Diffuse Large B-cell Lymphoma Histology Research Articles

Blinatumomab after R-CHOP bridging therapy for patients with Richter transformation: a phase 2 multicentre trial

Richter transformation (RT) is an aggressive lymphoma occurring in patients with chronic lymphocytic leukaemia. Here we investigated the anti-CD3/anti-CD19 T-cell-engager blinatumomab after R-CHOP (i.e. rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with untreated RT of diffuse large B-cell lymphoma histology (NCT03931642). In this multicentre phase 2 study, patients without complete response (CR) after two cycles of R-CHOP were eligible to receive an 8-week blinatumomab induction via continuous vein infusion with stepwise dosing until 112 μg/day. The primary endpoint was the CR rate after blinatumomab induction and secondary endpoint included safety, response duration, progression-free and overall survival. Thirty-nine patients started the first cycle of R-CHOP, 25 of whom received blinatumomab. After blinatumomab induction, five (20%) patients achieved CR, four (16%) achieved partial response, and six (24%) were stable. Considering the entire strategy, the overall response rate in the full-analysis-set was 46% (n = 18), with CR in 14 (36%) patients. The most common treatment-emergent adverse events of all grades in the blinatumomab-safety-set included fever (36%), anaemia (24%), and lymphopaenia (24%). Cytokine release syndrome (grade 1/2) was observed in 16% and neurotoxicity in 20% of patients. Blinatumomab demonstrated encouraging anti-tumour activity (the trial met its primary endpoint) and acceptable toxicity in patients with RT.

Golcadomide (GOLCA; CC-99282), a Novel CELMoD Agent, Plus R-CHOP in Patients (pts) with Previously Untreated Aggressive B-Cell Lymphoma (a-BCL): Safety and Efficacy Results from Phase 1b Dose Expansion

Introduction Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) relapse after first-line chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). CELMoD agents such as GOLCA potently degrade target proteins Ikaros/Aiolos, resulting in antiproliferative, apoptotic, and immunomodulatory activity. GOLCA preferentially distributes to tissues and lymphoid organs. In a phase 1 study, GOLCA demonstrated a manageable safety profile with promising clinical activity as monotherapy in relapsed/refractory non-Hodgkin lymphoma (Michot et al. Blood 2021). CC-220-DLBCL-001 (NCT04884035) is an ongoing open-label, multicenter, dose escalation and expansion trial to assess safety and preliminary efficacy of CELMoD agents + R-CHOP for untreated a-BCL. GOLCA demonstrated a manageable safety profile in the dose escalation phase (Munoz et al. ICML 2023 abstract 438); we report combined results from the GOLCA dose escalation and expansion phases. Methods Eligible pts were ≥ 18 years, had untreated a-BCL with measurable disease (Lugano 2014), ECOG performance status ≤ 2 and International Prognostic Index (IPI) score 0-5 (2-5 in dose expansion). Pts were treated with R-CHOP plus GOLCA in 21-day (D) cycles (C) for up to 6C, or until disease progression/unacceptable toxicity/study withdrawal/physician decision. During dose escalation, pts received GOLCA at dose levels (DL): 0.2 mg D1-7 (DL-1), 0.4 mg D1-7 (DL1), and 0.4 mg D1-10 (DL2). DL2 met the dose-limiting toxicity threshold and was not continued in the expansion phase. During dose expansion, pts were randomized 1:1 to R-CHOP plus GOLCA at DL-1 or DL1. The primary endpoint for the expansion phase was safety of GOLCA at the recommended phase 2 dose (DL1) (based on adverse events [AEs]); secondary endpoints included overall response rate (ORR) and complete metabolic response (CMR) rate (assessed at end of treatment [EoT] by PET-CT [Lugano 2014]). Circulating tumor DNA (ctDNA) was measured at C1D1, C2D1, C3D1, and EoT using the PhasED-Seq assay. Results Across escalation and expansion, 78 pts were treated (DL-1, n = 35; DL1, n = 37; DL2, n = 6). Median age was 63.0 years, 56.4% were male, most had high-intermediate/high IPI (3-5) score at diagnosis (64.1%), Ann Arbor stage III-IV disease (83.3%), and germinal center B cell as cell of origin (51.3%); 83.3% pts had DLBCL histology. At data extraction (May 25, 2023), across escalation and expansion, 38 pts had treatment ongoing, 31 completed treatment, and 35 continued to follow-up. A total of 3 pts discontinued due to AEs, 1 each at DL-1, DL1, and DL2. In the safety population (n = 78), median GOLCA relative dose intensity (RDI) was 99.4%; 82.1% of pts received RDI ≥ 85%. RDI for CHOP components was > 90%. A total of 73 (93.6%) pts had ≥ 1 treatment-emergent AE (TEAE); 70 (89.7%) pts had ≥ 1 TEAE considered related to GOLCA; 65 (83.3%) pts had ≥ 1 grade 3/4 TEAE, 62 (79.5%) pts had ≥ 1 grade 3/4 TEAE considered related to GOLCA. The most frequently occurring grade 3/4 TEAEs were neutropenia (76.9%) and thrombocytopenia (32.1%) ( Table). A total of 30 (38.5%) pts had serious TEAEs, most frequently febrile neutropenia (preferred term: 11 pts, 14.1%); 12 (15.4%) pts had serious TEAEs of infection or infestation (system organ class); 6 pts (7.7%) had venous thromboembolisms considered related to GOLCA (4 deep vein thrombosis, 1 superficial thrombosis, 1 pulmonary embolism). Treatment-related AEs leading to GOLCA dose reduction or discontinuation occurred in 11 (14.1%) pts and 6 (7.7%) pts, respectively. After a median follow-up time of 4.1 months (range 0.3-12.3) and among all treated pts with EoT response available, 21/25 had CMR; together, 14/14 pts who received GOLCA 0.4 mg (DL1 and DL2) achieved CMR at EoT ( Figure). Among efficacy-evaluable pts (n = 56), ORR was 91.1% (95% CI 80.4-97.0). Pts treated with GOLCA at DL-1 and DL1 who were ctDNA high-risk (≥ 2.5 log hGE/mL) responded to study treatment (CMR-PMR) and had early decreases in ctDNA (Kaplan et al. ASH 2023). Conclusions GOLCA demonstrated a manageable safety profile, showed good combinability with R-CHOP, and did not compromise delivery of curative treatment. Efficacy results and substantial ctDNA decrease indicate robust clinical activity in frontline DLBCL, with a high CMR rate at EoT, particularly among patients treated at DL1. Study support Bristol Myers Squibb.

Copanlisib in Combination with Nivolumab in Subjects with Relapsed/Refractory Diffuse Large B-Cell Lymphoma and Primary Mediastinal Large B-Cell Lymphoma: A Phase II Study

