Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.

BACKGROUND: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy. CONCLUSIONS: Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

Genomic landscape of patients in a phase II study of zanubrutinib in ibrutinib- and/or acalabrutinib-intolerant patients with B-cell malignancies.

Not available.

Association between elevated white blood cell counts and thrombotic events in polycythemia vera: analysis from REVEAL.

ABSTRACT: Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by clonal proliferation of hematopoietic progenitor cells and is associated with an increased risk of thrombotic events (TEs). Established risk factors for TEs in patients with PV include advanced age, TE history, and elevated hematocrit. Although an association of TE with elevated white blood cell (WBC) counts has been suggested by retrospective studies, this relationship needs further validation. The prospective observational study of patients with polycythemia vera in US clinical practices (REVEAL) study collected prospective clinical data from 2510 patients with PV with a median follow-up of 44.7 months (range, 2-59 months) from enrollment. Using time-dependent covariate Cox proportional hazards models, blood counts were individually modeled with sex, age, disease duration, TE history at enrollment (baseline covariates), and treatment (time-dependent covariate). Analysis of 2271 participants identified 142 TEs in 106 patients. Significant associations with initial TE occurrence during the study period were observed for hematocrit level >45% (hazard ratio [HR], 1.84; 95% confidence interval [95% CI], 1.234-2.749; P = .0028) and WBCs >11 × 109/L (HR, 2.35; 95% CI, 1.598-3.465; P < .0001). Elevated WBC count was significantly associated with initial TE occurrence in both low-risk and high-risk PV. When hematocrit was controlled at ≤45%, WBC count >12 × 109/L was significantly associated with TE occurrence (HR, 1.95; 95% CI, 1.066-3.554; P = .0300). The results support incorporation of WBC count into PV risk stratification and studies of treatment strategies, and indicate the importance of controlling both hematocrit and WBC count in disease management. This trial was registered at www.clinicaltrials.gov as #NCT02252159.

Mature B-cell lymphomas in adolescents and young adults.

Pediatric non-Hodgkin lymphoma includes over 30 histologies (many with subtypes), with approximately 800 cases per year in the US, compared to >60,000 cases of adult NHL annually. Improvements in survival in pediatric and adolescent mature B cell NHL over the past 5 decades align with the overall success of the cooperative trial model with dramatic improvements in outcomes through dose escalation of chemotherapy and, more recently, targeted therapy with rituximab. Pediatric dose-intense strategies carry risks of long-term consequences, but treatment failure is nearly universally fatal. By comparison, adult mature B cell lymphoma is typically less aggressive and treated with less intense chemotherapy. Optimizing therapy for adolescents and young adults remains a major challenge that requires creative solutions, including engineering study groups to combine biologically comparable adult and pediatric populations and developing effective salvage strategies that will ultimately be required for investigations of front-line dose reduction. In this review, we discuss challenges and opportunities for improving outcomes for adolescents and young adults with high-grade mature B cell lymphomas, diffuse large B cell lymphoma, and primary mediastinal B cell lymphoma.

Estimated impact of ECHELON-1 overall survival on productivity costs in stage III/IV classical Hodgkin lymphoma in the United States.

BACKGROUND: A 2010 study on the impact of cancer mortality on productivity costs found Hodgkin lymphoma to have the second largest productivity cost lost per death in the United States. The ECHELON-1 trial demonstrated that frontline brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) improves overall survival (OS) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in stage III/IV classical Hodgkin lymphoma (cHL), reducing the risk of death to 41% (hazard ratio = 0.59; 95% CI = 0.40-0.88; P = 0.009). OBJECTIVES: To assess the estimated impact of frontline treatment choice on mortality and productivity using an oncology simulation model informed by ECHELON-1 data. METHODS: Individual productivity was estimated using the human capital approach and reported via present value lifetime earnings (PVLE) estimates. Deaths avoided and lifeyears saved without and with A+AVD were calculated using a model informed by realworld treatment use, treatment-specific OS, and expert clinicians' opinions. A+AVD use in the base case was 27% (range: 0%-80%). Stage III/IV cHL prevalence over a 10-year period was estimated; downstream lifetime productivity costs were projected without and with A+AVD. RESULTS: In 2031, 3,645 patients were estimated to be newly diagnosed with stage III/IV cHL. Over 10 years with 27% A+AVD vs no A+AVD use, estimates predicted 14% fewer deaths (2,290 vs 2,650) and 14% less total PVLE losses ($1.438 vs $1.664 billion). Results from scenario analyses (40%-80% vs no A+AVD use) showed 20% to 32% decreases in PVLE losses ($1.331-$1.137 billion vs $1.664 billion), saving up to $527 million over 10 years. CONCLUSIONS: Productivity cost losses due to mortality in stage III/IV cHL are high. Increasing A+AVD use for patients with stage III/IV cHL would reduce productivity cost losses as deaths are avoided, based on ECHELON-1 OS results.

