Listen to genes : dealing with microarray data in the frequency domain

Background: We present a novel and systematic approach to analyze temporal microarray data. The approach includes normalization, clustering and network analysis of genes. Methodology: Genes are normalized using an error model based uniform normalization method aimed at identifying and estimating the sources of variations. The model minimizes the correlation among error terms across replicates. The normalized gene expressions are then clustered in terms of their power spectrum density. The method of complex Granger causality is introduced to reveal interactions between sets of genes. Complex Granger causality along with partial Granger causality is applied in both time and frequency domains to selected as well as all the genes to reveal the interesting networks of interactions. The approach is successfully applied to Arabidopsis leaf microarray data generated from 31,000 genes observed over 22 time points over 22 days. Three circuits: a circadian gene circuit, an ethylene circuit and a new global circuit showing a hierarchical structure to determine the initiators of leaf senescence are analyzed in detail. Conclusions: We use a totally data-driven approach to form biological hypothesis. Clustering using the power-spectrum analysis helps us identify genes of potential interest. Their dynamics can be captured accurately in the time and frequency domain using the methods of complex and partial Granger causality. With the rise in availability of temporal microarray data, such methods can be useful tools in uncovering the hidden biological interactions. We show our method in a step by step manner with help of toy models as well as a real biological dataset. We also analyse three distinct gene circuits of potential interest to Arabidopsis researchers

Impact of region of diagnosis, ethnicity, age, and gender on survival in acute myeloid leukemia (AML)

Aim: Acute myeloid leukemia (AML) is an aggressive hematopoietic clonal disorder characterized by the increased blasts and poor survival outcome, which is mainly driven by cytogenetic and molecular abnormalities. Here, we investigated the prognostic impact of other demographic parameters on the survival outcomes in AML patients. Method: We reviewed the Surveillance, Epidemiology, and End Result (SEER) database to collect demographic information, including age, diagnosis, gender, race, and geographic region in patients with non-acute promyelocytic leukemia AML, between 2004-2008. The primary end-point of our study was 3-year overall survival (OS), which was estimated by the Kaplan-Meier method and Cox regression model. Results: A total of 13,282 patients were included in our analyses. Increasing age (HR 1.2, p < .0001), male gender (HR 1.05, p = .01), and geographic region of Midwest (HR 1.07, p=.002) were associated with inferior 3-year OS in univariate analysis, and these parameters remained independent prognostic factors in multivariate analyses. Conclusions: AML is a heterogeneous myeloid neoplasm with patient outcomes largely dictated by the cytogenetics and somatic mutations. In our study, additional demographic factors, including advanced age, male gender, and geographic region of AML diagnosis were associated with OS outcome in non-APL AML patients.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Prospective study of serial 18F-FDG PET and 18F-fluoride (18F-NaF) PET to predict time to skeletal related events, time-to-progression, and survival in patients with bone-dominant metastatic breast cancer.