Introduction: Diffuse Large B-cell Lymphoma (DLBCL) are aggressive B-cell non-Hodgkin lymphomas (NHL). One particular subtype, Primary Mediastinal B-cell Lymphoma (PMBCL), is often grouped with DLBCL, but it possesses distinct biological and clinical characteristics. While initial therapy successfully cures approximately two-thirds of patients (pts), those who do not respond or experience progression within the first two years have a poor prognosis despite novel cellular therapies and bispecifics and ultimately succumb to their disease. There is a pressing need for more effective therapeutic approaches in this patient population. Recent advances in the understanding of DLBCL pathogenesis have led to the targeting of various signaling pathways, including the PI3K-AKT-mTOR pathway. One such drug, copanlisib (C), a pan-PI3K inhibitor with potent PI3K-α/PI3K-δ inhibition, exhibited activity in both indolent and aggressive NHL. In preclinical studies using a DLBCL mouse model, treatment with C effectively reduced the immunosuppressive tumor-infiltrating T-regulatory cells (Tregs). Moreover, when combined with a surrogate anti-mouse programmed death -1 (PD-1) blocker, C demonstrated significant in vivo responses (75%) compared to the monotherapy groups (0%). These findings support the rationale for exploring the combination of nivolumab, a PD-1 blocker, and copanlisib (C-N) in DLBCL. Thus, a phase 2 prospective study has been developed, focusing on two relapsed/refractory (RR) cohorts (DLBCL and PMBCL), treated with the combination of C-N. A prespecified interim analysis was planned upon enrollment of 14 pts. Herein, we report outcomes of the 12 enrolled pts, as the study was halted prematurely due to a safety signal deemed possibly related to the combination. Study design: C 60 mg was given intravenously on days 1, 8, and 15 during cycles 1-8, and on days 1 and 15 in subsequent cycles. N 240 mg IV was given on days 1 and 15 during cycles 1-8, and 480 mg on day 1 on subsequent cycles. Each treatment cycle is 28 days. Therapy was given for up to 2 years, as long as there is no disease progression or unacceptable side effects. The primary objective of the study is to determine the ORR, which includes complete and partial responses (CR+PR). Secondary objectives include evaluating the safety of the combination, as well as assessing progression-free survival (PFS), duration of response (DOR), CR, and overall survival (OS). The study plan was to enroll a maximum of 106 pts, including a safety cohort of 6 pts. The study received funding from Bayer and conducted through NCI-CTEP (NCI Protocol #10193; NCT03484819). Results: Twelve pts who received at least one cycle of C-N were included in this analysis. Pt characteristics are illustrated in table 1. All enrolled pts had DLBCL histology. Only one patient received a prior autologous stem cell transplant. Interestingly 4/12 received prior chimeric antigen receptor T-cell therapy (CART). Of the 12 enrolled pts, seven were evaluated for response. The ORR was 25% (3/12) (95% CI: 5 - 57%), all CR. The median number of cycles received was 2.5 (range 1-24) with two pts receiving 23 and 24 cycles. Observed grade 3 and higher adverse events (AEs) were as follows: non-hematologic AEs in 10/12 (83.3%), while hematologic AEs were seen in 5/12 (41.7%) pts. A relatively higher incidence of cardiac events (4/12) were noted including one cardiac arrest after one cycle of therapy, and four atrial fibrillation events, all grade 3, but only two were deemed possibly attributed to therapy. The cardiac arrest was deemed unrelated to therapy. Conclusions: C-N combination had modest clinical activity in pts with R/R DLBCL with some prolonged responses. However, due to the relatively high number of cardiac events and the changing therapeutic landscape with recent approvals, a decision was made to halt the study. These findings likely reflect possibly older and sicker patient population. Biomarker studies for predictors of response are under consideration.

Lisocabtagene Maraleucel as Second-Line Therapy for R/R Large B-Cell Lymphoma in Patients Not Intended for Hematopoietic Stem Cell Transplant: Final Analysis of the Phase 2 PILOT Study

Background: For the 30%-40% of patients with large B-cell lymphoma (LBCL) who are not cured after first-line therapy, traditional second-line therapy has been high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT). Recent studies have challenged this paradigm, showing a PFS/OS benefit to CAR T cell therapy over HDCT/HSCT in patients with high-risk, transplant-intended disease at first relapse. Given the lack of effective therapeutic options, outcomes have been historically poor for patients not intended to receive HDCT/HSCT. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. The open-label phase 2 PILOT study (NCT03483103) evaluated the efficacy and safety of liso-cel in patients with R/R LBCL not intended for HSCT after 1 prior line of therapy. In the primary analysis, the primary endpoint was met with an ORR of 80%. Here, we report the final analysis results from PILOT after a median follow-up of 18.2 mo (range, 1.2-32.8). Methods: Adults with R/R LBCL were eligible if they had received 1 prior line of therapy with an anthracycline and CD20-targeted agent, were not intended for HSCT, and met ≥ 1 transplant not-intended criterion by investigator (age ≥ 70 years, ECOG PS of 2, diffusing capacity of the lung for carbon monoxide ≤ 60%, LVEF < 50%, CrCl < 60 mL/min, or alanine aminotransferase/aspartate transaminase > 2 × upper limit of normal). Patients received lymphodepleting chemotherapy (intravenous fludarabine 30 mg/m² and intravenous cyclophosphamide 300 mg/m² daily for 3 days) followed by liso-cel infusion 2-7 days later. The primary endpoint was ORR by independent review committee (IRC) per Lugano 2014 criteria; secondary endpoints included safety; CR rate, duration of response (DOR), and PFS by IRC; and OS. Results: A total of 61 patients were included in the liso-cel-treated analysis set. Median age was 74 years (range, 53‒84 years; ≥ 75 years, 46%), 39% were female, 26% had ECOG PS of 2, 25% had CrCl < 60 mL/min, 54% had diffuse LBCL not otherwise specified, 30% had high-grade lymphoma with diffuse LBCL histology (HGBCL), 33% had double-/triple-hit disease, and 54% had refractory disease. ORR was 80.3% (95% CI, 68.2-89.4),with 54.1% (95% CI, 40.8-66.9) achieving CR (Table). Responses were durable, with a median DOR of 23.3 mo (95% CI, 6.2-not reached [NR]) after a median follow-up of 23.1 mo (95% CI, 22.9-23.3); median DOR for those with CR was NR (95% CI, 21.65-NR) versus 2.1 mos (95% CI, 1.4-3.3) for those with PR. Median PFS was 9.0 mo (95% CI, 4.2-NR) and median OS was NR (95% CI, 16.3-NR). Twenty-four patients died, mostly because of disease progression (n = 20). During the treatment-emergent (TE) period (≤ 90 days after liso-cel administration), 96.7% of patients had TEAEs (grade ≥ 3, 78.7%), 37.7% had cytokine release syndrome (CRS; grade 3, 1.6%; no grade 4-5), 31.1% had neurological events (NE; grade 3, 4.9%; no grade 4-5), 8.2% had hypogammaglobulinemia, and 6.6% had grade ≥ 3 infections. A total of 57 patients were included in the post-TE period (starting from 91 days after liso-cel administration, initiation of subsequent anticancer therapy, or liso-cel retreatment before Day 91, whichever came first). Of those patients, 50.9% experienced AEs (grade ≥ 3, 17.5%; Table). The most common grade ≥ 3 AEs in the post-TE period were anemia (5.3%) and thrombocytopenia (5.3%). In the post-TE period, 1 (1.8%) patient had hypogammaglobulinemia, and 1 (1.8%) had grade ≥ 3 infections (bacteremia and sepsis). Overall, 2 (3.5%) patients had second primary malignancies (squamous cell carcinoma of skin and malignant external ear neoplasm [n = 1] and myelodysplastic syndrome [n = 1]). Cellular kinetics and B-cell aplasia data will be presented. Conclusions: After a median of 18.2 mo of follow-up, the final analysis of the PILOT study demonstrated a high CR rate and durable CRs with liso-cel treatment in patients with R/R LBCL for whom HSCT was not intended. Despite the high incidence of HGBCL, primary refractory disease, advanced age, and comorbidities in this population, the safety profile was consistent with previous reports, with no new or increased safety signals. These results continue to support liso-cel as second-line therapy for this underserved population of patients with R/R LBCL.

Bone marrow biopsy can be omitted in the diagnostic workup of CNS lymphoma of DLBCL origin: a population-based retrospective study in the PET-CT era

Currently, bone marrow (BM) biopsy (BMB) is recommended in the initial staging of patients with the presumed primary central nervous system (CNS) lymphoma (PCNSL). However, the added value of BMB in the era of positron emission tomography (PET-CT) has been challenged in other lymphoma subtypes. We analyzed BM findings in patients with biopsy-proven CNS lymphoma and a negative PET-CT scan for disease outside CNS. A comprehensive Danish population-based registry search was performed to identify all patients with CNS lymphoma of diffuse large B cell lymphoma (DLBCL) histology with available BMB results and staging PET-CT without systemic lymphoma. A total of 300 patients fulfilled the inclusion criteria. Of them, 16% had a previous history of lymphoma, while 84% were diagnosed with PCNSL. None of the patients had DLBCL in the BM. A minority (8.3%) had discordant BMB findings, mainly low-grade histologies that did not influence treatment choice in any case. In conclusion, the risk of overlooking concordant BM infiltration in patients with CNS lymphoma of DLBCL histology and negative PET-CT scan is negligible. As we did not find any patient with DLBCL in the BMB, our results suggest that BMB can be safely omitted in the diagnostic workup in patients with CNS lymphoma and a negative PET-CT.

