Treatment of Childhood Acute Lymphoblastic Leukemia: Prognostic Factors and Clinical Advances

Current Hematologic Malignancy Reports

Volumn 11, Issue 5, 2016, Pages 385-394

  Vrooman, Lynda M ^a,b   Silverman, Lewis B ^a,b  

^a DANA FARBER CANCER INSTITUTE   (United States)

^b BOSTON CHILDREN S HOSPITAL   (United States)

Author keywords

Acute lymphoblastic leukemia; Relapse; Treatment

Indexed keywords

ANTHRACYCLINE; BCR ABL PROTEIN; BLINATUMOMAB; DASATINIB; IKAROS TRANSCRIPTION FACTOR; IMATINIB; METHOTREXATE; PREDNISONE; PROTEIN TYROSINE KINASE INHIBITOR; RAZOXANE; TRANSCRIPTION FACTOR ETV6; TRANSCRIPTION FACTOR RUNX1; IKZF1 PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR;

ACUTE LYMPHOBLASTIC LEUKEMIA; AGE; ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION; AUTOLOGOUS STEM CELL TRANSPLANTATION; CANCER PROGNOSIS; CANCER RADIOTHERAPY; CHILDHOOD CANCER; CLINICAL TRIAL (TOPIC); CYTOGENETICS; DIPLOIDY; DISEASE FREE SURVIVAL; DRUG EFFICACY; DRUG SAFETY; EVENT FREE SURVIVAL; GENE; GENE AMPLIFICATION; GENE DELETION; GENE REARRANGEMENT; HEART PROTECTION; HIGH RISK PATIENT; HUMAN; IKZF1 GENE; IMMUNOPHENOTYPING; IMMUNOTHERAPY; LEUKEMIA RELAPSE; LEUKOCYTE COUNT; META ANALYSIS (TOPIC); MULTICENTER STUDY (TOPIC); PATIENT COMPLIANCE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHILADELPHIA 1 CHROMOSOME; PRE T LYMPHOCYTE; PROGNOSTIC ASSESSMENT; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SOCIAL STATUS; TREATMENT OUTCOME; TREATMENT RESPONSE; TRISOMY; CHILD; DEFICIENCY; GENETICS; MEDICATION COMPLIANCE; PRECURSOR CELL LYMPHOBLASTIC LEUKEMIA-LYMPHOMA; PROGNOSIS; RECURRENT DISEASE; STEM CELL TRANSPLANTATION;

CHILD; CYTOGENETICS; HUMANS; IKAROS TRANSCRIPTION FACTOR; IMMUNOTHERAPY; MEDICATION ADHERENCE; PRECURSOR CELL LYMPHOBLASTIC LEUKEMIA-LYMPHOMA; PROGNOSIS; PROTEIN KINASE INHIBITORS; RECURRENCE; STEM CELL TRANSPLANTATION;

EID: 84981164475     PISSN: 15588211     EISSN: 1558822X     Source Type: Journal    
DOI: 10.1007/s11899-016-0337-y     Document Type: Review

References (79)

1. Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360:2730–41.
2. Veerman AJ, Kamps WA, van den Berg H, et al. Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004). Lancet Oncol. 2009;10:957–66.
3. Moricke A, Reiter A, Zimmermann M, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008;111:4477–89.
4. Vrooman LM, Stevenson KE, Supko JG, et al. Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study—Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol. 2013;31:1202–10.
5. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.
6. Oskarsson T, Soderhall S, Arvidson J, et al. Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome. Haematologica. 2016;101:68–76.
7. Mody R, Li S, Dover DC, et al. Twenty-five-year follow-up among survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Blood. 2008;111:5515–23.
8. Smith M, Arthur D, Camitta B, et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol. 1996;14:18–24.
9. Moricke A, Zimmermann M, Reiter A, et al. Prognostic impact of age in children and adolescents with acute lymphoblastic leukemia: data from the trials ALL-BFM 86, 90, and 95. Klin Padiatr. 2005;217:310–20.
10. Pieters R, Schrappe M, De Lorenzo P, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 2007;370:240–50.
11. Dreyer ZE, Hilden JM, Jones TL, et al. Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3). Pediatr Blood Cancer. 2015;62:419–26. Event-free survival remained less than 50% overall in infant MLL-rearranged ALL on this Children’s Oncology Group study which evaluated shortened (46 weeks), intensified therapy.
12. Forestier E, Schmiegelow K. The incidence peaks of the childhood acute leukemias reflect specific cytogenetic aberrations. J Pediatr Hematol Oncol. 2006;28:486–95.
13. Stock W, La M, Sanford B, et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Cancer and Leukemia Group B studies. Blood. 2008;112:1646–54.
14. Ramanujachar R, Richards S, Hann I, et al. Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer. 2007;48:254–61.
15. DeAngelo DJ, Stevenson KE, Dahlberg SE, et al. Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia. Leukemia. 2015;29:526–34.
16. Grace RF, Dahlberg SE, Neuberg D, et al. The frequency and management of asparaginase-related thrombosis in paediatric and adult patients with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute consortium protocols. Br J Haematol. 2011;152:452–9.
17. Liu C, Yang W, Devidas M, et al. Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia. J Clin Oncol. 2016;34(18):2133–40.
18. Hunger SP, Lu X, Devidas M, et al. 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. 2012;30:1663–9.
19. Paulsson K, Johansson B. High hyperdiploid childhood acute lymphoblastic leukemia. Genes Chromosomes Cancer. 2009;48:637–60.
20. Dastugue N, Suciu S, Plat G, et al. Hyperdiploidy with 58-66 chromosomes in childhood B-acute lymphoblastic leukemia is highly curable: 58951 CLG-EORTC results. Blood. 2013;121:2415–23.
21. Moorman AV, Ensor HM, Richards SM, et al. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol. 2010;11:429–38. This analysis presents cytogenetic data from a large cohort of 1725 children with B acute lymphoblastic leukemia included in the UK Medical Research Council ALL97/99 study, with median follow-up of 8.2 years.
22. Pui CH, Chessells JM, Camitta B, et al. Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia. 2003;17:700–6.
23. Biondi A, Schrappe M, De Lorenzo P, et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol. 2012;13:936–45.
24. Nachman JB, Heerema NA, Sather H, et al. Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood. 2007;110:1112–5.
25. Mullighan CG, Jeha S, Pei D, et al. Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels. Blood. 2015;126:2896–9.
26. Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013;45:242–52.
27. Stengel A, Schnittger S, Weissmann S, et al. TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis. Blood. 2014;124:251–8.
28. Muhlbacher V, Zenger M, Schnittger S, et al. Acute lymphoblastic leukemia with low hypodiploid/near triploid karyotype is a specific clinical entity and exhibits a very high TP53 mutation frequency of 93%. Genes Chromosomes Cancer. 2014;53:524–36.
29. Loh ML, Goldwasser MA, Silverman LB, et al. Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01. Blood. 2006;107:4508–13.
30. Harrison CJ, Moorman AV, Schwab C, et al. An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome. Leukemia. 2014;28:1015–21.
31. Moorman AV, Richards SM, Robinson HM, et al. Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21). Blood. 2007;109:2327–30.
32. Attarbaschi A, Mann G, Panzer-Grumayer R, et al. Minimal residual disease values discriminate between low and high relapse risk in children with B-cell precursor acute lymphoblastic leukemia and an intrachromosomal amplification of chromosome 21: the Austrian and German acute lymphoblastic leukemia Berlin-Frankfurt-Munster (ALL-BFM) trials. J Clin Oncol. 2008;26:3046–50.
33. Moorman AV, Robinson H, Schwab C, et al. Risk-directed treatment intensification significantly reduces the risk of relapse among children and adolescents with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21: a comparison of the MRC ALL97/99 and UKALL2003 trials. J Clin Oncol. 2013;31:3389–96. On the UK-ALL 2003 study, children with ALL with iAMP21 were treated as high risk, regardless of other presenting features. This study demonstrated that with higher intensity therapy (i.e., non-standard risk therapy), the previously described increased risk of relapse with iAMP21 was mitigated.
