• Progress in the treatment of acute lymphoblastic leukemia: 25 years of application of international protocols in the Department of Pediatric Hematology of the Western Ukrainian Specialized Children’s Medical Center
To content

Progress in the treatment of acute lymphoblastic leukemia: 25 years of application of international protocols in the Department of Pediatric Hematology of the Western Ukrainian Specialized Children’s Medical Center

SOVREMENNAYA PEDIATRIYA.2018.8(96):22-36; doi 10.15574/SP.2018.96.22

Dorosh O., Tsymbalyuk-Voloshyn I., Bodak Kh., Polishchuk R., Stepanyuk A., Vorobel O., Skoropad L., Troyanovska O., Kozlova O., Myh A., Seredych L., Hlynska O.
Lviv Regional Council Public Institution «Western Ukrainian Specialized Children's Medical Centre», Ukraine
D. Halytskyy Lviv National Medical University, Ukraine
Medical center of Saint Paraskevia, Lviv, Ukraine

The results of treatment for modified chemotherapy programs of the international BFM group from February 1993 to March 2018 in 370 patients with acute lymphoblastic leukemia (ALL) aged 0 to 18 years were analyzed. The event-free survival (EFS) indicator for the entire sample of patients is 73.2%. 143 (38.65%) patients received treatment based on programs ALL-BFM 90/95 (group 1); from November 2002 to June 2012 — 131 (35.41%) patients — ALL IC-BFM 2002 (group 2); from June 2012 — 88 (23.78%) patients — ALL IC-BFM2009 (group 3) correspondingly. Children under the age of 1 (8 persons) from August 2008 were treated according to INTERFANT'99/06 programs (group 4). EFS in group 1 is 68.0% with a median observation time (MO) for 220 months, in group 2 — 77.6% with MO 111 months, in group 3 — 85.2% with MO 39 months, in group 4 — 12.5% of MO 13.5 months. The statistically significant improvement of EFS indexes in group 3, the worst results in children under 1 year (p <0.05). The EFS for middle!risk group (MR) patients in the 1st group was 71.0%, in the 2nd group — 83.7%, and in the 3rd group — 90.6% (p = 0.04232). The EFS for the high-risk group (HR) patients in the 1st group was 50.0%, in the 2nd — 55.6% and in the 3rd group — 73.9% (p = 0.09653). The overall survival (OS) in the entire sample is 78.0%. Totally 73 died (18.7%). In 32 (43.8%) people, death was associated with the therapy of the 1st line of ALL, 11 of them (34.37%) died of toxic-septic complications until the remission of ALL during induction therapy; 19 children (59.37%) — from complications in 1st remission at different stages of intensive chemotherapy, 1 patient with HR — from post-transplant complications, 1 patient — for 160 months. after reaching a remission from the fulminant course of viral hepatitis B. The 39 (53.42%) patients, death occurred in the second acute period from the progression of leukemia and/or infectious complications. Relapse of ALL is diagnosed in 53 (16.21%) people. Disease-free survival (DFS) is 83.2%. A rare remote consequence of ALL treatment in children was secondary malignant diseases, which were registered in 5 (1.35%) children. Astrocytoma, meningioma, secondary acute myeloid leukemia (AML) have been successfully treated, oligodendroglioma and secondary myelodysplastic syndrome with transformation in to AML was a reason of lethal consequence. 8 persons from the HR-group in the 1st remission had allo-ВМТ (abroad), including 2 patients — for whom alloBMT was a second therapeutic line for treatment of secondary AML. The statistically significant improvement in the EFS indices in the application of program polychemotherapy ALL IC-BFM 2009 was revealed, the worst results of treatment in children under 1 year (p <0.05). Treatment of patients with high risk groups (HR) and in children of the first year of life requires further searching for ways to improve the effectiveness of therapy, and reduce its toxic effects.

Key words: children, acute lymphoblastic leukemia, treatment, international protocols.


1. Donska SB. (2012). Results of treatment of acute lymphoblastic leukemia in children in Ukraine. Zdorovia Ukrainy. http://health-ua.com/pics/pdf/ZU_2012_Onko_5-6/30-31.pdf.

2. Dudkin SA, Chunihovskiy SP, Streneva OV i dr. (2003). Intermediate analysis of the multicenter study ALL-MB 91 and ALL-BFM 90: results of treatment of children with initial hyperleukocytosis and T-cell variant of ALL. Aktualnyie problemy gematologii i transfuziologii: V s'ezd gematologov i transfuziologov Respubliki Belarus. Minsk: Strinko: 204–205.

