Acute Lymphoblastic Leukemia

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Transcript Acute Lymphoblastic Leukemia

Prof. Cengiz Canpolat M.D.
Pediatric Hematology-Oncology
Acıbadem University
Pediatric HematologyOncology
Leukemias
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Clonal expansion and arrest at a specific stage
of normal myeloid or lymphoid hematopoiesis
Acute leukemia consitutes %97 of childhood
leukemias
ALL(%75)
AML (%20)
Acute undifferentiated leukemia (<%0.5)
Acute mixed lineage leukemia (AMLL)
Chronic myeloid leukemias consitute %3
1-Ph-pozitive
2-Juvenile myelomonositic leukemia(JMML)
Leukemias (incidence)
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ALL: 3-4/100.000 cases white
children per year
AML: appr. 1/5-1/6 of ALL cases
Peak incidence between 2-5 y
%25-30 of all childhood cancers
Acute Leukemia
Etiology
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Environmental factors-ionizing radiation,
chemicals (benzene in AML)
Viral infections (EBV and Mature B cell
leukemia)
Drugs: alkylating agents+ XRT increases
the risk of AML
Acute Leukemia
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Etiology
Genetic considerations:
a-identical twins-if one twin develops
leukemia during the first 5 y of life the
risk in the second is %20
b-incidence of leukemia in a sibling of a
leukemia patient is X 4 general population
c-chromosomal abnormalities (trisomy 21,
bloom synd., fanconi anemia)
Acute Leukemia
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Etiology
Increased incidence with the following
genetically determined conditions:
a-congenital agamaglobulinemia
b-Shwachman-Diamond syndrome
c-Ataxia telengiectasia
d-Li-Fraumeni syndrome
e-NF
f-DB anemia
g-Kostmann disease
Acute Lymphoblastic Leukemia
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Epidemiology
Peak incidence at 4 years
More common in whites than blacks
Outcome white=black
Incidence higher among boys than girls
ALL rare in north Africa and middle east, NHL
more common
ALL more common in India and China but less
common than in western countries
Higher incidence of ALL in industrialized
countries
Acute Lymphoblastic Leukemia
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Clonal pathogenesis; ALL occurs as a
consequence of malignant transformation of a
single abnormal progenitor cell with a capacitiy
to expand by indefinite self-renewal
During normal development progenitor cells
are at higher risk for spontaneous mutation
There are two distinct genetic events in
leukemogenesis, one initiational, one
promotional
Acute Lymphoblastic Leukemia
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Molecular pathogenesis; single mutation or multiple
mutagenic events cause the induction of malignancy
Normal protooncogenes by changing their patterns
of expression or by direct mutation become
oncogenes which in turn cause malignancy
Tumor supressor genes by getting lost or by
mutation can lead to malignancy
Chromosomal translocations are the main
cytogenetic event, there are also deletions and
mutations in DNA
Acute Lymphoblastic Leukemia
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Molecular pathogenesis; p53, p16, p15, WT11,
TEL(12p12), KIP (12p13) are all tm supressor
genes
P53 is most frequenly found altered gene in
human cancers
Pediatric ALL can be associated with p53
mutations
Apoptosis (programmed cell death) is also
abnormal in pediatric ALL because of
mutations in the responsible gene
Acute Lymphoblastic Leukemia
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Evaluation of the patient;
Detailed Hx and PE
CBC, blood chemistries, coagulopathy secreen,
hepatitis screen, viral serologies, Tb skin test
BMA for light and EM, cytochemistry,
cytogenetics, flow cytometry, molecular
genetics
Gene rearrangement studies by PCR
CXR
ECHO
Acute Lymphoblastic Leukemia
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Evaluation of the patient;
LP
Cultures
Dental examination
Ophtalmic evaluation
Acute Lymphoblastic Leukemia
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Clinical manifestations;
Fever, malaise, anorexia, weakness, bleeding,
intractable infection. Onset may be insidious
PE shows pallor, petechiae, ecchymoses,
infection, HM, SM, LAP
Can imitate almost any disease: ARF, nephritis,
IMN, ITP, pertussis, aplastic anemia, etc
May present with consumptive coagulopathy
(esp. APL)
Renal involvement may cause hematuria,
hypertension, renal failure
Acute Lymphoblastic Leukemia
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Clinical manifestations;
Meningeal involvement may cause
headache, emesis, papilledema
Recurrent fever, frequent infections,
extremity pains may be confused with
other diseases
Acute Lymphoblastic Leukemia
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Laboratory findings;
Anemia, leukocytosis, leukopenia, neutropenia,
thrombocytopenia, blasts on PBS
Increased serum uric acid levels,
hyperpotasemia, hypercalcemia,
hyperphosphatemia
Increased LDH
Low serum Igs in 30%
aPT, aPTT may be prolonged
Serum chemistries may be abnormal
Acute Lymphoblastic Leukemia
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Prognostic factors;
Initial WBC count <50.000/mm3 good prognosis
Age (>1 y and <10y good prognosis, infants <1 y
worst prognosis)
Immunophenotype (early pre B cell best
prognosis, mature T cell worse, mature B cell
used to be bad)
DNA index>1.16, hyperdiploidy with >50 chr.
