On March 19, 2024, the Food and Drug Administration granted accelerated approval to ponatinib (Iclusig, Takeda Pharmaceuticals U.S.A., Inc.) with chemotherapy for adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Iclusig is indicated in adult patients with:...Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib, who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate...

Iclusig® (ponatinib) is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

INDUCTION REGIMENS FOR Ph-POSITIVE ALL: Other Recommended regimens…TKI + vincristine + dexamethasone…TKI options include (in alphabetical order): bosutinib, dasatinib, imanitib, nilotinib or ponatinib.

Ponatinib was superior to imatinib in combination with reduced-intensity chemotherapy in patients with newly diagnosed Ph+ ALL, with a significantly higher MRD-neg CR rate at EOI. Ponatinib resulted in deeper and more durable responses, with a trend toward improved EFS with comparable safety to imatinib.

...b) Evidence of Ph+ ALL, MPAL, or Ph-like ALL: i. Definite evidence of BCR-ABL1 fusion (Ph) for Ph+ ALL and MPAL, OR ii. ...

With a median follow-up of 80 months (range, 16-129 months), the estimated 6-year event-free survival rate was 65% and the overall survival rate was 75%...The long-term results of ponatinib and hyper-CVAD continue to demonstrate excellent outcome results and acceptable safety data, indicating that this strategy is another standard of care approach in frontline Ph-positive ALL.

The combination of hyper-CVAD and ponatinib results deep and durable remissions in pts with newly diagnosed Ph+ ALL. The overall CMR rate was 86% and the 5-year OS was 75%, which compares favorably with regimens using first- or second-generation TKIs in this population. The combination was safe; the use of lower doses of ponatinib maintained efficacy and mitigated the risk of ponatinib-related toxicity.

Three patients achieved a deep molecular response (DMR) following combined intensive treatment with ponatinib as induction chemotherapy...ponatinib at a concentration of least 30 mg exhibits anti-leukemia effects in Japanese patients with Ph + ALL.

...202 pts with newly diagnosed Ph+ALL who received the combination of intensive therapy (hyper-CVAD) with imatinib, dasatinib, or ponatinib were analyzed….Of the 76 pts who received HCVAD + ponatinib, the 5-year CRD were 63% and 93%, respectively (p=0.018); the 5-year OS rates were 23% and 91%, respectively (p<0.001).

In pts with newly diagnosed Ph+ ALL, the combination of hyper-CVAD plus ponatinib resulted in sustained responses with a CMR rate of 84% and an estimated 5-year OS rate of 73%.

Patients received eight cycles of 21 days, alternating between two drug combinations: hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and high-dose methotrexate and cytarabine...The combination of chemotherapy with ponatinib is effective in achieving long-term remission in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia.

Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response....ponatinib showed clinically significant activity in patients with CML and those with Ph-positive ALL.