Pediatric Annals

Acute Lymphoid Leukemia

W Archie Bleyer, MD

Abstract

Acute lymphoid leukemia (ALL) is the most common cancer in children. As recently as 30 years ago it was uniformly fatal and its victims seldom survived more than two or three months. Today it is still the most frequently encountered malignancy in children, but the majority of children are surviving more than five years without evidence that their disease has or will recur.1'4 From the 1950s until the mid-1970s, there was rapid progress in the treatment of childhood acute lymphoid leukemia (Figure 1), The disease is now curable in at least half of the affected children. During the last decade, however, there have been few therapeutic advances and the rate of progress has slowed (Figure 2). This article is intended to identify those factors which contributed to progress in the past, to outline current diagnostic and biological concepts, to review current therapy and remaining problems, and to summarize the current challenges and lines of investigation which are considered to be of potential value in breaking through the existing barriers to progress in treatment of leukemia.

EPIDEMIOLOGY AND ETIOLOGY

Acute lymphoid leukemia in children has a relatively sharp peak in incidence between two and six years of age. Of potential etiologic significance, this peak was first observed in Great Britain in the 1 92Os and did not emerge in the United States until the 1950s or in Japan until the 1960s. It has not yet been reported in the People's Republic of China, nor has it been noted in black children. But, as will be explained later, the majority of the children who are currently being cured were diagnosed at ages bracketed by this peak.

In the first three or four years of life, acute lymphoid leukemia is equally common in both sexes. In older children, it is more common in boys than in girls. The risk of a white child developing ALL during the first ten years of life is approximately one in 3500. The risk in a black child is less, primarily because black children do not have the age-related peak incidence. There is evidence that siblings of children with ALL and upper socioeconomic groups are also at higher risk.

The cause of leukemia is unknown. Possible contributing or predisposing factors include ionizing radiation, chemical carcinogens, certain viruses, genetic factors, and socioeconomic status. That radiation may induce leukemia is suggested by the Japanese atomic bomb experience, in which leukemia developed in one of every 60 survivors within 1,000 meters of the hypocenter. In adults, acute myeloid leukemia predominated, whereas in children acute lymphoid leukemia was most common. Thus, different cell lines may have vary ing susceptibilities to radiation leukernogenesis at different ages. There is no evidence that drugs or chemicals are causes of childhood ALL, with the possible exception of the few cases of second malignancies occurring in children previously treated with chemotherapy for another cancer.5

A viral cause is more plausible in that viral etiologies of leukemia have been shown in cats, fowl and mice. Although type C viral particles have been found in human my elob lasts, these particles have not been identified in lympnoblasts from children. Despite a reported increased incidence within certain families and the description of geographic "leukemia clusters," neither vertical nor horizontal transmission of human leukemia has been demonstrated.

There are a variety of genetic factors which appear to predispose children to ALL. The incidence of leukemia in siblings of leukemia patients is approximately one in 700, which is four times greater than in the general population. Approximately 14% of identical twins of children with leukemia develop the same disease. A variety of…

Acute lymphoid leukemia (ALL) is the most common cancer in children. As recently as 30 years ago it was uniformly fatal and its victims seldom survived more than two or three months. Today it is still the most frequently encountered malignancy in children, but the majority of children are surviving more than five years without evidence that their disease has or will recur.1'4 From the 1950s until the mid-1970s, there was rapid progress in the treatment of childhood acute lymphoid leukemia (Figure 1), The disease is now curable in at least half of the affected children. During the last decade, however, there have been few therapeutic advances and the rate of progress has slowed (Figure 2). This article is intended to identify those factors which contributed to progress in the past, to outline current diagnostic and biological concepts, to review current therapy and remaining problems, and to summarize the current challenges and lines of investigation which are considered to be of potential value in breaking through the existing barriers to progress in treatment of leukemia.

EPIDEMIOLOGY AND ETIOLOGY

Acute lymphoid leukemia in children has a relatively sharp peak in incidence between two and six years of age. Of potential etiologic significance, this peak was first observed in Great Britain in the 1 92Os and did not emerge in the United States until the 1950s or in Japan until the 1960s. It has not yet been reported in the People's Republic of China, nor has it been noted in black children. But, as will be explained later, the majority of the children who are currently being cured were diagnosed at ages bracketed by this peak.

