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Dynamics of T315I mutation in Philadelphia positive patients on tyrosine kinase inhibitor therapy (CROSBI ID 641928)

Prilog sa skupa u zborniku | sažetak izlaganja sa skupa | međunarodna recenzija

Horvat, Ivana ; Radić Antolić, Margareta ; Sertić, Dubravka ; Zadro, Renata Dynamics of T315I mutation in Philadelphia positive patients on tyrosine kinase inhibitor therapy // 18th Congress of the European Hematology Association : abstracts. 2013. str. xx-xx

Podaci o odgovornosti

Horvat, Ivana ; Radić Antolić, Margareta ; Sertić, Dubravka ; Zadro, Renata

engleski

Dynamics of T315I mutation in Philadelphia positive patients on tyrosine kinase inhibitor therapy

The discovery of imatinib, as a first smart drug, brought revolution into treatment of patients with Philadelphia positive chronic myeloid(CML)or acute lymphoblastic (ALL) leukemia. Development of ABL kinase domain mutations is still one of the major reasons for resistance to imatinib therapy. Second generation tyrosine kinase inhibitors (TKI) have the power to overcome all ABL mutations except T315I mutation which still represents one of the biggest challenges for treatment and indicates in most cases very low survival rate. The aim of the study was to investigate the dynamics of T315I mutation development and bcr-abl1 transcript level. kinetics in Philadelphia positive CML and ALL patients. Ten patients with T315I mutation (6 women and 4 men), median age of 49.5 years at the time of diagnosis(range 34-62 years) were included in the study. Nine of them had CML with major bcr- abl1 transcript (7 with b3a2 type and 2 with b2a2 type) and one had ALL with minor bcr-abl1 transcript (type e1a2). T315I mutation was detected by allele specific oligonucleotide PCR (Kang et al, Haematologica, 2006 ; 91:659) with declared sensitivity of 0.001%. Bcr-abl1 transcript level was measured by real time quantitative PCR and results were expressed according to International Scale(IS - CML patients only). Bcr-abl1 transcript quantification and T315I mutation detection were done in 8 diagnostic samples and in all follow-up RNA samples. Three patients who were diagnosed with CML before 2001 were treated with interferon-alpha, busulfan or hydroxyurea while the ALL patient was on chemotherapy before switching to imatinib. Other six patients had imatinib as a first line of therapy. After imatinib failure in 3 patients, therapy was switched to second generation TKI. Eight patients progressed to blast crisis (5 ALL and 3 AML) and 2 to accelerated phase. Eight patients died and 2 patients in whom T315I mutation was detected in August of 2012 and January of 2013 are still alive, one is in blast crisis and the other on chemotherapy after relapse and is waiting for hematopoietic cell transplantation. None of the investigated patients had T315I mutation at the time of diagnosis. Median time of the T315I occurrence after diagnosis was 30.5 months (1-121 months). Retrospective analysis of T315I mutation showed that in 3 patients mutation could be detected in earlier follow-up samples that correlated with bcr-abl1 transcript level elevation. Three patients became T315I positive after therapy with dasatinib, which can be the effect of dasatinib on other existing mutations that allow progression of T315I mutation clone. CML patients (except 1 unavailable patient’s RNA) had median of bcr-abl1 transcript level 28.2% IS (range 16.0- 41.3) at the time of detecting T315I while bcr-abl1 transcript level in ALL patient was 32.1%. Two patients developed T315I in less than 3 months from the time of diagnosis. Although other 4 patients had good response to therapy (3 patients were in MMR for 4-48 months), bcr-abl1 transcript level escalated because of T315I. Last 4 patients had constantly high bcr-abl1 transcript levels during follow-up, similar to diagnostic ones despite the fact that T315I mutation was detected 39-113 months after diagnosis. Summary / In conclusion, the use of sufficiently sensitive molecular method in patients with bcr-abl1 transcript level elevation is important because early detection of small numbers of mutated clone, particularly for T315I, can prevent inadequate treatment with TKI as well as blast crisis, allowing more time to search for hematopoietic cell donor.

BCR-ABL ; Chronic myeloid leukemia ; Mutation ; Tyrosine kinase inhibitor

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Podaci o prilogu

xx-xx.

2013.

objavljeno

Podaci o matičnoj publikaciji

18th Congress of the European Hematology Association : abstracts

Podaci o skupu

Congress of the European Hematology Association (18 ; 2013)

ostalo

13.06.2013-16.06.2013

Stockholm, Švedska

Povezanost rada

Kliničke medicinske znanosti