General Information

Cellular Classification And Prognostic Variables

Treatment Option Overview

Untreated Childhood Acute Lymphoblastic Leukemia

Childhood Acute Lymphoblastic Leukemia In Remission

Recurrent Childhood Acute Lymphoblastic Leukemia

GENERAL INFORMATION

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 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 in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. 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 aggressive supportive care (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 in whom specific clinical and laboratory features might confer a favorable prognosis. At the same time, 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.

ALL is the most common cancer occurring in children, representing 23% of cancer diagnoses among children younger than 15 years of age and occurring at an annual rate of approximately 31 per million.[2] There are approximately 2,400 children and adolescents younger than 20 years of age diagnosed with ALL each year in the United States.[3] There is a sharp peak in ALL incidence among children ages 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 ages 2 to 3 years is approximately fourfold greater than that for infants and is nearly 10-fold greater than that for children 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 of age for white children compared to black children.[3]

There are few identified factors associated with 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).[4] Children with Down syndrome have increased risk for developing both ALL and acute myeloid leukemia,[5] with a cumulative risk for developing leukemia of approximately 2.1% by aged 5 years and 2.7% by aged 30 years.[6] Approximately two-thirds of the cases of acute leukemia in children with Down syndrome are ALL.[6] Increased occurrence of ALL is also associated with certain genetic conditions, including neurofibromatosis,[7] Shwachman syndrome,[8,9] Bloom syndrome,[10] and ataxia telangiectasia.[11]

Seventy-five percent to 80% of children with ALL survive at least 5 years from diagnosis with current treatments that incorporate systemic therapy (e.g., combination chemotherapy) and specific central nervous system (CNS) preventive therapy (i.e., intrathecal chemotherapy with or without cranial irradiation).[2,3,12,13] Ten-year event-free survival of multiple large prospective trials conducted in different countries for children treated primarily in the 1980s is approximately 70%.[14-20] Since nearly all children with ALL achieve an initial remission, the major obstacle to cure is bone marrow and/or extramedullary (e.g., CNS, testicular) relapse. Relapse from remission can occur during therapy or after completion of treatment. While the majority of children with recurrent ALL attain a second remission, the likelihood of cure is generally poor, particularly for those with bone marrow relapse following a short initial remission duration.[21]

Lymphoblasts from a particular patient carry antigen receptors unique to that patient. There is evidence to suggest that the specific antigen receptor may be present at birth in some patients with ALL, suggesting a prenatal origin for the leukemic clone. Similarly, some patients with ALL characterized by specific translocations have been shown to have cells showing the translocation at the time of birth.[22,23]

Despite the treatment advances noted in childhood ALL, numerous important biologic and therapeutic questions remain to be answered in order 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 clinical trials.[24,25] Information about ongoing clinical trials is available from the NCI (Http: //cancer.gov/clinical_trials/).

References:

1. Sanders J, Glader B, Cairo M, et al.: 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): 139-141, 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 at: Http: //seer.cancer.gov/csr/1973_1996. Accessed April 25, 2002.
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, NIH Pub.No. 99-4649, 1999, pp 17-34.
4. Ross JA, Davies SM, Potter JD, et al.: Epidemiology of childhood leukemia, with a focus on infants. Epidemiologic Reviews 16(2): 243-272, 1994.
5. Avet-Loiseau H, Mechinaud F, Harousseau L: Clonal hematologic disorders in Down syndrome. Journal of Pediatric Hematology/Oncology 17(1): 19-24, 1995.
6. Hasle H, Clemmensen H, Mikkelsen M: Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 355(9199): 165-169, 2000.
7. Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. British Journal of Cancer 70(5): 969-972, 1994.
8. Strevens MJ, Lilleyman JS, Williams RB: Shwachman's syndrome and acute lymphoblastic leukaemia. British Medical Journal 2(6129): 18, 1978.
9. Woods WG, Roloff JS, Lukens JN, et al.: The occurrence of leukemia in patients with the Shwachman syndrome. The Journal of Pediatrics 99(3): 425-428, 1981.
10. Passarge E: Bloom's syndrome: the German experience. Annales de Genetique 34(3-4): 179-197, 1991.
11. Taylor AM, Metcalfe JA, Thick J, et al.: Leukemia and lymphoma in ataxia telangiectasia. Blood 87(2): 423-438, 1996.
12. Pui CH, Evans WE: Acute lymphoblastic leukemia. New England Journal of Medicine 339(9): 605-615, 1998.
13. Pui CH: Acute lymphoblastic leukemia in children. Current Opinion in Oncology 12(1): 3-12, 2000.
14. Gaynon PS, Trigg ME, Heerema NA, et al.: Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 14(12): 2223-2233, 2000.
15. 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. Leukemia 14(12): 2205-2222, 2000.
16. 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 on behalf of the COALL study group. Leukemia 14(12): 2234-2239, 2000.
17. 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): 2247-2256, 2000.
18. 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): 2276-2285, 2000.
19. Pui C-H, Boyett JM, Rivera GK, et al.: Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St Jude Children's Research Hospital. Leukemia 14(12): 2286-2294, 2000.
20. 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. Leukemia 14(12): 2307-2320, 2000.
21. Gaynon PS, Qu RP, Chappell RJ, et al.: Survival after relapse in childhood acute lymphoblastic leukemia: impact of site and time to first relapse--the Children's Cancer Group Experience. Cancer 82(7): 1387-1395, 1998.
22. 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): 264-268, 2000.
23. Fasching K, Panzer S, Haas OA, et al.: Presence of clone-specific antigen receptor gene rearrangements at birth indicates an in utero origin of diverse types of early childhood acute lymphoblastic leukemia. Blood 95(8): 2722-2724, 2000.
24. Vietti TJ, Land V, et al, for the Pediatric Oncology Group: Progress against childhood cancer: the Pediatric Oncology Group experience. Pediatrics 89(4 pt 1): 597-600, 1992.
25. Bleyer WA: The U.S. pediatric cancer clinical trials programmes: international implications and the way forward. European Journal of Cancer 33(9): 1439-1447, 1997.

CELLULAR CLASSIFICATION AND PROGNOSTIC VARIABLES

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; molecular characteristics of leukemia cells at diagnosis; and response to initial treatment. As in any discussion of prognostic factors, it is critical to remember that 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.[2,3] Because prognostic factors are treatment dependent, improvements in therapy may diminish the importance of or abrogate 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 post induction chemotherapy.[4]

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 for clinical trials in the United States.

Clinical and laboratory features at diagnosis which are associated with outcome include the following:

1. Age at diagnosis: Age at diagnosis has strong prognostic significance,
reflecting the different underlying biology of ALL in different age groups.

Infants with ALL have a particularly high risk of treatment failure, with the risk of treatment failure being greatest for young infants (< 6 months) compared to older infants (>/= 6-9 months).[5-8] Rearrangement of the MLL gene at chromosome band 11q23 can be detected in the leukemia cells of a large percentage of infants with ALL,[9] and the poor outcome for infants with ALL is strongly associated with the presence of the t(4;11) translocation involving the MLL gene.[10,11] ALL in infants is also associated with a constellation of other characteristics associated with poor outcome, including elevated white blood cell (WBC) count, central nervous system leukemia, lack of CD10 (cALLa antigen) expression, and poor response to initial treatment.[5,7]

Young children (1-9 years) have a favorable outcome in comparison to either older children and adolescents or in comparison to infants.[1,12,13]

Older children and adolescents (>/= 10 years) have a less favorable outcome than young children, and more aggressive treatments are generally employed in order to improve outcome for these patients.

2. WBC count at diagnosis: Patients with higher WBC counts at diagnosis have a
higher risk for treatment failure than do patients with lower WBC counts. A WBC count of 50,000/mm3 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.[13,14] Elevated WBC count is associated with other high-risk prognostic factors, including unfavorable chromosomal translocations such as t(4;11) and t(9;22) (see below).

