Pediatric Annals

Acute Non-Lymphoid Leukemia

Carlton Dampier, MD; Robert R Chilcote, MD

Abstract

The term acute non-lymphoid leukemia (ANLL) subsumes related groups of hématologie neoplasms of myeloid precursors. Many clinical and pathophysiologic features typical of bone marrow failure are common to both ANLL and acute lymphoid leukemia (ALL), but acute non-lymphoid leukemia is far more refractory to therapy.

In this article, we will review the clinical manifestations and recent advances in the biology of this group of disorders and outline current approaches to therapy.

EPIDEMIOLOGY

The most common malignancy of children in the United States under 15 years of age is acute leukemia, occurring with an incidence of 20 per 1 million.1 About three-quarters of these cases are acute lymphoid leukemia, while the remainder are due to ANLL. Incidence does not vary significantly with age, sex, race, or geographical location.

ETIOLOGY

The etiology of acute non-lymphoid leukemia is unknown. However, Table I lists a number of congenital conditions which increase the risk for ANLL.2'3 The majority of these conditions are associated with abnormalities of chromosomal number or chromosomal stability. The increased incidence of leukemia in WiskottAldrich syndrome (a sex-linked recessive disorder characterized by thrombocytopenia, eczema recurrent infections, and an inability to form specific antibody to polysaccharide antigens) suggests that immune dysfunction may be an additional risk factor for leukemia.4

Large doses of ionizing radiation, as experienced by the atomic bomb survivors near the epicenter, clearly predispose to acute non-lymphoid leukemia. Malignancy has not been associated with the doses of radiation customarily used for diagnostic imaging.

Of concern to pediatrie oncologists is the increased risk for acute non-lymphoid leukemia in long-term survivors of pediatrie malignancies. This problem is most evident in Hodgkin's disease, treated with both radiation therapy and alkylating agents, where the cumulative risk for development of ANLL over the first ten years after therapy may be as high as 5%.s

Perhaps the most exciting research topic in acute nonlymphoid leukemia is the association of non-random chromosomal abnormalities with malignant cells.6 These findings extend the epidemiological link between chromosomal abnormalities and leukemia to the cellular level. Unlike the congenital chromosomal abnormalities, such as the trisomy syndromes, the chromosomal abnormalities of individual leukemic cells are somatic mutations found only in the malignant cells and not in the normal cells from the same individual. As cytogenetic techniques for resolving chromosome structure improve, it is reasonable to hypothesize that every leukemic cell clone may have some form of chromosomal abnormality.7

Current studies of chromosomal abnormalities in acute non-lymphoid leukemia have identified abnormalities in both adults and children. The most common and consistent abnormalities in adults with acute myeloid leukemia or erythroleukemia are loss of all or part of chromosomes number 5 or number 7, or gain of chromosome number 8; in adult myelomonocytic leukemia (AMMOL) and in monocytic leukemia (AMOL) gain of chromosome number 8 is most common.8 Of considerable importance to our understanding of the etiology of leukemia is the frequent observation of the loss of chromosome number 5, loss of chromosome number 7, or loss of both, in adult acute non-lymphoid leukemia secondary to previous therapy for a malignant disease or occupational exposure to potentially mutagenie compounds.9 Early studies in children have revealed only rare abnormalities of chromosome number 5 and number 7.

1. Young JL, Miller RW: Incidence of malignant tumors in US children. J Pediair 1975, 86:254-258.

2. IhIe JN: Experimental models and conceptual approaches to studies of lymphomas and leukemia: etiology, biology, and control. Semin Hemaiol 1978; 15:95-115.

3. Harris CC (ed): Individual differences in cancer susceptibility. Ann Intern Med 1980; 92:809-8 25.

4. Louis S. Schwartz RS: Immunodeficiency and the paihogenesis of lymphoma and leukemia. Semit Hemaiol 1978; 15:177-238.

5.…

The term acute non-lymphoid leukemia (ANLL) subsumes related groups of hématologie neoplasms of myeloid precursors. Many clinical and pathophysiologic features typical of bone marrow failure are common to both ANLL and acute lymphoid leukemia (ALL), but acute non-lymphoid leukemia is far more refractory to therapy.

In this article, we will review the clinical manifestations and recent advances in the biology of this group of disorders and outline current approaches to therapy.

