated and 8 downregulated DEGs appeared in both cell lines after treatment. The top 5 upregulated common genes include ABHD4, DUSP5, JUN, RGS1 and SQSTM1. The top 5 downregulated common genes include ABCG1, DDN, GPX1, GPX4 and IKZF1. There were 284 upregulated and 174 downregulated DEGs only identified in Au-LNP treated RC cells. Among 284 upregulated DEGs the top 2 enriched clusters were Nrf2 survival signaling and nuclear receptors meta-pathways. Au-LNP treatment in RC cells showed log2 fold increase of NQO1 (4.6), FTH1 (1.28), FTL (2.1), and TXNRD1 (1.78), genes in the Nrf2 survival signaling pathway. In SUDHL-4 cells, only NQO1 and FTL1 showed significant differential expression with log2 fold increase of 0.7 and 0.45 after Au-LNP treatment. To confirm RNAseq results, we measured the expression of Nrf2 survival signaling genes, NQO1, FTH1, FTL, G6PD, TXNRD, NFE2L2, TXN, P4HB, and MGAT3 with or without Au-LNP in SUDHL4, RC, OCI-ly1, OCI-ly8, and OCI-ly18 cells by RT-qPCR. In SUDHL4 cells, compared with PBS control, Au-LNP treatment led to mild increase in expression of NQO1 (4.2 ± 0.6 fold). By contrast, in HGBCL cells, Au-LNPs increased NQO1 expression 19.9 ± 0.2 fold for RC cells, 9.0 ± 0.3 fold for OCI-ly1 cells and 36.5 ± 2.3 fold for OCI-ly8 cells compared with PBS control. Higher NQO1 and FTH1 protein expression in treated RC cells was also confirmed by western blot analysis. These data suggest that 1) HGBCL cell lines RC, OCI-ly1, OCI-ly8 and OCI-ly18 are more resistant to cell death by cholesterol depletion and that 2) this phenomenon is mediated by upregulation of genes in the Nrf2 pathway and NQO1, in particular. Conclusion: The redox related Nrf2 survival signaling pathway, especially the NQO1 gene, is upregulated after treatment with Au-LNPs. This was observed to a greater extent in the more resistant HGBCL cells (RC, OCI-ly1, OCI-ly8 and OCI-ly18) than the SUDHL4 cells. Strategies to target the Nrf2 pathway may reverse resistance to cholesterol depletion in lymphoma.

Primary thyroid lymphoma (PTL): a rare case report and review of the literature

Primary thyroid lymphoma (PTL) is a rare malignancy of the thyroid, accounting for 5% of all thyroid malignancies and approximately 2% of extranodal lymphomas. PTL occurs mainly in elderly females and diffuse large B-cell lymphoma (DLBCL) is most common. Here we report a case of non-germinal center diffuse large B-cell lymphoma (non-GC DLBCL) occurring in a 62-year-old female who was admitted to the hospital because of multiple palpable left neck masses. The patient then underwent thyroid ultrasound, detecting multiple nodules in the two lobes and isthmus of the thyroid gland, in which the largest nodule was in the left lobe with TIRADS 5 measuring 47x33 mm, and many cervical lymph nodes. Microscopically, thyroid tissue showed proliferation of tumor cells with large nuclei, coarse chromatin, narrow rims of cytoplasm, and scattered mitoses. There was 01 destructured lymph node, proliferating cells with characteristics similar to those in the thyroid gland; the remaining lymph nodes were chronically inflamed. Immunohistochemically, the tumor cells were positive for CD20, CD79a, Ki67 (40%), and negative for CD10, BCL6, MUM1, CD5, BCL2, c-MYC, CD15, CD30, EBV. Primary thyroid lymphomas are rare with the prognosis of patients depending on the histological classification of the tumor and the stage of the disease. They need to be evaluated and treated individually because there is no unified treatment due to their rarity.

An orally available small molecule BCL6 inhibitor effectively suppresses diffuse large B cell lymphoma cells growth in vitro and in vivo.