3. Gender: The prognosis for girls with ALL is slightly better than that for
boys with ALL.[15-17] 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 relapse for reasons that are not well understood.[17]

4. Race: Survival rates for black children with ALL are somewhat lower than
those for white children with ALL.[12,18-20] The reason for the better outcome for white children compared to black children is not known, but it can not be completely explained based on known prognostic factors.[19]

5. Cellular Morphology: In the past ALL lymphoblasts were classified using
the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology.[21] Due to the lack of independent prognostic significance and the subjective nature of this classification system, it is no longer used in the United States. The FAB L3 morphology is morphologically and cytogenetically identical to that of Burkitt's lymphoma. B-cell ALL (surface immunoglobulin (Ig) expression, generally with FAB L3 morphology and c-myc gene translocation) is a systemic manifestation of Burkitt's and Burkitt's-like non-Hodgkin's lymphoma, and its treatment is completely different from that for other forms of childhood ALL. (NOTE: Rare cases of FAB L3 ALL with c-myc gene translocations lack surface immunoglobulin expression, and these cases are appropriately treated as B-cell ALL).[22] Conversely, rare cases of ALL that express surface Ig but that lack L3 morphology and lack c-myc gene translocations are appropriately treated as B-precursor ALL rather than B-cell ALL.[23] (Refer to the PDQ summary on Childhood Non-Hodgkin's Lymphoma for more information.)

Molecular and biological characteristics of leukemia cells at diagnosis which are associated with outcome include:

1. Immunophenotype:

B-precursor ALL: B-cell precursor (or B-lineage) ALL, defined by the expression of CD19, HLA-DR, CD10 (cALLa), and other B-cell associated antigens, represents 80% to 85% of childhood ALL. Approximately 80% of B-precursor ALL express the cALLa, CD10 antigen. The lack of cALLa expression has also been shown in some series to be associated with a worse prognosis. For example, CD10 negativity is observed in a higher proportion of infants with B-precursor ALL and is associated with poor outcome.[5]

Stage of B-cell maturation: There are 3 major subtypes of B-lineage ALL:

early pre-B (no surface or cytoplasmic immunoglobulin), pre-B (presence of cytoplasmic immunoglobulin), and B-cell (presence of surface immunoglobulin). Approximately three quarters of patients with B-precursor ALL have the early pre-B phenotype and have the best prognosis. The leukemic cells of patients with pre-B ALL contain cytoplasmic immunoglobulin (cIg), an intermediate stage of B-cell differentiation. Twenty-five percent of patients with pre-B ALL have the t(1;19) translocation (see below).[24] Approximately 2% of patients present with B-cell ALL (surface Ig expression, generally with FAB L3 morphology and c-myc gene translocation).[25] B-cell ALL is a systemic manifestation of Burkitt's and Burkitt's-like non-Hodgkin's lymphoma, and its treatment is completely different from that for other forms of childhood ALL. (NOTE: Rare cases of FAB L3 ALL with c-myc gene translocations lack surface immunoglobulin expression, and these cases are appropriately treated as B-cell ALL).[22] Conversely, rare cases of ALL that express surface Ig but that lack L3 morphology and lack c-myc gene translocations are appropriately treated as B-precursor ALL rather than B-cell ALL.[23] (Refer to the PDQ summary on Childhood Non-Hodgkin's Lymphoma for more information on the treatment of children with B-cell ALL.)

T-cell ALL: T-cell ALL is defined by the leukemic cell expression of the T-cell-associated antigens CD2, CD7, CD5, or CD3 and is frequently associated with a constellation of clinical features including male sex, older age, leukocytosis, and mediastinal mass.[2] Approximately 15% of children with newly diagnosed ALL have the T-cell phenotype. With appropriately intensive therapy, however, children with T-cell ALL have an outcome similar to that for children with B-precursor ALL, when matched for age and WBC count.[2] Cytogenetic abnormalities common in B-cell lineage ALL (e.g. hyperdiploidy) are uncommon in T-cell ALL and when present, are not associated with prognostic significance.[26]

Myeloid antigen expression: A minority of childhood ALL cases have leukemia cells that express myeloid surface antigens. Myeloid antigen expression appears to be associated with specific ALL subgroups, notably those with MLL gene rearrangements and those with the TEL-AML1 gene rearrangement.[27] Early reports suggested a poorer prognosis for these patients,[28] but reports from large patient populations indicate no adverse prognostic significance for myeloid surface antigen expression.[27,29,30]

2. Chromosome number:

Hyperdiploidy: Hyperdiploidy (> 50 chromosomes per cell or DNA index > 1.16) is the presence of additional copies of whole chromosomes and occurs in 20% to 25% of cases of B-precursor ALL but very rarely in cases of T-cell ALL.[25] Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. Hyperdiploidy generally occurs in cases with favorable prognostic factors (age 1-9 years and low WBC count), and is itself associated with favorable prognosis.[12,31,32] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis, which may explain the favorable outcome commonly observed for these cases.[33]

Trisomies: For the treatment approaches utilized by both the Pediatric Oncology Group (POG) and the Children's Cancer Group (CCG), extra copies of certain chromosomes appear to be specifically associated with favorable prognosis among hyperdiploid ALL cases. In POG studies, patients whose leukemia cells have extra copies of both chromosome 4 and chromosome 10 appear to have particularly favorable outcome.[34] In CCG studies, children with trisomies of chromosomes 10 and 17 have an excellent prognosis.[35]

Hypodiploidy: Approximately 1% of children with ALL have leukemia cells showing hypodiploidy with less than 45 chromosomes. These patients are at high risk for treatment failure.[32,36,37]

3. 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.[25,38] Children with the t(12;21) cryptic translocation resulting in the TEL-AML1 fusion are generally 2 to 9 years of age.[38] Patients with the TEL-AML1 fusion have very good outcomes,[38-41] although there is controversy about whether the ultimate cure rate is actually superior to that of other patients with B-precursor ALL or whether the ultimate cure rate is similar but the timing of relapse is significantly later for patients with the TEL-AML1 fusion compared to other patients with B-precursor ALL.[32,39,42-45]

The Philadelphia chromosome t(9;22) is present in approximately 4% of pediatric ALL patients and confers an unfavorable prognosis, especially when it is associated with either a high WBC count or slow early response to initial therapy.[32,46-48] Philadelphia-positive ALL is more common in older patients with B-precursor ALL and high WBC count.

Translocations involving the MLL (11q23) gene occur in approximately 6% of childhood ALL cases, and are generally associated with increased risk for treatment failure.[25] The t(4;11) is the most common translocation involving the MLL gene in children with ALL and occurs in approximately 4% of cases.[49] Patients with t(4;11) generally present in infancy with high WBC count, and they are more likely than other children with ALL to have CNS disease and to have a poor response to initial therapy.[50] 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, although this observation is not consistent among all reports.[32,50-52] Another translocation involving the MLL gene in children with ALL is the t(11;19), which occurs in approximately 1% of cases and which occurs in both B-precursor and T-cell ALL.[53] 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.[53]

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.[24,25,54] 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.[24] Studies have shown that the poorer prognosis associated with t(1;19) can be largely overcome by more intensive therapy.[55,56] The improved outcome, however, appears to be primarily for patients with the unbalanced t(1;19)(approximately three fourths of all t(1;19) cases), with patients who have the balanced t(1;19) remaining at increased risk for treatment failure.[55,57]

The rapidity with which leukemia cells are eliminated following onset of treatment is also associated with outcome. Various ways of evaluating the leukemia cell response to treatment have been utilized, including:

1. Day 7 and day 14 bone marrow responses: Patients who have a rapid reduction
in the leukemia cells 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.[32,58-60] This "response to treatment" prognostic factor is used by the Children's Cancer Group to stratify patients into prognostic categories for treatment assignment.

2. Peripheral blood response to steroid prephase: Patients with a reduction in
peripheral blast count to less than 1000/mm3 after a 7-day induction prephase with prednisone and one dose of intrathecal methotrexate ("good prednisone response") have a more favorable prognosis than patients whose peripheral blast counts remain above 1000/mm3 ("poor prednisone response").[7,47,61] Treatment stratification for protocols of the German BFM clinical trials group is based on early response to the prednisone 7-day induction prephase. Patients whose blast counts are less than 1,000/mm3 at diagnosis have a slightly better outcome compared to other prednisone good responders.[62]

3. 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 to patients who have clearance of peripheral blasts within 1 week of therapy initiation.[63,64] Rate of clearance of peripheral blasts has been found to be of prognostic significance in T-lineage as well as B-lineage ALL.[65]

4. Minimal residual disease: Patients in clinical remission after induction
therapy may have "minimal residual disease," i.e., leukemia cells that can only be detected by highly sensitive techniques such as polymerase chain reaction (PCR) or specialized flow cytometry. Numerous groups have reported an association between minimal residual disease and outcome with early absence of minimal residual disease being associated with better outcome and presence of minimal residual disease being associated with poor outcome.[66-73]

No study to date has shown that decreasing therapeutic intensity for patients with early low-level or no minimal residual disease can maintain efficacy while decreasing morbidity. Likewise, no study to date has shown that increasing therapeutic intensity for patients with early high-level minimal residual disease improves outcome. Therapeutic adjustments based on molecular minimal residual disease determinations should only be utilized in clinical trials.

