Clinical activity of ponatinib in one patient with chronic myeloid leukemia in chronic phase with e19a2 transcript and T315I mutation.
BACKGROUND
Chronic myeloid leukemia (CML) is a hematological disorder that in rare cases, mainly in CML neutrophilic, presents the e19a2 rearrangement. The encoded product is a 230-KDa protein. Despite the remarkable responses to treatment of most patients, a small but significant fraction of them develop clinical resistance to the tyrosine kinase inhibitors (TKIs). The most common mechanism of resistance is point mutations in the ABL1 kinase domain. The recently approved third-generation TKI ponatinib demonstrated remarkable activity in patients with multi-TKI-resistant disease. Particularly impressive was its efficacy in patients with T315I mutation that is resistant to all other TKIs.


METHODS
Qualitative PCR was carried out by multiplex approach. Relative transcripts quantification was performed by one-step real-time PCR, with a specific Taqman probe and primers for the e19a2 rearrangement. We carried out a mutational screening by high-resolution melting, and the mutation was identified by Sanger method. The mutation burden was quantified by quantitative PCR using allele-specific primers.


RESULTS
In a patient with CML, we identified a PCR product corresponding to e19a2 rearrangement harboring T315I mutation. At the time of mutational analysis, during dasatinib treatment, the T315I clone was 100% and the quantification of BCR-ABL1 was 18%. After ponatinib therapy, the T315I mutation burden decreased down to undetectable levels and the BCR-ABL1 transcripts showed a very low value (0.011%).


CONCLUSIONS
Here, we report the hematological, cytogenetic, and molecular response of a patient with refractory CML in chronic phase with e19a2 transcripts, carrying T315I mutation that was successfully treated with ponatinib.
Instituto de Medicina Experimental (IMEX, CONICET-ANM), Academia Nacional de Medicina, Buenos Aires, Argentina.
Cristian A
CA
Ferri
Michele
M
Bianchini
Raquel M
RM
Bengió
Elena B
EB
Moiraghi
Mariana S
MS
Gonzalez
María F
MF
Noriega
Irene B
IB
Larripa
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D007093:Imidazoles / Q000627:therapeutic use*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D011724:Pyridazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D007093:Imidazoles; D011724:Pyridazines; D011743:Pyrimidines; D012333:RNA, Messenger; D013844:Thiazoles; C545373:ponatinib; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib; D006918:Hydroxyurea
T315I; chronic myeloid leukemia; e19a2; ponatinib