A drug previously reserved for hard-to-treat leukemia could soon be used much earlier in the disease course in Europe. EU regulators have recommended expanding the use of Iclusig (ponatinib; Incyte Biosciences), where the drug is combined with low-intensity chemotherapy for adults with newly identified Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). 

The recommendation was adopted by the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) and represents a new indication. If endorsed by the European Commission, the change would allow Iclusig to be used earlier in the disease course, rather than being reserved for patients with resistant or intolerant disease.

Ponatinib, the active substance in Iclusig, is a tyrosine kinase inhibitor. It exerts its therapeutic effect by inhibiting BCR-ABL tyrosine kinase, a constitutively active oncoprotein expressed in Ph+ leukemia cells. BCR-ABL drives uncontrolled cellular proliferation and survival signaling. By selectively blocking BCR-ABL-mediated kinase activity, ponatinib suppresses leukemic cell growth and helps limit disease progression.

Current Therapeutic Applications 

Iclusig is already authorized for use in adult patients with chronic myeloid leukemia in chronic, accelerated, or blast phases who are resistant to or intolerant of dasatinib or nilotinib, or for whom subsequent treatment with imatinib is not clinically appropriate. The drug was also approved for patients carrying the T315I mutation. 

In addition, Iclusig is authorized for adult patients with Ph+ ALL who are resistant to or intolerant of dasatinib when imatinib is unsuitable, as well as for those harboring the T315I mutation.

Clinical Evidence 

Although the CHMP opinion does not cite specific clinical trials, previously published studies provide context for the expanded recommendation.

In the phase 3 PhALLCON trial, 245 adults with newly diagnosed Ph+ ALL were randomized to ponatinib (n = 164) or imatinib (n = 81). At a median follow-up of 20 months in the ponatinib group and 18 months in the imatinib group, the primary endpoint was met. The rate of minimal residual disease (MRD)-negative complete remission at the end of induction was significantly higher with ponatinib than with imatinib (34% vs 17%). The MRD-negative rate irrespective of complete remission status was also higher (43% vs 21%). Median duration of MRD negativity and time to treatment failure were not reached with ponatinib but were 20.9 and 21.9 months, respectively, with imatinib. Event-free survival data were immature, though a trend favoring ponatinib was observed.

In the same study, among the 232 patients with centrally verified p190 or p210 BCR-ABL isoforms (ponatinib, n = 154; imatinib, n = 78), the MRD-negative complete remission rate was similarly higher with ponatinib (34.4% vs 16.7%). Median event-free survival was not reached with ponatinib and was 29 months with imatinib.

Ponatinib carries a high risk for arterial and venous vascular events. Clinicians should assess cardiovascular risk and monitor patients closely. Other adverse effects may include infections, pancreatitis, fever, gastrointestinal pain, cardiovascular and cerebrovascular events, peripheral arterial occlusion, hypertension, hematologic toxicity, acute kidney injury, cellulitis, and elevated lipase levels.

Implementation and Authorization Details 

The CHMP recommends that cardiovascular status be assessed before starting treatment and that alternative therapies be considered in certain clinical situations, as outlined in existing guidance.

Detailed recommendations for the new indication will be included in an updated Summary of Product Characteristics, which will be published on the EMA website in all official European Union languages after the European Commission adopts a final decision on the marketing authorization change.