non-GCB Subtype Research Articles

Sub-Cutaneous Rituximab-Minichop Versus Sub-Cutaneous Rituximab-Minichop + Lenalidomide (R2-miniCHOP) in Diffuse Large B Cell Lymphoma for Patients of 80 Years Old or More (SENIOR Study). a Multicentric Randomized Phase III Study of the Lysa

Sub-Cutaneous Rituximab-Minichop Versus Sub-Cutaneous Rituximab-Minichop + Lenalidomide (R2-miniCHOP) in Diffuse Large B Cell Lymphoma for Patients of 80 Years Old or More (SENIOR Study). a Multicentric Randomized Phase III Study of the Lysa

Tumor Microenvironment Differs between Germinal Centre B-Cell and Non-Germinal Centre B-Cell like Diffuse Large B-Cell Lymphomas and Has Subtype-Specific Prognostic Impact on Survival

Introduction Based on the cell of origin, diffuse large B-cell lymphoma (DLBCL) is divided into germinal center B-cell (GCB) and activated B-cell (ABC) like subtypes, which differ in their gene expression profiles and clinical presentation with the ABC DLBCLs showing a worse outcome in response to R-CHOP immunochemotherapy. However, composition of the tumor microenvironment (TME) of these molecular subtypes has not been characterized. Methods We used Hans algorithm to determine the molecular subtypes (GCB vs non-GCB) and multiplexed immunohistochemistry (mIHC) to characterize tumor infiltrating T-cell phenotypes, including cytotoxic T-cells (CTLs; CD8, Granzyme B, OX40, Ki67), T regulatory cells (Tregs; CD3, CD4, FoxP3), Th1 effector cells (CD3, CD4, TBET) and T-cell immune checkpoint (CD3, CD4, CD8, PD1, TIM3, LAG3) in 165 primary DLBCLs. The findings were correlated with the expression of human leukocyte antigens (HLA) I and II (beta-2 microglobulin (B2M), HLA-ABC and HLA-DR), and outcome of the patients treated with R-CHOP-like immunochemotherapy. Results In the whole cohort, 82 (50%) cases were classified as GCB and 83 (50%) as non-GCB DLBCLs. In the GCB subtype, cytotoxic T-cells were more often PD1+, and T-cells FoxP3+than in the non-GCB subtype (Figure 1A-B). Furthermore, GCB DLBCLs tended to be more commonly HLA-DR+(p=0.102). In the non-GCB DLBCLs in turn, HLA I positivity was more frequent (B2M, P=0.007; HLA-ABC, p=0.108), cytotoxic T-cells more often granzyme B+(Figure 1C), T-cells TBET+(p=0.018) and LAG3+TIM3+(p=0.033). A high proportion of granzyme B+cells (p=0.002), PD1+cells (p=0.02) and TIM3+CD4+T-cells (p=0.006) from all cells translated to adverse overall survival (OS) in the patients with non-GCB DLBCL, all independent of the IPI. In contrast, a high proportion of TIM3+cells (p=0.015), and FOXP3+TBET+T-cells (p=0.005) from all cells were associated with poor OS in the patients with GCB DLBCL, also independent of the IPI. Conclusions TME differs significantly between GCB and non-GCB DLBCLs and has subtype-specific prognostic impact on survival. Figure 1 Disclosures Leppa: Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees.

Diffuse Large B Cell Lymphoma (DLBCL) Experience in a Majority-Minority Community: The UT Health San Antonio Story

BACKGROUND: Diffuse Large B Cell Lymphoma (DLBCL) is the most common hematologic malignancy in adults. Unfortunately, more than one-third of patients will fail first line therapy, highlighting the need for a better understanding of biology of DLBCL and whether biological variables with clinical significance have the same impact across different ethnicities. Two clinically applicable prognostic models in DLBCL are the cell-of-origin (COO) classifier and the MYC/BCL2 expression pattern. The former classifies DLBCL in germinal center B-cell (GCB) and non-GCB subtypes. Patients diagnosed with GCB-like DLBCLs have significantly better outcome than those with non-GCB-like lymphomas. More recently, IHC-based quantification of MYC/BCL2 in DLBCL biopsies was shown to also impart prognostic value, with tumors positive for both markers, named dual-expresser (DE) DLBCL, harboring a particularly poor outcome. Moreover, DLBCL cases are further characterized into "double hit" (DH) or "triple hit" (TH) based on the rearrangements of MYC and BCL2, MYC and BCL6 or MYC, BCL2 and BCL6, which by far exhibit the poorest outcome. The paucity of data comparing the DLBCL biological variables and outcomes among different ethnicities establishes the basis of our analysis at the only NCI-designated cancer center of south Texas within a Hispanic (HI) predominant patient population. METHODS: This is an observational study where we identified patients with diagnosis of Lymphoma (Hodgkin and Non-Hodgkin) by International Classification of Diseases (ICD) codes. Only patients with DLBCL were retrospectively analyzed; the patients received care at UT Health San Antonio between 2008-2018. Key variables for each patient included age, gender, race/ethnicity, comorbidities, insurance status, stage, treatment received, characterization by COO, IHC markers, molecular rearrangements, outcome at 3 and 5 years and vitality status in 2018. Continuously distributed outcomes were summarized with the mean and standard deviation and categorical outcomes were summarized with frequencies and percentages. The primary endpoint is to compare whether there are differences between HI and non-Hispanics (NH) with respect to biologic variables and hence their outcomes. The study was approved by the local Institutional Review Board. The findings will be available to patients, funders and medical community through traditional publishing and social media. RESULTS: A total of 196 newly diagnosed patients met inclusion criteria, with 115 HI (59%) and 81 NH (41%). HI have a higher percentage (40%) of non-insured, Medicaid or a financial assistance program than NH (28%) . We were able to identify 172 patients with either GCB or non-GCB type. From our HI, 55 (48%) patients were GCB and 46 (40%) were non-GCB while within NH, 47 (58%) patients were GCB and 24 (30%) non-GCB. We gathered IHC data on 147 patients; DE with BCL2/MYC was found in 9 (8%) of HI patients and 14 (17%) of NH patients. There was around the same percentage of unavailable COO and IHC data for both groups, 12% and 25% respectively. Only 11 patients were identified as DH or TH. Among HI, 4 were DH and 1 was TH; while in NH, 5 were DH and 1 was TH (Fig 1A). When looking at survival, as of today 63% of patients are still alive in both groups. Among alive HI, 34 (62%) patients are of GCB origin and 31 (67%) are of non-GCB origin. On the other hand; within the alive NH patients, 34 (72% of GCB positive) are of GCB origin and 11 (46%) are of non-GCB origin (Fig 1B, 1C). Also, DE status apparently had no major difference in survival across ethnicities since 7 (50%) NH remain alive versus 4 (44%) HI (Fig 1D, 1E). Lastly, within HI there are only 2 DH and no TH patients alive, while within NH there are 3 DH patients alive 1 TH patient who is still not 3 years out. CONCLUSION: HI have similar and well-balanced molecular characteristics and outcomes compared to NH. As opposed to what we thought, the COO classifier does not seem to predict differences in prognosis in HI as they appear to have equal outcome irrespective of GCB vs non-GCB origin. The prognosis in HI with overexpression of MYC/BCL2 is bad and even worse if DH or TH as historically seen in NH. To our knowledge this is the first retrospective review that includes the largest Hispanic cohort in North America. Figure 1 Disclosures Hernandez: ASH MRHAP: Research Funding.

