2. Leukemia: Definition
⢠a progressive, malignant disease of
the blood-forming organs, marked by
distorted proliferation and
development of leukocytes and their
precursors in the blood and bone
marrow
http://medical-dictionary.thefreedictionary.com/leukemia
5. âgain or loss of function of
genesâ
ONCOGENES
TUMOR
SUPPRESSOR
GENES
6. Malignant Transformation 2
DNA
changes
DNA repair
Cellular
regulatory&
monitoring
mechanisms
Apoptosis
Immune system
proliferation
Mutagenic
Insults or germ
line mutations
1ST
HIT
More insults
2nd
HIT
Transformation
Loss of contact inhibition, growth factor
dependence/regulation, apoptosis
Additional hits
Invasion, Angiogenesis,
MetastasisâŚ
Clonal
selection
7. Two-Hit Hypothesis of
Leukmogenesis
Class I Mutations Class II Mutations
FLT3-ITD
FLT3-TKD
KIT
RAS
PTPN11
JAK2
PML-RARA
RUNX1-RUNX1T1
CBFB-MYH11
MLL fusions
CEBPA
NPM1?
AML
Proliferation and/or
survival advantage
Impaired differentiation,
apoptosis
Gilliland et al. Curr Opin Hematol (2001) 8:189-191.
WHO Book 2008
8. Acute vs. Chronic
Acute Chronic
Myeloid
Lymphoid
Acute myeloid leukemia Chronic myeloid leukemia
Other CMPNs
Acute lymphoblastic
leukemia (B or T)
Adult T lymphocytic leukemia
T-cell LGL Leukemia
T-Prolymphocytic leukemia
Aggressive NK/T leukemia
Chronic lymphocytic leukemia
Hairy cell leukemia
Other circulating B cell
lymphomas
Sezary Syndrome
Adult T lymphocytic leukemia
T-cell LGL Leukemia
T-Prolymphocytic leukemia
9. ACUTE CHRONIC
Onset Rapid Insidious
Time to death
or
complications
Minutes to
weeks
Weeks to
Years
Treatment Aggressive,
urgent
Long term,
milder
Predominant
Cell
Immature Mature
Curability Potential ?
10. Acute Leukemias â Initial Findings
⢠CBC abnormalities
â Leukocytosis or leukopenia
â Other cytopenias
â Blasts
⢠Related Issues
â Bleeding (thrombocytopenia, DIC)
â Infection
â Organ/Tissue infiltration
16. AML vs ALL: Morphology
⢠CAUTION: With the exception of Auer rods, there is
morphologic overlap between the two diagnoses.
Non-Lymphoblasts Lymphoblasts
Size 3-4 x size of RBC 1.5-2 x size of RBC
Auer rods May be present Absent
Granules Often present Rare
N:C ratio Moderate High
Chromatin Open or finely dispersed Moderately condensed
Nucleoli More, prominent Inconspicuous
17. Acute Leukemia - Management
Principles
⢠Stabilize
⢠Pre-treatment eval/prep
⢠Risk Stratify
⢠Remission Induction
⢠Consolidation â based on risk
⢠Maintenance/surveillance
27. More Examples for Targeted
Therapy in Acute Leukemias
⢠Imatinib in philadlephia positive ALL
⢠Rituximab in CD20 positive mature B ALL
⢠FLT3 inhibitors
⢠HIDAC inhibitors
34. Staging â Rai
Stage Feature Median Survival
0 Lymphocytosis only >150 mos
1 Lymphadenopathy 101
2 Spleno/Hepato megaly 71
3 Anemia 19
4 Thrombocytopenia 19
35. Dohner H et al. N Engl J Med 2000;343:1910-1916
Prognostic Variables: Cytogenetics
13q
deletion
12q trisomy,
Normal
11q
deletion
17q
deletion
36. CLL â When to Treat?
⢠Non-immune Anemia/
Thrombocytopenia
⢠Symptomatic
splenomegaly
⢠Symptomatic
Lymphadenompathy
Treat based on risk
Classic Paradigm
Proposed Paradigm
37. Copyright Š2003 American Society of Hematology. Copyright restrictions may apply.
Keating, M. J. et al. Hematology 2003;2003:153-175
Figure 4. Time-to-treatment failure and survival of 202 chronic
lymphocytic leukemia (CLL) patients treated with fludarabine,
cyclophosphamide, and rituximab (FCR) as initial therapy
Is CLL Curable?
