Chronic myeloid leukemia

G. Verhoef, department of

Hematology, Leuven

(seminar 7: postgraduate course MDS and MPN, BHS, October 4, 2014)

Chronic myeloid leukemia

• Diagnosis of CML

• Treatment modalities

• Follow up of a patient treated with TKI

Usual features of myeloid disorders at diagnosis

Disease BM

cellularity

% marrow

blasts

Maturation morphology hematopoiesis Blood

counts

Organo-

megaly

Mypro ++

Clinical presentation of CML

• 20-40 % of patients are asymptomatic and are diagnosed

when a blood cell count performed at the time of routine

medical examination is found to be abnormal

• Median age: 50-60 years, slight male predominance

• Common findings: fatigue, weight loss, night sweats,

splenomegaly and anemia

• Trombocytosis

• Presentation in accelerated or blast crisis is rare (

National Cancer Registry

Disease Incidence Male

(/100.000)

Incidence Female

(/100.000)

GI 72 63

Respiratory 86 15

Breast 1 95

Skin 9 11

Urinary tract 31 13

CML 1.2 1.0

56 year old male, 2 months history of fatigue and night

sweats. Splenomegaly (6 cm).

• Hb 10.5 g/dL

• Platelets 560 x 109/L

• WBC: 125 x 109/L

• Segmented neutrophils: 44%

• Band neutrophils: 4%

• Lymphocytes: 10%

• Eosinophils: 3%

• Basophils: 7%

• Promyelocytes: 2%

• Myelocytes 19%

• Metamyelocytes 10%

CML: peripheral blood

CML: small mega’s without dysplasia

normal

PV

CML: sea blue histiocytes

t(9;22)(q34;q11.2)

Recommendations for the diagnostic workup

and for assessing and monitoring response

Baseline To assess response To monitor the response

Blood counts and diff Yes Every 2 wks until CHR Every 3 months

Bone marrow cytology Yes No No

Bone marrow karyotype Yes At 3 and 6 months, then

every 6 months until CCgR

Every 12 months, once CCgR

only if molecular response

cannot be assessed

Blood, I-FISH No No Only if CBA of marrow cell

metaphases and molecular

response cannot be assesed

Blood, RT-PCR

(qualitative)

Yes No No

Blood, RT-Q-PCR

(quantitative, BCR-

ABL%)

No Every 3 months until MMR Every 6 months once a MMR

has been achieved

Mutational analysis Only AP

or BP

No Only in case of failure

Spleen size (cm) Yes

Why bone marrow cytology

• ELN criteria for accelerated or blast phase of CML

• Accelerated phase– Blasts 15-29 % blasts in blood or bone marrow

– blasts plus promyelocytes ≥30% in blood or bone marrow

– Basophils ≥20% basophils in blood

– Platelets

Why bone marrow karyotyping?

• FISH in case of Ph-negativity to identify variant, cryptic translocations

Qualitative PCR

• Qualitative PCR (identification of trancript

type

– p210: e13a2, e14a2

– P190: e2a2

• A negative result of routinely used PCR

cannot be used to rule out a diagnosis of

CML since rare transcripts (e13a3, e14a3,

e19a2) are not always detected

Why spleen size at diagnosis?

Sokal (1984) EURO (1998) EUTOS (2011)

Age yes yes

Spleen size yes yes yes

% blasts yes yes

Platelet count yes

Basophils % yes yes

Eosinophils % yes

Risk of CML patient can be calculated provided that the data are

collected prior to any treatment

Sokal EURO EUTOS

Age (years) 0.116 (age -43.4) 0.666 when > 50 yr NA

Spleen size (cm) 0.345 (spleen-7.51) 0.042 x spleen 4 x spleen

Platelet count (x 109/L) 0.188 x [(platelet/700)²-0.563] 1.0956 when plt>1500 NA

Blood blasts (%) 0.887 x (blast cells-2.1) 0.0584 x blast cells NA

Blood basophils (%) NA 0.20399 when basophils>3% 7 x basophils

Blood eosinophils (%) NA 0.0413 x eosinophils NA

Relative risk Exponential of the total Total x 1000 Total

Low 1.2 >1480 >87

PFS calculated for all 2010 patients with follow-up (log-rank test P = .0069).

Hasford J et al. Blood 2011;118:686-692

Initial work up

• Cardiovascular events? Medication?

