Severe CRS Research Articles

Practical guidelines for monitoring and management of coagulopathy following tisagenlecleucel CAR T-cell therapy

AbstractCytokine release syndrome (CRS) is a systemic inflammatory response associated with chimeric antigen receptor T-cell (CAR-T) therapies. In severe cases, CRS can be associated with coagulopathy and hypofibrinogenemia. We present our global multicenter experience with CRS-associated coagulopathy after tisagenlecleucel therapy in 137 patients with relapsed or refractory B-cell acute lymphoblastic leukemia from the ELIANA and ENSIGN trials. These trials included clinical guidelines for fibrinogen replacement during CRS-associated coagulopathy. Hypofibrinogenemia requiring replacement was observed only in patients with severe CRS. A higher percentage of patients who required replacement were <10 years old, compared with those who did not require replacement. Twenty-three patients received replacement for hypofibrinogenemia (<1.5 g/L); 9 of them developed marked hypofibrinogenemia (<1 g/L). Very low fibrinogen levels (<1 g/L) were documented in patients before maximal CRS (n = 1), during maximal CRS (n = 7), and at CRS improvement (n = 1). Although hypofibrinogenemia was the most clinically significant coagulopathy, some patients also developed prolonged prothrombin time and activated partial thromboplastin time and increased international normalized ratio, further increasing the risk of bleeding. Hypofibrinogenemia was effectively managed using fibrinogen concentrate or cryoprecipitate replacement; severe (grade 4) bleeding events were rare (n = 2). CRS-associated coagulopathy with hypofibrinogenemia is manageable according to empiric guidelines of fibrinogen replacement for CAR-T trials. Fibrinogen concentrate should be used when cryoprecipitate is not reliably available. Monitoring fibrinogen levels in patients with moderate or severe CRS is essential for avoiding potentially fatal bleeding events. These trials were registered at www.clinicaltrials.gov as #NCT02435849 and #NCT02228096.

Severe CRS management in CAR-T cell therapy

Severe CRS management in CAR-T cell therapy

Relmacabtagene autoleucel (relma-cel) CD19 CAR-T therapy for adults with heavily pretreated relapsed/refractory large B-cell lymphoma in China.

BackgroundDespite numerous chimeric antigen receptor T‐cell (CAR‐T) trials conducted in China, no CAR‐T has been registered in the country. Furthermore, China law and regulations restrict the export of patient material for CAR‐T manufacture abroad. Relma‐cel (JWCAR029), an anti‐CD19 product produced with a commercial‐ready process in China, was evaluated in the first prospective, single‐arm, multicenter, pivotal study of CAR‐T therapy conducted under Chinese IND to support an NMPA‐accepted BLA submission in relapsed/refractory (r/r) LBCL (NCT04089215).MethodsPatients were randomized to receive either 100 × 106 (low dose, n = 27) or 150 × 106 (high dose, n = 32) CAR+ T‐cells as a single infusion following lymphodepleting chemotherapy (fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 daily × 3), and then, monitored for efficacy and safety outcomes and pharmacokinetics. The primary endpoint was ORR at 3 months, as assessed by the investigators. Secondary endpoints included DOR, PFS, OS, and adverse event frequency/severity and cell expansion kinetics.ResultsAs of the data cutoff on 17 June 2020, 68 patients were enrolled, and 59 were treated. Among the 58 efficacy‐evaluable patients, the primary endpoint of 3 month ORR was 60.3% (95% CI, 46.6–73.0), excluding the null hypothesis rate of 20%. Any grade and severe grade CRS occurred in 47.5% and 5.1%, respectively, and any grade and severe grade neurotoxicity events occurred in 20.3% and 5.1%.ConclusionsRelma‐cel met the primary endpoint analysis and demonstrated a high rate of durable responses and low rate of CAR‐T‐associated toxicities in patients with r/r LBCL in a multicenter trial supporting regulatory submission in China.

Efficacy and Safety of Tisagenlecleucel in Adult Patients with Relapsed/Refractory Follicular Lymphoma: Interim Analysis of the Phase 2 Elara Trial

Efficacy and Safety of Tisagenlecleucel in Adult Patients with Relapsed/Refractory Follicular Lymphoma: Interim Analysis of the Phase 2 Elara Trial

Intention to Treat Analysis of Real-World Outcomes Following Tisgenlecleucel Therapy for Pediatric and Young Adult ALL through a National Access Programme

