Search

Patients with relapsed or refractory large B-cell lymphomas (rrLBCL) can achieve long-term remission after CD19 chimeric antigen receptor T-cell therapy (CART19). However, more than half of recipients will experience treatment failure. Thus, approaches are needed to identify high-risk patients who may benefit from alternative or consolidative therapy. We evaluated low-pass whole-genome sequencing (lpWGS) of cell-free DNA (cfDNA) before CART19 as a new approach for risk stratification. We performed lpWGS on pretreatment plasma samples from 122 patients at time of leukapheresis who received standard-of-care CART19 for rrLBCL to define DNA copy number alterations (CNAs). In multivariable selection, high focal CNA score (FCS) denoting genomic instability was the most significant pretreatment variable associated with inferior 3-month complete response rates (28% vs 56%, P = .0029), progression-free survival (PFS; P = .0007; hazard ratio, 2.11), and overall survival (OS; P = .0026; hazard ratio, 2.10). We identified 34 unique focal CNAs in 108 (89%) patients; of these, deletion 10q23.3 leading to loss of FAS death receptor was the most highly associated with poor outcomes, leading to inferior PFS (P < .0001; hazard ratio, 3.49) and OS (P = .0027; hazard ratio, 2.68). By combining FCS with traditional markers of increased tumor bulk (elevated lactate dehydrogenase and >1 extranodal site), we built a simple risk model that could reliably risk stratify patients. Thus, lpWGS of cfDNA is a minimally invasive assay that could rapidly identify high-risk patients and may guide patient selection for and targeted therapies to evaluate in future clinical trials.

Corticosteroids are commonly used for the management of severe toxicities associated with chimeric antigen receptor (CAR) T-cell therapy. However, it remains unclear whether their dose, duration, and timing may affect clinical efficacy. Here, we determined the impact of corticosteroids on clinical outcomes in patients with relapsed or refractory large B-cell lymphoma treated with standard of care anti-CD19 CAR T-cell therapy. Among 100 patients evaluated, 60 (60%) received corticosteroids for management of CAR T-cell therapy–associated toxicities. The median cumulative dexamethasone-equivalent dose was 186 mg (range, 8-1803) and the median duration of corticosteroid treatment was 9 days (range, 1-30). Corticosteroid treatment was started between days 0 and 7 in 45 (75%) patients and beyond day 7 in 15 (25%). After a median follow-up of 10 months (95% confidence interval, 8-12 months), use of higher cumulative dose of corticosteroids was associated with significantly shorter progression-free survival. More importantly, higher cumulative dose of corticosteroids, and prolonged and early use after CAR T-cell infusion were associated with significantly shorter overall survival. These results suggest that corticosteroids should be used at the lowest dose and for the shortest duration and their initiation should be delayed whenever clinically feasible while managing CAR T-cell therapy–associated toxicities.

Patients with chronic lymphocytic leukemia (CLL) who achieve blood or bone marrow (BM) undetectable minimal residual disease (U-MRD) status after first-line fludarabine, cyclophosphamide, and rituximab (FCR) have prolonged progression-free survival (PFS), when assessed by an assay with sensitivity 10-4 (MRD4). Despite reaching U-MRD4, many patients, especially those with unmutated IGHV, subsequently relapse, suggesting residual disease <10-4 threshold and the need for more sensitive MRD evaluation. MRD evaluation by next-generation sequencing (NGS) has a sensitivity of 10-6 (MRD6). To better assess the depth of remission following first-line FCR treatment, we used NGS (Adaptive Biotechnologies Corporation) to assess MRD in 62 patients, all of whom had BM U-MRD by multicolor flow cytometry (sensitivity 10-4) at end-of-FCR treatment. Samples from these patients included 57 BM samples, 29 peripheral blood mononuclear cell (PBMC) samples, and 32 plasma samples. Only 27.4% of the 62 patients had U-MRD by NGS. Rate of U-MRD by NGS was lowest in BM (25%), compared with PBMC (55%) or plasma (75%). No patient with U-MRD by NGS in BM or PBMC was MRD+ in plasma. Patients with mutated IGHV were more likely to have U-MRD by NGS at the end of treatment (EOT; 41% vs 13%, P = .02) than those with unmutated IGHV. Median follow-up was 81.6 months. Patients with U-MRD at EOT had superior PFS vs MRD+ patients, regardless of sample type assessed (BM, P = .02, median not reached [NR] vs 67 months; PBMC, P = .02, median NR vs 74 months). More sensitive MRD6 testing increases prognostic discrimination over MRD4 testing.

