6/29/2010

Leukemia Review:
Types, Diagnostics,
Treatments
Eyal C. Attar, M.D.
Massachusetts General Hospital
Cancer Center
June 25, 2010

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Myeloproliferative disorders

MPD
PRV
•PRV
AML
•ET CML
•MF

CMML

MDS
•RA
•RARS
•RAEB I
•RAEB II

Lymphoproliferative disorders

Low grade
CLL DLBCL lymphoma

Myeloma
Lymphoplasmacytic
lymphoma
(Waldenstrom’s)

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Clues a Disorder May Exist

 B symptoms
 Fevers
 Night
h sweats
 Weight loss
 Low blood counts
 Fatigue, malaise
 Bruising
 Infections
 Abnormally high blood counts
 Strokes
 Shortness of breath

Bone Marrow Aspiration and

Biopsy

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Elements of Bone Marrow Analysis

 Aspirate: The Juice

 Morphologic analysis: what the cells
look like under the microscope
 Flow cytometry: laser analysis of cells
using surface markers
 Cytogenetics: Chromosome analysis
 Molecular
M l l analysis,
l i C Correlatives
l i
 Bone: Architecture

Other Useful Diagnostic Tests

 CT/PET scans
 Lymph node enlargement
 Ultrasound
 Spleen enlargement
 Spinal tap
 Abnormal cells, leukemia
 Skeletal survey

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Differences Among MDS/MPDs/

Acute Leukemias
MPD MDS Acute Leukemia

Blood counts High Low Low or high

Bone marrow High High High

cellularity

Dysplasia Minimal Major Minimal

Terminal Present Absent Absent

Differentiation
Blasts <20% <20% ≥20%

Acquired mutations
enhance proliferation
and promote survival
Chronic myeloid leukemia BCR-ABL

Neutrophil

Hypereosinophilic leukemia FIP1L1-PDGFR

Eosinophil

Common
Myeloid Systemic mastocytosis KITD861V
Progenitor Mast
Cell

Hematopoietic
Stem Cell Chronic myelomonocytic X-PDGFR
Monocyte
leukemia

Common
Lymphoid
Progenitor
Polycythemia
y y vera J
JAK2V617F
JAK2K539L
T-lymphocyte Red blood cells

B-lymphocyte Essential thrombocythemia JAK2V617F

Myelofibrosis MPLW515L
Megakaryocyte

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Myeloproliferative disorders

 Clonal hematopoeitic disorders

 Proliferation of one of myeloid
lineages
 Granulocytic
 Erythroid
 Megakaryocytic
 Relatively normal maturation

History
 Duration of symptoms
 Leukocyte deficiencies
 sinopulmonary infections
 RBC alterations
 too much: headaches, plethora
 too little: fatigue
 Plt alterations
 too much: erythromelalgia
 too little: epistaxis, bruising

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Laboratory Evaluation
 CBC with differential
 MCV
 Reticulocytes
 Examination of the peripheral blood smear
 Iron studies
 Fe, TIBC, ferritin
 B12, folate
 Erythropoietin level
 Bone marrow biopsy with cytogenetics and,
possibly, FISH

Acquired mutations
enhance proliferation
and promote survival
Chronic myeloid leukemia BCR-ABL

Neutrophil

Eosinophil

Common
Myeloid
Progenitor Mast
Cell

Hematopoietic
Stem Cell

Monocyte

Common
Lymphoid
Progenitor

T-lymphocyte Red blood cells

B-lymphocyte

Megakaryocyte

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CML: Peripheral Blood Smear

CML: Epidemiology

 Comprises 15-20% of adult leukemia

 1 2 cases/100
1-2 cases/100,000
000 population
 Median age: 50 years
 Slight male predominance
 Only known risk factor: exposure to
ionizing radiation

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CML: Clinical Findings

 20-50% of patients asymptomatic

 LUQ abdominal pain
 splenomegaly
 splenic infarct
 Bone pain
 sternum, pelvis, long bones
 Gouty arthritis

CML: Laboratory Testing

 CBC
 Leukocytosis
 Thrombocytosis
 Basophilia
 Eosinophilia
 Chemistry
 Elevated LDH
 Normal leukocyte alkaline phosphatase
(LAP) score

