Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 del(17p) have an unfavorable prognosis and respond poorly to standard ...chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 - 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 - 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 - 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 - 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.
Summary Background Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, showed activity in many single-group studies in relapsed or refractory mantle cell ...lymphoma. The aim of this randomised study was to examine the efficacy and safety of lenalidomide versus best investigator's choice of single-agent therapy in relapsed or refractory mantle cell lymphoma. Methods The MCL-002 (SPRINT) study was a randomised, phase 2 study of patients with mantle cell lymphoma aged 18 years or older at 67 clinics and academic centres in 12 countries who relapsed one to three times, had Eastern Cooperative Oncology Group performance status of 0–2, at least one measurable lesion to be eligible, and who were ineligible for intensive chemotherpy or stem-cell transplantation. Using a centralised interactive voice response system, we randomly assigned (2:1) patients in a permuted block size of six to receive lenalidomide (25 mg orally on days 1–21 every 28 days) until progressive disease or intolerability, or single-agent investigator's choice of either rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine. Randomisation was stratified by time from diagnosis, time from last anti-lymphoma therapy, and previous stem-cell transplantation. Individual treatment assignment between lenalidomide and investigator's choice was open label, but investigators had to register their choice of comparator drug before randomly assigning a patient. Patients who progressed on investigator's choice could cross over to lenalidomide treatment. We present the prespecified primary analysis results in the intention-to-treat population for the primary endpoint of progression-free survival, defined as the time from randomisation to progressive disease or death, whichever occurred first. Patient enrolment is complete, although treatment and collection of additional time-to-event data are ongoing. This study is registered with ClinicalTrials.gov , number NCT00875667. Findings Between April 30, 2009, and March 7, 2013, we enrolled 254 patients in the intention-to-treat population (170 67% were randomly assigned to receive lenalidomide, 84 33% to receive investigator's choice monotherapy). Patients had a median age of 68·5 years and received a median of two previous regimens. With a median follow-up of 15·9 months (IQR 7·6–31·7), lenalidomide significantly improved progression-free survival compared with investigator's choice (median 8·7 months 95% CI 5·5–12·1 vs 5·2 months 95% CI 3·7–6·9) with a hazard ratio of 0·61 (95% CI 0·44–0·84; p=0·004). In the 167 patients in the lenalidomide group and 83 patients in the investigator's choice group who received at least one dose of treatment the most common grade 3–4 adverse events included neutropenia (73 44% of 167 vs 28 34% of 83) without increased risk of infection, thrombocytopenia (30 18% vs 23 28%), leucopenia (13 8% vs nine 11%), and anaemia (14 8% vs six 7%). Interpretation Patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell transplantation have longer progression-free survival, with a manageable safety profile when treated with lenalidomide compared with monotherapy investigator's choice options. Funding Celgene Corporation.
Vascular endothelial growth factor is involved in lymphoma growth, suggesting a potential role for anti-vascular endothelial growth factor therapies in hematologic malignancies. In this phase III ...study, patients with CD20-positive diffuse large B-cell lymphoma were randomized to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone plus either placebo (R-CHOP) or bevacizumab (RA-CHOP). Treatment was administered every 21 (8 cycles) or 14 days (6 cycles plus 2 rituximab cycles) as per institutional practice. An early analysis of risk/benefit by the Data and Safety Monitoring Board showed that RA-CHOP increased cardiotoxicity without prolonging progression-free survival compared with R-CHOP, and the trial was stopped early. The study protocol was amended to allow for 12 additional months of follow up to evaluate safety. With 787 patients enrolled, median follow up was 23.7 and 23.6 months for R-CHOP and RA-CHOP, respectively. Median progression-free survival for R-CHOP and RA CHOP was 42.9 and 40.2 months, respectively (hazard ratio=1.09; P=0.49). The proportion of deaths was identical for R-CHOP (83 of 387, 21%) and RA-CHOP (82 of 390, 21%). Relative to R-CHOP, RA-CHOP had a higher rate of left ventricular ejection fraction perturbation (18% vs. 8%; odds ratio=2.51; 95% confidence interval (CI): 1.60-3.93) and congestive heart failure (16% vs. 7%; odds ratio=2.79; 95%CI: 1.72-4.54). Bevacizumab added to R-CHOP increased cardiac events, without increasing efficacy, arguing against further evaluation of RA-CHOP in patients with diffuse large B-cell lymphoma. The MAIN study is registered at clinicaltrials.gov identifier:00486759.
Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Patients with DLBCL who ...received ≥2 prior therapies were stratified by DLBCL subtype germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC) and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis GCB vs. activated B-cell (ABC) using gene expression profiling (GEP) were exploratory endpoints.
Stage 1: 102 DLBCL patients (by IHC: non-GCB,
= 54; GCB,
= 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks;
= 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively;
= 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively;
= 0.550).
The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping.
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Rituximab (R) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the current standard therapy for diffuse large B cell lymphoma (DLBCL). Obinutuzumab (G), a glycoengineered, ...type II anti-CD20 monoclonal antibody, has shown activity and an acceptable safety profile when combined with CHOP (G-CHOP) in patients with advanced DLBCL. We present the final analysis results of the Phase III GOYA study (NCT01287741), which compared the efficacy and safety of G-CHOP versus R-CHOP in patients with previously untreated DLBCL.
Patients aged ≥ 18 years with previously untreated advanced DLBCL were randomly assigned to receive eight 21-day cycles of R or G, plus six or eight cycles of CHOP. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival, other time-to-event endpoints, and safety; investigator-assessed PFS by cell of origin subgroup was an exploratory endpoint.
A total of 1418 patients were randomized, with 1414 included in this final analysis (G-CHOP, N = 704; R-CHOP, N = 710). Five-year PFS rates were 63.8% and 62.6% for G-CHOP and R-CHOP, respectively (stratified hazard ratio 0.94, 95% CI 0.78-1.12; p = 0.48). The results of the secondary efficacy endpoints did not show a benefit of G-CHOP over R-CHOP. In the exploratory analysis, a trend towards benefit with G-CHOP over R-CHOP was apparent in the patients with germinal center B cell DLBCL. The safety profile of G-CHOP was as expected, and no new safety signals were observed. More grade 3-5 (75.1% vs 65.8%), serious (44.4% vs 38.4%), and fatal (6.1% vs 4.4%) adverse events (AEs) were observed in the G-CHOP arm compared with the R-CHOP arm, respectively, with the most common fatal AEs being infections. A higher incidence of late-onset neutropenia occurred in the G-CHOP arm (8.7%) versus the R-CHOP arm (4.9%).
The final analysis, similar to the primary analysis, did not show a PFS benefit of G-CHOP over R-CHOP in previously untreated patients with DLBCL. The results of the secondary endpoints were consistent with the primary endpoint. Further exploratory analyses and investigation of biomarkers are ongoing.
Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared ...zanubrutinib with bendamustine–rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL.
We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0–2. A central interactive web response system randomly assigned patients without del(17)(p13·1) to zanubrutinib (group A) or bendamustine–rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13·1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2–6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided α of 0·05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment.
Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13·1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine–rituximab (group B; n=238). At median follow-up of 26·2 months (IQR 23·7–29·6), median progression-free survival per independent review committee was not reached in either group (group A 95% CI not estimable NE to NE; group B 28·1 months to NE). Progression-free survival was significantly improved in group A versus group B (HR 0·42 95% CI 0·28 to 0·63; two-sided p<0·0001). The most common grade 3 or worse adverse event was neutropenia (27 11% of 240 patients in group A, 116 51% of 227 in group B, and 17 15% of 111 patients in group C). Serious adverse events occurred in 88 (37%) of 240 patients in group A, 113 (50%) of 227 patients in group B, and 45 (41%) of 111 patients in group C. Adverse events leading to death occurred in 11 (5%) of 240 patients in group A, 12 (5%) of 227 patients in group B, and three (3%) of 111 patients in group C, most commonly due to COVID-19 (four 2% of 240 patients in group A), diarrhoea, and aspiration pneumonia (two each 1% of 227 patients in group B).