The transcription factor B cell lymphoma 6 (BCL6) is an oncogenic driver of diffuse large B cell lymphoma (DLBCL) and mediates lymphomagenesis through transcriptional repression of its target genes by recruiting corepressors to its N-terminal broad-complex/tramtrack/bric-a-brac (BTB) domain. Blocking the protein-protein interactions of BCL6 and its corepressors has been proposed as an effective approach for the treatment of DLBCL. However, BCL6 inhibitors with excellent drug-like properties are rare. Hence, the development of BCL6 inhibitors is worth pursuing. We screened our internal chemical library by luciferase reporter assay and Homogenous Time Resolved Fluorescence (HTRF) assay and a small molecule compound named WK500B was identified. WK500B engaged BCL6 inside cells, blocked BCL6 repression complexes, reactivated BCL6 target genes, killed DLBCL cells and caused apoptosis as well as cell cycle arrest. In animal models, WK500B inhibited germinal center (GC) formation and DLBCL tumour growth without toxic and side effects. Moreover, WK500B displayed strong efficacy and favourable pharmacokinetics and presented superior druggability. Therefore, WK500B is a promising candidate that could be developed as an effective orally available therapeutic agent for DLBCL.

Prognostic Value of Baseline PET/CT Imaging in Diffuse Large B-Cell Lymphoma: Does the Largest Distance between Two Lesions Play a Role in Prognosis?

Background: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) has become the international standard for diffuse large B-cell lymphoma (DLBCL) staging and is widely used for response assessment. In the past few years, the prognostic value of a variety of imaging-derived quantitative parameters has been investigated. One of these parameters is the distance between the 2 lesions that are farthest apart (Dmax). Dmax is a simple feature that captures lymphoma dissemination and has been reported to be a strong prognosticator of shorter progression-free survival (PFS) and overall survival (OS) in DLBCL patients (pts).Methods: Retrospective analysis of 146 pts with newly diagnosed Ann Arbor stage III-IV DLBCL, NOS, treated with R-CHOP(-like) regimens, between January 2010 and December 2019 in a tertiary center. Dmax was normalized with the body surface area [standardized Dmax (SDmax)]. The receiver operating characteristic curve (ROC) method was applied in resetting the optimal cut-off point for predicting prognosis and treatment outcome. The Kaplan-Meier method was used to describe time-to-event end points. A p-value of 0,05 was used as cut-off for significance.Results: Dmax was available for 40 pts. The median age at diagnosis was 63 years (24-78); 58% of pts were male. Most pts (69%) presented lactate dehydrogenase (LDH) above the upper limit of normal (ULN); 40% presented lymphopenia (lymphocyte count below 1000/μL), and 26% had albumin levels below 3.2 g/dL. Bone marrow (BM) infiltration occurred in 41% of pts, and 5% had central nervous system (CNS) involvement at diagnosis. According to the international prognostic index (IPI), 74% of pts were high-intermediate (HI) and high (H) risk; according to National Comprehensive Cancer Network (NCCN)-IPI, 68% of pts were HI and H risk. According to the cell of origin (COO) 63% of pts presented non-germinal center DLBCL. A complete metabolic response (CMR) on interim PET/CT was observed in 65% of pts, and 71% presented a CMR on end-of-treatment (EOT) PET/CT. At EOT the overall response rate was 80%. Seven percent of pts presented CNS relapse. The 5-year PFS was 58.5% and the 5-year overall survival (OS) was 69.4%.Higher SDmax was significantly associated with BM and CNS involvement at diagnosis (p=0.034 and p=0.049, respectively), as well as with CNS relapse (p=0.048). No statistically significant association was found between SDmax and the following features: lymphocyte count of < 1000/μL (p=0.505), albumin levels < 3.2 g/dL (p=0.140), LDH > ULN (p=0.501), IPI risk ≥ HI risk (p=0.719), NCCN-IPI ≥ HI risk (p=0.239) and COO (p=0.493).There was a tendency, although not significant, towards a lower rate of CMR on interim and EOT PET/CT in pts with higher SDmax (p=0.072 and p=0.077, respectively). A higher SDmax had no statistically significant impact on either PFS (HR 0.456; p=0.500) or OS (HR 0.339; p=0.561).The combination of NCCN-IPI and SDmax allowed to identify a subgroup of pts with low (L) risk and low-intermediate (LI) risk NCCN-IPI and higher (≥ 4.1cm) SDmax with inferior 5-year OS (87.5% vs 50%; HR 4.64; p=0.031) and with a trend towards an inferior 5-year PFS (75% vs 50%; HR 1.92; p=0.166).Conclusions: In our cohort, a higher SDmax was associated with some high-risk features, as well as with a trend towards an inferior response to treatment. Additionally, the combination of SDmax and NCCN-IPI allowed to identify a subgroup of L risk and LI risk pts with inferior OS and a trend towards an inferior PFS. Interpretation of these results may be limited by the small sample size. The role of Dmax in DLBCL prognostication may therefore require further validation before widespread clinical use. DisclosuresGomes: Takeda: Consultancy; Gilead: Consultancy; Janssen: Consultancy.