good pr. (incr. apoptosis, incr. sensitivity to
chemo.)
Acute Lymphoblastic Leukemia
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Prognostic factors;
Certain type of translocations in leukemic
blasts
Early response to chemotherapy (day 8 and 15
blast % in BM)
Day 8 blast count in PB
Residual leukemia during treatment (day 8 in PB
and day 29 in BM)(MRD)
CNS disease at diagnosis adverse prognostic
factor
Acute Lymphoblastic Leukemia
Proposed risk classification system of pre B cell ALL
Risk group
Features
Low (treated same as standard)
age 1-9
WBC<50.000
tel-AML or
trisomy 4,10
Standard
Age1-9, WBC<50.000
not tel-AML or
trisomy 4,10
High
age>10, WBC>50.000
CNS 3 or testic. dis
Very high
Ph+ leukemia,
< 45 chr., induction
failure
881% 50% of events
0.8
4 y EFS
0.6
685%
0.4
515%
0.2
P<
0.0001
Day 29 Negative (n=1579)
Day 29 0.01-0.1% (n=173)
Day 29 >0.1% (n=208)
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Event-free survival probability
1.0
Day 29 BM Flow MRD P9904/5/6
MRD >.01% is an optimal cutoff (n=1960)
0
1
2
3
Ye
4
5
6
0.8
922%, 16% of events
0.4
0.6
4 y EFS
P < 0.0001
0.2
1: MRD Negative (sensitivity = 0.01%) (n=603)
2: 0.01% < MRD ≤ 0.1% (n=341)
3: 0.1% < MRD ≤ 1.0% (n=501)
4: 1.0% < MRD ≤ 10.0% (n=373)
5: MRD > 10% (n=116)
0.0
Event-free survival probability
1.0
Day 8 Blood Flow MRD P9904/5/6
(n=1933)
0
1
2
3
Years
4
5
6
Significant Prognostic Factors Based on
COG Studies Multivariate Analysis
 Day 29 MRD (0.01% cutoff): HR=3.86
 NCI risk group: HR=2.1
 Trisomy 4/10 status: HR=0.485
 Day 8 PB MRD: HR=1.63
 TEL/AML1 status: HR=0.699
2009 B-Precursor Classification (n=1687/yr)
EFS
Patients
Low– NCI Std Risk Trisomy 4/10 or TEL; D8 blood &
D29 BM MRD < 0.01%
95+%
16%
Standard– Std Risk w/o or High Risk with Trisomy
4/10,TEL; D29 MRD < 0.01%
85-94%
41%
High– High Risk or Std Risk w/ CNS/testes; D29 <
0.01% or D29 positive if SR T4/10, TEL
70-85%
28%
Very High– Std or High Risk; D29 MRD > 0.01%
<70%
15%
Acute Lymphoblastic Leukemia
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Most common cytogenetic abnormalities:
11q23 poor prognosis, 80% of infant ALL, 85% of 20
leukemia)
t(4;11), 2%, MLL-AF4 fusion, CD10- B phenotype, infancy,
hyperleukocytosis, dismal outcome with CT
t(11;19) 5-6%, E2A-PBX1 fusion, pre B phenotype, poor
prognosis, intensive therapy is necessary
t(12;21), 25% of pre B cases excellent prognosis
t(9;22), 3-5%, BCR-ABL fusion, B lineage, older age,
hyperleukocytosis, dismal outcome with CT
t(8;14), 1-2%, MYC-IGH fusion, B phenotype, boys>girls, L3
morphology, bulky extramed. disease, favorable prognosis
Acute Lymphoblastic Leukemia
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Immunophenotype distribution
1-pre B cell 80%
2-mature B cell 1-2%
3-T cell 15-20%
-older age
-high initial WBC
-extramedullary disease
-improved prognosis on intensified protocols
Acute Lymphoblastic Leukemia
Prognostic significance of chr. abnormalities in ALL
Chromosomal abn.