Assessing therapy response of breast cancer bone metastases is challenging. In retrospective studies, serial 18F-FDG PET was predictive of time to skeletal related events (tSRE) and time-to-progression (TTP). 18F-NaF PET improves bone metastasis detection compared to bone scans. We prospectively tested 18F-FDG PET and 18F-NaF PET to predict tSRE, TTP, and overall survival (OS) in patients with bone-dominant metastatic breast cancer (BD MBC). Methods: Patients with BD MBC were imaged with 18F-FDG PET and 18F-NaF PET prior to starting new therapy (scan1) and again at a range of times centered around approximately 4 months later (scan2). SUVmax and SULpeak were recorded for a single index lesion and up to 5 most dominant lesions for each scan. tSRE, TTP, and OS were assessed exclusive of the PET images. Univariate Cox regression was performed to test the association between clinical endpoints and 18F-FDG PET and 18F-NaF PET measures. mPERCIST (Modified PET Response Criteria in Solid Tumors) criteria were also applied. Survival curves for mPERCIST compared response categories of Complete Response+Partial Response+Stable Disease versus Progressive Disease (CR+PR+SD vs PD) for tSRE, TTP, and OS. Results: Twenty-eight patients were evaluated. Higher FDG SULpeak at scan2 predicted shorter time to tSRE (P = \u3c0.001) and TTP (P = 0.044). Higher FDG SUVmax at scan2 predicted a shorter time to tSRE (P = \u3c0.001). A multivariable model using FDG SUVmax of the index lesion at scan1 plus the difference in SUVmax of up to 5 lesions between scans was predictive for tSRE and TTP. Among 24 patients evaluable by 18F-FDG PET mPERCIST, tSRE and TTP were longer in responders (CR, PR, or stable) compared to non-responders (PD) (P = 0.007, 0.028 respectively), with a trend toward improved survival (P = 0.1). An increase in the uptake between scans of up to 5 lesions by 18F-NaF PET was associated with longer OS (P = 0.027). Conclusion: Changes in 18F-FDG PET parameters during therapy are predictive of tSRE and TTP, but not OS. mPERCIST evaluation in bone lesions may be useful in assessing response to therapy and is worthy of evaluation in multicenter, prospective trials. Serial 18F-NaF PET was associated with OS, but was not useful for predicting TTP or tSRE in BD MBC

Safety and Efficacy of Fully Human BCMA CAR T Cells in Combination with a Gamma Secretase Inhibitor to Increase BCMA Surface Expression in Patients with Relapsed or Refractory Multiple Myeloma

