Ponatinib-Related Vasospastic Angina.

Tyrosine kinase inhibitors (TKIs) are essential drugs for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Cardiovascular or arteriothrombotic adverse events have been reported in patients treated with TKIs. We report 3 cases of Ponatinib-related vasospastic angina, in which prophylactic administration of nitrates or calcium channel blockers was effective.

Long-term safety and tolerability of ambrisentan treatment for pediatric patients with pulmonary arterial hypertension: An open-label extension study.

This open-label, extension study assessed long-term safety, tolerability, and efficacy of ambrisentan in a pediatric population (age 8- < 18 years) with pulmonary arterial hypertension (PAH). Following completion of a 6-month, randomized study, participants entered the long-term extension at individualized ambrisentan dosages (2.5/5/7.5 or 10 mg/day). Safety assessments included adverse events (AEs), AEs of special interest, and serious AEs (SAEs); efficacy outcomes included 6-min walking distance (6MWD) and World Health Organization functional class (WHO FC). Thirty-eight of 41 (93%) randomized study participants entered the extension; 21 (55%) completed (reaching age 18 years). Most participants received concomitant phosphodiesterase-5 inhibitors (n = 25/38, 66%). Median ambrisentan exposure was 3.5 years. Most participants experienced ≥ 1 AE (n = 34/38, 89%), and 21 (55%) experienced SAEs, most commonly worsening PAH (n = 3/38, 8%), acute cardiac failure, pneumonia, or anemia (n = 2/38; 5% each); none considered ambrisentan-related. Seven participants (18%) died, with recorded reasons (MedDRA preferred term): cardiac failure (n = 2), PAH (n = 2), COVID-19 (n = 1), acute right ventricular failure (n = 1), and failure to thrive (n = 1); median time to death: 5.2 years. Anemia and hepatotoxicity AEs were generally mild to moderate and did not require ambrisentan dose adjustment. Assessed at study end in 29 participants (76%), mean 6MWD improved by 17% (standard deviation: 34.3%), and all (29/29, 100%) had improved or unchanged WHO FC.    Conclusion: Long-term weight-based ambrisentan dosing, alone or combined with other PAH therapies in children with PAH aged 8- < 18 years, exhibited tolerability and clinical improvements consistent with prior randomized study results.    Trial registration: NCT01342952, April 27, 2011. What is Known: • The endothelin receptor antagonist, ambrisentan, is indicated for treatment of pulmonary arterial hypertension (PAH). Previous studies have shown similar efficacy and tolerability in pediatric patients as in adults. What is New: • This open-label extension study assessed the long-term use of ambrisentan in pediatric patients (8-<18 years) with PAH, most of whom were also receiving recommended background PAH treatment. • Weight-based dosing of ambrisentan, given alone or in combination with other PAH therapies, was well tolerated with clinical improvements consistent with prior randomized study results.

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

BACKGROUND: Ponatinib is a third-generation tyrosine-kinase inhibitor (TKI), indicated in patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML), who are resistant or intolerant to ≥2 prior TKIs, patients for whom subsequent treatment with imatinib is not appropriate, and patients who have a T315I mutation. PATIENTS AND METHODS: We aimed to evaluate outcomes of ponatinib treatment, including safety, with focus on cardiovascular toxicity, in real-world patients from Argentina. Data from patients with CP CML treated with ponatinib was retrospectively retrieved from 2013 to 2023 in 7 centers. RESULTS: Seventy-two patients were included (median age: 44 years; male: 55.5%; T315I mutation: 32%: median treatment duration: 36 months. At baseline, 57 patients (79%) had a breakpoint cluster region-Abelson (BCR::ABL1) transcript level >10% on the international reporting scale (BCR::ABL1 IS). A molecular response (MR, BCR::ABL1 (IS) <1%) was achieved at 12 months in 51.6% of evaluable patients; 57% maintained MR at last follow-up. Overall, 43% and 25% maintained major MR (MMR) or deep MR (DMR) (MR4.0-MR5.0), respectively at last follow-up. Twelve (16.6%) ponatinib-resistant patients were rescued with allogeneic hematopoietic stem cell transplantation. The estimated 2-year progression-free survival (PFS) was 84%. Ponatinib dose was reduced during treatment in 22 patients; nevertheless, MMR was maintained in 50% of these patients. Severe arterial occlusive events (AOE) were reported in 10.9% of patients after a median treatment of 5 months. CONCLUSION: CV toxicity was consistent with clinical trials and other real-world registries. Older age, hypercholesterolemia and a SCORE risk >2% were significantly associated with higher risk of AOEs. Controlling CV risk factors and reducing doses at optimal time points may help to optimize ponatinib use in daily practice.