Zanubrutinib significantly improved progression-free survival versus bendamustine–rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL.
BeiGene.
Part one of the two-part SAWYER study predicted that subcutaneous rituximab 1600 mg would achieve trough serum concentrations that were non-inferior to those achieved with intravenous rituximab 500 ...mg/m(2) in patients with chronic lymphocytic leukaemia. In part two of the study, we aimed to confirm the pharmacokinetic non-inferiority of subcutaneous rituximab, and investigate its safety and efficacy.
We did this phase 1b, open-label, randomised controlled non-inferiority study at 68 centres in 19 countries in Europe, North America, South America, and Australasia. Patients aged 18 years or older with untreated chronic lymphocytic leukaemia were randomly assigned, via an interactive voice-response system with a permuted block randomisation scheme (block size of ten), to receive subcutaneous rituximab 1600 mg or intravenous rituximab 500 mg/m(2) plus fludarabine and cyclophosphamide every 4 weeks for up to six cycles. In cycle one, all patients received intravenous rituximab 375 mg/m(2). Randomisation was stratified by Binet stage and fludarabine and cyclophosphamide administration route (oral vs intravenous). Study investigators and patients were not masked to group allocation, but allocation was concealed from the statistician, clinical scientist, and clinical pharmacologist. The primary endpoint was trough serum concentration at cycle five, with a non-inferiority margin of 0·8 for the adjusted geometric mean ratio of the subcutaneous to the intravenous dose. We did the primary analysis in patients in the intention-to-treat population with complete pharmacokinetic data (pharmacokinetic population). This trial is registered with ClinicalTrials.gov, number NCT01292603, and is ongoing, although the treatment stage is now complete.
Between Aug 20, 2012, and June 17, 2013, we randomly assigned 176 patients to receive subcutaneous rituximab (n=88) or intravenous rituximab (n=88); 134 (76%) patients comprised the pharmacokinetic population. As of May 7, 2014, median follow-up was 13·9 months (IQR 11·9-16·0) for patients in the subcutaneous group and 14·1 months (11·6-16·5) for patients in the intravenous group. At cycle five, the geometric mean trough serum concentration in patients given subcutaneous rituximab was non-inferior to that in patients given intravenous rituximab (97·5 μg/mL vs 61·5 μg/mL), with an adjusted geometric mean ratio of 1·53 (90% CI 1·27-1·85). In the safety analysis, the proportion of patients reporting adverse events was similar between the subcutaneous and intravenous groups (all grades: 82 96% of 85 patients and 81 91% of 89 patients; serious adverse events: 25 29% and 29 33% patients; grade ≥3: 59 69% and 63 71% patients, respectively). The most common adverse event of grade 3 or higher was neutropenia (48 56% patients in the subcutaneous group and 46 52% patients in the intravenous group); the most common serious adverse event was febrile neutropenia (n=9 11% and n=4 4%, respectively). We recorded administration-related reactions in 37 (44%) patients given subcutaneous rituximab and 40 (45%) patients given the intravenous dose, with differences between administration routes for injection-site erythema (n=10 12% and n=0, respectively) and nausea (n=2 2% and n=11 12%, respectively). More patients reported local cutaneous reactions after subcutaneous rituximab (n=36 42%) than after intravenous rituximab (n=2 2%); most of these reactions were grade 1 or 2.
When combined with fludarabine and cyclophosphamide, subcutaneous rituximab 1600 mg achieved trough serum concentrations that were pharmacokinetically non-inferior to those achieved with intravenous rituximab 500 mg/m(2), with a similar safety and efficacy profile between the two groups. Treatment with subcutaneous rituximab should allow patients with chronic lymphocytic leukaemia to receive clinical benefit from the drug via a more convenient delivery method than the intravenous route, and might also be used in combination regimens with approved and emerging oral regimens.
F Hoffmann-La Roche.
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