Phase II Data for Venetoclax/Ibrutinib Combination in Relapsed or Refractory Chronic Lymphocytic Leukemia

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“Even at this very early stage, we are seeing over 30% of patients achieving MRD-negative remission, which was our target at the 12-month bone marrow stage with this combination.”
— Peter Hillmen, MD

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THE COMBINATION of ibrutinib (Imbruvica) plus venetoclax (Venclexta) achieved favorable responses in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to initial results of the phase II CLARITY trial presented at the 2017 American Society of Hematology (ASH) Annual Meeting & Exhibition.1 Although this is a small trial, results were greeted with enthusiasm, and the phase III FLAIR trial conducted by the National Cancer Research Institute in the United Kingdom is assessing ibrutinib plus venetoclax as front-line therapy for CLL. 

The combination of ibrutinib and venetoclax was well tolerated, with only one case of tumor-lysis syndrome, which is a major concern with venetoclax but was successfully managed in the study by delaying the dose. Side effects were predictable and mostly minor. 

“We showed that the combination could be given safely. All patients have an objective response, and 18 of 38 (47%) are in complete response or complete response incomplete [incomplete recovery of platelets] after 6 months of the combination therapy. Further, 32% of patients achieved undetectable minimal residual disease [MRD] status in the bone marrow after only 6 months of therapy,” said Peter Hillmen, MD, Professor of Experimental Hematology at the Leeds Institute of Cancer and Pathology in the United Kingdom. 

“Until recently, treatment options were limited for relapsing patients,” Dr. Hillmen said. “Two novel agents were recently approved for CLL. Ibrutinib acts against proliferation and is approved for all lines of therapy in CLL. It does not eradicate disease, and patients remain on treatment until progression. Venetoclax can eradicate MRD but also has a rapid effect that can lead to tumor-lysis syndrome,” Dr. Hillmen explained. 

CLARITY is a feasibility trial conducted at 11 centers to study the safety and efficacy of ibrutinib plus venetoclax in relapsed or refractory CLL. The primary endpoint is eradication of MRD in the marrow after 12 months of therapy. Key secondary endpoints are MRD eradication in the marrow after 6 and 24 months, response rate, progression-free survival, and overall survival, as well as toxicity. 

“If MRD eradication is achieved in the marrow within 12 months, then patients will stop therapy in CLARITY after 12 or 24 months, respectively,” Dr. Hillmen explained. 

Study Details 

PATIENTS WERE given ibrutinib monotherapy for 2 months to debulk the disease, and then venetoclax was added. Bone marrow was evaluated at 6, 12, and 24 months. Treatment was stopped at 14 months if the bone marrow was MRD-negative at 8 months; treatment will be stopped at 26 months if the 14-month assessment of bone marrow is MRD-negative. Patients will receive ibrutinib alone if the 26-month bone marrow assessment is MRD-positive. 

Median age was 64 years, about 20% of patients had 17p deletion (signaling poor prognosis), and the median number of prior therapies was 1 (range, 1–6). Approximately 81% were previously treated with fludarabine, cyclophosphamide, and rituximab (Rituxan) or bendamustine plus rituximab, and 44% relapsed within 3 years. About 20% had received previous idelalisib (Zydelig). No patient had previous exposure to ibrutinib or venetoclax. 

Few side effects were observed. Bruising was reported in 33 patients (32 cases were grade 1, and 1 was grade 2), and neutropenia was reported in 25 (16 were grade 3). The only case of tumor-lysis syndrome was managed by delaying venetoclax, and the drug was rapidly re-escalated with no further tumor-lysis syndrome. The protocol included growth factor support for patients with neutropenia. 

At 6 months, among 38 evaluable patients, 37% were MRD-negative in peripheral blood, and 32% were MRD-negative in bone marrow. At month 8, 47% achieved a complete response or complete response incomplete and 53% achieved a partial response, for an objective response rate of 100%. Response rates were similar for those who had treatment failure on front-line fludarabine/cyclophosphamide/rituximab or bendamustine/rituximab. 

“Even at this very early stage, we are seeing over 30% of patients achieving MRD-negative remission, which was our target at the 12-month bone marrow stage with this combination,” he said. 

Joseph Connors, MD

Joseph Connors, MD

Laurie Sehn, MD

Laurie Sehn, MD

Robert Brodsky, MD

Robert Brodsky, MD

Comments on CLARITY 

COMMENTING ON these phase II results, Joseph Connors, MD, said, “Eliminating MRD is the first step toward curing the disease. If these results bear out, the combination of ibrutinib/venetoclax will represent a paradigm shift to a potentially curative platform.” Dr. Connors is Clinical Director, Center for Lymphoid Cancer at the British Columbia Cancer Center in Vancouver. 

Laurie Sehn, MD, moderator of a press conference where these data were presented, said, “The treatment of CLL has changed dramatically with novel targeted therapies. The goal is to get the disease under control in patients [for whom chemotherapy fails]. Moving forward, the new therapies are less toxic and more selective.” Dr. Sehn is a medical oncologist at the British Columbia Cancer Agency and Clinical Professor at the University of British Columbia, Vancouver. 

“It is exciting to take two very different targeted therapies that act on unique aspects of cell biology in the hope that they would be synergistic and may be more effective than each agent singly. It is remarkable and impressive to see the high response rate in this study. Within a short period, MRD negativity was achieved in a percentage of patients and could be a step toward a cure in this disease,” Dr. Sehn said. 

In an interview with The ASCO Post, Robert Brodsky, MD, Director of Hematology at Johns Hopkins University School of Medicine, Baltimore, said, “These two drugs are changing the landscape of CLL treatment. We don’t yet know the best sequence of drugs. Venetoclax and ibrutinib are both oral targeted therapies. We are moving away from chemotherapy. These new drugs are game-changers.” ■

DISCLOSURE: Dr. Hillmen has been a consultant for AbbVie, Gilead, Janssen, GSK, Roche, and Alexion and has received honoraria or research funding from AbbVie, Gilead, Janssen, GSK, Celgene, Pharmacyclics, Novartis, Roche, and Alexion. Dr Connors’ institution, the British Columbia Cancer Agency, receives research funding from Amgen, Bayer, Bristol-Myers Squibb, Cephalon, F. Hoffmann-La Roche, Genentech, NanoString Technologies, Janssen, Lilly, Merck, Seattle Genetics, Inc., and Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Drs. Sehn and Brodsky reported no conflicts of interest. 


1. Hillmen P, Munir T, Rawstron A, et al: Initial results of ibrutinib plus venetoclax in relapsed refractory CLL (Bloodwise TAP CLARITY Study): High rates of overall response, complete remission, and MRD eradication after 6 months of therapy. 2017 ASH Annual Meeting. Abstract 428. Presented December 10, 2017.