Background: Tisagenlecleucel was approved in Europe for relapsed/refractory acute lymphoblastic leukemia (ALL) in young patients in 2018. In England, a national CAR T cell panel (NCCP ALL) ensures equity of access and assesses eligibility using inclusion and exclusion criteria based on the ELIANA study. All UK cases are discussed. Eligible cases are allocated to one of 9 JACIE-FACT IEC-approved centres based on age-appropriate service, capacity, distance and patient preference. We systematically reviewed all cases from panel inception providing an opportunity to analyse complete real-world ALL outcomes from this national access programme for tisagenlecleucel on an intention-to-treat (ITT) basis. Methods: We included all patients discussed in the NCCP ALL from Nov 2018 up to July 16th 2020. Clinical data were retrospectively reported in a standardised dataset to allow central analysis of disease and toxicity-related outcomes. Survival outcomes were assessed as for other CAR studies, using Kaplan-Meier estimates of survival from infusion. These included overall survival (interval to death from any cause) and event-free survival as defined in the ELIANA study (interval to death, disease relapse, or treatment failure defined in turn as failure to respond by day 30, with patients receiving further therapy being censored). In order to report outcomes on an ITT basis, survival outcomes were also assessed from time of treatment allocation for all patients considered eligible for tisagenlecleucel. Further, a more comprehensive event-free survival measure encompassing interval to molecular or frank relapse, further therapy, B cell recovery, death or treatment failure was analysed. Median follow up was calculated using a reverse Kaplan-Meier method. Results: Figure 1 demonstrates all patients: 66 patients were screened, 60 patients were deemed eligible for therapy (the ITT cohort), 57 patients were harvested and 49 infused. A total of 3 patients were not harvested and 2 not infused because of progressive disease (n=4) and 1 manufacturing failure. Patient and disease characteristics are summarised in Table 1. The cohort comprised patients with advanced ALL, having been treated with a median of 2.5 therapy lines not including HSCT (range 1-6), and with 47.5% of the cohort having had a prior HSCT. The median follow-up from infusion was 9.9 months and from treatment allocation for the ITT cohort was 11.9 months. The median lead time from allocation to infusion was 2 months. The CR/CRi rate was 95% in the first 90 days, 78.9% were MRD-. On an ITT basis, CR/CRi rate was 84.8%. Median OS and EFS as defined in the ELIANA study were not reached. Overall survival at 6 and 12 months for infused patients was 97.6% and 86.1%, and for the ITT cohort was 90.4% and 78.3%. EFS for infused patients at 6 and 12 months were 74.8% and 68.2%, and for the ITT cohort were 78.5% and 60.9%. Of 49 patients infused, 14 (28.5%) received further therapy including 6 (8.2%) who received allogeneic SCT for relapse or B cell recovery. For patients relapsing following CR (n=10 infused) there were 4/10 CD19- relapses. A composite EFS including molecular or frank relapse, further therapy, B cell recovery, death or treatment failure was analysed. Using this more stringent definition from infusion, the 6, 12 month EFS were 47.6%, and 33.6% and from treatment allocation for the ITT cohort were 63% and 34.3% Toxicity outcomes are summarised in Table 2. Severe (grade ≥3) CRS, neurotoxicity, infection or cytopenia after day 30 post infusion occurred in 20.4%, 10.2% 27.1% and 54.2% respectively. 71.4% of the cohort developed hypogammaglobulinaemia, (Figure 3A). The 6 and 12 month probabilities of B cell depletion were 67.1% and 51.3% respectively. Conclusions: Whilst registry data provide outcomes of large cohorts receiving Tisagenlecleucel, standardised data collection on complete populations are lacking. The framework of a national access scheme provides a unique opportunity to study outcomes on an ITT basis. The CR and MRD negative CR rates, as well as conventional EFS and OS and severe toxicities noted in our cohort compare favourably to published registry reports (Grupp et al., 2019). We found a greater proportion of CD19+ compared to CD19- relapses than noted in the ELIANA study. Consideration of OS and EFS on an ITT basis are informative for clinicians when screening patients for eligibility. If selected for presentation at ASH 2020, updated data will be presented Disclosures Ghorashian: Amgen: Honoraria; Novartis: Honoraria; UCLB: Patents &amp; Royalties. O'Reilly:Gilead: Honoraria; Novartis: Honoraria, Other: Travel support. Roddie:Celgene: Honoraria; Gilead: Honoraria; Novartis: Honoraria. Neill:Novartis: Other: Funded attendance at academic conferences; Celgene: Other: Funded attendance at academic conferences. Pagliuca:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Patel:Novartis: Honoraria, Other: travel support. Hough:Novartis: Other: Travel support.

Impact of IL-6R Blockade for Cytokine Release Syndrome in Haploidentical Donor Stem Cell Transplant Patients on Infections, Clinical Outcomes and Immune Reconstitution

Impact of IL-6R Blockade for Cytokine Release Syndrome in Haploidentical Donor Stem Cell Transplant Patients on Infections, Clinical Outcomes and Immune Reconstitution

Phase I Alexander study of AUTO3, the first CD19/22 dual targeting CAR T cell therapy, with pembrolizumab in patients with relapsed/refractory (r/r) DLBCL.

8001 Background: CD19 directed CAR T cells are effective in patients with r/r DLBCL, however relapses due to CD19 loss or PDL1 upregulation are common. In this study, we evaluate the safety and efficacy of AUTO3, a CAR T targeting CD19/22 with limited duration of PD-1 blockade. Methods: We constructed a bicistronic retroviral vector encoding both an anti-CD19 (OX40 co-stim) and an anti-CD22 (41BB co-stim) CAR with humanized binders. The cell product was manufactured in a semi-automated and closed process using CliniMACS Prodigy. Patients (≥ 18 years) with r/r DLBCL (NOS) or transformed (tDLBCL); ECOG &lt;2, adequate organ function are eligible. Lymphodepletion was Flu/Cy prior to AUTO3. Bridging therapy was allowed. The three dose levels explored are 50, 150, and 450 x 10^6 CAR T cells. Patients received AUTO3 alone, or with 3 doses of pembrolizumab (pem) 200 mg q 3 wks starting on D14 (regimen A), or with a single dose of pem 200 mg on D-1 (regimen B). The primary endpoint is frequency of DLTs and grade (G) 3-5 adverse events (AE) and secondary endpoints included ORR, CRR, and biomarkers. Results: As of Jan 21, 2020, 28 patients underwent leukapheresis, 27 successfully manufactured, 1 being manufactured, and 19 patients treated with AUTO3. The median age was 57 (28 - 71) and median number of prior therapies was 3 (2 - 10). 89% had refractory disease, 74% were DLBCL NOS, and 26% were tDLBCL. Dose escalation from 50 to 450 x 106 cells with pem regimen A and B have been completed without DLTs. G &gt; 3 treatment emergent AEs that occurred &gt; 15% were neutropenia (89%), thrombocytopenia (58%), anemia (47%), febrile neutropenia (16%), and hypophosphataemia (16%). Across all dose levels, there were 0% sCRS with primary infusion and 5% severe neurotoxicity (sNT) (1/19), which resolved. There were no cases of sCRS and no neurotoxicity of any grade at &gt; 50 x 106 cells. Eighteen patients were evaluable for efficacy. Among the 11 treated at dose &gt; 50 x 106, the ORR and CRR were 64% and 55%, and all CRs are ongoing (1-12 mth). Two out of 3 patients achieved CR at 450 x 106 cells on pem regimen B. Additional patients and longer follow up, as well as biomarkers, will be presented. Conclusions: AUTO3 at &gt; 50 x 106 CAR T cells with pembrolizumab induces CRs without severe CRS or neurotoxicities of any grade. Clinical trial information: NCT03287817 .

Retreatment (reTx) of patients (pts) with refractory large B-cell lymphoma with axicabtagene ciloleucel (axi-cel) in ZUMA-1.