In the first three or four years of life, acute lymphoid leukemia is equally common in both sexes. In older children, it is more common in boys than in girls. The risk of a white child developing ALL during the first ten years of life is approximately one in 3500. The risk in a black child is less, primarily because black children do not have the age-related peak incidence. There is evidence that siblings of children with ALL and upper socioeconomic groups are also at higher risk.

The cause of leukemia is unknown. Possible contributing or predisposing factors include ionizing radiation, chemical carcinogens, certain viruses, genetic factors, and socioeconomic status. That radiation may induce leukemia is suggested by the Japanese atomic bomb experience, in which leukemia developed in one of every 60 survivors within 1,000 meters of the hypocenter. In adults, acute myeloid leukemia predominated, whereas in children acute lymphoid leukemia was most common. Thus, different cell lines may have vary ing susceptibilities to radiation leukernogenesis at different ages. There is no evidence that drugs or chemicals are causes of childhood ALL, with the possible exception of the few cases of second malignancies occurring in children previously treated with chemotherapy for another cancer.5

A viral cause is more plausible in that viral etiologies of leukemia have been shown in cats, fowl and mice. Although type C viral particles have been found in human my elob lasts, these particles have not been identified in lympnoblasts from children. Despite a reported increased incidence within certain families and the description of geographic "leukemia clusters," neither vertical nor horizontal transmission of human leukemia has been demonstrated.

There are a variety of genetic factors which appear to predispose children to ALL. The incidence of leukemia in siblings of leukemia patients is approximately one in 700, which is four times greater than in the general population. Approximately 14% of identical twins of children with leukemia develop the same disease. A variety of known genetically determined disorders are associated with an increased risk of leukemia; these include Down's syndrome, Fancom's anemia, Klinefelter's syndrome, trisomy-G, Poland's syndrome, Schwachman's syndrome, congenital agammaglobulinemia, and neurofibromatosis. Also, multiple cases of leukemia have been observed in offspring of consanguinous marriages, in contrast to a control series in which there was no familial incidence.6 Also suggestive of genetic influences is the finding of a low level of the enzyme adenosine deaminase in lymphocytes from parents of children with ALL.7

Figure 1. Improvement in survival of children with acute lymphoid leukemia diagnosed between 1956 and 1976. Data from multiple studies of the Cancer and Acute Leukemia Group B, the Children's Cancer Study Group, and the Southwest Oncology Group. (From Hammond et al,1' with permission)

Figure 1. Improvement in survival of children with acute lymphoid leukemia diagnosed between 1956 and 1976. Data from multiple studies of the Cancer and Acute Leukemia Group B, the Children's Cancer Study Group, and the Southwest Oncology Group. (From Hammond et al,1' with permission)

Figure 2. Duration of the initial complete remission of 2,031 children with acute lymphoid leukemia treated according to recent studies of the Children's Cancer Study Group. All patients achieving complete remission were included in the analysis. (From Hammond et al," with permission)

Figure 2. Duration of the initial complete remission of 2,031 children with acute lymphoid leukemia treated according to recent studies of the Children's Cancer Study Group. All patients achieving complete remission were included in the analysis. (From Hammond et al," with permission)

A particularly notable contrast between countries with different socioeconomic status is the ratio between the incidence of lymphoma and leukemia. In the US and the United Kingdom, acute leukemia accounts for far more cancer deaths than the lymphomas, including Hodgkin's disease. In Uganda and Nigeria the ratio is reversed. Even more convincing support for a predominance of environmental over genetic factors is provided by a reversal in the lymphoma/ leukemia ratio in a single ethnic group subjected to profound socioeconomic change. Arab children living in the Gaza strip during the recent period of economic improvement (1972 to 1980) have had a dramatic reversal of the ratio.8

Most cases of acute leukemia probably arise as a result of a combination of multiple factors, including some which are genetic and some which are environmental. It is highly unlikely that a single factor can cause leukemia in a host free of predisposing factors.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The presenting clinical and laboratory features of 724 children with acute lymphoid leukemia are listed in Table 1. In general, the signs and symptoms at presentation reflect the consequences of bone marrow infiltration by leukemic cells. The most common complaints and findings are those due to bone marrow infiltration by leukemic cells and the resulting anemia, thrombocytopenia, and neutropenia. In addition, there may be fatigue, pallor, petechiae, purpura, bleeding, fever, and bone pain. The duration of symptoms is usually relatively short (several days or a few weeks), but it may be several months. Frequently, the first sign of disease may be the development of a limp or, in younger children, refusal to walk. These symptoms, and the occurrence of arthralgias secondary to leukemic joint infiltration, may be difficult to distinguish from nonmalignant conditions such as juvenile rheumatoid arthritis or osteomyelitis.