Comparative efficacy and safety of different doses of ponatinib versus other tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia: a systematic review and network meta-analysis.

OBJECTIVE: Ponatinib was recommended with caution because of its high risk of causing arterial occlusion events in chronic myeloid leukemia (CML) patients. The purpose of this study was to understand the efficacy and safety of different doses of ponatinib in the treatment of CML, and to compare it with other tyrosine kinase inhibitors (TKIs). METHOD: A network meta-analysis (NMA) was conducted by searching randomized controlled trials (RCTs) of ponatinib in patients with CML to compare the efficacy and safety of ponatinib, and ranked under the cumulative ranking curve (SUCRA) to evaluate the optimal treatment. RESULTS: A total of seven articles with eight RCTs were included in this study, involving 45 mg, 30 mg and 15 mg ponatinib doses. Seven outcome indexes were analyzed. The results showed that 45 mg ponatinib was superior to other doses of ponatinib and other TKIs in CCyR, MCyR and CHR, but the incidence of SAEs and AOEs was significantly higher than other treatment regimens. CONCLUSION: Ponatinib, with an initial dosage of 45 mg and a gradual reduction to 15 mg, may be a more favorable option for patients with CML at all stages of disease progression, rather than just those in the chronic phase of CML.

Safety of Levosimendan in Pediatric Patients: An Up-to-Date Systematic Review.

BACKGROUND: The potential risks associated with the use of levosimendan in the pediatric population has not been systematically evaluated. This study aimed to review the available evidence regarding the safety of this treatment. METHODS: Bio Med Central, PubMed, Embase, and the Cochrane Central Register of clinical trials were searched for studies describing levosimendan administration in the pediatric population in any setting. Relevant studies were independently screened, selected, and their data extracted by two investigators. The authors excluded: reviews, meta-analyses, as well as basic research and trials involving patients >18 years old. The primary outcome was the number and the type of adverse side effects reported during levosimendan administration. RESULTS: The updated systematic review included 48 studies, enrolling a total of 1,271 pediatric patients who received levosimendan as treatment (790 patients in the 11 studies that reported side effects). The primary adverse effects of levosimendan administration were hypotension and cardiac arrhythmias, particularly tachycardia. Hypotension occurred in approximately 28.9% of patients, while arrhythmia occurred in about 12.3% of patients. Meta analysis of RCTs revealed a rate of all-cause mortality of 2.0% (8 out of 385) in the levosimendan group compared to 3.9% (15 out of 378) in the control group (dobutamine, milrinone or placebo) (risk ratio [RR] = 0.55; 95% confidence interval [CI] = 0.25-1.21; P = 0.14; I2 = 0%) CONCLUSIONS: Hypotension and cardiac arrhythmia are the most reported side effects of levosimendan in pediatric patients. However, adverse events remain underreported, especially in randomized trials.

Dose optimisation of ponatinib in chronic phase chronic myeloid leukemia.

INTRODUCTION: Ponatinib exhibits a high inhibition potency on wild-type and most mutated forms of the BCR:ABL1 kinase, but also a significant cardiovascular toxicity. Improving the efficacy/safety ratio should allow patients to safely draw benefit from the drug. AREAS COVERED: Based on pharmacological findings and international guidelines on chronic myeloid leukemia and cardiovascular risk management, as well as on the most recent data collected in real-life studies and in a randomized phase II trial, we propose a decision-tree of dose selection of the drug. EXPERT OPINION: We distinguish (1) highly resistant patients according to poor previous response to second generation tyrosine kinase inhibitors (complete hematologic response or less) or to mutational status (T315I, E255V, alone or within compound mutations), requiring a starting daily dose of 45 mg, reduced to 15 or 30 mg according to the patient's profile, preferentially upon major molecular achievement (3-log reduction or MR3, BCR:ABL1 ≤ 0.1%IS); (2) less-resistant patients justifying an initial dose of 30 mg, reduced to 15 mg upon MR2 (BCR:ABL1 ≤ 1%IS) or preferentially MR3 in patients with a favorable safety profile; (3) intolerant patients to be treated by 15 mg.

