Abstract Acalabrutinib is a covalent Bruton tyrosine kinase inhibitor. In the phase 2 ACE-WM-001 trial, at 27.4-month median follow-up, acalabrutinib yielded durable responses in patients with treatment-naive (TN) or relapsed/refractory (R/R) Waldenström macroglobulinemia (WM). We report WM-001 results at 63.7-month median follow-up. Overall, 106 patients (TN, n = 14; R/R, n = 92) were treated; 52.8% discontinued treatment (TN, n = 7; R/R, n = 49), most commonly because of disease progression (19.8%; TN, n = 1; R/R, n = 20) and adverse events (AEs; 17.9%; TN, n = 4; R/R, n = 15). Overall response rates were 92.9% and 94.6%, and major response rates (partial response or better) were 78.6% and 81.5% in the TN and R/R cohorts, respectively. Median progression-free survival (PFS) was not estimable (NE; 95% confidence interval, 19.3 to NE) and 67.5 months (53.3 to NE), with estimated 66-month PFS rates of 83.6% (48.0-95.7) and 52.0% (39.3-63.2) in the TN and R/R cohorts, respectively. Median duration of response (DOR) was not reached (NR) (11.9 months to NE) and 64.7 months (54.5 to NE), with estimated 66-month DOR rates of 90.0% (47.3-98.5) and 44.8% (27.1-61.1) in the TN and R/R cohorts, respectively. Median overall survival (OS) was NR in both cohorts; estimated 66-month OS rates were 90.9% (50.8-98.7) and 71.2% (60.3-79.6), respectively. Cardiac events of clinical interest occurred in 22 (20.8%) patients. One grade 5 AE (intracranial hematoma) was considered treatment related. With 5 years of follow-up, the efficacy and safety of acalabrutinib in WM were maintained. This trial was registered at www.clinicaltrials.gov as NCT02180724.

Introduction: MCL is a rare B-cell non-Hodgkin lymphoma typically treated with first-line (1L) chemoimmunotherapy (CIT). While Bruton tyrosine kinase inhibitors (BTKis) are approved in CIT combinations in TN MCL, novel 1L chemotherapy-free BTKi combinations are of interest. The phase 1b ACE-LY-106 study supported development of acalabrutinib, venetoclax, and rituximab (AVR) in patients (pts) with TN MCL (Wang et al. Blood Adv. 2024;8:4539-48). We report preliminary AVR efficacy and safety in TN MCL in the ongoing, open-label, phase 2 TrAVeRse study (NCT05951959). Methods: Pts were aged ≥18 y with TN MCL requiring treatment (tx), radiologically measurable disease, sufficient tissue for baseline clone detection for minimal residual disease (MRD) testing (clonoSEQ), and ECOG PS 0‒2 (or 3 if due to MCL). Pts received AVR induction (1 cycle [C] = 28 d): A (100 mg BID, C1‒C13 [+ C14 post induction]), V (C2‒C13, escalating during C2 [20 mg up to 400 mg daily]), and R (375 mg/m2 on day [D] 1 of C1‒12). Primary endpoint was MRD-negative (MRD-neg) complete response (CR) rate (MRD-neg in peripheral blood by next-generation sequencing [10-5; clonoSEQ], CR by 2014 Lugano criteria) at end of AVR induction (C13). Pts with MRD-neg CR at end of C13 were randomized 1:1 at C15D1 to continued A monotherapy until progressive disease (PD) or observation until PD with the option to restart A at relapse. Results: In total, 108 pts were enrolled and treated in 7 countries (January–July 2024). Median age was 69 y (range 40–89) with 74.1% male and 87.0% White. Stage IV disease (90.7%), extranodal disease (93.5%), and marrow involvement (84.3%) were common. TP53 was mutated (TP53m) in 19.1% of pts (17/89 with available TP53), 30.6% had high-risk simplified MIPI score, 8.3% had blastoid/pleomorphic histology, and 38.0% had Ki-67 ≥30%. At data cutoff (DCO; March 31, 2025 [14 mo after 1st pt treated]), response assessments were completed by 106 (98.1%) pts at C4D1, 100 (92.6%) at C7D1, 93 (86.1%) at C10D1, and 12 (11.1%) at C14D1 (end of AVR induction). Median follow-up was 10.5 mo (range 1–14); 102 (94.4%) pts remained on study, and 93 (86.1%) remained on tx. Median tx duration was 10.1 mo (range 1‒14). Fifteen pts (13.9%) discontinued ≥1 study drug; 11 (10.4%) discontinued all txs (AE, n=5; PD, n=4; pt decision, n=1; investigator decision, n=1). Four pts died (PD, n=3; AE, n=1). At DCO, all 12 pts who had completed end of AVR induction response assessments achieved MRD-neg CR per Lugano criteria (primary endpoint). At time of DCO (most pts still on AVR induction), overall response rate was 95.4% (103/108); CR rates were 53.7% (58/108 per Lugano) and 63.0% (68/108 per PET-CT). Overall, 95.4% (103/108) achieved MRD-neg, including 76.9% (83/108) and 88.0% (95/108) at end of C3 and C6, respectively. Estimated 6-mo progression-free survival, overall survival, and duration of response rates were 97.1%, 98.1%, and 98.0%, respectively. Among the 17 pts with TP53m, 15 (88.2%) achieved objective response, 11 (64.7%) achieved CR, and 16 (94.1%) achieved MRD-neg any time during AVR induction; all 3 (100%) pts with TP53m who reached end of C13 achieved MRD-neg CR. Tx-emergent AEs (TEAEs; AVR induction + C14) in ≥30% of pts were diarrhea (45.4%), headache (41.7%), and neutropenia (38.9%). G≥3 TEAEs occurred in 63 (58.3%) pts, most commonly (≥5 pts) neutropenia (n=29; 26.9%), pneumonia (n=8; 7.4%), neutrophil count decreased (n=7; 6.5%), and thrombocytopenia (n=6; 5.6%). Serious TEAEs occurred in 33 (30.6%) pts, most commonly (≥2 pts) pneumonia (n=6; 5.6%), febrile neutropenia (n=4; 3.7%), and fungal pneumonia, neutropenic sepsis, sepsis, and pyrexia (n=2 each; 1.9%). TEAEs led to death in 1 pt (non-small cell lung cancer). Tumor lysis syndrome (G2) was reported in 1 pt. Atrial fibrillation/flutter was reported in 3 pts (G1, n=1; G2, n=1; G3, n=1); ventricular arrhythmia (extrasystole) was reported in 1 pt (G2).Conclusion: At this early DCO in pts with TN MCL, with most pts yet to complete induction tx, AVR demonstrated rapid, deep responses, with high CR and MRD negativity rates overall and in pts with TP53m. Among pts who completed AVR induction, all achieved MRD-neg CR. AVR had an acceptable toxicity profile. At the time of submission, 73 (97.3%) of the 75 pts who have reached C15D1 achieved MRD-neg CR per PET-CT. Further update of fully validated results when all pts are expected to have completed AVR induction will be presented.

