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

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General Information About Childhood Acute Lymphoblastic Leukemia (ALL)

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer, including ALL, has been slowly increasing since 1975.[1] Dramatic improvements in survival have been achieved in children and adolescents with cancer.[1,2,3] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1,2,3] 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.[4] Childhood and adolescent cancer survivors require close monitoring 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.)


ALL is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among children younger than 15 years.[2,3] In the United States, ALL occurs at an annual rate of approximately 41 cases per 1 million people aged 0 to 14 years and approximately 17 cases per 1 million people aged 15 to 19 years.[4] There are approximately 3,100 children and adolescents younger than 20 years diagnosed with ALL each year in the United States.[5] Since 1975, there has been a gradual increase in the incidence of ALL.[4,6]

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.[2,3] 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.[2,3]

The incidence of ALL appears to be highest in Hispanic children (43 cases per 1 million).[2,3,7,8] 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.[2,3,7]


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.

Almost all patients with ALL 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 and associated genes (when relevant) 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).
  • Previous treatment with chemotherapy.
  • Genetic conditions that include the following:
    • Down syndrome. (Refer to the Down syndrome section of this summary for more information.)
    • Neurofibromatosis (NF1).[9]
    • Bloom syndrome (BLM).[10]
    • Fanconi anemia (multiple genes; ALL is observed much less frequently than acute myeloid leukemia [AML]).[11]
    • Ataxia telangiectasia (ATM).[12]
    • Li-Fraumeni syndrome (TP53).[13,14,15]
    • Constitutional mismatch repair deficiency (biallelic mutation of MLH1, MSH2, MSH6, and PMS2).[16,17]
  • Low- and high-penetrance inherited genetic variants.[18] (Refer to the Low- and high-penetrance inherited genetic variants section of this summary for more information.)
  • Carriers of a constitutional Robertsonian translocation that involves chromosomes 15 and 21 are specifically and highly predisposed to developing iAMP21 ALL.[19]

Down syndrome

Children with Down syndrome have an increased risk of developing both ALL and AML,[20,21] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[20,21]

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.[22,23,24] While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year),[25] 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.[22,23]

Patients with ALL and Down syndrome have a lower incidence of both favorable (t(12;21)(p13;q22)/ETV6-RUNX1 [TEL-AML1]) and hyperdiploidy [51-65 chromosomes]) and unfavorable (t(9;22)(q34;q11.2)) or t(4;11)(q21;q23) and hypodiploidy [<44 chromosomes]) cytogenetic findings and a near absence of T-cell phenotype.[22,23,24,25,26]

Approximately 50% to 60% of cases of ALL in children with Down syndrome have genomic alterations affecting CRLF2 that generally result in overexpression of the protein produced by this gene, which dimerizes with the interleukin-7 receptor alpha to form the receptor for the cytokine thymic stromal lymphopoietin.[27,28,29]CRLF2 genomic alterations are observed at a much lower frequency (<10%) in children with precursor B-cell ALL who do not have Down syndrome.[29,30,31] Based on the relatively small number of published series, it does not appear that genomic CRLF2 aberrations in patients with Down syndrome and ALL have prognostic relevance.[26,28] 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.[28,32]

Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[27,28,33,34,35] 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 precursor B-cell ALL.[36] Almost all Down syndrome ALL cases with JAK2 mutations also have CRLF2 genomic alterations.[27,28,29] Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL,[28,34] but more study is needed to address this issue, as well as the prognostic significance of CRLF2 alterations and IKZF1 gene deletions in this patient population.

Low- and high-penetrance inherited genetic variants

Genetic predisposition to ALL can be divided into the following several broad categories:

  • Association with genetic syndromes. Increased risk can be associated with the genetic syndromes listed above in which ALL is observed, although it is not the primary manifestation of the condition.
  • Common alleles. Another category for genetic predisposition includes common alleles with relatively small effect sizes that are identified by genome-wide association studies. Genome-wide association studies have identified a number of germline (inherited) genetic polymorphisms that are associated with the development of childhood ALL.[18] For example, the risk alleles of ARID5B are associated with the development of hyperdiploid (51-65 chromosomes) precursor B-cell ALL. ARID5B is a gene that encodes a transcriptional factor important in embryonic development, cell type-specific gene expression, and cell growth regulation.[37,38] Other genes with polymorphisms associated with increased risk of ALL include GATA3,[39]IKZF1,[37,38,40]CDKN2A,[41]CDKN2B,[40,41]CEBPE,[37]PIP4K2A,[39,42] and TP63.[43]
  • Rare germline variants with high penetrance. A germline variant in PAX5 that substitutes serine for glycine at amino acid 183 and that reduces PAX5 activity has been identified in several families that experienced multiple cases of ALL.[44,45] Similarly, several germline ETV6 variants that lead to loss of ETV6 function have been identified in kindreds affected by both thrombocytopenia and ALL.[46,47,48] Sequencing of ETV6 in remission (i.e., germline) specimens identified variants that were potentially related to ALL in approximately 1% of children with ALL that were evaluated.[46] This suggests a previously unrecognized contribution to ALL risk that will need to be assessed in future studies.[46,47,48]