Prognostic Nomogram and Competing Risk Analysis of Death for Primary Thyroid Lymphoma: A Long-term Survival Study of 1638 Patients.

A total of 1638 PTL patients from 2000 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazard regression and competing risk analysis were applied. We have identified through Cox analysis that age in years, diffuse large B-cell lymphoma (DLBCL) pathology, lymph node dissection, radiation, and chemotherapy were independent prognostic factors for disease-specific survival (DSS). Based on these findings, we built a nomogram for predicting 5- and 10-year DSS and analyzed the overall survival (OS) by calculating cumulative incidence of death. The overall cumulative incidences of the 5- and 10-year PTL-specific cumulative death probabilities were 14.0% (95% CI: 12.3%-15.9%) and 16.3% (95% CI: 14.4%-18.4%), respectively, while the 5- and 10-year cumulative death probabilities from other causes were 12.4% (95% CI: 10.6%-12.3%) and 24.7% (95% CI: 22.1%-27.4%). Results from the competing risk hazards regression analysis revealed that older age and Ann Arbor grading were associated with a greater probability of death from other causes and death from PTL. Radioactive therapy by external beam radiation was associated with death from other causes only. DLBCL histology, lymph node dissection, and chemotherapy were correlated with death from PTL. Cumulative incidence curves demonstrated that the pathological type of lymphoma is the factor determining the likelihood of dying from PTL versus other causes. Patients' age, Ann Arbor stage, pathological type of lymphoma, and the use of specific therapy regimen should all be taken into consideration when devising individualized treatment strategies for PTL. Decision models based on our findings may help clinicians make better decisions by taking into account the competing risk of death from causes other than PTL.

Clinical Laboratory Mutation Analysis Performed on Tumor Biopsies from Patients with Newly-Diagnosed Germinal Center Aggressive B Cell Lymphoma

Background Comprehensive genomic analyses of tumor biopsies (bx) from patients (pts) with newly-diagnosed germinal center B cell (GCB) diffuse large B cell lymphoma (DLBCL) and high grade B cell lymphoma (HGBL) have identified molecular subtypes predictive of inferior survival outcomes following receipt of first-line immunochemotherapy (PMID: 29713087, 29641966, 30523719, 30523716). These experimentally-defined molecular subtypes are characterized by somatic mutations (mut), which can be detected through clinical laboratory mutation analysis (CLMA). We sought to identify the frequency and predictive value of these mut as detected by CLMA performed at our center on tumor bx from pts with newly-diagnosed GCB DLBCL/HGBL. Methods Pts diagnosed with de novo or previously-untreated transformed indolent GCB DLBCL/HGBL defined by Hans algorithm from 2015-21 who received R-CHOP or R-EPOCH in the first-line setting whose initial tumor bx underwent CLMA performed at the University of Pennsylvania with either the lymphoma sequencing panel (LSP) or PennSeq Lymphoma panel (PSLP) were retrospectively analyzed. Immunohistochemical staining (IHC) for MYC and BCL2 expression as well as fluorescence in situ hybridization (FISH) for MYC, BCL2 and BCL6 rearrangements were performed as per institutional standard. Therapy was given at the discretion of the treating physician. Disease free survival (DFS) was defined as the interval between diagnosis of DLBCL/HGBL to DLBCL/HGBL relapse or last follow-up in remission. Overall survival (OS) was defined as the interval between diagnosis and time of death or last follow-up while alive. Data were censored on 7/1/22. Results CLMA was performed on 59 pt tumor bx with 58 successful assays (98% success rate) and a median result turnaround time (TAT) of 16 days. 5 bx were excluded due to specific request for CLMA by treating clinician (3) or diagnosing pathologist (2) and 2 additional bx were excluded due to lack of clinical follow-up, resulting in analysis of 51 bx performed at random from pts evaluable for survival (n=32 LSP, n=19 PSLP). Baseline characteristics, including mut in genes of interest (GOI) identified in the above references, are listed in the Table. Of note, BCL2, MYC, DDX3X and PTEN mutations were not included the LSP and therefore not included in statistical analyses due to small sample size. R-EPOCH was received by 15 pts (29%) and R-CHOP by 36 pts (71%). With a median follow-up of 25.2 months, the Kaplan Meier estimate of 2 year (y) DFS was 60% (95% confidence interval [CI] 41-74%) and 2y OS 80% (95% CI 64-89%). As shown in the Figure, 2y DFS was significantly lower for pts with CREBBP mut vs not (45% [95% CI 18-68%] vs 67% [95% CI 44-83%], P=0.045), but not for pts based on other mut analyzed. All progression events for pts with CREBBP mut occurred ≤12 months (mo) from diagnosis. Of 16 bx with CREBBP mut, 15 mut were predicted to result in loss of function (LOF) (PMID: 28890946, 21390126). CREBBP mut were not significantly associated with baseline characteristics except for EZH2 mut (50% with CREBBP mut vs 11% no CREBBP mut, P=0.005 by Fisher's exact). Characteristics listed in the Table which were predictive of disease relapse by 2y with P<0.10 on univariate Cox regression analysis were International Prognostic Index Score ≥3 vs <3 (hazard ratio [HR] 2.3, 95% CI 0.86-6.5, P=0.098), HGBL vs DLBCL histology (HR 5.4, 95% CI 1.8-15.7, P=0.002), double hit lymphoma vs not (HR 9.0, 95% CI 2.6-30.8, P<0.001) and CREBBP mut vs not (HR 2.6, 95% CI 0.98-7.0, P=0.054). Conclusions In this cohort of pts with newly-diagnosed GCB DLBCL/HGBL treated with first-line immunochemotherapy whose tumor bx underwent CLMA at random, mut in CREBBP resulting in predicted LOF were frequently detected, not associated with routinely-analyzed baseline clinicopathologic characteristics and predicted for significantly lower 2y DFS with progression events occurring early. These findings may be of interest in light of availability of agents which may overcome loss of histone acetyltransferase function. Given the high success rate and rapid TAT of CLMA, results from this assay could inform the management of pts with newly-diagnosed DLBCL/HGBL in real-time, and additional efforts to incorporate findings from experimental molecular assays into CLMA-based studies as well as those to standardize CLMA gene panels may ultimately benefit this pt population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Primary Hepatic Lymphoma: Role of Low-Dose Radiotherapy at a Single Institution with Genetic Characterization and Paired Literature Review

