Among patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL), extended lead in-treatment with Imbruvica (ibrutinib) followed by two years of Imbruvica and Venclexta (venetoclax) was found to be beneficial.
“Our data indicate that a prolonged [Imbruvica] lead-in followed by a 24-month [Imbruvica and Venclexta] combination offers an acceptable benefit-risk profile in previously treated patients with CLL,” Dr. Adalgisa Condoluci and colleagues wrote in Blood. “This contributes to the growing evidence that a longer duration of [Imbruvica and Venclexta] therapy increases therapeutic effectiveness while minimizing the risk of acquiring resistance mutations by allowing time off treatment.”
Condoluci is a doctor and researcher at the Oncology Institute of Southern Switzerland in Bellinzona, Switzerland.
Prior studies investigating the combination of Imbruvica and Venclexta, researchers for the SAKK 34/17 phase 2 clinical trial wrote in Blood, have begun with a short initial course of Imbruvica, followed by a limited duration of Venclexta induction therapy — typically lasting 12 months.
Glossary:
Tumor lysis syndrome: when cancer cells break apart and flood a patient’s bloodstream.
Minimal residual disease: a small number of cancer cells that remain in a patient’s body during or after treatment.
Complete response: the disappearance of all signs of cancer.
Complete response with incomplete bone marrow recovery: when a patient achieves a complete response but their blood counts have not recovered.
Progression-free survival: the time that a patient lives without their disease spreading and worsening.
Overall survival: the time that a patient lives, regardless of disease status.
In the SAKK 34/17 trial, the lead-in phase with Imbruvica was six months in an effort to reduce both tumor burden and tumor lysis syndrome (TLS) risk, while the treatment phase with Imbruvica and Venclexta was extended to a minimum of 24 months in an attempt to enhance the undetectable minimal residual disease (uMRD) rate.
The primary endpoint of the study was the rate of complete response or complete response with incomplete bone marrow recovery (CR/Cri) with uMRD in both bone marrow and peripheral blood, with secondary endpoints including an assessment of the proportion of patients who transitioned to low-risk for TLS after being treated with Imbruvica lead-in therapy.
Researchers stated that 40% of the 30 patients with R/R CLL who were enrolled in the study achieved a status of uMRD CR/Cri, with 53.3% showing uMRD in the bone marrow and peripheral blood. Additionally, after the Imbruvica lead-in period, 57.1% of patients were at low risk for TLS.
The median progression-free survival and overall survival times were not reached, with estimated rates at cycle 31 being 89.9% and 93.3%, respectively.
More About the SAKK 34/17 Study
Patients with R/R CLL were recruited from 10 hospitals in Switzerland between March 2019 and August 2020, with a median age of 69 years and 73.3% of whom were male. Patients received 420 milligrams (mg) of Imbruvica daily for six 28-day cycles, followed by the addition of Venclexta at a five-weekly dose escalation up to 400 mg daily, researchers stated. Patients with a high TLS risk after the sixth cycle received the first two doses of Venclexta in an inpatient setting.
Combined therapy was administered for 24 28-day cycles, and patients who were not in uMRD with CR/Cri after the 30th cycle received consolidation treatment with the combination until achieving uMRD CR/Cri, disease progression, unacceptable toxicity or for a time up to five years.
Patients’ median time on treatment was 28.6 months. After a median follow-up of 42 months, one patient — who had discontinued study treatment after 2.4 months of Imbruvica lead-in due to a side effect — experienced disease progression 19.7 months after interrupting Imbruvica.
Researchers stated that five patients died, with one death due to a thrombotic stroke during the observation phase 1.5 months after completing treatment determined to be probably related to Imbruvica. The other four deaths were determined by investigators to be unrelated or unlikely to be related to the study drugs and happened after treatment discontinuation.
Regarding safety, the most frequent side effects of any grade were hypertension (60%), diarrhea (43.3%),contusion (40%), neutropenia (36.7%) and fatigue (33.3%). The most frequent grade 3 (severe) or higher side effects related to Imbruvica were hypertension (30%) and lung infection (3.3%), and for Venclexta was neutropenia (30%).
Serious side effects were experienced by 63.3% of patients, treatment-related serious side effects attributed to Imbruvica were experienced by 36.7% of patients and 30% of patients had treatment-related serious side effects that were attributed to the combination.
By the end of cycle 30, 36.7% of patients had discontinued treatment, with seven due to side effects, and dose modifications such as reductions, delays and omissions were reported for 70% of patients.
Reference:
“Ibrutinib Lead-in followed by Venetoclax Plus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia - SAKK 34/17” by Dr. Adalgisa Condoluci et al., Blood.
For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here.
