Clinical Outcome of Refractory Lymphoma Patients with Non Response to Chimeric Antigen Receptor T Cell Therapy

Background Chimeric antigen receptor T cell (CART) therapy has remarkably improved the outcome of patients (pts) with relapsed refractory B cell non-Hodgkin lymphoma. Anti-CD19 directed CART therapy have shown to yield durable remission in 40%-50% of patients with relapsed refractory (r/r) diffuse large B cell lymphoma (Neelapu et al. NEJM 2017; NCT 02348216). However, pts who had disease progression post CART therapy (non-responders) have poor outcomes. There is paucity of information regarding negative predictors for disease progression and outcome of non-responders post CART therapy. Methods We conducted a single center retrospective study of 11 patients with relapsed refractory large B cell lymphoma who underwent treatment with CART in our institution from December 2019 to June 2021 and further studied the baseline characteristics, and clinical outcome of 8 pts who were non responders to CART therapy. Results All patients received low dose fludarabine cyclophosphamide based lymphodepleting conditioning regimen followed by anti-CD19 directed CART cells using CD28 as costimulatory domain with a target dose of 2 x 10 6 cells /kilogram of body weight. Baseline characteristics as shown in [Table 1]. Median age at CART therapy was 61 years (range 49-71). Median ECOG score at CART therapy was 1. All patients had chemo refractory disease at time of CART therapy with 9 patients having refractory diffuse large B cell lymphoma and 2 patients had transformed large B cell lymphoma. Genomic studies showed high risk disease in 4 patients with double hit lymphoma, 3 patients with complex cytogenetics with one having 17 p deletion and 2 patients with double expressors of c-myc and bcl2. Only 5 patients had available Ki-67 score > 80%. All patients had stage III-IV disease at the time of CART therapy. Seven pts had extra nodal disease and one patient had CNS involvement. Median R-IPI score at time of CART therapy was 3 (range 2-4). Median LDH, serum ferritin and serum CRP at the time of CART therapy was 388 (range 136-1489); 831 (range 116.9-1503); and 28.1 (range 7.4-226) respectively. Median number of prior therapies were 3 (range 2-9). One patient had prior autologous stem cell transplant. Median absolute lymphocyte count (ALC) and platelet count at CART therapy was 0.01/ul (range 0.01-2.5) and 89 x 10 3/ul (range 10-385) respectively. Median time from last salvage chemotherapy to CART therapy was 62 days (range 28-492). Total six pts had cytokine release syndrome (CRS) with median time for CRS onset was 3.5 days (range 1-8) with all of them having grade 1-2 CRS. Total seven pts had neurotoxicity with median time for onset was 5 days (range 1-41) post CART with 4 pts having > grade 3 immune effector cell associated neurotoxicity syndrome (ICANS). Overall, six and seven pts received tociluzumab and steroids respectively for treatment of CART related CRS and ICANS. Day 30 PET/CT scan showed three responders (2CR,1PR) and eight non responder patients with disease progression. Non responder pts to CART, when compared with responders had higher value of median LDH (438 vs 300; p = 0.92); median CRP (29 vs 13; p = 0.497) ; higher extra nodal involvement ( 6 pts vs one), median R-IPI score at the time of CART ( 4 vs 3), median number of prior therapies (4 vs 3), and median time from last salvage therapy to CART ( 73 days vs 50 days ; p = 0.91). No difference in baseline ALC count and platelet count was noted between the two groups. Compared to responders, non-responder pts had lower incidence of CRS (100% vs 37.5%) and ICANS (100% vs 50%). Post CART therapy, non-responder pts were treated with Nivolumab based immunotherapy in 5 pts, Ipilimumab based therapy in 1 pt, Selinexor in 1 patient and Polatuzumab based therapy in 2 pts. Median progression free survival and overall survival of non-responders was only 30.5 days and 94 days respectively. 5 out of 8 non responder pts died (4 due to disease progression and 1 due to sepsis). All three responder pts were alive and disease free at the end of study. Median follow up of our study was 108 days (range 32- 561). Conclusions Despite smaller sample size, our study showed dismal outcome of pts who don't respond to CART therapy, showing an unmet need for better salvage therapies in such pts. Refractory lymphoma pts with extra nodal disease involvement, higher LDH and CRP at the time of CART therapy could be negative predictors for response. Further prospective studies with larger sample size required to further validate these findings. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma

Background This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. Methods Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.5 × 109/L, platelets < 75 × 109/L, ECOG > 1. Baseline HR23B expression was assessed by immunohistochemistry. Results Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3–4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2–5.4) in solid-organ cancers and 2.6 months (95%CI 1.2–5.6) in lymphomas. HR23B status did not predict response. Conclusions CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. Trial registration ClinicalTrials.gov identifier NCT01977638. Registered 07 November 2013.

Preliminary results of a first-in-human phase I dtudy of IMM01, SIRPα Fc protein in patients with relapsed or refractory lymphoma.

2550 Background: IMM01 is a recombinant human signal regulatory protein α (SIRPα) IgG 1 fusion protein that exerts dual-mechanism antitumor activity via engagement of activating tumor cell phagocytosis and stimulating T-cell anti-tumor responses by binding CD47 on tumor cell membrane. IMM01 displays promising preclinical characteristics regarding its receptor occupancy/tumor exposure/efficacy relationship. Unlike anti-CD47 monoclonal antibodies, IMM01 shows unique property of weak human erythrocyte conjugation so as avoiding severe hemolysis. Methods: Monotherapy of IMM01 was conducted in 14 enrolled subjects with relapsed or refractory lymphoma who had failed standard therapies. Dose escalation was performed in routine design of accelerated single-patient followed by standard 3+3 to establish the preliminary data of safety as well as determination of a recommended expansion dosage. Each cycle contains 4 dosing weekly followed by a week rest. The tumor responses were evaluated based on Lugano Classification 2014. IMM01 pharmacokinetics (PK) and pharmacodynamics (PD) analyses were performed. Results: As of February 08, 2021, a total of 14 patients (median age 49 y; median prior therapy 3) were enrolled in 6 escalated dose cohorts (0.003 mg/kg, 0.01 mg/kg, 0.05 mg/kg, 0.15 mg/kg, 0.5 mg/kg and 1.0 mg/kg). The common tumor types were follicular lymphoma, Hodgkin lymphoma, diffuse large B-cell lymphoma. No DLTs were observed up to 1.0 mg/kg. One SAE (grade 2 increased amylase and grade 3 increased lipase) was reported, which induced by disease progression on pancreas. The most common treatment related adverse events were thrombocytopenia (54%), neutrophil count decreased (36%), Pyrexia (36%) and Anaemia (27%). There were grade 1 or 2 except for one patient experienced a grade 3 platelet count decreased (lower baseline at 70×109/L). Transient platelet count decrease after 2 hours and return to baseline at 24 to 48 hours post first infusion. In 12 evaluated patients, one patient with FL had a CR and maintained a 26-week response at the dose of 0.01 mg/kg. One patient with HL who had failed PD-1 inhibitor was confirmed PR at 27 weeks and continues the therapy, and one patient with MZL maintained SD for 12 weeks at the dose of 0.15 mg/kg. One patient with HL failed PD-1 inhibitor and one patient with FL maintained a shrunk SD for 12 weeks at the dose of 0.5 mg/kg. One patient with AITL was evaluated as a shrunk SD after 5 doses treatment at the dose of 1.0 mg/kg. Terminal half-life of IMM01 range from 53.8 hours to 73.3 hours. The AUC and Cmax of IMM01 show nonlinear increases in the dose range of 0.05 mg/kg to 0.5 mg/kg. Conclusions: Preliminary data from the present phase 1 study of IMM01, a SIRPα IgG 1 fusion protein, demonstrate that IMM01 has an excellent preliminary safety, tolerability and promising anti-tumor activity up to doses of 1.0 mg/kg. Clinical trial information: ChiCTR1900024904.