Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood, accounting for approximately 25% of childhood cancer and approximately 4,900 cases per year in the United States. A second peak in incidence occurs after 50 years of age, and although ALL accounts for a smaller proportion of adult than of pediatric malignancies, the absolute number of adult cases is ten times greater. Survival in childhood ALL has improved dramatically over the past 50 years; once a nearly incurable disease, pediatric ALL now has overall survival rates of over 80%. Survival in adults has also improved over time but remains considerably poorer at approximately 40%. Some of the key principles responsible for the improvement in outcomes include the use of combination chemotherapy to prevent the emergence of resistant clones, preventive CNS-directed therapy, the introduction of a delayed intensification phase of treatment, and risk stratification based on cytogenetic features and early response to treatment. Nevertheless, significant challenges remain. Survival in certain subgroups, such as infants and cases with adverse genetic features (eg, hypodiploidy), has improved very little over time. In addition, salvage rates are dismal for most patients who relapse. This review will cover the key elements of modern ALL treatment regimens, focusing primarily on front-line treatment and concluding with a brief discussion of the management of relapsed disease. Childhood ALL will be the primary focus, since children constitute over 60% of ALL cases and the majority are enrolled in clinical research trials. Significant contrasts with adult ALL will be highlighted.
One of the key factors responsible for survival gains in ALL is the recognition that, rather than being treated as a single entity, ALL should be treated as a set of heterogeneous disease subgroups that each require tailored therapy. Table 1 lists the key risk factors that affect prognosis on current regimens. It should be noted that risk factors are not absolute; rather, they differ in significance depending on the treatment regimen. Host factors include age, gender, and race and ethnicity. Disease characteristics include initial white blood cell (WBC) count at diagnosis, immunophenotype, genetic features, extramedullary involvement, and treatment response. Both age (with the exception of infants under one year of age) and initial WBC count behave as continuous variables; increasing values are associated with increasingly poor prognostic impact. However, in most pediatric risk stratification schemas they are treated as categorical variables, and cut-off values known as the National Cancer Institute (NCI)/Rome criteria are used; in the NCI/Rome criteria, age <1 year and > 10 years, and initial WBC count > 50,000/µl are considered high risk. Increasing age and initial WBC are both significant prognostic factors in adults as well, with the age cutoffs for high risk on different protocols ranging anywhere from 35 to 65 years, and initial WBC counts from 5,000 to 30,000/µl. Males historically have had slightly worse survival, although this difference has diminished recently. Race and ethnicity also affect outcome, with Asians having the best outcomes, followed by Caucasians, blacks, and Hispanics. Racial and ethnic differences in outcome have multifactorial causes, including socioeconomic factors and biologic differences in disease features and host pharmacogenetics.[6,7] Indeed, a gene expression signature significantly associated with Hispanic ethnicity was recently identified, which may partially explain the survival disadvantage in Hispanics; also, a component of genomic variation cosegregating with Native American ancestry was recently reported to be associated with increased risk of relapse.
Immunophenotype is used to stratify patients to distinct treatment regimens for T-cell, B-precursor, or mature B-cell leukemia. Other immunophenotypic differences (eg, the adverse effects of CD10 negativity in B-precursor ALL, and a recently identified early T-cell precursor immunophenotype) affect prognosis but do not at present alter treatment. The genetic features of ALL have been intensively researched for decades, and new insights have been generated by each successive methodological advance that emerged, including karyotype, fluorescence in situ hybridization (FISH), gene expression and single nucleotide polymorphism (SNP) array profiling, conventional and next-generation sequencing, and other techniques. However, only a few features fulfill the criteria for incorporation into risk stratification schemas on a widespread basis:
• Occurrence in a clinically relevant proportion of patients.
• Contribution of independent prognostic information beyond that of other established risk factors.
• Ready availability in everyday clinical practice.