34. Heerema NA, Carroll AJ, Devidas M, et al. Intrachromosomal amplification of chromosome 21 is associated with inferior outcomes in children with acute lymphoblastic leukemia treated in contemporary standard-risk children's oncology group studies: a report from the children’s oncology group. J Clin Oncol. 2013;31:3397–402. The Children’s Oncology Group reported that iAMP21 was associated with inferior EFS and OS in Standard Risk patients (treated with less intensive therapy), but for High Risk patients (treated with more intensive therapy), iAMP21 was not associated with statistically significant differences in EFS or OS, suggesting that high risk therapy appeared to abrogate the adverse prognostic significance of this abnormality.
35. van der Veer A, Waanders E, Pieters R, et al. Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood. 2013;122:2622–9.
36. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360:470–80.
37. Clappier E, Grardel N, Bakkus M, et al. IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children’s Leukemia Group study 58951. Leukemia. 2015;29:2154–61. In this report of a large cohort of patients with Ph-negative B ALL treated on the EORTC-CLG trial 58951, patients with IKZF1-deleted ALL had significantly lower EFS compared with non-IKZF1 deleted cases. IKZF1 deletion was an independent predictor of outcome, retaining its prognostic importance in multivariable analysis.
38. Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371:1005–15. Detailed genomic analysis of 154 patients with Ph-like ALL identified kinase activating alterations in over 90% of patients, involving ABL1, ABL2, CRLF2, EPOR, JAK2, PDGFR, and other genes. The multiple genetic alterations appear to impact a limited number of signaling pathways, notably ABL-class and JAK-STAT pathways, suggesting the potential for targeted interventions.
39. Roberts KG, Pei D, Campana D, et al. Outcomes of children with BCR-ABL1-like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease. J Clin Oncol. 2014;32:3012–20.
40. Coustan-Smith E, Mullighan CG, Onciu M, et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 2009;10:147–56.
41. Zhang J, Ding L, Holmfeldt L, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 2012;481:157–63.
42. Inukai T, Kiyokawa N, Campana D, et al. Clinical significance of early T-cell precursor acute lymphoblastic leukaemia: results of the Tokyo Children’s Cancer Study Group Study L99-15. Br J Haematol. 2012;156:358–65.
43. Wood B, Winter S, Dunsmore K. T-lymphoblastic leukemia (T-ALL) shows excellent outcome, lack of significance of the early thymic precursor (ETP) immunophenotype, and validation of the prognostic value of end-induction minimal residual disease (MRD) in children’s oncology group (COG) study AALL0434. Blood. 2014;124:abstr 1.
44. Conter V, Valsecchi MG, Buldini B, et al. Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: a retrospective analysis. Lancet Haematol. 2016;3:e80–6.
45. Patrick K, Wade R, Goulden N, et al. Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003. Br J Haematol. 2014;166:421–4.
46. Silverman LB, Gelber RD, Young ML, et al. Induction failure in acute lymphoblastic leukemia of childhood. Cancer. 1999;85:1395–404.
47. Schrappe M, Hunger SP, Pui CH, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med. 2012;366:1371–81.
48. Panzer-Grumayer ER, Schneider M, Panzer S, et al. Rapid molecular response during early induction chemotherapy predicts a good outcome in childhood acute lymphoblastic leukemia. Blood. 2000;95:790–4.
49. Borowitz MJ, Devidas M, Hunger SP, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood. 2008;111:5477–85.
50. Borowitz MJ, Wood BL, Devidas M, et al. Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232. Blood. 2015;126:964–71.
51. Sutton R, Venn NC, Tolisano J, et al. Clinical significance of minimal residual disease at day 15 and at the end of therapy in childhood acute lymphoblastic leukaemia. Br J Haematol. 2009;146:292–9.
52. Bartram J, Wade R, Vora A, et al. Excellent outcome of minimal residual disease-defined low-risk patients is sustained with more than 10 years follow-up: results of UK paediatric acute lymphoblastic leukaemia trials 1997-2003. Arch Dis Child. 2016;101:449–54.
53. Vora A, Goulden N, Mitchell C, et al. Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2014;15:809–18. The randomized UKALL-2003 study demonstrated that intensification of therapy for non-high risk patients with high end induction MRD resulted in a superior event-free survival compared with those receiving standard therapy.
54. Vora A, Goulden N, Wade R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013;14:199–209. The UKALL-2003 trial tested de-intensification of therapy for non-high risk patients with low/favorable MRD, randomly assigning patients to receive one or two courses of delayed intensification. No significant difference in EFS was demonstrated, supporting the feasibility of treatment reduction in patients with favorable end-induction MRD.
