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
Author(s): ,
Peter Hillmen
Affiliations:
Experimental Haematology,University of Leeds,Leeds,United Kingdom
,
Andy Rawstron
Affiliations:
H.M.D.S.,St James's Institute of Oncology,Leeds,United Kingdom
,
Talha Munir
Affiliations:
Haematology,St. James's Institute of Oncology,Leeds,United Kingdom
,
Kristian Brock
Affiliations:
Cancer Research UK Clinical Trials Unit,University of Birmingham,Birmingham,United Kingdom
,
Samuel Munoz Vincente
Affiliations:
Cancer Research UK Clinical Trials Unit,University of Birmingham,Birmingham,United Kingdom
,
Yolande Jefferson
Affiliations:
Cancer Research UK Clinical Trials Unit,University of Birmingham,Birmingham,United Kingdom
,
Kathryn Paterson
Affiliations:
Cancer Research UK Clinical Trials Unit,University of Birmingham,Birmingham,United Kingdom
,
Christopher P. Fox
Affiliations:
NHS Nottingham University Hospitals,Nottingham,United Kingdom
,
John Gribben
Affiliations:
Barts Cancer Institute,London,United Kingdom
,
Adrian Bloor
Affiliations:
Christie Hospital NHS Trust,Manchester,United Kingdom
,
Anna Schuh
Affiliations:
Churchill Hospital,Oxford University Hospitals,Oxford,United Kingdom
Francesco Forconi
Affiliations:
Southampton General Hospital,Southampton,United Kingdom
EHA Learning Center. Hillmen P. Jun 25, 2017; 182057
Prof. Peter Hillmen
Prof. Peter Hillmen

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Abstract
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Abstract: S770

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:15 - 08:30

Location: Hall A

Background

Ibrutinib (IBR) is an oral BTK inhibitor with high response rates in CLL. Venetoclax (VEN) is a potent, highly selective, orally bioavailable small-molecule BCL2 inhibitor. Both IBR and VEN are approved by both the FDA and EMA as single agents for chronic lymphocytic leukaemia (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 in some patients where they cannot be detected. Two of the key cellular processes that are abnormal in CLL are proliferation and apoptosis. The combination of IBR with VEN is therefore logical as biologically the two drugs would be expected to be synergistic. The eradication of minimal residual disease (MRD) from blood and bone marrow is associated with improved outcome in any treatment of CLL where it has been reported.

Aims
The CLARITY trial (ISCRTN: 13751862) is a feasibility study to investigate the safety and efficacy of IBR combined with VEN in patients with relapsed/refractory CLL. Here we report for the first time the safety of the combination as well as early signs of potent synergy.

Methods
After 8 weeks of IBR monotherapy (420mg/day), VEN was added initially at a dose of 10mg/day with weekly escalations to 20mg, 50mg, 100mg, 200mg to a final dose of 400mg/day. After the initial 3 patients when there was no sign of tumour lysis syndrome (TLS) the starting dose of VEN was amended to 20mg/day. The primary end-point of the trial is MRD eradication (defined as less than 1 CLL cell in 10,000) in the bone marrow after 12 months of IBR+VEN. Key secondary end-points are MRD eradication from the bone marrow after 6 and 24 months of combined IBR and VEN as well as the safety of the combination. Important safety events that were considered critical were the incidence of laboratory and clinical TLS. All patients were given prophylactic treatment with uric acid reducing agents beginning at least 72 hours prior to their initial dose of VEN. Over the first three months of combined therapy the level of CLL in the peripheral blood was monitored weekly during VEN escalation and then monthly thereafter. 50 participants will be treated in total.

Results
A total of 35 patients have been recruited between May 2016 and January 2017. To date 21 patients have completed the dose escalation period of VEN in combination with IBR. To date there has been only a single case of laboratory TLS in a patient whose phosphate (1.21 to 1.48mmol/l) and creatinine (75 to 146 umol/l) both increased when VEN was increased from 100mg to 200mg. Dosing of VEN was interrupted for 7 days (due to the logistics of clinic closure periods over the Christmas break) and IBR for 24 hours. The biochemical abnormalities resolved within 24 hours and the patient subsequently escalated to 400mg/day of VEN with no further TLS. As yet there have been a total of 5 SAEs and 22 AE’s of special interest with notably lung infection (n=3) and neutropenia (n=11) occurring on more than one occasion. All SAE’s resolved with appropriate management and all patients remained on therapy. No SUSAR’s have been reported and no AE’s have been fatal. The level of CLL in the peripheral blood increased during the 8 weeks of IBR monotherapy at 420mg/day from a median of 50 x 109/l (range: 0 to 330) to 55 x 109/l (range: 0 to 237) and then fell during the first 8 weeks of combined IBR with VEN (4 weeks dose escalation followed by 4 weeks at 400mg/day) from a median of 55 x 109/l to a median of 0.017 x 109/l (range; 0 to 3.1). The rate of fall is rapid in all patients with a median of 3 log reduction in CLL level after 8 weeks of combined therapy.

Conclusion
The combination of IBR with VEN is well tolerated in relapsed, refractory CLL with to date only a single case of laboratory TLS. The rapid reduction in the peripheral blood CLL level even during the escalation phase of VEN with IBR is promising and suggests a potent synergy between the drugs. The initial bone marrow responses are expected after 6 months of combination therapy.

Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): Targeted therapy, Phase II, Chronic Lymphocytic Leukemia

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