Acute Leukemia and Myelodysplastic Syndromes

Gary Schiller

Mary C. Territo

Dennis A. Casciato

ACUTE LEUKEMIA

I. EPIDEMIOLOGY AND ETIOLOGY

A. Incidence. Acute leukemia afflicts 3 to 4/100,000 population annually (11,000 new cases/year) in the United States. Children account for 25% of cases. Acute leukemia is the most common malignant disease of childhood.

1. Cell type. Of cases of acute lymphoblastic leukemia (ALL), 80% occur in children, and 90% of cases of acute myelogenous leukemia (AML) occur in adults.

2. Age. In adults, AML rates begin to rise exponentially after 50 years of age; the age-specific incidence rate is 3.5/100,000 in adults 50 years of age, and increases significantly to 15 at age 70 and 35 at age 90. The mean age for AML in the United States is 63 years. A peak incidence of ALL occurs at 3 to 4 years of age; the incidence steadily decreases after 9 years of age and rises in incidence after 40 years of age. Despite being considered a childhood cancer, the age-related increase in incidence of most cancers also pertains to ALL.

3. Sex. Acute leukemia shows a male predilection only in very young and elderly patients.

B. Etiology

1. Hereditary

a. Hereditary syndromes that are associated with chromosomal abnormalities, a high risk of acute leukemia, and excessive chemosensitivity include the following:

(1) Bloom syndrome is a recessively transmitted disease occurring predominantly in people of Jewish ancestry. Chromosome breaks are readily found in cytogenetic studies. The syndrome is characterized by short and thin stature, delicate features, telangiectatic lesions over the malar eminences of the face, photosensitivity, and a variety of other cutaneous abnormalities (acanthosis nigricans, hypertrichosis, ichthyosis, and café au lait spots). AML is the type of leukemia that develops in these patients.

(2) Fanconi congenital pancytopenia (Fanconi anemia) is an autosomal recessive disease often associated with multiple chromosomal abnormalities. Clinical features include skeletal abnormalities (absence of radii, hypoplasia of the thumbs), squinting, microcephaly, small stature, and hypogonadism. AML, as well as skin carcinoma, often complicates this syndrome.

(3) Down syndrome (mongolism, trisomy 21) is associated with an increased risk for both AML and ALL.

(4) Ataxia telangiectasia is associated with an increased incidence of lymphoid malignancies, including ALL.

b. Siblings of younger patients with acute leukemia have a fivefold increased risk of developing leukemia. There is about a 15% concordance if one member of a pair of monozygotic twins develops AML, although this may be due to placental metastasis.

2. Radiation is a well-documented leukemogenic factor in humans. Increased incidence of leukemia proportional to the cumulative radiation dose has been demonstrated in populations exposed to atomic bombs, in patients irradiated for ankylosing spondylitis, and in radiologists (before current protective precautions). Doses <100 cGy are not believed to be associated with the development of leukemia. The types of leukemia induced by radiation are ALL, AML, and chronic myelogenous leukemia (CML), but not chronic lymphocytic leukemia.

3. Viruses have not been shown to be etiologic for acute leukemias in humans, although an association is seen with Epstein-Barr virus with ALL-L3 (Burkitt leukemia). HTLV-1 is discussed in Chapter 21, in “Non-Hodgkin Lymphoma.”

4. Chemicals. The ability of chemicals to produce acute leukemia and pancytopenia is likely related to their ability to mutate or ablate the bone marrow stem cells.

a. Benzene and toluene were identified as carcinogens associated with acute leukemia a century ago. Acute leukemia develops 1 to 5 years after exposure and is often preceded by bone marrow hypoplasia, dysplasia, and pancytopenia.

b. Drugs. Drug-induced acute leukemia is usually preceded by myelodysplasia. Alkylating agents and topoisomerase II inhibitors given for prolonged periods are associated with a markedly increased risk of AML when compared with the general age-matched population. Exposure to arsenicals has also been implicated as an increased risk factor for leukemia development. Secondary AML currently accounts for 10% to 20% of all AML cases.

5. Hematologic diseases. Transformation into acute leukemia (“blast crisis”) is seen in >80% of cases of CML and is part of its natural history. Patients with myelodysplastic syndromes (MDS) clearly have an increased likelihood of evolution to AML. The incidence of AML in myeloproliferative disorders (MPD), myeloma, and certain solid tumors is increased by the use of chemotherapy.