The initial signs and symptoms may include manifestations of extramedullary leukemic spread. Approximately 4% of patients have laboratory or clinical evidence of central nervous system leukemia at the time of diagnosis, but it is unusual for this complication to be symptomatic. H epa tos p le n omega Iy is found in approximately twothirds of the patients and lymphadenopathy in about half (Table 1 ). An anterior mediastinal mass is found in 5% to 10% of these children.

Laboratory findings nearly always demonstrate one or more abnormalities in the hemogram (Table 1). Approximately 80% of patients have leukemic blasts which have neither ?-rosette receptors nor surface immunoglobulin and are known as non-T, non-B cells or null cells. With few exceptions the remaining patients have T cell blasts. Nearly 85% of patients have blasts with LI morphology, according to the French-American-British(FAB) classification system. Approximately 15% of patients have Li morphology and less than 1% have L3 morphology. Although L3 cells nearly always have surface immunoglobulin, making them identifiable as B cells, there is no correlation between null or T cell leukemia and LI and Lz morphology.9 Nearly one-fifth of the patients have a depression in one or more serum immunogiobulins.

Table

TABLE 1CLINICAL AND LABORATORY FINDINGS IN 724 CHILDREN WITH ACUTE LYMPHOID LEUKEMIA2

TABLE 1

CLINICAL AND LABORATORY FINDINGS IN 724 CHILDREN WITH ACUTE LYMPHOID LEUKEMIA2

In the absence of a definitive bone marrow diagnosis, a number of conditions may mimic acute lymphoid leukemia. These conditions include aplastic anemia (which sometimes later converts to ALL), infectious mononucleosis, cytomegalovirus and Epstein-Barr virus infections, idiopathic thrombocytopenic purpura, pertussis and para pert uss is, osteomyelitis, juvenile rheumatoid arthritis, and other rheumatic disorders. Several cases have been reported in which the classical findings of the hypereosinophilic syndrome, which consists of elevated peripheral eosinophil count, pulmonary infiltrates, and cardiomegaly, have been the presenting features of acute leukemia. A variety of malignancies, many of which may present with bone marrow involvement, must also be differentiated from leukemia. These include neuroblastoma, non-Hodgkin's lymphoma, rhabdomyosarcoma, and retinoblastoma.

Table

TABLE 2CHARACTERIZATION OF LEUKEMIC LYMPHOBLASTS

TABLE 2

CHARACTERIZATION OF LEUKEMIC LYMPHOBLASTS

Analysis of the presenting clinical features of children with acute lymphoid leukemia has shown that many of the initial characteristics are of prognostic value.

Figure 3. Duration of complete remission in 1,637 children with acute lymphoid leukemia according to the white blood cell count at diagnosis (CCSG studies). (From Hammond"1 with permission)

Figure 3. Duration of complete remission in 1,637 children with acute lymphoid leukemia according to the white blood cell count at diagnosis (CCSG studies). (From Hammond"1 with permission)

Figure 4. Duration of complete remission in 1,637 children with acute lymphoid leukemia according to age at diagnosis (CCSG studies). (From Hammond1" with permission)

Figure 4. Duration of complete remission in 1,637 children with acute lymphoid leukemia according to age at diagnosis (CCSG studies). (From Hammond1" with permission)

STAGING AND PROGNOSTIC FACTORS

It is clear that acute lymphoid leukemia is not a homogeneous disease. It may not even be a single disease. Subgroups of patients can be identified at the time of diagnosis that have an excellent prognosis for survival and cure with standard therapies, while other subgroups have an extremely poor outcome. The accurate identification of multiple prognostic variables has become important in order to advance our understanding of the clinical manifestations and course of leukemia. In addition, this information may permit development of improved treatment strategies appropriate for the patient's prognosis and essential for accurate design, stratification and analysis of clinical studies.

Patients providing specimens for preclinical studies on the pathophysiology of leukemia also must be characterized by multiple prognostic variables, otherwise the results of the biological tests may be either misinterpreted or even uninterpretable.10 Thus, to obtain clear answers to the specific questions posed by a clinical trial, patients must be stratified into relatively homogeneous groups. Likewise, for a group with an excellent prognosis, the therapy recommended should be less aggressive, less toxic and less likely to cause late adverse effects of treatment. For those patients who can be identified at diagnosis as being expected to have a very unfavorable response to current therapy, novel therapeutic strategies must be applied. In this subgroup, the risks of increased therapy are justified.