EPIDEMIOLOGY

The most common malignancy of children in the United States under 15 years of age is acute leukemia, occurring with an incidence of 20 per 1 million.1 About three-quarters of these cases are acute lymphoid leukemia, while the remainder are due to ANLL. Incidence does not vary significantly with age, sex, race, or geographical location.

ETIOLOGY

The etiology of acute non-lymphoid leukemia is unknown. However, Table I lists a number of congenital conditions which increase the risk for ANLL.2'3 The majority of these conditions are associated with abnormalities of chromosomal number or chromosomal stability. The increased incidence of leukemia in WiskottAldrich syndrome (a sex-linked recessive disorder characterized by thrombocytopenia, eczema recurrent infections, and an inability to form specific antibody to polysaccharide antigens) suggests that immune dysfunction may be an additional risk factor for leukemia.4

Large doses of ionizing radiation, as experienced by the atomic bomb survivors near the epicenter, clearly predispose to acute non-lymphoid leukemia. Malignancy has not been associated with the doses of radiation customarily used for diagnostic imaging.

Of concern to pediatrie oncologists is the increased risk for acute non-lymphoid leukemia in long-term survivors of pediatrie malignancies. This problem is most evident in Hodgkin's disease, treated with both radiation therapy and alkylating agents, where the cumulative risk for development of ANLL over the first ten years after therapy may be as high as 5%.s

Perhaps the most exciting research topic in acute nonlymphoid leukemia is the association of non-random chromosomal abnormalities with malignant cells.6 These findings extend the epidemiological link between chromosomal abnormalities and leukemia to the cellular level. Unlike the congenital chromosomal abnormalities, such as the trisomy syndromes, the chromosomal abnormalities of individual leukemic cells are somatic mutations found only in the malignant cells and not in the normal cells from the same individual. As cytogenetic techniques for resolving chromosome structure improve, it is reasonable to hypothesize that every leukemic cell clone may have some form of chromosomal abnormality.7

Current studies of chromosomal abnormalities in acute non-lymphoid leukemia have identified abnormalities in both adults and children. The most common and consistent abnormalities in adults with acute myeloid leukemia or erythroleukemia are loss of all or part of chromosomes number 5 or number 7, or gain of chromosome number 8; in adult myelomonocytic leukemia (AMMOL) and in monocytic leukemia (AMOL) gain of chromosome number 8 is most common.8 Of considerable importance to our understanding of the etiology of leukemia is the frequent observation of the loss of chromosome number 5, loss of chromosome number 7, or loss of both, in adult acute non-lymphoid leukemia secondary to previous therapy for a malignant disease or occupational exposure to potentially mutagenie compounds.9 Early studies in children have revealed only rare abnormalities of chromosome number 5 and number 7.

Figure 1. Translocation, t(15, 17), chromosome abnormality found in a nine-year-old white boy with acute promyelocytic leukemia (M3 type). (Courtesy of Drs. Janet Rowley and Koji Kondo, Department of Medicine, University of Chicago, Pritzker School of Medicine.)

Figure 1. Translocation, t(15, 17), chromosome abnormality found in a nine-year-old white boy with acute promyelocytic leukemia (M3 type). (Courtesy of Drs. Janet Rowley and Koji Kondo, Department of Medicine, University of Chicago, Pritzker School of Medicine.)

Table

TABLE 1CONGENITAL SYNDROMES WHICH INCREASE RISK FOR ACUTE NON-LYMPHOID LEUKEMIA

TABLE 1

CONGENITAL SYNDROMES WHICH INCREASE RISK FOR ACUTE NON-LYMPHOID LEUKEMIA

Specific translocation genotypes are uniquely associated with certain subsets of acute non-lymphoid leukemia in adults and children.10 A portion of chromosome number 8 is translocated to chromosome number 21 [expressed t(8,21)] only in patients with acute myeloid leukemia with maturation (M2 type). Acute promyelocytic leukemia (M3 or APL) frequently has a translocation between chromosomes number 15 and number 17, t(15, 17) (Figure 1). A rearrangement of chromosome number Il is found in many cases of childhood acute monocytic leukemia (M5) and less commonly in acute myelomonocytic leukemia (M4) and acute myeloid leukemia (M I, M 2).

