Optimizing the Use of FLT3 Inhibitor Therapy for AML

Transcript:Harry Erba, MD: Except in the case of the type 1 versus type 2 FLT3 inhibitors, where type 2 inhibitors may not be active against the FLT3 TKD [tyrosine kinase domain], it’s not clear how different drugs could be matched to the specific mutational profile of a patient. Some have suggested that having a broader kinase inhibitor in the therapeutic program at the time of initial diagnosis may be more beneficial, then using a more specific inhibitor, such as an FLT3 inhibitor, later on when FLT3 is driving the relapse. But there’s very few clinical data to support that. Of course, the other thing that we have to consider as we develop specific inhibitors against different driver mutations, such as FLT3, isocitrate dehydrogenase 1 and 2, and others, is how these drugs will be combined. We have virtually no information on that at this point.

Richard F. Schlenk, MD: It’s not so difficult to explain this to the patients. We know that a patient with FLT3 internal tandem duplication [ITD] has a disease that is typically proliferative and high in white blood cell count; there are blasts in the bone marrow greater than 50%; and the patient is quite ill when coming into the hospital. I think it can be easily explained that this mutation really tries the disease. If a patient is FLT3 internal tandem duplication positive, then the patient realizes that if this specific mutation is inhibited, the chance of curing the disease is higher. Furthermore, I think it’s not so difficult to explain to patients that the mutational testing has to be done very early during the clinical course of the disease.

Harry Erba, MD: With the availability of multiple FLT3 inhibitors that vary based on mechanism of action in type 1 versus type 2 and how specific they are, the first-generation less specific and second-generation more specific, it does beg the question of whether these FLT3 inhibitors should be used in some known sequence. Would it be better, for example, to use a less specific inhibitor initially at the time of diagnosis when we’re not quite certain of the various mutations driving the disease, and reserve a more specific mutation inhibitor for a mutation later? There are few clinical data here to argue one way or another. The one piece of information that we might be able to cite is to look at studies of single-agent, second-generation FLT3 inhibitors in which some of the patients were already exposed to some of the first-generation inhibitors such as sorafenib and midostaurin, which could be used prior to patients relapsing and going on a second-generation inhibitor such as quizartinib, gilteritinib, or crenolanib.

In the analysis that Mark Levis presented at the ASCO [American Society of Clinical Oncology] meeting in 2018, there were still very high response rates in patients who had been exposed to midostaurin and sorafenib initially at diagnosis and then relapsed and received a second-generation drug such as gilteritinib. The response rates were somewhat lower than expected in patients who were FLT3-inhibitor exposed, as opposed to inhibitor naïve. But the number of patients in these studies were so small, it’s hard to really make important comparisons.

Transcript Edited for Clarity

Related Videos
Combination of Zanubrutinib + Venetoclax for Treatment-naive CLL/SLL With del(17p) and/or TP53: Preliminary Results From SEQUOIA Arm D
Results from the randomized phase 3 DREAMM-8 study of belantamab mafodotin plus pomalidomide and dexamethasone (BPd) vs pomalidomide plus bortezomib and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM)
Hannah Choe, MD, an expert on GVHD
Hannah Choe, MD, an expert on GVHD
Indirect Comparison of Efficacy of Zanubrutinib Versus Acalabrutinib in the Treatment of Patients With Relapsed or Refractory Mantle Cell Lymphoma
Hua-Jay “Jeff” Cherng, MD, assistant professor, medicine, Lymphoma Program, Division of Hematology and Oncology, Columbia University Irving Medical Center
Naval G. Daver, MD
DREAMM-7 update: Subgroup analyses from a phase 3 trial of belantamab mafodotin (belamaf) + bortezomib and dexamethasone (BVd) vs daratumumab, bortezomib, and dexamethasone (DVd) in relapsed/refractory multiple myeloma (RRMM)
Joseph Maakaron, MD, assistant professor, medicine, Division of Hematology, Oncology, and Transplantation, the University of Minnesota Medical School
Marie Hu, MD, assistant professor, medicine, Division of Hematology, Oncology and Transplantation, the University of Minnesota Medical School