Introduction

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare and aggressive variant of large B-cell lymphoma. A substantial subset of THRLBCL patients (pts) relapse after frontline anthracycline-based therapy. There is a scarcity of outcome data on therapy options for relapsed/refractory (r/r)THRLBCL, particularly CD19 CAR-T therapy.A recent genetic and spatial analysis provided critical insights into the complex interactions at the tumor-immune interface in THRLBCL. Understanding the mechanisms by which tumor cells evade the immune system is crucial in designing treatment strategies. This retrospective study aims to analyze clinicopathologic data in pts with r/r THRLBCL with the goal of identifying patterns that may influence response rates and long-term survival.

Background. We previously reported pro-tumoral macrophages may be associated with resistance to lenalidomide and rituximab (R 2) treatment in follicular lymphoma (FL) ( Marques-Piubelli, Blood Adv 2022). As pre-clinical studies suggest that BTK inhibition can mitigate the crosstalk between monocyte/macrophages and FL B cells, we hypothesized that acalabrutinib, a specific BTK inhibitor, may synergize with R 2without increasing toxicity. In agreement with this, the combination of acalabrutinib and R 2(aR 2) was shown to be safe and effective in patients with relapsed FL ( Strati P et al, ASH 2022). Here, we investigated the safety and efficacy of aR 2in previously untreated FL patients and analyzed the biological effects of this combination on peripheral blood immune cells.

Background:Despite recent advances, first-line (1L) chemoimmunotherapy (CIT) for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades.In the Smart Start trial, we established the feasibility of targeted chemotherapy-free 1L therapy with rituximab (R), lenalidomide (L), and ibrutinib, prior to chemotherapy in patients with newly diagnosed DLBCL with an overall response rate (ORR) and complete response rate (CRR) of 86% and 36%, respectively, prior to chemotherapy, and a 2 year progression free survival rate of 91.3% following 6 cycles of standard CIT (Westin et al, JCO 2023, PMID: 35952327). One patient withdrew from the study after achieving CR and prior to receiving CIT and remains in remission without further therapy at >4 years. BTK inhibitors like acalabrutinib (A) and the immunomodulatory agent L result in synthetic lethality in non-GCB DLBCL models. Both the CD20 antibody R and CD19 antibody tafasitamab (T) demonstrate clinical activity when combined with L in patients with DLBCL. L, T, R, and A are immunomodulatory, driving an anti-tumor immune response. Based upon these data, we are conducting the Smart Stop trial (NCT04978584) to evaluate if the number of CIT cycles can be reduced or omitted after response to targeted therapy, and now report the preplanned interim results from cohort 1.

Background and Significance.While a sentinel role of macrophages in channeling immune responses has long been recognized, the opportunity to harvest, harness and deploy macrophages for therapeutic potential has been underappreciated clinically.

Background. Increasing data have demonstrated that acquired genetic aberrations, including TP53mutations in the tumor cells and clonal hematopoiesis, can impact the efficacy and/or toxicity of anti-CD19 autologous CAR T-cell therapy (CART) in patients with large B-cell lymphoma (LBCL). Recent data have suggested that germline genetic aberrations, including polymorphisms in CD19, ABCB1, MISPand CPVL(Strati P et al, Leukemia 2022) and deleterious germline variants in STXBP2, can also affect outcomes in these patients. However, a comprehensive analysis of germline determinants of response and toxicity after CART in this patient population has not yet been described.