Purpose/Objective: Primary hepatic lymphomas (PHL) are an extremely rare form of non-Hodgkin Lymphoma (NHL) for which there are no established treatment guidelines, with available literature largely comprised of small case reports. Therefore, we evaluate our institutional experience treating PHL within the context of existing literature to better understand treatment modalities, role of radiotherapy (RT), and outcomes. Traditionally, radiotherapy for indolent lymphomas has involved treatment of up to 2400cGy in 12 fractions, however the use of low-dose radiotherapy of 400cGy in 1-2 fractions has been increasingly utilized. However to our knowledge, use of low-dose RT for liver lymphomas has not previously been reported in the literature. Materials/Methods: We conducted a single institutional retrospective analysis of all PHL patients (pts) diagnosed from 2000-2021 with a biopsy-proven liver lesion without other lymphomatous solid organ involvement, except for concurrently diagnosed splenic lymphomas. Subgroup analysis was performed for diffuse large B-cell lymphoma (DLBCL) and indolent lymphomas, which included marginal zone (MZL), follicular (FL), and low-grade B-cell lymphoma (BCL), NOS. Univariable (UVA) and multivariable analysis (MVA) for overall survival (OS) was performed using the Cox proportional hazards model. A literature review was also conducted using key words "liver", "lymphoma", and "treatment" to identify all available reported cases of PHL. An institutional targeted sequencing database was queried to identify patients with PHL of DLBCL histology. Results: We identified 30 PHL pts within the institutional cohort and 192 pts from comprehensive literature review. Sixteen patients were male (53%), and 25 (83%) were ECOG 0. Twenty five (83%) were Lugano Stage I, 3 (10%) were Stage III, and 2 (7%) were Stage IV. Six (20%) patients had bulky disease and 3 (10%) had nodal involvement. Systemic therapy was the most common treatment modality with 20 patients (67%), and 4 patients (13%) each received surgery, radiation and observation in our institutional cohort. In the paired literature review, 96 patients (50%) received systemic therapy, 69 (36%) underwent surgery, 10 (5%) received radiation and 11 (6%) underwent observation. Seventeen (57%) of patients were alive and 5 (17%) lost to follow-up within our institutional cohort, compared with 97 patients (51%) alive and 3 (2%) lost to follow-up. Median survival in our cohort was 6 years, compared with 2 years among the literature review cohort. Subgroup analysis of DLBCL included 15 pts (Table 1). On MVA for OS, only ECOG score (p=0.02) and Lugano stage (p=0.04) remained significant. Subgroup analysis of the indolent lymphoma group included 9 pts (Figure 1). On MVA for OS, only age remained significant. Six DLBCL patients with available targeted sequencing data were identified, with 4 mutations mutated more than once: TP53 (50%), MEF2B (33%), P2RY8 (33%), and IRF8 (33%). Pathway mapping of genetic mutations was notable for alterations in cell cycle pathway genes TP53 and ATM (17%). No other pathways had greater than one genetic alteration. Conclusion: PHLs are a rare subtype of NHL without clear treatment consensus. Primary hepatic DLBCL is predominantly treated with chemotherapy in both our institutional experience and as reported in the literature, with reasonable disease control. Importantly, indolent PHL patients in the institutional cohort have been treated with various modalities including low-dose radiotherapy, which appears to achieve comparable disease control. However radiotherapy was not utilized as a modality for indolent PHL within the literature review. Therefore, this is the first report of the use of low-dose radiotherapy for treatment of indolent liver lymphomas. Our RT data is limited by short follow-up duration of RT pts compared to pts who received chemotherapy, surgery or observation. However, our results are encouraging for the consideration of low-dose radiotherapy as a management option for appropriate patients with indolent PHL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Is It Possible to Omit Bone Marrow Biopsy in Diagnostic Workup in Patients with Newly Diagnosed Primary CNS Lymphoma? a Retrospective Analysis in the PET/CT Era

Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extra-nodal non-Hodgkin lymphoma (NHL) confined to the brain, eyes, leptomeninges, and spinal cord. More than 90% of patients belong to diffuse large B-cell lymphoma (DLBCL). The consensus around the extensive systematic staging in patients with suspected or proven PCNSL is still a matter of debate. Current diagnostic and staging guidelines recommend extensive workup to exclude systemic disease with computed tomography (CT) scan of the chest, abdomen, and pelvis, a bone marrow biopsy (BMB), and testicular ultrasonography in males. Whole-body 18F-fluorodeoxyglucose positron emission tomography (PET-CT) is currently considered optional in diagnostic workup in patients with presumed PCNSL. The utility of BMB in the era of PET-CT has been challenged in systemic lymphomas, but data are lacking for patients with PCNSL. Among patients with PCNSL, BMB is often normal or reveals low-grade lymphomas or just clonal B-cells. In rare instances, aggressive lymphoma involves both bone marrow (BM) and the central nervous system (CNS). However, the role of BMB in PCNSL patients in the PET-CT era is yet to be established. This study aimed to analyze whether BMB could be safely omitted in the diagnostic workup in patients with PCNSL of DLBCL histology without signs of systemic lymphoma on PET-CT scans. Methods: A comprehensive nationwide retrospective multicenter study with enrollment of patients from the referent medical centers in Denmark for treatment of PCNSL was performed. Patients included in the study were diagnosed between 2002 and 2020 and identified through the Danish Pathology Register. All patients with CNS involvement were potential candidates. Inclusion criteria were the following: 1) patients should be diagnosed with DLBCL in brain, eyes, leptomeninges, cerebrospinal fluid, and spinal cord; 2) have available BMB; and 3) have available PET-CT without signs of lymphoma outside of CNS. Patients with PCNSL and prior history of other lymphoma were also included in the study. Patients were excluded if they were diagnosed with systemic lymphoma or PCNSL other than DLBCL. Patients who did not have PET-CT and BMB performed or in whom this information could not be retrieved through medical records were also excluded from further analysis. Results: Of 1238 potential candidates identified through the Danish pathology register, only 300 patients fulfilled the inclusion criteria. Most patients were excluded due to a lack of information on PET-CT scans and BMB. All included patients had available BMB and no signs of systemic lymphoma on PET-CT. Of the included patients, 252 (84%) were diagnosed with PCNSL without a previous lymphoma diagnosis, while 48 (16%) had a previous history of lymphoma. The median age of patients was 68 years. There was a slight predomination of men (60%) compared to women (40%). Twenty-three (7.7%) patients were found to have discordant findings in BMB. However, none of these showed infiltration with DLBCL. The histologies included various low-grade lymphomas found in 17 patients (5.7%), monoclonal B-cells in 3 patients (1%), and smoldering multiple myeloma in one patient. Conclusion: In this retrospective study of 300 patients with PCNSL with PET-CT scans without signs of systemic lymphoma outside CNS, we found no cases with BM infiltration of DLBCL. A small proportion of patients with PCNSL have a discordant, often low-grade lymphoma in the bone marrow. With a sample size of 300, the chance of overlooking DLBCL infiltration in the BM is ≤ 1 % (95% CI). Therefore, the results of this, so far the most extensive study evaluating BMB in PCNSL in the PET-CT era, suggest that BMB can safely be omitted in patients with PCNSL of DLBCL histology and no signs of systemic lymphoma on PET-CT scans.

Predictors of Adverse Clinical Outcome in Diffuse Large B-Cell Lymphoma Richter Transformation of CLL/SLL: A Consortium of Richter Transformation Investigators (CORTI) Multicenter Study across 8 US, UK, and Australian Academic Centers