3. Kolenkova GV. (2002). Markers of acute leukemia in the diagnosis and prognosis of the disease in children. Gematologiya i transfuziologiya. 47(2): 28–35..

4. Lenskaya RV, Kolenkova GV, Timakov AT. (2000). The clinical significance of the expression of blast cell CD-antigens in children with acute lymphoblastic leukemia. Eksperimentalnaya onkologiya. 22(4): 191–194.

5. Armata J, Boguslawska_Jaworska D, Kolecki P, Kowalszyk J, Ochocka M, Radwanska U, Sonta-Jakimczyk D, Wachowiak J. (1998). Bialaczki u dzieci. Pod redakcja U. Radwalskiej. Wrocnaw (Poland): Volumed: 234.

6. Aung L, Khyne T, Yeoh AE, Quah TC, Tan AM. (2009). A report from the Singapore Childhood Cancer Survivor Study (SG-CCSS): a multi-institutional collaborative study on long-term survivors of childhood cancer, initial analysis reporting for the SG-CCSS. Ann Acad Med Singapore. 38(8): 684—689.

7. Barredo JC, Hastings C, Lu X, Devidas M, Chen Y, Armstrong D et al. (2017). Isolated late testicular relapse of B-cell acute lymphoblastic leukemia treated with intensive systemic chemotherapy and response-based testicular radiation: A Children's Oncology Group study. Pediatr Blood Cancer. 65(5): e26928. https://doi.org/10.1002/pbc.26928; PMCid:PMC6136835

8. Bene MC, Castoldi G, Knapp W et al. (1995). Proposals for the immunological classification of acute leukaemias: European Group for the Immunological Characterization of Leukemias (EGIL) Leukemia 9: 1783—1786.

9. Bessho F, Takayama N, Fronkova E, Zuna J. (2013). Reappearance of acute lymphoblastic leukemia 34 years after initial diagnosis: a case report and study of the origin of the reappeared blasts.Int J Hematol. 97(4): 525—528. https://doi.org/10.1007/s12185-013-1289-9

10. Bhatia S. (2013). Therapy-related myelodysplasia and acute myeloid leukemia. Semin Oncol. 40(6): 666—675. https://doi.org/10.1053/j.seminoncol.2013.09.013; PMCid:PMC3867743

11. Bien E, Stachowicz-Stencel T, Szalewska M, Krawczyk M, Synakiewicz A, Dubaniewicz-Wybieralska M et al. (2009). Poor-risk high-grade gliomas in three survivors of childhood acute lymphoblastic leukaemia — an over-view of causative factors and possible therapeutic options. Childs Nerv Syst. 25(5): 619—626. https://doi.org/10.1007/s00381-009-0838-2

12. Bierings M, Szczepanski T, van Wering ER, Willemse MJ, Langerak AW, Revesz T et al. (2001). Two consecutive immunophenotypic switches in a child with immunogenotypically stable acute leukaemia. Br J Haematol. 113(3): 757—762. https://doi.org/10.1046/j.1365-2141.2001.02772.x

13. Borowitz MJ, Bene M-C, Harris NL, Porwit A, Matutes E. (2008). Acute leukemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Geneva: WHO Press: 150—151.

14. Borowitz MJ, Chan JKC. (2008). B lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Geneva: WHO Press: 171—175.

15. Borowitz MJ, Chan JKC. (2008). B lymphoblastic leukaemia/lymphoma, not otherwise specified. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Geneva: WHO Press: 168—170.

16. Borowitz MJ, Chan JKC. (2008). T lymphoblastic leukemia/lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Geneva: WHO Press: 176—178.

17. Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grumayer R, Moricke A et al. (2010). Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. 115: 3206—3214. https://doi.org/10.1182/blood-2009-10-248146

18. Donadieu J, Auclerc MF, Baruchel A et al. (1998). Critical study of prognostic factors in childhood acute lymphoblastic leukemia: differences in outcome are poorly explained by the most significant prognostic variables. FRALLE Group Frensh Acute Lymphoblastic Leukemia study group. Br.J.Haematol. 102: 729—739. https://doi.org/10.1046/j.1365-2141.1998.00818.x

19. Dordelmann M, Reiter A, Borkhardt A, Ludwig WD. (1999). Prednisone response in the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood. 94(4): 1209—1217.

