Ian W. Flinn

In the multinational, phase 3 RELEVANCE trial, 1030 patients with previously untreated follicular lymphoma were randomized to receive rituximab + lenalidomide (R2; n = 513) or rituximab-based immunochemotherapy (R-Chemo; n = 517). In the final analysis, at 120 months of follow-up, median progression-free survival (PFS) was comparable between the treatment groups: 110.6 months with R2 vs 102.8 months with R-Chemo, according to the independent review committee assessment. The 10-year PFS rates were 46.4% for R2 and 46.6% for R-chemo. Median overall survival (OS) and time-to-next lymphoma treatment (TTNLT) were not reached in either arm; 10-year OS rates were 82.4% for R2 and 81.1% for R-chemo, and 10-year TTNLT rates were 62.2% for R2 and 66.3% for R-chemo. Overall, patients with progression of disease within 24 months (POD24) had a poorer prognosis than those without POD24 (hazard ratio, 6.215; P< .0001); however, no difference was observed between the study groups. The incidence of second primary malignancies (SPMs) was 2.11 cases per 100 patient-years (95% confidence interval, 1.80-2.46). Only 9 transformations occurred after 24 months (3 with R2 vs 6 with R-chemo). In each study group, 87 patients died, mainly because of lymphoma progression and SPMs. This long-term follow-up of RELEVANCE confirmed that R2 provides a chemotherapy-free alternative to immunochemotherapy in this patient population. This trial was registered at www.clinicaltrials.gov as NCT01476787 and NCT01650701 and at EudraCT as 2011-002792-42.

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who harbor del(17p) and/or tumor protein p53 (TP53) mutations represent a high-risk population with a historically poor prognosis. To assess zanubrutinib efficacy and safety outcomes in patients with CLL/SLL with del(17p) and/or TP53 mutations (N = 301; n = 132, treatment-naive [TN]; n = 169, relapsed/refractory [R/R]), data from SEQUOIA (phase 3; TN; zanubrutinib; NCT03336333), ALPINE (phase 3; R/R; zanubrutinib vs ibrutinib; NCT03734016), and AU-003 (NCT02343120) (phase 1/2; zanubrutinib) were evaluated. In SEQUOIA (n = 127; median follow-up, 64.8 months), median progression-free survival (PFS) and overall survival (OS) were not reached; estimated 60-month PFS and OS were 70.7% and 82.3%, respectively. In ALPINE (n = 75, each treatment arm; median follow-up, 39.0 months), 36-month PFS rates were 59.2% among patients treated with zanubrutinib and 38.5% among those treated with ibrutinib, and OS rates were 73.6% and 72.5%, respectively. In AU-003 (n = 24; median follow-up, 69.6 months), 10 of 24 patients experienced progressive disease. Rate of response with zanubrutinib in SEQUOIA was 96.9% (95% confidence interval [CI], 95.2-98.8), and in ALPINE was 89.3% (95% CI, 80.1-95.3) with zanubrutinib vs 76.0% (95% CI, 64.7-85.1) with ibrutinib. Responses deepened over time in both TN and R/R populations. The most frequent nonhematologic treatment-emergent adverse events occurring in >20% of patients treated with zanubrutinib with del(17p) and/or TP53 mutations in SEQUOIA and ALPINE were COVID-19, upper respiratory tract infection, arthralgia, diarrhea, and contusion. In conclusion, zanubrutinib demonstrated strong efficacy in high-risk del(17p) and/or TP53 CLL/SLL, with a tolerable safety profile, further supporting use of zanubrutinib in both frontline and R/R settings.

Change in frequency of Nkp46+ NK cells in the peripheral blood of patients with ianalumab treatment (3.0 mg/kg), as assessed by flow cytometry.

VAF (%) kinetics for patients with baseline ibrutinib resistance mutation.

Model predicted receptor occupancy (RO) in (A) serum, (B) tissue assuming 30% tissue penetration.

Percentage of immunoglobulin change across visits.

Baseline counts of NK cells and NKG2D-expressing NK cells in the peripheral blood of patients.

. Changes in CLL cells in bone marrow measured by flow cytometry by baseline ibrutinib resistance mutation status, at baseline and C9D1

Ianalumab serum concentration-time profiles dose (escalation phase and expansion phase).

Changes in B cell concentration by baseline ibrutinib resistance mutation status, at baseline and C9D1.