8012 Background: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is approved in the US and EU for pts with relapsed/refractory large B cell lymphoma after ≥ 2 prior therapies. In the ZUMA-1 pivotal study (NCT02348216), the objective response rate (ORR) was 83% (58% complete response [CR] rate; Locke et al. Lancet Oncol. 2019). While axi-cel has demonstrated durable responses in a subset of pts, approximately half of all responders relapsed, and little is known on the viability of reTx with CAR T cell therapy. Here we report outcomes of pts retreated with axi-cel in ZUMA-1. Methods: Pts with progressive disease (PD) were eligible for reTx if there was no evidence of CD19 loss by local review, and if during 1st Tx they did not experience any dose-limiting toxicities, as defined in Phase 1, or comparable toxicities in Phase 2. Pts received the same regimen at reTx as at 1st Tx: 2 × 106 CAR T cells/kg after conditioning chemotherapy. Results: Thirteen pts in Cohorts 1 – 4 received axi-cel reTx. Prior to 1st Tx, most pts (69%) had an IPI score 3-4, 85% had disease stage 3-4, and the median number of prior regimens was 3 (range, 2 – 6). At first Tx, 6 pts achieved a CR, 6 achieved partial response (PR), and 1 pt had stable disease (SD) prior to PD. Median duration of first response was 96 days (range, 56 – 274). There was no Grade ≥ 3 cytokine release syndrome (CRS; 6 pts each had Grade 1 and 2). There were no Grade 4 or 5 neurologic events (NEs; 2 pts had Grade 1, 1 had Grade 2, and 7 had Grade 3). Upon reTx, 54% of pts achieved response (4 CR, 3 PR). Response to reTx was more common among pts who achieved CR at 1st Tx (83%; 4/6 CR, 1 PR, 1 SD) than in pts who achieved PR at 1st Tx (33%; 2/6 PR, 1 SD, 3 PD), and no response was observed in the pt with SD at 1st Tx. Median duration of response at reTx was 81 days (range, 1 – 225+). Response with reTx was longer than that with 1st Tx for 2 pts. One pt remains in response 255 days post-reTx. Comparable rates of CRS were observed with reTx as with 1st Tx. Compared with 1st Tx, fewer pts experienced NEs with reTx, and those that did occur were of lower grade: 23% (3 of 13 pts) had Grade 3; 23% (3 of 13 pts) had Grade 1, and 8% (1 of 13 pts) had Grade 2. Peak CAR T cell expansion was lower upon reTx vs 1st Tx (median, 4.3 vs 66.1 CAR gene-marked cells/µL blood). Conclusions: Based on this limited sample size, reTx with axi-cel may have clinical efficacy, although transient, in some pts, especially those who achieve CR with 1st Tx. CAR T cell expansion and severe CRS and NEs may be attenuated at reTx. Further studies with additional pts are needed to confirm these results. Clinical trial information: NCT02348216 .

Infectious Complications Following CD19 Chimeric Antigen Receptor T-cell Therapy for Children, Adolescents, and Young Adults.

BackgroundInfectious complications of chimeric antigen receptor (CAR) T-cell immunotherapy in children and young adults have not been well described.MethodsMedical records of patients ≤26 years old receiving CD19 CAR T-cell infusion (CTI) at a single institution between 2014 and 2017 were reviewed. The number of infections per 100 days-at-risk (infection density) in the 90 days preceding and 0–28 and 29–90 days after CTI was calculated. Poisson regression and Cox analyses were utilized to identify risk factors for infections.ResultsEighty-three patients received CTI during the study period. Most patients (98%) had refractory or relapsed acute lymphoblastic leukemia (ALL). Infections occurred in 54% of patients in the 90 days before CTI (infection density, 1.23) and in 40% of patients in the first 28 days following CTI (infection density, 2.89). Infection density decreased to 0.55 in the 29–90 days post-CTI. Most infections were bacteremias (39%) or respiratory viral infections (43%). Pre-CTI risk factors associated with infection included prior hematopoietic cell transplantation (HCT), immunoglobulin G (IgG) level <400 mg/dL, and lymphodepletion other than cyclophosphamide plus fludarabine; post-CTI risk factors included higher-severity CRS and IgG <400 mg/dL.ConclusionsInfection rates in children and young adults receiving CD19 CAR T-cell therapy increase in the first month and then decline. Understanding types and timing of infections and contributing risk factors may help inform prophylactic and monitoring strategies. Specific attention should be given to patients with prior HCT, severe hypogammaglobulinemia, and severe CRS.

Real-World Quality and Cost Burden of Cytokine Release Syndrome Requiring Tocilizumab or Steroids during CAR-T Infusion Encounter

Introduction Chimeric Antigen Receptor T-cell (CAR-T) Immunotherapy was first approved by the FDA in October 2017 for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. CAR-T immunotherapy uses a patient's own T cells and modifies them in a laboratory to recognize and kill the patient's cancer. Cytokine release syndrome is a known serious adverse event after CAR-T infusion which results in symptoms including fever, nausea, headache, and hypotension. Tocilizumab is an anti-IL-6 receptor antagonist approved for the treatment of CRS in CAR-T patients. For patients with Grade III CRS or Grade II with neurotoxicity, tocilizumab plus corticosteroids is indicated for treatment. However, corticosteroids alone can also be used for patients with lower grade neurotoxicity. Objectives To compare cost and quality outcomes for patients with DLBCL who receive a CAR-T infusion with or without tocilizumab or steroids. Methods A retrospective cohort of 1570 CAR-T infusion encounters for patients 18 years and older undergoing CAR-T procedures for DLBCL was identified from the Vizient Clinical Database/Resource Manager from 71 hospitals between October 2017 and July 2019. Patients with a tocilizumab, dexamethasone or prednisolone charge during the infusion encounter were identified through charge data and/or CPT coding. Cost information was analyzed for patients who were not in a clinical trial and who had complete charge information. Results Of the 1570 infusion encounters, 739 patients (47.1%) received tocilizumab during their index visit. 839 patients (53.4%) received a dexamethasone or prednisolone during their index encounter, with 574 (36.6%) of patients receiving both tocilizumab and a corticosteroid. Patients who did not receive steroids or tocilizumab had a lower LOS (14.3 days) compared to patients with steroids (19.4 days), tocilizumab (16.2 days) or tocilizumab+steroids (23.3 days). Patients who did not receive steroids or tocilizumab had the lowest in-hospital mortality rate (1.4%) compared to patients who received steroids (3.4%), tocilizumab (1.8%) or tocilizumab+steroids (8.4%). Patients who did not receive steroids or tocilizumab had the lowest mean cost ($376,982) compared to patients who received steroids ($394,113), tocilizumab ($409,142) or tocilizumab+steroids ($429,415). Conclusion Understanding the risks associated with CAR-T therapy is important. While CRS is a known serious adverse event, characterizing the impact of how CRS affects LOS, in-hospital mortality and cost is important for both providers and patients to assess when deciding which therapies to consider. More severe CRS can lead to longer lengths of stay, higher in-hospital mortality, and higher costs of care.

