“So far, treatment of asymptomatic, early-stage CLL patients has not been proven beneficial; ibrutinib is a Bruton tyrosine kinase inhibitor with impressive clinical efficacy in advanced or relapsed CLL that has not been tested in treatment-naïve, early-stage CLL,” Dr Langerbeins explained. To address this gap, Dr Langerbeins and the German CLL Study Group conducted the double-blind, randomised, placebo-controlled, phase 3 CLL12 trial evaluating whether ibrutinib prolonged event-free survival (EFS; primary endpoint) in patients with early-stage CLL and increased risk of progression, as defined using a score system newly developed by this group.
Median EFS was not reached in the ibrutinib arm compared with 47.8 months in the placebo group (HR 0.25; 95% CI 0.14-0.43; P<0.0001). Median progression-free survival (PFS) was also not reached with ibrutinib vs 14.8 months with placebo (HR 0.18; 95% CI 0.12-0.27; P<0.0001). The time to next treatment was longer in the ibrutinib arm vs the placebo arm (HR 0.21; 95% CI 0.11-0.39; P<0.0001), with a median observation time of 31 months. The trial enrolled treatment-naïve, asymptomatic Binet A patients with intermediate, high, or very high risk of progression. Of these, 182 were randomly assigned to receive ibrutinib at 420 mg per day and 181 were randomised to placebo. The median patient age in both cohorts was 64 years, and approximately 89% of patients were ECOG PS 0. In the ibrutinib and placebo arms, 75.8% and 82.9% of patients, respectively, had thymidine kinase >10 U/L, and fewer than 10% of patients in either arm had mutated TP53 or 17p deletions. In the ibrutinib and placebo arms, 11.5% and 10.5% of patients, respectively, had 11q deletions.
The primary endpoint was EFS and secondary endpoints included PFS and time to next treatment. The 152 patients with low-risk disease were not included in the primary endpoint analysis. Dr Langerbeins noted that EFS, PFS, and TTNT improvement were consistent across all risk groups analysed, except in the very high-risk group where there were just 8 patients.
The safety evaluation included 185 patients on ibrutinib and 178 patients on placebo and noted no differences in most adverse events for ibrutinib compared with placebo. The incidence of any grade adverse events (AEs) was 82.2% vs 84.8% with ibrutinib and placebo, respectively. AEs leading to treatment interruption occurred in 41.6% vs 21.3% of patients, respectively. The most commonly reported AEs in the respective cohorts leading to interruption included cardiac arrhythmias (18 vs 0 patients), bleeding (8 vs 1 patients), diarrhoea (4 vs 3 patients), and neoplasia (4 vs 3 patients). Treatment discontinuation was reported for 34.1% of ibrutinib vs 45.9% of placebo patients, respectively; the primary cause of discontinuation was disease progression in 2 and 45 patients, respectively. AEs were the primary cause of discontinuation in the ibrutinib arm (n=53).
Six deaths on study occurred in the ibrutinib arm, and 5 deaths occurred in the placebo arm. “The results of this study allow us to conclude that ibrutinib significantly improves EFS, PFS, and time to next treatment in asymptomatic patients with treatment-naïve early stage CLL when compared with placebo,” concluded Dr Langerbeins.
- Langerbeins P, et al. Abstract LB2602, 24th Congress of the EHA, 13-16 June 2019, Amsterdam, the Netherlands.
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Table of Contents: EHA 2019
Featured articles
Editor Biography
Interview with EHA President Prof. Pieter Sonneveld
Myeloid Malignancies
Residual disease in AML patients prior to stem cell transplant increases relapse risk
Gilteritinib prolongs overall survival in patients with FLT3-mutated relapsed/refractory AML
Initial data on AMV564 in patients with relapsed/refractory AML
Overcoming the “don’t eat me” signal in AML and MDS
Asciminib plus imatinib in patients with heavily pre-treated chronic myeloid leukaemia
Guadecitabine vs treatment of choice in AML
Lymphoid Malignancies
Unmutated IGHV as predictive factor for venetoclax/obinutuzumab benefit in frontline CLL
CAR-T cell therapy in ALL as breakthrough advance
Brentuximab vedotin continues to demonstrate superior clinical activity in classical Hodgkin lymphoma
Infectious complications mild and not common in patients receiving CAR-T therapy for diffuse large B cell lymphoma
Obinutuzumab/polatuzumab in follicular lymphoma
Exciting survival data for ibrutinib vs placebo in treatment-naïve, early-stage CLL
ASCEND study: Acalabrutinib improves progression-free survival in relapsed/refractory CLL
Venetoclax-obinutuzumab combination elicits high response rates in CLL
Myeloma
CASSIOPEIA trial: Phase 3 results of daratumumab + bortezomib/thalidomide/dexamethasone in multiple myeloma
Chimeric antigen receptor T cell therapy in multiple myeloma
Higher levels of treatment satisfaction without compromising efficacy: subcutaneous daratumumab in RRMM
Adding isatuximab to pomalidomide and dexamethasone improves PFS and ORR in RRMM
Subcutaneous daratumumab + cyclophosphamide, bortezomib, and dexamethasone in patients with newly diagnosed amyloid light chain amyloidosis
Venetoclax for multiple myeloma: effective but some safety concerns
Benign Haematology
New sickle cell drug voxelotor boosts levels of haemoglobin
Positive initial data evaluating the safety and efficacy of IMR-687 for treatment of sickle cell disease
Haematopoietic stem cell transplantation improves stroke risk in children with sickle cell anaemia
Early trial data shows positive results for treating anaemia in patients with end-stage renal failure
Bench-to-Bedside
Transformation of foetal haematopoietic stem and progenitor cells in the background of trisomy 21
Treating thalassemia twice, in mice
Haematopoietic stem cells can sense tissue damage in the gut
Promising news for gene therapy for sickle cell disease
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