• Lipase, amylase, TSH, glycemia, HbA1c,

lipid profile, β-HCG for women of

childbearing age

• ECG to excluse QT syndrome

• Echocardiography to rule out pulmonary

hypertension

Differentiaal diagnose CML• Leukemoïde reactie

• Atypical CML, CMML, CNL, ET

Fusion gene Translocation

BCR-ABL

ETV6-ABL

t(9;22)(q34;q11)

t(9;12)(q34;p13)

ZNF198-FGFR1

FOP-FGFRI

CEP110-FGFR1

BCR-FDGFR1

Myeloid/lymphoid neoplasms

with FGFR1 (8p11 mypro)

t(8;13)(p11;q12)

t(6;8)(q27;p11)

t(8;9)(p11;q33)

t(8;22)(p11;q22)

ETV6-PDGFRB

HIP1-PDGFRB

H4-PDGFRB

RAB5-PDGFRB

Myeloid/lymphoid neoplasms

with PDGFRB (5q33 mypro)

t(5;12)(q33;p13)

t(5;7)(q33;q11)

t(5;10)(q33;q21)

t(5;17)(q33:p13)

ETV6-JAK2

BCR-JAK2

t(9;12)(p24;p13)

t(9;22)(p24;q11)

ETV6-SYK2 t(9;12)(q22;p12)

Three phases of the Disease(before imatinib)

chronic phase accelerated blast phase

36-48 months 6 months 3-6 months

Surv

ivin

g p

erce

nt

Years after diagnosis

Treatment of CML before 2000

• Busulfan

• hydroxyurea

• interferon

• Standard treatment if no donor available:

interferon and low dose of Ara-C

• Standard treatment if donor available:

allo-SCT

Before 2000: hydrea

•Interferon: difficult but a small survival advantage for 15% of pts

Lessons from interferon

Lessons from allogeneic stem cell

transplantation in CML?

If you and/or your patient consider an

allogeneic SCT • At present the only proven curative therapy (for 18% of all CML

patients), thus certainly not for all patients !

• Only available for 30 % of all CML patients

• Molecular remissions are frequent!

• Rather toxic treatment!

• Start treatment in chronic phase of CML and don’t wait to long!

treatment

“past, present” “present, future”

The importance of basic research: CML as an example

Some Important Landmarks in the

Biology of CML1845 – Described almost simultaneously in Berlin (Rudolph

Virchow) and in Scotland (John Hughes Bennett)

1960 – The Philadelphia chromosome (22q-)

1970 – Discovery of the Abelson proto-oncogene

1973 – Reciprocal translocation involving one member of the

chromosome pairs 9 and 22

1984 – The breakpoint cluster region on chromosome 22

1986 – BCR-ABL fusion gene on 22q-

1990 – BCR-ABL causes leukaemia in mice

1994 – BCR-ABL transcripts in normal people

Nowell PC, Hungerford DA. J Nat Cancer Inst 1960:25:85–109.

Chromosome Studies on Normal and

Leukaemic Human Leukocytes

1960

“…I noted some extra chromosomal material at the end of

chromosome 9. I immediately analyzed the chronic phase sample

from both patients by Q-banding. I could see the added material on

the end of chromosome 9 (9q+) in these samples. I confirmed the

translocation in 2 more patients, both in blast crisis, and sent the

paper to Nature. It was rejected... with comments suggesting that this

was an unusual chromosomal variant that was normal.”

1973

The 9;22 Chromosomal Translocation

J.D. Rowley

The t(9;22) Translocation Produces a Philadelphia (Ph)

Chromosome and the BCR-ABL1 Fusion Gene

22q- (Ph)

ABL1

22

BCR

9 9q+

Expresses a fusion

oncoprotein with

enhanced tyrosine

kinase (TK) activity

BCR-ABL1

ABL1-BCR

Normal

chromosomes CML chromosomes

Reviewed in Goldman JM, Melo JV. Acta Haematol 2008;119:212–217.

1984: John Groffen, Nora Heisterkamp

Gerard Grosveld, Owen Witte

Goldman et al. N Engl J Med 2003; 349:1451-64

↑Proliferation ↓Adherence ↓Apoptosis

http://content.nejm.org/content/vol349/issue15/images/large/11f3.jpeghttp://content.nejm.org/content/vol349/issue15/images/large/11f3.jpeg

1990s—Oncologist Brian Druker

discovers how BCR-ABL triggers

excessive division of white blood

cells and shows that STI571, a

compound developed by

Novartis, has anti-BCR-ABL

activity in cell cultures.

