C-myc Rearrangements Research Articles

Plasmablastic lymphoma: current knowledge and future directions.

Plasmablastic lymphoma (PBL) is an aggressive non-Hodgkin lymphoma associated with HIV infection and immunodeficiency. However, PBL can also be seen immunocompetent individuals in recent studies. PBL was characterized by distinct clinical and pathological features, such as plasmablastic morphology and universal expression of plasma cell markers. The clinicopathologic features were different between HIV-negative and HIV-positive patients. Gene expression analysis identified the unique molecular feature in PBL, including frequent c-MYC rearrangement and downregulation of BCR signaling pathway. Despite the recent advances in the treatment of PBL, the prognosis of PBL patients remains dismal. The objectives of this review are to summarize the current knowledge on the epidemiology, molecular profiles, clinical and pathological features, differential diagnosis, treatment strategies, prognostic factors, and potential novel therapeutic approaches in PBL patients.

Treatment of Relapsed/Refractory Hgbcl and Bukitt's Lymphoma with c-Myc Rearrangement: A Multi-Center, Open-Label, Phase 2 Study of PC-002 (SepB), a First-in-Class Deubiquitinase Inhibitor Inducing Myc Degradation

Background: Burkitt lymphoma (BL) is one of the most aggressive B cell malignancies that is a high unmet need and characterized classically by c-Myc rearrangement. However, c-Myc is considered “undruggable” due to its structure and a lack of kinase activity. Degradation of c-Myc is mediated through the ubiquitin-proteasome system. Therefore, modulation of deubiquitination catalysis process may reduce the stability of c-Myc. PC-002 (also known as Sepantronium Bromide, or SepB) is a small molecule previously identified as a survivin suppressant with antitumor activity against a range of tumor types. More recently, we discovered that PC-002 has another novel mechanism of targeting cancers with Myc gene amplification by inhibiting the deubiquitinase activity of ubiquitin-specific proteases (USPs), which leads to Myc protein degradation. Preclinically, PC-002 shortens the half-life of c-Myc protein, induces rapid apoptosis of cells with c-Myc rearrangement, and demonstrates rapid tumor regression in c-Myc-rearranged BL and high grade B cell lymphoma (HGBCL) murine xenograft models. This discovery prompted us to initiate a Phase 2 proof-of-concept clinical trial in patients with relapsed/refractory c-Myc rearranged HGBCL, including Burkitt Lymphoma ( https://clinicaltrials.gov/ ct2/show/NCT05263583). Aims: The aim of this trial ( https://clinicaltrials.gov/ct2/show/NCT05263583) is to study safety and efficacy of PC-002 as monotherapy for c-Myc rearranged HGBCL, including Burkitt Lymphoma. Methods: NCT05263583 is a multicenter, open-label, Phase 2 dose-finding study of PC- 002 (Sepantronium Bromide, or SepB) in patients with relapsed/refractory HGBCL and Burkitt's lymphoma with c-Myc rearrangement. Patients will be treated with escalating doses (3.6 and 4.8 mg/m 2/day) of single-agent PC-002 administered by continuous intravenous infusion for 168 hours in 21-day cycles at two dose levels. The primary objective is to determine the safety, tolerability and recommended Phase 2 dose of PC-002. Cohorts of three patients will be enrolled at each dose level for PC-002 with expansion to six patients, if necessary, to assess toxicity. An additional 6 patients will be enrolled at the RP2D. Secondary objectives are Objective Response Rate (ORR), Duration of Response (DoR), Clinical Benefit Rate (CBR), Overall Survival (OS) and Progression-Free Survival (PFS). Exploratory objectives are aimed to measure PC-002 exposure and its relationship to clinical outcome and to assess the relationship between biomarkers and PC-002 efficacy. Results: As of 28 July 28, 2023, 3 patients of cohort 1 (3.6 mg/m 2/day) with a median age of 33 years (range 19-67 years) had received ≥ 2 cycles of dosing (A cycle is defined as 7 days of treatment plus 14 days of rest). Two of the patients (2 males) have Burkitt Lymphoma and one (female) has HGBCL (DLBCL-TH). Adverse events deemed related to PC-002 included anemia and neutropenia. No dose-limiting toxicities have been reported. Preliminary assessment by image analysis and Lugano criteria showed partial response (PR) in 2 heavily pre-treated patients with relapsed/refractory BL after receiving 2 cycles of treatment. The duration of response in these two patients was 3 months and patients received at least 4 cycles of treatment. ORR of the 3 patients in Cohort 1 is 66.7% at 3.6 mg/m 2/day dose. To date, 3 patients with a median age of 58 years (range 25-60 years) had been enrolled of cohort 2 (4.8 mg/m 2/day) and completed at least one cycle of treatment. Summary/Conclusion: At the time of abstract submission, the 1 st cohort (3.6 mg/m 2/day) of 3 patients have completed at least four cycles of treatment. PC-002 is generally well-tolerated at 3.6 mg/m 2/day and progression to Cohort 2 at a dose of 4.8 mg/m 2/ day was approved by the Safety Review Committee. Two patients with relapsed/refractory Burkitt Lymphoma at the starting dose of 3.6 mg/m 2/day achieved a confirmed PR. ORR of the 3 patients in Cohort 1 is 66.7% after 2 cycles of 3.6 mg/m 2/day (2 PRs). Three patients have been enrolled in Cohort 2 (4.8 mg/m 2/day) and completed at least one cycle of treatment to date.

