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ACUTE
LEUKEMIA
2012-2013
Leukemia
Group of malignant disorders of the
hematopoietic
tissues
characteristically
associated with increased numbers of white
cells in the bone marrow and / or peripheral
blood
Classification
• Classified based on cell type involved and
the clinical course
– Acute :
• ALL
• AML
– Chronic :
• CLL
• CML
Acute Leukemias
• Acute leukemias are clonal malignant hematopoietic
disorders resulting from genetic alterations in normal
hematopoietic stem cells.
• These alterations disrupt normal differentiation and/or
cause excessive proliferation of abnormal immature
“leukemic” cells or “blasts.”
• As the disease progresses, leukemic cells accumulate in
the bone marrow, blood, and organs, displacing normal
progenitor cells and suppressing normal hematopoiesis
Acute Leukemia - Essentials
• Short course of symptoms
• Fatigue, fever, easy bruising, bleeding
• Cytopenias - or pancytopenia
• More than 20% blasts in bone marrow
• Blasts in peripheral blood in 90% cases
AL - EPIDEMIOLOGY
• The frequency of AL varies between 1 and 6,5
cases to 100.000 population each year. The
frequency of AL varies with subtype and age.
• AL represents 10% of the neoplastic diseases and
is the principal cause of neoplastic for ages 0-35
years.
ALL - Epidemiology
• Approximately 3,000 new cases per year
• Mostly affects children, accounts for 2/3 of childhood
leukemia (peak age 4 years)
• Comprises less than 20% of leukemia in young adults
• May be B-cell, T-cell, or null-type (non-B, non-T cell)
•Only 20-40% of adults with ALL are cured with current
regimens.
AML - Epidemiology
• 2.3 per 100,000 people per year
• Higher among men than women (2.9 vs 1.9). The
difference is even more apparent in older patients.
• Most common leukemia in adults (80% of cases)
• Vast majority of patients 65 years or older
• AML is more common in whites than in other
populations.
ALL - Etiology
• Uncertain, but several proposed linkages:
· Genetic - Philadelphia chromosome
· Viral infection (EBV, HIV)
· Exposure to high energy radiation (T-cell ALL)
· Toxic chemical exposure
· Smoking
AML - Etiology
• Primary AML
– Increased incidence
• Genetic fragility
– Bloom syndrome
– Faconi anemia
– Wiskott Aldrich
– Down, Klinefelter, Patau syndromes
• tobacco use?
• herbicides?, pesticides?
• benzene exposure
• Secondary AML
– XRT
– Topoisomerase II inhibitors (e.g etopisode), alkylating agents
– MDS
– other cell proliferation disorders
• CML, polycythemia vera, primary thrombocytosis, PNH
Clinical features
General :
Onset is abrupt & stormy
(usually present within 3 months)
– Bone marrow failure
(anemia, infection ,bleeding)
– Bone pain & tenderness
Clinical presentation:
• Will present with sign or symptoms related to :
– Pancytopenia:
• WBCinfection  infectious syndrome
• Hb anemia  anemic syndrome
• Platelets bleeding – hemorragic syndrome
– Organ infiltration  tumoral syndrome
•
•
•
•
Lymphadenopathy.
More common with ALL than AML.
Splenomegally.
Hepatomegally.
CNS:5-10% of patient with ALL
Clinical features - specials
• L mediastinal tumoral mass
• L CNS infiltration
• M2 : Chloroma:-presents as a mass lesion ‘tumor
of leukemic cells’
• M3 : DIC
• M4/M5 : Infiltration of soft tissues,
gum infiltration, skin deposits ,Meningeal
involvement-headache, vomiting, eye symptoms
Gingival Infiltration in Monocytic
(AML M4 eos) Variant of AML
•
Mani, A, Lee, DA. Leukemic Gingival Infiltration. N Engl J Med 2008; 358(3): 274. Copyright ©2008 Massachusetts Medical Society
Gum hypertrophy
Chloromas
A
B
C
NEJM 1998
Clinical symptoms/Physical
Findings
• Extramedullary disease (ie, myeloid sarcoma)
– Can also have involvement of lymph nodes, intestine,
mediastinum, ovaries, uterus
Clinical features - specials
Skin Infiltration with AML (Leukemia Cutis)
Leukostasis
• Leukostasis – predominantly in those with WBC counts
> 100,000 (10% of patients); can also be seen in patients
with WBC > 50,000
– Most common in those with M4 or M5 leukemia
– Function of the blast cells being less deformable than mature
myeloid cells. As a result, intravascular plugs develop.
