Iclusig (ponatinib)

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.

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.

P1/2, N=17, Completed, Heidelberg University | Not yet recruiting --> Completed

P2, N=33, Recruiting, University of Washington | Not yet recruiting --> Recruiting

Viability, cytotoxicity, and caspase-3/7 activity were assessed following single-agent treatment with asciminib, ponatinib, bortezomib, or panobinostat. Co-inhibition of proteasomes and histone deacetylases eliminates TKI-refractory BCR::ABL1-driven leukaemia cells by inducing mitochondrial apoptosis and loss of clonogenic potential. These findings indicate a clinically actionable, TKI-independent strategy for the salvage treatment of multidrug-resistant CML.

Six thousand six hundred twenty-five dasatinib (age 59.7±15.2 years, 44.0% women), 5205 nilotinib (age 55.4±15.0 years, 44.2% women), 2421 bosutinib (age 63.8±14.2 years, 42.1% women),1358 ponatinib (age 57.3±14.9 years, 46.1% women), and 922 asciminib (age 64.3±13.8 years, 43.7% female) new users were each matched with the maximum of available imatinib users on time-conditional propensity score and on duration of prior imatinib use (prevalent users). This study, designed to emulate a randomized trial, suggests that, in French patients with chronic myeloid leukemia treated with BCR-ABL TKIs, dasatinib use is associated with a higher risk of PAH compared with imatinib, while bosutinib and ponatinib exposure may aggravate or trigger a recurrence of PAH in patients with preexisting dasatinib exposure. Whether bosutinib and ponatinib could induce PAH without preexposure to dasatinib remains to be explored.

P2/3, N=1200, Recruiting, Assistance Publique - Hôpitaux de Paris | Not yet recruiting --> Recruiting

Consistent with prior preclinical studies, we demonstrate that dasatinib and ponatinib, unlike SRC sparing TKIs (imatinib, nilotinib), antagonize blinatumomab's T-cell engaging efficacy by potently inhibiting LCK Y394 phosphorylation, a critical step in proximal TCR signaling. We show that TKI-induced T-cell suppression and antagonism can be significantly improved by supplementing co-cultures with common gamma-chain cytokines, particularly IL-7. IL-7 robustly enhances human T-cell proliferation, reduces exhaustion, and significantly improves blinatumomab's cytotoxic efficacy in the presence of Src/BCRABL1 TKIs.

Successive generations of TKIs have transformed Ph + ALL from a uniformly fatal leukemia into a highly treatable disease, with dasatinib or ponatinib-based and TKI-blinatumomab regimens achieving high rates of complete molecular remission...Novel agents, including asciminib and olverembatinib, are expanding options for resistant or relapsed disease, while CAR-T cell therapy and next-generation bispecific T-cell engagers are emerging as promising tools for refractory and post-TKI settings...Integrating potent TKIs with immunotherapy enables deep and durable remissions, potentially eliminating the need for upfront transplantation in selected patients. Future research should define molecular predictors of treatment-free remission, optimize CNS prophylaxis in targeted regimens, and establish standardized monitoring for safe TKI discontinuation.