Serial chromosome analyses in patients with acute nonlymphoid leukemia show that the leukemic clone is absent from bone marrow samples during remission; but at relapse the original leukemic clone reappears, often with additional karyotypic abnormalities." These additional abnormalities are frequently extra chromosome number 8, number 18, or both, or rearrangement of parts of these chromosomes.

An increased frequency of mutational events lead ing t o specific chromosomal abnormalities is thought to underlie the association between the syndromes listed in Table 1 and acute non-lymphoid leukemia. Chromosomal abnormalities which arise in normal individuals during cancer therapy may reflect inherent chromosomal instability in neoplastic cell populations.13

There are at least two explanations for the association of non-random chromosomal abnormalities with specific neoplasms.6'13 These chromosomal abnormalities may be the product of the most common mutational event. Alternatively, one abnormality may confer such a proliferative advantage that it becomes the predominant neoplastic cell line.

Clonality of neoplastic cells has also been studied in individuals heterozygous for glucose-6-phosphate dehydrogenase who show a mixture of A and B isoenzymes in normal tissues, but show only a single isoenzyme in leukemic cells. The presence of only a single G-6-PD isoenzyme suggests that the leukemic cells arose from a single cell clone.14 In some cases, analysis of granulocytic and erythroid precursors in these patients also suggests that the leukemic transformation occurred in a stem cell pleuripotent for both granulocytemacrophage cells and erythroid cells (Figure 2). In other cases, it appears that a cell already committed to granulocyte-macrophage differentiation underwent malignant conversion.15

Figure 2. The pluripotent stem cell commits cells to myeloid and lymphoid differentiation. These cells mature in the thymus to T cells or, under the influence of the bursa-equi valent, mature to B cells. Myeloid differentiation further commits the cells to the granulocyte-monocyte pathways to become granulocytes or monocytes. Other pathways lead to erythroid and megakaryocyte development.

Figure 2. The pluripotent stem cell commits cells to myeloid and lymphoid differentiation. These cells mature in the thymus to T cells or, under the influence of the bursa-equi valent, mature to B cells. Myeloid differentiation further commits the cells to the granulocyte-monocyte pathways to become granulocytes or monocytes. Other pathways lead to erythroid and megakaryocyte development.

In vitro, acute non-lymphoid leukemia cells respond to regulatory factors, but the majority fail to differentiate completely into mature granulocytes or monocytes.16"19 Since these growth characteristics appear to be heritable features of the leukemic cells, they are potentially helpful in distinguishing normal from malignant blasts in bone marrow with equivocal morphology.20

Table

TABLE 2THE FRENCH-AMERICAN-BRITISH MORPHOLOGICAL CLASSIFICATION OF ACUTE NON-LYMPHOID LEUKEMIA

TABLE 2

THE FRENCH-AMERICAN-BRITISH MORPHOLOGICAL CLASSIFICATION OF ACUTE NON-LYMPHOID LEUKEMIA

CLASSIFICATION

The French-American-British (FAB) schema21 classifies acute non-lymphoid leukemia into six groups based on the direction of differentiation and the degree of maturation of the blasts (Table 2).

Ml, or und iff ere ntia ted myeloid leukemia, shows evidence of granulocytic differentiation, with some blast cells having a few azurophilic granules or demonstrating a positive stain for myeloperoxidase. M2 leukemic blasts show some maturation to the promyelocyte stage, with most cells containing many azurophilic granules and occasional Auer rods (Figure 3).

The M3 type refers to promyelocytic leukemia in which the predominant blast cells contain heavy granulation (Figure 4). These hypergranular blasts contain clumps or meshworks of Auer rods, which by electron microscopy are composed of longitudinal bundles of hexagonallyarranged tubules in a crystalloid array with a periodicity of 250 Angstroms.22

The M4 type refers to myelomonocytic leukemia, which is characterized by the presence of varying proportions of myeloblasts and promonocytes in the bone marrow (Figure 5). These leukemic cells are differentiated just beyond the branch point where monocytes and myeloid cells separate (Figure 2), which suggests that the transformation actually occurs in a more primitive "promyelomonoblast." Many of the leukemic cells show a positive fluoride inhibitable esterase reaction.

Figure 3. Auer rod (arrow) in the cytoplasm of myeloblast of a patient with M2 (AML) type of leukemia, Wright's stain, X1000.

