AC220 and AraC cause differential inhibitory dynamics in patient-derived M5-AML with FLT3-ITD and, thus, ultimately distinct therapeutic outcomes.
Engrafting the bone marrow cells of a patient with M5 acute myeloid leukemia into immunocompromised mice (AM7577) resulted in serially transferrable stable AML and eventual mortality. The disease starts in the bone marrow and then expands to peripheral areas, which is typical of M5 leukemogenesis, where high leukemic burden in blood is coincident with symptoms/mortality. The leukemic cells in the mice had myeloid morphology, phenotypes, and genotypes (including the internal tandem duplication of FMS-like tyrosine kinase receptor 3 gene [FLT3-ITD]) similar to those of the original patient. Autocrine mechanisms of human granulocyte-macrophage colony-stimulating factor/interleukin-3 likely support AM7577 growth in mice. Treatment with FLT3 TKI (AC220) caused complete remission in peripheral blood, spleen, and bone, along with relief of symptoms and extended life, hinting that FLT3-ITD may be a key leukemogenic driver maintaining the disease. Interestingly, withdrawal of AC220 (high dose) did not result in relapse of disease, suggesting cure. These results, however, are in contrast to cytarabine (AraC) induction treatment: First, although AraC significantly suppresses the diseases in blood, and to a lesser degree in bone marrow and spleen, the suppression is temporary and does not prevent eventual onset of disease/death. Second, the withdrawal of AraC always resulted in rapid relapse in peripheral blood and eventually death. Our observation in this patient-derived model may provide useful information for clinical applications of the two drugs.
Crown Bioscience, Inc., Santa Clara, CA, USA.
Xiaoyu
X
An
Crown Bioscience, Inc., Santa Clara, CA, USA.
Jinping
J
Liu
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Na
N
Wang
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Di
D
Wang
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Liang
L
Huang
Crown Bioscience, Inc., Santa Clara, CA, USA.
Likun
L
Zhang
Crown Bioscience, Inc., Santa Clara, CA, USA.
Jie
J
Cai
Crown Bioscience, Inc., Santa Clara, CA, USA.
Jean-Pierre
JP
Wery
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
Demin
D
Zhou
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Jianfeng
J
Zhou
Crown Bioscience, Inc., Santa Clara, CA, USA; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
Qi-Xiang
QX
Li
D000368:Aged; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D003561:Cytarabine / Q000494:pharmacology* / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D020440:Gene Duplication; D005838:Genotype; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010641:Phenotype; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020080:Tandem Repeat Sequences; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D000964:Antimetabolites, Antineoplastic; D052160:Benzothiazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D003561:Cytarabine; C544967:quizartinib; D051941:fms-Like Tyrosine Kinase 3