Significant favorable features used for risk stratification for most modern regimens include the ETV6-RUNX1 fusion gene generated by the t(12;21) translocation, and high hyperdiploidy (particularly trisomies 4, 10, and 17). Adverse features include the BCR-ABL1 fusion gene generated by the t(9;22) translocation, hypodiploidy, and MLL rearrangements. Recent studies have identified additional novel adverse prognostic factors that are beginning to be incorporated in risk stratification schemas: Ikaros (IKZF1) deletions or mutations, Janus kinase 2 (JAK2) activating mutations and/or cytokine receptor–like factor 2 (CRLF2) overexpression, and chromosome 21 intrachromosomal amplification (iAMP21). Genetically defined subtypes have specific drug sensitivity patterns; enhanced sensitivity to asparaginase is seen in ETV6-RUNX1-positive ALL, and to methotrexate in hyperdiploid ALL, whereas ETV6-RUNX1-positive, TCF3-PBX1-positive, and T-cell ALL require higher methotrexate doses to yield equivalent intracellular concentrations of the active methotrexate polyglutamate metabolites.
Treatment response has assumed importance relatively recently, as technologic advances have made detection of minimal residual disease (MRD) possible on a routine clinical basis. MRD assays are based either on flow cytometric detection of an aberrant combination of surface markers characteristic of the leukemic clone, or on polymerase chain reaction (PCR) detection of a fusion transcript, gene mutation, or clonal immunoglobulin or T-cell receptor rearrangement. Many current regimens include measurements of MRD during and at the end of induction, and sometimes at later time points as well. MRD positivity generally necessitates intensification of therapy (see Figure 1), and MRD negativity in some cases may warrant consideration of decreased treatment intensity—eg, for selected favorable-risk patients with low MRD at days 8 and 29, a recent series reported 5-year event-free survival (EFS) of 97% ± 1%. Bone marrow morphology following one or two weeks of induction therapy was previously used as a measure of early response, but this is generally being replaced by measures of either bone marrow or peripheral blood MRD due to the superior sensitivity of these tests. The Berlin-Frankfurt-Mnster (BFM) Study Group continues to employ another measure of early response as well, namely, response to an initial seven-day prednisone window.
1. Margolin JF, Rabin KR, Steuber CP, Poplack DG. Acute lymphoblastic leukemia. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. Philadelphia: Lippincott Williams & Wilkins;2011:518-65.
2. Stat bite: estimated new leukemia cases in 2008. J Natl Cancer Inst. 2008;100:531.
3. Pui CH, Robison LL, Look AT: Acute lymphoblastic leukaemia. Lancet. 2008;371:1030-43.
4. Faderl S, O'Brien S, Pui CH, et al. Adult acute lymphoblastic leukemia: concepts and strategies. Cancer. 2010;116:1165-76.
5. 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.
6. Bhatia S. Influence of race and socioeconomic status on outcome of children treated for childhood acute lymphoblastic leukemia. Curr Opin Pediatr. 2004;16:9-14.
7. Yang JJ, Cheng C, Yang W, et al. Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA. 2009;301:393-403.
8. Harvey RC, Mullighan CG, Wang X, et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood. 2010;116:4874-84.
9. Yang JJ, Cheng C, Devidas M, et al. Nature genetics. 2011;43:237-41.
10. 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.
11. Mullighan CG. Genomic analysis of acute leukemia. Int J Lab Hematol. 2009;31:384-97.
12. Harrison CJ, Haas O, Harbott J, et al. Detection of prognostically relevant genetic abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: recommendations from the Biology and Diagnosis Committee of the International Berlin-Frankfurt-Münster Study Group. Br J Haematol. 2010;151:132-42.
13. 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.
14. Roll JD, Reuther GW. CRLF2 and JAK2 in B-progenitor acute lymphoblastic leukemia: a novel association in oncogenesis. Cancer Res. 2010;70:7347-52.
15. 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.
16. Pui CH, Relling MV, Evans WE. Role of pharmacogenomics and pharmacodynamics in the treatment of acute lymphoblastic leukaemia. Best Pract Res Clin Haematol. 2002;15:741-56.
17. Campana D. Progress of minimal residual disease studies in childhood acute leukemia. Curr Hematol Malig Rep. 2010;5:169-176.
18. 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.
19. Moricke A, Zimmermann M, Reiter A, et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia. 2010;24:265-84.
20. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006;354:166-178.
21. McNeer JL, Nachman JB. The optimal use of steroids in paediatric acute lymphoblastic leukaemia: no easy answers. Br J Haematol. 2010;149:638-52.
22. Raetz EA, Salzer WL. Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2010;32:554-63.
23. Beneficial and harmful effects of anthracyclines in the treatment of childhood acute lymphoblastic leukaemia: a systematic review and meta-analysis. Br J Haematol. 2009;145:376-88.