Figure 3. Auer rod (arrow) in the cytoplasm of myeloblast of a patient with M2 (AML) type of leukemia, Wright's stain, X1000.

Figure 4. Hypergranular promyelocytes in a patient with M3 (APL) type of leukemia, Wright's stain, X 1000.

Figure 4. Hypergranular promyelocytes in a patient with M3 (APL) type of leukemia, Wright's stain, X 1000.

Figure 5. Monotonous pattern of very immature myeloid cells replacing normal erythroid, myeloid, and megakaryocytic elements in a patient with the M4 (AMMOL) type of leukemia, Wright's stain. XlOOO.

Figure 5. Monotonous pattern of very immature myeloid cells replacing normal erythroid, myeloid, and megakaryocytic elements in a patient with the M4 (AMMOL) type of leukemia, Wright's stain. XlOOO.

The M5 type, also called monocytic leukemia, differs from the M4 type by the absence of myeloblasts and the presence of more obvious monocytic features. The bone marrow smear may contain primitive promonoblastic forms, while the peripheral blood in the same patient may show malignant monocytes. Tissues may accumulate cells, possibly as a result of che m o taxis, that resemble macrophages. These cells may cause skin nodules or gingival infiltrates.

The last category, M6 or erythro leukemia (Figure 6), has a predominant population of bizarre erythroblasts with a variable percentage of myeloblasts and promyelocytes. Splenomegaly and hemolytic anemia may be presenting signs.

Unlike acute lymphoid leukemia, where many monoclonal and hetero-antisera are available, classification of acute non-lymphoid leukemia by surface marker phenotype is still rudimentary. Current studies show that many acute non-lymphoid leukemic blasts have variable amounts of myeloid, monocytic, or erythroid features, suggesting some degree of disordered differentiation.23'14 Future studies will try to establish a relationship between cell surface phenotype and morphology. In addition to being diagnostically useful to distinguish acute nonlymphoid leukemia from acute lymphoid leukemia, such immunological and morphological studies also will help to define normal and pathologic myeloid differentiation.

CLINICAL PRESENTATION

In common with childhood acute lymphoid leukemia, the usual presenting symptoms of acute non-lymphoid leukemia develop when leukemic cells infíltrate the bone marrow and suppress normal hematopoiesis.25'26 Signs of bone marrow failure such as pallor, bacterial infection and hemorrhage may develop. Bone, joint pain and fever may also occur. About half of children have significant hepatosplenomegaly or lymphadenopathy. The initial leukocyte count is less than 50,000/ mm3 in over half of children, but is over 100,000/ mm5 in about 20%. About 40% of patients may have a normal or reduced leukocyte count at diagnosis. The platelet count is less than 50,000/ mm' in over half of cases, and less than 10,000/ mm3 in 15%.

Monocytic leukemias (the M4 and M5 subtypes) are frequently associated with hyperleukocytosis, with leukocyte counts of over 100,000/ mm3, and leukemic cells may infiltrate gingiva, skin, and the central nervous system.27'28 Serum and urinary lysozyme is elevated in patients with the M4 or M5 type of leukemia.

Figure 6. M6 erythroleukemia cells with a predominance of erythroblasts (arrow), Wright's stain, X1000.

Figure 6. M6 erythroleukemia cells with a predominance of erythroblasts (arrow), Wright's stain, X1000.

Promyelocytic leukemia (the M3 type) is frequently associated with a disseminated intra vascular coagulation (DlC)-like syndrome, either at presentation or shortly after induction.22'29 The bleeding can be life-threatening, in contrast to the other types of acute non-lymphoid leukemia where extensive hemorrhage is uncommon.

Acute non-lymphoid leukemia can occasionally present as a solid tumor mass, in the form of a chloroma, granulocytic sarcoma, or myeloblastoma.30 Ocular chloromas in acute myelomonocytic leukemia is a common presentation in Turkish children. When located in the skin, these leukemic infiltrates must be distinguished from lymphoblastic lymphomas and from uticaria pigmentosa, which is a non-neoplastic proliferation of mast cells which can occur in the skin or involve internal organs in the form of systemic mastocytosis. Other neoplasms can occasionally mimic ANLL by causing bone marrow damage and a resulting leukoerythroblastosis; neuroblastoma in young children would be one such example.

