Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the outcomes for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a concern. Pre-existing neurological disorders such as Parkinson's disease (PD) introduce additional, poorly studied challenges due to the risk of unpredictable complications. We report a 62-year-old man with relapsed DLBCL and pre-existing PD who was treated with lisocabtagene maraleucel. Baseline assessments by neurology, physiotherapy, and speech-language teams enabled tailored monitoring, including use of a modified Immune Effector Cell-Associated Encephalopathy (ICE) score. His dopaminergic regimen was optimised prior to therapy. Following lymphodepletion and CAR-T infusion, he experienced grade 1 cytokine release syndrome, which resolved with tocilizumab and ward-based supportive care. Although a stable partial response was observed on PET-CT scan at 1 and 3 months, the absence of ICANS or PD worsening up to his most recent follow-up on Day +86 suggests that CAR-T therapy can be safely delivered in patients with pre-existing PD when tailored strategies are applied, including a multidisciplinary approach, modified neurotoxicity monitoring, and careful selection of the CAR-T construct. Further studies and longer follow-up are needed to clarify long-term safety in this population.

Abstract Acalabrutinib is a selective, covalent Bruton tyrosine kinase inhibitor approved for marketing in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report final, long-term phase 1/2 study results in 99 patients with treatment-naive (TN) and 134 with relapsed/refractory (R/R) CLL/SLL. At final data cutoff, 71% and 31% of patients in the TN and R/R cohorts, respectively, remained on acalabrutinib treatment (median follow-up of 73.7 and 52.6 months). Among the events of clinical interest (any grade) in the TN and R/R cohorts, atrial fibrillation was reported in 6.1% and 9.0%, hypertension in 29.3% and 23.1%, other malignancies (excluding nonmelanoma skin cancer) in 14.1% and 17.2%, and major bleeding in 8.1% and 8.2% of patients, respectively. The incidence of the most common adverse events decreased over time. Overall response rates were 97.0% and 94.8% in the TN and R/R cohorts, respectively, with similar response findings among patients with standard and high-risk genomic features. In the TN cohort, median progression-free survival (PFS) was not reached and the 72-month PFS rate was 86.7% (95% confidence interval [CI], 77.0-92.5). For the R/R cohort, median PFS was 66.1 months (range, 0.4-87.8) and the 72-month PFS rate was 45.1% (95% CI, 35.6-54.1). This final analysis extends the duration of benefit observed with acalabrutinib, demonstrates that no new safety signals are apparent with longer follow-up, and confirms the safety and tolerability of acalabrutinib monotherapy for patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Background Tisagenlecleucel is approved in the United States and Europe for adults with r/r FL after ≥2 lines of prior therapy. We report the final analysis from the phase 2 ELARA trial (NCT03568461) with >5-y median follow-up (mFU). Methods Pts with r/r FL (grade 1-3A) and ≥2 prior lines of systemic therapy (including an anti-CD20 monoclonal antibody [Ab] and alkylating agent) received a single tisagenlecleucel infusion (0.6-6 × 108 CAR+ viable T cells). Bridging therapy was permitted. Long-term efficacy and safety outcomes were evaluated. Cellular kinetics were assessed by qPCR. Results As of May 28, 2025, 97 pts were infused (mFU, 61.0 mo [range: 3.1–67.0]). At baseline, pts with high-risk (HR) disease included 60% with high FLIPI score of ≥3, 62% with POD24, 64% with bulky disease (>7 cm or 3 lesions >3 cm), 68% with double refractory to prior CD20 Ab and alkylating agent, and 21% with high tumor burden. The ORR (86.2%) and CRR (68.1%) were consistent with prior data (Dreyling M, Blood 2024). The mDOR was not reached (NR; 95% CI: 35.8–NE); estimated 4-y DOR in all responders was 61% (95% CI, 48.8–71.1) and 71.2% (95% CI, 57.7–81.1) in pts with CR. The mPFS was 53.2 mo (95% CI,18.2–NE); estimated 5-y PFS was 46% (95% CI, 35.0–56.3) in all infused pts and 59.8% (95% CI, 46.2–71.1) in pts with CR. In pts with HR disease, 5-y estimated PFS was 35.5% (high FLIPI), 41.1% (POD24), 45.1% (bulky disease), 50.5% (double refractory). In pts with high tumor burden, 5-y PFS was NE due to small subgroup size. Among all infused pts, median OS and estimated 5-y OS were NR and 74.1% (95% CI, 63.0–82.3). Among pts with HR disease, estimated 5-y OS was 64.4% (high FLIPI), 74.6% (POD24), 71.1% (bulky disease), 79.8% (double refractory), and 65.5% (high tumor burden). CAR transgene persistence (Tlast) was observed up to 60.9 mo; median Tlast was 8.6 mo (range: 0.6–60.9). Blood and lymphatic system disorders occurring >1 y after infusion were reported in 11 (13.1%) pts (neutropenia [6.0%], anemia [4.8%], and thrombocytopenia [3.6%]), and infection and infestations in 34 (40.5%) pts (COVID-19 [17.9%] and pneumonia [11.9%]). A total of 11 second primary malignancies were reported in 7 (7.2%) pts: 2 events each of basal cell carcinoma, myelodysplastic syndrome, squamous cell carcinoma of skin, and 1 event each of acute myeloid leukemia, bladder transitional cell carcinoma, Bowen’s disease, malignant melanoma, and metastatic squamous cell carcinoma. In total, 22 pts died during the study due to disease progression (n=8), AEs (n=13, mostly infections), and euthanasia. Conclusions After >5 y mFU, tisagenlecleucel continues to demonstrate durable responses and prolonged survival in pts with r/r FL including pts with HR disease. No new safety signals were reported. More than 75% of pts were alive, and approximately half remained progression-free at this final analysis, indicating the curative potential of tisagenlecleucel in r/r FL.