Background Richter transformation (RT) of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a known but uncommon complication with dismal prognosis despite improvements in CLL outcomes with novel agents. Previously published studies are characterized by cohort heterogeneity with respect to CLL treatments (predating the rituximab era and novel agents) and RT histology [diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (cHL)], limiting their generalizability in the modern era. To this end, we examined characteristics and outcomes in 222 DLBCL-RT cases, enriching for patients treated with novel agents. Methods We collected 247 RT cases diagnosed between 1995-2022 across eight academic institutions, excluding 23 with cHL-RT and 2 with "pseudo-transformation" after BTKi withdrawal (final n = 222; 41% of cases post-2010). We analyzed > 65 CLL/RT biologic, pathologic, and clinical parameters. Primary outcomes included complete response (CR) to first line of therapy [in CLL (iwCLL 2008/2018) and RT (Lugano 2014)] and 5-year overall survival (5yr-OS) after RT, estimated using Cox proportional hazards [yielding hazard ratios (HRs) and 95% confidence intervals (CIs)] and flexible parametric survival models (for prediction of standardized survival). Results The antecedent CLL included: 11% cases with atypical CLL, 84% IGHVUM, and 70% ZAP70+ with 46% and 43% of patients harboring del(13q) and del(17p), respectively. CLL/RT was synchronous (CLL diagnosis within 2 months of RT diagnosis) in 13% of cases. Only del(17p) correlated with C/HC (≥ 3 / ≥ 5 chromosome abnormalities) karyotype (p < 0.0001), and ZAP70/CD38 had no association with IGHV status. RT was primarily nodal (47.3%), non-GCB (90.3%), and EBV-negative (95%) with p53 IHC-positive large cells in 60% of cases and MYC translocation in 10%. Preceding CLL was treated with a median of 2 lines of therapy (range: 1-7) with 53% heavily-treated (≥ 2 lines). The most common first lines (LOT1) were chemotherapy (fludarabine-based or bendamustine/CHOP equivalents; 73.6%) and BTKi/novel agents (17%); 37% received BTKi as any LOT, while 44% received any novel agent (BTKi, BCL2i, PI3Ki, or SYKi). CLL CRLOT1 was achieved in 41.2% with overall response of 77%. Median time to RT from CLL diagnosis (sequential group) was 47.6 months pre-2010 (IQR: 87.8) vs. 21.8 months post-2010 (IQR: 34.6, p < 0.0001). During a median follow up of 10.2 months (IQR: 27.1 months) post-RT, 59% of patients died. Median OS was 17.4 months (range: 11.3-24.2) with 28% 5yr-OS. In the pre-rituximab era (i.e. prior to 2010), median OS was significantly shorter compared to the present era (8 vs. 19.9 months). Indicators of inferior 5yr-OS on univariable analysis included: sequential transformation (HR: 2.34 [95% CI: 1.25-4.35]), not achieving CRLOT1 for CLL (HR: 1.62 [95% CI: 1.01-2.58]), heavily-treated CLL (HR: 1.98 [95% CI: 1.36-2.88]), and C/HC karyotype (HR: 1.59 [95% CI: 1.02-2.46]). While trisomy 12 predicted superior outcome (HR: 0.54 [95% CI: 0.32-0.94]), del(13q) and del(17p) had no impact. Adverse baseline covariates at RT diagnosis were low (< 3.5 g/dL) serum albumin (HR: 3.13 [95% CI: 2.09-4.69]), low (< 150x103/uL) platelet count (HR: 2.38 [95% CI: 1.64-3.47]), LDH > 1.5x ULN (HR: 1.63 [95% CI: 1.12-1.38]), and ECOG-PS ≥ 2 (HR: 2.4 [95% CI: 1.51-3.81]). Notably, p53 IHC positivity in RT predicted increased all-cause mortality (HR: 2.13 [95% CI: 1.27-3.5]), retaining significance in both minimally- and heavily-treated CLL subsets. RT was treated using CHOP-R or EPOCH-R in 62%. Not achieving CRLOT1 for RT predicted worse 5yr-OS (HR: 3.90 [95% CI: 2.09-7.29]). A multivariable, main effects Cox model was constructed using five variables (age at transformation, CLL treatment number, LDH > 1.5x ULN, albumin, and p53 IHC). In this age-adjusted model, all variables retained adverse prognostic significance (Figure 1). Marginal OS was predicted by p53 IHC, standardizing over remaining covariates, and with a trend towards inferior 5yr-OS in p53-positive vs. -negative RT (13% vs. 38%; Figure 2). Conclusion This multicenter, international study is the largest cohort of RT in the era of novel therapies with solely DLBCL histology. We confirmed the utility of several traditional predictors. In addition, we identified p53 IHC as a promising predictor of adverse outcome (in univariable and multivariable analyses) based on these preliminary analyses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Role of local treatment in primary breast B-cell non-Hodgkin's lymphoma: a propensity score matching-based analysis from SEER database.

Primary breast lymphoma (PBL) has been defined as disease localized to breast with or without ipsilateral axillary nodal involvement. Primary breast B-cell non-Hodgkin's lymphoma is rare to be diagnosed clinically. The role of surgery and radiotherapy (RT) as local treatment is unclear. The aim of this study was to evaluate the prognostic factors and investigate the effect of local treatment in patients with primary breast B-cell non-Hodgkin's lymphoma. We identified patients with primary breast B-cell non-Hodgkin's lymphoma diagnosed between 1998 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was performed to reduce possible bias between groups. The overall survival (OS) and disease-specific survival (DSS) were calculated using the Kaplan-Meier method. Multivariate Cox regression analysis was used to identify independent prognostic factors. Altogether 956 patients with primary breast B-cell non-Hodgkin's lymphoma were included. Most patients were white women over the age of 60. The most common histological type was diffuse large B cell lymphoma (DLBCL), and most patients present with stage I disease. Furthermore, old age (>60 years), DLBCL histology and stage IIE disease were the statistically significant factors associated with worse OS and DSS. Surgery did not improve survival of patients, and surgery combined with RT did not achieve a better prognosis than RT alone. RT was associated with better survival in patients with stage IE DLBCL, but patients with stage IE MZL and FL and stage IIE primary breast B-cell non-Hodgkin's lymphoma could not benefit from RT. In local treatment, surgery offered no survival benefit for patients with primary breast B-cell non-Hodgkin's lymphoma, while RT is an effective choice because it can improve both OS and DSS in the stage IE DLBCL subgroup.

Blinatumomab for Patients with Richter's Syndrome: A Multicenter Phase 2 Trial from the Filo Group

BackgroundRichter syndrome (RS) refers to the onset of aggressive lymphoma, mostly diffuse large B cell lymphoma (DLBCL), in patients with chronic lymphocytic leukemia (CLL). The outcome of RS patients is usually very poor with both low response rates to chemoimmunotherapy and short survival. While BCR and BCL2 inhibitors have transformed the management of CLL patients, these drugs do not prevent the onset of RS. Modulating anti-tumor immunity has recently been suggested as a promising approach in RS (Ding, 2017).Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells, inducing T-cell activation and subsequent lysis of tumor cells. It has been approved for the treatment of patients with relapsed or refractory B-ALL and has also been evaluated in the setting of persisting minimal residual disease. Recently, blinatumomab (stepwise dosing 9-28-112 μg/d) has been evaluated in patients with relapsed or refractory DLBCL and demonstrated promising results (ORR 43%) with acceptable safety (Viardot, 2016).We hypothesized that blinatumomab would improve response in RS patients failing to achieve CR after initial debulking with R-CHOP.MethodsWe report here the first results of a phase 2 multicenter study investigating the efficacy and safety of blinatumomab after R-CHOP debulking therapy for patients with untreated RS of DLBCL histology (NCT03931642). The patients with persisting (PR, SD) or progressive disease (PD) after 2 cycles of R-CHOP were eligible to receive an 8-week course of blinatumomab induction. Blinatumomab was administered at a stepwise dose of 9 μg/d in the first week, 28 μg/d in the second week, and 112 μg/d thereafter. The primary endpoint was CR rate according to the revised Lugano criteria after the 8-week induction course of blinatumomab. An additional 4-week consolidation cycle was optional. Allo-HSCT was further allowed for eligible patients.ResultsA total of 34 patients out of 41 has already been enrolled in the trial to date. Median age was 66 years (range, 38-82) and sex ratio M/F was 23/12. CLL features at baseline were as follows: 57% had 17p deletion and 67% TP53 mutations. Sixty-five percent had complex karyotype and 79% unmutated IGHV status. Median number of prior therapeutic lines for CLL was 2 (range, 0-7): 19 (54%) patients previously received chemo-immunotherapy, 23 (66%) patients were exposed to ibrutinib and 11 (31%) to venetoclax.As of the data cut-off of June 1st, 2021, the blinatumomab induction course has been completed for 18 patients. Ten patients did not receive blinatumomab for the following reasons: 7 patients achieved CR after R-CHOP, 2 patients died because of febrile neutropenia after R-CHOP and 1 patient presented severe pneumonia after R-CHOP. Three patients are still on R-CHOP and 3 others on blinatumomab to date.Regarding toxicity during blinatumomab, data are available for the 18 patients having completed the blinatumomab induction to date. All patients had at least one grade 1 adverse event (AE), 10 had grade ≥3 AE. The most common AE (> 1 case), regardless of relationship to blinatumomab, were fever (4 patients), CRS (2 patients), sepsis (2 patients), vein thrombosis (2 patients), anemia (4 patients), neutropenia (3 patients), lymphopenia (5 patients), thrombocytopenia (3 patients) and hyperglycemia (5 patients). In terms of neurologic events, 5 (28%) experienced neurotoxicity (all recovered) including grade 3 encephalopathy, grade 4 confusion, grade 3 anxiety, grade 1 myoclonus, grade 2 ataxia, grade 1 sleep disorder and grade 1 ICANS (each in 1 pt). Blinatumomab was temporarly stopped in 3 patients and permanently in 2.In terms of efficacy, after R-CHOP debulking therapy (n=31 evaluable patients), 7 patients achieved CR, 6 patients were in PR, 7 patients were stable and 11 patients were progressive. At evaluation after the blinatumomab induction (n=18 evaluable patients), 4 (22.2%) patients achieved CR, 4 (22.2%) patients PR, 2 (11.1%) patients were stable and the remaining 8 (44.5%) were progressive. Considering the whole strategy (including R-CHOP debulking) (n=28), 15 (54%) patients achieved overall response including 11 (39%) CR.ConclusionsOur preliminary data suggest that blinatumomab suggests encouraging anti-tumor activity and acceptable toxicity in patients with RS. DisclosuresYsebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. Ferrant: AstraZeneca: Honoraria; Janssen: Other: Travel, Accommodations, Expenses; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses. de Guibert: Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Laribi: Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Novartis: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; IQONE: Other: Personal Fees; Jansen: Research Funding; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; AbbVie: Other: Personal Fees, Research Funding. Feugier: Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. OffLabel Disclosure:blinatumomab is approved for acute lymphoblastic leukemia. The aim of this phase 2 study is to evaluated it in patients with Richter's syndrome.