Figure 3 shows the complete remission duration of 1,637 children with acute lymphoid leukemia treated by the Children's Cancer Study Group, for whom the regimen was chosen according to the white blood cell count at diagnosis. Note that the higher the white cell count, the worse the prognosis. Moreover, in virtually all analyses performed since the late 1960s when CNS prophylaxis was introduced, the initial white blood cell count is the most powerful predictor of outcome. The next most predictive factor is the patient's age at diagnosis ( Figure 4). Fewer than 20% of children less than one year of age at diagnosis were in remission six years after diagnosis, while 60% of those between one and ten years remained in continuous complete remission. Age and white blood cell count are now widely accepted as the strongest predictors of outcome. Obviously, a balanced clinical trial cannot be designed without taking white count and age of the patient into account. Thus, if a small number of patients with a very poor prognosis were entered by chance into a comparative trial, they could markedly influence the analysis of the trial and produce spurious therapeutic results.10

Figure 5. Schematic representation of the stages of normal T- and B-lymphocyte differentiation. Various immunological subtypes of acute lymphoid leukemia are indicated next to the normal cell type from which they presumably arise. (Adapted from Poplack1, Leventhal,12 and Bowman")

Figure 5. Schematic representation of the stages of normal T- and B-lymphocyte differentiation. Various immunological subtypes of acute lymphoid leukemia are indicated next to the normal cell type from which they presumably arise. (Adapted from Poplack1, Leventhal,12 and Bowman")

A large number of other variables have been correlated with prognosis. Features of the blast cell which have been associated with a worse outcome include T cell leukemia as characterized by the ?-rosette test, L2 or LÏ FAB morphology, hand mirror cell morphology, decreased density of giucocorticoid receptor levels, presence of a positive acid phosphatase reaction, presence of paranuclear beta-glucuronidase, presence of a positive acid alp ha nap ht hy !acetate esterase reaction, aneuploidy, and a slow response to therapy .4'U~1S Other "predictors" of a poor prognosis are an elevated hemoglobin level, a low platelet count, presence of infection or hemorrhage at diagnosis, presence of CNS leukemia at diagnosis, low serum immunoglobulins, black race, male sex, and the presence of lymphadenopathy, splenomegaly, kidney enlargement, hepatomegaly, or mediastinal mass at the time of diagnosis. Also patients who have leukocytes of HLA types B12, B18, and ALL/B35 have a poor prognosis.

The problem with these kinds of analyses is that they are univariate and frequently identify parameters which are dependent on other factors and of themselves do not influence the outcome. Multivariate analysis using the Cox regression method serves to sort out the relatively more important, independent variables. Recently, the Children's Cancer Study group evaluated the relative order of significance of front-end factors predictive of event-free survival in 1,387 children treated for acute lymphoid leukemia between 1976 and 1982. Age and white blood cell count are the most important determinants of prognosis in this group (p<.0001). FAB morphology and sex are the next most important factors (p<.001) followed by the platelet count and hemoglobin level (p<.0 1 ). The hemoglobin level is inversely related to prognosis. The presence of a large anterior mediastinal mass and depression of the serum levels of IgG, IgM, and IgA (all three depressed) are weakly correlated with outcome.

Certain additional clinical features are not significant predictors of prognosis at the p=0.05 level of statistical significance. These features are the presence of Erosetting blasts, CNS leukemia at diagnosis, massive lymphadenopathy, massive splenomegaly, massive hepatomegaly, and depression of only one or two serum immunoglobulins. Thrombocytopenic boys have a worse outcome than boys with a normal platelet count or than girls regardless of platelet count. These observations illustrate the interrelationships of prognostic factors; they emphasize the need to apply multivariate analysis or related statistical methods to sort out the clinically significant, biologically meaningful variables.

One of the best explanations for the heterogeneity of acute lymphoid leukemia is that the leukemic transformation and clonal expansion in various patients occurs in cells at different stages of lymphoid differentiation (Figure 5). Thus, the best prognosis is present when the common acute lymphoid leukemia cell gives rise to the leukemic clone. Greaves and his colleagues" have characterized these cells with an antiserum raised in rabbits immunized with ALL cells. They designated this anti-ALL reactive subset of non-T, non-B cell patients "common-ALL," to differentiate it from the anti-ALL nonreactive non-T, non-B cell group designated "nullceH" ALL (Table 2)." Several monoclonal antibodies with similar specificity for this common ALL antigen (CALLA) are now available.

