Iclusig (ponatinib)

P2, N=84, Recruiting, National Cancer Institute (NCI) | N=64 --> 84

All TKIs are not recommended during the first trimester due to their risk of teratogenesis, but imatinib and nilotinib may be cautiously used from Weeks 16-18 onward. Non-TKI therapies, such as hydroxyurea and interferon-α, are considered safe throughout pregnancy. Data on ponatinib and asciminib remain insufficient to allow the safe use of these agents during pregnancy. Future research should aim to improve treatment-free remission rates through novel agents and combination strategies to allow a higher proportion of younger patients to discontinue therapy. Clinicians should always counsel women on pregnancy risks during therapy while reassuring male patients of TKI safety when fathering children.

GATA-1 knockdown eliminated DUSP21's effects on erythroid differentiation and ponatinib sensitivity in K562 and K562R cells. Collectively, these findings suggest that DUSP21 acts as a positive regulator of erythroid differentiation in CML cells, and its overexpression sensitizes imatinib-resistant CML cells to ponatinib via GATA-1-mediated erythroid differentiation.

Among four prioritized compounds, Ponatinib demonstrated the most favorable binding free energy, while Pimavanserin exhibited stable conformational behavior during simulation. These findings provide an in-silico prioritization framework for potential KIF11-targeting compounds in GBM. Experimental validation in relevant cellular and in vivo models will be required to determine biological and therapeutic relevance.

For resistance, assessment of BCR::ABL1 mutations is essential, and second-line agents should be chosen according to the initial TKI and mutation sensitivity. This article summarizes the criteria and timing for switching to second-line therapy and key considerations for selecting and managing second-line TKIs, and briefly reviews the evidence for asciminib and ponatinib in second-line and later settings.

P3/4, N=136, Active, not recruiting, Stichting Radboud universitair medisch centrum | Not yet recruiting --> Active, not recruiting

P2, N=32, Active, not recruiting, Gruppo Italiano Malattie EMatologiche dell'Adulto | Recruiting --> Active, not recruiting | Trial primary completion date: Feb 2025 --> Mar 2026

The combination of TKIs (imatinib or ponatinib) with CX-4945 significantly extended the survival and reduced the tumor burden in the IKZF1 deletion (Ik6+) Ph+ ALL patient-derived xenograft (PDX) mouse model; particularly, the patient died of relapse shortly after treatment with the third-generation TKI and the CD19/CD3 bispecific antibody blinatumomab. The combination of TKIs with CX-4945 demonstrates the synergistic efficacy through restoring IKAROS transcriptional repression of GLUT1 and further suppressing glycolysis in Ph+ ALL. Our results identify new mechanisms underlying TKI sensitivity and novel approaches to overcome TKI resistance through transcriptional repression of the key genes in glycolysis in Ph+ ALL.

VEGF inhibitors, such as bevacizumab and VEGFR-TKIs (e.g., sorafenib, sunitinib), significantly elevate the risk of ATEs, with hypertension and proteinuria as common comorbidities. BCR-ABL-TKIs, especially nilotinib and ponatinib, are linked to rapid-onset PAD, even in patients without prior cardiovascular risk factors...Hormonal therapies, including tamoxifen and androgen deprivation therapy, also contribute to ATEs through metabolic and vascular mechanisms...Monitoring and prevention strategies, such as regular cardiovascular risk assessments, lipid management, and arterial ultrasound surveillance, are critical for high risk patients. Multidisciplinary onco-vascular teams are essential to mitigate these risks and optimize patient outcomes.

Currently, most leukemias are effectively treated with immunotherapies (highly effective monoclonal antibodies targeting CD19 [blinatumomab], or CD22 [inotuzumab ozogamicin]), BCR::ABL1 tyrosine kinase inhibitors (TKIs; e.g., dasatinib, ponatinib), Bruton TKIs (e.g., ibrutinib, acalabrutinib), BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, olutasidenib, and enasidenib), FLT3 inhibitors (e.g., midostaurin, quizartinib, and gilteritinib), menin inhibitors (revumenib, ziftomenib), and chimeric antigen receptor T-cell therapies. Herein, we provide a high-level overview of prominent clinical developments across all leukemias. In contemporary times, harnessing the benefits of novel targeted therapies and the evolving treatment landscape bolster the optimistic view that most, if not all, leukemias are curable.

The combined ponatinib and VK2 treatment synergistically impairs AML cell survival by enhancing apoptosis, suppressing clonogenic growth, and disrupting mitochondrial function. This dual targeting of oncogenic kinase signaling and metabolic integrity supports the ponatinib-VK2 combination as a promising therapeutic strategy for AML.

Following induction therapy, sequential therapy with blinatumomab and ponatinib achieved qualitatively PCR-negative minor BCR::ABL1 transcripts, indicating that residual transcripts below the qualitative assay's detection limit were undetectable. She received an allogeneic bone marrow transplant and remains well with PCR-negative minor BCR::ABL1 at 15 months after transplantation. This sequential therapy suggests a potential utility as a bridge to hematopoietic stem cell transplantation for secondary CML-BP with CD19+ mixed phenotype.