Background ENRICH is the first randomised open-label phase II/III trial comparing Ibrutinib plus rituximab (IR) with Rituximab-chemotherapy (R-chemo, clinician choice of RCHOP or Bendamustine plus rituximab (BR)), each followed by maintenance rituximab (MR) for two years. IR was superior to R-chemo with respect to progression-free survival (PFS), with an adjusted hazard ratio (HR) of 0.69 (95% CI, 0.52–0.90; p = 0.003). However, there was little evidence of a difference between IR and BR (HR 0.91; 95% CI, 0.66–1.25). In contrast, IR demonstrated a substantial benefit vs RCHOP (HR 0.37; 95% CI, 0.22–0.62). This could reflect differences in patient (pt) characteristics between the choice groups or a difference in efficacy between the selected chemotherapy regimens (BR vs RCHOP). BR has been shown to be superior to RCHOP in randomised studies (eg Rummel et al, Lancet, 2013) but these studies were performed without MR, and the benefit for MR has previously been demonstrated post RCHOP but, not BR, in a trial setting. No study thus far has compared BR with RCHOP with routine MR in both arms. This analysis presents an indirect comparison between BR and RCHOP with both arms receiving MR, using data from the ENRICH trial. By allowing physician choice of chemotherapy (BR or RCHOP), the trial design enabled a comparison between BR and RCHOP with IR serving as a common comparator. Methods Pts ≥60 years with untreated, stage II-IV MCL were recruited into ENRICH. Pre-randomisation, clinician choice of chemotherapy (BR or RCHOP) was determined; this choice was the treatment administered if the pt was randomised to the control arm. Pts were then randomised to receive either IR or R-chemo, stratified by chemotherapy choice. Treatment consisted of 6-8 cycles of chemotherapy or daily ibrutinib, both combined with rituximab administered according to the chemotherapy schedule. All participants received MR for two years, and intervention participants continued daily ibrutinib until disease progression or unacceptable toxicity. A planned secondary analysis of the ENRICH trial data evaluated PFS between the control arm chemotherapies of BR and RCHOP using the common comparator, IR. A Cox proportional hazards model adjusted for the pre-randomisation choice of chemotherapy type and allocated treatment group was used to determine the HR and 95% CI of RCHOP/BR. Results 397 pts from the UK and Nordic countries were recruited to ENRICH, of which 270 had the pre-randomisation choice of BR and 107 RCHOP. Pts were randomised to receive IR (n=199) or R-chemo(n=198, n=145 BR and n=53 RCHOP). Pt characteristics were strikingly similar across the choice of chemotherapy and across allocated treatment arms (BR vs RCHOP: median age 74 vs 72 years, high risk MIPI 59% vs 52%, Ki67>30% 44% vs 49%, blastoid morphology 8% vs 6%, TP53 mutation 26% vs 19%). However, the choice of RCHOP differed between countries, with 37.8% (99/262) of UK pts having the pre-randomisation chemotherapy choice of RCHOP compared to just 5.9% (8/135) of patients in the Nordic countries. The 5-year PFS probability for those treated with BR was 47.4% (95% CI 39.5% to 56.9%), R-CHOP was 19.2% (95% CI 10.6% to 35.1%), and IR was 51.1% (95% CI 44.2% to 59.2%). The analysis of PFS showed the adjusted HR for R-CHOP/BR was 2.41 (95% CI 1.33 to 4.37). The adjusted HR for Overall Survival was 1.59 (95% CI 0.81 - 3.11) for RCHOP/BR. Grade>= 3 (G3) adverse events (AE)s were more common in RCHOP treated patients; 35/52 (67%) experienced at least one G3 AE vs 73/143 (51%) for BR. Neutropenic sepsis was more common in RCHOP treated patients at 15% vs 1% in BR during induction. During maintenance, G3 AEs were more experienced by 44/143 (31%) of BR patients vs 11/52 (21%) of RCHOP patients. G3 Infections including COVID-19 were experienced by 10/143 (7%) of BR patients during maintenance compared with 1/52 (2%) of RCHOP patients. Conclusions ENRICH is the first study with BR and RCHOP in the first line treatment of MCL with the routine use of MR in both arms. Whilst the comparison of BR vs RCHOP was not randomised, the two groups were well matched and an adjusted analysis demonstrated a PFS benefit in favour of BR over R-CHOP, with more G3 AEs in RCHOP patients, and a trend for an improved OS in BR treated patients.