Ingle-Institutional Experience with the Use of PD-1 Inhibitors for the Treatment of Richter's Syndrome

BACKGROUNDRichter's syndrome (RS), an aggressive lymphoma in a chronic lymphocytic leukemia (CLL) patient, has a poor prognosis and new therapies are needed. Recently, a clinical trial of the programmed death receptor-1 (PD-1) blocking antibody, pembrolizumab, in relapsed CLL and RS reported responses in RS. Two PD-1 inhibitors, nivolumab and pembrolizumab, are approved by the US FDA for other cancers. Based on reported responses in RS with pembrolizumab and the favorable toxicity profile of these agents we have prescribed them for RS outside of clinical trials. We reviewed our institutional experience. METHODSMedical records of all patients with a diagnosis of RS treated outside of a clinical trial with at least 1 dose of either pembrolizumab or nivolumab at the Ohio State University (OSU) were reviewed. Baseline characteristics, CLL and RS disease features, and treatment were abstracted from medical records. Treatment failure was defined as disease progression documented by the treating physician, start of a new treatment for RS other than planned allogeneic stem cell transplant, or death while taking a PD-1 inhibitor. Time to treatment failure was calculated from initiation of a PD-1 inhibitor. Patient and disease characteristics were described using summary statistics and time to treatment failure and overall survival were estimated using the method of Kaplan-Meier. RESULTSA total of 10 patients received PD-1 inhibitors for RS. The median age was 69 (range 52-79) and 4/10 (40%) were men. The median time from CLL diagnosis to biopsy demonstrating RS was 8.1 (range 1-14) years. The cohort was enriched for high-risk genetic features in the underlying CLL: 8/10 (80%) IGHV unmutated, 7/10 (70%) deletion 17p by FISH, and 5/10 (50%) complex CLL karyotype. Patients had a median of 3.5 (range 1-11) treatments for CLL prior to RS diagnosis and all 10 had prior BTK inhibitor exposure. All patients had biopsy proven RS with diffuse large B-cell lymphoma histology. The PD-1 inhibitor used was nivolumab in 7/10 (70%) patients and pembrolizumab in 3/10 (30%). The majority of patients (6/10, 60%) received a PD-1 inhibitor as an initial treatment for RS, and the median time from RS biopsy to first dose of PD-1 inhibitor was 27 (range 13-86) days. Three patients had 1 prior RS treatment: R-EPOCH, rituximab and high-dose methylprednisolone, or radiation therapy, respectively. One patient was more extensively pre-treated and had received hyper-CVAD, pulse dexamethasone, radiation therapy, and single-agent rituximab. For patients that received nivolumab the total number of doses was known for 6/7 (86%) and the median doses received was 2.5 (range 1-5). For patients treated with pembrolizumab the number of doses received was known for 2/3 (67%) patients with 1 patient receiving only 1 dose and 1 receiving 10 doses. One patient in each drug group received doses outside of OSU. In 4/10 (40%) cases a targeted therapy for CLL was given concurrently with the PD-1 inhibitor. This was single agent ibrutinib in 3 cases and combination ibrutinib and venetoclax in 1. Two of these patients were taking the targeted therapy at the time of developing RS and the PD-1 inhibitor was added. Therapy outcome was known for all 10 patients. The majority of patients (9/10, 90%) had treatment failure: 3 had disease progression, 2 started a new therapy due to lack of response, and 4 died prior to documentation of response. Median time to treatment failure from the first dose of PD-1 inhibitor was 36 days (95% CI: 4-56 days) (Figure 1). Only 1 patient received a sustained course of a PD-1 inhibitor (pembrolizumab) and underwent allogeneic stem cell transplant without experiencing RS relapse. That patient had disease features distinct from the rest of the cohort in that the only site of RS was brain parenchyma and they had a complete resection at time of diagnosis. Median overall-survival for the cohort from RS biopsy was 123 (95% CI: 33-not reached) days with median follow-up of 125 days and 4/10 (40%) of patients were alive at last follow-up. CONCLUSIONSReview of our institutional experience with the use of PD-1 inhibitors for the treatment of RS demonstrates poor efficacy with a very short time to treatment failure. This may be due to the aggressive nature of RS or a highly enriched population of patients already on immune modulatory therapy with ibrutinib. Our data do not support the use of monotherapy PD-1 inhibitors outside of clinical trials for RS. [Display omitted] DisclosuresByrd:Genentech: Research Funding; Janssen: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S.

PRIMARY ORAL CAVITY LYMPHOMAS (POCL). FEATURES OF 67 PATIENTS TREATED AT A SINGLE INSTITUTION IN ARGENTINA

Introduction: POCL represents 2-8% of head and neck cancers. They are characterized by their locoregional growth, low specificity of the initial symptoms, and a predominance of aggressive histology. Objective: To describe the characteristics of 67 patients with POCL. Methods: the medical records and pathological anatomy studies of patients admitted to the Hematology and Stomatology Services between the years 1996 and 2020 were evaluated. Results: Ages: 19 to 88 years old, mean: 52; Masc. 44 and, Fem. 23. Locations: lower jaw: 45% upper jaw 27%, base of tongue 13%, hard palate 11%, floor of mouth 4%. Histology: diffuse large B-cell lymphoma (DLBCL): 52%, plasmablastic lymhoma (PBL): 24%, Follicular L 10%; PTCL NOS 7%; Burkitt 2%, NK/T-cell L: 1,5%; MALT: 1,5%. Stages: I: 66%, II: 25% IV: 9%, due to bone marrow infiltration Increased LDH was observed in 33% of patients, β-2microglobulin in 23%, and erythrocyte sedimentation in 23%. Toxic antecedents: tobacco 30% and dental prostheses in 15%. The initial symptoms were mobility and pain of the teeth, a rapidly growing painful tumor in the jugal mucosa, and torpid oral ulcers. HIV positive in 16 patients, 13 with PBL and 7 with DLBCL. Treatment: it was carried out according to the histology, the patient's PS, viral status and date of diagnosis. The following regimes were used: CHOP, R-CHOP, CVP; R-CVP, CAVPE, CNOP; DA-EPOCH. In 15 patients there are no data on the treatment carried out. 6 cases received local radiotherapy. CNS prophylaxis with systemic methotrexate or intrathecal drugs was performed according to the schedule chosen and the patient's risk factors. Responses: complete remission (CR) in 37%, partial remission (PR) in 16% of those who underwent treatment. There's no data in 22 patients due to loss of follow-up. Follow-up time ranged from 1 year to 21 years. Conclusions: In this series of patients, we observed most aggressive histology, with fast growing locoregional tumors. Dental alterations led to consultations with stomatologists, who took diagnostic biopsies. There was a predominance of males, of B lineage, with middle ages predominate. The IPI and the stage were not useful tools for the evaluation of this pathology. The association with HIV was observed in 28% of the cases, the majority were PBL (68%), with increased DLBCL histology. Favorable responses were observed, with prolonged survival in cases with less aggressive histology. Keywords: Extranodal non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV− HIV− PCNSL and 2 EBV− HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV− PCNSL. As with prior studies, EBV− HIV− PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV− PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV− HIV− PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.