Hybridoma technology should yield important information regarding the biological heterogeneity of acute lymphoid leukemia. Monoclonal antibodies have been prepared, for example, that are capable of subclassìfying normal thymocytes according to different stages of intrathymic differentiation.17 Early, common, and late stages of thymocyte differentiation have been identified. Using monoclonal antibodies, a majority of children with the T cell type of ALL have been found to have blast cells derived from the early stage of intrathymic differentiation. T cell leukemias derived from more mature thymocytes appear to have a better prognosis. A few patients have been found to have T cell lymphoblasts that seem to represent clonal expansion of fully mature thymocytes with functional activities. Examples of such cells are T cell lymphoblasts capable of pro-suppressor, suppressor, and helper functions. It has also been observed recently that most common or null cell lymphoblasts may be early B cells18 possessing either intracytoplasmic immunoglobulin19 or having the potential for in vitro differentiation into cells possessing classical B markers.20

Table

TABLE 3THE FIVE STAGES OF CHILDHOOD ACUTE LYMPHOID LEUKEMIA AS DEFINED BY THE CHILDREN'S CANCER STUDY GROUP

TABLE 3

THE FIVE STAGES OF CHILDHOOD ACUTE LYMPHOID LEUKEMIA AS DEFINED BY THE CHILDREN'S CANCER STUDY GROUP

Prognostic factors are of greater value in predicting remission duration than for determiningthe likelihood of remission induction because the rate of remission induction is extremely high. After a prolonged duration of complete remission, the predictive value of prognostic factors is also lost. Patients remaining in complete remission for 18 to 24 months have an equal probability of subsequent relapse regardless of the white cell count at diagnosis, age at presentation, or sex.21 However, beyond 24 months of remission duration, male sex and older age re-emerge as predictors of a poor prognosis.21 The late relapses in boys are due at least in part to the development of testicular relapse.

During the past few years childhood ALL has been staged into two or three categories. More recently the Children's Cancer Study Group has chosen to create five stages (Table 3). At one end of the spectrum, wit h a dismal prognosis, are infants less than one year of age. Two other subgroups have a poor prognosis, albeit not quite as unfavorable as that for infants. These poor-prognosis subgroups differ in the nature of the relapses. Children with the lymp ho ma-type of leukemia, characterized by bulky extramedullary disease, have the majority of relapses in sanctuary areas, rather than in the bone marrow. In boys with the lymphoma-leukemia type of ALL there is an increased incidence of testicular relapses. The other poor-prognosis group is primarily affected by bone marrow relapses and consists of children over 12 months of age with either an initial white cell count of over 50,000/ mm3 or with a lower initial white cell count but in whom less than 90% of the lymphoblasts in the bone marrow have FAB LI morphology. At the other end of the spectrum, with a very good prognosis, are children two to nine years of age with an initial while cell count below 10,000/mm2 and in whom more than 90% of lymphoblasts in the bone marrow have FAB LI morphology. Excluded from the latter group are boys with a platelet count less than 10,000/ mmj at diagnosis and children with lymphoma-leukemia. The latter and the remaining patients constitute a fifth group, with a favorable intermediate prognosis.

CURRENT THERAPY AND PROBLEMS

Despite the remarkable progress in the treatment of childhood ALL, there is still a substantial number of therapeutic failures as indicated by the nearly 50% relapse rate. There are unacceptable adverse acute and delayed effects of therapy, and there has been a reduced rate of therapeutic progress during the past decade.