39. CML â Clinical Presentation
⢠Non-specific constitutional symptoms
⢠Symptoms related to elevated abnormal
WBC â Leukostasis, tissue infiltration,
Sweetâs syndrome, Urticaria
⢠Symptoms related to splenomegaly or other
sites of extramedullary hematopoiesis
⢠Symptoms related to high metabolic rate â
fever, weight loss, hyperuricemia
⢠Incidental finding
40. Goldman J and Melo J. N Engl J Med 2003;349:1451-1464
The t(9;22) Translocation and Its Products: the BCR-ABL Oncogene on the Ph Chromosome and
the Reciprocal ABL-BCR on the Derivative 9q+ Chromosome
41. Goldman J and Melo J. N Engl J Med 2003;349:1451-1464
Physiologic Regulation by the Normal ABL Protein and Deregulation by BCR-ABL of Key Cellular
Processes Such as Proliferation, Adherence, and Apoptosis
42. Diagnosis - Molecular
⢠Cytogenetic analysis (Karyotype) will be
positive for t(9:22) in ~90%
⢠PCR or FISH for the BCR-ABL transcript
are positive in >95%
⢠The remainder are atypical cases, and may
be positive for variant translocations or
other abnormalities
43. CML â Management
⢠An allogeneic stem cell transplant is still the
only proven curative modality, but involves
high upfront mortality and morbidity
⢠Tyrosine Kinase inhibitors are the mainstay
of treatment, likely do not cure the disease
completely, but can afford long term
survival
44. Savage D and Antman K. N Engl J Med 2002;346:683-693
Mechanism of Action of BCR-ABL and of Its Inhibition by Imatinib
45. Copyright Š2005 American Society of Hematology. Copyright restrictions may apply.
Deininger, M. W.N. Hematology 2005;2005:174-182
Figure 1. Progression-free survival of newly diagnosed chronic
myeloid leukemia patients treated with 400 mg imatinib daily
according to molecular responses at 12 months
46. Chronic Leukemias â changing
principles
⢠Treat for symptoms ď treat by risk
⢠Nonspecific cytoreduction ď targeted
therapies
⢠MRD based surveillance
⢠Palliative intent ď curative?
Editor's Notes
Figure 1. Probability of Survival from the Date of Diagnosis among the Patients in the Five Genetic Categories.
The median survival times for the groups with 17p deletion, 11q deletion, 12q trisomy, normal karyotype, and 13q deletion as the sole abnormality were 32, 79, 114, 111, and 133 months, respectively. Twenty-five patients with various other chromosomal abnormalities are not included in the analysis.
Figure 1. The t(9;22) Translocation and Its Products: the BCR-ABL Oncogene on the Ph Chromosome and the Reciprocal ABL-BCR on the Derivative 9q+ Chromosome.
In classic CML, BCR-ABL is transcribed into messenger RNA (mRNA) molecules with e13a2 or e14a2 junctions, which are then translated into the p210BCR-ABL oncoprotein. This oncoprotein is a hybrid containing functional domains from the N-terminal end of BCR (dimerization [DD], SRC-homology 2 [SH2]-binding, and the Rho GTP-GDP exchange-factor [GEF] domains) and the C-terminal end of ABL. (Only SRC-homology regions 2, 3, and 1 [SH2, SH3, and SH1, respectively], and the DNA- and actin-binding domains are shown.) Tyrosine 177 (Y177) in the BCR portion of the fusion gene and tyrosine 412 (Y412) in the ABL portion are important for the docking of adapter proteins and for BCR-ABL autophosphorylation, respectively. P-S/T denotes phosphoserine and phosphothreonine.
Figure 2. Physiologic Regulation by the Normal ABL Protein and Deregulation by BCR-ABL of Key Cellular Processes Such as Proliferation, Adherence, and Apoptosis.
The enzymatic (tyrosine kinase) activity of the normal ABL protein (p145ABL), encoded by its SRC-homology 1 (SH1) domain, is kept under tight control, probably by the intramolecular binding of an N-terminal cap region encompassed by the first exon (1b or 1a) and the first part of exon a2.53 In the BCR-ABL fusion protein (p210BCR-ABL), lack of the ABL cap region and a dimerization domain encoded by the first exon of BCR are responsible for constitutive activation of the ABL SH1 domain, resulting in uncontrolled signal transduction and an abnormal cellular phenotype. The various functional domains of the ABL protein include the SRC-homology 3 and 2 regulatory domains (SH3 and SH2, respectively), the SH1 domain with its ATP-binding site, the nuclear-localization signal motif, the nuclear-export signal motif, the DNA-binding domain, and the G-actin and F-actin DNA-binding domains. The last two are important for the control of cytoskeletal organization, cell adherence, cell motility, and integrin receptor-mediated signal transduction.54,55
Figure 2. Mechanism of Action of BCR-ABL and of Its Inhibition by Imatinib.
Panel A shows the BCR-ABL oncoprotein with a molecule of adenosine triphosphate (ATP) in the kinase pocket. The substrate is activated by the phosphorylation of one of its tyrosine residues. It can then activate other downstream effector molecules. When imatinib occupies the kinase pocket (Panel B), the action of BCR-ABL is inhibited, preventing phosphorylation of its substrate. ADP denotes adenosine diphosphate. Adapted from Goldman and Melo1 with the permission of the publisher.