Pediatric Annals

ACUTE LEUKEMIA IN CHILDREN

Donald J Fernbach, MD; Kenneth A Starling, MD

Abstract

Cancer is now the number one cause of death from disease in children between 1 and 15 years of age. Its incidence is approximately 10 per 100,000 children annually. Acute leukemia is the most common malignancy; it occurs in nearly four per 100,000 children.

Conventional mortality tables do not accurately reflect the true incidence of childhood cancer because data collected from death certificates obviously do not include patients who survive (Table 1). Hopefully, the gap between incidence figures and data from death certificates will widen further as better therapy is developed for all cancers.

The number of five-year survivors among children with acute leukemia registered with the Southwest Oncology Group has increased dramatically since 1965. 1 This improved survival time is the result of many factors, but the greatest contribution has been the development of new principles of chemotherapy.

Acute leukemia is a complex entity whose cause remains obscure. Some groups of children can be clearly identified as being at increased risk of developing leukemia (Table 2); the most prominent group (in terms of actual numbers) is children with Down's syndrome. Some of the large epidemiologic programs now in progress may clarify further this information on high-risk groups.

Serial population studies indicate that there has been a decline over the last 10 to 15 years in the occurrence of acute leukemia in all age groups below 75 years of age; this decline has been most marked in the under five age group.2 The role of environmental factors that might account for this decrease is being given careful attention. The peak incidence of acute lymphocytic leukemia (ALL) among white children in the United States occurs at approximately three years of age, and the range is predominantly in the preschool-age group. This peak is not observed in children with acute myelogenous leukemia (AML) nor in children of nonwhite racial groups.3

For practical purposes, acute leukemia in children may be considered a primary disorder of the bone marrow in which the normal marrow elements are replaced by immature or undifferentiated blast cells. When the quantity of normal marrow has been depleted below the level necessary to maintain peripheral blood elements within normal ranges, anemia, neutropenia, and thrombocytopenia follow.

CLINICAL PICTURE

The presenting complaints of leukemic patients depend upon the degree to which the bone marrow has been compromised and the extent and location of extramedullary infiltration. The child with acute leukemia seen by the primary physician may have pallor, infection, bleeding, organomegaly, bone pain, and so forth, as isolated complaints or in any combination or sequence. By a heightened awareness of the pathogenesis of this disease, the primary physician may establish a diagnosis in many cases before the development of multiple complications. The protean nature of the disease makes it a "great imitator." For example, the initial symptoms may be limited to fever of undetermined origin, sudden pallor in the absence of other findings, arthralgia simulating rheumatoid arthritis or osteomyelitis, or purpura with organomegaly or anemia. By maintaining a high index of suspicion, the primary physician can initiate the proper diagnostic studies promptly.

1. George. S.. Fernbach. D.. Vietti. T.J. , et al. Factors influencing survival in pediatric acute leukemia; the SWCCSG experience, 1958-1970. Cancer (in press).

2. Miller. R.W. Decline in U.S. childhood leukaemia mortality. Lancet 2(1969), 1189.

3. Fernbach, D.J. Natural History of Acute Leukemia. WW. Sutow. T.J. Vietti. and D.J. Fernbach, eds. In Clinical Pediatric Oncology. St. Louis. TheC.V. MosbyCo., 1973.

4. Hardgrove, CB. Working with parents on the pediatric unit. Ped. Ann. 1 (1972). 44.

5. Fernbach, D.J.. Henrich. W. L.. and Starling. KA Acute leukemia in children ;…

Cancer is now the number one cause of death from disease in children between 1 and 15 years of age. Its incidence is approximately 10 per 100,000 children annually. Acute leukemia is the most common malignancy; it occurs in nearly four per 100,000 children.

Conventional mortality tables do not accurately reflect the true incidence of childhood cancer because data collected from death certificates obviously do not include patients who survive (Table 1). Hopefully, the gap between incidence figures and data from death certificates will widen further as better therapy is developed for all cancers.

