Clinical trialPhase 3Blood cancers (leukaemia, lymphoma and myeloma)Leukaemia

Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia

N Engl J Med · 2015269 patients

Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, et al. N Engl J Med. 2015. 373:2425-2437

Study type: Clinical trial
Study name: RESONATE-2
Phase: Phase 3
Design: International, randomised, open-label trial
Sample size: 269 patients
Source: N Engl J Med · 2015
Trial registration: NCT01722487

In plain words

In this study, people aged 65 and older with chronic lymphocytic leukaemia that had not yet been treated were given one of two oral tablets, ibrutinib or chlorambucil. Patients who took ibrutinib stayed longer without the disease getting worse, and at 2 years of follow-up a higher percentage of them were alive. Side effects such as diarrhoea, tiredness and cough were common, and a small number of patients had serious bleeding. The right treatment should be chosen by the treating doctor based on each patient's situation.

Key results

Median not reached vs 18.9 months

Progression-free survival (median)

Ibrutinib vs chlorambucil; HR 0.16; P<0.001; 84% reduction in the risk of progression or death; median follow-up 18.4 months

98% vs 85%

Estimated overall survival at 24 months

HR 0.16; P=0.001; 84% reduction in the risk of death

86% vs 35%

Overall response rate

P<0.001

87% of patients in the ibrutinib group

Continued ibrutinib use

Were still on ibrutinib treatment

Drugs in this study:Ibrutinib (Imbruvica)

Dose and schedule cards

Ibrutinib monotherapy (A041202, RESONATE-2)

CLL/SLL requiring treatment (iwCLL), including with TP53 abnormalities; continuous treatmentCycle length: ContinuousOn the page “Leukaemia” · Regimens and dosing in CLL: continuous BTK inhibitor therapy

CLL/SLL requiring treatment (iwCLL), including with TP53 abnormalities; continuous treatment

Drug	Dose	Route	Schedule
Ibrutinib	420 mg once daily	Oral, with a glass of water	Continuous

Cycle length: Continuous
Duration: Until progression or unacceptable toxicity

Atrial fibrillation, heart failure and sudden death, hypertension (monitor blood pressure regularly) and bleeding (caution with anticoagulants and antiplatelet agents; withhold for 3 to 7 days before and after surgery depending on bleeding risk) are important adverse effects; monthly blood counts and liver function monitoring.

On the page “Leukaemia” · Regimens and dosing in CLL: continuous BTK inhibitor therapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Ibrutinib

Ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity.

2Chlorambucil

Oral chlorambucil 0.5 mg/kg on days 1 and 15 of each 28-day cycle; if tolerated, increased from cycle 2 in steps of 0.1 mg/kg up to a maximum of 0.8 mg/kg; up to 12 cycles (mean dose per administration 0.6 mg/kg).

Source of the regimen details: Full text of the NEJM 2015 paper in PMC (PMC4722809) and ClinicalTrials.gov NCT01722487

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 65 or older with untreated CLL or SLL requiring treatment, ECOG 2 or less, neutrophils at least 1000 per microlitre, platelets at least 50,000 per microlitre and adequate liver and kidney function; patients with 17p13.1 deletion were not enrolled. Median age 73 years.

Endpoints

Primary endpoint: progression-free survival (PFS) assessed by an independent review committee. Secondary endpoints included overall survival, overall response rate and improvement in haematological parameters (haemoglobin and platelets).

Safety and side effects

Adverse events of any grade in at least 20% of patients in the ibrutinib group: diarrhoea, fatigue, cough and nausea. In the chlorambucil group: nausea, fatigue, neutropenia, anaemia and vomiting. In the ibrutinib group, 4 patients had grade 3 haemorrhage and 1 patient grade 4 haemorrhage.

Clinical significance and place in guidelines

This trial showed that oral ibrutinib is superior to chlorambucil in older patients with untreated CLL or small lymphocytic lymphoma for progression-free survival, overall survival and response rate, and can be an effective option for initial therapy. The status of drug approvals and its place in current clinical guidelines should be checked separately, as they are not mentioned in the abstract.

Limitations

Based on the abstract: the trial was open-label, and median follow-up was short (18.4 months); the comparison was only with chlorambucil, and the population was patients aged 65 and older. The study was funded by Pharmacyclics and others.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.