Leukemia

History
Means white blood in Greek
Discovered by Dr. Alfred Velpeau in France, 1827 Named by pathologist Rudolf Virchow in Germany, 1845

Leukemia
Is a malignant hematologic disorder characterized by proliferation of abnormal white cells that infiltrate the bone marrow, peripheral blood and organs. Acute Leukemias Blast (precursor) cells Rapidly fatal if not treated Chronic Leukemias More mature cells Longer life expectancy

Classification of leukemias
Acute Myeloid origin
Acute Myeloid Leukemia (AML)

Chronic
Chronic Myeloid Leukemia (CML)

Lymphoid origin

Acute Lymphoblastic Leukemia (ALL)

Chronic Lymphocytic Leukemia (CLL)

ALL
nave B-lymphocytes Plasma cells T-lymphocytes

Lymphoid progenitor

AML
Hematopoietic stem cell Myeloid progenitor Neutrophils Eosinophils Basophils Monocytes Platelets

Red cells

Myeloid maturation
myeloblast promyelocyte myelocyte metamyelocyte band neutrophil

MATURATION
Adapted and modified from U Va website

Pictures Of Blood
Platelet White Cell Red Cell White Cell Red Cell Platelet Blasts

Normal human blood

Sources from Arginine.umdnj.edu

Blood with leukemia

Sources from beyond2000.com

Acute Lymphoblastic Leukemia

Proliferation of lymphoblasts
anemia, thrombocytopenia, increased WBC lymphadenopathy/splenomegaly

B- or T-cell
flow cytometry

Most common leukemia of childhood

Acute Lymphoblastic Leukemia

Acute Myelogenous Leukemia

Proliferation of myeloblasts
anemia, thrombocytopenia, increased WBC

Myeloid, monocytic, RBC, or megakaryocytic

flow cytometry myeloperoxidase +, TdT-

Auer rods Over age of 20

Acute Myelogenous Leukemia

Chronic Myelogenous Leukemia

One of myeloproliferative diseases (PV, ET) Proliferation of more mature granulocytes
normal to increased platelet count anemia

Splenomegaly t(9;22) (bcr-abl) (Philadelphia chromosome)

Chronic Myelogenous Leukemia

Chronic Lymphocytic Leukemia

Proliferation of small mature Blymphocytes
flow cytometry (monoclonal Kappa or lambda)

Lymphadenopathy
relationship to small lymphocytic lymphoma

May have Ab production 50% 5-year survival

Chronic Lymphocytic Leukemia

Development of Leukemia in the Bloodstream

Stage 1- Normal

Stage 2- Symptoms

Stage 3- Diagnosis

Legend White Cell Red Cell Platelet Blast Germ

Stage 5b- Infection
Stage 4- Worsening
Sources from Leukemia, by D. Newton and D. Siegel

Stage 5a- Anemia

ACUTE MYELOID LEUKEMIA (AML)

ACUTE MYELOID LEUKEMIA (AML) Clinical Overview

Acute myeloid leukemia (AML) is one of four types of leukemia. AML is cancer of the blood-forming tissue (bone marrow). Normal bone marrow produces red cells, white cells, and platelets. AML causes bone marrow to produce too many immature white blood cells (blast cells). Suppresses normal blood cell production. Anemia, leucopenia, thrombocytopenia

Classification of AML

APL, PML

Signs and Symptoms

Fatigue Shortness of breath on exertion Easy bruising Petechiae Bleeding in the nose or from the gums Prolonged bleeding from minor cuts Recurrent minor infections or poor healing of minor cuts Loss of appetite or weight loss Mild fever

Causation
Genetic changes in AML
Chromosomal changes lead to activation of oncogenes
Translocation between chromosomes 8 and 12 Translocation between chromosomes 15 and 17 Deletion of a segment of chromosome 5 or 7

Genetic factors that predispose an individual to AML

Fanconis anemia Down syndrome Blooms syndrome

Causation
Environmental factors
Exposure to ionizing radiation Exposure to benzene Treatment with alkylating agents or procarbazine Treatment with other drugs Viral oncogenesis (speculative)

