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Chronic Myeloid Leukaemia and Treatment Overview CML&MPN Annual Nurses Meeting 2018 Simone Claudiani, MD Clinical Research Fellow – Haematology Department Hammersmith Hospital 09/03/2018
Chronic Myeloid Leukaemia
and
Treatment
Overview
CML&MPN Annual Nurses Meeting 2018
Simone Claudiani, MD
Clinical Research Fellow – Haematology Department
Hammersmith Hospital
09/03/2018
Topics
• What CML is and its clinical presentation
• History, molecular pathogenesis of CML and old treatments
• Principles and outcomes of targeted therapy in CML
• Stopping therapy and new esperimental therapies in CML
• Role of allogeneic stem cell transplantation in CML
What CML is?
• Clonal stem cell disorder; one of a group of diseases known as the
myeloproliferative disorders (MPD).
Chronic myeloid leukaemia
CML
ET
PV
MF
MPD
Chronic phase Advanced Phases
Acceleration Blast crisis
Stable for a median of
5-6 years
Duration 6-12 months
Survival 3-6 months
Natural History of CML
CML - Epidemiology
CML: phase CML: BCR-ABL pos
‘types’
Chronic: 90%
balst
accelerated
Ph positive >
95%
Ph negative,
BCR-ABL pos: <5%
Adapted from SEER statistics and NCCN 2017
99% p210, 1% p190
&
CML and its presentation
CML in
chronic
phase
- WCC raised (very rarely normal or low)
- Hb low > normal
- Plts raised>>low>>normal
- Splenomegaly (variable)
- Peripheral blood smear:
granulocytes in all the different stage of maturation till
early rpecursors (blasts)
- blast % in PB and BM should be <19% (ELN) / <10%
(WHO)/<15% (MDACC); basophils < 20%
- Cytogenetic: Ph chromosome (WHO 2016: without major
route abnormalities)
- No extramedullary blast proliferation
Often diagnosed
INCIDENTALLY
History, molecular pathogenesis and old
treatments
1960-1973
Rowley JD. A new consistent chromosomal
abnormality in chronic myelogenous
leukaemia identified by quinacrine
fluorescence and Giemsa banding.
Nature 1973; 243: 290-293
Nowell & Hungerford. A minute
chromosome in chronic granulocytic
leukaemia. Science 1960; 132: 1497
The Molecular Years
Analysis breakpoints on chromosome 22
Groffen J, Stephenson JR, de Klein A, Bartram
CR, Grosveld G. Philadelphia chromosomal
breakpoints are clustered within a limited region,
bcr, on chromosome 22.
Cell, 1984
Nature 1985 315: 550-4
Philadelphia chromosome 1960 Karyotype: 46,XY,t(9;22)(q34;q11)
9q+
22q-
9 9q(+) 22 Ph
q34.1
q11.2
The t(9;22) translocation produces the Philadelphia (Ph) chromosome
22q- (Ph)
bcr-abl
abl
22
bcr
9 9q+
expresses a fusion
oncoprotein with
tyrosine kinase activity
abl-bcr
Classical t(9;22)(q34.1;q11.2) Dual Fusion (D-FISH) Signal Pattern
Ph
22 der(9)
9
BCR
ABL
9 der(9) Ph 22
Vysis
Proliferation, decreased apoptosis, increased myeloid compartment
BCR-ABL Genetic instability DNA damage Impairment of DNA repair
Progression to BC
CP Stimulation of signaling
ROS
DNA-damage
H2O-
H2O2
-OH
Role of BCR-ABL in CML
Hehlmann and Saußele, Haematologica 2008; 93:1765
CML – history of therapy
• 1865 First treatment (arsenic)
• 1903 Splenic irradiation
• 1917 / 1924 First reports on survival in CML
• 1953 Busulfan in CML treatment
• 1964 Hydroxyurea in CML
• 1979 Transplantation for CML
• 1986 IFN in CML
Targeted therapy in CML - TKI era
28 May 2001
Tyrosin kinase inhibitors (TKIs)
Imatinib (1st generation TKI)
Nilotinib (2nd generation TKI)
Dasatinib (2nd generation TKI)
Bosutinib (2nd generation TKI)
Ponatinib (3rd generation TKI)
BCR-ABL
RAS-GDP
RAF-1
SHC CRKL
BAD
SOS
GRB-2 CBL CRK
14-3-3
BCLXL
Mitochondria
BCLXL
Cytoskeletal
proteins
P
STAT1+5
P
RAS-GTP
SAPK
P
P
AKT P
14-3-3
BAD
P
RAS-GAP DOK
?
