Expanded Access Program Of Ponatinib (AP24534) For Patients (Pts) With Refractory Chronic Myeloid Leukemia (CML) Or Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)
Authors: Jeyakumar Ghayathri , Kantarjian Hagop M. , Sweet Kendra L. , Arana Yi Cecilia Y , Jain Nitin , Jabbour Elias , Quintas-Cardama Alfonso , O'Brien Susan , Walker Brenda , Pierce Sherry R. , Kadia Tapan M. , Ravandi Farhad , Pinilla Javier , Cortes Jorge E. 
Published: October 2019

Abstract

Background
Ponatinib is a pan-BCR-ABL inhibitor with activity against BCR-ABL, including the TKI resistant T315I and all other clinically relevant mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in pts with CML in chronic (CP-CML), accelerated (AP-CML), or blastic (BP-CML) phase, or Ph+ ALL were evaluated in an expanded access program.

Methods
49 pts, including 24 CP-CML, 5 AP-CML, 8 BP-CML (100% Myeloid Blasts), and 12 Ph+ ALL were registered at 2 institutions. Pts were resistant or intolerant (R/I) to dasatinib or nilotinib, or had the T315I mutation at baseline. For this analysis, pts were grouped in cohorts according to the disease stage and presence or not of T315I.

Results
The median age for CP-CML, AP-CML, BP-CML, and Ph+ ALL pts was 44, 36, 56, and 57 yrs, respectively. Median yrs from diagnosis to start of ponatinib were 7, 1, 3 and 2, respectively. 94% had received imatinib, 80% dasatinib, 59% nilotinib, 2% bosutinib, and 24% had undergone prior SCT. Among 37 pts evaluable for response to prior dasatinib or nilotinib, 84% had history of resistance to these agents, 16% were intolerant. 92% pts had received at least 2 prior TKI, and 45% had received at least 3. Reported response rates with the most recent TKI were 63% (15/24) MCyR for CP-CML, and CHR 60% AP-CML, 0% BP-CML, 33% Ph+ ALL. After a follow-up of 9 months on therapy, 49% of CP-CML, 60% of AP-CML, 25% of BP-CML, and 9% of Ph+ ALL pts remain on study. The reasons for discontinuation were progressive disease (38%, 40%, 75%, and 83%, respectively) and adverse events (13%, 0%, 0% and 8%, respectively). Among the 49 pts, 58% (14/24) pts in CP-CML have achieved MCyR (46% CCyR). 60% (3/5) AP-CML achieved MCyR (2 of them CCyR), and 35% (7/20) BP/Ph+ALL achieved MCyR (5 of them CCyR). MMR is available by IS only for 40 pts and 26% achieved MMR, and at 9 mos. MMR was achieved by 21% CP, 0% in AP, 0% in BP-CML and 38% Ph+ ALL. The median PFS for all pts was 5.8 mos. Estimated PFS at 9 mos. was 50% overall, and 71% in CP, and 75% in AP, 25% in BP-CML and 17% in Ph+ ALL. In CP-CML, AP- CML, BP-CML and Ph+ALL the median PFS was estimated as 12.5 mos., 13.3 mos., 3.5 mos. and 1.4 mos. respectively. Overall median OS was not reached. The probability of OS at 9 mos. for all pts was 80%.; in CP-CML it was 100%, in AP-CML was 75%, in BP-CML 58% and in Ph+ ALL was 53% at 9 mos. The most common AEs were thrombocytopenia (18%), G1-2 rash (14%), and neutropenia (12%) and the G3-4 AEs were thrombocytopenia (4%) and pancreatitis (6%) with G3-4 lipase elevation 8% and G3 amylase 8%.

Conclusions
Ponatinib has clinical activity in refractory CML and pretreated Ph+ leukemia patients who have limited treatment options. The results of this expanded access study match those of the pivotal PACE trial confirming the clinical benefit with ponatinib in this setting.

Disclosures:
Kantarjian: ARIAD: Research Funding. Jabbour:Ariad, BMS, Novartis, and Pfizer: Consultancy. O'Brien:ARIAD: Research Funding. Pinilla:Ariad: Advisory Board Other, Research Funding, Speakers Bureau. Cortes:Ariad, Pfizer and Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.