Zanubrutinib for treatment-naïve and relapsed/refractory chronic lymphocytic leukaemia: long-term follow-up of the phase I/II AU-003 study.

The phase I/II AU-003 study in patients with treatment-naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma.

Zanubrutinib (BGB-3111) is a next-generation Bruton tyrosine kinase inhibitor designed to be more selective with fewer off-target effects. We conducted a phase 1 study to assess the safety of its combination with obinutuzumab and evaluate early efficacy in 81 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or relapsed/refractory (R/R) follicular lymphoma (FL). In this phase 1b study, zanubrutinib was tolerable at 160 mg twice daily or 320 mg once daily combined with IV obinutuzumab in patients with CLL/SLL (n = 45) and FL (n = 36). Common adverse events (AEs) included upper respiratory tract infection (51%; n = 23), neutropenia (44%; n = 20), contusion (33%; n = 15), cough, diarrhea, or fatigue (27%; n = 12 each), and pyrexia (22%; n = 10) in CLL/SLL patients and upper respiratory tract infection (39%; n = 14), contusion (28%; n = 10), fatigue (25%; n = 9), and cough (22%; n = 8) in FL patients. Neutropenia was the most common grade 3/4 AE (CLL/SLL, 31% [n = 14]; FL, 14% [n = 5]). Five patients required temporary dose reductions, and 5 discontinued the study drug because of AEs. Overall response rate (ORR) was 100% (n = 20) in treatment-naïve CLL patients and 92% (n = 23) in R/R CLL patients. ORR in 36 R/R FL patients was 72% (n = 26), with 14 complete and 12 partial responses. Median follow-up was 29 months (range, 8-37) for CLL patients and 20 months (range, 2-37) for FL patients. Zanubrutinib and obinutuzumab combination therapy was generally well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02569476.

Preference for monthly darbepoetin alfa dosing in patients with chronic kidney disease not receiving dialysis.

OBJECTIVE: To determine patient preference for once-weekly Epoetin alfa versus once-monthly (QM) darbepoetin alfa in patients with chronic kidney disease (CKD) not receiving dialysis. METHODS: AMPS (Aranesp Monthly Preference Study) consisted of two studies of similar design, each with a 2-week screening/baseline period, a 20-week QM darbepoetin alfa dosing period, and an 8-week follow-up period. Patients aged > or = 18 years had a nephrologist-reported diagnosis of CKD but were not receiving dialysis, and were required to have at least two hemoglobin levels within 10-12 g/dL and to have been receiving a stable dose (< 25% change) of once-weekly or once-every-other-weekly Epoetin alfa for at least 8 weeks. At week 21, patients could continue on QM darbepoetin alfa or revert back to their previous Epoetin alfa regimen. The primary analysis assessed patient preference at week 21 for QM darbepoetin alfa versus previous once-weekly Epoetin alfa. RESULTS: AMPS enrolled 442 patients: 54% were female, 67% were Caucasian, and mean (SD) age was 68.3 (13.5) years. At week 21, 346 patients remained on study. Of the patients converted from once-weekly Epoetin alfa, 86% (138/161) preferred darbepoetin alfa QM, and of all patients who expressed a preference, regardless of previous Epoetin alfa dosing frequency, 96% (305/319) preferred QM darbepoetin alfa. Mean (SD) hemoglobin at week 29 of the study was similar to mean hemoglobin at baseline (for those who completed the study and were receiving QM darbepoetin alfa at week 29: 11.2 [1.1] g/dL at week 29 versus 11.4 [0.7] g/dL at baseline). QM darbepoetin alfa was well tolerated. CONCLUSION: These data show that the majority of study patients preferred QM darbepoetin alfa to more frequent Epoetin alfa, and that QM darbepoetin alfa maintained hemoglobin levels at week 29 and was well tolerated over the study period. The single-item questionnaire could be a potential limitation of this study and further investigation with a multi-question instrument may be helpful in confirming these results.