Front-Line therapy in CLL: Assessment of Ibrutinib-containing Regimens (FLAIR) demonstrated improved progression-free survival for ibrutinib and rituximab (IR) compared with fludarabine, cyclophosphamide and rituximab (FCR) in previously untreated chronic lymphocytic leukaemia (CLL). This report presents the secondary end-point of health-related quality of life (HR-QoL). FLAIR was a phase 3, open-label, randomised trial across 101 hospitals. Eligible patients were aged 18-75 years, World Health Organization performance status (PS) ≤2, requiring treatment; those with >20% 17p deletion were excluded. IR was administered for up to 6 years and FCR for six cycles. Participants completed European Organisation for Research and Treatment of Cancer Quality of Life C30 Questionnaire (EORTC-QLQ-C30), QLQ CLL Module (QLQ-CLL16), three-level EQ-5D (EQ-5D-3L) and EQ5D visual analogue (EQ-VAS) at baseline and follow-up. Function and symptom trajectories were analysed using repeated-measures multilevel regression. 84.4% of participants completed baseline questionnaires and subsequent compliance was 67.6%-83.5%. Median age was 63 years; most participants were white and male. HR-QoL trajectories were similar. FCR recipients had worse scores at end of treatment but recovered thereafter. By 48 months, more FCR-treated participants showed meaningful improvements in several scales. Statistically significant differences (p < 0.05) favoured IR for physical, role and social function; emotional function favoured FCR. Diarrhoea was more common with IR; fatigue and dyspnoea were more common with FCR, though differences did not exceed minimally important thresholds. Overall, scales were comparable between treatment groups, indicating that continuous IR does not compromise HR-QoL.

