10/18/2010
Trends in the
Diagnosis
ag oss and
a d Management
a age e
of Haematological Malignancies
Dr Sajir G Mohamedbhai
Specialist Registrar, Haematology
University College Hospital, London
13 October 2010
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Aims & Objectives
¾ Highlight the importance of haematological
cancers
¾ Discuss advances in diagnosis
g
¾ Discuss new approaches to treatment
¾ Go through case studies
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Epidemiological importance
¾ 4th commonest cancer in men/3rd in women
¾ ALL is the commonest childhood cancer
¾ 1 iin 20 iindividuals
di id l b
by age 75
¾ Increasing incidence worldwide
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Relative frequency of haematological
malignancies
Hodgkin
(7%)
Myeloma
(14%)
AML (10%)
ALL (4%)
CLL (10%)
CML (4%)
NHL (50%)
SEER 2004, NCI
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Incidence in Mauritius 1997-2001
Diagnosis
Male
Female
Leukaemias
and Myeloma
No. of cases
213
166
% of total
7.3%
4.7%
Lymphomas
No. of cases
156
94
% of total
5.3%
2.6%
124 cases/year
10 per 100000/year
Source: Manraj SS et al. Cancer incidence in the Republic of Mauritius- 5 Years Review 1997 to
2001.
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Disease
Percentage surviving ≥ 5 years
1974-1976
1996-2003
2010
AML
6
21
30
ALL
38
65
>80% children
30% adults
CLL
68
75
80
CML
23
44
95
NHL
47
60
60
Hodgkin
71
86
80-90
Myeloma
24
34
40
5-year survival rates for hematological malignancies (1996-2003
compared with 1974-1976); SEER data
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What has led to these improvements?
Biology
Supportive
Care
Accurate
Diagnosis
BETTER
OUTCOME
Monitoring
Better drugs
Prognostic
information
Bone
Marrow
Transplants
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Better Diagnosis
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Conventional diagnostic tools
¾ FBC
C
¾ Biochemistry
¾ Morphology
¾ Histology (H&E)
¾ Imaging
¾ Sensitivity low
¾ Not specific
¾ Inter-reporter error
high
i
¾ Do not give
biological/genetic
information about the
disease
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Novel diagnostic tools complement
conventional methods
¾ Immunophenotyping
¾ Immunohistochemistry
¾ Cytogenetics
C t
ti
¾ Molecular methods- FISH, PCR
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Immunophenotyping
¾ Identifies specific antigens on cells in suspension
¾ Monoclonal antibody labelled cells are processed
in a flow cytometer, a laser-based instrument
capable
bl off analyzing
l i
th
thousands
d off cells
ll per second
d
¾ Specific cell marker profile helps make diagnosis
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Immunohistochemistry
Lymph node
H&E
Bcl6
CD20
Bcl2
FOLLICULAR LYMPHOMA
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Cytogenetics
-Recurrent acquired abnormalities (structural/
numerical) are common in haematological cancers
-Usually
Usually lead to alterations in oncogenes and tumour
suppressor genes
-Correlate with distinct subtypes
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FISH
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Polymerase Chain Reaction
¾ Synthetic
complementary
oligonucleotide
sequence (cDNA probe) specific only to target
DNA sequence
¾ Amplification steps makes it highly sensitive
¾ Q-PCR:
method allowing
assessment of mutation load
semiquantitative
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Uses of novel techniques
¾ In conjunction with conventional methods
¾ At Diagnosis:
- Rapidly
R idl and
d reliably
li bl confirm
fi
di
diagnosis
i
- Prognostic information
¾ During treatment: Monitoring of response and
residual disease
¾ After treatment: Detection of relapse
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Advances in Therapy
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Conventional Therapy
¾ Radiotherapy
¾ Non-targeted
¾ Steroids
¾ Significant toxicity
¾ Chemotherapy
Ch
th
¾ Resistance
R it
¾ Combination therapy
¾ Except for Hodgkin’s
(additive/synergistic/d
ose intensity/cycling)
disease and childhood
ALL, cure rates low
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Bone marrow transplantation
¾ High dose therapy for patients with higher risk disease
¾ Matched donor stem cells salvage recipient from
marrow aplasia
¾ Donor immune cells
- mediate graft versus host disease
- BUT have an important graft versus tumour effect
¾ Cure is the goal but there is a price to pay
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Targeted Therapy
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Novel therapeutic targets
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Cases
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Case 1
¾ 45 year old male
¾ Lethargy, weight loss, LUQ discomfort
¾ Headaches,
H d h
bl
blurred
d vision
ii
¾ Hepatosplenomegaly
¾ Fundal haemorrhages
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Case 1
FBC
BCR-ABL fusion
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Philadelphia chromosome in CML
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Case 1- Treatment & Outcome
Treatment
¾ Rapid cytoreduction- hydroxycarbamide + leucocytopheresis
¾ Allopurinol
¾ Imatinib (Glivec™) 400mg PO OD
Outcome
¾ FBC normalised by 3 months
¾ Bone marrow normal with no detectable Ph chromosome by
FISH at 6 months
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Imatinib targets the cause of CML
Cell Proliferation
Cell cycle arrest
and cell death
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IRIS study: 18 month follow-up
CHR= complete haematological response
MCR=major cytogenetic response
CCR=Complete cytogenetic response
PD=progressive disease
AP=accelerated phase
BC=blast crisis
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IRIS study- BCR-ABL load at 12 months
with imatinib predicts progression risk
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Imatinib has changed the treatment
of CML in the last 10 years
•>90% survival at 5 years
•compared to 20% in 1975
•Imatinib failures do still
occur and monitoring bcrabl on treatment is
essential
•Second-line treatments
available for Imatinib
f il
failures
•Imatinib needs to be
continously taken- cost!