55. Bhatia S, Landier W, Hageman L, et al. 6MP adherence in a multiracial cohort of children with acute lymphoblastic leukemia: a Children’s Oncology Group study. Blood. 2014;124:2345–53. This report from the Children’s Oncology Group (COG) demonstrated that poor adherence to oral 6-mercaptopuine, a key component of maintenance therapy in childhood ALL, is an important predictor of relapse.
56. Bhatia S, Landier W, Shangguan M, et al. Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the children’s oncology group. J Clin Oncol. 2012;30:2094–101.
57. Kadan-Lottick NS, Ness KK, Bhatia S, et al. Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia. JAMA. 2003;290:2008–14.
58. Harvey RC, Mullighan CG, Chen IM, et al. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood. 2010;115:5312–21.
59. Xu H, Cheng C, Devidas M, et al. ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol. 2012;30:751–7.
60. Bona K, Blonquist TM, Neuberg DS, et al. Impact of socioeconomic status on timing of relapse and overall survival for children treated on Dana-Farber Cancer Institute ALL Consortium Protocols (2000-2010). Pediatr Blood Cancer. 2016;63:1012–8.
61. Conter V, Valsecchi MG, Parasole R, et al. Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study. Blood. 2014;123:1470–8. In a report from the AIEOP group, after adjusting for waiting time to HSCT, there was no benefit demonstrated for HSCT in first CR for patients with high end-consolidation (week 10-12) MRD. This study further illustrates the need for novel therapies for these patients.
62. Uckun FM, Nachman JB, Sather HN, et al. Clinical significance of Philadelphia chromosome positive pediatric acute lymphoblastic leukemia in the context of contemporary intensive therapies: a report from the Children’s Cancer Group. Cancer. 1998;83:2030–9.
63. Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol. 2009;27:5175–81.
64. Schultz KR, Carroll A, Heerema NA, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s Oncology Group study AALL0031. Leukemia. 2014;28:1467–71. This study supports the feasibility and efficacy of incorporation of TKI therapy into multi-agent therapy for Ph + ALL.
65. Topp MS, Kufer P, Gokbuget N, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29:2493–8.
66. Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16:57–66.
67. Topp MS, Gokbuget N, Zugmaier G, et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012;120:5185–7.
68. Hoffman LM, Gore L. Blinatumomab, a Bi-specific anti-CD19/CD3 BiTE((R)) antibody for the treatment of acute lymphoblastic leukemia: perspectives and current pediatric applications. Front Oncol. 2014;4:63.
69. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509–18.
70. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17. In this report, 30 children and adults with multiply relapsed or refractory ALL were treated with autologous CD19-directed CAR-modified T cells. Notably, 90% of patients in this heavily pre-treated grouped achieved complete remission, with 6-month EFS reported of 67% (95% CI 51-88) and OS of 78% (95% CI 65-95), demonstrating the potential for this treatment approach.
71. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385:517–28. This study of the use of of CD 19-directed CAR T-cells in patients aged 1-30 years, further demonstrates the feasibility, safety, and, anti-leukaemic activity of this treatment approach.
72. Hijiya N, Hudson MM, Lensing S, et al. Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA. 2007;297:1207–15.
73. Goshen Y, Stark B, Kornreich L, et al. High incidence of meningioma in cranial irradiated survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2007;49:294–7.
74. Armstrong GT, Reddick WE, Petersen RC, et al. Evaluation of memory impairment in aging adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiotherapy. J Natl Cancer Inst. 2013;105:899–907.
75. Sirvent N, Suciu S, Rialland X, et al. Prognostic significance of the initial cerebro-spinal fluid (CSF) involvement of children with acute lymphoblastic leukaemia (ALL) treated without cranial irradiation: results of European Organization for Research and Treatment of Cancer (EORTC) Children Leukemia Group study 58881. Eur J Cancer. 2011;47:239–47.
76. Vora A, Andreano A, Pui CH, et al. Influence of cranial radiotherapy on outcome in children with acute lymphoblastic leukemia treated with contemporary therapy. J Clin Oncol. 2016;34:919–26.
77. Lipshultz SE, Scully RE, Lipsitz SR, et al. Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol. 2010;11:950–61.
78. Chow EJ, Asselin BL, Schwartz CL, et al. Late mortality after dexrazoxane treatment: a report from the Children’s Oncology Group. J Clin Oncol. 2015;33:2639–45.
79. Asselin BL, Devidas M, Chen L, et al. Cardioprotection and safety of dexrazoxane in patients treated for newly diagnosed T-cell acute lymphoblastic leukemia or advanced-stage lymphoblastic non-Hodgkin lymphoma: a report of the Children’s Oncology Group Randomized Trial Pediatric Oncology Group 9404. J Clin Oncol. 2016;34:854–62. In this a report of the Pediatric Oncology Group 9404 trial which included random assignment of patients with T ALL or T lymphoblastic lymphoma to receive therapy with or without dexrazoxane prior to each dose of doxorubicin, dexrazoxane was found to be cardioprotective, based upon echocardiographic measurements of left ventricular function and structure, without difference in EFS between the two randomized arm, supporting the use of dexrazoxane in childhood ALL patients.