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CML: Laboratory Testing

 RT-PCR bcr-abl transcript

 present in the bone marrow and blood
 Bone marrow aspiration and biopsy
 hypercellular
 myeloid predominance
 left shift
 hyperplastic megakaryocytes
 abnormal cytogenetics (9;22)

The Philadelphia Chromosome

1 2 3 4 5

6 7 8 9 1 11 12
0

13 14 15 16 17 18

19 20 21 22 X Y

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Clinical Course: Phases of CML

Ad
Advanced
d phases
h
Chronic phase
Accelerated Blastic phase (blast
phase crisis)

Median 4–6
years Median duration Median survival
stabilization up to 1 year 3–6 months
Terminal phase

CML: Management
 Chronic phase
 Tyrosine kinase inhibitors (TKIs)
 imatinib, dasatinib, nilotinib
 Interferon
 Cytarabine
 Hydroxyurea, busulfan
 Accelerated phase
 Consider TKI, organize stem cell
transplant

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CML: Management

 Blast crisis
 Induction chemotherapy with TKI to
achieve remission
 AML
 Antracycline + cytarabine
 ALL (p190 BCR-ABL vs p210)
 5-drug regimen (cyclophosphamide,
daunorubicin, vincristine, prednisone, L-
asparaginase)
i )
 Follow with allogeneic SCT if in
remission

Mechanism of Action of Imatinib

Bcr-Abl
Bcr-Abl
Substrate
Substrate
Imatinib
P
ATP P
P

Y = Tyrosine
P = Ph
Phosphate
h
P

Goldman JM. Lancet. 2000;355:1031-1032

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CML: Overall Treatment Scheme

Young with a Start Imatinib at

well-matched donor 400mg/day

Poor response or
Consider for Initial response Good response
Allograft
g Followed by y maintained
Loss of response

Add or substitute
Continue Imatinib
Allogeneic SCT Other agents
indefinitely
Allo-SCT

Acquired mutations
enhance proliferation

Chronic myeloid leukemia BCR-ABL

Myelofibrosis
Neutrophil

Hypereosinophilic leukemia FIP1L1-PDGFR

Eosinophil

Common
Myeloid Systemic mastocytosis KITD861V
Progenitor Mast
Cell

Hematopoietic
Stem Cell Chronic myelomonocytic X-PDGFR
Monocyte
leukemia
Myelofibrosis
Common
Lymphoid
Progenitor Polycythemia vera J
JAK2V617F
JAK2K539L
T-lymphocyte Red blood cells

B-lymphocyte Essential thrombocythemia JAK2V617F

MPLW515L
Megakaryocyte

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Conclusions
Acquired mutations Targeted therapy
enhance proliferation

Chronic myeloid leukemia BCR-ABL imatinib

dasatinib
nilotinib
il ti ib

Hypereosinophilic leukemia FIP1L1-PDGFR imatinib

Systemic mastocytosis KITD816V PKC412

Chronic myelomonocytic X PDGFR

X-PDGFR imatinib
leukemia
Myelofibrosis
Polycythemia vera JAK2V617F clinical trials, ex XL-019
Essential thrombocythemia JAK2K539L
Myelofibrosis MPLW515L

Myelodysplastic Syndromes

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NL MDS

Sinusoidal
Mature cells blood vessel

Maturation and migration

Progenitor cells CLP CMP

Stem cells

MDS: Characteristics

 Disease of the elderly

 median diagnosis age 65
65-75
75
 M>F
 Annual incidence: 15,000-
30,000/year
 Prevalence: 50,000
50 000-100
100,000
000

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MDS: de novo vs. secondary

 de novo MDS
 no preceding hematologic abnormality
 secondary MDS
 follows chemotherapy or radiation used to
treat other diseases (HL, NHL, carcinoma,
rheumatoid arthritis, renal transplantation)
 2-3 years after topo II inhibitor therapy (etoposide)
 balanced translocations of MLL at 11q, overt AML
 5-10 years after alkylator therapy
 involves chromosomes 5 and 7, 11p NUP 98, p53
 10-15 years after radiation

MDS: Clinical Signs/Symptoms

 Attributed to cytopenias:
 Anemia: fatigue
fatigue, depression
 Leukopenia: infection
 leading cause of death in MDS
 Thrombocytopenia: bruising, bleeding