Age
Adults are more likely to develop AML
Smoking 20% of AML cases are linked to smoking Doubles the risk of disease in people older than 60

t(15;17) translocation in AML

Clincal manifestations
symptoms due to:
marrow failure tissue infiltration leukostasis constitutional symptoms other (DIC)

usually short duration of symptoms

Marrow failure
neutropenia: infections, sepsis anemia: fatigue, pallor thrombocytopenia: bleeding

Infiltration of tissues/organs
enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ

Gum hypertrophy

Chloromas

A B

C
NEJM 1998

Laboratory features
WBC usually elevated, but can be normal or low blasts in peripheral blood normocytic anemia thrombocytopenia neutropenia DIC

Auer rods in AML

Treatments for AML

Chemotherapy Phase One Remission induction therapy Phase Two Remission continuation therapy Radiation therapy for certain cases Bone marrow transplantation

Treatments
Chemotherapy
Induction therapy
Initial stage of therapy to eradicate systemic and marrow-localized leukemic cells leading to remission Combination of an anthrocycline antibiotic and a cytarabine
Both prevent DNA synthesis thus stopping growth and leading to their death

If remission is not achieved with the first round of induction therapy, another round is begun

Treatments
Post-remission therapy
Consolidation therapy
Goal is to destroy any undetectable leukemic cells Many different approaches all of which involve short doses of intensive therapy

Maintenance therapy
months to years of less intensive therapy to prevent further recurrence

Treatments
Bone marrow transplant
Used as a last resort if 3 rounds of induction therapy have been unsuccessful Used as or along with post-remission therapy Two types of transplants are used
Autologous Allogeneic

Radiation therapy
Only used in rare cases where leukemic cells are centralized in one part of the body

Goal of treatment: Remission

Blood cell counts return to normal Leukemic cells can no longer be found in blood or marrow

After remission
If at any time after remission is achieved a relapse occurs the initial treatment may be repeated usually with minor changes in protocol If after five years of remission there have been no new outbreaks of leukemic cells the patient is considered cured

Two-hit model of leukemogenesis

Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR

differentiation block

enhanced proliferation

Acute Leukemia

Leukemic progenitor cell

BLOOD STEM CELL

Normal progenitor cell

1% of leukemic cells Leukemic mutation

99% of leukemic cells

LEUKEMIA
Brian J. P. Huntly & D. Gary Gilliland

Leukemia stem cells could be targeted with chemo

different from that killing leukemic cell

Conventional Chemotherapy Disease recurrence Stem cell killing

True Tumor involution

Stem cell killing + Conventional Chemotherapy Brian J. P. Huntly & D. Gary Gilliland

Disease remission

To understand the difference between leukemic cell and normal blood cell we shall look into differentiation related pathways

common lymphoid progenitor (CLP) Lymphoid cells

Upregulation PU.1

hematopoietic stem cells

CCAAT/enhancer binding protein(C/EBP) upregulation

Myeloid cells

Downregulation PU.1

Factor interplay fork Erythroid cells

common myeloid progenitor (CMP)

Transcription factors involved in normal hematopoiesis

AML1 GATA1

PU.1
(C/EBP)

(C/EBP)

(C/EBP)

1. Signaling event changes the ratio of PU.1 and GATA proteins in a stem cell. 2. GATA protein inhibit PU.1 blocking its interaction with c-JUN 3. PU.1 inhibitions GATA function through inhibition of GATA DNA binding.

4. GMCSF and EPO facilitate differentiation along either the myeloid or erythroid pathways

Nature Cancer Review

Upregulation PU.1

Lymphoid cells

+ PU.1 - GATA = Myeloid

Myeloid cells

Downregulation PU.1

- PU.1 + GATA =Erythroid

Erythroid cells

PU.1 factor
DUAL ROLE OF PU.1 factor
development of a lymphoid precursor
Degradation

development of monocytes/ macrophages

Basal transcription factors

C-Jun positive GATA1, C/EBP negative

PU.1 regulates almost every myeloid gene, including GM-CSF receptor, macrophage M-CSF, granulocyte G-CSF

http://images.medscape.com/pi/editorial/cmecircle/2002/1023/nimer_intro/slide03.gif

The Future
Clinical trials New drug treatments Vaccines Immunotherapy Leukemia type-specific therapy Gene therapy
Block encoding instructions of an oncogene Target the oncoprotein

Blood and marrow stem cell transplantation

Bone marrow transplantation provides long-term, disease-free survival among patients in remission