ASH 2017 | Combination of venetoclax and ibrutinib: promising phase II results in high-risk and R/R CLL 

On Sunday 10 December 2017 during an oral abstract session at the 59^th Annual meeting American Society of Hematology (ASH), Nitin Jain of MD Anderson Cancer Center in Houston, TX, on behalf of his colleagues, presented results from a phase II study, which investigated the safety and efficacy of venetoclax plus ibrutinib in previously untreated, high-risk and relapsed/refractory chronic lymphocytic leukemia (CLL) patients.

This abstract (#429), “Combined Venetoclax and Ibrutinib for Patients with Previously Untreated High-Risk CLL, and Relapsed/Refractory CLL: A Phase II Trial,” was presented during Oral Session: 642. “CLL: Therapy, excluding Transplantation: Targeting MRD Negative CLL Through Combinations of Novel Agents and Antibody”. The summary here provides data from the presentation at the session and may supersede date in the pre-published ASH abstract.

Highlights

• All patients who completed at least three months of therapy in either cohort had a response
• Significant decrease in bone marrow infiltrate with the addition of VEN, including MRD-negativity or MRD <0.1% in several patients with high-risk cytogenetics

Treatment

• Two patient cohorts were enrolled, a total of 78 patients are planned, 39 in each cohort
  • Cohort 1: relapsed/refractory CLL
  • Cohort 2: untreated pts with at least one high-risk feature: del(17p), mutated TP53, del(11q), non-mutated IGHV, ≥65 years)
• Treatment consisted of ibrutinib (IBR) monotherapy 420mg daily for the first 3 months, followed by addition of venetoclax (VEN), weekly dose escalation to the target dose of 400mg daily
  • IBR may be continued indefinitely, VEN for a total of 2 years
• Primary endpoint was achievement of CR/CRi
  • Response assessment with bone marrow and CT scans every 3 months during the first year, then every 6 months

Efficacy

• 72 pts initiated treatment (Cohort 1, n=33; Cohort 2, n=39), median follow-up was 7.5 months
  • 61 patients have completed IBR monotherapy, and have initiated VEN dose escalation
• Three months of IBR monotherapy resulted in 51% (31/61) down-grade of TLS risk category
  • 2/61 (3%) high-risk for TLS at the time of initiation of VEN

Cohort 1

• 29 pts received IBR monotherapy then initiated VEN dose escalation
• All 14 pts who completed at least 3 months of combination therapy had a response (CR/Cri n=9, PR n=5)
• Significant decrease in bone marrow infiltrate with the addition of VEN

Cohort 2

• 32 patients received IBR monotherapy then initiated VEN dose escalation
• All 16 patients who completed at least 3 months of the combination therapy had a response ( CR/CRi n=9, PR n=7)
• Several of these patients also achieved undetectable bone marrow MRD status with addition of VEN

Safety

• 24% of pts required dose reduction of IBR, 18% required dose reduction of VEN
  • Most common reason for dose reduction was neutropenia
• Eight patients (11%) developed atrial fibrillation, likely secondary to IBR
  • One patient had laboratory TLS, no patient had clinical TLS
• Total of 10 pts have come off study (Cohort 1, n=5; Cohort 2, n=5):
  • 6 during the IBR monotherapy phase due to skin rash (n=2), hypertension and gait imbalance (n=1), need for chronic azole therapy (n=1), infection (n=1), and consent withdrawal (n=1)
  • 4 after starting VEN due to cytopenia (n=1), Hodgkin’s transformation (n=1), hypertension (n=1), and second malignancy (fallopian tube cancer) (n=1) 

This was one of many promising presentations of this combination at ASH. The investigators noted that ibrutinib plus venetoclax was both safe and active in CLL patients. Of note was the significant improvement in bone marrow CLL infiltrate in several patients, along with achieving undetectable MRD status as early as 3 months with this combination.