NEJM, 346, 683, 2002

Imatinib targets CML at its source [t(9;22)]

CGP57148B: A Phenylaminopyrimidine

Derivative

N

N

N N

H

N

H

O

N

N

Potent inhibition of ABL-K, c-kit and PDGF-R

Salts are soluble in water

Orally bioavailable

Not mutagenic

Batch 1:

331 mg, 26 August 1992

Cellular permeability

No PKC inhibition

Tyrosine kinase inhibitory activity

Stability to hydrolysis

Solubilisation

1992PDGF-R=platelet-derived growth factor receptor; PKC=protein kinase C.

Capdeville R, et al. Nat Rev Drug Discov 2002;1:493–502.

1996

Nature Medicine 1996;2:561–566

Druker BJ, et al. Nature Medicine 1996;2:561–566.

100

10

1

0 30 60 90 120 150

Duration of treatment with STI571 (days)

Wh

ite-

cell

co

un

t (c

ells

/10

-

3/m

m³)

Imatinib is highly effective in Interferon-

resistent CML patients:

A phase I dose finding study

Druker et al. NEJM, 2001

2001

Phase II results with Imatinib in CML

Chronic phase

(IFN failure)1

Accelerated

phase2Blast crisis3

N=532 N=235 N=260

CHR 95% 34% 8%

MCR 60% 24% 16%

CCR 41% 17% 7%

Disease

progression

11% 40% 80%

1Kantarjian et al.,N Engl J Med, 346: 645 (2002), 2Talpaz et al., Blood, 99: 1928 (2002)3Sawyers et al., Blood, 99: 99: 3530 (2002)

2002

The IRIS Study

International Randomized Study of

Interferon + Ara-C Vs. STI571* in

patients with a newly diagnosis of

Chronic Myeloid Leukemia

* Imatinib / Gleevec / Glivec

N Eng J Med 348, 11:994-1004 (2003)

Study Design and Current

Patient Status

IFN-α+

Ara-C

Imatinib

Crossover

R

A

N

D

O

M

I

Z

E

n = 553

n = 553

382 (69%)

16 (3%)

Deininger M, et al.

Blood.

2009;114(22):462.

Abstract # 1126.

IRIS 8-Year Update

Results: Overall Survival (Intent-to-Treat) – Imatinib Arm

Estimated overall survivalat 8 years was 85%

(93%, considering onlyCML related deaths)

0

10

20

30

40

50

60

70

80

90

100

Alive,%

0 12 24 36 48 60 72 84 96 108

Months Since Randomization

Survival: deaths associated with CML

Overall Survival

% A

live

TKIs: Changing the course of a

disease

Adapted from: Björkholm M, et al. J Clin Oncol 29:2514-20.

Cum

ula

tive

Rela

tive

Su

rviv

al

Time Since Diagnosis (years)

1 2 3 4 5 6 7 8 9 10

0.20

0.40

0.60

0.80

1.00

0

1973 - 1979

1980 – 1986

1987 – 1993

1994 – 2000

2001 - 2008

Survival of patients with CML

Transplant activities Europa 2004

Gratwohl et al, The Hematology Journal 2006, 91(4)

STI= stop transplant immediately!

Outcome of patients treated first with imatinib

Study patients High risk PFS OS

IRIS 553 18% 92% 85%

Hammersmith 204 29% 83% 83%

Houston 258 8% 92% 97%

PETHEMA 210 16% 94% 97%

Czech 342 22% 90% 88%

Spirit 319 24% 92% NR

GINEMA 559 22% 87% 90%

German CML 1551 12% 86% 88%

Seoul 363 22% 88% 94%

New perspectives in CML

• More than a decade has passed since the introduction of

imatinib in clinical practice

• Its introduction led to rapid and important changes in the

management of CML and outcomes

• The prevalence of CML is increasing, therefore also the

costs of therapy are cumulating!

• Full life span and (near) normal quality of life are now

attainable treatment goals

• To reach these goals, optimised testing and monitoring

in CML management is an important objective

European recommendations for

optimal care

• Other recommendations and/or guidelines do exist

• These recommendations will evolve as knowledge about CML and its

treatment increases

Overview of 2013 ELN

recommendations

• ELN has conducted a review of recent trials and

established monitoring tests to be conducted at specific

time points

• On the basis of the degree and timing of test results (hematological,

cytogenetic, molecular), the ELN defined overall treatment response

in these terms

Diagnosis Every 2 weeks 3 months 6 months 9 months 1 year Long term

Optimal Warning Failure

Baccarani M, et al. J Clin Oncol 2009; 27:6041-51.

