3. Overview of the myeloid malignancies
• The most up-to-date classfication is the 2008
WHO CLASSIFICATION
• The FAB Classification of AML (“M0” to “M7”),
although still used is out-dated and does not
take into new molecular understanding of
AML.
4. Overview of the myeloid malignancies
MYELOPROLIFERATIVE
NEOPLASMS
MYELODYSPLASTIC
SYNDROME
ACUTE MYELOID
LEUKEMIA
ALL ARE CLONAL DISORDERS OF HEMATOPOIESIS
•Increased mature-appearing
Cells
•Less fulminant clinical course
than AML in many instances
(chronic)
•Variable risk of transformation
To AML
•Decreased circulating
Peripheral blood cells
•Abnormal differentiation of
Blood cells in marrow
•Less fulminant clinical course
than AML in many instances
(chronic)
•Variable risk of transformation
To AML
•Decreased circulating mature
Peripheral blood cells
•Presence of immature cells
In BM and/or periphery
•Fulminant clinical course,
Almost invariably lethal without
Therapy.
5. 2008 WHO classification of myeloid malignancies
• Myeloproliferative neoplasms
• Myeloid/lymphoid neoplasms associated with
eosinophilia and abnormalities of PDGFRA,
PDGFRB, or FGFR1
• Myelodysplastic/Myeloproliferative
neoplasms
• Myelodysplastic Syndrome (MDS)
• Acute myeloid leukemia
6. Acute myeloid leukemia
• DIAGNOSIS: ANY ONE OF THESE 3 THINGS
– > 20% blasts in the bone marrow OR peripheral
blood OR
– Cytogenetic alteration diagnostic of AML:
t(15;17), t(8;21), inv(16), t(16;16)
– Accumulation of blasts in an extramedullary site
(choloroma, myeloid sarcoma, granulocytic
sarcoma)
7. Acute myeloid leukemia
The best current guideline on how to diagnose, classify (based on 2008 WHO),
And treat AML in adults.
8. Types of AML
• Former, out of date, classification: FAB CLASS
M3 AML = ACUTE PROMYELOCYTIC LEUKEMIA (APL)
A specific subtype of AML, genetically and clinically
Distinct from any other myeloid malignancy.
A medical emergency; VERY CURABLE!!
Highest mortality is in initial Dx due to DIC.
Except for M3AML the
FAB Subtype of AML
Does not inform prognosis
or management!!
Risk of death from DIC reduced massively with ATRA.
9. CASE:
• A 54-year-old man presents with gingival
hypertrophy and bleeding.
• At presentation his WBC is 39 000/L
• the hemoglobin is 7.9 g/dL, and the platelet
count is 6000/L.
10. M3 AML
Majority of patients:
t(15;17)
PML-RARa translocation
Responsive to ATRA.
-Check Smear and DIC labs (PT, PTT,
Fibrinogen, D-dimer) whenever AML
Is suspected
-Start ATRA asap. Oral medication,
Minimal side-effects in short-term
Administration of a few days.
Current standard of care:
ATRA + Cytotoxic chemotherapy
Arsenic Trioxide consolidation
ATRA maintenance
Very high rate of cure
11. M6 AML
M6 AML
-acute leukemia of eryrthroid
Precursors
-”Di Guglielmo” disease for
Person who first described it
12. M7 AML
M7 AML
-acute leukemia of
Megakaryocyte lineage
~1-3% of adult AML cases
-often accompanied by
Fibrosis in BM
-poor px histologic subtype
-more common in children
-Some important associations:
1/3 patients with M7 AML
Have Down Syndrome
Another 1/3 have a
t(1;22)(p13;q13) translocation
The last 1/3 have a novel
Fusion not even published
Yet.
13. CASE CONT’D:
• A 54-year-old man presents with gingival
hypertrophy and bleeding.
• At presentation his WBC is 39 000/L
• the hemoglobin is 7.9 g/dL, and the platelet
count is 6000/L.
• SMEAR: 60% blasts. BMA/Bx confirms >20%
blasts. Appear of monocytic lineage (M5)
15. CASE CONT’D:
• A 54-year-old man presents with gingival hypertrophy
and bleeding.
• At presentation his WBC is 39 000/L
• the hemoglobin is 7.9 g/dL, and the platelet count is
6000/L.
• SMEAR: 60% blasts. BMA/Bx confirms >20% blasts.
Appear of monocytic lineage (M5)
• Flow confirms myeloid lineage AML, monocytic lineage
• Cytogenetics and FISH reveal normal karyotype
• Additional molecular analysis reveals presence of FLT3
ITD
16. 2008 WHO CLASSIFICATION OF AML
• AML with recurrent genetic abnormalities
• AML with myelodysplasia-related changes
• Therapy-related myeloid neoplasms (t-MDS or
t-AML)
• AML not otherwise specified
• Myeloid sarcoma (granulocytic sarcoma,
chloroma)
17. 2008 WHO CLASSIFICATION OF AML
• AML with recurrent genetic abnormalities
–
–
–
–
–
–
–
–
–
T(8;21)
Inv(16)
T(16;16)
T(15;17)
T(9;11)
T(6;9)
Inv(3)
t(1;22)
AML with mutated NPM1 or mutated CEBPA
18. Genetic abnormalities in AML
• Why do we care?
