Concomitant use of venetoclax 100 mg and ketoconazole, a strong CYP3A4 inhibitor, is clinically equivalent to venetoclax 400 mg for treating relapsed or refractory chronic lymphocytic leukemia (CLL): A real-world analysis from the brazilian CLL regis

Abstract Background: Venetoclax is a selective BCL-2 inhibitor that has demonstrated significant efficacy in chronic lymphocytic leukemia (CLL), resulting in durable responses and improved survival. Since venetoclax is primarily metabolized via CYP3A4, co-administration with strong CYP3A4 inhibitors (e.g., ketoconazole) can markedly increase plasma levels. This necessitates dose adjustments to mitigate toxicity, particularly tumor lysis syndrome. In the Brazilian public health context, access to venetoclax is often limited. To optimize drug availability, a strategy combining 100 mg of venetoclax with ketoconazole was implemented. This study aimed to compare the efficacy and safety of low-dose venetoclax plus ketoconazole (“Ketoven” protocol) versus standard-dose venetoclax (400 mg), with or without rituximab, in patients with relapsed/refractory CLL. Methods: This real-world analysis included 112 patients from the Brazilian CLL Registry. All patients initiated venetoclax on day 22 of cycle 1 with a five-week ramp-up (20–200 mg). Patients then received either venetoclax 100 mg plus ketoconazole 200 mg daily (n = 23) or venetoclax 400 mg daily (n = 89) for up to 24 cycles. Rituximab (375 mg/m² in cycle 1 and 500 mg/m² in cycles 2–6) was administered to 76 patients. All patients had at least six months of follow-up at the data cutoff. Results: The median age was 66 years, and 61% of the patients were male. Treatment was administered as follows: second line in 45% of patients, third line in 26%, fourth line in 22%, and fifth line or higher in 7%. The overall response rate (ORR) was 97% (96% in the Ketoven group versus 98% in the standard treatment group). No grade ≥2 hepatic toxicity attributed to ketoconazole was observed. After a median follow-up of 21 months (range 6–92 months), the time to next treatment (TTNT) had not been reached. The TTNT at 2 years was 73%. TTNT at 2 years was significantly shorter in patients who received venetoclax in later lines compared to those treated in second line (TTNT at 2 years: 59% vs. 89%, respectively; P=0.03). There was a trend to shorter TTNT at 2 years in patients with del(17p)/TP53 mutations compared to patients without these genetic alterations (44% vs. 74%, P = 0.06). TTNT at 2 years was similar between patients receiving the ketoven protocol (67%) and the regular protocol (73%, P=0.76) and in patients that received rituximab (74%) as compared to those who received monotherapy (71%; P = 0.46). TTNT remained similar between patients treated with or without ketoconazole, even after adjusting for del(17p)/TP53 mutations and line of therapy. The median overall survival (OS) was not reached, and the OS at 2 years was 74%. There was no significant difference in OS at 2 years between the groups (74% for those who received regular treatment and 75% for those who received treatment in combination with ketoconazole). Conclusion: Low-dose venetoclax plus ketoconazole demonstrated similar efficacy and tolerability to standard-dose venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). This cost-saving approach may be a viable alternative in settings with limited resources. Further prospective studies are needed to validate these findings and support broader implementation.