CCG makes initial assignment of patients as "standard risk" or "high risk" based on the NCI consensus age and WBC criteria.[1] The standard-risk category includes patients 1 to 9 years of age who have a WBC count at diagnosis less than 50,000/uL. The remaining patients are classified as having high-risk ALL. Final treatment assignment for CCG protocols is 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.

POG defines its "low risk" group based on the NCI consensus age and WBC criteria for low risk, and additionally requires 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 requires 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.[74] The "standard risk" category includes patients not meeting the criteria for inclusion in any of the other risk group categories.

The "very high-risk" category for both CCG and POG is defined by one of the following, 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). Infants with ALL are considered "high risk" and are treated on special protocols designed specifically for infants.

Children with T-cell ALL are much more likely than children with B-precursor ALL to meet "high risk" age and WBC criteria (75% for T-cell ALL versus 32% for B-precursor ALL).[1] In POG, children with T-cell ALL are grouped together with children who have lymphoblastic lymphoma and are treated on T-cell specific protocols. In CCG, children with T-cell ALL are treated on the same protocols as children with B-precursor ALL, with protocol assignment based on the same risk factor criteria for both patient populations.

References:

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31. Raimondi SC, Pui CH, Hancock ML, et al.: Heterogeneity of hyperdiploid (51-67) childhood acute lymphoblastic leukemia. Leukemia 10(2): 213-224, 1996.
32. Hann I, Vora A, Harrison G, et al.: Determinants of outcome after intensified therapy of childhood lymphoblastic leukaemia: results from Medical Research Council United Kingdom acute lymphoblastic leukaemia XI protocol. British Journal of Haematology 113(1): 103-114, 2001.
33. Ito C, Kumagai M, Manabe A, et al.: Hyperdiploid acute lymphoblastic leukemia with 51 to 65 chromosomes: a distinct biological entity with a marked propensity to undergo apoptosis. Blood 93(1): 315-320, 1999.
34. Harris MB, Shuster JJ, Carroll A, et al.: Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: a Pediatric Oncology Group study. Blood 79(12): 3316-3324, 1992.
35. Heerema NA, Sather HN, Sensel MG, et al.: Prognostic impact of trisomies of chromosomes 10, 17, and 5 among children with acute lymphoblastic leukemia and high hyperdiploidy (>50 chromosomes). Journal of Clinical Oncology 18(9): 1876-1887, 2000.
36. Pui CH, Carroll AJ, Raimondi SC, et al.: Clinical presentation, karyotypic characterization, and treatment outcome of childhood acute lymphoblastic leukemia with a near-haploid or hypodiploid less than 45 line. Blood 75(5): 1170-1177, 1990.
37. 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): 4036-4045, 1999.
38. McLean TW, Ringold S, Neuberg D, et al.: TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia. Blood 88(11): 4252-4258, 1996.
39. Rubnitz JE, Shuster JJ, Land VJ, et al.: Case-control study suggests a favorable impact of TEL rearrangement in patients with B-lineage acute lymphoblastic leukemia treated with antimetabolite-based therapy: a Pediatric Oncology Group study. Blood 89(4): 1143-1146, 1997.
40. Borkhardt A, Cazzaniga G, Viehmann S, et al.: Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian Multicenter Therapy Trials. Blood 90(2): 571-577, 1997.
41. Uckun FM, Pallisgaard N, Hokland P, et al.: Expression of TEL-AML1 fusion transcripts and response to induction therapy in standard risk acute lymphoblastic leukemia. Leukemia and Lymphoma 42(1-2): 41-56, 2001.
42. Rubnitz JE, Behm FG, Wichlan D, et al.: Low frequency of TEL-AML1 in relapsed acute lymphoblastic leukemia supports a favorable prognosis for this genetic subgroup. Leukemia 13(1): 19-21, 1999.
43. Seeger K, Adams HP, Buchwald D, et al.: TEL-AML1 fusion transcript in relapsed childhood acute lymphoblastic leukemia. The Berlin-Frankfurt-Munster Study Group. Blood 91(5): 1716-1722, 1998.
44. Seeger K, Buchwald D, Taube T, et al.: TEL-AML1 positivity in relapsed B cell precursor acute lymphoblastic leukemia in childhood. Berlin-Frankfurt-Munster Study Group. Leukemia 13(9): 1469-1470, 1999.
45. Hubeek I, Ramakers-van Woerden NI, Pieters R, et al.: TEL/AML1 fusion is not a prognostic factor in Dutch childhood acute lymphoblastic leukaemia. British Journal of Haematology 113(1): 254-255, 2001.
46. Arico M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. New England Journal of Medicine 342(14): 998-1006, 2000.
47. Schrappe M, Arico M, Harbott J, et al.: Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood 92(8): 2730-2741, 1998.
48. Ribeiro RC, Broniscer A, Rivera GK, et al.: Philadelphia chromosome-positive acute lymphoblastic leukemia in children: durable responses to chemotherapy associated with low initial white blood cell counts. Leukemia 11(9): 1493-1496, 1997.
49. Rubnitz JE, Look AT: Molecular genetics of childhood leukemias. Journal of Pediatric Hematology/Oncology 20(1): 1-11, 1998.
50. Pui CH, Frankel LS, Carroll AJ, et al.: Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): a collaborative study of 40 cases. Blood 77(3): 440-447, 1991.
51. Pui CH, Carroll LA, Raimondi SC, et al.: Childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): an update. Blood 83(8): 2384-2385, 1994.
52. Johansson B, Moorman AV, et al, on behalf of the European 11q23 Workshop participants: Hematologic malignancies with t(4;11)(q21;q23) - a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases. Leukemia 12(5): 779-787, 1998.
53. Rubnitz JE, Camitta BM, Mahmoud M, et al.: Childhood acute lymphoblastic leukemia with the MLL-ENL fusion and t(11;19)(q23;p13) translocation. Journal of Clinical Oncology 17(1): 191-196, 1999.
54. Hunger SP: Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis. Blood 87(4): 1211-1224, 1996.
55. Uckun FM, Sensel MG, Sather HN, et al.: Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children's Cancer Group. Journal of Clinical Oncology 16(2): 527-535, 1998.
56. Raimondi SC, Behm FG, Roberson PK, et al.: Cytogenetics of pre-B-cell acute lymphoblastic leukemia with emphasis on prognostic implications of the t(1;19). Journal of Clinical Oncology 8(8): 1380-1388, 1990.
57. Secker-Walker LM, Berger R, Fenaux P, et al.: Prognostic significance of the balanced t(1;19) and unbalanced der(19)t(1;19) translocations in acute lymphoblastic leukemia. Leukemia 6(5): 363-369, 1992.
58. Gaynon PS, Bleyer WA, Steinherz PG, et al.: Day 7 marrow response and outcome for children with acute lymphoblastic leukemia and unfavorable presenting features. Medical and Pediatric Oncology 18(4): 273-279, 1990.
59. Gaynon PS, Desai AA, Bostrom BC, et al.: Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review. Cancer 80(9): 1717-1726, 1997.
60. Steinherz PG, Gaynon PS, Breneman JC, et al.: Cytoreduction and prognosis in acute lymphoblastic leukemia - the importance of early marrow response: report from the Childrens Cancer Group. Journal of Clinical Oncology 14(2): 389-398, 1996.
61. Arico M, Basso G, et al, for the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP): Good steroid response in vivo predicts a favorable outcome in children with T-cell acute lymphoblastic leukemia. Cancer 75(7): 1684-1693, 1995.
62. Lauten M, Stanulla M, Zimmermann M, et al.: Clinical outcome of patients with childhood acute lymphoblastic leukaemia and an initial leukaemic blood blast count of less than 1000 per microliter. Klinische Padiatrie 213(4): 169-174, 2001.
63. Gajjar A, Ribeiro R, Hancock ML, et al.: Persistence of circulating blasts after 1 week of multiagent chemotherapy confers a poor prognosis in childhood acute lymphoblastic leukemia. Blood 86(4): 1292-1295, 1995.
64. Rautonen J, Hovi L, Siimes MA: Slow disappearance of peripheral blast cells: an independent risk factor indicating poor prognosis in children with acute lymphoblastic leukemia. Blood 71(4): 989-991, 1988.
65. Griffin TC, Shuster JJ, Buchanan GR et al.: Slow disappearance of peripheral blood blasts is an adverse prognostic factor in childhood T cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. Leukemia 14(5): 792-795, 2000.
66. Cave H, van der Werff ten Bosch J, Suciu S, et al.: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer--Childhood Leukemia Cooperative Group. New England Journal of Medicine 339(9): 591-598, 1998.
67. Dibenedetto SP, Lo Nigro L, Mayer SP, et al.: Detectable molecular residual disease at the beginning of maintenance therapy indicates poor outcome in children with T-cell acute lymphoblastic leukemia. Blood 90(3): 1226-1232, 1997.
68. Roberts WM, Estrov Z, Ouspenskaia MV, et al.: Measurement of residual leukemia during remission in childhood acute lymphoblastic leukemia. New England Journal of Medicine 336(5): 317-323, 1997.
69. van Dongen JJ, Seriu T, Panzer-Grumayer ER, et al.: Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352(9142): 1731-1738, 1998.
70. Panzer-Grumayer 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): 790-794, 2000.
71. Coustan-Smith E, Sancho J, Hancock ML, et al.: Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia. Blood 96(8): 2691-2696, 2000.
72. 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): 1253-1258, 2002.
73. Dworzak MN, Froschl G, Printz D, et al.: Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia. Blood 99(6): 1952-1958, 2002.
74. 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.

