The paper presents the results of a multicenter randomized study of two-dose COLI-ASP regimens in therapy of consolidation of standard risk-group (SRG) children and adolescents with acute lymphoblastic leukemia (ALL) treated by the ALL-MB-2002 protocol. The principal aim of the study was to elucidate whether the dose of COLI-ASP might be reduced without losing the efficiency of therapy. The analysis covered primary ALL patients notified at 36 clinics of Russia and Belarus, enrolled for the study in the period of May 1, 2002, to October 10, 2006. Out of 819 patients to be examined, 414 received COLI-ASP in a dose of 10,000 U/m2 (a control group), and 405 children took it in a dose of 5,000 U/m2 (a study group). No statistically significant differences were found between the patients in gender, age, baseline leukocytosis, and spleen size. The study showed no statistically and clinically significant differences in event-free, overall, and relapse-free survival (EFS, OS, and RFS, respectively) and relapse rates with the use of two-dose COLI-ASP regimens. However, in the control group, the death rate in remission was twice greater than that in the study group (p = 0.02). Detailed analysis of the outcomes of therapy in some subgroups revealed no differences between the control and study groups. The Cox multiple regression analysis has indicated that the factors influencing EFS and RFS are the baseline sizes of the spleen, baseline leukocytosis, age, and a response to treatment in the period of induction, rather than the dose of E. coli asparaginase. The authors have also found that among the SRG patients, there is a subgroup of patients without risk factors, in whom the reduction in the COLI-ASP dose may substantially increase survival rates, by lowering toxicity and mortality in remission.

Проанализирована значимость прогностических факторов эффективности терапии у детей с острым лимфобластным лейкозом (ОЛЛ), получающих терапию по протоколу ALL-MB-2002, в зависимости от группы риска. В исследование были включены 1544 первичных больных ОЛЛ в возрасте от 1 года до 18 лет, получавших лечение в 36 клиниках России и Беларуси в период с 15 апреля 2002 г. до 1 января 2008 г. Из 1544 больных, включенных в анализ, пациенты группы стандартного риска (SRG) составили 69,2 %, промежуточного риска (ImRG) — 24,5 % и 6,3 % пациентов были отнесены к группе высокого риска. Анализ, проведенный у пациентов SRG, продемонстрировал резкие различия в выживаемости между отдельными подгруппами больных. Выявлены достоверные различия в показателях выживаемости пациентов в зависимости от возраста (старше и младше 10 лет), инициального лейкоцитоза (более и менее 30 × 10 9 /л), инициального пальпаторного увеличения селезенки (более и менее 4 см из-под края реберной дуги) и параметров раннего ответа на терапию (8-й и 15-й день). При ретроспективном определении больных, относящихся к SRG, с использованием новых критериев (инициальный лейкоцитоз <30 × 10 9 /л; селезенка < 4 см), прогностическая значимость раннего ответа на терапию нивелировалась. Среди пациентов ImRG не обнаружено никаких достоверных различий в показателях бессобытийной, общей и безрецидивной выживаемости и риске развития изолированных нейрорецидивов в зависимости от инициального иммунофенотипа бластных клеток (Т-ОЛЛ/не-Т-ОЛЛ). Шестилетний кумулятивный риск развития изолированных нейрорецидивов не различался у пациентов с Т- и не-Т-ОЛЛ, однако был выше у больных с инициальным лейкоцитозом ≥ 100 × 10 9 /л независимо от иммунофенотипа. Наихудшие показатели выживаемости отмечены у пациентов с не-Т-ОЛЛ и количеством лейкоцитов ≥ 100 × 10 9 /л — бессобытийная выживаемость в этой подгруппе составила всего 58 ± 7 %. При проведении многофакторного анализа выявлено, что для пациентов с Т-ОЛЛ независимое прогностическое влияние на выживаемость оказывает только величина инициального лейкоцитоза (р = 0,0333), тогда как для больных не-Т-ОЛЛ независимое значение имеют возраст (р = 0,0063), инициальный лейкоцитоз (р = 0,0066) и наличие поражения центральной нервной системы (р = 0,0112).Перенести в английский вариант Prognostic significance of different risk factors in children with acute lymphoblastic leukemia (ALL) treating according to ALL-MB 2002 protocol depending on risk group is analyzed. 1544 primary patients aged from 1 to 18 years, treating in 36 clinics of Russia and Belarus from April, 15 th , 2002 to January, 1th, 2008, was included in the study. From 1544 patients included, 69.2% were standard risk group (SRG), 24.5 % — intermediate risk group (ImRG) and 6.3% — high risk group. The expressed differences in survival rate between certain patient’s subgroups were revealed. Significant survival differences according to age (older and younger 10 years), initial leukocyte count (more and less than 30 × 10 9 /l), spleen size (more and less 4 cm below a costal arch at a palpation) and early therapy response (8th and 15th days of induction) are revealed. At retrospective definition of SRG patients with use of new criteria (initial leukocytosis < 30 × 10 9 /l and spleen size <4 cm), prognostic significance of therapy response was leveled in this subgroup of patients. Among ImRG patients any significant differences in EFS, OS, RFS and cumulative risk of isolated CNS (CIR IN ) relapse according to blast cells immunophenotype (T-ALL/non-T-ALL) were not shown. 6-years CIRIN was not different between patients with T-ALL and non-T-ALL, however was high in patients with initial leukocyte count ≥ 100 × 10 9 /l irrespective to immunophenotype. The worst survival appeared in patients with non-T-ALL and leukocyte count ≥100 × 10 9 /l — EFS in this subgroup was only 58±7%. Only initial leukocytosis had prognostic significance for patients with T-ALL (р=0.0333), whereas age (р = 0.0063), initial leukocytosis (р = 0.0066) and CNS involvement (р = 0.0112) as independent prognostic factors for patients with non-T-ALL in multifactorial analysis was revealed.

AIMTo evaluate the efficiency of the original ALL-MB-2002 protocol within the multicenter study of treatment of acute lymphoblastic leukemia (ALL) in children.SUBJECTS AND METHODSA total of 1873 primary patients with ALL aged 1 to 18 years, of whom 1544 patients were enrolled in this study, were notified at 36 clinics of Russia and Belarus from April 15, 2002, to January 1, 2008.RESULTSWith the median observation of 4.12 years, 7-year event-free survival (EFS) was 73 +/- 13%; overall survival (OS) 78 +/- 2%; relapse-free survival 82 +/- 1%. The rates of EFS and OS were equal and amounted to 76 +/- 2 and 80 +/- 2% in the standard-risk group (SRG) and intermediate-risk group (ImRG), respectively. In the high-risk group (HRG) patients, EFS and OS were as high as 30 +/- 6 and 37 +/- 6%, respectively. The frequency of relapses with central nervous system lesion was as much as 4.7% in all the patients, 6-year cumulative risk for isolated neurorecurrences being 2.5% in the SRG patients. Adolescents, patients with the baseline leukocytosis (more than 100 x 10(9)/l), and those with a splenic size of over 4 cm or more from the costal arch margin had substantially worse survival rates. A poor early response to therapy (on induction days 8 and 15) was also associated with its lower efficiency.CONCLUSIONDespite a considerable rise in the number of centers and a slight increase in the intensity of therapy, the results of the new ALL-MB-2002 protocol are as minimum equivalents obtained in the use of the previous ALL-MB-91 protocol. A significant improvement in the overall results of therapy and a reduction in the cumulative risk for isolated neurorecurrences were noted in the ImRG patients.