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

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

Genomic Profiling of Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System Suggests Novel Potential Therapeutic Targets

Primary diffuse large B-cell lymphoma of the primary central nervous system (CNS-DLBCL) is an aggressive disease, with dismal prognosis despite the use of high-dose methotrexate-based polychemotherapy. Our study aimed to expand the biologic profiles of CNS-DLBCL and to correlate them with clinical/imaging findings to gain diagnostic insight and possibly identify new therapeutic targets. We selected 61 CNS-DLBCL whose formalin-fixed paraffin-embedded samples were available at first diagnosis. These were investigated by immunohistochemistry, cMYC rearrangements were explored by fluorescence in situ hybridization, and CNS-DLBCL mutated genes were evaluated by next-generation sequencing. CD10, BCL6, and IRF4 were observed in 16%, 83.6%, and 93% of cases, respectively. As typical of CNS lymphoma, 10 (16.4%) of 61 cases were classified as germinal center (GCB) type and 51 (83.6%) of 61 as non-germinal center (non-GCB) type according to the Hans algorithm. Double-expression status for BCL2 and cMYC was detected in 36 (59%) of 61 cases whereas 25 (41%) of 61 were non-DE. Rearrangement of the cMYC gene was detected in 2 cases, associated with BCL6 translocation only in 1 case MYD88, PIM1, CD79B, and TP53 were mutated in 54.5%, 53.5%, 30.2%, and 18.4% cases, respectively. Novel mutations not previously reported in CNS-DLBCL were found: AIP in 23.1%, PI3KCA in 15%, NOTCH1 in 11.4%, GNAS in 8.1%, CASP8 in 7.9%, EGFR in 6.4%, PTEN in 5.1, and KRAS in 2.6% of cases. Survival was significantly longer for patients with mutated MYD88 (8.7 months vs 1.7 months; log-rank test = 5.43; P = .020) and for patients with mutated CD79B (10.8 months vs 2.5 months; log-rank test = 4.64; P = .031). MYD88 and CD79B predicted a longer survival in patients affected by CNS-DLBCL. Notably, we identified novel mutations that enrich the mutational landscape of CNS-DLBCL, suggest a role of PTEN-PI3K-AKT and receptor tyrosine kinase-RAS-mitogen-activated protein kinase signaling in a subset of CNS-DLBCL, and provide new potential therapeutic targets.

Causes of death and treatment-related mortality in newly diagnosed childhood acute lymphoblastic leukemia treatment with Chinese Children's Cancer Group study ALL-2015.

To investigate the possible risk factors for death at post-treatment in children with acute lymphoblastic leukemia (ALL). A multivariate competing risk analysis was performed to retrospectively analyze the data of children with ALL who died after treatment with CCCG-ALL-2015 in China and to determine the possible risk factors for death at post-treatment in children with ALL. Age at the first diagnosis of ≥10 years; final risk level of high-risk; D19 minimal residual disease (MRD) (≥0.01%) and D46 MRD (≥0.01%); genetic abnormalities, such as KMT2A-rearrangement, c-Myc rearrangement, and PDGFRB rearrangement; and the presence of CNS3 (all P values, <0.05) were identified as independent risk factors, whereas the risk level at the first diagnosis of low-risk (LR) and ETV6::RUNX1 positivity was considered as independent protective factors of death in children with ALL. Among the 471 cases of death, 45 cases were treated with CCCG-ALL-2015 only, and 163 (34.61%) were treatment-related, with 62.42% due to severe infections. 55.83% of treatment-related mortality (TRM) occurred in the early phase of treatment (induction phase). TRM has a significant impact on the overall survival of pediatric patients with ALL. Moreover, the CCCG-ALL-2015 regimen has a better safety profile for treating children with ALL, with rates close to those in developed countries (registration number: ChiCTR-IPR-14005706; date of registration: June 4, 2014).

A case of triple hit lymphoma and rapid deterioration

Triple hit lymphomas (THL) comprise a rare, heterogenous group of lymphomas and like many B-cell lymphomas, chromosomal translocations are biologic and diagnostic hallmarks of disease. Traditionally referred to as a subset of double hit lymphomas (DHL) in literature, THLs characteristically involve chromosomal rearrangements of c-MYC, BCL-2, and BCL-6 oncogenes. Many case series of high-grade B-cell lymphoma, especially MYC/BCL2 double hit lymphoma, have been described in the literature, but relatively few cases of triple hit lymphoma have been reported. Additionally, without chemotherapy, triple hit lymphomas are known to have a rapid clinical course and poor prognosis compared to double hit lymphomas. Here we present a case of MYC/BCL2/BCL6 triple hit lymphoma in a patient previously diagnosed with marginal B-cell lymphoma at stage IIA after biopsy of intra-abdominal lymph nodes status post one treatment with rituximab and bendamustine. Unfortunately, this patient had a rapid decline and presumed central nervous system (CNS) infiltration and passed away within 30 days of diagnosis.

Images in haematology: Primary cutaneous diffuse large B cell lymphoma, leg type with an unusual presentation: A diagnostic challenge.