TREATMENT OPTION OVERVIEW

Nationwide clinical trials are generally available for children with ALL, with specific protocols designed for children at standard (or 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 pediatric cancer center.[8]

Successful treatment of children with ALL requires the control of systemic disease (marrow, liver and spleen, lymph nodes, etc.) as well as the treatment (or prevention) of extramedullary disease particularly in the central nervous system (CNS). Only 3% of patients have detectable CNS involvement by accepted criteria at diagnosis (>/= 5 WBC/mm3 with lymphoblast cells present), however, unless specific therapy is directed toward the CNS (intrathecal medication, cranial irradiation, high-dose systemic chemotherapy with methotrexate or cytarabine) 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, patients with documented CNS leukemia at diagnosis receive intrathecal therapy followed by cranial irradiation with or without concurrent spinal 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. The average duration of maintenance therapy for children with ALL ranges between 2 and 3 years.

Subgroups of patients who have a poor prognosis with current standard therapy may require different treatment. For example, infants with ALL represent a distinct category of patients at higher risk for treatment failure, with the poorest prognosis for those with MLL gene rearrangements.[9-11] These children are generally treated with regimens designed specifically for infants.[12-15] Current regimens for infants employ intensified treatment approaches and may offer improved disease control compared to previously utilized, less intensive approaches, but long-term outcome and toxicity are unknown.[15-17] Certain children with ALL older than 1 year of age also have a less than 50% likelihood of long-term remission with current therapy (e.g., t(9;22) Philadelphia chromosome positive ALL and patients with hypodiploid lymphoblasts). For these patients in first remission, allogeneic bone marrow transplantation from a HLA- matched sibling should be considered.[18-20] However, HLA-matched sibling donor transplant has not been proven to be of benefit in patients defined as high-risk solely by WBC count, gender, and age.[21]

Since myelosuppression and generalized immunosuppression are an anticipated consequence of both leukemia and its treatment with chemotherapy, it is imperative that patients be closely monitored during treatment. Adequate facilities must be immediately available both for hematologic support and for the treatment of infectious complications throughout all phases of leukemia treatment.

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

References:

1. Gaynon PS, Trigg ME, Heerema NA, et al.: Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 14(12): 2223-2233, 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. Leukemia 14(12): 2205-2222, 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): 2247-2256, 2000.
4. Pui CH, Evans WE: Acute lymphoblastic leukemia. New England Journal of Medicine 339(9): 605-615, 1998.
5. Pui CH: Acute lymphoblastic leukemia in children. Current Opinion in Oncology 12(1): 3-12, 2000.
6. Vietti TJ, Land V, et al, for the Pediatric Oncology Group: 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. European Journal of Cancer 33(9): 1439-1447, 1997.
8. Sanders J, Glader B, Cairo M, et al.: 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): 139-141, 1997.
9. 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): 570-573, 1994.
10. Hilden JM, Frestedt JL, Moore RO, et al.: Molecular analysis of infant acute lymphoblastic leukemia: MLL gene rearrangement and reverse transcriptase-polymerase chain reaction for t(4;11)(q21;q23). Blood 86(10): 3876-3882, 1995.
11. Pui C, Behm FG, Downing JR, et al.: 11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia. Journal of Clinical Oncology 12(5): 909-915, 1994.
12. Frankel LS, Ochs J, Shuster JJ, et al.: Therapeutic trial for infant acute lymphoblastic leukemia: the Pediatric Oncology Group experience (POG 8493). Journal of Pediatric Hematology/Oncology 19(1): 35-42, 1997.
13. Chessells JM, Eden OB, Bailey CC, et al.: Acute lymphoblastic leukaemia in infancy: experience in MRC UKALL trials. Report from the Medical Research Council Working Party on Childhood Leukaemia. Leukemia 8(8): 1275-1279, 1994.
14. Ferster A, Bertrand Y, Benoit Y, et al.: Improved survival for acute lymphoblastic leukaemia in infancy: the experience of EORTC-Childhood Leukaemia Cooperative Group. British Journal of Haematology 86(2): 284-290, 1994.
15. 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): 2285-2295, 1997.
16. Dreyer ZE, Steuber CP, Bowman WP, et al.: High risk infant ALL--improved survival with intensive chemotherapy. Proceedings of the American Society of Clinical Oncology 17: A2032, 529a, 1998.
17. 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. Journal of Clinical Oncology 17(2): 445-455, 1999.
18. 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): 2053-2058, 1999.
19. Arico M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. New England Journal of Medicine 342(14): 998-1006, 2000.
20. 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. Medical and Pediatric Oncology 37(5): 426-431, 2001.
21. 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): 2412-2418, 2000.

UNTREATED CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

Induction Chemotherapy

Dexamethasone is preferred over prednisone for younger patients with acute lymphoblastic leukemia (ALL) receiving 3-drug induction therapy based on data from a Children's Cancer Group (CCG) study in which dexamethasone was compared to prednisone for children 1 to 9 years of age with lower risk ALL.[8] Patients randomized to receive dexamethasone had significantly fewer CNS relapses and bone marrow relapses, and a significantly better event-free survival rate.[8] The benefit of using dexamethasone in induction therapy for adolescents requires investigation, because of the increased risk of steroid-induced aseptic necrosis in this age group.[9] Dexamethasone should be used with caution in patients receiving intensive induction therapy (more than 3 drugs) as its use appears to increase the frequency and severity of infectious complications.[10]

Several forms of L-asparaginase are available for use in the treatment of children with ALL, with E. coli L-asparaginase being most commonly used.[11] Pegaspargase is an alternative form of L-asparaginase in which the E. coli enzyme is modified by the covalent attachment of polyethylene glycol. Pegasparagase has a much longer serum half-life than native E. coli L-asparaginase, allowing it to produce asparagine depletion with less frequent administration.[12] A single intramuscular dose of pegaspargase 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).[13] In a randomized trial of patients with standard risk ALL comparing the use of pegaspargase versus native E. coli asparaginase in induction and each of two delayed intensification
courses, the use of pegaspargase was associated with more rapid blast clearance and a lower incidence of neutralizing antibodies.[14] All patients on the current Children's Cancer Group (CCG) standard risk trial receive only pegaspargase.

In general, patients will achieve a complete remission within the first 4 weeks. Patients who require more than 4 weeks to achieve remission have a poor prognosis.[15,16] 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 induction therapy,[2,17,18] and protocols of the Children's Cancer Group base treatment decisions on the day 7 bone marrow response (for high-risk protocols) or day 14 bone marrow response (for standard-risk protocols).[19] (Information about ongoing clinical trials is available from the NCI (Http: //cancer.gov/clinical_trials/).

Central Nervous System Sanctuary Therapy

Intrathecal chemotherapy may be the sole form of presymptomatic CNS therapy or it may be combined with systemic moderate to high dose infusion methotrexate with leucovorin rescue and/or cranial radiation (1200-1800 cGy). Appropriate systemic therapy combined with IT chemotherapy results in CNS relapse rates of less than 5% for children with standard risk ALL.[6,21,22] Whether patients at high risk of CNS relapse (for example, age greater than or equal to 10 years, presence of hyperleukocytosis, or T cell ALL) continue to require cranial radiation in addition to extended intrathecal therapy is controversial,[23,24] although patients designated as high risk generally receive cranial radiation as part of their CNS sanctuary therapy.[19,25,26] High-risk patients with rapid early response to therapy, however, appear to have adequate CNS prophylaxis with intrathecal therapy alone.[27] Children with ALL who present with CNS disease at diagnosis (defined as greater than or equal to 5 white cells per cubic millimeter in cerebral spinal fluid (CSF) with lymphoblasts present) generally receive cranial radiation with or without concurrent spinal radiation in addition to appropriate systemic and intrathecal chemotherapy.

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 behavioral and neuropsychological, and neuroendocrine disturbances.[28]

The long-term deleterious effects of cranial radiation when used for CNS prophylaxis, particularly at doses greater than 1800 cGy, have been recognized for years. Children receiving these higher doses of cranial radiation were at significant risk for neurocognitive and neuroendocrine sequelae.[29-32] Children receiving 1800 cGy of cranial radiation may be at diminished risk for neurologic toxicity compared to those receiving 2400 cGy,[26] although neurocognitive and neuroendocrine effects have been noted at this lower dose.[33,34]. In the German BFM studies, many patients receive only 1200 cGy of central nervous system radiation.[35] Longer follow-up is needed to determine whether 1200 cGy will be associated with a lower incidence of neurologic sequelae. Young children (e.g., younger than four years) are at increased risk for neurocognitive decline and other sequelae following cranial radiation.[33,36,37] It appears that girls may be at a higher risk for radiation-induced neuropsychologic and neuroendocrine sequelae than boys.[36-38] In general, high-dose methotrexate should not be given following cranial radiation.

The most common toxicity associated with intrathecal therapy alone in the absence of cranial radiation is seizures. Approximately 5% to 10% of patients with ALL will have at least one seizure during therapy.[39] Patients with ALL who develop seizures during the course of treatment and who require anticonvulsant therapy should not receive phenobarbital or dilantin as anticonvulsant treatment, as these drugs may increase the clearance of some chemotherapeutic drugs. Valproic acid or gabapentin are alternative anticonvulsants with less enzyme-inducing capabilities.[40] In general, patients who receive intrathecal therapy without cranial radiation as CNS prophylaxis 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.[34,41,42] However, regimens that utilize a bi-weekly schedule of 12 doses of intravenous high-dose methotrexate with leucovorin rescue and intrathecal chemotherapy in the off-week have been associated with excessive neurologic toxicity.[43] There is controversy regarding whether patients who receive dexamethasone are at risk for neurocognitive disturbances.[44]

References:

1. Pui CH, Evans WE: Acute lymphoblastic leukemia. New England Journal of Medicine 339(9): 605-615, 1998.
2. Gaynon PS, Bleyer WA, Steinherz PG, et al.: Day 7 marrow response and outcome for children with acute lymphoblastic leukemia and unfavorable presenting features. Medical and Pediatric Oncology 18(4): 273-279, 1990.
3. 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. Journal of Clinical Oncology 11(3): 527-537, 1993.
4. 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. Journal of Clinical Oncology 11(11): 2234-2242, 1993.
5. LeClerc JM, Billett AL, Gelber RD, et al.: Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber ALL Consortium protocol 87-01. Journal of Clinical Oncology 20(1): 237-246, 2002.
6. Veerman AJ, Hahlen 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. Journal of Clinical Oncology 14(3): 911-918, 1996.
7. Mahoney DH Jr, Shuster J, Nitschke R, et al.: Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial. Journal of Clinical Oncology 16(1): 246-254, 1998.
8. Bostrom B, Gaynon PS, Sather S, et al.: Dexamethasone (DEX) decreases central nervous system (CNS) relapse and improves event-free survival (EFS) in lower risk acute lymphoblastic leukemia (ALL). Proceedings of the American Society of Clinical Oncology 17: A2024, 527a, 1998.
9. Ojala AE, Lanning FP, Paakko E, et al.: Osteonecrosis in children treated for acute lymphoblastic leukemia: a magnetic resonance imaging study after treatment. Medical and Pediatric Oncology 29(4): 260-265, 1997.
10. Hurwitz CA, Silverman LB, Schorin MA, et al.: Substituting dexamethasone for prednisone complicates remission induction in children with acute lymphoblastic leukemia. Cancer 88(8): 1964-1969, 2000.
11. Muller HJ, Boos J: Use of L-asparaginase in childhood ALL. Critical Reviews in Oncology/Hematology 28(2): 97-113, 1998.
12. Asselin BL, Whitin JC, Coppola DJ, et al.: Comparative pharmacokinetic studies of three asparaginase preparations. Journal of Clinical Oncology 11(9): 1780-1786, 1993.
13. Cohen A, Ettinger L, Ettinger P, et al.: Randomized trial of PEG-vs native-asparaginase in children with newly diagnosed acute lymphoblastic leukemia (ALL): CCG study 1962. Blood 94(10 pt 1): A-2790, 628a, 1999.
14. Avramis VI, Sencer S, Periclou AP, et al.: A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 99(6): 1986-1994, 2002.
15. Silverman LB, Gelber RD, Young ML, et al.: Induction failure in acute lymphoblastic leukemia of childhood. Cancer 85(6): 1395-1404, 1999.
16. Ogden AK, Pollock BH, Bernstein ML, et al.: Intermediate-dose methotrexate and intravenous 6-mercaptopurine chemotherapy for children with acute lymphoblastic leukemia who did not respond to initial induction therapy. Journal of Pediatric Hematology/Oncology 24(3): 182-187, 2002.
17. Gajjar A, Ribeiro R, Hancock ML, et al.: Persistence of circulating blasts after 1 week of multiagent chemotherapy confers a poor prognosis in childhood acute lymphoblastic leukemia. Blood 86(4): 1292-1295, 1995.
18. Steinherz PG, Gaynon PS, Breneman JC, et al.: Cytoreduction and prognosis in acute lymphoblastic leukemia - the importance of early marrow response: report from the Childrens Cancer Group. Journal of Clinical Oncology 14(2): 389-398, 1996.
19. Nachman JB, Sather HN, Sensel MG, et al.: Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. New England Journal of Medicine 338(23): 1663-1671, 1998.
20. Thyss A, Suciu S, et al, for the European Organization for Research and Treatment of Cancer Children's Leukemia Cooperative Group: Systemic effect of intrathecal methotrexate during the initial phase of treatment of childhood acute lymphoblastic leukemia. Journal of Clinical Oncology 15(5): 1824-1830, 1997.
21. Tubergen DG, Gilchrist GS, O'Brien RT, et al.: Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Childrens Cancer Group report. Journal of Clinical Oncology 11(3): 520-526, 1993.
22. Conter V, Arico M, Valsecchi MG, et al.: Extended intrathecal methotrexate may replace cranial irradiation for prevention of CNS relapse in children with intermediate-risk acute lymphoblastic leukemia treated with Berlin-Frankfurt-Munster-based intensive chemotherapy. Journal of Clinical Oncology 13(10): 2497-2502, 1995.
23. Schrappe M, Reiter A, Riehm H: Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia. Journal of Neuro-Oncology 38(2-3): 159-165, 1998.
24. Laver JH, Barredo JC, Amylon M, et al.: Effects of cranial radiation in children with high risk T cell acute lymphoblastic leukemia: a Pediatric Oncology Group report. Leukemia 14(3): 369-373, 2000.
25. Pui CH, Mahmoud HH, Rivera GK, et al.: Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 92(2): 411-415, 1998.
26. Waber DP, Shapiro BL, Carpentieri SC, et al.: Excellent therapeutic efficacy and minimal late neurotoxicity in children treated with 18 grays of cranial radiation therapy for high-risk acute lymphoblastic leukemia. Cancer 92(1): 15-22, 2001.
27. Nachman J, Sather HN, Cherlow JM, et al.: Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children's Cancer Group. Journal of Clinical Oncology 16(3): 920-930, 1998.
28. Moore IM, Espy KA, Kaufman P, et al.: Cognitive consequences and central nervous system injury following treatment for childhood leukemia. Seminars in Oncology Nursing 16(4): 279-290, 2000.
29. Stubberfield TG, Byrne GC, Jones TW: Growth and growth hormone secretion after treatment for acute lymphoblastic leukemia in childhood. 18-Gy versus 24-Gy cranial irradiation. Journal of Pediatric Hematology/Oncology 17(2): 167-171, 1995.
30. Rowland JH, Glidewell OJ, Sibley RF, et al.: Effects of different forms of central nervous system prophylaxis on neuropsychologic function in childhood leukemia. Journal of Clinical Oncology 2(12): 1327-1335, 1984.
31. Halberg FE, Kramer JH, Moore IM, et al.: Prophylactic cranial irradiation dose effects on late cognitive function in children treated for acute lymphoblastic leukemia. International Journal of Radiation Oncology, Biology, Physics 22: 13-16, 1992.
32. Hill JM, Kornblith AB, Jones D, et al.: A comparative study of the long term psychosocial functioning of childhood acute lymphoblastic leukemia survivors treated by intrathecal methotrexate with or without cranial radiation. Cancer 82(1): 208-218, 1998.
33. Jankovic, M, Brouwers P, Valsecchi MG, et al.: Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia. Lancet 344(8917): 224-227, 1994.
34. Butler RW, Hill JM, Steinherz PG, et al.: Neuropsychologic effects of cranial irradiation, intrathecal methotrexate, and systemic methotrexate in childhood cancer. Journal of Clinical Oncology 12(12): 2621-2629, 1994.
35. 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. Blood 95(11): 3310-3322, 2000.
36. Sklar C, Mertens A, Walter A, et al.: Final height after treatment for childhood acute lymphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2400 centigrays of cranial irradiation. Journal of Pediatrics 123(1): 59-64, 1993.
37. Christie D, Leiper AD, Chessells JM, et al.: Intellectual performance after presymptomatic cranial radiotherapy for leukaemia: effects of age and sex. Archives of Disease in Childhood 73(2): 136-140, 1995.
38. Waber DP, Tarbell NJ, Kahn CM, et al.: The relationship of sex and treatment modality to neuropsychologic outcome in childhood acute lymphoblastic leukemia. Journal of Clinical Oncology 10(5): 810-817, 1992.
39. Ochs JJ, Bowman WP, Pui CH, et al.: Seizures in childhood lymphoblastic leukaemia patients. Lancet 2(8417-8418): 1422-1424, 1984.
40. Relling MV, Pui CH, Sandlund JT, et al.: Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia. Lancet 356(9226): 285-290, 2000.
41. Espy KA, Moore IM, Kaufmann PM, et al.: Chemotherapeutic CNS prophylaxis and neuropsychologic change in children with acute lymphoblastic leukemia: a prospective study. Journal of Pediatric Psychology 26(1): 1-9, 2001.
42. Copeland DR, Moore BD III, Francis DJ, et al.: Neuropsychologic effects of chemotherapy on children with cancer: a longitudinal study. Journal of Clinical Oncology 14(10): 2826-2835, 1996.
43. Mahoney DH, Shuster JJ, Nitschke R, et al.: Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy. Journal of Clinical Oncology 16(5): 1712-1722, 1998.
44. Waber DP, Carpentieri SC, Klar N, et al.: Cognitive sequelae in children treated for acute lymphoblastic leukemia with dexamethasone or prednisone. Journal of Pediatric Hematology/Oncology 22(3): 206-213, 2000.

CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IN REMISSION

Consolidation/Intensification

In children with standard-risk disease, there has been an attempt to limit exposure to drugs, such as the anthracyclines and alkylating agents, which are associated with an increased risk of late toxic effects.[3,11,12] For example, regimens utilizing a limited number of courses of intermediate- or high-dose methotrexate have been used with good results for treating children with standard-risk acute lymphoblastic leukemia (ALL).[1,3,4] Another treatment approach for decreasing late effects of therapy utilizes anthracyclines and alkylating agents, but limits their cumulative dose to an amount not associated with substantial long-term toxicity. An example of this approach is the use of "delayed intensification," in which patients receive an anthracycline-based "reinduction" regimen and a cyclophosphamide-containing "reconsolidation" regimen at approximately 3 months after remission is achieved. The use of "delayed intensification" improves outcome for children with standard-risk ALL, in comparison to that achieved without an intensification phase.[5,13] Two blocks of "delayed intensification" may improve outcome for some patients with standard-risk ALL, although further studies are needed to define those patients that benefit from the additional therapy.[14]

In high-risk patients, a number of different approaches have been used with comparable efficacy.[6,7,15-17] Treatment for high-risk patients generally includes blocks of intensified therapy, such as the "delayed intensification" blocks (reinduction/reconsolidation) used by the Children's Cancer Group (CCG) and by the German Berlin-Frankfurt-Munster (BFM) group.[2,8,15] For high-risk patients with slow early response to therapy (M3 marrow on day 7 of induction therapy), augmented BFM therapy has been shown to improve outcome.[18] The augmented BFM regimen utilizes 2 courses of "delayed intensification", while also intensifying therapy with repeated courses of intravenous methotrexate (without leucovorin rescue) given with vincristine and asparaginase. The augmented BFM regimen is now being evaluated for other groups of high-risk patients. The incidence of osteonecrosis is increased with the use of steroids in this treatment approach.[19]

Maintenance

Pulses of vincristine and prednisone/dexamethasone are often added to the standard maintenance regimen. A CCG randomized trial demonstrated improved outcome for patients receiving vincristine/prednisone pulses,[24] and a meta-analysis combining data from 6 clinical trials showed an event-free survival advantage for vincristine/prednisone pulses.[24,25] Dexamethasone is preferred over prednisone for younger patients with ALL based on data from a CCG study, in which dexamethasone was compared to prednisone for children 1 to 9 years of age with lower risk ALL.[26] Patients randomized to receive dexamethasone had significantly fewer CNS relapses and a significantly better event-free survival rate.[26] The benefit of using dexamethasone in adolescents requires investigation, because of the increased risk of steroid- induced aseptic necrosis and a higher incidence of bone fractures in this age group.[27,28]

Maintenance chemotherapy generally continues until 2 to 3 years of continuous complete remission. Extending the duration of maintenance therapy to 5 years does not improve outcome.[25,29]

Role of Bone Marrow Transplant for Philadelphia Chromosome-Positive ALL

Treatment Options Under Clinical Evaluation

Children with standard or lower risk of relapse:

1. The Pediatric Oncology Group (POG) is evaluating whether high-dose
methotrexate can be administered as a more convenient 4-hour infusion rather than as the standard 24-hour infusion and is also evaluating whether delayed intensification with a multiagent regimen improves outcome when added to a treatment backbone that includes sequential courses of high-dose methotrexate.

2. The CCG protocol for standard-risk patients is comparing oral methotrexate
versus escalating-dose intravenous methotrexate without leucovorin rescue following remission induction therapy. The protocol also addresses the question of whether 2 courses of delayed intensification improves outcome compared to a single course of delayed intensification.

Children with higher risk of relapse:

1. POG is evaluating the augmented BFM regimen in comparison to its previously
utilized therapy for children with ALL at high risk for relapse.

2. The CCG protocol for children with higher risk of relapse is stratified
based on whether patients have a rapid response or a slow response to the first 7 days of induction therapy. For children with a rapid early response, the primary question of therapy is to determine whether components of the augmented BFM regimen, a regimen previously identified as effective for children with slow early response to induction therapy,[31] can improve outcome in comparison to standard therapy with delayed intensification. For children with a slow early response to induction therapy, the primary question of therapy is whether intensification of therapy with idarubicin and cyclophosphamide can improve outcome in comparison to treatment with the augmented BFM regimen.

