Chronic Myeloid Leukaemia and Treatment Overview · 2018-03-16 · Chronic Myeloid Leukaemia and...

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