Prenatal origin of childhood ALL

Development of ALL is in most cases a multistep 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 to support 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.[49,50] Similarly, in ALL characterized by specific chromosomal abnormalities, some patients have blood cells that carry at least one leukemic genomic abnormality at the time of birth, with additional cooperative genomic changes acquired postnatally.[49,50,51] Genomic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[49,52]

Evidence also exists 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.[53] Other reports confirm [54] or do not confirm [55,56] this finding, and methodological issues related to fluorescence in situ hybridization testing complicate interpretation of the initial 1% estimate.[57]

Clinical Presentation

The typical and atypical symptoms and clinical findings of childhood ALL have been published.[58,59,60]


The diagnostic evaluation needed to definitively diagnose childhood ALL has been published.[58,59,60,61]

The 2016 revision to the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for acute lymphoid leukemias:[62]

B-lymphoblastic leukemia/lymphoma

  • B-lymphoblastic leukemia/lymphoma, not otherwise specified (NOS).
  • B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities.
  • B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2); BCR-ABL1.
  • B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A rearranged.
  • B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1.
  • B-lymphoblastic leukemia/lymphoma with hyperdiploidy.
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy.
  • B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3); IL3-IGH.
  • B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1.
  • Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1-like.
  • Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21.

T-lymphoblastic leukemia/lymphoma

  • Provisional entity: Early T-cell precursor lymphoblastic leukemia.

Key clinical and biological characteristics, as well as the prognostic significance for these entities, are discussed in the Cytogenetics/genomics alterations section of this summary.

Overall Outcome for ALL

Among children with ALL, approximately 98% attain remission, and approximately 85% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors, with over 90% surviving at 5 years.[63,64,65,66]

Despite the treatment advances 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 and 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.


  1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
  2. 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 January 27, 2017.
  3. 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 May 31, 2017.
  4. Howlader N, Noone AM, Krapcho M: SEER Cancer Statistics Review (CSR) 1975-2013. Bethesda, Md: National Cancer Institute, 2015. Available online. Last accessed January 27, 2017.
  5. Special Section: Childhood and Adolescent Cancers. In: American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014, pp 25. Available online. Last accessed January 27, 2017.
  6. Shah A, Coleman MP: Increasing incidence of childhood leukaemia: a controversy re-examined. Br J Cancer 97 (7): 1009-12, 2007.
  7. 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, 2017.
  8. Barrington-Trimis JL, Cockburn M, Metayer C, et al.: Rising rates of acute lymphoblastic leukemia in Hispanic children: trends in incidence from 1992 to 2011. Blood 125 (19): 3033-4, 2015.
  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. Passarge E: Bloom's syndrome: the German experience. Ann Genet 34 (3-4): 179-97, 1991.
  11. Alter BP: Cancer in Fanconi anemia, 1927-2001. Cancer 97 (2): 425-40, 2003.
  12. Taylor AM, Metcalfe JA, Thick J, et al.: Leukemia and lymphoma in ataxia telangiectasia. Blood 87 (2): 423-38, 1996.
  13. Holmfeldt L, Wei L, Diaz-Flores E, et al.: The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 45 (3): 242-52, 2013.
  14. Powell BC, Jiang L, Muzny DM, et al.: Identification of TP53 as an acute lymphocytic leukemia susceptibility gene through exome sequencing. Pediatr Blood Cancer 60 (6): E1-3, 2013.
  15. Hof J, Krentz S, van Schewick C, et al.: Mutations and deletions of the TP53 gene predict nonresponse to treatment and poor outcome in first relapse of childhood acute lymphoblastic leukemia. J Clin Oncol 29 (23): 3185-93, 2011.
  16. Ilencikova D, Sejnova D, Jindrova J, et al.: High-grade brain tumors in siblings with biallelic MSH6 mutations. Pediatr Blood Cancer 57 (6): 1067-70, 2011.
  17. Ripperger T, Schlegelberger B: Acute lymphoblastic leukemia and lymphoma in the context of constitutional mismatch repair deficiency syndrome. Eur J Med Genet 59 (3): 133-42, 2016.
  18. Moriyama T, Relling MV, Yang JJ: Inherited genetic variation in childhood acute lymphoblastic leukemia. Blood 125 (26): 3988-95, 2015.
  19. 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.
  20. Hasle H: Pattern of malignant disorders in individuals with Down's syndrome. Lancet Oncol 2 (7): 429-36, 2001.
  21. Whitlock JA: Down syndrome and acute lymphoblastic leukaemia. Br J Haematol 135 (5): 595-602, 2006.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. Hanada I, Terui K, Ikeda F, et al.: Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in Down syndrome-associated acute lymphoblastic leukemia in Japan. Genes Chromosomes Cancer 53 (11): 902-10, 2014.
  33. 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.
  34. 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.
  35. 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