Combination of Nivolumab, Lenalidomide and Rituximab in Relapsed/Refractory Non-Germinal Center Diffuse Large B Cell Lymphoma: Results from a Dose-Escalation Cohort

Background: Ten to 15% of diffuse large B cell lymphoma (DLBCL) patients exhibit primary refractory disease (nonresponse or relapse within 3 months of therapy) and an additional 20-25% relapse following initial response. There is an unmet need for effective therapeutic regimens in relapsed/refractory (R/R) DLBCL. Lenalidomide is an immune modulator that reverses T cell dysfunction and also inhibits the NFκB pathway, which is constitutively active in non-germinal center (non-GCB) DLBCL. Lenalidomide and nivolumab, an anti-PD-1 antibody, each have single agent activity in R/R DLBCL. Here, we report the results of the dose-escalation cohort of this investigator-initiated, single-arm open-label study of the combination of nivolumab, lenalidomide and rituximab (NiLeRi) in R/R non-GCB DLBCL. Methods: Adult patients with R/R non-GCB DLBCL, as determined by the Hans algorithm, with adequate organ function and an ECOG performance status of ≤2 were eligible for the study. The primary objective was to evaluate the safety of NiLeRi, and determine the maximum tolerated dose (MTD) of lenalidomide in combination with fixed doses of rituximab and nivolumab, using a 3+3 dose escalation design. The secondary objectives were to determine efficacy in terms of overall response rate (ORR), progression free survival (PFS), and overall survival (OS) of patients treated with NiLeRi. All patients received nivolumab IV 3 mg/kg on days 1 and 15 and rituximab IV 375mg/m2 on day 1 of each 28-day cycle. Lenalidomide was initiated at 5 mg po once daily on days 1-21. Additional planned dose levels were 10 mg, 15 mg and 20 mg. Patients were evaluable for toxicity if they received all doses of nivolumab and rituximab and at least 16 doses of lenalidomide during cycle 1 or if they experienced a dose limiting toxicity (DLT), regardless of the number of doses. NiLeRi was given for 8 cycles and patients with partial response could receive lenalidomide and nivolumab for an additional 4 cycles. Response was assessed by PET-CT after 2, 5 and 8 cycles and defined by Lugano criteria. Results: Six patients with non-GCB subtype of DLBCL were enrolled in this study. The median age was 60.5 years (range 28-79), and 5 patients were male. The median number of prior lines of therapy was 4 (range 2-5), and the median IPI score was 3. None of the patients had bone marrow involvement. One patient each had been treated with autologous stem cell transplant (Auto-SCT) and CAR-T cell therapy. One patient withdrew consent before completing cycle 1 and was not evaluable for safety or efficacy. Safety: Five out of the six enrolled patients were evaluable for safety. All patients received lenalidomide 5 mg dose. Two patients experienced DLTs (grade 3 rash) resulting in lenalidomide discontinuation during cycle 2. The most common grade 3/4 toxicities were fatigue (20%), neutropenia (60%), thrombocytopenia (40%), and rash (40%). A total of 3 patients experienced grade 1/2 diarrhea and elevated liver enzymes. One patient experienced a grade 1 infusion reaction with rituximab. Efficacy: Patients who completed at least 1 cycle of therapy were evaluable for response, and this included 5 out of the 6 enrolled patients. The ORR and complete response (CR) rate were both 40%. Patients who responded did so early, with one patient achieving CR after 2 cycles and another patient achieving CR after 5 cycles. The best response seen in patients with primary refractory disease was PR. At a median follow up of 9.5 months, median PFS was 8.4 months (95% CI; 4.3 to not reached), and median OS was not reached. Discussion: This is the first study reporting the safety results of the combination of lenalidomide, nivolumab and rituximab in non-Hodgkin lymphoma. Rash was the most common DLT, limiting dose escalation of lenalidomide above 5mg in this cohort of patients. Two patients experienced durable CR early in the study after 2 and 5 cycles, respectively. This ORR and CR rate of 40% each in this small cohort of patients who had relapsed after multiple prior lines of therapy is encouraging. Correlative studies, including whole exome sequencing of patient samples, are underway, in an attempt to explore predictive markers for response and toxicity. Figure. Disclosures Mason: Sysmex: Honoraria. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Morgan:Biogen: Equity Ownership; Eli Lilly: Equity Ownership; Vertex: Equity Ownership; Zoetis: Equity Ownership; Pfizer: Equity Ownership; Novo Nordisk: Equity Ownership; Gilead: Equity Ownership; Johnson and Johnson: Equity Ownership; Merck: Equity Ownership. Reddy:Abbvie: Consultancy; Genentech: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding; KITE Pharma: Consultancy. OffLabel Disclosure: Nivolumab and lenalidomide are not FDA approved for use in diffuse large B cell lymphoma

