Clinical trialPhase 3Leukaemia

Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL

N Engl J Med · 2018547 patients (183 BR, 182 ibrutinib, 182 ibrutinib + rituximab)

Woyach JA, Ruppert AS, Heerema NA, et al. N Engl J Med. 2018. 379:2517-2528

A newer report of this study has been published: Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL (2024)

Study type: Clinical trial
Study name: Alliance A041202
Phase: Phase 3
Design: Three-arm randomised trial, Alliance cooperative group (supported by the US National Cancer Institute)
Sample size: 547 patients (183 BR, 182 ibrutinib, 182 ibrutinib + rituximab)
Source: N Engl J Med · 2018
Trial registration: NCT01886872

In plain words

In older people with CLL, this study showed that a daily ibrutinib tablet controlled the disease better and for longer than chemotherapy combined with rituximab, and that adding rituximab to the tablet gave no extra benefit. Blood-related side effects were less common with the tablet, but some other side effects, such as high blood pressure and an irregular heartbeat, were seen more often.

Key results

87% vs 74%

2-year PFS: ibrutinib vs BR

HR 0.39 (95% CI 0.26–0.58); P<0.001

88% vs 74%

2-year PFS: ibrutinib + rituximab vs BR

HR 0.38 (95% CI 0.25–0.59); P<0.001

HR 1.00

Ibrutinib + rituximab vs ibrutinib

95% CI 0.62–1.62; P=0.49 (no difference)

No significant difference

Overall survival

Median follow-up 38 months

Drugs in this study:Bendamustine Ibrutinib (Imbruvica)Rituximab (Rituxan/MabThera)

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

1Bendamustine + rituximab (BR)

Six 28-day cycles: bendamustine 90 mg/m² on days 1 and 2 (cycle 1 dose 70 mg/m² at the investigator's discretion) with rituximab 375 mg/m² one day before day 1 of cycle 1, then 500 mg/m² on day 1 of cycles 2 to 6.

2Ibrutinib

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

3Ibrutinib + rituximab

Ibrutinib 420 mg daily continuously with rituximab 375 mg/m² weekly for 4 weeks starting on day 1 of cycle 2, then on day 1 of cycles 3 to 6.

Source of the regimen details: Full text of the paper in PMC (PMC6325637), Methods section

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 years or older with untreated chronic lymphocytic leukaemia (CLL) who had an indication for treatment.

Endpoints

Primary endpoint: progression-free survival.

Secondary endpoints: overall survival, response rate and safety.

Safety and side effects

Grade 3 to 5 haematological adverse events were more frequent with BR (61% versus 41% with ibrutinib and 39% with ibrutinib + rituximab), but grade 3 to 5 non-haematological adverse events were less frequent with BR (63% versus 74% in each of the ibrutinib-containing regimens).

Clinical significance and place in guidelines

Together with the E1912 and iLLUMINATE trials, this study led to chemoimmunotherapy being abandoned as the preferred first-line treatment for most patients with CLL. Today BTK inhibitors (preferably second-generation) or the fixed-duration venetoclax-obinutuzumab regimen are the standard first-line treatments. Another important finding was that adding rituximab to ibrutinib is not necessary.

Limitations

The study was open-label. With 38 months of follow-up no difference in overall survival was seen (crossover to ibrutinib after progression was allowed). Ibrutinib is a continuous treatment with no defined end, which is challenging in terms of cumulative toxicity and cost.

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.