4. Part 1: Acute Myeloid Leukemia
1. Basic Science and Pathophysiology
2. Epidemiology and Risk Assessment
3. Diagnosis
4. Management and Treatment
5. Acute Myeloid Leukemia
1. Basic Science and Pathophysiology
2. Epidemiology and Risk Assessment
3. Diagnosis
4. Management and Treatment
6. Recurring Cytogenetic Lesions
• Correlate clinical characteristics with chromosomal
abnormalities in acute myeloid leukemia
• Understand the significance of rearrangements of the
ATRA receptor gene in M3 acute myeloid leukemia
• Recognize specific clinical syndromes associated with
t(8;21), inv(16), t(9;11), t(15;17), and monosomy 7 or
7q- in acute myeloid leukemia
• Know the molecular abnormalities with which specific
and recurring chromosomal abnormalities are
associated in acute nonlymphoblastic leukemia
7. Cytogenetic Molecular FAB Characteristics
t(8;21)
AML1-ETO
(RUNX1-
RUNX1T1)
M2
Auer Rods
Chloromas
Good px
t(15;17),
variants
PML-RARA
{variant}-RARA
M3
Granules/Auer rods
DIC/bleeding
Good px (with
ATRA/Arsenic)
inv(16)/
t(16;16)
CBFB-MYH11 M4Eo
Eos w/ baso granules
Chloromas
Good px
abnormal
11q23
MLL-{partner}
M4
M5
Infant
WBC/skin/CNS/gums
t-AML after topo II inh
“The Big 4”
8. t(15;17) and ATRA
• Understand the significance of rearrangements of the
ATRA receptor gene in M3 AML
myeloblast
promyelocyte metamyelocyte band neutrophil
myelocyte
promyelocyte
metamyelocyte band neutrophil
myelocyte
promyelocyte
normal
PML-RARα
PML-RARα
+ ATRA
• Production of abnormal RARα protein
• Repression of RARα target genes
• Blocked differentiation
• APL
ATRA-induced myeloid differentiation
10. Major Leukemia Predispositions
• Marrow failure syndromes – MDS, AML
• JMML-related conditions (NF1, Noonan)
• Down syndrome – ALL, TMD/AMKL
• Others
• Ataxia-telangiectasia (ALL, NHL) – ATM mutations; defective
DNA repair, immunodeficiency
• Bloom syndrome (broad) – BLM mutations; short stature, sun
rash, sister chromatid exchanges
• Li-Fraumeni syndrome (broad) – TP53 mutations
11. Marrow Failure and MDS/AML
Disorder Clinical features Molecular genetic features
Fanconi anemia
Characteristic congenital
abnormalities (skeletal,
renal, mental retardation),
progressive bone marrow
failure
Mutations in one of several
components of FA/BRCA multi-
protein complex involved in
homology-directed DNA repair,
resulting in chromosomal instability,
increased sensitivity to genotoxic
agents (mitomycin C,
diepoxybutane), cancer risk
Dyskeratosis
congenita
Abnormal skin
pigmentation, nail
dystrophy, leukoplakia,
progressive bone marrow
failure
Mutations in one of several
components of telomerase complex
mutations (DKC1 (XR), TERC (AD),
TINF2 (AD), others), resulting in
defective telomere maintenance
• Pancytopenia
12. Marrow Failure and MDS/AML
Disorder Clinical features Molecular genetic features
Diamond-Blackfan
anemia
Pure red cell aplasia,
characteristic congenital
abnormalities (facial,
skeletal, genitourinary)
Mutations in one of several
ribosomal protein genes
(RPS19, RPL5, others)
• Anemia
13. Marrow Failure and MDS/AML
Disorder Clinical features Molecular genetic features
Schwachman-
Diamond syndrome
Neutropenia, exocrine
pancreatic insufficiency,
skeletal abnormalities
SBDS mutations, affecting rRNA
processing and 40S subunit
biogenesis
Severe congenital
neutropenia
(Kostmann
syndrome)
Severe congenital
neutropenia
Mutations in ELA2 (elastase) most
common, others include GFI1 and
HAX1; result in agranulocytosis;
secondary activating mutations of G-