BACKGROUND:Ibrutinib, a Bruton tyrosine kinase inhibitor, prolongs progression-free survival when added to immunochemotherapy as first line treatment. The ENRICH trial compared the chemotherapy-free combination of ibrutinib and the anti-CD20 antibody rituximab (ibrutinib-rituximab) with standard immunochemotherapy (R-CHOP [rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisolone] or bendamustine-rituximab) in patients 60 years and older with untreated mantle-cell lymphoma. METHODS:This randomised, open-label, phase 2/3 superiority trial was performed at 66 sites in the UK, Sweden, Norway, Finland, and Denmark. Patients 60 years and older with untreated mantle-cell lymphoma (Ann-Arbor stage II-IV disease, an Eastern Cooperative Oncology Group performance-status score of 0-2) were randomly assigned to receive either rituximab plus immunochemotherapy or ibrutinib-rituximab in a 1:1 ratio, stratified by investigator choice of immunochemotherapy. Patients randomly allocated to the ibrutinib-rituximab (intervention) group received 560 mg oral ibrutinib daily in combination with six to eight cycles of 375 mg/m2 intravenous rituximab on day 1 of each cycle in the matched schedule of the pre-randomisation choice of immunochemotherapy (every 21 days for R-CHOP or every 28 days for rituximab-bendamustine). R-CHOP comprised 750 mg/m2 of cyclophosphamide, 50 mg/m2 of doxorubicin, and 1·4 mg/m2 vincristine on day 1 of each 21-day cycle, with 100 mg prednisolone on days 1-5 of each cycle. Rituximab-bendamustine comprised 90 mg/m2 of bendamustine on days 1 and 2 of each cycle, in combination with 375 mg/m2 rituximab on day 1 of each cycle. All responding patients in both groups at the end of induction received maintenance rituximab administered every 8 weeks for 2 years, and patients allocated to the intervention group continued ibrutinib until disease progression or unacceptable toxicity. The primary outcome was investigator-assessed progression-free survival, stratified by immunochemotherapy choice and analysed in the intention-to-treat population. The trial was registered with EudraCT (2015-000832-13) and is closed for recruitment. FINDINGS:Between Feb 15, 2016, and June 30, 2021, 397 patients were randomly allocated to immunochemotherapy (control) or ibrutinib-rituximab (intervention). Of the 397, 107 (27%) were pre-allocated to the immunochemotherapy choice of R-CHOP and 290 (73%) were pre-allocated to rituximab-bendamustine. In total, 198 were allocated to the control group (53 to R-CHOP and 145 to bendamustine-rituximab) and 199 were allocated to intervention. The median age was 74 years (IQR 70-77) for the intervention group and 74 years (70-78) in the control group. 296 patients (75%) were male and 101 patients (25%) were female; ethnicity data were not collected. At a median follow-up of 47·9 months, the median progression-free survival of ibrutinib-rituximab was superior to immunochemotherapy, with an adjusted hazard ratio (HR) of 0·69 (95% CI 0·52-0·90); p=0·0034. For those with pre-randomisation choice R-CHOP, the HR was 0·37 (0·22-0·62), and with bendamustine-rituximab, the HR was 0·91 (0·66-1·25). Across induction and maintenance, 67% of patients assigned to ibrutinib-rituximab and 70% of patients receiving immunotherapy reported grade 3 or above adverse events. INTERPRETATION:To our knowledge, this is the first randomised trial in untreated mantle-cell lymphoma to demonstrate significant improvement in progression-free survival for ibrutinib-rituximab compared to immunochemotherapy. This study suggests that ibrutinib-rituximab should be considered a new standard of care option for first-line treatment of older patients with mantle-cell lymphoma. FUNDING:Cancer Research UK (C7627/A17938) and Johnson and Johnson Pharmaceuticals.