SUPPORTIVE THERAPY

It is considerably more difficult to induce remission in acute non-lymphoid leukemia than in acute lymphoid leukemia. Since current therapy for acute non-lymphoid leukemia also eradicates normal myeloid cells, treatment causes prolonged marrow aplasia even after major reduction of the leukemic clone. The treatment itself can be a major source of morbidity and mortality. Superior supportive care by teams of specialists in major pediatrie oncology centers is strongly recommended during induction therapy.

Hyperuricemia occurs uncommonly during therapy of acute non-lymphoid leukemia. Most clinicians routinely use measures to prevent this complication such as h yd ration, urinary alkalinization and allopurinol only in patients with extreme leukocytosis. Hyperviscosity secondary to extreme hyperleukocytosis, with leukocyte counts of over 200,000/ mm3, may cause obstruction of intracerebral capillaries by leukemic cells and result in intracerebral infarction and hemorrhage.31 Pulmonary complications and priapism have also been attributed to hyperleukocytosis and severe leukostasis. Treatment approaches include immediate low dose cranial irradiation (at a dose of 600 rad), administration of hydroxyurea, or performance of leukopheresis. Red cells should be transfused with caution in such patients since transfusion may precipitously raise the cytocrit (which is the sum of the percent of white blood cells plus percent of red blood cells) and exacerbate the tendency to leukostasis.

Platelet transfusions, given at a dose of 1 unit/ 13 pounds body weight, are indicated for serious bleeding episodes. Although they are associated with alloimmunization, use of prophylactic platelet transfusions should be considered during induction therapy to maintain the platelet count at a level over 10,000 to 20,000/ mm3.

Hemorrhage may also be secondary to a coagulopathy or DIC-like syndrome when rapid lysis of tumor cells results in release of thromboplastin-!ike material. This complication has been most frequently associated with the M3 (promyelocytic) variant of acute non-lymphoid leukemia. Systemic heparinization during the early induction phase has been advocated to prevent hemorrhage and DIC.32

Serious bacterial infection is the major life-threatening complication of therapy of children with acute nonlymphoid leukemia. Broad spectrum parenteralantibiotic coverage is urgently needed by the febrile patient with acute non-lymphoid leukemia who has a granulocyte count (ie, total white cell count multiplied by the percentage of bands plus percentage of polys) of less than 200/ mm.3 This antibiotic coverage should consist of a semisynthetic penicillin with activity against pseud o - monas, an aminoglycoside, and a penicillinase-resistant antistaphylococcal agent. Typical signs of local infection may not be obvious, since the profound granulocytopenia may diminish the inflammatory response. It is not clear whether laminar air flow rooms, oral nonabsorbable antibiotics, or oral prophylactic trimethoprim sulfamethoxazole lessen the risk of overwhelming bacterial infection in these immunocompromised patients. Thus far, routine prophylactic granulocyte transfusions have not been advantageous.33

Graft vs host disease following washed red cell transfusions and platelet transfusions has been reported in children who have been immu no sup pressed by vigorous chemotherapy.34 These blood products contain viable donor lymphocytes which can partially engraft the vulnerable immunosuppressed host. Many centers irradiate blood products (such as packed red cells, platelets, and granulocytes) with a dose of 1800 rad to destroy donor lymphocytes prior to transfusion of immunosuppressed patients.

Table

TABLE 3CHEMOTHERAPY PROTOCOLS FOR ACUTE NON-LYMPHOID LEUKEMIA16

TABLE 3

CHEMOTHERAPY PROTOCOLS FOR ACUTE NON-LYMPHOID LEUKEMIA16

Table

TABLE 4PROTOCOL FOR ALLOGENIC BONE MARROW TRANSPLANTATION IN ACUTE NON-LYMPHOID LEUKEMIA41

TABLE 4

PROTOCOL FOR ALLOGENIC BONE MARROW TRANSPLANTATION IN ACUTE NON-LYMPHOID LEUKEMIA41

TREATMENT STRATEGIES

Induction chemotherapy reduces the population of leukemic cells to "undetectable" levels and allows normal cells to repopulate the bone marrow. However, an Ml (remission) marrow can still have leukemic blast cells, even though they are undetectable by morphological examination. Additional chemotherapy is given, either as short-term (consolidation) or long-term (maintenance) therapy, in an attempt to eradicate completely all malignant cells.