Zanubrutinib monotherapy for relapsed or refractory non-germinal center diffuse large B-cell lymphoma

AbstractThe non-germinal center B-cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) has poor clinical outcomes. Bruton tyrosine kinase (BTK) inhibitors have established therapeutic activity in B-cell malignancies, with modest activity in DLBCL. Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in patients with relapsed or refractory (R/R) non-GCB DLBCL. The BGB-3111-207 study (NCT03145064) was a multicenter single-arm phase 2 study. Patients received twice-daily oral zanubrutinib, 160 mg, until disease progression or unacceptable toxicity. The primary end point was the overall response rate (ORR). Secondary end points included progression-free survival (PFS) and duration of response (DOR). Overall survival (OS) was an exploratory end point. Forty-one patients were enrolled in China after having progressed or not responded to prior therapy. At data cutoff, 4 patients continued treatment with 37 discontinuations. The median follow-up was 6.8 months, the ORR was 29.3%, and the complete response rate was 17.1%. Median DOR, PFS, and OS were 4.5, 2.8, and 8.4 months, respectively. Adverse events (AEs) leading to treatment discontinuation were reported in 4 patients, and grade ≥ 3 AEs were reported in 48.8% of patients. Major hemorrhage, atrial fibrillation, and/or flutter were not observed. Zanubrutinib demonstrated modest antitumor activity in non-GCB DLBCL, like other BTK inhibitors, as well as a safety profile consistent with previous studies. Through retrospective biomarker testing, potential antitumor activity was observed in patients with both CD79B and MYD88 mutations, who have inferior outcomes to immunochemotherapy. Future studies of zanubrutinib in R/R non-GCB DLBCL will focus on developing mechanism-based treatment combinations and biomarker-driven patient selection.

Comparison of the Effectiveness and Safety of the Oral Selective Inhibitor of Nuclear Export, Selinexor, in Diffuse Large B Cell Lymphoma Subtypes

BackgroundThe SADAL study evaluated oral selinexor in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of systemic therapy. In this post-hoc analysis, we analyzed the outcomes of the SADAL study by DLBCL subtype to determine the effects of DLBCL subtypes on efficacy and tolerability of selinexor. Patients and MethodsData from 134 patients in SADAL were analyzed by DLBCL subtypes for overall response rate (ORR), overall survival (OS), duration of treatment response, progression-free survival, and adverse events rate. ResultsORR in the entire cohort was 29.1%, and similar in patients with germinal center (GCB) versus non-GCB DLBCL (31.7% vs. 24.2%, P = 0.45); transformed DLBCL showed a trend towards higher ORR than de novo DLBCL: 38.7% vs. 26.2% (P = 0.23). Despite similar prior treatment regimens and baseline characteristics, patients with DLBCL and normal C-MYC/BCL-2 protein expression levels had a significantly higher ORR (46.2% vs.14.8%, P = 0.012) and significantly longer OS (medians 13.7 vs. 5.1 months, hazard ratio 0.43 [95% CI, 0.23-0.77], P = 0.004) as compared with those whose DLBCL had C-MYC and BCL-2 overexpression. Among patients who had normal expression levels of either C-MYC or BCL-2 and baseline hemoglobin levels ≥ 10g/dL, ORR was 51.5% (n = 47), with median OS of 15.5 months and median PFS of 4.6 months. Similar rates of adverse events were noted in all subgroups. ConclusionsOverall, single agent oral selinexor showed strong responses in patients with limited treatment alternatives regardless of germinal center B-cell type or disease origin.