MYC
PI3K P
ERK
P
MEK1/2
P
Improvement of survival of CML 1983 – 2010
German CML Study Group
Year after diagnosis
Surv
ival
pro
pab
ility
n = 3140
Imatinib, 2002 – 2010 (CML IV) 5-year survival 91%
IFN or SCT, 1997 – 2003 (CML IIIA) 5-year survival 71%
IFN or SCT, 1995 – 2001 (CML III) 5-year survival 63%
IFN, 1986 – 1994 5-year survival 53%
Hydroxyurea, 1983 – 1994, 5 yr surv. 46%
Busulfan, 1983 – 1994 5-year survival 38%
(CML I, II)
NEJM 9th March 2017
IRIS trial
2262 patients from the Swedish Cancer Registry
1973-2013
Bower H, JCO 2016
Bower H, JCO 2016
Chronic myeloid leukaemia – risk stratification
HASFORD
(or Euro s., 1998) SOKAL (1984) EUTOS (2011)
Age
Plt count
Blast % on pb
Spleen size
Age
Plt count
Blast % on pb
Spleen size
Basophil % on pb
Eosinophil % on pb
Basophil % on pb
Spleen size
low/intermediate/high risk low/intermediate/high risk low/high risk
CML – Prognostic scores
EUTOS long-
term survival
(ELTS) score
• Age
• Spleen
• Blast % in pb
• Plts
developed on the basis of
2,205 adult patients with
Philadelphia chromosome-
positive and/or BCR-
ABL1-positive chronic-
phase CML, transcript
type b2a2 and/or b3a2,
and any form of imatinib-
based treatment within six
months from diagnosis
The probability of dying of CML was significantly increased by
higher age, a bigger spleen size, a higher percentage of
peripheral blasts and low platelet counts.
the ELTS score provided a superior prognostic
discrimination of the probabilities of
CML-related death and of overall survival as
compared with the Sokal, the Euro or the
EUTOS score
Leukemia 2016 Jan;30(1):48-56
CML – approved TKIs for CML chronic phase
Imatinib: 1L
Nilotinib: 1L
2 or > L in case of previous Imatinib or Dasatinib or
Bosutinib failure or intolerance
Dasatinib: 1L
2 or > L in case of previous Imatinib or Dasatinib or
Bosutinib failure or intolerance
Bosutinib: 1L (not yet licensed in UK)
2 or > L in case of previous Imatinib or Dasatinib or
Nilotinib failure or intolerance
Ponatinib: 3 or > L (with or without T315I); 2L after I/D or N if
T315I
Baccarani et al, Blood 2013
CP treatment - ELN 2013 recommendations
Baccarani et al, Blood 2013
AP and BP treatment - ELN 2013 recommendations
Parameter result
WBC <10 x 109/L
Plts <450 x 109/L
Differential no immature granulocytes and
<5% basophils
Spleen size No splenomegaly
Complete haematological Response (Full blood count and physical examination)
Level of response % Philadephia chromosome
Complete (CCyR) 0
Partial 1-35
Minor 36-65
Minimal 66-95
Cytogenetic Response (cytogenetic analysis)
Level of response % of BCR-ABL/normal ABL
MR1 <10
MR2 <1
MR3 <0.1
MR4 <0.01
MR4.5 <0.0032
MR5 <0.001
Molecular Response (PCR - molecular lab test)
Time Failure Warnings Optimal
Diagnosis - High risk
ACA in Ph+ cells -
3 mos Non CHR
Ph+ > 95%
BCR-ABL1 > 10%,
Ph+ 36-95%
BCR-ABL1 ≤ 10%
Ph+ < 35%
6 mos BCR-ABL1 > 10%,
Ph + > 35%
BCR-ABL1 1-10%,
Ph + 1-35%
BCR-ABL1 < 1%
Ph + 0
12 mos BCR-ABL1 > 1%,
Ph + > 0 BCR-ABL1 0.1-1 % BCR-ABL1 ≤ 0.1%
Anytime
