Childhood Acute Lymphoblastic Leukemia

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of childhood acute lymphoblastic leukemia.

Childhood Acute Lymphoblastic Leukemia

General Information

This cancer treatment information summary provides an overview of the prognosis, diagnosis, classification, and treatment of childhood acute lymphoblastic leukemia (ALL).

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology specialists.

Cancer in children and adolescents is rare. 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 primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.¹ Since treatment of children with ALL entails many potential complications and requires intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support), this treatment is best coordinated by pediatric oncologists and performed in cancer centers or hospitals with all of the necessary pediatric supportive care facilities. Specialized care is essential for all children with ALL, including those for whom specific clinical and laboratory features might confer a favorable prognosis. It is equally 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.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. 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 Late Effects of Treatment for Childhood Cancer summary 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 23% of cancer diagnoses among children younger than 15 years. ALL occurs at an annual rate of approximately 30 to 40 per million.² There are approximately 2,400 children and adolescents younger than 20 years diagnosed with ALL each year in the United States,³ and there has been a gradual increase in the incidence of ALL in the past 25 years.⁴ A sharp peak in ALL incidence is observed among children aged 2 to 3 years (>80 per million per year), with rates decreasing to 20 per million for ages 8 to 10 years. The incidence of ALL among children aged 2 to 3 years is approximately fourfold greater than that for infants and is nearly tenfold greater than that for adolescents who are 19 years old. For unexplained reasons, the incidence of ALL is substantially higher for white children than for black children, with a nearly threefold higher incidence at 2 to 3 years for white children compared to black children.³ The incidence of ALL appears to be highest in Hispanic children (43 per million).^5,

There are few identified factors associated with an increased risk of ALL.³ The primary accepted nongenetic risk factors for ALL are prenatal exposure to x-rays and postnatal exposure to high doses of radiation (e.g., therapeutic radiation as previously used for conditions such as tinea capitis and thymus enlargement).⁶ Children with Down syndrome have increased risk for developing both ALL and acute myeloid leukemia (AML),⁷ with a cumulative risk for developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.⁸ Approximately one half to two thirds of the cases of acute leukemia in children with Down syndrome are ALL. Patients with ALL and Down syndrome have a lower incidence of both favorable and unfavorable cytogenetic findings and a lower incidence of T-cell phenotype.^8,^9,^10,¹¹ While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year),^8,¹¹ 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.^8,¹¹ Outcome for Down syndrome children with ALL has generally been reported as poorer than that of non–Down syndrome children.^9,^10,¹² The lower event-free survival and overall survival for children with Down syndrome appear to be related to higher rates of treatment-related mortality, especially during induction therapy,^10,¹¹ and to the absence of favorable biological features.¹¹ ⁹ Increased occurrence of ALL is also associated with certain genetic conditions, including neurofibromatosis,¹³ Shwachman syndrome,^14,¹⁵ Bloom's syndrome,¹⁶ and ataxia telangiectasia.^17,

Many cases of ALL that develop in children have a prenatal origin. 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.^18,¹⁹ Similarly, there are data to support that patients with ALL characterized by specific chromosomal abnormalities had blood cells carrying the abnormalities at the time of birth.^18,^19,²⁰ Genetic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.^21,

Among children with ALL, more than 95% attain remission and 75% to 85% survive free of leukemia recurrence at least 5 years from diagnosis with current treatments that incorporate systemic therapy (e.g., combination chemotherapy) and specific central nervous system preventive therapy (i.e., intrathecal chemotherapy with or without cranial radiation).^2,^3,^22,²³ ^24,^25,^26,^27,^28,^29,^30,

Despite the treatment advances noted in childhood ALL, numerous important biologic and therapeutic questions remain to be answered to achieve the goal of curing every child with ALL. 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 potentially better therapy with therapy that is currently accepted as standard. Much of the progress made in identifying curative therapies for childhood ALL and other childhood cancers has been achieved through investigator-driven discovery tested in carefully randomized, controlled clinical trials.^31,³² Information about ongoing clinical trials is available from the NCI Web site.

¹ Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.

² Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review, 1973-1996. Bethesda, Md: National Cancer Institute, 1999. Also available online. Last accessed April 19, 2007.

³ 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 April 19, 2007.

⁴ Xie Y, Davies SM, Xiang Y, et al.: Trends in leukemia incidence and survival in the United States (1973-1998). Cancer 97 (9): 2229-35, 2003.

⁵ McNeil DE, Coté TR, Clegg L, et al.: SEER update of incidence and trends in pediatric malignancies: acute lymphoblastic leukemia. Med Pediatr Oncol 39 (6): 554-7; discussion 552-3, 2002.

⁶ Ross JA, Davies SM, Potter JD, et al.: Epidemiology of childhood leukemia, with a focus on infants. Epidemiol Rev 16 (2): 243-72, 1994.

⁷ Hasle H: Pattern of malignant disorders in individuals with Down's syndrome. Lancet Oncol 2 (7): 429-36, 2001.

⁸ Hasle H, Clemmensen IH, Mikkelsen M: Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 355 (9199): 165-9, 2000.

⁹ Bassal M, La MK, Whitlock JA, et al.: Lymphoblast biology and outcome among children with Down syndrome and ALL treated on CCG-1952. Pediatr Blood Cancer 44 (1): 21-8, 2005.

¹⁰ 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.

¹¹ 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.

¹² Whitlock JA, Sather HN, Gaynon P, et al.: Clinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 106 (13): 4043-9, 2005.

¹³ Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer 70 (5): 969-72, 1994.

¹⁴ Strevens MJ, Lilleyman JS, Williams RB: Shwachman's syndrome and acute lymphoblastic leukaemia. Br Med J 2 (6129): 18, 1978.

¹⁵ 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.

¹⁶ Passarge E: Bloom's syndrome: the German experience. Ann Genet 34 (3-4): 179-97, 1991.

¹⁷ Taylor AM, Metcalfe JA, Thick J, et al.: Leukemia and lymphoma in ataxia telangiectasia. Blood 87 (2): 423-38, 1996.

¹⁸ Yagi T, Hibi S, Tabata Y, et al.: Detection of clonotypic IGH and TCR rearrangements in the neonatal blood spots of infants and children with B-cell precursor acute lymphoblastic leukemia. Blood 96 (1): 264-8, 2000.

¹⁹ 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.

²⁰ Greaves MF, Wiemels J: Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 3 (9): 639-49, 2003.

²¹ Greaves MF, Maia AT, Wiemels JL, et al.: Leukemia in twins: lessons in natural history. Blood 102 (7): 2321-33, 2003.

²² Pui CH, Relling MV, Downing JR: Acute lymphoblastic leukemia. N Engl J Med 350 (15): 1535-48, 2004.

²³ Pui CH, Campana D, Evans WE: Childhood acute lymphoblastic leukaemia--current status and future perspectives. Lancet Oncol 2 (10): 597-607, 2001.

²⁴ Gaynon PS, Trigg ME, Heerema NA, et al.: Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 14 (12): 2223-33, 2000.

²⁵ Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95 (11): 3310-22, 2000.

²⁶ Harms DO, Janka-Schaub GE: Co-operative study group for childhood acute lymphoblastic leukemia (COALL): long-term follow-up of trials 82, 85, 89 and 92. Leukemia 14 (12): 2234-9, 2000.

²⁷ Silverman LB, Gelber RD, Dalton VK, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 97 (5): 1211-8, 2001.