US cost-effectiveness analysis of polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma.

AIMS: We evaluated the pharmacoeconomic value of polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) in previously untreated diffuse large B-cell lymphoma (DLBCL) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MATERIALS AND METHODS: A 3-state partitioned survival model was used to estimate life years (LYs), quality-adjusted LYs (QALYs), and cost impacts of Pola-R-CHP versus R-CHOP. Analyses utilized mixture-cure survival modelling, assessed a lifetime horizon, discounted all outcomes at 3% per year, and examined both payer and societal perspectives. Progression-free survival, overall survival (OS), drug utilization, treatment duration, adverse reactions, and subsequent treatment inputs were based on data from the POLARIX study (NCT03274492). Costs included drug acquisition/administration, adverse reaction management, routine care, subsequent treatments, end-of-life care, and work productivity. RESULTS: Incremental cost-effectiveness ratios of Pola-R-CHP versus R-CHOP were $70,719/QALY gained and $88,855/QALY gained from societal and payer perspectives, respectively. The $32,824 higher total cost of Pola-R-CHP versus R-CHOP was largely due to higher drug costs ($122,525 vs $27,694), with cost offsets including subsequent treatment (-$52,765), routine care (-$1,781), end-of-life care (-$383), and work productivity (-$8,418). Pola-R-CHP resulted in an increase of 0.47 LYs and 0.46 QALYs versus R-CHOP. Pola-R-CHP was cost-effective in 60.9% and 58.0% of simulations at a willingness-to-pay threshold of $150,000/QALY gained from societal and payer perspectives, respectively. LIMITATIONS: There was uncertainty around the OS extrapolation in the model, and costs were derived from different sources. Recommended prophylactic medications were not included; prophylactic use of granulocyte colony-stimulating factor for all patients was assumed to be equal across treatment arms in POLARIX. Work productivity loss was estimated from a general population and was not specific to patients with DLBCL. CONCLUSION: Pola-R-CHP was projected to be cost-effective versus R-CHOP in previously untreated DLBCL, suggesting that Pola-R-CHP represents good value relative to R-CHOP in this setting.

Cost of Disease Progression in Diffuse Large B-Cell Lymphoma After Frontline Treatment With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.

BACKGROUND: In recent years, novel agents have become available to treat relapsed/refractory diffuse large B-cell lymphoma (DLBCL); the impact of such agents on treatment costs has not been formally studied. We present results from 2 independent, retrospective, real-world cohort analyses to determine the cost of disease progression after first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MATERIALS AND METHODS: Analyses were conducted using the IQVIA PharMetricsⓇ Plus claims database and the Surveillance, Epidemiology, and End Results registry-Medicare-linked database (SEER-Medicare) and included patients ≥18 years and ≥66 years, respectively. "No progression" was defined as no second-line therapy for ≥2 years after the end of first-line R-CHOP and "treated progression" as initiating a second-line therapy within 2 years following the end of first-line R-CHOP. Analyses were adjusted for baseline covariates, and per-patient-per-month (PPPM) costs were compared between progressors and nonprogressors. RESULTS: The IQVIA PharMetrics Plus analysis (January 1, 2010-June 30, 2018) included 871 patients (nonprogressors, n = 725; progressors, n = 146), including 10 patients who received chimeric antigen receptor T-cell therapy (CAR-T). Treated progression was associated with significantly higher adjusted PPPM costs than no progression ($10,554 vs. $1561, P < .001). The SEER-Medicare analysis (January 1, 2010-December 31, 2017) included 4099 patients (nonprogressors, n = 3389; progressors, n = 710), including 12 patients receiving CAR-T. Treated progression was associated with significantly higher adjusted PPPM costs than no progression ($10,928 vs. $2902, P < .001). CONCLUSION: Treated progression of DLBCL increases adjusted PPPM costs by over $8000 compared with no progression.

Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated with a DNA Damage Repair Gene Alteration: Final Results from the Phase 2 TRITON2 Study.

BACKGROUND: Initial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration. OBJECTIVE: To present the final data from TRITON2. DESIGN, SETTING, AND PARTICIPANTS: TRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was objective response rate (ORR; as per the modified Response Evaluation Criteria in Solid Tumor Version 1.1/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease by independent radiology review [IRR]); prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) was a key secondary endpoint. RESULTS AND LIMITATIONS: As of July 27, 2021 (study closure), TRITON2 had enrolled 277 patients, grouped by mutated gene: BRCA (n = 172), ATM (n = 59), CDK12 (n = 15), CHEK2 (n = 7), PALB2 (n = 11), or other DDR gene (Other; n = 13). ORR by IRR was 46% (37/81) in the BRCA subgroup (95% confidence interval [CI], 35-57%), 100% (4/4) in the PALB2 subgroup (95% CI, 40-100%), and 25% (3/12) in the Other subgroup (95% CI, 5.5-57%). No patients within the ATM, CDK12, or CHEK2 subgroups had an objective response by IRR. PSA50 response rates (95% CI) in the BRCA, PALB2, ATM, CDK12, CHEK2, and Other subgroups were 53% (46-61%), 55% (23-83%), 3.4% (0.4-12), 6.7% (0.2-32%), 14% (0.4-58%), and 23% (5.0-54%), respectively. CONCLUSIONS: The final TRITON2 results confirm the clinical benefit and manageable safety profile of rucaparib in patients with mCRPC, including those with an alteration in BRCA or select non-BRCA DDR gene. PATIENT SUMMARY: Almost half of TRITON2 patients with BRCA-mutated metastatic castration-resistant prostate cancer had a complete or partial tumor size reduction with rucaparib; clinical benefits were also observed with other DNA damage repair gene alterations.

Safety and efficacy of tafasitamab with or without lenalidomide added to first-line R-CHOP for DLBCL: the phase 1b First-MIND study.

Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Open-label, phase 1b, First-MIND study assessed safety and preliminary efficacy of tafasitamab + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) ± lenalidomide as first-line therapy in patients with DLBCL. From December 2019 to August 2020, 83 adults with untreated DLBCL (International Prognostic Index 2-5) were screened and 66 were randomly assigned (33 per arm) to R-CHOP-tafasitamab (arm T) or R-CHOP-tafasitamab-lenalidomide (arm T/L) for 6 cycles. Primary end point was safety; secondary end points included end-of-treatment (EoT) overall response rate (ORR) and complete response (CR) rate. All patients had ≥1 treatment-emergent adverse event, mostly grade 1 or 2. Grade ≥3 neutropenia and thrombocytopenia occurred, respectively, in 57.6% and 12.1% (arm T) and 84.8% and 36.4% (arm T/L) of patients. Nonhematologic toxicities occurred at similar rates among arms. R-CHOP mean relative dose intensity was ≥89% in both arms. EoT ORR was 75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L; best ORR across visits was 90.0% and 93.9%. Eighteen-month duration of response and of CR rates were 72.7% and 74.5% (arm T) and 78.7% and 86.5% (arm T/L); 24-month progression-free and overall survival rates were 72.7% and 90.3% (arm T) and 76.8% and 93.8% (arm T/L). Manageable safety and promising signals of efficacy were observed in both arms. Potential benefit of adding tafasitamab + lenalidomide to R-CHOP is being investigated in phase 3 frontMIND (NCT04824092). This study is registered at www.clinicaltrials.gov as #NCT04134936.

Estimating long-term outcomes in classic Hodgkin lymphoma: a United States population-based oncology simulation model based on overall survival from the ECHELON-1 trial.

