Geethakumari, Praveen Ramakrishnan

Background: Autologous CAR-T therapy targeting CD19 is an effective treatment for relapsed or refractory large B-cell lymphoma (LBCL). However, morbidity and mortality related to CAR-T toxicity remain significant concerns. This study aims to evaluate the patterns, risk factors, and implications of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) following CD19-CAR-T therapy in LBCL. Methods: This retrospective analysis includes 1916 LBCL patients treated with CD19-CAR-T cell therapy (axicabtagene-ciloleucel [axi-cel] 75% and tisagenlecleucel 25%) between 2018 and 2020 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patient demographics, baseline characteristics, treatment-related variables, and clinical outcomes were collected. The incidence, severity and timing of onset of CRS and ICANS (according to median time to onset) were analyzed, factors associated with these outcomes and their impact on overall survival as time dependent covariates were done using Cox Regression multivariate analyses. Results: The median age of the patients was 64 years, with a majority having a Karnofsky performance status (KPS) below 90% (61%) and not receiving bridging therapy (67%). CRS was observed in 75.1% of patients, with 9% experiencing severe CRS (grades ≥ 3). Similarly, 43% of patients experienced ICANS, with 20% having severe ICANS (grade ≥ 3). The median time to toxicity was shorter for CRS (4 days) compared to ICANS (7 days). Nearly all the patients who developed ICANS also experienced CRS (98%; ), and the correlation between these two events and respective severities are shown in the Figure 1a. In the multivariate analyses, factors associated with development of CRS were gender (women, Odds ratio [OR] 1.39, 95% confidence interval [CI] 1.10- 1.76, p=0.006), high LDH at time of infusion (OR 1.56; 95% CI 1.22 - 2.00, p=0.002) and product (axi-cel OR 4.60, 95% CI 3.56 -5.81, p<0.001). Factors associated with the development of ICANS included age (> 65 years, OR 1.83; 1.50-2.24, p<0.001), KPS (<80%, OR 2.48; 1.88-3.27, p<0.001), disease status at infusion (treatment resistant disease, OR 1.98; 1.09-3.58, p=0.024; and untreated relapse OR 2.62, 1.35-5.10, p=0.004) and product (axi-cel, OR 5.85; 4.47-7.64, p<0.0001). Factors associated with severe and early onset CRS and ICANS are listed in the table below. The median follow-up of 14.2 months, the estimated 12-month overall survival, progression-free survival (PFS), and treatment-related mortality were 61.6% (95% CI: 59.4-63.9), 42.2% (39.9-44.5), and 4.3% (3.4-5.3), respectively. Overall CRS, early onset CRS and overall ICANS were not associated with higher mortality, however grade >3 CRS (HR 1.79; 1.41-2.28, p<0.001), grade >3 ICANS (hazard ratio [HR] 1.34; 95% CI 1.13-1.59, p=0.002) and early onset ICANS (<7 days, HR 1.23; 1.05-1.44, p=0.01) were associated with higher mortality. The impact of severe CRS on survival are shown in the landmark analysis at 30 days from infusion in the figure 1B. Conclusion: In the largest analysis of CD19-CAR-T cell therapy toxicities to date, we observed a high burden of CRS and ICANS among LBCL patients. The CAR T cell product type was consistently associated with higher incidence, shorter onset and higher severity of both toxicities. High LDH, older age and low performance score also influence the severity and onset of these outcomes. Additionally, patients who developed higher grades of CRS/ICANS and earlier onset ICANS had a higher mortality, stressing the need to develop novel strategies to mitigate the incidence and optimize management of these patients to improve their outcomes.

LBA7564 Background: Patients with r/r B-NHL have a dismal prognosis. DIAL (Dual Immunomodulation in Aggressive Lymphoma) was a multi-center randomized phase II study testing the efficacy of nivolumab (PD-1 inhibitor) plus varlilumab (CD27 agonist) in this population. Methods: Patients were randomized (1:1) to nivolumab (240 mg IV every 2 weeks for 4 months, 480 mg IV monthly thereafter; group 1) alone or combined with varlilumab (3 mg/kg IV monthly; group 2). Cross-over (group 1 to 2) was allowed for progression. Primary endpoint was overall response (ORR) per LYRIC criteria. A sample size of 48 patients per arm would provide 80% power to detect increase in ORR from 25% to 45% using a one-sided test (p = 0.15). Pre-specified interim analysis occurred after half of the patients completed first radiologic assessment. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Exploratory endpoints included tumor genomic assessment and immune profiling of blood and tumor. Results: 53 patients were enrolled (27 in group 1; 26 in group 2). Interim analysis included 24 patients from each arm. Mean age was 65.2 years, 34 (70.8%) were male, and 36 (75%) received prior CAR-T cell therapy. Baseline characteristics were balanced between arms. Grade ≥ 3 AEs were observed in 8 (33.3%) and 7 (30.4%) of patients in groups 1 and 2, respectively. Common AEs (> 5%) of any grade included fatigue, lymphopenia, diarrhea, rash. There were no treatment-associated deaths. Toxicity profile was similar between arms. Table summarizes efficacy outcomes. ORR was achieved in 6 patients (12.5%), not statistically different between arms; 4 responses were complete. Seven patients crossed over (1 responded after crossing). Median OS (8.6 vs 7.3 months; p = 0.39) and PFS (2.7 vs 1.4 months; p = 0.06) were similar between arms. Subgroup analysis of patients with prior CAR-T cell therapy showed similar ORR (5/36; 14%), not statistically different between arms. Correlative analysis results will be presented at conference. The trial met futility criterion on interim analysis and enrollment ceased based on pre-specified stopping rule. Conclusions: Dual immunomodulatory therapy did not enhance anti-tumor activity in patients with aggressive B-NHL compared to nivolumab alone. Response rates were low and consistent with previous data using PD-1 inhibitors in this population. Prior therapy with CAR-T cell does not seem to sensitize patients to PD-1 blockade. Toxicity profile was acceptable and dual therapy did not increase the rate of AEs. Clinical trial information: NCT03038672. [Table: see text]

Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in immune cells including B lymphocytes. It forms the Myddosome complex with the MYD88 adaptor protein, with IRAK4 being essential for downstream signaling, maximal activation of NFkB with inflammatory and immune response and tumor promotion [Treon 2012; Rhyasen 2015]. CA-4948 is a novel small molecule, oral inhibitor of IRAK4, first-in-class and only suppressor of the TLR pathway currently tested in hematological malignancies. When combined with the BTK inhibitor ibrutinib that blocks parallel BCR signaling and NF-kB activating pathway, it has shown synergy in in-vivo B-cell NHL models, providing strong rationale for clinical evaluation [Booher 2018]. Recent preclinical studies demonstrated the role of IRAK4 activation as a driver of secondary, adaptive tumor resistance and survival mechanisms of hematological and solid tumor malignancies [Melgar 2019] that could be blocked by CA-4948 to delay or reverse resistance. Study Design and Methods: This is a multicenter, open-label trial of oral CA-4948 combined with ibrutinib in adult patients with relapsed or refractory hematologic malignancies. (NCT03328078). It has 2 parts: a dose escalation (Part A2), and expansion basket of 4 cohorts (Part B). Part A2: Is a truncated 3+3 design: CA-4948 starting is 200 mg BID with subsequent escalation to 300 mg BID. Both dose are safe and active against NHL as seen in the nearly completed monotherapy Part A1 of this trial Patients will receive CA-4948 with ibrutinib at the labeled dose for the respective NHL subtype (560 mg or 420 mg) until toxicity or progression. Primary objectives are safety/tolerance (MTD, RP2D); 2nd objectives are pharmacokinetics and preliminary efficacy; exploratory objectives include biomarker correlations (e.g., MYD88-L265P mut, IRAK4 pathway, NFκB inhibition). Part B basket has four cohorts: 1 -MZL, 2 - ABC-DLBCL, 3 - PCNSL, and 4 - NHL with adaptive ibrutinib resistance. Cohorts 1-3 must be BTK-inhibitor naïve. Cohort 4 includes ibrutinib treated NHLs after developing adaptive, secondary resistance. All will receive the combination of ibrutinib and CA-4948. Cohort 4 patients will be allowed a <3 weeks gap since prior ibrutinib therapy. Primary objectives include CR or ORR and DOR compared to (matched) historical controls (closely matched if possible). 2nd objectives include tolerance/safety, PFS, and pop-PK sampling for CA-4948. Exploratory objectives; response correlation with biomarkers including MYD88-L265P or other genetic mutations, gene expressions, cell of origin, IRAK4 signaling, and resistance. Treatment: CA-4948 at RP2D+ibrubinib at labelled doses; 21-day cycles to be repeated in the absence of toxicity or progression. Samples sizes, statistical considerations: Approx. 18 patients in Part A2. In Part B, a Simon 2-Step design will be applied to each cohort. Early stopping rule for futility after approx. 20 patients in Stage 1: full accrual with Stage 2 will add about 25 patients. Successful signal efficacy identification in a cohort may support further expansion or a subsequent controlled trial. The safety population will include all patients in the study who received any test dose. The efficacy population will have a valid baseline and post-baseline disease assessment. Safety assessments include TEAEs, safety labs, vitals, physical exams, PK, and ECGs; efficacy assessments: tumor imaging, para-protein determination, and histo/cyto-morphologic examinations. Part A2 inclusion: Histopathologically confirmed B-cell NHL as per the WHO 2016 classification. Eligible NHL subtypes: FL, MZL, MCL, DLBCL (including extranodal lymphomas of leg, testicle, or other sites, excluding mediastinal lymphoma), CLL/SLL, primary or secondary CNS lymphoma, and WM/LPL. Patients with FL, MCL, MZL, WM/LPL, or CLL/SLL should meet clinical treatment criteria. Part B inclusion: Cohorts 1-3 include patients with MZL, ABC-DLBCL, or PCNSL who are BTK-inhibitor naïve. Cohort 4 will include ibrutinib pre-treated MCL, MZL, CLL/SLL, WM/LPL, ABC-DLBCL, or PCNSL with adaptive resistance. Exclusions for both Parts A2 and B: Significant acute or chronic toxicity from prior anti-cancer therapy that has not resolved to Grade ≤ 1, as determined by NCI CTCAE v 4.03 within 7 days prior to start of study or serious co-morbidities. Disclosures Nowakowski: NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Kymera: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees. Leslie:TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Lunning:Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Research Funding; Verastem: Consultancy, Honoraria; Acrotech: Consultancy; ADC Therapeutics: Consultancy; Legend: Consultancy; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Curis: Research Funding; Gilead: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Patel:Adaptive Biotechnologies: Consultancy; Kite: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Landsburg:Takeda: Research Funding; Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, 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. Fenske:Medical College of Wisconsin: Current Employment. Ramchandren:Merck, Seattle Genetics, Janssen, Genentech: Research Funding; Seattle Genetics, Sandoz-Novartis, Pharmacyclics, an AbbVie Company, Janssen, Bristol-Myers Squibb: Consultancy. Skarbnik:Alexion: Consultancy; Beigene: Speakers Bureau; Verastem: Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tun:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding.

