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

Abstract

Summary 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.

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

“…The survival data reported here not only confirm estimates from earlier reports, but also compare well with reports from other investigator‐initiated prospective and real‐world studies with ibrutinib in similar patient groups with high‐risk CLL. In a phase 2 study of single‐agent ibrutinib, investigators reported an estimated 24‐month PFS rate of 82% among patients with CLL and TP53 abnormalities, of whom 35 of 51 had previously untreated disease (Farooqui et al , 2015). Similarly, in a study combining ibrutinib and rituximab for patients with high‐risk CLL, a subgroup of mostly R/R patients with del(17p) or TP53 mutation had an 18‐month PFS rate that was 72% (Burger et al , 2014).…”

Chronic lymphocytic leukemia (CLL)—Then and now

“…Ibrutinib is also tested in the frontline setting and has improved OS compared to chlorambucil in elderly patients [125]. Other trials of ibrutinibmainly comparison with ofatumumab (RESONATE) [95], combination with rituximab in high risk patients [97], combination with ofatumumab [98], in patients with TP53 mutations [96], with BR [99] Rai and Jain are summarized in Table III. CLL12 trial is first in kind trial as this trial will study ibrutinib in patients with early stage CLL who have high risk of progression depending upon the comprehensive prognostic index [126].…”

Immunoglobulin genes in chronic lymphocytic leukemia: key to understanding the disease and improving risk stratification

“…17 More specifically, M-CLL cases treated with FCR in the context of clinical trials or general practice were independently reported to achieve prolonged responses, often with no detectable minimal residual disease, thus differing significantly from U-CLL cases. [18][19][20] Interestingly, upon treatment with newer therapeutic agents such as ibrutinib and idelalisib, CLL patients appear to benefit equally and experience similar overall responses irrespective of the IGHV mutational status; [21][22][23] however, the follow-up time is still limited thus precluding definitive conclusions. That said, differences have been noted between the two mutational groups regarding certain clinical parameters following the administration of novel drugs, for example, the initial ibrutinib-induced rise in lymphocyte count and also the duration of lymphocytosis is reported to be greater in M-CLL than that found in U-CLL patients.…”

“…That said, differences have been noted between the two mutational groups regarding certain clinical parameters following the administration of novel drugs, for example, the initial ibrutinib-induced rise in lymphocyte count and also the duration of lymphocytosis is reported to be greater in M-CLL than that found in U-CLL patients. 21 While further investigations into the patterns of lymphocytosis and their association with a clinical response are warranted, these observations may hold value for follow-up assessment.…”