Children with T-cell ALL:

1. CCG treats children with T-cell ALL on the same protocols as children with
B-precursor ALL. Protocol and treatment assignment are based on the clinical characteristics of the patient (e.g., age and WBC) and their response to initial therapy.

2. POG treats children with T-cell ALL distinctly from children with
B-precursor ALL. The POG protocol for patients with T-cell ALL was designed to evaluate the role of high-dose methotrexate and the role of the cardioprotectant dexrazoxane. The multi-agent chemotherapy backbone for this protocol is based on an effective leukemia regimen developed at the Dana Farber Cancer Institute (DFCI) that produced a 5-year event-free survival (EFS) rate of 79% in a relatively small number of children with T-cell ALL (n=29).[7] Results of an interim analysis of the POG protocol led investigators to conclude that the addition of high-dose methotrexate to the DFCI-based chemotherapy regimen results in significantly improved EFS, due in large measure to a decrease in the rate of CNS relapse.[32] The POG study is the first clinical trial to provide convincing evidence that high-dose methotrexate can improve outcome for children with T-cell ALL, and based on these results, all patients entered onto the POG protocol now receive high-dose methotrexate.

Infants with ALL:

Because of their distinctive biological characteristics and their high risk for leukemia recurrence, infants with ALL are treated on protocols specifically designed for this patient population.

1. Currently under evaluation is the role of intensive induction and
consolidation chemotherapy including high-dose methotrexate.

2. For infants with ALL whose leukemia cells have chromosome 11q23
abnormalities and who therefore have a very high risk of treatment failure, the role of bone marrow transplantation with HLA-matched related or unrelated donors is under evaluation.

References:

1. Harris MB, Shuster JJ, Pullen DJ, et al.: Consolidation therapy with antimetabolite-based therapy in standard-risk acute lymphocytic leukemia of childhood: a Pediatric Oncology Group study. Journal of Clinical Oncology 16(8): 2840-2847, 1998.
2. Reiter A, Schrappe M, Ludwig W, et al.: Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86. Blood 84(9): 3122-3133, 1994.
3. Veerman AJ, Hahlen 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. Journal of Clinical Oncology 14(3): 911-918, 1996.
4. Mahoney DH Jr, Shuster JJ, Nitschke R, et al.: Intensification with intermediate-dose intravenous methotrexate is effective therapy for children with lower-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group study. Journal of Clinical Oncology 18(6): 1285-1294, 2000.
5. 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. Journal of Clinical Oncology 11(3): 527-537, 1993.
6. Richards S, Burrett J, et al, for the Medical Research Council Working Party on Childhood Leukaemia: Improved survival with early intensification: combined results from the Medical Research Council childhood ALL randomised trials, UKALL X and UKALL XI. Leukemia 12(7): 1031-1036, 1998.
7. 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): 1211-1218, 2001.
8. Hann I, Vora A, Richards S, et al.: Benefit of intensified treatment for all children with acute lymphoblastic leukaemia: results from MRC UKALL XI and MRC ALL97 randomised trials. Leukemia 14(3): 356-363, 2000.
9. Harris MB, Shuster JJ, Pullen J, et al.: Treatment of children with early pre-B and pre-B acute lymphocytic leukemia with antimetabolite-based intensification regimens: a Pediatric Oncology Group study. Leukemia 14(9): 1570-1576, 2000.
10. Rizzari C, Valsecchi MG, Arico M, et al.: Effect of protracted high-dose L-asparaginase given as a second exposure in a Berlin-Frankfurt-Munster-based treatment: results of the randomized 9102 intermediate risk childhood acute lymphoblastic leukemia study--a report from the Associazione Italiana Ematologia Oncologia Pediatrica. Journal of Clinical Oncology 19(5): 1297-1303, 2001.
11. Camitta B, Leventhal B, Lauer S, et al.: Intermediate-dose intravenous methotrexate and mercaptopurine therapy for non-T, non-B acute lymphocytic leukemia of childhood: a Pediatric Oncology Group study. Journal of Clinical Oncology 7(10): 1539-1544, 1989.
12. Gustafsson G, Kreuger A, et al. for the Nordic Society of Paediatric Haematology and Oncology (NOPHO): Intensified treatment of acute childhood lymphoblastic leukaemia has improved prognosis, especially in non-high-risk patients: the Nordic experience of 2648 patients diagnosed between 1981 and 1996. Acta Paediatrica 87(11): 1151-1161, 1998.
13. Riehm H, Gadner H, Henze G, et al.: Results and significance of six randomized trials in four consecutive ALL-BFM studies. Haematologie und Bluttransfusion 33(Suppl): 439-450, 1990.
14. Lange BJ, Bostrom BC, Cherlow JM, et al.: Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 99(3): 825-833, 2002.
15. 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. Journal of Clinical Oncology 11(11): 2234-2242, 1993.
16. Rivera GK, Pui CH, Hancock ML, et al.: Update of St Jude Study XI for childhood acute lymphoblastic leukemia. Leukemia 6(suppl 2): 153-156, 1992.
17. Lauer SJ, Shuster JJ, Mahoney DH Jr, et al.: A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial. Leukemia 15(7): 1038-1045, 2001.
18. Nachman J, Sather HN, Gaynon PS, et al.: Augmented Berlin-Frankfurt-Munster therapy abrogates the adverse prognostic significance of slow early response to induction chemotherapy for children and adolescents with acute lymphoblastic leukemia and unfavorable presenting features: a report from the Children's Cancer Group. Journal of Clinical Oncology 15(6): 2222-2230, 1997.
19. Mattano LA Jr, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. Journal of Clinical Oncology 18(18): 3262-3272, 2000.
20. Schmieglow K, Glomstein A, Kristinsson J, et al.: Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. Journal of Pediatric Hematology/Oncology 19(2): 102-109, 1997.
21. Davies HA, Lilleyman JS: Compliance with oral chemotherapy in childhood lymphoblastic leukaemia. Cancer Treatment Reviews 21(2): 93-103, 1995.
22. Relling MV, Hancock ML, Rivera GK, et al.: Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. Journal of the National Cancer Institute 91(23): 2001-2008, 1999.
23. Andersen JB, Szumlanski C, Weinshilboum RM, et al.: Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatrica 87(1): 108-111, 1998.
24. Bleyer WA, Sather HN, Nickerson HJ, et al.: Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group. Journal of Clinical Oncology 9(6): 1012-1021, 1991.
25. Richards S, Gray R, Peto R, et al.: Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children. Childhood ALL Collaborative Group. Lancet 347(9018): 1783-1788, 1996.
26. Bostrom B, Gaynon PS, Sather H, et al.: Dexamethasone decreases central nervous system relapse and improves event-free survival in lower risk acute lymphoblastic leukemia. Proceedings of the American Society of Clinical Oncology 17: A2024, 1998.
27. Ojala AE, Lanning FP, Paakko E, et al.: Osteonecrosis in children treated for acute lymphoblastic leukemia: a magnetic resonance imaging study after treatment. Medical and Pediatric Oncology 29(4): 260-265, 1997.
28. Strauss AJ, Su JT, Dalton VM, et al.: Bony morbidity in children treated for acute lymphoblastic leukemia. Journal of Clinical Oncology 19(12): 3066-3072, 2001.
29. Miller DL, Leikin SL, Albo VC, et al.: Three versus five years of maintenance therapy are equivalent in childhood acute lymphoblastic leukemia: a report of the Childrens Cancer Study Group. Journal of Clinical Oncology 7(3): 316-325, 1989.
30. Arico M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. New England Journal of Medicine 342(14): 998-1006, 2000.
31. Nachman JB, Sather HN, Sensel MG, et al.: Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. New England Journal of Medicine 338(23): 1663-1671, 1998.
32. Asselin B, Shuster J, Amylon M, et al.: Improved event-free survival (EFS) with high dose methotrexate (HDM) in T-cell lymphoblastic leukemia (T-ALL) and advanced lymphoblastic lymphoma (T-NHL): a Pediatric Oncology Group (POG) study. Proceedings of the American Society of Clinical Oncology A-1464, 2001.