Combinations of anti-leukemic drugs which are effective in the childhood acute lymphoid leukemia, such as vincristine and prednisone, are much less effective in ANLL.

Most remission induction programs (Baehner RL, Bernstein ID, Sather H, et al; unpublished data, 1982)36 (Table 3) now include an anthracycline antibiotic (daunorubicin or doxorubicin) plus prolonged infusions of cytosine arabinoside (Ara-C) with, or without the addition of 6-th iogua nine, prednisone and vincristine. These chemotherapy regimens produce remission rates of 60% to 85%, with low rates (5% to 10% of cases) of refractory disease. Toxicity is frequently severe and 10% to 30% of patients may die from infectious or, less commonly, hemorrhagic complications.

These and other chemotherapy regimens have produced prolonged remission duration by adding"early"or "late" consolidation therapy.37 Maintenance therapy is of unknown merit in prolonging remission duration. The best results to date show that about half of patients (children and young adults) who attain a complete remission will remain in remission for two years or more.38,39

Table

TABLE 5REINDUCTION SCHEDULES USED IN CHEMOTHERAPY OF ACUTE NON-LYMPHOID LEUKEMIA

TABLE 5

REINDUCTION SCHEDULES USED IN CHEMOTHERAPY OF ACUTE NON-LYMPHOID LEUKEMIA

As was true for childhood acute lymphoid leukemia prior to use of routine central nervous system prophylaxis, CNS leukemic relapse is becoming an increasingly frequent complication in long-term survivors of childhood ANLL. In a recent study,58 children with ANLL who were not given CNS prophylaxis had a 17% CNS relapse rate, with a median time to CNS relapse of 5.5 months. Preliminary results of another study" suggest that routine CNS prophylaxis with cranial radiotherapy and intrathecal methotrexate lessens CNS relapses and prolongs remission duration.

Allogeneic bone marrow transplantation in children with acute non-lymphoid leukemia has attracted considerable attention.40 Early studies of leukemic patients transplanted while in relapse had few long-termsurvivors. With improvements in supportive care, there has been a trend to transplant ANLL patients during remission. By reducing tumor burden with remission induction therapy, it is believed that the intensive chemotherapy and radiation therapy given prior to bone marrow transplantation is more likely to be curative.

Recent results from several centers (Table 4) have shown that 70% to 80% of children with acute nonlymphoid leukemia treated with bone marrow transplantation (while in first remission) are in complete remission and off therapy two years after the transplantation.41 Infections, graft vs host disease, and therapy-related toxicity, rather than leukemic relapse, are factors which limit survival. Longer follow-up of these patients will be needed to determine whether bone marrow transplantation prolongs remission or produces more cures than that produced by chemotherapy alone.

REINDUCTION THERAPY

Most patients with acute non-lymphoid leukemia relapse in spite of maintenance chemotherapy. Reinduction is usually attempted with cyt osine arabinoside and daunorubicin; 25% to 50% of patients successfully attain a good partial or complete second remission. Patients unresponsive to conventional induction chemotherapy are given reinduction protocols (Table 5). H igh-dose cytosine arabinoside given by intermittent infusions, either alone42 or in combination with L-asparaginase,43 daunorubicin,44 or m-AMSA (an acridine derivative),45 has produced complete remissions in 40% to 60% of children with otherwise refractory acute non-lymphoid leukemia. Similar results have been obtained with conventional doses of cytosine arabinoside given in combination with m-AMSA, VP-16-213 (an epipodophyllotoxin derivative), and 6-thioguanine,46 and with 5azacytidine in combination with m-AMSA.47

OTHER NON-LYMPHOID LEUKEMIAS

Neonatal Leukemia

Neonatal leukemia is defined as leukemia occurring in infants from birth to four weeks of age. This is a rare disorder which poses considerable diagnostic and therapeutic difficulties.48 In many instances, this disorder appears to be congenital, but no specific maternal or fetal risk factor has been identified.

The neonatal leukemias have two different natural histories. Frank acute non-lymphoid leukemia may infiltrate skin, lungs, and abdominal organs. Anemia, thrombocytopenia, and leukocytosis are common; the bone marrow is packed with blasts. The process is frequently refractory to therapy. Occurrence of severe infections limit survival to days or months.