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

ABSTRACT: The authors present a case of a 57-year-old patient with chronic myeloid leukemia who was treated with ponatinib and subsequently treated with dasatinib. The patient showed a major molecular response; however, the BCR-ABL1 signal increased with low ponatinib and dasatinib trough concentrations. Cobicistat was used as a pharmacokinetic booster to increase ponatinib and dasatinib exposure, as opposed to increasing the dose. However, ponatinib exposure was not sufficiently increased by cobicistat. The peak dasatinib concentration was successfully increased with cobicistat treatment. Dasatinib and cobicistat cotreatment induced a response in BCR-ABL1 PCR signal, was well tolerated, and led to a substantial reduction in drug costs.

Management of Chronic Myeloid Leukemia Patients in Later Lines: The Role of Ponatinib and New Compounds.

Limited therapeutic options and poor response probability still represent some unresolved issue in later lines chronic myeloid leukemia (CML) patients. In addition, sequential treatment is associated with reduced overall survival and may select new mutation, including the T315I, further reducing the therapeutic chances: outside the United States, ponatinib and allogenic stem cell transplant are the only available options. In the last decade, ponatinib improved outcomes in third-line patients, although limited by the risk of severe adverse occlusive events. Dose optimization strategies with lower doses of ponatinib in selected patients have shown to reduce toxicity while retaining efficacy, but higher doses are needed in T315I patients for an adequate disease control. Recently approved by FDA, the first-of-its-kind STAMP inhibitor asciminib has proven safe and effective, obtaining deep and stable molecular responses even in heavily pretreated patients and with T315I mutation. Unfortunately, a significant proportion of patients remain intolerant or refractory, making it crucial to develop new therapeutic options. Among these, novel agents such as vodobatinib and olverembatinib have provided promising result in clinical trials, representing valuable therapeutic possibilities in intolerant or refractory patients. Therefore, a more complex therapeutic paradigm is expected in the near future.

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

Ponatinib is a novel multi-tyrosine kinase inhibitor (TKI) with potent inhibitory activity against refractory chronic myeloid leukemia (CML). Despite its high clinical efficacy, ponatinib induces various adverse events due to its multi-target characteristic. However, renal complications associated with ponatinib are rare. A 76-year-old woman had a history of chronic myeloid leukemia (CML) resistant to imatinib and nilotinib. Our patient developed proteinuria and renal function deterioration during treatment with ponatinib but not with imatinib or nilotinib. We herein report the first case of a patient with secondary focal segmental glomerulosclerosis (FSGS) with partial glomerular collapse induced by ponatinib treatment.

Incidence of adverse effects in patients receiving ponatinib with concomitant azole antifungals.

Ponatinib plus Hyper-CVAD yields a five-year overall survival of 73% in patients with Philadelphia-positive acute lymphoblastic leukemia. Ponatinib dose intensity is associated with increased incidence of adverse effects (AEs), including vascular events. Ponatinib combined with azole antifungals may further increase the risk of AEs due to increased ponatinib exposure. We reviewed 53 patients who received ponatinib with intensive (n = 39; 74%) or low-intensity chemotherapy (n = 14; 26%). Forty-eight patients (91%) received concomitant azole. Ponatinib was commonly initiated at 30 mg (n = 30; 57%) or 45 mg daily (n = 21; 40%). Twenty-six patients (49%) experienced at least one grade ≥3 AE possibly related to ponatinib; 19 (73%) were receiving a ponatinib dose equivalent ≥30mg and 58% >45mg. Eight patients (15%) experienced 10 vascular events, including 1 arterial event; 9 occurred on a ponatinib dose equivalent ≥30mg and 5 occurred while on an azole. Vascular events pose a clinical challenge with the risk potentially increasing with concomitant azoles.

Pediatric Population Pharmacokinetic Modeling and Exposure-Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data.

This study aimed to develop a population pharmacokinetic (PK) model of ambrisentan in pediatric patients (8 to <18 years) with pulmonary arterial hypertension (PAH) and compare pediatric ambrisentan systemic exposure with previously reported adult data. Association of ambrisentan exposure with efficacy (6-minute walking distance) and safety (adverse events) were exploratory analyses. A population PK model was developed using pediatric PK data. Steady-state systemic exposure metrics were estimated for the pediatric population and compared with previously reported data in adult patients with PAH and healthy subjects. No covariates had a significant effect on PK parameters; therefore, the final covariate model was the same as the base model. The pediatric population PK model was a 2-compartment model including the effect of body weight (allometric scaling), first-order absorption and elimination, and absorption lag time. Steady-state ambrisentan exposure was similar between the pediatric and adult population when accounting for body weight differences. Geometric mean area under the concentration-time curve at steady state in pediatric patients receiving ambrisentan low dose was 3% lower than in the adult population (and similar in both populations receiving high dose). Geometric mean maximum plasma concentration at steady state in pediatric patients receiving low and high doses was 11% and 18% higher, respectively, than in the adult population. There was no apparent association in the pediatric or adult population between ambrisentan exposure and change in 6-minute walking distance or incidence of ambrisentan-related adverse events in pediatric patients. The similar ambrisentan exposure and exposure-response profiles observed in pediatric and adult populations with PAH suggests appropriateness of body-weight-based dosing in the pediatric population with PAH.

Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia.

Ponatinib, the only third-generation pan-BCR::ABL1 inhibitor with activity against all known BCR::ABL1 mutations including T315I, has demonstrated deep and durable responses in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to prior second-generation (2G) TKI treatment. We present efficacy and safety outcomes from the Ponatinib Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and CML Evaluation (PACE) and Optimizing Ponatinib Treatment in CP-CML (OPTIC) trials for this patient population. PACE (NCT01207440) evaluated ponatinib 45 mg/day in CML patients with resistance to prior TKI or T315I. In OPTIC (NCT02467270), patients with CP-CML and resistance to ≥2 prior TKIs or T315I receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR::ABL1IS or received 15 mg/day continuously. Efficacy and safety outcomes from patients with CP-CML treated with ≥1 2G TKI (PACE, n = 257) and OPTIC (n = 93), 45-mg starting dose cohort, were analyzed for BCR::ABL1IS response rates, overall survival (OS), progression-free survival (PFS), and safety. By 24 months, the percentages of patients with ≤1% BCR::ABL1IS response, PFS, and OS were 46%, 68%, and 85%, respectively, in PACE and 57%, 80%, and 91%, respectively, in OPTIC. Serious treatment-emergent adverse events and serious treatment-emergent arterial occlusive event rates were 63% and 18% in PACE and 34% and 4% in OPTIC. Ponatinib shows high response rates and robust survival outcomes in patients whose disease failed prior to 2G TKIs, including patients with T315I mutation. The response-based dosing in OPTIC led to improved safety and similar efficacy outcomes compared with PACE.

Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.

Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.

[Novel therapies for chronic myeloid leukemia].

Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of chronic myeloid leukemia (CML). Five types of TKIs, including the third-generation TKI, ponatinib, are available in Japan, and TKI resistance has almost been overcome. However, TKI-related adverse events, such as vascular occlusive diseases that are frequently associated with ponatinib use, have become a critical concern. A recent dose optimization study of ponatinib demonstrated a dosing regimen that balances its risks and benefits in CML therapy. Furthermore, asciminib, a CML therapeutic drug with a new mechanism of action, has become available and is being applied clinically in Europe and the USA. This article outlines the latest treatments developed for CML in the chronic phase with prior therapy.

An evaluation of ponatinib as a therapy in adult patients with resistant/intolerant chronic-phase chronic myeloid leukemia.

INTRODUCTION: Chronic myeloid leukemia is now a highly treatable leukemia due to the availability of multiple tyrosine kinase inhibitors (TKIs) inhibiting the BCR-ABL1 oncogene. Some patients with CML can display resistance or intolerance to multiple TKIs, oftentimes due to the presence of mutations in BCR-ABL1, such as T315I, which limits effective treatment options. Ponatinib is a third-generation, rationally-designed TKI with clinically meaningful activity in this difficult-to-treat population. Ponatinib is associated with an increased risk of arterial occlusive events (AOEs) which has required a reexamination of its dosing in order to limit the risk of these events. AREAS COVERED: This review will provide an overview of the mechanism of action of ponatinib and the safety and efficacy data from clinical trials in chronic myeloid leukemia. EXPERT OPINION: Ponatinib is a potent pan-BCR-ABL1 TKI with substantial activity in patients with more resistant or advanced CML. Its efficacy needs to be balanced with the increased risk of vascular events, which seems to be at least partially diminished by the implementation of mitigation strategies aimed at modifying cardiovascular risk factors and adaptive dosing of the drug.

Comparative Effectiveness and Safety of Milrinone and Levosimendan as Initial Inotrope Therapy in Patients With Acute Heart Failure With Renal Dysfunction.