The six-year ECHELON-1 update showed a survival advantage for frontline (1 L) A + AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine) vs ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for stage III/IV classic Hodgkin lymphoma (cHL). As clinical trials have limited ability to track patients for extended periods, we developed an oncology simulation model using ECHELON-1 data to estimate population-based cHL outcomes in the US over 10 years (through 2031). The model included a scenario without (64.5% ABVD, 35.5% PET-adapted ABVD utilization) and scenarios with 1 L A + AVD (27%-80%k utilization). At 27%-80% A + AVD utilization, the model estimated 13.6%-31.7% fewer deaths, 2.4%-6.3% more patients ≥5 years progression free, 9.4%-24.4% fewer stem cell transplants (SCTs), and 7.8%-22.5% fewer second cancers over 10 years. These results suggest that the improved outcomes observed in the ECHELON-1 update with A + AVD vs ABVD may translate to more patients alive and fewer with primary relapsed/refractory cHL, SCTs, and second cancers.

Retrospective Analysis With Propensity Score Matching of Peripheral T-Cell Lymphoma Treated Frontline With Brentuximab Vedotin and Chemotherapy.

BACKGROUND: Since Food and Drug Administration approval of brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (A + CHP) as initial therapy for previously untreated CD30-expressing peripheral T-cell lymphoma (PTCL), there has been limited research on real-world patient characteristics, treatment patterns, and clinical outcomes. METHODS: We retrospectively analyzed claims of patients with PTCL treated with frontline A + CHP or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) using the Symphony Health Solutions database. Adults with International Classification of Diseases-9/10 PTCL diagnosis codes who initiated A + CHP or CHOP between November 2018 and July 2021 were included. A 1:1 propensity score matching analysis was performed that adjusted for potential confounders between groups. RESULTS: A total of 1344 patients were included (A + CHP, n = 749; CHOP, n = 595). Before matching, 61% were men; median age at index was 62 (A + CHP) and 69 (CHOP) years. The most common A + CHP-treated PTCL subtypes were systemic anaplastic large cell lymphoma (sALCL; 51%), PTCL-not otherwise specified (NOS; 30%), and angioimmunoblastic T-cell lymphoma (AITL; 12%); the most common CHOP-treated subtypes were PTCL-NOS (51%) and AITL (19%). After matching, similar proportions of patients treated with A + CHP and CHOP received granulocyte colony-stimulating factor (89% vs. 86%, P = .3). Fewer patients treated with A + CHP received subsequent therapy than CHOP overall (20% vs. 30%, P < .001) and specifically with the sALCL subtype (15% vs. 28%, P = .025). CONCLUSIONS: Characteristics and management of this real-world PTCL population who were older and had a higher comorbidity burden than that in the ECHELON-2 trial demonstrate the importance of retrospective studies when assessing the impact of new regimens on clinical practice.

A next generation mathematical model for the in vitro to clinical translation of T-cell engagers.

T-cell engager (TCE) molecules activate the immune system and direct it to kill tumor cells. The key mechanism of action of TCEs is to crosslink CD3 on T cells and tumor associated antigens (TAAs) on tumor cells. The formation of this trimolecular complex (i.e. trimer) mimics the immune synapse, leading to therapeutic-dependent T-cell activation and killing of tumor cells. Computational models supporting TCE development must predict trimer formation accurately. Here, we present a next-generation two-step binding mathematical model for TCEs to describe trimer formation. Specifically, we propose to model the second binding step with trans-avidity and as a two-dimensional (2D) process where the reactants are modeled as the cell-surface density. Compared to the 3D binding model where the reactants are described in terms of concentration, the 2D model predicts less sensitivity of trimer formation to varying cell densities, which better matches changes in EC50 from in vitro cytotoxicity assay data with varying E:T ratios. In addition, when translating in vitro cytotoxicity data to predict in vivo active clinical dose for blinatumomab, the choice of model leads to a notable difference in dose prediction. The dose predicted by the 2D model aligns better with the approved clinical dose and the prediction is robust under variations in the in vitro to in vivo translation assumptions. In conclusion, the 2D model with trans-avidity to describe trimer formation is an improved approach for TCEs and is likely to produce more accurate predictions to support TCE development.

Estimating long-term progression-free and overall survival in patients with peripheral T-cell lymphoma: A US population-based oncology simulation model based on 5-year results from the ECHELON-2 trial.