Immunohistochemical overexpression of BCL-2 protein predicts an inferior survival in patients with primary central nervous system diffuse large B-cell lymphoma

This study was designed to analyze the clinical characteristics and prognostic value of c-MYC and BCL-2 proteins expression in patients with primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL).82 patients newly diagnosed with PCNS-DLBCL, from January 2008 to November 2018, were enrolled in this study. Clinical characteristics, immunohistochemical features, laboratory examinations, and treatment outcome were analyzed among these patients.Among these 82 cases, 45 were males (54.9%) and 37 were females (45.1%). Age ranged from 16 to 78 years old, and 29 patients (35.4%) were elder than 60 years old, with median age at 57 years old. According to Hans classification, 25 were accounted for origin of germinal center B-cell (GCB) subtype (30.5%) and 49 were accounted for non-GCB subtype (59.8%), respectively. Eight patients were unclassified due to lack of detailed pathological results. The median survival of these 82 patients was 30 months, and 1-year, 3-year, and 5-year overall survival (OS) rate was 59.7%, 44.6%, and 34.1%, respectively. Patients treated with sequential HD-MTX based chemotherapies showed a superior prognosis than those without. In combination with rituximab, the outcome was further improved. The median OS was 55 months in HD-MTX + R group, 27 months in HD-MTX group, and 9 months in other groups, respectively. Univariate analysis identified age ≥60, ECOG score ≥ 2 points, and overexpression of BCL-2 protein (≥85%) were adverse prognostic factors for OS. Co-expression of c-MYC (≥40%) and BCL-2 (≥50%) proteins was associated with poor ECOG score, high Ki-67 expression, and trended towards an inferior outcome. Gender, lesion location, number of lesions, lactic dehydrogenase (LDH), cell of origin, BCL-6 protein expression, expression of c-MYC protein alone and Ki-67 ≥85% had no significant impact on OS.In patients with PCNS-DLBCL, age ≥60 years old, ECOG score ≥2 points, and overexpression of BCL-2 protein (≥85%) were associated with a poor survival. HD-MTX based chemotherapies in combination with rituximab could improve the prognosis.

Impact of concurrent indolent lymphoma on the clinical outcome of newly diagnosed diffuse large B-cell lymphoma

AbstractSome patients with diffuse large B-cell lymphoma (DLBCL) present with a concurrent indolent lymphoma at diagnosis. Their outcomes in the rituximab era are not fully defined. Using a prospectively followed cohort of 1324 newly diagnosed DLBCL patients treated with immunochemotherapy, we defined the prevalence, characteristics, and outcome of DLBCL with concurrent indolent lymphoma. Compared with patients with DLBCL alone (n = 1153; 87.1%), patients with concurrent DLBCL and follicular lymphoma (FL) (n = 109; 8.2%) had fewer elevations in lactate dehydrogenase, lower International Prognostic Index (IPI), and predominantly germinal center B-cell–like (GCB) subtype, whereas patients with concurrent DLBCL and other indolent lymphomas (n = 62; 4.7%) had more stage III-IV disease and a trend toward higher IPI and non-GCB subtype. After adjusting for IPI, patients with concurrent DLBCL and FL had similar event-free survival (EFS) (hazard ratio [HR] = 0.95) and a trend of better overall survival (OS) (HR = 0.75) compared with patients with DLBCL alone, but nearly identical EFS (HR = 1.00) and OS (HR = 0.84) compared with patients with GCB DLBCL alone. Patients with concurrent DLBCL and other indolent lymphomas had similar EFS (HR = 1.19) and OS (HR = 1.09) compared with patients with DLBCL alone. In conclusion, DLBCL patients with concurrent FL predominantly had the GCB subtype with outcomes similar to that of GCB DLBCL patients. DLBCL patients with concurrent other indolent lymphoma had similar outcomes compared with patients with DLBCL alone. These patients should not be summarily excluded from DLBCL clinical trials.

Clinical significance of ‘double-hit’ and ‘double-expression’ lymphomas

Background‘Double-hit’ lymphoma (DHL) and ‘double-expression’ lymphoma (DEL) involving gene rearrangement and protein expression of MYC and BCL2/BCL6 have recently become the most commonly used terms to describe the poor prognostic...

Relationship between p53 rs1625895 polymorphism and prognosis in diffuse large B-cell lymphoma

OBJECTIVE p53 gene, as guardian of the genome, is the most widely studied tumor suppressor gene. Previous studies have shown that about 50 percent of tumors have P53 dysfunction. This article aims to retrospectively analyze the correlation between p53 rs1625895 polymorphism and the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). METHODS PCR combined with Sanger sequencing were used to detect rs1625895 genotype in 384 DLBCL patients. The relationship between rs1625895 polymorphisms and the clinical characteristics, first-line therapeutic effects and the prognosis of the patients were analyzed. RESULTS Among all the patients, 2 (0.5%) patients with AA genotype, 34 (8.9%) patients with AG genotype and 348 (90.6%) patients with GG genotype were identified. The patients with different rs1625895 genotypes did not have any difference in terms of age, gender, B symptoms (developing any of the following symptoms: unexplained recurrent fever (often above 38 °C), night sweats, and unexplained weight loss of 10% within 6 months ), erythrocyte sedimentation rate (ESR), international prognostic index (IPI) and molecular subtype (P>0.05). The overall response rate (ORR) was 82.9% and 82.8% in AA/AG and GG, respectively. There was no significant difference between the first-line therapeutic effects of the two groups (P>0.05). And there was also no difference between A allele carriers and homozygous G allele carriers for the 5-year progressionfree survival rate (PFS) (71.8% vs. 62.3%, χ2=1.351, P=0.245) and 5-year overall survival rate (OS) (72.2% vs. 64.1%, χ2=1.267, P=0.260). But in the subgroup with Germinal Center B-cell (GCB) type, the patients carrying A allele for rs1625895 had an obviously longer PFS (91.7% vs. 72.7%, χ2=4.493, P=0.034) and OS (91.7% vs. 76.7%, χ2=4.246, P=0.039) compared with the patients homozygous for the G allele. As for the patients with non-GCB subtype, there was no significant difference in PFS and OS between different rs1625895 genotypes (P>0.05). According to whether the first-line regimen contained rituximab or not, the patients were divided into two groups treated with cyclophosphoramide, doxorubicin, vincristine and prednisone (CHOP) or with rituximab and CHOP (R-CHOP). But in both subgroups, there was no significant difference in the 5-year PFS and OS between the AA/AG and GG patients, too (P>0.05). CONCLUSION For DLBCL patients receiving CHOP regimen chemotherapy in the first line, p53 rs1625895 cannot predict the clinical efficacy and prognosis of the patients, but in the patients with GCB subtype, this polymorphism may be a prognostic indicator.