Abstract Background: Chimeric antigen receptor T cells (CAR T cells) targeting B cell maturation antigen (BCMA) have demonstrated rapid and deep responses among patients with multi-agent refractory multiple myeloma (MM). BCMA is shed from tumor cells mediated through enzymatic cleavage by the gamma secretase complex, and tumor cells with low levels of BCMA could potentially escape CAR T recognition. We showed previously that gamma secretase inhibitors (GSI) increase BCMA surface density on tumor cells, decrease soluble BCMA levels, and enhance efficacy of BCMA CAR T cells in an immunodeficient mouse model. We have completed accrual to a phase 1 first-in-human trial of escalating doses of BCMA targeted CAR T cells in combination with a GSI (JSMD194) for patients with relapsed or refractory multiple myeloma, and herein report results on the 18 patients accrued to this trial. Methods: Eligible patients had relapsed/refractory MM, with ≥ 10% plasma cells in the bone marrow by CD138 IHC, and measurable disease. CD8+ and CD4+ T cells were enriched by To assess the discrete impact of the GSI on plasma cell BCMA expression, patients received a GSI (JSMD194) monotherapy "run-in" consisting of three oral doses (25 mg) administered 48 hours apart over 5 days. A bone marrow sample was obtained on day 5 and BCMA expression was compared to baseline. Following lymphodepleting chemotherapy, BCMA CAR T cells were infused at a starting dose of 5 x 10 7 CAR+ cells, in combination with JSMD194 dosed orally at 25 mg thrice weekly for three weeks, starting on the day of CAR infusion. Results: From June 2018 to March 2021, 18 patients underwent leukapheresis, run-in with JSMD194, and treatment with BCMA CAR T cells. The median age was 65 years, and patients had received a median of 10 prior lines of therapy (range, 4-19). 67% of patients were refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab, 72% had high-risk cytogenetic features, and 28% had extramedullary disease. 7/18 (39%) had prior BCMA targeted therapy; other BCMA targeted CAR T cell products had previously been administered to 4/18 patients (22%). All 18 treated patients completed the 5-day run-in with JSMD194. After three oral doses of GSI, increased from a median of 610 to 9563 receptors per cell, or a median of 12-fold (range, 0.2-fold to 157-fold; Figure 1). The only patient that did not demonstrate an increase in BCMA ABC after GSI run-in had previously received BCMA targeted therapy and BCMA expression at screening was virtually absent. 5 patients were treated at 5x10 7 CAR+ cells, 3 were treated at 15x10 7 CAR+ cells, 3 were treated at 30x10 7 CAR+ cells, and 7 were treated at 45x10 7 CAR+ cells dose levels. Treatment was consistent with other BCMA CAR T therapy, with manageable toxicities. One patient experienced a DLT. 95% of patients experienced cytokine release syndrome (CRS), mostly grade 1-2 (83%), and 66% of patients experienced ICANS, predominantly grades 1-2. The overall response rate was 89%, with 14 patients achieving ≥ VGPR, and 8 patients achieving CR (including 5 with sCR). Deep responses were observed at all dose levels; including the first patient treated on trial at (dose level 1) who has maintained a stringent CR (sCR) for over 35 months and 3 of 5 patients at dose level 1 had no evidence of progressive disease for >18 months. With a median follow-up of 20 months, the median PFS is 11 months (95% CI, 6 mos to not reached). Amongst patients without prior exposure to BCMA targeted therapy (n=11), the median PFS has not been reached, while amongst those previously exposed to BCMA targeted therapy (n=7), the median PFS was 2 months. Discussion: In this study combining a GSI with BCMA CAR T cells, we have demonstrated that the combination is safe and tolerable. GSI administration routinely increased BCMA surface density on plasma cells. Further, we have observed durable, rapid responses in a heavily pretreated refractory population of MM patients, of whom a significant proportion had prior treatment with BCMA targeted therapy and CAR T therapy. The combination of BCMA CAR T and GSI may augment anti-tumor activity, even when very low doses of BCMA CAR T cells are administered. Figure 1 Figure 1. Disclosures Cowan: Harpoon: Research Funding; Secura Bio: Consultancy; Sanofi Aventis: Consultancy, Research Funding; GSK: Consultancy; Abbvie: Consultancy, Research Funding; Nektar: Research Funding; Cellectar: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy, Research Funding. Pont: Lyell Immunopharma: Other: Has equity interest; SpringWorks Therapeutics: Other: Received consulting income; CellPoint B.V.: Current Employment. Sather: Lyell Immunopharma: Current Employment. Turtle: Arsenal Bio: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; PACT Pharma: Consultancy; Amgen: Consultancy; Eureka Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; AstraZeneca: Consultancy, Research Funding; Juno Therapeutics/BMS: Patents & Royalties: Right to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics, Research Funding; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; TCR2 Therapeutics: Research Funding; T-CURX: Other: Scientific Advisory Board; Asher Bio: Consultancy; Allogene: Consultancy; Century Therapeutics: Consultancy, Other: Scientific Advisory Board; Nektar Therapeutics: Consultancy, Research Funding; Precision Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Caribou Biosciences: Consultancy, Current holder of stock options in a privately-held company, Other: Scientific Advisory Board. Till: Mustang Bio: Consultancy, Patents & Royalties, Research Funding. Libby: GSK: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; Genentech: Research Funding. Tuazon: BMS: Current Employment. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Chapuis: Karkinos Therapeutics: Other: Ownership; Lonza: Other: Intellectual Property; Cullian: Other: Intellectual Property; TScan Therapeutics, Inc.: Consultancy, Other: Ownership; SignalOne Bio: Consultancy, Other: Ownership; Bluebird bio: Other: Intellectual Property; Juno therapeutics: Other: Intellectual Property; Adapyive Biotechnologies Corporation: Other: Ownership/Intellectual Property; Pfizer: Other: Intellectual Property; Affini-T: Other: Ownership; Ridgeline: Consultancy; BioNTech: Consultancy. Maloney: MorphoSys: Honoraria; Genentech: Honoraria; Navan Technologies: Honoraria, Other: Stock options; Celgene: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Novartis: Honoraria; Kite Pharma: Honoraria, Other: Research funding was paid to my institution, Research Funding; Juno therapeutics: Other: Research funding was paid to my institution, Research Funding; Celgene: Other: Research funding was paid to my institution, Research Funding; Amgen: Honoraria; BMS: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Juno Therapeutics: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Umoja: Honoraria; Legend Biotech: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options; Janssen: Honoraria. Riddell: Lyell Immunopharma: Other. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. OffLabel Disclosure: JSMD194 - an oral gamma secretase inhibito