Background:CAR-T cell therapies have revolutionized cancer therapeutics with durable responses in hematologic malignancies. However, toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are well-established off-target effects of CAR-T therapy. Immune effector cell (IEC) therapy can result in hemophagocytic lymphohistiocytosis (HLH)-like events, which are now understood as separate entities. Rare and fatal, HLH is characterized by abnormal activation of natural killer (NK) cells, macrophages, and cytotoxic T-lymphocytes; this leads to supraphysiologic production of cytokines and immune-mediated organ system damage. Expert consensus review defines IEC-HS as the development of pathologic features of HLH/macrophage activation independent from CRS and ICANS attributed to IEC therapy, including new onset or worsening cytopenia, hyperferritinemia (>2 times the upper limit of normal), coagulopathy with hypofibrinogenemia, and elevated transaminases. Few clinical studies have shown IEC-HS in Acute Lymphocytic Leukemia (ALL), especially in the pediatric and adolescent populations. However, the incidence and risk of IEC-HS exposure to CD19 and BCMA CAR-T are yet to be determined in B-cell lymphomas and Myelomas. The FDA Adverse Event Reporting System (FAERS) contains circumstantial case reports and serious post-CAR-T therapy IEC-HS. This retrospective analysis from the FAERS aims to address these questions and estimate the risk of IEC-HS with CAR-T cell therapies.

Background:

Background:Cytokine storm is a complex syndrome driven by hyperinflammation leading to multi-organ dysfunction and high mortality rates. Patients with hematological malignancies are susceptible to different types of cytokine storm syndromes (CSS) including those driven by their disease (e.g., malignancy-associated hemophagocytic lymphohistiocytosis (MA-HLH)), treatment toxicities (e.g., cytokine release syndrome (CRS) related to CAR-T) or infections (e.g., COVID associated cytokine storm). The precise nature of the inflammatory mechanisms of different CSS and their impact on clinical outcomes are poorly understood.

Background and Significance. Approximately 30% of patients with large B-cell lymphoma (LBCL) treated with autologous anti-CD19 CAR T-cell therapy (CART) achieve a partial response (PR) on day 30 (D30) assessment. Of those, up to 30% may spontaneously convert to a complete response (CR) during subsequent re-staging. While up to 70% of patients with D30 PR eventually progress, reliable biomarkers that help identify patients at risk are not yet available, and the current standard approach is close monitoring. CD19 expression is retained in most tumors of patients who relapse or progress after CART. Potential reasons for resistance in these tumors include T-cell dysfunction and tumor intrinsic mechanisms that resist T-cell mediated killing. Therefore, targeting such tumors with agents that have an alternative mechanism of action is likely to improve outcomes. To this regard, loncastuximab tesirine (Lonca) is an anti-CD19 antibody conjugated to a cytotoxic pyrrolobenzodiazepine dimer approved by the FDA for LBCL patients who relapse after at least 2 lines of systemic therapy. In the phase 2 LOTIS-2 study, Lonca was associated with an overall response rate of 48% and a CR rate of 24%, and included patients previously treated with CART. Grade 3-4 adverse events were observed in less than one third of patients, and were mainly represented by myelosuppression, skin toxicity and isolated GGT elevation.