CD47 Expression Defines Efficacy of Rituximab with CHOP in Non-Germinal Center B-cell (Non-GCB) Diffuse Large B-cell Lymphoma Patients (DLBCL), but Not in GCB DLBCL.

Addition of rituximab (R) to "CHOP" (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy improved outcome for diffuse large B-cell lymphoma (DLBCL) patients. Approximately 40% of patients who receive R-CHOP still succumb to disease due to intrinsic resistance or relapse. A potential negative regulator of DLBCL treatment outcome is the CD47 "don't eat me" immune checkpoint. To delineate the impact of CD47, we used a clinically and molecularly well-annotated cohort of 939 DLBCL patients, comprising both germinal center B-cell (GCB) and non-GCB DLBCL subtypes, treated with either CHOP or R-CHOP. High (above median) CD47 mRNA expression correlated with a detrimental effect on overall survival (OS) when DLBCL patients received R-CHOP therapy (P = 0.001), but not CHOP therapy (P = 0.645). Accordingly, patients with low CD47 expression benefited most from the addition of rituximab to CHOP [HR, 0.32; confidence interval (CI), 0.21-0.50; P < 0.001]. This negative impact of high CD47 expression on OS after R-CHOP treatment was only evident in cancers of non-GCB origin (HR, 2.09; CI, 1.26-3.47; P = 0.004) and not in the GCB subtype (HR, 1.16; CI, 0.68-1.99; P = 0.58). This differential impact of CD47 in non-GCB and GCB was confirmed in vitro, as macrophage-mediated phagocytosis stimulated by rituximab was augmented by CD47-blocking antibody only in non-GCB cell lines. Thus, high expression of CD47 mRNA limited the benefit of addition of rituximab to CHOP in non-GCB patients, and CD47-blockade only augmented rituximab-mediated phagocytosis in non-GCB cell lines. Patients with non-GCB DLBCL may benefit from CD47-targeted therapy in addition to rituximab.

Differential Activity of ATR and WEE1 Inhibitors in a Highly Sensitive Subpopulation of DLBCL Linked to Replication Stress.

DNA damage checkpoint kinases ATR and WEE1 are among key regulators of DNA damage response pathways protecting cells from replication stress, a hallmark of cancer that has potential to be exploited for therapeutic use. ATR and WEE1 inhibitors are in early clinical trials and success will require greater understanding of both their mechanism of action and biomarkers for patient selection. Here, we report selective antitumor activity of ATR and WEE1 inhibitors in a subset of non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL) cell lines, characterized by high MYC protein expression and CDKN2A/B deletion. Activity correlated with the induction of replication stress, indicated by increased origin firing and retardation of replication fork progression. However, ATR and WEE1 inhibitors caused different amounts of DNA damage and cell death in distinct phases of the cell cycle, underlying the increased potency observed with WEE1 inhibition. ATR inhibition caused DNA damage to manifest as 53BP1 nuclear bodies in daughter G1 cells leading to G1 arrest, whereas WEE1 inhibition caused DNA damage and arrest in S phase, leading to earlier onset apoptosis. In vivo xenograft DLBCL models confirmed differences in single-agent antitumor activity, but also showed potential for effective ATR inhibitor combinations. Importantly, insights into the different inhibitor mechanisms may guide differentiated clinical development strategies aimed at exploiting specific vulnerabilities of tumor cells while maximizing therapeutic index. Our data therefore highlight clinical development opportunities for both ATR and WEE1 inhibitors in non-GCB DLBCL subtypes that represent an area of unmet clinical need. SIGNIFICANCE: ATR and WEE1 inhibitors demonstrate effective antitumor activity in preclinical models of DLBCL associated with replication stress, but new mechanistic insights and biomarkers of response support a differentiated clinical development strategy.

Late Relapses in Patients With Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy.

In patients with diffuse large B-cell lymphoma (DLBCL), most relapses occur within the first 2 years of diagnosis. We sought to define the rate and outcome of late relapses that occurred after achieving event-free survival at 24 months (EFS24). We prospectively followed 1,324 patients with newly diagnosed DLBCL from 2002 to 2015 and treated with immunochemotherapy. Cumulative incidences of late DLBCL and indolent lymphoma relapses were analyzed as competing events. Postrelapse survival was defined as time from first relapse to death from any cause. In 847 patients who achieved EFS24, the cumulative incidence of late relapse was 6.9% at 3 years, 9.3% at 5 years, and 10.3% at 8 years after EFS24. The incidence of DLBCL relapse was similar in patients with DLBCL alone at diagnosis (6.3% at 5 years), compared with patients with concurrent indolent lymphoma at diagnosis (5.2%; P = .46). However, the rate of indolent lymphoma relapse was higher in patients with concurrent indolent lymphoma (7.4% v 2.1% at 5 years; P < .01). In patients with DLBCL alone, the rate of DLBCL relapse was similar in the germinal center B-cell-like (GCB) (4.1% at 5 years) and non-GCB (4.0%; P = .71) subtypes, whereas the rate of indolent lymphoma relapse was higher in patients with the GCB subtype (3.9% v 0.0% at 5 years; P = .02). Postrelapse survival was inferior for patients who relapsed with DLBCL than for those who relapsed with indolent lymphoma (median 29.9 months v unreached; P < .01). Patients with DLBCL with a concurrent indolent lymphoma and those with the GCB subtype had a higher rate of late relapse, owing to increased relapses with indolent lymphoma. Patients who relapsed with DLBCL had a worse prognosis than those who relapsed with indolent lymphoma.

