What are the key studies investigating use of ponatinib (Iclusig)?

Comment by InpharmD Researcher

Across clinical trials of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and resistant chronic-phase chronic myeloid leukemia (CP-CML), ponatinib demonstrated favorable and durable complete response rates, including when compared to imatinib, another tyrosine kinase inhibitor (TKI), in Ph + ALL patients. Arterial occlusive events were an important safety signal consistently observed across the studies; however, rates were typically low in individual studies. Please see Tables 1-6 for details on the study designs, efficacy outcomes, and safety findings of key primary literature on ponatinib (Iclusig).
Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What are the key studies investigating use of ponatinib (Iclusig)?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→


Please see Tables 1-6 for your response.

 

Ponatinib vs Imatinib in Frontline Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial
Design

Phase 3, open-label, global, randomized clinical trial (PhALLCON)

N= 232 (intention-to-treat population)
Objective To compare frontline ponatinib vs imatinib in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)
Study Groups

Ponatinib (n= 154)

Imatinib (n= 78)
Inclusion Criteria Patients ≥18 years with newly diagnosed Ph+ ALL, verified p190 or p210 dominant isoforms, and an Eastern Cooperative Oncology Group (ECOG) performance status score 2 or better, bilirubin ≤1.5x the ULN, ALT or AST ≤2.5x ULN, SCr ≤1.5x ULN and estimated CrCl ≥30 mL/min, serum lipase and amylase ≤1.5x ULN, QT interval ≤450 ms (males) or ≤470 ms (females)
Exclusion Criteria History or current diagnosis of chronic-phase, accelerated-phase, or blast-phase chronic myeloid leukemia, prior/current systemic anticancer therapy and/or radiotherapy for ALL, taking drugs with a known risk of causing prolonged QT corrected interval or torsades de pointe, taking medications or herbal supplements known to be strong inhibitors or strong inducers of cytochrome P450 3A4 ≤14 days before first dose of study drug, history of acute pancreatitis in ≤1 y of screening or history of chronic pancreatitis, triglycerides >450 mg/dL, history/presence of clinically relevant CNS pathology, CNS or extramedullary involvement with ALL other than lymphadenopathy or hepatosplenomegaly, poorly controlled diabetes, clinically significant or uncontrolled cardiovascular disease, cerebrovascular, or peripheral vascular disease, or history of or active VTE disease, lactating, breastfeeding, pregnant
Methods

Patients received ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. Ponatinib dose was reduced to 15 mg upon achieving MRD-negative complete remission. Patients continued treatment until loss of efficacy, unacceptable toxicity, or proceeding to hematopoietic stem cell transplant (HSCT).

Intrathecal therapy (methotrexate, cytarabine, and corticosteroids) was given twice monthly for the first 6 cycles for central nervous
system disease prophylaxis.
Duration January 2019 to May 2022, with follow-up until August 12, 2022
Outcome Measures

Primary: MRD-negative complete remission rate at the end of induction

Secondary: Event-free survival, duration of complete remission and MRD-negative complete remission, MRD negativity (MR4), BCR::ABL1IS ≤0.0032% (MR4.5), time to treatment failure, overall survival, adverse events
Baseline Characteristics   Ponatinib (n= 164) Imatinib (n= 81)
Age, median (range), years 54 (19-82) 52 (19-75)
Age ≥60 61 (37.2%) 30 (37.0%)
Female 90 (54.9%) 43 (53.1%)

ECOG score

0 (best)

1

2 (worst)

 

72 (43.9%)

85 (51.8%) 

7 (4.3%) 

 

33 (40.7%)

43 (53.1%)

5 (6.2%)

Central nervous system disease/extramedullary disease

10 (6.1%) 

3 (3.7%)

BCR::ABL1 dominant isoform

p190

p210

 

114 (69.5%)

40 (24.4%)

 

53 (65.4%)

25 (30.9%)

Cardiovascular comorbidities

≥1

≥2

Hypertension

Diabetes

Obesity

Dyslipidemia

History of smoking

 

92 (56.4%)

45 (27.6%)