²⁸ Maloney KW, Shuster JJ, Murphy S, et al.: Long-term results of treatment studies for childhood acute lymphoblastic leukemia: Pediatric Oncology Group studies from 1986-1994. Leukemia 14 (12): 2276-85, 2000.

²⁹ Pui CH, Sandlund JT, Pei D, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 104 (9): 2690-6, 2004.

³⁰ Eden OB, Harrison G, Richards S, et al.: Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980-1997. Medical Research Council Childhood Leukaemia Working Party. Leukemia 14 (12): 2307-20, 2000.

³¹ Progress against childhood cancer: the Pediatric Oncology Group experience. Pediatrics 89 (4 Pt 1): 597-600, 1992.

³² Bleyer WA: The U.S. pediatric cancer clinical trials programmes: international implications and the way forward. Eur J Cancer 33 (9): 1439-47, 1997.

Cellular Classification and Prognostic Variables

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 for children with ALL so that those children who have a very good outcome with modest therapy can be spared more intensive and toxic treatment, while a more aggressive, thus more toxic, therapeutic approach can be provided for patients who have a lower probability of long-term survival.^1,^2,

Risk-based treatment assignment requires the availability of prognostic factors that reliably predict outcome. For children with ALL, a number of clinical and laboratory features have demonstrated prognostic value, some of which are described below. The factors described are grouped into the following categories: clinical and laboratory features at diagnosis; leukemic cell characteristics at diagnosis; and response to initial treatment. 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.^3,⁴ Because prognostic factors are treatment dependent, improvements in therapy may diminish or abrogate the significance of any of these presumed prognostic factors. For example, a report from the Children’s Cancer Group (CCG) showed that the adverse prognostic significance of slow early response disappears when these patients receive intensified postinduction chemotherapy.^5,

Outcome for Down syndrome children with ALL has generally been reported as poorer than that of non–Down syndrome children.^6,^7,⁸ The lower event-free survival (EFS) and overall survival (OS) for children with Down syndrome appear to be related to higher rates of treatment-related mortality, especially during induction therapy,^7,⁸ and to the absence of favorable biological features.^6,^8,

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear.⁹ The role of radiation therapy for testicular involvement is also unclear. A study from St. Jude Children's Research Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.⁹ The Children's Oncology Group has also adopted this strategy.

A subset of the prognostic factors discussed below is used for the initial stratification of children with ALL for treatment assignment, and at the end of this section there are brief descriptions of the prognostic groupings currently applied to clinical trials in the United States.

Clinical and Laboratory Features at Diagnosis

Age at Diagnosis
Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in different age groups.¹⁰ Young children (aged 1–9 years) have a better disease-free survival than older children, adolescents, or infants.^1,^11,¹² The improved prognosis in younger 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, or the t(12;21) (TEL-AML1 translocation).^10,¹³ Multiple retrospective studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.^14,^15,^16,

Infants with ALL have a particularly high risk of treatment failure. Treatment failure is most common in infants younger than 3 months and in those with a poor response to a prednisone prophase.^17,^18,^19,^20,^21,^22,²³ Infants with ALL can be divided into two subgroups on the basis of the presence or absence of MLL gene rearrangements.²⁴ Approximately 80% of infants with ALL have an MLL gene rearrangement.^24,²⁵ An MLL gene rearrangement is most common in infants younger than 6 months; from 6 months to 1 year, the incidence of MLL rearrangements decreases.²⁶ Infants with leukemia and MLL gene rearrangements have very high white blood cell (WBC) counts, increased incidence of central nervous system (CNS) involvement, and a poor outcome.²⁶ Blasts from infants with MLL gene rearrangements are typically CD10/cALLa negative and express high levels of FLT3.²⁷ Conversely, infants whose leukemia has a germline (nonrearranged) MLL gene frequently present with CD10/cALLa-positive precursor B-cell immunophenotype. These infants have a significantly better outcome than infants with ALL and MLL gene rearrangements.^28,²⁹

WBC Count at Diagnosis
Higher WBC counts at diagnosis represent an increased risk for treatment failure in patients with precursor B-cell ALL. 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.^12,³⁰ Elevated WBC count is often associated with other high-risk prognostic factors, including unfavorable chromosomal translocations such as t(4;11) and t(9;22) (see below).

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

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 at diagnosis (i.e., CNS3) are at a higher risk for treatment failure (both within the CNS and systemically) compared with patients not meeting the criteria for CNS disease at diagnosis. Patients with small numbers of leukemic cells in the CSF at diagnosis that are below those required for a diagnosis of CNS disease (i.e., CNS2) may be at increased risk of CNS relapse,³¹ though this observation may not apply to all treatment regimens.³² Any increased risk associated with CNS2 status on overall outcome can apparently be overcome by more intensive intrathecal therapy.^33,³⁴ A traumatic lumbar puncture (≥10 erythrocytes/ µl) that includes blasts at diagnosis appears to be associated with increased risk of CNS relapse and indicates an overall poorer outcome.^34,³⁵

Gender
In some studies, the prognosis for girls is slightly better than it is for boys with ALL.^36,^37,³⁸ One reason for the superior prognosis for girls is the occurrence of testicular relapses among boys, but boys also appear to be at increased risk for bone marrow and CNS relapse for reasons that are not well understood.^36,^37,³⁸ However, in clinical trials with high 5-year EFS rates (>80%), male gender is no longer an adverse risk factor.^39,^40,

Race
Survival rates for black and Hispanic children with ALL have been somewhat lower than the rates for white children with ALL,⁴¹ though this difference may be therapy-dependent because a report from St. Jude Children's Research Hospital found no difference in outcome by racial groups.⁴² Asian children with ALL fare slightly better than white children.^42,⁴³ The reason for the better outcome for white or Asian children compared to black and Hispanic children is not known, but it cannot be completely explained based on known prognostic factors.^43,

Leukemic Cell Characteristics

Morphology
In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology.⁴⁴ Because of the lack of independent prognostic significance and the subjective nature of this classification system, it is no longer used in the United States. Most cases of ALL that show L3 morphology express surface immunoglobulin and have a C-MYC gene translocation identical to the findings for Burkitt lymphoma (e.g., 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's Lymphoma Treatment for more information on the treatment of B-cell ALL and Burkitt lymphoma.)

Immunophenotype
Precursor B-cell ALL: Precursor B-cell ALL, defined by the expression of cytoplasmic CD79a, CD19, HLA-DR, and other B-cell–associated antigens, represents 80% to 85% of childhood ALL. Approximately 80% of precursor B-cell ALL express CD10 (cALLa). Absence of CD10 is associated with MLL gene rearrangements, particularly t(4;11), and a poor outcome.^17,⁴⁵ It is not clear if CD10-negativity has any independent prognostic significance in the absence of MLL gene rearrangements.^46,

Immunologic subtypes of precursor B-cell ALL: There are three major subtypes of precursor B-cell ALL:
Pro-B ALL-CD10 negative and no surface or cytoplasmic immunoglobulin.

Common precursorB-cell ALL-CD10 positive and no surface or cytoplasmic immunoglobulin.

Pre-B ALL-presence of cytoplasmic immunoglobulin.

