Table of Contents

HK J Paediatr (New Series)
Vol 1. No. 1, 1996

HK J Paediatr (New Series) 1996;1:5-13

Feature Article

Acute Lymphoblastic Leukemia

CH Pui

Keyword : Acute lymphoblastic leukemia; Children; Risk factors

Acute lymphoblastic leukemia (ALL), the most common form of cancer in children, accounts for one-fourth of all pediatric malignancies in the U.S.. A recent survey from the Surveillance, Epidemiology and End Results (SEER) program indicated that over the period 1973-1991, the age-adjusted incidence of childhood ALL rose from 2.7 to 3.3 per 100,000 children aged 0 to 14 years.1 Although this result was attributed to increased childhood or parental exposure to environmental or occupation hazards, such as electromagnetic fields, dietary nitrites, pesticides and ionizing radiation,2-5 none of these factors have been conclusively linked to the development of ALL.6 In fact, changes in diagnostic specificity from mid 1970's to later eras, resulting in recognition of not-otherwise-specified forms of lymphoid leukemia as ALL, could easily account for this apparent increase in incidence.7 Regardless of ALL incidence, the mortality rate in childhood ALL decreased sharply from 1.4 to 0.5 per 100,000 during the same 18-year period,1 as a result of improved diagnostic methods, the development of more effective therapy in controlled clinical trials, and advances in supportive care. As many as 70% of patients can be cured with contemporary treatment regimens in developed countries (Table I).8-15 However, modern therapy for childhood ALL has introduced new complications that need to be controlled if we hope to achieve further progress in the clinical management of this disease. This review summarizes recent advances in treatment and indicates likely directions for future research.

Table I Current Results of International Studies of Childhood ALL
Study No. of children Event-free survival rate (±SE)
AIEOP ALL88 (1988-1992) 396 66.6% (2.4%) at 5 yr
BFM (1986-1990) 998 72% (2%) at 6 yr
CCG 100 series (1983-1989) 3712 66% at 5 yr
Dana-Farber 85-01 (1985-1987) 220 78% (3%) at 7 yr
Dutch (1984-1988) 291 72% (3%) at 6 yr
FRALLE 83 (1983-1987) 559 57% (2%) at 7 yr
MRC UKALL X (1985-1990) 1612 62% (2%) at 5 yr
POG ALinC + T-cell + infant protocols (1986-1990) 2404 66.4% (2.4%) at 4 yr
SJCRH XI (1984-1988) 358 71% (4%) at 8 yr
TCCSG L84-11 (1984-1989) 490 63.8% (3.2%) at 7 yr
AIEOP, Associazione Italiana Ematologia Oncologia Pediatrica; BFM, Berlin Frankfurt-Münster; CCG, Childrens Cancer Group (Arcadia, CA); Dana-Farber, Dana-Farber Cancer Institute/Children's Hospital ALL Consortium (Boston, MA); Dutch, Dutch Childhood Leukemia Study Group; FRALLE, French ALL Cooperative Group; MRC, Medical Research Council (United Kingdom); POG, Pediatric Oncology Group (Chicago, IL); ALinC, Acute Leukemia in Childhood (protocol); SJCRH, St. Jude Children's Research Hospital (Memphis, TN); TCCSG, Tokyo Children's Cancer Study Group.

Pathologic Diagnosis and Classification Systems

Childhood ALL comprises many clinically and biologically distinct subtypes. Multiple attempts to classify this disease by the morphologic characteristics of lymphoblasts have not proved useful in clinical management strategies. Immunologic classifications schemes, first introduced in the mid-1970's based on the pattern of cellular reactivity to a panel of lineage-associated monoclonal antibodies, remain a valuable tool in the clinic. The availability of large panels of antibodies and the development of sophisticated techniques of antigen detection (e.g., flow cytometry) have not only improved the precision of diagnosis, but have allowed the detection of minimal residual disease as well.16 By immuno-phenotyping cases of ALL, one can broadly classify the disease as having a B- or T-lineage origin.17 Further classification according to the stage of maturation within normal B-cell (e.g., early pre-B, pre-B, transitional pre-B, B-cell) or normal T-cell (e.g., early thymocyte, intermediate thymocyte, late thymocyte) ontogeny is feasible, but this approach has limited clinical utility. The only exception is the identification of B-cell ALL, which requires specific therapy and will be discussed later.