– High metabolic activity of blast cells and local production of
various cytokines contribute to underlying hypoxia
Leukostasis
Thornton, KA, Levis, M. FLT3 Mutation and Acute Myelogenous Leukemia with Leukostasis. N Engl J Med 2007; 357:1639. Copyright
©2007 Massachusetts Medical Society
Leukostasis
• Common symptoms
– Pulmonary: dyspnea, chest pain
– CNS: headaches, altered mentation, CN palsies,
ocular symptoms
– Priapism
– Myocardial Infarction
Acute leukemia - Diagnosis
– Lab evaluation
•The lab diagnosis is based on two things
–Finding a significant increase in the number of immature
cells in the bone marrow including blasts, promyelocytes,
promonocytes (>30% blasts is diagnostic)
–Identification of the cell lineage of the leukemic cells
Investigations
•
•
•
•
•
•
CBC:
– 60% of pts have an elevated WBC.
– Most are anemic
– Most are thrombocytopenic
– 90%have blast in the periphral blood film.
electrolytes:
– Hypo/hyper kalemia
– Hypomagnesimia
– hyperphosphatemia
Hypermetabolism:
– LDH.
– uric acid.
DIC:
– Most common with promyelocytic leukemia,small% monocytic leukemia&ALL
Bone marrow biopsy and aspirate:
– 30%or more of all nucleated cells are blast.
Radiology:
– CXR:mediastinal mass(T-cell ALL)
– Osteopenia or lytic lesion 50% of patients with ALL.(itractable pain).
Acute leukemia - Diagnosis
– Peripheral blood:
• Anemia (normochromic, normocytic)
• Decreased platlets
• Variable WBC count
– The degree of peripheral blood involvement determines classification:
» Leukemic – increased WBCs due to blasts
» Subleukemic – blasts without increased WBCs
» Aleukemic – decreased WBCs with no blasts
Acute Leukemias - CBC
• Hb – 5,6 g/dl
• Plt – 15.000/mmc
• WBC – 34.000/mmc
–
–
–
–
PN – 10%
L - 6%
M – 3%
Bl – 81%
• Hb – 3,5 g/dl
• Plt – 5.000/mmc
• WBC – 1.500/mmc
– PN - 15%
– L – 80%
– M – 5%
Acute leukemia - Diagnosis
• Bone marrow aspirate & trephine:
Hypercellular,
– blast cells ( > 20%),
– presence of Auer rods - AML type
• Cytochemistry :
Special stains to differentiate AML from ALL ;
Positivity with Sudan black & Myeloperoxidase
(MPO) in AML
Jemshidi trephine &
Salah aspiration needle
Acute leukemia - Diagnosis
• Diagnosis and classification of
the immature cells involved may
be done by :
–Morphology
–Cytochemistry
–Immunophenotyping
–Cytogenetic
Classification
• Criteria:
- Morphology :apperance of cell under microscope.
- Cytochemistry:chemical activity of the cell.
(myeloperoxidase , Sudan Black B)
- immunophenotyping: antigen pressent in the cell membrane
- Cytogenetics: chromosome of the cell
- Molecular biology:
• Classification:
3 groups of acute leukemias:
- acute myeloid leukemias AML(M1 –M6).
- acute lymphoblastic leukemias ALL (L1-L3).
- Biphenotypic leukemias or Acute undifferentiated
leukemia
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)
Classification of ALL
Immunologic Subtype
FAB Type % of Cases
Cytogenetic Abnl
Pre-B cell ALL
L1, L2
75
t(9:22) t(4:11) t(1:19)
T-cell ALL
L1, L2
20
14q11 or 7q34
B-cell ALL
L3
5
t(8:14) t(8:22) t(2:8)
L1 - 85% of childhood ALL
L2 - Majority of adult ALL
L3 - Includes Burkitt’s. < 5% of ALL
ALL – L1/periferal blood smear
ALL – L2/periferal blood smear
ALL3/bone marrow smear
FAB Classification of AML
• M0 undifferentiated acute myeloblastic leukemia (5%)
• M1 AML with minimal maturation (20%)
• M2 AML with maturation (30%)
– t(8;21)
• M3 Acute promyelocytic leukemia (5%)
– t(15;17)
• M4 Acute myelomonocytic leukemia (20%)
• M4 eos Acute myelomonocytic leukemia with eosinophilia (5%)
– inv (16)
• M5 Acute monocytic leukemia (10%)
– t(9;11)
• M6 Acute erythroid leukemia (3%)
• M7 Acute megakaryoblastic leukemia (3%)
WHO Classification
•
•
•
•
•
AML with certain genetic abnormalities
– t(8;21), t(16), inv(16), chromosome 11 changes
– t(15;17) as usually seen with AML M3
AML with multilineage dysplasia (more than one abnormal myeloid cell type is
involved)
AML related to previous chemotherapy or radiation
AML not otherwise specified
– undifferentiated AML (M0)
– AML with minimal maturation (M1)
– AML with maturation (M2)
– acute myelomonocytic leukemia (M4)
– acute monocytic leukemia (M5)
– acute erythroid leukemia (M6)
– acute megakaryoblastic leukemia (M7)
– acute basophilic leukemia
– acute panmyelosis with fibrosis
– myeloid sarcoma (also known as granulocytic sarcoma or chloroma)
Undifferentiated or biphenotypic acute leukemias (leukemias that have both
lymphocytic and myeloid features. Sometimes called ALL with myeloid markers, AML
with lymphoid markers, or mixed lineage leukemias.)
