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Summary: The combination of the phosphatidylinositol 3‐kinase delta (PI3Kδ) inhibitor zandelisib with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib was hypothesized to be synergistic and prevent resistance to single‐agent therapy. This phase 1 study (NCT02914938) included a dose‐finding stage in patients with relapsed/refractory (R/R) B‐cell malignancies (n = 20) and disease‐specific expansion cohorts in follicular lymphoma (FL; n = 31) or mantle cell lymphoma (MCL; n = 19). The recommended phase 2 dose was zandelisib 60 mg on Days 1–7 plus zanubrutinib 80 mg twice daily continuously in 28‐day cycle. In the total population, the most common adverse events (AEs; all grades/grade 3–4) were neutropenia (35%/24%), diarrhoea (33%/2%), thrombocytopenia (32%/8%), anaemia (27%/8%), increased creatinine (25%/0%), contusion (21%/0%), fatigue (21%/2%), nausea (21%/2%) and increased aspartate aminotransferase (24%/6%). Three patients discontinued due to AEs. The overall response rate was 87% (complete response [CR] = 33%) for FL and 74% (CR = 47%) for MCL. The median duration of response and progression‐free survival (PFS) were not reached in either group. The estimated 1‐year PFS was 72.3% (95% confidence interval [CI], 51.9–85.1) for FL and 56.3% (95% CI, 28.9–76.7) for MCL (median follow‐up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone. [ABSTRACT FROM AUTHOR]

Targeted therapies have largely replaced chemoimmunotherapy (CIT) in first-line treatment of chronic lymphocytic leukemia (CLL). We aimed to develop a prognostic model to determine who would benefit from first-line CIT vs target therapy. In follicular lymphoma, time from diagnosis to second treatment (TT2T) correlates better with overall survival (OS) than time from diagnosis to first treatment (TT1T). We hypothesized that TT2T is a potential surrogate for OS in CLL. In a model-building cohort (n = 298), we evaluated potential predictors for TT2T and derived a risk score, which we validated in an external cohort (n = 1141). Our data demonstrated that TT2T and OS were more strongly correlated than TT1T and OS. Our risk score model consisted of three predictors (unmutated IGHV, β2-microglobulin >297 nmol/L, and Rai stage I–IV), and was prognostic for TT2T and OS. TT2T is a promising surrogate for OS in CLL, but further validation is needed to establish this association. [ABSTRACT FROM AUTHOR]