Since the early 1980s, it has been recognized that blast cells in some cases of leukemia can coexpress antigens associated with more than one lineage; however, standard nomenclature and uniform diagnostic criteria for these cases are still lacking. Since virtually all antigens lack strict lineage specificity, excluding CD3 and the T-cell receptor for T-lineage ALL, CD79a and immunoglobulin for B-lineage ALL, and myeloperoxidase for AML,18 we have advocated a more stringent definition for these cases (expression of two or more markers of the opposite lineage).19 Therapeutically, it seems appropriate to subdivide these so-called mixed-lineage leukemias into myeloid antigen-positive ALL and lymphoid antigen-positive acute myeloid leukemia (AML). The major lineage can be identified by its cytochemical staining properties (e.g., myeloperoxidase and alpha naphthyl butyrate esterase for AML), characteristic morphologic features (e.g., Auer rods for AML), and specific patterns of antigen expression (as mentioned above). While both subtypes would benefit from intensive chemotherapy, lymphoid antigen-positive AML requires treatment directed against both lymphoid and myeloid leukemias.19

Since one or more genetic alterations underlie every case of leukemia,20 a gene-based classification system may prove superior to ones relying solely on indirect measures of blast cell diversity, such as morphology and immunophenotype.21 By cytogenetic analysis, ALL can be readily classified according to the modal chromosomal number per leukemic cell (ploidy). Major ploidy groups recognized to date include hypodiploid (<46 chromosomes), diploid (normal, 46 chromosomes), pseudodiploid (46 chromosomes with numerical or structural abnormalities), hyperdiploid with 47 to 50 chromosomes, hyperdiploid with more than 65 chromosomes, and triploid/tetraploid with more than 65 chromosomes.20 DNA flow cytometry has proved a useful adjunct to cytogenetic analysis because it is automated and rapid, and can sometimes detect near-haploid or tetraploid leukemic lines that were missed by routine karyotyping. 22,23

The most prominent cytogenetic hallmarks of the acute leukemias are phenotype-specific reciprocal chromosomal translocations, which have diagnostic and, in many instances, prognostic implications (to be discussed later)20,21 The most common of these rearrangements are the t(1;19), t(9;22), t(4;11), and t(8;14). Deletions or unbalanced translocation resulting from the loss of genetic material from the long arm of chromosome 6 (6q-), short arm of chromosome 9 including bands p21 and p22, or chromosome 12 at the band p12 are also common, each occurring in approximately 10% of ALL cases.20 Molecular analysis of the breakpoint regions of specific chromosomal rearrangements has identified many genes whose protein products are important in malignant transformation and proliferation. Chromosomal translocations generally activate cellular proto-oncogenes by moving them into the vicinity of an active promoter/enhancer element or through fusion event that "stitch together" normally discrete genetic components, while deletions lead to the loss of function of a tumor suppressor gene (e.g., p16 and p53).21,24,25

Despite the growing use of cytogenetics in leukemia classification, there are compelling reasons to focus on molecular systems. First, some potentially important genetic alterations are not identifiable at the karyotypic level: e.g., TAL1 rearrangements26,27 and TEL/AML1 fusions28,29 are the most common specific genetic abnormalities in T-lineage and B-lineage ALLs, respectively, occurring in approximately one-fourth of the cases in each disease category. Likewise, deletions of most tumor suppressor genes are revealed only by molecular analysis.30-34 Second, cases with clinically important genetic rearrangement may be missed by cytogenetic evaluation, even in centers with a high rate of successful analysis.35 Finally, some lesions that appear identical by karyotyping prove quite different in critical ways when examined at the molecular level; ALL with the t(l;l9) rearrangement illustrates this point well.36