BACKGROUND: The ECHELON-2 5-year update showed continued clinically meaningful improvements in progression-free survival (PFS) and overall survival with frontline (1L) A+CHP (brentuximab vedotin in combination with cyclophosphamide, doxorubicin, prednisone) vs CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in CD30-expressing peripheral T-cell lymphomas (PTCLs). OBJECTIVE: To estimate PTCL annual prevalence in the United States in 2031 without and with A+CHP using data from the ECHELON-2 5-year update. METHODS: Population-level outcomes were estimated using a dynamic oncology simulation model. Utilization of 1L CHOP (65% utilization) and CHOP plus etoposide (35% utilization) were varied over time and compared with scenarios incorporating 1L A+CHP (20%-50% utilization; base case: 40% utilization) per expert clinicians' opinion. Additional inputs included PTCL incidence and PFS for consolidation and post-1L therapies from published sources. PFS (51.4% [95% CI = 42.8%-59.4%] vs 43.0% [35.8%-50.0%]) and overall survival (hazard ratio = 0.72 [0.53-0.99]) for A+CHP and CHOP came from ECHELON-2. RESULTS: In 2031, an estimated 2,082 patients will be diagnosed with PTCL. Approximately 1,412 additional patients will be alive and progression free, and 106 fewer patients will require second-line therapy with 40% A+CHP utilization vs no A+CHP utilization. Varying 1L A+CHP utilization from 20%-50% vs no 1L A+CHP utilization added 732 to 1,752 patients alive and progression free. CONCLUSIONS: In this oncology simulation model, the improvements in survival outcomes seen with A+CHP vs CHOP in the ECHELON-2 5-year results translated into more estimated patients with PTCL progression free and alive for at least 5 years following 1L A+CHP vs CHOP and a decreased need for post-1L therapy. DISCLOSURES: This study was funded by Seagen Inc. Dr Liu and Dr Yu are employees and shareholders of Seagen Inc. Mr Bloudek is and Dr Mordi was an employee of Curta Health, which received funding from Seagen Inc. for the conduct of this study. Dr Burke received consulting fees from Genentech/Roche, AbbVie, Seattle Genetics, Bayer, AstraZeneca, Adaptive Biotechnologies, Verastem, MorphoSys, Kura, Epizyme, BeiGene, Kymera, Novartis, Bristol Myers Squibb, TG Therapeutics, Lilly, and Nurix; and received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events in speakers bureaus for BeiGene and Seagen Inc. Dr Phillips received consulting fees from AstraZeneca, MorphoSys, Epizyme, Roche/Genentech, Epizyme Eli Lilly, AbbVie, BeiGene, Pharmacyclics, Bristol Myers Squibb, Xencor, Seagen Inc., TG Therapeutics, Bayer, Incyte, and Gilead; and received payment for honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Epizyme and Seagen Inc.

Quantitative systems pharmacology model of GITR-mediated T cell dynamics in tumor microenvironment.

T cell interaction in the tumor microenvironment is a key component of immuno-oncology therapy. Glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) is expressed on immune cells including regulatory T cells (Tregs) and effector T cells (Teffs). Preclinical data suggest that agonism of GITR in combination with Fc-γ receptor-mediated depletion of Tregs results in increased intratumoral Teff:Treg ratio and tumor shrinkage. A novel quantitative systems pharmacology (QSP) model was developed for the murine anti-GITR agonist antibody, DTA-1.mIgG2a, to describe the kinetics of intratumoral Tregs and Teffs in Colon26 and A20 syngeneic mouse tumor models. It adequately captured the time profiles of intratumoral Treg and Teff and serum DTA-1.mIgG2a and soluble GITR concentrations in both mouse models, and described the response differences between the two models. The QSP model provides a quantitative understanding of the trade-off between maximizing Treg depletion versus Teff agonism, and offers insights to optimize drug design and dose regimen.

Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open-label, single-arm study.