Abstract Clinical trials indicate that acalabrutinib, a second-generation Bruton tyrosine kinase inhibitor, is safe and effective for treating patients with chronic lymphocytic leukemia (CLL), but real-world evidence on its clinical effectiveness is limited. This ongoing multicenter retrospective chart review included UK adults with previously untreated CLL who received acalabrutinib monotherapy as part of a UK-wide early access program. These patients received their first dose of acalabrutinib between 1 April 2020 and 1 April 2021. Data from 282 patients (male patients, n = 156 [55%]) collected from 29 sites across the United Kingdom revealed a median age of 73.9 years (interquartile range [IQR], 68.6-79.4) at acalabrutinib initiation (index date) and a median time of 3.0 years (IQR, 1.2-5.7; n = 281) from CLL diagnosis to treatment. The median follow-up was 48.9 months (IQR, 45.0-52.3). At the 3-year landmark, real-world progression-free survival was 82.5% (95% confidence interval [CI], 78.2-87.1), and real-world overall survival was 84.3% (95% CI, 80.2-88.7). Additionally, 72.3% of patients (95% CI, 67.3-77.8) remained on acalabrutinib treatment. The most common reasons for acalabrutinib discontinuation were adverse events (AEs; 31/87 [36%]), death (16/87 [18%]), and disease progression (14/87 [16%]). Of the 270 patients with recorded information, 99 patients (37%) experienced ≥1 prespecified AE, of which the most frequent were upper respiratory tract infection (n = 21 patients [8%]), rash (n = 13 [5%]), and neutropenia (n = 12 [4%]). This study adds to a body of clinical trial and further postmarketing evidence demonstrating the effectiveness and safety of acalabrutinib within routine UK clinical practice.

BACKGROUND:Chronic lymphocytic leukaemia is the commonest leukaemia and is associated with profound immunosuppression. Bruton tyrosine kinase inhibitors (BTKi) have revolutionised chronic lymphocytic leukaemia management; however, therapy impairs vaccine-induced immunity. We evaluated whether a 3-week pause of BTKi treatment improved spike protein receptor binding domain (RBD) immunity to SARS-CoV-2 booster vaccination while maintaining disease control. METHODS:We performed an open-label, two-arm, parallel-group, randomised trial in secondary-care haematology clinics in 11 UK hospitals. Participants aged 18 years or older, diagnosed with chronic lymphocytic leukaemia, and currently taking BTKi therapy (frontline or relapsed setting) for at least 12 months were eligible. Participants were randomly allocated (1:1, by a centralised computer randomisation program, stratified by BTKi therapy line) to pause BTKi for 3 weeks, starting 6 days before their SARS-CoV-2 vaccination booster date, or to continue therapy as usual. Neither participants nor clinical staff were blinded but laboratory staff were. Intramuscular injection of either original BA.1 or original BA.4/5 bivalent mRNA vaccine (50 μg mRNA-1273 or 30 μg BNT162b2), or 5 μg protein-based Vidprevtyn Beta (Sanofi Pasteur, Lyon, France) were received according to the national vaccination programme schedule. The primary outcome measure was anti-spike-RBD-specific antibody titre 3 weeks after vaccination and analysis performed by intention to treat (as randomly allocated, irrespective of compliance) following trial completion. This trial is registered with ISRCTN, 14197181, and has been completed. FINDINGS:Between Oct 10, 2022, and June 8, 2023, 99 individuals (71 [72%] male and 28 [28%] female, with 89 [90%] of White ethnicity) were randomly allocated to groups pausing (n=50 [51%]) or continuing (n=49 [49%]) their BTKi therapy, and followed up for 12 weeks. At 3 weeks after vaccination, the geometric mean anti-spike-RBD-specific antibody titre was 218·8 U/mL (SD 122·9) in the continue group and 153·4 U/mL (103·2) in the pause group, with geometric mean ratio 1·104 (95% CI 0·565-2·158, p=0·77) using a mixed-effects model. The only serious adverse event during the 12-week follow-up was the death of one participant in the pause group due to COVID-19 infection 2 months after randomisation. INTERPRETATION:Although the study was slightly underpowered, the results suggest that pausing BTKi around the time of vaccination is not beneficial for immunity and should not be recommended in clinical practice. FUNDING:National Institute for Health and Care Research.

