Together Not Apart: Combining Ibrutinib and Venetoclax Therapy in Chronic Lymphocytic Leukemia

CLARITY: Assessment of Venetoclax (ABT-199) in Combination With Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia

ISCRTN13751862

University of Birmingham, United Kingdom

55

Eight centers within the United Kingdom

This was a single-arm study for patients with relapsed or refractory chronic lymphocytic leukemia (CLL), defined as failure to respond to, or relapse within six months of, a purine analogue alone or with chemotherapy; relapse within three years after fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab; or with del(17p) and failed at least one line of therapy. Patients must not have had previous treatment with Bruton tyrosine kinase (BTK) inhibitor (BTKi) or venetoclax (VEN). Treatment consists of eight weeks of IBR monotherapy (420 mg/day) followed by the addition of weekly escalating doses of VEN from 10 mg/day until a final dose of 400 mg/day.

Eradication of minimal residual disease (MRD) within bone marrow (BM) defined as less than 0.01 percent CLL cells in BM after 12 months of treatment.

BM MRD after six and 24 months, overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events/serious adverse events (AEs/SAEs).

Eradication of MRD is associated with improved outcome in chronic lymphocytic leukemia (CLL) and, importantly, this is observed regardless of the therapy used to achieve it. Ibrutinib, which inhibits the BTK enzyme, and VEN, an oral Bcl-2 inhibitor, are both highly active in CLL and are used typically in sequential fashion. Although the drugs have different primary mechanisms of action, IBR also reduces the level of anti-apoptotic molecules and might potentiate the effect of VEN. This trial aims to test this hypothesis by combining ibrutinib with venetoclax. Researchers want to see whether the combination is superior to historical experience of either drug alone in patients with relapsed/refractory CLL.

Treatment of CLL has been transformed within the past five years. Although combination treatment with chemotherapy and an anti-CD20 antibody remains the first-line option for most patients, the development of ibrutinib, idelalisib, and venetoclax has led many hematologists to wonder how long they must continue to prescribe chemotherapy. Nevertheless, these new agents have almost always been used as monotherapy in combination with the anti-CD20 agent rituximab. The CLARITY trial, which is part of the Trials Acceleration Programme funded by the charity Bloodwise, uses the oral agents ibrutinib and venetoclax in combination.

This principle would seem to make a lot of sense. Ibrutinib rapidly reduces nodal disease and redistributes CLL into the peripheral blood, whereas venetoclax leads to depletion of CLL in circulation and in the bone marrow. Ibrutinib’s effect on molecules such as MCL1 may also theoretically potentiate the effect of venetoclax. Additionally, venetoclax is associated with a risk of tumor lysis syndrome, and the CLARITY trial introduces ibrutinib at full dose of 420 mg/day for eight weeks prior to the introduction of venetoclax. Venetoclax is then increased weekly from an initial 20 mg/day dose to the full dose of 400 mg/day, in its typical “ramp up” regimen.

As currently tested, ibrutinib must be taken continuously, which is both costly and challenging for patient compliance. This study has the advantage of, in certain patients, allowing for discontinuation — a benefit with downstream cost implications. Venetoclax is also highly effective for many patients but is most effective in combination therapy. Its use with ibrutinib offers the potential to avoid the need for anti-CD20 monoclonal antibodies and attendant visits to the day unit. A combination of two novel oral agents may also serve as an exciting platform for next-generation protocols.

Academic arguments aside, how did this combination therapy perform in clinical practice? The answer is that it performed very well indeed, and the results augur positively for future therapy.

The primary endpoint in the study was the clearance of MRD. Not many centers currently use MRD to guide the management of CLL, but this is likely to change as evidence accumulates about its predictive power. The two main technologies for measuring MRD are eight-color flow cytometry and polymerase chain reaction, and the former was used in this study with a sensitivity of one tumor cell per 10,000 cells.

Assessment after the first six months of combination therapy in 38 patients was reported at the 2017 ASH Annual Meeting.¹  All patients showed a response, and complete responses were seen in 47 percent, with the remaining partial remissions reflecting only residual modest lymphadenopathy. Importantly, 32 percent of patients were MRD-negative within the bone marrow at that time.

Venetoclax was given for a maximum of two years, and ibrutinib continues for those who remain MRD-positive after this period. However, both drugs are stopped if patients can achieve MRD negativity; the study incorporated a novel stratification based on the time taken for individual patients to reach MRD. Specifically, after reaching MRD, patients continue dual therapy for the same duration of time as it took them to achieve it. For instance, those who are MRD-negative after six months of combination ibrutinib and venetoclax will stop both drugs after 12 months. This “stopping rule” is based on the premise that the trajectory of the initial response to therapy reflects the intrinsic sensitivity of the disease to treatment and that a “time to MRD × 2” duration of dual treatment will achieve the same depth of response in all patients whilst minimizing drug exposure to those who really need it.

In relation to side effects, biochemical tumor lysis syndrome was noted in two patients as a rise in phosphate level and resolved with short-term venetoclax discontinuation, before escalation to full dose. Neutropenia is a recognized side effect of venetoclax, but although grade 3 or 4 suppression was observed in around 40 percent of patients, this did not translate into a high incidence of infectious complications.

Similar findings have been reported by Dr. Nitin Jain and colleagues from the MD Anderson Cancer Center,²  who also noted that 8 percent of patients became MRD-negative after only three months of combination therapy. This group also included a cohort of treatment-naïve patients, and although patient numbers are currently modest, they observed a rate of 80 percent MRD negativity after nine months of therapy. Obinutuzumab will also not be sidelined, and combination therapy with either venetoclax or ibrutinib/venetoclax is achieving impressive MRD rates in treatment-naïve patients.

Data of this sort are now encouraging combination therapy with ibrutinib and venetoclax for large-scale studies for first-line therapy of CLL. It is highly likely that relatively short-term treatment will drive patients into a deep MRD, and the ultimate hope is that this may translate into effective “cure” of disease. Whether the immune system can then suppress such low levels of disease, or whether relapse remains inevitable, are important questions to consider. Nevertheless, in the 57 years since David Galton reported on the first use of chlorambucil in CLL,³  this once relatively unfashionable area of hemato-oncology is now chasing chronic myeloid leukemia toward eradicating the use of chemotherapy.