An 83-year-old woman with a history of arterial hypertension treated with amlodipine, and a well-differentiated cutaneous squamous cell carcinoma completely excised during the past year, was referred to dermatology consultations for the progressive appearance of indurated nodular skin lesions over the last two months, which began on the right lower extremity and progressed to the upper extremities, trunk and buttocks, with no other symptoms associated. With the differential between cutaneous lymphoma versus subcutaneous metastases, a punch biopsy of one of the lesions was performed. Histopathological examination demonstrated a dense hypodermal infiltrate composed of atypical large lymphocytes showing a round-shaped nucleus with vesicular chromatin and prominent single or multiple nucleoli. The immunohistochemical study showed positivity in neoplastic cells for CD79a, CD20, Bcl-2, MUM-1, c-myc and IgM, along with a high expression of Ki-67; and negativity for CD3, CD10, Bcl-6, CD30, p53, PD-L1 and Epstein-Barr Virus Encoded RNA. Molecular analyses were then performed without detecting BCL-2, BCL-6 or c-MYC rearrangements by fluorescence in situ hybridization, as well as the absence of p.L265P mutation in MYD88 through a quantitative polymerase chain reaction. Taking into account both histopathological and clinical findings, a primary cutaneous diffuse large B cell lymphoma, leg type (PCDLBCL-LT) and skin involvement in the course of a systemic DLBCL were considered, so blood tests and a positron emission tomography (18-FDG PET/CT) were then solicited. Blood tests showed a haemoglobin value of 12.5 g/dl with a normal white blood cell count and a slight β-2-microglobulin elevation (3.33 mg/L) in the context of a decreased renal function (54.38 ml/min/1.73m2). 18-FDG PET/CT revealed 23 hypermetabolic subcutaneous nodules distributed predominantly in the right arm and lower extremities, with no sign of disease in other locations (Figure 1), confirming the primary cutaneous origin of the disease and the final diagnosis of a PCDLBCL-LT. The patient underwent treatment with 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, with progressive improvement of the skin lesions and complete resolution of them, and is currently being followed up by haematology and dermatology departments. Although the majority of PCDLBCL-LT, arise in the lower limbs (80%–85%), some patients can develop the disease in other areas, but in those cases, the lesions are usually individual or few in number, contrary to our case. PET imaging tests have a major role in the initial staging of the disease and treatment response evaluation, and they could even avoid bone marrow biopsy in selected patients. The double expression of bcl-2 and c-myc is frequent in PCDLBC-LT, although the prognostic value of this dual expression is yet unclear, whereas the absence of the MYD88 mutation could be associated with both better response to lenalidomide as well as better prognosis. For these reasons, immunohistochemical and molecular techniques can be helpful in defining prognosis and deciding therapeutic options in patients with PCDLBCL-LT and should be performed in routine practice. In conclusion, we present an extremely rare 18-FDG PET/CT image of a PCDLBCL-LT with 23 subcutaneous nodules, underlying the importance of this test for the study of these patients. Lucía Prieto-Torres – Attending the case and performing clinical research and manuscript revision. Pablo Villagrasa-Boli – Attending the case, revising existing literature and manuscript writing. Luis Ignacio Sancho-Val – Attending the case and manuscript revision. Pedro Paul – Attending the case and manuscript revision. Ana Leticia Tardin-Cardoso – Performing the imaging tests and their clinical interpretation. Mar García-García – Pathology diagnosis, taking microscopic images and manuscript revision. Mariano Ara-Martín – Proof checking. The authors have nothing to report. The authors declare that they have no conflict of interest. No funding has been received for this article.

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.

Expression of c-Myc, Bcl2, Bcl6, and Cyclin D1 in High-Grade B-Cell Lymphoma.

BackgroundHigh-grade B-cell lymphomas (HGBLs), with c-Myc, Bcl2, and/or Bcl6 rearrangement, are aggressive neoplasms with poor clinical outcomes. Cyclin D1 is a proto-oncogene that is generally expressed by mantle cell lymphoma, its variants, and many other neoplasms.AimThe aim of this study is to investigate the expression and frequency of cyclin D1 in HGBL and its association with double expressor and triple expressor lymphomas. A few pieces of research have been reported on the expression of cyclin D1 in triple-hit lymphoma, renaming it quadruple-hit lymphoma. In the present study, we also used immunohistochemical (IHC) stains to look at the expression of cyclin D1 in double expressor and triple expressor.MethodologyThis is a cross-sectional descriptive study involving 60 cases, including both double and triple expressors, diagnosed by using hematoxylin and eosin (H&E) staining with subsequent IHC stains. We analyzed the expression of cyclin D1 in double expressor and triple expressor.ResultsThe expression and frequency of cyclin D1 were interpreted in terms of positivity in double expressors and triple expressors. Cyclin D1 positivity was observed in three (5%) cases of double expressors and two (3.33%) cases of triple expressors. Overall, five (9%) cases of HGBL were positive for cyclin D1.ConclusionThis study showed a very low frequency of cyclin D1 expression in double and triple expressor lymphomas. However, a few cases of HGBL showed expression of cyclin D1 and were not limited to only mantle cell lymphoma and its variants.

P-160 Primary gastrointestinal lymphoma in Latin American patients. A 10-year follow-up

