Хронический лимфолейкоз высокого риска: история, определение, диагностика и лечениеХронический лимфолейкоз высокого риска: история, определение, диагностика и лечение

Е.А. Никитин, А.Б. Судариков

Федеральное государственное бюджетное учреждение «Гематологический научный центр Министерства здравоохранения Российской Федерации», Москва, Российская Федерация


РЕФЕРАТ

Хронический лимфолейкоз высокого риска – новое и все более уточняемое понятие, которое появилось в эру флударабина. Клиническое значение ХЛЛ высокого риска объясняется очень плохим прогнозом по сравнению с остальной группой пациентов. В статье представлен краткий исторический обзор, а также современное определение этого понятия, рассматриваются молекулярные механизмы, лежащие в основе ХЛЛ высокого риска, а также подходы к терапии.


Ключевые слова: хронический лимфолейкоз, TP53, делеция 17p, флударабин.

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ЛИТЕРАТУРА

  1. Montserrat E. CLL therapy: progress at last! Blood. 2005; 105: 2–3.
  2. Byrd J.C., Stilgenbauer S., Flinn I.W. Chronic lymphocytic leukemia. In: Hematology 2004: American Society of Hematology Education Program Book. Washington, DC: American Society of Hematology, 2004: 163–83.
  3. Hallek M., Fischer K., Fingerle-Rowson G. et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376(9747): 1164–74.
  4. Keating M.J., O’Brien S., Albitar M. et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J. Clin. Oncol. 2005; 23(18): 4079–88.
  5. Tam C.S., O’Brien S., Wierda W. et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008; 112(4): 975–80.
  6. Badoux X.C., Keating M.J., Wang X. et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood 2011; 117(11): 3016–24.
  7. Montserrat E., Moreno C., Esteve J. et al. How I treat refractory CLL. Blood 2006; 107(4): 1276–83.
  8. Gribben J.G. How I treat CLL up front. Blood 2010; 115(2): 187–97.
  9. Catovsky D., Richards S., Matutes E. et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007; 370(9583): 230–9.
  10. Eichhorst B.F., Busch R., Hopfinger G. et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006; 107(3): 885–91.
  11. Flinn I.W., Neuberg D.S., Grever M.R. et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. Clin. Oncol. 2007; 25(7): 793–8.
  12. Dreger P., Dohner H., Ritgen M. et al. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood 2010; 116(14): 2438–47.
  13. Stilgenbauer S., Zenz T., Winkler D. et al. Genomic aberrations, VH mutation status and outcome after fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR) in the CLL8 trial [abstract]. Blood (ASH Annual Meeting Abstracts) 2008; 112(11): 781.
  14. Zenz T., Busch R., Fink A. et al. Genetics of patients with F-refractory CLL or early relapse after FC or FCR: results from the CLL8 Trial of the GCLLSG [abstract]. Blood (ASH Annual Meeting Abstracts) 2010; 116(21): 2427.
  15. Tsimberidou A.M., Keating M.J. Treatment of fludarabine-refractory chronic lymphocytic leukemia. Cancer 2009; 115(13): 2824–36.
  16. Keating M.J., Flinn I., Jain V. et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002; 99(10): 3554–61.
  17. Stilgenbauer S., Zenz T. Understanding and managing ultra high-risk chronic lymphocytic leukemia [abstract]. Hematology Am. Soc. Hematol. Educ. Program 2010; 2010: 481–8.
  18. Wierda W.G., Kipps T.J., Mayer J. et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J. Clin. Oncol. 2010; 28(10): 1749–55.
  19. Rai K.R., Sawitsky A., Cronkite E.P. et al. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46(2): 219–34.
  20. Binet J.L., Auquier A., Dighiero G. et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48(1): 198–206.
  21. Silver R.T., Sawitsky A., Rai K., Holland J.F., Glidewell O. Guidelines for protocol studies in chronic lymphocytic leukemia. Am. J. Hematol. 1978; 4(4): 343–58.
  22. Sawitsky A., Rai K.R., Glidewell O., Silver R.T. Comparison of daily versus intermittent chlorambucil and prednisone therapy in the treatment of patients with chronic lymphocytic leukemia. Blood 1977; 50(6): 1049–59.
  23. Cheson B.D., Bennett J.M., Rai K.R. et al. Guidelines for clinical protocols for chronic lymphocytic leukemia: recommendations of the National Cancer Institute-sponsored working group. Am. J. Hematol. 1988; 29(3): 152–63.
