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FLT3 in AML


Crenolanib

A next-gen tyrosine kinase inhibitor for use in FLT3-mutated AML

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FLT3 in AML


Crenolanib

A next-gen tyrosine kinase inhibitor for use in FLT3-mutated AML


THE ROLE OF FLT3 MUTATIONS IN AML

Roughly one-third of AML patients harbor an internal tandem duplication (ITD) in FLT3, a receptor tyrosine kinase. Mutations of FLT3 at D835, a point mutation in the tyrosine kinase domain (TKD), have also been observed in AML patients. Both ITD and TKD mutations lead to constitutive activation of the tyrosine kinase function, making FLT3 an attractive drug target in AML patients. Both ITD and TKD mutations render FLT3 resistant to currently approved inhibitors. Moreover, novel activating FLT3 mutations are being identified in patients with AML. As the clinical development of FLT3 inhibitors proceeds into advanced phase trials, FLT3 mutations will represent a new obstacle in the care of FLT3-mutated AML patients.


CRENOLANIB IS A SELECTIVE TYPE I PAN-FLT3 INHIBITOR

Crenolanib, a type I TKI, is a potent inhibitor of FLT3-ITD and secondary KD mutants. Crenolanib represents the first TKI to exhibit both kinase selectivity and invulnerability to resistance-conferring KD mutations. Crenolanib , which spares cKIT, represents a promising therapy for achieving deep and durable responses in FLT3-mutant AML.
 


Crenolanib


Crenolanib



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THERE ARE SEVERAL ATTRIBUTES THAT SET CRENOLANIB APART FROM OTHER THERAPEUTIC OPTIONS

  1. Crenolanib, whether delivered by itself or as part of a drug combination, has shown benefit in FLT3 mutant AML.

  2. Patients who progress after treatment with prior TKIs may still remain sensitive to crenolanib.

  3. Crenolanib has favorable pharmacokinetics and does not accumulate with repeated dosing.

  4. Crenolanib is a selective type I TKI that does not inhibit wild-type cKIT.


Recent Pubs and Presentations


Recent Pubs and Presentations


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Recent Conference Presentations


  1. Collins R, Kantarjian HM, Levis MJ, et al. Clinical Activity Of Crenolanib In Patients With D835 Mutant FLT3-Positive Relapsed/Refractory Acute Myeloid Leukemia (AML). J Clin Oncol 2014; 32:5s (suppl; abstr 7027).
  2. Collins, R., et al., Full Doses of Crenolanib, a Type I FLT3 Inhibitor, Can be Safely Administered in AML Patients Post Allogeneic Stem Cell Transplant. Blood, 2015. 126(23): p. 4359-4359.
  3. Panetta, J.C., et al., Population Pharmacokinetics of Crenolanib, a Type I FLT3 Inhibitor, in Patients with Relapsed/Refractory AML. Blood, 2015. 126(23): p. 3695-3695.
  4. Zhang, H., et al., Exome Sequencing Informs Mechanisms of Clinical Resistance to the FLT3-D835 Inhibitor Crenolanib. Blood, 2015. 126(23): p. 2468-2468.
  5. Inaba, H., et al., Pilot Study of Combined Type I FLT3 Tyrosine Kinase Inhibitor, Crenolanib with Sorafenib in Pediatric Patients with Relapsed/Refractory FLT3+Ve AML. Blood, 2016. 128(22): p. 3937-3937.
  6. Iyer, S.P., et al., Safety Study of Salvage Chemotherapy High-Dose Ara-C/Mitoxantrone (HAM) and Type I FLT3-TKI Crenolanib in First Relapsed/Primary Refractory AML. Blood, 2016. 128(22): p. 3983-3983.
  7. Ohanian, M., et al., Efficacy of a Type I FLT3 Inhibitor, Crenolanib, with Idarubicin and High-Dose Ara-C in Multiply Relapsed/Refractory FLT3+ AML. Blood, 2016. 128(22): p. 2744-2744.
  8. Wang, E.S., et al., Crenolanib, a Type I FLT3 TKI, Can be Safely Combined with Cytarabine and Anthracycline Induction Chemotherapy and Results in High Response Rates in Patients with Newly Diagnosed FLT3 Mutant Acute Myeloid Leukemia (AML). Blood, 2016. 128(22): p. 1071-1071.
  9. Cortes JE, Kantarjian HM, Kadia TM, et al. Crenolanib Besylate, a Type I Pan-FLT3 Inhibitor, to Demonstrate Clinical Activity in Multiply Relapsed FLT3-ITD and D835 AML. J Clin Oncol 2016; 34 (suppl; abstr 7008).
  10. Stone RM, Collins R, Tallman MS, et al. Effect of Cytarabine/Anthracycline/Crenolanib Induction on Minimal Residual Disease (MRD) in Newly Diagnosed FLT3 Mutant AML. J Clin Oncol 2017; 35(15_suppl): 7016.
  11. Wang E, Stone R, Collins R, Agrawal T, Urity V, Tallman M. Variant FLT3 Mutations Can be Eridicated by Cytarabine/Anthracycline/Crenolanib Induction in Adult Patients with Newly Diagnosed FLT3 (ITD/TKD) Mutant AML.  Haematologica; 2017; 2017. p. 212.
  12. Tarlock K, Hylkema T, Pollard J, et al. Functional Assessment of Novel Diagnostic FLT3 Mutations and Inhibition by Kinase Inhibitors. Haematologica; 2017; 2017. p. 40-1.

Recent Peer-Reviewed Publications


Recent Peer-Reviewed Publications


RECENT PEER-REVIEWED PUBLICATIONS


  1. Zimmerman EI, Turner DC, Buaboonnam J, et al. Crenolanib is Active Against Models of Drug-Resistant FLT3-ITD-Positive Acute Myeloid Leukemia. Blood 2013; 122(22): 3607-15.
  2. Fathi AT. Emergence of Crenolanib for FLT3-Mutant AML. Blood 2013; 122(22): 3547-8.
  3. Smith CC, Lasater EA, Lin KC, et al. Crenolanib is a Selective Type I Pan-FLT3 Inhibitor. Proc Natl Acad Sci U S A 2014; 111(14): 5319-24.
  4. Zhang W, Gao C, Konopleva M, et al. Reversal of Acquired Drug Resistance in FLT3-Mutated Acute Myeloid Leukemia Cells via Distinct Drug Combination Strategies. Clin Cancer Res 2014; 20(9): 2363-74.
  5. Galanis A, Ma H, Rajkhowa T, et al. Crenolanib is a Potent Inhibitor of FLT3 with Activity Against Resistance-Conferring Point Mutants. Blood 2014; 123(1): 94-100.
  6. Smith CC, Lin K, Stecula A, Sali A, Shah NP. FLT3 D835 Mutations Confer Differential Resistance to Type II FLT3 Inhibitors. Leukemia 2015; 29(12): 2390-2.

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For More Information


For more information visit clinicaltrials.gov or contact us directly.

5420 LBJ Freeway, Suite 410
Dallas, TX 75240
Email: info@arogpharma.com

For More Information


For more information visit clinicaltrials.gov or contact us directly.

5420 LBJ Freeway, Suite 410
Dallas, TX 75240
Email: info@arogpharma.com