Correlative Analyses of Patient and Clinical Characteristics Associated with Efficacy in Tisagenlecleucel-Treated Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients in the Juliet Trial

Correlative Analyses of Patient and Clinical Characteristics Associated with Efficacy in Tisagenlecleucel-Treated Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients in the Juliet Trial

Impact of Tisagenlecleucel Chimeric Antigen Receptor (CAR)-T Cell Therapy Product Attributes on Clinical Outcomes in Adults with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL)

Impact of Tisagenlecleucel Chimeric Antigen Receptor (CAR)-T Cell Therapy Product Attributes on Clinical Outcomes in Adults with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL)

Therapy of Paediatric B-ALL with a Fast Off Rate CD19 CAR Leads to Enhanced Expansion and Prolonged CAR T Cell Persistence in Patients with Low Bone Marrow Tumour Burden, and Is Associated with a Favourable Toxicity Profile

Introduction: The CARPALL study (NCT02443831) employed a novel CD19CAR (CAT-41BBz CAR) with a faster off rate than the Kymriah FMC63-41BBz CAR (CAT 3.1x10-3s-1, FMC 6.8 x 10-5s-1), with equivalent on-rate (CAT 2.2 x 105, FMC 2.1 x 105). We herein report updated outcomes and CAR T cell persistence with an additional 6 months follow up from a submitted manuscript (Ghorashian et al., Nat Med, submitted) Methods: Patients aged &amp;lt;25 years with high risk, relapsed CD19+ B-ALL were eligible on this multi-centre, open label, non-randomised phase I study of autologous CAT-41BBz CAR T cells. Patients were followed to a data cut-off of 07/18/2019. CAT-41BBz CAR T cells were generated by magnetic bead activation of leucapheresed PBMCs, lentiviral transduction, followed by bioreactor expansion and magnetic bead removal prior to cryopreservation. All patients received lymphodepletion (fludarabine + cyclophosphamide) followed by 1x106/kg CAR T cells. Presence of CAR T cells in the blood and bone marrow (BM) was assessed (flow cytometry and qPCR) monthly for 6 months, then 6 weekly to 1 year and then 3 monthly. BM MRD was assessed (IgH qPCR, flow cytometry) at the same time-points up to 2 years to establish durability of responses as a stand-alone therapy. Primary end-points were incidence of grade 3-5 toxicity and the proportion of patients achieving molecular remission. Results: Of 17 patients recruited, 14 were treated due to manufacturing failure in 3 patients.The median age was 9 years (range 1-19 years). All patients had advanced ALL with a median of 4 prior therapy lines. 10 of 14 patients (71%) had relapsed post allogeneic SCT. Prior to lymphodepletion, 4 patients had &amp;gt;5% BM disease, 6 had disease between 5x10-2and 1x10-5, 4 were BM MRD negative having had recurrent isolated CNS disease. Median transduction efficiency was 31% (range 16.5 to 96.4%). 12/14 treated patients received the anticipated dose of 1x106CAR T cells/kg (2 received 0.9x106/kg). Considering all evaluable patients, (n=14 for CAR T cell persistence by qPCR, n=13 by flow) the geometric mean of Cmax was 128 912/µg DNA and of the area under the curve between D0 and D28 was 1,721,355 copies/ µg DNA (Table 1). At the point of maximal expansion, a median of 35% of circulating T cells were CAR+. Median half-life was 34 days (range 3-102). CAR T cells continued to be detectable by qPCR in 11 of 14 (79%) patients at last assessment and by flow cytometry up to 30 months post infusion in 8 of 13(61%). Median duration of CAR T persistence by flow was 261 days (range 7-917). 3 patients failed to have persistence of CAR T cells beyond 1 month. T cell mediated anti-CAR specific cytotoxic activity was detected in 2/2 evaluable patients. Updated persistence data will be presented at the meeting Cytokine release syndrome (CRS) occurred in 13 (93%, grade 1 n=9, grade 2 n=4). None developed ≥grade 3 CRS, had CRS-related ICU admission, or received Tocilizumab. CRS was associated with modest elevations of IL-6, IFN-γand IL-10. Grade 2 neurotoxicity was observed in 3 patients and resolved spontaneously. One patient had grade 4 leucoencephalopathy presumed due to chemotherapy as well as grade 5 sepsis. Ten patients (71%) had grade 3-4 cytopenia persisting beyond day 28 or recurring afterthis. 12/14 (86%) patients achieved molecular complete or continuing complete remission at a median of 30 days post infusion (range 30-90 days, Table 2). At a median follow-up of 20.3 months, 4/14 (29%) evaluable patients remain MRD negative. 5 relapsed with CD19-disease, 1 with CD19+ disease. The median duration of EFS (based on death or morphological relapse) has not been reached, 12 month EFS = 52%, OS = 70% (Figures 1, 2 and Table 3). Conclusion: We noted excellent CAR T cell expansion and persistence in a ALL cohort treated with the fast off-rate CAT-41BBz CAR despite their lower BM disease at treatment compared to other studies. The kinetics documented for all evaluable patients showed a 5-fold greater CAR T cell expansion and 2-fold longer half-life than responders in published series utilising tisagenlecleucel in a similar ALL cohort (Mueller et al., Blood 2017). Patients had a favourable toxicity profile with no severe (grade 3-4) CRS and equivalent disease outcomes to the ELIANA study despite having similarly advanced disease (Maude et al., NEJM 2018292). These data suggest long lived CAR T cell persistence supports stand-alone therapy for ALL with durable responses. Disclosures Ghorashian: Celgene: Honoraria; novartis: Honoraria; UCLB: Patents &amp; Royalties: UCLB. Kramer:UCLB: Patents &amp; Royalties. Ciocarlie:Servier: Other: Financial Support. Farzaneh:Autolus Ltd: Equity Ownership, Research Funding. Pule:Autolus: Employment, Equity Ownership, Patents &amp; Royalties. Amrolia:UCLB: Patents &amp; Royalties.