Background:Inotuzumab Ozogamicin (INO) is a humanized anti-CD22 monoclonal antibody that has emerged as an attractive therapeutic target for CD22+ b-cell lymphoid malignancies. We prospectively studied the safety and efficacy of INO when added to our standard nonmyeloablative allogeneic stem cell transplant (alloSCT) conditioning regimen of BFR (bendamustine, fludarabine and rituximab) (Khouri IF, et al. Blood 2014;124:2306). We also compared results to patients who received BFR+alloSCT without INO in prior trial. Methods:INO was infused intravenously (IV) on day -13 outpatient, with a dose cohort of 0.6, 1.2 or 1.8 mg/m2, to determine the maximum tolerated dose. Bendamustine 130 mg/m2IV daily on days -5 to -3 together with 30 mg/m2IV of fludarabine on days -5 to -3 were given prior to transplantation. Rituximab was given at a dose of 375 mg/m2IV on days -6, +1, and +8. Tacrolimus and mini-methotrexate were used for graft versus host disease (GVHD) prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving a matched unrelated donor (MUD) transplant. Results: AlloSCT with INO.The study group included 26 patients treated between December 2012 and September 2019. Median age was 59 (range, 26-70) years. Eleven (42% had an HCT-CI >3. Disease types: CLL [n=7 (27%) ; 2 with TP53mutations, 2 others with 17p-; 4 with unmutated immunoglobulin heavy chain gene], Richter’s (n=4, 15%), mantle cell lymphoma (MCL) [n=8 (31%); 6/6 patients tested had Ki 67 >30%; 1 had blastoid histology and 1 had 17p-], follicular lymphoma (n=5, 19%), and diffuse large b cell (DLBCL[n= 2 (8%); including 1 double-expressor subtype]. Median prior treatments was 2.5 (range, 1-6). CLL patients were previously treated with ibrutinib (n=6, 86%; 5 had the drug discontinued due to refractoriness to ibrutinib, one had poor tolerance, and 1 was bridged to transplant), idelalisib (n=2, refractory), venetoclax (n=4; sensitive), CAR-T cell (n=1, refractory). One patient with Richter refractory to nivolumab+chemotherapy. Four MCL patients were previously treated with ibrutinib (2 had progression, 2 were bridged to transplant). At study entry, 18 (69%) patients were in CR, 7 (27%) in PR, and 1 (4%) had SD. Eleven (42%) received their transplants from HLA-compatible siblings and 15 (58%) from MUDs.The number of patients who received the 0.6, 1.2 or 1.8 mg/m2 of INO were 4, 2 and 20 patients, respectively. No DLT was observed. Neutrophil counts recovered to > 0.5 x 109/L a median of 6 days after transplantation (range, 0-12). Eleven patients (42%) never experienced an ANC < 0.5 x 109/L and 20 (77%) never experienced a platelet counts < 20K x 109/L. All patients engrafted donor cells and no secondary graft failure occurred. By day 30, median donor myeloid and T-cells were 92% and 99%, respectively. Both increased to 100% by day 90. The CI acute grade 2-4 GVHD, 3-4 GVHD and 1-year chronic extensive GVHD were 27%, 4 % (none had grade 4) and 31%, respectively. Non-relapse mortality (NRM) at 5-years was 11.7%. With a median follow-up time of 49 (range, 4-83) months, the 5-year OS and PFS rates were 84% and 81%, respectively (Figure 1). Control group: AlloSCT without INO.We compared results to a group of patients (n=56) with relapsed lymphoid malignancies who received alloSCT at our center on a preceding prospective trial between April 2009 and February 2013, using BFR conditioning without INO and the same GVHD prophylaxis. There was no statistically significant difference in patients, disease or transplant characteristics between the 2 groups. We also found no statistically significant differences in engraftment times, % donor cell, 5-year NRM (12.5%), risk of acute 2-4 or 3-4 GVHD. Liver toxicity encountered between the two groups is summarized in Table 1. The 5-year OS and PFS was 75% and 62%, respectively (Figure 2). Conclusions:Our results show that INO at a dose level of 1.8 mg/m2 is well-tolerated when combined with the BFR nonmyeloablative allogeneic conditioning regimen for lymphoid malignancies. No added toxicity or increased myelosuppression were observed compared to patients who received BFR alone. An ongoing trial at our center includes patients with acute lymphoblastic leukemia evaluating INO added during conditioning and post- alloSCT for maintenance.