P-NJ002. Myasthena gravis, a great ‘mimicker’ as an initial autoimmune presentation of diffused large B cell lymphoma: a case report

Introduction . Myasthenia gravis (MG) belongs to a spectrum of autoimmune diseases mediated by antibodies to acetylcholine receptors (AChRs) or muscle specific tyrosine kinase (MuSK). About 10-15% of MG cases have concurrent thymoma. However, only few reported cases of MG had been associated with lymphoid malignancies. Results . We report a case of MG in association with non-germinal center Diffuse Large B cell lymphoma (DLBCL) in a 40 years old gentleman. He initially presented with MG in crisis with bulbar and respiratory involvement in 2015. He was given intravenous immunoglobulin, steroid and pyridostigmine. He improved, however, defaulted his follow-up. Three years later, he presented back with MG in crisis. AChR antibody was positive and CT thorax showed anterior mediastinal mass with differential of thymoma or teratoma. Intravenous immunoglobulin was administered, but he developed acute extensive myocardial infarction. Thus, he underwent plasma exchange and tracheostomy due to prolonged ventilation. He was discharged well with steroid, pyridostigmine and azathioprine. He presented back 6 months later due to upper airway obstruction. Direct laryngoscope revealed enlarged fungating mass. Biopsy from right tonsil showed non germinal center DLBCL. He, subsequently, developed overwhelming sepsis with multiorgan failure and succumbed to death. Discussion . There are more than one pathogenetic mechanism that underlie the association between MG and lymphoma. There are pathways and genes involved in uninhibited lymphocytic proliferation which could result in both autoimmunity and lymphoma. Alternatively, lymphoid malignancy occurring after longstanding MG might be that the lymphoid malignancy is the result of chronic MG. MG also occur with higher frequency in lymphomas with mediastinal involvement due to the close proximity of lymphoma to the thymocytes that express proteins with antigenic similarities to AChR leading to autoimmune reaction to the latter. Conclusion . The association between MG and lymphoma although rare, can occur especially in those with mediastinal involvement.

Central Nervous System Relapse in Diffuse Large B Cell Lymphoma—Predictors at Diagnosis

