Durable Response After Tisagenlecleucel in Adults With Relapsed/Refractory Follicular Lymphoma: ELARA Trial Update

Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the ≥3rd-line setting. The primary analysis (median follow-up: 17 months) of the Phase II ELARA trial (ClinicalTrials.gov identifier: NCT03568461) reported high response rates and excellent safety profile in extensively pretreated patients with r/r FL. Here we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after a median follow-up of 29 months. As of March 29, 2022, 97 patients with r/r FL (grades 1-3A) after ≥2 lines of therapy or who relapsed after autologous stem cell transplant received tisagenlecleucel infusion (0.6-6×108 CAR+ viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment (TME), blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached after 29 months median follow-up (IQR, 22.2-37.7). Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% CI, 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2). Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T-cells and higher baseline levels of naïve CD8+ T-cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA

Ibrutinib Plus Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: The CLARITY Study.

PURPOSE:The treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeted therapies that either inhibit proliferation (ibrutinib) or reactivate apoptosis (venetoclax). Both significantly improve survival in CLL and replace chemoimmunotherapy for many patients. However, individually, they rarely lead to eradication of measurable residual disease (MRD) and usually are taken indefinitely or until progression. We present the CLARITY trial that combined ibrutinib with venetoclax to eradicate detectable CLL with the intention of stopping therapy. PATIENTS AND METHODS:CLARITY is a phase II trial that combined ibrutinib with venetoclax in patients with relapsed or refractory CLL. The primary end point was eradication of MRD after 12 months of combined therapy. Key secondary end points were response by International Workshop on CLL criteria, safety, and progression-free and overall survival. RESULTS:In 53 patients after 12 months of ibrutinib plus venetoclax, MRD negativity (fewer than one CLL cell in 10,000 leukocytes) was achieved in the blood of 28 (53%) and the marrow of 19 (36%). Forty-seven patients (89%) responded, and 27 (51%) achieved a complete remission. After a median follow-up of 21.1 months, one patient progressed, and all patients were alive. A single case of biochemical tumor lysis syndrome was observed. Other adverse effects were mild and/or manageable and most commonly were neutropenia or GI events. CONCLUSION:The combination of ibrutinib plus venetoclax was well tolerated in patients with relapsed or refractory CLL. There was a high rate of MRD eradication that led to the cessation of therapy in some patients. The progression-free and overall survival rates are encouraging for relapsed and refractory CLL

Outcomes after chimeric antigen receptor T-cell therapy across large B-cell lymphoma subtypes

Not available

Case report: Successful treatment of refractory immune thrombocytopenia in chronic lymphocytic leukaemia with venetoclax monotherapy

Peer reviewed: TrueIn chronic lymphocytic leukaemia (CLL), immune dysregulation is common and can manifest as immune thrombocytopenia (ITP). Corticosteroids are the mainstay for front-line management of CLL-associated ITP. Therapy refractoriness represents a clinical challenge and is an indication to commence CLL-directed treatment, historically with anti-CD20 antibody-based chemoimmunotherapy. There is a small but growing body of evidence supporting the use of Bruton’s tyrosine kinase (BTK) inhibitors in this setting, but not the B-cell lymphoma-2 inhibitor, venetoclax. Here, we describe two cases of refractory ITP in patients with CLL who successfully achieved and sustained complete remission with fixed-duration venetoclax monotherapy. Responses were rapid and durable and not explained by the concomitant use of an anti-CD20 antibody. This supports a dual role for single-agent venetoclax in managing active CLL and associated ITP as an alternative to BTK inhibitors and anti-CD20 monoclonals

Ibrutinib Plus Venetoclax with MRD-Directed Duration of Treatment Is Superior to FCR and Is a New Standard of Care for Previously Untreated CLL: Report of the Phase III UK NCRI FLAIR Study