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MDS: Initial Tests

 CBC
 degree and number of cytopenias*
cytopenias
 MCV, reticulocytes
 Examine peripheral blood smear
 Anemia panel:
 Fe, TIBC, Ferritin
 B12, Folate
 EPO

*component of IPSS

MDS: Additional Tests

 Bone marrow aspiration and biopsy

 aspirate (or touch preps if dry tap)
 blast percentage
 dysplasia
 biopsy
 dysplasia
 ALIP, CD34+
 cytogenetics
 abnormal in 40
40-75%
75% of patients with de novo,
novo >80%
in secondary
 trisomy 8, 5q-, 7q-, 20q- most common

*component of IPSS

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Peripheral Blood-WBCs

Leukopenia
 50% of MDS patients
 reduced neutrophils
 hypogranulation
 pseudo-Pelger-Huet
cells
 circulating
myeloblasts

Courtesy of Dr. Robert Hasserjian,

MGH

Bone Marrow

Hypercellular
Dysplasia
 single or multilineage
Perturbed Fe
metabolism
 ringed sideroblasts

Courtesy of Dr. Robert Hasserjian,

MGH

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International Prognosis Scoring

System (IPSS) Score
Score

0 0.5 1.0 1.5 2.0

% BM blasts <5 5-10 - 11-20 21-30

Karyotype Good Intermediat Poor - -

(NL, Y-, e (all (complex, Chr
5q-, 20q-) others) 7)
Cytopenias
y p 0/1 2/3 - - -

RBCHgB < 10
WBCANC<1800
Plt<100K

Greenberg, et. al, Blood, 1997; 9:2079

IPSS Accurately Predicts Prognosis

in de novo MDS
Score Overall Time to
Median 25% of
Survival, patients tx
years to AML,
years
Low 0 5.7 9.4

Int-1 0.5-1.0 3.5 3.3

Int-2 1.5-2.0 1.2 1.1

High 2.5-3.5 0.4 0.2

Greenberg, et. al, Blood, 1997; 9:207

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5q- Syndrome
 interstitial deletion 5q
 region between bands q31-q33 encodes IL-3,
IL-4
IL 4, IL-5
IL 5, IL-9
IL 9, GM-CSF
GM CSF, c
c-fms
fms (M
(M-CSFR)
CSFR), others
 W>M 7:3
 median age at diagnosis: 68
 anemia
 macrocytosis, marked erythroid dysplasia,
>80% transfusion-dependent anemia
 normal or slightly elevated plts
 mild leukopenia
 low risk of tranformation to AML (15%)
 Uniquely responsive to Imids

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MDS: Treatment Approach

IPSS
Int-2 and High
Low and Int-1 or
therapy-related

5q- deletion
with or without Intensive therapy
other cytogenetic candidate?
alterations?

Yes No Yes No

Azacitidine
Serum Decitabine
Lenalidomide Donor available?
EPO ≤ 500 mU/ml? Supportive care
Clinical trial

Yes No Yes No

Epo ± GCSF ATG ± cyclosporine Intensive therapy

Lenalidomide Allogeneic stem cell
Supportive care Supportive care
Azacitidine transplantation
Clinical trial Clinical trial
Decitabine
Supportive care
Clinical trial

Acute Myeloid Leukemia

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Myeloblasts

Wiley & Sons Inc., Hayhoe & Flemans, Atlas of Hem

1970

Definition and Features

 Malignant neoplasm of myeloid cells

 Reside within
 bone marrow
 blood
 extramedullary tissues
 Cells lack maturation and function
 Suppression normal hematopoiesis

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Important Pathogenesis
Questions
 What are the important oncogenes
and tumor suppressor genes?
 Are all cells within the leukemia
equally able to perpetuate the
disease? Is there a leukemia stem
cell?
 What is the role of the bone marrow
microenvironment?

