Prognostic Value of Genetic Mutations in Patients with Acute Myeloid Leukemias: Results of a Cooperative Study of Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Germany)

Aim. To analyze the effect on prognosis of mutations that are typical of acute myeloid leukemia (AML) patients.

Materials & Methods. The study included 620 AML patients surveyed at Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Berlin, Germany). G-banding of chromosomes was employed for cytogenetic testing. Aberration screening in DNMT3A, IDH1/2 genes was based on real-time polymerase chain reaction (PCR) with subsequent analysis of melting and sequencing profiles. Mutations in FLT3, NPM1 genes were revealed by PCR.

Results. Mutations were identified in 343 (55.3 %) out of 620 patients. Significantly more often mutations were discovered in patients with normal karyotype (NK) (p = 0.001). FLT3-ITD mutation was associated with reduced medians of overall survival (OS) and disease-free (DFS) survival: 11.3 vs. 15.8 months with FLT3-ITD– (p = 0.005) and 10.0 vs. 13.3 months with FLT3-ITD+ (p = 0.009), respectively. The relation of FLT3-ITD allele burden to OS duration was also assessed. In the ITD^low/ITD– group the OS median was considerably longer than in the ITD^high group (p = 0.028). In the group of patients with 1 mutation in NPM1 gene OS and DFS were much better in comparison with other patients (medians of 27.4 and 13.9 months, respectively, p = 0.040; 19.3 and 12.0 months, p = 0.049). Negative impact of mutations in DNMT3A gene was noticed while assessing OS median: 12 (DNMT3A+) and 15 months (DNMT3A–), respectively (p = 0.112). Mutations in IDH1 gene correlated with a better OS than in the group without mutations (p = 0.092). The rs11554137 polymorphism in IDH1 gene was associated with worse OS in the group of patients with NK (p = 0.186). In 144 patients various mutation combinations (from 2 to 5) were identified. It was demonstrated that mutations in FLT3 (FLT3-ITD), NPM1, DNMT3A, and IDH2 were identified significantly more often in combinations with other mutations (p = 0.001): NPM1+/FLT3-ITD+ (20.8 %), NPM1+/FLT3-ITD+/DNMT3A+ (8.3 %), and FLT3-ITD+/DNMT3A+ (8.3 %). Patients with 1 mutation had a noticeably longer OS median compared with patients with 2 mutations (18.1 and 12.2 months; p = 0.003). In patients with NPM1+ according to their OS the most unfavorable additional mutation was FLT3-ITD (median 27.4 vs. 9.2 months; p = 0.019) and the combination of NPM1+/FLT3-ITD+/DNMT3A+ (median 27.4 vs. 14.6 months; p = 0.141). OS of patients with DNMT3A+ showed a downward trend if FLT3-ITD additional mutation was identified (17.3 vs. 7.1 months; p = 0.074).

Conclusion. Mutations in FLT3, DNMT3A, IDH1/2, NPM1 genes frequently occur in AML intermediate-risk patients, i.e. they determine the intermediate prognosis group in AML. The studied mutations considerably impact prognosis. It is important to take into consideration mutation type, its allele burden, and the presence of additional mutations. A patient with 2 mutations has a considerably worse OS compared with a patient with 1 mutation. The studied group of patients with the combination of NPM1+/FLT3-ITD+, NPM1+/FLT3-ITD+/DNMT3A+, DNMT3A+/FLT3-ITD+ mutations has the poorest prognosis. Comprehensive analysis of genetic damages in AML patients allows to most accurately predict the course and prognosis of the disease and to plan targeted therapy.

• Ekaterina Vadimovna Motyko Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024
• O.V. Blau Charite Clinic, Berlin Medical University, 30 Hindenburgdamm, Berlin, Germany, 12200 ; Клиника Шарите, Берлинский медицинский университет, ул. Хинденбургдамм, д. 30, Берлин, Германия, 12200
• L.B. Polushkina Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024
• L.S. Martynenko Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024
• M.P. Bakai Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024
• N.Yu. Tsybakova Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024
• Yu.S. Ruzhenkova Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024
• E.V. Kleina Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024
• N.B. Pavlenko Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024
• A.M. Radzhabova Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024
• E.V. Karyagina Municipal Hospital No. 15, 4 Avangardnaya str., Saint Petersburg, Russian Federation, 198205 ; ГБУЗ «Городская больница № 15», ул. Авангардная, д. 4, Санкт-Петербург, Российская Федерация, 198205
• O.S. Uspenskaya Leningrad Regional Clinical Hospital, 45–49 Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291 ; ГБУЗ «Ленинградская областная клиническая больница», пр-т Луначарского, д. 45–49, Санкт-Петербург, Российская Федерация, 194291
• S.V. Voloshin Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024
• A.V. Chechetkin Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024
• I.S. Martynkevich Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА», 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024

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