In This Article
- Venetoclax plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia
- Adding Antiandrogen to Radiation Therapy Extends Survival in Relapsed Prostate Cancer
Monotherapy with venetoclax has demonstrated improvement in overall response and complete remission in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Encouraging synergistic effects seen in preclinical models combining venetoclax with rituximab led to a study evaluating the safety, pharmacokinetics, and activity of this combination in the treatment of patients with relapsed or refractory CLL (Seymour JF, et al. Lancet Oncol. 2017;18:230-240).
This phase 1b clinical trial included 49 patients with relapsed or refractory CLL or small lymphocytic lymphoma, all of whom were given oral venetoclax in a daily, stepwise increase to target doses ranging from 200 mg to 600 mg, plus monthly infusions of rituximab (375 mg/m² in month 1, and 500 mg/m² in months 2-6). The primary end points were safety profile, defining a maximum tolerated dose, and determining the recommended phase 2 venetoclax dose in combination with rituximab. Secondary end points were evaluation of the pharmacokinetic profile and analysis of efficacy (eg, overall response, duration of response, and time until tumor progression).
A total of 42 (86%) patients achieved an overall response with the combination treatment; 51% of patients had a complete response, and 57% achieved negative marrow minimal remaining disease in their bone marrow with acceptable safety. The 2-year estimates for ongoing response and progression-free survival were 89% and 82%, respectively. Eleven patients experienced disease progression during therapy; 6 of these patients achieved a partial response before their CLL progressed.
The adverse event profile and pharmacokinetics of the treatment were not significantly altered by the addition of rituximab. Grade 3 to 4 adverse events occurred similarly to how they did in previous studies of venetoclax monotherapy, with no significant increase in the incidence or severity of neutropenia, and without an increase in the percentage of patients who had a severe infection.
“These results demonstrate that venetoclax and rituximab can be safely delivered without compromise of venetoclax dose, offering a treatment strategy that yields high rates of deep responses that can be maintained for substantial time periods when patients cease therapy,” the study authors concluded. The maximum tolerated dose was not defined.
Patients with prostate cancer who undergo radical prostatectomy and have disease relapse often require salvage radiation therapy, which can lead to further disease progression in 50% of patients. Combining radiation therapy with antiandrogen therapy has prolonged survival in certain men with intact prostates, and the investigators of this study sought to assess whether adding antiandrogen therapy (bicalutamide) to salvage radiation therapy for 24 months could extend overall survival compared with placebo and radiation therapy in men whose diseases relapse postoperation (Shipley WU, et al. N Engl J Med. 2017;376:417-428).
This double-blind, placebo-controlled trial randomized 760 patients with relapsed prostate cancer following radical prostatectomy with lymphadenectomy to receive radiation therapy combined with 24 months of antiandrogen therapy (bicalutamide tablets, 150 mg daily) or placebo. Patients were given salvage radiation therapy within 12 weeks of randomization, with a total dose of 64.8 Gy administered in 36 daily fractions of 1.8 Gy. Placebo or bicalutamide 150 mg was administered daily for 24 months, starting when radiation therapy commenced. The primary end point was the rate of overall survival. Secondary end points included disease-specific death, distant metastases (ie, metastatic prostate cancer), local disease progression, non–disease-specific death, any prostate cancer progression, including a second biochemical recurrence, and adverse events.
Median follow-up was conducted at 13 years. Adding antiandrogen therapy to radiation therapy resulted in a higher overall survival rate (76.3%) at 12 years in patients with persistent or recurrent postoperative disease, compared with those who received placebo (71.3%). At 12 years, the cumulative occurrence of metastatic prostate cancer was 14.5% and 23.0% in the bicalutamide and placebo groups, respectively, whereas the cumulative incidence of a second relapse was 44.0% and 67.9%, respectively. Rates of local disease progression and disease progression of any type (eg, a second biochemical recurrence) were lower in the patients who received bicalutamide compared with placebo.
Multivariate analyses demonstrated that negative prognostic factors significantly affecting overall survival included being in the placebo group, having a prostate-specific antigen (PSA) level >1.5 ng/mL at trial entry, having a prostate cancer Gleason score of 8 to 10, and being aged ≥65 years.
Adverse events were similar between the 2 trial groups; however, grade 1 to 3 gynecomastia occurred in 69.7% of patients receiving bicalutamide, and in 10.9% of those receiving placebo.
“The addition of an antiandrogen agent to salvage radiation therapy resulted in higher rates of overall, disease-specific, and metastasis-free survival than radiation therapy plus placebo among patients who were treated for biochemical (PSA) recurrence of prostate cancer after radical prostatectomy,” the study researchers concluded, noting that the higher rate of overall survival became more apparent in the second decade posttherapy.