CSF receptor often responsible for
progression to AML
• Neutropenia
14. Marrow Failure and MDS/AML
Disorder Clinical features Molecular genetic features
Congential
amegakaryocytic
thrombocytopenia
Congenital
thrombocytopenia,
progressive bone marrow
failure
MPL (thrombopoietin receptor)
mutations
Familial platelet
disorder with
predisposition to AML
Qualitative and quantitative
platelet defects
AML1(myeloid transcription factor)
mutations
• Thrombocytopenia
15. t-AML
• Know the characteristic chromosomal abnormalities
and clinical characteristics in secondary acute myeloid
leukemia resulting from topoisomerase II inhibitors and
from alkylators, respectively
16. t-AML
• Alkylating agents and radiation
• Long latency (5 -7 year) from exposure, common preceding
MDS
• Cytogenetics: -7, del(7q), -5, del(5q); complex cytogenetics
• Topoisomerase II inhibitors (etoposide > anthracyclines)
• Short latency (1-2 years) from exposure, rare preceding MDS
• Cytogenetics: 11q23 rearrangements most common, but
t(8;21), t(15;17), t(9;22) and inv(16) can also occur
• Regardless of age at presentation or etiology, t-MDS/t-
AML tends to be more refractory to therapy than de novo
MDS or AML
17. Acute Myeloid Leukemia
1. Basic Science and Pathophysiology
2. Epidemiology and Risk Assessment
3. Diagnosis
4. Management and Treatment
18. Epidemiology
• Know the incidence of ALL, AML and CML, and
the peak age at which each of these occur
19. 0
10
20
30
40
50
60
70
80
90
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
ALL
AML
Age
Rate
per
million
0
10
20
30
40
50
60
70
80
90
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
ALL
AML
Age
Rate
per
million
CML
Epidemiology
20. 0
10
20
30
40
50
60
70
80
90
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
ALL
AML
Age
Rate
per
million
0
10
20
30
40
50
60
70
80
90
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
ALL
AML
Age
Rate
per
million
0
50
100
150
200
0 25 50 75 100
ALL
AML
CML
Age Rate per
million
< 2 0
2-14 1
15-19 2
20-24 4
25-34 8
-- --
80-84 80
CML
Epidemiology
22. Monozygotic twins
• Index case < 1 yo
• Very high (close to 100%) concordance with short latency
(weeks)
• Prenatal preleukemic event (MLL-r, e.g), intrauterine transfer
• MLL-r promotes rapid development of cooperating “hits”
• Index case 1-6 yo
• ~10-20% concordance (most clonal), longer latency
• Prenatal preleukemic event (TEL-AML1, AML1-ETO, e.g),
intrauterine transfer
• Compared to MLL-r, relatively low risk of cooperating “hits”
• Index case > 6 yo
• Minimal increased risk
• No prenatal preleukemic event
23. Prognostic Factors &
Risk Stratification
• Know prognosis of various sub-types of acute myeloid
leukemia
• Know the prognostic significance of the non-random
cytogenetic abnormalities in acute myeloid leukemia
• Know the prognostic importance of Down syndrome in
acute nonlymphoblastic leukemia
Risk Stratification is the prospective use of
prognostic factors to assign patients to specific
treatments. Only a subset of prognostic factors
are used in risk stratification
24. Prognostic Factors not used
• Host characteristics
• Age and sex: not independent on most recent studies
• Race: non-whites - inferior survival
• BMI: under- or over-weight - inferior survival
• Pharmacogenomics
• Disease characteristics
• High WBC – no longer used, except in APL (> 10K is high risk –
use anthracycline immediately)
• FAB – supplanted by cyto/molecular
25. Recent Risk Stratification
• Favorable
• Down syndrome-related (esp. if < 4 y.o.)