Pathogenesis
Class Mutation
 Two hits:
 Proliferation Type I RAS
Activate FLT3R
 Block proliferation
differentiation Enhance survival

 Hypermethylation
 Chromatin Type II CEBP
Block MLL
alterations differentiation NPM1
 Increased stromal
adhesion

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Causes

 Ionizing radiation
 Occupational exposures: benzene
 Chemotherapy (0.1% of patients)
 topoisomerase inhibitors (11q23)
 alkylating agents (deletions of 5 and
7)
 Antecedent hematologic disorder, MDS
 Viruses
 Retroviruses in animals
l
 T-cell leukemia virus
 Hereditary conditions

Epidemiology

 11,930 new cases of AML in the United

States with 9,040 deaths in 2006
 2.3 new cases/100,000/year
 18 new cases/100,000/year > 60 yo
 Median age 70 years
 Adults:
 85% AML
 15% ALL

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Age-specific incidence rates:

1998-2002 (NCI-SEER Program)

Tallman, M. S. Hematology 2005;2005:143-150

Classification

 FAB (French, American, British) – older

 > 30% blasts in bone marrow
 M0 – M7
 WHO (World Health Organization) – newer
 Need >= 20% in bone marrow or blood
 Considers cytogenetic and molecular lesions
 Considers p
prior diseases and treatments

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Classification (WHO 2008)

 Acute myeloid leukemia with recurrent genetic abnormalities
 AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
 APL with t(15;17)(q22;q12); PML-RARA
 AML with t(9;11)(p22;q23); MLLT3-MLL
 AML with t(6;9)(p23;q34); DEK
DEK-NUP214
NUP214
 AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
 AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
 Provisional entity: AML with mutated NPM1
 Provisional entity: AML with mutated CEBPA
 Acute myeloid leukemia with myelodysplasia-related changes
 Therapy-related myeloid neoplasms
 Acute myeloid leukemia, not otherwise specified (NOS)
 Acute myeloid leukemia with minimal differentiation, Acute myeloid leukemia
without maturation, Acute myeloid leukemia with maturation, Acute
myelomonocytic leukemia, Acute monoblastic/monocytic leukemia, Acute
erythroid leukemia, Pure erythroid leukemia, Erythroleukemia,
erythroid/myeloid,
h id/ l id AAcute megakaryoblastic
k bl i lleukemia,
k i A Acute b
basophilic
hili
leukemia, Acute panmyelosis with myelofibrosis (syn.: acute myelofibrosis;
acute myelosclerosis)
 Myeloid sarcoma (syn.: extramedullary myeloid tumor; granulocytic sarcoma;
chloroma)
 Myeloid proliferations related to Down syndrome
 Blastic plasmacytoid dendritic cell neoplasm
 Acute leukemias of ambiguous lineage
Blood, 21 January 2010, Vol. 115, No. 3, pp. 453-474

Initial Workup
 History
 ? AHD, ? prior chemo/XRT
 Performance status
 Assessment of comorbidities
 CBC with differential, chemistries, coagulation profile
 BM bx with flow cytometry, cytogenetics, and
molecular testing (FLT3R, NPM1, others)
 Hepatitis testing
 HLA-typing
 Sperm banking
 Echocardiogram
 Central venous access

Blood, 21 January 2010, Vol. 115, No. 3, pp. 453-474

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Treat Urgent Issues First

 Assess the CBC, CXR, EKG, and coagulation
panel
 Transfuse RBCs and platelets
 Antibiotics
 Correct coagulopathy – if DIC
consider ATRA (? APL)
 Hydroxyurea and/or leukapheresis
 Blasts >50,000/uL and signs of leukostasis

Immunophenotype –
Flow Cytometry
 Immature markers
 34, 38, 117, 133, HLA-DR
 Granulocytic
G l markers
k
 13, 15, 16, 33, 65, MPO
 Monocytic markers
 NSA, 11c, 14, 64, lysozyme, 4, 11b, 36
 Megakaryocytic markers
 41 (IIb/IIIa), 61 (IIIa), 42 (1b)
 Erythroid markers
 235a (glycophorin A)

Blood, 21 January 2010, Vol. 115, No. 3, pp. 453-474

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Relationship of Cytogenetics to
Prognosis

Giles, ASH Education,. 2002 Byrd et al., Blood, 2002

Prognostic single-gene markers in CN-AML

Gene Alteration Gene Prognostic
Location Impact
FLT3-ITD 13q12 Adverse
WT1 mutation 11p13 Adverse
NPM1 mutation 5q35 Favorable
CEBPA mutation 19q13.1 Favorable
BAALC 8q22.3 Adverse
overexpression
ERG 21q22.3 Adverse
overexpression
EVI1 expression Adverse
3q26.2
MN1 22q21.1 Adverse
Courtesy of
Dr. G. Marcucci
overexpression
FLT3-TKD 13q12 ? Adverse
MLL-PTD 11q23 ? Neutral