Approximately three quarters of patients with precursor B-cell ALL have the common precursor B-cell immunophenotype and have the best prognosis. Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common immunophenotype seen in young infants and is often associated with a t(4;11) translocation. The leukemic cells of patients with pre-B ALL contain cytoplasmic immunoglobulin (cIg), an intermediate stage of B-cell differentiation, and 25% of patients with pre-B ALL have the t(1;19) translocation (see below).⁴⁷

Approximately 3% of patients have transitional pre-B ALL with expression of surface immunoglobulin heavy chain without light chain, C-MYC gene involvement, or L3 morphology. Patients with this phenotype respond well to therapy used for precursor B-cell ALL.^48,

Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with FAB L3 morphology and C-MYC gene translocation), also called Burkitt leukemia. This leukemia is a systemic manifestation of Burkitt and Burkitt-like non-Hodgkin lymphoma and its treatment 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 Burkitt leukemia.⁴⁹ (Refer to the PDQ summary on Childhood Non-Hodgkin's Lymphoma Treatment for more information on the treatment of children with B-cell ALL and Burkitt lymphoma.)

Precursor T-cell ALL: T-cell ALL is defined by the leukemic cell expression of the T-cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) and is frequently associated with a constellation of clinical features, including male gender, older age, leukocytosis, and mediastinal mass.^47,^50,⁵¹ With appropriately intensive therapy, children with T-cell ALL have an outcome similar to that for children with B-lineage ALL.^47,^50,⁵² Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy) are uncommon in T-cell ALL.⁵³ Neither the presence of a mediastinal mass at diagnosis nor the rate of resolution when receiving treatment have prognostic significance.^52,⁵⁴ NOTCH1 mutations occur in approximately 50% of cases of T-cell ALL, but the prognostic significance is unclear.^55,⁵⁶ In the context of ALL-BFM 2000 therapy, NOTCH1 mutations appear to be associated with a favorable prognosis.⁵⁶ Another report, however, observed an unfavorable prognosis for the presence of NOTCH1 mutations in a cohort of children and adults with T-cell ALL, with the negative prognostic effect being most pronounced for adults.^57,

Myeloid antigen expression: Up to one third of childhood ALL cases have leukemia cells that express myeloid-associated surface antigens. Myeloid-associated antigen expression appears to be associated with specific ALL subgroups, notably those with MLL gene rearrangements and those with the TEL-AML1 gene rearrangement.⁵⁸ No independent adverse prognostic significance exists for myeloid-surface antigen expression.^58,^59,

Cytogenetics
Chromosome number
Hyperdiploidy: Hyperdiploidy (>50 chromosomes per cell or a DNA index >1.16) is the presence of additional copies of whole chromosomes and occurs in 20% to 25% of cases of precursor B-cell ALL but very rarely in cases of T-cell ALL. Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. Interphase fluorescence in situ hybridization (iFISH) may detect hidden hyperdiploidy in cases either with a normal karyotype or where cytogenetic analysis was unevaluable.⁶⁰ Hyperdiploidy generally occurs in cases with favorable prognostic factors (aged 1–9 years and a low WBC count) and is itself associated with favorable prognosis.^11,^61,⁶² Outcome of children with hyperdiploidy, however, is heterogeneous and depends on age, sex, and specific trisomies.^10,⁶³ Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis⁶⁴ and accumulate methotrexate and high levels of its active polyglutamate metabolites,⁶⁵ which may explain the favorable outcome commonly observed for these cases. Certain patients with hyperdiploid ALL and more than 64 chromosomes may have a hypodiploid clone that has doubled. These cases may be interpretable based on the pattern of gains and losses of specific chromosomes. These patients have an unfavorable outcome.^66,

Trisomies: For the treatment approaches utilized by both the former Pediatric Oncology Group (POG) and the former CCG, extra copies of certain chromosomes appear to be specifically associated with favorable prognosis among hyperdiploid ALL cases. Patients with triple trisomies (4, 10, and 17) have been shown to have an improved outcome as demonstrated by both POG and CCG analyses in National Cancer Institute (NCI) standard but not high-risk ALL.^67,^68,^69,⁷⁰ A United Kingdom Medical Research Council study showed that trisomies 4 and 18 were independent favorable prognostic indicators among hyperdiploid ALL cases.^63,

Hypodiploidy: A significant trend is observed for a progressively worse outcome with a decreasing chromosome number. Cases with 24 to 28 chromosomes (near haploidy) have the worst outcome.^71,^72,

Chromosomal translocations
Recurring chromosomal translocations can be detected in a substantial number of cases of childhood ALL, and some of these translocations, as described below, have prognostic significance.

TEL-AML1 (t(12;21) cryptic translocation): Fusion of the TEL (ETV6) gene on chromosome 12 to the AML1 (CBFA2) gene on chromosome 21 can be detected in 20% to 25% of cases of B-precursor ALL but is rarely observed in T-cell ALL.⁷³ Children with the t(12;21) cryptic translocation resulting in the TEL-AML1 fusion are generally aged 2 to 9 years and have an excellent outcome.^10,^73,^74,^75,⁷⁶ Hispanic children with ALL have a lower incidence of t(12;21) compared with White children.⁷⁷ Reports indicate favorable EFS and OS for children with the TEL-AML1 fusion. However, this favorable prognosis may be modified by factors such as slow response to treatment, NCI risk category, and treatment regimen.^78,^79,^80,^81,⁸² In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not TEL-AML1, to be independent progostic factors.⁷⁸ Patients with TEL AML1 fusion seem to have a better outcome after relapse than do other patients; however, because of small numbers, the difference is not statistically significant.⁸³ Some relapses in patients with t(12;21) may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the TEL AML1 translocation).^84,

The Philadelphia chromosome t(9;22) is present in approximately 3% of children with ALL and confers an unfavorable prognosis, especially when it is associated with either a high WBC count or slow early response to initial therapy.^62,^85,^86,^87,^88,⁸⁹ Philadelphia-positive ALL is more common in older patients with precursor B-cell ALL and high WBC count.

Rearrangements involving the MLL (11q23) gene occur in approximately 8% of childhood ALL cases and are generally associated with an increased risk for treatment failure.⁶⁴ The t(4;11) is the most common translocation involving the MLL gene in children with ALL and occurs in approximately 2% of cases.⁹⁰ Patients with t(4;11) are usually infants with high WBC counts; they are more likely than other children with ALL to have CNS disease and to have a poor response to initial therapy.⁹¹ While both infants and adults with the t(4;11) are at high risk for treatment failure, children with the t(4;11) appear to have a better outcome than either infants or adults.^62,^91,⁹² Irrespective of the type of 11q23 abnormality, infants with leukemia cells that have 11q23 abnormalities have a worse treatment outcome than older patients whose leukemia cells have an 11q23 abnormality.^22,²⁶ Of interest, the t(11;19) occurs in approximately 1% of cases and occurs in both early B-lineage and T-cell ALL.⁹³ Outcome for infants with t(11;19) is poor, but outcome appears relatively favorable for children with T-cell ALL and the t(11;19) translocation.^22,^93,

The t(1;19) translocation occurs in 5% to 6% of childhood ALL, and involves fusion of the E2A gene on chromosome 19 to the PBX1 gene on chromosome 1.^94,⁹⁵ The t(1;19) may occur as either a balanced translocation or as an unbalanced translocation and is primarily associated with pre-B ALL (cytoplasmic immunoglobulin positive). Its presence was initially associated with inferior outcome in the context of antimetabolite-based therapy.⁹⁴ Studies have shown that the poorer prognosis associated with t(1;19) can be largely overcome by more intensive therapy.^96,^97, Some studies suggested that cases with a balanced translocation t(1;19) had a worse outcome than did those with an unbalanced translocation der(19)t(1;19),⁹⁵ but this finding has not been observed consistently.^98,

Other Chromosomal Abnormalities
Amplification of the AML1 gene occurs in fewer than 5% of ALL cases and may be associated with a poor outcome.^60,^99,

Early Response to Treatment

The rapidity with which leukemia cells are eliminated following onset of treatment is also associated with outcome. Because treatment response is influenced by the drug sensitivity of leukemic cells and host pharmacodynamics and pharmacogenomics,¹⁰⁰ this measure has strong prognostic significance. Various ways of evaluating the leukemia cell response to treatment have been utilized, including:

Day 7 and day 14 bone marrow responses:
Patients who have a rapid reduction in the leukemia cells to less than 5% in their bone marrow within 7 or 14 days following initiation of multiagent chemotherapy have a more favorable prognosis than do patients who have slower clearance of leukemia cells from the bone marrow.^62,^101,¹⁰² Morphologic response to treatment continues to be used in new COG ALL trials to stratify patients into prognostic categories for treatment assignment.