The number of five-year survivors among children with acute leukemia registered with the Southwest Oncology Group has increased dramatically since 1965. 1 This improved survival time is the result of many factors, but the greatest contribution has been the development of new principles of chemotherapy.

Acute leukemia is a complex entity whose cause remains obscure. Some groups of children can be clearly identified as being at increased risk of developing leukemia (Table 2); the most prominent group (in terms of actual numbers) is children with Down's syndrome. Some of the large epidemiologic programs now in progress may clarify further this information on high-risk groups.

Serial population studies indicate that there has been a decline over the last 10 to 15 years in the occurrence of acute leukemia in all age groups below 75 years of age; this decline has been most marked in the under five age group.2 The role of environmental factors that might account for this decrease is being given careful attention. The peak incidence of acute lymphocytic leukemia (ALL) among white children in the United States occurs at approximately three years of age, and the range is predominantly in the preschool-age group. This peak is not observed in children with acute myelogenous leukemia (AML) nor in children of nonwhite racial groups.3

For practical purposes, acute leukemia in children may be considered a primary disorder of the bone marrow in which the normal marrow elements are replaced by immature or undifferentiated blast cells. When the quantity of normal marrow has been depleted below the level necessary to maintain peripheral blood elements within normal ranges, anemia, neutropenia, and thrombocytopenia follow.

CLINICAL PICTURE

The presenting complaints of leukemic patients depend upon the degree to which the bone marrow has been compromised and the extent and location of extramedullary infiltration. The child with acute leukemia seen by the primary physician may have pallor, infection, bleeding, organomegaly, bone pain, and so forth, as isolated complaints or in any combination or sequence. By a heightened awareness of the pathogenesis of this disease, the primary physician may establish a diagnosis in many cases before the development of multiple complications. The protean nature of the disease makes it a "great imitator." For example, the initial symptoms may be limited to fever of undetermined origin, sudden pallor in the absence of other findings, arthralgia simulating rheumatoid arthritis or osteomyelitis, or purpura with organomegaly or anemia. By maintaining a high index of suspicion, the primary physician can initiate the proper diagnostic studies promptly.

The diagnosis of leukemia is usually suspected on the basis of altered peripheral blood counts. Examination of the bone marrow quickly establishes an unequivocal diagnosis in all but a small percentage of cases. This latter group poses difficult problems in establishing a definite diagnosis, and a biopsy of other tissues, such as the liver or lymph nodes, may be required. In rare cases, in which acute leukemia of childhood may be preceded by a hypoplastic or aplastic anemia, the diagnosis may be delayed until it is quite evident that a malignant transformation has occurred. If a prompt response to steroid therapy is observed in either of these conditions, the prognosis should be guarded. Distinguishing between a primary lymphosarcoma and acute lymphocytic leukemia (ALL) may be impossible once generalized bone marrow involvement develops. Most hematologists have seen a small number of disorders of the reticuloendothelial system which defy classification by present terminology.

Table

TABLE 1MALIGNANCY IN CHILDREN: HARRIS COUNTY INCIDENCE (1958-1970)* COMPARED WITH UNITED STATES MORTALITY (1960-1966)**

TABLE 1

MALIGNANCY IN CHILDREN: HARRIS COUNTY INCIDENCE (1958-1970)* COMPARED WITH UNITED STATES MORTALITY (1960-1966)**

Table

TABLE 2GROUPS AT EXCEPTIONALLY HIGH RISK OF LEUKEMIA*

TABLE 2

GROUPS AT EXCEPTIONALLY HIGH RISK OF LEUKEMIA*

Because the bone marrow specimen is so critical to correct diagnosis, it should be obtained by someone with expertise in the collection and evaluation of this material from children. Aspiration of sternal bone marrow is contraindicated in children because the sternum is a relatively thin structure in the small child , and fatalities have occurred following attempted sternal aspiration. Adequate marrow specimens can be obtained easily and safely from the posterior iliac spine, an area remote from virtually all vital organs, nerves, or blood vessels. A bone marrow biopsy also can be obtained, if necessary, from this area, and both procedures in this area require only a local anesthetic.