20. Dreyer ZE, Hilden JM, Jones TL, Devidas M, Winick NJ, Willman CL et al. (2015). Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3). Pediatr Blood Cancer. 62: 419—426. https://doi.org/10.1002/pbc.25322; PMCid:PMC5145261

21. Erduran E, Gedik Y, Orhan F et al. (1999). Brief report. Leukemic infiltrations of the peritoneum at diagnosis and the breast at relapse in a child with acute B-ceIl lymphoblastic leukemia. Med Pediatr Oncol. 32: 71—72. https://doi.org/10.1002/(SICI)1096-911X(199901)32:1<71::AID-MPO18>3.0.CO;2-1

22. Fink FM, Koller U, Mayer H et al. (1993). Prognostic significance of myeloid-associated antigen expression on blast cells in children with acute lymphoblastic leukemia. Med PediatrOncol. 21: 340—346. https://doi.org/10.1002/mpo.2950210506

23. Firat H, Favier R, Adam M et al. (2001). Determination of myeloid antigen expression on childhood acute lymphoblastic leukaemia cells: discrepancies using different monoclonal antibody clones. Leuk Lymphoma. 42(4): 675—682. https://doi.org/10.3109/10428190109099329

24. Fisher KE, Hsu AP, Williams CL, Sayeed H, Merritt BY, Elghetany MT, Holland SM, Bertuch AA, Gramatges MM. (2017). Somatic mutations in children with GATA2-associated myelodysplastic syndrome who lack other features of GATA2 deficiency. Blood Adv. 1(7): 443—448. https://doi.org/10.1182/bloodadvances.2016002311; PMCid:PMC5738979

25. Griffin TC, Shuster JJ, Buchanan GR et al. (2000). Slow disapperarance of periferall blood blasts in as adverse prognostic factor in childhood T cell acute lymphoblastic leukemia: a Pedoatric Oncology Group study. Leukemia. 14(5): 792—795. https://doi.org/10.1038/sj.leu.2401768

26. Haarman EG, Kaspers G-JP, Veerman AJP. (2003). Glucocorticoid resistence in childhood leuaemia: mechanisms and modulation. Br J Haematol. 120(6): 919—929. https://doi.org/10.1046/j.1365-2141.2003.04189.x

27. Haddy TB, Mosher RB, Reaman GH. (2009). Late effects in long-term survivors after treatment for childhood acute leukemia. Clin Pediatr (Phila). 48(6): 601—608. https://doi.org/10.1177/0009922809332680

28. Hannson CA, Abaza M, Sheldon S et al. (1993). Acute biphenotypic leukemia: immunophenotypic and cytogenetic analysis. Br J Haematol. 84(1): 49—60. https://doi.org/10.1111/j.1365-2141.1993.tb03024.x

29. Howard MR, Thomas L, Reid MM. (1994). Variable detection antigen in childhood acute lymphoblastic leukemia. J Clin Patology. 47: 1006—1009. https://doi.org/10.1136/jcp.47.11.1006

30. Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ et al. (2012). Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol. 30: 1663—1669. https://doi.org/10.1200/JCO.2011.37.8018; PMid:22412151 PMCid:PMC3383113

31. Janka-Schaub GE, Stuhrk H, Kortam B et al. (1991). Initiales Ansprechen auf die Therapie als wichtigster prognostischer Factor bei der akuten lymphoblastischen Leukamia in Kindesalter. Klin. Padiatr. 203(4): 231—235. https://doi.org/10.1055/s-2007-1025434; PMid:1942930

32. Kachel L, Rudzka E, Krzemien S et al. (1995). Wznowy w osrodkowym ukladzie nerwowym w przebiegu ostrej bialaczki limfoblastycznej a sposob postepowania profilaktycznego. Acta Haematologica Polonica (Poland). 26(1): 47—56.