• APL with t(15;17) or variant
• Cytogenetics: inv(16), t(8;21)
• Molecular: NPM1, CEBPA
• Unfavorable
• t-AML, MDS-related AML
• Cytogenetics: -7, 5q-, abn(3q)
• Molecular: FLT3/ITD (high allelic ratio)
• Primary induction failure (>5% blasts after course 2)
• Intermediate: everything else
Separate protocols
26. Update: incorporation of MRD
• Intermediate Risk
• Sub-classified into favorable or unfavorable according to
end-course 1 flow cytometric MRD
• centralized laboratory, using +/- threshold of 0.1%
• Grouped with “traditional” favorable/unfavorable groups
Republished with permission of Blood: Journal of the American Society of Hematology, from
Residual disease detected by multidimensional flow cytometry signifies high relapse risk in
patients with de novo acute myeloid leukemia: a report from Children's Oncology Group,
Loken, et all, 120, 8, 2012; permission conveyed through Copyright Clearance Center, Inc.
27. Current Risk Stratification
• Favorable (Low Risk, LR)
• Down syndrome-related (esp. if < 4 y.o.)
• APL with t(15;17) or variant
• Cytogenetics: inv(16), t(8;21)
• Molecular: NPM1, CEBPA
• Intermediate with end course 1 MRD negative
• Unfavorable (High Risk, HR)
• t-AML, MDS-related AML
• Cytogenetics: -7, 5q-, abn(3q)
• Molecular: FLT3/ITD (high allelic ratio)
• Primary induction failure (>5% blasts after course 2)
• Intermediate with end course 1 MRD positive
Separate protocols
28. Acute Myeloid Leukemia
1. Basic Science and Pathophysiology
2. Epidemiology and Risk Assessment
3. Diagnosis
4. Management and Treatment
29. Classification
• Know the FAB (old) and WHO (new)
classifications of AML
• Know the characteristic clinical presentations of
AML, and associate these with specific AML
subtypes
DIC/bleeding
Hyperleukocytosis
CNS leukemia
Leukemia cutis
Chloromas
30. FAB: morph/phenotype; 30% blasts
AML Subtype Comments
M0 AML without differentiation Difficult to distinguish from ALL; diagnosis requires expression of
surface markers such as CD13, CD33 and CD117 (c -kit) in the
absence of lymphoid differentiation
M1 AML with minimal differentiation Myeloperoxidase detectable by special stains/flow cytom etry
M2 AML with differentiation Auer rods; common t(8;21) -> AML1-ETO fusion, good prognosis ,
chloromas
M3 Acute promyelocytic leukemia
(APL), hypergranular type
Auer rods; DIC/bleeding;; t(15;17) -> PML-RARa fusion, good
prognosis with ATRA therapy
M3v APL, microgranular variant Cytoplasm of promyelocytes demonstrates a fine granularity, and
nuclei are often folded. Same clinical, cytogenetic and therapeutic
implications as FAB M3.
M4 Acute myelomonocytic leukemia
(AMML)
Mixture of myeloblasts (at le ast 20%) and monocytic blasts; often
with peripheral monocytosis
M4Eo AMML with eosinophilia AMML with >5% abnormal eosinophil precursors in marrow (with
basophilic granules), common inv(16), good prognosis
M5 Acute monocytic leukemia >80% of bone marrow non-erythroid cells are monocytic; M5a:
monoblastic; M5b: monocytic (more differentiated); for both M4
and M5: infant age, MLL 11q23 rearrangements, CNS involvement,
chloromas, gingival hyperplasia
M6 Acute erythroblastic leukemia Rare in children
M7 Acute megakaryoblastic leukemia Seen mostly in children with Down syndrome (good prognosis if < 2
years old; GATA1 mutations ) or mosaicism for trisomy 21; rare in
normal children (poor prognosis , t(1;22) -> OTT-MAL fusion, often
infants); myelofibrosis commo n
31. WHO: clinical/molecular; 20% blasts
• Is the AML due to prior XRT/chemo?
• If yes: Dx is Therapy-related AML (t-AML)
• Is the AML in a child with Down syndrome?
• If yes: Dx is DS-related AML
• Is major (“Big 4”) recurring abnormality present?
• If yes: Dx is AML w/ t(8;21); inv(16); t(15;17); MLL-r
• NOTE: No minimum blast % needed
• Is there dysplasia, prior MDS and/or MDS-related
mutation (-7, del(5q), etc.)?