Risk Factors and Characteristics of CRS in CAR-T Treatment

Background and objective Clinical trials have confirmed that CAR-T treatment has become one of the important treatments for many relapse and refractory hematological tumors. CRS is a high incidence of adverse events in CAR-T treatment. A deeply understanding of the characteristics and related risk factors of CRS is important for the effective management of CRS. The characteristics and risk factors of CRS occurred in 142 patients during CAR-T treatment were analyzed in detail to provide a direct and reliable basis for clinicians to diagnose and predict CRS. Patients and Methods We collected 142 patients with different hematologic malignancies who underwent CAR-T treatment from January 2015 to December 2018. All patients were screened according to the inclusion and exclusion criteria at the time of trial design. Patients received Fludarabine and cyclophosphamide to remove T cells before infusion of CAR-T. Infused CAR-T cells include anti-CD19 CAR-T, anti-BCMA CAR-T and anti-CD20 CAR-T. Glucocorticoids were not used to prevent allergic reactions prior to infusion. Adverse events were assessed using the CRS evaluation criteria proposed by Lee et al. and the Common Terminology Criteria for Adverse Events (CTCAEs, version 4.0) criteria. Results: 1.General characteristics of patients and CRS Of all patients, 87 (61.3%) were male and 55 (38.7%) were female; the median age was 45 (IRQ = 24-59). The incidence of CRS in ALL, lymphoma and myeloma were: 82%, 90% and 90%, respectively. Fever is the main first symptom of CRS. The median time to onset of fever is 3 days for ALL (IRQ 0-7 days), 1 day for lymphoma (IRQ 0-5 days), and 8.5 days for MM (1.75-12.75 days). There was a statistically significant difference between MM and ALL (p=0.0044) or MM and lymphoma (p=0.0002). The duration of fever was different between CRS grade 1-2 and grade 3-5 (P=0.007), but there was no difference between ALL, lymphoma, and MM [3 (0-7 days) vs 5 (3-8 days) vs 4(3-8 days)]. Levels of serum ferritin, IL-6, and CRP were consistent with CRS, but there was no significant difference in different time points after CAR-T infusion except for IL-6 levels of ALL patients between days 7 and 10. However, the peak concentration of ferritin, IL-6, and CRP is different from the baseline. 2.General risk factors for CRS In the univariate analysis, the maximum concentration of serum IL-6 (p=0.000) and CRP (p=0.001) were different between CRS3-5, CRS1-2, and patients without CRS. For further analysis, the IL-6 was statistically different between CRS3-5 and CRS1-2 (p=0.03), CRS3-5 and Non-CRS (p=0.00), or CRS1-2 and Non-CRS (p=0.00). The CRP was statistically different between CRS3-5 and Non-CRS (p=0.00), CRS1-2 and Non-CRS (p=0.01). There were no differences in age, gender, pre-transplantation, type of disease, dose of CAR-T cells, and costimulatory molecules. In multivariate analysis, disease (ALL vs MM (p=0.043), ALL vs MM (p=0.021)), costimulatory molecules (p=0.022), peak concentration of IL-6 (p=0.000) and CRP (p=0.001) are independent risk factors. 3.Specific risk factors For ALL patients, in the univariate analysis, the number of lymphoblasts in the bone marrow before FC deplete lymphocytes chemotherapy was different between CRS3-5 and Non-CRS of patients with CRS3-5, CRS1-2, and patients without CRS (p=0.00). There was no significant difference in the number of lymphoblasts after FC deplete lymphocytes chemotherapy, CAR species, and costimulatory molecules. In the multivariate analysis, hematopoietic stem cell transplantation before CAR-T treatment, the numbers of lymphoblasts in the bone marrow before FC deplete lymphocytes chemotherapy, and the CAR species were independent risk factors. For patients with lymphoma, there was no difference in IPI scores, clinical staging, and infused number of CAR-T cells. There were no significant differences in β2-MG, light chain type, myeloma cell number, and ISS stage in patients with MM. Conclusion: The occurrence of CRS in different B-cell tumors has its own characteristics. Compared with ALL and lymphoma, the incidence of severe CRS in MM patients is lower and occurs later. 2. The risk factors of CRS in different B-cell tumors are different. Individualized treatment of is needed in clinical practice. Figure 1 Characteristics of CRS (A. the incidence of CRS, B. days of fever onset after CAR-T infusion, C. duration of fever, D. peak temperature of fever) Figure 1 Disclosures No relevant conflicts of interest to declare.

Safety and Efficacy of Tisagenlecleucel (CTL019) in B-Cell Acute Lymphoblastic Leukemia in Children, Adolescents and Young Adults: The French Experience