Prognostic Factors and Therapeutically Relevant Risk Groups

Because ALLs comprise many prognostically and therapeutically distinct subtypes (Table II), attempts to develop a uniform approach to treatment would be inappropriate. Currently, most treatment centers emphasize early and rigorous assessment of the relapse hazard in individual patients, so that only patients at high risk for a relapse are treated intensively, with less toxic treatment reserved for patients at a lower risk. This strategy has led to striking improvements in outcome among the different subtypes of ALL. For example, B-cell ALL, once associated with a dismal prognosis, now has a cure rate of 80% or better with the use of intensive but short-term chemotherapy (<six months) with high-dose cyclophosphamide, cytarabine, and methotrexate, as well as repeated intrathecal chemotherapy.37,38 The improved treatment outcome of T-cell ALL observed in two clinical trials (5-year event-free survival of approximately 70%) was attributed to the intensive use of L-asparaginase and doxorubicin in one study11 and to the introduction of high-dose methotrexate (5 g/m2 as a 24-hour infusion) in the other.10 In a randomized study of methotrexate "upfront-window" therapy preceding conventional remission induction in patients with newly diagnosed ALL, T-lineage blasts accumulated less methotrexate and its active polyglutamate metabolites than did B-lineage blasts when the drug dosage was constant.39 However, when exposed to higher methotrexate dosages, T-lineage blasts accumulated concentrations of polyglutamates that were comparable to those of B-lineage blasts exposed to lower drug dosages, supporting the use of high-dose methotrexate to treat patients with T-cell ALL. Two antimetabolites, methotrexate and 6-mercaptopurine, characterized by a virtual lack of long-term sequelae, are particularly effective in B-lineage cases with hyperdiploid karyotypes (>50 chromosomes), producing long-term event-free survival rates greater than 80%.40,41 The addition of antileukemic agents to this basic regimen did not appear beneficial.15 Thus, treatment is the single most important prognostic factor in childhood ALL.

Table II Clinically and Biologically Relevant Subtypes of ALL

Frequency (%)

Associated Features
T-cell 13-15 Male predominance, increased leukocyte count, mediastinal mass, CNS leukemia, improved outcome with high-dose methotrexate, daunorubincin plus L-asparaginase.
B-cell 2 Male predominance, bulky extra-medullary disease, favorable prognosis with short-term intensive therapy with high-dose metho-trexate plus cytarabine plus cyclophosphamide.
B-linkage Hyperdiploidy >50 27 Decreased leukocyte count, favorable age between 1 and 10 years, favorable prognosis with antimetabolite therapy.
t(1;19)(q23;p13.3) 5 or 6 Pre-B phenotype, increased leukocyte count, black race, CNS leukemia, unfavorable prognosis with antimetabolite therapy.
MLL rearrangement 4 Predominantly in infants, increased leukocyte count, CNS leukemia, dismal outcome with chemo- therapy.
t(9;22)(q34;q11) 3-5

Older age, increased leukocyte count, dismal outcome with chemotherapy in the subgroup with leukocyte count >= 25 x 109/L.

TEL/AML1 fusion

24 Favorable age between 1 and 10 years, decreased leukocyte count, favorable prognosis.

The history of leukemia therapy has been marked by the frequent appearance of risk factors whose prognostic utility has disappeared with the development of more specific treatment. Unfortunately, many cases do not possess features known to warrant specific therapy, resulting in generalized methods of risk assignment based on various combinations of clinical and lymphoblast biological characteristics.42 Age and leukocyte count have consistently shown prognostic strength regardless of the treatment regimen used; however, there has been little agreement over the worth of other factors commonly employed in risk assessment. To facilitate comparison of treatment results and the identification of effective treatment, participants in a workshop sponsored by the National Cancer Institute of the U.S. adopted a uniform risk classification based on these two factors in B-lineage ALL.43 That is, cases with age <1 or >10 years or those with leukocyte count >= 50 x 109/L are considered to be at higher risk. They also agreed to determine, prospectively, the clinical importance of several other variables hyperdiploidy >50 chromosomes, or cellular DNA content more than 1.16 times that of normal G0/G1 cells; the presence of the t(9;22) (so-called Philadelphia chromosome) or t(4; 11) rearrangement; the presence of central nervous system (CNS) leukemia; and 5% or more blasts identifiable in bone marrow on day 14 of remission induction. Although the prognostic significance of the t(l;19) and the myeloid-associated antigen expression remains controversial, it appears that intensive chemotherapy can nullify any adverse prognostic impact by either of these factors.44-46 Approximately two-thirds of infants with ALL have extremely poor outcomes (long-term event-free survival < 10% with chemotherapy alone), attributable to MLL gene rearrangements, while the remaining third, who lack these genetic abnormalities, have an intermediate prognosis.35,47,48