ABSTRACT:With up to 10 years of follow-up, we report results from the final analysis of RESONATE- 2, a phase 3 study of first-line ibrutinib vs chlorambucil for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients aged ≥65 years with previously untreated CLL/SLL without del(17p) were randomly assigned to receive either single-agent ibrutinib (420 mg/d; n = 136) or chlorambucil (0.5-0.8 mg/kg; ≤12 cycles; n = 133). With a median follow-up of 9.6 years in the ibrutinib arm, the median progression-free survival (PFS) was 8.9 years (95% confidence interval [CI], 7.0 to not estimable [NE]) vs 1.3 years (95% CI, 0.9-1.6) for the chlorambucil arm. Among patients with unmutated immunoglobulin heavy chain variable (uIGHV), del (11q), mutated TP53, or complex karyotype, the median PFS was 8.4 years (95% CI, 6.8 to NE) with ibrutinib and 0.7 years (95% CI, 0.4-1.2) with chlorambucil. Median overall survival (OS) with ibrutinib was not reached. The most common adverse events (AEs) of any grade included diarrhea (52%), fatigue (41%), cough (39%), nausea (32%), arthralgia (31%), peripheral edema (31%), and hypertension (30%). During the entire study period, 34 of 136 patients (25%) had an ibrutinib dose reduction due to AEs; these AEs improved in 30 of 34 patients (88%). At study completion, 27% of patients remained on first-line ibrutinib treatment. This landmark RESONATE-2 study defines median PFS and demonstrates continued OS benefit of first-line ibrutinib treatment for patients with CLL/SLL, including those with high-risk genomic features. Sustained efficacy and tolerability of ibrutinib reemphasize the favorable benefit-risk profile. This trial was registered at www.ClinicalTrials.gov as NCT01722487/NCT01724346.

Objective: This review assesses the efficacy of machine learning (ML) models for classification and management of Chronic Lymphocytic Leukaemia (CLL).Methods: Twenty studies published between 2014 and 2023 were reviewed, focusing on supervised ML models to predict patient outcomes or guide treatment decisions. Studies were identified through PubMed, Google Scholar, and IEEExplore, with the final search in March 2023. Inclusion criteria consisted of studies focused on ML applications in CLL. Exclusion criteria included studies lacking sufficient methodology or focused solely on experimental settings without clinical validation. Most studies used small, single-centre datasets, potentially contributing to overfitting and limited applicability to real-world settings.Results: Despite dataset limitations, all reviewed studies reported positive outcomes, with some demonstrating improvements in clinical workflows. Our findings advocate developing ML models using larger, multimodal, and multi-institutional datasets. Improved model interpretability and NLP implementation to harness unstructured clinical data were identified as key areas for advancement. Additionally, innovations like cross-site federated learning and automated redaction could help address data integration and privacy challenges.Conclusion: This review underscores the transformative potential of ML in CLL management. However, addressing limitations, including diverse datasets and enhanced model interpretability, is crucial for fully leveraging ML capabilities in haemato-oncology.