RECURRENT CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

The selection of therapy for the child whose disease recurs on or shortly after therapy depends on many factors including prior treatment, whether the recurrence is medullary or extramedullary, and individual patient considerations. Aggressive approaches including bone marrow transplantation should be strongly considered for patients with marrow relapse occurring while on treatment or within 6 months of termination of therapy, or late marrow relapse with high tumor load as indicated by a peripheral blast count of 10,000/uL or more.[8] For patients with an early marrow relapse, allogeneic transplant from an HLA identical sibling or matched unrelated donor that is performed in second remission has resulted in longer leukemia free survival when compared with a chemotherapy approach.[5,12-14] A retrospective case control study suggests that transplant conditioning regimens which include total body irradiation (TBI) produce higher cure rates than chemotherapy only preparative regimens.[15] The potential neurotoxic effects of TBI should be considered, particularly for very young patients. For patients with a late marrow relapse, a primary chemotherapy approach should be considered with bone marrow transplantation reserved for a subsequent marrow relapse.[7,16,17] The value of matched unrelated stem cell transplantation in the therapy of children with recurrent ALL is under investigation.[18-21]

With the improved success of treatment of children with ALL, the incidence of isolated extramedullary relapse has decreased. The incidence of both isolated central nervous system (CNS) and testicular relapse is less than 10%. While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal therapy combined with craniospinal irradiation has improved the outlook particularly for patients who did not receive cranial irradiation during their first remission.[22-24] For children whose initial remission was 18 months or greater, 4-year event-free survival (EFS) rates of approximately 80% have been observed using this strategy, compared to EFS rates of approximately 45% for children with CNS relapse within 18 months of diagnosis.[24] The results of treatment of isolated testicular relapse depend on the timing of the relapse. The 3-year event-free survival (EFS) of boys with overt testicular relapse during therapy is approximately 40%, and it is approximately 85% for boys with late testicular relapse.[25] A study that looked at testicular biopsy at the end of therapy failed to demonstrate a survival benefit for patients with early detection of occult disease.[26]

Treatment options under clinical evaluation:

Clinical trials investigating new agents and new combinations of agents are available for children with recurrent ALL and should be considered. Targeted therapies specific for ALL are being developed, including monoclonal antibody based therapies and using drugs that inhibit signal transduction pathways required for leukemia cell growth and survival. Information about ongoing clinical trials is available from the NCI (Http: //cancer.gov/clinical_trials/).

References:

1. Gaynon PS, Qu RP, Chappell RJ, et al.: Survival after relapse in childhood acute lymphoblastic leukemia: impact of site and time to first relapse--the Children's Cancer Group Experience. Cancer 82(7): 1387-1395, 1998.
2. Uderzo C, Conter V, Dini G, et al.: Treatment of childhood acute lymphoblastic leukemia after the first relapse: curative strategies. Haematologica 86(1): 1-7, 2001.
3. Henze G, Fengler R, Hartmann B, et al.: Six-year experience with a comprehensive approach to the treatment of recurrent childhood acute lymphoblastic leukemia (ALL-REZ BFM 85): a relapse study of the BFM group. Blood 78(5): 1166-1172, 1991.
4. Schroeder H, Garwicz S, Kristinsson J, et al.: Outcome after first relapse in children with acute lymphoblastic leukemia: a population-based study of 315 patients from the Nordic Society of Pediatric Hematology and Oncology (NOPHO). Medical and Pediatric Oncology 25(5): 372-378, 1995.
5. Wheeler K, Richards S, et al. for the Medical Research Council Working Party on Childhood Leukaemia: Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukemia: the MRC UKALL X experience. British Journal of Haematology 101(1): 94-103, 1998.
6. Buchanan GR, Rivera GK, Pollock BH, et al.: Alternating drug pairs with or without periodic reinduction in children with acute lymphoblastic leukemia in second bone marrow remission: a Pediatric Oncology Group study. Cancer 88(5): 1166-1174, 2000.
7. Rivera GK, Hudson MM, Liu Q, et al.: Effectiveness of intensified rotational combination chemotherapy for late hematologic relapse of childhood acute lymphoblastic leukemia. Blood 88(3): 831-837, 1996.
8. Buhrer C, Hartmann R, Fengler R, et al.: Peripheral blast counts at diagnosis of late isolated bone marrow relapse of childhood acute lymphoblastic leukemia predict response to salvage chemotherapy and outcome. Journal of Clinical Oncology 14(10): 2812-2817, 1996.
9. Sadowitz PD, Smith SD, Shuster J, et al.: Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood 81(3): 602-609, 1993.
10. Abshire TC, Buchanan GR, Jackson JF, et al.: Morphologic, immunologic and cytogenetic studies in children with acute lymphoblastic leukemia at diagnosis and relapse: a Pediatric Oncology Group study. Leukemia 6(5): 357-362, 1992.
11. Eckert C, Biondi A, Seeger K, et al.: Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet 358(9289): 1239-1241, 2001.
12. Barrett AJ, Horowitz MM, Pollock BH, et al.: Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission. New England Journal of Medicine 331(19): 1253-1258, 1994.
13. Uderzo C, Valsecchi MG, Bacigalupo A, et al.: Treatment of childhood acute lymphoblastic leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: ten-year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association. Journal of Clinical Oncology 13(2): 352-358, 1995.
14. Harrison G, Richards S, Lawson S, et al.: Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. Annals of Oncology 11(8): 999-1006, 2000.
15. Davies SM, Ramsay NK, Klein JP, et al.: Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia. Journal of Clinical Oncology 18(2): 340-347, 2000.
16. Borgmann A, Baumgarten E, Schmid H, et al.: Allogeneic bone marrow transplantation for a subset of children with acute lymphoblastic leukemia in third remission: a conceivable alternative? Bone Marrow Transplantation 20(11): 939-944, 1997.
17. Schroeder H, Gustafsson G, Saarinen-Pihkala UM, et al.: Allogeneic bone marrow transplantation in second remission of childhood acute lymphoblastic leukemia: a population-based case control study from the Nordic countries. Bone Marrow Transplantation 23(6): 555-560, 1999.
18. Hongeng S, Krance RA, Bowman LC, et al.: Outcomes of transplantation with matched-sibling and unrelated-donor bone marrow in children with leukaemia. Lancet 350(9080): 767-771, 1997.
19. Casper J, Camitta B, Truitt R, et al.: Unrelated bone marrow donor transplants for children with leukemia or myelodysplasia. Blood 85(9): 2354-2363, 1995.
20. Weisdorf DJ, Billett AL, Hannan P, et al.: Autologous versus unrelated donor allogeneic marrow transplantation for acute lymphoblastic leukemia. Blood 90(8): 2962-2968, 1997.
21. Saarinen-Pihkala UM, Gustafsson G, Ringden O, et al.: No disadvantage in outcome of using matched unrelated donors as compared with matched sibling donors for bone marrow transplantation in children with acute lymphoblastic leukemia in second remission. Journal of Clinical Oncology 19(14): 3406-3414, 2001.
22. Ribeiro RC, Rivera GK, Hudson M, et al.: An intensive re-treatment protocol for children with an isolated CNS relapse of acute lymphoblastic leukemia. Journal of Clinical Oncology 13(2): 333-338, 1995.
23. Kumar P, Kun LE, Hustu HO, et al.: Survival outcome following isolated central nervous system relapse treated with additional chemotherapy and craniospinal irradiation in childhood acute lymphoblastic leukemia. International Journal of Radiation Oncology, Biology, Physics 31(3): 477-483, 1995.
24. Ritchey AK, Pollock BH, Lauer SJ, et al.: Improved survival of children with isolated CNS relapse of acute lymphoblastic leukemia: a Pediatric Oncology Group study. Journal of Clinical Oncology 17(12): 3745-3752, 1999.
25. Wofford MM, Smith SD, Shuster JJ, et al.: Treatment of occult or late overt testicular relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. Journal of Clinical Oncology 10(4): 624-630, 1992.
26. Trigg ME, Steinherz PG, Chappell R, et al.: Early testicular biopsy in males with acute lymphoblastic leukemia: lack of impact on subsequent event-free survival. Journal of Pediatric Hematology/Oncology 22(1): 27-33, 2000.

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