Several notable advances in the identification of prognostic factors have been made since the workshop was convened. The presence of circulating leukemic blasts after one week of multiagent remission induction chemotherapy in 14% of children with ALL was shown to confer a poor prognosis.49 Measurement of this variable is simple and noninvasive and should prove to be universally applicable. In another study, MLL rearrangement was correlated with a very poor outcome (4-year event-free survival of 10%) even when infants or patients with the t(4; 11) were excluded from the analysis, establishing the independent adverse prognostic impact of this genetic abnormality.50 We have also identified a subset of Philadelphia chromosome-positive patients with a low presenting leukocyte count (<= 25 x 109/L) who appear highly curable with chemotherapy alone.51 The cases with higher leukocyte counts still require allogeneic bone marrow transplantation for cure. Finally, overt testicular leukemia, found in 2% of boys at diagnosis, was shown to confer a poor survival probability.52 On the basis of these and earlier findings, we have devised a new risk classification system for use in our current total therapy study of ALL (Table III). We anticipate that approximately equal numbers of newly diagnosed ALL patients will fall into the lower- and higher-risk groups and that the former subset should have a long-term event-free survival approaching 90%.

Risk-Adapted Treatment

Although specific approaches to therapy may differ from center to center, all modern treatment regimens (except those for B-cell ALL) comprise four major components: remission induction, intensification/consolidation, CNS-directed therapy, and continuation treatment.

Remission induction

Induction treatment typically comprises a glucocorticoid (prednisone, prednisolone, or dexamethasone), vincristine, and L-asparaginase. The substitution of dexamethasone for prednisone or prednisolone could reduce the incidence of central nervous system relapse.53 Because more rapid reduction of the leukemic cell population during the initial phase of treatment correlates with better leukemia-free survival, many clinical protocols now specify intensive early therapy with an increased number of antileukemic agents.42 With modern chemotherapy and supportive care, 98% to 99% of children with ALL attain complete remission, defined as the absence of clinical signs and symptoms of disease and the recovery of normal blood cell counts and normocellular bone marrow. The relative effectiveness of different induction regimens is difficult to assess, as current definitions of "complete remission" do not consider different levels of minimal residual leukemia, which cannot be appreciated by morphologic examination alone. This obstacle may soon be overcome by quantitative molecular or immunologic methods currently being tested in prospective clinical trials.16

Consolidation or intensification

Most contemporary protocols require a consolidation or intensification phase of therapy immediately or soon after remission induction; such treatment may consist of increased doses of drugs used previously or entirely new agents with little cross-resistance. Although reserved primarily for high-risk patients, this strategy was recently credited with improvement of outcome in lower-risk patients.10,14 Determining the relative effectiveness of the various postremission intensification/consolidation regimens now in use will require improved methods of detecting minimal residual leukemia.

