Effects of ponatinib: A Synthesis of Findings from 24 Studies

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Original Abstract of the Article

Major findings

Ponatinib is an effective treatment for chronic myeloid leukemia (CML), especially for patients who are resistant or intolerant to other tyrosine kinase inhibitors (TKIs). 13 Ponatinib has been shown to be effective in treating CML, even in cases where the disease has progressed to a more aggressive stage, such as accelerated phase (AP) or blast phase (BP). 21 The combination of ponatinib with other medications, such as hyper-CVAD chemotherapy, has been shown to be effective in treating Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL), with high rates of complete molecular remissions and survival without the need for stem cell transplantation (SCT). 10 However, ponatinib is associated with cardiovascular adverse events (CVAEs), which can be a serious concern for patients. 17 The use of cobicistat, a pharmacokinetic booster, can increase the exposure of ponatinib and dasatinib in patients with CML, but the effectiveness of this approach has not been definitively established. 18

Ponatinib may also have beneficial effects in treating obesity-related metabolic syndrome. 9 It has been shown to improve insulin sensitivity, reduce hyperlipidemia, and inhibit ectopic lipid deposition in the liver. 9 However, the exact mechanisms underlying these effects are not fully understood. 9 Ponatinib has also been shown to have preclinical activity as an LCK inhibitor, a potential target in T-cell acute lymphoblastic leukemia (T-ALL). 8

Benefits and risks

Benefits summary

Ponatinib can be effective in treating CML, especially for patients who have not responded to other TKIs. 13 It may have beneficial effects in treating obesity-related metabolic syndrome. 9

Risks summary

Ponatinib is associated with cardiovascular adverse events (CVAEs), which can be serious and can potentially lead to death. 17 15 It is important to monitor patients closely for signs of cardiovascular problems and to adjust the dose of ponatinib as needed. 11

Comparison of studies

Commonalities of studies

Many studies have shown that ponatinib is an effective treatment option for CML, particularly for patients who are resistant or intolerant to other TKIs. 13 The studies also generally agree that ponatinib is associated with cardiovascular adverse events (CVAEs). 17

Differences of studies

Studies differ in the specific patient populations that they studied, the dosages of ponatinib used, and the length of follow-up. 13 These differences may explain the variability in the reported effectiveness and side effects of ponatinib. 13

Consistency and contradictions of results

The results of the studies generally support the conclusion that ponatinib is an effective treatment option for CML, especially in cases where other TKIs have not been successful. 13 However, the risk of cardiovascular adverse events (CVAEs) is a significant concern. 17

Points to note regarding application to real life

It is important to weigh the benefits and risks of ponatinib before using it to treat CML. 13 Patients should be carefully monitored for signs of cardiovascular problems, and the dose of ponatinib may need to be adjusted accordingly. 11

Limitations of current research

More research is needed to better understand the long-term effects of ponatinib, including the risks and benefits of using it in different patient populations and the best ways to manage cardiovascular adverse events. 13

Future directions for research

Research should focus on developing strategies to minimize the risk of cardiovascular adverse events associated with ponatinib. 15 14 Researchers should also explore the potential of ponatinib in other diseases, such as obesity-related metabolic syndrome and T-ALL. 9 8

Conclusion

Ponatinib is a potent TKI that can be effective in treating CML, particularly in cases where other TKIs have failed. 13 However, it is important to be aware of the risk of cardiovascular adverse events. 15 Patients should be carefully monitored for these side effects, and the dose of ponatinib may need to be adjusted accordingly. 11 More research is needed to better understand the long-term effects of ponatinib and to develop strategies to minimize the risk of cardiovascular adverse events. 13

Literature analysis of 24 papers
Positive Content
23
Neutral Content
1
Negative Content
0
Article Type
2
0
0
4
24
1.

Effects of ketoconazole on the pharmacokinetics of ponatinib in healthy subjects.

Author: NarasimhanNarayana I, DorerDavid J, NilandKatie, HaluskaFrank, SonnichsenDaryl

Leukemia treatment
Drug interactions

Coadministration of ponatinib with ketoconazole, a CYP3A4 inhibitor, increased ponatinib exposure by 78% and decreased exposure to its metabolite AP24567 by 71%. Caution should be exercised when ponatinib is used concurrently with strong CYP3A4 inhibitors.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Randomized Controlled TrialA clinical trial that randomly assigns participants to treatment and control groups to evaluate the effects of an intervention.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

3.

Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial.

Author: JabbourElias, ShortNicholas J, JainNitin, HuangXuelin, Montalban-BravoGuillermo, BanerjeePinaki, RezvaniKatayoun, JiangXianli, KimKun Hee, Kanagal-ShamannaRashmi, KhouryJoseph D, PatelKeyur, KadiaTapan M, DaverNaval, ChienKelly, AlvaradoYesid, Garcia-ManeroGuillermo, IssaGhayas C, HaddadFadi G, KwariMonica, ThankachanJennifer, DelumpaRicardo, MacaronWalid, GarrisRebecca, KonoplevaMarina, RavandiFarhad, KantarjianHagop

Chemotherapy-free treatment
Complete molecular response
Cerebrovascular ischemia
Coronary artery stenosis
Hypertension
Increased alanine aminotransferase or aspartate aminotransferase
Increased amylase or lipase
Infection
Pain
Portal vein thrombosis
Tremor

A chemotherapy-free combination of ponatinib and blinatumomab resulted in high rates of complete molecular response (87%) in patients with newly diagnosed Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia and overall response (92%) in patients with relapsed or refractory Ph-positive acute lymphoblastic leukaemia. The most common grade 3-4 adverse events were infection (37%), increased amylase or lipase concentration (8%), increased alanine aminotransferase or aspartate aminotransferase concentration (7%), pain (7%), and hypertension (7%).

Clinical Trial, Phase IIA Phase II trial is a trial that further evaluates the efficacy and safety of a new drug or treatment, whose safety has been confirmed to some extent in a Phase I trial, in a small number of patients.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

4.

Overcoming phenotypic switching: targeting protein-protein interactions in cancer.

Author: LadiasChristos, PapakotoulasPavlos, PapaioannouMaria, PapanikolaouNikolaos A

Cancer treatment
PPI targeting
Drug resistance

This review examines the challenges of targeting protein-protein interactions (PPIs) for drug development, particularly in the context of phenotypic switching in cancer, and discusses potential strategies for overcoming these obstacles.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

5.

Focal Segmental Sclerosis Associated with the Novel Multi-tyrosine Kinase Inhibitor Ponatinib.

Author: AraiHiroyuki, YamamotoShinya, MatsubaraTakeshi, MiyakeTakafumi, TochioAkira, MiiAkiko, ShimizuAkira, MinamiguchiSachiko, MusoEri, YanagitaMotoko

CML treatment
Renal complications

This case report describes a 76-year-old woman with chronic myeloid leukemia (CML) who developed proteinuria and renal function deterioration during treatment with ponatinib. This is the first reported case of secondary focal segmental glomerulosclerosis (FSGS) induced by ponatinib treatment. While ponatinib is a potent TKI for refractory CML, it can cause various adverse events, including rare renal complications.

Case ReportsIn the medical field, a report that describes in detail a unique case, an unusual medical condition, or the effect of a treatment. Provides new insights and possibilities for treatment through individual patient cases.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

6.

Dose optimisation of ponatinib in chronic phase chronic myeloid leukemia.

Author: HuguetFrançoise, RéaDelphine, CayssialsEmilie, EtienneGabriel, NicoliniFranck-Emmanuel

Improved hematologic response
Reduced all-cause mortality
Reduced major cardiovascular events
Arterial thrombosis
Bleeding
Cardiovascular toxicity
Hypertension

Ponatinib is a tyrosine kinase inhibitor used to treat chronic myeloid leukemia. Its dosage should be tailored to the patient's risk profile, including prior response to treatment and mutational status.

Clinical Trial, Phase IIA Phase II trial is a trial that further evaluates the efficacy and safety of a new drug or treatment, whose safety has been confirmed to some extent in a Phase I trial, in a small number of patients.
Randomized Controlled TrialA clinical trial that randomly assigns participants to treatment and control groups to evaluate the effects of an intervention.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

7.

Elabela-apelin-12, 17, 36/APJ system promotes platelet aggregation and thrombosis via activating the PANX1-P2X7 signaling pathway.

