Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. Despite enormous improvement of prognosis during the last half century, ALL remains a major cause of childhood cancer-related mortality. During the past decade, whole genomic methods have enhanced our knowledge of disease biology. Stratification of therapy according to early treatment response measured by minimal residual disease allows risk group assignment into different treatment arms, ranging from reduction to intensification of treatment. Progress has been achieved in academic clinical trials by optimization of combined chemotherapy, which continues to be the mainstay of contemporary treatment. The availability of suitable volunteer main histocompatibility antigen-matched unrelated donors has increased the rates of hematopoietic stem cell transplantation (HSCT) over the past two decades. Allogeneic HSCT has become an alternative treatment for selected, very-high-risk patients. However, intensive treatment burdens children with severe acute toxic effects that can cause permanent organ damage and even toxic death. Immunotherapeutic approaches have recently come to the forefront in ALL therapy. Monoclonal antibodies blinatumomab and inotuzumab ozogamicin as well as gene-modified T cells directed to specific target antigens have shown efficacy against resistant/relapsed leukemia in phase I/II studies. Integration of these newer modalities into combined regimens with chemotherapy may rescue a subset of children not curable by contemporary therapy. Another major challenge will be to incorporate less toxic regimens into the therapy of patients with low-risk disease who have a nearly 100% chance of being cured, and the ultimate goal is to improve their quality of life while maintaining a high cure rate.

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Zobrazit více v PubMed

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(14):1663–9. 10.1200/JCO.2011.37.8018 PubMed DOI PMC

Pui CH, Pei D, Campana D, et al. : A revised definition for cure of childhood acute lymphoblastic leukemia. Leukemia. 2014;28(12):2336–43. 10.1038/leu.2014.142 PubMed DOI PMC

Stary J, Zimmermann M, Campbell M, et al. : Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol. 2014;32(3):174–84. 10.1200/JCO.2013.48.6522 PubMed DOI

van Dongen JJ, van der Velden VH, Brüggemann M, et al. : Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood. 2015;125(26):3996–4009. 10.1182/blood-2015-03-580027 PubMed DOI PMC

Flohr T, Schrauder A, Cazzaniga G, et al. : Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia. 2008;22(4):771–82. 10.1038/leu.2008.5 PubMed DOI

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(8):964–71. 10.1182/blood-2015-03-633685 PubMed DOI PMC

Nachman JB, Sather HN, Sensel MG, et al. : Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med. 1998;338(23):1663–71. 10.1056/NEJM199806043382304 PubMed DOI

Seibel NL, Steinherz PG, Sather HN, et al. : Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2008;111(5):2548–55. 10.1182/blood-2007-02-070342 PubMed DOI PMC

Lange BJ, Bostrom BC, Cherlow JM, et al. : Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood. 2002;99(3):825–33. 10.1182/blood.V99.3.825 PubMed DOI

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(8):809–18. 10.1016/S1470-2045(14)70243-8 PubMed DOI

Matloub Y, Bostrom BC, Hunger SP, et al. : Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2011;118(2):243–51. 10.1182/blood-2010-12-322909 PubMed DOI PMC

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(3):199–209. 10.1016/S1470-2045(12)70600-9 PubMed DOI

Conter V, Bartram CR, Valsecchi MG, et al. : 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. 2010;115(16):3206–14. 10.1182/blood-2009-10-248146 PubMed DOI

Schrappe M, Valsecchi MG, Bartram CR, et al. : Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011;118(8):2077–84. 10.1182/blood-2011-03-338707 PubMed DOI

Wood BL, Winter SS, Dunsmore KP, et al. : 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(21):1 Reference Source PubMed

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(2):147–56. 10.1016/S1470-2045(08)70314-0 PubMed DOI PMC

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(2):e80–6. 10.1016/S2352-3026(15)00254-9 PubMed DOI

Möricke A, Zimmermann M, Valsecchi MG, et al. : Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016;127(17):2101–12. 10.1182/blood-2015-09-670729 PubMed DOI

Jackson RK, Irving JA, Veal GJ: Personalization of dexamethasone therapy in childhood acute lymphoblastic leukaemia. Br J Haematol. 2016;173(1):13–24. 10.1111/bjh.13924 PubMed DOI

