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:

Peak

at age 2-5 Second increased incidence after age 50

Pathogenesis

Acquired Genetic Change in Chromosome

Change

in number, ie ploidy Change in structure

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

Unknown ? Genetic Predisposition

Increased incidence amongst monozygotic and dizygotic twins

Down Syndrome Disorder with chromosomal fragility:

Fanconis anemia Bloom Syndrome Ataxia-Telangiectasia

? Infections

HTLV1 in T cell leukemia/lymphoma EBV in mature B cell ALL HIV in lymphoproliferative DO

Presentation

Nonspecific Symptoms
Fatigue/decreased Fever Easy

energy

bruising Bleeding Dyspnea Dizziness Infection

Joint, extremity pains CNS involvement

Clinical Presentation

Physical Exam
Pallor Ecchymoses Petechiae LAD Hepatosplenomegaly

Lab Abnormalities
anemia wbc

vary

0.1 (20-40%) - >100 k (10-16%) Platelets usually LD, uric acid CXR: eval for thymic mass CSF to eval for involvement

Diagnosis

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)

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

Classification of ALL
Immunologic Subtype
Pre-B ALL

% of cases
75

FAB Subtype
L1, L2

Cytogenetic Abnormalities
t(9;22), t(4;11), t(1;19) 14q11 or 7q34

T cell ALL

20

L1, L2

B cell ALL

L3

t(8;14), t(8;22), t(2;8)

From: Harrisons 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

Treatment
1 Remission Induction 2 Intensification (Consolidation) Therapy 3 Maintenance Therapy 4 CNS Prophylaxis 5 Allogeneic Stem Cell Transplant

Treatment

Remission Induction
Goals:

restore normal hematopoiesis, induce a complete remission rapidly in order to prevent resistance to drugs Standard induction regimen

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

Maintenance Therapy
Daily

po 6MP, weekly MTX, monthly pulses of vincristine and prednisone for 2-3 yrs

CNS Prophylaxis
Given

during induction and intensification Intrathecal: MTX, Cytarabine, corticosteroids Systemic: high dose mtx, cytarabine, L-asparaginase +/- Cranial Irradiation

Treatment

Stem Cell Transplant

Done

during first CR Indications:

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

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:

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:

Increasing

age, >60 Increased wbc count at presentation

Sources

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. Harrisons Principles of Internal Medicine, 16th ed. 2005. Chapter 97, Malignancies of lymphoid cells.