Abstract
We assessed the prognostic significance of IKZF1 gene deletions in 141 pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) on Russian multicenter trial in pediatric clinics of Ekaterinburg and Orenburg. IKZF1 deletions were estimated by multiplex ligation-dependent probe amplification. IKZF1 deletions were revealed in 15 (10.6 %) patients. IKZF1 deletions were associated with age older than 10 years (p = 0.007), initial white blood cell count higher than 30 × 109/l (p = 0.003), t(9;22)(q34.q11) (p = 0.003) and delayed blast clearance: М3 status of bone marrow at day 15 of remission induction (p = 0.003), lack of hematological remission at day 36 (p < 0.001) and high levels of minimal residual disease at days 15, 36 and 85 (p = 0.014; p < 0.001; p = 0.001 correspondingly). Patients with IKZF1 deletions had significantly lower event-free survival (EFS) (0.30 ± 0.15 vs 0.89 ± 0.03; p < 0.001) and overall survival (OS) (0.44 ± 0.19 vs 0.93 ± 0.02; p < 0.001), while cumulative incidence of relapse was higher (0.67 ± 0.18 vs 0.07 ± 0.02; p < 0.001). In the multivariate analysis IKZF1 deletions were associated with decreased EFS (hazard ratio (HR) 4.755; 95 % confidence interval (CI) 1.856–12.185; p = 0.001), and OS (HR 4.208; 95 % CI 1.322–13.393; p = 0.015), but increased relapse risk (HR 9,083; 95 % CI 3.119–26.451; p < 0.001). IKZF1 deletions retained their prognostic significance in the intermediate risk group patients (p < 0.001), but not in standard or high-risk groups. Majority of IKZF1 deletions – 12 (80 %) of 15 – were revealed in the “B-other” group (n = 83). In this cohort of patients IKZF1 deletions led to inferior EFS (HR 6.172; 95 % CI 1.834–20.767; p = 0.003) and higher relapse rate (HR 16.303; 95 % CI 3.324–79.965; p = 0.015). Thus, our results showed that IKZF1 deletions are independent risk factor in BCP-ALL patients.
Highlights
Введение Использование интенсивной программной полихимиотерапии значительно улучшило прогноз течения острого лимфобластного лейкоза (ОЛЛ) у детей
IKZF1 deletions retained their prognostic significance in the intermediate risk group patients (p < 0.001), but not in standard or high-risk groups
Majority of IKZF1 deletions – 12 (80 %) of 15 – were revealed in the “B-other” group (n = 83). In this cohort of patients IKZF1 deletions led to inferior event-free survival (EFS) (HR 6.172; 95 % confidence interval (CI) 1.834–20.767; p = 0.003) and higher relapse rate (HR 16.303; 95 % CI 3.324–79.965; p = 0.015)
Summary
Выявленная нами частота делеций IKZF1 у больных ВП-ОЛЛ (10,6 %) оказалась несколько ниже, чем данные, полученные в Швеции (15,0 %) [45], Нидерландах (13,7 %) [11], Италии (13,2 %) [27] и Германии (12,1 %) [24], но близка к результатам, опубликованным исследователями из Тайваня (10,7 %) [44]. Опубликованные данные о спектре делеций IKZF1 показали, что наиболее частыми являются делеции экзонов 4–7 и всего гена (экзоны 1–8), на долю которых суммарно приходится около 70 % всех делеций [17, 24, 27]. Неоднократно в рамках разных терапевтических протоколов показано, что делеции гена IKZF1 независимо от их типа и количества вовлеченных экзонов [13] являются фактором, ассоциированным с неблагоприятным исходом при BCR-ABL1-негативном ВП-ОЛЛ у детей [10, 11, 24, 26, 27, 45]. На сегодняшний день особый интерес для исследователей представляет группа «другие B-линейные ОЛЛ», что связано, с одной стороны, с отсутствием
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