Objectives: Tisagenlecleucel (CTL019) is a chimeric antigen receptor T cell- therapy that reprograms autologous T cells to target CD19+ leukemia cells, approved in the US (2017) and in the EU (2018). This study reports the feasibility, safety and efficacy of CTL019 in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) treated in Robert-Debré and Saint-Louis University Hospitals (Assistance Publique-Hôpitaux de Paris/Université de Paris). Methods: Patients (pts) with an apheresis performed between march 1, 2016 and june 15, 2019, included in sponsored-clinical trials or treated within the French compassionate program or with the commercial product, were analyzed. All infused pts received a fludarabine-cyclophosphamide based lymphodepletion before a single infusion of CAR-T cells (2 to 5 x 106 CTL019/kg if less than 50 kg; a fixed dose of 1 to 2.5 x 108 CTL019/kg if &gt; 50 kg) Results: 55 pts were referred from 25 French centers. Forty-one pts with a median number of relapses of 2 (range, 1-5) were infused with CTL019 at a median age of 18.2 y (range, 1-29.2). Eight pts were not infused due to progressive disease (n=4), screen failure (n=3) or fatal septic shock (n=1). Six pts were waiting to be infused at time of analysis. Out of the 41 infused pts, 26 had a prior history of allogeneic SCT (63%), 11 had received blinatumomab (27%). Among the 40 pts evaluable at one month post-infusion, 38 were in CR/CRi (95%) (one progression at day 5 after infusion and one toxic death at D6), 35/38 (92.1%) being clone-specific Ig-TCR MRD negative. After 3 months 21 out of 26 evaluable pts (81%) had a negative MRD. The 5 remaining MRD positive pts did relapse. No pt underwent allogeneic HSCT while in CR after CTL019 infusion. Median event free survival (EFS) and overall survival (OS) were not reached with a median follow up of 7.2 months (range, 0.2-36.3). The 18-month OS probability was 80% (95%CI, 58%-92%). The 18-month EFS probability was 58 % (95%CI, 37%-74%). Ten pts relapsed after a median time of 3.4 months (range, 1.9-10): 3 relapses were CD19+ and 5 CD19- (4 out of these 5 pts had a preexposure to blinatumomab), 2 being of undetermined status. Loss of B-cell aplasia (BCA) occurred in 9 pts after a median time of 3 months (range, 2-12), followed by relapse for 2 pts (one concomitant with loss of BCA and one 7 months later). Three pts received a second infusion of CTL019 for loss of BCA with no further expansion of CAR-T cells. Prior treatment with blinatumomab was a significant predictive factor for relapse (HR=6.082, 95%CI, 1.2-30, p=0.0005) in a univariate analysis. There was a trend toward increased risk of relapse with increased disease burden (≥ 5%) before lymphodepletion regimen (HR=2.4, 95%CI, 0.7-8, p=0.14). Twenty-two pts experienced a CRS (≥ grade 3: n=13, all ≥ 10 y). ICU was required for 14 pts (34%). One 29 year-old pt died of an uncontrollable CRS at day 6. Ten pts received tocilizumab, 4 pts siltuximab and 9 pts corticosteroids. Age ≥ 10 y (p=0.04) and a high disease burden just before lymphodepletion (marrow blasts ≥ 5%) (p=0.01) were associated with a higher risk of CRS ≥ grade 3. Nine neurological events have been reported, being reversible except in 2 cases (one death in combination with grade 5 CRS-cf supra-, one HHV6-related encephalitis with neurological sequelae). Among the 9 pts who presented neurological events, 8 experienced CRS grade ≥ 3 (RR=17.2, 95%CI, 3.22-100.3, p=0.0001). By day 28, unresolved neutropenia grade ≥ 3 was reported for 13 pts. G-CSF treatment was required in 21 pts overall. Thrombocytopenia grade ≥3 was reported for 14 pts. Conclusion: CTL019 confirms its efficacy with a high response rate after infusion and very encouraging early outcomes in a cohort of pts heavily pretreated for refractory or multiply relapsed B-ALL. Persistent remissions with a potential for cure were observed without additional HSCT, relapses occurring within the first year after infusion of CTL019. Accurate assessment of a potentially deleterious effect of Blinatumomab preexposure notable on CD19 negative relapse will need more pts and a longer follow-up. Toxicity profile was tolerable and manageable thanks to collaboration between intensivists, neurologists and hematologists. The identification of severe CRS predictive risk factors (high disease burden just before lymphodepletion and age ≥ 10 y) points towards the reinforcement of toxicity monitoring and treatment anticipation in these cases. Disclosures Boissel: NOVARTIS: Consultancy. Baruchel:NOVARTIS: Consultancy.

AUTO1, a Novel Fast Off CD19CAR Delivers Durable Remissions and Prolonged CAR T Cell Persistence with Low CRS or Neurotoxicity in Adult ALL

Introduction: In adults, prognosis for B-ALL is poor, patients are more vulnerable to CD19 CAR immunotoxicity and there is currently no CD19 CAR therapeutic with acceptable toxicity and durable efficacy. We have developed a novel second generation CD19CAR (CAT-41BBz CAR), with a faster off-rate but equivalent on rate than the FMC63-41BBz CAR (Kd 116 nM vs 0.9 nM, T1/2 9s vs 4.2 hours) designed to result in more physiological T-cell activation, reduce toxicity and improve engraftment. Preliminary paediatric clinical data of this novel CD19 CAR (AUTO1) supports this assertion. We here describe preliminary data from ALLCAR19 (NCT02935257), a multi-centre, Phase I clinical study of AUTO1 as therapy for r/r adult B-ALL. Methods: Manufacturing: AUTO1 utilises non-mobilised autologous leucapheresate. The first 6 trial products were generated using a standard dynal bead/WAVE Bioreactor process and subsequent products using a semi-automated closed process. Study design: ALLCAR19 is a phase I/II study recruiting subjects 16-65y with r/r B ALL. Lymphodepletion with fludarabine (30mg/m2 x3) and cyclophosphamide (60mg/kg x1) is followed by split dose CAR T cell infusion (Day 0: if ≥20% BM blasts, infuse 10 x 106 CAR T cells ; if &amp;lt;20% BM blasts, infuse 100 x 106 CAR T cells. Day +9: if no Grade 3-5 CRS/CRES, infuse Dose 2, to a total dose of 410 x 106 CAR T cells). Study endpoints include feasibility of manufacture, grade 3-5 toxicity and remission rates at 1 and 3 months Results: As of 24 July 2019, 16 patients have been leukaphresed, 14 products manufactured (one failed leukaphresis and one currently in manufacture) and 13 patients have received at least 1 dose of AUTO1. Of the 16 patients, median age was 35.5 (range 18-63), 10/16 (63%) had prior blinatumomab or inotuzumab ozogamicin and 12/16 (75%) had prior HSCT. At the time of pre-conditioning, 9/13 (69%) patients were in morphological relapse with &amp;gt;5% leukemic blasts of which 6/13 (46%) had ≥50% blast. 9/13 patients (69%) received the total target split dose of 410 x 106 CAR T cells while 1/13 patients (8%) received a reduced split total dose of 51.3 x 106 CAR T cells due to manufacturing constraints. 3/13 patients (23%) received only a first dose of 10 x 106 CAR T cells. The dose was administered safely to date: No patients experienced ≥Grade 3 CRS (using Lee criteria) and only 1/13 (8%) experienced Grade 3 neurotoxicity (dysphasia) that resolved swiftly with steroids. All patients had robust CAR expansion (median peak expansion 172 CAR/uL blood). Of the 13 patients dosed (1/13 pending 28 day follow up), 10/12 (83%) achieved MRD negative CR at 1 month and all patients had ongoing CAR T cell persistence at last follow up. Two patients experienced CD19 negative relapse (one at M3, one at M6), 1 patient died on D17 before first response evaluation, 1 died in molecular CR from sepsis, and 1 died from persistent disease. Currently, 7/12 remain on study and continue in flow/molecular MRD negative remission with a median follow up of 9.0 months (range 1.2-14.8). Conclusions: AUTO1 delivers excellent early remission rates with initial data showing 83% MRD negative CR and robust CAR expansion and persistence. Despite high tumour burden, the safety profile compares favourably to other CD19 CARs, with no cases of severe CRS and only one case of Gr3 neurotoxicity. This is consistent with experience in the paediatric cohort. Updated results will be presented. Disclosures Roddie: Novartis: Consultancy; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. O'Reilly:Kite Gilead: Honoraria. Farzaneh:Autolus Ltd: Equity Ownership, Research Funding. Linch:Autolus: Membership on an entity's Board of Directors or advisory committees. Pule:Autolus: Membership on an entity's Board of Directors or advisory committees. Peggs:Gilead: Consultancy, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees.