Background Although rituximab‐based high‐dose therapy is frequently used in diffuse large B cell lymphoma (DLBCL) patients undergoing autologous hematopoietic cell transplantation (auto‐HCT), data supporting the benefits are not available. Herein, we report the impact of rituximab‐based conditioning on auto‐HCT outcomes in patients who have DLBCL. Methods Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, 862 adult DLBCL patients undergoing auto‐HCT between 2003 and 2017 using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning regimen were included. All patients received frontline rituximab‐containing chemoimmunotherapy and had chemosensitive disease pre‐HCT. Early chemoimmunotherapy failure was defined as not achieving complete remission (CR) after frontline chemoimmunotherapy or relapse within 1 year of initial diagnosis. The primary outcome was overall survival (OS). Results The study cohort was divided into 2 groups: BEAM (n = 667) and R‐BEAM (n = 195). On multivariate analysis, no significant difference was seen in OS ( P = .83) or progression‐free survival (PFS) ( P = .61) across the 2 cohorts. No significant association between the use of rituximab and risk of relapse ( P = .15) or nonrelapse mortality ( P = .12) was observed. Variables independently associated with lower OS included older age at auto‐HCT ( P < .001), absence of CR at auto‐HCT ( P < .001) and early chemoimmunotherapy failure ( P < .001). Older age ( P < .0002) and non‐CR pre‐HCT ( P < .0001) were also associated with inferior PFS. There was no significant difference in early infectious complications between the 2 cohorts. Conclusion In this large registry analysis of DLBCL patients undergoing auto‐HCT, the addition of rituximab to the BEAM conditioning regimen had no impact on transplantation outcomes. Older age, absence of CR pre auto‐HCT, and early chemoimmunotherapy failure were associated with inferior survival.

BACKGROUNDEarly treatment failure (ETF) in follicular lymphoma (FL), defined as relapse or progression within 2 years of frontline chemoimmunotherapy, is a newly recognized marker of poor survival and identifies a high‐risk group of patients with an expected 5‐year overall survival (OS) rate of approximately 50%. Transplantation is an established option for relapsed FL, but its efficacy in this specific ETF FL population has not been previously evaluated.METHODSThis study compared autologous hematopoietic stem cell transplantation (auto‐HCT) with either matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic hematopoietic cell transplantation (allo‐HCT) as the first transplantation approach for patients with ETF FL (age ≥ 18 years) undergoing auto‐HCT or allo‐HCT between 2002 and 2014. The primary endpoint was OS. The secondary endpoints were progression‐free survival, relapse, and nonrelapse mortality (NRM).RESULTSFour hundred forty FL patients had ETF (auto‐HCT, 240; MSD hematopoietic stem cell transplantation [HCT], 105; and MUD HCT, 95). With a median follow‐up of 69 to 73 months, the adjusted probability of 5‐year OS was significantly higher after auto‐HCT (70%) or MSD HCT (73%) versus MUD HCT (49%; P = .0008). The 5‐year adjusted probability of NRM was significantly lower for auto‐HCT (5%) versus MSD (17%) or MUD HCT (33%; P < .0001). The 5‐year adjusted probability of disease relapse was lower with MSD (31%) or MUD HCT (23%) versus auto‐HCT (58%; P < .0001).CONCLUSIONSPatients with high‐risk FL, as defined by ETF, undergoing auto‐HCT for FL have low NRM and a promising 5‐year OS rate (70%). MSD HCT has lower relapse rates than auto‐HCT but similar OS. Cancer 2018;124:2541‐51. © 2018 American Cancer Society.