Efficacy and Safety of Fully Human Bcma CAR T Cells in Combination with a Gamma Secretase Inhibitor to Increase Bcma Surface Expression in Patients with Relapsed or Refractory Multiple Myeloma

Background: Although the median survival for patients with multiple myeloma has improved dramatically, almost all patients will eventually relapse and become resistant to standard therapies. Chimeric antigen receptor T cells (CAR T cells) targeting B cell maturation antigen (BCMA) have shown early promise in MM, with high initial response rates. Responses are often incomplete and durability has been a key concern, with most patients relapsing within 1 year (Raje N et al NEJM 2019). We have previously demonstrated that gamma secretase inhibitors (GSI) increase BCMA surface density, decrease soluble BCMA levels and augment anti-tumor efficacy of BCMA CAR T cells in preclinical models. In a phase I first-in-human trial (NCT03502577), we combined CAR T cells expressing a fully human BCMA scFv with an orally administered gamma secretase inhibitor (JSMD194). Methods: Eligible patients had relapsed/refractory MM, with ≥ 10% plasma cells in the bone marrow by CD138 IHC, and measurable disease by IMWG criteria. BCMA was measured on CD138+ plasma cells by flow cytometry. CD8+ and CD4+ T cells were isolated via positive selection. The T cells were stimulated in separate cultures and transduced with lentiviral vector encoding a fully human BCMA scFv in conjunction with 41BB and CD3 zeta signaling domains. Following expansion, the cell product was formulated in a 1:1 ratio of CD4+:CD8+ BCMA CAR T cells. To assess the discreet impact of the GSI on plasma cell BCMA expression, patients received a GSI (JSMD194) monotherapy "run-in" involving three oral doses (25 mg) administered 48 hours apart over 5 days. A bone marrow aspirate was obtained on day 5 and BCMA expression on tumor cells was compared to baseline. Then, after lymphodepleting chemotherapy, BCMA CAR T cells were infused at a total starting dose of 5 x 10^7 EGFRt+ cells, in combination with JSMD194 dosed at 25 mg thrice weekly for three weeks, starting on the day of CAR infusion. Results: Eight patients, with a median age of 64.5 (range, 50-70 years) and a median of 10 prior regimens (range, 4-23), were screened, and seven patients have been treated. One patient had not responded to prior treatment with BCMA CAR T cells using a different construct, and another had progressed on a clinical trial employing a BCMA bispecific antibody. Median bone marrow plasma cell involvement by IHC was 32.5% (range, 10-80%) at enrollment. High-risk features were present in 75% of patients. Median involved serum free light chain at screening was 68.7 mg/dL (range18.45 - 365.61 mg/dL) and median monoclonal protein was 2.55 g/dL (range 0.1 - 5.1 g/dL). Following 3 oral doses (run in) of JSMD194, the percent of plasma cells expressing BCMA increased from 75% to 99% (7.6 to 98% pre, 75 to 100% post), soluble BCMA decreased by 2.0 fold (range 1.6 to 2.6 fold) after 3 oral doses, and BCMA antigen binding capacity increased from a median of 718 receptors to 13355 receptors per cell, or a median of 20-fold (range, 7.55-fold to 156.68-fold). Among 6 assessable patients, the best overall response rate was 100% (5 VGPR, 1 PR), with 5/6 patients MRD negative by flow. At data cutoff of July 15, 2019, no patient has relapsed, with a median follow-up of 5 months (range 1-11 months). One patient died at day 33 post-CAR T cell in the setting of cytokine release syndrome and concurrent fungal infection. The most common non-hematologic ≥ Grade 3 AE was neutropenic fever in 70%. CRS occurred in 100% of patients, primarily grades 1-2 (Lee Criteria), and neurotoxicity in 70%. Conclusions: Although BCMA CAR T cell therapy has demonstrated potent anti-tumor efficacy in multiple myeloma, a significant proportion of patients relapse. The mechanism of myeloma recrudescence requires further study, however BCMA antigen loss has been observed after CAR T cell therapy and is a putative pathway for tumor escape. In this study we demonstrate that gamma secretase inhibition with JSMD194 routinely increases BCMA surface density on myeloma cells in treated patients and reduces soluble BCMA. The combination of a gamma secretase inhibitor with BCMA CAR T cells leads to rapid responses including in patients that have failed prior BCMA targeted therapy. These responses are achieved with low CAR T cell doses. Longer follow up is required to determine if the durability of response is improved. Disclosures Cowan: Cellectar: Consultancy; Juno: Research Funding; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbvie: Research Funding. Pont:Fred Hutchinson Cancer Research Center: Other: Inventor on a patent. Sather:Lyell Immunopharma: Employment. Turtle:T-CURX: Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Humanigen: Other: Ad hoc advisory board member; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Novartis: Other: Ad hoc advisory board member. Till:Mustang Bio: Patents & Royalties, Research Funding. Libby:Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy; Akcea: Consultancy. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria. Blake:Celgene: Employment, Equity Ownership. Works:Celgene: Employment, Equity Ownership. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options . Riddell:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Adaptive Biotechnologies: Consultancy; Lyell Immunopharma: Equity Ownership, Patents & Royalties, Research Funding. Green:Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; GSK: Consultancy; Celgene: Consultancy; Seattle Genetics: Research Funding; Cellectar: Research Funding. OffLabel Disclosure: Gamma secretase inhibitor to increase BCMA expression in multiple myelom