  24. International Workshop on Chronic Lymphocytic Leukemia. Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and response criteria. Intern. Med. 1989; 110(3): 236–8.
  25. Cheson B.D., Bennett J.M., Grever M. et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87(12): 4990–7.
  26. Hallek M., Cheson B.D., Catovsky D. et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111(12): 5446–56.
  27. Dreger P., Corradini P., Kimby E. et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 2007; 21(1): 12–7.
  28. Eichhorst B.F., Busch R., Stilgenbauer S. et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009; 114(16): 3382–91.
  29. Oscier D., Wade R., Davis Z. et al. Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation. Haematologica 2010; 95(10): 1705–12.
  30. Lin K.I., Tam C.S., Keating M.J. et al. Relevance of the immunoglobulin VH somatic mutation status in patients with chronic lymphocytic leukemia treated with fludarabine, cyclophosphamide, and rituximab (FCR) or related chemoimmunotherapy regimens. Blood 2009; 113(14): 3168–71.
  31. Abrisqueta P., Pereira A., Rozman C. et al. Improving survival in patients with chronic lymphocytic leukemia (1980–2008): the Hospital Clinic of Barcelona experience. Blood 2009; 114(10): 2044–50.
  32. Gisselbrecht C., Glass B., Mounier N. et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. Clin. Oncol. 2010; 28(27): 4184–90.
  33. Zenz T., Gribben J.G., Hallek M. et al. Risk categories and refractory CLL in the era of chemoimmunotherapy. Blood. 2012; 119(18): 4101–7.
  34. Knauf W.U., Lissichkov T., Aldaoud A. et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J. Clin. Oncol. 2009; 27(26): 4378–84.
  35. Hillmen P., Skotnicki A.B., Robak T. et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J. Clin. Oncol. 2007; 25(35): 5616–23.
  36. Grever M.R., Lucas D.M., Dewald G.W. et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J. Clin. Oncol. 2007; 25(7): 799–804.
  37. Dohner H., Fischer K., Bentz M. et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 1995; 85(6): 1580–9.
  38. Zenz T., Habe S., Denzel T. et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial. Blood 2009; 114(13): 2589–97.
  39. Zenz T., Eichhorst B., Busch R. et al. TP53 mutation and survival in chronic lymphocytic leukemia. Clin. Oncol. 2010; 28(29): 4473–9.
  40. Rossi D., Cerri M., Deambrogi C. et al. The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness. Cancer Res. 2009; 15: 995–1004.
  41. Malcikova J., Smardova J., Rocnova L. et al. Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage. Blood 2009; 114(26): 5307–14.
  42. Pospisilova S., Gonzalez D., Malcikova J. et al. European Research Initiative on CLL (ERIC). ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia. Leukemia 2012; 26(7): 1458–61.
  43. Mohr J., Helfrich H., Fuge M. et al. DNA damage-induced transcriptional program in CLL: biological and diagnostic implications for functional p53 testing. Blood 2011; 117(5): 1622–32.
  44. Quesada V., Conde L., Villamor N. et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat. Genet. 2011; 44(1): 47–52.
  45. Wang L., Lawrence M.S., Wan Y. et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. Engl. J. Med. 2011; 365(26): 2497–506.
  46. Rossi D., Bruscaggin A., Spina V. et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood 2011; 118(26): 6904–8.
  47. Rossi D., Rasi S., Fabbri G. et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood 2012; 119(2): 521–9.
  48. Fabbri G., Rasi S., Rossi D. et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J. Exp. Med. 2011; 208(7): 1389–401.
  49. Best O.G., Gardiner A.C., Davis Z.A. et al. A subset of Binet stage A CLL patients with TP53 abnormalities and mutated IGHV genes have stable disease. Leukemia 2009; 23(1): 212–4.
  50. Dreger P., Dohner H., Ritgen M. et al. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the GCLLSG CLL3X trial. Blood 2010; 116(14): 2438–47.
  51. Stilgenbauer S., Zenz T., Winkler D. et al. Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J. Clin. Oncol. 2009; 27: 3994–4001.