Larsen EC, Devidas M, Chen S, et al. : Dexamethasone and High-Dose Methotrexate Improve Outcome for Children and Young Adults With High-Risk B-Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group Study AALL0232. J Clin Oncol. 2016;34(20):2380–8. 10.1200/JCO.2015.62.4544 PubMed DOI PMC

Pieters R, Hunger SP, Boos J, et al. : l-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer. 2011;117(2):238–49. 10.1002/cncr.25489 PubMed DOI PMC

Tong WH, Pieters R, Kaspers GJ, et al. : A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia. Blood. 2014;123(13):2026–33. 10.1182/blood-2013-10-534347 PubMed DOI PMC

Place AE, Stevenson KE, Vrooman LM, et al. : Intravenous pegylated asparaginase versus intramuscular native Escherichia coli l-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015;16(16):1677–90. 10.1016/S1470-2045(15)00363-0 PubMed DOI

Salzer WL, Asselin B, Supko JG, et al. : Erwinia asparaginase achieves therapeutic activity after pegaspargase allergy: a report from the Children's Oncology Group. Blood. 2013;122(4):507–14. 10.1182/blood-2013-01-480822 PubMed DOI PMC

Schmiegelow K, Levinsen MF, Attarbaschi A, et al. : Second malignant neoplasms after treatment of childhood acute lymphoblastic leukemia. J Clin Oncol. 2013;31(19):2469–76. 10.1200/JCO.2012.47.0500 PubMed DOI PMC

Cheung YT, Krull KR: Neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia treated on contemporary treatment protocols: A systematic review. Neurosci Biobehav Rev. 2015;53:108–20. 10.1016/j.neubiorev.2015.03.016 PubMed DOI PMC

Richards S, Pui CH, Gayon P, et al. : Systematic review and meta-analysis of randomized trials of central nervous system directed therapy for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2013;60(2):185–95. 10.1002/pbc.24228 PubMed DOI PMC

Pui CH, Campana D, Pei D, et al. : Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360(26):2730–41. 10.1056/NEJMoa0900386 PubMed DOI PMC

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(9):919–26. 10.1200/JCO.2015.64.2850 PubMed DOI PMC

Jacola LM, Krull KR, Pui CH, et al. : Longitudinal Assessment of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia Treated on a Contemporary Chemotherapy Protocol. J Clin Oncol. 2016;34(11):1239–47. 10.1200/JCO.2015.64.3205 PubMed DOI PMC

Peters C, Schrappe M, von Stackelberg A, et al. : Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial. J Clin Oncol. 2015;33(11):1265–74. 10.1200/JCO.2014.58.9747 PubMed DOI

Schrappe M, Hunger SP, Pui CH, et al. : Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med. 2012;366(15):1371–81. 10.1056/NEJMoa1110169 PubMed DOI PMC

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(15):2345–53. 10.1182/blood-2014-01-552166 PubMed DOI PMC

Eden T, Pieters R, Richards S, et al. : Systematic review of the addition of vincristine plus steroid pulses in maintenance treatment for childhood acute lymphoblastic leukaemia - an individual patient data meta-analysis involving 5,659 children. Br J Haematol. 2010;149(5):722–33. 10.1111/j.1365-2141.2010.08148.x PubMed DOI

Conter V, Valsecchi MG, Silvestri D, et al. : Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial. Lancet. 2007;369(9556):123–31. 10.1016/S0140-6736(07)60073-7 PubMed DOI

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(11):2154–61. 10.1038/leu.2015.134 PubMed DOI

O'Connor D, Bate J, Wade R, et al. : Infection-related mortality in children with acute lymphoblastic leukemia: an analysis of infectious deaths on UKALL2003. Blood. 2014;124(7):1056–61. 10.1182/blood-2014-03-560847 PubMed DOI

Schmiegelow K, Attarbaschi A, Barzilai S, et al. : Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus. Lancet Oncol. 2016;17(6):e231–9. 10.1016/S1470-2045(16)30035-3 PubMed DOI

Navarrete M, Rossi E, Brivio E, et al. : Treatment of childhood acute lymphoblastic leukemia in central America: a lower-middle income countries experience. Pediatr Blood Cancer. 2014;61(5):803–9. 10.1002/pbc.24911 PubMed DOI