Post-CAR-T Checkpoint Inhibition Can Result in Durable Responses in a Minority of Patients with Multiple Myeloma (MM) or Non-Hodgkin's Lymphoma (NHL): Results of a Phase 2 Study of Nivolumab after CAR-T Failure

While checkpoint inhibition may theoretically improve T-cell effector function following CAR-T failure, a prospective trial of pembrolizumab following CAR-T in non-Hodgkin lymphoma (NHL) showed an ORR of only 25% (Chong Blood 2022). Nivolumab (nivo) has not been studied prospectively in this setting, and the efficacy of post-CAR-T checkpoint inhibition in multiple myeloma (MM) has not been characterized. We conducted a single-center phase 2 trial (NCT04205409) of nivo 480mg IV every 4 weeks for MM or NHL pts with relapse following any CAR-T product as last line of therapy. The primary endpoint was overall response rate (ORR). Secondary endpoints included AEs, immune-related AEs (irAEs), and CRS/ICANS. Other endpoints included PFS, CAR-T expansion following first nivo dose, and PD-L1/PD-1 IHC expression on tumor biopsies. We enrolled 20 pts (11 MM, 9 NHL) as shown in Table 1. Prior to nivo, the best response to CAR-T had been CR in 64% of MM pts and 44% of NHL pts, while 1 MM pt and 1 NHL pt had had PD as best response. Median time from infusion to post-CAR-T relapse was 537 days (range 30-1100) in MM and 134 days (range 28-434) in NHL. Median time between CAR-T infusion & C1D1 nivo was 624 days (range 59-1211) in MM and 149 days (range 34-506) in NHL. The ORR was 15% overall: 18% (2/11) for MM and 11% (1/9) for NHL. In all 3 responders (Table 2), clinical benefit was evident following a single nivo dose. Both MM patients achieved VGPR by light chains within 4 weeks, with one also showing rapid resolution of an 8.6-cm plasmacytoma. For these two patients, median duration of response is 15 months (Table 2). The responding NHL patient [who had had a pre-enrollment Deauville Score (DS) 5 response at Day +60 following axi-cel] – achieved a complete response (DS3) one month following nivo initiation. Conversely, in all non-responders, PD was evident within one month of nivo as well. Two irAEs (one Gr2 pneumonitis, one Gr2 rash) occurred in non-responders, both of which resolved with brief courses of prednisone. CRS or ICANS did not occur following nivo initiation. There were 3 deaths within 100 days, all unrelated to treatment and all in non-responders: PD (n = 2) and hypotensive cardiac arrest without myocarditis (n = 1). The results of ongoing analyses with CAR T-cell expansion and PD-1 staining will be presented at the meeting. To our knowledge, this is the first prospective evaluation of nivo following CAR-T failure. While our study's 18% ORR in MM was numerically higher than the 4% figure previously described with nivo monotherapy in R/R MM (Lesokhin JCO 2016), responses to PD-1 blockade following CAR-T failure in NHL were rare. irAEs were relatively uncommon and manageable with steroids, while CRS and ICANS did not occur. The durable responses achieved by a subset of MM patients is of interest, and further correlative analyses are ongoing to better understand the mechanism of response