Introduction ENRICH compared Ibrutinib + Rituximab (IR) with immunochemotherapy (R-CHEMO) as first line treatments for mantle cell lymphoma (MCL) in older people. A key secondary outcome was quality of life (QOL), measured using the EORTC QLQ-C30 (QLQ-C30), a patient-reported outcome measure (PROM) used widely in cancer clinical trials. PROMs have fixed and restricted measurement ranges. These can constrain the magnitude of observed changes when samples are not well aligned to PROMs. We demonstrate, using ENRICH study QLQ-C30 physical functioning subscale (PF-5) data, that the PF-5 constrained measurement. When this constraint was reduced, remarkably different results were found. Patients and methods People aged ≥60ys with untreated, stage II-IV MCL were randomised to IR or R-CHEMO. The treatment arms were 6-8 cycles of chemotherapy or daily Ibrutinib. Both arms received Rituximab; 6-8 cycles then maintenance for 2ys. Ibrutinib participants continued daily treatment until disease progression or unacceptable toxicity. QLQ-C30 data were collected at baseline (BL), end of treatment (EOT) and end of maintenance (EOM). PF-5 data were analysed using the modern psychometric method Rasch measurement theory (RMT). Unlike conventional PROM data analyses, RMT provides forensic, context-specific information enabling measurement problems to be diagnosed and managed. Specifically, changes in PF-5 physical functioning estimates from BL to EOT in the total sample (TS), where measurement of many people was constrained (see below), were compared with changes in the subset of people whose physical functioning measurement was unconstrained (UC sample). PF-5 changes were compared at the group-level (p-values from paired samples t-tests, effect sizes [ES]) and individual-level (percent of sample with a significant improvement in PF-5 estimate, SI%). Results ENRICH randomized 397 patients (IR=199; R-CHEMO=198). QLQ-C30 data were available for n=376 at BL, and n=297 at BL and EOT. In the people with data at BL and EOT (TS; n=297), PF-5's measurement range was poorly aligned to the BL physical functioning of ENRICH participants. The distribution of PF-5 estimates was artificially skewed, and the ceiling effect was 30%, indicating constrained measurement as many people could not improve their PF-5 estimate. Only n=151 (50.8%) participants had unconstrained measurement as they could have a significant change from their BL estimate (UC sample) The group-level and individual-level changes for the two treatment arms, in the TS and UC samples are below. They show: A) group level changes were statistically and clinically trivial in the total sample, but significant in the UC sample. B) more individuals had significant changes in NC than TS sample. C) IR was superior to R-CHEMO, albeit not significantly. R-CHEMO [p (ES), SI%] TS: p=0.816, ES=-0.02, SI%=4.3%; UC: p=0.026, ES=0.25, SI%=7.4%. I-R [p (ES), SI%] TS: p=0.111, ES=0.13, SI%=8.3%; UC: p=<0.001, ES=0.43, SI%=17.1%. The Fatigue and Global Health Status QLQ-C30 subscales were also examined fully. The same pattern of results was found. The other six multi-item QLQ-30C subscales were examined partially. All had evidence of constrained measurement implying the same pattern of results would be found. Conclusion ENRICH was associated with statistically and clinically significant gains in QoL that conventional total sample analyses underestimated and misrepresented. IR was consistently superior to R-CHEMO. Results imply clinical trial PROM data should be examined pro-actively for constrained measurement. This supports the routine use of modern psychometric methods like RMT, to better capture patient-perceived benefits. .

PURPOSE:The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS:Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m2 once daily; days 1 and 2) and rituximab (375 mg/m2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS:In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION:The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Introduction: Mantle cell lymphoma (MCL) comprises 5-6% of NHL and has heterogenous clinical outcomes. There is growing recognition of an indolent subtype which current prognostic scores may not represent. [18F]FDG PET/CT (PET) has prognostic value for many lymphoma subtypes. In particular, metabolic tumour volume (MTV) combining disease dissemination and proliferation, has emerged as an independent risk factor for progression free survival (PFS) and overall survival (OS) in other lymphoma types. PET can upstage MCL at diagnosis and is recommended in response assessment. There is conflicting evidence to support the prognostic role of radiomics in MCL, chiefly from retrospective series of aggressive disease. Method: The MCL Biobank Observational Study prospectively enrolled untreated MCL patients >16 years (y) old from 73 sites across the UK from 2014-19. Baseline characteristics, tissue samples, clinician assigned grouping: active monitoring (AM) or active treatment (AT), treatment and survival outcomes were collected. This study specifically investigates the prognostic role of PET in the MCL biobank cohort. PET were centrally reviewed using MIM (v7.3.4) semi-automated Lesion ID and source data. SUVmax, MTV and Total Lesion Glycolysis (TLG) were recorded by PERCIST criteria. Data was log-transformed. Medians of SUVmax, MTV and TLG were studied further. Lesions < PERCIST were recorded as 0. Baseline demographics were compared using Pearson correlation (r), Chi-Square and Two-sided t-tests. Outcomes of time to first treatment (TTT), time to next treatment or death (TTNTD) and OS were assessed against radiomics by Kaplan Meier log-rank (KM), Cox regression, and Fine-Gray (FG). Competing risks were non-MCL deaths. Proportional hazards assumption was checked and met for all reported CR; log-log plots were assessed for FG. Results: 588 patients were recruited. Median follow-up was 5.2y. Baseline PET scans were obtained for 150/588. Median time from diagnosis to PET was 13 days (-110 to +67). All had PET avid disease, with wide variation in radiomics. Median PERCIST (liver/MBP)=3.9. Within the PET cohort, 45 underwent AM; 105 had AT (akin to the non-PET cohort). AM v AT differed in: B symptoms (29% v 47%, p=0.04), anaemia (38% v 59% p=0.02), high LDH (17% v 39% p=0.01), splenic involvement (29% v 66% p<0.01) stage (stage I 13% v 4%, stage IV 56% v 78% p<0.05) and Ki67 <30% (89% v 53%, p=0.001). There was no difference in MIPI groupings. SUVmax distribution about the median (8.45) was equal (IQR 6.57). AM had a significantly lower median MTV (11.03, IQR 43.8) v AT (139.24, IQR 726.05). Correlations between radiomics and Ki67% or MIPI were weak. Within the PET cohort, MTV above the median was associated with immediate treatment (TTT <90d = 88% v 58%, p<0.001) and successive treatment lines (23% v 11%, p<0.05). 49% of deaths were non-MCL related. 139/150 received treatment: within AM = 34/45, median TTT 701d; within AT = 105/105, median TTT of 33d. Higher MTV predicts inferior outcomes. Median TTT for high MTV was 34d v low 85d, respectively, (95% confidence interval (95%CI) 27-41d v 0-258d, p<0.01), FG Sub-distribution hazard ratio (SHR) 2.4, (95%CI 1.6-3.4, p<0.001). Median TTNTD was 5y v Not Reached, p=0.047, SHR 2.3, (1.1-5, p=0.04). 5y OS was 48% v 60%, p=0.07, disease specific survival (DSS) SHR 3.1 (1.4-7, p<0.01). TLG results were similar. Within the AM subgroup, higher MTV and TLG trended towards significance for shorter TTT: median TTT for high MTV was 511d v low 805d, p=0.5. Only 7/34 had 2nd line treatment. Radiomics did not correlate with TTNTD, DSS or OS. Differences in SUVmax high/low were not significantly associated with disease outcomes. Discussion: This study of unselected, untreated patients confirms the prognostic role of baseline PET in MCL. Higher MTV is predictive of shorter TTT and inferior TTNTD and OS, and a need for successive treatment lines. Patients assigned to AM were characterised by lower MTV which could potentially aid clinicians to identify patients appropriate for AM at diagnosis. This warrants further study, especially within the more indolent subset where limited patient numbers and MCL events likely precluded significant results. High SUVmax has been postulated to correlate with aggressive disease. We found no significant correlation between SUVmax and disease outcomes. Censoring competing risks had a significant impact on “p” values reflecting the specificity of PET for MCL, and a highly comorbid group.