Gastrointestinal lymphomas constitute 10-15% of non-Hodgkin´s Lymphomas and 30-40% of extra-nodal lymphomas. Primary gastric lymphoma (PGL) is the most common site (75%) and is most diagnosed in man with a mean age of 60 years. Even when prognosis is favorable at early stages of disease, most patients are diagnosed with advanced disease and treatment pattern remains under debate with not enough evidence to support optimal management. The aim of this study was to describe incidence, clinicopathological characteristics, treatment modalities and outcome of Latin American patients with PGL treated at the National Cancer Institute. Retrospective, observational study. Included patients diagnosed with EGJ adenocarcinoma, treated at the National Cancer Institute between 2011 and 2021. Statistical analysis required: X2 and t test, Kaplan Meier, Log Rank and Cox Regression. Statistical significance differences were assessed when p was bilaterally < 0.05. A total of 62 patients were included in the analysis. The 63%(n=39) of cases were male with a median age at diagnosis of 61 (26-83) years old. Comorbidities included type 2. Diabetes (14%), and systemic arterial hypertension (21%). Additionally, 42% of patients had history of smoking and alcoholism. History of disease pretreatment was a median of 3.5 (1-40). According to symptomatology, the most prevalent symptoms were weight loss (85%, n= 53), abdominal pain (80%, n= 50), bleeding (60%, n= 37) and vomiting (58%, n= 136). Regarding histology the 90%(n=56) of cases were B cell lineage. Most common immunohistochemistry markers were CD20 (95%; n=59), BCL6 (63%; n=39), and CD10 (47%; n=29), also c-MYC rearrangement was found in (21%; n=13). Respecting clinical stage, most patients were diagnosed at metastatic disease (44%; n=27), the most common extranodal site of disease was the liver (76%). Oncological treatment, the 89% (n=55) were treated with chemotherapy, being CHOP-R scheme the most common modality of treatment. Moreover, the 29% (n=18), received radiotherapy. At OS analysis, the Five-year-OS rate for total population was 54% (95%CI 54.1-85.52). Furthermore, OS analysis was conducted comparing clinical stage, clinical stage I-III patients did not reach the median-OS, compared to patients with metastatic PGL was 11 months (p=0.50). PGL is an uncommon neoplasia known for its bad prognosis and outcome, due most of PGL patients are diagnosed at metastatic disease and historically the management of PGL has been controversial. Nevertheless, the addition of Rituximab to standard chemotherapy have demonstrated to significantly increase the OS of patients. Further studies remain necessary to promote an early diagnosis and to establish the optimal management of PGL.

De Novo CD5-positive diffuse large B-cell lymphoma: A genomic profiling study and prognostic analysis of 46 patients

We reported 46 cases of Diffuse Large B-cell lymphoma which abnormally expressed CD5 protein (De Novo CD5-positive DLBCL), which had attracted researcher's attention for a period of time for its poor prognosis. However, there were few studies on its molecular change. In the present article, we summarized the genetic alterations using a lymphopanel detection method by Next Generation Sequencing(NGS). The most frequently mutated genes were MYD88L265P (20/46, 43.5%), followed by PIMI (19/46, 41.3%), IGLL5 (13/46, 28.3%)and CD79B (11/46, 23.9%). We further investigated the relationship between gene alterations and prognosis using OS(Overall survival) and PFS(Progression-free survival). MYD88, CREBBP, and ACTB mutation were significantly associated with inferior OS (P = 0.032, 0.000, 0.001), PIMI, CREBBP, ACTB and CXCR4 mutation were significantly associated with inferior PFS (P = 0.016, 0.001, 0.045, 0.024). Meanwhile, we found that De Novo CD5-positive DLBCL had BCL-6(9/46,19.6%), C-MYC (4/46, 8.7%) and IRF4 (2/19, 10.5%) rearrangement, but without BCL-2 rearrangement, there were no significantly associations with prognosis. In summary, our research explored the gene alterations of De Novo CD5-positive DLBCL in a relatively large scale for the first time, the most common gene mutation was MYD88L265P which was also a potential prognostic factor, providing a potential therapeutic target for the patients of De Novo CD5-positive DLBCL.

High-grade B-cell lymphoma

Introduction. Aggressive B-cell lymphomas are a heterogeneous group of diseases with various clinical, patohistological, genetic characteristics and a variety of treatment outcomes. Diffuse large B-cell lymphoma is the most common lymphoma in European countries, some lymphomas are recognized as specifically aggressive, providing non-adequate response to the standard treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). High-grade B-lymphomas. One group consists of those which are carriers of the c-myc, bcl-2 or bcl-6 rearrangement established by Fluorescence in situ hybridization, and are called high grade B lymphomas, which can be double hit or triple hit. The other group consists of those with blastoid morphology, which are not carriers of the c-myc, bcl-2 and bcl- 6 rearrangement and are called Not Otherwise Specified. This heterogeneous group is a carrier of a single myc mutation in 45% of cases, in 15% of patients, an additional analysis of gene expression profiling indicates the presence of high grade B lymphomas double hit sig+. Extranodal localization with Central Nervous System involvement is frequently reported. Clinical staging and disease progression along with risk assessment by means of IPI scores and aaIPI scores in patients with high-grade B-lymphomas. Diagnostic procedures during the clinical interview, physical examination, laboratory analyses and various additional diagnostic procedures. High-grade Blymphomas treatment. Studies indicate more intensive induction chemotherapy including central nervous system prophylaxis for these patients. Conclusion. The question of how to choose the most effective therapeutic strategy in high grade B lymphomas is still open at this moment, and examinations are focused on the research of molecular mechanisms of lymphomagenesis.