24. Kantarjian HM, O'Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000;18:547-61.
25. Stock W. Adolescents and young adults with acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2010;2010:21-9.
26. Chessells JM, Bailey C, Richards SM. Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Medical Research Council Working Party on Childhood Leukaemia. Lancet. 1995;345:143-8.
27. Schrappe M, Reiter A, Zimmermann M, et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster. Leukemia. 2000;14:2205-22.
28. Pui CH, Pei D, Sandlund JT, et al. Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia. 2010;24:371-82.
29. Moghrabi A, Levy DE, Asselin B, et al. Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood. 2007;109:896-904.
30. Pession A, Valsecchi MG, Masera G, et al. Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia. J Clin Oncol. 2005;23:7161-7.
31. 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.
32. 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;338:1663-71.
33. 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;111:2548-55.
34. Matloub Y, Bostrom B, Hunger SP, et al. Escalating dose intravenous methotrexate without leucovorin rescue during interim maintenance is superior to oral methotrexate for children with standard risk acute lymphoblastic leukemia: Children's Oncology Group Study 1991. Blood (ASH Annual Meeting Abstracts).. 2008;112:9.
35. Matloub Y, Angiolillo A, Bostrom B, et al. Double delayed intensification (DI) is equivalent to single DI in children with NCI standard-risk acute lymphoblastic leukemia treated on CCG-1991. Blood. 2006;108:146a.
36. Nathan PC, Wasilewski-Masker K, Janzen LA. Long-term outcomes in survivors of childhood acute lymphoblastic leukemia. Hematol Oncol Clin North Am. 2009;23:1065-1vii.
37. Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360:2730-41.
38. Waber DP, Silverman LB, Catania L, et al. Outcomes of a randomized trial of hyperfractionated cranial radiation therapy for treatment of high-risk acute lymphoblastic leukemia: therapeutic efficacy and neurotoxicity. J Clin Oncol. 2004;22:2701-7.
39. Matloub Y, Lindemulder S, Gaynon PS, et al. Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group. Blood. 2006;108:1165-73.
40. Lin TL, Vala MS, Barber JP, et al. Induction of acute lymphocytic leukemia differentiation by maintenance therapy. Leukemia. 2007;21:1915-20.
41. Schmiegelow K, Glomstein A, Kristinsson J, et al. Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO). J Pediatr Hematol Oncol. 1997;19:102-9.
42. Relling MV, Hancock ML, Boyett JM, et al. Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood. 1999;93:2817-23.
43. Relling MV, Dervieux T. Pharmacogenetics and cancer therapy. Nat Rev Cancer. 2001;1:99-108.
44. Harms DO, Gobel U, Spaar HJ, et al. Thioguanine offers no advantage over mercaptopurine in maintenance treatment of childhood ALL: results of the randomized trial COALL-92. Blood. 2003;102:2736-40.
45. Vora A, Mitchell CD, Lennard L, et al. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet. 2006;368:1339-48.
46. Stork LC, Matloub Y, Broxson E, et al. Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial. Blood. 2010;115:2740-8.
47. van der Werff ten Bosch, Suciu S, Thyss A, et al. Value of intravenous 6-mercaptopurine during continuation treatment in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma: final results of a randomized phase III trial (58881) of the EORTC CLG. Leukemia. 2005;19:721-6.
48. Toyoda Y, Manabe A, Tsuchida M, et al. Six months of maintenance chemotherapy after intensified treatment for acute lymphoblastic leukemia of childhood. J Clin Oncol. 2000;18:1508-16.
49. Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children. Childhood ALL Collaborative Group. Lancet. 1996;347:1783-8.
50. De MB, Suciu S, Bertrand Y, et al. Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood. 2010;116:36-44.
51. 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;99:825-33.
52. 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;369:123-31.
53. 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.
54. Hahn T, Wall D, Camitta B, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidence-based review. Biol Blood Marrow Transplant. 2006;12:1-30.
55. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008;111:1827-33.
56. Harned TM, Gaynon P. Relapsed acute lymphoblastic leukemia: current status and future opportunities. Curr Oncol Rep. 2008;10:453-8.
57. Nguyen K, Devidas M, Cheng SC, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia. 2008;22:2142-50.
58. Ko RH, Ji L, Barnette P, et al. Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium study. J Clin Oncol. 2010;