Loss of CHR
Loss of CCyR
Confirmed loss of MMR
Mutations
CCA/Ph +
CCA/Ph- (-7, or 7q) BCR-ABL1 ≤ 0.1%
Definition of failure and optimal response
to 1st line (Baccarani et al. 2013)
BCR-ABLIS n 5Y-OS
≤10% 501 95%
>10% 191 87%
<0.001
p-value
>10%
≤10%
Hanfstein et al Leukemia 2012
German CML V: OS by BCR-ABLIS at 3 mths
TTF
Outcome of first line imatinib
De Lavallade et al, JCO, 2008
Apperley J et al, Haematol Clin Oncol N Am 2014
Why Do Patients Fail Imatinib?
Apperley, Lancet Oncology 2007.
• Records the time of opening the
container
• Most reliable method of measuring
compliance
– Pill counts: overestimate adherence
– Self reporting: overestimates adherence
Microelectronic Monitoring System MEMS 6
Trackcap
Six-year probability of MMR according to
the measured adherence rate
726660544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Months from start of imatinib therapy
Pro
babili
ty
of
MM
R
Adherence >90%, n= 64
Adherence ≤90%, n= 23
p <0.0001
726660544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
726660544842363024181260 726660544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Months from start of imatinib therapy
Pro
babili
ty
of
MM
R
Adherence >90%, n= 64
Adherence ≤90%, n= 23
p <0.0001
Marin D et al, JCO 2010 May10;28(14):2381-8
Incidence of Mutations in Imatinib ‘Failures’
0
20
40
60
80
100
120
Nu
mb
er o
f p
atie
nts
(to
tal n
= 8
11)
0%
2%
4%
6%
8%
10%
12%
14%
Apperley, Lancet. 2007
15 mutations ~ 90% all cases
BCR-ABL kinase domain mutational screening
Ponatinib: a ‘pan-BCR-ABL kinase inhibitor’
exhibits potent activity against native, T315I, and all other clinically relevant mutants, and showed better
inhibition than the previously known inhibitors Cortes JE et al, NEJM 2012
Comparison of 2GTKIs in 2nd line, after 24
months of therapy
Hochhaus A al, Ann Hematol 2015, 94(Suppl 2): S133-S140
Pre-2G-TKI therapy independent predictive factors for
CCyR in 90 CP patients
Milojkovic, et al. Haematologica 2010
21%
100%
58%
Independent predictors for
CCyR:
1. Sokal risk group
2. Best cytogenetic response on
imatinib
3. Neutropenia on imatinib
4. Time from failure to
commencement of 2nd-
generation TKI
30 24 18 12 6 0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Months from starting 2G-TKI therapy
Cu
mu
lative
in
cid
en
ce o
f C
CyR
Good risk n=20
Intermediate risk n=26
Poor risk n=34
p<0.0001
p=0.001
30 24 18 12 6 0
1.0
0.8
0.6
0.4
0.2
0.0
p<0.0001
p=0.001
2GTKI and 3GTKI first line
ENESTnd: Nilotinib vs Imatinib in CML-CP
Larson R. A. et al.JCO 28:7s ASCO 2010 (suppl; abs 6501, Oral) 47
Study Design and Endpoints
• Primary endpoint: MMR at 12 months
• Key secondary endpoint: Durable MMR at 24 months
• Other endpoints: CCyR by 12 months, time to MMR
and CCyR, EFS, PFS, time to AP/BC on
study treatment, OS including follow-up
*Stratification by Sokal risk score
Imatinib 400 mg QD (n = 283)
Nilotinib 300 mg BID (n = 282) R A N D O M I Z ED *
Nilotinib 400 mg BID (n = 281)
• N = 846
• 217 centers
• 35 countries
Follow-up
5 years
80%85%
78%82%
65%
74%
0%
20%
40%
60%
80%
100%
Month 12 Overall
Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD
CCyR Rates* by 12 Months and Overall
P < .0001
P < .001
% C
CyR
Data cut-off: 2Jan2010
n = 282 n = 281 n = 283
P < .001
P = .017
• Among patients who had a cytogenetic assessment at 18 months (n = 442/846), the rates of CCyR were:
• 99%, 99%, and 89% for nilotinib 300 mg BID, 400 mg BID, and imatinib
*ITT population
n = 282 n = 281 n = 283
ENESTnd: Nilotinib vs Imatinib in CML-CP
Larson R. A. et al.JCO 28:7s ASCO 2010 (suppl; abs 6501, Oral)
Cumulative Incidence of MMR*
40%
66% (P < .0001)
62% (P < .0001)
Pts
24
55% (P < .0001)
51% (P < .0001)
27%
100
90
80
70
60
50
40
30
20
10
0
3 6 9 12 15 18 21
Pati
en
ts w
ith
MM
R (
%)
Time Since Randomization (mo)
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
282
281
283
0
Best response
by 12 mo.
Overall
best response
Data cut-off: 2Jan2010 *ITT population 49
ENESTnd: Nilotinib vs Imatinib in CML-CP
Larson R. A. et al.JCO 28:7s ASCO 2010 (suppl; abs 6501, Oral) 50
Progression to AP/BC on Study Treatment*
Data cut-off: 2Jan2010
With a median follow-up of 18.5 months.
P-values are based on log-rank test stratified by Sokal risk group vs imatinib for time to AP/BC.
*ITT population
Nu
mb
er
of
Pa
tie
nts
P = .006
P = .003
1
12
10
15
20
Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD
4.2%
0.4% 0.7%
2
0
5
ENESTnd: Nilotinib vs Imatinib in CML-CP
Larson R. A. et al.JCO 28:7s ASCO 2010 (suppl; abs 6501, Oral) Hochhaus A, et al Leukemia 2016
5 years follow-up update
52 ASCO 2010, Abstract # LBA6500
Dasatinib Versus Imatinib Study In Treatment-naïve CML: DASISION (CA180-056). Design
● Primary endpoint: Confirmed CCyR by 12 months
● Secondary/other endpoints: Rates of CCyR and MMR; times to
confirmed CCyR, CCyR and MMR; time in confirmed CCyR and
CCyR; PFS; overall survival
Follow-up
5 years Randomize
d* Imatinib 400 mg QD (n=260)
Dasatinib 100 mg QD (n=259) • N=519
• 108 centers
• 26 countries
*Stratified by Hasford risk score
53 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. CCyR rates (ITT)
54
7378
83
31
59
6772
0
20
40
60
80
100
Mo 3 Mo 6 Mo 9 Mo 12
P=0.0011
Dasatinib 100mg QD Imatinib 400mg QD
CCyR
(%)
• By analysis of time to CCyR, likelihood of achieving CCyR at any time ~50%
higher with dasatinib than with imatinib (stratified log-rank P<0.0001; HR=1.53)
54 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. MMR Rates (ITT)
8
27
39
4652
0.4
8
18
2834
0
20
40
60
80
100Dasatinib 100 mg QD
Imatinib 400 mg QD
P<0.0001
MMR
(%)
Mo 3 Mo 6 Mo 9 Mo 12 Any time
P<0.00003
55 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Time to MMR
• Patients were twice as likely to achieve MMR at any time with dasatinib vs. imatinib
• In patients achieving MMR, median time to MMR 6.3 mos with dasatinib vs. 9.2 mos
with imatinib
MMR
(%)
Mos 0 3 6 9 12 15 18 21 24 27
100
80
60
40
20
0
P<0.0001 (stratified log-rank)
Hazard ratio for dasatinib
over imatinib: 2.01
Dasatinib
Imatinib