ACALABRUTINIB PLUS PEMBROLIZUMAB IN RELAPSED/REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA: A PHASE 1/2 STUDY

Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase inhibitor, has a 24% overall response rate as a single agent in relapsed/refractory diffuse large B-cell lymphomas (DLBCL). Pembrolizumab targets PD-1, an immune checkpoint that limits anticancer responses. Pembrolizumab showed responses in patients with Richter transformation who failed ibrutinib and can augment acalabrutinib activity in vitro. This study assessed acalabrutinib plus pembrolizumab in relapsed/refractory DLBCL. Methods: Patients with DLBCL, ≥1 prior chemoimmunotherapy and no prior allogeneic transplant received oral acalabrutinib 100 mg twice daily until progressive disease plus pembrolizumab 200 mg/kg intravenously every 3 weeks for up to 2 years. Germinal center B-cell (GCB) vs non-GCB subtype was assessed by immunohistochemistry. Primary endpoint was safety. Results: Sixty-one patients (30 GCB; 31 non-GCB) were accrued, with a median age of 67 years (range, 30 to 85) and a median of 3 (range, 1 to 8) prior therapies; 1 patient had prior autologous transplant. The most common grade 3/4 adverse events were neutropenia (15%) and anemia (11%). Grade 5 adverse events were respiratory failure (n = 3), sepsis, septic shock, and abdominal abscess (n = 1 each). All-grade atrial fibrillation was 5% (n = 3), and major hemorrhage (≥ Grade 3) was 11% (4 gastrointestinal, 1 pulmonary, 1 epistaxis, 1 hematuria). Grade 3/4 immune-mediated events were elevated alanine aminotransferase (n = 4), pneumonitis (n = 2), and colitis (n = 1). The overall response rate was 26% (Table) and was similar in GCB (27%) and non-GCB (26%) tumors. The median time on study was 5.2 months (0.4 to 30.4+). Acalabrutinib/pembrolizumab discontinuations were due to progressive disease (62%/56%) and adverse events (15%/26%). As of June 2018, 10 patients remain on study; 6 on active therapy and 7 without progressive disease. Conclusions: Acalabrutinib plus pembrolizumab was well tolerated, with meaningful activity and some exceptional responders (>24 months) in these relapsed/refractory DLBCL patients. Randomized trials of the combination vs single agent are needed. Keywords: acalabrutinib; diffuse large B-cell lymphoma (DLBCL); Pembrolizumab. Disclosures: Witzig, T: Honoraria: Sandoz; Immune Design; Research Funding: Acerta; Celgene; Novartis; Spectrum. Maddocks, K: Consultant Advisory Role: AstraZeneca, Pharmacyclics, Bayer, Teva, Sandoz; Honoraria: AstraZeneca, Pharmacyclics, Bayer, Teva, Sandoz; Research Funding: Pharmacyclics, BMS, Novartis, Merck. Lyons, R: Employment Leadership Position: Texas Oncology; Stock Ownership: Texas Oncology; Research Funding: avvie, Celgene, Gilead, GenetechIncye, Rigel, Takeda. Sharman, J: Consultant Advisory Role: Celgene, Pfizer, Genentech, TG therapeutics, AbbVie, pharmacyclics GILEAD; Research Funding: Celgene, Pfizer, Genentech, TG therapeutics, AbbVie, pharmacyclics GILEAD. Yimer, H: Consultant Advisory Role: Seattle Genetics, AstraZeneca, Jenssen. Wei, H: Employment Leadership Position: Acerta Pharma. Chan, E: Employment Leadership Position: Acerta Pharma, Genentech/Roche; Stock Ownership: Acerta Pharma, Genentech/Roche, Eli Lilly & Company. Patel, P: Employment Leadership Position: Acerta/AstraZeneca; Stock Ownership: Acerta/AstraZeneca. Kolibaba, K: Employment Leadership Position: Compass Oncology; Consultant Advisory Role: Gilead; Honoraria: TG Therapeutics; Research Funding: Acerta; Celgene; CTI; Genentech; Gilead; Pharmacyclics; Novartis; Seattle Genetics; TG Therapeutics; Other Remuneration: TG Therapeutics. Cheson, B: Consultant Advisory Role: Abbvie, AstraZeneca, Bayer, Celgene, Roche Genentech, TG Therapeutics, Epizyme, GIlead, Karyopharm, Morphosys, Pharmacyclics; Research Funding: Abbvie, AstraZeneca, Roche Genentech, TG Therapeutics, Epizyme, GIlead, Trillium.