Tre-P-28 - Primary cutaneous B-cell lymphoma leg-type related to an anti-TNF-alpha therapy

<h3>Introduction:</h3> Drug-induced primary cutaneous B-cell lymphomas are rare. <h3>Observation:</h3> A 63 year old woman was referred for a lumbar cutaneous lesion which had been rapidly growing for 1 month. Her past medical history included multiple allergies and a rheumatoid arthritis which was treated with oral methotrexate 10 mg per week and adalimumab. Methotrexate had been taken for 8 years, while adalimumab had been initiated 6 months earlier. Physical examination revealed a solitary thick, violaceous plaque of 6 X 4 cm in diameters, without enlarged lymph nodes. No fatigue, fever or pruritus were present. The first clinical hypothesis was a cutaneous B-cell lymphoma. The histological examination of a skin biopsy specimen showed a monomorphous dermal proliferation of large centroblast-like cells with large round, sometimes irregular, nuclei. Only rare reactive small cells were present. The infiltrate spared the epidermis, with a Grenz zone. The tumor cells were positive for CD45, CD20, bcl2, bcl6, MUM1, highly proliferating (Ki67 95%), and negative for CD3, CD30, CD10 and EBV/EBER. No CD21 or CD23 positive follicular dendritic cell network was identified. Fluorescence in situ hybridization showed no BCL2, BCL6 or CMYC rearrangement, while high resolution melting identified the MYD88 L265P mutation. A B-cell rearrangement was detected in the lesion. Whole body FDG-PET/CT showed a single hypermetabolic activity corresponding to the cutaneous lombar lesion, without distant tumours. Although the Borrelia burgdorferi serology was negative, a 15 days course of doxycyline 200 mg daily was given. Once the diagnosis of primary cutaneous large B-cell lymphoma, leg type (PCLBCL-LT) was made, adamimumab (but not methotrexate) was discontinued. The tumor completely disappeared within 4 months. No other TNF inhibitors were later given. No recurrence was observed after a follow-up time of 4 years. <h3>Discussion:</h3> PCDLBCL-LT are aggressive B-cell lymphomas mainly (but not exclusively) located on the leg, characterized by a monomorphous proliferation of large CD20+, Bcl2+, Mum1+, CD10 - B cells, frequently exhibiting the MYD88 L265P mutation, as observed in our patient. In contrast with indolent subtypes of primary cutaneous B-cell lymphomas, spontaneous regressions in PCLBCL-LT are exceptional, and constantly followed by recurrences. Progression of undiagnosed cutaneous lymphomas after anti-TNF-alpha therapy (mainly cutaneous T-cell lymphomas misdiagnosed as psoriasis or eczema) have been reported [1]. However, the role of anti-TNF-alpha in the occurrence of new lymphoproliferative disorders remains controversial [2,3]. To our knowledge, no PCLBCL-LT related to TNF-alpha inhibitors has been reported to date. Although methotrexate may play a role as a cofactor for the development of this B-cell malignancy, the negative EBV staining and the long-term complete remission after adalimumab withdrawal while methotrexate was continued, strongly argue for a predominant role of the anti-TNF-alpha in the occurrence of this lymphoma.

Comprehensive Genomic Characterization of Refractory Multiple Myeloma Reveals a Complex Mutational and Structural Landscape Associated with Drug Resistance

Comprehensive Genomic Characterization of Refractory Multiple Myeloma Reveals a Complex Mutational and Structural Landscape Associated with Drug Resistance

Clinical Outcomes of Anti PD-1 Immunotherapy in Patients with Relapsed/Refractory Non Hodgkin Lymphomas

Introduction: Immune checkpoint blockade with anti PD-1 antibodies in Hodgkin Lymphoma has been transformative, changing the standard of care in the relapsed/refractory settings. Limited prospective data exist to support a role for anti PD-1 monotherapy for patients (pts) with diffuse large B cell lymphoma (DLBCL) and T cell lymphomas (ORR 36% DLBCL, n=11 ORR 17% T cell lymphomas, Lesokhin et al, JCO 2016). However, in clinical practice, agents such as pembrolizumab and nivolumab are sometimes administered to non-Hodgkin lymphoma (NHL) pts who are without other conventional treatment options. We performed an analysis of all NHL pts treated with anti PD-1 antibodies at our institution to assess activity and safety of anti PD-1 antibodies in the management of relapsed/refractory NHL.Patients and Methods: We conducted a retrospective cohort study of all adult pts receiving pembrolizumab or nivolumab for management of NHL at the University of Pennsylvania between 1/2014 and 6/2017. Demographics, duration of therapy, reason for discontinuation, overall response rates, survival, and toxicity were examined. The primary endpoint was progression-free survival (PFS) defined as the time of immune checkpoint blockade start to progression, death, or last-follow-up via Kaplan Meier (KM) method. All other analyses were descriptive.Results: We identified 23 NHL pts for this analysis. NHL subtypes included DLBCL (86%) and peripheral T-cell lymphomas (14%). Median age at time of initiation of PD-1 inhibitor was 65 years old (Range: 21-79). Pts had an Ann Arbor Stage 2 or greater (78%) and median ECOG performance status of 1 (Range: 0-3). High risk features, defined as C-myc rearrangement, Ki-67>80%, high IPI, or ABC subtype, were observed in 15 pts (65%). Majority of pts had no history of autoimmune disease (91%). Pts had a median of 5 prior therapies (Range: 1-14, 91% ≥ 3 prior therapies) including 7 pts who had a prior autologous stem cell transplant (30%). Time to initiating PD-1 inhibitor from last active therapy was 2 months (Ranging from 0.5 to 15 months). In our cohort, 14 pts (61%) received pembrolizumab and 9 pts (39%) received nivolumab. The majority (%) of both groups were administered weight based dosing given in standard frequencies according to each respective package label. Median time on immunotherapy was 1 month ranging from 0.5 to 19 months. Pts most commonly discontinued PD-1 therapy for progression or lymphoma associated mortality (73.4%), and 5 pts (21.7%) remain on active therapy. Overall response rate (ORR) for the entire cohort was 23% (9% CR) and ORR in DLBCL of 26% (N=19). Median PFS for the entire cohort and DLBCL subset was 2 months (median follow-up of 2 months, figure 1). Of the responders (n=5), the median duration of response was 17 months (median of 6 prior therapies).No pt experienced opportunistic infections while on anti PD-1 therapy. Roughly 47.8% experienced at least 1 toxicity. There were 3 pts (13%) who were documented with at least two concomitant adverse events (AEs). Observed AEs included: pneumonitis (30%), elevated liver function tests (LFT's) (7%), diarrhea/colitis (7%), infusion related reactions (7%), nausea (7%), sepsis (7%), tumor flare (7%), graft versus host disease (GVHD) exacerbation (7%), headache (7%), idiopathic thrombocytopenic purpura (ITP) (7%), and rash (7%). Only 2 (14%) pts required dose interruptions and 57% of AEs resolved, with standard management of immune mediated AEs.Conclusion: Our results are consistent with the published literature in that we identified a subset of heavily pre-treated multi-refractory NHL pts who achieved durable responses to anti PD-1 antibody monotherapy. While the median PFS / OS for the entire cohort is 2 months, responders, with 6 median prior therapies, achieved a median PFS of 17 months. These results underscore the importance of immune check point blockade in some lymphomas and the critical need to identify biomarkers of response to anti PD-1 therapies so that this therapeutic approach can be delivered to the appropriate pts. A multicenter analysis with correlative studies is in progress. [Display omitted] DisclosuresSvoboda:Kite: Consultancy; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; BMS: Consultancy, Research Funding; Celgene: Research Funding. Schuster:Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Seattle Genetics: Consultancy. Landsburg:Curis: Consultancy, Research Funding; Takeda: Research Funding. Dwivedy Nasta:Incyte: Research Funding; Takeda: Research Funding; Immunogen: Research Funding. Mato:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Portola: Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy; Regeneron: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Kite: Consultancy; AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees.