Jabeen K, Ashraf MS, Iftikhar S, et al. : The Impact of Socioeconomic Factors on the Outcome of Childhood Acute Lymphoblastic Leukemia (ALL) Treatment in a Low/Middle Income Country (LMIC). J Pediatr Hematol Oncol. 2016;38(8):587–596. 10.1097/MPH.0000000000000653 PubMed DOI

Zaliova M, Hovorkova L, Vaskova M, et al. : Slower early response to treatment and distinct expression profile of childhood high hyperdiploid acute lymphoblastic leukaemia with DNA index < 1.16. Genes Chromosomes Cancer. 2016;55(9):727–37. 10.1002/gcc.22374 PubMed DOI

Moorman AV: New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia. Haematologica. 2016;101(4):407–16. 10.3324/haematol.2015.141101 PubMed DOI PMC

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(26):2896–9. 10.1182/blood-2015-09-671131 PubMed DOI PMC

Mullighan CG, Su X, Zhang J, et al. : Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470–80. 10.1056/NEJMoa0808253 PubMed DOI PMC

Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. : A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10(2):125–34. 10.1016/S1470-2045(08)70339-5 PubMed DOI PMC

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(27):3012–20. 10.1200/JCO.2014.55.4105 PubMed DOI PMC

Schwab C, Ryan SL, Chilton L, et al. : EBF1-PDGFRB fusion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL): genetic profile and clinical implications. Blood. 2016;127(18):2214–8. 10.1182/blood-2015-09-670166 PubMed DOI

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(11):1005–15. 10.1056/NEJMoa1403088 PubMed DOI PMC

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(9):936–45. 10.1016/S1470-2045(12)70377-7 PubMed DOI PMC

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(7):1467–71. 10.1038/leu.2014.30 PubMed DOI PMC

Zaliova M, Fronkova E, Krejcikova K, et al. : Quantification of fusion transcript reveals a subgroup with distinct biological properties and predicts relapse in BCR/ABL-positive ALL: implications for residual disease monitoring. Leukemia. 2009;23(5):944–51. 10.1038/leu.2008.386 PubMed DOI

Bleckmann K, Schrappe M: Advances in therapy for Philadelphia-positive acute lymphoblastic leukaemia of childhood and adolescence. Br J Haematol. 2016;172(6):855–69. 10.1111/bjh.13896 PubMed DOI

Pui CH, Pei D, Campana D, et al. : Improved prognosis for older adolescents with acute lymphoblastic leukemia. J Clin Oncol. 2011;29(4):386–91. 10.1200/JCO.2010.32.0325 PubMed DOI PMC

Pichler H, Reismüller B, Steiner M, et al. : The inferior prognosis of adolescents with acute lymphoblastic leukaemia (ALL) is caused by a higher rate of treatment-related mortality and not an increased relapse rate--a population-based analysis of 25 years of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) Study Group. Br J Haematol. 2013;161(4):556–65. 10.1111/bjh.12292 PubMed DOI

Sanjuan-Pla A, Bueno C, Prieto C, et al. : Revisiting the biology of infant t(4;11)/MLL-AF4 + B-cell acute lymphoblastic leukemia. Blood. 2015;126(25):2676–85. 10.1182/blood-2015-09-667378 PubMed DOI PMC

Buitenkamp TD, Izraeli S, Zimmermann M, et al. : Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. Blood. 2014;123(1):70–7. 10.1182/blood-2013-06-509463 PubMed DOI PMC

Arber DA, Orazi A, Hasserjian R, et al. : The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405. 10.1182/blood-2016-03-643544 PubMed DOI

Bene MC, Bernier M, Casasnovas RO, et al. : The reliability and specificity of c-kit for the diagnosis of acute myeloid leukemias and undifferentiated leukemias. The European Group for the Immunological Classification of Leukemias (EGIL). Blood. 1998;92(2):596–9. PubMed

Bene MC, Porwit A: Acute leukemias of ambiguous lineage. Semin Diagn Pathol. 2012;29(1):12–8. 10.1053/j.semdp.2011.08.004 PubMed DOI

Mejstrikova E, Volejnikova J, Fronkova E, et al. : Prognosis of children with mixed phenotype acute leukemia treated on the basis of consistent immunophenotypic criteria. Haematologica. 2010;95(6):928–35. 10.3324/haematol.2009.014506 PubMed DOI PMC

