Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial

Abstract

Background: Patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy, resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53 aberrations.

Methods: In this investigator-initiated, single-arm phase 2 study, we enrolled eligible adult patients with active CLL with TP53 aberrations at the National Institutes of Health Clinical Center (Bethesda, MD, USA). Patients received 28-day cycles of ibrutinib 420 mg orally once daily until disease progression or the occurrence of limiting toxicities. The primary endpoint was overall response to treatment at 24 weeks in all evaluable patients. This study is registered with ClinicalTrials.gov, number NCT01500733, and is fully enrolled.

Findings: Between Dec 22, 2011, and Jan 2, 2014, we enrolled 51 patients; 47 had CLL with deletion 17p13.1 and four carried a TP53 mutation in the absence of deletion 17p13.1. All patients had active disease requiring therapy. 35 enrolled patients had previously untreated CLL and 16 had relapsed or refractory disease. Median follow-up was 24 months (IQR 12.9-27.0). 33 previously untreated patients and 15 patients with relapsed or refractory CLL were evaluable for response at 24 weeks. 32 (97%; 95% CI 86-100) of 33 previously untreated patients achieved an objective response, including partial response in 18 patients (55%) and partial response with lymphocytosis in 14 (42%). One patient had progressive disease at 0.4 months. 12 (80%; 95% CI 52-96) of the 15 patients with relapsed or refractory CLL had an objective response: six (40%) achieved a partial response and six (40%) a partial response with lymphocytosis; the remaining three (20%) patients had stable disease. Grade 3 or worse treatment-related adverse events were neutropenia in 12 (24%) patients (grade 4 in one [2%] patient), anaemia in seven (14%) patients, and thrombocytopenia in five (10%) patients (grade 4 in one [2%] patient). Grade 3 pneumonia occurred in three (6%) patients, and grade 3 rash in one (2%) patient.

Interpretation: The activity and safety profile of single-agent ibrutinib in CLL with TP53 aberrations is encouraging and supports its consideration as a novel treatment option for patients with this high-risk disease in both first-line and second-line settings.

Funding: Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Cancer Institute, Danish Cancer Society, Novo Nordisk Foundation, National Institutes of Health Medical Research Scholars Program, and Pharmacyclics Inc.

Conflict of interest statement

Declaration of interests: AW and MZHF received research funding from Pharmacyclics Inc. CUN reports grants from Danish Cancer Society, during the conduct of the study; personal fees from Janssen, grants from Roche, outside the submitted work; and Principal investigator / national coordinator for upcoming clinical trials sponsored by Roche, the German CLL study group and Acerta Pharma.

Dr. Geisler reports grants from Novo Nordisk Foundation, during the conduct of the study; personal fees from Roche, personal fees from GSK, personal fees from Janssen, personal fees from Novartis, personal fees from Gilead, personal fees from Celgene, other from Norpharma, outside the submitted work; and Principal investigator, Roche. Principal investigator, GSK.

All other authors declare no competing interests.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Trial profile

Figure 2. Disease control in diff erent anatomic compartments

(A, B) Reduction of tumour burden in each compartment for each patient during treatment. (A) Previously untreated patients vs patients with relapsed or refractory disease. (B) Patients with IGHV-mutated CLL vs patients with IGHV-unmutated CLL. The mean is indicated by the central black horizontal lines; error bars are 95% CI. The mean decrease in tumour burden at 24 weeks in lymph node was 69·34% (SEM 1·98), in spleen 79·75% (SEM 2·66), and in bone marrow 73·49% (SEM 3·83). Disease reduction was similar in subgroups defined by previous treatment history or by IGHV mutation status. (C, D) Mean (SEM) percentage change in lymphocyte count during treatment compared with baseline. (C) Previously untreated patients vs patients with relapsed or refractory disease. (D) Patients with IGHV-mutated CLL vs patients with IGHV-unmutated CLL. IGHV=immunoglobulin heavy chain variable gene. CLL=chronic lymphocytic leukaemia.

Figure 3. Estimates of progression-free and overall survival, and of cumulative incidence of disease progression

(A) Progression-free survival and (B) overall survival for all patients. (C) Overall survival in subgroups by treatment history and (D) by IGHV mutation status. The p value was calculated by log-rank test. (E) Estimated cumulative incidence of disease progression in subgroups by treatment history and (F) by IGHV mutation status. The p value was calculated by Gray's test. IGHV=immunoglobulin heavy chain variable gene. CLL=chronic lymphocytic leukaemia.