Phase II trial CLARITY demonstrates efficacy and safety of ibrutinib plus venetoclax in R/R CLL

Pathophysiology of chronic lymphocytic leukemia (CLL) converges on the accumulation of malignant B cells due to uncontrolled proliferation driven by B-cell receptor (BCR) signaling coupled with a failure of apoptosis due to overexpression of anti-apoptotic B-cell lymphoma 2 (Bcl-2). Therapies targeting those pathways significantly improved the outcomes of patients with CLL and have replaced the use of chemoimmunotherapy (CIT) in many patients. However, their use as monotherapies has limitations.

Ibrutinib, an inhibitor of Bruton’s tyrosine kinase (Btk) that interferes with BCR signaling, is effective in patients with CLL. However, used as a single agent it rarely leads to eradication of measurable residual disease (MRD).^1-3 Moreover, patients are often required to remain on treatment indefinitely. This can lead to adverse events (AEs), and therapy discontinuation in approximately 10% of patients.^2-3 Venetoclax, a Bcl-2 inhibitor, shows efficacy alone⁴ and in combination with rituximab.⁵ It is usually well tolerated⁵ and does not require continuous treatment.⁶

Peter Hillmen from St. James Institute of Oncology, Leeds, UK, and colleagues, designed and conducted the clinical trial CLARITY (ISRCTN13751862). The study aimed to investigate the safety and potential synergy of ibrutinib and venetoclax combination for the treatment of patients with relapsed/refractory (R/R) CLL. The results of this single-arm, phase II study were recently published⁷ and are summarised below.

Study design and patient characteristics

In total, 54 patients (see Table 1) with R/R CLL were recruited into the study, excluding those previously exposed to ibrutinib or venetoclax, with high comorbidities or central nervous system involvement. Treatment consisted of ibrutinib monotherapy (420mg/day) for the first 8 weeks, followed by the addition of venetoclax at 20mg/day. This dosing schedule was determined by the absence of tumor lysis syndrome (TLS) in the first three patients who were started at a 10mg/day dose with weekly ramp-up to 20 mg, 50mg, 200mg and finally 400mg (maximum dose). The duration of therapy was defined by the confirmed MRD response. MRD assessments of peripheral blood (PB) and bone marrow (BM), plus computed tomography (CT) scans were performed before the start of the treatment, at 8 weeks, as well as after 6 and 24 months of combination therapy.

The primary endpoint was the eradication of MRD to less than one CLL cell in 10,000 leucocytes (MRD4) in PB and BM after 12 months of the combination therapy. Secondary endpoints included <MRD4 after 6 and 24 months of combination therapy, response rates, progression-free survival (PFS), overall survival (OS), and toxicity.

Table 1. Patient characteristics

BR, bendamustine and rituximab; ECOG, Eastern Cooperative Oncology Group; FCR, fludarabine, cyclophosphamide, and rituximab; NK, not known; IGVH, immunoglobulin variable heavy chain gene

Characteristics

Patients, No. (%)

No of patients

54

Sex

Male

Female

 

37 (69)

17 (31)

Median age, years (range)

64 (31–83)

Binet stage

A

B

C

NK

 

12 (22)

18 (33)

22(41)

2 (4)

ECOG status

0

1

2

NK

 

32 (59)

18 (33)

3 (6)

1 (2)

IGVH status

Mutated

Unmutated

VH3-21

Failed

 

10 (19)

40 (74)

3 (6)

1 (2)

Del(17p)

11 of 50 (22)

Del(11q) without del(17p)

9 of 45 (20)

Prior therapies, median (range)

1 (1–6)

Previous FCR or BR

45 of 54 (83)

Previous idelalisib

11 of 54 (20)

Main findings (at data cut off on 5^th November 2018)

Four patients discontinued ibrutinib in the first 8 weeks due to AEs, and 50 patients completed the dose ramp-up of combination.

Efficacy

• In total, 53 patients were included in the analysis (49 patients completing 12 months of ibrutinib and venetoclax plus four patients who did not respond to ibrutinib therapy)

• The overall response was observed in 89% of patients, with 51% achieving complete response (CR) or CR with incomplete BM recovery, and 38% partial response

• Values of <MRD4 after 12 months of combination therapy in BM or PB were achieved in 36% and 53% of patients, respectively

• The depth of MRD reduction in PB and BM further improved by month 26 (44%)

• Two patients in remission since month 14 have stopped therapy and remain below MRD4 in PB and BM

• After a median follow-up of 21.1 months, one patient (with adverse IGHV) had progressive disease and no deaths were recorded

Toxicity

• Two patients had suspected unexpected serious adverse reactions, and 1,049 AEs were recorded, including 36 serious AEs and 99 grade 3–4 AEs (see Table 2)

• All serious AEs resolved upon management and patients remained in the study

• A single incidence of TLS was reported (grade 3) but was resolved after venetoclax interruption; the dose was subsequently increased to 400mg/day without further problems

• Ibrutinib treatment was interrupted in 28 patients for a median of 9 days (range, 1–80) and reduced in eight patients for a median of 6 days (range, 5–121)

• Venetoclax treatment was interrupted in 23 patients for a median of 8 days (range, 1–62) and reduced in 11 patients for a median of 15 days (range, 3–78)

Table 2. Grade 3 adverse events recorded in >1 patient and all grade 4 adverse events

AEs

Grade 3

Grade 4

Abdominal pain

2

0

Blood and lymphatic system disorders

2

0

Diarrhea

4

0

Infections and infestations

3

0

Neutrophil count decreased

23

10

Platelet count decreased

7

7

Headache

3

0

Skin and subcutaneous tissue disorders

2

0

Hypertension

5

0

Pneumonitis

0

1

Conclusion

Targeting the key pathways involved in the pathogenesis of CLL using a combination of ibrutinib plus venetoclax was well tolerated and showed efficacy in patients with R/R CLL, including those with poor prognosis and/or refractory to CIT. The high level of MRD negativity suggests that the regimen may be given for a limited time rather than continuously until disease progression. However, longer follow-up is required to assess the durability of response and further study in a larger cohort of patients to confirm the findings.