Pb1740: the combination of ponatinib plus chemotherapy upfront achieves durable complete molecular remissions in adults patients with philadelphia chromosome-positive (ph+) acute lymphoblastic leukemia.

Topic: 2. Acute lymphoblastic leukemia - Clinical Background: Ponatinib is a third-generation inhibitor of BCR-ABL effective against most mutations including T315I that cause resistance to first and second generation BCR-ABL tyrosine kinase inhibitors (TKIs). Promising early efficacy of the combination of ponatinib plus chemotherapy has been reported in adults with Philadelphia chromosome-positive B-acute lymphoblastic leukemia (Ph+ B-ALL), however long-term durability of responses and safety is under investigation. Aims: The present study reports the experience of administering Ponatinib in combination with chemotherapy as a frontline treatment after a long-term follow-up of the patients at our center. Methods: 7 consecutive adults patients with Ph+ B-ALL diagnosed between October 2017 and February 2022 were treated upfront with the combination of ponatinib plus intensive (IC) or non-intensive chemotherapy (non-IC) in our center. IC consisted of 8 cycles hyper-CVAD alternating with high-dose methotrexate/cytarabine every 21 days, while non-IC consisted of a three-month prophase with corticosteroids and vincristine, followed by six alternating cycles of low-dose methotrexate and cytarabine and one year of monthly vincristine. Ponatinib was given at 45 mg daily for the first 14 days of cycle 1. From cycle 2 onwards, due to concern for thromboembolic events, ponatinib was given at a dose of 30 mg daily with a further dose reduction to 15 mg after achieving a complete molecular response (CMR). Additionally, all patients received ponatinib 15 mg continuously for another 2 years after the end of chemotherapy as maintenance. Patients also received 12 doses of prophylactic intrathecal chemotherapy with 12mg methotrexate and 4 mg dexamethasone. Results: The baseline characteristics of the 7 treated patients are shown in Table 1. Four patients were ≥70 years of age and they had at least one baseline cardiovascular risk factor. With a median follow-up of 42.53 months, (range: 11.8-65.37), all patients are alive. They all showed morphologic response at 3 months. All four patients who received IC achieved CMR by 3 months, while two patients who received non- IC achieved CMR at 9 and 15 months and one has not achieved CMR after 12 months of treatment (figure 1). No patient lost molecular remission and none underwent hematopoietic stem cell transplantation in first remission. The treatment was overall well-tolerated with most adverse events being Grade 1-2. Three patients required dose reductions of ponatinib due to adverse events; 1 patient with hypeamylassemia, 1 patient with deep vein thrombosis and 1 with hypertension. Summary/Conclusion: In newly diagnosed Ph+ B-ALL the combination of ponatinib plus intensive or non-intensive chemotherapy is safe and effective resulting in sustained molecular responses in the majority of patients and raises questions for the need to perform HSCT in first CR in these patients. Future studies are needed to determine whether the combination of ponatinib with novel agents such as blinatumomab will allow the definitive elimination of chemotherapy in Ph+ B-ALL. Table 1: Baseline characteristics of patients - Parameter N (%)/ Median [range] Age (years) min-max (26- 81) ≥ 50 5 (72) ≥ 70 4 (57) Performance status 0-1 4 (57) 2 3 (43) WBC (x 109/ L) 10.7 (5.1-13.3) BCR-ABL transcript p190 5 (72) p210 1 (14) p190 + p210 1 (14) Baseline CV risk factors Hypertension 2 (28.5) Diabetes 2 (28.5) Dyslipidaimia 3 (43) Coronary artery disease 1 (14) Chemotherapy Hyper-CVAD 4 (57) Non-intensive chemo 3 (43) Keywords: ALL, Philadelphia chromosome