Background: Treatment strategies for patients (pts) with relapsed/refractory follicular lymphoma (r/r FL) require consideration of prior therapies and pt-related factors to identify those who are likely to benefit from available treatment options. Tisagenlecleucel is a CAR-T cell therapy approved in the United States and Europe for adults with r/r FL after ≥2 lines of prior therapy. The primary analysis of the phase 2 ELARA trial reported high response rates and a favorable safety profile in pts with high-risk r/r FL. Here we report 4-year follow-up of efficacy, safety, and pharmacokinetics findings. Methods: Eligible pts with r/r FL (grades 1-3A) previously treated with ≥2 lines of systemic therapy (including an anti-CD20 monoclonal antibody and alkylating agent) received a single tisagenlecleucel infusion (0.6-6×108 CAR+ viable T cells). Bridging therapy was permitted. Baseline clinical characteristics and circulating blood naive T cells were correlated with progression-free survival (PFS) and overall survival (OS). Cellular kinetics were determined by measurement of transgene levels by quantitative polymerase chain reaction. Minimal residual disease (MRD) levels were determined via clonoSEQ® Next Generation Sequencing assay performed at Adaptive Biotechnologies (Seattle, WA, USA): pre-infusion tissue samples were used for the clonotype identification; MRD tracking was performed in post-infusion plasma (ctDNA) samples. Results: As of March 27, 2024, 97 pts were infused. Ninety-four pts were evaluable for efficacy with a median follow-up of 53 months (range: 46-62). At baseline, among efficacy-evaluable pts, key pt subgroups at high-risk were identified; 72.3% of pts had FL that was refractory to ≥2 prior regimens, 66.0% had bulky disease (>7 cm or 3 lesions >3 cm), 64.9% had progression of disease within 2 years of frontline systemic therapy (POD24), 60.6% had high Follicular Lymphoma International Prognostic Index (FLIPI; ≥3), and 21.3% had high tumor burden (total metabolic tumor volume >510 mL). Median PFS was 53.3 months (95% CI: 18.2-NE) by independent review committee (IRC) among all pts; 48-mo PFS was 50.2% in all pts and 66.1% in pts with a best overall response of complete response. Among identified pt subgroups at high risk, 48-mo PFS by IRC was 45.5% (POD24), 45.5% (high FLIPI), 45.2% (bulky disease), 52.8% (double refractory), and 23.2% (high tumor burden). Median OS was not reached; 48-mo OS was 79.3% in efficacy-evaluable pts. Among identified pt subgroups at high risk, 48-mo OS was 80.8% (POD24), 73.2% (high FLIPI), 73.0% (bulky disease), 83.7% (double refractory), and 65.5% (high tumor burden). MRD data were available on 32/97 pts (33.0%); 28/32 pts (87.5%) achieved MRD negativity at any time point. MRD-negative status was achieved in 82.8% (24/29) of evaluable pts at day 28, 77.8% (14/18) at month 3, 72.7% (16/22) at month 6, and 82.4% (14/17) at month 12, respectively. CAR transgene persistence (Tlast; time to last quantifiable transgene level) was observed for up to 1680 days; median Tlast was 210 days (range: 13-1680). No new safety signals have been reported since the last data cut. Second primary malignancies (defined as any new cancer occurring post infusion regardless of tisagenlecleucel relationship) were reported in 6 (6.2%) pts and included basal cell carcinoma (n=2), squamous cell carcinoma (n=2), acute myeloid leukemia (n=1), bladder transitional cell carcinoma (n=1), Bowen's disease (n=1), malignant melanoma (n=1), metastatic squamous cell carcinoma (n=1), and myelodysplastic syndrome (n=1). As of the data cutoff, 19 pts have died during the study: 8 due to progressive disease, 10 due to AEs (1 pt each; acute myeloid leukemia, bladder transitional cell carcinoma, cardiac arrest, CRS, encephalitis, gastrointestinal hemorrhage, infection, metastatic squamous cell carcinoma, pneumonia, sepsis), and 1 from euthanasia. Conclusions: Updated long-term follow-up from the ELARA trial continues to demonstrate robust durable responses >4 years post infusion, alongside a favorable safety profile. Correlative analyses suggest that most baseline high-risk disease characteristics (double-refractory disease, bulky disease, POD24, and high FLIPI) are not associated with inferior efficacy following tisagenlecleucel infusion in pts with r/r FL. Furthermore, high frequencies of MRD-negative status were achieved in a subset of evaluable pts.

Chronic Lymphocytic Leukemia (CLL)is the most common leukemia in adults in Western countries, and its incidence is increasing. It is a complex, chronic disease with highly variable behavior. People living with CLL deserve an accurate diagnosis and should be empowered to play an active role in their care. They should be treated holistically as a person, not simply by their diagnosis. This charter has been developed with input from patient advocacy organizations, people living with CLL, and clinical specialists. It highlights the elements of care and support that matter most to people living with CLL as they navigate life with their diagnosis. We urge governments, decision-makers, healthcare providers, patient advocacy organizations, and professional organizations worldwide to embed these principles in their work and ensure they are hardwired into healthcare systems and support services to reform and improve CLL care.

Chronic lymphocytic leukaemia/small lymphocytic lymphoma is a common subtype of non-Hodgkin lymphoma that is often diagnosed after finding an incidental lymphocytosis on a routine blood count. Key diagnostic tests are peripheral blood morphology and immunophenotyping. At all stages of disease, patients are vulnerable to infections and other malignancies. Treatment is only indicated in those who develop significant disease-related constitutional symptoms, and/or bulky lymphadenopathy, massive splenomegaly, or cytopenia. An increasing number of prognostic biomarkers are now available to assess likely disease outcome and response to different types of treatment. Use of newer agents such as Bruton's tyrosine kinase inhibitors and B cell lymphoma 2 inhibitors have started to replace more traditional chemo-immunotherapy and have increased overall life expectancy.

Chronic lymphocytic leukemia (CLL) is an indolent malignancy with modest proliferation in the lymph nodes and accumulation of quiescent B cells in the peripheral blood. Targeted agents, including BTK inhibitors such as ibrutinib and the BCL2 antagonist venetoclax, have transformed therapy by disrupting proliferation, survival, and lymph node retention of CLL cells, yet CLL remains incurable. Recent studies reveal that CLL cells exist along a spectrum of proliferating, activated, and quiescent states, with dynamic transitions that shape intraclonal behavior. Whilst proliferation occurs mainly in lymph nodes, most emigrant cells in the peripheral blood become quiescent, with only a minority remaining activated. Quiescent, activated, and proliferating fractions display distinct phenotypes and CXCR4 and CD5 levels can be used to distinguish these states in the CLL life cycle. While proliferating and activated cells are more susceptible to BTK inhibition, quiescent subsets show greater sensitivity to BCL2 blockade. These functional differences, together with emerging evidence that phenotypic markers may correlate with residual disease activity, point to potential translational significance. Understanding how CLL cells switch between proliferative, activated and quiescent states will be important to uncover novel vulnerabilities and inform rational treatment strategies.

BACKGROUND:An interim analysis of progression-free survival in this trial showed that ibrutinib-venetoclax was superior to fludarabine-cyclophosphamide-rituximab (FCR) among patients with chronic lymphocytic leukemia (CLL). Whether ibrutinib-venetoclax is more effective than ibrutinib alone is unclear. METHODS:In this phase 3, multicenter, open-label trial, we randomly assigned patients with CLL to receive ibrutinib-venetoclax, ibrutinib alone, or FCR. The primary end points were undetectable measurable residual disease (MRD) in bone marrow within 2 years in the ibrutinib-venetoclax group as compared with the ibrutinib-alone group and progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group. A powered secondary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the ibrutinib-alone group. Other secondary end points included overall survival. RESULTS:A total of 172 of the 260 participants (66.2%) in the ibrutinib-venetoclax group had undetectable MRD in bone marrow within 2 years, as compared with none of the 263 participants in the ibrutinib-alone group (P<0.001) and 127 of the 263 participants (48.3%) in the FCR group. With a median follow-up of 62.2 months, disease progression or death occurred in 18 participants (6.9%) in the ibrutinib-venetoclax group, as compared with 59 (22.4%) in the ibrutinib-alone group (hazard ratio, 0.29; 95% confidence interval [CI], 0.17 to 0.49; P<0.001) and 112 (42.6%) in the FCR group (hazard ratio, 0.13; 95% CI, 0.08 to 0.21; P<0.001). Progression-free survival at 5 years was 93.9% with ibrutinib-venetoclax, 79.0% with ibrutinib alone, and 58.1% with FCR. Death occurred in 11 participants (4.2%) in the ibrutinib-venetoclax group, as compared with 26 (9.9%) in the ibrutinib-alone group (hazard ratio, 0.41; 95% CI, 0.20 to 0.83) and 39 (14.8%) in the FCR group (hazard ratio, 0.26; 95% CI, 0.13 to 0.50). Sudden death occurred in 3, 8, and 4 participants in the ibrutinib-venetoclax, ibrutinib-alone, and FCR groups, respectively. CONCLUSIONS:With extended follow-up and increased enrollment, our trial showed that undetectable MRD and extended progression-free survival were more common with ibrutinib-venetoclax than with ibrutinib alone or FCR. The results for overall survival were also consistent with a benefit of ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).

Purpose/Objective(s) Radiotherapy is an accepted bridging prior to CD19 CAR T in large B cell lymphoma (LBCL) and is sometimes used post CAR T for residual disease. However, consolidation (cRT) is not well established and there is no agreed standard for patient selection, timing, doses or techniques. Concern also exists regarding effect on circulating CAR T in responding patients. We initiated a prospective protocol for the use of RT with CAR T to: (1) standardize the selection of patients, (2) promote the use of RT consolidation post CAR T according to pre defined criteria, and (3) optimize the use of CAR T sparing RT in the consolidation setting. Materials/Methods The eligibility criteria included LBCL patients approved for CD19 CAR T and no contraindication for RT. Patients were selected for pathway A (Bridging RT alone) if most sites of disease can be covered with RT. Pathway B (bridging systemic therapy ± cRT) was selected for rapidly progressing disease, wide-spread extranodal disease (e.g. liver, lung, bone, peritoneum) or LDH >2xULN. Baseline PET CT was reviewed and sites at high risk for local recurrence (≥5cm or SUVmax ≥15) were recorded. cRT post CAR T was given to high-risk lesions which on D28 PET CT showed a Deauville score (DS) 3-4 or 5 (but partial response). RT was planned 6-8 weeks post CAR T, with CAR T sparing technique. Results 28 patients were entered between Nov 2021 – Oct 2023, 10 in pathway A & 18 in pathway B. Median age was 55 years. 51.7% had stage 4 (20% vs. 68.4% in A vs. B). 44.8% had bulky disease, 24.1% ≥2 extranodal sites, and 48.2% high LDH. 1 patient in pathway A did not receive CAR T due to PD. RT dose was 20-36Gy (10-12#) in pathway A, all delivered with VMAT and with no gaps. Pathway B doses were 25-37.5Gy / 5-15# (23/26 sites treated with VMAT) and with no gaps. Planning modifications for early cRT post CAR T included: (1) contouring and dose-optimisation of blood vessels (BV) and blood-rich OARs (BR-OAR) to reduce doses to blood, and (2) measures to reduce beam-on time to account for the circulating nature of blood; hypofractionation (2.5 – 5 Gy/#, median = 3), limited beam angles (e.g. partial single arcs) avoiding BV and BR-OAR, and flattening filter free (FFF) beams. Overall response rate at 1 month was 86.2% (41.4% DS 1-3) and 48.2% at 6 months. With a median follow-up of 180 days, 9 patients progressed (4 in pathway A and 5 in pathway B) and 5 died, all due to disease progression. Data on local disease control, progression-free and overall survival will be provided at the meeting. Significant toxicity included 2 G3 ICANS but no CRS G≥ 3. No G≥3 toxicity reported after cRT. Conclusion Implementing a comprehensive protocol of RT bridging and post CAR T RT consolidation with selection of patients based on pre-defined criteria was feasible. All patients but one completed treatment according to protocol. The disease control outcomes and the toxicity are promising, particularly in the RT consolidation setting.

Loss-of-function (LoF) mutations frequently found in human cancers are generally intractable by classical small molecule inhibitor approaches. Among them are mutations affecting Polycomb-group (PcG) epigenetic regulators, enhancer of zeste homolog 2 (EZH2) and Additional sex combs like 1 (ASXL1), frequently found in hematological malignancies of myeloid or lymphoid lineage, and their concurrent mutations associates with particularly poor prognosis. Although there is a clear need to develop novel and effective treatments for these patients, the lack of appropriate disease models and mechanistic insights have significantly hindered the progress. Here, we show that genetic inactivation of Asxl1 and Ezh2 in murine hematopoietic stem/progenitor cells results in highly penetrant hematological malignancies as observed in corresponding human diseases. These PcG proteins regulate both coding and noncoding genomes, leading to marked reactivation of transposable elements (TEs) and DNA damage responses in PcG LoF-mutated cells, which create a novel vulnerability for poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi)-induced synthetic lethality. Using both mouse models and primary patient samples, we demonstrate that Asxl1/Ezh2-mutated cells are highly sensitive to PARPis that induce excessive DNA damage and significantly extend disease latency. Intriguingly, the observed PARPi sensitivity can be specifically overridden by reverse transcriptase inhibitors that interrupt target site-primed reverse transcription and life cycle of TEs. This mechanism is contrastingly different from the current concept of BRCAness associated PARPi-induced synthetic lethality, which largely rely on deficient homologous recombination, and is independent on reverse transcriptase inhibitors. Together, this study reveals a novel application and mechanism of PARPi-induced synthetic lethal targeting of blood cancers with reactivated TEs such as those carrying PcG epigenetic mutations.