• If yes, Dx is AML with MDS-related changes
• If no to all: Dx is AML, NOS - use FAB to subclassify
32. Immunophenotype
• Know the immunophenotypic differences between
acute lymphoid and acute myeloid leukemia
• Know how to identify lymphoid/myeloid mixed lineage
acute lymphoblastic leukemia and biphenotypic
leukemia (by immunophenotyping)
34. Acute Leukemia of Ambiguous Lineage
• Acute Undifferentiated Leukemia (AUL)
• Express no lineage-specific markers
• Mixed Phenotype Acute Leukemia (MPAL)
• Distinct populations of blasts of different lineages; and/or
single population of blasts co-expressing antigens of multiple
lineages
• Often MLL-rearranged
• T/myeloid, B/myeloid most common
35. Acute Myeloid Leukemia
1. Basic Science and Pathophysiology
2. Epidemiology and Risk Assessment
3. Diagnosis
4. Management and Treatment
36. Therapy
• Know which drug combinations are most effective in the
treatment of acute myeloid leukemia
• Know that high-dose cytarabine is effective in the treatment of
acute myeloid leukemia
• Know the role of CNS prophylaxis in the treatment of acute
myeloid leukemia
• Know the evidence against the use of extended maintenance
therapy for AML
• Know the indications for allogeneic HSCT in AML
• Know the various components of prophylactic and acute
supportive care for children with acute myeloid leukemia
receiving treatment
37. Current Standard Therapy
Remission induction
• 2 courses of intense chemotherapy (Ara-C, Doxo, Etoposide); high risk
of invasive infection; CR rate ~ 75-80%
• Current protocol “switches” 2nd induction course to mitoxantrone/ HD
Ara-C for HR patients
Post-remission consolidation
• BMT
• All HR with best donor (matched sib preferred, MUD/UCB donors acceptable)
• No LR (even with matched sib)
• Additional chemo “intensification” courses (2)
• HR w/o any donor, and all LR
• Usually HD Ara-C combined with drugs not used in induction (mitoxantrone, L-
asp, e.g.)
38. Current Standard Therapy
CNS Prophylaxis
• Much less intense than in ALL due to low rates of CNS relapse
with standard therapy
• For CNS+ at diagnosis, weekly IT Ara-C until CSF clears, then
once per course; no cranial XRT
Maintenance
• Unlike ALL, there is no role for extended maintenance (a survival
benefit has never been demonstrated)
39. Current Standard Therapy
Supportive care
• Admission during periods of neutropenia recommended, due to
significant risk of life-threatening infections
• Most infections are episodes of bacteremia and sepsis
• Strep. Viridans
• Gram negative enterics (E. coli, Klebsiella, Pseudomonas, etc.)
• Aggressive empiric treatment with broad spectrum antibiotics to
cover these organisms is standard
• Bacterial prophylaxis is controversial and not considered standard
due to concerns re: antibiotic resistance
• Fungal and pneumocystis prophylaxis are commonly used
• G-CSF and other growth factors are not commonly used due to
concerns re: promoting leukemia cell growth/survival
40. Clinical aspects of APL
• High risk of life-threatening bleeds (~10% mortality) due to
DIC/fibrinolysis + low plts
• Basics: close monitoring of PT, aPTT, fibrinogen, D-dimer, plts with liberal use
of products: plts, cryo, FFP
• Start ATRA immediately with suspected APL: rapidly improves coag
parameters and reduces bleeding risk
• Other interventions controversial (heparin, amicar, rVIIa, …)
• Differentiation syndrome
• Fever, edema, pulm infiltrates, hypoxia, resp distress, hypotension,
renal/hepatic dysfunction, effusions, rash
• Risk correlates with high WBC; can occur in absence of ATRA
• Rx: Prompt recognition and use of dexamethasone, hold ATRA until resolving
• Arsenic Trioxide
• Increasingly incorporated into consolidation for APL in effort to reduce
cumulative anthracycline exposure - recent data suggests that “low risk” APL
(<10k WBC) is curable with ATRA and Arsenic only!
41. MDS vs. AML
• Know the relationship between myelodysplastic
syndromes and acute myeloid leukemia
• In children (unlike adults), the vast majority of AML cases are
“de novo” (i.e., not preceded by MDS)
• MDS in children commonly arises in setting of underlying
constitutional disorder (DS, marrow failure syndrome, etc.)
