Transcript CML

Myeloprolipherative diseases
(MPD)
Chronic myeloid leukemia(CML)
Polycythaemia Vera (PV)
Essential thrombocythaemia (ET)
Primary myelofibrosis (MF)
Common signes: proliferation 1-3 cell lines with
excess in peripheral blood, extramedullary
haemopoiesis, bone marrow fibrosis
CML- historical milestones
1845: John Hughes Bennet (Edinburgh)
Rudolf Virchow (Berlín)
„Unusual“ cases of splenomegaly and blood „suppuration“
resulting in death
 1872: Ernst Neumann: primary site is bone marrow
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1882 LANCET: XXX Response of patient
with splenomegaly to arsenic treatment
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1973: BLOOD: J. Rowley: Ph chromosome… BCR-ABL
1992: FASEB Journal: A. Levitzki: tyrohosthins – small
molecules to inhibit ABL (future Tyrosine kinase
inhibitors)
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Scotish physician
Writer
Military awards &
aristocratic state from
Burs wars
Driver´s licence No. 1
UK
First downhill ski teacher
in UK
Planned to build tunnel
under the la Manche
channel
Died 1930
The ‘Philadelphia chromosome’
Philadelphia chromosome
described in 1960
>95% of CML patients
have the Philadelphia
chromosome
Genetic fault, BCR-ABL,
described in mid 80s
In previous studies:
The less Philadelphia
chromosomes there are in
the bone marrow - the
longer you live
Chronic myeloid leukaemia
(CML)
Definition: myeloprolipherative clonal disease derived from a stem
cell, bcr/abl rearrangement involved
Epidemiology: incidence 1/100 000
Etiology: unknown
Risk factors: radiation
Pathophysiology: gene rearrangment bcr, abl
bcr/abl –
tyrosinkinase. Cytogenetic marker: t(9;22) = Ph chromosome.
Course of the disease
Chronic phase: 50% patients diagnosed incidentialy:
sweating, weight loss, pruritus, left hypochondrium
pressure
Acceleration phase: symptoms stressed, treatment with
decreased effect (need for increase effect)
Blastic phase: anaemic syndrome, infection,
haemorhagia, left hypochondrial tension – splenomegaly
Diagnosis of CML
Blood counts:
Chronic phase: leukocytosis with left shift to myeloblasts
Acceleration phase: Number of blasts in peripheral blood or bone
marrow: 10-30%, eosinophils and basophils: > 20%
Blastic phase: blasts >30%, blasts and promyelocytes > 50%
Bone marrow cytology: rich BM with majority of myelocytes (chronic
phase)
Bone marrow - histology: different degree of fibrosis
Other: erythrocytosis, thrombocytosis, splenomegaly, hepatomegaly
low ALP index in leukocytes, uric acid
CYTOGENETICS: Ph chromosome,
MOL. GENETICS: bcr/abl +
Treatment of CML
• Risk assessment according to Hasford´s index
• IMATINIB MESYLATE (GLIVEC): treatment of choice for
1.line in patients with low H. index
• Young patients (pod 45 let) with higher Hasford´s index and
available HLA donnor: alogenneic stem cell transplantation
• Patients reafractory to GLIVEC or in relaps: allogeneic stem cell
transplantation or new thyrosine kinase generation (dasatinib,
nilotinib)
• Alternative and obsolete: Interferon-, hydroxyurea, busulfan
Imatinib mesylate (Glivec®)
• first specific inhibitor of tyrosinkinase bcr/abl (TKI)
• mode of action: occupies binding site ATP
• standard dose: 400mg/D p.o.
