Iclusig is a kinase inhibitor indicated for the:...Treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

Ponatinib is a treatment option for patients with a T315I mutation and/or CP-CML with resistance or intolerance to at least 2 prior TKIs or for patients with AP-CML or BP-CML for whom no other TKI is indicated.

Ponatinib should be considered the agent of choice in patients with CML and T315I mutation, and in instances where other TKIs are not indicated.

Patients with CP-CML resistant to ≥2 TKIs or with the BCR::ABL1 T315I mutation were randomized to ponatinib starting doses of 45, 30, or 15 mg once daily…. Among patients with the T315I mutation, the 45-mg cohort had a higher 3-year PFS rate (75%) than the30-mg (40%) or 15-mg (61%) cohorts; the 3-year OS rate was similar in the 45-mg (86%) and 15-mg (85%)cohorts...

Patients with CP-CML resistant to ≥2 TKIs or with the BCR::ABL1 T315I mutation were randomized to ponatinib starting doses of 45 mg, 30 mg, and 15 mg once daily….Results from the 3-year follow-up of the Phase 2 OPTIC study provide the robust long-term efficacy and manageable safety profile of ponatinib in a highly resistant CP-CML population.

This ongoing prospective multi-center registry (NCT03678454) includes ≥18-year-old patients with CML or Ph+ALL eligible for ponatinib treatment per product label.... MMR was achieved in 58% of CML and 52% of Ph+ALL patients. The median time-to-MMR was 170 days in CML and 86 days in Ph+ALL patients. Of the 37 patients who started ponatinib due to intolerance to previous TKIs, 59% (15 CML, 7 Ph+ALL) achieved MMR.... MMR was achieved in 58% of CML and 52% of Ph+ALL patients. The median time-to-MMR was 170 days in CML and 86 days in Ph+ALL patients. Of the 37 patients who started ponatinib due to intolerance to previous TKIs, 59% (15 CML, 7 Ph+ALL) achieved MMR.

Among patients with CP, AP and BP CML, median age at study entry was 59.1, 33.7 and 48.5 years, respectively; among 37 evaluable patients, 12 (32.4%), 1 (2.7%) and 1 (2.7%) patient(s) had a confirmed BCR-ABL1 mutation. Of evaluable patients, 4 (10.8%) had the T315I mutation. The starting dose of ponatinib for patients with CP CML was 45 mg once daily in 41.5% of patients, 30 mg in 39.6% of patients and 15 mg in 17.0% of patients; 1 (1.9%) patient started ponatinib at another dose....Estimated progression-free survival rates for patients with CP CML at Months 12 and 24 were 86.6% (95% CI, 77.8-96.4%) and 83.7% (95% CI, 73.8-94.9%), respectively. Corresponding overall survival rates were 96.2% (95% CI, 91.1-100.0%) and 93.1% (95% CI, 85.6-100.0%), respectively....Data show that ponatinib has a favorable efficacy and safety profile in patients with CML treated in standard clinical practice in Italy. By Month 6, most patients had achieved CCyR and 44% of patients achieved MMR in 2/3L.

Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation...

After adjustment for potential confounders, 24-month and 48-month OS rates were significantly higher in patients with chronic-phase CML (CP-CML) who received ponatinib compared with those who underwent allo-SCT (24 months: 84% vs 60.5%, respectively; P = .004; 48 months: 72.7% vs 55.8%, respectively; P = .013)...This study is the first demonstrating that patients with T315I‐positive CP‐CML who received ponatinib alone had significantly longer OS than patients who underwent allo‐SCT.

Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively)....Ponatinib had significant antileukemic activity across categories of disease stage and mutation status.

...only AP24534 demonstrated activity against the T315I mutant…The anti-tumor activity of AP24534 was further assessed in a xenograft model in which Ba/F3 BCR-ABLT315I cells were injected subcutaneously into mice. Tumor growth was inhibited by AP24534 in a dose-dependent manner (Figure 5B, left) compared to vehicle-treated mice, with significant suppression of tumor growth upon daily oral dosing at 10 and 30 mg/kg (%T/C = 68% and 20%, respectively; p<0.01 for both dose levels). Daily oral dosing of 50 mg/kg AP24534 caused significant tumor regression (%T/C = 0.9%, p<0.01), with a 96% reduction in mean tumor volume at the final measurement compared to the start of treatment.