• MDS in children has similar implications as in adults
• Eventual progression to AML is the general rule; pace of
progression is variable
• Generally requires HSCT for cure
• Questionable role for pre-HSCT chemotherapy
42. Hyperleukocytosis
• Recognize the potential complications of
hyperleukocytosis in acute myeloid leukemia
• Plan the management of hyperleukocytosis in acute
myeloid leukemia
43. Hyperleukocytosis
• Risk factors: Elevated WBC (>100K); AML>ALL
• Etiology: Sludging of viscous blood in brain, lungs,
kidneys, other organs
• Features:
• Management
• Treat leukemia ASAP
• Exchange transfusion or leukopheresis if symptomatic
Organ system Clinical Manifestation(s)
CNS
Decreased level of consciousness, stroke,
intracranial bleeding
Respiratory Hypoxia, respiratory distress, diffuse infiltrates
Renal
Renal insufficiency (multifactorial, exacerbated
by renal infiltration, tumor lysis syndrome)
44. Late Effects in AML
• After chemotherapy only
• Anthracyclines: cumulative exposure ~ 450 mg/m2
doxorubicin equivalents – cardiotoxicity
• Etoposide: t-MDS/AML
• High dose Ara-C: neurotoxicity
• After HSCT
• Above, plus HSCT-related risks
Recognize the late complications of therapy for AML
45. Radiation in AML
• Generally limited to emergent treatment of life-
threatening complications of chloromas (e.g., spinal
cord compression)
• TBI is not a typical component of HSCT prep regimens
for AML
• Cranial XRT is generally not required to control CNS
disease in AML
Know the indications for radiotherapy in AML
46. Part 2: Chronic Myeloid Leukemia
1. Basic Science and Pathophysiology
2. Epidemiology and Risk Assessment
3. Diagnosis
4. Management and Treatment
47. Chronic Myeloid Leukemia
1. Basic Science and Pathophysiology
2. Epidemiology and Risk Assessment
3. Diagnosis
4. Management and Treatment
48. CML: Biology
• Know the clinical, laboratory, and prognostic features of CML
• Recognize the hematologic changes associated with a blast crisis
in chronic myeloid leukemia
• Know that a blast crisis in chronic myeloid leukemia can involve
other cell lines
• Know the association of BCR-ABL1 oncogene with chronic
myeloid leukemia
• Know the clinical, laboratory and molecular characteristics that
differentiate Ph+ chronic myeloid leukemia from Ph+ acute
lymphocytic leukemia
51. Chronic Myeloid Leukemia
1. Basic Science and Pathophysiology
2. Epidemiology and Risk Assessment
3. Diagnosis
4. Management and Treatment
52. CML: Clinical Features
• Most pts diagnosed in Chronic Phase (CP)
• 20-40% asx, dx’d due to abnl CBC (incidental findings of
leukocytosis with left shift, +/- anemia, +/- thrombocytosis,
basophilia, +/- eosinophilia)
• Sx: abd pain, dysphagia, inc abd girth (all from splenomegaly),
fatigue, wt loss, night sweats, bleeding, (rarely)
leukostasis/priapism(?)
• Natural history: progression (widely variable latency)
• Accelerated phase (AP): decreased response to treatment, clonal evolution,
inc blasts (<20%), inc basophilia
• Blast crisis (BC): acute leukemia (2/3 AML, 1/3 ALL)
Distinguishing CML-CP or CML-AP from Ph+ ALL is simple due to
obvious differences in CBC and PB smear; CML presenting with
lymphoid BC vs. Ph+ ALL is a more challenging distinction –
molecular studies are crucial.
53. CML: Diagnosis
• Demonstration of p210 BCR-ABL1 fusion (PCR) in
blood in proper clinical context is likely sufficient
• Marrow typically included to definitively rule out
accelerated phase and improve karyotyping
Republished with permission of Blood: Journal of the American Society of Hematology, from Clinical
Significance of Cytogenetic Abnormalities in Adult Acute Lymphoblastic Leukemia, Faderl, et al, 91, 11, 1998;
permission conveyed through Copyright Clearance Center, Inc.
