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iwAL 2019 | Venetoclax and FLT3 inhibitor combination therapy for AML

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Naval Daver

In this video, Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, TX, discusses the use of venetoclax in combination with FLT3 inhibitors as therapies for acute myeloid leukemia (AML). This video was recorded at the International Workshop on Acute Leukemias (iwAL) 2019, held in Barcelona, Spain.

Transcript (edited for clarity):

Naval Daver, MD:            The other combinations that I’m very excited about is the combination of FLT3 inhibitors, so we have a two combinations. One of Venetoclax with Gilteritinib, which is a very potent second generation FLT3 inhibitor that was just approved by the US FDA and the other is Venetoclax with Quizartinib. Also a very, very potent FLT3 inhibitor that we think will be approved in the next few months and there is a lot of preclinical data showing that the FLT3 inhibitors suppress MCL one, which is one of the major mechanisms of escape for the Venetoclax based therapies because Venetoclax is a BCL2 inhibitor, when you block BCL2 the normal biological responses to upregulate and escape to MCL1, so inhibiting MCL1 directly either with an MCL1 inhibitor or indirectly with a FLT3 inhibitor could be quite effective...

Naval Daver, MD:            The other combinations that I’m very excited about is the combination of FLT3 inhibitors, so we have a two combinations. One of Venetoclax with Gilteritinib, which is a very potent second generation FLT3 inhibitor that was just approved by the US FDA and the other is Venetoclax with Quizartinib. Also a very, very potent FLT3 inhibitor that we think will be approved in the next few months and there is a lot of preclinical data showing that the FLT3 inhibitors suppress MCL one, which is one of the major mechanisms of escape for the Venetoclax based therapies because Venetoclax is a BCL2 inhibitor, when you block BCL2 the normal biological responses to upregulate and escape to MCL1, so inhibiting MCL1 directly either with an MCL1 inhibitor or indirectly with a FLT3 inhibitor could be quite effective.

Naval Daver, MD:            The other important thing is we have started seeing with longer follow up that the patients who do poorly on asa Venetoclax are the patients who have either FLT3 mutation or asa mutation or PTPN11s. So, the FLT3 itself seems to be emerging on treatment with Venetoclax and assecidiline. And so we again feel that adding the FLT3 inhibitor here is going to be very, very effective. So, those studies are just starting. We probably have data on both of those at ASH this year, but we think that again, this could be a very potent low or no chemotherapy approach with Venetoclax. And the third one, which is probably the one that’s most mature, we’ve presented it twice now at ASH, is a combination of Venetoclax with an MDM2 inhibitor Idasanutlin. So, as some may know Idasanutlin is one of the MDM2 inhibitors that’s most advanced in AML development.

Naval Daver, MD:            There’s a phase three study in relapsed AML looking at Idasanutlin alone, sorry, Idasanutlin with intermediate era-c Versus intermediate era-c, and that studies almost completed accrual and if positive will result in approval of the Idasanutlin in AML.

Naval Daver, MD:            We have a study combining Idasanutlin with Venetoclax in patients who are 60 years and above and relapsed AML where historically response rates with Chemo HMA are about 15 20% and with this combination at the recommended phase two dose, we’re seeing about 45% CR, CRI. So again, I think the next three, four years are really going to be not just getting new drugs approved, but focusing on how we can minimize chemotherapy, how we can move these doublets and triplets upfront and potentially then the next question will be, can we start stopping therapy in some people at one year if they’ve received an effective doublet with IDH FLT3 if they’re MRD negative, could we start, you know, stopping therapy, something that’s being looked at in CLL, for example, with Ibrutinib Venetoclax. So, we’re learning I think from these other leukemias as to how we may apply less chemotherapy. And improve cure rates in AML and the thing is going to be very, very, very busy, but very, very exciting time in the next few years.

 

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