Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]

Skip to the navigation

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

General Information About Childhood Acute Lymphoblastic Leukemia (ALL)

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer, including ALL, has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

  • Primary care physicians.
  • Pediatric surgical subspecialists.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child life professionals.
  • Psychologists.

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] Because treatment of children with ALL entails complicated risk assignment and therapies and the need for intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support), evaluation and treatment are best coordinated by pediatric oncologists in cancer centers or hospitals with all of the necessary pediatric supportive care facilities. It is important that the clinical centers and the specialists directing the patient's care maintain contact with the referring physician in the community. Strong lines of communication optimize any urgent or interim care required when the child is at home.

Dramatic improvements in survival have been achieved in children and adolescents with cancer.[1,3,4] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1,3,4] For ALL, the 5-year survival rate has increased over the same time from 60% to approximately 90% for children younger than 15 years and from 28% to more than 75% for adolescents aged 15 to 19 years.[1,5] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Incidence and Epidemiology

ALL is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among children younger than 15 years.[3,4] ALL occurs at an annual rate of 35 to 40 cases per 1 million people in the United States.[3,4,6] There are approximately 2,900 children and adolescents younger than 20 years diagnosed with ALL each year in the United States.[6,7] Over the past 25 years, there has been a gradual increase in the incidence of ALL.[3,4,8]

A sharp peak in ALL incidence is observed among children aged 2 to 3 years (>90 cases per 1 million per year), with rates decreasing to fewer than 30 cases per 1 million by age 8 years.[3,4] The incidence of ALL among children aged 2 to 3 years is approximately fourfold greater than that for infants and is likewise fourfold to fivefold greater than that for children aged 10 years and older.[3,4]

The incidence of ALL appears to be highest in Hispanic children (43 cases per 1 million).[3,4,6] The incidence is substantially higher in white children than in black children, with a nearly threefold higher incidence of ALL from age 2 to 3 years in white children than in black children.[3,4,6]

Anatomy

Childhood ALL originates in the T- and B-lymphoblasts in the bone marrow (refer to Figure 1).

Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.
Figure 1. Blood cell development. Different blood and immune cell lineages, including T- and B-lymphocytes, differentiate from a common blood stem cell.

Marrow involvement of acute leukemia as seen by light microscopy is defined as follows:

  • M1: Fewer than 5% blast cells.
  • M2: 5% to 25% blast cells.
  • M3: Greater than 25% blast cells.

Most patients with acute leukemia present with an M3 marrow.

Risk Factors for Developing ALL

Few factors associated with an increased risk of ALL have been identified. The primary accepted risk factors for ALL include the following:

  • Prenatal exposure to x-rays.
  • Postnatal exposure to high doses of radiation (e.g., therapeutic radiation as previously used for conditions such as tinea capitis and thymus enlargement).
  • Genetic conditions that include the following:
    • Down syndrome.
    • Neurofibromatosis.[9]
    • Shwachman syndrome.[10,11]
    • Bloom syndrome.[12]
    • Ataxia telangiectasia.[13]
  • Inherited genetic polymorphisms.[14]
  • Carriers of a constitutional Robertsonian translocation that involves chromosomes 15 and 21 are specifically and highly predisposed to developing iAMP21 ALL.[15]

Down syndrome

Children with Down syndrome have an increased risk of developing both ALL and acute myeloid leukemia (AML),[16,17] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[16,17]

Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are ALL, and about 2% to 3% of childhood ALL cases occur in children with Down syndrome.[18,19,20] While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year),[21] ALL in children with Down syndrome has an age distribution similar to that of ALL in non–Down syndrome children, with a median age of 3 to 4 years.[18,19]

Patients with ALL and Down syndrome have a lower incidence of both favorable (t(12;21) and hyperdiploidy) and unfavorable (t(9;22) or t(4;11) and hypodiploidy) cytogenetic findings and a near absence of T-cell phenotype.[18,19,20,21,22] Approximately 50% to 60% of cases of ALL in children with Down syndrome have genomic alterations affecting CRLF2 that generally result in overexpression of this gene.[23,24,25]CRLF2 genomic alterations are observed at a much lower frequency (<10%) in children with B-precursor ALL who do not have Down syndrome.[25,26,27] It does not appear that genomic CRLF2 aberrations in patients with Down syndrome and ALL have prognostic relevance.[24] However, IKZF1 gene deletions, observed in up to 35% of patients with Down syndrome and ALL, have been associated with a significantly worse outcome in this group of patients.[24]

Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[23,24,28,29,30] a finding that is uncommon among younger children with ALL but that is observed in a subset of primarily older children and adolescents with high-risk B-precursor ALL.[31] Almost all Down syndrome ALL cases with JAK2 mutations also have CRLF2 genomic alterations.[23,24,25] Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL,[24,29] but more study is needed to address this issue and the prognostic significance of IKZF1 gene deletions.