54. Chronic Myeloid Leukemia
1. Basic Science and Pathophysiology
2. Epidemiology and Risk Assessment
3. Diagnosis
4. Management and Treatment
55. CML: Treatment
• Know the principles of using targeted therapy (such as
imatinib) in patients with chronic myeloid leukemia
• Plan the treatment of a blast crisis in a patient with chronic
myeloid leukemia
• Know the indications for and timing of HSCT in a patient with
chronic myeloid leukemia
• Know the therapeutic options for a patient who has a
recurrence of chronic myeloid leukemia after HSCT
56. CML: Impact of Tyrosine Kinase Inhibitors
• Pre-TKI Era
• The only curative long term curative therapy is allogeneic stem cell
transplant, so essentially all children receive HSCT with best available
donor
• Hydroxyurea and interferon used to control disease prior to SCT
• Post-TKI Era
• Begin TKI, continue indefinitely
• Consider HSCT in chronic phase only for patients with HLA-matched
family donor (even then controversial)
• For recurrent or refractory chronic phase, try higher dose TKI and/or
new TKI first (guided by mutation analysis), then HSCT for treatment
failure
• For accelerated phase or blast crisis, attempt to induce remission with
chemotherapy (AML or ALL, depending on blast phenotype) + TKI, and
then take to HSCT
57. CML: Treatment of CML-CP
• ABL tyrosine kinase inhibitors (TKI)
• Imatinib
• Kids: 340 mg/m2 qd (600 mg max)
• Adol/adult: 400 mg qd (may increase to 600 mg and 800 mg as needed for response)
• Dasatinib (100 mg qd)
• Nilotinib (400 mg bid)
• *Ponatinib (45 mg qd) – active against T315I mutant
• HSCT – controversial
• HSCT remains the only proven cure for CML – TKI’s achieve sustained disease
control, but recurrence likely upon discontinuation
• Major prognostic factor for HSCT: disease phase (CP>AP>BC)
• CML is very sensitive to graft vs. leukemia (GVL) effect – relapses post-HSCT can be
effectively treated with donor lymphocyte infusions (DLI), especially if no GVH
with first HSCT
• When HSCT is used, TKI “maintenance” is typically added post-engraftment in
effort to prevent relapse
More rapid and sustained
cytogenetic/molecular responses
58. CML: Response
• There are three principal strategies to assess response
– Hematologic response (HR; determined with PB and exam)
• Complete (CHR): normal counts, no HSM
– Cytogenetic response (CyR; determined with BCR-ABL FISH on BMA)
• Complete (CCyR): no Ph+
• Partial (PCyR): major <= 35%; minor 36-95%
– Molecular response (MR; determined with BCR-ABL qPCR on PB)
• Complete (CMR): PCR neg
• Major (MMR): BCR-ABL:ABL ratio <0.1% (international scale), or 3 log
reduction in copy#
• Most recent guidelines
– BMA for response not needed if validated qPCR testing available
– Every 3 month testing until MMR, then every 3-6 months
59. CML: Response
Timepoint Suboptimal Failure
3 mo No PCyR (major) and/or
BCR-ABL1 qPCR >10%
No CHR and/or
no PCyR (minor)
6 mo No CCyR and/or
BCR-ABL qPCR >1%
No PCyR (major)
and/or
BCR-ABL1 qPCR >10%
12 mo No MMR (qPCR > 0.1%) No CCyR and/or
BCR-ABL qPCR >1%
18 mo - No MMR (qPCR > 0.1%)
60. CML: Response
• Response to TKI treatment is the most important prognostic
factor in CML
• Patients with a rapid and sustained response to TKI have an
excellent outcome
• TKI resistance
• Primary – treatment failure or suboptimal response with TKI
• Secondary - loss of response (rising qPCR, recurrence of FISH+,
development of CML-AP, etc.)
• Both types are most commonly caused by acquired mutations in ATP-
binding pocket of ABL – T315I mutations have been most problematic,
since they are also resistant to 2nd and 3rd line TKI’s – recently approved
ponatinib has T315I activity
• TKI-resistant patients generally require HSCT for cure
