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

Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia

N Engl J Med · 2025867 patients

Brown JR, Seymour JF, Jurczak W, Aw A, Wach M, Illes A, et al. N Engl J Med. 2025. 392:748-762

Study type: Clinical trial
Study name: AMPLIFY
Phase: Phase 3
Design: Randomised, open-label, three-arm trial with 1:1:1 randomisation
Sample size: 867 patients
Source: N Engl J Med · 2025
Trial registration: NCT03836261

In plain words

In this study, people with chronic lymphocytic leukaemia who had not yet been treated received either a fixed-length oral treatment with two drugs (acalabrutinib and venetoclax), the same two drugs plus obinutuzumab, or chemoimmunotherapy. After about three years, a higher percentage of patients who had the acalabrutinib combinations were still free of disease progression. A low white blood cell count (neutropenia) was the most common important side effect. Talk to your own doctor about choosing the right treatment.

Key results

76.5% (vs 66.5% with chemoimmunotherapy)

36-month progression-free survival: acalabrutinib-venetoclax

HR for progression or death 0.65 (95% CI 0.49–0.87), P = 0.004; median follow-up 40.8 months

83.1% (vs 66.5% with chemoimmunotherapy)

36-month progression-free survival: acalabrutinib-venetoclax-obinutuzumab

P<0.001

94.1% with acalabrutinib-venetoclax, 87.7% with acalabrutinib-venetoclax-obinutuzumab and 85.9% with chemoimmunotherapy

36-month overall survival (estimated)

32.3%, 46.1% and 43.2% (in the three groups, respectively)

Grade 3 or higher neutropenia

The most common clinically important grade ≥3 adverse event

10, 25 and 21 patients (in the three groups, respectively)

Deaths from COVID-19

Drugs in this study:Bendamustine Cyclophosphamide (Endoxan)Rituximab (Rituxan/MabThera)Venetoclax (Venclexta)Acalabrutinib (Calquence)

Dose and schedule cards

Fixed-duration acalabrutinib + venetoclax (AMPLIFY)

Untreated CLL/SLL in adultsCycle length: Every 28 daysOn the page “Leukaemia” · Regimens and dosing in CLL: fixed-duration targeted therapy

Untreated CLL/SLL in adults

Drug	Dose	Route	Schedule
Cycles 1–14
Acalabrutinib	100 mg every 12 hours	Oral	Continuous
From cycle 3: 5-week ramp-up
Venetoclax	20, 50, 100, 200 and then 400 mg once daily (one step each week)	Oral, with food	Weeks 1–5
Until the end of cycle 14
Venetoclax	400 mg once daily	Oral	Continuous

Cycle length: Every 28 days
Duration: 14 cycles (about 13 months)

For grade 3 or 4 neutropenia or thrombocytopenia, interrupt the drug(s); on recurrence, resume venetoclax at one dose level lower.

On the page “Leukaemia” · Regimens and dosing in CLL: fixed-duration targeted therapy

Venetoclax + acalabrutinib (AMPLIFY)

Previously untreated CLLCycle length: Every 28 daysOn the page “Venetoclax (Venclexta)” · Dose and schedule (FDA label)

Previously untreated CLL

Drug	Dose	Route	Schedule
From day 1 of cycle 1
Acalabrutinib	100 mg	Oral	About every 12 hours
From day 1 of cycle 3
Venetoclax	Week 1: 20; week 2: 50; week 3: 100; week 4: 200; from week 5: 400 mg	Oral, with food and water	Once a day
After the ramp-up
Venetoclax	400 mg	Oral	Daily

Cycle length: Every 28 days
Duration: Both drugs until the last day of cycle 14

On the page “Venetoclax (Venclexta)” · Dose and schedule (FDA label)

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

1Acalabrutinib + venetoclax (AV)

Acalabrutinib 100 mg orally twice daily from day 1 of cycle 1, 14 cycles in total (or until disease progression or unacceptable toxicity); venetoclax from day 1 of cycle 3 with a 5-week ramp-up: starting at 20 mg and increasing weekly to 50, 100, 200 and finally 400 mg once daily, 12 cycles in total. 28-day cycles (291 patients).

