MD2B - Acute Leukemias

Paul Aridgides MSIV, Upstate Medical University and Neha Vapiwala, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 31, 2007

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Introduction

Leukemia is defined as a malignant, marrow-based neoplasm of hematopoietic or lymphoid cells. The key feature of leukemia is the presence of tumor cells circulating in the blood. Acute leukemia involves aberrant differentiation and proliferation of malignantly transformed progenitor cells, and can be rapidly fatal if untreated. The two main types of acute leukemia are named for the stem cell of origin: acute lymphoblastic leukemia (ALL)if it involves lymphocytes, and acute myeloid leukemia (AML) if it involves myelocytes. Of note, both lymphocytes and myelocytes are subtypes of white blood cells. While ALL and AML are clinically similar in that they both typically present with symptoms secondary to cytopenias (lowered cell counts), there are significant laboratory features and prognostic factors that can be used to distinguish ALL from AML and to dictate therapy, as discussed below.

Differences between ALL and AML [1]

  • Clinical differences in early complications

COMPLICATIONS

ALL

AML

Metabolic

14%

5%

Hemorrhagic

2%

20%

Chemotherapy induction deaths

1%

10%

  • Morphologic differences

FEATURES

ALL

AML

Nuclear/cytoplasmic Ratio

high

low

Nuclear chromatin

clumped

spongy

Nucleoli, number of

0-2

2-5

Granules

absent

often present

Cytoplasm staining

blue

blue-gray

  • Cytochemical differences

STAIN

ALL

AML

Sudan black

(-)

(+)

Peroxidase

(-)

(+)

Acid phosphatase

(+)

(-)

  • Immunophenotypic differences
    • Lymphoid stem cells are TdT+
    • Other markers help distinguish B-cell ALL from T-cell ALL
    • Some ALL blasts also express myeloid antigens, but the presence of these antigens has no prognostic effect [2].

Acute Lymphoblastic Leukemia

  • Classification
    • French-American-British (FAB) Morphologic Classification [1]

FAB Type

Blast characteristics

L1 (more common pediatric)

Blast size <2RBC, scant nucleoli, round or oval nucleus

L2 (more common in adults)

Blast size >2RBC, prominent nucleoli, >20% cytoplasm, folded nucleus

L3

Blast big, blue, and vacuolated, called “Burkitt’s” cell, most have characteristic c-myc translocation t[8;14]

    • Classification by Immunophenotype (World Health Organization recommended [3])

Immunophenotype

Expressed antigens

Precursor B-cell ALL (85% of childhood ALL)

B-cell associated antigens including CD19, HLA-DR, cytoplasmic CD79a. Subtypes include:

Pro-B ALL, Common precursor B-cell ALL, and PreB ALL

Precursor T-cell ALL

T-cell associated antigens including CD7, CD2, cytoplasmic CD3, CD5

  • Epidemiology, Etiology, and Pathogenesis
    • Most common malignancy in children; accounts for 80% of acute leukemia in children and 20% of acute leukemia in adults.
    • Incidence of ALL in children is 2300 new cases per year in the US, with a peak incidence seen between ages 2 - 5 [4]
    • Incidence is 20% higher in boys than girls, 100% higher in whites than blacks (Gurney children)
    • 5 year survival for ALL in children is 87% [5]
    • Etiology is possibly viral, but not well established.
    • Hereditary link is likely, as siblings of leukemia patients typically show a threefold higher risk of developing disease.
    • Increased risk is associated with Down's syndrome (15 X) and atomic bomb survivors (linear dose-response relationship) [6].
  • Clinical Presentation
    • History: Generally cytopenia-related symptoms, such as fatigue, dyspnea, infections, bruising, weight loss, as well as bone pain
    • Physical Exam: Pallor, petechiae, signs of organ/tissue infiltration, fever, lymphadenopathy
    • Labs: Cytopenias (white blood cells, red blood cells and/or platelets)
    • Diagnostic Studies: peripheral smear, bone marrow biopsy, cytogenetic abnormalities
    • Note: The characteristic presentation of T cell ALL is an older age boy with mediastinal mass and leukocytosis.
  • Natural Course
    • Staging is not clearly defined for ALL, and patients with confirmed diagnoses are grouped as:
      1. untreated (not in remission) - defined as an abnormal white blood cell count and differential, abnormal hematocrit/hemoglobin and platelet counts, abnormal bone marrow with more than 5% blasts, and signs and symptoms of the disease.
      2. in remission - where a patient has received remission-induction treatment and now has normocellular bone marrow with less than 5% blasts, no signs or symptoms of the disease, no signs or symptoms of central nervous system leukemia or other extramedullary infiltration, and all normal hematologic laboratory values.
      3. recurrence – defined as any failure since starting treatment, further characterized according to time since diagnosis and relapse site (bone marrow, extramedullary)
    • Prognosis – grouped into low-, standard-, and high-risk; grouping schemes (particularly genetic analysis) are an area of active research [7] Worse prognoses if:
      • age is <2 y or >9 y
      • male gender
      • high WBC counts
      • T-cell phenotype
      • low ploidy
      • presence of (4;11) or (9;22) chromosomal translocations [8].
      • presence of CNS disease
      • poor early response to treatment
  • Treatment [7]
    • Risk assessment is critical to achieving cure with an acceptable degree of toxicity. Generally, patients with higher-risk disease receive more aggressive therapy.
    • High-dose chemotherapy regimens with at least two rounds of induction (prednisone or dexamethasone, vincristine, L-asparaginase, +/- an anthracycline), consolidation and maintenance.
      • Long-term, disease-free survival is seen in 30-40% of patients [7]
    • Delayed intensification was a major advance in 1983, followed by advances in bone marrow transplantation (high dose chemo +/- total body irradiation followed by marrow infusion) [9]. Allogenic transplantation is of particular benefit in high-risk disease (chromosomal translocations) and after poor response to initial therapy.
    • Central nervous system coverage to prevent or treat disease (intrathecal chemotherapy or irradiation) is critical for long term control

Acute Myeloid Leukemia

  • Classification
    • FAB Morphologic Classification

M0 - AML undifferentiated

M1 - AML without maturation

M2 - AML with maturation

M3 - Acute promyelocytic leukemia (APL)

M4 - Acute myelomonocytic leukemia (AMML)

M4eo -AMML with abnormal eosinophils

M5 - Acute monoblastic leukemia

M6 - Acute erythroleukemia

M7 - Acute megakaryoblastic leukemia

    • WHO Classification (preferred for prognostic significance [10])

AML with recurrent genetic abnormalities

             t(8;21) FAB M2, inv(16)/t(16;16), t(15;17) FAB M3, 11q23

AML with multilineage dysplasia (MPD)

             following MDS/MPD, dysplasia in 2 or more cell lines

AML and myleodysplastic syndromes (MDS), therapy related

             alkylating agents/radiation-related, topoisomerase II inhibitor-related

AML, not otherwise categorized

             with subtypes identical to FAB classification

  • Epidemiology, Etiology and Pathogenesis
    • Incidence of AML is 13,000 cases per year in the US [11]. AML accounts for 80-90% of adult acute leukemias, 10% of childhood leukemias and virtually all neonatal acute leukemias.
    • Etiologic factors are thought to include exposure to carcinogens and mutagens, such as benzene, alkylating agents and ionizing radiation; inherited genetic conditions such as Fanconi's anemia and Down's syndrome; and viruses.
    • Pathogenesis involves clonal evolution through multiple steps. AML etiology and pathogenesis is considered similar to myelodysplasia, (also known as MDS, refractory anemia, preleukemia or smoldering leukemia), which is a clonal abnormality of pluripotential stem cells with defective maturation and ineffective hematopoiesis
  • Clinical Presentation
    • History: Present with cytopenia-related symptoms, as with ALL
    • Physical Exam: Pallor, petechiae, fever, organ involvement
    • Labs: Cytopenias common; consider a medical emergency if WBC count is >100,000 or there are DIC-type indices
    • Diagnostic Studies: Peripheral smear, bone marrow biopsy
  • Natural Course
    • Staging is similar to ALL in that there is no clear-cut system; patients are classified as
      1. untreated - newly diagnosed leukemia with no prior treatment, abnormal bone marrow with more than 20% blasts, signs and symptoms of the disease, and typically abnormal hematologic cell counts
      2. in remission - a normal peripheral blood cell count and normocellular marrow with less than 5% blasts in the marrow, no signs or symptoms of the disease, and no signs or symptoms of central nervous system leukemia or other extramedullary infiltration.
      3. relapsed or refractory- evidence of disease as described above after achieving remission or unsuccessful treatment
    • Prognosis - three most important factors are age, WBC count, and cytogenetics [12]
      Unfavorable prognoses [6,12,13] for patients with:
      • age >60 y
      • WBC > 30,000
      • CNS involvement
      • disease secondary to MDS, chemo or XRT
      • CD34 +
      • MDR 1-positive
      • Complex karyotypic abnormalities