Peripheral blood response to steroid prophase:
Patients with a reduction in peripheral blast count to less than 1,000/ µL after a 7-day induction prophase with prednisone and 1 dose of intrathecal methotrexate (a good prednisone response) have a more favorable prognosis than do patients whose peripheral blast counts remain above 1,000/ µL (a poor prednisone response).^19,^86,¹⁰³ Treatment stratification for protocols of the German Berlin-Frankfurt-Munster clinical trials group is partially based on early response to the 7-day prednisone prophase (administered immediately prior to the initiation of multiagent remission induction). Patients whose blast counts are less than 1,000/ µL at diagnosis have a slightly better outcome compared with other patients with a good prednisone response.^104,

Peripheral blood response to multiagent induction therapy:
Patients with persistent circulating leukemia cells at 7 to 10 days after the initiation of multiagent chemotherapy are at increased risk of relapse compared with patients who have clearance of peripheral blasts within 1 week of therapy initiation.^105,¹⁰⁶ Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T- cell and B-lineage ALL.^107,

Minimal residual disease after induction therapy:
Patients in clinical remission after induction therapy may have minimal residual disease (MRD), (i.e., leukemia cells in the blood or bone marrow) ¹⁰⁸ that can only be detected by highly sensitive techniques such as polymerase chain reaction or specialized flow cytometry. Numerous groups have reported that patients with higher levels of MRD have a poorer prognosis than those who have lower levels of MRD.^109,^110,^111,^112,¹¹³ ¹¹⁴ ^115,^116,^117,¹¹⁸ Even for patients with the TEL-AML1 translocation, a population with generally favorable outcomes, higher levels of MRD at the end of induction therapy appear to be associated with higher risk of subsequent relapse.^81,⁸² Measuring MRD in the peripheral blood of patients with T-cell ALL has been studied and demonstrates a high concordance with MRD measurements using bone marrow.^108,

No study to date has shown that decreasing therapeutic intensity for patients with early low-level MRD or without MRD can maintain efficacy while decreasing morbidity. Likewise, no study to date has shown that increasing therapeutic intensity for patients with early high-level MRD improves outcome. Therapeutic adjustments based on MRD determinations in ALL should only be utilized in clinical trials.

Prognostic Groups

This subsection does not discuss infants as a prognostic group. For information about infants with acute lymphoblastic leukemia, refer to the Postinduction Treatment for Childhood Acute Lymphoblastic Leukemia Subgroups section of this summary.

Former CCG studies made an initial risk assignment of patients older than 1 year as standard risk or high risk based on the NCI consensus age and WBC criteria.¹ The standard-risk category included patients aged 1 to 9 years who had a WBC count at diagnosis less than 50,000/µL. The remaining patients were classified as high risk. Final treatment assignment for CCG protocols was based on the early response to therapy (day 7 or day 14 bone marrow response) with slow early responders being assigned to receive more aggressive treatment.

Former POG studies defined the low-risk group based on the NCI consensus age and WBC criteria and required the absence of adverse translocations, absence of CNS disease and testicular disease, and the presence of either the TEL/AML1 translocation or trisomy of chromosomes 4 and 10. The high-risk group required the absence of favorable translocations and the presence of CNS or testicular leukemia, or the presence of MLL gene rearrangement, or unfavorable age and WBC count.¹¹⁹ The standard-risk category includes patients not meeting the criteria for inclusion in any of the other risk group categories. In POG studies, patients with T-cell ALL were treated on different protocols than patients with precursor B-cell ALL.

The very high-risk category for CCG and POG was defined by one of the following factors taking precedence over all other considerations: presence of the t(9;22), M3 marrow on day 29 or M2 or M3 marrow on day 43, or hypodiploidy (DNA index <0.95).¹²⁰

Historically, the Berlin Frankfurt Muenster (BFM) group in Germany categorized risk groups differently than POG or CCG. Age and initial WBC count were not considered when assigning risk groups. Patients with an absolute blast count of 1000/μL or greater at the end of a 7-day prednisone prophase (prednisone poor responders) were considered to be high risk. Prednisone good responders (those with absolute blast count <1000/μL at the end of the prophase) were classified as either standard risk or moderate risk depending on whether their estimated leukemic cell mass estimate was relatively low (standard risk) or high (moderate risk). All patients with T-cell phenotype, mediastinal mass, or CNS involvement were considered moderate risk, and all patients with the t(9;22) were considered high risk.^12,

Since 2000, risk stratification on BFM protocols has been based almost soley on treatment response criteria. In addition to prednisone prophase response, treatment response is assessed via MRD measurements at two timepoints: 5 and 12 weeks after inititation of therapy. Patients who are MRD negative at both timepoints are classified as standard risk, those who have low MRD (<10-3) at week 12 are considered moderate risk, and those with high MRD (≥10-3) at week 12 are high risk. Patients with a poor response to the prednisone prophase are also considered high risk, regardless of subsequent MRD. Phenotype, leukemic cell mass estimate (BFM-RF) and CNS status at diagnosis do not factor into the current risk classification schema. However, patients with either the t(9;22) or the t(4;11) are considered high risk, regardless of early response measures.

Prognostic groups under clinical evaluation

In current COG ALL trials, patients with precursor B-cell ALL are initially assigned to a standard-risk or high-risk group based on age and initial WBC count (aged 1–9.99 years, and <50,000 WBC/µL is considered standard risk). All children with T-cell phenotype are considered high risk regardless of age and initial WBC count. Early treatment response (assessed by morphology and MRD) and cytogenetics are subsequently used to modify initial risk-group classification. NCI standard-risk patients with rapid morphologic response (Day 14 M1 marrow) and MRD less than 0.1% and an M1 marrow on day 29 are assigned to one of two groups based on cytogenetics. Patients with either t(12;21) or trisomies of chromosomes 4, 10, and 17 are considered "standard risk-low" while patients with neither of these two cytogenetics abnormalities are considered "standard risk-average." Standard-risk patients with either slow morphologic response (Day 14 M2 or M3 marrow) and/or MRD more than 0.1% on day 29 are assigned to a third group (standard risk-high) and receive a more intensive postinduction treatment. High-risk patients with precursor B-cell ALL are divided into rapid-responder (rapid morphologic response and low MRD) or slow-responder groups. Patients are classified as very high risk if they have any of the following features (regardless of initial risk group): t(9;22), hypodiploidy less than 44 chromosomes, MLL translocation with a slow early morphologic response, M3 marrow on day 29 or M2 marrow and/or MRD greater than 1% at days 29 and 43.