• 90,3% of patients survive after 54 months of therapy
Tolerance: very good
Side effects: swellings, rush, neutropenia
New TK inhibitors: dasatinib (SPRYCEL®), nilotinib
(TASIGNA®)
% responding
Cumulative Best Response at 12 and
60 months on First-line Imatinib
100
96%
90
85%
84%
80%
80
98%
92%
87%
69%
70
60
50
40
30
CHR
MCyR
CCyR
20
10
0
0
6
12
18
24
30
36
42
48
54
60
66
Event-free Survival and Survival
Without AP/BC on First-line Imatinib
100
90
% without event
80
70
Estimated rate at 60 months (with 95%CI)
60
93% (90-96)
50
83% (80-87)
40
Survival without AP/BC
30
Event-free Survival
Actual Events
6.3% AP/BC (n=35)
5.1% loss of MCyR (n=28)
2.5% loss of CHR (n=14)
1.6% CML-unrelated deaths (n=9)
20
10
0
0
6
12
18
24
30
36
42
48
Months since randomization
54
60
66
Survival Without AP/BC by Sokal Group in
Patients with CCyR on First-line Imatinib
100
% without PD to AP/BC
90
80
70
60
50
40
Estimated rate at 60 months
30
Low risk
Intermediate risk
High risk
20
10
n= 179
n= 91
n= 49
99%
95%
95%
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 p=0.09
p=0.16
p=0.200 (overall)
0
0
6
12
18
24
30
36
42
48
54
60
66
IRIS study – complete cytogenetic response
100
Imatinib
IFN+Ara-C
90
% responding
80
76%
69%
70
63%
60
51%
50
p<0.001
40
30
25%
20
10
1% 3%
9%
14%
12%
0
0
3
6
9
12
15
18
MonthsMonths
after randomization
since randomization
21
24
CML- terms definition
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Complete hematological response (CHR)
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No cytogenetic response:
>95% Ph+
Minimal cytogenetic response:
66-95% Ph+
Minor cytogenetic response:
36-65% Ph+
Parcial cytogenetic response (PCyR):
1-35% Ph+
Complete cytogenetic response(CCyR):
0% Ph+
MAJOR cytog. Resp.:
CCyR + PCyR
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MAJOR cyt. resp. : <0,1% RQ-PCR
CMR: RQ-PCR neg.
Aim - imatinib tratment
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Complete hematol. remision:
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Parcial cytogenet. remision:
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Complete cytogenet. remision:
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Major molecular response:
3m
6m
12m
18m
Treatment failure in CML
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Hematologic response
No hematol. Response in 3m, loss of
CHR any time
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Cytogenetic response
No cytogenet. Response in 6 m
MCyR not completed in 12m
CCyR not completed in 18m
Loss of CCyRany time
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Molecular response
NA
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Rezistent mutants
Detection of imatinib-rezistant
variant of BCR/ABL any time
IMATINIB: treatment failure or
suboptimal response
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Primar rezistance
Patients seldomly don´t reach CHR
But : 20-25% do not reach CCyR
Secundary rezistance
20-25% pacients, who reach CHR and
CCyR but do not withold
Molecular response? (>0,1%)?
Reasons for resinstance to (TKI)
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Farmakokinetics: biol. availability and blood levels differs
inter-individually
In future :dose according to blood levels
•Reasons for rezistence due to the clone
1.Mutation Bcr-Abl
2.Increased expression of Bcr-Abl
3. increased expression ofMDR1 (
P-glykoprotein)
4.Src family kinase activation
5.„sleeping“ CML stem cells
BCR-ABL mutation
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Highly resistent to imatinib, nilotinib,
dasatainib: T315I
Mutation relatively resistant to nilotinib :
E255/KV
Mutation relatively rezistant to dasatinib:
F317L/I
Approach in case of imatinib
rezistance
Not reaching or loss of CHR and/or CCyR
Not reaching major molecular response (?)
Imatinib
600-800mg/D
Nilotinib
Dasatinib
Allogeneic HSCT
Acceleration phase and blastic phase
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AP CML: blasts 10-19%, basophilia ≥20%,
↑ splenomeglia, constitution sy,
thrombocytosis + leukocytosis.