Inherited genetic polymorphisms

Genome-wide association studies show that some germline (inherited) genetic polymorphisms are associated with the development of childhood ALL.[32,33] For example, the risk alleles of ARID5B are strongly associated with the development of hyperdiploid B-precursor ALL. ARID5B is a gene that encodes a transcriptional factor important in embryonic development, cell type–specific gene expression, and cell growth regulation.[34,35] Also, germline ETV6 variations have been associated with predisposition to childhood ALL.[36] Several studies, including a meta-analysis of 11 published papers, have indicated that a polymorphism of CEBPE, a transcription factor essential for neutrophil development, is also associated with an increased risk of developing ALL.[37]

In another genome-wide association study in the adolescent and young adult population, unique GATA3 polymorphisms were identified that strongly influence the susceptibility to leukemia in this population.[38]

Prenatal origin of childhood ALL

Development of ALL is in most cases a multi-step process, with more than one genomic alteration required for frank leukemia to develop. In at least some cases of childhood ALL, the initial genomic alteration appears to occur in utero. Evidence in support of this comes from the observation that the immunoglobulin or T-cell receptor antigen rearrangements that are unique to each patient's leukemia cells can be detected in blood samples obtained at birth.[39,40] Similarly, in ALL characterized by specific chromosomal abnormalities, some patients appear to have blood cells carrying at least one leukemic genomic abnormality at the time of birth, with additional cooperative genomic changes acquired postnatally.[39,40,41] Genomic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[39,42]

There is also evidence that some children who never develop ALL are born with very rare blood cells carrying a genomic alteration associated with ALL. For example, in one study, 1% of neonatal blood spots (Guthrie cards) tested positive for the ETV6-RUNX1 translocation, far exceeding the number of cases of ETV6-RUNX1 ALL in children.[43] Other reports confirm [44] or do not confirm [45,46] this finding, and methodological issues related to fluorescence in situ hybridization testing complicate interpretation of the initial 1% estimate.[47] Nonetheless, if confirmed, it would support the hypothesis that additional postnatal genomic changes are needed for the development of this type of ALL and that in most cases in which a leukemia-associated alteration is present at birth, the additional leukemogenic genomic changes do not occur and no leukemia develops.

Clinical Presentation

The typical and atypical symptoms and clinical findings of childhood ALL have been published.[48,49,50]

Diagnosis

The diagnostic evaluation needed to definitively diagnose childhood ALL has been published.[48,49,50,51]

Overall Outcome for ALL

Among children with ALL, more than 95% attain remission, and approximately 80% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors.[52,53,54,55,56,57]

Despite the treatment advances noted in childhood ALL, numerous important biologic and therapeutic questions remain to be answered before the goal of curing every child with ALL with the least associated toxicity can be achieved. The systematic investigation of these issues requires large clinical trials, and the opportunity to participate in these trials is offered to most patients/families.

Clinical trials for children and adolescents with ALL are generally designed to compare therapy that is currently accepted as standard with investigational regimens that seek to improve cure rates and/or decrease toxicity. In certain trials in which the cure rate for the patient group is very high, therapy reduction questions may be asked. Much of the progress made in identifying curative therapies for childhood ALL and other childhood cancers has been achieved through investigator-driven discovery and tested in carefully randomized, controlled, multi-institutional clinical trials. Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References:

  1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
  2. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004.
  3. Childhood cancer. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. Bethesda, Md: National Cancer Institute, 2013, Section 28. Also available online. Last accessed March 16, 2016.
  4. Childhood cancer by the ICCC. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. Bethesda, Md: National Cancer Institute, 2013, Section 29. Also available online. Last accessed March 03, 2016.
  5. 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 30 (14): 1663-9, 2012.
  6. Smith MA, Ries LA, Gurney JG, et al.: Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, pp 17-34. Also available online. Last accessed January 27, 2016.
  7. Dores GM, Devesa SS, Curtis RE, et al.: Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood 119 (1): 34-43, 2012.
  8. Shah A, Coleman MP: Increasing incidence of childhood leukaemia: a controversy re-examined. Br J Cancer 97 (7): 1009-12, 2007.
  9. Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer 70 (5): 969-72, 1994.
  10. Strevens MJ, Lilleyman JS, Williams RB: Shwachman's syndrome and acute lymphoblastic leukaemia. Br Med J 2 (6129): 18, 1978.
  11. Woods WG, Roloff JS, Lukens JN, et al.: The occurrence of leukemia in patients with the Shwachman syndrome. J Pediatr 99 (3): 425-8, 1981.
  12. Passarge E: Bloom's syndrome: the German experience. Ann Genet 34 (3-4): 179-97, 1991.
  13. Taylor AM, Metcalfe JA, Thick J, et al.: Leukemia and lymphoma in ataxia telangiectasia. Blood 87 (2): 423-38, 1996.
  14. Moriyama T, Relling MV, Yang JJ: Inherited genetic variation in childhood acute lymphoblastic leukemia. Blood 125 (26): 3988-95, 2015.
  15. Li Y, Schwab C, Ryan SL, et al.: Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia. Nature 508 (7494): 98-102, 2014.
  16. Hasle H: Pattern of malignant disorders in individuals with Down's syndrome. Lancet Oncol 2 (7): 429-36, 2001.
  17. Whitlock JA: Down syndrome and acute lymphoblastic leukaemia. Br J Haematol 135 (5): 595-602, 2006.
  18. Zeller B, Gustafsson G, Forestier E, et al.: Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol 128 (6): 797-804, 2005.
  19. Arico M, Ziino O, Valsecchi MG, et al.: Acute lymphoblastic leukemia and Down syndrome: presenting features and treatment outcome in the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Cancer 113 (3): 515-21, 2008.
  20. Maloney KW, Carroll WL, Carroll AJ, et al.: Down syndrome childhood acute lymphoblastic leukemia has a unique spectrum of sentinel cytogenetic lesions that influences treatment outcome: a report from the Children's Oncology Group. Blood 116 (7): 1045-50, 2010.
  21. Chessells JM, Harrison G, Richards SM, et al.: Down's syndrome and acute lymphoblastic leukaemia: clinical features and response to treatment. Arch Dis Child 85 (4): 321-5, 2001.
  22. 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 123 (1): 70-7, 2014.
  23. Hertzberg L, Vendramini E, Ganmore I, et al.: Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group. Blood 115 (5): 1006-17, 2010.
  24. Buitenkamp TD, Pieters R, Gallimore NE, et al.: Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia 26 (10): 2204-11, 2012.
  25. Mullighan CG, Collins-Underwood JR, Phillips LA, et al.: Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet 41 (11): 1243-6, 2009.
  26. 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 115 (26): 5312-21, 2010.
  27. Schwab CJ, Chilton L, Morrison H, et al.: Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: association with cytogenetics and clinical features. Haematologica 98 (7): 1081-8, 2013.
  28. Bercovich D, Ganmore I, Scott LM, et al.: Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet 372 (9648): 1484-92, 2008.
  29. Gaikwad A, Rye CL, Devidas M, et al.: Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia. Br J Haematol 144 (6): 930-2, 2009.
  30. Kearney L, Gonzalez De Castro D, Yeung J, et al.: Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. Blood 113 (3): 646-8, 2009.
  31. Mullighan CG, Zhang J, Harvey RC, et al.: JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 106 (23): 9414-8, 2009.
  32. de Jonge R, Tissing WJ, Hooijberg JH, et al.: Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood 113 (10): 2284-9, 2009.
  33. Migliorini G, Fiege B, Hosking FJ, et al.: Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype. Blood 122 (19): 3298-307, 2013.
  34. Papaemmanuil E, Hosking FJ, Vijayakrishnan J, et al.: Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet 41 (9): 1006-10, 2009.
  35. Treviño LR, Yang W, French D, et al.: Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet 41 (9): 1001-5, 2009.
  36. Moriyama T, Metzger ML, Wu G, et al.: Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study. Lancet Oncol 16 (16): 1659-66, 2015.
  37. Wang C, Chen J, Sun H, et al.: CEBPE polymorphism confers an increased risk of childhood acute lymphoblastic leukemia: a meta-analysis of 11 case-control studies with 5,639 cases and 10,036 controls. Ann Hematol 94 (2): 181-5, 2015.
  38. Perez-Andreu V, Roberts KG, Xu H, et al.: A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults. Blood 125 (4): 680-6, 2015.
  39. Greaves MF, Wiemels J: Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 3 (9): 639-49, 2003.
  40. Taub JW, Konrad MA, Ge Y, et al.: High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia. Blood 99 (8): 2992-6, 2002.
  41. Bateman CM, Colman SM, Chaplin T, et al.: Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia. Blood 115 (17): 3553-8, 2010.
  42. Greaves MF, Maia AT, Wiemels JL, et al.: Leukemia in twins: lessons in natural history. Blood 102 (7): 2321-33, 2003.
  43. Mori H, Colman SM, Xiao Z, et al.: Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci U S A 99 (12): 8242-7, 2002.
  44. Zuna J, Madzo J, Krejci O, et al.: ETV6/RUNX1 (TEL/AML1) is a frequent prenatal first hit in childhood leukemia. Blood 117 (1): 368-9; author reply 370-1, 2011.
  45. Lausten-Thomsen U, Madsen HO, Vestergaard TR, et al.: Prevalence of t(12;21)[ETV6-RUNX1]-positive cells in healthy neonates. Blood 117 (1): 186-9, 2011.
  46. Olsen M, Hjalgrim H, Melbye M, et al.: RT-PCR screening for ETV6-RUNX1-positive clones in cord blood from newborns in the Danish National Birth Cohort. J Pediatr Hematol Oncol 34 (4): 301-3, 2012.
  47. Kusk MS, Lausten-Thomsen U, Andersen MK, et al.: False positivity of ETV6/RUNX1 detected by FISH in healthy newborns and adults. Pediatr Blood Cancer 61 (9): 1704-6, 2014.
  48. Rabin KR, Gramatges MM, Margolin JF, et al.: Acute lymphoblastic leukemia. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2015, pp 463-97.
  49. Chessells JM; haemostasis and thrombosis task force, British committee for standards in haematology: Pitfalls in the diagnosis of childhood leukaemia. Br J Haematol 114 (3): 506-11, 2001.
  50. Onciu M: Acute lymphoblastic leukemia. Hematol Oncol Clin North Am 23 (4): 655-74, 2009.
  51. Heerema-McKenney A, Cleary M, Arber D: Pathology and molecular diagnosis of leukemias and lymphomas. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2015, pp 113-30.
  52. Möricke 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 111 (9): 4477-89, 2008.
  53. 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 109 (3): 896-904, 2007.
  54. Pui CH, Campana D, Pei D, et al.: Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 360 (26): 2730-41, 2009.
  55. 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 10 (10): 957-66, 2009.
  56. Salzer WL, Devidas M, Carroll WL, et al.: Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984-2001: a report from the children's oncology group. Leukemia 24 (2): 355-70, 2010.
  57. Gaynon PS, Angiolillo AL, Carroll WL, et al.: Long-term results of the children's cancer group studies for childhood acute lymphoblastic leukemia 1983-2002: a Children's Oncology Group Report. Leukemia 24 (2): 285-97, 2010.