The Dana-Farber Cancer Institute (DFCI) ALL Consortium is also testing a new risk classification system for patients with precursor B-cell ALL. All patients are initially classified as either standard risk or high risk based upon age, presenting leukocyte count, and the presence or absence of CNS disease. At the completion of a five-drug remission induction regimen (4 weeks from diagnosis), the level of MRD is determined. Patients with high MRD (≥ 0.1%) are classified as very high risk and receive a more intensive postremission consolidation. Patients with low MRD (<0.1%) continue to receive treatment based on their initial risk-group classification. The goal of this new classification schema is to determine whether intensification of therapy will improve the outcome of patients with high MRD at the end of remission induction. Patients with T-cell ALL are treated as high risk, regardless of MRD status. All patients with MLL translocations or hypodiploidy (<45 chromosomes) are classified as very high risk, regardless of MRD status or phenotype. Patients with the Philadelphia chromosome are treated as high risk, but receive an allogeneic stem cell transplant in first remission.

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¹¹² Panzer-Grümayer ER, Schneider M, Panzer S, et al.: Rapid molecular response during early induction chemotherapy predicts a good outcome in childhood acute lymphoblastic leukemia. Blood 95 (3): 790-4, 2000.

¹¹³ Coustan-Smith E, Sancho J, Hancock ML, et al.: Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia. Blood 96 (8): 2691-6, 2000.

¹¹⁴ Nyvold C, Madsen HO, Ryder LP, et al.: Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome. Blood 99 (4): 1253-8, 2002.

¹¹⁵ Dworzak MN, Fröschl G, Printz D, et al.: Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia. Blood 99 (6): 1952-8, 2002.

¹¹⁶ Willemse MJ, Seriu T, Hettinger K, et al.: Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL. Blood 99 (12): 4386-93, 2002.

¹¹⁷ Gameiro P, Moreira I, Yetgin S, et al.: Polymerase chain reaction (PCR)- and reverse transcription PCR-based minimal residual disease detection in long-term follow-up of childhood acute lymphoblastic leukaemia. Br J Haematol 119 (3): 685-96, 2002.

¹¹⁸ Björklund E, Mazur J, Söderhäll S, et al.: Flow cytometric follow-up of minimal residual disease in bone marrow gives prognostic information in children with acute lymphoblastic leukemia. Leukemia 17 (1): 138-48, 2003.

¹¹⁹ Shuster JJ, Camitta BM, Pullen J, et al.: Identification of newly diagnosed children with acute lymphocytic leukemia at high risk for relapse. Cancer Research, Therapy and Control 9(1-2): 101-107, 1999.

¹²⁰ Heerema NA, Nachman JB, Sather HN, et al.: Hypodiploidy with less than 45 chromosomes confers adverse risk in childhood acute lymphoblastic leukemia: a report from the children's cancer group. Blood 94 (12): 4036-45, 1999.

Treatment Option Overview

Risk-based treatment assignment is an important therapeutic strategy utilized for children with acute lymphoblastic leukemia (ALL). This approach allows children who historically have a very good outcome to be treated with modest therapy and to be spared more intensive and toxic treatment, while allowing children with a historically lower probability of long-term survival to receive more intensive therapy that may increase their chance of cure. As discussed in the Cellular Classification and Prognostic Variables section of this summary, a number of clinical and laboratory features have demonstrated prognostic value. A subset of the known prognostic factors (e.g., age, white blood cell (WBC) count at diagnosis, presence of specific cytogenetic abnormalities) are used for the initial stratification of children with ALL into treatment groups with varying degrees of risk for treatment failure. Event-free survival (EFS) rates exceed 80% for children meeting good-risk criteria for age and WBC; for children meeting high-risk criteria, EFS rates are approximately 70%.^1,^2,^3,⁴ Application of biological factors (e.g., specific chromosomal translocations, and hypodiploidy) can identify patient groups with expected outcome survival rates ranging from less than 40% to greater than 85%.^5,

Nationwide clinical trials are generally available for children with ALL, with specific protocols designed for children at standard (low) risk of treatment failure and for children at higher risk for treatment failure. Clinical trials for children with ALL are generally designed to compare therapy that is currently accepted as standard for a particular risk group with a potentially better treatment approach that may improve survival outcome and/or diminish toxicities associated with the standard treatment regimen. Many of the improvements in therapy that have led to increased survival rates for children with ALL have been made through nationwide clinical trials,^6,⁷ and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial. In addition, treatment planning by a multidisciplinary team of pediatric cancer specialists with experience and expertise in treating leukemias of childhood is required to determine and implement optimum treatment. This treatment is best accomplished in a center with specialized expertise in pediatric cancer.^8,

Older children and adolescents (≥10 years) and infants (<12 months) have a less favorable outcome than children aged 1 to 9 years at diagnosis, and more aggressive treatments are generally employed for these patients.⁹ Increasing evidence demonstrates a significant advantage for adolescents with ALL being treated on pediatric-based treatment protocols.¹⁰ A report from France for 15- to 20-year-old patients diagnosed between 1993 and 1999 showed superior outcome for patients treated on a pediatric trial (67% 5-year EFS) compared to patients treated on an adult trial (41% 5-year EFS).¹¹ The reason for these differences is not known, though possible explanations include treatment setting (i.e., site experience in treating ALL), adherence to protocol therapy, and components of protocol therapy itself.

Successful treatment of children with ALL requires the control of systemic disease (e.g., marrow, liver and spleen, lymph nodes) as well as the prevention or treatment of extramedullary disease particularly in the central nervous system (CNS). Only 3% of patients have detectable CNS involvement by conventional criteria at diagnosis (≥5 WBC/μL with lymphoblast cells present). Unless specific therapy is directed toward the CNS, however, 50% to 70% or more of children will eventually develop overt CNS leukemia. Therefore, all children with ALL should receive systemic combination chemotherapy together with some form of CNS prophylaxis. At present, most groups treat patients with documented CNS leukemia at diagnosis (>5 WBC/μl with blasts; CNS3) with intrathecal therapy and subsequent cranial radiation.

Treatment for children with ALL is divided into stages: remission induction, consolidation or intensification, and maintenance (continuation) therapy, with CNS sanctuary therapy generally provided in each stage. An intensification phase of therapy following remission induction is used for all patients. The intensity of both induction therapy and postinduction therapy is determined by the clinical and biologic prognostic factors utilized for risk-based treatment assignment and some type of early response assessment. This assessment may include day 7 and/or day 14 marrow blast percentage, day 8 peripheral blood blast count, and at the end of induction, minimal residual disease burden measured by polymerase chain reaction and/or flow cytometry).^5,^12,^13,¹⁴ The duration of therapy for children with ALL ranges between 2 and 3 years.

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear.¹⁵ The role of radiation therapy for testicular involvement is also unclear. A study from St. Jude Children's Research Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.¹⁵ The Children's Oncology Group has also adopted this strategy.

Subgroups of patients who have a poor prognosis with current standard therapy may require different treatment. For example, infants with ALL are at higher risk for treatment failure, with the poorest prognosis for those with MLL gene rearrangements.^16,^17,^18,¹⁹ These children are generally treated with regimens designed specifically for infants.^19,^20,^21,²² Current regimens for infants employ intensified treatment approaches and may offer improved disease control compared with previous, less intensive approaches, but long-term outcome and toxicity are unknown.^21,^23,²⁴ Certain children (older than 1 year) with ALL may have a less than 50% likelihood of long-term remission with current therapy (e.g., t(9;22) Philadelphia chromosome-positive ALL, hypodiploid patients and those with initial induction failure). For these patients, allogeneic bone marrow transplantation from an HLA-matched sibling should be considered during first remission.^25,^26,^27,^28,²⁹ HLA-matched sibling donor transplant, however, has not been proven to be of benefit in patients defined as high-risk solely by WBC count, gender, and age.^30,^31,

Since myelosuppression and generalized immunosuppression are an anticipated consequence of both leukemia and its treatment with chemotherapy, patients must be closely monitored during treatment. Adequate facilities must be immediately available both for hematologic support and for the treatment of infectious and other complications throughout all phases of leukemia treatment. Approximately 1% of patients die during induction therapy and another 1% to 3% die during first remission from treatment-related complications.^32,

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

¹ Gaynon PS, Trigg ME, Heerema NA, et al.: Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 14 (12): 2223-33, 2000.