Objective In the absence of head-to-head clinical trials, matching-adjusted indirect comparison (MAIC) was used to compare two Bruton tyrosine kinase inhibitors (BTKis) approved for the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL). This analysis compares the efficacy and safety of acalabrutinib versus ibrutinib using a more mature dataset than a previously published MAIC. Methods Individual patient data from 122 patients treated with acalabrutinib in a phase 2 study were weighted to match aggregate baseline characteristics of patients pooled from three separate trials of ibrutinib. Patients were matched on Eastern Cooperative Oncology Group performance status, simplified Mantle Cell Lymphoma International Prognostic Index, lactate dehydrogenase, prior lines of therapy, tumor burden, and blastoid histology. Outcomes assessed included progression-free survival (PFS), overall survival (OS), and adverse events. Results After matching, differences in PFS between acalabrutinib (median = 17.8 months) and ibrutinib (median = 12.8 months) were not statistically significant (hazard ratio [HR] = 0.92; 95% confidence interval [CI] = 0.74-1.15; p = 0.48). Similarly, after matching, OS differences between acalabrutinib (median = 36.5 months) and ibrutinib (median = 27.9 months) did not reach statistical significance (HR = 0.87; 95% CI = 0.64-1.17; p = 0.35). Acalabrutinib was associated with an improved safety profile compared with ibrutinib, with statistically significantly lower rates of grade >= 3 atrial fibrillation and thrombocytopenia. Conclusions This comparison of two BTKis used in the treatment of R/R MCL showed that PFS and OS risk was not statistically different between the treatments; however, acalabrutinib had an improved safety profile compared with ibrutinib.

Chronic lymphocytic leukemia (CLL) progression during Bruton tyrosine kinase (BTK) inhibitor treatment is typically characterized by emergent B-cell receptor pathway mutations. Using peripheral blood samples from relapsed/refractory CLL patients in ELEVATE-RR (NCT02477696) (median 2 prior therapies), we report clonal evolution data for patients progressing on acalabrutinib or ibrutinib (median follow-up 41 months). Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) acalabrutinib-treated and 30 (excluding 6 Richter) ibrutinib-treated patients. At progression, emergent BTK mutations were observed in 31 (66%) acalabrutinib-treated and 11 (37%) ibrutinib-treated patients (median variant allele fraction [VAF]: 16.1% vs 15.6%). BTK C481S mutations were most common in both groups; T474I (n = 9; 8 co-occurring with C481) and the novel E41V mutation within the pleckstrin homology domain of BTK (n = 1) occurred with acalabrutinib, while neither mutation occurred with ibrutinib. L528W and A428D co-mutations presented in one ibrutinib-treated patient. Pre-existing TP53 mutations were present in 25 (53.2%) acalabrutinib-treated and 16 (53.3%) ibrutinib-treated patients at screening. Emergent TP53 mutations occurred with acalabrutinib and ibrutinib (13% vs 7%; median VAF: 6.0% vs 37.3%, respectively). Six acalabrutinib-treated patients and one ibrutinib-treated patient had emergent TP53/BTK co-mutations. Emergent PLCG2 mutations occurred in 3 (6%) acalabrutinib-treated and 6 (20%) ibrutinib-treated patients. One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK/PLCG2 co-mutations. While common BTK C481 mutations were observed with both treatments, patterns of mutation and co-mutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W, A428D) in this patient population.

Introduction: Current standard of care approaches for older patients with untreated mantle cell lymphoma (MCL) are rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) or Bendamustine-rituximab (BR) followed by maintenance rituximab (MR). The addition of the Bruton tyrosine kinase inhibitors (BTKis) ibrutinib and acalabrutinib to chemotherapy improve progression-free survival (PFS) versus BR, but the use of a first-line ibrutinib (+/- rituximab) (IR) has not been prospectively compared to immunochemotherapy. ENRICH is the first randomised open-label phase II/III trial comparing IR with R-chemotherapy (clinician choice of R-CHOP or BR, R-chemo), each with MR. Patients & methods: Patients>=60 years (ys) with untreated, stage II-IV MCL were randomised to IR or R-chemo, stratified by clinician choice of BR or R-CHOP. Baseline tumour biopsies were collected for molecular analysis. Treatment consisted of 6-8 cycles of chemotherapy or daily ibrutinib, both in combination with 6-8 cycles of rituximab in the schedule of pre-randomisation choice of chemotherapy. MR was given in both arms for 2 ys and intervention participants continued daily ibrutinib until disease progression or unacceptable toxicity. The primary outcome was PFS, analysed with a test of superiority at the 2.5% level from a Cox proportional hazards model, stratified by choice of chemotherapy. Results: Between December 2015 and June 2021, 397 patients were randomised to IR (n=199) and R-chemo (n=198; R-CHOP n=53, BR n=145) from 65 United Kingdom and Nordic sites. Median age was 74 years, 74.6% were male, 94.5% had ECOG 0-1, 56.5% had high-risk MIPI score, and 6.4% had blastoid MCL. Baseline characteristics were well balanced between treatment arms and choice of R-chemo. The median follow-up was 47.9 months. The PFS with IR was superior to R-chemo, with a hazard ratio (HR) of 0.69, (95% CI 0.52-0.90, p=0.003), median PFS 65.3 vs 42.4 months, respectively. There were 94/199 (47.2%) PFS events in the IR arm compared to 121/198 (61.1%) in the R-chemo arm, of which 49 (52.1%) and 77 (63.6%) were progressive disease, respectively. There was a significant interaction (p=0.004) between choice of chemotherapy and treatment effect. For the pre-randomisation choice R-CHOP subgroup, the HR = 0.37 (95% CI 0.22-0.62), median PFS NR vs 26.6 mo. For the subgroup with selection BR, the HR = 0.91 (95% CI 0.66-1.25), median PFS 65.3 vs 50.5 mo. The 5 y Overall Survival (OS) for IR is 57.7% compared to 54.5% for R-Chemo, HR = 0.87 (95% CI 0.64-1.18). For the pre-randomisation choice R-CHOP subgroup, the HR = 0.64 (95% CI 0.36-1.13), 5 year OS probability 59.4% vs 46.3%, for IR and R-CHOP, respectively. For the subgroup with selection BR, the HR = 1.00 (0.70, 1.44), 5 year OS probability 57.2% vs 58.1%, for IR and BR, respectively. Across the treatment and maintenance phases, 61.1%, 51.9% and 51.7% of the IR, R-CHOP and BR participants reported grade ≥3 non-haematological adverse events (AEs), respectively. Grade≥3 haematological AEs were reported in 16.7%, 50.0% and 33.6%, respectively. Grade≥3 atrial fibrillation was reported in 6.6% of IR and 0.5% of R-chemo participants. Quality of life (EORTC QLQ-C30) at mid-treatment was higher for the IR arm compared to R-chemo, median (IQR) 91 (84, 95) and 85 (76, 92), respectively. COVID-19 accounted for 19 deaths in the IR arm and 14 deaths in R-Chemo (2 R-CHOP, 12 BR), these events contributed to 16 PFS events in the IR arm (17.0%) and 10 in the R-chemo arm (8.3%) (2/44 (4.5%) for R-CHOP and 8/77 (10.4%) for BR). A PFS sensitivity analysis censoring at COVID-19 death did not alter the primary analysis conclusions. Conclusions: With a median follow up of 47.9 months, ENRICH is the first randomised trial to demonstrate a significant improvement in PFS for IR compared to R-chemo. When PFS was analysed by choice of chemotherapy IR was superior to R-CHOP, and comparable to BR despite more Covid-19 events in the IR arm. Haematological toxicity was lower with IR, and quality of life scores were improved at mid-treatment. IR is the first non-chemotherapy approach to demonstrate superiority over R-chemotherapy and should be considered a standard of care for first-line treatment for older patients with MCL. Further data on high-risk subgroups including those with TP53 mutation will be presented.

Background Novel treatments for Mantle Cell Lymphoma (MCL) have led to improvements in overall survival (OS). Despite this MCL remains incurable; almost all patients will relapse and require multiple lines of treatment. There is a paucity of prospective, real-world data characterising the outcome of relapsed MCL patients following subsequent treatment lines. Methods The MCL Biobank Observational study is a prospective study with all patients over the age of 16 years with newly diagnosed MCL being eligible. Recruitment was open across 73 UK sites between October 2014-19. Patients were enrolled prior to receiving systemic therapy with no specific exclusion criteria. Baseline characteristics were collected. The primary outcome measure was time to treatment (TTT). Data was collected on treatment choice and date of treatment lines. OS and TTT/death were assessed using the Kaplan Meier method. Prespecified subgroup analysis was performed on patients by age group: < 65, 65-80 and > 80 years. Event free survival (EFS) was defined as TTNT/death following the initiation of each line of therapy. POD24 was defined as POD within 24 months of commencement of 1L therapy. The log-rank test was used to compare survival between subgroups. Results A total of 588 patients were recruited. Median follow up is 5.7 years. The median age was 70 years (range 30-93), 72% were male. 497 (84.1%) had stage III/IV disease and simplified MIPI was low, intermediate and high in 112 (20%), 227 (41%) and 220 (39%) respectively. 507 (86.2%) patients were treated at a median TTT of 1.4 months (range:0-80). 507 received first line (1L) treatment, 149 (29.4%) received second line (2L), 33 (6.5%) received third line, 9 (1.8%) received fourth line, 2 (0.4%) received over 4 lines of treatment. 120 (23.8%) patients received a line of treatment within clinical trial. 6 (1.0%) underwent allogeneic stem cell transplantation. The median OS and EFS after 1L treatment was 69.5 and 46.0 months (mo) respectively. POD 24 (n=102) was associated with shorter OS (P=<0.001, med. OS 25.3 vs 70.1 mo) and shorter EFS following 2L treatment (P=0.02, 9.8 vs 24.3 mo). 127 (25.0%) patients died after 1L treatment with no 2L treatment; 54 (42.5%) died of lymphoma and 67 (52.8%) died of other causes (cause unknown n=6). Following 2L treatment median OS and EFS was 20.3 and 15.0 mo respectively. 75 (50.3%) patients died with no 3L treatment; 54 (72%) died of lymphoma and 13 (17.3%) died of other causes (unknown n=8). Following 3L treatment median OS and EFS was 6.7 and 6.7 mo respectively and 4.5 and 2.6 mo following 4L treatment. Age <65 years was associated with a longer OS and EFS after 1L treatment but not after subsequent lines. Choice of 1L treatment had a significant effect on OS (P=<0.01). The most frequent 1L treatments were NORDIC (24.9%), Bendamustine containing regimes (23.9%) (R-Bendamustine n=95.0%), R-CHOP (20.0%) and BTKi containing regimens (16.4%). Median OS was 69.1 mo in patients receiving BTKi containing regimes, 48.0 mo in Bendamustine containing regimens (R-Bendamustine=95.0%), 52.1 mo with R-CHOP. Median OS was not reached in patients receiving NORDIC or high dose cytarabine containing regimens. Of patients receiving NORDIC 1L 78 (61.9%) underwent autologous stem cell transplant. The most frequent 2L treatment was a BTKi alone or in combination with rituximab (n=119, 79.9%). Amongst patients receiving 2L treatment following 1L BTKi (n=15), EFS was 10.5 mo (46.7%=RBAC, 26.7%=RCHOP, 3.3%=R-Bendamustine, 6.7%=Bendamustine and 6.7%=RDHAP). In January 2021 CART for MCL was approved as 3L treatment in the UK following chemotherapy and Ibrutinib. Of 11 patients that relapsed following two prior lines of treatment from this time, four (36.4%) had CART as 3 or 4L treatment. Conclusion This prospective analysis confirms a progressive reduction in survival and response with successive treatment lines for relapsed MCL. This patient-level longitudinal follow up highlights the need to optimise 1L treatment. Advancing age impacts OS and TTNT/death following 1L treatment. Time to POD from 1L treatment was associated with OS. RBAC was the most common 2L treatment following 1L BTKi.

This analysis investigated the incidence of sudden deaths (SDs) and non-fatal and fatal ventricular arrhythmias (VAs) in five acalabrutinib clinical trials. In total, 1299 patients received acalabrutinib (exposure, 4568.4 patient-years). Sixteen (1.2%) patients experienced SD or VA (event rate, 0.350/100 patient-years). Non-fatal VAs occurred in 11 (0.8%) patients, nine (0.7%) of whom had premature ventricular contractions only. SD and fatal VAs occurred in five (0.4%) patients (event rate, 0.109/100 patient-years; median time to event: 46.2 months). SDs and VAs with acalabrutinib occurred at low rates, and there are insufficient data to point to an increased risk of SD or VA with acalabrutinib.

Background: With the advances made in novel anti-cancer therapies, Chronic Lymphocytic Leukemia (CLL) patient remission rates have significantly improved over the years. Minimal or measurable residual disease (MRD) is emerging as an independent predictor of progression-free survival (PFS) and overall survival (OS) in several heme indications and has been proposed as a potential surrogate endpoint for long term CLL survival in clinical trials. While next generation sequencing (NGS) methods are emerging for establishing MRD measurements in CLL, flow cytometry remains as an option of choice for measuring MRD in CLL. Methods: In order to assess MRD in CLL patients using flow cytometry, Labcorp Biopharma Services validated a CLL MRD assay that was initially developed by the European Research Initiative on CLL (ERIC) (Rawstron et al, 2013). Assay validation was performed in several Labcorp central laboratories across the globe using bone marrow and whole blood samples from both healthy donors and CLL patients, characterizing precision performance, sample stability and B CLL cells assay sensitivity. This validated assay has been utilized in several clinical studies including ELEVATE- TN (NCT02475681; Sharman JP, 2020) as part of exploratory endpoints with 10-4 cut-off. Results: Validation of this assay demonstrated good performance for critical reportable measurement CLL B cells with a lower limit of quantitation (LLOQ) of 0.009%/of total nucleated cells (TNC) and 0.008% of TNC for whole blood and bone marrow respectively and when target total events is set at 2x106 cells in total. Using a similar setup, we also demonstrated an ambient specimen stability for CLL B cells of 72 hours for whole blood samples and 48 hours for bone marrow samples. Precision performance for repeatability and reproducibility for both matrices was below ≤10% CV, confirming high readout precision and suitability of the assay for implementation in multi-centric clinical trials. As part of the exploratory endpoints from the ELEVATE- TN study, peripheral blood samples were collected from patients in complete remission (CR) or complete remission with incomplete count recovery (CRi). Patients with CR or CRi in the acalabrutinib-obinutuzumab arm achieved higher rates of undetectable MRD (uMRD) in peripheral blood samples vs patients with CR or CRi receiving acalabrutinib monotherapy and chlorambucil-obinutuzumab (40.9% vs 8.8% and 8.3%, respectively). Conclusions: Validated six- color flow cytometry CLL- MRD assay is a robust test that has been successfully implemented (exploratory) and proven useful for global clinical studies, as demonstrated by clinical results obtained in ELEVATE-TN study. This flow cytometry assay is being implemented in several global clinical studies as an endpoint (secondary) including in an ongoing phase 3 study AMPLIFY (ACE-CL-311; NCT03836261).

