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

Abstract

Summary 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.

Management of chronic lymphocytic leukemia (CLL) in the era of B‐cell receptor signal transduction inhibitors

“…In the front line setting ibrutinib demonstrated a 71% objective response rate with an additional 13% nodal response with lymphocytosis. Responses were durable (96.3% PFS at 24 months, 96.6% OS at 24 months) with an acceptable toxicity profile similar to previous reports [113].…”

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

“…Study designs for the individual trials are described in Table SI. PCYC‐1102 (NCT01105247) (Byrd et al , 2013; O'Brien et al , 2014), with long‐term follow‐up data from the extension study PCYC‐1103 (NCT01109069) (Byrd et al , 2015), was a multi‐institutional, phase 1b/2 study of single‐agent ibrutinib in patients with R/R or treatment‐naïve CLL. This analysis only included patients with R/R CLL from PCYC‐1102/1103.…”

“…TP53 mutation analysis was not performed for enrolment in these trials. Peripheral blood samples from patients enrolled on PCYC‐1102/1103 were further assessed for CpG mitogen‐stimulated complex karyotype according to methods previously described (O'Brien et al , 2014). Twenty metaphases were completely analysed whenever possible.…”

“…To provide a more robust description of outcomes in the prospective trials in this important high‐risk patient population, we conducted a combined analysis of 243 patients with R/R del(17p) CLL who received treatment with single‐agent ibrutinib (420 mg) in 1 of 3 prospective clinical studies (Byrd et al , 2013, 2014, 2015; O'Brien et al , 2014, 2016a). This analysis characterizes disease‐specific and overall survival (OS) outcomes among these patients, and describes the results of exploratory analyses conducted to better identify factors associated with variation in survival of patients with this aggressive subtype of CLL.…”

Absorption, Metabolism, and Excretion of Oral 14C Radiolabeled Ibrutinib: An Open-Label, Phase I, Single-Dose Study in Healthy Men

“…The U.S. Food and Drug Administration declared ibrutinib as a breakthrough therapy in February 2013 for the treatment of relapsed/ refractory mantle cell lymphoma and gave approval for this indication in November 2013 (Wang et al, 2013). Recently, in February 2014 the Food and Drug Administration provided accelerated approval for ibrutinib for chronic lymphocytic leukemia in patients who had received at least one previous therapy (Byrd et al, 2013;O'Brien et al, 2014). Ibrutinib could change the paradigm for treatment of patients with mantle cell lymphoma and chronic lymphocytic leukemia wherein intensive combination therapies are used.…”