Lenalidomide is clinically active in chronic lymphocytic leukemia (CLL), but its effectiveness in the context of the CLL mutational landscape is unknown. We performed targeted capture sequencing of 295 cancer genes in specimens from 102 CLL patients with treatment-naïve disease (TN patients) and 186 CLL patients with relapsed/refractory disease (R/R patients) who received lenalidomide-based therapy at our institution. The most frequently mutated gene was SF3B1(15%), followed by NOTCH1(14%) and TP53(14%), with R/R patients having significantly more TP53mutations than did TN patients. Among all lenalidomide-treated patients, del(17p) (P≤ .001), del(11q) (P= .032), and complex karyotype (P= .022), along with mutations in TP53(P≤ .001), KRAS(P= .034), and DDX3X(P≤ .001), were associated with worse overall response (OR). R/R patients with SF3B1and MGAmutations had significantly worse OR (P= .025 and .035, respectively). TN and R/R patients with del(17p) and TP53mutations had worse overall survival (OS) and progression-free survival (PFS). In R/R patients, complex karyotype and SF3B1mutations were associated with worse OS and PFS; DDX3Xmutations were associated with worse PFS only. Weibull regression multivariate analysis revealed that TP53aberrations (del(17p), TP53mutation, or both), along with complex karyotype and SF3B1mutations, were associated with worse OS in the R/R cohort. Taken together, cancer gene mutations in CLL contribute to the already comprehensive risk stratification and add to prognosis and response to treatment. The related trials were registered at www.clinicaltrials.govas #NCT00267059, #NCT00535873, #NCT00759603, #NCT01446133, and #NCT01002755.

Since the first description of the natural history of chronic lymphocytic leukemia (CLL) by David Galton in 1966, the considerable heterogeneity in the disease course has been well recognized. The Rai and Binet staging systems described ∼40 years ago have proven to be robust prognostic tools. Over the past 2 decades, several novel biological, genetic, and molecular markers have been shown to be useful adjuncts to the Rai and Binet staging systems. In this systematic review, we examined the role of immunoglobulin heavy-chain variable region gene (IGHV) mutation status and genetic abnormalities determined by interphase fluorescence in situ hybridization (FISH) in patients with newly diagnosed CLL. The cumulative evidence presented in this systematic review is sufficient to recommend that FISH and IGHV be performed as standard clinical tests for all patients with newly diagnosed CLL in those countries with the resources to do so. In addition to clinical stage, these parameters could represent the minimal standard initial prognostic evaluation for patients with CLL. This approach will allow the application of powerful, recently developed prognostic indices (all of which are dependent on IGHV and FISH results) to all patients with newly diagnosed CLL.

Monoclonal B lymphocytosis (MBL) is defined as the presence of a clonal B-cell population in the peripheral blood with fewer than 5 × 109/L B-cells and no other signs of a lymphoproliferative disorder. The majority of cases of MBL have the immunophenotype of chronic lymphocytic leukemia (CLL). MBL can be categorized as either low count or high count based on whether the B-cell count is above or below 0.5 × 109/L. Low-count MBL can be detected in ∼5% of adults over the age of 40 years when assessed using standard-sensitivity flow cytometry assays. A number of biological and genetic characteristics distinguish low-count from high-count MBL. Whereas low-count MBL rarely progresses to CLL, high-count MBL progresses to CLL requiring therapy at a rate of 1% to 2% per year. High-count MBL is distinguished from Rai 0 CLL based on whether the B-cell count is above or below 5 × 109/L. Although individuals with both high-count MBL and CLL Rai stage 0 are at increased risk of infections and second cancers, the risk of progression requiring treatment and the potential to shorten life expectancy are greater for CLL. This review highlights challenging questions regarding the classification, risk stratification, management, and supportive care of patients with MBL and CLL.