5-y EFS
Hyperdiploidy
>50 chr.
47-50 chr.
Near triploid, 66-73 chr.
Near tetraploid, 82-94 chr.
Normal diploid, 46 chr.
Hypodiploidy,<46 chr.
Pseudodiploid
t(1;19)
t(4;11)
t(9;22)
80%(65-90%)
90%(50-98%)
Not known, good?
Not konown,<60%
80%(65-90)
71% (55-85%)
73% (55-85%)
53%
45%
14%
Acute Lymphoblastic Leukemia
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Leukemia or lymphoma?
Sometimes pts. present with massive HSM,
LAP and mediastinal mass (esp. T cell
leukemia)
How do we decide whether it is leukemia or
lymphoma?
Look at the blast % in BM, if greater than
%25 it is leukemia, otherwise lymphoma
Acute Lymphoblastic Leukemia
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CNS leukemia: (occurs<5% in ALL)
Signs and sypmtoms of raised IC pressure (morning
headaches, vomiting, pailledema, sixth nerve palsy)
Signs and sypmtoms of parenchymal involvement
(hemiparesis, cranial nerve palsies, convulsions, ataxia,
dysmetria etc.)
Hypothalamic syndrome (polyphagia with excessive
weight gain, hirsutism,
Diabetes insipidus (posterior pituitary inv.)
Chloromas of the spinal cord (back and leg pain,
numbness, weakness)
CNS hemorrhage (AML>ALL; leukocytosis,
thrombocytopenia)
Acute Lymphoblastic Leukemia
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Testicular leukemia:
Painless swelling in one or both testicles
Incidence of testicular relaps is 10-23% during
treatment; median time 13 months
Diagnose established by testicular Bx on both sides
10% of false negativity on Bx
High initial wbc (>20.000), T cell origin, mediastinal
mass, significant LAP and HSM; high chance of
testicular leukemia
Initial screening unnecessary at the time of
diagnosis unless suspected in PE
Acute Lymphoblastic Leukemia
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Treatment: phases
Remission induction
CNS preventive therapy
Consolidation
Interim maintenance I and II
Intensification I / II
Maintenance
Acute Lymphoblastic Leukemia
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Aims of therapy
1-to induce a clinical and hematologic
remission
2-to maintain remission by systemic
chemotherapy and prophylactic CNS
therapy
3-to treat the complications of therapy
and disease
Acute Lymphoblastic Leukemia
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Complete remission
No symptoms attributable to the disease (eg.
fever, bone pain)
No hepatosplenomegaly, lymphadenopathy, or
other clinical evidence of residual leukemic tissue
infiltration)
Normal PB findings
Less than 5% blasts in a normocellular BM
No CNS or extramedullary disease
Blasts fall from 1012 to 109
Acute Lymphoblastic Leukemia
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CNS preventive therapy:
High increased WBC count, T cell disease, very
young age, thrombocytopenia, LAP, HSM, black race
increase the risk of CNS leukemia
CNS, because of the blood-brain barrier, acts as a
sanctuary for blasts
Cranial XRT unnecessary for standard-risk pts
Cranial XRT indicated only for those who have CNS
leukemia and for those who are poor responders to
chemo
Acute Lymphoblastic Leukemia
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CNS preventive therapy:
XRT has long term adverse CNS sequela
Prophylaxis and treatment usually done with IT
MTX or TIT (MTX, ARA-C, Hydrocortisone)
IT MTX can cause arachnoiditis (Headaches,
N/V, meningitis) but self-limited
Encephalopathy, myelopathy, seizures
Acute Lymphoblastic Leukemia
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Duration of treatment:
2.5 to 3.5 years of Rx required for ALL in
most modern protocols
Duration of Rx longer for boys than for girls
Prognosis better if relaps occurs after Rx is
finished
Prognosis poor if relaps occurs during Rx
In mature B cell ALL, treatment is shorter
because there is rapid growth rate
Acute Lymphoblastic Leukemia
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Bone marrow transplantation:
Currently allogeneic BMT is routinely
advocated for pts in 2nd remission
Pts who suffer late relapses (longer than 30
mo after remission or after completing Rx) is
to be treated with chemo. BMT is reserved
for subsequent relapse
5-Year Survival Rates for Children (< 15 yrs)
Acute Lymphoblastic Leukemia: 1960 - 2004
100%
83%
80%
88%
71%
60%
40%
34%
20%
3%
0%
1960-63
1970-73
1981-83
1990-92
1996-2004
Acute Lymphoblastic Leukemia
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Supportive care:
