Clinical trialPhase 3Leukaemia

Ponatinib vs Imatinib in Frontline Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

JAMA · 2024245 patients randomised (232 patients in the primary endpoint analysis)

Jabbour E, Kantarjian HM, Aldoss I, Montesinos P, Leonard JT, Gómez-Almaguer D, et al. JAMA. 2024. 331:1814

Study type: Clinical trial
Study name: PhALLCON
Phase: Phase 3
Design: International registrational, randomised (2:1), open-label trial
Sample size: 245 patients randomised (232 patients in the primary endpoint analysis)
Source: JAMA · 2024
Trial registration: NCT03589326

In plain words

In this study, adults newly diagnosed with a particular type of acute lymphoblastic leukaemia (with the Philadelphia chromosome) received either the drug ponatinib or the drug imatinib together with gentler chemotherapy. At the end of the first phase of treatment, more patients in the ponatinib group reached a state in which remaining disease could not be detected with sensitive tests (34.4% vs 16.7%). Side effects were similar in the two groups. More time is still needed to draw conclusions about survival or how long the disease stays under control.

Key results

34.4% (53 of 154) vs 16.7% (13 of 78)

MRD-negative complete remission (primary endpoint)

Risk difference 0.18 (95% CI: 0.06 to 0.29); P = 0.002

Not reached (ponatinib) vs 29 months (imatinib)

Median event-free survival

The prespecified number of events had not been reached at the data cut-off

2.5% (ponatinib) vs 1.2% (imatinib)

Arterial occlusive events

Few and comparable between the two groups

Drugs in this study:Imatinib (Gleevec)

Dose and schedule cards

Ponatinib + reduced-intensity chemotherapy (PhALLCON)

Newly diagnosed Philadelphia-positive (Ph+) ALL in adultsEach drug’s schedule in the tableOn the page “Leukaemia” · Regimens and dosing in Philadelphia-positive ALL

Newly diagnosed Philadelphia-positive (Ph+) ALL in adults

Drug	Dose	Route	Schedule
Induction (cycles 1–3)
Ponatinib	30 mg once daily	Oral	Continuous
Vincristine	1.4 mg/m² (maximum 2 mg)	IV	Days 1 and 14, every 28 days
Dexamethasone	Under 60 years: 40 mg; 60 years and older: 20 mg	Oral	Days 1–4 and 11–14, every 28 days
Consolidation (cycles 4, 6 and 8)
Methotrexate	Under 60 years: 1000 mg/m²; 60 years and older: 250 mg/m²	IV	Day 1 of cycles 4, 6 and 8 (each cycle 28 days)
Consolidation (cycles 5, 7 and 9)
Cytarabine	Under 60 years: 1000 mg/m²; 60 years and older: 250 mg/m², every 12 hours	IV	Days 1, 3 and 5 of cycles 5, 7 and 9 (each cycle 28 days)
Maintenance (cycles 10–20)
Vincristine	1.4 mg/m² (maximum 2 mg)	IV	Day 1, every 28 days
Prednisone	Under 60 years: 200 mg; 60 to 69 years: 100 mg; 70 years and older: 50 mg	Oral	Days 1–5, every 28 days

Cycle schedule: Chemotherapy in 28-day cycles; ponatinib daily and continuously
Duration: 20 cycles with chemotherapy (ponatinib continues through consolidation and maintenance); in the trial, followed by single-agent ponatinib until relapse, transplantation or toxicity

After induction, once MRD-negative complete remission is achieved (BCR::ABL1/ABL1 ≤0.01%), the ponatinib dose is reduced to 15 mg, and it returns to 30 mg if MRD negativity is lost. Boxed warning: arterial occlusive events, venous thromboembolism, heart failure and hepatotoxicity; monitor cardiovascular risk factors and liver enzymes. Continuing ponatinib alone after chemotherapy, and the imatinib 600 mg comparator, are not FDA-approved regimens.

On the page “Leukaemia” · Regimens and dosing in Philadelphia-positive ALL

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

1Ponatinib + reduced-intensity chemotherapy

28-day cycles. Induction (cycles 1 to 3): ponatinib 30 mg once daily + vincristine 1.4 mg/m² IV (maximum 2 mg) on days 1 and 14 + oral dexamethasone on days 1 to 4 and 11 to 14 (under 60 years 40 mg; 60 years and over 20 mg). Consolidation (cycles 4 to 9, alternating): IV methotrexate on day 1 of cycles 4, 6 and 8 (under 60 years 1000 mg/m²; 60 years and over 250 mg/m²) and IV cytarabine every 12 hours on days 1, 3 and 5 of cycles 5, 7 and 9 (under 60 years 1000 mg/m²; 60 years and over 250 mg/m²). Maintenance (cycles 10 to 20): vincristine 1.4 mg/m² (maximum 2 mg) on day 1 + oral prednisone on days 1 to 5 (under 60 years 200 mg; 60 to 69 years 100 mg; 70 years and over 50 mg). After induction and achievement of MRD-negative CR, ponatinib was reduced to 15 mg and returned to 30 mg on loss of MRD negativity. After 20 cycles, single-agent ponatinib until relapse, progression, transplantation or toxicity. An optional pre-phase without a TKI was allowed before randomisation.

2Imatinib + reduced-intensity chemotherapy

Imatinib 600 mg once daily with the same reduced-intensity chemotherapy for 20 cycles, then single-agent imatinib.

Source of the regimen details: FDA label for ponatinib (DailyMed; section 14: full description of the PhALLCON regimen) and abstract of the paper

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

Adults aged 18 and over with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+‎ ALL), at 77 centres. Median age 54 years and 133 (54.3%) were women. The primary endpoint analysis included 232 patients with a predominant p190 or p210 isoform confirmed by the central laboratory.

Endpoints

Primary endpoint of this interim analysis: MRD-negative complete remission (BCR::ABL1 of 0.01% or less [MR4] by central RT-qPCR) with complete remission maintained for at least 4 weeks at the end of cycle 3. Key secondary endpoint: event-free survival.

Safety and side effects

The most common adverse events were similar in the two treatment groups. Arterial occlusive events were few and comparable (ponatinib 2.5%; imatinib 1.2%). The rate of grade 3 or higher adverse events is not stated in the abstract.

Clinical significance and place in guidelines

This trial showed that ponatinib with reduced-intensity chemotherapy as first-line treatment for Ph+‎ ALL leads to a higher rate of MRD-negative complete remission than imatinib, with a comparable safety profile. However, at the time of this interim analysis event-free survival had not yet reached the prespecified number of events, and the primary endpoint is a surrogate (MRD). The status of regulatory approvals and clinical guideline recommendations should be checked separately.

Limitations

This is an interim analysis and event-free survival had not yet reached the prespecified number of events. The trial was open-label. The primary endpoint is a surrogate endpoint (MRD) at the end of induction, and it was analysed in 232 of the 245 randomised patients (with a confirmed p190 or p210 isoform). In addition, several authors were employees of the drug's manufacturer (Takeda).

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.