6. Smoking. Cigarette smoking is associated with approximately 50% increase in leukemia risk. Cigarette smoking has a deleterious effect on survival in AML by shortening complete remission duration and subsequent survival. It has been associated with severe infections during aplasia. Leukemogenic compounds favoring complex karyotypic abnormalities could also be involved.

II. PATHOLOGY, CLASSIFICATION, AND NATURAL HISTORY OF ACUTE LEUKEMIA

A. Classification

1. Morphologic features of acute leukemias

a. The French—American—British (FAB) histopathologic classification of acute leukemia was originally proposed in 1976. This system has been supplanted by the World Health Organization (WHO) classification below. The FAB defined the M1—M7 and L1—L3 subtypes of acute leukemia as follows but is frequently left out in modern interpretations of AML:

FAB subtype	Acute leukemia type
M0:	Myeloblastic without maturation
M1:	Myeloblastic with minimal maturation
M2:	Myeloblastic with maturation
M3:	Promyelocytic; M3v: promyelocytic (“microgranular”)
M4:	Myelomonocytic; M4 Eos: myeloblastic with abnormal eosinophils (Eos)
M5:	Monocytic: poorly (M5a) or well differentiated (M5b)
M6:	Erythroleukemia
M7:	Megakaryoblastic
L1:	ALL, childhood form
L2:	ALL, adult form
L3:	ALL, Burkitttype

b. Auer rods are abnormal condensations of cytoplasmic granules. Their presence in the immature cells distinguishes AML from ALL; their absence is not diagnostically helpful.

c. Cytologic features of the acute leukemia subtypes, particularly the nuclear configurations, cytoplasm granularity, and prevalence of Auer rods, are shown in Appendix C7.

d. Cytochemistry. Identifying the type of early cell may be difficult, but it is facilitated by flow cytometry. Traditionally used histochemical techniques, particularly for myeloperoxidase and nonspecific esterase (see Appendix C7), are seen in AML. Myeloperoxidase activity can be assessed by both cytochemistry and flow cytometry.

e. Immunologic markers assessed by flow cytometry usually distinguish ALL from AML as well as identify their subtypes. These markers are also summarized in Appendix C7. Antibodies against platelet glycoproteins (CD41 or CD61) are useful in distinguishing megakaryocytic (M7) leukemia. Flow cytometry has largely replaced cytochemistry for classification of acute leukemias in most centers. Flow cytometry is most useful when using antibodies against panmyeloid antigens (CD13 and CD33), monocyte antigens (especially CD11b and CD14), and hematopoietic progenitor cell antigens (CD34 and HLA-DR).

2. The WHO classification has replaced the FAB classification. The FAB classification, which provided a consistent morphologic and cytochemical framework, did not reflect the cytogenetic or clinical diversity of the disease. The WHO classification system takes into account the developing knowledge of the biology of AML, its distinct subtypes divided into diseases characterized by proliferative biology and diseases characterized by disorders of maturation. The WHO classification of AML is as follows (with corresponding FAB designations and approximate proportions of AML cases in brackets):

a. AML with recurrent cytogenetic abnormalities (Table 25.1)

AML with abnormal bone marrow eosinophils and inv(16)(p13;q22) or t(16;16)(p13;q22) [M4 Eo, 10% to 12%]

Acute promyelocytic leukemia and variants; t(15;17)(q21;q11) and its variants [M3, M3v; 5% to 8%]

AML with t(8;21)(q22;q22); (AML1/ETO) [M2, 5% to 12%]

AML with 11q23 (MLL) abnormalities [M5 or M1, 5% to 6%]

Table 25.1 Cytogenetic Abnormalities and Prognosis of Acute Myelogenous Leukemia in Adults