Risk-Based Treatment Assignment

Introduction to Risk-Based Treatment

Children with acute lymphoblastic leukemia (ALL) are usually treated according to risk groups defined by both clinical and laboratory features. The intensity of treatment required for favorable outcome varies substantially among subsets of children with ALL. Risk-based treatment assignment is utilized in children with ALL so that patients with favorable clinical and biological features who are likely to have a very good outcome with modest therapy can be spared more intensive and toxic treatment, while a more aggressive, and potentially more toxic, therapeutic approach can be provided for patients who have a lower probability of long-term survival.[1,2,3]

Certain ALL study groups, such as the Children's Oncology Group (COG), use a more or less intensive induction regimen based on a subset of pretreatment factors, while other groups give a similar induction regimen to all patients. Factors used by the COG to determine the intensity of induction include immunophenotype and the National Cancer Institute (NCI) risk group classification. The NCI risk group classification stratifies risk according to age and white blood cell (WBC) count:[1]

  • Standard risk—WBC count less than 50,000/µL and age 1 to younger than 10 years.
  • High risk—WBC count 50,000/µL or greater and/or age 10 years or older.

All study groups modify the intensity of postinduction therapy based on a variety of prognostic factors, including NCI risk group, immunophenotype, early response determinations, and cytogenetics.[3]

Risk-based treatment assignment requires the availability of prognostic factors that reliably predict outcome. For children with ALL, a number of factors have demonstrated prognostic value, some of which are described below.[4] The factors described are grouped into the following three categories:

  • Patient characteristics affecting prognosis.
  • Leukemic cell characteristics affecting prognosis.
  • Response to initial treatment affecting prognosis.

As in any discussion of prognostic factors, the relative order of significance and the interrelationship of the variables are often treatment dependent and require multivariate analysis to determine which factors operate independently as prognostic variables.[5,6] Because prognostic factors are treatment dependent, improvements in therapy may diminish or abrogate the significance of any of these presumed prognostic factors.

A subset of the prognostic and clinical factors discussed below is used for the initial stratification of children with ALL for treatment assignment. (Refer to the Prognostic (risk) groups under clinical evaluation section of this summary for brief descriptions of the prognostic groupings currently applied in ongoing clinical trials in the United States.)

(Refer to the Prognostic Factors After First Relapse of Childhood ALL section of this summary for information about important prognostic factors at relapse.)