S1634 A PHASE I FIRST‐IN‐HUMAN CLINICAL TRIAL OF CD19‐TARGETED 19–28Z/4–1BBL “ARMORED” CAR T CELLS IN PATIENTS WITH RELAPSED OR REFRACTORY NHL AND CLL INCLUDING RICHTER TRANSFORMATION

Background:Second generation, CD19‐specific chimeric antigen receptor (CAR) T cell therapy containing either the CD28 or 41BB co‐stimulatory domain have demonstrated long‐term complete remission (CR) rates of 40–50% in relapsed or refractory (R/R) NHL and 20–30% in CLL. The suboptimal activity of the 2nd generation CAR T cells in NHL and in particular CLL may be due, in part, to poor proliferation and cytolytic activity of T cells in the inhibitory tumor microenvironment. We have previously demonstrated that binding of 4–1BBL to its cognate receptor enhances T cell proliferation, IL‐2 secretion, survival and cytolytic activity of the T cells compared to 19–28z, 19–41BBz and 1928BBz (Zhao Z et al. Cancer Cell 2015;28:415–428). Herein, we report updated results ona study of adult patients with CLL and NHL treated with escalating doses of autologous 19–28z/4–1BBL+ CAR T cells (NCT03085173).Aims:The primary objective of this study was to determine the toxicity and MTD of 1928z‐41BBL CAR T cells in patients with relapsed or refractory CD19+ hematologic malignancies. Secondary objectives was to assess the anti‐tumor efficacy and in vivo persistence of the CAR T cells. Exploratory objectives were to assess the level of MRD when applicable and to assess the impact of infused CAR T cells on endogenous anti‐tumor immune response and changes in cellular and cytokine tumor microenvironment.Methods:Pts with R/R NHL (DLBCL, follicular lymphoma (FL), transformed FL (tFL), Waldenström's macroglobulinemia (WM)), CLL including Richter's transformation and B‐ALL were eligible for the trial. Pts received conditioning chemotherapy of cyclophosphamide (Cy) alone or combined with fludarabine (Flu) followed by escalating doses of CAR T cells. CAR T cells were administered at dose level (DL) 1 (1x105 CAR T cells/kg), DL2 (3x105 CAR T cells/kg), DL 3 (1x106 CAR T cells/kg), and DL4 (3x106 CAR T cells/kg).Results:28 pts were enrolled with R/R CLL (n = 9), de novo DLBCL (n = 9), tFL (n = 3), FL and WM (n = 4), Richter's transformation (n = 3) and a single pt with B‐ALL. Median age was 70 (range, 53–81), and median number of prior treatments was 5 (range, 2–17). 3 pts received DL1 CAR T cells, 3 pts DL2 CAR T cells, 3 pts DL3 CAR T cells and remaining 19 pts received DL4 CAR T cells. No dose‐limiting toxicity (DLT) was observed. All 28 pts are at least 2 weeks from T cell infusion and evaluable for toxicity. Overall, 11 pts experienced CRS (39.3%), which were mostly grade 1 (n = 6) and grade 2 (n = 4) and 11 pts (39.3%) experienced neurotoxicity (NTX), including 8 pts with grade 1–2 and 3 pts with grade 3 NTX. 16 of 28 pts (57%) achieved a CR, including 7 of 9 pts (78%) with large cell lymphoma, 2 of 3 pts with FL (67%), 3 of 10 pts (30%) with CLL, 2 pts with Richter's transformation (67%) and the one pt with B‐ALL. The pt with WM achieved a VGPR. With a median follow‐up of 169 days (24–534 days), 8 pts (29%) remain in CR. Peak CAR T cell expansion occurred at a median of 9 days after CAR T cell infusion (range, 2–82). CAR T cell detection beyond 160 days has been noted.Summary/Conclusion:Treatment with 19–28z/41BBL armored CAR T cells is safe. No severe CRS was observed and severe NTX occurred in 8% of the pts. The overall CR rate of 57% is encouragingCR rates were higher in pts with large cell lymphoma (78%) compared to CLL (20%), though small number of pts limits any firm conclusions. Pts with CLL may require higher doses of CAR T cells or incorporation of the CAR therapy in earlier lines of treatments. Detailed cytokine and CAR T cell expansion analysis as well as updated data will be presented.image

MDS AS A CAUSE FOR PROLONGED HEMATOLOGIC TOXICITY AFTER TREATMENT WITH CD19 TARGETED CAR‐T CELL THERAPY IN PATIENTS WITH RELAPSED REFRACTORY LYMPHOMA