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Molecular Distribution of
Cytogenetically Normal AML

Blood, 21 January 2010, Vol. 115, No. 3, pp. 453-474

Molecular and Cytogenetic

Risk Groups

Blood, 21 January 2010, Vol. 115, No. 3, pp. 453-474

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Principles of Treatment
 Induction: goal is to achieve CR
 7 + 3 (7 days CI cytarabine, 3 days of anthracycline)
 IA (idarubicin and cytarabine)
 ADE
 Consolidation phase: Continued reduction in disease
burden, curative for some patients
 High-dose cytarabine if < 60 yrs
 Intermediate-dose cytarabine if > 60 yrs
 Maintenance: unclear if beneficial
 Stem cell transplantation
 Allogeneic in CR1
 Autologous or allogeneic in CR2

How Can We Improve Treatment

Outcomes?
 Induction:
 Tyrosine kinase inhibitors
 Sorafenib, AC220, dasatinib
 Nucleoside analogues
g
 Clofarbine, cladribine
 Leukocyte priming
 GCSF
 Interrupt leukemia-microenvironment interactions
 Plerixifor
 Reverse DNA and chromatin alterations
 Hypomethylating agents, HDACi
 Immunotherapy:
 Lenalidomide
 Proteasome inhibition
 Bortezomib
 Consolidation
 Chemotherapy vs. autologous SCT vs. allogeneic SCT
 Maintenance
 Immune modulation (lenalidomide, IL-2, hypomethylation)

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FLT3 Receptor
 FLT3 = Fms-like tyrosine kinase 3
 Single transmembrane domain
receptor tyrosine kinase
 Overexpressed
O d iin 70
70-100%
100% off AML
 Cytoplasmic domain triggers:
 PI3K, SRC family, STAT5
 Leads to proliferation and survival
activities
 Mutations
 ITD: internal tandem duplication,
25% of AML, adverse
 TKD: tyrosine kinase domain
domain, 5%
5%,
prognosis unclear

Litzow MR. Blood. 2005;106:3331-3332.

Small D, et al. Hematology Am Soc Hematol Educ Program. 2006:178–1

AML FLT3/ITD is a Predictor

of Poor Prognosis 100

75
e Free

50 ITD-
46%
% Disease

25 30%
ITD+
P < .001

Relapse rate at 5 years 0

0 1 2 3 4 5
was 44% for patients with Years from Remission
no mutation compared to 100

64% in patients with 75

FLT3/ITD (N=854)
Alive

50
ITD-
% Still A

44%
25 32%
ITD+
P < .001

0
0 1 2 3 4 5
Years from Entry

Kottaridis PD, et al. Blood. 2001;98:1752–1759.

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FLT3 Receptor Inhibitors

 PKC 412
 MLN 518
 CEP 701
 sorafenib

CALGB 10603: Prospective Phase III, Double-blinded Randomized Study of

Induction and Consolidation
+/- Midostaurin in Newly Diagnosed Patients
< 60 years with FLT3 mutated AML

Primary endpoint: OS
P
R R
E A DNR Midostaurin
CR HiDAC X4
R N Ara-C MAINTENANCE
Midostaurin
E FLT3 D Midostaurin 12 months
G ITD O
I or M
S TKD I
Z DNR X4 Placebo
T CR HiDAC
E ARA-C MAINTENANCE
E Placebo
Placebo 12 months
R

Central lab Study drug (50mg BID) is given on Days 8-21 after each course
within 48h of chemotherapy, and Days 1-28 of each 28 day maintenance cycle

Courtesy of Dr. Richard Stone

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CALGB 10503: Phase II Study of Maintenance Decitabine Following

Cytogenetically Risk-Adapted Therapy for Newly Diagnosed Adults < 60

R R
C HiDAC X 3
E E
Y
G G
T
I I
DNR O
S CR S Decitabine X 6-8
Ara-C G
T T
Etoposide E
R R
N Mobilization
A A
E and
T T
I Autologous
g SCT
I I
C
O O
S
N N