56 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Progression to AP/BP
● No patient who achieved MMR progressed to accelerated or blast phase
● 2 patients who achieved CCyR progressed to accelerated or blast phase
(1 with dasatinib, 1 with imatinib)
5
9
0
5
10
15
Progressed
to AP/BP
(n)
3.5%
1.9%
Dasatinib 100 mg QD
Imatinib 400 mg QD
5 years follow-up update
DASISION: Dasatinib vs Imatinib in 1st line
Bosutinib 1st line
Brummendorph TH et al, BJH 2015;168: 69-81
BELA study 24 months follow-up
• 2y-CI of MMR: 59% (B) vs 49% (I)
• 2y PFS: 92% vs 88%
• 2y OS: 97% vs 95%
• Transformations to AP/BP: 4 (B) vs 14 (I)
• Treatment discontinuation due to tox in
the 1st year: 25% (B) vs 9% (I)
Ponatinib 1st line
Lipton et al, ASH 2014
EPIC study: closed due to serious
cardiovascular events associated with
Ponatinib
Overall 103/109 (94.5%)
Overall 77/114 (67.5%)
List of Vascular Occlusive AEs (serious AEs indicated by *)
Ponatinib n=12a
Imatinib n=3a
• Cardiac discomfort (n=1)
• Coronary artery stenosis (n=1)
• Intermittent claudication (n=1)
• Acute myocardial infarction (n=2)*
• Angina pectoris (n=2)*
• Coronary artery disease (n=2)*
• Cerebrovascular accident (n=1)*
• Dysarthria (n=1)*
• Peripheral artery thrombosis (n=1)*
• Retinal vein thrombosis (n=1)*
• Transient ischemic attack (n=1)*
• Peripheral arterial occlusive disease (n=2)*
• Electrocardiogram ST-segment depression (n=1)
• Peripheral vascular disorder (n=1) • Hypoxic-ischemic encephalopathy (n=1)*
EPIC study - Vascular Occlusive Events
Which TKI 1st line? ……
CML – Which TKI in 1st line? TKI toxicities
Apperley JF, Lancet 2015
Apperley J et al, Haematol Clin Oncol N Am 2014
Stopping therapy and new
experimental therapies in CML
Imatinib discontinuation after:
- Imatinib therapy duration > 3 years AND
- sustained MR4.5 for at least 2 years
100 patients
After a median followup of 77 months:
- 61 lost CMR4.5 (of whom 17 lost MMR)
- 38 in TFR (treatment free remission)
- 1 patient died in TFR
The majority of molecular relapses occurred within 6 months
(median 2.5 months)
96.5% of those restarting Imatinib achieved again a molecular
remission
STIM trial
6-years STIM follow-up, JCO 2017
STIM trial
6-years STIM follow-up, JCO 2017
Features of CML and TKI therapy that guide attempts to stop therapy
Saußele S et al, Leukemia 2016
Emerging NON-TKI therapies for CML
Kavanagh S et al, Expert Opinion on Emerging Drugs 2018
New experimental therapies in CML
Mahon XF, Ann Hematol 2015
Allogeneic bone marrow transplant in CML
Pavlu J, Szydlo R, Goldman JM and Apperley J Blood 2011
Mughal TI at al, Haematologica 2016
Apperley J, Lancet 2015
Factors affecting the outcome of bone marrow transplant in
CML – The EBMT score
Pavlu J, Szydlo R, Goldman JM and Apperley J Blood 2011
ELN 2013 recommendations
Acknowledgements
CML Clinical Team: George Nesr, Simone Claudiani, Dragana Milojkovic and Jane
Apperley & Irene Caballes
CML Lab Team: Georgios Nteliopoulos, Mary Alikian, Katya Mokretar, Jamshid
Khorashad, Letizia Foroni