  52. Fiegl M., Erdel M., Tinhofer I. et al. Clinical outcome of pretreated B-cell chronic lymphocytic leukemia following alemtuzumab therapy: a retrospective study on various cytogenetic risk categories. Ann. Oncol. 2010 May 13.
  53. Rai K.R., Freter C.E., Mercier R.J. et al. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. Clin. Oncol. 2002; 20: 3891–7.
  54. Ferrajoli A., O’Brien S.M., Cortes J.E. et al. Phase II study of alemtuzumab in chronic lymphoproliferative disorders. Cancer 2003; 98: 773–8.
  55. Moreton P., Kennedy B., Lucas G. et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. Clin. Oncol. 2005; 23: 2971–9.
  56. Cortelezzi A., Pasquini M.C., Sarina B. et al. A pilot study of low-dose subcutaneous alemtuzumab therapy for patients with chemotherapy-refractory chronic lymphocytic leukemia. Haematologica 2005; 90: 410–2.
  57. Wierda W.G., Padmanabhan S., Chan G.W. et al.; Hx-CD20-406 Study Investigators. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood 2011; 118(19): 5126–9.
  58. Bosanquet A.G., McCann S.R., Crotty G.M., Mills M.J., Catovsky D. Methylprednisolone in advanced chronic lymphocytic leukaemia: rationale for, and effectiveness of treatment suggested by DiSC assay. Acta Haematol. 1995; 93: 73–9.
  59. Thornton P.D., Hamblin M., Treleaven J.G. et al. High dose methyl prednisolone in refractory chronic lymphocytic leukaemia. Lymphoma 1999; 34: 167–70.
  60. Thornton P.D., Matutes E., Bosanquet A.G. et al. High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities. Ann. Hematol. 2003; 82: 759–65.
  61. Castro J.E., Sandoval-Sus J.D., Bole J., Rassenti L., Kipps T.J. Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia 2008; 22: 2048–53.
  62. Bowen D.A., Call T.G., Jenkins G.D. et al. Methylprednisolone-rituximab is an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia including those with unfavorable cytogenetic features. Lymphoma 2007; 48: 2412–7.
  63. Pileckyte R., Jurgutis M., Valceckiene V. et al. Dose-dense high-dose methylprednisolone and rituximab in the treatment of relapsed or refractory high-risk chronic lymphocytic leukemia. Leuk. Lymphoma 2011; 52: 1055–65.
  64. Pettitt A.R., Matutes E., Oscier D. Alemtuzumab in combination with high-dose methylprednisolone is a logical, feasible and highly active therapeutic regimen in chronic lymphocytic leukaemia patients with p53 defects. Leukemia 2006; 20: 1441–5.
  65. Stilgenbauer S., Cymbalista F., Leblond V. et al. Alemtuzumab Plus Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Transplantation in Ultra High-Risk CLL: Interim Analysis of a Phase II Study of the GCLLSG and fcgcll/MW. Blood (ASH Annual Meeting Abstracts) 2011; 118: 2854.
  66. Castro J.E., Barajas-Gamboa J.S., Melo-Cardenas J. et al. Ofatumumab and high-dose methylprednisolone is an effective salvage treatment for heavily pretreated, unfit or refractory patients with chronic lymphocytic leukemia: Single institution experience. Blood 2010; 116(21):
  67. Badoux X.C., Keating M.J., Wang X. et al. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. Blood 2011; 118(8): 2085–93.
  68. Tsimberidou A.M., Wierda W.G., Plunkett W. et al. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter’s syndrome or fludarabine-refractory chronic lymphocytic leukemia. J. Clin. 2008; 26(2): 196–203.
  69. Wierda W., O’Brien S., Wen S. et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J. Clin. Oncol. 2005; 18: 1–9.
  70. Bosch F., Ferrer A., Lopez-Guillermo A. et al. Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukemia. J. Haematol. 2002; 119: 976–84.
  71. Elter T., Borchmann P., Schulz H. et al. Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial. J. Clin. 2005; 23(28): 7024–31.
  72. Tsimberidou A., Wierda W.G., Plunkett W. et al. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter’s syndrome of fludarabine-refractory chronic lymphocytic leukemia. Clin. Oncol. 2008; 26: 196–203.
  73. Mauro F.R., Foa R., Meloni G. et al. Fludarabine, ara-C, novantrone and dexamethasone (FAND) in previously treated chronic lymphocytic leukemia patients. Haematologica 2002; 87: 926–33.
  74. Ferrajoli A., Lee B.N., Schlette E.J. et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008; 111(11): 5291–7.