Author: ChenZhe, LuoXuling, LiuMeiqing, JiangJinyong, LiYao, HuangZhen, WangLingzhi, CaoJiangang, HeLu, HuangShifang, HuHaoliang, LiLanfang, ChenLinxi

Antithrombotic effects

Elabela and apelin, peptides that activate the APJ receptor, were found to induce platelet aggregation and thrombosis by activating the PANX1-P2X7 signaling pathway. Spironolactone, a PANX1 inhibitor, effectively alleviated these effects. Cobicistat and Schisandrin A, drugs that block the APJ receptor, also prevented elabela- and apelin-induced thrombosis. These findings suggest potential new therapies for thrombosis by targeting the elabela-apelin/APJ axis.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

8.

Preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib for the treatment of T-cell acute lymphoblastic leukemia.

Author: YoshimuraSatoshi, PanettaJohn C, HuJianzhong, LiLie, GochoYoshihiro, DuGuoqing, UmezawaAkihiro, KarolSeth E, PuiChing-Hon, MullighanCharles G, KonoplevaMarina, StockWendy, TeacheyDavid T, JainNitin, YangJun J

T-ALL treatment

Dasatinib and ponatinib are LCK inhibitors with potential for treating T-cell acute lymphoblastic leukemia (T-ALL). This study evaluated the pharmacokinetic and pharmacodynamic profiles of these drugs in LCK-activated T-ALL. Both drugs showed similar cytotoxic activity, with ponatinib exhibiting slightly greater potency.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.

Language : English

10.

Frontline combination of ponatinib and hyper-CVAD in Philadelphia chromosome-positive acute lymphoblastic leukemia: 80-months follow-up results.

Author: KantarjianHagop, ShortNicholas J, JainNitin, SasakiKoji, HuangXuelin, HaddadFadi G, KhouriIssa, DiNardoCourtney D, PemmarajuNaveen, WierdaWilliam, Garcia-ManeroGuillermo, KebriaeiPartow, GarrisRebecca, LoghaviSanam, JorgensenJeffrey, KwariMonica, O'BrienSusan, RavandiFarhad, JabbourElias

Complete molecular remissions
Survival
Infection
Liver transaminases
Myocardial infarction

Ponatinib, a third-generation BCR::ABL1 tyrosine kinase inhibitor, combined with hyper-CVAD chemotherapy, achieves high rates of complete molecular remission (86%) and survival (75%) in patients with Philadelphia chromosome-positive acute lymphocytic leukemia (ALL). This regimen is a promising standard of care for frontline Ph-positive ALL, potentially eliminating the need for stem cell transplantation in most patients.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

13.

Long-Term Follow-Up in Patients With Chronic Myeloid Leukemia Treated With Ponatinib in a Real-World Cohort: Safety and Efficacy Analysis.

Author: Mela OsorioMaría José, MoiraghiBeatriz, OsyckaMaría Victoria, PavlovskyMiguel A, VarelaAna Inés, Bendek Del PreteGeorgina Emilia, TosinMaría Fernanda, PérezMariel Ana, RivaMaría Elisa, BerriosRoxana Ramírez, FernándezIsolda, Sackmann MassaFederico, GiereIsabel, SighelCarolina, PavlovskyCarolina

CML treatment

Ponatinib is a third-generation tyrosine-kinase inhibitor (TKI) indicated in patients with chronic myeloid leukemia (CML) who are resistant or intolerant to ≥2 prior TKIs.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

14.

Ponatinib: An update on its drug targets, therapeutic potential and safety.

Author: GaoYue, DingYue, TaiXin-Ran, ZhangChen, WangDong

Cancer treatment
Leukemia treatment
Cardiovascular toxicity

Ponatinib is a third-generation tyrosine kinase inhibitor that targets BCR-ABL and other kinases, making it effective for treating various cancers. However, it has significant cardiovascular toxicity, which limits its clinical use. This review discusses the pharmacokinetics, targets, therapeutic potential, and toxicity of ponatinib and explores ways to mitigate its toxicity.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

16.

Antitumor effects and molecular mechanisms of ponatinib on endometrial cancer cells harboring activating FGFR2 mutations.

Author: KimDo-Hee, KwakYeonui, KimNam Doo, SimTaebo

EC treatment

This study investigated the effects of AP24534 (ponatinib), a multi-targeted tyrosine kinase inhibitor, on endometrial cancer cells harboring activating FGFR2 mutations. AP24534 significantly inhibited the proliferation of these cells and mainly induced G1/S cell cycle arrest leading to apoptosis.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

17.

