Citations

Abstract Background An accurate discrete spot scanning (DSS) beam delivery time (BDT) model is essential, particularly as 4D dynamic dose accumulation calculations rely on machine‐specific time models for reliable interplay evaluation. Purpose To derive a BDT model for a synchrotron‐based Hitachi Probeat PBS proton system from oscilloscope measurements of key BDT structures, including multi‐energy extraction (MEE) characteristics. Methods Key BDT structures were characterized using oscilloscope measurements, supplemented by delivery log files where appropriate. Spot‐to‐spot scanning trajectories were visualized using a CROSSmini 2D strip ionization chamber (Liverage Biomedical Inc, Taiwan) via the dose‐driven continuous scanning (DDCS) mode. The MEE design and MEE charge recapture efficiencies were also characterized. In addition, the impact of the number of delivered spots on both the extractable fraction of charge and MEE recapture efficiency was investigated. Results An improved synchrotron‐based BDT model was derived that incorporates dead times between radiofrequency knockout (RFK) and high‐speed steering magnet (HSST) signals. Spot‐to‐spot movement follows a “hockey‐stick”‐like behavior where the effective spot‐to‐spot move time is governed by the slower axis. An energy‐dependent variation in the number of MEE layers deliverable per spill was also observed, with fewer MEE layers per spill (1–3) was observed in low and high energy ranges compared to the mid‐energy range (4–5), deviating from the nominal vendor value of five MEE layers per spill per block. A reduction in the extractable fraction of charge was observed with an increasing number of spots per spill, while increasing the number of delivered spots in the preceding layer significantly reduced the MEE recapture efficiency. Conclusion MEE characteristics should be incorporated into synchrotron‐based time models for accurate beam delivery modeling. The methodology presented here also provides a framework for centers seeking to derive machine‐specific delivery time models for their proton systems.

LBA7000 Background: ~40% of DLBCL pts are not cured with first-line (1L) R-CHOP, underscoring a significant unmet need for more effective 1L regimens. Tafa (anti-CD19 mAb) + Len-R-CHOP in the phase 1b First-MIND study demonstrated safety and efficacy in pts with newly diagnosed disease. frontMIND, a phase 3, double-blind, placebo-controlled study, compared Tafa-Len-R-CHOP vs R-CHOP in pts with high-risk aggressive BCLs. Methods: Pts aged 18–80 y with newly diagnosed, high-intermediate/high-risk DLBCL or HGBL (IPI 3–5, aaIPI 2–3 if ≤60 y) and ECOG PS 0–2 were randomized 1:1 to Tafa-Len-R-CHOP or R-CHOP. Primary endpoint was investigator-assessed PFS; secondary endpoints included: EFS, OS, CR, ORR, safety. Results: At primary analysis (data cutoff Oct 20, 2025), 899 pts were randomized to Tafa-Len-R-CHOP (n=448) or R-CHOP (n=451); baseline characteristics were similar between arms. With a median follow-up of 35.2 mo, Tafa-Len-R-CHOP achieved a statistically significant improvement in PFS vs R-CHOP (HR 0.75 [95% CI: 0.59, 0.96]; P =0.019) in the overall population; in pts with centrally confirmed lymphoma subtypes (n=773), PFS HR was 0.68 (95% CI: 0.52, 0.88) and 24-mo PFS was 72.7% vs 62.2%. PFS benefit was observed with Tafa-Len-R-CHOP in both molecular COO subtypes, ABC and GCB (data will be presented). Tafa-Len-R-CHOP significantly improved EFS vs R-CHOP; CR and ORR were similar between arms and HR for OS was 0.85 (final OS planned at 5y) (Table). Any-grade TEAEs were similar in treatment arms (98.6% vs 97.1%); more grade ≥3 TEAEs occurred with Tafa-Len-R-CHOP vs R-CHOP (86.7% vs 76.1%). Discontinuations due to TEAEs occurred in 25.7% vs 17.9% and deaths due to TEAEs in 5.9% vs 3.8% of pts for Tafa-Len-R-CHOP vs R-CHOP. Overall, there were fewer deaths with Tafa-Len-R-CHOP vs R-CHOP (18.5% vs 21.7%). Conclusions: The primary endpoint of frontMIND was met; Tafa-Len-R-CHOP resulted in a significant 25% reduction in risk of disease progression or death compared with R-CHOP, with an 8.2% difference in 24-month PFS rate in the overall population and 10.5% difference in pts with centrally confirmed lymphoma subtypes. TEAEs were manageable and consistent with the expected safety profile. Tafa-Len-R-CHOP represents a potential new 1L standard of care for pts with both COO subtypes of high-risk DLBCL or HGBL. Clinical trial information: NCT04824092 . Efficacy outcomes by treatment arm.* Variable Tafa-Len-R-CHOP(n=448) R-CHOP(n=451) HR or OR(95% CI) P value PFS, # events (%) † 121 (27.0) 155 (34.4) 0.75 (0.59, 0.96) 0.019 PFS rate at 24 mo, % 71.1 62.9 − − PFS rate at 36 mo, % 67.3 60.7 − − EFS, # events (%) 154 (34.4) 191 (42.4) 0.79 (0.64, 0.97) 0.026 OS, # events (%) 82 (18.3) 95 (21.1) 0.85 (0.63, 1.14) 0.270 CR at EOT, n (%) 292 (65.2) 294 (65.2) 0.998 (0.76, 1.31) 0.987 ‡ ORR at EOT, n (%) 360 (80.4) 343 (76.1) 1.290 (0.94, 1.78) 0.120 ‡ *Investigator-assessed. † Progressive disease or death from any cause. ‡ Nominal P value.