Management and Outcomes of Testicular Lymphoma in the Rituximab Era at an Australian Tertiary Centre

INTRODUCTION Testicular lymphoma accounts for &amp;lt;5% of all testicular neoplasms and 1-2% of non-Hodgkin's lymphoma (NHL). Historically, outcomes for testicular lymphoma have generally been inferior to systemic diffuse large B cell lymphoma (DLBCL) with a higher incidence of central nervous system (CNS) relapse. Although intrathecal methotrexate is currently considered standard of care for testicular lymphoma, there has been significant debate about its efficacy in preventing CNS relapse. Due to the rarity of testicular lymphoma, prospective data in this field is lacking. Our study aims to examine treatment practices and outcomes for all newly diagnosed patients with testicular lymphoma in a large tertiary centre in Australia since the introduction of rituximab. METHODS We conducted a retrospective review of all patients diagnosed with primary testicular lymphoma (PTL) between 2003 and 2019 at the Princess Alexandra Hospital, Brisbane, Queensland, Australia (Human Research Ethics Approval: LNR/2019/QMS/56644). RESULTS During this period, 18 patients were diagnosed with PTL; all patients had DLBCL histology. The median follow-up period for living patients was 6.5 years (range 1.3-13.4 years). The median age was 61.3 years (interquartile range: 58.3 - 71.1 years). All patients were HIV negative. The majority of patients had an Eastern Cooperative Oncology Group (ECOG) score of zero (n = 13; 72.2%) with no B symptoms (n = 14; 77.7%) and a normal LDH (n = 11; 61.1%). 50% of patients had Stage IV disease (Table 1). 17 patients (94.4%) underwent an orchidectomy (unilateral: 16, bilateral: 1) at diagnosis. Following on, as first-line systemic therapy, 14 patients (77.7%) received R-CHOP chemotherapy. Other regimens used were CHOP (n=1), modified HyperCVAD (n=1), R-HyperCVAD (n=1) and R-CVP (n=1). 17 patients (94.4%) received CNS prophylaxis with intrathecal chemotherapy; one patient declined intrathecal therapy and was given high dose intravenous methotrexate instead. 15 (83.3%) patients received loco-regional radiation therapy. Outcomes to first-line treatment were: 13 patients (72.2%) achieved complete remission (CR); one patient (5.5%) achieved partial remission (PR) (Deauville score 4 on interim PET assessment, prompting escalation to salvage therapy); three patients (16.6%) had progressive disease (and were subsequently managed with salvage chemotherapy) and one patient elected for palliation after a single cycle of R-CVP. Among the four patients who received salvage therapy, two patients (50%) achieved CR and two patients had progressive disease and were palliated. Among the 15 patients who achieved CR (n=13 R-CHOP; n=2 salvage chemotherapy), two patients relapsed, and both had CNS involvement (n=1 CNS only relapse; n=1 CNS and systemic relapse). Despite intrathecal prophylaxis, the CNS relapse rate was 12% (n=2/17). Of note, the patient who did not receive intrathecal chemotherapy remained in CR at the date of last follow-up. In total, there were seven deaths. The causes of death were: lymphoma (n=4), treatment-related mortality (n=2) and other (n=1; due to aspiration pneumonia after stroke). The 2-year and 5-year progression free survival (PFS) rates were 77.8% and 52.4%, respectively (Figure 1A). The 2-year and 5-year overall survival (OS) rates were 83.3% and 56.8%, respectively (Figure 1B). CONCLUSION With the practice of R-CHOP, intrathecal prophylaxis for CNS disease and loco-regional radiation therapy, our outcomes are comparable to the literature (5y OS ~50%). Despite intrathecal prophylaxis, our CNS relapse rate was 12%. Better strategies are required to improve the control of systemic disease and reduce the incidence of CNS relapse in patients with testicular lymphoma. Disclosures Mollee: Janssen:Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS/Celgene:Membership on an entity's Board of Directors or advisory committees;Amgen:Membership on an entity's Board of Directors or advisory committees;Takeda:Membership on an entity's Board of Directors or advisory committees;Pfizer:Membership on an entity's Board of Directors or advisory committees;Caelum:Membership on an entity's Board of Directors or advisory committees.

Analysis of Adct-602 Pre-Clinical Activity in B-Cell Lymphoma Models and Identification of Potential Biomarkers for Its Activity

Analysis of Adct-602 Pre-Clinical Activity in B-Cell Lymphoma Models and Identification of Potential Biomarkers for Its Activity

Blinatumomab after R-CHOP Debulking Therapy for Patients with Richter Transformation: Preliminary Results of the Multicenter Phase 2 Blinart Trial from the Filo Group

