Transcript Hematology: Digital Image Study Sets:Hemolytic Anemias

The Leukemias
Sherron R. Helms, M.D.
 March 24, 2005
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Leukemias
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Proliferation of abnormal clone of
hematopoietic cells
Poor response to normal regulatory
signals
 Diminished capacity for differentiation
 Ability to expand at expense of normal
cells
 Ability to suppress growth of normal
cells
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Leukemias- Etiology
Generally unknown
 Host susceptibility- DNA repair
mechanisms, Down syndrome
 Chromosomal damage- physical
(XRT) or chemical (alkylating
agents, benzene)
 Viral- EBV in Burkitt, HTLV-I in T cell
ALL
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Leukemias- Diagnosis
Generally requires bone marrow
biopsy and aspirates with flow
cytometry and cytogenetics
 CLL can be reliably diagnosed by
flow cytometry on peripheral blood
 There must be > 20% blasts in
marrow for diagnosis of acute
leukemia
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Leukemias- Classification
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Acute vs Chronic
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Based on natural history of the
untreated disease
Myeloid vs Lymphoid
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Based on the primary cell line involved
Leukemias
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Lymphoid
CLL
 ALL
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Myeloid
CML
 AML
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Chronic Lymphocytic
Leukemia
CLL
Relatively indolent clonal lymphoid
disease
 Primarily B cell
 Includes Hairy Cell Leukemia
 Most common leukemia in adults
 Median age at diagnosis: 62 y
 Etiology unknown
 Morphology: Normal B cells
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CLL- Molecular Biology
Normal appearance, abnormal
function
 CD 5 expression
 Defective apoptosis
 Overexpression of bcl-2 gene
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CLL- Clinical Presentation
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Asymptomatic
Lymphocytosis noted on routine CBC
Lymphadenopathy and/or splenomegaly
in ~50% at diagnosis
Staph, Strep, Herpes infections common
Autoimmune hemolytic anemia in 10%
ITP in 2%
CLL- Immune dysfunction
CLL B cells produce reduced levels of
immunoglobulin in response to
antigenic stimuli
 Quantitative and qualitative
abnormalities in B, T, NK cells
 Impaired complement activation
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CLL- Staging
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LOW RISK
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INTERMEDIATE RISK
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Lymphocytosis only
Average survival >10 yrs
+ Adenopathy and/or splenomegaly
Average survival 7 yrs
HIGH RISK
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+ Anemia and/or thrombocytopenia
Average survival 1.5 yrs
CLL- Clinical course
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Generally, indolent with gradual increase
in lymphocytosis, adenopathy,
splenomegaly. May be years before Rx
required
Richter syndrome- ~5% transform to
aggressive large cell lymphoma/leukemia
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Develop fever, weight loss, worsening anemia
& thrombocytopenia, rising lymphocyte count
Short survival, poor response to therapy
CLL- Treatment
No survival advantage to therapy at
time of diagnosis in low risk patients
 Indications for therapy:
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B symptoms
 AIHA, ITP (steroids)
 Massive hepatosplenomegaly
 Bulky adenopathy
 Recurrent infections
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CLL- Treatment Options-I
Chlorambucil- Oral alkylator, ~50%
RR, rare complete response
 Fludarabine- IV purine analog, 70%
RR, 30% CR, prolonged T cell
suppression
 IVIG: Only in pts with repeated
bacterial infections
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CLL- Treatment Options-II
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Monoclonal Antibodies
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Rituximab- antiCD20; when combined with
chemo, 95% RR, 68% CR
Alemtuzumab- antiCD52- effective in clearing
blood and marrow; less effective on nodes.
Prolonged, severe T cell suppression
Bone Marrow Transplantation- autologous
and allogeneic under study for healthy pts
under 70yo
Hairy Cell Leukemia
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Male predominance
Cytopenias, splenomegaly
Therapy: Cladribine- nucleoside analog
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Single course of therapy
90% response rate
Responses very durable
Resistant disease- BL-22: MoAb antiCD22
+ pseudomonas exotoxin induces
apoptosis- 75% RR in clinical trials
Acute lymphocytic
leukemia
Acute lymphoblastic
leukemia
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Malignant disease of early B and T cells
Aberrant differentiation and proliferation
Cells accumulate in marrow and suppress
normal hematopoiesis
In addition to marrow and peripheral
blood, involves nodes, liver, spleen, CNS,
and skin
A.L.L.