33. Karrman K, Johansson B. (2017). Pediatric T-cell acute lymphoblastic leukemia. Genes Chromosomes Cancer. 56(2): 89—116. https://doi.org/10.1002/gcc.22416; PMid:27636224

34. Khan M, Siddiqi R, Naqvi K. (2018). An update on classification, genetics, and clinical approach to mixed phenotype acute leukemia (MPAL). Ann Hematol. (Epub ahead of print). https://doi.org/10.1007/s00277-018-3297-6; PMCid:PMC6097748

35. Killick S, Matutes E, Powles RL, Hamblin M, Swansbury J, Treleaven JG et al. (1999). Outcome of biphenotypic acute leukemia. Haematologica. 84(8): 699—706. PMid:10457405

36. Krawczuk-Rybak M, Zak J, Jaworowska B. (2003). A lineage switch from AML to ALL with persistent translocation t(4;11) in congenital leukemia. Med Pediatr Oncol. 41(1): 95—96. https://doi.org/10.1002/mpo.10276; PMid:12764763

37. Kurec AS, Belair P, Stefanu C et al. (1991). Significance of aberrant immunophenotypes in childhood acute lymphoblastic leukemia. Cancer. 67: 3081. https://doi.org/10.1002/1097-0142(19910615)67:12<3081::AID-CNCR2820671224>3.0.CO;2-Y

38. Lawson SE, Harrison G, Richards S et al. (2000). The UK experience in treating relapsed childhood acute lymphoblastic leukemia: a report on the Medical Research Coucil UKALLR1 study. Br J Haematol. 108(3): 531—543. https://doi.org/10.1046/j.1365-2141.2000.01891.x; PMid:10759711

39. Le Clerc JM, Billett AL, Gelber RD et al. (2002). Treatment of childhood acute lymphoblastic leukemia: result of Dana-Farber ALL Consorcium Protocol 87—01. J Clin Oncology. 20(1): 237—246. https://doi.org/10.1200/JCO.20.1.237; https://doi.org/10.1200/JCO.2002.20.1.237; PMid:11773175

40. Lee JW, Kim SK, Jang PS, Jeong DC, Chung NG, Cho B et al. (2016). Treatment of children with acute lymphoblastic leukemia with risk group based intensification and omission of cranial irradiation: A Korean study of 295 patients. Pediatr Blood Cancer. 63: 1966—1973. https://doi.org/10.1002/pbc.26136; PMid:27463364

41. Lee JW, Cho B. (2017). Prognostic factors and treatment of pediatric acute lymphoblastic leukemia. Korean J Pediatr. 60(5): 129—137. https://doi.org/10.3345/kjp.2017.60.5.129; PMid:28592975 PMCid:PMC5461276

42. Legrand O, Perrot JY, Simonin G et al. (1998). Adult biphenotypic acute leukemia: an ently with poor prognosis which is related to unfavorable cytogenetics and P-glycoprotein over-expression. Br J Haematol. 100(1): 147—155. https://doi.org/10.1046/j.1365-2141.1998.00523.x; PMid:9450804

43. Lo Coco F. (1991). Hybrid phenotypes and lineage promiscuity in acute leukemia. Haematologica. 76(3): 215—225. PMid:1743592

44. Loning L, Zimmermann M, Reiter A et al. (2000). Secondary neoplasms subsequent to Berlin-Frankfurt-Munster therapy of acute lymphoblastic leukemia in childhood: significantly lower risk without cranial therapy. Blood. 95: 2770—2775. PMid:10779419

45. Ludwig WD, Thiel E, Koller U et al. (1990). Incindence and clinical implications of acute hybrid leukemia in childhood. Haematol.Blood Transfus. (Acute Leukemias II): 516—522. PMid:2323652

46. Madeja G. (1994). Chemioterapia onkologiczna doroslych i dzieci. Pod redakcja G. Madeja — Warszawa: Wydawnictwo Lekarskie PZWL: 315.

47. Matsuzaki A, Okamura J, Ishii E et al. (1999). Treatment of standard-risk acute lymphoblastic leukemia in children: The results of Protocol AL 841 from the Kyushu-Yamaguchi Children's Cancer Study Group in Japan. Pediatr Hematol Oncol. 16: 187—199. https://doi.org/10.1080/088800199277245; PMid:10326217

48. Mejstrikova E, Kalina T, Trka J, Stary J, Hrusak O. (2005). Correlation of CD33 with poorer prognosis in childhood ALL implicates a potential of anti-CD33 frontline therapy. Leukemia. 19(6): 1092—1094. https://doi.org/10.1038/sj.leu.2403737; PMid:15830012

49. Mejstrikova E, Volejnikova J, Fronkova E, Zdrahalova K et al. (2010). Prognosis of children with mixed phenotype acute leukemia treated on the basis of consistent immunophenotypic criteria. Haematologica. 95(6): 928—935. https://doi.org/10.3324/haematol.2009.014506; PMid:20145275 PMCid:PMC2878790

50. Mi Y, Bian S, Meng Q et al. (2000). Study on the clinical characteristics of biphenotypic acute leukemia. Zhonghua Xue Ye Za Zhi. 21(7): 352—354.