SMART START: RITUXIMAB, LENALIDOMIDE, AND IBRUTINIB ALONE PRIOR TO COMBINATION WITH CHEMOTHERAPY FOR PATIENTS WITH NEWLY DIAGNOSED DIFFUSE LARGE B‐CELL LYMPHOMA

Background: The non-germinal center (non-GCB) subtype of Diffuse Large B-cell Lymphoma (DLBCL) is associated with inferior outcomes with standard therapies. The BTK inhibitor ibrutinib (I) and immunomodulatory agent lenalidomide (L) have promising activity in non-GCB DLBCL as single agents, and result in synthetic lethality in non-GCB DLBCL models when combined. In relapsed non-GCB DLBCL, rituximab (R), L and I result in overall response rate (ORR) of 55% (Ramchandren, ASH 2018). We conducted an investigator initiated, single-arm, open-label, phase 2 study (NCT02636322) of RLI alone and then with chemotherapy in newly diagnosed non-GCB DLBCL patients, and report the final results of the RLI lead in. Methods: Adult patients with newly diagnosed non-GCB DLBCL, determined by the Hans method, with adequate organ function and performance status were eligible. The primary objectives were to determine (1A) the ORR of two cycles of RLI as initial therapy, and (1B) the complete response rate (CRR) after 6 cycles of chemotherapy combined with RLI. All patients were treated with rituximab 375 mg/m2 IV day 1, ibrutinib 560 mg po daily, and lenalidomide 25 mg po days 1-10 of 21 day cycles for 2 cycles, followed by 6 additional cycles of RLI with chemotherapy (CHOP or EPOCH per treating MD choice). Responses were assessed with PET/CT as per the Lugano criteria. Growth factors, venous thromboembolism prophylaxis, and pneumocystis pneumonia prophylaxis were required for all patients. Results: The protocol accrued 60 patients from May 2016 – February 2019, with 52 patients evaluable for disease response (2 withdrew consent prior to restaging, 6 pending restaging prior to abstract deadline). The median age was 64 years (range: 30-83), 28% were >= 70 years, and 50% were female. Half the patients had poor risk IPI, 61% had advanced stage, and 71% had a Ki-67 of >= 80%. One patient had a fatal fungal infection (CNS aspergillosis) attributed to high dose corticosteroids for symptom control during screening and with RLI, leading to prohibition of corticosteroids during the RLI only cycles with no further fungal infections identified. The ORR for 2 cycles of RLI alone was 84.6% (n = 44), and the CRR was 38.5% (n = 20). One patient refused to proceed with the pre-planned chemotherapy after achieving a CR with 2 cycles of RLI, and remains relapse free with no additional therapy 18 months later. Preliminary results demonstrate a CRR of 100% for the full therapy (RLI for 2 cycles, RLI-chemo for 6 cycles), with updates to be presented at the meeting. Conclusions: The Smart Start trial demonstrates the chemotherapy-free combination of rituximab 375 mg/m2, ibrutinib 560 mg, and lenalidomide 25mg is highly effective in patients with newly diagnosed non-GCB DLBCL. Further studies are planned with other novel agents and with fewer cycles of chemotherapy consolidation for patients achieving a CR with RLI alone. Keywords: activated B-cell-like (ABC); BTK inhibitors; IMiDs. Disclosures: Westin, J: Consultant Advisory Role: Celgene, Janssen, Novartis, Kite, Juno, Genentech.

Generalized crystal-storing histiocytosis with diffuse large B-cell lymphoma and monoclonal gammopathy in a Chinese elderly woman: a case report

BackgroundCrystal-storing histiocytosis (CSH) is a rare lesion characterized by sheets of crystal-laden non-neoplastic histiocytes. CSH shows a prominent association with lymphoproliferative disorders that express monoclonal immunoglobulins, mainly multiple myeloma (MM), lymphoplasmacytic lymphoma (LPL) and monoclonal gammopathy of undetermined significance (MGUS). However, no aggressive B cell lymphoma has been reported to be associated with CSH.Case presentationA 74-year-old Chinese woman presented with multiple subcutaneous masses, abdominal pain, and fever. An IgM kappa type of monoclonal gammopathy (MG) was noted by immunofixation performed on the patient’s serum. Computed tomographic (CT) scan revealed subcutaneous masses on the left upper arm and at the waist and multiple low-density lesions in the spleen. Microscopically, sections of subcutaneous masses revealed sheets of large polygonal and spindle cells with abundant eosinophilic cytoplasm, round to ovoid eccentric nuclei, reticulate chromatin, and median nucleoli. Massive needle-shaped crystals were confined to the cytoplasm. Immunohistochemically, these crystal-containing cells were positive for CD68/PGM1, CD163, IgM, and Igκ. Meanwhile, the splenic tumour was diagnosed as diffuse large B-cell lymphoma (DLBCL), non-germinal-centre B (non-GCB) subtype (Hans algorithm). Immunohistochemistry for IgM was positive in the cytoplasm of some neoplastic cells. Immunoglobulin heavy chain (IgH) gene rearrangement was detected by PCR analysis of the subcutaneous mass and the splenic tumour.ConclusionTo the best of our knowledge, this is the first case of generalized CSH with DLBCL and MG. Although the rarity of CSH and separate locations of CSH and lymphoma led to a diagnostic dilemma, the presence of MG was a clue to appreciate the relation between CSH and DLBCL. This case stressed a full investigation into the underlying lymphoproliferative disorder for integrated diagnosis and correct treatments.

Both chronic HBV infection and naturally acquired HBV immunity confer increased risks of B-cell non-Hodgkin lymphoma

BackgroundPrevious studies examining the relationship between hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL) show inconsistent results in different endemic areas. Furthermore, studies evaluating the association between stratified HBV status and NHL with a well-matched case-control design are rare.MethodsWe conducted a 1:2 case-control study enrolling 3502 NHL cases and 7004 controls, and performed an updated meta-analysis evaluating the association between HBV and NHL subtypes.ResultsThe HBsAg-negative/anti-HBc-positive/anti-HBs-positive population, implying naturally acquired immunity after infection, had increased B-NHL risk (Adjusted odds ratio (AOR) (95% confidence interval (95% CI)): 2.25 (1.96–2.57)). The HBsAg-positive/HBeAg-positive population, indicating current HBV infection, had high risk of B-NHL (AOR (95% CI): 6.23 (3.95–9.82)). Specifically, for diffuse large B-cell lymphoma (DLBCL), there was no significant difference in HBsAg status between the germinal centre B (GCB) and non-GCB subtypes. Additionally, our meta-analysis showed in a random effects model, HBV-infected individuals had a pooled OR of 2.09 (95% CI 1.76–2.50; P < 0.01) for NHL.ConclusionsChronic HBV infection was positively associated with B-NHL in China. However, acquired immunity by natural infection also increased B-NHL risk. Thus, we further speculated that regardless of whether HBsAg was cleared, the infected population had higher risk of B-NHL. Our study might expand our knowledge on tumorogenesis of NHL and thus provides clues for novel treatment strategies.

