Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial

Abstract

Background: Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia.

Methods: In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247.

Findings: Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65-84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1-2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22.1 months (IQR 18.4-23.2), 22 (71%) of 31 patients achieved an objective response (95% CI 52.0-85.8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response.

Interpretation: The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials.

Funding: Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.

Conflict of interest statement

Conflicts of interest

RRF has received an honorarium for advisory board participation from Pharmacyclics. SEC has received consultancy fees from Pharmacyclics. JPS has received research funding from Pharmacyclics, Gilead, Genentech, Seattle Genetics, and Celgene. JAB has received research funding from Pharmacyclics. JAJ has received consultancy fees and is an advisory board member for Pharmacyclics. BYC, TG, FC, and DFJ are employees and stockholders of Pharmacyclics. AH is a former employee of Pharmacyclics. JJB is a former employee and is a stockholder of Pharmacyclics. All other authors declare that they have no conflicts of interest.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Treatment duration by best response

CR=complete response. PR=partial response. AE=adverse event. *Discontinued treatment. †Patient with small lymphocytic lymphoma.

Figure 2. Overall responses by subgroup analyses

Overall responses defined as complete or partial responses according to International Workshop on Chronic Lymphocytic Leukemia criteria. ECOG=Eastern Cooperative Oncology Group. IgHV=immunoglobulin variable heavy chain. *95% exact binomial CI. †Haemoglobin ≤110 g/L or platelet counts of ≤100 × 109 platelets per L or absolute neutrophil count ≤1·5 × 109 cells per L. ‡ZAP-70 methylated refers to CpG3 ≥15%, non-methylated refers to CpG3 <15%; data were not available for one patient.

Figure 3. Median absolute lymphocyte counts (ALC) and the sum of the products of lymph node diameters (SPD)

Data are median (95% CI).

Figure 4. Kaplan-Meier curves of progression-free survival (A) and overall survival (B)

+=censored.

Figure 5. Percentage of Bruton tyrosine kinase occupancy in peripheral blood mononuclear cells of patients before ibrutinib, and at 4 h and 24 h after ibrutinib treatment

Boxplots include the 25–75th percentile of the distribution of the population. Line within the boxplot shows the median and the diamond shows the mean of the population. Line bars show the standard deviation and circles show outliers.

Figure 6. Median blood counts for all treated patients

Data are median (95% CI). (A) Haemoglobin concentrations. (B) Platelet counts. (C) Absolute neutrophil counts (ANC).

Figure 7. Serum immunoglobulin changes for previously untreated patients who did not receive immunoglobulins during treatment

Data show median (95% CIs).