CNS-directed therapy

Effective therapy to eradicate subclinical CNS leukemia is an integral part of successful therapy for ALL. It not only increases the chance of cure but decreases morbidity due to intensive retrieval therapy for overt CNS leukemia. Concern about the adverse effects of cranial irradiation has led to the development of alternative modes of treatment.54 In most instances, intrathecally injected age-adjusted doses of either methotrexate or triple-agent chemotherapy (methotrexate, hydrocortisone, and cytarabine) can be substituted for irradiation, provided that effective systemic therapy is used.9,55,56 We currently reserve cranial irradiation for patients who have>= 5 WBC/μL of cerebrospinal fluid with identifiable blasts at diagnosis, as well as those with other features indicative of a high risk of CNS relapse (e.g., B-lineage ALL with WBC >= 100 x 109/L, T-cell ALL with WBC >= 50 x 109/ L, and blast cells with the Philadelphia chromosome).57 Whether intensification of intrathecal treatment and the use of intensive systemic chemotherapy, including dexamethasone, can avert the need for CNS irradiation in these patients remains to be determined. In a retrospective study we found that patients with small numbers of leukemic blast cells in the cerebrospinal fluid (i.e., <5 WBC/μL) were also at increased risk of CNS relapse,58 a finding confirmed by two subsequent studies employing different systemic therapies.59,60 Recognition of this finding prompted us to intensify intrathecal therapy for this group of patients, with encouraging preliminary results. Of 230 patients treated since 1991, only one has relapsed in the CNS (CH Pui, unpublished observation). Though not tested in a randomized trial, this observation suggests that intensification of intrathecal therapy early in therapy (e.g., 4 weekly doses following remission induction) offers an preventive measure against CNS relapse.

Table III Criteria for Lower-Risk ALL*
1. DNA index >= 1.16 and <= 1.60, or Age between 1 and 9 years and WBC <50 x 109/L

2. Absence of t(9;22), t(4;11), MLL rearrangement, t(1;19) with pre-B phenotype, T-cell phenotype, CNS leukemia, testicular leukemia, or >5% bone marrow blasts on day 15 of induction therapy.

*Patients who do not meet these criteria are considered to have higher-risk ALL.

Continuation treatment

The persistence of small numbers of leukemic cells well into the clinical course is a defining feature of childhood ALL, requiring prolonged therapy (2 to 2.5 years) to reduce the relapse hazard. Boys appear to require a longer treatment course than girls.61-63 There are compelling reasons to extend chemotherapy; it may kill slowly dividing leukemic cells, allow the normal immune system to eradicate blast cells, and suppress leukemic cell growth leading to programmed death.64-66 Antimetabolite drugs (e.g., methotrexate and 6-mercaptopurine) are the backbone of most continuation protocols. By virtue of its inhibitory effect on de novo purine synthesis, methotrexate is synergistic with 6-mercaptopurine, enhancing the conversion of 6-mercaptopurine to 6-thioguanine nucleotides, the active metabolites.67 Some studies have demonstrated a better response when 6-mercaptopurine is given at bedtime to patients with an empty stomach and when the combination is administered to the limits of tolerance, as indicated by low leukocyte counts.68-70 Whether intensified continuation therapy would be beneficial to patients with higher-risk leukemia remains to be determined. Also uncertain is the clinical utility of detecting minimal residual leukemia during the postremission phase of treatment. In theory, early detection of residual leukemia cells while they are still sensitive to treatment would allow more timely (and potentially curative) intervention.

Bone marrow transplantation

The role of allogeneic hematopoietic stem cell (bone marrow or peripheral blood) transplantation for patients with ALL in first remission remains controversial because of the lack of well-designed controlled studies with adequate numbers of patients.71 Currently, we would offer this procedure to patients with Philadelphia chromosome-positive ALL and high leukocyte counts at diagnosis (>25 x 109/L) and to those refractory to induction therapy, given their extremely poor outcome on chemotherapy.51 Patients with MLL rearrangements also appear to be candidates for transplantation,50 as do those with early hematologic relapse.72-74

Late Sequelae

Second cancers are a devastating late complication of leukemia therapy. In a retrospective study of 9720 children treated for ALL, the overall estimated risk of second cancer was 2.5% at 15 years after diagnosis.75 Brain tumors were most common, followed by new leukemias and lymphomas. Compared with the risk in the general population, there was a seven-fold excess of all cancers and a 22-fold excess of brain tumors. Children who underwent cranial irradiation at or before the age of five years had the greatest suspectibility to brain tumors. In another study of patients who had undergone bone marrow transplantation, a seven-fold excess of second cancers -- mainly non-Hodgkin's lymphoma, brain tumors, and melanoma -- was observed.76 A recent increase in cases of AML among patients treated intensively for ALL has been attributed to the genotoxic effects of the epipodophyllotoxins, which inhibit intranuclear enzyme topoisomerase II.77 Epipodophyllotoxin-induced AML lacks a myelodysplastic phase, has monoblastic morphology, and carries an 11q23 chromosomal translocation involving the MLL gene.77-79 In contrast to second solid tumors, which usually arise at least 5 years after the original diagnosis, epipodophyllotoxin-induced leukemias almost invariably develop within 6 years and sometimes as early as a few months from the start of treatment.77,78 Frequent administration of these agents (weekly or twice weekly), an increased cumulative dosage, and co-administration with alkylating agents, cisplatin or L-asparaginase increase the risk of this complication.78,80-83