BACKGROUND: We hypothesised that zanubrutinib, a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor, would be a safe and active treatment for patients intolerant of ibrutinib, acalabrutinib, or both. We aimed to assess whether zanubrutinib would prolong treatment duration by minimising treatment-related toxicities and discontinuations in patients with previously treated B-cell malignancies. METHODS: This ongoing, phase 2, multicentre, open-label, single-arm study was done in 20 centres in the USA. Patients aged 18 or older with previously treated B-cell malignancies (chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinaemia, or marginal zone lymphoma) who became intolerant of ibrutinib, acalabrutinib, or both, were orally administered zanubrutinib 160 mg twice daily or 320 mg once daily per investigator. The primary endpoint was recurrence and change in severity of ibrutinib or acalabrutinib intolerance events based on investigator-assessed adverse events. Secondary endpoints were investigator-assessed overall response rate; duration of response; disease control rate; and progression-free survival. Analyses included all patients who received any dose of the study drug. This study is registered with ClinicalTrials.gov, NCT04116437. FINDINGS: Between Oct 14, 2019, and Sept 8, 2021, 67 patients (36 [54%] men and 31 [46%] women) who were intolerant of ibrutinib (n=57; cohort 1) or of acalabrutinib or acalabrutinib and ibrutinib (n=10; cohort 2) were enrolled. 63 (94%) patients were White, one (2%) had multiple ethnicities, and three (5%) had unreported or unknown ethnicity. Most intolerance events (81 [70%] of 115 for ibrutinib; 15 [83%] of 18 for acalabrutinib) did not recur with zanubrutinib. Of the recurring events, seven (21%) of 34 ibrutinib intolerance events and two (67%) of three acalabrutinib intolerance events recurred at the same severity with zanubrutinib; 27 (79%) ibrutinib intolerance events and one (33%) acalabrutinib intolerance event recurred at a lower severity with zanubrutinib. No events recurred at higher severity. No grade 4 intolerance events recurred. 64 (96%) of 67 patients had one or more adverse events with zanubrutinib; the most common adverse events were contusion (in 15 [22%] of 67 patients), fatigue (14 [21%]), myalgia (ten [15%]), arthralgia (nine [13%]), and diarrhoea (nine [13%]). Atrial fibrillation occurred in three (4%) patients (all grade 2). Eight (12%) of 67 patients had serious adverse events (anaemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reaction, trigeminal nerve disorder, and urinary tract infection). No treatment-related deaths occurred. The median follow-up time was 12·0 months (IQR 8·2-15·6). Among the 64 efficacy-evaluable patients, disease control rate was 93·8% (60; 95% CI 84·8-98·3) and overall response rate was 64·1% (41; 95% CI 51·1-75·7). The median duration of response was not reached; the 12-month event-free duration of response rate was 95·0% (95% CI 69·5-99·3). Similarly, median progression-free survival was not reached; 18-month progression-free survival was 83·8% (95% CI 62·6-93·6). INTERPRETATION: Patients intolerant of previous BTK inhibitors have limited treatment options. These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib. FUNDING: BeiGene.

Safety and efficacy of atezolizumab with rituximab and CHOP in previously untreated diffuse large B-cell lymphoma.

Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the current standard therapy for patients with diffuse large B-cell lymphoma (DLBCL) and is curative in ∼60% of patients. Atezolizumab is a humanized immunoglobulin G1 monoclonal antibody that targets programmed death-ligand 1 and has previously shown antitumor activity in several tumor types. In a phase 1b/2 trial (NCT02596971), we evaluated the safety and efficacy of atezolizumab in combination with R-CHOP (atezo-R-CHOP; for 6-8 cycles) in patients with previously untreated DLBCL. Patients achieving a complete response (CR) at the end of induction received consolidation therapy with atezolizumab on day 1 of each 21-day cycle for an additional 17 cycles. Overall, 42 patients with DLBCL were included in this analysis. The primary endpoint, CR rate at the end of induction, as assessed by an independent review committee (modified Lugano 2014 criteria), was 77.5% (95% confidence interval [CI], 64.0-87.7; n = 40). Investigator-assessed progression-free survival and overall survival at 3 years were 77.4% (95% CI, 59.7-88.0) and 87.2% (95% CI, 71.9-94.5), respectively. All treated patients experienced ≥1 adverse event (AE; 32 patients [76.2%] had grade 3-4 AE). One patient had a fatal AE (unconfirmed progressive multifocal leukoencephalopathy) that was considered related to atezolizumab and rituximab, and 17 patients (40.5%) experienced atezolizumab-related AEs of special interest. In previously untreated patients with DLBCL, atezo-R-CHOP demonstrated encouraging clinical efficacy and a safety profile consistent with the known toxicities of the individual drugs. This trial was registered at www.clinicaltrials.gov as #NCT02596971.

