Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study

Abstract

Background: Ibrutinib, an orally administered covalent inhibitor of Bruton's tyrosine kinase (BTK), is an effective treatment for relapsed chronic lymphocytic leukaemia (CLL). We investigated the activity and safety of the combination of ibrutinib with the monoclonal antibody rituximab in patients with high-risk CLL.

Methods: In this single-arm phase 2 study, we enrolled adult patients with high-risk CLL at the MD Anderson Cancer Center (Houston, TX, USA). All enrolled participants had high-risk cytogenetic abnormalities (deletion 17p, TP53 mutation, or deletion 11q) or a short progression-free survival (PFS <36 months) after previous first-line chemoimmunotherapy. Patients with symptomatic disease requiring therapy received 28-day cycles of once-daily ibrutinib 420 mg together with rituximab (375 mg/m(2), intravenously, every week during cycle 1, then once per cycle until cycle 6), followed by continuous daily single-agent ibrutinib 420 mg until disease progression or until toxicities or complications precluded further treatment. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov number NCT01520519, and is no longer accruing patients.

Findings: Between Feb 28, 2012, and Sept 11, 2012, we enrolled 40 patients with CLL with high-risk disease features, 20 of whom had deletion 17p (del[17p]) or TP53 mutations (16 previously treated, four untreated), 13 had relapsed CLL with deletion 11q (del[11q]), and seven a PFS less than 36 months after first-line chemoimmunotherapy. 18-month PFS in all patients was 78·0% (95% CI 60·6-88·5), whereas in those with a del(17p) or TP53 mutation it was 72·4% (45·6-87·6) Toxicity was mainly mild to moderate in severity (grade 1-2). Diarrhoea occurred in ten (25%) patients (grade 1 in nine patients and grade 2 in one), bleeding events in 14 (33%) patients (eight grade 1 and five grade 2), nausea or vomiting in 15 patients (38%) (ten grade 1 and five grade 2), and fatigue in seven (18%) patients (four grade 1 and three grade 2). Five patients (13%) had grade 3 infections (two lung infections, one upper respiratory tract infection, one sepsis, and one mucositis), and no grade 4 or 5 infections occurred. One patient had grade 4 neutropenia.

Interpretation: The encouraging safety and activity of ibrutinib and rituximab in this population of patients with high-risk CLL merits further investigation of this combination.

Funding: Pharmacyclics Inc, Cancer Prevention and Research Institute of Texas, Leukemia and Lymphoma Society, National Cancer Institute, MD Anderson Cancer Center.

Figure 1. Changes in lymphocyte counts (A)lymph node sizes (B) and bone marrow (C) during iR therapy

(A) Trended absolute lymphocyte counts (ALC) in CLL patients during therapy with ibrutinib and rituximab. The horizontal axis shows the time of treatment. Please note the early, transient lymphocytosis, which peaked during the first week of therapy, and then continuously declined and resolved. (B) Best responses in 34 evaluable patients evaluated by computed tomography scan for change from baseline in the sum of the largest diameter of each target lesion; negative values indicate tumor shrinkage. Among the 34 patients with measurable lesions both at baseline and after baseline, all 34 patients (100%) had improvements in lymphadenopathy, as assessed by changes in the sums of the products of the perpendicular dimensions (SPD) of index lesions. The dashed line shows the percentage change that represents the criterion for lymphadenopathy response.(C) The bar diagrams depict the mean (+/− SEM) relative numbers of bone marrow lymphocytes before therapy and after 3, 6, and 12 months of iR therapy. There was a continuous significant decline in marrow lymphocytes, indicating improvements in marrow infiltration by the CLL cells.

Figure 2. Kaplan–Meier curves for overall survival (OS) and progression-free survival (PFS)

The top panels show the probability of overall survival (left hand panel) and progression-free survival (right hand panel) for all 40 patients. The bottom graphs depict OS and PFS with respect to the del(17p) status; patients without del(17p) are indicated as solid line, and patients carrying del(17p) as hatched line. Tick marks indicate censored data.