ASH 2018 | Results from the CLARITY phase II trial on ibrutinib and venetoclax combo in R/R CLL

On Saturday 1 December 2018, Oral Session 642 took place at the 60^th American Society of Hematology (ASH) Annual Meeting, San Diego, CA. During that session, Abstract #182 was presented by Peter Hillmen from the University of Leeds, Leeds, UK.

This presentation provided results from the phase II clinical trial CLARITY, which investigates the combination treatment with ibrutinib and venetoclax in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients. The aim of the trial was to investigate the safety and efficacy of this combination treatment with primary endpoint the eradication of minimal residual disease (MRD) in blood (PB) and bone marrow (BM) after 12 months of therapy.

Study design & baseline characteristics

• N = 50 R/R CLL patients received treatment
• Patients with Richter’s transformation or central nervous system involvement were excluded
• Dosing:
  • Ibrutinib monotherapy for 8 weeks (420 mg daily). Then, venetoclax was added at initial dose of 10 mg daily, and was weekly escalated to 20 mg, 50 mg, 100 mg, 200 mg, and finally to 400 mg daily
• Data cut-off: 14 May 2018
• Median number or prior lines (range) = 1 (1–6)
  • Previous fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR): 82%
  • Previous idelalisib: 20%
• The 17p deletion was detected in 20% of patients, the 11q deletion (but not 17p) in 25%, while 75% of patients had no immunoglobulin variable region heavy chain (IGVH) mutations
• Primary endpoint: undetectable (< 0.01%) MRD in BM after 12 months of treatment

Results

• At month 12 of treatment:
  • 57% (n = 28/49) were PB MRD negative
  • 39% (n = 19/49) were BM MRD negative
  • A 94% overall response rate (ORR) was observed, with:
    • 54% achieving a complete response (CR [44%] or CRi [10%])
    • 40% achieving a partial response (PR)
  • 87% of patients had no morphological CLL evidence in BM biopsy
• At month 24 of treatment:
  • 36% (n = 9/25) were MRD negative

Safety

• Only one case of tumor lysis syndrome (TLS) occurred at the 200 mg venetoclax dose, which was managed by delaying venetoclax. Later re-escalation did not result in TLS
• Most common hematological Grade ≤ 3 adverse events (AEs):
  • Bruising: n = 40
  • Neutropenia: n = 27
  • Bleeding/blood blisters: n = 13
  • Eye hemorrhage: n =6
  • Atrial fibrillation: n = 3
  • Febrile neutropenia: n = 1
  • TLS: n = 1
• Most common hematological Grade 4 AEs:
  • Neutropenia: n =10
• Thirty-one serious AEs were observed, which all resolved with appropriate treatment management
• In total, 312 Grade 1–2 (n = 302) and Grade 3 (n = 9) gastrointestinal disorders occurred

 Conclusions

• Ibrutinib and venetoclax combination is generally tolerable and easily managed in R/R CLL patients
• ORR of 94% after 12 months of combination therapy
• BM MRD was achieved in 39% of patients after 12 months of treatment
• Because of these results, the study design of the phase III NCRI FLAIR trial (EudraCT 2013-001944-76) has been modified to include ibrutinib and venetoclax combination as a front-line CLL regimen