AML < 60: Summary

Diagnose
>= 20% BM or PB
blasts

Prognosis

Cytogenetics

Good, including NL Bad, including NL

Intermediate
cytogenetic with NPM1mut cytogenetic with FLT3ITD

1. Remission Induction 1. Remission Induction 1. Remission Induction

2 Consolidation
2. C ld chemotherapy
h h 2 Consolidation
2. C ld chemotherapy
h h 2 Allogeneic
2. ll transplant
l
or allogeneic transplant if
matched related donor

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AML > 60

 Treatment considerations
y of life
 Quality
 Performance status
 Treatment options
 Supportive care
 Growth factors, blood products, antibiotics
 Low dose chemotherapy agents
 Induction chemotherapy
 Allogeneic stem cell transplantation

Age, Performance Status,

Induction-related Mortality

Appelbaum. Blood
2006

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Age-related CR Rate:
CALGB Study 8923

CALGB Memorandum 1995

CALGB 10502: Phase II/I Study of Bortezomib with Daunorubicin and

Cytarabine for Adults with AML Ages 60-75

R R
E E
G G
I I
DNR
S S Int-Ara-C Int-Ara-C
Ara-C CR
T T Bortezomib Bortezomib
Bortezomib
R R X mg/m2 X mg/m2
1.3 mg/m2
A A D1, 4, 8, 11 D1, 4, 8, 11
D1, 4,8, 11
T T
I I X 0.7,
X= 07 11.0,
0 11.3
3
O O mg/m2
N N

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Epigenetics in Myeloid Malignancies

Hypermethylation
Methyl-
M th l
binding
protein
DNA Tumor Suppressor Tumor Suppressor

Normal MDS/AML
• Hypermethylation leads to gene silencing
– Methyl-binding
Methyl binding proteins inhibit binding of
transcription factors
• Results in loss of transcription of tumor suppressor
genes and cyclin-dependent kinase inhibitors

Herman JG, et al. N Engl J Med. 2003;349:2042-2054.

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AZA-001 Phase III Survival

Study Schema
AZA-C 75 mg/m2 x 7 days every 28 days
(N = 179)
Stratify (FAB, IPSS) (N = 358)
Eligibility
Treatment until disease progression
 RAEB, RAEB-T, CMML
 10%–29% blasts (N = 179)
 IPSS int-2/high risk CCR
1. BSC onlyy ( = 105))
(n
2. Low-dose AraC (n = 49)
3. Induction/consolidation (n = 25)
 Primary end point: Overall survival
 Secondary end points: IWG CR, PR, HI
Fenaux et al., Lancet Oncol, 2009

CCR = conventional care regimen.

Fenaux et al, 2009.

Survival in RAEB-T,
Azacitidine vs. BSC

Fenaux et al., JCO, 2010

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AML > 60: Summary

Diagnose
>= 20% BM or PB
blasts

1. Performance
f status
2. Comorbid Conditions
3. Age
4. Cytogenetics

1. Non-good Cytogenetics 1. Non-good Cytogenetics

Good Cytogenetics
2. Patient Transplantable 2. Patient Not Transplantable

1. Remission Induction 1. Remission Induction 1. Supportive care

2 Consolidation chemotherapy
2. 2 Allogeneic transplant
2. 2 Hypomethylating agent
2.

Transplantation

 Autologous
 CR1: Probably not beneficial over consolidation
chemotherapy
 CR2: An option for patients without allogeneic donors
 Allogeneic: high risk CR1, all CR2
 Full (myeloablative)
 < 61 yo from related donor
 < 56 yo from unrelated donor
 Mini (non-myeloablative), RIC (reduced-intensity
conditioning)
 <61 with comorbidities
 61-75: related or unrelated donors

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Acute Promyelocytic Leukemia

 10% of AML
 FAB-M3
 Cytogenetics: t(15;17)
 Younger age
 Pancytopenia
 DIC

Promyeloblasts

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S0521: A randomized trial of maintenance versus observation for patients

with previously untreated low and intermediate risk acute promyelocytic
leukemia (APL)