Definitive therapy should be avoided until the diagnosis has been made unless supportive therapy is essential to prevent progression of lifethreatening complications.

MANAGEMENT

Once the diagnosis has been made, initiation of therapy should be preceded by a detailed and honest discussion of the clinical problem with both parents. This discussion is most valuable if given by the person who will be responsible for directing the treatment, as the manner of orientation of the parents and child will have a major effect on their attitude and cooperation in the future.

Emphasis has been placed on referral of leukemic children to centers best equipped to manage their problems. Experience indicates that most physicians who treat children are characteristically compassionate individuals who do not hesitate to refer their difficult problems to the subspecialist. Perhaps one of the least emphasized aspects about referrals is the immediate establishment of good, prompt, and direct communications between the specialist and the referring physician. This becomes a continuous source of postgraduate education for the referring practitioner and enables him or her to perform a more valuable service to the child and family, particularly if they live any distance from the referral center. In addition, if the pediatrician or family physician is able to manage interim problems with confidence within the limit of his or her ability and local physical facilities, the specialist at the center gains more freedom to engage in research activities. Thus, all involved benefit.

PSYCHOLOGICAL FACTORS

In a recent issue of this journal, C.B. Hardgrove4 devoted considerable attention to the concept of having the parents of hospitalized children live in the hospital with their children. This concept has been in practice at Texas Children's Hospital since it opened its doors in 1954. Given the limits of practicality and finances in the construction of this type of facility, it is inconceivable that anyone should revert to a ward-type arrangement that excludes parents. Having parents livein means the child does better, the parents take a positive role by participating in care, the strain on nursing personnel is relieved, and the entire situation is more gratifying.

Occasionally, parents have difficulty adjusting to the hospital situation but their presence is generally more valuable than their absence. In some cases, children react more favorably to the medical staff in the absence of their parents. However, as only five per cent of the duration of the disease involves hospitalization, parents continue to be a dominant influence.5 Common sense dictates that it is abnormal for parents to live harmoniously with their child in the closely-confined quarters of a hospital room for 24 hours a day. Inevitably, there are some problems, particularly in families with strained finances or with many young siblings at home. However, the sum of 20 years' experience is favorable, and with some support from the hospital medical and social service staffs, the majority of problems are easily resolved.

Depending upon the age of the leukemic child, explanations of events should be given in a forthright, honest manner. Surprisingly few children at any age want to know their exact diagnoses, particularly when they are the recipients of their physicians' attention in every situation except the first counseling session with the parents. Once school-age or even older preschool-age children grasp the concept that they have "passed" or "failed" their bone marrow or peripheral white blood cell tests, they quickly comprehend the reasons for social isolation or changes in medication. In effect, once they have developed confidence in their physicians, their trust is unwavering.

Lack of direct communication between the physician and the child can result in utter catastrophe because fear of the unknown exceeds the concern about bad news that is accompanied by a logical explanation. It is obvious that many children, particularly teenagers, understand their diagnoses, but it is still a rare child who wants to know all the details. The key is to eliminate the fear of these communications for the physician, parent, or patient and to approach the medical problem exactly as it is.

TOTAL THERAPY

The lengthening survival of children with acute leukemia is related to the following key factors:

1. Improved chemotherapy

2. Improved antimicrobial therapy

3. Improved blood transfusion therapy

4. Improved skill of pediatric hematologists.

Although there is no universally accepted standard therapy for the treatment of children with acute leukemia, standard therapy for the practitioner is the most current therapy available in the child's community.

The basic concept of therapy is achievement of complete remission with restoration of normal (relative to bone marrow) peripheral blood, physical findings, and symptoms. Complete remission is usually achieved after a period of remission induction therapy and is prolonged by maintenance therapy of some type.