AML2 – bone marrow smear
AML3 – bone marrow smear
Prognosis in ALL
parameters
Good
poor
WBC
low
High(>50x10 9 /l)
Gender
Girls
Boys
Immunophenotype
C-ALL
B-ALL
Age
Child
Adult or infant.
Cytogenetic
Normal,hyperdiploid,
Ph+,11q23rearrangeme
nts.
Time to clear blast from
blood
< 1week
>1week
Time to remission
<4weeks
>4weeks
Cns disease at
presentation
Absent
Present
Minimal residual
disease.
Negative at 1-3 months
Still positive at 3-6
months.
Prognosis in ALL
• Good risk includes
– (1) no adverse cytogenetics,
– (2) age younger than 30 years
– (3) WBC count of less than 30,000/mL, and
– (4) complete remission within 4 weeks.
• Intermediate risk
– does not meet the criteria for either good risk or poor risk.
• Poor risk includes
– (1) adverse cytogenetics [(t9;22), (4;11)],
– (2) age older than 60 years,
– (3) precursor B-cell WBCs with WBC count greater than
100,000/mL, or
– (4) failure to achieve complete remission within 4 weeks.
Prognosis in AML
Prognostic Factors:
• Age at diagnosis
• Comorbidities (acute vs chronic)
• Chromosomal findings
• Symptomatic interval preceding diagnosis
• Presenting Leukocyte count
• Circulating myeloblast count
• FAB classification
• Morphologic characteristics of the leukemic cell
Treatment of acute leukemias
Choice of Rx is influenced by:
• type (AML vs ALL)
• age
• curative vs palliative intent
Principles of treatment
• combination chemotherapy
– first goal is complete remission
– further Rx to prevent relapse
• supportive medical care
– transfusions, antibiotics, nutrition
• psychosocial support
– patient and family
Supportive measures:
-isolation in positive laminer flux room
-insertion of central line
-family and patient support by permanent social worker
-Alkaline diuresis to prevent tumor lysis syndrome
-oropharynx/GIT decontamination to prevent fungal infection
-IV antibiotics for infection
-Blood transfusion if anemia and thrombocytopenia.
Chemotherapy for acute
leukemias
• Phases of ALL treatment
–
–
–
–
induction
intensification
CNS prophylaxis
maintenance
post-remission therapy
• Phases of AML treatment
– induction
– consolidation (post-remission therapy)
ALL Treatment
• 1 – Remission Induction
• 2 – Intensification (Consolidation) Therapy
• 3 – Maintenance Therapy
• 4 – CNS Prophylaxis
• 5 – Allogeneic Stem Cell Transplant
ALL 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, L-asparaginase, +/cyclophosphamide
– 80-90% complete remission
• Intensification
– High doses of multiple agents not used during induction or readministration of the induction regimen
ALL 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
ALL 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
AML Treatment
•
Remission induction therapy
–
Commonly anthracycline (ie, daunorubicin, idarubicin) and cytarabine
→ (“3+7 regimen”)
•
•
•
Cytarabine has ample CNS penetration so no need for prophylactic
intrathecal chemotx (also, ↓ risk in patients with AML compared to ALL)
60-80% achieve complete remission
Postremission therapy
1.