Background Central nervous system (CNS) relapse of diffuse large B cell lymphoma (DLBCL) is an infrequent outcome with very poor prognosis. Initial studies have identified risk factors for CNS relapse and the CNS international prognostic score ((CNS-IPI) (Schmitz et al, JCO 2016) has been validated in various cohorts. Biologic characteristics of the disease are not included in the derivation of this model. We sought to validate this risk factor model in our single center DLBCL population in search for additional disease - specific factors that could further improve prediction of CNS relapse.Methods The hematologic malignancies database of the University Hospitals Seidman Cancer Center was accessed to identify newly diagnosed DLBCL patients between 2002 and 2014. Patients with extra-nodal CNS involvement at diagnosis were excluded. Through retrospective chart review data, we identified patient and disease characteristics, and outcomes data including response, relapse and death was collected. Patients who underwent therapy and had follow up data were included for final analysis. Univariate Cox proportional hazards analysis was conducted on the risk factors and those reaching statistical significance (p < 0.05) were selected for inclusion in multivariate proportional hazards model to help identify predictors for CNS relapse. CNS IPI score was applied to our population and cumulative incidence (with death as competing risk) was used to estimate the incidence of CNS relapse with the Gray test performed for comparisons between groups.Results: Five hundred and twenty-four patients were included for final analysis. Median age in our cohort was 64 years, with 312 (59.5 %) patients above the age of 60 years. 322 (63 %) patients had stage (III-IV), and 220 patients (37%) had elevated LDH at diagnosis. Two hundred and eighty five patients had extra-nodal disease involvement at the time of diagnosis with 88 patients involving more than one site. Baseline patient and disease characteristics are listed in Table 1. Four hundred (76%) patients received R CHOP as first line therapy, 395 patients achieved complete remission with first line therapy. At a median follow up of 64 months, 187 patients died and 171 patients had relapsed.Twenty-one patients developed CNS relapse in the follow up period, at median of 8.2 months after treatment initiation (95% CI 6.2-9.6) months. Applying the CNS-IPI risk scoring among the evaluable patients, 149 patients (36%) were found to be low risk (0-1 factors), 222 patients (53%) were intermediate risk (2-3 factors) and 47 patients (9%) were high risk (4-6 factors) for CNS relapse. Univariate analysis showed advanced stage (stage III-IV), number of extra-nodal sites involved, liver involvement, non- GCB subtype, translocation t (14; 18) and body mass index were significantly associated with CNS relapse (p<0.05). In multivariate analysis, only non- GCB subtype and translocation t (14; 18) (p = 0.023 and 0.028 respectively) were significant. Table 2 summarizes the results of Cox proportional hazards analysis.We evaluated the cumulative incidence of CNS relapse in the high-risk group, defined as CNS-IPI >1, (n=269, 64%). The 2-year CNS relapse cumulative incidence was at 5.1 % (95% CI: 2.8- 9%) compared to 0% for patients with CNS IPI ≤ 1 (p=0.027) (Figure 1).Median survival after CNS relapse was 3.6 months (0 - 150.2 months). Overall survival from start of initial therapy was 16 months (95% CI 9.5 -81.9 months) for patients with CNS relapse vs 170 months (95% CI 120.3 months - not reached), p<0.001]. (Figure 2)SummaryPrognosis of CNS relapsed of DLBCL is very poor. CNS IPI score helps identify a cohort that may benefit from CNS prophylaxis, and may help avoid unnecessary diagnostic and therapeutic intervention in the low risk cohort, i.e., CNS- IPI score <1. Hepatic involvement at diagnosis may be an additional clinical characteristic associated with high risk of CNS relapse. Biological features including non-GCB subtype and translocation t (14; 18) are novel risk factors that should be considered in the development of future risk models. [Display omitted] DisclosuresMalek:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau. Cooper:Novartis: Research Funding. de Lima:Celgene Corporation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Caimi:Seattle Genetics: Equity Ownership; Abbvie: Equity Ownership; Incyte: Equity Ownership; Celgene: Speakers Bureau.

Marked Re-Expansion of Chimeric Antigen Receptor (CAR) T Cells and Tumor Regression Following Nivolumab Treatment in a Patient Treated with Axicabtagene Ciloleucel (axi-cel; KTE-C19) for Refractory Diffuse Large B Cell Lymphoma (DLBCL)