Abstract Background and Significance Diffuse large B-cell lymphoma (DLBCL) and other LBCLs account for 35–40% of non-Hodgkin lymphoma cases in North America, Europe, and East Asia. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line treatment for DLBCL, achieving cure rates in approximately 60–70% of patients. However, 30–40% of patients will relapse or become refractory (R/R) to treatment, facing poor prognosis. Patients with high International Prognostic Index (IPI) scores (3–5) and those with IPI 1–2 who have bulky disease and/or very high lactate dehydrogenase (LDH) are recognized as high-risk (HR) subsets with suboptimal outcomes (Maurer et al, ASH 2023, #4512). Novel combination strategies are an area of focus for improving efficacy in this population. GOLCA is a potential, first-in-class, oral CELMoD agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin [COO]) and immunomodulatory activity. In the Phase 1b study CC-220-DLBCL-001, GOLCA in combination with R-CHOP demonstrated a predictable and manageable safety profile with high rates of durable responses, irrespective of COO, in previously untreated aggressive B-cell lymphomas (BCL), including promising activity in HR patients (Amzallag et al, ASH 2024, #579). The median relative dose intensity for GOLCA and CHO components was high (97–99%), indicating uncompromised delivery of curative standard-of-care treatment and combinability. GOLCA ± rituximab has also shown encouraging efficacy and safety in patients with R/R DLBCL (Bachy et al, ICML, #148). These findings support the further study of GOLCA + R-CHOP combination in the Phase 3 setting. Study Design and Methods GOLSEEK-1 (NCT06356129) is a randomized, double-blind, placebo-controlled, Phase 3 study evaluating GOLCA + R-CHOP versus placebo + R-CHOP in patients with previously untreated HR LBCL. Approximately 850 patients with previously untreated LBCL will be randomized 1:1 to either GOLCA + R-CHOP or placebo + R-CHOP. Eligible patients include those with histologically confirmed LBCL per WHO 2022 criteria—including DLBCL (not otherwise specified [NOS], ABC/GCB), high-grade BCL with MYC and BCL2 rearrangements or NOS, T-cell/histiocyte–rich LBCL, or Epstein Barr Virus-positive DLBCL. HR status is defined by IPI ≥3, or IPI 1–2 with HR features: LDH >1.3× upper limit of normal and/or bulky disease (≥7 cm lesion). All patients must have measurable disease as defined by Lugano criteria. Key exclusion criteria are other lymphoma subtypes such as primary mediastinal LBCL; primary cutaneous DLBCL-leg type, grade 3b follicular lymphoma (FL); transformed indolent lymphoma; anaplastic lymphoma kinase (ALK) positive LBCL; primary effusion lymphoma; and Burkitt lymphoma and known or suspected central nervous system involvement. Randomization will be stratified by IPI score (HR 1–2 and 3 vs 4–5) and bulky disease status (≥7 cm vs <7 cm). After a screening period of ≤4 weeks, patients will receive either GOLCA (0.4 mg) or placebo orally once daily for 7 consecutive days in each of 6 cycles, combined with R-CHOP every 21 days. The primary endpoint is progression-free survival (PFS) by investigator assessment per Lugano Response Criteria. Key secondary endpoints include PFS in non–high-grade BCL, event-free survival, independently assessed complete metabolic response, undetectable minimal residual disease by PhasED-Seq (defined as undetectable circulating tumor DNA levels at end of treatment), and overall survival. Patients will be followed up for up to approximately 67 months after beginning treatment. This study is currently recruiting at 309 sites in 36 countries , across the United States, Europe, Latin America, and East Asia. Acknowledgement BMS Artificial Intelligence was used to revise existing text with human author oversight.