ABSTRACT: Levosimendan and milrinone are 2 effective inotropic drugs used to maintain cardiac output in acute heart failure (AHF). Using data from patients with AHF with and without abnormal renal function, we performed this single-center, retrospective cohort study to compare the effectiveness and safety of milrinone and levosimendan for the initial management of AHF. Patients admitted for heart failure between December 2016 and September 2019 who received levosimendan or milrinone as initial inotrope therapy in the cardiology department were identified. A total of 436 levosimendan and 417 milrinone patients with creatinine clearance (CrCl) ≥30 mL/min and 50 levosimendan and 71 milrinone patients with CrCl <30 mL/min or on dialysis were included. The primary outcome was a composite of changes in clinical status at 15 and 30 days after initial inotrope therapy discontinuation. Between subgroups of patients with CrCl ≥30 mL/min, there were no significant differences in primary outcomes; milrinone was associated with more frequent hypotension and cardiac arrhythmias during the infusion period (P < 0.01), while levosimendan was associated with more frequent cardiac arrhythmias within 48 hours after discontinuation (P < 0.05). Of the patients with CrCl <30 mL/min or on dialysis, more initial levosimendan than milrinone patients and those who switched to alternative inotropes experienced clinical worsening at 15 days and 30 days (P < 0.05). According to our results, patients with AHF with severe renal dysfunction should avoid initial inotrope therapy with levosimendan.

Safety of Tepotinib in Patients With MET Exon 14 Skipping NSCLC and Recommendations for Management.

INTRODUCTION: The MET inhibitor tepotinib demonstrated durable clinical activity in patients with advanced MET exon 14 (METex14) skipping NSCLC. We report detailed analyses of adverse events of clinical interest (AECIs) in VISION, including edema, a class effect of MET inhibitors. PATIENTS AND METHODS: Incidence, management, and time to first onset/resolution were analyzed for all-cause AECIs, according to composite categories (edema, hypoalbuminemia, creatinine increase, and ALT/AST increase) or individual preferred terms (pleural effusion, nausea, diarrhea, and vomiting), for patients with METex14 skipping NSCLC in the phase II VISION trial. RESULTS: Of 255 patients analyzed (median age: 72 years), edema, the most common AECI, was reported in 69.8% (grade 3, 9.4%; grade 4, 0%). Median time to first edema onset was 7.9 weeks (range: 0.1-58.3). Edema was manageable with supportive measures, dose reduction (18.8%), and/or treatment interruption (23.1%), and rarely prompted discontinuation (4.3%). Other AECIs were also manageable and predominantly mild/moderate: hypoalbuminemia, 23.9% (grade 3, 5.5%); pleural effusion, 13.3% (grade ≥ 3, 5.1%); creatinine increase, 25.9% (grade 3, 0.4%); nausea, 26.7% (grade 3, 0.8%), diarrhea, 26.3% (grade 3, 0.4%), vomiting 12.9% (grade 3, 1.2%), and ALT/AST increase, 12.2% (grade ≥ 3, 3.1%). GI AEs typically occurred early and resolved in the first weeks. CONCLUSION: Tepotinib was well tolerated in the largest trial of a MET inhibitor in METex14 skipping NSCLC. The most frequent AEs were largely mild/moderate and manageable with supportive measures and/or dose reduction/interruption, and caused few withdrawals in this elderly population.

Ponatinib for the treatment of adult patients with resistant or intolerant Chronic-Phase Chronic Myeloid Leukemia.

INTRODUCTION: Patients with chronic myeloid leukemia in chronic phase (CP-CML) who are resistant or intolerant to second-generation tyrosine kinase inhibitors (TKIs) may benefit from treatment with a third-generation TKI, like ponatinib. AREAS COVERED: In this review, the authors discuss the role of ponatinib, an oral pan-inhibitor of BCR-ABL1, with potent activity in heavily pretreated patients, including T315I mutation. In the long-term follow-up of the PACE trial, 60% of patients with prior TKIs exposure achieved a major cytogenetic response with ponatinib and 40% a major molecular response; 5-year overall survival was 73%. Cardiovascular adverse events represent the major toxicity associated with ponatinib. Adopting a dose-reduction approach appeared to be safe: starting with 45 or 30 mg and decreasing to 15 mg once BCR-ABL1/ABL1≤1% is achieved. In patients who are not candidates for ponatinib therapy, asciminib or other novel TKIs like HQP1351, represent alternative options. EXPERT OPINION: In patients with CP-CML resistant or intolerant to second-generation TKIs, we favor using a third-generation TKI such as ponatinib. Although we initiate a donor search as soon as a patient fails a second-generation TKI, we still prefer treating patients with ponatinib and will only consider transplantation in the event of no response or disease progression.