² 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 14 (12): 2205-22, 2000.

³ Silverman LB, Declerck L, Gelber RD, et al.: Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995). Leukemia 14 (12): 2247-56, 2000.

⁴ Pui CH, Sandlund JT, Pei D, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 104 (9): 2690-6, 2004.

⁵ Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 354 (2): 166-78, 2006.

⁶ Progress against childhood cancer: the Pediatric Oncology Group experience. Pediatrics 89 (4 Pt 1): 597-600, 1992.

⁷ Bleyer WA: The U.S. pediatric cancer clinical trials programmes: international implications and the way forward. Eur J Cancer 33 (9): 1439-47, 1997.

⁸ Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.

⁹ Nachman J: Clinical characteristics, biologic features and outcome for young adult patients with acute lymphoblastic leukaemia. Br J Haematol 130 (2): 166-73, 2005.

¹⁰ Ramanujachar R, Richards S, Hann I, et al.: Adolescents with acute lymphoblastic leukaemia: emerging from the shadow of paediatric and adult treatment protocols. Pediatr Blood Cancer 47 (6): 748-56, 2006.

¹¹ Boissel N, Auclerc MF, Lhéritier V, et al.: Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol 21 (5): 774-80, 2003.

¹² Szczepański T, Orfão A, van der Velden VH, et al.: Minimal residual disease in leukaemia patients. Lancet Oncol 2 (7): 409-17, 2001.

¹³ Gaynon PS, Desai AA, Bostrom BC, et al.: Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review. Cancer 80 (9): 1717-26, 1997.

¹⁴ Campana D: Determination of minimal residual disease in leukaemia patients. Br J Haematol 121 (6): 823-38, 2003.

¹⁵ Hijiya N, Liu W, Sandlund JT, et al.: Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation. Leukemia 19 (8): 1399-403, 2005.

¹⁶ Rubnitz JE, Link MP, Shuster JJ, et al.: Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood 84 (2): 570-3, 1994.

¹⁷ Biondi A, Cimino G, Pieters R, et al.: Biological and therapeutic aspects of infant leukemia. Blood 96 (1): 24-33, 2000.

¹⁸ Pui CH, Gaynon PS, Boyett JM, et al.: Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 359 (9321): 1909-15, 2002.

¹⁹ Silverman LB, McLean TW, Gelber RD, et al.: Intensified therapy for infants with acute lymphoblastic leukemia: results from the Dana-Farber Cancer Institute Consortium. Cancer 80 (12): 2285-95, 1997.

²⁰ Chessells JM, Harrison CJ, Watson SL, et al.: Treatment of infants with lymphoblastic leukaemia: results of the UK Infant Protocols 1987-1999. Br J Haematol 117 (2): 306-14, 2002.

²¹ Reaman GH, Sposto R, Sensel MG, et al.: Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children's Cancer Group. J Clin Oncol 17 (2): 445-55, 1999.

²² Dreyer ZE, Steuber CP, Bowman WP, et al.: High risk infant ALL--improved survival with intensive chemotherapy. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A2032, 529a, 1998.

²³ Kosaka Y, Koh K, Kinukawa N, et al.: Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation. Blood 104 (12): 3527-34, 2004.

²⁴ Hilden JM, Dinndorf PA, Meerbaum SO, et al.: Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood 108 (2): 441-51, 2006.

²⁵ Snyder DS, Nademanee AP, O'Donnell MR, et al.: Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission. Leukemia 13 (12): 2053-8, 1999.

²⁶ Aricò M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 342 (14): 998-1006, 2000.

²⁷ Mori T, Manabe A, Tsuchida M, et al.: Allogeneic bone marrow transplantation in first remission rescues children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) studies L89-12 and L92-13. Med Pediatr Oncol 37 (5): 426-31, 2001.

²⁸ Appelbaum FR: Hematopoietic cell transplantation beyond first remission. Leukemia 16 (2): 157-9, 2002.

²⁹ Balduzzi A, Valsecchi MG, Uderzo C, et al.: Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet 366 (9486): 635-42, 2005 Aug 20-26.

³⁰ Wheeler KA, Richards SM, Bailey CC, et al.: Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukemia in first remission: results from Medical Research Council UKALL X and XI. Blood 96 (7): 2412-8, 2000.

³¹ 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 children: an evidence-based review. Biol Blood Marrow Transplant 11 (11): 823-61, 2005.

³² Christensen MS, Heyman M, Möttönen M, et al.: Treatment-related death in childhood acute lymphoblastic leukaemia in the Nordic countries: 1992-2001. Br J Haematol 131 (1): 50-8, 2005.

Untreated Childhood Acute Lymphoblastic Leukemia

Induction Chemotherapy

Three-drug induction therapy using vincristine, prednisone/dexamethasone, plus L-asparaginase in conjunction with intrathecal therapy (IT), results in complete remission rates of greater than 95%.¹ For patients at high risk for treatment failure, a more intense induction regimen (four or five agents) may result in improved event-free survival (EFS),^2,^3,⁴ and high-risk patients generally receive induction therapy that includes an anthracycline (e.g., daunomycin) in addition to vincristine, prednisone/dexamethasone, plus L-asparaginase. For patients who are at standard risk or low risk of treatment failure, four-drug induction therapy does not appear necessary for favorable outcome provided that adequate postremission intensification therapy is administered.^2,⁵ Because of the likelihood of increased toxicity with four-drug induction therapy, Children's Oncology Group (COG) protocols recommend treating standard-risk or lower-risk patients with a glucocorticoid (e.g., prednisone, dexamethasone), vincristine, and L-asparaginase, and reserve the use of induction regimens using four or more agents for higher risk patients.^2,^5,^6,

Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy. The Children's Cancer Group (CCG) conducted a randomized trial comparing dexamethasone and prednisone in standard-risk patients, and reported that dexamethasone was associated with a superior EFS.⁷ Results from another randomized trial conducted by the United Kingdom Medical Research Council (MRC) demonstrated that dexamethasone was associated with a more favorable outcome than prednisolone in all patient subgroups.⁸ In the MRC trial, patients who received dexamethasone had a significantly lower incidence of both central nervous system (CNS) and non-CNS relapses than prednisolone.⁸ However, a third randomized trial (conducted in Japan) did not confirm a survival advantage with dexamethasone.⁹ This discrepant result might have been due to the use of a higher dose of prednisolone during induction therapy, the use of a more intensive backbone chemotherapy regimen, and/or the smaller number of patients included in that trial.

