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