2Acalabrutinib + venetoclax + obinutuzumab (AVO)

Acalabrutinib and venetoclax at the same dose and schedule as the AV group (acalabrutinib 100 mg twice daily from day 1 of cycle 1 for 14 cycles; venetoclax from day 1 of cycle 3 with a 5-week ramp-up of 20, 50, 100, 200 and 400 mg once daily for 12 cycles) plus obinutuzumab: 1000 mg on day 1 or days 1 and 2 of cycle 2 (100 mg on day 1 and 900 mg on day 1 or 2), 1000 mg on days 8 and 15 of cycle 2 and then 1000 mg on day 1 of cycles 3 to 7. 28-day cycles (286 patients). This three-drug combination is not approved in the FDA label.

3Chemoimmunotherapy (control group)

Investigator's choice (290 patients; 143 FCR and 147 BR), 28-day cycles:

FCR: fludarabine 25 mg/m² and cyclophosphamide 250 mg/m² on days 1 to 3, up to 6 cycles; rituximab 375 mg/m² on day 1 of cycle 1 and 500 mg/m² on day 1 of cycles 2 to 6.
BR: bendamustine 90 mg/m² on days 1 and 2, up to 6 cycles; rituximab 375 mg/m² on day 1 of cycle 1 and 500 mg/m² on day 1 of cycles 2 to 6.

Source of the regimen details: EMA Summary of Product Characteristics (SmPC) for Calquence, section 5.1 (doses of all drugs in the three AMPLIFY groups); FDA label for Calquence (DailyMed, sections 5.1, 6 and 14); inclusion criteria from ClinicalTrials.gov NCT03836261

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 18 years and older with untreated CLL and active disease requiring treatment according to iwCLL 2018, ECOG 0 to 2, without 17p deletion or TP53 mutation. Significant cardiovascular disease (symptomatic arrhythmia, heart failure or myocardial infarction within the past 6 months; controlled asymptomatic atrial fibrillation was allowed), Richter transformation, CNS involvement and active hepatitis B or C infection were exclusion criteria. Median age 61 years (range 26 to 86), 64.5% male and 58.6% with unmutated IGHV.

Endpoints

Primary endpoint: progression-free survival (PFS) comparing acalabrutinib-venetoclax with chemoimmunotherapy in the intention-to-treat (ITT) population, assessed by blinded independent central review. The comparison of acalabrutinib-venetoclax-obinutuzumab with chemoimmunotherapy and overall survival are also reported in the abstract.

Safety and side effects

Neutropenia was the most common clinically important grade 3 or higher adverse event, reported in 32.3% of patients in the acalabrutinib-venetoclax group, 46.1% in the acalabrutinib-venetoclax-obinutuzumab group and 43.2% in the chemoimmunotherapy group. Deaths from COVID-19 occurred in 10, 25 and 21 patients in the three groups (respectively).

According to the FDA label: serious or grade 3 or higher infections in 25% of the AVO group versus 14% of the AV group, and fatal infections in 6% versus 3.1% (mostly COVID-19). In the AV group, serious adverse events in 25% (most common: COVID-19 including COVID pneumonia 9%, second primary malignancy 2.7% and neutropenia 2.1%), fatal events in 3.4%, discontinuation of acalabrutinib due to adverse events in 8% and dose reduction in 6%.

Clinical significance and place in guidelines

According to the abstract, fixed-duration acalabrutinib-venetoclax-based treatment (with or without obinutuzumab) improved progression-free survival compared with chemoimmunotherapy in fit patients with untreated CLL without 17p deletion or TP53 mutation. These results support replacing first-line chemoimmunotherapy with fixed-duration chemotherapy-free regimens. The status of drug approvals and clinical guideline recommendations should be checked separately and is not mentioned in the abstract.

Limitations

The trial was open-label. Patients with 17p deletion or TP53 mutation were excluded, and the results cannot be generalised to them. The conclusions apply to fit patients. In the abstract, overall survival is reported only descriptively, and longer follow-up is needed. The number of COVID-19 deaths differed between the three groups.

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.