The remission induction segment of the current regimen for therapy of ALL produces the most consistently favorable results and is the most widely accepted. The addition of L-asparaginase or an anthracycline drug to the basic combination of vincristine and prednisone (Table 4) induces complete remission in all but 5% of patients. Adding a fourth drug to the regimen for remission induction does not influence the duration of remission and, therefore, it appears that a three-drug regimen is optimal when using presently available agents.22

Consolidation chemotherapy including CNS prophylaxis is presently receiving the greatest attention of clinical investigators. Although administration of 2400 rad cranial radiation along with intrathecal methotrexate still remains the standard by which other forms of central nervous system therapy must be measured,22 concern for potential delayed effects of this regimen has led to the trial of alternate methods of CNS prophylaxis (Table 4). It is now apparent that cranial radiation is not needed for good prognosis patients21 and the dose of cranial radiation can be reduced to 1800 rad for intermediate prognosis patients and probably also for poor prognosis patients without causing an increased incidence of CNS relapse. Also, a regimen including maintenance intrathecal methotrexate and intensive systemic chemotherapy appears to be as effective as regimens including a course of cranial irradiation.25 Other studies to evaluate the effectiveness of intrathecal chemotherapy and high dose intravenous methotrexate infusions to prevent CNS relapse are underway (Table 4). It is likely that a variety of forms of CNS prophylaxis will be found to be effective, but it will take time to determine the relative toxicity of each regimen and to determine which regimen is most effective and appropriate for various subgroups of patients.22

Table

TABLE 4COMMONLY USED, THOUGH SUBOPTIMAL, REGIMENS FOR TREATMENT OF CHILDREN WITH ACUTE LYMPHOIP LEUKEMIA*

TABLE 4

COMMONLY USED, THOUGH SUBOPTIMAL, REGIMENS FOR TREATMENT OF CHILDREN WITH ACUTE LYMPHOIP LEUKEMIA*

The basic treatment standard for maintenance therapy continues to be a combination of 6-mercaptopurine and methotrexate. There is no convincing evidence that the addition of other drugs during remission significantly prolongs duration of remission, provided both 6mercaptopurine and methotrexate are given in maximum tolerated dosage (Table 4)."" During recent years, the maintenance phase of the leukemia therapy regimen has received the least attention, and yet it is during this phase that the vast majority of treatment failures occurs. A very promising new approach was reported from West Germany. Using intensive induction/ consolidation anda period of intensive reinduction/ reconsolidation early in maintenance, this group has achieved prolonged relapsefree survival in 75% to 80% of patients.26 In children with poor prognosis ALL, they have reported a rate of complete remission after three years in 74% of patients.26 . The optimal duration of chemotherapy is also unknown. Randomized trials of 1.5 or two years vs three years and of three years vs five years of maintenance therapy have clearly shown that girls do not need the additional therapy.27'28 In general, the additional maintenance therapy in boys appears to merely delay occurrence of the cluster of relapses observed soon after therapy is discontinued and does not improve the overall cure rate. The Medical Research Council of the United Kingdom reports that disease free survival five years after ra ndomization to stop or continue treatment was 76% for girls and only 40% for boys.27 Because of the relatively high frequency of testicular relapse in boys after discontinuation of therapy, many investigators are performing bilateral testicular biopsies prior to planned discontinuation of chemotherapy. Regimens of endtherapy consolidation chemotherapy are also under study, but as yet these regimens have not shown an advantage in childhood ALL.

As previously mentioned, another important aspect of therapy is recognition of the heterogeneity of childhood ALL and the tailoring of the leukemia therapy regimen according to the predicted prognosis and pattern of relapse as determined by initial assessment of the patient. Children with a very good prognosis should have the minimum therapy required to achieve the same long-term favorable result. The objective in this group is to decrease acute and delayed toxicities. In all other groups, intensification of therapy is warranted in an attempt to improve the prognosis. Since certain subgroups of poor prognosis patients, such as infants and patients with I y mpho ma- leukemia have unique needs, specific therapy should be designed especially for them.

Table

TABLE 5TUTORE OBJECTIVES IN THE TREATMENT OF CHILDHOOD ACUTE LYMPHOID LEUKEMIA

TABLE 5

TUTORE OBJECTIVES IN THE TREATMENT OF CHILDHOOD ACUTE LYMPHOID LEUKEMIA

Patients with acute lymphoid leukemia treated outside a children's cancer center and not according to a regimen which is part of a cooperative group or nationally known protocol, have a significantly higher death rate than children treated in centers or by trained physicians in noncancer centers using modern leukemia therapy protocols.29 The best interests of patients and science are served by referral of patients to children's cancer centers.

INVESTIGATIONAL MODALITIES

There has been relatively little progress in treatment of childhood leukemia during the last decade. Acute lymphoid leukemia still kills nearly half of the affected children. The objectives of future studies should be focused on the issues listed in Table 5.