Prognostic Factors Affecting Risk-Based Treatment

Patient characteristics affecting prognosis

Patient characteristics affecting prognosis include the following:

  1. Age at diagnosis.
  2. WBC count at diagnosis.
  3. Central nervous system (CNS) involvement at diagnosis.
  4. Testicular involvement at diagnosis.
  5. Down syndrome (trisomy 21).
  6. Gender.
  7. Race.
  8. Obesity at diagnosis.

Age at diagnosis

Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in different age groups.[7]

  1. Infants (younger than 1 year)

    Infants with ALL have a particularly high risk of treatment failure. Treatment failure is most common in the following groups:[8,9,10,11]; [12][Level of evidence: 2A]

    • Infants younger than 6 months (with an even poorer prognosis for those aged =90 days).
    • Infants with extremely high presenting leukocyte counts.
    • Infants with a poor response to a prednisone prophase.
    • Infants with an MLL gene rearrangement.

    Approximately 80% of infants with ALL have an MLL gene rearrangement.[10,13,14] The rate of MLL gene translocations is extremely high in infants younger than 6 months; from 6 months to 1 year, the incidence of MLL translocations decreases but remains higher than that observed in older children.[10,15] Black infants with ALL are significantly less likely to have MLL translocations than white infants.[15] Infants with leukemia and MLL translocations typically have very high WBC counts and an increased incidence of CNS involvement. Overall survival (OS) is poor, especially in infants younger than 6 months.[10,11] A gene expression profile analysis in infants with MLL-rearranged ALL revealed significant differences between patients younger than 90 days and older infants, suggesting distinctive age-related biological behaviors for MLL-translocation ALL that may relate to the significantly poorer outcome for the youngest infants.[16]

    Blasts from infants with MLL translocations are typically CD10 negative and express high levels of FLT3.[10,11,14,17] Conversely, infants whose leukemic cells show a germline MLL gene configuration frequently present with CD10-positive precursor-B immunophenotype. These infants have a significantly better outcome than do infants with ALL characterized by MLL translocations.[10,11,14]

  2. Young children (aged 1 to <10 years)

    Young children (aged 1 to <10 years) have a better disease-free survival than older children, adolescents, and infants.[1,7,18] The improved prognosis in young children is at least partly explained by the more frequent occurrence of favorable cytogenetic features in the leukemic blasts including hyperdiploidy with 51 or more chromosomes and/or favorable chromosome trisomies, or the ETV6-RUNX1 (t(12;21), also known as the TEL-AML1 translocation).[7,19,20]

  3. Adolescents and young adults (aged =10 years)

    In general, the outcome of patients aged 10 years and older is inferior to that of patients aged 1 to younger than 10 years. However, the outcome for older children, especially adolescents, has improved significantly over time.[21,22,23] Five-year survival rates for adolescents aged 15 to 19 years increased from 36% (1975–1984) to 72% (2003–2009).[24,25,26] Multiple retrospective studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[27,28,29] (Refer to the Postinduction Treatment for Specific ALL Subgroups section of this summary for more information about adolescents with ALL.)

WBC count at diagnosis

A WBC count of 50,000/µL is generally used as an operational cut point between better and poorer prognosis,[1] although the relationship between WBC count and prognosis is a continuous rather than a step function. Patients with B-precursor ALL and high WBC counts at diagnosis have an increased risk of treatment failure compared with patients with low initial WBC counts.[30]

The median WBC count at diagnosis is much higher for T-cell ALL (>50,000/µL) than for B-precursor ALL (<10,000/µL), and there is no consistent effect of WBC count at diagnosis on prognosis for T-cell ALL.[6,30,31,32,33,34,35,36,37] One factor that might explain the lack of prognostic effect for WBC count at diagnosis may be the very poor outcome observed for T-cell ALL with the early T-cell precursor phenotype, as patients with this subtype appear to have lower WBC count at diagnosis (median, <50,000/µL) than do other T-cell ALL patients.[38]

CNS involvement at diagnosis

The presence or absence of CNS leukemia at diagnosis has prognostic significance. Patients who have a nontraumatic diagnostic lumbar puncture may be placed into one of three categories according to the number of WBC/µL and the presence or absence of blasts on cytospin as follows:

  • CNS1: Cerebrospinal fluid (CSF) that is cytospin negative for blasts regardless of WBC count.
  • CNS2: CSF with fewer than 5 WBC/µL and cytospin positive for blasts.
  • CNS3 (CNS disease): CSF with 5 or more WBC/µL and cytospin positive for blasts.