Recommendations for the diagnostic workup

and for assessing and monitoring response

Baseline To assess response To monitor the response

Blood counts and diff Yes Every 2 wks until CHR Every 3 months

Bone marrow cytology Yes No No

Bone marrow karyotype Yes At 3 and 6 months, then

every 6 months until CCgR

Every 12 months, once CCgR

only if molecular response

cannot be assessed

Blood, I-FISH No No Only if CBA of marrow cell

metaphases and molecular

response cannot be assesed

Blood, RT-PCR

(qualitative)

Yes No No

Blood, RT-Q-PCR

(quantitative, BCR-

ABL%)

No Every 3 months until MMR Every 6 months once a MMR

has been achieved

Mutational analysis Only AP

or BP

No Only in case of failure

Spleen size (cm) Yes

Definition of response to 1st-line TKI

Definition of response to 1st-line TKIs in CP-CMLDefinition of response to 1st-line TKIs in CP-CML

Time Optimal Warning Failure

Diagnosis _• High risk, or

• CCA in Ph+ ‘major route’_

3 months • BCR-ABL1 ≤10%

• And/or Ph+ ≤35%

• BCR-ABL1 >10%

• And/or Ph+ 36-95%

• Non CHR

• And/or Ph+ >95%

6 months• BCR-ABL1 10%

• And/or Ph+ >35%

12 months • BCR-ABL1 ≤0.1% • BCR-ABL1 0.1-1 %• BCR-ABL1 >1%

• And/or Ph+ >0

>12 months,

and at any

time

• BCR-ABL1 ≤0.1% • CCA/Ph- (-7, or 7q-)

• Loss of CHR

• Loss of CCyR

• Confirmed loss of MMR*

• Mutations

• CCA/Ph +

Adapted from:

Baccarani M, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood

2013;122:872-84.

*In two consecutive tests, of which one with a BCR-ABL1 transcripts level ≥ 1%. NA = Not Applicable.

MMR = Major molecular response (BCR-ABL1 ≤ 0.1% = MR3.0 or better). CCA/Ph+ = Clonal Chromosome Abnormalities in Ph+ cells. CCA/Ph- = Clonal

Chromosome Abnormalities in Ph- cells

OPTIMAL response is associated with the best long-term outcome

New ELN

2013

Intolerance Occurs in Some Patients

With Ph+ CML-CP

Deininger M. et al. Blood. 2009;114(22):462 [abstract 1126].

IRIS, international randomized study of interferon and STI571.

Figure 2 Mechanisms of imatinib resistance ABCB1=ATP-binding competitor B1. OCT1=organic cation transporter 1. CYP3A4=cytochrome

P450 isoenzyme 4A. AGP=alpha-1 acid glycoprotein.

Apperley, The Lancet Oncology Volume 8, Issue 11 2007 1018 - 1029

Prevalence, determinants, and outcomes of nonadherence to imatinib therapy

in patients with chronic myeloid leukemia: the ADAGIO study

Lucien Noens1, Marie-Anne van Lierde2, Robrecht De Bock3, Gregor Verhoef4,

Pierre Zachée5, Zwi Berneman6, Philippe Martiat7, Philippe Mineur8, Koen Van

Eygen9, Karen MacDonald10, Sabina De Geest11, Tara Albrecht10,12, and Ivo

Abraham10,131 Universitair Ziekenhuis (UZ) Gent, Gent, Belgium; 2 Novartis Pharma, Vilvoorde, Belgium; 3 Ziekenhuisnetwerk Antwerpen

(ZNA) Middelheim, Antwerpen, Belgium; 4 UZ Gasthuisberg, Leuven, Belgium; 5 ZNA Stuivenberg, Antwerpen, Belgium; 6 UZ

Antwerpen, Antwerpen, Belgium; 7 Institut Jules Bordet, Bruxelles, Belgium; 8 Hôpital St Joseph, Gilly, Belgium; 9 Algemeen

Ziekenhuis Groeninge, Kortrijk, Belgium; 10 Matrix45; Earlysville, VA; 11 Institute of Nursing Science, University of Basel,

Basel, Switzerland; 12 School of Nursing, University of Virginia, Charlottesville; 13 College of Nursing, and Center for Health

Outcomes and PharmacoEconomic Research, College of Pharmacy, University of Arizona, Tucson

Blood, 28 May 2009, Vol. 113, No. 22,

pp. 5401-5411.