Combination of BR101801 and Venetoclax Demonstrates Synergistic Activity in DLBCL Cell Lines Harboring Double Hit and Double Expressor Alterations

Introduction: Double hit DLBCL with concurrent rearrangement of c-Myc and BCL-2 as well as double expressor DLBCL with concomitant overexpression of c-Myc and BCL-2 are characterized to have very poor outcomes in the following standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy as well as short survival in progressing clinical courses. In DLBCL patients, about 20% to 30% of patients have shown the dual c-Myc and BCL-2 aberrance. Thus, several new drugs are being developed to achieve a durable response in double hit and double expressor DLBCL. The phase I study in patients with RR DLBCL using Venetoclax monotherapy which is a BCL-2 inhibitor, showed a disappointing objective response [CR:4/34(12%), PR:2/34(6%)]. This result shows that a combined approach involving a c-Myc controlling agent and BCL-2 inhibitor may be required to overcome the poor response of RR DLBCL, especially double hit and double expressor DLBCL. BR101801 is a first-in-class, oral, dual target inhibitor of DNA-PK and PI3Kδ. The combined inhibition of dual targets tightly regulates the protein stability of c-Myc independent of genetic alterations such as translocation, amplification, and overexpression. The purpose of this study is to investigate the functional significance of BR101801 on the growth inhibition and c-Myc regulation in double hit and double expressor DLBCL cell lines.Methods: Westernblot of protein expression levels was analyzed with the human DLBCL cell lines that were treated with BR101801, PI3Kδ-specific inhibitors (Idelalisib, TGR-1202) and DNA-PK inhibitor (NU-7441) or DMSO for 24 hr. After treating SU-DHL-4 cell with cyclohexamide (CHX, 20 ug/ml), and BR101801 (0.5 μM) alone or in combination, the lysates was analyzed with the westernblot. Cells (5x103/well) were incubated with various concentrations of compounds and the cell viability was determined after 72 hr by the WST-8 assay. Cell lines were classified as c-Myc translocation (DOHH2, SU-DHL-6, SU-DHL-10, OCI-LY-18), c-Myc amplification (SU-DHL-4, OCI-LY-3), and c-Myc expressor (U2932). Cell lines additionally showed BCL-2 alteration such as translocation (DOHH2, SU-DHL-4, SU-DHL-6, OCI-LY-18) and amplification (OCI-LY-3, U2932).Results: BR101801 showed potent inhibitory activity on c-Myc protein stability whereas no activity was found in Idelalisib, TGR-1202, or NU7441 (Figure 1A; SU-SHL-4, 1B; SU-DHL-6). Using CHX to block de novo protein synthesis on SU-DHL-4 cells, the increased rate of c-Myc degradation by GSK3β regulation was observed (Figure 1C). SU-DHL-10 cell lines harboring c-Myc alterations exhibited no sensitivity to the PI3Kδ inhibitor such as Idelalisib (IC50≒4.4 μM) and TGR-1202 (IC50>10 μM) and DNA-PK inhibitor such as NU7441 (IC50≒1.1 μM). However, the combination of Idelalisib and NU7441 resulted in 200-fold (IC50≒ 0.02 uM) growth inhibition (Figure 1D), which was comparable to the effect of BR101801. SU-DHL-6 cells showed low sensitivity to Venetoclax alone with IC50≒0.16 μM. However, the IC50 value of Venetoclax at 0.1, 1, 10 nM of BR101801 was decreased to 0.12 uM, 0.003 uM and < 0.001 uM (11 pM), respectively in a dose-dependent manner (Figure 1E).Conclusions: In this study, the rationale of co-targeting of PI3Kδ and DNA-PK in c-Myc regulation and growth inhibition were demonstrated. The dual targets of DNA-PK and PI3Kδ were essential to control the protein stability of c-Myc in DLBCL cell lines harboring various c-Myc alterations. In conclusion, the potent effect of BR101801 with Venetoclax in DLBCL cells harboring alterations on both c-Myc and BCL-2 suggests a mechanistic rationale as a breakthrough treatment for RR DLBCL patients. To ensure translation to humans, the study on the efficacy of BR101801 in primary cells isolated from double hit and double expressor as well as RR DLBCL patients is currently conducted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Aberrant expression and genetic alteration of c-MYC in anaplastic large cell lymphoma.