Cytogenetic Abnormalities		Fusion Genes	Frequency in Adults (%)			Frequency of FLT3-ITD^a (%)
			<45 y	All Ages	>45 y
Favorable Prognosis
t(8;21)(q22;q22)		AML1/ETO	5-8 (<55 y)		Rare	9
inv(16)(p13;q22)		CBFβ/MYH11	10		Rare	7
t(16;16)(p13;q22)
t(15;17)(q21;q11)		PML-RARα	15		Rare	37
	*Variants:*
	t(11;17)(q23;q11)	PLZF-RARα
	t(5;17)(q32;q11)	NPM-RARα
	t(11;17)(q13;q11)	NuMA-RARα
Intermediate Prognosis
Normal karyotype			5-20			34
+8			10			28
Others: -Y, +6
All other karyotypes not considered favorable or unfavorable			—			20-30
Unfavorable Prognosis
Abnormal 11q23^b		MLL		5-7	0
	Common variants:
	t(4;11)(q21;q23)	MLL/AF4
	t(9;11)(p22;q23)	MLL/AF9
	t(11;19)(q23;p13.1)	MLL/ELL
	t(11;19)(q23;p13.3)	MLL/ENL
t(6;9)(p23;q34)		DEK/CAN		<10		—
t(3;3)(q21;q26)		Ribophorin/EV1		3-5		17
-5/del (5q)			<10		>10	0
-7/del (7q)			<10		>10	7
^aFLT (a tyrosine kinase growth factor receptor) mediates hematopoietic stem cell proliferation and differentiation. FLT3 mutations (internal tandem duplication of exon 11 and 12 termed FLT3-ITD) are common in AML and could be an important prognostic indicator. ^b>50% of AML cases in infants.

b. AML with multilineage dysplasia [M2 or M6]

Following MDS or MDS/MPD

Without antecedent MDS

c. AML and MDS, therapy-related (alkylating agents, topoisomerase inhibitors, other types)

d. AML not otherwise categorized AML minimally differentiated [M0, 5%]

AML without maturation [M1, 10%]

AML with maturation [M2, 30% to 45%]

Acute myelomonocytic leukemia [M4, 15% to 25%]

Acute monoblastic and monocytic leukemia [M5a, M5b; 5% to 8%]

Acute erythroid leukemia [M6, 5% to 6%]

Acute megakaryoblastic leukemia [M7, 3% to 5%]

Acute panmyelosis with myelofibrosis [M7, rare; “acute myelofibrosis”]

Acute basophilic leukemia (very rare)

e. Myeloid sarcoma (“chloroma,” “granulocytic sarcoma”; extramedullary masses of monoblasts or myeloblasts)

f. Acute lymphocytic leukemias are now included in the WHO classification of lymphoid tissues as “precursor B-cell lymphoblastic leukemia/lymphoma” and “precursor T-cell lymphoblastic leukemia/lymphoma” (see Appendix C6). These were designated as L1, L2 or L3 subtypes of ALL in the FAB system.

3. The two most significant differences between the FAB and the WHO classifications are

a. A lower blast threshold for the diagnosis of AML: The WHO defines AML when the blast percentage reaches 20% in the bone marrow (rather than 30% as defined by FAB).

b. Patients with recurring clonal cytogenetic abnormalities should be considered to have AML regardless of the blast percentage: t(8;21)(q22;q22), t(16;16)(p13;q22), inv(16)(p13;q22), or t(15;17) (q22;q12).

4. A more clinically relevant classification of AML can be achieved if two distinct subgroups with different biologic features are recognized.

a. AML that evolves from MDS is associated with multilineage dysplasia, poor-risk cytogenetics, and a poor response to therapy. The incidence of this type increases with age and is consistent with the hypothesis that MDS and MDS-related leukemia results through multiple insults to the molecular constitution of the hematopoietic stem cell.

b. AML that arises de novo usually lacks significant multilineage dysplasia. It is often associated with favorable-risk cytogenetic findings and has a better response to therapy with a higher likelihood of failure-free and overall survival. This type of leukemia has a relatively constant incidence throughout life and is the type most likely to be observed in children and young adults. Some types are clearly related to disorders of differentiation such as AML characterized by core-binding-factor abnormalities, t(8;21) or inv(16) or t(15;17). Others are characterized more by proliferative defects such as AML with normal cytogenetics (often with FLT3 mutations).

B. Pathology. Bone marrow examination in acute leukemia demonstrates hypercellularity with a monotonous infiltration of immature cells. Normal marrow elements are markedly decreased. Erythroblast maturation is commonly megaloblastoid in all types of AML, especially subtype M6. Cytologic features of the AML subtypes are shown in Appendix C7.