Darbepoetin alfa administration to achieve and maintain target hemoglobin levels for 1 year in patients with chronic kidney disease.

OBJECTIVE: To assess the efficacy and safety of every-other-week darbepoetin alfa therapy in treating anemia and maintaining hemoglobin levels for 1 year in patients with chronic kidney disease (CKD) who were not undergoing dialysis and who had not previously received erythropolesis-stimulating proteins (ESPs). PATIENTS AND METHODS: This multicenter 52-week study (evaluation period, weeks 20-32), a subanalysis of the Simplify the Treatment of Anemia with Aranesp study, enrolled patients with CKD who were not receiving dialysis (creatinine clearance < or =70 mL/min or estimated glomerular filtration rate [GFR] < or =60 mL/min). Patients evaluated in this analysis were not receiving ESPs, had hemoglobin concentrations less than 11 g/dL, and had transferrin saturation of 20% or higher during screening. Patients Initiated every-other-week darbepoetin alfa therapy at 0.75 microg/kg, with the dose subsequently titrated to maintain hemoglobin levels not to exceed 12 g/dL. The first study participant was enrolled on February 4, 2002, and the last participant completed the study on March 31, 2004. RESULTS: The analysis included 911 patients (mean [SD] age, 66.4 [14.2] years; 54.3% female; 55.3% white). The least squares mean evaluation hemoglobin concentration was 11.54 g/dL (95% confidence interval, 11.47-11.61 g/dL), and the change from baseline was 1.6 g/dL (95% confidence interval, 1.5-1.7 g/dL). The mean (SD) every-other-week darbepoetin alfa dose during evaluation was 44.5 (33.7) microg. Iron supplementation was administered to 573 patients (62.9%) during the study. Darbepoetin alfa was well tolerated throughout the study period. CONCLUSION: Darbepoetin alfa initiated every other week safely and effectively treated anemia and maintained hemoglobin for 1 year in patients with CKD who were not undergoing dialysis and who were not receiving prior ESP therapy.

Darbepoetin alfa administered every other week maintains hemoglobin levels over 52 weeks in patients with chronic kidney disease converting from once-weekly recombinant human erythropoietin: results from simplify the treatment of anemia with Aranesp (STAAR).

BACKGROUND/AIM: Darbepoetin alfa, an effective treatment for anemia of chronic kidney disease (CKD), can be administered at extended intervals. Simplify the Treatment of Anemia with Aranesp (STAAR), a multicenter, 52-week study, was conducted to assess the efficacy of darbepoetin alfa administered subcutaneously every other week (Q2W) in maintaining hemoglobin (Hb) in CKD patients not receiving dialysis. METHODS: This is a subgroup analysis of subjects converted from once-weekly (QW) recombinant human erythropoietin (rHuEPO; US Aranesp package insert) and who received up to 52 weeks of darbepoetin alfa therapy (evaluation period 20-32 weeks). Enrolled subjects had a creatinine clearance < or = 70 ml/min or an estimated glomerular filtration rate < or = 60 ml/min and transferrin saturation > or = 20%. Darbepoetin alfa doses were titrated to maintain Hb levels < or = 12 g/dl. The primary endpoint was mean Hb during evaluation. RESULTS: There were 524 subjects enrolled in the study who were previously receiving rHuEPO QW. Mean Hb +/- standard deviation was 11.2 +/- 1.27 g/dl at baseline, and the least squares mean +/- SE was 11.4 +/- 0.04 during evaluation. The mean +/- SD Q2W darbepoetin alfa dose was 49.7 +/- 21.9 microg at baseline and 48.9 +/- 35.5 microg at evaluation. Darbepoetin alfa was well tolerated. CONCLUSIONS: Study subjects with CKD receiving QW rHuEPO were effectively converted to Q2W darbepoetin alfa, which was well tolerated. Hb levels were maintained over 52 weeks without a significant change in darbepoetin alfa dose.