Frontline Hyper-CVAD with Ponatinib for Patients (pts) with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia: Results of a Phase II Study
Authors: Sasaki Koji , O'Brien Susan , Ravandi Farhad , Thomas Deborah A , Moore Haim G , Cortes Jorge E. , Pemmaraju Naveen , Yilmaz Musa , Kadia Tapan , Garris Rebecca , Garcia-Manero Guillermo , Jeanis Twilla Victoria , Chahoud Jad , Borthakur Gautam , Wierda William , Ferrajoli Alessandra , Kantarjian Hagop M. , Jabbour Elias 
Published: October 2019

Abstract
Background: Addition of tyrosine kinase inhibitors (TKIs) to chemotherapy improves outcome in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is a more potent BCR-ABL inhibitor, and covers the T315I clones. The combination of hyper-CVAD with ponatinib may contribute to better response rates and higher likelihood of eradication of minimal residual disease (MRD) than those reported with other TKIs.
Methods: Pts 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/day for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Pts in CR received maintenance with ponatinib 45 mg/day and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely.
Results: From 11/2011 to 9/2013, 34 pts with untreated Ph+ ALL and 3 pts previously treated (2 pts not in CR were treated with one cycle of chemotherapy before the detection of BCR-ABL1; 1 pt in CCyR after 2 cycles of chemotherapy and dasatinib) have received a median of 6 cycles (2-8); 13 are receiving maintenance in CR; 9 underwent ASCT after a median of 4 cycles. Baseline pt characteristic and outcome are described in table 1. The overall CCyR, MMR, and CMR rates were 100%, 95%, and 78%, respectively. The median time to MMR and CMR were 3 (range, 2-14) and 11 (range, 2-96) weeks, respectively. The median time to MRD negativity was 3 weeks (range, 3-14). Median time to platelet and neutrophil recovery for cycle 1 was 22 and 18 days, respectively, and 22 and 16 days for subsequent cycles. Grade ≥ 3 toxicity included infections during induction (54%), increased liver functional tests (38%), thrombotic events (8%), myocardial infarction (14%), hypertension (16%), skin rash (22%), and pancreatitis (22%). With a median follow up of 26 months, 29 (78%) remain alive and in CR. Six pts died in CR: 1 pt died in CR from an unrelated cardiac event after being taken off therapy and placed on imatinib, 1 from MOF (C2D13), 1 from NSTEMI (C2D41; ponatinib 45 mg daily), 1 from potential MI (C4D42; ponatinib 30 mg daily), 1 from head injury sustained after a fall (C4D13), and 1 from sepsis post ASCT. Two (5%) in CMR relapsed with no identifiable T315I mutations after a median of 18 months. One of these pts achieved a second CR after blinatumomab and dasatinib therapy. To date, 13 pts are receiving maintenance therapy in CR. After the increased incidence of vascular toxicities was recognized, we offered our pts the option to switch TKIs or to reduce the dose of ponatinib to 30 mg and further decreased to 15 mg in pts in CMR. Thirteen pts remained on ponatinib at a dose of 15 mg daily in 12 and 30 mg daily in 1 (transcript levels of 0.04%). No further vascular events were observed in pts receiving lower doses of ponatinib. Nine pts elected to switch TKIs to dasatinib (n=7), nilotinib, or imatinib (1 each). One pt was lost to follow-up. Of 9 patients who underwent ASCT while in first CR (7 with MMR and 2 with CMR before transplantation), all but one are alive and disease-free after transplantation. There was no difference in OS by whether patients were censored or not at the time of ASCT. After transplantation, TKI therapy was resumed in all but one patient (1 imatinib, 4 dasatinib, 1 nilotinib, and 1 ponatinib). The 2-year event-free and overall survival rates are 81% and 80%, respectively (Figures 1).
Conclusion: The combination of hyperCVAD with ponatinib is highly effective in pts with Ph+ ALL. Due to the vascular events observed, the ponatinib dose was modified to 30 mg daily during consolidation with subsequent reduction to 15 mg in pts in CMR without further episode of cardiovascular events.
Table 1. Patient characteristic and outcome N(%); Median [range] N= 37 Age (yr) 51 [27-75] Age ≥50 20 (54%) Age ≥60 12 (32%) Performance status, No. (%)  0-1 31 (84)  2 6 (16)  WBC (x 109/L) 8 [1-630]  Presence of CNS disease, No. (%) 3 (8)  CD20 positivity, No. (%) 11 (30) Type of BCR-ABL1 transcript, No. (%)  p190 27 (73)  p210 10 (27) Cytogenetics abnormality, No. (%)  Diploid 5 (14)  Philadelphia-chromosome positive 32 (86) Baseline cardiovascular risk factors, No. (%)  Hypertension 18 (49)  Dyslipidemia 4 (11)  Coronary artery disease 4 (11)  Peripheral arterial disease 1 (3) Overall response, No. (%)  CR 36/36 (100)  CCyR 32/32 (100)  MMR 35/37 (95)  CMR 29/37 (78)  Flow negativity 35/36 (97)  Early death 0
Figure 1. a) Event-free survival, b) overall survival Figure 1. a) Event-free survival, b) overall survival

Disclosures
O'Brien: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; BMS: Consultancy, Research Funding; Teva: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Chahoud:American Society of Hematology (ASH): Other: 2015 HONORS Award recipient. Wierda:Glaxo-Smith-Kline Inc.: Research Funding; Celgene Corp.: Consultancy.