Anthracycline therapy can cause cardiomyopathy in a dose- and age-related manner.84 Doses in excess of 200 mg/m2 and age less than 4 years are significantly correlated with cardiotoxic effects. A recent study indicated that female patients are particularly susceptible to this complication.85

Cranial irradiation has been implicated in the neuropsychologic deficits and endocrine dysfunction seen in ALL patients, most often young girls.86-90 Elimination of cranial irradiation dose with increased use of both intrathecal and high-dose systemic chemotherapy for CNS treatment may lower the frequency and severity of these neuropsychologic sequeles. Short stature, obesity and precocious puberty (in girls) are also common in children who have undergone cranial irradiation, particularly those treated at a very young age.91-96 Intensive chemotherapy and particularly the preparative therapies (busulfan and cyclophosphamide) used in bone marrow transplantation can also cause growth hormone deficiencies.93,97 Many patients with growth retardation are receiving growth hormone replacement. Although potentially beneficial, this treatment might stimulate the growth of leukemic cells, a possibility that has led to the creation of a registry to monitor these patients for such an effect.98 Currently, no published findings suggest curtailment of hormone replacement therapy. To end on a positive note, studies of the offspring of patients previously treated for childhood leukemia have not demonstrated an increased frequency of congenital disorders or cancer.99,100

Future Considerations

The major challenge in the management of ALL is the development of effective therapy for the 30% children who are not expected to achieve complete remission or experience relapse on available chemotherapeutic regimens. Although bone marrow transplantation performed during first or second remission has improved the outlook for some of these patients,72-74 this procedure still carries a high risk of therapy-related death, graft-versus-host disease, and adverse long-term sequelae, especially for young children. While human recombinant hematopoietic growth factors may decrease the morbidity associated with intensive chemotherapy, they have not yet been shown to improve long-term survival rates.101 Thus, more effective but less toxic agents are needed to ensure continued progress in ALL treatment. More reliable information on the chemosensitivity of leukemic cells would greatly aid the development of effective therapy. Several approaches have been used for this purpose, including in vitro drug sensitivity testings and the use of murine models of severe combined immuno-deficiency.102-106 As a result, several new anticancer agents have been identified and are being tested in clinical trials (e.g., interleukin-4105 and CD19 immuno-conjugates106). It may be possible to devise gene therapy targeted to specific genetic lesions in leukemic cells;107-109 however, such therapy must take into account that leukemia probably results from multiple genetic defects, so that correction of a single abnormality may not be adequate to destroy the cell or cause it to differentiate. Another promising concept is the circumvention of drug resistance by modulating genes that encode multidrug-resistance proteins or by inhibiting the gene products themselves.107-110 Finally, the long-standing promise of an effective cancer vaccine could be realized with the availability of improved immunologic techniques.111

For the 70% of patients who are curable on current protocols, efforts are being made to reduce the delayed complications of treatment, and to improve the therapeutic index of antileukemic drugs by targeting drug doses to achieve predetermined serum concentrations.112 In all likelihood, additional subsets of patients will be identified for treatment with antimetabolite-based, hence less toxic, therapy. Promising candidates include patients whose blast cells grow poorly on bone marrow-derived stromal layers,113 those with transitional pre-B ALL,114 and those with TEL/AML1 fusion genes.29 In the near future, it should be possible to combine immunologic assays, the polymerase chain reaction, fluorescence in situ hybridization, and Southern blotting in ways that will make the detection of minimal residual disease a reliable clinical tool.16


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