Introduction: Ibrutinib (I), an irreversible Btk inhibitor, and venetoclax (V), a Bcl-2 inhibitor, improve CLL outcomes in trials compared to chemoimmunotherapy. I and V target two key pathophysiological pathways in CLL and should be synergistic. This is supported both by in vitro studies and Phase II trials in which I+V results in high proportions of measurable residual disease (MRD) negativity. A Phase III trial comparing I+V (15 months [mo]) with chlorambucil-obinutuzumab led to the approval of I+V. However, mathematical disease modelling and Phase II studies favor defining duration of I+V according to individual patient sensitivity. We hypothesized that I+V is more effective than FCR in CLL and that treatment duration personalised using MRD response would optimize outcome.Methods: FLAIR (ISRCTN01844152) is a phase III, multicentre, randomised, controlled, open, parallel group trial for untreated CLL. Patients (pts) with >20% 17p deleted cells were excluded. FLAIR was adapted in 2017 to add 2 arms, I alone and I+V compared to FCR. Here we report the planned analysis of I+V vs FCR. In I+V after 2 mo I, V was added with a 4-week dose escalation to 400mg/day and then I+V for up to 6 years with duration of I+V defined by MRD (65yo) and 40.9 % Binet Stage C. IGHV unmutated (≥98% homology to germline) in 56.9%, 37.6% IGHV mutated and 5.5% Subset 2. Hierarchical FISH: 20.6% 11q del, 20.1% trisomy 12, 27.8% normal and 31.4% 13q del. At 2 yrs 111/260 (42.7%) and 3 yrs 135/232 (58.1%) pts stopped I+V according to the MRD stopping rules. At a median 43.7 months there were 87 progressions - 75 FCR and 12 I+V. The hazard ratio (HR) for PFS for I+V vs FCR is 0.13 (95% CI: [0.07, 0.24]; p<0.0001; Fig). This result was consistent for gender, age or stage. At 3 yrs 2.8% had progressed on I+V compared to 23.2% on FCR. There have been 34 deaths (25 FCR and 9 I+V) resulting in improved overall survival for I+V vs FCR: HR 0.31 (95% CI: [0.15, 0.67]; p=0.0029; Fig). At 3 years 2.0% of I+V pts had died compared to 7.0% for FCR. At 9 months (3 mo post-FCR) 48.3% FCR pts became MRD neg in BM compared to 41.5% for I+V. However, with continued I+V more pts became MRD neg: the odds of MRD negativity at any time for I+V vs FCR were 2.03 (95% CI: [1.43, 2.89]; P<0.001) in BM and 3.91 (95% CI: [2.55, 6.00]; P<0.001) in PB. 90.6% pts achieved PB MRD negativity at up to 5 yrs I+V and 88% of these were BM MRD negative 6 mo after their first PB MRD neg result. At 9 months a higher proportion achieved CR and overall response for I+V; CR - FCR 49.0% (95% CI: [42.9%, 55.3%]), I+V 59.2% (53%, 65.3%); ORR - FCR 76.4% (70.8%, 81.4%); I+V 86.5% (81.8%, 90.4%). This difference was greater for best response at any time: ORR 83.7% (78.6%, 87.9%) for FCR vs 95.4% (92.1%, 97.6%) for I+V; CR 71.5% (65.6%, 76.9%) for FCR vs 92.3% (88.4%, 95.2%) for I+V. The odds ratios estimate to achieve CR with I+V vs FCR is 1.51 (95% CI: [1.07, 2.14]; p<0.05). Responses and outcomes by FISH and IGHV will be presented. SAEs were reported in 252 (51.3%) pts (129 FCR vs 123 I+V). Notable SAEs by organ class for FCR vs I+V were: infections 18.8% of FCR pts vs 22.2% for I+V; blood and lymphatic 31% vs 5%; and cardiac in 0.4% vs 10.7%. 4 pts had sudden or cardiac deaths - 2 FCR and 2 I+V. 69 other cancers were diagnosed (45 in FCR, 24 in I+V) in 51 pts (34 FCR, 17 I+V). The incidence of other cancers per 100 pt-years was greater for FCR than I+V; 5.4 (95% CI: [5.11, 5.68]) vs. 2.6 (2.40, 2.79). There were 7 cases of MDS/AML with FCR and 1 with I+V.Conclusion: Ibrutinib plus venetoclax significantly improved progression-free and overall survival compared to FCR in untreated CLL. Using MRD to direct the duration of I+V maximizes outcome with 97.2% progression free survival at 3 years The efficacy seen in FLAIR is superior to previous Phase III CLL trials indicating that I+V with duration guided by MRD is a new gold standard for CLL treatment

A national service for delivering CD19 CAR-Tin large B-cell lymphoma - The UK real-world experience

CD19 CAR-T have emerged as a new standard treatment for relapsed/refractory (r/r) large B-cell lymphoma (LBCL). CAR-T real-world (RW) outcomes published to date suggest significant variability across countries. We provide results of a large national cohort of patients intended to be treated with CAR-T in the UK. Consecutive patients with r/r LBCL approved for CAR-T by the National CAR-T Clinical Panel between December 2018 and November 2020 across all UK CAR-T centres were included. 404/432 patients were approved [292 axicabtagene ciloleucel (axi-cel), 112 tisagenlecleucel (tisa-cel)], 300 (74%) received the cells. 110/300 (38.3%) patients achieved complete remission (CR) at 6 months (m). The overall response rate was 77% (52% CR) for axi-cel, 57% (44% CR) for tisa-cel. The 12-month progression-free survival was 41.8% (axi-cel) and 27.4% (tisa-cel). Median overall survival for the intention-to-treat population was 10.5 m, 16.2 m for infused patients. The incidence of grade ≥3 cytokine release syndrome and neurotoxicity were 7.6%/19.6% for axi-cel and 7.9%/3.9% for tisa-cel. This prospective RW population of CAR-T eligible patients offers important insights into the clinical benefit of CD19 CAR-T in LBCL in daily practice. Our results confirm long-term efficacy in patients receiving treatment similar to the pivotal trials, but highlight the significance of early CAR-T failure