Long-Term Safety and Efficacy of Hyper-CVAD Plus Ponatinib As Frontline Therapy for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Authors: Short Nicholas J. , Kantarjian Hagop M. , Ravandi Farhad , Huang Xuelin , Daver Naval G. , DiNardo Courtney D. , Konopleva Marina Y , Pemmaraju Naveen , Wierda William G. , Garcia-Manero Guillermo , Sasaki Koji , Cortes Jorge E. , Garris Rebecca , Ward Marygrace , Huang Binru , Encarnacion Corabelle , Loiselle Christopher , Khoury Joseph D. , Jorgensen Jeffrey L. , Jain Nitin , Alvarez Joie , Tippett Nicole , O'Brien Susan M. , Jabbour Elias 
Published: February 2020

Background: Ponatinib is a potent, third-generation inhibitor of BCR-ABL that is active against T315I mutations of the ABL1 gene; these mutations are a common mechanism of resistance to earlier-generation BCR-ABL tyrosine kinase inhibitors (TKIs). Promising early efficacy of the combination of chemotherapy plus ponatinib has been reported in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), although long-term safety and durability of responses is less well-established.

Methods: Adults with newly diagnosed Ph+ ALL and those who had received ≤2 courses of prior chemotherapy with or without TKIs were eligible. Patients (pts) received 8 cycles of hyper-CVAD alternating with high-dose methotrexate/cytarabine approximately every 21 days. Initially, ponatinib was given at 45 mg daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Rituximab was administered during the first 4 cycles in pts with CD20 expression ≥ 20%; pts also received 12 doses of prophylactic intrathecal chemotherapy with alternating methotrexate and cytarabine. Pts in complete remission (CR) received maintenance with ponatinib daily with vincristine/prednisone monthly for 2 years, followed by ponatinib indefinitely. Due to concern for vascular toxicity with long-term use of high-dose ponatinib, the protocol was amended after 37 pts were treated; this amendment reduced ponatinib to 30 mg starting at cycle 2 with further reduction to 15 mg once a complete molecular response (CMR) was achieved. The primary endpoint for the study was event-free survival (EFS); secondary endpoints included response rates, overall survival (OS), and safety.

Results: The baseline characteristics of the 86 treated pts are shown in Table 1. The median age was 46 years (range, 21-80). Twenty pts (23%) were ≥60 years of age. Thirty-nine pts (45%) had at least one baseline cardiovascular risk factors (hypertension, diabetes, dyslipidemia, coronary artery disease, and/or peripheral arterial disease). Of 68 pts with active disease at enrollment, all pts achieved CR. The 3-month CMR rate was 74%, and overall CMR rate was 84%. There were no early deaths. Eighteen pts (21%) underwent hematopoietic stem cell transplantation (HSCT) in first remission.

With a median follow-up of 43 months (range, 2-92 months), 61 pts (71%) remain alive in remission. The 3-year continuous CR, EFS and OS rates were 84%, 70%, and 78%, respectively, and estimated 5-year continuous CR, EFS and OS rates were 84%, 68%, and 73%, respectively (Figure 1A-B). Eleven pts (13%) relapsed after a median of 20 months in remission (range, 5 to 64 months). Six pts relapsed while on another TKI, 2 pts while not on a TKI, and 3 pts while still on ponatinib. Of the 3 relapses on ponatinib, 2 pts were found to have an E255K ABL1 kinase domain mutation and 1 pt had no mutation identified. A 6-month landmark analysis showed a trend for better OS in pts who did not undergo HSCT in first remission. The 3-year OS rate was 66% for pts who underwent HSCT (n=18) and 90% for pts who did not undergo HSCT (n=57; P=0.07).

The treatment was overall well-tolerated with most adverse events being Grade 1-2. Overall, 37% of pts required dose reductions of ponatinib due to adverse events; the most common causes included rash (n=7), liver function test abnormalities (n=5), pancreatitis (n=3), deep vein thrombosis (n=2), and thrombocytopenia (n=2). Nine pts (10%) died in CR. Two ponatinib-related deaths from myocardial infarction were observed in pts treated before the protocol amendment to use lower doses of ponatinib; no further ponatinib-related deaths occurred after this amendment.

Conclusions: 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%. Among pts who did not undergo HSCT in first remission, the 3-year OS rate was 90%. Future studies are needed to determine whether the incorporation of effective novel agents such as blinatumomab into frontline regimens will allow for reduction of chemotherapy while also deepening responses and increasing the proportion of pts with Ph+ ALL who are cured without need for HSCT.

Disclosures

Short: AstraZeneca: Consultancy; Amgen: Honoraria; Takeda Oncology: Consultancy, Research Funding. Kantarjian:Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding. Ravandi:Selvita: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding. Daver:Abbvie: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; NOHLA: Research Funding; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy; Servier: Research Funding; Otsuka: Consultancy; Astellas: Consultancy; Forty-Seven: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Jazz: Consultancy; Sunesis: Consultancy, Research Funding; Glycomimetics: Research Funding. DiNardo:medimmune: Honoraria; abbvie: Consultancy, Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; jazz: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria. Konopleva:Agios: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Wierda:Juno Therapeutics: Research Funding; Acerta Pharma Inc: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding. Garcia-Manero:Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Cortes:Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Khoury:Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Jain:ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. O'Brien:Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Astellas: Consultancy; Celgene: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Kite: Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy. Jabbour:Cyclacel LTD: Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding.

OffLabel Disclosure:

The use of ponatinib as frontline therapy for patients with Ph+ ALL.