– Risk stratification of patients (good, intermediate,
adverse risk)
– Clinical management of AML
19. Pre-2012 Risk Stratification of AML
CYTOGENETICS
FAVORABLE
MOLECULAR GENETICS
Mutated CEBPA
t(9;11)
Mutated FLT3 ITD (+/NPM1 mutation)
tri(8)
ADVERSE
Mutated NPM1 without
FLT3-ITD
Inv16 or t(16;16)
INTERMEDIATE
t(8;21)(q22;q22)
No NPM1, CEBPA, FLT3ITD
mutations
Inv(3)
t(6;9)
t(v;11)
-5 or del(5q); -7; abn(17p);
>3 abnormalities
Schlenk RF, et al. N Engl J Med 2008;358:190918.
21. Management of AML: 2012
(1) Clinical trial if at all possible!!
(2) No clinical trial:
Induction chemotherapy:
“7+3” chemotherapy
Daunorubicin (3d) + Cytarabine (cont IV infusion x 7d)
--If <60 give 90mg/m2 DNR dose, proven survival benefit
Consolidation chemotherapy:
4-6 cycles of high-dose cytarabine
Possible post-consolidation therapy:
If intermediate risk or adverse risk allogeneic transplant
23. Challenges in AML mgmt
(1) Few established therapeutic options for
induction
(2) No established options for RELAPSED or
REFRACTORY AML
(3) Role of allogeneic transplant not totally clear
(4) Few studies on consolidation chemotherapy
(other agents, # of cycles needed)
(5) Challenge in clinical trials of newer targeted
agents
24. CASE CONT’D:
• A 54-year-old man presents with gingival hypertrophy
and bleeding.
• At presentation his WBC is 39 000/L
• the hemoglobin is 7.9 g/dL, and the platelet count is
6000/L.
• SMEAR: 60% blasts. BMA/Bx confirms >20% blasts.
Appear of monocytic lineage (M5)
• Flow confirms myeloid lineage AML, monocytic lineage
• Cytogenetics and FISH reveal normal karyotype
• Additional molecular analysis reveals presence of FLT3
ITD
27. Overview of the myeloid malignancies
MYELOPROLIFERATIVE
NEOPLASMS
MYELODYSPLASTIC
SYNDROME
ACUTE MYELOID
LEUKEMIA
ALL ARE CLONAL DISORDERS OF HEMATOPOIESIS
•Increased mature-appearing
Cells
•Less fulminant clinical course
than AML in many instances
(chronic)
•Variable risk of transformation
To AML
•Decreased circulating
Peripheral blood cells
•Abnormal differentiation of
Blood cells in marrow
•Less fulminant clinical course
than AML in many instances
(chronic)
•Variable risk of transformation
To AML
•Decreased circulating mature
Peripheral blood cells
•Presence of immature cells
In BM and/or periphery
•Fulminant clinical course,
Almost invariably lethal without
Therapy.
30. Case #2:
• A 68yo M presents for routine physical exam.
Routine CBC reveals WBC of 25,000, Hb of 12
and Plt of 600,000.
• Prior CBC 1 year prior was normal.
31. Case #2:
• A 68yo M presents for routine physical exam.
Routine CBC reveals WBC of 25,000, Hb of 12
and Plt of 600,000.
• Prior CBC 1 year prior was normal.
W/U:
-Differential
-Iron studies (ferriting, Fe, TIBC)
-Smear
-BMA/Bx for review, FISH/cytogenetics,
BCR-ABL translocation testing by qRTPCR,
and JAK2V617F mutation (possibly also MPL
Mutation)
32. CML
• Pre-TKI’s
Chronic phase Accelerated phase
Survival
Blast phase
8+ years
<1.5 years
< 6 months
High or
normal
High or low
Decreased
>20
-
-
<10%
>10%
>30%
Basophils
Platelets
WBC count
Blasts
QUESTIONS NOW
1) Which TKI to start first? Imatinib, Dasatinib, Nilotinib
2) Can you ever stop the TKI?
3) Do the “T315I” drugs work?
35. PV
Median age @ Dx: 70yo
Compared to age- and sex-matched
controls total mortality is
1.2 higher in PV.
45% of deaths were due to
cardiovascular disease.
GRADE A Treatment Recommendation
Aspirin 75 - 100 mg/day
Grade B recommendation
Phlebotomy to maintain the Hct to <0.45
Cytoreduction should be given to:
-All patients with platelets > 1.5 million
IFN or Hydroxyurea
-leukocyte count > 15 x109/L
36. ET
It is unclear if ET shortens
Life expectancy on
average.