R 6-MP
A ATRA
R PCR - N MTX
E D
G O
I X2 M
S X2 I
ATRA CR ATRA Z
T AsO3
DNR DNR E OBS
R
Ara-C
A
T
I
PCR +
O
Gemtuzumab
N

SWOG: A Phase II Study of ATRA, AsO3, and Gemtuzumab in High-Risk APML

R
E
G
I
S X2 X2
ATRA CR X2 6-MP
T ATRA
Gemtuzumab AsO3 Gemtuzumab ATRA
R DNR
AsO3 MTX
A
T
I
O
N

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Summary

 Suspected APL requires immediate

care
 Assess for DIC and treat accordingly
 ATRA is a critical component of
therapy
 Stratify low vs
vs. high risk
 Excellent survival: 80%

Chronic Lymphocytic Leukemia

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CLL

Definition
 Clonal B cell malignancy
 Progressive accumulation of long
lived mature lymphocytes
 Increase in anti-apoptotic protein
bcl-2
 Intermediate stage between pre-B
pre B
and mature B-cell

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Epidemiology
 Most common leukemia of Western world
 Less frequent in Asia and Latin America
 Male to female ratio is 2:1
 Median age at diagnosis is 65-70 years
 In US population, incidence is similar in
different races
 High familial risk with 2-7
2 7 fold higher risk

Cancer statastics 2000; CA J Clin 2000;

50:7-33

Clinical Features
 Disease of elderly with wide
spectrum of clinical features
 20% are asymptomatic
 Classic B symptoms
 Variable physical findings with
normal to diffuse LAD,
LAD HSM

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Diagnostic Criteria
 Defined by NCI & IWCLL
 Persistent lymphocytosis
 Absolute lymphocyte count
exceeding 5000/uL
 Mature appearing B-cells with <10%
of prolymphocytes
 CD5+23+ by flow

Blood 1996; 87: 4990

Staging: Rai and Binet staging systems for CLL

Clinical staging systems for CLL
Stage
Median
Value Rai Binet
survival
Lymphocytosis 150 months
0 -
(>15,000/mm3) (12.5 years)
Lymphocytosis
<3 101-108 months
plus nodal I A node groups (8.5-9 years)
involvement
Lymphocytosis >3 60-71 months
plus organomegaly
II B node groups (5-6 years)
III H b <10
Hgb 10 g/dL
/dL 19-24 months
Anemia (RBCs)
Hgb <11 g/dL C (1.5-2 years)
Lymphocytosis
IV
plus PLT
PLT
thrombocytopenia <100,000/mm3
<100,000/mm3
(platelets)
1. Rai KR, et al. Blood. 1975;46:219-234.
2. Binet JL, et al. Cancer. 1981;48:198-206.
3. Binet JL, et al. Cancer. 1977;40:855-864.

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Genetic abnormalities in CLL

Median
Genetic Incidence survival
abnormality (%) (months) Clinical correlation
13 14
13q14 55 62
55-62 133 292
133-292 Typical
T i l morphology
h l
Mutated VH genes
Stable disease
+ 12 16-30 114-122 Atypical morphology
Progressive disease
del 11q23 18 79-117 Bulky lymphadenopathy
Unmutated VH genes
Progressive disease
Early relapse
post autograft
p g
p53 7 32-47 Atypical morphology
loss/mutation Unmutated VH genes
Advanced disease
Drug resistance

1. DÖhner H, et al. N Engl J Med. 2000;343:1910-1916.

2. Oscier DG, et al. Blood. 2002;100:1177-1184.

In CLL
Effect of genetic abnormalities
on survival1
Effects of genetic abnormalities on survival in patients with CLL (N=325)1

1. Döhner H, et al. N Engl J Med. 2000;343:1910-1916.

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Prognosis: effect of VH gene mutations

on survival

100 Unmutated VH gene

Percent surviving (%) 90 Median = 117 months
Mutated VH gene
80
Median = 293 months
70
60
50
40
30
P

20
10
0
0 25 50 75 100 125 150 175 200 225 250 275 300 325

Months

1. Hamblin TJ, et al. Blood. 1999;94:1848-1854.

Other Disease Characteristics

 Hypogammaglobulinemia seen
>50%
 5-10% have small monoclonal peak
 Positive Coombs’ test in 30%
 Autoimmune hemolytic anemia &
thrombocytopenia in <10%
 Richter’s transformation to DLBCL
 Prolymphocytic leukemia

