ponatinib
Regulatory sources consulted
Approved indications
- Resistant/intolerant Ph+ CML or Ph+ ALL and T315I-mutated disease; newly diagnosed Ph+ ALL only in the authorized combination regimen. It is not indicated for newly diagnosed chronic-phase CML.
Contraindications
Absolute
- Hypersensitivity to ponatinib or excipients.
Clinical warnings
- It may cause arterial or venous occlusion, heart failure, and fatal hepatotoxicity. Assess cardiovascular risk, monitor blood pressure, and discontinue according to severity. — CIMA/AEMPS, ficha técnica 63020
- Monitor blood counts, hepatic and renal function, fluid retention, bleeding, infection, and tumor lysis syndrome. Adjust or interrupt only according to the indication-specific table. — CIMA/AEMPS, ficha técnica 63020
- Monitor pancreatitis/lipase, neuropathy, ocular toxicity, bleeding, fluid retention, arrhythmia, PRES, perforation, wound healing, and blood counts every 2 weeks for 3 months, then monthly. — CIMA/AEMPS, ficha técnica 63020
Drug interactions
- HighStrong CYP3A inhibitors or inducers
Mechanism: They alter ponatinib exposure.
Recommendation: Avoid both. If a strong inhibitor is unavoidable, reduce 45→30 mg, 30→15 mg, or 15→10 mg; avoid the inhibitor if already taking 10 mg.
CIMA/AEMPS, ficha técnica 63020
- HighP-gp or BCRP substrates
Mechanism: Ponatinib inhibits P-gp and BCRP and may increase exposure to digoxin, dabigatran, colchicine, pravastatin, methotrexate, rosuvastatin, or sulfasalazine.
Recommendation: Closely monitor toxicity and concentrations when appropriate.
CIMA/AEMPS, ficha técnica 63020
Pregnancy and lactation
It may cause fetal harm. Verify pregnancy; women use contraception during treatment and for 3 weeks afterward. Do not breastfeed during treatment or for 1 week afterward. It may impair female fertility.
Recent literature (PubMed)
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an annual incidence of two cases/100 000. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. CML is characterized by a balanced genetic translocation, t(9;22) (q34;q11.2), involving a fusion of the Abelson murine leukemia (ABL1) gene from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR::ABL1 fusion oncogene, which in turn translates into a BCR::ABL1 oncoprotein. Four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib, are approved by the United States Food and Drug Administration (FDA) for first-line treatment of newly diagnosed CML in the chronic phase (CML-CP). Clinical trials with second and third-generation TKIs in frontline CML-CP therapy reported significantly deeper and faster responses but had no impact on survival prolongation, likely because of their potent efficacy and the availability of effective TKIs salvage therapies for patients who have a cytogenetic relapse with frontline TKI therapy. All four TKIs are equivalent if the aim of therapy is to improve survival. In younger patients with high-risk disease and in whom the aim of therapy is to induce a treatment-free remission status, second-generation TKIs may be favored. For CML post-failure on frontline therapy, second-line options include second and third-generation TKIs. Although potent and selective, these TKIs exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities and financial status, disease stage, and BCR::ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib, asciminib, and olverembatinib. Allogeneic stem cell tr
Chronic myeloid leukemia (CML) has an annual incidence of 2 cases per 100 000 people and is newly diagnosed in approximately 9300 individuals per year in the US. Approximately 150 000 people in the US and 5 million worldwide have CML. Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome, which is defined by the BCR::ABL1 oncogene that develops after fusion of the ABL1 proto-oncogene to the constitutively active BCR gene. Approximately 90% of people with CML present with an indolent chronic phase of CML, defined as blasts of less than 10% in the blood or bone marrow, absence of extramedullary evidence of leukemia, basophils of less than 20%, and platelet counts of 100 to 1000 × 109/L. The most advanced stage is CML blastic phase (CML-BP), characterized by the World Health Organization as 20% or more blasts/immature cells and by the MD Anderson Cancer Center and European LeukemiaNet as 30% or more. Approximately 1% to 2% of patients with CML present with CML-BP. Since 2000, first-generation tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1, such as imatinib, and second-generation TKIs, such as bosutinib, dasatinib, and nilotinib, have improved CML-related mortality from 10% to 20% per year to 1% to 2% per year, such that patients with CML have survival rates similar to those of a general age-matched population. Six BCR::ABL1 TKIs have been approved by the US Food and Drug Administration, including 5 that are first-line treatment (imatinib, dasatinib, bosutinib, nilotinib, and asciminib) and 5 approved for treatment after disease progression despite initial therapy (dasatinib, bosutinib, nilotinib, ponatinib, asciminib). Effects on improved survival are similar with all TKIs, although more patients are able to promptly achieve and maintain BCR::ABL1 clearance with second- and third-generation TKIs. Medication adherence is important to maintain treatment responsiveness. All TKIs are associated with he
Ponatinib and blinatumomab are effective therapies in patients with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia, and their combination might be a promising treatment option. In this study, we aimed to evaluate this chemotherapy-free strategy. We did a single-centre, single-arm, phase 2 study at the University of Texas MD Anderson Cancer Center, Houston, TX, USA, in patients aged 18 years or older with newly diagnosed or relapsed or refractory Ph-positive acute lymphoblastic leukaemia or chronic myeloid leukaemia in lymphoid blast phase. Patients with an ECOG performance status of 2 or less who had a total bilirubin concentration two-times the upper limit of normal (ULN) or less (≤2·4 mg/dL), alanine aminotransferase and aspartate aminotransferase concentration no more than three-times the ULN, and serum lipase and amylase concentrations no more than three-times the ULN were eligible for inclusion. Ponatinib 30 mg orally and continuous intravenous blinatumomab 28 μg over 24 h (for 28 days each cycle) were given in combination for up to five 42-day cycles, followed by ponatinib monotherapy. Patients received 12 doses of intrathecal chemotherapy as CNS prophylaxis. The primary endpoints were complete molecular response (defined as absence of a detectable BCR-ABL1 transcript by PCR at a sensitivity of 0·01%) in patients with newly diagnosed disease and overall response in patients with relapsed or refractory disease or chronic myeloid leukaemia in lymphoid blast phase. All assessments were done according to the intention-to-treat principle. The trial completed its original target accrual and was amended on March 23, 2022, to enrol an additional 30 patients, thus increasing the sample size to 90 patients. The trial is registered with ClinicalTrials.gov, NCT03263572, and it is ongoing. Between Feb 6, 2018, to May 6, 2022, 60 (83%) of 72 patients assessed were enrolled and received ponatinib and blinatumomab (40 [67%] patients had newly dia
Research in acute lymphoblastic leukemia (ALL) is translating into rapid changes in therapy and outcomes. Historically, adult ALL was treated with intensive chemotherapy extending over 2.5 to 3 years. This established tradition, accepted because of the high cure rates in childhood ALL, has been challenged by the development of highly active targeted therapies. Treatment modalities, combined with less and shorter chemotherapy durations, have produced better results than chemotherapy. The novel therapies include using the more potent BCR::ABL1 tyrosine kinase inhibitors (eg, ponatinib, dasatinib) with the bispecific CD3-CD19 T-cell engager antibody blinatumomab in Philadelphia chromosome-positive ALL and combining blinatumomab and/or inotuzumab (CD22 antibody drug conjugate) with standard chemotherapy in B-cell ALL. These have been associated with improved 4-year survival rates of 85% to 90% in Philadelphia chromosome-positive ALL and 80% to 85% in B-cell ALL. The management of ALL is changing rapidly. Investigators have evaluated frontline and later-line regimens with combinations of tyrosine kinase inhibitors and immunotherapies with less or no chemotherapy. Future research will evaluate CD19, CD20, and CD22 multitargeting antibodies and chimeric antigen receptor T-cell therapies, new antibody formulations, and less intensive/shorter regimens.
Chronic myeloid leukemia (CML) has an annual incidence of approximately two cases per 100,000. The reduction in annual mortality from 10%-20% to 1% with BCR::ABL1 tyrosine kinase inhibitors (TKIs) has resulted in an increased prevalence in the United States of an estimated 150,000 cases in 2025. This translates into a worldwide estimated prevalence of approximately 5 million cases, and hence the need to make TKIs available and affordable to all patients. The four main goals of CML therapy are to (1) improve survival; (2) achieve a durable deep molecular response, which may lead to a treatment-free remission status; (3) reduce short- and long-term side effects; and (4) provide good treatment value. Today, the six approved BCR::ABL1 TKIs, five in frontline therapy (imatinib, dasatinib, bosutinib, nilotinib, and asciminib) and all six in later line therapy (including ponatinib), fulfill in one form or another these requirements. Third-generation TKIs that target the ABL1 kinase domain (olverembatinib and ELVN-001) or the myristoyl pocket (TGRX-678 and TERN-701) are under development. Allogeneic hematopoietic stem cell transplantation is a one-time, cost-effective, curative treatment in patients with CML resistant to second-generation TKIs, which is perhaps surprisingly underused in 2025, given the high enthusiasm for it before the development of TKIs. However, serious complications, such as graft-vs-host disease, or death could occur. This review summarizes relevant information concerning the management of CML in 2025, and addresses some CML treatment pathways that became entrenched in the management of CML in the first 15-20 years of TKI experience, which may need to be revisited.