Studies which found a shorter life
expectancy:
Fenaux et al: 73.5% survival 7
years after diagnosis
Jensen et al: 76% survival
at 5 years
REACTIVE THROMBOCYTOSIS CAUSES:
iron deficiency, splenectomy, surgery,
infection, inflammation, connective tissue
disease, metastatic cancer, and
lymphoproliferative disorders
37. Management of ET
Grade A recommendation
• Platelet lowering therapy should be given to;
- all patients over 60 years of age
- all patients with earlier thromboembolic complications
-all patients with platelets >1.5million
• Aspirin 75-100 mg daily to all ET patients except when platelets are >1500 x 109/L, in
patients with bleeding symptoms or in patients with other contraindications to aspirin.
• The goal of platelet lowering therapy should be platelets < 400 x 109/L
(Grade B recommendation)
Choice of cytoreductive therapy in ET:
• Hydroxyurea is the best documented therapy in ET
• However, due to the concern of possible increased risk of leukemia transformation with
long-term use it is not recommended as 1st line therapy in younger patients
• <60 years: 1st line interferon-α or anagrelide, 3rd line Hydroxyurea
• >75 years: 1st line Hydroxyurea, 2nd line consider combination therapy (HU-Ana, HU-IFN),
42. Questions now in MPN’s
1) Do JAK inhibitors change the natural history of PMF?
2) Should we use combination strategies of JAKi + something else?
3) Many newer JAK inhibitors coming are they better than ruxolitinib? (JAK2 specific,
JAK1 specific, JAK2V617F specific)
4) What is the genetic abnormality present in the 50% of ET and PMF without
JAK2 or MPL mutations?
5) Are JAK2 mutations really driving the disease?
43. Myelodysplastic Syndrome
MDS with low blast % can be very difficult to diagnose and the true incidence of
MDS is likely not known.
Definition: >10% of the cells >1 myeloid BM lineage (erythroid, granulocytic, megakaryocytic
must show morphologic dysplasia.
Also, in setting of persistent cytopenia, if the patient has one of the following cytogenetic
Abnormalities, MDS may be diagnosed:
44. Case #3
78y F presents with CC of slight increase in DOE over last few months. She has a
h/o HTN and type II DM. Physical exam is unrevealing. CBC reveals Hb 8.2g/dL,
WBC 1.8, and Plt 170,000.
45. What is dysplasia?
Some common morphologic features characteristic of MDS:
-hypolobated neutrophils in peripheral blood
-increased reticulocytes in peripheral blood
-abnormal contours of erythroid precursors in bone marrow
-micromegakaryocytes in bone marrow
-increased RBC precursors with rings of iron around the nuclei
(ringed sideroblasts)
-Also MDS usually characterized by a hypercellular bone marrow
(but not always)
46. 2008 WHO CLASSIFICATION OF MDS
Disease
Blood findings
BM findings
Refractory cytopenia with
unilineage dysplasia
1-2 cytopenias
>10% of the cells in one myeloid
lineage dysplasia;
<5% blasts
<15% RBC prec with ringed
sideroblasts
Refractory anemia with
ringed sideroblasts (RARS)
Anemia
>15% ringed sideroblasts
Erythroid dysplasia only
<5% blasts
Refractory cytopenia with
multilineage dysplasia
(RCMD)
Cytopenias
Dysplasia, <5% blasts
Refractory anemia with
excess blasts 1 (RAEB-1)
Cytopenias
5-9% blasts
Refractory anemia with
excess blasts 2 (RAEB-2)
Cytopenias
10-19% blasts
MDS with isolated del 5q
Anemia with normal to
High plt count
Isolated deletion 5q
47. Assessing risk in MDS
MDS CLASSIFICATION SCORING SYSTEM
IPSS
R-IPSS
WHO PSS (takes into account WHO category of MDS)
MDACC MDS Scoring System (takes into account peformance status)
Newer systems incorporating molecular mutations coming….
49. Treatment options for MDS
1) Supportive care: transfusions, ESA, GCSF, ESA + GCSF
2) Lenalidomide especially for MDS with Isolated deletion 5q
3) Hypomethylating agents Decitabine or 5-Azacitidine
4) If RAEB-1 or -2 in young patient, sometimes treated as if AML with induction
Chemotherapy +/- allogeneic transplant
50. MPN, MPN/MDS overlap, MDS
TET2
ASXL1
SRSF2
JAK2
MPL
BCR-ABL
MPN
PV
ET
CML
PMF
RARS-t
EZH2
MDS/MPN
MDS with
fibrosis
del5q
MDS
RA
RARS--SF3B1
53. CMML
Monocytosis of >1 X 109/l + dyplasia
(less than 20% of cells in bone marrow).
CMML-1: <10% blasts in BM
CMML-2: 10-19% blasts in BM
RARS-t
RA + Ringed Sideroblasts + Thrombocytosis
Mixed MPN (JAK2 or MPL mutation) and MDS
>15% ringed sideroblasts + Plt count >450K