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Case 2
¾ 60 year old male
¾ Weight loss, sweats
¾ CT- mesenteric mass and paraaortic adenopathy
¾ USS-guided biopsy
¾ Histology and immunohistochemistry shows diffuse
large B cell lymphoma
¾ Stage
g 2B
¾ What treatment?
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CHOP chemotherapy
¾ DLBCL is the commonest NHL
¾ CHOP chemotherapy used since 1970s
¾ 3-weekly
3
kl
Cyclophosphamide/Doxorubicin/Vincristine/Pre
dnisolone combination
¾ Outpatient treatment
¾ No other combination found to be superior
¾ Until the advent of Rituximab
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Rituximab
¾ Chimeric mouse/human
monoclonal antibody
(reduces allergic
reactions)
¾ First Mab licensed in
human cancer
¾ Used in a range
g of CD20-
expressing B-cell
lymphomas (DLBCL, FL
CLL)
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GELA study
GELA Coiffier et al 2002
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Chemo-immunotherapy improves 5year survival in DLBCL
15% difference in
OS at 5y
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Case 3
¾ 55 yo female
¾ Tiredness, lethargy, excessive spontaneous
bruising for 1 week + gum bleeding
¾ Unwell, febrile
¾ Hb 8.5 Platelets 15 WBC 25
¾ Fibrinogen <100
100 mg/dL
¾ PT 22s APTT 50s
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Case 3
PML probe
RARA probe
PML-RARA fusion arises
from t(15;17)
ACUTE PROMYELOCYTIC LEUKAEMIA
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Management
Supportive care:
¾ Antibiotics
¾ Keep platelets >50
¾ Cryoprecipitate
C
i it t tto replace
l
fibrinogen
fib i
¾ FFP to correct DIC
Definite treatment:
¾ Oral
O l All-trans
All t
Retinoic
R ti i Acid
A id
¾ Anthracycline
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Acute Promyelocytic
Leukaemia
¾ Unique among acute myeloid leukaemias
¾ t(15;17) produces Pml-Rara fusion protein that blocks
cell differentiation at promyelocyte stage
¾ Differentiation therapy with ATRA plus chemotherapy
leads to >95% remission
¾ From one of the most fatal leukaemias to one of the
most curable- 90% cure rates!
¾ Arsenic trioxide also active upfront and in
relapse/refractory disease
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Other new concepts
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Myeloma- new kids on the block
¾ Thalidomide based induction therapies
(Melphalan/Prednisone,
Cyclophosphamde/Dexamethasone)
¾ Bone marrow autograft improves survival
¾ Newer agents like Lenalidomide and bortezomib
active upfront and in relapse/refractory setting
¾ No cure yet,
yet but myeloma patients live longer
¾ Median survival now 5 years
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AML- cytogenetics predicts
outcome
¾ Cytogenetic abnormalities in 40% at diagnosis
¾ Large collaborative studies have shown three
groups, favorable, intermediate and poor,
based on cytogenetic results at diagnosis.
¾ Important independent prognostic factors for
achievement of remission, risk of relapse and
survival
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Cytogenetic risk group predicts
survival after treatment
65 %
35 %
<10%
Dastague et al. Leukaemia 1995
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ALL- Minimal residual disease predicts
outcome
¾ >90% patients achieve CR at the end of induction (by
bone marrow morphology), yet some still relapse
¾ Early fall in leukaemia cell burden during induction
reflects sensitivity/resistance to chemotherapy used
¾ Immunophenotyping and PCR to assess MRD is more
specific and sensitive than Day 15 or 28 bone marrow
and has excellent prognostic value
¾ Identifies
Id tifi llow-risk
i k and
d hi
high-risk
h i k patients,
ti t which
hi h may
benefit from treatment reduction or escalation
respectively
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Relapse-free survival according to MRD-based
risk groups of paediatric ALL- International BFM
Study Group
Hoelzer, D. et al. Hematology 2002;2002:162-192
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Conclusion
¾ Dramatic changes have occurred in the field of
haematological malignancies in the last 30 years
¾ New ways of classifying, diagnosing and treating
haematological cancers
¾ Together, these strategies have improved outcomes
¾ There is probably not a single cure for cancer but
many, reflecting the biological diversity of these
tumours
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Thank you
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Malignant
Bleeding
and
Coagulation
Consultative
Clinical
Haematology
Laboratory
Red cell
Transfusion
49