▪Background: ZUMA-1 is a pivotal, multicenter trial of axi-cel, an autologous anti-CD19 CAR T therapy, for the treatment of patients (pts) with refractory, aggressive non-Hodgkin lymphoma. At the primary analysis, the objective response rate was 82% with a 54% complete response rate; 44% had ongoing responses (Locke et al. ASCO 2017. #7512). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 13% and 28% of pts, respectively. Programmed cell death-1 (PD-1) is expressed on antigen-activated CAR T cells (Perez et al. ASH 2015. #2042) and checkpoint genes, including programmed cell death-ligand 1 (PD-L1), may be upregulated in the tumor tissue of pts treated with axi-cel (Galon et al. ASCO 2017. #3025). Thus, there is a strong scientific rationale and significant clinical interest in exploring the role of immune checkpoint inhibitors to augment anti-tumor responses of axi-cel. Here we report a case of a pt with rapidly progressing refractory DLBCL whose disease did not respond to axi-cel, who then went on to receive the anti-PD-1 monoclonal antibody nivolumab (nivo) off-study and experienced rapid tumor regression.Methods and Results: A 46-y-old male with germinal center DLBCL without Myc, Bcl-2, or Bcl-6 translocations and with markedly positive PD-L1 expression had lymphoma refractory to R-CHOP, R-ICE, and R-DHAP and was enrolled in ZUMA-1. After lymphodepletion (cyclophosphamide 500 mg/m2 + fludarabine 30 mg/m2 daily × 3 days) and axi-cel infusion, he developed fevers, tachycardia, hypotension, and hypoxia consistent with grade 3 CRS. He received tocilizumab on d 3 with resolution of CRS. Shortly after infusion, the pt developed signs of rapid tumor progression. Abdominal pain, serum LDH, and total bilirubin increased progressively from d 5 to d 9, and repeat CT-PET demonstrated interval progression of abdominal disease relative to pre-infusion imaging. His serum LDH increased from a nadir of 538 U/L on d 4 to 940 U/L on d 10. He developed gastric outlet and recurrent common bile duct obstruction. Due to objective evidence of progressive disease and rapid clinical decline, the pt went to the long-term follow-up portion of the study and was allowed to receive subsequent therapy.On d 11, he received nivo 3 mg/kg. Within 24 h, serum LDH increased from 934 U/L to 1856 U/L and by 3 d after nivo administration, the patient developed grade 3 CRS, grade 1 NE, and marked peripheral lymphocytosis to a peak of 7700 lymphocytes/uL from 2400 lymphocytes/uL before nivo. His abdominal pain improved and oral intake was restored. Remarkably, after 1 cycle of nivo, abdominal CT showed regression of abdominal lymphadenopathy with a 67% reduction in index lesion volume, consistent with partial response. The pt received additional doses of nivo on d 23, 35, and 51. CT scan after 2 additional cycles of nivo confirmed continued disease volume reduction, but the patient's disease progressed on d 64.To determine the contribution of axi-cel on the highly unusual rapid tumor regression following nivo, correlative blood specimens collected before and after nivo on d 7, 13, 27, 51, 65, 90, and 93 and were analyzed for CAR T cells. At day 7 following axi-cel infusion, CAR T cells had expanded to 30 cells/uL, equivalent to the median level measured on d 7 in ZUMA-1 (28 cells/uL). On day 13, two days following nivo administration, dramatic CAR T cell re-expansion was observed, reaching a peak of 1927 CAR T cells/uL, a 64-fold increase above d 7 and a > 150-fold increase over the median d 14 level in ZUMA-1. Levels were elevated at 3 months compared with ZUMA-1 (20 CAR T cells/uL vs median, 0.4 CAR T cell/uL). Additional correlative results including cytokines will be presented.Conclusions:A patient with PD-L1-expressing DLBCL with rapidly progressive disease despite axi-cel treatment experienced a marked secondary expansion of CAR T cells and brisk tumor regression upon subsequent treatment with nivo. This case highlights the possibility that immune checkpoints play a role in preventing response to axi-cel and provides evidence that checkpoint blockade may work synergistically with CAR T cells when delivered in combination with axi-cel treatment. DisclosuresRoberts:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Smith:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; Kite Pharma: Research Funding.

An unusual cause of encephalopathy in the setting of a new diagnosis of DLBCL

A 69-year-old woman presented with progressive lethargy and encephalopathy of two weeks duration. Initial laboratory workup revealed hypercalcemia; imaging was notable for a 16 cm by 16 cm right lower quadrant abdominal mass. Core biopsy revealed germinal center Diffuse Large B-Cell Lymphoma (DLBCL). Despite correction of her hypercalcemia, the patient’s encephalopathy persisted. Brain imaging, thyroid stimulating hormone (TSH), folate, B12, urinalysis and culture, antinuclear antibody (ANA), and ammonia were normal. Cerebrospinal fluid (CSF) was negative for leptomeningeal disease. A thiamine level was sent and found to be low. Aggressive repletion was pursued; following the first cycle of chemotherapy, the patient’s mental status normalized. This is a rare case in which the rapid turnover of cells in the setting of active malignancy is believed to play a role in the development of thiamine depletion and resultant encephalopathy.

Characterizing Specificities of Chronic Lymphoid Leukemia Harboring a BCL2 rearrangement

Characterizing Specificities of Chronic Lymphoid Leukemia Harboring a BCL2 rearrangement

Primary and Secondary Central Nervous System Lymphoma: Outcomes from Houston Methodist Cancer Center