58 (35.6%)

39 (23.9%) 

33 (20.2%)

29 (17.8%)

44 (27.0%)

 

52 (64.2%)

27 (33.3%)

30 (37.0%)

24 (29.6%)

19 (23.5%)

23 (28.4%)

26 (32.1%)
Results   Ponatinib (n= 154) Imatinib (n= 78) p-value
MRD-negative complete remission rate 53 (34.4%) 13 (16.7%) 0.002
Event-free survival, median, months Not reached 29 -
Duration of MRD-negative complete remission, median (95% CI), months NE (16.6-NE) 18.0 (8.4-27.8) -
MR4 61 (43.0%)  15 (22.1%) 0.002
MR4.5 26.8% 14.7% -
Time to treatment failure, median, months Not reached  21.9 -
Overall survival Not reached  Not reached  -
NE= not estimable.
Adverse Events

Adverse events were similar between treatment groups.

Arterial occlusive events: ponatinib, 2.5%; imatinib, 1.2%.

VTE events: ponatinib, 11.7%; imatinib, 12.3%.
Study Author Conclusions Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib.
Critique The study's strengths include its randomized design and the use of a global, multicenter approach, which enhances the generalizability of the findings. However, the short duration of follow-up limits the ability to assess long-term survival outcomes. Additionally, the comparator, imatinib, is not the current standard of care in all regions, which may affect the applicability of the results in settings where second-generation tyrosine kinase inhibitors are more commonly used.

 

Table 1 References:
[1] Jabbour E, Kantarjian HM, Aldoss I, et al. Ponatinib vs Imatinib in Frontline Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2024;331(21):1814-1823. doi:10.1001/jama.2024.4783

Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial
Design

Randomized, open-label phase 2 clinical trial

N= 283
Objective To assess the benefit/risk ratio across 3 ponatinib starting doses in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs) or with a BCR-ABL1 T315I mutation, using a novel, response-based, dose-reduction strategy
Study Groups

Ponatinib 45 mg (n= 94)

Ponatinib 30 mg (n= 94)

Ponatinib 15 mg (n= 94)
Inclusion Criteria Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation
Exclusion Criteria Not explicitly stated in the provided text
Methods

Patients were randomly assigned to receive ponatinib 45, 30, or 15 mg once daily. In the 45- and 30-mg cohorts, the dose was reduced to 15 mg upon achieving a response (BCR-ABL1IS transcript levels ≤1%). 
Duration August 2015 through May 2019
Outcome Measures

Primary: ≤ 1% BCR-ABL1IS at 12 months
Baseline Characteristics   45 mg (n= 94) 30 mg (n= 94) 15 mg (n= 94)
Age, median y (range) 46 (19-81) 51 (21-77) 49 (18-81)
Sex - Male 50 (53%) 38 (40%) 53 (56%)
ECOG PS score 0 or 1 93 (99%) 93 (99%) 94 (100%)
Time since diagnosis, median y (range) 5.5 (1-21) 5.1 (1-29) 5.7 (1-22)
Patients with CV risk factors - Hypertension 26 (28%) 25 (27%) 22 (23%)
Patients with CV risk factors - Diabetes mellitus 5 (5%) 3 (3%) 7 (7%)
Patients with CV risk factors - Hyperlipidemia 19 (20%) 14 (15%) 16 (17%)
Patients with ≥1 CV risk factor 32 (34%) 30 (32%) 32 (34%)
Current or former smokers 29 (31%) 37 (39%) 33 (35%)
Body mass index, median, kg/m2 (range) 27 (17-45) 26 (17-49) 26 (18-49)
Results   45 mg (n= 94) 30 mg (n= 94) 15 mg (n= 94)
≤ 1% BCR-ABL1IS at 12 months 44.1% (31.7-57.0) 29.0% (18.4-41.6) 23.1% (13.4-35.3)
Grade 3 or above treatment-emergent AOEs 5 5 3
Adverse Events Treatment-emergent adverse events (TEAEs) included arterial hypertension (28%), headache (18%), and lipase increase (17%). Hematologic TEAEs included thrombocytopenia (40%), neutropenia (26%), and anemia (19%). Grade 3 to 5 treatment-emergent arterial occlusive events (TE-AOEs) were reported in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively.
Study Author Conclusions All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response.
Critique The study demonstrated the feasibility of a response-based dose-reduction strategy, showing benefit across all dosage regimens. However, the open-label design and small sample size in some subgroup analyses may limit the generalizability of the findings. The study also did not directly compare overall survival across different doses, which could have provided more comprehensive insights into long-term outcomes.
Table 2 References:
[2] Cortes J, Apperley J, Lomaia E, et al. Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial. Blood. 2021;138(21):2042-2050. doi:10.1182/blood.2021012082. (OPTIC)

Five-year follow-up of OPTIC: long-term efficacy, safety, and mutation analyses of ponatinib in chronic-phase chronic myeloid leukemia from a randomized phase 2 trial
Design

Randomized phase 2 trial

N=283
Objective To report 5-year long-term outcomes of response-based ponatinib dosing in patients with tyrosine kinase inhibitor-resistant or T315I-positive chronic-phase chronic myeloid leukemia
Study Groups

45-mg cohort (n=94)

30-mg cohort (n=95)

15-mg cohort (n=94)
Inclusion Criteria Adults (age ≥18 years) with CP-CML resistant to ≥2 prior TKIs or with a BCR::ABL1 T315I mutation in any line of therapy (see previous table for OPTIC study)
Exclusion Criteria See previous table for OPTIC study
Methods Patients were randomly assigned to receive oral ponatinib once daily at a starting dose of 45 mg, 30 mg, or 15 mg. Dose reduction to 15 mg was implemented upon achieving ≤1% BCR::ABL1IS. Dose could be re-escalated if response was lost. Molecular responses were analyzed using peripheral blood samples, and BCR::ABL1 mutations were assessed at baseline and at EOT or upon transition to PTA.
Duration Minimum of 5 years follow-up
Outcome Measures

Primary: Achievement of ≤1% BCR::ABL1IS at 12 months

Secondary: Progression-free survival (PFS), overall survival (OS)
Baseline Characteristics   45 mg (n=94) 30 mg (n=95) 15 mg (n=94)
BCR::ABL1 T315I mutation 24% 17% 58%
Resistant to prior TKI therapy 99% 99% 99%
Received ≥3 prior TKIs 55% 55% 55%
Results   45 mg (n=94) 30 mg (n=95) 15 mg (n=94)
≤1% BCR::ABL1IS by 5 years 60% 41% 40%
5-year PFS 63% 57% 60%
5-year OS >80% >80% >80%
Adverse Events Exposure-adjusted rates of adjudicated arterial occlusive events were 4.1, 3.8, and 2.0 patients per 100 patient-years in the 45-mg, 30-mg, and 15-mg cohorts, respectively. Common adverse events included hypertension, headache, and alanine aminotransferase increase.
Study Author Conclusions Response-based ponatinib dosing provides durable efficacy and sustained mutation control with a favorable benefit:risk profile in patients with TKI-resistant CP-CML, particularly for those with T315I mutations.
Critique The study provides comprehensive long-term data supporting the efficacy and safety of response-based ponatinib dosing. However, the open-label design and relatively small sample sizes in some analyses may limit the generalizability of the findings. Additionally, the study did not include a comparison with other TKIs in a randomized setting, which could provide more robust comparative efficacy data.
Table 3 References:
[3] Kantarjian H, Deininger M, Apperley JF, et al. Five-year follow-up of OPTIC: long-term efficacy, safety, and mutation analyses of ponatinib in chronic-phase chronic myeloid leukemia from a randomized phase 2 trial. Leukemia. 2026;40(9):1882-1892. doi:10.1038/s41375-026-03009-x. (OPTIC five-year follow-up)
Ponatinib After Failure of Second-Generation Tyrosine Kinase Inhibitor in Resistant Chronic-Phase Chronic Myeloid Leukemia
Design

Analysis of two Phase 2 trials: PACE (single-arm) and OPTIC (randomized, open-label)

N= 350
Objective To evaluate the efficacy and safety of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to second-generation tyrosine kinase inhibitors (2G TKIs)
Study Groups

PACE (n= 257)

OPTIC (n= 93)
Inclusion Criteria

PACE: Adults (≥18 years) with resistant/intolerant CML or Ph+ ALL resistant to the 2G TKIs dasatinib or nilotinib or with the BCR::ABL1 T315I mutation

OPTIC: Adults (≥18 years) with CP-CML resistant to ≥2 prior 2G TKIs or with the BCR::ABL1 T315I mutation
Exclusion Criteria Refer to original studies.
Methods

PACE: Ponatinib 45 mg/day, dose reductions (45 to 30 mg/day or 15 mg/day) to manage AEs

OPTIC: Randomized to 45, 30, or 15 mg/day, with patients who received 45 or 30 mg/day getting a dose reduction to 15 mg upon achieving response (≤1% BCR::ABL1IS)
Duration

PACE: Median follow-up 57 months

OPTIC: Median follow-up 32 months
Outcome Measures

Primary: BCR::ABL1IS response rates, progression-free survival (PFS), overall survival (OS)

Secondary: Adverse events
Baseline Characteristics   PACE (n= 257) OPTIC (n= 93)
Received ≥2 prior 2G TKIs 98% 100%
Received ≥3 prior 2G TKIs 62% 54%
≤1% BCR::ABLIS 5% 3%
T315I mutation 21% 26%
BCR::ABL1 mutation 47% 43%
Discontinued prior therapy due to resistance 96% 98%
Results   PACE (n= 257) OPTIC (n= 93)

≤1% BCR::ABL1IS response

at 12 months

at 24 months

at 60 months

 

42%

46%

47%

 

52%

57%

-
2-year PFS 68% 80%
2-year OS 85% 91%
Adverse Events

Serious treatment-emergent adverse events: 63% in PACE, 34% in OPTIC.

Serious treatment-emergent arterial occlusive events: 18% in PACE, 4% in OPTIC.
Study Author Conclusions Ponatinib shows high response rates and robust survival outcomes in patients whose disease failed prior to 2G TKIs, including those with T315I mutation. Response-based dosing in OPTIC improved safety with similar efficacy compared to PACE.
Critique The study demonstrates significant efficacy of ponatinib in a difficult-to-treat population, but differences in trial design and dosing strategies between PACE and OPTIC limit direct comparison. The open-label design and retrospective adjudication of arterial
occlusive events (AOEs) in PACE may introduce bias.

 

Table 4 References:
[4] Kantarjian HM, Jabbour E, Deininger M, et al. Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia. Am J Hematol. 2022;97(11):1419-1426. doi:10.1002/ajh.26686

A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias
Design

Phase 2, open-label, multinational trial

N= 449
Objective To evaluate the efficacy and safety of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL) who have resistance to or unacceptable side effects from dasatinib or nilotinib or who have the BCR-ABL T315I mutation
Study Groups Chronic-phase CML with resistance or side effects (n= 203) Chronic-phase CML with T315I mutation (n= 64) Accelerated-phase CML with resistance or side effects (n= 65) Accelerated-phase CML with T315I mutation (n= 18) Blast-phase CML or Ph-positive ALL with resistance or side effects (n= 48) Blast-phase CML or Ph-positive ALL with T315I mutation (n= 46)
Inclusion Criteria Patients aged ≥18 years with CML or Ph-positive ALL, resistance to or unacceptable side effects from dasatinib or nilotinib, or BCR-ABL T315I mutation
Exclusion Criteria History of pancreatitis, abnormal QT interval, inadequate renal or hepatic function
Methods Patients received an initial dose of 45 mg ponatinib orally once daily. Efficacy was assessed by major cytogenetic response in chronic-phase CML and major hematologic response in accelerated-phase CML, blast-phase CML, or Ph-positive ALL. Safety was monitored through adverse events and laboratory evaluations.
Duration Median follow-up: 15 months
Outcome Measures

Primary: Major cytogenetic response in chronic-phase CML, major hematologic response in accelerated-phase CML, blast-phase CML, or Ph-positive ALL

Secondary: Complete cytogenetic response, major molecular response
Baseline Characteristics   Chronic-phase CML (n= 267) Accelerated-phase CML (n= 83) Blast-phase CML (n= 62) Ph-positive ALL (n= 32)
Median age, years 58 55 53 45
Male 57% 60% 65% 50%
Previous TKI therapy 100% 100% 100% 100%
T315I mutation 24% 22% 29% 34%
Results   Chronic-phase CML Accelerated-phase CML Blast-phase CML Ph-positive ALL
Major cytogenetic response 56% 39% 23% 47%
Major hematologic response - 55% 31% 41%
Complete cytogenetic response 46% 24% 18% 38%
Major molecular response 34% 16% - -
Adverse Events Common adverse events: thrombocytopenia (37%), rash (34%), dry skin (32%), abdominal pain (22%) Serious arterial thrombotic events: 9% (treatment-related in 3%) 12% of patients discontinued treatment due to adverse events.
Study Author Conclusions Ponatinib demonstrated significant antileukemic activity across different stages of CML and Ph-positive ALL, with responses observed regardless of mutation status. However, arterial thrombotic events require careful monitoring.
Critique The study demonstrated significant efficacy of ponatinib in a heavily pretreated population, with durable responses. However, the open-label design and the occurrence of serious arterial thrombotic events are limitations. The study's findings may not be generalizable to less heavily pretreated populations or those without the T315I mutation.
Table 5 References:
[5] Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783-1796. doi:10.1056/NEJMoa1306494. (PACE)

Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: Final 5-year results of the phase 2 PACE trial
Design

Phase 2 trial

N=449
Objective To evaluate the efficacy and safety of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) who are resistant or intolerant to dasatinib or nilotinib, or have the BCR-ABL1T315I mutation
Study Groups

CP-CML (n=270)

AP-CML (n=85)

BP-CML (n=62)

Ph+ ALL (n=32)
Inclusion Criteria Adult patients with CML or Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the BCR-ABL1T315I mutation; see previous table for PACE trial
Exclusion Criteria See previous table for PACE trial
Methods Ponatinib was administered at a starting dose of 45 mg once daily. Dose reductions to 30 mg or 15 mg were implemented to manage adverse events or proactively to reduce arterial occlusive events. Efficacy was assessed through cytogenetic and molecular responses, and safety was monitored continuously
Duration Median follow-up of 56.8 months for CP-CML patients
Outcome Measures

Primary: Major cytogenetic response (MCyR) by 12 months for CP-CML

Secondary: Major molecular response (MMR), progression-free survival (PFS), overall survival (OS), safety
Baseline Characteristics   All patients (n= 449)
Median age, years (range) 59 (18–94)
Female 47%
Received ≥2 TKIs 93%
Received ≥3 TKIs 56%
BCR-ABL1T315I mutation 29%
Results   CP-CML (n= 267)
Achieved MCyR 60%
Achieved CCyR 54%
Achieved MMR 40%
Achieved MR4.5 24%
5-year OS 73%
5-year PFS 53%
Adverse Events Common Adverse Events: Rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), constipation (41%) Serious Adverse Events: Pancreatitis (7%), atrial fibrillation (6%), pneumonia (6%), angina pectoris (5%) Cumulative incidence of arterial occlusive events: 31% in CP-CML patients.
Study Author Conclusions Ponatinib provides durable and clinically meaningful responses in heavily pretreated CP-CML patients, with acceptable tolerability over 5 years. Dose reductions did not compromise response maintenance.
Critique The study demonstrates significant efficacy of ponatinib in a heavily pretreated population, with durable responses. However, the risk of arterial occlusive events remains a concern, necessitating careful patient monitoring and dose management. The lack of a control group limits the ability to compare directly with other treatments.
Table 6 References:
[6] Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132(4):393-404. doi:10.1182/blood-2016-09-739086. (PACE five-year follow-up)