Leukemia information

[Vu Huu Vinh <vu@kuhp.kyoto-u.ac.jp>]

GENERAL INFORMATION

This state-of-the-art statement on childhood acute lymphocytic leukemia
(ALL) is an overview of prognosis, diagnosis, classification, and
patient treatment. The National Cancer Institute created the PDQ
database to increase the availability of new treatment information and
its use in treating patients. Information and references from the most
recent published literature are included after review by pediatric
oncology specialists.
Cancer in children is rare. A team approach that incorporates the skills
of the local physician, pediatric surgeon, radiation oncologists,
pediatric medical oncologists/hematologists, rehabilitation specialists,
and social workers is imperative to ensure that patients receive
treatment, supportive care, and rehabilitation that will achieve optimal
survival and quality of life. For advances to be made in treating these
patients, therapy should be delivered in the context of a clinical trial
at a major medical center that has expertise in treating children. Only
through entry of all eligible children into appropriate, well-designed
clinical trials will progress be made against these diseases. Guidelines
for pediatric cancer centers and their role in the treatment of
pediatric cancer patients have been outlined by the American academy of
Pediatrics.[1]
Approximately 70% of children with ALL are cured with current
protocol-based treatments that incorporate systemic therapy (e.g.,
combination chemotherapy) and specific central nervous system (CNS)
preventive therapy (i.e., intrathecal chemotherapy and/or cranial
irradiation).[2] While more than 95% of patients can be expected to
attain a complete remission (CR), the duration of CR and potential for
cure are correlated with a number of prognostic variables. These
variables include clinical parameters at the time of diagnosis (e.g.,
age and white blood cell [WBC] count) and biologic features of the
leukemic cells (e.g., immunophenotype, cytogenetics, and DNA content).
The intensity of the therapeutic regimen is based on the prognostic
classification of the child's leukemia. This risk-based approach to
treatment has improved survival and reduced toxic effects.[3]
It is well appreciated that children with ALL have a better prognosis
when treated in established clinical trials.[4] Additionally, despite
the treatment advances noted in childhood ALL, numerous important
biologic and therapeutic questions remain to be answered. The systematic
investigation of these issues requires the entry of all eligible
patients in clinical trials. Since treatment entails many potential
complications and requires aggressive supportive care (transfusions;
management of infectious complications; and emotional, financial, and
developmental support), these protocols are 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.
Since nearly all children with ALL achieve an initial remission, the
major obstacle to cure is bone marrow and/or extramedullary relapse.
Relapse can occur during therapy or after completion of treatment. While
the majority of children with ALL whose disease relapses can experience
two or more remissions, the likelihood of cure is substantially reduced.

Prognostic variables
Although there is no standardized staging of ALL analogous to that used
for solid tumors and lymphomas, patients with ALL are usually treated
according to risk groups defined by both clinical and laboratory
features. When analyzed retrospectively, these features appear to have
prognostic significance and have important implications for both
treatment and outcome. Stratification of patients with ALL depends on
patient-related (clinical) features and on the histochemical,
morphologic, immunophenotypic, cytogenetic, and biochemical
characteristics of the patient's leukemia cells.
A number of clinical and laboratory features have demonstrated
prognostic value for children with ALL. These include age at diagnosis,
WBC count at diagnosis, sex, CNS leukemia at diagnosis, lymphomatous
presentation (mediastinal mass, massive organomegaly, and/or massive
adenopathy), platelet count, hemoglobin level, race, serum
immunoglobulin levels, peripheral blood and marrow response to
treatment, rate of cytoreduction, blast cell morphology (FAB),
immunophenotype, DNA content (ploidy), and certain chromosomal
translocations.[5-8] The Philadelphia chromosome t(9;22) is present in
about 5% of pediatric ALL patients and confers an unfavorable
prognosis.[9] The t(12;21) (tel-AML-1 fusion) is associated with an
excellent prognosis.[10] In patients with T-cell ALL, CD2 appears to
confer a favorable prognosis.[11] 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.[12] Only age, WBC count at
diagnosis, and the Philadelphia chromosome have been consistently
associated with outcome regardless of the treatment.[2]
Representatives of the major pediatric oncology cooperative groups in
the United States have developed a uniform approach to risk
classification and treatment assignment for children with ALL. For
patients with B-precursor (i.e., non-T, non-B) ALL, the standard-risk
category includes patients 1-9 years of age who have a WBC count at
diagnosis less than 50,000 per microliter. The remaining patients are
classified as having high-risk ALL. Other prognostic factors that may
modify the age/WBC risk category include DNA index, early response to
therapy, cytogenetics, immunophenotype, and CNS disease at diagnosis.
The uniform age and WBC criteria define prognostic categories that
provide a framework for comparing different treatment
approaches, while allowing for evaluation of the biologic basis for
therapeutic success and failure.[3]

Current issues that require further investigation and clarification
include 1) dynamic interactions between prognostic "front-end" variables
and subsequent treatment; 2) inconsistent application and interpretation
of multivariate analyses; and 3) ambiguity of prognostic factors that
are highly predictive of outcome but are biologically inexplicable. Most
major centers have access to laboratories that perform the necessary
studies. It should be emphasized that improvements in therapy may
diminish the importance of or abrogate any of these presumed prognostic
factors.

References:

   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): 139-141,
1997.

   2.Pui CH, Crist WM: Biology and treatment of acute lymphoblastic
leukemia. Journal of Pediatrics 124(4): 491-503, 1994.

   3.Smith M, Arthur D, Camitta B, et al.: Uniform approach to risk
classification and treatment assignment for children with acute
lymphoblastic leukemia. Journal of Clinical Oncology 14(1): 18-24, 1996.

   4.Shah NR: The community physician's involvement in clinical trials
and home treatment. Cancer 58(2, Suppl): 504-507, 1986.

   5.Steinherz PG, Siegel SE, Bleyer WA, et al.: Lymphomatous
presentation of childhood acute lymphoblastic leukemia: a subgroup at
high risk of early treatment failure. Cancer 68(5): 751-758, 1991.

   6.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.

   7.Heerema NA, Arthur DC, Sather H, et al.: Cytogenetic features of
infants less than 12 months of age at diagnosis of acute lymphoblastic
leukemia: impact of the 11q23 breakpoint on outcome: a report of the
Childrens Cancer Group. Blood 83(8): 2274-2284, 1994.

   8.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.

   9.Fletcher JA, Lynch EA, Kimball VM, et al.: Translocation (9;22) is
associated with extremely poor prognosis in intensively treated children
with acute lymphoblastic leukemia. Blood 77(3): 435-439, 1991.

  10.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.

  11.Uckun FM, Steinherz PG, Sather H, et al.: CD2 antigen expression on
leukemic cells as a predictor of event-free survival after chemotherapy
for T-lineage acute lymphoblastic leukemia: a Children's Cancer Group
study. Blood 88(11): 4288-4295, 1996.

  12.Bleyer WA, Sather H, Coccia PF, et al.: The staging of childhood
acute lymphoblastic leukemia: strategies of The Childrens Cancer Study
Group and a three-dimensional technic of multivariate analysis. Medical
and Pediatric Oncology 14(5): 271-280, 1986.