C. Natural history. Leukemia cells generally replicate more slowly than their normal counterparts. Hematopoiesis is disturbed even before the proportion of blast cells in the marrow is conspicuously increased. Immature and malfunctioning leukocyte progenitors progressively replace the normal bone marrow and infiltrate other tissues. Relapse is inevitable in most patients unless
complete remission after induction and consolidation therapy persists at least 4 years. Relapse is associated with progressively poorer response to therapy and, if second or subsequent remission is achieved, progressively shorter duration of remission. Unsuccessful therapy is usually followed by death within 2 months. Death in acute leukemia is usually caused by either infection or hemorrhage.

D. Biology of acute promyelocytic leukemia (APL)

1. Morphology. Classified as M3 in the FAB classification, APL is characterized morphologically by the presence of blasts cells with heavy azurophilic granules, bundles of Auer rods, and a bilobed or reniform nucleus. Although most APL cases fit the description of hypergranular blasts, a cytologic microgranular variant (M3v) has been identified. The blasts in M3v have a bilobed, multilobed, or reniform nucleus and, under the usual staining, are devoid of granules or contain only a few fine azurophilic granules. The apparent paucity of granules is a result of their submicroscopic size. M3v is commonly associated with hyperleukocytosis and accounts for 15% to 20% of APL cases.

2. Immunophenotyping. APL blasts are positive for CD33 and CD13 but negative for HLA-DR and usually have a low-level expression of CD34. M3v blasts tend to be positive for CD34, CD2, and CD19.

3. Cytogenetics. Both the classic and the M3v forms of APL are associated with a specific cytogenetic abnormality, t(15;17)(q22;q21). This translocation disrupts the PML gene on chromosome 15 and the retinoic acid receptor α (RARα) on chromosome 17, resulting in a fusion gene (PML/RARα). The protein product of PML/RARα retains the retinoic acid (RA) ligand-binding domain and plays a key role in leukemogenesis, as well as in mediating the response to retinoids. Expression profiling by microarray is likely to be used in the future as an adjunct to cytogenetics or as a replacement.

a. Four other alternative translocations associated with APL have been characterized:

t(11;17)(q23;q21) involving the PLZF gene on chromosome 11

t(5;17)(q35;q21) involving the NPM gene on chromosome 5

t(11;17)(q13;q21) involving the NuMA gene on chromosome 11

t(1;17) occurs but is rare.

b. PML/RARα-mediated APL is sensitive to retinoids, as are the variants NPM/RARα- and NuMA/RARα-mediated APL. In contrast, PLZF/ RARα-associated APL is considered resistant to retinoids as well as to arsenic trioxide.

III. DIAGNOSIS

A. Symptoms

1. Nonspecific fatigue and weakness are the most common symptoms. Bruising, fever, and weight loss are frequent.

2. Central nervous system (CNS) involvement may be manifested by headaches, nausea, vomiting, blurred vision, or cranial nerve dysfunction.

3. Abdominal fullness usually reflects hepatosplenomegaly, which is more frequent in ALL or the monocytic subtype of AML.

4. Oliguria may result from dehydration, uric acid nephropathy, or disseminated intravascular coagulation (DIC).

5. Obstipation may signify disorders of hypercalcemia or hypokalemia; potassium wasting may occur in monocytic leukemia.

B. Physical findings

1. General examination

a. Pallor, petechiae, and purpura are the most frequent findings in acute leukemia.

b. Sternal tenderness to palpation, lymphadenopathy, and hepatosplenomegaly are much more common in ALL than in AML.

c. Meningismus may indicate CNS involvement. CNS leukemia is most common in ALL. When seen in patients with AML, M4 (particularly with abnormal bone marrow eosinophils) and M5 subtypes are commonly involved. It is far less common in the remaining AML subtypes but can be seen at relapse.

d. Leukemia infiltrates in the optic fundus appear like Roth spots with flame hemorrhages.

2. Extramedullary infiltration or masses of blasts, especially involving the skin, orbits, breasts, gingivae, or testes, are most likely to occur in acute monocytic leukemias (M5) and ALL.

3. Bleeding out of proportion to the degree of thrombocytopenia suggests the presence of DIC, which is particularly common in APL.

