Duvelisib Plus Venetoclax Is Active in Relapsed/Refractory CLL and Richter Syndrome

Duvelisib (Copiktra) plus venetoclax (Venclexta) was shown to be active in relapsed/refractory chronic lymphocytic leukemia (CLL) and Richter syndrome (RS), including in patients with high-risk, TP53-aberrant disease and those who had received prior treatment with BTK inhibitors, according to data from the phase 2 portion of a phase 1/2 trial (NCT03534323) that were presented at the 2024 ASH Annual Meeting.1

The complete remission (CR) and CR with incomplete count recovery (CRi) rates were 62% in patients with CLL or small lymphocytic lymphoma (SLL; n = 29). After cycle 12, the CR/CRi rate was 44% in this population. The CR/CRi rate in the TP53-aberrant patient subgroup (n = 14) was 64%; in patients with TP53-aberrant disease who had received prior BTK inhibition (n = 13), this rate was 46%.

Among the patients with RS (n = 9), 3 achieved CR, 1 of whom proceeded to allogeneic stem cell transplantation (alloSCT) and remained in remission 2.3 years later.

“The all-oral, minimal residual disease [MRD]–driven, time-limited regimen duvelisib plus venetoclax is active in relapsed/refractory CLL and RS, including in high-risk patients with TP53-aberrant disease and [those who received treatment] post-BTK inhibitor,” lead study author Jennifer L. Crombie, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, said during a presentation of the data.

Phase 2 Trial Design and Baseline Patient Characteristics

Duvelisib was granted standard approval by the FDA in September 2018 for the treatment of patients with relapsed/refractory CLL/SLL following at least 2 prior lines of therapy.2

The phase 1 portion of the phase 1/2 trial, findings from which have been previously reported, evaluated the safety of duvelisib plus venetoclax to determine the appropriate dose of venetoclax plus duvelisib and monitor adverse effects (AEs).3

Patients included in the phase 2 portion had confirmed diagnoses of CLL/SLL requiring treatment per iwCLL 2008 criteria or RS confirmed by biopsy.1 Study inclusion criteria included disease progression or relapse following at least 1 prior line of CLL/SLL therapy for the CLL/SLL cohort (no prior therapy was required for the RS cohort); age of 18 years or older; absolute neutrophil counts of at least 500 cells/mm3 and platelet counts of at least 25,000 cells/mm3 (unless there was marrow involvement); adequate renal and hepatic function; and an ECOG performance status of 2 or lower.

Treatment with the duvelisib and venetoclax combination included a 7-day lead-in period in which patients received duvelisib at 25 mg twice daily and the start of venetoclax dosing on day 8 at 10 mg administered in the outpatient setting or 20 mg administered in the inpatient setting with weekly ramp-up to 400 mg daily. Patients with RS could be treated with accelerated daily venetoclax ramp-up dosing to 400 mg over 5 days.

The combination was given for 12 cycles, after which patients with CR with undetectable MRD (uMRD) discontinued treatment, and those who had detectable MRD continued venetoclax monotherapy. Retreatment with venetoclax was permitted in patients with recurrent MRD. Toxicity was assessed by CTCAE 4.03 criteria, and response was assessed by 2008 iwCLL criteria for CLL/SLL and Lugano 2014 criteria for RS.

The primary end point of the study was best rate of CR with the combination. Secondary end points included best objective response rate (ORR), duration of response, progression-free survival (PFS), overall survival (OS), and rates of MRD in the peripheral blood and bone marrow.

Patients included in the study were characterized based on disease (CLL vs RS). In these respective cohorts, the median ages were 69 (range, 50-79) and 64 (range, 55-72) years; 65.5% and 77.8% of patients were male; 72.4% and 44.4% of patients had unmutated IGHV status; 44.8% and 22.2% of patients had TP53 mutations; and 58.6% and 33.3% of patients had been previously treated with BTK inhibitors. Furthermore, 41.3% of patients in the CLL cohort had Rai stage III or IV disease. The median numbers of prior therapies were 1 (range, 1-5) and 2 (range, 1-4), respectively. Fluorescence in situ hybridization cytogenetics included 17p deletion (CLL, 31.0%; RS, 11.1%), 11q deletion (13.8%; 0%), trisomy 12 (17.2%; 25.0%), and complex karyotype (24.1%; 33.3%).

Additional Efficacy and Safety Data

The best ORR was 97% in the CLL/SLL cohort, with an ORR of 72% after cycle 12. The best peripheral blood and bone marrow uMRD rates were 60% and 49%, respectively. Following 12 cycles of treatment, the peripheral blood and bone marrow uMRD rates were 45% and 41%, respectively. Eleven patients with uMRD elected to discontinue therapy after treatment with the combination. Three patients experienced recurrent MRD and began venetoclax retreatment; the median length of time off treatment was 1.2 years (range, 0.97-3.7).

In the CLL/SLL cohort, the 3-year PFS and OS rates were 68% and 89%, respectively, and the median PFS was 3.9 years. In patients with TP53 aberrations and prior BTK inhibition, the 3-year PFS rates were 47% and 46%, respectively; the median PFS in both groups was 2.1 years.

In the CLL and RS cohorts combined, the median number of cycles was 13, and reasons for treatment discontinuation included achievement of bone marrow uMRD (CLL, n = 11; RS, n = 0), alloSCT (n = 0; n = 1), disease progression (n = 3; n = 6), unacceptable toxicity (n = 4; n = 1), and fatal COVID-19 pneumonia (n = 1; n = 0).

Serious AEs included colitis (any-grade, 11%; grade 3, 3%), tumor lysis syndrome (grade 3/4, 5%), febrile neutropenia (grade 3, 5%), and infection (grade 3, 5%). Grade 3 or higher neutropenia occurred in 93% of patients, and no opportunistic infections were reported. One patient with gastric perforation required surgical repair during treatment with high-dose steroids to manage diarrhea. Grade 5 AEs included hepatic failure after progressive RS (n = 1) and COVID-19 pneumonia (n = 1).

“Our data support exploration of duvelisib plus venetoclax in larger studies of patients with relapsed/refractory CLL and RS,” Crombie concluded during the presentation.

References

1. Crombie JL, Ryan CE, Ren Y, et al. A phase 2 study of duvelisib and venetoclax in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or Richter’s Syndrome. Blood. 2024;144(suppl 1):4628. doi:10.1182/blood-2024-199234
2. FDA approves duvelisib (Copiktra, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). FDA. September 24, 2018. Accessed January 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/duvelisib-copiktra-verastem-inc-adult-patients-relapsed-or-refractory-chronic-lymphocytic-leukemia
3. Duvelisib and venetoclax in relapsed or refractory CLL or SLL or RS. ClinicalTrials.gov. Updated January 7, 2025. Accessed January 8, 2025. https://clinicaltrials.gov/study/NCT03534323