ESH ALL 2021 | Next generation TKIs for Ph+ ALL
Nicholas Short, MD, University of Texas MD Anderson Cancer Center, Houston, TX, discusses the use of next generation tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), particularly ponatinib. Dr Short describes the differences between the different generations of TKIs, highlighting the main benefit of the third-generation, which covers the BCR-ABL T315I mutation. Although ponatinib, a third-generation TKI especially effective against the T315I mutation, was approved to treat adults with Ph+ ALL in 2012, the agent has not been widely adopted, mainly in the frontline setting. Dr Short argues in favor of considering the use of ponatinib in the frontline and the relapsed/refractory setting. This interview took place during the 2021 European School of Hematology (ESH) 2nd Translational Research Conference on Acute Lymphoblastic Leukemia.
Transcript (edited for clarity)
I’m talking about kind of newer TKIs in this field, predominantly discussing ponatinib. Now, this is a drug that has been around for a while. It’s a third-generation TKI, it’s active against T315I mutations, which are the dominant mechanism of relapse in Ph-positive ALL. So even though it’s been around for a while, it’s still not widely been adopted, particularly in the frontline setting...
I’m talking about kind of newer TKIs in this field, predominantly discussing ponatinib. Now, this is a drug that has been around for a while. It’s a third-generation TKI, it’s active against T315I mutations, which are the dominant mechanism of relapse in Ph-positive ALL. So even though it’s been around for a while, it’s still not widely been adopted, particularly in the frontline setting. So I’m going to, I’m presenting some of the data, I would say, arguing for consideration of the use of ponatinib in the frontline setting, and then also some of the data in the relapsed/refractory setting. And there are also some other new TKIs that are in development that I think are exciting potentially that might be used in Ph-positive ALL, although most of them are currently being developed predominantly in CML at this time.
There’s first-generation TKI, which was imatinib, and then second-generation TKIs dasatinib, nilotinib, and Bosutinib. and now there’s a third-generation with ponatinib and then there are several others potentially on the horizon, but probably still several years out until they’re widely used in the setting.
The primary difference is the coverage of different mutation types or ABL kinase domain mutations. So you get better coverage for different ABL mutations with the second-generation TKIs versus the first-generation TKIs, and then even better with ponatinib, a third-generation TKI versus the others. And again, the main benefit for these later generation TKIs, in particular, is coverage of the T315I mutation. So those are present in about 75% of patients who relapse on imatinib or second-generation TKI based regimens. And so it’s very important that we have TKIs that cover these mutations. And that’s something that ponatinib offers.
Also in general, as we treat patients with later generations of TKIs in the frontline setting, we see deeper responses with each of these subsequent generations of TKIs. And this seems to correlate with better long-term survival.
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Disclosures
Consulting fees from AstraZeneca, NGMBio, Jazz Pharmaceuticals.
Research funding from Takeda Oncology and Astellas Pharma Inc.
Honoraria from Amgen and Novartis.
