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CML Learning
Programme
EBMT Slide template
for NursesBarcelona
& Other
Allied
Health Care
7 February
2008
Professionals
The
The European
European Group
Group for
for Blood
Blood and
and Marrow
Marrow Transplantation
Transplantation
Module 2
CML Treatments
The European Group for Blood and Marrow Transplantation
Aims of Module 2
To understand:
- The treatment strategies of caring for patients
with CML
- Historical treatments of CML, the new era of
targeted treatments and future developments in
treatment
The European Group for Blood and Marrow Transplantation
Aims of Module 2
• How the outlook has changed for CML patients following
the landmark IRIS trial and trials of second generation TKIs
in frontline treatment
• Mechanisms for imatinib resistance and need for the
development of second generation TKIs
• Remaining role for stem cell transplantation
• Whether patients can ever stop treatment
The European Group for Blood and Marrow Transplantation
Ten years ago few treatments
were available for CML:
• Chemotherapy (hydroxyurea)
• Interferon α (IFN- α based treatments)
• Stem Cell Transplants (SCT)
The European Group for Blood and Marrow Transplantation
CML treatments in the preimatinib era
• Pre-1980s: hydroxyurea
– Hydroxyurea was not as effective, but had a more
favorable toxicity profile1
• Interferon-a (IFN-a) introduced in 1985
– Higher rates of CyR and increased survival2-4
– 50% survival at 6 years compared with 19% without
therapy1,5
– Favorable responses, but toxicity limited its usefulness1
1. Cortes J.E. et al. Am J Med 1996,100:555-570;
2. Cortes J. et al. Hematol Oncol Clin N Am 2004,18:569-584;
3. Rosti G.et al. Semin Hematol 2003,40(2 Suppl 3):56-61;
4. Kantarjian H.M.,et al. Cancer. 2003,97:1033-1041;
5. Italian Cooperative Study Group on Chronic Myeloid Leukemia. Blood 1998,92:1541-1548
The European Group for Blood and Marrow Transplantation
Survival 1983-2008
Primary imatinib, 2002-2008 (CML IV)
5-year survival 93%
Survival probability
n = 2830
IFN or SCT, 1997-2008
(CML IIIA) 5-year survival 71%
IFN or SCT, 1995-2008 (CML III)
5-year survival 63%
(CML I, II)
IFN, 1986-2003
5-year survival 53%
Hydroxyurea, 1983-1994
Busulfan, 1983-1994 5-year survival 38%
Courtesy of the German CML Study Group
Year after diagnosis
The European Group for Blood and Marrow Transplantation
The European Group for Blood and Marrow Transplantation
Stem Cell Transplantation
(SCT)
STC involves the introduction of donor (allogeneic)
or the patient’s own treated (autologous) stem cells
into the patient in the hope that the procedure will
replace the damaged stem cells causing the CML
The European Group for Blood and Marrow Transplantation
Stem Cell Transplantation
(SCT)
In this procedure, the patient is first treated with
high doses of chemotherapy and/or radiation to
destroy all bone marrow cells (cells used for
autologous transplant are withdrawn prior to this
step)
The European Group for Blood and Marrow Transplantation
Stem Cell Transplantation
(SCT)
• Stem cells from the donor’s marrow or peripheral blood are
then transfused into the patient, with the intent of repopulating
the patient’s marrow
• In the case of CML, autologous transplantation has generally
been unsuccessful because many of the patient’s stem cells
contain the genetic defect causing the disease
• SCT is the only currently available therapy able to cure patients
with CML
The European Group for Blood and Marrow Transplantation
SCT can cure but carries high
risk of morbidity and mortality
Survival by disease stage, June 2001,
based on transplants 1987–Feb 2001.
100
90
90
80
80
70
70
60
60
First Chronic Phase (n=1903)
50
50
40
40
Survival (%)
Survival (%)
100
Accelerated and 2nd CP (n=744)
30
30
20
20
Blast Phase (n=159)
10
10
P=0.0001
0
0
0
1
2
3
5 Years after transplant
4
National Marrow Donor
Program (NMDP)
overview slide
presentation.
Available at:
http://www.marrow.org/
NMDP/SLIDESET/sld03
1.htm. Accessed June
5, 2003
The European Group for Blood and Marrow Transplantation
Tyrosine Kinase Inhibitors
(TKIs)
Then came the TKI treatments ...