Abstract Background Dose‐driven continuous scanning (DDCS) is a type of beam delivery in Hitachi pencil beam scanning (PBS) particle therapy system. Particle beam is irradiated continuously between spots to achieve a higher effective dose rate and a shorter beam delivery time. The beam is only turned off at break spots, the end of a treatment layer and during spill change. The break spot is a unique feature of the DDCS introduced by the treatment planning system (TPS) to interrupt continuous scanning. DDCS separates the dose delivery of a spot into a move dose and stop dose components. The move dose is controlled by the scanning speed and beam current, while the stop dose delivers the remaining monitor units (MUs). Hence, rigorous quality assurance (QA) of the scanning speed and functionality of break spot are required to ensure safe and successful DDCS delivery. Purpose We aim to report for the first time the QA methodology and result for DDCS, focusing on the scanning speed and break spot validation. Methods A rectangular spiral irradiation pattern with different degree of break spots were irradiated on a 2D strip ionization chamber (CROSSmini) detector using 50 time resolution to validate the break spots. Four methods of measuring scanning speeds were proposed. Using a spiral irradiation pattern, methods one and two applied linear regression to the scanning time measured by the CROSSmini for different inter‐spot distances, with measurements taken at sampling rates of 5 and 20 kHz, respectively. Methods three and four measured the scanning time of single inter‐spot distances in the X and Y directions. Method three measured the scanning time with the CROSSmini while method four measured the rise and fall time of the scanning magnet (SCM) current. All measurements were performed with 70.2, 150.2 and 228.7 MeV proton beam energies and three different beam currents of 8, 14 and 20 MU/s. Lastly, the scanning speed tolerance limit was calculated analytically under the requirement of avoiding a beam abort when the stop dose was less than zero. Results The data recorded by the CROSSmini under the spiral irradiation patterns with break spots was reconstructed into a 2D dose, and the break spots’ operations were visually validated for all the energies and beam currents. There were no statistically significant difference in the measured X and Y scanning speeds across the four methods. However, the last method involving the SCM current yielded the largest type A uncertainty of up to 25% () due to the noisy signal. The first method with the linear regression and 5 kHz acquisition rate was preferred due to a smaller type A uncertainty of up to 2.0% and a lower false negative rate in detecting the rising and falling edges during scanning. The calculated tolerance limit based on our current DDCS setting was found to be 0.50 times of the expected scanning speed. Conclusion We have introduced QA protocols for DDCS, designed to ensure complete and safe beam delivery without interruptions caused by move doses exceeding planned spot doses.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

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/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 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 Age correlates with survival in patients (pts) with DLBCL, which has a median age at diagnosis of 67 y. Recent therapeutic advances, including bispecifics and cell therapy, have promising efficacy, but safety and accessibility continue to be limited for older pts. The randomized, global, phase 3 ECHELON-3 study (NCT04404283) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) with brentuximab vedotin (BV) + lenalidomide (Len) + rituximab (R; BV+Len+R) vs placebo+Len+R in pts with R/R DLBCL after ≥ 2 prior systemic therapies who were