Leukemias

Acute Leukemias

 

 

Introduction

From a kinetic standpoint the acute leukemias are characterized by proliferation of immature cells (blasts, type I and II) in the bone marow and peripheral blood, and may involve any of the hematopoietic lineages. The appearance is that of proliferation without maturation (maturation arrest). They are classified under two broad categories: acute lymphoblastic (lymphocytic) leukemia (ALL), and acute myeloid (myelogenous, myelocytic, myeloblastic, granulocytic, nonlymphocytic) leukemia (AML). The rather arbitrary figure of 20% blasts on a differential count of nucleated cells on a bone marrow aspirate is considered necessary to make a diagnosis. What about 18% blasts without myelodysplasia in a patient with progressive pancytopenia over a period of 6 weeks or even with a less percentage of blasts with Auer rods? Do these patients have acute leukemia? Of course they do. One might want to refer to such cases as "early acute leukemia" as opposed to "overt acute leukemia", but such minor differences should not delay the institution of therapy when indicated.

In some subtypes of AML what are counted as blasts are not just the agranular type I blasts, but also type II blasts. Type II blasts have a variable number of azurophilic granules in the cytoplasm, but otherwise the appearance is that of a type I blast. A very important morphologic feature of type II blasts is the absence of a well developed Golgi apparatus that is such a characteristic feature of normal promyelocytes. In acute agranulocytosis normal appearing promyelocytes are the predominant myeloid cell seen on a bone marrow aspirate and must not be confused with acute promyelocytic leukemia (M3 AML) or other subtypes of AML in which type II blasts may represent a significant portion of the immature cells counted. An occasional cell with the appearance of type II blasts are seen in normal and reactive bone marrow aspirates. They probably represent the very earliest stage of granulocytic maturation prior to the appearance of the Golgi apparatus. In M2 AML, type II blasts may represent a significant percentage of the total blast count. In other subtypes of AML, granular blasts are the predominant proliferating cells (M3, M5b and M7 subtypes). In the micromegakaryoblastic subtype of M7 AML, the predominant cells have the appearance of type II blasts but are smaller than those in the M2 subtype.

Further classifications of ALLs and AMLs are based more on cytochemical, immunophenotypic, cytogenetic, and molecular genetic analyses, although morphology remains a major determinant in these subclassifications. The cytochemical and immunophenotypic profiles used to further subtype the acute leukemias are not absolute. Much overlap is seen, and the designation, "usually negative or positive" is the rule in some cases. Degree of positivity, weak versus strong, is also an important consideration. In the lymphoblastic leukemias, determination of clonality by kappa or lambda predominance in the B cell subtypes or by demonstration of a B or T cell receptor gene rearrangement by pcr-DNA or Southern blot.

Classification of ALL

The French-American-British (FAB) classification has gained widespread use, but does not encompass all variants. Three subtypes are recognized: 

 Classification of AML

FAB Classification: (with modifications)

WHO Classification: (adapted from)

  • AML with recurrent cytogenetic abnormalities
    • AML with the t(8;21)- most are M2 AMLs
    • AML with the inv(16) or t(16;16)- most are M4 AMLs with abnormal eosinophils
    • AML with the t(15;17)- M3 AML
    • AML with 11q23 abnormalities- usually has monocytic features
  • AML with multilineage dysplasia
    • AML emerging from a myelodysplastic or myeloproliferative disorder
    • DeNovo AML with multilineage dysplasia
  • M6 AML- two variants
    • M6a- mixed erythroid and myeloid blasts
    • M6b- pure erythroid leukemia
  • AML, therapy-related (secondary acute leukemias)- Includes  those associated with exposure to alkylating agents, topoisomerase type II inhibitors, other drugs, and radiation.
  • Acute panmyelosis (acute malignant myelofibrosis or myelosclerosis)

Other Variants: (based on other histopathologic and clinical features):

  • Hypoplastic acute leukemia: The bone marrow cellularity is decreased similar to aplastic anemia, but the cells that are seen are blasts, mostly myeloblasts. In aplastic anemia the cells that remain are mostly mature lymphocytes, plasma cells, and histiocytes.
  • Smoldering acute leukemia: This is a clinical term used to define a subset of patients with acute leukemia, usually AML, who progress very slowly if treated only with supportative measures. Some survive 1-2 years or even longer.
  • Blast crisis: This term was initially used to describe the transformation of chronic myelocytic leukemia to acute leukemia, mostly AML but some ALL. Before allogeneic bone marrow transplantation and targeted therapy were available, transformation occurred in essentially 100% of cases. Transformation to acute leukemia in other chronic myeloproliferative disorders such as polycythemia vera, essential thrombocytopenia, and primary or idiopathic myelofibrosis was also referred to as "blast crisis"; "blast crisis" occurs much less frequently in these disorders (10%-20%). Transformation to acute leukemia in myelodysplastic disorders can also be referred to as "blast crisis", but the term "acute leukemic transformation" is more frequently used. Blast crisis in chronic B cell lymphocytic leukemia is distinctly unusually (<1% of cases), whereas prolymphocytic transformation is more common (10%-20%) as is transformation to large cell B cell lymphoma (Richter's syndrome) which occurs in approximately 5% of cases.
  • Secondary acute leukemia A term used in cases of acute leukemia in which there is a history of exposure to toxins such as benzene, radiation, or drugs (e.g. alkylating agents, epipodophyllotoxin derivatives) that are known to be leukemogenic agents. These leukemias usually have abnormalities of chromosome 5 and/or 7, and the prognosis is poor.
  • Chloroma (granulocytic sarcoma) A term used when AML presents as a mass lesion in extramedullary sites. These tumors may occur at any time during the course of acute leukemias, and chronic myeloproliferative and myelodysplastic disorders. In some instances chloromas may occur as the initial manifestation of acute leukemia with no morphologic evidence of leukemia in the blood or bone marrow; essentially all eventually progress to AML. They are usually of granulocytic lineage, but some are monocytic. Lymphoblastic lymphomas without bone marrow or peripheral blood involvement often progress to a leukemic phase, especially if untreated. Involvement of extranodal and extramedullary sites in patients with ALL is referred to as extranodal spread of the leukemia. 