The high complete remission rate with first-line combined fludarabine, cyclophosphamide, and rituximab (FCR) begs the question of the value of minimal residual disease (MRD)–negative status as a treatment end point. We report on 237 patients with chronic lymphocytic leukemia who received first-line FCR. MRD was prospectively assessed by 4-color flow cytometry in bone marrow after course 3 and at final response assessment. After course 3 and at final response assessment, 17% and 43% of patients were MRD negative in bone marrow, respectively. A mutated immunoglobulin heavy chain variable gene and trisomy 12 were independently associated with MRD-negative status both after 3 courses of FCR and at final response assessment in multivariable analyses (MVAs). MRD-negative status was independently associated with significantly longer progression-free survival (PFS) and overall survival (OS) in MVA (P = .03 and .02, respectively). This association was confirmed also on landmark MVA at the time of MRD assessment (P = .04 and .05, respectively). MRD-negative patients had comparable PFS and OS, independent of the number of courses received or interim staging. Early MRD eradication may be a desirable goal, prompting consideration of early discontinuation of treatment. This trial was registered at www.clinicaltrials.gov as #NCT00759798.

Parmar: Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Nastoupil:Pfizer: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; LAM Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; Gamida Cell: Honoraria; Merck: Research Funding; Novartis: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Gilead/KITE: Honoraria. Nieto:Affimed: Consultancy, Other: Grant Support; Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Secura Bio: Other: Grant Support. Hosing:NKARTA Inc.: Consultancy. Lee:Takeda: Research Funding; Oncternal Therapeutics: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Guidepoint Blogal: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau. Westin:Novartis: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Amgen: Consultancy; Janssen: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Curis: Consultancy, Research Funding; 47: Research Funding; Genentech: Consultancy, Research Funding. Champlin:Actinium: Consultancy; Takeda: Patents & Royalties; Johnson and Johnson: Consultancy; Genzyme: Speakers Bureau; Omeros: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Wang:Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Nobel Insights: Consultancy; Dava Oncology: Honoraria; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Guidepoint Global: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Verastem: Research Funding; Molecular Templates: Research Funding; OncLive: Honoraria; Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding. Vega:NCI: Research Funding. Neelapu:Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Pfizer: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Legend Biotech: Other; Precision Biosciences: Other: personal fees, Research Funding; Adicet Bio: Other; Calibr: Other; Cell Medica/Kuur: Other: personal fees; Cellectis: Research Funding; Karus Therapeutics: Research Funding; Acerta: Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; N/A: Other; Unum Therapeutics: Other, Research Funding; Poseida: Research Funding; Takeda Pharmaceuticals: Patents & Royalties; Allogene Therapeutics: Other: personal fees, Research Funding; Incyte: Other: personal fees. Flowers:National Cancer Institute: Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Eastern Cooperative Oncology Group: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; Burroughs Wellcome Fund: Research Funding; TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; BeiGene: Consultancy; V Foundation: Research Funding. Iyer:Spectrum: Research Funding; Merck: Research Funding; Target Oncology: Honoraria; Afffimed: Research Funding; Seattle Genetics, Inc.: Research Funding; Rhizen: Research Funding; CRISPR: Research Funding; Trillium: Research Funding; Daiichi Sankyo: Consultancy; Curio Biosciences: Honoraria; Legend Biotech: Consultancy.

Introduction. The outcome of patients with large B-cell lymphoma (LBCL) relapsing or progressing after anti-CD19 CAR T-cell therapy is dismal, and novel therapeutic strategies are needed. Polatuzumab vedotin (PV) is a CD79b-directed antibody-drug conjugate, approved by the FDA in combination with bendamustine and rituximab for the treatment of patients with LBCL who relapse or progress after at least 2 lines of systemic therapy. CD79b targeting is an appealing strategy after failure of anti-CD19 CAR T-cell therapy, but the activity of PV in this setting has not been investigated.

Introduction

Introduction

BACKGROUND:

Introduction

Nastoupil: TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding; Gamida Cell: Honoraria; Gilead/KITE: Honoraria; Bayer: Honoraria; Pfizer: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Karus Therapeutics: Research Funding. Westin:Janssen: Consultancy, Research Funding; Amgen: Consultancy; Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; 47: Research Funding; Morphosys: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding. Lee:Guidepoint Blogal: Consultancy; Celgene: Research Funding; Seattle Genetics: Research Funding; Oncternal Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau; Takeda: Research Funding. Kebriaei:Kite: Other: Served on advisory board; Novartis: Other: Served on advisory board; Ziopharm: Other: Research Support; Amgen: Other: Research Support; Pfizer: Other: Served on advisory board; Jazz: Consultancy. Shpall:Takeda: Other: Licensing Agreement; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Jain:Cellectis: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Incyte: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Green:KDAc Therapeutics: Current equity holder in private company. Flowers:Kite: Research Funding; Pharmacyclics/Janssen: Consultancy; Spectrum: Consultancy; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; AbbVie: Consultancy, Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Karyopharm: Consultancy; V Foundation: Research Funding; National Cancer Institute: Research Funding; Bayer: Consultancy; Denovo Biopharma: Consultancy; Cancer Prevention and Research Institute of Texas: Research Funding; Millennium/Takeda: Consultancy, Research Funding; BeiGene: Consultancy; OptumRx: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; TG Therapeutics: Research Funding. Champlin:Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy; Omeros: Consultancy; Johnson and Johnson: Consultancy; Actinium: Consultancy; Takeda: Patents & Royalties. Wargo:Imedex, Dava Oncology, Omniprex, Illumina, gilead, PeerView, PET, MedImmune and Bristol-Myers Squibb: Honoraria, Speakers Bureau; Merck: Consultancy; Microbiome DX: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Astrazeneca: Consultancy; Biothera Pharmaceuticals: Consultancy. Neelapu:Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Novartis: Other: personal fees; N/A: Other; Precision Biosciences: Other: personal fees, Research Funding; Incyte: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties; Poseida: Research Funding; Cellectis: Research Funding; Karus Therapeutics: Research Funding; Calibr: Other; Legend Biotech: Other; Adicet Bio: Other; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Unum Therapeutics: Other, Research Funding.

Lee: Takeda: Research Funding; Celgene: Research Funding; Guidepoint Blogal: Consultancy; Oncternal Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau; Seattle Genetics: Research Funding. Iyer:Legend Biotech: Consultancy; Daiichi Sankyo: Consultancy; Seattle Genetics, Inc.: Research Funding; Merck: Research Funding; Afffimed: Research Funding; Trillium: Research Funding; Curio Biosciences: Honoraria; CRISPR: Research Funding; Spectrum: Research Funding; Rhizen: Research Funding; Target Oncology: Honoraria. Nastoupil:Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Merck: Research Funding; Karus Therapeutics: Research Funding; TG Therapeutics: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead/KITE: Honoraria; Gamida Cell: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria. Parmar:Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Wang:Juno: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Dava Oncology: Honoraria; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; Guidepoint Global: Consultancy; Targeted Oncology: Honoraria; Molecular Templates: Research Funding; OncLive: Honoraria; VelosBio: Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria; MoreHealth: Consultancy; Acerta Pharma: Research Funding; Verastem: Research Funding; Loxo Oncology: Consultancy, Research Funding. Shpall:Takeda: Other: Licensing Agreement; Magenta: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees. Kebriaei:Pfizer: Other: Served on advisory board; Ziopharm: Other: Research Support; Amgen: Other: Research Support; Jazz: Consultancy; Novartis: Other: Served on advisory board; Kite: Other: Served on advisory board. Westin:Genentech: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Curis: Consultancy; 47 Inc: Consultancy; Kite: Consultancy; Juno: Consultancy; MorphoSys: Consultancy; Unum: Consultancy. Neelapu:N/A: Other; Takeda Pharmaceuticals: Patents & Royalties; Karus Therapeutics: Research Funding; Pfizer: Other: personal fees; Novartis: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Precision Biosciences: Other: personal fees, Research Funding; Legend Biotech: Other; Unum Therapeutics: Other, Research Funding; Acerta: Research Funding; Adicet Bio: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Poseida: Research Funding; Cellectis: Research Funding; Calibr: Other; Celgene: Other: personal fees, Research Funding.

Introduction

Background:With the incorporation of positron emission tomography (PET) imaging as part of the standard staging evaluation of follicular lymphoma (FL), it is generally recommended to obtain the diagnostic biopsy from a lesion with the highest standardized uptake value (SUV) to rule out de novo histologic transformation (HT). In some cases such an approach might be impractical, while in other cases a biopsy from a diseased area with a high SUV may still demonstrate an indolent histology. To date, there is no data to guide treatment choices in patients (pts) with FL with high SUVmaxbut with no documented evidence of HT. Specifically, it remains unclear whether anthracycline-containing regimens, such as R-CHOP, provide a better outcome than R-Bendamustine (BR). Furthermore, it is unknown whether rituximab (R) maintenance is beneficial in this setting. Therefore, we aimed to compare the efficacy of R-CHOP vs BR in newly diagnosed FL pts with high SUVmaxat baseline PET and to clarify the role of maintenance.

Westin: Kite: Consultancy; Genentech: Consultancy; 47 Inc: Consultancy; MorphoSys: Consultancy; Unum: Consultancy; Juno: Consultancy; Curis: Consultancy; Novartis: Consultancy; Janssen: Consultancy. Lee:Guidepoint Blogal: Consultancy; Celgene: Research Funding; Oncternal Therapeutics: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau. Neelapu:Celgene: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Takeda Pharmaceuticals: Patents & Royalties; Cellectis: Research Funding; Adicet Bio: Other; Calibr: Other; Unum Therapeutics: Other, Research Funding; Poseida: Research Funding; Incyte: Other: personal fees; Precision Biosciences: Other: personal fees, Research Funding; Legend Biotech: Other; Acerta: Research Funding; Allogene Therapeutics: Other: personal fees, Research Funding; Karus Therapeutics: Research Funding; Pfizer: Other: personal fees; N/A: Other; Novartis: Other: personal fees; Cell Medica/Kuur: Other: personal fees. Vega:NCI: Research Funding. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding. Nastoupil:Karus Therapeutics: Research Funding; Gamida Cell: Honoraria; Celgene: Honoraria, Research Funding; Gilead/KITE: Honoraria; Novartis: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Pfizer: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria.

Introduction.Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common adverse effects of chimeric antigen receptor (CAR) T-cell therapy. Elevated biomarkers, such as ferritin and LDH, have been shown to correlate with more severe toxicity. The endothelial activation and stress index (EASIX) is a surrogate of endothelial activation, and correlates to other biomarkers of endothelial dysfunction. In allogeneic hematopoietic cell transplantation (HCT), it is predictive of toxicity such as fluid overload, which is correlative with endothelial dysfunction, as well as sinusoidal obstruction syndrome, non relapse mortality and overall survival (Luft et al, BMT2019, Varma et al, BBMT, 2020, Jiang et al, Haematologica, 2020). In this study we describe the correlation of EASIX to CAR T cell related CRS and ICANS.

Background

Introduction:Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of rare neoplasms, the majority characterized by an aggressive course and short survival. Angioimmunoblastic T-cell lymphoma (AITL) is the second most common subtype (19%) of PTCLs, with generally poor long-term prognosis. The outcomes for most reported cases of AITL are derived from cohorts which include other PTCL subtypes. There is limited data for the role of autologous stem cell transplantation (ASCT) in AITL, and the associated predictive factors for prognosis. We present the largest single center cohort of AITL patients who underwent ASCT either upfront or at time of relapse.

Background:There are few treatment options for relapsed/refractory (r/r) T cell lymphoma (TCL). We previously reported the safety and efficacy of a single center, single arm, trial of the check-point inhibitor (CPI) pembrolizumab in combination with the Histone deacetylase inhibitor (HDACi) romidepsin in r/r TCL pts who progressed after at least one prior systemic regimen (NCT03278782). The rationale for combining CPI with HDACi was that TCLs often carry multiple gene mutations in epigenetic modifier genes TET2, IDH2, DNMT3Aand TCR related genes CD38, RHOA,and FYNthat may impair immunogenicity and promote immune escape. Herein, we report the updated results of the Phase II study along with the correlative PDL1 evaluation.