51. Miller RW, Young JL, Novakovic B. (1995). Childhood cancer. Cancer. 75: 395—405. https://doi.org/10.1002/1097-0142(19950715)76:2<167::AID-CNCR2820760203>3.0.CO;2-K; https://doi.org/10.1002/1097-0142(19950101)75:1+<395::AID-CNCR2820751321>3.0.CO;2-W; https://doi.org/10.1002/1097-0142(19950115)75:2<495::AID-CNCR2820750212>3.0.CO;2-S; https://doi.org/10.1002/1097-0142(19950515)75:10<2410::AID-CNCR2820751004>3.0.CO;2-D; https://doi.org/10.1002/1097-0142(19950515)75:10<2403::AID-CNCR2820751002>3.0.CO;2-B; https://doi.org/10.1002/1097-0142(19950215)75:4<968::AID-CNCR2820750411>3.0.CO;2-Y

52. Moricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H et al. (2010). Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia. 24: 265—284. https://doi.org/10.1038/leu.2009.257; PMid:20010625

53. Nachman JB, Heerema NA, Sather H et al. (2007). Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood. 110: 1112—1115. https://doi.org/10.1182/blood-2006-07-038299; PMid:17473063 PMCid:PMC1939895

54. Neglia JP, Friedman DL, Yasui Y et al. (2001). Second Malignant Neoplasms in Five-Year Survivors of Childhood Cancer: Childhood Cancer Survivor Study. JNCI J Natl Cancer Inst. 93(8): 618—629. https://doi.org/10.1093/jnci/93.8.618; PMid:11309438

55. Neglia JP, Meadows AT, Robison LL et al. (1991). Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med. 325(19): 1330—1336. https://doi.org/10.1056/NEJM199111073251902; PMid:1922234

56. Neglia JP, Robison LL, Stovall M et al. (2006). New Primary Neoplasms of the Central Nervous System in Survivors of Childhood Cancer: a Report From the Childhood Cancer Survivor Study. JNCI J Natl Cancer Inst. 98(21): 1528—1537. https://doi.org/10.1093/jnci/djj411; PMid:17077355

57. Ng SM, Ariffin WA, Lin HP et al. (2000). Clinical features and treatment outcome of children with myeloid antigen coexpression in B-lineage acute lymphoblastic leukemia: a study of 151 Malaysian children. J Trop Pediatr. 46(2): 73—78. https://doi.org/10.1093/tropej/46.2.73; PMid:10822932

58. Nielsen SN, Eriksson F, Rosthoej S, Andersen MK, Forestier E, Hasle H, Hjalgrim LL, Aasberg A, Abrahamsson J, Heyman M, Jonsson OG, Pruunsild K, Vaitkeviciene GE, Vettenranta K, Schmiegelow K. (2017). Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers. Pediatr Blood Cancer. 64(10). https://doi.org/10.1002/pbc.26518

59. Otsubo K, Yabe M, Yabe H, Fukumura A, Morimoto T, Kato M, Mochizuki H. (2016). Successful acute lymphoblastic leukemia-type therapy in two children with mixed-phenotype acute leukemia. Pediatr Int. 58(10): 1072—1076. https://doi.org/10.1111/ped.13045; PMid:27577674

60. Owaidah TM, Al Beihany A, Iqbal MA, Elkum N, Roberts GT. (2006). Cytogenetics, molecular and ultrastructural characteristics of biphenotypic acute leukemia identified by the EGIL scoring system. Leukemia. 20(4): 620—626. https://doi.org/10.1038/sj.leu.2404128; PMid:16437134

61. Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M et al. (2007). A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 370: 240—250. https://doi.org/10.1016/S0140-6736(07)61126-X

62. Pituch-Noworolska A, Gawlicka M, Balwierz W et al. (1997). Atypical phenotypes of leukemic cells in acute leukaemia in children. Acta Haematologica Polonica (Poland). 28(1): 53—63.

63. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC et al. (2009). Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 360: 2730—2741. https://doi.org/10.1056/NEJMoa0900386; PMid:19553647 PMCid:PMC2754320

64. Pui CH, Raimondi SC, Head DR et al. (1991). Characterization of childhood acute lymphoblastic leukemia with multiple myeloid and lymphoid markers at diagnosis and relaps. Blood. 78: 1327—1337. PMid:1878594

65. Pui CH, Yang JJ, Hunger SP, Pieters R, Schrappe M, Biondi A et al. (2015). Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration. J Clin Oncol. 33(27): 2938—2948. https://doi.org/10.1200/JCO.2014.59.1636; PMid:26304874 PMCid:PMC4567699

66. Pui CH. (1998). Acute lymphoblastic leukemia. N Engl J Medicine. 339(9): 605—615. https://doi.org/10.1056/NEJM199808273390907; PMid:9718381

67. Putti MC, Rondelli R, Cocoto MG et al. (1998). Expression of myeloid markers lacks prognostic impact in children treated for acute lymphoblastic leukemia: Italian experience in AIEOP-ALL 88—91 stidies. Blood. 92: 795—801. PMid:9680347

68. Reiter A, Schrappe M, Ludwig WD et al. (1994). Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Result and conclusions of the multicenter trial ALL-BFM 86. Blood. 84: 3122—3133. PMid:7949185

69. Riehm H, Reiter A, Schrappe M et al. (1987). Corticosteroid-dependent reduction of leucocyte count in blood as a prognostic factor in acute lymphoblastic leukemia in childhood (therapy study ALL-BFM 83). Klinische Padiatrie. 199: 151—160. https://doi.org/10.1055/s-2008-1026781; PMid:3306129

70. Rihani R, Bazzeh F, Faqih N, Sultan I. (2010). Secondary hematopoietic malignancies in survivors of childhood cancer: an analysis of 111 cases from the Surveillance, Epidemiology, and End Result-9 registry. Cancer. 116(18): 4385—4394. https://doi.org/10.1002/cncr.25313; PMid:20549819

71. Rubnitz JE, Onciu M, Pounds S, Shurtleff S, Cao X, Raimondi SC et al. (2009). Acute mixed lineage leukemia in children: the experience of St. Jude Children's Research Hospital. Blood. 113(21): 5083—5089. https://doi.org/10.1182/blood-2008-10-187351; PMid:19131545 PMCid:PMC2686179

72. Salek C, Folber F, Fronkova E, Prochazka B, Marinov I, Cetkovsky P, Mayer J, Doubek M; Czech Leukemia Study Group — for Life. (2016). Early MRD response as a prognostic factor in adult patients with acute lymphoblastic leukemia. Eur J Haematol. 96(3): 276—284. https://doi.org/10.1111/ejh.12587; PMid:25997106

73. Schmiegelow K, Levinsen MF, Attarbaschi A, Baruchel A, Devidas M et al. (2013). Second malignant neoplasms after treatment of childhood acute lymphoblastic leukemia. J Clin Oncol. 31(19): 2469—2476. https://doi.org/10.1200/JCO.2012.47.0500; PMid:23690411 PMCid:PMC3807139

74. Schrappe M, Reiter A, Sauter S und andere. (1994). Konzeption und Zwischenergebnis der Therapiestudie ALL-BFM 90 zur Behandlung der akuten lympphoblastischen Leukamie bei Kindern und Jugendlichen: Die Behandlung des initialen Therapieansprechens in Blut und Knochenmark. Klin Padiatr. 206: 208—221. https://doi.org/10.1055/s-2008-1046607; PMid:7526027

75. Schrappe M, Reiter A, Zimmermann M et al. (2000). Long-term result of four consecutiwve trials in childhood ALL perfomed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Munster. Leukemia. 14(12): 2205—2222. https://doi.org/10.1038/sj.leu.2401973; PMid:11187912

76. Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grumayer R, Moricke A et al. (2011). Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 118: 2077—2084. https://doi.org/10.1182/blood-2011-03-338707; PMid:21719599

77. Stary J, Zimmermann M, Campbell M, Castillo L et al. (2014). Intensive Chemotherapy for Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Intercontinental Trial ALL IC-BFM 2002. J Clin Oncol. 32: 174—185. https://doi.org/10.1200/JCO.2013.48.6522; PMid:24344215

78. Stiller CA, Parkin DM. (1996). Geographic and ethnic variations in the incidence of childhood cancer. Br Med Bull. 52: 682—703. https://doi.org/10.1093/oxfordjournals.bmb.a011577; PMid:9039726

