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 Combination Therapy

Background: A major aim of treatment in Chronic Lymphocytic Leukemia (CLL) is to eradicate detectable minimal residual disease (MRD) which is associated with improved outcome regardless of the therapy used to achieve it. Antigen-mediated proliferation & Bcl-2 mediated survival are key to CLL pathogenesis. Ibrutinib (IBR) is an oral BTK inhibitor affecting antigen-induced proliferation & cell adhesion/migration whilst venetoclax (VEN) is a potent, highly selective, orally bioavailable Bcl-2 inhibitor affecting CLL cell survival. Both IBR & VEN are approved as single agents for CLL. IBR leads to a rapid nodal response with re-distribution of CLL into the peripheral blood, whereas VEN leads to depletion of CLL cells to levels where they cannot be detected in some patients. IBR leads to reduction of anti-apoptotic molecules such as MCL1, hence theoretically potentiating the effect of VEN. Therefore we tested the hypothesis that combining IBR & VEN would improve the efficacy of either on its own. The CLARITY trial (ISCRTN13751862) is a feasibility study to investigate the safety & efficacy of IBR combined with VEN in patients with relapsed/refractory CLL.

Methods: A total of 50 patients with CLL requiring therapy who had either relapsed within 3 years of FCR or BR or had 17p deletion & had failed at least one line of therapy were to be recruited. After 8 weeks of IBR monotherapy (420mg/day), VEN was added first at a dose of 10mg/day with weekly escalations to 20mg, 50mg, 100mg, 200mg to a final dose of 400mg/day. No tumour lysis syndrome (TLS) was seen for the first 3 patients starting at 10mg/day of VEN so all subsequent patients began VEN at 20mg/day.

The primary end-point is MRD eradication (defined as <1 CLL cell in 10⁴ assessed by 8-color flow) in the marrow after 12 months of IBR+VEN. Key secondary end-points are MRD eradication from the marrow after 6 & 24 months of IBR+VEN as well as safety. Critical safety events were the incidence of laboratory & clinical TLS. All patients were given prophylactic uric acid reducing agents beginning at least 72 hours prior to starting VEN. Over the first 3 months of combined therapy the level of CLL in the peripheral blood was monitored weekly during VEN escalation & monthly thereafter. Here we report the first key secondary end-point of response after 6 months IBR+VEN.

Results: 50 patients were recruited from May 2016 to July 2017. The median number of prior therapies was 2 (range: 1-6) including FCR or BR in 44/47(94%). 9/45 (20%) 17p deleted, 12/45 (27%) 11q deleted, & 36/47 (77%) have unmutated VH genes. To date 41 patients have completed the dose escalation of VEN combined with IBR. Two biochemical TLS events were reported - one with an increase in creatinine & phosphate, & the other an isolated phosphate increase (which does not meet the definition of TLS). Dosing of VEN was interrupted until the biochemical abnormalities resolved & the patients subsequently escalated to 400mg/day of VEN with no further TLS. As yet there have been no SUSARs, 22 SAEs, & 43 grade 3 or 4 AEs reported. Notably there were five grade 3 or 4 infections & 19 episodes of grade 3 or 4 neutropenia. All SAEs resolved with appropriate management & all patients remain on therapy following resolution. No AEs have been fatal. 25 patients have reached their 8 month (6 months of IBR+VEN) marrow & CT-scan assessments. All 25 patients have responded (25/25 [100%] overall response rate) & 15/25 (60%) have achieved a CR or CRi with all of the remaining PR's due to small volume lymphadenopathy at the site of larger nodes at baseline. After 6 months of IBR+VEN 21/25 (84%) have no morphological evidence of CLL in the marrow biopsy, 19/25 (76%) have less than 1% CLL cells in the marrow & 7/25 (28%) have achieved an MRD negative remission (<10^-4). Patients will continue IBR+VEN for the same duration of time as it took them to achieve MRD negativity (i.e. patients who are MRD negative after 6 months IBR+VEN will stop both drugs after 12 months of IBR+VEN). Therefore all patients will continue on IBR+VEN until at least the 14 month assessment (after 12 months of IBR+VEN).

Conclusion: The combination of IBR with VEN is well tolerated in relapsed, refractory CLL with only two of 41 patients experiencing biochemical TLS to date. All 25 patients reaching the initial response assessment after 6 months of IBR+VEN have responded, 60% are in CR & 28% have achieved an MRD negative remission in the marrow. These early results suggest a potent synergy between ibrutinib & venetoclax.