Anakinra for Refractory Cytokine Release Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome after Chimeric Antigen Receptor T Cell Therapy

Chimeric antigen receptor-engineered (CAR)-T cell therapy remains limited by significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The optimal management of severe and/or refractory CRS/ICANS remains ill- defined. Anakinra has emerged as a promising agent based on preclinical data, but its safety and efficacy in CAR-T therapy recipients are unknown. The primary objective of this study was to evaluate the safety of anakinra to treat refractory CRS and ICANS after CAR-T therapy. The secondary objective was to evaluate the impact of key treatment-, patient-, and disease-related variables on the time to CRS/ICANS resolution and treatment-related mortality (TRM). We retrospectively analyzed the outcomes of 43 patients with B cell or plasma cell malignancies treated with anakinra for refractory CRS or ICANS at 9 institutions in the United States and Spain between 2019 and 2022. Cause- specific Cox regression was used to account for competing risks. Multivariable cause-specific Cox regression was used to estimate the effect of anakinra dose on outcomes while minimizing treatment allocation bias by including age, CAR-T product, prelymphodepletion (pre-LD) ferritin, and performance status. Indications for anakinra treatment were grade >/=2 ICANS with worsening or lack of symptom improvement despite treatment with high-dose corticosteroids (n = 40) and grade >/=2 CRS with worsening symptoms despite treatment with tocilizumab (n = 3). Anakinra treatment was feasible and safe; discontinuation of therapy because of anakinra-related side effects was reported in only 3 patients (7%). The overall response rate (ORR) to CAR-T therapy was 77%. The cumulative incidence of TRM in the whole cohort was 7% (95% confidence interval [CI], 2% to 17%) at 28 days and 23% (95% CI, 11% to 38%) at 60 days after CAR-T infusion. The cumulative incidence of TRM at day 28 after initiation of anakinra therapy was 0% in the high-dose (>200 mg/day i.v.) recipient group and 47% (95% CI, 20% to 70%) in the low-dose (100 to 200 mg/day s.c. or i.v.) recipient group. The median cumulative incidence of CRS/ICANS resolution from the time of anakinra initiation was 7 days in the high-dose group and was not reached in the low-dose group, owing to the high TRM in this group. Univariate Cox modeling suggested a shorter time to CRS/ICANS resolution in the high-dose recipients (hazard ratio [HR], 2.19; 95% CI, .94 to 5.12; P = .069). In a multivariable Cox model for TRM including age, CAR-T product, pre-LD ferritin level, and pre-LD Karnofsky Performance Status (KPS), higher anakinra dose remained associated with lower TRM (HR, .41 per 1 mg/kg/day increase; 95% CI, .17 to .96; P = .039. The sole factor independently associated with time to CRS/ICANS resolution in a multivariable Cox model including age, CAR-T product, pre-LD ferritin and anakinra dose was higher pre-LD KPS (HR, 1.05 per 10% increase; 95% CI, 1.01 to 1.09; P = .02). Anakinra treatment for refractory CRS or ICANS was safe at doses up to 12 mg/kg/day i.v. We observed an ORR of 77% after CAR-T therapy despite anakinra treatment, suggesting a limited impact of anakinra on CAR-T efficacy. Higher anakinra dose may be associated with faster CRS/ICANS resolution and was independently associated with lower TRM. Prospective comparative studies are needed to confirm our findings