4. Signs of infection should be carefully elicited.

C. Laboratory studies. Evaluation of the peripheral blood smear should be done in every case where leukemia is in the differential diagnosis. Finding circulating leukemic blasts establishes the diagnosis, but this should be confirmed by the evaluation of the bone marrow from which successful cytogenetic analysis is more likely. Fluorescent in situ hybridization (FISH) for common, recurring molecular abnormalities may identify distinct clonal abnormalities not easily elicited by conventional cytogenetics.

1. Hemogram

a. Leukocytes. The WBC count is elevated in about 60% of cases, normal in 15%, and decreased in 25%, depending on the referral base of the treatment center. Circulating blasts are demonstrated in virtually every case of acute leukemia; however, some patients present with a very low percentage of circulating blasts.

b. Erythrocytes. 90% of patients have a normocytic, normochromic anemia, which is usually severe. Reticulocytes are nearly always decreased. Macrocytosis usually reflects megaloblastic maturation and suggests a history of prior MDS. Circulating nucleated red blood cells should always prompt further evaluation of the bone marrow.

c. Platelets are decreased in 90% of cases and are <50,000/µL in about 40%.

2. Biochemical tests that should be obtained include the following:

a. Serum uric acid, ionized calcium, phosphorus, magnesium, and lactic dehydrogenase (LDH) levels

b. Serum renal and liver function tests

c. Coagulation tests for DIC

3. Bone marrow findings are discussed earlier, in Section II. Blasts in excess of 20% establish the diagnosis of acute leukemia.

4. Flow cytometry results for AML are shown in Appendix C7. Results for ALL are shown in Appendix C5.

5. Cytogenetic testing is essential in every new patient because of its prognostic significance. Standard banded chromosome evaluation as well as FISH using a panel of the common acute leukemia probes should be obtained. Cytogenetic abnormalities distinguish unique types of AML and are the single most predictive factor for response to treatment, duration of
response, and relapse. The abnormalities are categorized as “favorable-,” “standard- or intermediate-,” and “unfavorable- or poor-” risk cytogenetics (Table 25.1).

6. Molecular studies. Advances in defining genomic variations have identified a number of molecular markers that are independent prognostic factors for AML outcome and are particularly important in patients with normal cytogenetics (45% of AML patients). So far, the most clinically relevant abnormalities have been identified in FLT3 (Fms-like tyrosine kinase 3), NPM1 (nucleophosmin 1), and CEBPA (CCAAT enhancer-binding protein-alpha).

FLT3-ITD (internal tandem duplications) and MLL-PTD (MLL gene partial tandem duplications) impart an unfavorable prognosis, whereas NPM1 and CEBPA mutants are more favorable. FTL3 mutations are now considered one of the most common mutations in AML (35% in older adults). Determining these markers at the time of diagnosis is important for determining prognosis of the patient and treatment approaches.

7. Radiographic studies that should be obtained include the following:

a. Chest radiograph to look for leukemic or infectious infiltrates

b. Bone radiographs of painful or tender areas to look for periosteal elevation or bony destruction from extramedullary bone masses

c. CT scans of the chest and abdomen/pelvis should be obtained on patients with ALL to evaluate lymphadenopathy and organomegaly.

8. Cerebrospinal fluid (CSF) examination should be performed at some time in all patients with ALL, where it is usually part of the induction therapy. CSF evaluation should be done in patients with acute monocytic leukemia and in those patients with AML who have meningismus or CNS abnormalities. Cytarabine or methotrexate may be instilled into the CSF at the completion of the examination because of the possibility of leukemic contamination from the blood (see Section IX.B).

The fluid should be cultured for acid-fast bacilli, fungi, and bacteria. Meningeal involvement with leukemia is associated with decreased sugar and increased protein concentrations, pleocytosis, and leukemia cells identified by cytologic examination.

9. Surveillance bacterial cultures of the nose, pharynx, axillae, and perianal regions identify organisms that may have colonized the patient. These cultures, however, are not commonly helpful in determining the etiologic agents responsible for serious infection in the patient with neutropenia. Cultures of the blood, urine, sputum, and any symptomatic areas should be obtained in all febrile leukemia patients.

IV. PROGNOSTIC FACTORS AND SURVIVAL

Complete remission (CR) is the paramount prognostic factor in all forms of acute leukemia. A CR is defined as all of the following: