Crenolanib for Treating FLT3 Mutated Proliferative Disorders Associated Mutations

[0102]Effect of Crenolanib Besylate Therapy in a Newly Diagnosed AML Patient with FLT3-ITD, NPM1, and DNMT3A Mutations with Normal Karyotype: Achievement of reduction in bone marrow blasts to less than 5% with hematologic recovery.

[0103]A 54-year-old female was diagnosed with AML positive for both FLT3-ITD and FLT3-TKD mutations. The patient's leukemic blasts also had mutations in the NPM1 and DNMT3A genes. As the FLT3-ITD, NPM1, and DNMT3A mutations are characterized as independent driver mutations, and are together associated with a particularly poor prognosis, the patient's presentation of these triple mutations placed her in a significantly high-risk group for AML patients, associated with poor response rates, increased cumulative incidence of relapse, and shortened survival. Half of patients with these mutations are expected to die within 1 year of diagnosis. See Papaemmanuil, E., “Genomic Classification and Prognosis in Acute Myeloid Leukemia,” New England J. Med. Vol. 374, No. 2

[0107]Effect of Crenolanib Besylate Therapy in a Newly Diagnosed AML Patient with FLT3-ITD and RUNX1 Mutations with Normal Karyotype: Achievement of reduction in bone marrow blasts to less than 5% with hematologic recovery.

[0108]A 23-year-old female was diagnosed with AML positive for FLT3-ITD, RUNX1, and DNMT3A mutations. FLT3-ITD and RUNX1 mutations both independently categorize her as a high-risk AML patient, which is associated with poor response rate, increased cumulative incidence of relapse, and shortened survival.

[0109]At diagnosis, the patient was found to have 70% bone marrow blasts. Following diagnosis, the patient was provided with oral crenolanib besylate on a clinical trial newly diagnosed AML patients (NCT02283177). The patient was initially treated with induction chemotherapy, comprised of seven days of cytarabine and three days of daunorubicin; the patient began therapy with 100 mg of crenolanib besylate three times daily on day 9.

[0110]A bone marrow biopsy taken on da

[0112]Effect of Crenolanib Besylate Therapy in a Newly Diagnosed AML Patient with FLT3-ITD and RUNX1 Mutations, Trisomy 8, and Trisomy 13: Achievement of reduction in bone marrow blasts to less than 5% with hematologic recovery.

[0113]A 34-year-old female was diagnosed with AML, positive for FLT3-ITD and RUNX1 mutations. These mutations independently categorize her as a high-risk AML patient, which is associated with poor response rate, increased cumulative incidence of relapse, and shortened survival.

[0114]The patient was further shown to exhibit an abnormal karyotype, characterized by the appearance of trisomy 8 and trisomy 13. Trisomy 8 has been characterized as an independent driver mutation separate and apart from other driver mutations characteristic of AML (such as the patient's FLT3 mutational status) and has itself been independently associated with a poor prognosis. Trisomy 13 is also an independent, poor prognostic factor and has been strongly associated with RUNX1 mutations.