BCR-ABL Fusion Transcripts In Patients With Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Experience With Ponatinib From MD Anderson Cancer Center
Authors: Jain Preetesh , Kantarjian Hagop M. , Romo Carlos Guillermo , Luthra Rajyalakshmi , Quintas-Cardama Alfonso , Jabbour Elias , Kadia Tapan M. , Borthakur Gautam , Cardenas-Turanzas Marylou , PH Dr , Pierce Sherry , Ravandi Farhad , O'Brien Susan M. , Cortes Jorge E. 
Published: October 2019

Abstract

Introduction
The presence of the BCR-ABL fusion gene, resulting from the Philadelphia chromosome is the hallmark of CML. The most commonly observed transcripts in CML are b3a2 (e14a2) and b2a2 (e13a2). It is not known whether the transcript type may impact response to newer TKI. We report our experience of ponatinib in patients with CML-CP with different BCR-ABL transcripts.

Methods
A total of 85 pts with CML-CP [47 relapsed refractory (RR) and 38 frontline] who were treated at our institution between 2008 and 2013 on clinical trials with ponatinib were included in this analysis. Conventional cytogenetic analysis was done in bone marrow (BM) cells using a G-banding technique, and the BCR-ABL fusion transcripts were identified by the use of quantitative real-time polymerase chain reaction assay.

Results
Among the 47 RR patients, 14 (30%) had the b2a2 transcript (median age 47 years; range 21–82), 23 (49%) had a b3a2 transcript (median age 61; range 24–94 years), and 10 (21%) co-expressed both transcripts (median age 45; range 49–79). Two pts with e1a2 transcripts were not included in the analysis. RR patients received a median of 3 prior therapies including interferon, imatinib, nilotinib, dasatinib, bosutinib, omacetaxine and SCT. Ten (71 %) of those with b2a2 were previously treated with ≥3 different TKI (imatinib, dasatinib, nilotinib and bosutinib); of the pts with b3a2, 12 (52%) were treated with ≥3 different TKI (imatinib, dasatinib, nilotinib and bosutinib) and in the group of pts with both transcripts 5 (50%) received 3 different TKI (imatinib, dasatinib, nilotinib). T315I mutation was present in 9 (19%) pts of which 2 were b2a2, 5 were b3a2 and 2 were both. After a median follow-up of 22.4 months, the rates of overall complete cytogenetic (CCyR) and major molecular responses (MMR) were 55% and 40%. Among these RR patients, the response with b2a2, b3a2 and both transcripts, were CCyR: 50% vs. 61% vs. 50% and MMR 29% vs. 52% vs. 30%, respectively. The 3-year probability of failure free survival (FFS) was 54%, 87% and 68% for pts with b2a2, b3a2 and both groups (P=0.08). The 3-year probability of overall survival (OS) was 62%, 100% and 100% for pts with b2a2, b3a2 and both groups (P=0.03).
Among the 38 pts in the frontline setting, 17 (44%) had the b2a2 transcript (median age 50.7 years; range 21–74), 14 (36%) had b3a2 transcript (median age 49.7; range 29–72 years), and 7 (18%) presented with both transcripts (median age 56; range 38–63). The Sokal risk group for those with the b2a2 transcript was high in 2/17 (12%), intermediate in 4/17 (23%), and low in 11/17 (65%). For pts with b3a2 all 14/14 (100%) were low risk, and the group with both transcripts had 0%, 1/7(14%) and 6/7 (85%), respectively. There were two pts who went off study due to toxicity. For the evaluable pts with b2a2, b3a2 and both transcripts, the median levels of transcripts at 3 months were 0.098, 0.091 and 0.042 respectively. Similarly the median levels of transcripts at 6 months were 0.00525, 0.0035 and 0.0035 respectively. The magnitude of early CCyR was very high in all groups thus not allowing to discriminate among the transcripts. The median OS was 6.6 months and none of the pts have died.

Conclusions
Although all pts have a good overall survival those receiving ponatinib after prior TKI failure with b3a2 transcripts have a higher rate of CCyR and MMR vs. patients with b2a2 transcripts. This mirrors what we have reported with other TKI. With early results, no difference is seen in the frontline setting perhaps because of the overall excellent results. The mechanism of differential responsiveness of pts with b2a2 transcripts and b3a2 transcripts warrants further investigation.

Disclosures:
Kantarjian: ARIAD, Novartis, BMS, Phizer: Research Funding. Jabbour:Ariad, BMS, Novartis, and Pfizer: Consultancy. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.