BP CML blasts ≥20%, chloroma
Dasatinib,
Nilotinib
Allogeneic SCT
IF- α, hydroxyurea, ARA-C
Nilotinib (Tasigna®)
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Molecule obtained by crystalization of imatinib
30-50x more active inhibition of Bcr-Abl and
most variants excepta T315I
Based on results of studies phase II – indication
in patients with CP and AP CML resistant to
imatinib (or intolerance to imatinib)
Minimal toxicity: hematologic toxicity, QT interval
prolongation.
Structure of nilotinib - optimaliztion of bonding and
inactivation of ABL kinase domaine
Hydrogen bridges with certain
amino acids
More effective bonding to
ATB binding site
Imatinib
ATP binding site
Nilotinib
Lipofile interactions instead of hydrogen
bridges => smaller sensitivity towards
point mutations Bcr-Abl
Dasatinib (Sprycel®)
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„multi target“ kinase inhibitor (Bcr-Abl,
SRC, TEC, PDGFR, kit etc.)
cca 100x more active then imatinib , but
inactive in T315I
Inactive in F317L variant
Unable to eliminate sleeping CML stem
cells (CD34+CD38-)
Toxic profile: hematological toxicity,
fluidothorax
Bosutinib (SKI-606, Wyeth)
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Effective in resistant variants: Y253F,
E255K, atd.
Ineffective in T315I
Ineffective inc-kit a PDGFR
Very promising toxic profile (GIT,
hematological toxicity–only in advanced
CML)
Other medicaments in CML
treatment
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heat shock proteinu 90 inhibitors
Arsenic trioxide (Trisenox)
Homoharringtonine
Histondeacetylase inhibitors
Farnesyltransferase inhibitors (RAS)
Etc.
Polycythaemia vera (PV)
Incidence: 0,5 – 0,8/100 000
Median: 60 years
Etiology: unknown in most cases (some: ionizing
radiation)
Definition: myeloprolipherative clonal disease derived
from a stem cell with major erythrocyte prolipheration
Patophysiology: > 25% erythrocyte mass, erythrocytosis,
hyperviscosity, hyperuricaemia, trend to vessel
complications
PV – diagnosis
1. Exclude secondary and relative erythrocytosis
(ChOBPD, EPO doping, plasma depletion, etc.)
2. Exclude other MPDs (bcr/abl),endo EPO level
JAK-2 mutation +
If JAK-2 negative, than
1. Erythrocyte mass > 25% above normal, practically:
hematocrit in females > 0,56, in males: > 0,60.
2. Bone marrow: cytology only supportive, histology:
degree of fibrosis + erythropoiesis prolipheration
3. BM cultivation in EPO presence, EPO level
PV - treatment
1. Blood draw ( 300-500 cc (1x in 6 – 8 weeks). Aim:
HCT < 0,45
2. If venepunction is not effective: Litalir (hydroxyurea) in
older patients
3. Interferon alfa in younger patients and in women of
fertile age
4. Anagrelide (Tromboreduktin)
All patients: antiaggregation therapy (Acetylsalic acid) if
not contraindicated
Essential thrombocythaemia
(ET)
Incidence: 0,1/100000
In majority clonal disease with accelerated proliferation of
megakaryocyte line
Peripheral blood count: PLT > 600 x109/l, slight leukocytosis
with a left shift.
Blood counts: 1. Bleeding (PLT > 1500 x109/l), 2.
Thrombosis (PLT < 1500 x109/l). Thrombosis in atypical
sites: v. jugularis, v. portae etc.
Dif. diagnosis: iron deficiency, reactive thrombocytosis
(chron. Inflammatory diseases), tumors.
Treatment of ET
Risk factors: younger patients(< 60 let) without thrombosis
or haemorrhagia in history: no therapy
Other:
1. Hydroxyurea in men, women after fertile age
2. Interferon -  (3MU 3 x in a week) in women in fertile age
3. Anagrelide
Supportive treatment: Anopyrine, thrombocytapheresis.