R-thrombopoietin (not available everywhere)
RBC and platelet transfusions
Empiric use of broad spectrum of ab in F/N
pts
PCP prophylaxis with TMP/SMZ
VZIG within 72-96 hrs of exposure to VZV
Infusion of blood products
Better management of tm lysis syndrome
Acute Myeloid Leukemia
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15-20% of all childhood leukemia
Only 40-50% of newly diagnosed cases can be
expected to be cured
AML/ALL ratio is 1:4, except congenital leukemia
cases (in the first 4 weeks of life) which is mainly
AML
Incidence stable from birth to age 10 exept for a
peak in the neonatal period and a slight increase
during adolescence
Equally distributed among all ethnic groups
(significantly more in hispanics)
AML associated with orbital granulocytic sarcoma
(OGS) in Turkish children
Males=females
Acute Myeloid Leukemia
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Predisposing factors: Acquired factors;
XRT, benzene
EMF contraversial
Smoking and marijuana use during pregnancy,
increased AML in fetus
Rx with alkylating agents (Nitrogen Mustard,
Cyclophosphamide, Melphalan) increased AML
risk 4-5 years after Rx, deletion of chr. 5 and
7 common
Long exposure to VP-16, VM-26; AML shortly
after Rx, subtype M4-M5
Acute Myeloid Leukemia
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Predisposing factors: Genetic factors;
Identical twins-100% concordance
Fanconi’s anemia->50% by 40 yrs of age
Bloom syndrome
DB anemia
Kostmann syndrome-risk increases with age
Down syndrome; most common prognostic
factor -14 fold increase
NF-1-activation of RAS
Acute Myeloid Leukemia
Secondary AML can evolve from
1-MDS and MPS
2-ionizing radiation+chemotherapy
-nitrogen mustard
-CTX
-IFX
-chlorambucil
-melphalan
-VP-16
Acute Myeloid Leukemia
Classification:
 M1: AML without maturation (less than 10% PMN)
 M2: AML with maturation (more than 10% PMN)
 M3: Acute promyelocytic leukemia
 M4: Acute myelomonocytic leukemia
 M5a: Acute monoblastic leukemia
 M5b: Acute monocytic leukemia
 M6: Erythroleukemia
 M7: Megakaryoblastic leukemia
 M0: Acute undifferantiated leukemia
%20 or more blasts are required for the Dx of AML
FAB classification is being replaced by WHO
classification
WHO Classification of AML
1-With recurrent genetic abnormalities
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t(8;21)(q22;q22), (AML1/ETO)
Abnormal bone marrow eosinophilis and
inv(16)(p13q22) or t(16;16)(p13;q22),
(CBFβMYH11)
Acute promyelocytic leukemia
11q23 (MLL) abnormalities
Vardinman JW, et al. Blood 2002; 100:2292-2302
WHO Classification of AML
2-With multilineage dysplasia
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Following MDS
Without MDS, but with dysplasia in at least
50% cells in >2 myeloid lineages
3-Therapy-related
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Alkylating agent / radiation-related type
Topoisomerase II inhibitor-related type
Others
4-Not otherwise categorized
Potential Risk Factors
Prognostic Factor
Cytogenetics
Mutations of Signal
Transduction Pathways
Response to Therapy
High Risk
Deletion 5q
Monsomy 5 or 7
Favorable Risk
t(15;17)
inv (16)
t(8;21)
FLT3-ITD, high
ITD-AR
Poor response
to therapy
Meschinchi, Arceci. Oncologist. 2007;21:341-355
Rapid response
to therapy
Molecular Alterations
FLT3 Internal Tandem Duplication (ITD)
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Activating mutations in the gene result in
autonomous, cytokine-independent cell
proliferation
Age-dependent increase in prevalence
 12% of pediatric AML patients have FLT3-ITD
Strongly correlated with older age, higher initial
WBC counts, and poorer overall outcome
Ratio of ITD to wild-type allele (ITD-AR) greater
than 0.4 associated with high risk for relapse and
a survival rate <20%
Meshinchi S, et al. Blood. 2006;108(12):3654-3661; Golub TR, Arceci RJ. Acute Myelogenous Leukemia. In: Pizzo
PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 5th edition. Philadelphia, PA: Lippincott
Williams & Wilkins. 2006;591-644
Outcomes: Impact of Treatment Response
At 2 years
Overall
BM Day “28”
<20%
>20%
pEFS (%)
(95% CI)
28
(23-34)
38
(31-45)
2
(0-5)
pOS (%)
(95% CI)
39
(34-45)
49
(42-56)
14
(6-23)
• BM blasts day 28 ≥ 20% (RR 2.8, 95% CI 1.7-4.7, P <0.001)
*Day 28 bone marrows obtained between days 28 and 42 from start of the first
course. pEFS = probability of event free survival; pOS = probability of overall
survival
Kaspers GJ, et al. Blood. 2007;110. Abstract 1843.