Adagio study

• One-third of patients were considered to be nonadherent.

• Only 14.2% of patients were perfectly adherent with 100% of prescribed imatinib taken.

• On average, patients with suboptimal response had significantly higher mean percentages of imatinib not taken(23.2%, standard deviation [SD] = 23.8) than did those withoptimal response (7.3%, SD = 19.3, P = .005; percentages calculated as proportions x 100).

• Nonadherence is more prevalent than patients, physicians, and family members believe it is, and therefore should be assessed routinely. It is associated with poorer response to imatinib. Several determinants may serve as alert signals,many of which are clinically modifiable.

Patient adherence to imatinib therapy and probability of MMR.

Figure 2 Mechanisms of imatinib resistance ABCB1=ATP-binding competitor B1. OCT1=organic cation transporter 1. CYP3A4=cytochrome

P450 isoenzyme 4A. AGP=alpha-1 acid glycoprotein.

Apperley, The Lancet Oncology Volume 8, Issue 11 2007 1018 - 1029

Part 1. Alimentary tract and metabolism

Imatinib Dasatinib Nilotinib

PPI

Omeprazole

• Inhibition of Pgp

by omeprazole:

↑ imatinib

exposure9,18,64

• ↓ dasatinib

absorption9

(↓ dasatinib

solubility)

• Inhibition of Pgp

by omeprazole:

↑ dasatinib

exposure9,18,64

—

Esomeprazole

• Inhibition of Pgp

by esomeprazole:

↑ imatinib

exposure9,18,64

• ↓ dasatinib

absorption9

(↓ dasatinib

solubility)

• Inhibition of Pgp

by esomeprazole:

↑ dasatinib

exposure9,18,64

—

Pantoprazole

• Inhibition of Pgp

by pantoprazole:

↑ imatinib

exposure9,18,64

• ↓ dasatinib

absorption9

(↓ dasatinib

solubility)

• Inhibition of Pgp

by pantoprazole:

↑ dasatinib

exposure9,18,64

—

Observed or potential drug interactions between TKIs and

commonly concomitantly prescribed drugs

Haouala et al, Blood 2011

Figure 2 Mechanisms of imatinib resistance ABCB1=ATP-binding competitor B1. OCT1=organic cation transporter 1. CYP3A4=cytochrome

P450 isoenzyme 4A. AGP=alpha-1 acid glycoprotein.

Apperley, The Lancet Oncology Volume 8, Issue 11 2007 1018 - 1029

Pink= P-loop

Blue=activation loop

Interaction of BCR-ABL with imatinib

Order of mutation sensitivity to dasatinib and nilotinib

Branford et al, Blood 114: 5426-5435, 2009

http://bloodjournal.hematologylibrary.org/content/114/27/5426/T1.large.jpghttp://bloodjournal.hematologylibrary.org/content/114/27/5426/T1.large.jpghttp://bloodjournal.hematologylibrary.org/content/114/27/5426/T1.large.jpg

T315I mutant (10-15% of mutants) confers

complete resistance to all clinically available kinase

inhibitors including AMN107 and dasatinib

Nilotinib was Rationally Designed for More

Effective Binding to BCR-ABL

Weisberg E, et al. Cancer Cell. 2005;7:129-141.

Other first line studies: ENEST

Imatinib (400 mg) Nilotinib (300 mg x 2) Nilotinib (400 mg x 2)

MMR (5 yr) 60 77 77

MR4 (3 yr) 26 50 44

MR4.5 (( yr) 31 54 52

Transformation 7.1 3.5 2.1

Sokal low 0 0 0.35

Sokal Interm 2.8 0.35 0.35

Sokal high 1.4 0.35 0.35

Vascular event 2.1 6.8 12.6

Still on TKI (5 yr) 51.2 62.4 65.1

OS (5 yr) 91.6 93.6 96

CML-related death 4.9 1.8 1.4

Other first line studies: Dasision

Imatinib (400 mg) Dasatinib (100 mg)