Consolidation
–
–
2.
longer survival than maintence alone
typically high dose cytarabine
Maintenance – continue chemotx monthly for 4-12 months
–
nonmyelosuppressive doses
COMPLICATIONS TREATMENT
Tumor Lysis Syndrome
• Characterized by metabolic derangements caused
by massive release of cellular components
following lysis of malignant cells
• Commonly seen in malignancies with high rates
of cell proliferation (esp. ALL, Burkitt’s
lymphoma); also can be seen with AML
Tumor Lysis Syndrome
• Tumor lysis syndrome - hyperphosphatemia,
hyperkalemia, hyperuricemia, hypocalcemia and uremia
– Retrospective study of 788 patients (433 adults) found
incidence of hyperuricemia and TLS to be 14.7%/3.4% in
patients with AML compared to 21.4%/5.2% in patients with
ALL and 19.6%/6.1% in patients with NHL
• Electrolyte abnormalities can occur without the entire
spectrum of TLS or even before tx is initiated
– Hyperuricemia
– Lactic acidosis
Tumor Lysis Syndrome
• Release of intracellular proteins →catobilized to hypoxanthine →
xanthine → uric acid → Crystalization of uric acid and in renal
tubules → impaired renal function
• Release of phosphate from malignant cells → calcium phosphate
precipitation and further renal impairment along with
hypocalcemia and resultant symptoms from ↓Ca
– Hyperphosphatemia: nausea, vomiting, diarrhea, seizures, lethargy
– Hypocalcemia: arrhythmia, hypotension, tetany, cramps
– Hyperkalemia: arrhythmia, cramps, paresthesia
Tumor Lysis Syndrome
• Prevention and management
– IV hydration : promotes excretion of uric acid and phosphate; improves renal blood
flow/GFR
– Allopurinol → competitive inhibitor for xanthine oxidase. Therefore, ↓ conversion
of purine metabolites to uric acid
• However, must consider buildup of xanthine crystals → acute obstructive uropathy
(HYDRATE!!!)
– Recominant urate oxidase (rasburicase)
• Promotes conversion of uric acid to allantoin (highly soluble; urinary excretion)
• Indicated in patients at high risk of TLS (Burkitt’s Lymphoma, B-ALL, ALL (WBC
>100,000), AML (WBC >50,000)
• Also indicated in patients that develop hyperuricemia despite allopurinol
– Dialysis can be used in severe cases
– Urine alkalization is NOT recommended – does not increase solubility of
xanthine/hypoxanthine with an increased propensity to develop xanthineobstructive uropathies (esp with allopurinol use)
DIC
• Common symptoms/findings
–
–
–
–
–
in addition to weakness (anemia), infections/fever (malfunctioning WBCs)
petechiae, ecchymoses, hematuria, bleeding from venipuncture sites
migratory thrombophlebitis (Trousseau’s syndrome)
nonbacterial thrombotic (marantic) endocarditis
DVT/PE
• Lab findings
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–
–
–
–
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Prolonged PT/INR, PTT
microangiopathic anemia (schistocytes)
thrombocytopenia
elevated fibrin split products
elevated D-dimer
low fibrinogen
•
Treatment
DIC
1. Supportive therapy
•
•
•
Platelets
Cryoprecipitate (fibrinogen)
FFP
2. Treatment for obvious thrombosis (e.g
thrombophlebitis, mural thrombus)
•
•
UFH or LMWH; often resistant to coumadin
activated protein C
3. Treatment of underlying malignancy
•
In the case of AML M3 → All-Trans Retinoic Acid (PML-RARα)
–
–
•
•
Induces differentiation beyond promyelocyte phase
Only with the more common t(15;17) translocation; t(11;17) and t(5;17) do not respond to
ATRA
Remission rates of greater than 90% with AML M3 patient treated with ATRA and
chemotx (eg, anthracyclines (idarubicin)) with 60-70% disease free survival
Arsenic trioxide in those that relapse – achieves complete remission in >90%
CNS Involvement
• Occurs in less than 5% of AML patients (highest
incidence in relapsed promyelocytic (M3) variant)
– Routine LP is not performed unless symptoms suggestive of
CNS pathology
• Common symptoms
– headache
– mental status changes
– CN palsies (commonly CN III or VI)
– CSF findings
• blast cells
• moderate increase in protein and moderate decrease in glucose
CNS Involvement
• Treatment
– Intrathecal chemotherapy (methotrexate or
cytarabine) +/- whole brain XRT
• addition of XRT depends on response to intrathecal
chemotx and whether there is cranial nerve involvement
• high relapse rate
– Commonly administer prophylactic intrathecal
chemotx in relapsed promyelocytic disease