Activity and Safety of Venetoclax without Anti-CD20 Lead-in Therapy in Treatment Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia

Background:

Venetoclax-based therapies have shown high efficacy in treating chronic lymphocytic leukemia (CLL). In treatment-naïve (TN) patients, these therapies lead to deep and long-lasting responses, with a five-year progression-free survival (PFS) rate of 63% (Al-Sawaf O, Nat Commun, 2023). However, for relapsed/refractory (RR) CLL patients previously treated with Bruton’s Tyrosine Kinase Inhibitor (BTKi) , the median PFS is reportedly shorter, at approximately 24 months (Jones JA, Lancet Oncology, 2018; Lew TE, Blood Advances, 2024). Current strategies to mitigate TLS risk include lead-in anti-CD20 therapy weekly x3 in TN patients. In patients discontinuing BTKi therapy due to progressive disease (PD), disease flare is common and may be uncomfortable (Hampel PJ, Oncologist, 2020). Retrospective evidence suggests that overlapping venetoclax with BTKi therapy during BTKi progression can prevent CLL disease flare (Hampel PJ, Am J Hematol, 2020). In this prospective phase 2 study (NCT03986034), we evaluated the efficacy, safety, and depth of response in CLL patients treated with venetoclax without anti-CD20 lead-in (for all patients) and without BTKi overlap (for RR patients).

Methods:

Patients with active TN or RR CLL requiring treatment received venetoclax 400 mg once daily for 12 28-day cycles (TN) or 24 cycles (RR) following a 5-week ramp-up. Patients could opt for venetoclax monotherapy or add anti-CD20 therapy (rituximab or obinutuzumab) for 6 cycles after the 5-week ramp-up. Response assessments were conducted at one year with CT scans, followed by physical examinations and complete blood counts. Minimal residual disease (MRD) was assessed annually using peripheral blood flow cytometry, with undetectable MRD (uMRD) defined as <1 CLL cell per 10,000 leukocytes.

Results:

Among 50 patients, 24 (48%) were TN, and 26 (52%) were RR. The median follow-up was 31 months for all patients, 22 months for TN patients, and 40 months for RR patients. The median age was 62.0 years for TN and 65.5 years for RR patients (p=0.07). A complex karyotype (≥3 abnormalities) was present in 8 (33%) TN and 11 (42.3%) RR patients (p=0.6). Among RR patients, 24 (92%) had prior BTKi; 21 (88%) discontinued BTKi due to PD and 3 (13%) discontinued due to toxicity. BTK and/or PLCG2 resistance mutations were detected in 13 (54%) patients with prior BTKi exposure. All TN patients received anti-CD20 therapy (96% with obinutuzumab and 4% with rituximab). Among RR patients, 88.5% received anti-CD20 therapy (46% with obinutuzumab and 42% with rituximab). The PFS rate at 2 years was 87% for all patients, 92% for TN and 83% for RR patients (p=0.1). The proportion of TN and RR patients with uMRD at the end of treatment (EOT) was 88% and 85%, respectively. At 1 year after EOT, 92% of TN patients and 40% of RR patients had uMRD. There have been 1 TN patient and 6 RR patients who have developed PD, of whom 40% had uMRD at EOT.

The most common adverse event (SAE) was laboratory TLS, occurring in 2 (4%) patients at the 100 mg dose. Both were RR patients with medium TLS risk at baseline; one had a complex karyotype and lymph nodes >5 cm, and the other developed TLS upon resuming venetoclax after an 8-day dose interruption due to neutropenia. CLL flares during the venetoclax ramp-up were observed in 5 (21%) RR patients after discontinuing BTKi therapy. Symptoms included swollen/painful lymph nodes and fever, with three patients receiving short-course steroids (prednisone 20 mg for 3 days or methylprednisolone 50 mg for 1 day). All flares resolved by the start of venetoclax 400 mg once daily. Neutropenia led to venetoclax interruptions during the ramp-up in 6 (12%) patients, with a median drug hold duration of 6 days (range 3-9). All 6 patients responded to G-CSF administration and only one patient required long-term dose-reduction due to neutropenia.

Conclusions:

In this prospective study of venetoclax-based therapy, the 2-year PFS rate was 92% in TN and 83% in RR CLL patients. In RR patients mostly with prior BTKi therapy, this 2-year PFS rate compares favorably to recent reports. The venetoclax ramp-up without anti-CD20 lead-in proved safe for TN and RR CLL patients, exhibiting low rates of laboratory TLS. CLL flares following BTKi discontinuation occurred in 21% of RR patients but were self-limiting and manageable with short courses of steroids. An additional cohort has been opened to assess the effect of venetoclax and BTKi overlap on preventing CLL disease flare.