c-MYC plays an important role in regulating cellular growth and apoptosis, and it is aberrantly expressed in many human malignancies. Although c-MYC has been extensively investigated in Burkitt lymphoma and diffuse large B cell lymphoma, little has been reported in anaplastic large cell lymphoma (ALCL). The aim of this study was to investigate the expression and genetic alterations of c-MYC in primary systemic ALCL, characterize its clinicopathologic features and immunophenotypes, and discuss their implications in prognosis. Tissue microarrays using samples from 85 ALCL patients were used to evaluate expression of c-MYC and anaplastic lymphoma kinase (ALK). c-MYC and ALK genetic alterations were detected using fluorescence in situ hybridization. The Kaplan-Meier and multivariate Cox regression methods were used for survival analysis. c-MYC was expressed in 24 of 85 samples (28.2%), and ALK was expressed in 54 (63.5%). c-MYC and ALK were co-expressed in 16 samples (18.8%). c-MYC expression and c-MYC and ALK co-expression increased with ALCL clinical stages and the International Prognostic Index (IPI) score (p < 0.05). Fifty of the samples (58.8%) had ALK rearrangement, and 18 (22.1%) had aneuploidy. c-MYC rearrangement was not detected, but aneuploidy was observed in 19 cases (22.4%). c-MYC aneuploidy was significantly different based on c-MYC expression and the IPI score (p < 0.05). c-MYC was a significant independent prognostic factor for progression-free survival and overall survival in patients with ALCL. c-MYC protein expression and c-MYC aneuploidy could predict worse survival in patients with ALCL.

The combination of C-Myc rearrangement and 1q21 gain is associated with poor prognosis in multiple myeloma

The prognostic value of chromosomal 1q21 gain in newly diagnosed multiple myeloma (NDMM) remains controversial. Add-on Myc aberrations may further worsen the outcome. To investigate whether specific genes located at the 1q21 region, such as myeloid cell leukemia 1 (Mcl-1), are involved in NDMM progression, we examined bone marrow cytogenetic abnormalities in 153 patients with NDMM by fluorescence in situ hybridization. Their response to treatment and survival was also analyzed. C-Myc and Mcl-1 expressions in bone marrow samples were analyzed by RT-PCR. The expression of Mcl-1 was evaluated in bone marrow sections by immunohistochemistry. MM cell lines were transfected with Mcl-1 siRNA. 1q21 gain was present in 55/153 (35.9%) patients and strongly associated with Myc rearrangement (31/153, 20.3%, P = 0.004). A positive correlation was observed between Myc and Mcl-1 mRNA levels in bone marrow cells from 47 patients (r = 0.57, P < 0.001). The combination of 1q21 gain and Myc rearrangement was associated with poorer overall survival than Myc rearrangement alone (16.8 vs. 27.9 months, P = 0.077) or 1q21 gain alone (16.8 vs. 60.7 months, P < 0.01). High Mcl-1 protein expression in bone marrow plasma cells was associated with Myc rearrangement. Mcl-1 silencing by siRNA inhibited Myc protein expression in three myeloma cell lines. Treatment with the small-molecule Mcl-1 inhibitor, UMI-77, produced similar results. Overall, the combination of Myc rearrangement and 1q21 gain was associated with particularly poor prognosis in patients with MM. Furthermore, our data are consistent with Mcl-1-dependent Myc protein activation.

Frequent Mutation of the 5′ Noncoding Region of the BCL-6 Gene in Acquired Immunodeficiency Syndrome-Related Non-Hodgkin's Lymphomas

AbstractAcquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHL), a major source of morbidity and mortality among human immunodeficiency virus (HIV)-infected individuals, are derived from B cells and are classified into two major categories, Burkitt's lymphoma (BL) and diffuse large cell lymphoma (DLCL). Anaplastic large cell lymphoma (ALCL) and body-cavity-based lymphoma (BCBL) represent less frequent AIDS-NHL types. The molecular pathogenesis of AIDS-NHL is characterized by distinct genetic pathways, including chromosomal rearrangements of c-MYC and BCL-6 in AIDS-BL and AIDS-DLCL, respectively. In addition to gross rearrangements, recent evidence has suggested that BCL-6 may also be affected by mutations of the gene 5′ noncoding regions. Here we have investigated the distribution of BCL-6 mutations in a panel representative of all the AIDS-NHL subtypes. Forty-three AIDS-NHL were analyzed for mutations in the first exon-first intron boundary region of BCL-6. Mutations were detected in all categories of AIDS-NHL (25 of 43 cases; 58%), including 12 of 20 AIDS-BL, 10 of 15 AIDS-DLCL, two of three AIDS-ALCL, and one of five of AIDS-BCBL. BCL-6 mutations occurred independent of BCL-6 rearrangements and presence of other genetic lesions frequently associated with AIDS-NHL. These results indicate that mutations of BCL-6 5′ noncoding regions represent the most common genetic alteration presently detectable in AIDS-NHL. The frequency of these mutations, as well as their location in the proximity of BCL-6 regulatory sequences, suggest that they may play a role in AIDS-related lymphomagenesis.