Transcriptomics of developing wild sunflower seeds from the extreme ends of a latitudinal gradient differing in seed oil composition.

Seed oil composition, an important agronomic trait in cultivated sunflower, varies latitudinally across the native range of its wild progenitor. This pattern is thought to be driven by selection for a higher proportion of saturated fatty acids in southern populations compared with northern populations, likely due to the different temperatures experienced during seed germination. To investigate whether these differences in fatty acid composition between northern and southern populations correspond to transcriptional variation in the expression of genes involved in fatty acid metabolism, we sequenced RNA from developing seeds of sunflowers from Texas, USA, and Saskatchewan, Canada (the extreme ends of sunflower's latitudinal range) grown in a common garden. We found 4,741 genes to be differentially expressed between Texas and Canada, including several genes involved in lipid metabolism. Several differentially expressed lipid metabolism genes also colocalized with known oil quantitative trait loci (QTL). The genes producing stearoyl-ACP-desaturases (SAD) were of particular interest because of their known role in the conversion of fully saturated into unsaturated fatty acids. Two SAD genes were more highly expressed in seeds from Canadian populations, consistent with the observation of increased levels of unsaturated fatty acids in seeds from that region. We also constructed a gene co-expression network to investigate regional variation in network modules. The results of this analysis revealed regional differentiation for eight of 12 modules but no clear relationship with oil biosynthesis. Overall, the differential expression of SAD genes offers a partial explanation for the observed differences in seed oil composition between Texas and Canada, while the expression patterns of other metabolic genes suggest complex regulation of fatty acid production and usage across latitudes.

Genomic regions associate with major axes of variation driven by gas exchange and leaf construction traits in cultivated sunflower (Helianthus annuus L.).

Stomata and leaf veins play an essential role in transpiration and the movement of water throughout leaves. These traits are thus thought to play a key role in the adaptation of plants to drought and a better understanding of the genetic basis of their variation and coordination could inform efforts to improve drought tolerance. Here, we explore patterns of variation and covariation in leaf anatomical traits and analyze their genetic architecture via genome-wide association (GWA) analyses in cultivated sunflower (Helianthus annuus L.). Traits related to stomatal density and morphology as well as lower-order veins were manually measured from digital images while the density of minor veins was estimated using a novel deep learning approach. Leaf, stomatal, and vein traits exhibited numerous significant correlations that generally followed expectations based on functional relationships. Correlated suites of traits could further be separated along three major principal component (PC) axes that were heavily influenced by variation in traits related to gas exchange, leaf hydraulics, and leaf construction. While there was limited evidence of colocalization when individual traits were subjected to GWA analyses, major multivariate PC axes that were most strongly influenced by several traits related to gas exchange or leaf construction did exhibit significant genomic associations. These results provide insight into the genetic basis of leaf trait covariation and showcase potential targets for future efforts aimed at modifying leaf anatomical traits in sunflower.

Daratumumab, cyclophosphamide, bortezomib, and dexamethasone for multiple myeloma: final results of the LYRA study.

In the primary analysis of LYRA, daratumumab + cyclophosphamide/bortezomib/dexamethasone (DARA + CyBorD) was effective and well tolerated in newly diagnosed multiple myeloma (NDMM) and relapsed multiple myeloma (RMM). We report the final analysis of LYRA (median months of follow-up: NDMM, 35.7; RMM, 35.3) after all patients completed study therapy, were followed for 36 months, or discontinued. Patients received DARA + CyBorD induction, autologous stem cell transplant (if eligible), and 12 months of daratumumab maintenance. Eighty-seven NDMM patients enrolled, 39 underwent transplant, and 63 completed maintenance. Rates of complete response or better were 48.7% and 29.8% for NDMM transplant and NDMM non-transplant patients, respectively, and 36-month progression-free survival rates were 69.3% and 72.6%. Grade 3/4 treatment-emergent adverse events occurred in 61.6% of NDMM patients. Efficacy and safety data are also reported for the smaller RMM cohort (n = 14). DARA + CyBorD followed by daratumumab maintenance was well tolerated and achieved deep, durable responses in NDMM and RMM.