Background: Phosphatidylinositol 3-kinase p110δ (PI3Kδ) inhibitors are efficacious in B-cell malignancies. Immune-related adverse events might be mitigated with intermittent dosing. We aimed to evaluate the safety and antitumour activity of zandelisib, a potent novel PI3Kδ inhibitor, with continuous or intermittent dosing as monotherapy or in combination with rituximab, in patients with relapsed or refractory B-cell malignancy.Methods: We conducted a first-in-patient, dose-escalation and dose-expansion, phase 1b trial at ten treatment centres across Switzerland and the USA. Eligible patients were aged 18 years or older with relapsed or refractory B-cell malignancy (limited to follicular lymphoma or chronic lymphocytic leukaemia during dose escalation) and an Eastern Cooperative Oncology Group performance status of 0-2, and had received at least one previous line of therapy and no previous PI3Kδ inhibitor treatment. In the dose-escalation study, participants received oral zandelisib once daily (60 mg, 120 mg, or 180 mg; we did not evaluate four additional planned dose levels). The 60 mg dose was further evaluated as monotherapy or with intravenous rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3-6, using a continuous daily schedule or intermittent dosing therapy (days 1-28 of cycles 1-2 and days 1-7 of subsequent cycles) in 28-day cycles. Treatment was continued until evidence of disease progression, intolerance, or withdrawal of consent by the patient. Primary endpoints were safety (dose-limiting toxicities and maximum tolerated dose), minimum biologically effective dose, and a composite endpoint to assess the activity of each dose level, and were analysed by intention to treat. The zandelisib monotherapy and zandelisib-rituximab combination cohorts have completed accrual, but accrual to a cohort evaluating zandelisib with zanubrutinib is ongoing. This study is registered with ClinicalTrials.gov, NCT02914938.Findings: Between Nov 17, 2016, and June 2, 2020, 100 patients were assessed for eligibility and 97 were enrolled and received zandelisib monotherapy (n=56) or zandelisib plus rituximab (n=41), with zandelisib administered on either a continuous schedule (n=38) or with intermittent dosing (n=59). No dose-limiting toxicities were observed, the objective of determining the maximum tolerated dose was abandoned, and antitumour activity was similar across the evaluated doses activity (objective responses in 11 [92%; 95% CI 61·5-99·8] of 12 patients at both 60 mg and 120 mg doses, and in five [83%; 95% CI 35·9-99·6] of six patients at 180 mg). With a median duration of exposure of 15·2 months (IQR 3·7-21·7), the most common grade 3-4 adverse events were neutrophil count decrease (ten [17%] of 59 patients in the intermittent dosing group and four [11%] of 38 in the continuous dosing group), diarrhoea (three [5%] and eight [21%]), pneumonia (one [2%] and six [16%]), alanine aminotransferase increase (three [5%] and two [5%]), and colitis (two [3%] and one [3%]). 26 (44%) of 59 patients in the intermittent dosing group and 29 (76%) of 38 patients in the continuous dosing group had grade 3-4 adverse events. Treatment-related serious adverse events occurred in eight (21%) patients in the continuous dosing group and five (8%) patients in the intermittent dosing group. There were no treatment-related deaths.Interpretation: Zandelisib 60 mg once daily on an intermittent dosing schedule was safe, with low frequency of grade 3 or worse adverse events, warranting the ongoing global phase 2 and phase 3 trials.Funding: MEI Pharma. [ABSTRACT FROM AUTHOR]

Although treatment with anti-CD20 monoclonal antibodies (mAb) has improved outcomes in B-cell malignancies, it's associated with increased risk of hypogammaglobulinemia (HG). Our study aimed to determine the effects of anti-CD20 mAb on serum immunoglobulins (Ig) in follicular lymphoma (FL). Ig concentrations, infectious complications, and need for intravenous Ig were evaluated by level of exposure to anti-CD20 mAb in 380 patients. Prevalence of HG significantly differed by level of treatment exposure (p < 0.001). Single course anti-CD20 mAb was associated with rising IgG (+10.3 mg/dL/year), whereas the addition of maintenance therapy (−7.4 mg/dL/year) or multiple courses of treatment (−10.3 mg/dL/year) was associated with declining IgG. Among patients treated with anti-CD20 mAb, 45.2% developed IgG-HG and 10.3% developed symptomatic IgG-HG. Pretreatment IgG levels gradually declined in all patients, suggesting tumor burden may contribute to HG. Baseline and periodic monitoring of serum Ig is appropriate in patients with FL, including those managed with active surveillance. [ABSTRACT FROM AUTHOR]

It is difficult to demonstrate an overall survival (OS) benefit in trials of immediate therapy vs observation in follicular lymphoma (FL). Time to 2nd treatment (TT2T) may be a preferred endpoint. We identified 584 consecutive patients at our institution with advanced stage FL grade 1–3 A for whom intention was observation (n = 248) or therapy (n = 338). Median time to 1st treatment (TT1T), TT2T, and OS were estimated (subdistribution function). Modified Kendall's tau (mKτ) was used to assess correlation between survival endpoints. Among initially observed patients, median TT1T was 3.3 years, TT2T was 12.1 years, 10-year treatment-free survival was 23%, and 10-year OS was 82%. TT2T was strongly correlated with OS following initial observation (mKτ 0.46, p =.004) or therapy (mKτ 0.53, p <.0001), while duration of observation was not. TT2T is a potential surrogate for OS. Given the outstanding survival in this population, early intervention trials should focus on identifying high risk patients. [ABSTRACT FROM AUTHOR]