Background Richter syndrome (RS) refers as to the onset of aggressive lymphoma, mostly diffuse large B cell lymphoma (DLBCL), in patients (pts) with chronic lymphocytic leukemia (CLL). The outcome of RS pts is usually very poor with both low response rates to chemoimmunotherapy and short survival, except for the minority of them whose tumor cells are clonally unrelated to the underlying CLL. While BCR and BCL2 inhibitors have transformed the management of CLL pts, these drugs do not prevent the onset of RS. Modulating anti-tumor immunity has recently been suggested as a promising approach in RS (Ding, 2017). Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells, inducing T-cell activation and subsequent lysis of tumor cells. It has been approved for the treatment of pts with relapsed or refractory B-ALL and has also been evaluated in the setting of persisting minimal residual disease. More recently, blinatumomab (stepwise dosing 9-28-112 μg/d) has been evaluated in pts with relapsed or refractory DLBCL and demonstrated promising results (ORR 43%) with acceptable safety (Viardot, 2016). We hypothesized that blinatumomab would improve response in RS pts failing to achieve CR after initial debulking with R-CHOP. Methods We report here the first results of a currently ongoing phase 2 multicenter study investigating the efficacy and safety of blinatumomab after R-CHOP debulking therapy for pts with untreated RS of DLBCL histology (NCT03931642). The pts achieving complete remission (CR) after 2 cycles of R-CHOP21 discontinued study while those with persisting (PR, SD) or progressive disease (PD) were eligible to receive an 8-week course of blinatumomab induction. An additional 4-week consolidation cycle was optional and might be proposed according to the treating-physician decision, especially in pts who were ineligible for stem-cell transplantation. Blinatumomab was administered at a stepwise dose of 9 μg/d in the first week, 28 μg/d in the second week, and 112 μg/d thereafter. The primary endpoint was CR rate according to the revised Lugano criteria after the 8-week induction course of blinatumomab. Interim analysis (Simon two-stage design) was planned after completion of blinatumomab induction in 10 pts. Results A total of 15 pts out of 35 has already been enrolled in the trial to date. Median age was 67 years (range, 38-80) andsex ratioM/F was 12/3. CLL features at baseline were as follows: 9/15 (60%) pts hadTP53alterations and 10/13 (77%) unmutated IGHV status. Median number of prior therapeutic lines for CLL was 2 (range, 0-4): 10 (67%) pts previously received chemo-immunotherapy, 10 (67%) pts were exposed to BCR inhibitors and 3 (20%) to venetoclax. As of the data cut-off of July 1st, 2020, the blinatumomab induction course has been completed for 5 pts while it is still on-going in 3 others. Three pts are still on R-CHOP debulking. Four pts discontinued study before receiving blinatumomab for the following reasons: 2 pts achieved CR after R-CHOP, 1 patient died because of febrile neutropenia after R-CHOP and 1 patient discontinued study before starting R-CHOP (no RS criteria after pathology review). Regarding toxicity during blinatumomab, data are available for the 5 pts having completed the blinatumomab induction to date. Four pts had at least one grade 1 adverse event (AE), 2 had grade ≥3 AE. The most common AE, regardless of relationship to blinatumomab, were grade 1 fever (2 pts) and grade 2 leukopenia (2 pts). Other grade &amp;gt;1 AE were observed in 1 pt only (grade 3 anxiety, grade 2 anemia, grade 2 neutropenia, grade 3 lymphopenia). In terms of neurologic event, 1 pt had grade 1 AE (paresthesia, myoclonus and muscle contraction) and another one presented grade 4 confusion while on first 9 μg/d dose leading to permanent discontinuation of blinatumomab. In terms of efficacy, after R-CHOP debulking therapy (n=10 evaluable pts), 2 pts achieved CR (and did not pursuit on study), 5 pts were in PR and 3 pts were progressive. At evaluation after the blinatumomab induction (n=5 evaluable pts), 2 pts achieved CR, 1 patient PR and 2 pts were progressive. Conclusions Our preliminary data suggest that blinatumomab shows encouraging anti-tumor activity and acceptable toxicity in pts with RS. Further analyses are warranted to validate these conclusions. Updated efficacy/safety in the remaining pts enrolled in the trial will be presented at the meeting. Disclosures Guieze: astrazanecka:Honoraria, Other: advisory board;gilead:Honoraria, Other: travel funds;janssen cilag:Honoraria, Other: advisory board, travel funds;roche:Other: travle funds;abbvie:Honoraria, Other: advisory board, travel funds.Ysebaert:AbbVie:Consultancy;Janssen:Consultancy;Roche:Consultancy.Fornecker:Roche:Consultancy;Takeda:Consultancy.Broséus:Gilead:Honoraria;AstraZeneca:Consultancy, Honoraria;Janssen:Honoraria, Research Funding;Novartis:Honoraria, Research Funding.Feugier:astrazeneca:Consultancy, Honoraria, Research Funding;abbvie:Consultancy, Honoraria, Research Funding;roche:Consultancy, Honoraria, Research Funding;gilead:Consultancy, Honoraria, Research Funding;janssen:Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells. It has been approved as a second line treatment for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia.

Epidemiology, outcomes, and prognostic factors of orbital lymphoma in the United States

ABSTRACT Purpose We performed an epidemiological study of orbital lymphoma in the United States to determine how histological subtypes confer differing prognosis, and understand other factors associated with survival. Methods All patients in the Surveillance, Epidemiology and End Results database diagnosed with a histologically confirmed orbital lymphoma between 1973 and 2014 were included. Exclusion criteria included diagnosis at autopsy and the presence of other malignancies. Measures included patient demographic information, histological subtype and treatment modalities. Outcomes included overall and disease specific survival. Results Of the 1504 cases identified, 702 were male (46.7%, mean age: 64.4 years, standard deviation [SD]: 15.3) and 802 were female (53.3%, mean age: 67.5 years, SD: 14.3). Mucosal associated lymphoid tissue (MALT) (49.5%) and diffuse large B cell lymphoma (DLBCL) (19.5%) were the two most common histologic subtypes. MALT lymphoma conferred the best prognosis (10-year cancer specific survival [CSS] 90.2%, 95% Confidence Interval [CI] 87.4% – 93.1%) and DLBCL conferred the worst prognosis (10-year CSS 68.6%, 95% CI 62.5% – 75.3%) (p < .001, log-rank test). Older age (Hazard Ratio [HR]: 3.71, 95% Confidence Interval [CI]: 2.94–4.66, p < .001), male sex (HR: 1.22, 95% CI: 1.039–1.441, p = .015), no radiation (HR: 1.72, 95% CI: 1.46–2.02, p < .001) and DLBCL histology were significant predictors of worse overall survival. Conclusions DLBCL histology confers the worst outcomes whereas MALT lymphoma confers the best outcome in orbital lymphoma. Age, gender, and radiation treatment also influence survival. These epidemiological results can be used clinically to communicate outcomes on the basis of patient characteristics and disease histology.

Primary Thyroid Lymphoma: An Analysis of the National Cancer Database.

IntroductionPrimary thyroid lymphoma (PTL) is a rare malignancy, representing only 1% to 5% of thyroid malignancies and 2.5% to 7% of all extranodal lymphomas. Most cases of PTL are of B-cell origin, and 98% of all PTL cases are non-Hodgkin’s lymphoma. Case series and case reports represent the majority of the available studies on PTL, with a paucity of large retrospective population studies available for this disease. This is the first National Cancer Database (NCDB) study completed on PTL and the only large retrospective study to examine the use of chemotherapy and immunotherapy in the treatment of this specific population.MethodsThe NCDB for non-Hodgkin's lymphoma was utilized to identify 3,466 patients diagnosed with PTL between 2004 and 2015. The database was used to examine demographic information including age, race, gender, histology, stage, and treatment modality. Bivariate Kaplan-Meier analysis with log-rank tests was used to analyze overall survival. Multivariate analysis was performed with Cox proportional hazards regression models to obtain hazard ratios to assess the association of patient characteristics and treatment methods with survival.ResultsThe median all-cause survival for PTL was 11.6 years (95% confidence interval [CI]: 11.1 to 12.1 years). The majority of PTL patients were female (68%) and white (93%), with a mean age of 65.8 years. Histologically, 59.5% of cases were diffuse large B-cell lymphoma (DLBCL), 18.3% marginal zone lymphoma, 8% follicular lymphoma, and 1.9% Burkitt lymphoma. Regarding treatment, 40.6% received beam radiation, and 54% underwent surgical resection. Single-agent chemotherapy was used in only 3.5% of patients, where 60.7% received multiagent chemotherapy. Additionally, immunotherapy was used in 16.2% of patients.There was a significantly increased risk of mortality associated with increasing age, DLBCL histology, and higher disease stage. Multivariate analysis of treatment methods revealed that lobectomy (hazard ratio [HR]: 0.58, 95% CI: 0.47-0.73) and total or subtotal thyroidectomy (HR: 0.58, 95% CI: 0.47-0.71) had significantly improved survival rates over no surgical management (p < 0.001). Beam radiation (HR 0.67, 95% CI: 0.58-0.79) had a significant survival benefit over treatment regimens that did not include radiation therapy (p < 0.001). Multiagent (HR: 0.40, 95% CI: 0.33-0.49) and single-agent chemotherapy (HR: 0.43, 95% CI: 0.30-0.63) had significant improvement over treatment regimens that did not include chemotherapy (p < 0.001). Immunotherapy had a survival benefit (HR 0.87) although this was not found to be statistically significant (95% CI: 0.68-1.11). Other factors associated with decreased risk of mortality include treatment at academic medical centers (HR: 0.846) and integrated cancer centers (HR: 0.76) as compared to community centers (p < 0.05).ConclusionThis is the largest study to date of PTL and the first to analyze the NCDB database. Patient characteristics, treatment modalities, and overall survival in PTL were examined to further characterize this rare disease. Beam radiation, chemotherapy, and surgical resection all reveal significant survival benefit, with multiagent chemotherapy having the greatest advantage.