ineligible for hematopoietic stem cell transplant and/or chimeric antigen receptor (CAR) T-cell therapy. Here, we present safety and efficacy in pts aged ≥65 y. Methods In ECHELON-3, pts were randomized 1:1 to receive BV (1.2 mg/kg) or placebo every 3 weeks (q3w), in combination with R (375 mg/m2) q3w and Len (20 mg) once daily. Granulocyte colony-stimulating factor was required in all cycles. Efficacy was assessed by investigators per Lugano 2014 classification. The primary endpoint was OS, with key secondary endpoints of PFS and ORR. Other secondary endpoints included detailed safety and tolerability. This subgroup analysis comprises pts aged ≥65 y. P values are descriptive. Results A total of 155 pts aged ≥65 y were enrolled from April 2021 to November 2023 and randomized to BV+Len+R (n=79) or placebo+Len+R (n=76). The median age was 75 y (range, 65-89 y); 54% of pts were male, 59% were White, and 19% were Asian. Twenty-three percent and 54% had Ann Arbor stage III and IV disease, respectively, and 64% had high-intermediate or high International Prognostic Index scores (3-5) at enrollment. The most common DLBCL subtype was DLBCL not otherwise specified (58%). Twenty-nine percent of pts had transformed DLBCL. Approximately half (49%) of pts had primary refractory disease, and 81% had disease refractory to their most recent prior line of therapy. Seventy percent of pts had <1% CD30 expression via IHC; 48% of cases had germinal center B-cell origin. Prior CAR-T was reported in 21.9% of pts. At a median follow-up of 16.8 mo (95% CI, 14.3-19.5 mo), median OS was 15.9 mo (95% CI, 11.7 mo-not estimable [NE]) with BV+Len+R vs 8.5 mo (95% CI, 5.5-11.5 mo) with placebo+Len+R (hazard ratio [HR], 0.540; 95% CI, 0.351-0.830; P=.0043). Median PFS was 5.7 mo (95% CI, 4.1-12.7 mo) with BV+Len+R vs 2.8 mo (95% CI, 1.9-4.1 mo) with placebo+Len+R (HR, 0.478; 95% CI, 0.318-0.718; P=.0003). ORR was 70.9% (95% CI, 59.6%-80.6%) with BV+Len+R vs 46.1% (95% CI, 34.5%-57.9%) with placebo+Len+R (P=.0020); complete response (CR) rate was 45.6% vs 19.7%, respectively. Median time to CR was 1.61 mo with both BV+Len+R and placebo+Len+R (range, 1.2-7.3 vs 0.7-4.6 mo, respectively). Median duration of CR was 18.9 mo (95% CI, 12.4 mo-NE) with BV+Len+R vs 5.4 mo (95% CI, 2.8 mo-NE) with placebo+Len+R (HR, 0.416; 95% CI, 0.139-1.250). In total, 154 pts were evaluable for safety analysis (75 pts in placebo+Len+R group). The median number of cycles was 5 (range, 1-34) vs 3 (range, 1-31) in the BV+Len+R and placebo+Len+R groups, respectively. The percentage of pts with any treatment-emergent adverse event (TEAE) was similar between groups (97% with BV+Len+R and 99% with placebo+Len+R); grade ≥3 TEAEs occurred in 89% of pts in the BV+Len+R group and 76% in the placebo+Len+R group. Serious TEAEs and TEAEs leading to death were reported more frequently in the BV+Len+R group (62% and 13%, respectively) than the placebo+Len+R group (47% and 8%, respectively). More pts discontinued study treatment due to TEAEs in the BV+Len+R group than the placebo+Len+R group (20% vs 8%). In total, 39% of pts on BV+Len+R had a peripheral neuropathy event vs 27% of pts on placebo+Len+R; however, the majority of cases were grade 1 (22% and 17%, respectively). Additional information on older pts will be presented. Conclusions BV+Len+R demonstrated a clinically meaningful improvement in all key efficacy outcomes in pts aged ≥65 y, which is consistent with the overall ECHELON-3 population (median age 74 y; 70.5% of pts aged ≥65 y in BV+Len+R group). Differences in some safety endpoints are likely attributable to longer duration of treatment in the BV+Len+R group. No clinically meaningful safety trends in pts aged ≥65 y were identified. These results suggest that BV+Len+R may be an effective treatment option in older pts with R/R DLBCL.