MMR (5 yr) 63 76

MR4 (5 yr) 42 53

MR4.5 (5 yr) 30 37

Transformation 6.9 4.6

Vascular event 1.2 3.9

Pleural effusion 0 10

Still on TKI (5 yr) 65 67

OS (5 yr) 92.1 92.9

CML-related death 4 3

Other first line studies: BELA

Imatinib 400 mg Bosutinib 500 mg

MMR (5 yr) 27 41

Transformation 4 2

Still on TKI 80 71.6

OS (I yr) 97 99

CML-related death 4 1.6

Activity of new generation TKI on mutants

resistant to Imatinib

T315I

Evolution of ELN treatment recommendations

for CP-CML: 2009 vs. 2013

Evolution of ELN treatment recommendations for CP-CML: 20091 vs. 20132

20091 20132

First-line treatment Imatinib Imatinib, dasatinib or nilotinib

Risk groups 3 risk groups:•Low

•Intermediate

•High

2 risk groups:

•Low (including intermediate)

•High

Treatment objective Response to imatinib Achievement of response, irrespective of the Tyrosine kinase inhibitor (TKI) used

Early switch

at 3 months

N/A Not recommended – BCR-ABL transcript level

not sufficient to define failure necessitating

change in treatment

Treatment

discontinuation in

optimal responders

Not recommended – imatinib should be

continued indefinitely

Continue TKI therapy indefinitely or consider

enrolling patients achieving a deeper molecular

response in controlled studies of treatment

discontinuation

References:

1. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of

European LeukemiaNet. J Clin Oncol.2009;27:6041-51.

2. Baccarani M, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood

2013;122:872-84.

TKI=Tyrosine kinase inhibitor (class of pharmaceutical agents that inhibit or block the enzyme tyrosine kinase).

Choise of first line therapy: some

considerations

• Goal of therapy: controlling disease or stopping treatment?

• Sokal or EUTOS risk score

• Dasatinib or nilotinib:

– high % of CCgR and Molecular response

– No survival advantage (yet?)

– At 5 years: around 40% changed therapy with limited possibilities

– More patients in Cmol R, thus the possibility to discontinue treatment

• Imatinib:

– 55% of patients continued treatment at 9 yrs of follow up

– Lower CcgR and molecular response

– Possibility of early intervention,

– Still 2 other TKI as second line therapy

– Patent will soon finish: cheaper treatment

BosutinibDiarrhea, nausea/emesis,

rash

TKI safety profile and adverse events should

be a factor in the choice of therapy

Nilotinib

Pancreatic enzyme ,

indirect hyperbilirubinemia,

hyperglycemia

QT prolongation,

cardiovascular events

Common Effects

Myelosuppression

Transaminase

Electrolyte Δ

DasatinibPleural/pericardial

effusions,bleeding risk,

pulmonary arterial hypertension

Ponatinib

Pancreatic

enzyme , hypertension,

skin toxicity, thrombotic

events

Imatinib

Edema/fluid retention,

myalgia, hypophosphatemia ,

GI effects (diarrhea, nausea)

Treatment recommendations:

Chronic phaseLine Treatment

1st line- Imatinib or nilotinib or dasatinib

- HLA type patients and siblings only in case of baseline warnings (high risk,

major route CCA/Ph1)

2nd line: intolerance to the 1st TKI - Anyone of the other TKIs approved first line (imatinib, nilotinib, dasatinib)

2nd line: failure of imatinib 1st line- Dasatinib or nilotinib or bosutinib or ponatinib (medical need)

2nd line: failure of nilotinib 1st line - Dasatinib or bosutinib or (ponatinib ??)- HLA type patients and siblings; search for an unrelated stem cell donor;

consider alloSCT

2nd line: failure of dasatinib 1st line - Nilotinib or bosutinib or (ponatinib ??)- HLA type patients and siblings; search for an unrelated stem cell donor;

consider alloSCT

3rd line, failure of, or/and intolerance

to, two TKIs- Anyone of the remaining TKIs; alloSCT recommended in all eligible patients

Any line, T315I mutation- Ponatinib

- HLA type patients and siblings; search for an unrelated stem cell donor;

consider alloSCT

1864 1903 1953 1964 1975 1983 1999 2005 2007 2008 2009

Palliative therapy Currative therapy

arsenic

Spleen irradication

Busulfan

Hydroxyurea

Stem cell transplantation

Combination chemo

Interferon

Imatinib

Dasatinib

Nilotinib

Bosutinib

“first generation TKI”

“second generation TKI”

MK0457,Pha739358

XL228, Ponatinib“third generation TKI”

Developments of treatment for CML

69

Guidelines for CML

• Nederlands tijdschrift voor Hematologie

– Jaargang 11, n. 5, 2014

• Belgian Hematology Journal, Benghiat et

al., Practical management of CML in

Belgian, in press