Introduction Primary Central Nervous System Lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin Lymphoma (NHL), with diffuse large B-cell Lymphoma (DLBCL) reported in 90% of cases. Secondary CNS lymphoma (SCNSL) may occur as an isolated recurrence of previously diagnosed NHL or occur simultaneously as a manifestation of systemic disease. Comparative data on survival in treated PCNSL and SCNSL in the real-world setting is lacking. We present a retrospective analysis of outcomes in PCNSL and SCNSL patients treated at the Houston Methodist Cancer Center. Methods We retrospectively identified patients with a diagnosis of PCNSL or SCNSL from 2015 to 2020. Data collected included age, race, sex, diagnosis (PCNSL, SCNSL), histology and immunohistochemistry, treatment type (chemotherapy, radiation), transplant rates as well as outcomes (alive/dead). Responses were classified as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Survival was analyzed using Kaplan-Meier methodology, and log-rank tests were used to compare survival distributions. P &amp;lt; 0.05 was considered statistically significant. Results There were 50 patients with CNS lymphoma identified between 2015 and 2020; 68% were PCNSL. Out of 43 with available pathology, 2 patients were T-cell lymphomas and 41 DLBCL. Out of the DLBCL cases, 95% of cases expressed CD20 while close to 60% were positive for MUM1, bcl-2 and bcl-6. Less than 15% of cases were positive for CD10. CD30 was positive in 17% of cases. Cerebral hemispheres (76%) was the most common organ involved, followed by ocular (8%), intraventricular space (6%) and cerebellum (6%). Median age at diagnosis was 67 years; male to female ratio was 1.27. Caucasian (62%) and Hispanic (24%) were most common ethnicities. Epstein-Barr Virus was positive in 14% of patients (5 in PCNSL and 2 in SCNSL). One patient with SCNSL had human immunodeficiency virus. The median follow-up time was 9.1 months. Multiagent chemotherapy including high dose methotrexate (MTX), cytarabine and rituximab was given to 48% of the patients while 32% received high dose MTX alone plus rituximab. From the latter group, five out of sixteen patients received temozolomide. Other regimens were used in 6% of the cases. Median dose of MTX in a multiagent chemotherapy regimen was 2.5gr/m2 and 2.25gr/m2 when used alone or with temozolomide. Median number of cycles given was 3. Radiation therapy alone was given to 8% of cases. Three patients did not receive treatment. For patients with PCNSL, overall response rate (ORR) was 82.8% (CR 65.5%, PR 13.8%, SD 3.4%). ORRs were similar between multiagent chemotherapy and methotrexate alone (+/- temozolomide) with 86.7% and 83.3% respectively. ORR for SCNSL was 57.1% (CR 35.7%, PR 21.4%); only 1 patient was treated with MTX alone. Further lines of therapy were required in 9.3% of patients. Consolidation with whole brain radiation was given in 22% of the cases (29.4% for PCNSL and 6.3% for SCNSL). Autologous stem cell transplant was performed in 10% of the patients (2 PCNSL, 3 SCNSL). Overall survival for patients with PCNSL was 74.8 months and 10.1 months for SCNSL (p=0.0444) (Figure 1). Survival was not significant between patients receiving multiagent chemotherapy and MTX alone or in combination with temozolomide (3-year OS 57.3% vs 73.4%, p= 0.5652) (Figure 2). Conclusion Most patients diagnosed with PCNSL are non-germinal center DLBCL. Median MTX dose was lower than 3gr/m2 with excellent ORR of over 80% in PCNSL. Response rates were lower in SCNSL and in general, patients with PCNSL had better outcomes. Survival did not differ significantly between regimens, suggesting that a lower intensity therapy may perform similarly to multiagent chemotherapy. These results need to be confirmed by prospective studies. Disclosures No relevant conflicts of interest to declare.

Abstract PO-08: Understanding the properties and oncogenic mechanisms of EZH2 Y641 mutations in lymphoma