Clinical and Laboratory Manifestations of Acute Leukemia 

The clinical features of acute leukemia are mostly non-specific and are due either to cytopenias, organ infiltration by the leukemic cells, or leukostasis.

Cytopenias:

  • Anemia: weakness, easy fatigue, shortness of breath, pale appearance
  • Neutropenia: infections
  • Thrombocytopenia: bleeding, easy bruising, patechiae

Organ infiltration: 

  • Leukemic meningitis
  • Hepatosplenomegaly
  • Lymphadenopathy
  • Bone pain
  • Leukemia cutis

Leukostasis:

Results from stasis of blood flow that occurs when the peripheral blood leukemic blast count is very high, usually >200,000/mm³. The clinical manifestations are due to hypoxia, and are manifested mainly in the central nervous system and lungs; seen more frequently in the M5 and M4 subtypes.

Prognostic Factors in Acute Leukemia

Of the many prognostic factors that have emerged in the treatment of acute leukemia, cytogenetic findings probably are the most important. In AML, the finding of a good cytogenetic abnormality trumps the finding of bad cytogenetic abnormalities in the same patient. The opposite is true in chronic lymphocytic leukemia where the bad trumps the good. In AML, a good cytogenetic abnormality also trumps other bad prognostic factors such as secondary leukemia and an associated myelodysplasia disorder. The presence of bad cytogenetics alone is a poor prognostic factor, especially in the clinical setting of secondary leukemia.

Blast crisis in chronic myeloproliferative is a very poor prognostic factor. In CML, the availability of targeted therapies has improved outcome to some extent.

A well established preceeding myelodysplastic phase which is usually accompanied by bad cytogenetics represents a poor prognostic group. Other factors, good or bad, must be used in context with other findings in each individual case.

Acute Lymphocytic Leukemia (ALL)

By far the most important factors are age at diagnosis and immunophenotype. In children between the age of 1-10 years at diagnosis, with a common ALL immunophenotype, a cure rate approaching 95% is observed using conventional chemotherapy regimens alone. In adults over the age of 30 years at diagnosis of ALL, the cure rate using conventional chemotherapy regimens alone is probably 20% or less. Cytogenetic abnormalities such as hyperdiploidy and t(12;21) are favorable whereas abormalities such as t(9;22) and translocations involving chromosome 11 are unfavorable. T cell ALL in children has a worse prognosis whereas the opposite is observed in adults.

High tumor burden and CNS involvement are poor prognositc factors.

Acute Myelogenous Leukemia (AML)

Good prognostic factors:

  • Young age- due, in part, to the more frequent occurrence of good cytogenetics in younger patients
  • Good performance status
  • Low tumor burden
  • FAB subtypes M3, M4Eo, and M2Eo 
  • Good cytogenetics- t(15;17), t(8;21), and inv 16.
  • Normal cytogenetics when compared to the presence of bad cytogenetic abnormalities. Within the normal cytogenetic group, which accounts for approximately 50% of all cases, molecular genomic studies have identified other somatic mutations that confer a good prognosis: mutation in the nucleophosmin gene (NPMI) or the CCAAT/enhancer binding protein α gene (CEBPA) in the absence of a mutation in the fems-related tyrosine kinase 3 gene (FLT3) (N Engl J Med 358:1909, 2008)
  • Micro RNA profiling has identified some subgroups with good as well as bad outcomes (N Engl J Med 358:1919,2008)

Bad prognostic factors:

  • Older age
  • Poor performance status
  • High tumor burden- usually defined as the presence of a high peripheral blood blast count with or without extramedullary involvement.
  • CNS involvement
  • Preceeding myelodysplastic phase
  • Presence of trilineage dysplasia at diagnosis
  • Blast crisis of a chronic myeloproliferative disorder
  • FAB subtypes M0, M5, M6 and M7
  • Secondary AML
  • Bad cytogenetics- complex abnormalities, abnormalities involving chromosomes 5, 7 and 8, and t(9;22).

General References

  • Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumors of hematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumors, Lyon, France: IARC Press, 2001
  • Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-American-British Cooperative Group. Am Intern Med 103:620, 1985
  • Bennett JM, Catovsky D, Daniel MT, et al: French-American-British (FAB) Cooperative Group: The morphological classification of acute lymphoblastic leukemia- concordance among observers and clinical correlations. Br J Haematol 47:553, 1981
  • Kantarjian HM, Hoelzer D, Larson RA, eds. Advances in the treatment of acute lymphoblastic leukemia, Part I and II/ Hematol/Oncol Clinics of N Am, vol 14 (6), 2000
  • Kantarjian HM, Hoelzer D, Larson RA, eds. Advances in the treatment of acute lymphoblastic leukemia, Part I and II/ Hematol/Oncol Clinics of N Am, vol 15  (1), 2001
  • Fröhling S, Scholl G, Gilliland DG, Levine RL. Genetics of myeloid malignancies- pathogenetic and clinical implications. J Clin Oncol 23:6285, 2005
  • Mrozek K, Dohner H, Bloomfield CD. Influence of new molecular prognostic markers in patients with karyotypically normal acute myeloid leukemia: recent advances. Curr Opin Hematol 14:106, 2007

 

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Charles  E.  Hess,  M.D.,FACP    [more information]
Professor of Internal Medicine
Department: Medicine
Division: Hematology/Oncology