Children with ALL who present with CNS disease (CNS3) at diagnosis are at a higher risk of treatment failure (both within the CNS and systemically) than are patients who are classified as CNS1 or CNS2.[39] Some studies have reported increased risk of CNS relapse and/or inferior event-free survival (EFS) in CNS2 patients, compared with CNS1 patients,[40,41] while others have not.[39,42,43,44]

A traumatic lumbar puncture (=10 erythrocytes/µL) that includes blasts at diagnosis has also been associated with increased risk of CNS relapse and overall poorer outcome in some studies,[39,43,45] but not others.[40,42] Patients with CNS2, CNS3, or traumatic lumbar puncture have a higher frequency of unfavorable prognostic characteristics than do those with CNS1, including significantly higher WBC counts at diagnosis, older age at diagnosis, an increased frequency of the T-cell ALL phenotype, and MLL gene rearrangements.[39,42,43]

Some clinical trial groups have approached CNS2 and traumatic lumbar puncture by utilizing more intensive therapy, primarily additional doses of intrathecal therapy during induction.[39,46]; [42][Level of evidence: 2A] Other groups have not altered therapy based on CNS2 status.[40,47]

To determine whether a patient with a traumatic lumbar puncture (with blasts) should be treated as CNS3, the COG uses an algorithm relating the WBC and red blood cell counts in the spinal fluid and the peripheral blood.[48]

Testicular involvement at diagnosis

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males, most commonly in T-cell ALL.

In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, it does not appear that testicular involvement at diagnosis has prognostic significance.[49,50] For example, the European Organization for Research and Treatment of Cancer (EORTC [EORTC-58881]) reported no adverse prognostic significance for overt testicular involvement at diagnosis.[50]

The role of radiation therapy for testicular involvement is unclear. A study from St. Jude Children's Research Hospital (SJCRH) suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[49] The COG has also adopted this strategy for boys with testicular involvement that resolves completely by the end of induction therapy. The COG considers patients with testicular involvement to be high risk regardless of other presenting features, but most other large clinical trial groups in the United States and Europe do not consider testicular disease to be a high-risk feature.

Down syndrome (trisomy 21)

Outcome in children with Down syndrome and ALL has generally been reported as somewhat inferior to outcomes observed in children who do not have Down syndrome.[51,52,53,54,55]

The lower EFS and OS of children with Down syndrome appear to be related to higher rates of treatment-related mortality and the lower frequency of favorable biological features such as ETV6-RUNX1 or trisomies of chromosomes 4 and 10.[51,52,53,54,56,57] In a report from the COG, among B-precursor ALL patients who lacked MLL translocations, BCR-ABL1, ETV6-RUNX1, or trisomies of chromosomes 4 and 10, the EFS and OS were similar in children with and without Down syndrome.[56] In a large retrospective study of patients with Down syndrome and ALL (N = 653), age younger than 6 years, WBC count of less than 10,000/µL, and the presence of the ETV6-RUNX1 fusion (observed in 8% of patients) were independent predictors of favorable EFS. Failure to achieve remission and treatment-related mortality are also higher in patients with Down syndrome.[57] Certain genomic abnormalities, such as IKZF1 deletions, CRLF2 aberrations, and JAK mutations are seen more frequently in ALL arising in children with Down syndrome than in those without Down syndrome.[58,59,60,61,62] In one study of Down syndrome children with ALL, the presence of IKZF1 deletions (but not CRLF2 aberrations or JAK mutations) was associated with an inferior prognosis.[62]

Gender

In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[63,64,65] One reason for the better prognosis for girls is the occurrence of testicular relapses among boys, but boys also appear to be at increased risk of bone marrow and CNS relapse for reasons that are not well understood.[63,64,65] While some reports describe outcomes for boys as closely approaching those of girls,[46,66] larger clinical trial experiences and national data continue to show somewhat lower survival rates for boys.[24,25,67]

Race

Survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL.[68,69] Asian children with ALL fare slightly better than white children.[69]

The reason for better outcomes in white and Asian children than in black and Hispanic children is at least partially explained by the different spectrum of ALL subtypes. For example, black children have a higher relative incidence of T-cell ALL and lower rates of favorable genetic subtypes of precursor B-cell ALL. Differences in outcome may also be related to treatment adherence, as illustrated by two studies of adherence to oral 6-mercaptopurine in maintenance therapy. In the first study, there was an increased risk of relapse in Hispanic children compared with non-Hispanic white children, depending on the level of adherence, even when adjusting for other known variables. However, at adherence rates of 90% or more, Hispanic children continued to demonstrate increased rates of relapse.[70] Ancestry-related genomic variations may also contribute to racial/ethnic disparities in both the incidence and outcome of ALL.[71] For example, the differential presence of specific host polymorphisms in different racial/ethnic groups may contribute to outcome disparities, as illustrated by the occurrence of single nucleotide polymorphisms in the ARID5B gene that occur more frequently among Hispanics and are linked to both ALL susceptibility and to relapse hazard.[72] In the second study, adherence rates were significantly lower in Asian American and African American patients than in non-Hispanic white patients. A greater percentage of patients in these ethnic groups had adherence rates of less than 90%, which was associated with a 3.9-fold increased risk of relapse.[73]

Weight at diagnosis and during treatment

Studies of the impact of obesity on the outcome of ALL have had variable results. In most of these studies, obesity is defined as weight above the 95th percentile for age and height. Three studies have not demonstrated an independent effect of obesity on EFS.[74][Level of evidence: 2Dii]; [75,76][Level of evidence: 3iiDi] Two studies have shown obesity to be an independent prognostic factor only in patients older than 10 years or in patients with intermediate-risk or high-risk disease.[77,78][Level of evidence: 3iiDi] In a retrospective study of patients treated at a single institution, obesity at diagnosis was linked to an increased risk of having minimal residual disease (MRD) at the end of induction and an inferior EFS.[79][Level of evidence: 3iiDi]

The COG reported on the impact of obesity on outcome in 2,008 children, 14% of whom were obese, who were enrolled on a high-risk ALL trial (CCG-1961 [NCT00002812]).[80][Level of evidence: 2Di] Obesity was found to be an independent variable for inferior outcome compared with nonobese patients (5-year EFS, 64% vs. 74%; P = .002.) However, obese patients at diagnosis, who then normalized their weight during the premaintenance period of treatment had outcomes similar to patients with normal weight at diagnosis.

In a study of 762 pediatric patients with ALL (aged 2–17 years), the Dutch Childhood Oncology Group found that those who were underweight at diagnosis (8% of the population) had an almost twofold higher risk of relapse compared with nonunderweight patients (after adjusting for risk group and age), although this did not result in a difference in EFS or OS. Patients with loss of body mass index during the first 32 weeks of treatment had similar rates of relapse as other patients, but had significantly worse OS, primarily because of poorer salvage rates after relapse.[81]

Leukemic cell characteristics affecting prognosis

Leukemic cell characteristics affecting prognosis include the following:

  1. Morphology.
  2. Immunophenotype.
  3. Cytogenetics/genomic alterations.

Morphology

In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology.[82] However, because of the lack of independent prognostic significance and the subjective nature of this classification system, it is no longer used.

Most cases of ALL that show L3 morphology express surface immunoglobulin (Ig) and have a C-MYC gene translocation identical to that seen in Burkitt lymphoma (i.e., t(8;14)). Patients with this specific rare form of leukemia (mature B-cell or Burkitt leukemia) should be treated according to protocols for Burkitt lymphoma. (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information about the treatment of B-cell ALL and Burkitt lymphoma.)

Immunophenotype

The World Health Organization (WHO) classifies ALL as either:[83]

  • B lymphoblastic leukemia.
  • T lymphoblastic leukemia.

Either B or T lymphoblastic leukemia can coexpress myeloid antigens. These cases need to be distinguished from leukemia of ambiguous lineage.

  1. Precursor B-cell ALL (WHO B lymphoblastic leukemia)

    Before 2008, the WHO classified B lymphoblastic leukemia as precursor-B lymphoblastic leukemia, and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL. Mature B-cell ALL is now termed Burkitt leukemia and requires different treatment than has been given for precursor B-cell ALL. The older terminology will continue to be used throughout this summary.

    Precursor B-cell ALL, defined by the expression of cytoplasmic CD79a, CD19, HLA-DR, and other B cell-associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of precursor B-cell ALL cases express the CD10 surface antigen (formerly known as common ALL antigen [cALLa]). Absence of CD10 is associated with MLL translocations, particularly t(4;11), and a poor outcome.[10,84] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of an MLL gene rearrangement.[85]

    The major subtypes of precursor B-cell ALL are as follows:

    • Common precursor B-cell ALL (CD10 positive and no surface or cytoplasmic Ig)

      Approximately three-quarters of patients with precursor B-cell ALL have the common precursor B-cell immunophenotype and have the best prognosis. Patients with favorable cytogenetics almost always show a common precursor B-cell immunophenotype.

    • Pro-B ALL (CD10 negative and no surface or cytoplasmic Ig)

      Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common immunophenotype seen in infants and is often associated with MLL gene rearrangements.

    • Pre-B ALL (presence of cytoplasmic Ig)

      The leukemic cells of patients with pre-B ALL contain cytoplasmic Ig, and 25% of patients with pre-B ALL have the t(1;19) translocation with TCF3-PBX1 (also known as E2A-PBX1) fusion (see below).[86,87]

      Approximately 3% of patients have transitional pre-B ALL with expression of surface Ig heavy chain without expression of light chain, C-MYC gene involvement, or L3 morphology. Patients with this phenotype respond well to therapy used for precursor B-cell ALL.[88]

      Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with FAB L3 morphology and a translocation involving the C-MYC gene), also called Burkitt leukemia. The treatment for mature B-cell ALL is based on therapy for non-Hodgkin lymphoma and is completely different from that for precursor B-cell ALL. Rare cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with C-MYC gene translocations should also be treated as mature B-cell leukemia.[88] (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information about the treatment of children with B-cell ALL and Burkitt lymphoma.)

  2. T-cell ALL

    T-cell ALL is defined by expression of the T cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-cell ALL is frequently associated with a constellation of clinical features, including the following:[18,31,66]

    • Male gender.
    • Older age.
    • Leukocytosis.
    • Mediastinal mass.

    With appropriately intensive therapy, children with T-cell ALL have an outcome approaching that of children with B-lineage ALL.[18,31,34,35,66]

    There are few commonly accepted prognostic factors for patients with T-cell ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-cell ALL.[6,31,32,33,34,35,36,37] The presence or absence of a mediastinal mass at diagnosis has no prognostic significance. In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance.[89]

    Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy) are rare in T-cell ALL.[90,91]

    Multiple chromosomal translocations have been identified in T-cell ALL, with many genes encoding for transcription factors (e.g., TAL1, LMO1 and LMO2, LYL1, TLX1/HOX11, and TLX3/HOX11L2) fusing to one of the T-cell receptor loci and resulting in aberrant expression of these transcription factors in leukemia cells.[90,92,93,94,95,96] These translocations are often not apparent by examining a standard karyotype, but are identified using more sensitive screening techniques, such as fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR).[90] High expression of TLX1/HOX11 resulting from translocations involving this gene occurs in 5% to 10% of pediatric T-cell ALL cases and is associated with more favorable outcome in both adults and children with T-cell ALL.[92,93,94,96] Overexpression of TLX3/HOX11L2 resulting from the cryptic t(5;14)(q35;q32) translocation occurs in approximately 20% of pediatric T-cell ALL cases and appears to be associated with increased risk of treatment failure,[94] although not in all studies.

    Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene mutations in T-cell ALL.[97]NOTCH1-activating gene mutations occur in approximately 50% to 60% of T-cell ALL cases, and FBXW7-inactivating gene mutations occur in approximately 15% of cases, with the result that approximately 60% of cases have Notch pathway activation by mutations in at least one of these genes.[98] The prognostic significance of Notch pathway activation by NOTCH1 and FBXW7 mutations in pediatric T-cell ALL is not clear, as some studies have shown a favorable prognosis for mutated cases,[99,100,101,102] while other studies have not shown prognostic significance for the presence of NOTCH1 and/or FBXW7 mutations.[98,103,104,105]

    A NUP214–ABL1 fusion has been noted in 4% to 6% of T-cell ALL cases and is observed in both adults and children with a male predominance.[106,107,108] The fusion is cytogenetically cryptic and is seen in FISH on amplified episomes or more rarely, as a small homogeneous staining region.[108] T-cell ALL may also uncommonly show ABL1 fusion proteins with other gene partners (e.g., ETV6, BCR, and EML1).[108]ABL tyrosine kinase inhibitors, such as imatinib or dasatinib, may have therapeutic benefit in this T-cell ALL subtype,[106,107,109] although clinical experience with this strategy is very limited.[110,111,112]

    Early T-cell precursor ALL

    Early T-cell precursor ALL, a distinct subset of childhood T-cell ALL, was initially defined by identifying T-cell ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors.[38] The subset of T-cell ALL cases, identified by these analyses represented 13% of all cases and they were characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and coexpression of stem cell or myeloid markers). Detailed molecular characterization of early T-cell precursor ALL showed this entity to be highly heterogeneous at the molecular level, with no single gene affected by mutation or copy number alteration in more than one-third of cases.[113] Compared with other T-ALL cases, the early T-cell precursor group had a lower rate of NOTCH1 mutations and significantly higher frequencies of alterations in genes regulating cytokine receptors and Ras signaling, hematopoietic development, and histone modification. The transcriptional profile of early T-cell precursor ALL shows similarities to that of normal hematopoietic stem cells and myeloid leukemia stem cells.[113] Initial reports describing early T-cell precursor ALL suggested that this subset has a poorer prognosis than other cases of T-cell ALL.[