Kotrova M, Musilova A, Stuchly J, et al. : Distinct bilineal leukemia immunophenotypes are not genetically determined. Blood. 2016; pii: blood-2016-07-725861. 10.1182/blood-2016-07-725861 PubMed DOI

Rossi JG, Bernasconi AR, Alonso CN, et al. : Lineage switch in childhood acute leukemia: an unusual event with poor outcome. Am J Hematol. 2012;87(9):890–7. 10.1002/ajh.23266 PubMed DOI

Slamova L, Starkova J, Fronkova E, et al. : CD2-positive B-cell precursor acute lymphoblastic leukemia with an early switch to the monocytic lineage. Leukemia. 2014;28(3):609–20. 10.1038/leu.2013.354 PubMed DOI

Clappier E, Auclerc MF, Rapion J, et al. : An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions. Leukemia. 2014;28(1):70–7. 10.1038/leu.2013.277 PubMed DOI

Hrusak O, Luks A, Janotova I, et al. : Acute Leukemias of Ambiguous Lineage; Study on 247 Pediatric Patients. Blood. 2015;126(23):252 Reference Source

Irving JA: Towards an understanding of the biology and targeted treatment of paediatric relapsed acute lymphoblastic leukaemia. Br J Haematol. 2016;172(5):655–66. 10.1111/bjh.13852 PubMed DOI

Locatelli F, Schrappe M, Bernardo ME, et al. : How I treat relapsed childhood acute lymphoblastic leukemia. Blood. 2012;120(14):2807–16. 10.1182/blood-2012-02-265884 PubMed DOI

Mullighan CG: Mutant PRPS1: a new therapeutic target in relapsed acute lymphoblastic leukemia. Nat Med. 2015;21(6):553–4. 10.1038/nm.3876 PubMed DOI

Ma X, Edmonson M, Yergeau D, et al. : Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia. Nat Commun. 2015;6: 6604. 10.1038/ncomms7604 PubMed DOI PMC

Meyer JA, Wang J, Hogan LE, et al. : Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia. Nat Genet. 2013;45(3):290–4. 10.1038/ng.2558 PubMed DOI PMC

Li B, Li H, Bai Y, et al. : Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL. Nat Med. 2015;21(6):563–71. 10.1038/nm.3840 PubMed DOI PMC

Mullighan CG, Zhang J, Kasper LH, et al. : CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature. 2011;471(7337):235–9. 10.1038/nature09727 PubMed DOI PMC

Parker C, Waters R, Leighton C, et al. : Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010;376(9757):2009–17. 10.1016/S0140-6736(10)62002-8 PubMed DOI PMC

Eckert C, Henze G, Seeger K, et al. : Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group. J Clin Oncol. 2013;31(21):2736–42. 10.1200/JCO.2012.48.5680 PubMed DOI

Krentz S, Hof J, Mendioroz A, et al. : Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia. Leukemia. 2013;27(2):295–304. 10.1038/leu.2012.155 PubMed DOI

Eckert C, Hagedorn N, Sramkova L, et al. : Monitoring minimal residual disease in children with high-risk relapses of acute lymphoblastic leukemia: prognostic relevance of early and late assessment. Leukemia. 2015;29(8):1648–55. 10.1038/leu.2015.59 PubMed DOI

Maude SL, Frey N, Shaw PA, et al. : Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17. 10.1056/NEJMoa1407222 PubMed DOI PMC

Maus MV, Grupp SA, Porter DL, et al. : Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood. 2014;123(17):2625–35. 10.1182/blood-2013-11-492231 PubMed DOI PMC

Brudno JN, Kochenderfer JN: Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127(26):3321–30. 10.1182/blood-2016-04-703751 PubMed DOI PMC

Gore L, Locatelli F, Zugmaier G, et al. : Initial Results from a Phase 2 Study of Blinatumomab in Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia [abstract]. Blood. 2014;124:3703 Reference Source

Schlegel P, Lang P, Zugmaier G, et al. : Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab. Haematologica. 2014;99(7):1212–9. 10.3324/haematol.2013.100073 PubMed DOI PMC

Kantarjian HM, DeAngelo DJ, Stelljes M, et al. : Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. N Engl J Med. 2016;375(8):740–53. 10.1056/NEJMoa1509277 PubMed DOI PMC