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Long‐term treatment results of Polish pediatric and adolescent patients enrolled in the ALL IC‐BFM 2002 trial

The aim of study was analysis of the treatment results of the ALL IC-BFM 2002 trial in patients with acute lymphoblastic leukemia (ALL) treated in Polish pediatric oncohematology centres. Between November 2002 and November 2011, 1872 children aged 1-17 with newly diagnosed ALL were consecutively enrolled in the ALL IC BFM 2002 protocol. The follow-up was updated as of December 31, 2016. The study group included 56.6% males and 43.4% females. According to risk stratification, 32.6% of the children were qualified for a standard risk group (SR), 48.1% - intermediate risk (IR), 19.3% - high risk (HR). A total of 268 (14.3%) deaths were noted in the entire group. Cumulative death risk in SR group after 5 years was estimated at 4.4%, 14.2% in IR group, and 37.3% in HR. The incidence of death at complete remission (CR) was significantly higher in children aged ≥10 versus younger children (9.3% v 2.6%; P<0.001), in T-ALL versus BCP-ALL (9% v 3.5%; P<0.001), but differences were not found between girls and boys (4.0% v 4.5%; P=0.7). Relapses occurred in 275 children (14.7%), of which 51 cases occurred in SR group (8.4% of the patients who were stratified for the SR group), 147 in IR (16.4%), 77 in HR (21.2%). Overall survival for 1872 children with ALL was 86% after 5 years, whereas the EFS rate was 79%. ALL IC-BFM 2002 proved as a highly effective protocol for treatment of children with ALL in Polish pediatric oncohematology centres. This article is protected by copyright. All rights reserved.

and compared using a two-tailed log-rank test. Cumulative incidence (CI) curves for the events were estimated according to risk groups, and were compared using the Gray test. All statistical calculations were performed using STATISTICA13. The study was approved by the local institutional review board and a written informed consent from the guardians was a prerequisite.
A total of 1872 patients (56.6% males and 43.4% females) were treated under the ALL IC-BFM 2002 Protocol. A median follow up time for the entire group was 6.4 years (Q1 = 4.32, Q3 = 8.53). The median age at diagnosis was 5.3 years, ranging from more than 1 to 17 years of age. Most children (55%) were in the age range 1 to <6 years, while the group aged 6 to <10 years accounts for 19% of the cohort, 10 to <15 years was 17%, and those older than 15 years constitute 9%. For WBC counts at diagnosis below 20×10 9 /l was revealed in 64.3% of the children while in 10.1% WBC was more than 100×10 9 /l. CNS status 1 in 88%, 2-7% and 5% showed signs of CNS involvement. Mediastinal involvement from the leukemic process was found in 7.8%, testicular involvement was shown in 20 boys (1.9%).
The immunophenotype in most children was revealed as preB cell lineage (89%) and T cell lineage was shown in 11%. The conventional cytogenetic analysis was performed in all subjects with newly diag-   Figure S1). In 36 cases, deaths happened during the induction therapy, before CR1 was achieved, and the estimated death rate at induction was 1.92% (0.82% for the SR group, 2.23% for IR, and 3.04% for the HR group). A total of 81 deaths were noted at the CR1 phase (death rate of 4.55%, with 1.19% in SR, 3.26% in IR, and 13.77% in the HR group). Deaths related to relapse were noted in 106 children.
Treatments using standardized regimens or protocols have led to unprecedented improvements in survival of children with cancer, but most published regimens are based on therapies developed and delivered in high-income countries. 2 The ALL IC-BFM 2002 trial was designed to be conducted in countries with inadequate skills and resources for PCR-based MRD monitoring enabling, however, the stratification and treatment of children with ALL according to a BFM-based backbone protocol. 1 The EFS in our cohort at 5 years is estimated to be as high as 79%, and OS of 86% at 5 years. These results are clearly comparable to treatment outcomes presented by several major study groups or institutions, since over the last two decades the world's leading leukemia groups have achieved 5-year OS rates of approximately 90% with 2% to 3% deaths resulting from toxicity in childhood ALL. 3 A major concern regarding BFM-type chemotherapy for less experienced groups with limited resources was the potential risk of excessive therapy related mortality (TRM In conclusion, ALL IC-BFM 2002 proved as a highly effective protocol for treatment of children with ALL in Polish pediatric oncohematology centers. The design of the study allowed us to achieve outcomes comparable to those reported by study groups in several countries with high health-related expenditures. The study based on inexpensive and accessible stratification criteria was highly successful.

ACKNOWLEDGMENTS
We thank all staff members of the collaborating institutes. Special thanks are due to data manager Radosław Nowakowski.