Future investigations should be designed to determine the specific clinical and biological characteristics of patients who relapse early.2 It should be determined whether the subset of patients with Iymphomatous presentations will respond better to a lymphoma therapy regimen than to a leukemia therapy regimen. Whether the intensive induction/ consolidation and intensive reinduction/ reconsolidation approach reported from West Germany benefits poor prognosis patients to the extent indicated by this study26 requires confirmation. If confirmed, prospective clinical trials should determine whether it is the intensive induction/ consolidation or the delayed intensification which is primarily responsible for the improvement. Because of the unique leukemia therapy requirements of infants, a separate regimen designed exclusively for this small but important group should be developed. The value of experimental approaches, including interferon therapy and immunotherapy with antileukemic monoclonal antibodies4'17 await reporting of the results of controlled trials that are now in progress.

The currently accepted definition of complete remission is probably inadequate and more sensitive laboratory techniques are needed to detect residual leukemic cells. Fluorescent-activated cell sorting, monoclonal antibody detection assays, and other new diagnostic methods may eventually provide the increased sensitivity needed to detect these residual leukemic cells. Being able to detect one leukemic cell among hundreds or thousands of cells would provide a better way of assessing the effectiveness of therapy given during remission (maintenance or consolidation/ reinduction therapy). Currently, of course, the only clue to when resistance has developed is the occurrence of overt relapse. Detection of minimal residual disease may be facilitated by techniques such as cell phenotyping with monoclonal antibodies and flow cytofluorimetry with cell separation capability.

The preliminary results of bone marrow transplantation performed during the second or subsequent remission of acute lymphoid leukemia indicate that the proportion of long-term survivors may be as high as 30% to 50%. For patients who are expected to have a very poor prognosis, bone marrow transplantation during the initial remission or for certain sanctuary relapses on current therapy may be justified. We now have wellestablished criteria for accurately predicting prognosis at the time of initial diagnosis of leukemia to be able to identify patients with an expected two year survival rate of less than 25% to 30%. In this group of patients having a poor prognosis, it seems reasonable to incur the risks of early mortality from graft-vs-host disease as a complication of bone marrow transplantation.

The answers to a number of other questions should be sought. Should patients with a relapse limited to an isolated sanctuary be treated on an entirely different regimen utilizing non-cross-resistant agents and aggressive systemic chemotherapy? Why are the testes a sanctuary and will testicular biopsies identify patients who are at risk of subsequent relapse? What is the ideal duration of leukemia therapy in boys and in girls? What is the true incidence of leukoencephalopathy, subclinical neuropsychologic and endocrine dysfunction, and second malignancies? Can immunodiagnostic studies such as monoclonal antibody phenotyping provide a simpler, more accurate method of staging childhood acute lymphoid leukemia? Should acute lymphoid leukemia be considered as a group of diseases, each requiring treatment with stage-specific therapy? Can entirely new agents with novel mechanisms of action be developed and identified? Efforts are now being turned to the understanding of the biology of the disease. Future progress will depend on our ability to apply the newly obtained knowledge to the design of innovative therapeutic strategies.2

SUMMARY

During the past decade progress in the treatment of childhood acute lymphoblastic leukemia has slowed. A 50% to 60% cure barrier has frustrated a multitudinous array of therapeutic attempts to overcome this obstacle. With few exceptions, intensifications of induction, consolidation, or maintenance therapies have not overcome this obstacle. Current effort to break through this impasse include improved staging, biological characterization of the leukemia with newer immunodiagnostic methods, and novel approaches to therapy. The latter include continuous intensive therapy in poor prognosis patients and a combination of intensive induction/ consolidation and delayed intensification.

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TABLE 1

CLINICAL AND LABORATORY FINDINGS IN 724 CHILDREN WITH ACUTE LYMPHOID LEUKEMIA2

TABLE 2

CHARACTERIZATION OF LEUKEMIC LYMPHOBLASTS

TABLE 3

THE FIVE STAGES OF CHILDHOOD ACUTE LYMPHOID LEUKEMIA AS DEFINED BY THE CHILDREN'S CANCER STUDY GROUP

TABLE 4

COMMONLY USED, THOUGH SUBOPTIMAL, REGIMENS FOR TREATMENT OF CHILDREN WITH ACUTE LYMPHOIP LEUKEMIA*

TABLE 5

TUTORE OBJECTIVES IN THE TREATMENT OF CHILDHOOD ACUTE LYMPHOID LEUKEMIA

10.3928/0090-4481-19830401-02

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