Transcript Acute Lymphoblastic Leukemia

Acute
Lymphoblastic
Leukemia
Maggie Davis Hovda
5/26/2009
Definition
Neoplastic disease which results from a
mutation in a single lymphoid progenitor
cell at one of several discrete stages of
development
 B Cell or T Cell

Epidemiology
Most common childhood acute leukemia,
~80%
 Incidence in adults ~20%
 Bimodal distribution of occurrence:
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 Peak
at age 2-5
 Second increased incidence after age 50
Pathogenesis
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Acquired Genetic Change in Chromosome
 Change
in number, ie ploidy
 Change in structure
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Translocations (most common)
Inversions
Deletions
Point mutations
Amplifications
Changes in normal means of cell differentiation, proliferation, and
survival
Mechanisms of Leukemia Induction

1 – Activation of a protooncogene OR creation of
a fusion gene with
oncogenic properties
- Ph Chromosome t(9;22)
2 – Loss or inactivation
of ≥ 1 tumor
suppressor gene
- p53 (p16 mutation)
Etiology
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Unknown
? Genetic Predisposition
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Down Syndrome
Disorder with chromosomal fragility:
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Increased incidence amongst monozygotic and dizygotic twins
Fanconi’s anemia
Bloom Syndrome
Ataxia-Telangiectasia
? Infections
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HTLV1 in T cell leukemia/lymphoma
EBV in mature B cell ALL
HIV in lymphoproliferative DO
Presentation
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Nonspecific Symptoms
 Fatigue/decreased
energy
 Fever
 Easy
bruising
 Bleeding
 Dyspnea
 Dizziness
 Infection
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Joint, extremity pains
CNS involvement
Clinical Presentation
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Physical Exam
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Lab Abnormalities
 Pallor
 anemia
 Ecchymoses
 wbc
 Petechiae
 LAD
 Hepatosplenomegaly
0.1 (20-40%) - >100 k
(10-16%)
Platelets – usually ↓
↑ LD, uric acid
CXR: eval for thymic mass
CSF to eval for
involvement
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vary
Diagnosis
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Morphologic
 French
American British Classification
L1: small uniform blasts (pediatric ALL)
 L2: larger, more variable sized blasts (adult ALL)
 L3: uniform cells with basophilic and sometimes
vacuolated cytoplasm (mature B cell ALL)
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Immunophenotyping
From: Jabbour, E. et al. Adult Acute Lymphoblastic
Leukemia. Mayo Clinic Proc. 2005;80(11):1517-1527
Cytogenetic Abnormalities
From: Jabbour, E. et al. Adult Acute Lymphoblastic
Leukemia. Mayo Clinic Proc. 2005;80(11):1517-1527
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Classification of ALL
Immunologic
Subtype
% of cases
FAB Subtype
Cytogenetic
Abnormalities
Pre-B ALL
75
L1, L2
t(9;22), t(4;11),
t(1;19)
T cell ALL
20
L1, L2
14q11 or 7q34
B cell ALL
5
L3
t(8;14), t(8;22),
t(2;8)
From: Harrison’s Principles of Internal Medicine, 16th
ed. 2005. Chapter 97, Malignancies of lymphoid cells.
Differential Diagnosis
ITP
 Aplastic Anemia
 Infectious mononucleosis
 Rheumatoid Arthritis
 Rheumatic Fever
 Collagen Vascular Disease
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Treatment
1 – Remission Induction
 2 – Intensification (Consolidation) Therapy
 3 – Maintenance Therapy
 4 – CNS Prophylaxis
 5 – Allogeneic Stem Cell Transplant
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Treatment
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Remission Induction
 Goals:
restore normal hematopoiesis, induce a
complete remission rapidly in order to prevent
resistance to drugs
 Standard induction regimen
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4 or 5 drugs: vincristine, prednisone, anthracycline, Lasparaginase, +/- cyclophosphamide
Intensification
 High
doses of multiple agents not used during
induction or re-administration of the induction regimen
Treatment
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Maintenance Therapy
 Daily
po 6MP, weekly MTX, monthly pulses of
vincristine and prednisone for 2-3 yrs
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CNS Prophylaxis
 Given
during induction and intensification
 Intrathecal: MTX, Cytarabine, corticosteroids
 Systemic: high dose mtx, cytarabine, L-asparaginase
 +/- Cranial Irradiation
Treatment
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Stem Cell Transplant
 Done
during first CR
 Indications:
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Ph Chromosome
t(4;11) mutation
Poor initial response to induction therapy
Other
 Adolescents
benefit significantly from pediatric ALL
regimens vs. adult regimens
Relapse & Prognosis
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Relapse
 Most
occur during treatment or within the first 2 years
 Bone Marrow is the most common site
 Poor prognostic factors in patients previously treated:
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Relapse on therapy
Short initial remission after intense therapy
T-cell immunophenotype
Ph Chromosome
Circulating blasts
High leukocyte count at relapse
Prognosis
Overall better in children than in adults
 In adults, worse outcomes with:
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 Increasing
age, >60
 Increased wbc count at presentation
Sources
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Jabbour, E. et al. Adult Acute Lymphoblastic Leukemia.
Mayo Clinic Proc. 2005;80(11):1517-1527
Xavier, T. Chemotherapy of acute leukemia in adults.
Expert Opin. Pharmacother. (2009) 10(2):221-237
Williams Hematology, 6th ed. 2001. Chapter 97, Acute
Lymphoblastic Leukemia.
Harrison’s Principles of Internal Medicine, 16th ed. 2005.
Chapter 97, Malignancies of lymphoid cells.