Phase II Study of the Frontline Hyper-CVAD in Combination with Ponatinib for Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

• Published in: Blood 2016-12, Vol.128 (22), p.757-757
• Main Authors: Sasaki, Koji, Jabbour, Elias J., Ravandi, Farhad, Daver, Naval G., Pemmaraju, Naveen, Thomas, Deborah A, Khouri, Rita B., Yilmaz, Musa, Kadia, Tapan M., Short, Nicholas J., Garris, Rebecca, Garcia-Manero, Guillermo, DiNardo, Courtney D, Konopleva, Marina, Estrov, Zeev, Jain, Nitin, Wierda, William G., Jeanis, Twilla Victoria, Cortes, Jorge E., O'Brien, Susan M., Kantarjian, Hagop M.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V128.22.757.757

Background: The combination of tyrosine kinase inhibitors (TKIs) with chemotherapy is highly effective in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is a more potent BCR-ABL inhibitor, and is effective against the T315I clone which commonly causes disease recurrences. The combination of hyper-CVAD with ponatinib may produce better response rates and higher likelihood of eradication of minimal residual disease (MRD) as compared to that reported with other TKIs. Methods: Patients with newly diagnosed Ph+ ALL received 8 cycles of hyper-CVAD alternating with high dose methotrexate and cytarabine every 21 days. Ponatinib was given at 45 mg po daily for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Patients in complete response (CR) received maintenance with ponatinib 45 mg daily and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. After an increased incidence of vascular toxicities was recognized, patients were offered the option to switch TKIs or to continue with a reduced dose of ponatinib of 30 mg with further decrease to 15 mg in patients in CMR. The evaluation of MRD status was performed by multicolor flow cytometry (FCM), and reverse transcription polymerase chain reaction (RT-PCR). The objective of this study is to evaluate response rates, CR duration, and overall survival (OS), and to assess the safety of this regimen. Rituximab and intrathecal chemotherapy were given for the first 4 courses. Results: To date, 53 patients with untreated Ph+ ALL and 4 patients previously treated (2 patients in CR; 2 patients not in CR) have received a median of 6 cycles (2-8); 11 patients are receiving maintenance in CR; 10 patients underwent allogeneic stem cell transplantation (ASCT) after a median of 4 cycles. Baseline patient characteristics and outcomes are described in table 1. The overall complete cytogenetic response (CCyR), major molecular response (MMR), and complete molecular response (CMR) rates were 100%, 96%, and 79%, respectively. The median time to MMR and CMR were 3 weeks (range, 2-14) and 11 weeks (range, 2- 96), respectively. The median time to MRD negativity by 6-color flow cytometry (FCM) was 3 weeks (range, 3-14). Median time to platelet and neutrophil recovery for cycle 1 was 22 days (range, 17-35) and 18 days (range, 13-29), respectively, and 22 days (range, 0-35) and 16 days (range, 0-28) for subsequent cycles. Grade ≥ 3 toxicity included inf