While dexamethasone may be more effective than prednisone, there are also data suggesting that dexamethasone may also be more toxic, especially in the context of more intensive induction regimens. Several reports indicate that dexamethasone may increase the frequency and severity of infections and/or other complications in patients receiving intensive (more than three drugs) induction regimens.^10,¹¹ The Berlin-Frankfurt-Muenster (BFM) Group observed increased mortality in adolescent patients who received dexamethasone instead of prednisone during a four-drug induction regimen. However, the MRC group did not observe any toxicity or mortality differences between dexamethasone and prednisone during a four-drug induction regimen.³ Dexamethasone appears to have a greater suppressive effect on short-term linear growth than prednisone,¹² and has been associated with a higher risk of osteonecrosis, especially in adolescent patients.^13,

Several forms of L-asparaginase are available for use in the treatment of children with ALL, with Eschericia coli L-asparaginase being most commonly used. PEG-L-asparaginase is an alternative form of L-asparaginase in which the E coli enzyme is modified by the covalent attachment of polyethylene glycol. PEG-L-asparaginase has a much longer serum half-life than native E coli L-asparaginase, allowing it to produce asparagine depletion with less frequent administration.¹⁴ A single intramuscular dose of PEG-L-asparaginase given in conjunction with vincristine and prednisone during induction therapy appears to have similar activity and toxicity as 9 doses of intramuscular E coli L-asparaginase (3 times a week for 3 weeks).¹⁵ In a randomized comparison of PEG-L-asparaginase versus native E coli asparaginase in which each agent was to be given over a 30-week period following achievement of remission, similar outcome and similar rates of asparaginase-related toxicities were observed for both groups of patients.^16, In another randomized trial in which patients with standard-risk ALL were randomly assigned to receive PEG-L-asparaginase versus native E coli asparaginase in induction and each of two delayed intensification courses, the use of PEG-L-asparaginase was associated with more rapid blast clearance and a lower incidence of neutralizing antibodies.¹⁵ Current COG protocols utilize a three-drug induction regimen that includes PEG L-asparaginase for standard-risk trials. If Erwinia L-asparaginase is utilized, the shorter half-life of the Erwinia preparation requires more frequent administration and a higher dose. In two studies, patients randomly assigned to receive Erwinia L-asparaginase on the same schedule and dosage as E coli L-asparaginase had a significantly worse EFS.^17,¹⁸ Erwinia L-asparaginase is currently utilized as a substitute for native E coli or PEG L-asparaginase in patients who have experienced an allergic reaction to one or both of these preparations.^19,

More than 95% of children with newly diagnosed ALL will achieve a complete remission within the first 4 weeks of treatment. Of the 2% to 4% of patients who fail to achieve complete remission within the first 4 weeks, approximately half will experience a toxic death during the induction phase (usually due to infection) and the other half will have resistant disease (persistent morphologic leukemia).^18,^20,²¹ Patients who require more than 4 weeks to achieve remission have a poor prognosis and may benefit from an allogeneic stem cell transplant once complete remission is achieved.^22,²³ ²⁴ Outcome is also less favorable for patients who demonstrate more than 25% blasts in the bone marrow or persistent blasts in the peripheral blood after 1 week of intensive multiagent induction therapy,^3,^25,²⁶ and protocols of the former CCG-based treatment decisions on the day 7 bone marrow response (for high-risk patients) or day 14 bone marrow response (for standard-risk patients).²⁷

Options under clinical evaluation for end-induction treatment assignment

The COG is evaluating a new end-induction classification system. Standard-risk patients (aged 1 to 9.99 years, <50,000 WBC/µL, precursor B-cell ALL) receive a three-drug induction regimen with dexamethasone, PEG-L-asparaginase, and vincristine. High-risk precursor B-cell ALL patients receive a four-drug induction regimen including daunomycin and are randomly assigned to receive either dexamethasone for 14 days or prednisone for 28 days. Patients with T-cell ALL receive a four-drug induction regimen with prednisone as the induction steroid. Patients with ALL undergo an evaluation on day 28 that includes a bone marrow biopsy/aspiration for morphology and minimal residual disease (MRD) determinations. On the basis of day 14 marrow morphology, day 28 marrow morphology, and day 28 MRD determination, ALL patients are classified as rapid responders, slow responders, very slow responders, or induction failures. Patients with t(9;22) and hypodiploidy with fewer than 44 chromosomes move to the very high-risk protocol at the end of induction therapy, regardless of response classification. Patients with MLL gene rearrangements who do not show a rapid response also move to the very high-risk treatment protocol. Patients with ALL and slow or rapid response to induction receive consolidation on the appropriate standard or high-risk precursor B-cell ALL or T-cell treatment protocol. Patients with very slow response to induction therapy receive an additional 2 weeks of induction therapy and then have a day 42 bone marrow evaluation for morphology and MRD. Patients with an M1 day 42 marrow and less than 0.1 MRD go onto consolidation therapy; all other patients are considered induction failures and move to the very high-risk treatment protocol.

Table 1. COG End-Induction Response Classification
Early Marrow MorphologyMRD Day 28Marrow Morphology Day 28COG ClassificationDay 7 Day 14 M1-<0.1%M1Rapid responseM2/M3M1<0.1%M1Rapid response-M2/M3<1.0%M1Slow responseAnyAny0.1%-1.0%M1Slow responseAny Any>1.0%M1, M2Very slow response; extended inductionAnyAnyAnyM2Very slow response; extended inductionAnyAnyAnyM3Induction failure

The Dana-Farber Cancer Institute (DFCI) ALL Consortium is also testing a new risk classification system for patients with precursor B-cell ALL. All patients are initially risk classified as either standard risk or high risk based upon age, presenting leukocyte count, and presence or absence of CNS disease. At the completion of a 5-drug remission induction regimen (4 weeks from diagnosis), the level of MRD is determined. Patients with high MRD (≥0.1%) are classified as very high risk and receive a more intensive postremission consolidation. Patients with low MRD (<0.1%) continue to receive treatment based on their initial risk group classification. The goal of this new classification schema is to determine whether intensification of therapy will improve the outcome of patients with high MRD at the end of remission induction. Patients with T-cell ALL are treated as high risk, regardless of MRD status. All patients with MLL translocations or hypodiploidy (<45 chromosomes) are classified as very high-risk, regardless of MRD status or phenotype. Patients with the Philadelphia chromosome are treated as high risk, but receive an allogeneic stem cell transplant in first remission.

Central Nervous System Therapy

The early institution of adequate CNS therapy is critical for eliminating clinically evident CNS disease at diagnosis and for preventing CNS relapse in patients without overt CNS involvement at diagnosis. IT chemotherapy is usually started at the beginning of induction, intensified during consolidation (4–8 doses of IT given every 2–3 weeks), and often continued throughout maintenance. A current goal of ALL therapy design is to achieve effective CNS therapy while minimizing neurotoxicity. Every patient with ALL receives IT chemotherapy with methotrexate alone or methotrexate with cytarabine plus hydrocortisone.²⁸ IT methotrexate may also have a significant systemic effect that could result in a decrease in marrow relapse rate.²⁹ Historically, significant control of bone marrow relapse did not occur until CNS therapy was instituted. Conversely, the type and extent of systemic intensification also appears to influence the efficacy of the CNS therapy. Systemically administered drugs such as dexamethasone, L-asparaginase, high-dose methotrexate, and high-dose cytarabine may provide some degree of CNS protection. For example, in a CCG study for patients with standard-risk ALL, oral dexamethasone decreased the CNS relapse rate by 50% compared with patients receiving oral prednisone (patients received IT methotrexate alone for CNS prophylaxis).^7,