Introduction: The advent of adoptive cellular therapy utilizing autologous T cells expressing chimeric antigen receptors (CAR-T) against CD19 has revolutionized relapsed and refractory B cell lymphoma treatment. CAR-T cell therapy, however, is not without toxicity. Other than cytokine release syndrome and neurotoxicity, hematologic toxicity occurs commonly as well. Grade 3 and above prolonged neutropenia and thrombocytopenia (longer than 4 weeks since T cell infusion) was seen in 15 to 40% and 18 to 40% of patients treated with CD19 CAR T cells in clinical trials respectively. The exact mechanism underlying the pathogenesis of prolonged hematologic toxicity in CAR-T cell therapy is not well understood. Interestingly, we identified four cases of prolonged cytopenias after CAR-T cell therapy due to the presence of myelodysplastic syndrome in patients receiving this treatment for relapsed refractory B cell lymphoma. Methods: We performed a retrospective review of four patients with relapsed refractory aggressive B cell lymphoma treated at our institution with CD19 directed autologous CAR-T cells. Results: Median age was 74 (range: 57-76). Two patients had GCB type, 2 had non-GCB type DLBCL. The median number of lines of therapy prior to CAR-T cell therapy was 5. All four patients had prior autologous stem cell transplantation. Median time to MDS diagnosis from CAR T infusion was 3 months (range: 2 to 3). One patient developed MDS after additional chemotherapy was given for relapsed disease. One patient had evidence of a dysplastic clone prior to CAR-T cell therapy. The remaining two patients did not have evidence of MDS until immediately after CAR-T cell therapy. Two patients developed severe CRS requiring tocilizumab and corticosteroids. One patient showed partial response to CAR-T cell therapy, while three others achieved CR, two of which have since relapsed. Discussion: We identified four patients with prolonged hematologic toxicity after CAR-T cell therapy due to MDS. These patients have multiple risk factors for the development of MDS including advanced age, and heavy pretreatment. In fact, one patient had evidence of MDS prior to CAR-T cell therapy, underscoring the potential benefit of providing CAR-T cell therapy earlier in the course of treatment. In addition, our findings suggest that a bone marrow study should be performed in patients with prolonged cytopenias post CAR T cell therapy. It is not clear if there is any direct contribution of CAR T cells and the resulting immune system disturbance to the development of MDS. Long term follow up of all patients receiving CAR T cell therapy is therefore crucial to assessment true incidence of MDS and establish association. Keywords: B-cell lymphoma; CD19. Disclosures: Herrera, A: Consultant Advisory Role: Gilead. Siddiqi, T: Consultant Advisory Role: Juno Therapeutics. Budde, E: Consultant Advisory Role: Gilead. 480 – WITHDRAWN

The role of doxycycline in the management of chronic rhinosinusitis with nasal polyps.

Many theories on the pathophysiology of chronic rhinosinusitis with nasal polyposis (CRSwNP) exist. The most effective management of CRSwNP has not been elucidated. Doxycycline, which has anti-inflammatory and anti-bacterial properties, has shown durable effects; however, its efficacy in combination with standard therapy has not been examined. We hypothesized that its addition to the standard anti-inflammatory regimen would improve patient outcomes. We performed a double-blind, placebo-controlled trial at a tertiary level institution. Patients with moderate or severe CRSwNP were randomized into two groups, each receiving a 20-day course of oral corticosteroids and doxycycline or placebo. The 22-item Sinonasal Outcome Test (SNOT-22), nasal polyp scores, and visual analog scale (VAS) scores were recorded at the initial, 3-, 8- and 12-week visits. 49 patients were enrolled, 24 in the experimental and 25 in the placebo group with 3 moderate disease patients in each group. There were 12 dropouts in the treatment group and 14 in the placebo group. The most common reasons for dropout were severe CRS and asthma exacerbations. There was no significant difference in SNOT-22 scores, nasal polyp scores, and VAS scores between the two arms. Non-surgical management of patients with CRSwNP remains challenging. Our conclusions are limited given the high dropout rate and thus, limited sample size with inadequate power. This study is important, however, because a high dropout rate of mostly severe disease patients may illustrate that this patient population may not be optimally managed with medical therapy alone.

Efficacy and Toxicity of CD19-Specific Chimeric Antigen Receptor T Cells Alone or in Combination with Ibrutinib for Relapsed and/or Refractory CLL

Background In relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients (pts) who had previously failed ibrutinib, we observed durable responses after CD19 chimeric antigen receptor-modified T-cell immunotherapy (Turtle CJ et al, JCO, 2017; NCT01865617). The combination of CD19 CAR-T cells with ibrutinib might improve response and decrease toxicity. Objectives To evaluate the efficacy and toxicity of CD19 CAR-T cell immunotherapy alone or in combination with ibrutinib for R/R CLL. Methods Our phase 1/2 study of CD19 CAR-T cell immunotherapy established a preferred regimen for R/R CLL pts of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by 2 × 106 CD19 CAR-T cells/kg (Turtle, JCO, 2017). We then compared outcomes of these pts (No-ibr cohort) with a subsequent cohort receiving Cy/Flu with 2 × 106/kg JCAR014 CAR-T cells with concurrent ibrutinib (420 mg/d) from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion (Ibr cohort). Results We treated 19 and 17 pts in the No-Ibr and Ibr cohorts, respectively. Pt characteristics were comparable (Table 1). Median follow-up in responders was 764 and 98 days in the No-ibr and Ibr cohorts, respectively. Administration of ibrutinib with Cy/Flu and CD19 CAR-T cells was well tolerated in most pts; ibrutinib was reduced or discontinued in 6 pts (35%) at a median of 21 days after JCAR014 infusion. In the Ibr cohort 1 pt with grade 2 CRS (Lee, Blood, 2014) developed fatal presumed cardiac arrhythmia and 1 pt developed a subdural hematoma in the setting of trauma and thrombocytopenia. Although the proportions of pts with grade ≥1 CRS were similar between cohorts (76% vs 89%, P = 0.39), the severity of CRS (grade ≥3 CRS: Ibr, 0%; No-Ibr, 26%; P = 0.05) and serum peak IL-8 (P = 0.04), IL-15 (P = 0.003) and MCP-1 (P = 0.004) concentrations were lower in the Ibr cohort. However, we found higher peak CD4+ CAR-T cell counts (P = 0.06) and comparable peak CD8+ CAR-T cell counts (P = 0.29) in blood in the Ibr compared to the No-Ibr cohort. Sixteen pts (94%) and 18 pts (95%) in the Ibr and No-ibr cohorts, respectively, were evaluable for response. We observed a higher proportion of responders (complete response and partial response) by 2008 IWCLL criteria in the Ibr compared to the No-ibr cohort (88% vs 56%, respectively, P = 0.06). In pts with no disease by BM flow cytometry after treatment (N = 23), a higher proportion of pts in the Ibr cohort had no malignant IgH sequences at 4 weeks (83% vs 60%, P = 0.35). Using multivariable logistic regression (Table 2), treatment in the Ibr cohort and a lower pre-treatment SUVmax were associated with a higher probability of response (Ibr cohort, OR = 14.02, P = 0.05; SUVmax, OR = 1.31 per SUV unit decrease, P Conclusion The combination of ibrutinib with CD19 CAR-T cell immunotherapy was well tolerated in most pts, and might decrease the incidence of severe CRS and improve responses in pts with R/R CLL.