Recently, the duration of diseasefree remissions has been increased by the addition of prophylactic therapy of the central nervous system with supravoltage radiotherapy or intrathecal methotrexate therapy or a combination of both.6 In an attempt to avoid the immunosuppressive effects of continuous chemotherapy, the maintenance schedules now being used involve intermittent doses of multiple agents in combination, followed by rest periods without therapy, or moderate daily dose schedules periodically reinforced with "induction" agents. Present research programs include attempts to define the minimal amount of therapy necessary to achieve the maximum result.

Figure 1. Necrotizing infection of the nares during Pseudomonas septicemia, a. Acute phase, b. Healing after therapy.

Figure 1. Necrotizing infection of the nares during Pseudomonas septicemia, a. Acute phase, b. Healing after therapy.

The role of bactericidal antimicrobial agents in prolonging survival cannot be understated. Many children have survived severe bacterial infections to go into long remissions (Figure 1). Because most of the bacterial infections are from organisms indigenous to the host, rigid reverse isolation is no longer used on our service. There has been no apparent change in the infections encountered, although more infections due to exotic organisms are being observed in late-stage disease (Pneumocystis carinii, systemic fungi, and others). Platelet transfusions have effectively controlled thrombocytopenic bleeding. The indications for platelet transfusions vary but it is advisable to use as many units as are necessary to control bleeding (one unit of platelets = the amount extracted from 500 ml. of whole blood). We do not use platelets in a patient without purpura, regardless of the platelet count.

CHEMOTHERAPY

The agents listed in Table 3 are known to be effective in induction of remission or as remission maintenance agents. Various combinations of these drugs are still being studied to determine the optimum method of inducing and maintaining remission. By use of these agents and many experimental drugs not listed, the lifespan of children with acute leukemia has been lengthened and many children not in continuous remission survive five years or more.7 The first relapse from complete remission can be considered a poor prognostic indicator of further long-term survival. Thus, all research regimens have been devised hopefully to prevent the first relapse; some even at the risk of exposing the patient to the hazards of severe drug toxicity. Our recommended therapy regimen for children with acute leukemia is outlined in Table 4.

Table

TABLE 3LEUKEMIA CHEMOTHERAPY AGENTS

TABLE 3

LEUKEMIA CHEMOTHERAPY AGENTS

Table

TABLE 4A SUGGESTED CONTEMPORARY TREATMENT REGIMEN FOR A CHILD WITH ACUTE LYMPHOCYTIC LEUKEMIA

TABLE 4

A SUGGESTED CONTEMPORARY TREATMENT REGIMEN FOR A CHILD WITH ACUTE LYMPHOCYTIC LEUKEMIA

The basic mystery - that is, why certain children with leukemia have shown very prolonged complete remission even without therapy - has been documented by the Leukemia Task Force in their collection and study of long-term survivors.' This mystery may be solved during the era of the increasing role of immunology in cancer. In this review, no common denominator was found to explain why some patients have remained in symptom-free remission in excess of 5 and 10 years, in spite of receiving only what would be considered minimal therapy by modern standards. The answer may be found by understanding the defense mechanisms of the host. Clarification of the role of defense mechanisms would significantly influence future therapy. Immunotherapy has received an increasing amount of attention; it will be dealt with in an article in the June issue.

Table

TABLE 5FACTORS POSSIBLY RELATED TO SURVIVAL IN 1,024* CHILDREN WITH ACUTE LEUKEMIA (1958-70), Southwest Cancer Chemotherapy Study Group1

TABLE 5

FACTORS POSSIBLY RELATED TO SURVIVAL IN 1,024* CHILDREN WITH ACUTE LEUKEMIA (1958-70), Southwest Cancer Chemotherapy Study Group1

PROGNOSIS

In retrospective analysis of the patterns of responsiveness of large groups of children with acute leukemia, a variety of prognostic factors have been identified. These are listed in Table 5, as reported by George, Fernbach, and Vietti et al. of the Southwest Oncology Group.1 It can be seen that any type of patient selection which might influence these factors could distort results and possibly lead to erroneous conclusions when small numbers of patients are used in a study.