79. Theunissen P, Mejstrikova E, Sedek L, van der Sluijs-Gelling AJ, Gaipa G, Bartels M, Sobral da Costa E, Kotrova M et al.; EuroFlow Consortium. (2017). Standardized flow cytometry for highly sensitive MRD measurements in B-cell acute lymphoblastic leukemia. Blood. 129(3): 347—357. https://doi.org/10.1182/blood-2016-07-726307; PMid:27903527 PMCid:PMC5291958

80. Trigg ME, Steinherz PG, Chappell R et al. (2000). Early testicular biopsy in males with acute lymphoblastic leukemia: lack of impact on subsequent event-free survival. J Pediatr Hematol Oncol. 22(1): 27—33. https://doi.org/10.1097/00043426-200001000-00005; PMid:10695818

81. Tsuruchi N, Okamura J. (1996). Childhood acute lymphoblastic leukemia relapse in the uterine cervix. J Pediatr Hematol Oncol. 18(3): 311—313. https://doi.org/10.1097/00043426-199608000-00017; PMid:8689350

82. Tzortzatou-Stathopoulou F, Papadopoulou AL, Moschovi M, Botsonis A, Tsangaris GT. (2001). Low relapse rate in children with acute lymphoblastic leukemia after risk-directed therapy. J Pediatr Hematol Oncol. 23(9): 591—597. https://doi.org/10.1097/00043426-200112000-00008; PMid:11902303

83. Uckun FM, Sather HN, Gaynon PS. (1997). Clinical features and treatment outcome of children with myeloid antigen positive acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood. 90(1): 28—35. PMid:9207434

84. Volejnikova J, Mejstrikova E, Valova T, Reznickova L, Hodonska L, Mihal V, Sterba J, Jabali Y, Prochazkova D, Blazek B, Hak J, Cerna Z, Hrusak O, Stary J, Trka J, Fronkova E. (2011). Minimal residual disease in peripheral blood at day 15 identifies a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with superior prognosis. Haematologica. 96(12): 1815—1821. https://doi.org/10.3324/haematol.2011.042937; PMid:21880630 PMCid:PMC3232264

85. Vora A, Andreano A, Pui CH, Hunger SP, Schrappe M, Moericke A, Biondi A et al. (2016). Influence of Cranial Radiotherapy on Outcome in Children with Acute Lymphoblastic LeukemiaTreated with Contemporary Therapy. J Clin Oncol. 34(9): 919—926. https://doi.org/10.1200/JCO.2015.64.2850; PMid:26755523 PMCid:PMC4871998

86. Vrooman LM, Neuberg DS, Stevenson KE, Asselin BL, Athale UH, Clavell L et al. (2011). The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: a report from the Dana-Farber Cancer Institute ALL Consortium. Eur J Cancer. 47(9): 1373—1379. https://doi.org/10.1016/j.ejca.2011.03.022; PMid:21514146 PMCid:PMC3736806

87. Weir EG, Ali Ansari-Lari M, Batista DA, Griffin CA, Fuller S, Smith BD et al. (2007). Acute bilineal leukemia: a rare disease with poor outcome. Leukemia. 21(11): 2264—2270. https://doi.org/10.1038/sj.leu.2404848; PMid:17611554

88. Weir EG, Borowitz MJ. (2001). Flow cytometry in the diagnosis of acute leukemia. Semin Hematol. 38(2): 124—138. https://doi.org/10.1016/S0037-1963(01)90046-0; https://doi.org/10.1053/shem.2001.21924; PMid:11309694

89. Wiersma S, Ortega J, Sobel E et al. (1991). Clinical importance of myeloid antigen expression in acute lymphoblastic leukemia of childhood. N Engl J Med. 324: 800—808. https://doi.org/10.1056/NEJM199103213241204; PMid:1997852

90. Yeoh AE, Ariffin H, Chai EL, Kwok CS, Chan YH, Ponnudurai K et al. (2012). Minimal residual disease-guided treatment deintensification for children with acute lymphoblastic leukemia: results from the Malaysia-Singapore acute lymphoblastic leukemia 2003 study. J Clin Oncol. 30: 2384—392. https://doi.org/10.1200/JCO.2011.40.5936; PMid:22614971

Article received: Aug 02, 2018. Accepted for publication: Dec 04, 2018.