Evaluation of Dose-Adjusted EPOCH-R Compared with R-CHOP for the Treatment of High-Risk, Aggressive B-Cell Lymphomas: A Single-Center Experience

Introduction High-risk subtypes of DLBCL, including high-grade B-cell lymphomas (HGBCL) with rearrangements of c-MYC (MYC-R), BCL2 and/or BCL6 [or double hit and triple hit lymphomas (DHL/THL)], double expressor lymphoma (DEL), and patients with International Prognostic Index (IPI) scores of 3-5 have a poor prognosis with standard R-CHOP chemotherapy. Treatment intensification with DA-EPOCH-R did not improve outcomes when compared to R-CHOP in the CALGB 50303 trial (Bartlett et al JCO 2019). However, high-risk patients were underrepresented as 36% of patients had IPI scores of 3-5, 0.61% of patients had DHL or THL, 2.6% of patients had MYC-R, and 8.6% of patients had DEL (Bartlett et al JCO 2019). Our purpose was to retrospectively compare DA-EPOCH-R to R-CHOP in the treatment of high-risk DLBCL. Methods Patients ≥ 18 years old who received either DA-EPOCH-R or R-CHOP at Moffitt Cancer Center between 1/2010 - 9/2019 were included. Patients with a diagnosis of DLBCL with IPI score of 3-5, DHL/THL, and/or DEL were included. Patients with primary mediastinal B-cell lymphoma (PMBCL), DLBCL with testicular or central nervous system (CNS) involvement, grade 3b follicular lymphoma, Richter's transformation or IPI score &amp;lt; 2 were excluded. The primary endpoint was complete response (CR) rate and secondary endpoints included progression-free survival (PFS), overall survival (OS), CNS relapse rate, and adverse events (AE). PFS and OS were estimated using Kaplan-Meier curves and differences were established using the log-rank test. Statistically significant difference was considered if p &amp;lt; 0.05. Results The study included 128 patients: DA-EPOCH-R (n=36) and R-CHOP (n=92). General characteristics were similar between groups and included: median age = 66 years (33-85), stage III/IV = 89%, IPI score 3-5 = 87.6%, non-germinal center B-cell (GCB) = 32.8%, DEL = 26.6%, and DHL/THL = 18%. Of note, more patients in the DA-EPOCH-R group were &amp;lt; 60 years old, had MYC-R, and/or were DHL/THL or HGBCL, NOS cases. The CR rates for DA-EPOCH-R and R-CHOP were 72.2% (95% CI: 54.8, 85.8) vs. 68.5% (95% CI: 57.8,78.0), respectively (p=0.831). In a pre-planned subgroup analysis, the CR rates across subgroups, including IPI score 3-5, DEL, and DHL/THL, were not different. There was no difference in PFS between DA-EPOCH-R and R-CHOP (p= 0.33; Figure 1). The 1-year (y) PFS for DA-EPOCH-R and R-CHOP was 69% (95% CI: 56.0, 86.0) and 62% (95% CI: 52.0, 73.0), respectively. The 3 y PFS for DA-EPOCH-R and R-CHOP was 66% (95% CI: 53.0, 84.0) and 46% (95% CI: 35.0, 59.0), respectively. PFS was higher in the DA-EPOCH-R arm for patients with MYC-R (p=0.0224) and DHL/THL (p=0.045). There was no difference in OS between DA-EPOCH-R and R-CHOP (p=0.83). The 1 y OS was 77% (95% CI: 65.0, 92.0) for the DA-EPOCH-R group compared with 81% (95% CI: 73.0, 90.0) for the R-CHOP group. The 3 y OS was 71% and 65% for the DA-EPOCH-R and R-CHOP groups, respectively. The CNS relapse rate was 6.2% in the DA-EPOCH-R group and 2.4% in the R-CHOP group (p=0.301). Of the 4 patients with CNS relapse, 3 were DHL, THL or DEL. There were more grade ≥ 3 AEs in DA-EPOCH-R vs. R-CHOP (97.2% vs. 77.2%; p=0.003). There was significantly more grade ≥ 3 hematologic toxicity in the DA-EPOCH-R group regarding neutropenia (DA-EPOCH-R 91.7% vs. R-CHOP 69.6%; p=0.017) and thrombocytopenia (DA-EPOCH-R 50% vs. R-CHOP 16.3%; p=0.0003). Neuropathy and mucositis were significantly more common in the DA-EPOCH-R arm. Conclusions R-CHOP remains standard of care for high-risk DLBCL subgroups when compared to DA-EPOCH-R (such as non-GCB DLBCL, DEL, and patients with IPI score &amp;gt; 3). Patients with DHL/THL or MYC-R had greater benefit from DA-EPOCH-R compared to R-CHOP. DA-EPOCH-R was associated with increased rates of AEs, including significantly more hematologic toxicity. Disclosures Chavez: AstraZeneca: Speakers Bureau; Celgene: Consultancy; Bayer: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Novartis: Consultancy; Merck: Research Funding; Morphosys: Consultancy, Speakers Bureau; BeiGene: Speakers Bureau; Karyopharm: Consultancy; Genentech: Speakers Bureau; AbbVie: Consultancy; Verastem: Consultancy; Pfizer: Consultancy; Epizyme: Speakers Bureau; Gilead: Consultancy.