      Favorable prognosis with [12]:

          • t (8;21), inv(16)/t(16;16), t(15;17)
  • Treatment
    • AML chemotherapy is administered in two basic phases, induction and post-remission.
    • Induction with daunorubicin + anthracycline with 70-80% complete remission rate, but also 100% relapse rate if no further therapy is given [14].
    • Post-remission therapy consists of consolidation chemo, giving 40-50% cure rates, or autologous and allogeneic bone marrow transplants, giving improved cure rates of 45-65% [15]
    • For APL t(15;17), whose unique fusion product PML-RARα contains retinoic acid receptor, regimens containing all-trans-retinoic acid (ATRA) as a differentiation agent results in remission rates around 90% and a 70% cure rate [16]
    • A retrospective analysis of long-term AML survivors showed a 13% incidence of malignancies secondary to treatment [17]

References

1. Catovsky D, Matukis E, Buccheri V, et al: A classification of acute leukemia for the 1990's. Ann Hematol 62:16-21, 1991

2. Matutes E, Morilla R, Farahat N, et al: Definition of acute biphenotypic leukemia. Haematologia 82:64-66, 1997

3. Harris NL, Jaffe ES, Diebold J, et al: The World Health Organization classification of neoplastic diseases of the hematopoeitic and lymphoid tissues. Ann Oncol 10:1419-1432, 1999

4. Gurney JG, Severson RK, Davis S et al: Incidence of cancer in children in the United States. Sex -, race-, and 1-year age-specific rates by histologic type. Cancer75:2186-2195, 1995

5. Smith MA, Ries LA, Gurney JG, et al.: Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program Leukemia, 1999.

6. Preston DI, Kusumi S, Tomonaga M, et al: Cancer incidence in atomic bomb survivors: part III. Radiat Res 137:S68-S97, 1994 (suppl)

7. Pui C and Evans WE: Treatment of Acute Lymphoblastic Leukemia. NEJM 354:166-178, 2006

8. Faderl S, Kantarjian HM, Talpaz M, et al: Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood 91:3995-4019, 1998

9. Laport GF, Larson RA: Treatment of adult acute lymphoblastic leukemia. Semin Oncol 24:70-82, 1997

10. Vardiman JW, Harris NL, Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100:2292-2302, 2002

11. Jemal A, Siegel R, Ward E et al: Cancer Statistics, 2007. CA Cancer J Clin57:43-66, 2007

12. Byrd JC, Mrozek K, Dodge RK et al: Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 100:4325-4336, 2002

13. Estey EH: Prognostic factors in acute myelogenous leukemia. Leukemia 15:670-672, 2001.

14. Bishop JF: The treatment of adult acute myeloid leukemia. Semin Oncol 24:57-69, 1997

15. Zittoun RA, Mandelli F, Willemze R, et al: Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med 332:217-223, 1995

16. Ohno R, Asou N, and Ohnishi K: treatment of acute promyelocytic leukemia: strategy toward further increase of cure. Leukemia 17:1454-1463, 2003

17. Micallef IN, Rohatiner AZ, Carter M et al: Long-term outcome of patients surviving for more than ten years following treatment for acute leukaemia. Br J Haem 113:443-445, 2001



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