Involvement of Rho-Associated Coiled-Coil Containing Kinase (ROCK) in BCR-ABL1 Tyrosine Kinase Inhibitor Cardiovascular Toxicity.

Author: YuBrian, OsmanAfaf E G, SladojevicNikola, PrabhuNicole, TaiHaw-Chih, ChenDaiqing, PerlaGerardo, ParkLinus, LarsonRichard A, LiaoJames K

ROCK inhibition
CVAEs
Endothelial dysfunction

Patients receiving second- and third-generation BCR-ABL1 TKIs had elevated ROCK activity, associated with an increased incidence of CVAEs. ROCK inhibition may be a promising approach to reduce the incidence of CVAEs.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

18.

Cobicistat as a Potential Booster of Ponatinib and Dasatinib Exposure in a CML Patient: A Case Study.

Author: HofmanSusan, TouwDaan J, SpanBart F R, Oude MunninkThijs H

Reduced drug costs

This case report describes a patient with chronic myeloid leukemia treated with ponatinib and dasatinib. The patient showed a major molecular response; however, the BCR-ABL1 signal increased with low drug concentrations. Cobicistat was used to increase drug exposure, which led to a response in BCR-ABL1 PCR signal and reduced drug costs.

Case ReportsIn the medical field, a report that describes in detail a unique case, an unusual medical condition, or the effect of a treatment. Provides new insights and possibilities for treatment through individual patient cases.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

20.

Investigating Potential Cardiovascular Toxicity of Two Anti-Leukemia Drugs of Asciminib and Ponatinib in Zebrafish Embryos.

Author: LinHuan-Chau, SaputraFerry, AudiraGilbert, LaiYu-Heng, RoldanMarri Jmelou M, AlosHoneymae C, AventuradoCharlaine A, VasquezRoss D, TsaiGuan-Jhe, LimKen-Hong, HsiaoChung-Der

CML treatment
Cardiovascular side effects

This study investigated the potential cardiovascular-related side effects of combining asciminib (ASC) and ponatinib (PON) in zebrafish. While the combination did not significantly affect cardiac performance, it caused a significant increase in nkx2.5 expression and a decrease in blood flow velocity, suggesting mild cardiovascular-related side effects.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

21.

An Update on the Management of Advanced Phase Chronic Myeloid Leukemia.

Author: ShortNicholas J, SenapatiJayastu, JabbourElias

Improved CML treatment
Increased survival
Advanced phase CML
CML progression

Chronic myeloid leukemia (CML) usually has a normal life expectancy, but some patients progress to more aggressive phases. This article discusses the diagnosis and treatment of these advanced phases of CML.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

22.

Addendum to the German Consensus Recommendations on Ponatinib in the Treatment of Chronic Myeloid Leukemia.

Author: SausseleSusanne, La RoséePaul, KianiAlexander, HaverkampWilhelm, Jentsch-UllrichKathleen, StegelmannFrank, RiegerChristina, WallerCornelius F, FrankeGeorg-Nikolaus, JunghanssChristian, KirchmairRudolf, TheurlMarkus, le CoutrePhilipp

Dose optimization

This addendum to the German consensus paper on ponatinib updates the recommendations based on new data from the OPTIC (Optimizing Ponatinib Treatment in CP-CML) trial on dose optimization of ponatinib in patients with chronic phase (CP)-CML.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

23.

The outcomes of patients with chronic myeloid leukemia treated with third-line BCR::ABL1 tyrosine kinase inhibitors.

Author: JabbourElias J, SasakiKoji, HaddadFadi G, IssaGhayas C, Garcia-ManeroGuillermo, KadiaTapan M, JainNitin, YilmazMusa, DiNardoCourtney D, PatelKeyur P, Kanagal-ShamannaRashmi, ChamplinRichard, KhouriIssa F, DellasalaSara, PierceSherry A, KantarjianHagop

Better survival with ponatinib
Improved CML outcomes
Cardiovascular risks
Higher disease burden

Ponatinib is a tyrosine kinase inhibitor (TKI) effective as a third-line therapy for patients with chronic myeloid leukemia (CML) who have failed two prior TKIs. A study of 354 patients found that ponatinib was associated with better survival compared to other TKIs.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

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