Until now the stratification of children into treatment groups has been made primarily by an arbitrary division into two morphologic categories: acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML). Approximately 80 per cent of children less than 15 years of age at the time of diagnosis have been categorized as ALL; the other 20 per cent (including everything that is non-ALL) have been grouped as AML. Until the more recent introduction of cytosine arabinoside, which has improved the response rate of AML, it could be said that these clinical categories actually represented a "responsive" type (ALL) and a "less responsive" type (AML). In order for results of treatment to be evaluated in a comparable manner, it is important that the term "acute leukemia" be clearly defined.

CONCLUSION

Acute leukemia in children may have many causes. While the pathogenesis is being unraveled and the search for causative agents is continued, the clinician has to treat the patient. A more organized approach to the management of these children has emerged as a result of many preliminary, controlled studies. There is no doubt that affected children are living longer and with less morbidity because of these cooperative studies. The ultimate objective is to cure the patient. It is difficult, however, to define the term "cure" because late relapses still occur after long remissions.9 True cures may actually result from present-day therapy but, regardless of semantics, there is no doubt that the disease is treatable and longer survival time has been achieved.

BIBLIOGRAPHY

1. George. S.. Fernbach. D.. Vietti. T.J. , et al. Factors influencing survival in pediatric acute leukemia; the SWCCSG experience, 1958-1970. Cancer (in press).

2. Miller. R.W. Decline in U.S. childhood leukaemia mortality. Lancet 2(1969), 1189.

3. Fernbach, D.J. Natural History of Acute Leukemia. WW. Sutow. T.J. Vietti. and D.J. Fernbach, eds. In Clinical Pediatric Oncology. St. Louis. TheC.V. MosbyCo., 1973.

4. Hardgrove, CB. Working with parents on the pediatric unit. Ped. Ann. 1 (1972). 44.

5. Fernbach, D.J.. Henrich. W. L.. and Starling. KA Acute leukemia in children ; Time spent in hospitalization. Pediatrics 49 (1972), 765.

6. Sullivan, M. P. and Hrgovic, M. Extramedullar Leukemia WW. Sutow, T.J. Vietti, and D.J. Fernbach, eds. In Clinical Pediatric Oncology. St. Louis: The C.V. MosbyCo., 1973.

7. Fernbach. D.J. Data from the Pediatric Division, Southwest Oncology Group. Unpublished data.

8. Burchenal. J.J. Formal discussion: Longterm survival in Burkitt's tumor and in acute leukemia. Cancer Res. 27(1967), 2616.

9. Nesbit. M.. Jr., Gilchrist. G., Beatty, E., Jr., Hartmann. J., and Krivit. W. Increased survival or cure following cyclic-sequential therapy of acute lymphoblastic and undifferentiated leukemia (ALL/ AUL) of childhood? Proc. Amer. Assoc. Cancer Research /4(1973), 46.

10. Duttera, M.J., Bleyer. WA,. Pomeroy. T.C., Levinthal, C.M., and Levinthal, BG. Irradiation, methotrexate toxicity, and the treatment of meningeal leukemia. lancef 2(1973), 703.

TABLE 1

MALIGNANCY IN CHILDREN: HARRIS COUNTY INCIDENCE (1958-1970)* COMPARED WITH UNITED STATES MORTALITY (1960-1966)**

TABLE 2

GROUPS AT EXCEPTIONALLY HIGH RISK OF LEUKEMIA*

TABLE 3

LEUKEMIA CHEMOTHERAPY AGENTS

TABLE 4

A SUGGESTED CONTEMPORARY TREATMENT REGIMEN FOR A CHILD WITH ACUTE LYMPHOCYTIC LEUKEMIA

TABLE 5

FACTORS POSSIBLY RELATED TO SURVIVAL IN 1,024* CHILDREN WITH ACUTE LEUKEMIA (1958-70), Southwest Cancer Chemotherapy Study Group1

10.3928/0090-4481-19740501-06

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