Ibrutinib/Venetoclax Yields Dramatic Blood Response in Patients With Relapsed/Refractory CLL

Peter Hillman, MB ChB, PhD

Combination ibrutinib (Imbruvica) and venetoclax (Venclexta) set the bar high and aims to achieve eradication of minimal residual disease (MRD) within a year of treatment in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), investigators reported on the CLARITY TAP feasibility study during the 2017 European Hematology Association (EHA) Congress in Madrid.

Thus far, the ibrutinib/venetoclax combination has been well tolerated, with just 1 case of manageable tumor lysis syndrome (TLS) occurring. The initial bone marrow responses are expected after 6 months of combination therapy and survival data are not yet mature, but the combination of ibrutinib and venetoclax has already demonstrated a blood response of rapid reduction in CLL levels.

Data from a preliminary analysis of 35 patients receiving ibrutinib induction followed by 12 weeks of ibrutinib and venetoclax revealed that 47% of patients had circulating CLL levels of <0.02 x 109 cells/L.

“After 8 weeks of combined ibrutinib and venetoclax therapy, patients demonstrated a 3-log reduction in CLL level,” said lead author Peter Hillman, MB ChB, PhD, professor of experimental hematology and an honorary consultant hematologist at Leeds Teaching Hospitals NHS Trust in the United Kingdom. “This reduction was observed even during the escalation phase and suggests a potential synergy between the drugs.”

The fall in peripheral blood CLL count has been detailed so far in 18 patients who initially had CLL cell levels >10 x 1010 cells/L. During 8 weeks of induction with ibrutinib monotherapy, CLL levels increased from a median 50 x 109 cells/L (range, 0.002-330) to 60 x 109 cells/L (range, 0.3-510). During the first 8 weeks of combined ibrutinib/venetoclax, the level of CLL cells decreased from median 60 x 109 cells/L to 0.042 x 109 cells/L (range, 0.0-7.4).

This reduction has been maintained up to 20 weeks following initiation of combined treatment.

“Ibrutinib has demonstrated improved progression-free survival [PFS] and altered the natural history of CLL, but does not lead to eradication of the disease, so long-term therapy is required,” Hillman explained. This prompted investigators to consider adding venetoclax to improve responses.

According to Hillman, the pathophysiology of CLL involves cell proliferation that is unbridled by apoptosis due to expression in the lymph nodes of the B-cell lymphoma—2 (BCL-2) protein, which interferes with cell death. Venetoclax targets BCL-2 and has demonstrated an ability to restore apoptosis in cancer cells.

The European Medicine Agency granted venetoclax conditional approval in 2016 for patients with CLL and either 17p deletion or TP53 mutation markers.

“Venetoclax has demonstrated a dramatic effect in CLL and has resulted in eradication of detectable MRD in a proportion of patients,” Hillman noted.

The ongoing CLARITY study enrolled 50 patients with R/R CLL to investigate the safety and efficacy of the ibrutinib/venetoclax combination. The primary endpoint is MRD eradication, defined as fewer than 0.01% of CLL cells in the marrow at 12 months after combination treatment. Key secondary endpoints included MRD eradication at 6 months, response rate, PFS, and overall survival (OS).

Seventy-one percent of patients are male with a median age of 64 years (range, 31 to 83). ECOG performance status was 0 in 60% of patients who had received a median of 2 prior therapies (range 1-6), and 44% of patients had 17p or 11q deletions.

The patients received 8 weeks of ibrutinib (420 mg) monotherapy followed by continued ibrutinib plus venetoclax at doses beginning at 20 mg weekly and escalating to 400 mg over 5 weeks. MRD negativity is evaluated at 3, 6, 12, and 24 months; patients showing evidence of MRD negativity will be taken off treatment and the other patients can continue ibrutinib as clinically indicated and venetoclax for up to 24 months.

Since venetoclax has been associated with TLS in CLL, venetoclax dosing was designed to be slowly escalated to yield a gradual reduction of tumor burden. Other TLS measures included supportive medication with allopurinol, rasburicase, and hydration, as needed, plus hematology and biochemistry reviews.

One case of TLS occurred after 8 weeks of treatment; the largest pretreatment lymph node was 7.4 x 3.5 cm and the white cell count was 74 x 109/L, indicating the patient was at high risk of TLS but had tolerated venetoclax at 20, 50, and 100 mg, and had shown a reduction in lymphocyte concentration. Between the 100 mg to 200 mg dose escalation, the patient developed grade 3 TLS, demonstrating a phosphate increase and EGFR decrease. The patient’s condition was resolved within 12 hours following rasburicase, insulin, and dextrose treatment; the patient resumed treatment at 400 mg venetoclax and is currently tolerating ibrutinib/venetoclax.

Grade 3 adverse events (AEs) included 5 infections, 2 administration site reactions, 2 metabolism and nutrition disorders, and 1 each of blood and lymphatic, cardiac, eye, gastrointestinal, respiratory, and vascular disorders.

Grade 3 AEs of interest included 13 cases of decreased neutrophil count and 1 hematoma, and 4 patients had grade 4 decreased neutrophil count.

Based on these encouraging findings, Hillman described the randomized NCRi FLAIR trial being conducted at the University of Leeds comparing ibrutinib plus rituximab (Rituxan; IR) to fludarabine, cyclophosphamide, and rituximab (FCR) in patients with R/R CLL which has been modified to include ibrutinib monotherapy and combination ibrutinib/venetoclax. The target enrollment has been increased to approximately 1576 patients.

“It is planned to drop 1 control arm, either IR or ibrutinib monotherapy when FLAIR is fully recruited, which is anticipated in early 2018,” said Hillman.

Hillmen P, Rawstron A, Munir T, et al. The initial report of the bloodwise tap CLARITY study combining ibrutinib and venetoclax in relapsed, refractory CLL shows acceptable safety and promising early indications of efficacy. Presented at: 2017 EHA Congress; June 22-25, 2017; Madrid, Spain. Abstract S770.

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