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20% of adult leukemia
Most common malignant disease in
childhood
Symptoms: fatigue, fevers, bone pain,
infection, bleeding, adenopathy
CNS involvement in 5-10%
Blasts in peripheral blood in 90%
Leukostasis uncommon even with WBC
100,000
A.L.L. Treatment
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Induction, consolidation, maintenance
Use multiple chemotherapy agents to
prevent resistance (vincristine,
prednisone, daunorubicin, asparaginase)
Use prophylactic Rx of CNS (intrathecal
methotrexate and AraC)
Postremission chemo to eliminate minimal
residual disease
Adults: 65-90% remission; 20-30% cure
Allogeneic transplants in high risk pts
Acute Myelogenous
Leukemia
A.M.L.
Most common acute leukemia in
adults
 Median age at diagnosis: 60 yrs
 The most common type of leukemia
induced by alkylating agents
(nitrogen mustard [7y]) or
epipodophyllins (VP16, 1-2 y)
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AML
Auer rods: accumulation of
lysosomal granules in cytoplasm,
seen in ~10%
 Diagnosis by flow cytometry,
cytogenetics on marrow
 FAB classification has 8 subtypes
(M0- M7); WHO classification has 19
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AML- Clinical Features
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Presenting symptoms: fatigue, bruising,
infection
Acute promyelocytic subtype presents
with bleeding, sometimes frank DIC
Acute myelomonocytic subtype often has
gum and/or skin involvement
Leukostasis (pulm and CNS) common
when blast count >50,000
A.M.L.- Therapy
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Remission induction with cytarabine and
daunorubicin
all-trans retinoic acid (ATRA) is added in
acute promyelocytic leukemia (APL)
Postremission: consolidation chemo using
high dose cytarabine for 2 cycles
40% cure rate in young and middle aged
adults
Maintenance therapy only in APL (ATRA)
Allogeneic transplant in high risk pts
<70y who have match and are in CR
AML in Elderly
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Poorer outcome, ~10% long term
survivors
Less able to withstand intensive
chemotherapy and complication of
prolonged marrow suppression
Less marrow regenerative capacity
More often have poor-prognosis subtypes
of leukemia
More often have MDS evolving into AML,
multiple mutations and drug resistant
Acute Promyelocytic
Leukemia (APL)
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M3 subtype of AML
Promyelocytes contain granules with
procoagulant and fibrinolytic activity
t(15;17) juxtaposes the RARa gene on 17
with the PML gene on 15
The resulting PML/RARa represses
transcription of the RAR needed for
differentiation/apoptosis
High doses of ATRA cause release of the
corepressor
A.P.L.
Retinoic acid + standard
chemotherapy with daunorubicin
and cytosine arabinoside (AraC)
 95% remission rate, 70% cure rate
 Arsenic trioxide active in relapsed
disease (causes histone acetylation,
differentiation, & apoptosis)
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Chronic Myelogenous
Leukemia
Chronic Myelogenous
Leukemia
A myeloproliferative disorder (CML,
P. Vera, E.T.)
 Clonal disorder of pluripotential stem
cell
 Median age 45-55 yrs
 Philadelphia chromosome [t(9;22)]
in 95%
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CML
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Expansion of myeloid cells at various
stages of maturation
Three clinical phases: chronic,
accelerated, and blast crisis
Patients proceed through these phases
over ~4yrs if untreated
Symptoms: fatigue, night sweats, sx
related to splenomegaly
High WBC, increased basophils, high
platelet count
Ph Chromosome
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BCR-ABL –protein product of the
translocation
Transfection of BCR-ABL in mice causes
CML
Inhibition of BCR-ABL in patients reverses
CML
Acquired disorder
Cause of mutation unknown- radiation in
some
Ph Chromosome- BCR-ABL
Tyrosine kinase activity
 Leads to increased transcription of
genes that control cell proliferation
 Inhibits expression of cell adhesion
molecules
 Suppresses apoptosis
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CML- Treatment
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The BCR-ABL proteins must be
phosphorylated to have tyrosine kinase
activity
Imatinib (Gleevec) blocks phosphorylation
Oral agent, well tolerated
87% RR, 76% complete cytogenetic
response
Allogeneic stem cell transplant cures 75%
of pts under age 70