Introduction: The primary analysis of the phase 3 ECHO trial (NCT02972840) demonstrated that acalabrutinib plus bendamustine-rituximab (ABR) significantly improved progression-free survival (PFS) vs placebo plus bendamustine-rituximab (PBR) in older patients (pts) with previously untreated mantle cell lymphoma (MCL) (Wang et al. EHA 2024, Abstract #LB3439). Here we present additional efficacy and safety results from the ECHO trial. Methods: Pts aged ≥65 years (y) with previously untreated MCL and ECOG PS ≤2 were randomly assigned 1:1 to receive ABR or PBR. Acalabrutinib (100 mg twice daily) or placebo was administered until progressive disease (PD) or unacceptable toxicity. Induction with BR was administered for 6 cycles followed by rituximab maintenance (A±R maintenance, cycles 7-30) in pts achieving a partial or complete response (PR or CR). Pts progressing on PBR could cross over to receive acalabrutinib monotherapy. PFS (primary endpoint) was assessed by independent review committee. Minimal residual disease (MRD) negativity rate (10-5) was assessed in peripheral blood (every 24 weeks [wks], at CR, and at PD) and bone marrow (at CR) by NGS-based ClonoSEQ assay (Adaptive Biotechnologies). Results: Among the 598 pts randomized to ABR or PBR (299 in each arm), high-risk baseline characteristics included high-risk simplified MIPI score in 24.1% and 24.4%, blastoid histology in 8.7% and 6.7%, pleomorphic histology in 5.0% and 6.0%, centrally tested Ki-67 ≥30% in 46.5% and 49.2%, and known TP53 mutation in 7.4% and 9.7%, respectively. PFS hazard ratios (HRs) for subgroups were 0.78 (95% confidence interval [CI] 0.51-1.19) in pts with high-risk simplified MIPI score, 0.68 (95% CI 0.29-1.58) in pts with blastoid histology, 0.64 (95% CI 0.25-1.66) in pts with pleomorphic histology, 0.69 (95% CI 0.49-0.98) in pts with Ki-67 ≥30%, and 0.88 (95% CI 0.42-1.78) in pts with known TP53 mutation. In the ABR arm, median PFS was 22.2 months (mo) among pts who discontinued acalabrutinib during induction for reasons other than PD or death, 29.4 mo in pts who discontinued acalabrutinib during A±R maintenance (cycles 7-30) for reasons other than PD or death, and not reached in pts who received acalabrutinib for 31 cycles or more. Among evaluable patients who were MRD negative at the end of induction (24 wks), the rate of conversion to MRD positive during maintenance was lower in the ABR arm (5.85%; n=11/188) than in the PBR arm (15%; n=26/171). Conversely, among evaluable pts who were MRD positive at the end of induction (24 wks), 37.5% (n=3/8) in the ABR arm and 20% (n=3/15) in the PBR arm converted to MRD negative during maintenance. Overall rates of AEs were similar in each arm during induction, but were higher in ABR during A±R maintenance (cycles 7-30) and more so in the monotherapy phase (cycle 31+). Grade ≥3 TEAEs (ABR vs PBR) were 70.0% vs 68.7% during induction, 64.9% vs 62.9% during A±R maintenance (cycles 7-30), and 57.0% vs 45.3% during monotherapy (cycle 31+). Similarly, rates of TEAEs leading to discontinuation of acalabrutinib/placebo were 8.1% vs 8.8% during induction, 23.9% vs 19.0% during A±R maintenance (cycles 7-30), and 25.9% vs 13.7% during monotherapy (cycle 31+). Exposure-adjusted incidence rates per 100 person-years reduced the difference between ABR and PBR for clinically relevant TEAE rates (32.6 vs 29.3 for grade ≥3 serious TEAEs; 4.2 vs 4.0 for grade 5 TEAEs; 15.5 vs 12.4 for TEAEs leading to acalabrutinib/placebo discontinuation), possibly due to longer median exposure to acalabrutinib (28.6 vs 24.6 mo). Conclusion: Acalabrutinib in combination with BR provides a significant PFS benefit in pts with previously untreated MCL, including those with high-risk features. Furthermore, the addition of acalabrutinib to BR provided a greater PFS effect among pts in the ABR arm with the longest exposure to acalabrutinib. The PFS improvement may be partially driven by the contribution of acalabrutinib to sustained MRD-negative status and deepened responses after the end of induction. ABR provides this clinical benefit without excess toxicity as shown by attenuated differences between arms in exposure-adjusted incidence rates, suggesting that higher AE rates in the ABR arm are likely due in part to the longer duration of acalabrutinib treatment vs placebo. These data emphasize the benefits of acalabrutinib in frontline MCL treatment in high-risk pts and the additional benefit of continuous therapy.