Outcomes: Impact of MRD
Sievers EL, et al. Blood. 2003;101(9):3398-3406
Acute Myeloid Leukemia
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Mixed lineage leukemia:
6% of ALL cases demonstrate expression of 2 or
more myeloid antigen expression
17% of AML cases demonstrate 2 or more
lymphoid antigen expression
Rare cases have distinct populations of
lymhoblast and myeloblasts; biphenotypic
leukemia
Mixed-lineage expression does not affect
prognosis if treated with aggressive multiagent
Rx
Rx should be initially based on the predominat
cell population then followed by Rx for the
second lineage
Acute Myeloid Leukemia
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Most common cytogenetic abnormalities:
-5 or del5q 11-q35
-7 or del 7q22-q36 (myeloproliferative disorders,
JCML)
Trisomy 8 (20 AML)
t(8;21)
t(9;22)
t(15;17) presence establishes dx regardles of
BM blast count
inv (16)
t(16;16)
Acute Myeloid Leukemia
Clinical and LAB features:
 Same as ALL
 Leukemia cutis is often the 1st sign in infant leukemia
 DIC especially in M3
 ¼ have wbc greater than 100.000
 HM or SM in more than 50%
 Massive LAP less than 25% esp. in M4, M5
 Chloromas in bones and soft tissues or around the orbis;
more common in M4 or M5
 Testicular involvement relatively uncommon
 CNS leukemia in 5-15%
Acute Myeloid Leukemia
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Prognostic factors:
1-well accepted adverse factors
Wbc greater than 100.000
Secondary AML or prior MDS
Monosomy 7
FLIT3 ITD
MRD present after induction
2-possible adverse factors:
Splenomegaly
FAB M4 or M5
More than 1 course of CT for complete response
Age
M1 with auer rods
Acute Myeloid Leukemia
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Possible favorable factors:
t(8;21)
t(15;17)
survival 72%
t(9;11/M3 subtype)
Inv 16/M4eo
Intermediate karyotype-survival 43%
Unfavorable karyotype: monosomy 5, monosomy 7,
del(5q), and del(3q), other complex karyotypessurvival 17%
Acute Myeloid Leukemia
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Treatment:
Bleeding: keep plt level above 20.000
Empirical abs for F/N
Manage tumor lysis syndrome with hydration,
alkalinization, allopurinol
Manage leukostasis with leukophoresis or
exchange transfusion
CT: RI with DNM, ARA-C, Mitoxantrone, DXM, 6TG
Most recent protocols use double RI Rx
Acute Myeloid Leukemia
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Treatment:
15-20% fail to enter remission
Less than 10% die early from induction,
hemorrhage
Those who fail may be treated with other active
combination of drugs
After RI those who have suitable donors may go
to BMT, agressive postremission Rx is also
justified with ARA-C, L-Asp and sometimes with
IL-2
Acute Myeloid Leukemia
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Treatment of refractory or recurrent disease
Treatment is difficult
Induction may be attempted with HD Ara-C
and L-asp regimen or
ID Ara-C, mitoxantrone and etoposide regimen
The second one achieves a remission rate of
76%
AHSCT should be carried out once the
remission has been attained (30-50% long
term survival)
Prognosis of those who fail to enter remission
is very poor (10% 1 y DFS)
Thank you for
your attention