Abstract Introduction . Dispersion in an accelerator quantifies the deviation of the proton trajectory when there is a momentum deviation. We present for the first time a safe method of measuring dispersion in the clinic, using a scintillator detector and the momentum deviations within a spill. This is an important accelerator quantity as we found that this is the reason behind the large dose fluctuation in our absolute dosimetry measurement. Methods . Dispersions are measured for nine energies in a Hitachi ProBeat system at three locations (isocenter and at two profile monitors) and at two gantry angles (0 and 90 degrees) by first measuring the spot position and momentum drift within a spill. The spot position drift is measured by the XRV-4000 at the isocenter, and by the two profile monitors located at 0.57 and 2.27 m from the isocenter. The momentum drift is calculated from the intra-spill range drift which is measured using the Ranger accessory. The dispersion at isocenter and its gradient are calculated using the weighted least square regression on the measured dispersions at the three locations. A constraint is formulated on the dispersion and its gradient to ensure minimal intra-spill spot position deviation around the isocenter. Results . The measured intra-spill range and spot positional drift at isocenter are less than 0.25 mm and 0.7 mm respectively. The momentum spread calculated from the range drift are less than 0.08%. The dispersion at the isocenter ranged from 0.50 to 4.30 m and the zero-crossing happens upstream of isocenter for all energies. 2 of the 9 energies (168.0 and 187.5 MeV) violated the constraint and has an intra-spill spot positional deviation greater than 1.0 within 5 cm from the isocenter. Conclusion . This measurement is recommended as part of commissioning and annual quality assurance for accelerator monitoring and to ensure intra-spill spot deviations remain low.

AbstractBackgroundAbsolute dosimetry measurement is an integral part of Treatment Planning System (TPS) commissioning and it involves measuring the integrated absorbed dose to water for all energies in a pencil beam scanning delivery system. During the commissioning of Singapore's first proton therapy center, a uniform scanned field with an Advanced Markus chamber method was employed for this measurement, and a large dose fluctuation of at least 5% was observed for 10% of the energy layers during repeated measurements.PurposeThis study aims to understand the root cause of this fluctuation by relating the actual delivered spot information in the log file with the charge measurement by the ion chambers.MethodsA dedicated pencil beam dose algorithm was developed, taking into account the log file parameters, to calculate the dose for a single energy layer in a homogeneous water phantom. Three energies, 70.2, 182.7, and 228.7 MeV were used in this study, with the 182.7 MeV energy exhibiting large dose fluctuation. The dose fluctuation was investigated as a function of detector's sizes (pinpoint 3D, Advanced Markus, PTW 34070, and PTW 34089) and water depth (2 , 6, and 20 cm). Twelve ion chambers measurements were performed for each chamber and depth. The comparison of the theoretically predicted integrated dose and the charge measurement served as a validation of the algorithm.ResultsAbout 5.9% and 9.6% dose fluctuation were observed in Advanced Markus and pinpoint 3D measurements at 2 cm depth for 182.7 MeV, while fluctuation of 1.6% and 1.1% were observed in Advanced Markus with 228.7 and 70.2 MeV at similar depth. Fluctuation of less than 0.1% was observed for PTW34070 and PTW 34089 for all energies. The fluctuation was found to diminish with larger spot size at 20 cm depth to 1.3% for 182.7 MeV. The theoretical and measured charge comparison showed a high linear correlation of for all datasets, indicating the fluctuation originated from the delivered spot characteristics. The cause of fluctuation was identified to be due to the spill change occurring close to the detector, and since the spot positional deviation profiles were different between two spills, this resulted in local hot spots between columns of spots. The actual position of spill change varies randomly during measurement, which led to a random occurrence of hot spot within the detector's sensitive volume and a fluctuating dose measurement.ConclusionThis is the first report of a dose fluctuation greater than 5% in absolute dosimetry measurement with a uniform scanned field and the cause of the fluctuation has been conclusively determined. It is important to choose the MU and scanning pattern carefully to avoid spill change happening when the spot delivery is near the detector.

Abstract Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton’s tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being ≤ grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment because of adverse events. Response was assessed by an independent review committee for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and the complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit–risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This trial was registered at www.clinicaltrials.gov as #NCT02343120.