Phase 1/2 trial of acalabrutinib plus pembrolizumab (Pem) in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL).

7519 Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase (BTK) inhibitor, has a 24% overall response rate (ORR) as a single agent in R/R DLBCL. Pem targets PD-1, an immune checkpoint that limits anticancer responses. Pem showed responses in patients (pts) with Richter transformation who failed ibrutinib and can augment acalabrutinib activity in vitro. This study assessed acalabrutinib + Pem in R/R DLBCL. Methods: Pts with DLBCL, ≥1 prior chemoimmunotherapy and no prior allogeneic transplant received acalabrutinib 100 mg PO BID until progressive disease (PD) + Pem 200 mg/kg IV Q3W up to 2 y. Germinal center B-cell (GCB) vs non-GCB subtype was assessed by immunohistochemistry. Primary endpoint was safety. Results: Sixty-one pts (30 GCB; 31 non-GCB) were accrued, with a median age (range) of 67 y (30-85) and a median of 3 (1-8) prior therapies; 1 pt had prior autologous transplant. The most common Gr 3/4 adverse events (AEs) were neutropenia (15%) and anemia (11%). Gr 5 AEs were respiratory failure (n=3), sepsis, septic shock and abdominal abscess (n=1 each). All Gr atrial fibrillation was 5% (n=3), and major hemorrhage (≥ Gr 3) was 11% (4 gastrointestinal, 1 pulmonary, 1 epistaxis, 1 hematuria). Gr 3/4 immune-mediated events were elevated alanine aminotransferase (n=4), pneumonitis (n=2) and colitis (n=1). The ORR was 26% (Table) and was similar in GCB (27%) and non-GCB (26%) tumors. The median time on study was 5.2 mo (0.4-30.4+). Acalabrutinib/Pem discontinuations were due to PD (62%/56%) and AEs (15%/26%). As of June 2018, 10 pts remain on study; 6 on active therapy and 7 without PD. Conclusions: Acalabrutinib + Pem was well tolerated, with meaningful activity and some exceptional responders (&gt;24 mo) in these R/R DLBCL pts. Randomized trials of the combination vs single agent are needed. Clinical trial information: NCT02362035. [Table: see text]

Phase 2 study of parsaclisib (INCB050465) for relapsed or refractory diffuse large b-cell lymphoma (DLBCL) (CITADEL-202).

e19038 Background: Parsaclisib, a potent, highly selective, next-generation PI3Kδ inhibitor, showed preliminary efficacy as monotherapy for relapsed or refractory non-Hodgkin lymphoma, including DLBCL (Abstract 410, ASH 2017), in a phase 1/2 study. This phase 2 study further assessed parsaclisib in patients (pts) with relapsed or refractory DLBCL (NCT02998476). Methods: Pts enrolled into 2 groups (A, Bruton tyrosine kinase [BTK] inhibitor naïve; B, BTK inhibitor experienced) and received oral parsaclisib 20 mg QD for 8 wks, then 20 mg QW. In a planned interim futility analysis conducted in the first 40 pts treated in Group A, if ≤13 (≤32.5%) responded by IRC assessment, Group A was to be terminated. Results: At data cutoff (22 Jun 2018), 60 pts (Group A, n = 55; Group B, n = 5) were treated (median age, 71 y [range, 36—94]; men, 63.3%; ≥3 prior systemic therapies, 60%). At the planned interim analysis in Group A, ORR (by PET) was 25% (10/40 pts; 5 CMR, 5 PMR); the futility boundary was crossed. At data cutoff, ORR in Group A was 25.5% (14/55 pts; 8 CMR, 6 PMR); median PFS was 2.2 mo (95% CI: 2.0‒4.1); median DOR was 4.5 mo (95% CI: 2.1‒5.1). ORs were observed in germinal center B-cell (GCB) and non-GCB subtypes. ORR in Group B was 20% (1/5 pts; 1 CMR). The most common non-hematologic treatment-emergent adverse events (TEAEs) occurring in &gt; 10% of all pts (all grade [Gr]; Gr 3/4) were rash events (21.7%; 1.7%), colitis/diarrhea events (16.7%; 5%), nausea (16.7%; 0%), cough (15%; 0%), and pyrexia (15%; 8.3%). Gr 3/4 AST and ALT elevations occurred in 5% and 1.7% of pts, respectively; Gr 3/4 neutropenia and anemia occurred in 5% of pts each. The most frequent ( &gt; 5%) serious TEAEs were pyrexia (8.3%), general physical health deterioration (6.7%), and hypercalcemia (6.7%). TEAEs led to therapy discontinuation in 7 pts (2 treatment-related), dose interruption in 20 pts (10 treatment-related), and dose reduction in 3 pts (all treatment-related). Median duration of therapy was 57.5 d (range, 11–318). Conclusions: Parsaclisib monotherapy using a QD followed by QW dosing regimen was well tolerated with no new safety signals reported. Further evaluation of parsaclisib in all subtypes of DLBCL is ongoing in a combination study Clinical trial information: NCT02998476.

Smart start: Final results of rituximab, lenalidomide, and ibrutinib lead in prior to combination with chemotherapy for patients with newly diagnosed diffuse large B-cell lymphoma.