Other neonatal "leukemias" occur in infants with Down's syndrome or in its mosaic variants. The clinical presentation of these cases may be identical to that described above, or may be less symptomatic with only modest hematopoietic abnormalities. This disease may resolve spontaneously over weeks to a few months. Death is usually due to complications of the underlying Down's syndrome, rather than due to the hématologie disorder. This disorder is considered by some investigators to represent ineffective granulopoiesis, while others consider it to be a myelopro life rati ve syndrome.49 Chromosomal analyses of the transient "leukemias"have shown only trisomy of chromosome number 21 , without other abnormalities. In the two reported cases of late leukemia occurring one to two years after transient neonatal "leukemia," additional karyotypic abnormalities were present when the fatal leukemic processes were diagnosed.50,52

Severe leukocytosis in the neonate can be caused by other conditions and diseases that must be considered in the differential diagnosis of neonatal leukemia. These include bacterial sepsis, severe hypoxia, severe hemolysis or extravascular blood loss, congenital TORCH syndromes (toxoplasmosis, rubella, cytomegolovirus infections, and congenital herpes), and disseminated neuroblastoma. These can usually be distinguished from leukemia on the basis of bone marrow findings and routine laboratory tests.

Infants suspected of having neonatal leukemia, particularly when stigmata of Down's syndrome are present, should be judiciously monitored clinically for several weeks. Hématologie evaluations should include detailed chromosome analysis. If consistent clinical or hématologie deterioration is observed, combination chemotherapy similar to that used in older children with ANLL should be started. Cranial vault irradiation is not done in neonates because of the risk of impairing skull and brain growth. The prognosis for any given neonate with leukemia is difficult to estimate.

Other Rare Leukemlas

There are several reports of a form of acute nonlymphoid leukemia consistent with acute megakaryocytic leukemia.52 Clinical and laboratory manifestations are similar to those observed in other types of acute nonlymphoid leukemia. Myeloid and monocyte cytochemical markers are absent from bone marrow blast cells, and light microscopy and electron microscopy show evidence of membrane budding of the leukemic cells. Monoclonal antibodies to platelet surface antigens may prove to be helpful in identifying this subset of acute non-lymphoid leukemia.

Well-documented cases of true eosinophiuc leukemia are rare in children. However, massive eosinophilia may be present in association with either acute non-lymphoid leukemia or acute lymphoid leukemia.53 In at least one case, despite remission induction of acute lymphoid leukemia and disappearance of eosinophilia, damage caused by the eosinophiua was sufficiently profound to cause the hypereosinophiiic syndrome with fatal cardiomyopathy,54

SUMMARY AND OUTLOOK

Acute non-lymphoid leukemia is a group of hématologie neoplasms which have been the subject of intensive basic and clinical research. These studies have led to a better understanding of the genetic basis of leukemia and may ultimately help establish the molecular mechanisms of malignant transformation. They also have increased our understanding of myeloid differentiation.

As a result of clinical trials, we can now induce a clinical remission in a large majority of patients with acute nonlymphoid leukemia. Future studies will attempt to lessen toxicity and to maximize the response rate. Many of these advances will come from improvements in supportive care given during the periods of therapy-related marrow aplasia. The role of intensive chemotherapy to prolong remission duration and to increase the usefulness of allogenic bone marrow transplantation will be clarified during the next several years.

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TABLE 1

CONGENITAL SYNDROMES WHICH INCREASE RISK FOR ACUTE NON-LYMPHOID LEUKEMIA

TABLE 2

THE FRENCH-AMERICAN-BRITISH MORPHOLOGICAL CLASSIFICATION OF ACUTE NON-LYMPHOID LEUKEMIA

TABLE 3

CHEMOTHERAPY PROTOCOLS FOR ACUTE NON-LYMPHOID LEUKEMIA16

TABLE 4

PROTOCOL FOR ALLOGENIC BONE MARROW TRANSPLANTATION IN ACUTE NON-LYMPHOID LEUKEMIA41

TABLE 5

REINDUCTION SCHEDULES USED IN CHEMOTHERAPY OF ACUTE NON-LYMPHOID LEUKEMIA

10.3928/0090-4481-19830401-03

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