No clinical evidence of CNS involvement at diagnosis

Intrathecal chemotherapy may be the sole form of presymptomatic CNS therapy, or it may be combined with systemic moderate-dose to high-dose infusions of methotrexate with leucovorin rescue and/or cranial radiation (12–18 Gy).³⁰ Appropriate systemic therapy combined with IT chemotherapy results in CNS relapse rates of less than 5% for children with standard-risk ALL.^5,^20,^31,³² The question of whether to use triple (methotrexate, prednisone, cytarabine) IT therapy or single (methotrexate) IT therapy in nonirradiated standard-risk patients was studied as a randomized question in the CCG-1952 clinical trial.³³ The results showed an isolated CNS relapse rate of 3.4 ± 1.0% for triple IT therapy and 5.9 ± 1.2% for single IT therapy (P = .004). There were, however, more bone marrow relapses in the group that received the triple IT therapy, leading to a worse overall survival (OS) in this group (90.3 ± 1.5%) compared with the single IT therapy group (94.4 ± 1.1%; P = .01). When the analysis was restricted to patients with precursor B-cell ALL and rapid early response (M1 marrow on day 14), there was no difference between triple and single IT therapy in CNS relapse rate, OS, or EFS.³³ Patients with blasts in the cerebrospinal fluid (CSF) but less than 5 WBC/µL (CNS2) are at increased risk of CNS relapse and may require more intensive IT chemotherapy (but not cranial radiation).^34,³⁵ Data also suggest that a traumatic lumbar puncture with blasts at the time of diagnosis is associated with an increased risk of CNS relapse, however, with more intensive IT chemotherapy, the risk is abrogated.^35,^36,

Approximately 15% to 20% of children with ALL receive cranial radiation as part of their CNS-directed therapy, even if they present without CNS involvement at diagnosis, including those with T-cell phenotype and subsets of patients with high-risk precursor B-cell ALL.^37,³⁸ Whether some or all of these patients could be as effectively treated without radiation is controversial and is currently under investigation.^39,

Toxic effects of CNS-directed therapy for childhood ALL can be divided into two broad groups. Acute/subacute toxicities include seizures, stroke, somnolence syndrome, and ascending paralysis. Chronic toxicities include leukoencephalopathy and a range of neurocognitive, behavioral, and neuroendocrine disturbances.⁴⁰

Long-term deleterious effects of cranial radiation, particularly at doses higher than 1,800 cGy, have been recognized for years.⁴¹ Children receiving these higher doses of cranial radiation are at significant risk for neurocognitive and neuroendocrine sequelae.^42,^43,^44,^45,⁴⁶ Young children (e.g., younger than 4 years) are at increased risk for neurocognitive decline and other sequelae following cranial radiation.^47,^48,⁴⁹ Girls may be at a higher risk for radiation-induced neuropsychologic and neuroendocrine sequelae than boys.^48,^49,⁵⁰ In general, high-dose methotrexate should not be given following cranial radiation because of the increased risk of neurologic sequelae, including leukoencephalopathy. In addition, higher doses of radiation are associated with the development of second neoplasms (many of which are benign or of low malignant potential).^46,⁵¹ Attempts at reducing the adverse sequelae of cranial radiation have included lowering the dose and utilizing alternative fractionation schedules. Children receiving 18 Gy of cranial radiation may be at diminished risk for neurologic toxicity compared with those receiving 24 Gy,⁵² although neurocognitive and neuroendocrine effects have been noted at this lower dose.^47,^53,⁵⁴ In the German BFM and DFCI ALL Consortium studies, many of the patients treated with cranial radiation receive a dose of only 12 Gy.⁵³ Longer follow-up is needed to determine whether 12 Gy will be associated with a lower incidence of neurologic sequelae. In a randomized trial, hyperfractionated radiation (at a dose of 18 Gy) did not decrease neurologic late effects when compared with conventionally fractionated radiation, although cognitive function for both groups was not significantly impaired.⁵⁵

The most common toxicity associated with IT chemotherapy alone is seizures. Approximately 5% to 10% of patients with ALL treated with frequent doses of IT chemotherapy will have at least one seizure during therapy.⁶ Patients with ALL who develop seizures during the course of treatment and who receive anticonvulsant therapy should not receive phenobarbital or phenytoin as anticonvulsant treatment, as these drugs may increase the clearance of some chemotherapeutic drugs and adversely affect treatment outcome.⁵⁶ Valproic acid or gabapentin are alternative anticonvulsants with less enzyme-inducing capabilities.⁵⁶ In general, patients who receive IT without cranial radiation as CNS therapy appear to have a low incidence of neurocognitive sequelae, and the deficits that do develop represent relatively modest declines in a limited number of domains of neuropsychological functioning.^57,^58,⁵⁹ This modest decline is especially seen in young children and girls.⁶⁰ Regimens that utilize a biweekly schedule of 12 doses of intravenous high-dose methotrexate with leucovorin rescue and IT in the off-week have been associated with excessive neurologic toxicity.⁶¹ Controversy exists about whether patients who receive dexamethasone are at risk for neurocognitive disturbances.^62,

Presymptomatic CNS therapy options under clinical evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

In the COG AALL0232 study, patients with high-risk precursor B-cell ALL receive either IT methotrexate alone (rapid early responders) or IT methotrexate with cranial radiation (slow early responders). One goal of this study is to determine whether oral dexamethasone, high-dose methotrexate, or both agents will decrease the incidence of CNS relapse.

In the COG AALL0434,⁶³ protocol for patients with T-cell ALL, low-risk T-cell patients will be treated without cranial radiation, and intermediate-risk T-cell patients will receive 12 Gy (instead of 18 Gy) cranial radiation. High-risk T-cell patients will continue to receive 18 Gy cranial radiation.

A clinical trial at St. Jude Children's Research Hospital is testing whether intensive IT and systemic chemotherapy without radiation can be used for CNS prophylaxis in all patients regardless of initial CNS status.

DFCI ALL Consortium Protocol 05-01 ⁶⁴ is testing whether IT chemotherapy alone can replace cranial radiation in some high-risk patients. Approximately 20% of patients will receive cranial radiation, including B-lineage patients with high presenting leukocyte counts (≥100,000 μ/L), CNS3 disease at diagnosis, or high MRD levels at the end of remission induction, and all T-cell ALL patients. The remaining 80% of patients will receive triple IT chemotherapy, but no radiation. The goal of this treatment schema is to reduce neurotoxicity and other CNS late effects without compromising efficacy by limiting the number of patients exposed to radiation and by lowering the radiation dose (12 Gy instead of 18 Gy) to those still receiving radiation.

Clinically evident CNS involvement at diagnosis

Standard treatment for ALL patients with clinically evident CNS disease (>5 WBC/μl with blasts on cytospin; CNS3) at diagnosis includes IT chemotherapy and cranial radiation (usual dose: 18 Gy). Spinal radiation is no longer used.

Treatment options under clinical evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

A clinical trial at St. Jude Children's Research Hospital is testing whether patients with clinically evident CNS disease at diagnosis can be treated with intensive IT and systemic chemotherapy without radiation.

¹ Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 354 (2): 166-78, 2006.

² Tubergen DG, Gilchrist GS, O'Brien RT, et al.: Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial. J Clin Oncol 11 (3): 527-37, 1993.

³ Gaynon PS, Steinherz PG, Bleyer WA, et al.: Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Childrens Cancer Group Study CCG-106. J Clin Oncol 11 (11): 2234-42, 1993.

⁴ LeClerc JM, Billett AL, Gelber RD, et al.: Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber ALL Consortium Protocol 87-01. J Clin Oncol 20 (1): 237-46, 2002.

⁵ Veerman AJ, Hählen K, Kamps WA, et al.: High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia. Results of protocol ALL VI from the Dutch Childhood Leukemia Study Group. J Clin Oncol 14 (3): 911-8, 1996.

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