7508 Background: The non-germinal center (non-GCB) subtype of Diffuse Large B-cell Lymphoma (DLBCL) is associated with inferior outcomes from standard immuno-chemotherapy. The BTK inhibitor ibrutinib (I) and immunomodulatory agent lenalidomide (L) have promising activity in non-GCB DLBCL as single agents, and result in synthetic lethality in non-GCB DLBCL models when combined. In relapsed non-GCB DLBCL, rituximab (R), L and I result in overall response rate (ORR) of 55% (Ramchandren, ASH 2018). We report the final results of RLI prior to chemotherapy in newly diagnosed non-GCB DLBCL patients, an investigator initiated, single-arm, open-label, phase 2 study. Methods: Adult patients with non-GCB DLBCL, determined by the Hans method, with adequate organ function and performance status were eligible. The primary objectives were to determine (1A) the ORR of two cycles of RLI as initial therapy, and (1B) the complete response rate (CRR) after 6 cycles of chemotherapy combined with RLI. All patients were treated with rituximab 375 mg/m2 IV day 1, ibrutinib 560 mg po daily, and lenalidomide 25 mg po days 1-10 of 21 day cycles for 2 cycles, followed by 6 additional cycles of RLI with chemotherapy. Results: The protocol accrued 60 patients from May 2016 – February 2019, with 52 patients evaluable for disease response (2 withdrew consent prior to restaging, 6 pending restaging prior to abstract deadline). The median age was 64 years (range: 30-83), 28% were ≥ 70 years, and 50% were female. Half the patients had poor risk IPI, 61% had advanced stage, and 71% had a Ki-67 of ≥ 80%. One patient had a fatal fungal infection (CNS aspergillosis) attributed to high dose corticosteroids and RLI, leading to prohibition of corticosteroids during the RLI only cycles with no further fungal infections identified. The ORR for 2 cycles of RLI was 84.6% (n=44), and the CRR was 38.5% (n=20). One patient refused to proceed with the pre-planned chemotherapy after achieving a CR with 2 cycles of RLI, and remains relapse free 18 months later. Conclusions: The Smart Start trial demonstrates the chemotherapy-free combination of rituximab 375 mg/m2, ibrutinib 560 mg, and lenalidomide 25 mg is highly effective in patients with newly diagnosed non-GCB DLBCL. Additional studies evaluating more cycles of RLI with less chemotherapy consolidation are planned. Clinical trial information: NCT02636322.

The prognostic impact of hypermethylation for a panel of tumor suppressor genes and cell of origin subtype on diffuse large B-cell lymphoma.

Diffuse Large B-cell lymphoma (DLBCL) is an aggressive disease with heterogeneous outcome and marked variable response to chemotherapy. We assessed promoter hypermethylation (PM) for a panel of tumor suppressor genes in 75 DLBCLs compared to 20 lymphoid hyperplasia (LH) and 30 normal control, using methylation specific PCR. Results were correlated to patients' clinic-pathological characteristics, immunophenotyping, and patients' outcome. DAPK1, RUNX3, MT1G, MGMT, CDH1 and p16 PM were detected in 38.7% (29/75), 49.3% (37/75), 46.7% (35/75), 44% (33/75), 49.3% (37/75) and 42.7% (32/75);respectively, of DLBCL patients compared to LH group (P < 0.05). Aberrant PM of RUNX3, MGMT, CDH1 and p16 was significantly higher in non-germinal central B-cell like (non-GCB) compared to GCB (58.3% vs. 33.3%, 56.2% vs. 22.2, 62.5% vs. 25.9, and 56.2% vs. 18.5%, respectively). PM of studies genes in DLBCL associated significantly with worse survival outcome and resistance to chemotherapy (P ≤ 0.01). In non-GCB group, DAPK1, MT1G, RUNX3, CDH1 and p16 PM associated significantly with reduced DFS (P ≤ 0.004) and OS (P ≤ 0.015). Multivariate analysis indicated that RUNX3 and CDH1 PM were independent prognostic factors for OS (P = 0.03 and 0.04; respectively), while DAPK1, RUNX3 and MT1G PM were independent prognostic factors for DFS (P = 0.002, 0.037& 0.007; respectively). DAPK1, RUNX3, MT1G, CDH1 and p16 PM are promising prognostic and/or predictive markers for non-GCB independent of IPI. Upregulation of those genes using new demethylating agents is a promising approach that sensitize chemoresistant DLBCL patients, especially the non-GCB subtype.

Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective ‘proof of concept’ phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)

BackgroundPrimary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal center B-cell (non-GCB) subtype. This study aimed to determine the efficacy of rituximab plus lenalidomide (R2) in DLBCL–PCNSL. Patients and methodsPatients with refractory/relapsed (R/R) DLBCL–PCNSL or primary vitreoretinal lymphoma (PVRL) were included in this prospective phase II study. The induction treatment consisted of eight 28-day cycles of R2 (rituximab 375/m2 i.v. D1; lenalidomide 20mg/day, D1-21 for cycle 1; and 25mg/day, D1-21 for the subsequent cycles); in responding patients, the induction treatment was followed by a maintenance phase comprising 12 28-day cycles of lenalidomide alone (10mg/day, D1-21). The primary end point was the overall response rate (ORR) at the end of induction (P0=10%; P1=30%). ResultsFifty patients were included. Forty-five patients (PCNSL, N=34; PVRL, N=11) were assessable for response. The ORR at the end of induction was 35.6% (95% CI 21.9–51.2) in assessable patients and 32.0% (95% CI 21.9–51.2) in the intent-to-treat analysis, including 13 complete responses (CR)/unconfirmed CR (uCR; 29%) and 3 partial responses (PR; 7%). The best responses were 18 CR/uCR (40%) and 12 PR (27%) during the induction phase. The maintenance phase was started and completed by 18 and 5 patients, respectively. With a median follow-up of 19.2months (range 1.5–31), the median progression-free survival (PFS) and overall survival (OS) were 7.8months (95% CI 3.9–11.3) and 17.7months (95% CI 12.9 to not reached), respectively. No unexpected toxicity was observed. The peripheral baseline CD4/CD8 ratio impacted PFS [median PFS=9.5months (95% CI, 8.1–14.8] for CD4/CD8≥1.6; median PFS=2.8months, [95% CI, 1.1–7.8) for CD4/CD8<1.6, P = 0.03). ConclusionsThe R2 regimen showed significant activity in R/R PCNSL and PVRL patients. These results support assessments of the efficacy of R2 combined with methotrexate-based chemotherapy as a first-line treatment of PCNSL. Clinical trials numberNCT01956695.