Data on the impact of ethnic and socioeconomic factors on Chimeric antigen receptor (CAR) T-cell therapy (access and outcomes are limited, but key to understand whether results from the registration trials are generalizable to real-world patient populations. Here, we analysed ethnicity, socioeconomic deprivation and referral patterns in a cohort of 314 large B-cell lymphoma patients approved for third-line CD19 CAR-T across three large UK CAR-T centres. Patients from deprived areas had a lower infusion rate compared to low deprivation areas (73% vs. 86%, p = 0.04). CAR-T response rates, toxicities, progression-free survival or non-relapse mortality were similar with respect to ethnicity or deprivation. We did not find evidence of referral barriers according to ethnicity, but potential regional barriers for socioeconomically deprived patients in two of three centres. Intention-to-treat overall survival was significantly inferior in patients from deprived areas (1-year OS 44.5% vs. 58% for high vs. low deprivation; p = 0.02), likely reflecting general health disparities and higher drop-out rates in this group. Our data suggest similar outcomes of CD19 CAR-T-treated patients across a socioeconomically and ethnically heterogeneous real-world population. Results demonstrate broad access to CAR-T within the UK national delivery system, but the high drop-out rate and potential regional referral barriers for deprived communities should be further investigated.

Context With up to 10 years of follow-up, RESONATE-2 provides the longest-term outcomes and safety data of any targeted agent for treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Objective To report final efficacy and safety analyses of RESONATE-2 (NCT01722487). Patients Older adults (≥65 years) with previously untreated CLL/SLL without del(17p). Interventions Patients were randomly assigned to receive single-agent ibrutinib (n=136, 420 mg/day) or chlorambucil (n=133, 0.5–0.8 mg/kg) until progressive disease (PD) or unacceptable toxicity. Post-PD chlorambucil-ibrutinib crossover was allowed. Main Outcome Measures: Progression-free survival (PFS), overall survival (OS), overall response rate (ORR) evaluated per iwCLL 2008 criteria, and safety. Results With a median follow-up of 9.6 years (ibrutinib) and 5.6 years (chlorambucil), median PFS was significantly longer (hazard ratio [HR], 0.16; 95% CI, 0.11–0.22; P<0.0001) for ibrutinib (8.9 years, 95% CI, 7.0–NE) versus chlorambucil (1.3 years, 95% CI, 0.9–1.6), regardless of age, sex, race, Rai stage, Eastern Cooperative Oncology Group performance status, or high-risk mutational status (mutated TP53/unmutated IGHV/del[11q]; HR, 0.09; 95% CI, 0.05–0.15; P<0.0001). At 9 years, the PFS rate was 49.7% (95% CI, 40.2–58.4) in the ibrutinib arm and 4.4% (95% CI, 1.1–11.5) in the chlorambucil arm. Median OS with ibrutinib was not estimable; the 9-year OS rate was 68%. ORR and complete response (CR/CRi) rates for ibrutinib (91% and 36%, respectively) remained unchanged with this follow-up. Rates of hypertension in the ibrutinib arm during years 8–9 and 9–10 were 28% and 26%, respectively, and 8% and 9% for atrial fibrillation, respectively. During the entire study period, 25% and 33% and of patients receiving ibrutinib had any grade AEs leading to dose reduction and discontinuation, respectively. Following dose reduction, 82% of patients had all AEs resolved. At study completion, 27% of patients remained on ibrutinib, with a median duration of treatment of 6.2 years (range, 0.06–10.2). Conclusion: This final analysis of the landmark RESONATE-2 study defines median PFS and demonstrates sustained OS benefit of continuous single-agent first-line ibrutinib treatment for patients with CLL/SLL, including those with high-risk genomic features. Funding Pharmacyclics LLC, an AbbVie company