Лечение рефрактерных форм острого лимфобластного лейкоза у детей и подростков: реиндукция ремиссии с последующей аллогенной трансплантацией гемопоэтических стволовых клеток

Е.В. Семёнова, Н.В. Станчева, С.Н. Бондаренко, В.Н. Вавилов, Д.А. Багге, О.В. Паина, С.В. Разумова, А.С. Боровкова, Т.А. Быкова, А.А. Рац, Л.С. Зубаровская, Б.В. Афанасьев

Институт Детской Гематологии и Трансплантологии им. Р.М. Горбачевой, Санкт-Петербургский Государственный Медицинский Университет им. академика И. П. Павлова, Санкт-Петербург, Российская Федерация


РЕФЕРАТ

Цель исследования: оценка эффективности программ химиотерапии, содержащих нуклеозидные аналоги (флударабин и неларабин) с последующим применением аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при рефрактерных формах острого лимфобластного лейкоза (ОЛЛ) у детей и подростков.

Материал и методы: Пациентам (n=33) в возрасте от 1 до 21 года (медиана – 11,5) с рецидивами и рефрактерными формами острого лимфобластного лейкоза с целью индукции ремиссии выполнена химиотерапия по схемам, содержащим флударабин (FLAG±Ida) (n=23) или неларабин (n=10). В последующем 24 пациентам в последующем проведена алло-ТГСК.

Результаты: Из 23 пациентов, получивших FLAG и FLAG-Ida полная ремиссия (ПР)  достигнута у 11 (48%). Среди 10 пациентов, которым провели лечение по схемам с неларабином, ПР получена у 7 (70%). Длительность ПР составила, в среднем, 4,9 мес (1-18 мес). Общая 3-х летняя выживаемость (ОВ) пациентов после алло-ТГСК, выполненной в ремиссии, составила 58%, в рецидиве – 8%, без алло-ТГСК – 0%.

Заключение: схемы химиотерапии, содержащие флударабин или неларабин, могут применяться  как этап подготовки с целью достижения ремиссии перед аллогенной трансплантацией гемопоэтических стволовых клеток у детей и подростков с прогностически неблагоприятными формами острого лимфобластного лейкоза.


Ключевые слова: флударабин, неларабин, алло-ТГСК, острый лимфобластный лейкоз, резистентные формы, дети, подростки.

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ЛИТЕРАТУРА

  1. Schrappe M., Reiter A., Ludwig W.D. et al. Improved outcome in childhood acute Lymphoblastic leukemia despite reduced use of antracyclines and cranial radiotherapy: results of trial ALL-BFM 90. Blood 2000; 95(11): 3310–22.
  2. Silverman L.B., Gelber R.D., Dalton V.K. et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 2001; 97(5): 1211–8.
  3. Pui C.-H., Schrappe M., Ribeiro R.C., Niemeyer C.M. Childhood and adolescent lymphoid and myeloid leukemia. Hematology 2004; 84: 124–32.
  4. Pui C.H., Evans W.E. Treatment of acute lymphoblastic leukemia. N. Engl. J. Med. 2006; 354(2): 166–78.
  5. Chessells J.M., Veys P., Kempski H. et al. Long-term follow-up of relapsed childhood acute lymphoblastic leukaemia. Br. J. Haematol. 2003; 123: 396–405.
  6. Nguyen K., Devidas M., Cheng S.C. et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: A Children’s Oncology Group study. Leukemia 2008; 22: 2142–50.
  7. Афанасьев Б.В., Зубаровская Л.С. Трансплантация гемопоэтических стволовых клеток крови. Детская онкология: Руководство. СПб., 2002: 90–108. [Afanas’ev B.V., Zubarovskaya L.S. Transplantatsiya gemopoeticheskikh stvolovykh kletok krovi. Detskaya onkologiya: Rukovodstvo (Hematopoietic stem cell transplantation. Pediatric oncology. Manual). , 2002: 90–108.]
  8. Румянцев А.Г., Масчан А.А. Трансплантация гемопоэтических стволовых клеток у детей: Руководство для врачей. М., 2003. [Rumyantsev A.G., Maschan A.A. Transplantatsiya gemopoeticheskikh stvolovykh kletok u detei: Rukovodstvo dlya vrachei (Hematopoietic stem cell transplantation in children. Manual for medical practitioners)., 2003.]
  9. McCarthy A.J., Pitcher L.A., Hann I.M., Oakhill A. FLAG (fludarabine, high-dose cytarabine, and G-CSF) for refractory and high-risk relapsed acute leukemia in children. Med. Pediatr. Oncol. 1999; 32(6): 411–5.
  10. Yang S.W. et al. Dual mode of inhibition of purified DNA ligase from human cells by 9-β-D-arabinosyl-2-fluoroadenine triphosphate. J. Biol. Chem. 1992; 267: 2345–9.
  11. Ross S.P. et al. Fludarabine: a review of its pharmacological properties and therapeutic potential in malignancy. Drug 1993; 45: 737–59.
  12. Gandhi V. et al. Combination of fludarabine and arabinosyl-cytosine for the treatment of chronic lymphocytic leukemia: clinical efficacy and modulation of arabinosyl-cytosine pharmacology. Cancer Chem. Pharmacol. 1994; 34: 30–6.
  13. Tavil B., Aytac S., Balci Y.I. et al. Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) for the treatment of children with poor-prognosis acute leukemia: the Hacettepe experience. Hematol. Oncol. 2010; 27(7): 517–28.
  14. Quarello P., Berger M., Rivetti E. et al. FLAG-liposomal doxorubicin (Myocet) regimen for refractory or relapsed acute leukemia pediatric patients. J. Pediatr. Hematol. Oncol. 2012; 34(3): 208–16.
  15. Berg S.L., Blaney S.M., Devidas M. et al. Phase II study of Nelarabine in children and young adults with refractory T-cell malignancies: a report from the Children’s Oncology Group. J. Clin. Oncol. 2005; 23(15): 3376–82.
  16. Commander L.A., Seif A.E., Insogna I.G., Susan R. Rheingold. Salvage therapy with nalarabine, etoposide and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma. J. Haem. 2010; 150: 345–51.
  17. Trotti A., Colevas A.D. et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Radiat. O 2007; 13: 176–81.