Abstract EZH2 (Enhancer of Zeste Homolog 2) is the catalytic component of the Polycomb Repressive Complex group 2 (PRC2), which establishes the repressive epigenetic mark histone 3 lysine 27 trimethylation (H3K27me3), resulting in silencing of gene expression. EZH2 was originally identified as a tumor suppressor since loss-of-function events were observed in myelodysplastic syndrome, acute myeloid, and T-cell leukemias. However, next-generation sequencing identified recurrent activating point mutations at tyrosine residue 641 (Y641) in 25% of germinal center diffuse large B-cell lymphoma and 15% of follicular lymphomas, suggesting that EZH2 also functions as an oncogene in a cell type-dependent manner. Using a faithful genetically engineered mouse model, we previously demonstrated that the Ezh2Y641F mutation drives formation of B-cell lymphoma as a single event and in cooperation with Bcl2 amplification or p53 loss. Unexpectedly, at the chromatin level, expression of Ezh2Y641F did not monotonically increase abundance of global H3K27me3 but rather resulted in redistribution of this mark across the genome, exhibiting loss of H3K27me3 at many loci, with direct effects on transcription. Others have shown that EZH2 mediates germinal center proliferation via repression of p21 and cooperation with Bcl6; however, given the global effect of Ezh2Y641F on chromatin, the oncogenic mechanisms of these mutations remain underexplored. These include the timing of the mutation during hematopoietic development, its role during differentiation, and the oncogenic activity of downstream targets. In order to investigate the effect of Ezh2Y641 mutations on hematopoietic development and differentiation, we used Cre alleles to drive expression of the mutant protein at different stages of hematopoietic development. Our data demonstrate that expression of Ezh2Y641 in early B cells is sufficient to drive oncogenic transformation. However, expression of Ezh2Y641 in hematopoietic stem cell (HSC) is not sufficient to drive oncogenic transformation despite the presence of mature healthy B cells. Additionally, expression of Ezh2Y641F in HSCs results in loss of self-renewal, differentiation bias towards the lymphoid lineages, and a partial block at the pre-pro B-cell stage. With regards to direct downstream targets, we identified upregulation of several HoxC cluster genes in Ezh2Y641F-mutant B cells prior to transformation. Upregulation of these genes is mediated via loss of H3K27me3 at the HoxC cluster and focal gains of H3K27 acetylation (H3K27ac). Overall, our findings underline the complicated biology and oncogenic activity of EZH2Y641 mutations in lymphoma, shed light on the effect of these mutations during hematopoietic development, and underscore some of the consequences of the paradoxical loss of H3K27me3 at certain loci. Citation Format: Samantha J. Nixon, Sarah Zimmerman, Jeremy M. Simon, George P. Souroullas. Understanding the properties and oncogenic mechanisms of EZH2 Y641 mutations in lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-08.

Zanubrutinib monotherapy for patients with relapsed or refractory non-germinal center diffuse large B-cell lymphoma: Results from a phase II, single-arm, multicenter, study.

e20051 Background: The non-germinal center (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) is associated with poor clinical outcomes. Inhibitors of Bruton’s tyrosine kinase (BTK) have established therapeutic activity in mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenstrom macroglobulinemia and have shown modest activity in DLBCL. Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 2 study in patients with relapsed or refractory (R/R) non-GCB DLBCL. Methods: The BGB-3111-207 study (NCT03145064) is a multicenter, single arm, phase 2 study in patients with R/R non-GCB DLBCL who were ineligible for intensive chemotherapy and bone marrow transplantation. Subjects received zanubrutinib 160 mg by mouth twice daily until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate (ORR) using the Lugano criteria. Secondary endpoints included progression free survival (PFS) and duration of response (DOR). Overall survival (OS) was the exploratory endpoint. Results: Forty-one patients were enrolled at 11 sites in China between June 2017 and May 2018. Patients were 61% male, with a median age of 62 years. The median number of prior therapies was 2. International Prognostic Index risk was high-intermediate or high for 48.8% of patients, and 56.1% of patients had extranodal disease at study entry. As of the data cutoff date of May 24, 2019, four patients were continuing treatment and 37 patients had discontinued. With a median follow-up time of 6.8 months, the ORR was 29.3% and the complete response rate was 17.1%. The median DOR was 4.5 months, the median PFS was 2.8 months, and the median OS was 8.4 months. Adverse events (AEs) leading to treatment discontinuation were reported in four patients. Grade 3 or higher AEs were reported in 48.8% of patients. Major hemorrhage, atrial fibrillation and/or flutter, second primary malignancy, and tumor lysis syndrome were not observed. Conclusions: In this study zanubrutinib demonstrated modest antitumor activity in non-GCB DLBCL, similar to other BTK inhibitors. The safety profile was tolerable and consistent with previous reports of zanubrutinib treatment. Future studies of zanubrutinib in R/R non-GCB DLBCL will focus on the development of mechanism-based treatment combinations and biomarker-driven patient selection. Clinical trial information: NCT03145064 .