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Treatment

 Chlorambucil, CVP, CHOP

 Fludarabine
 Rituximab
 Campath (alemtuzamab)
 Bendamustine
 T
Treat
t early
l vs. wait?
it?
 Allogeneic SCT

Blood 1996; 88 (suppl 1): 141a

Multiple Myeloma

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Spectrum of B-Cell Dyscrasias

 MM, solitary plasmacytoma, MGUS

 Waldenstrom
Waldenstrom’s s macroglobulinemia,
macroglobulinemia
lymphoplasmacyctic lymphoma
 NHL
 Primary amyloidosis
 Cryoglobulinemia

Plasma Cells in MM

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 6/29/2010

Monoclonal Gammopathy of
Undetermined Significance
(MGUS)
 Monoclonal protein ≤ 3 g/dL in serum or urine
without
ith t evidence
id off MM,
MM WWaldenstrom’s,
ld t ’
amyloidosis, or other lymphoproliferative
disorder
 Incidence: up to 2% of individuals ≤ 50 yo
 < 3 g/L monoclonal Ig, little or no proteinuria
 <10% monoclonal BM plasma cells
 No bone lesions
lesions, anemia
anemia, or hypercalcemia
 Overall 1% progress each year

Multiple Myeloma

 Prevalence
 45,000
, Americans have MM
 Median age at diagnosis
 Men, 62 yr (75% > 70 yr)
 Women, 61 yr (79% > 70 yr)
 Median survival from diagnosis: 33
months
 16,570 new diagnoses and 11,310
deaths expected in US in 2006

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Multiple Myeloma

 Population subgroups
 Incidence higher in African Americans
 Slightly more frequent in men than
women
 Remains mostly incurable

Criteria for Diagnosis of MM

 MM (all 3 required)
 Monoclonal plasma cells in bone
marrow 10% and/or presence of
biopsy-proven plasmacytoma
 Monoclonal protein present in serum
and/or urine
 Myeloma-related organ dysfunction (1
or more): Ca > 10
10.5
5 mg/L
mg/L, SCr > 2
mg/dL, HgB < 10 g/dL, lytic bone
lesions or osteopenia

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Initial Diagnostic Evaluation

 Hx and PE
 Blood
 CBC with diff
 BUN, SCr
 Electrolytes, Ca, albumin
 Quantitative immunoglobulins
 SPEP
 2-microglobulin
c og obu
 Skeletal Survey

Lytic Bone Lesions

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Presenting Features

Mayo Clin Proc., 2003, 78, 21.

Durie-Salmon Staging System

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International Staging System

Greipp PR, et al., J Clin Oncol.,

2005;23:3412.

Chromosomal Alterations in MM
 IgH translocations (50%), chromosome 14
 11q13; cyclin D1 (15-20%)
 4p16.3; FGFR3, MMSET (12%)
 16q23; c-MAF (5-10%)
 8q24; c-MYC (<10%)
 6p21; cyclin D3 (5%)
 6p25; IRF4 (5%)
 20q11; MAFB (5%)
 Chromosome 13q deletion (50% by FISH)
 Rb tumor suppressor
 Coexistence with t(4;14)(p16.3;q32)
 Chromosome 1q amplification (45%)
 Amplification of 1q21 genes in high-risk MM (BCL9, ILR6,
CKS1B)

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Treatment
Strategy for Newly
Diagnosed
Myeloma

Kyle and Rajkumar, New Engl J Med, 2004;351:1860.

Therapies for Multiple Myeloma

 Primary therapy
p p
 Melphalan/prednisone (MP)
 Vincristine/doxorubicin/dexamethasone
(VAD)
 Dexamethasone
 Thalidomide, Lenalidomide
 Doxil
 Bortezomib
B ib
 Transplantation: Auto (1 or 2?) vs. Allo

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Summary

 Disorder of neoplastic plasma cells

 The bone microenvironment plays a critical role
i di
in disease pathogenesis
h i
 Treatment
 Conventional chemotherapeutic agents
 IMIDs
 Combinations
 Maintenance
 Stem cell transplantation
 Bone fortifying agents

Thank you

Eyal Attar
 [email protected]
eattar@partners org
 617-724-1124

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