First Generation:
• Imatinib (Glivec ®)
• FDA approval for advanced stage CML - May 2001;
EMA approval November 2001
• FDA approval for front line CML treatment December 2002; EMA approval December 2002
The European Group for Blood and Marrow Transplantation
Tyrosine Kinase Inhibitors
(TKIs)
Second Generation:
Dasatinib (Sprycel®)
• FDA approval for imatinib resistant/intolerant CML treatment –
June 2006; EMA approval November 2006
• FDA approval for front line CML treatment - November 2010;
EMA approval December 2010
Nilotinib (Tasigna®)
• FDA approval for second line CML treatment - November
2007; EMA approval - November 2007
• FDA approval front line CML treatment June 2010;
EMA approval - December 2010
The European Group for Blood and Marrow Transplantation
TKIs change outlook in CML
• The main reason for changing outlook for CML
patients was the development of TKIs:
imatinib, nilotinib and dasatinib
• In the last 10 years CML has changed from an
inevitably lethal condition to a chronic disease
where patients can expect to live a normal life
span with a limited impact on their daily lives
The European Group for Blood and Marrow Transplantation
Data showing how TKIs have
changed outlook for CML
• IRIS trial data (imatinib):
• The 5 year overall survival rate in the
IRIS trial
(of imatinib was 95%)
Druker B.J. et al. N Engl J Med 2006, 355: 2408-2417
The European Group for Blood and Marrow Transplantation
Data showing how TKIs have
changed outlook for CML
• The 6 year overall survival rate of the IRIS trial was
88%
• The 7 year overall survival rate of the IRIS trial was
86%
• The 8 year overall survival rate of the IRIS trial was
85 %
Deininger M. et al. ASH 2009
The European Group for Blood and Marrow Transplantation
Data showing how TKIs have
changed outlook for CML
• Normal life expectancy
• In a recent study when 832 CML patients were
followed for a median of 5.8 years, 20 died, giving
a death rate of 4.8% (standardised incidence ratio
0.7), with only 6 of these deaths ( 30%) associated
with CML
Gambacorti Passerini C. et al. J Natl Cancer Inst 2011, 103:553-561
The European Group for Blood and Marrow Transplantation
Glivec® Targets the Cause of CML
Glivec®: A Specific Inhibitor of a Small Family
of Tyrosine Kinases, Including BCR-ABL
Bcr-Abl
Bcr-Abl
ATP
Glivec®
Tyrosine
Tyrosine
Adapted from Gastrointestinal Stromal Tumours Knowledge Centre. Imatinib –
mechanism of action.
Available at www.epgonline.org. Accessed 20 August 2009
The European Group for Blood and Marrow Transplantation
Imatinib:
First targeted therapy for cancer
• Understanding the molecular basis of the disease
enabled the development of the first molecularly
targeted cancer therapy – the BCR-ABL inhibitor
imatinib (Glivec®)
Deininger M.W. et al. Blood 2000, 96:3343-3356
The European Group for Blood and Marrow Transplantation
Imatinib as a first line treatment
International Randomized Interferon versus ST1571
(IRIS) trial
• Imatinib versus IFN-α +Ara C in newly diagnosed,
previously untreated, early chronic phase PH+ CML
patients
• Phase III, multicentre, randomized, open label trial
The European Group for Blood and Marrow Transplantation
Imatinib as a first line treatment
Primary endpoint – primary progression defined as increasing
WBC count, loss of major cytogenetic response or complete
haematological response, accelerated or blast crisis, death
Secondary endpoints – quality of life assessment, rate +
duration complete hematologic response, rate + duration major
cytogenetic response, overall survival
O’Brien S.G. et al. N Engl J Med, 2003, 348:994-1004
The European Group for Blood and Marrow Transplantation
IRIS Study Design:
imatinib versus IFN-a + ara-C
1106 patients enrolled from June 2000 to January 2001
Imatinib
S
IF:
 Loss of response
 Increasing WBC count
 Intolerance of treatment
 Failure to achieve MCR or CHR
R
Crossover
at 12 months*
IFN-a + ara-C
S = screening.
R = randomization.
*Independent Data Monitoring Board Recommended Protocol Amendments.
O’Brien S.G. et al. N Engl J Med 2003,348:994-1004.
The European Group for Blood and Marrow Transplantation
IRIS Study: Patient Characteristics
Imatinib
IFN-a + ara-C
(n=553)
(n=553)
Age in years (median)
50
51
Sex (M/F)
62% / 38%
56% / 44%
Months from diagnosis (median)
2.1
1.8
WBC count—x 10-3/mm3 (median)
17.9
20.2
Platelet count—x 10-3/mm3 (median)
336
340
Peripheral-blood basophils—%
3.0
3.0
O’Brien S.G. et al. N Engl J Med 2003, 348:994-1004
The European Group for Blood and Marrow Transplantation
IRIS 8-year update: CML became a chronic
disease for most patients on imatinib
93% CML relevant survival
at 8 years
100
90
80
85% estimated overall survival
at 8 years
% Alive
70
60
50
40
30
20
CML relevant survival, including only CML-related deaths
Overall survival, including all deaths regardless of cause
10
0
0
12
24
36
48
60
72
84
96
108
Months Since Randomization
IRIS, International Randomized Interferon versus STI571 (Imatinib, Glivec)
Deininger M. et al. Blood 2009, (ASH Annual Meeting) 114: Abstract 1126
The European Group for Blood and Marrow Transplantation
IRIS: Grade 3/4 adverse events
with first line imatinib
% of Patients
Overall Toxicity
(n=551)
After 18 Months
(n=484)
Neutropenia
15.4
2.7
Thrombocytopenia
8.5
1.2
Anemia
4.0
1.8
Elevated liver enzymes
5.3
<1
15.1
3.1
Hematologic/Liver
Other drug-related AEs
Cervantes F. on behalf of the IRIS study group. Blood 2003,102:181a. Abstract 633 and oral presentation
The European Group for Blood and Marrow Transplantation
Imatinib: Iris Study Conclusions
• Imatinib induces significantly higher rates of rapidhaematologic and cytogenetic responses compared
with IFNα and Ara-C
• Imatinib should be considered as first line drug
therapy for CML
The European Group for Blood and Marrow Transplantation
Imatinib: Iris Study Conclusions
• Imatinib maintained quality of life
• Responses improve with time:
69% of patients receiving imatinib achieved a
complete cytogenetic response by 12 months
compared with 83% by 8 years
• Although many patients benefit from imatinib
therapy clinical resistance has emerged as a
significant barrier to treatment
The European Group for Blood and Marrow Transplantation
Recommended Starting Dose
of Imatinib
60
50
40
30
18
16
20
Accelerated Phase,
Phase II Study
Blast Crisis,
Phase II Study
600mg, n=223
600mg, n=119
400mg, n=62
400mg, n=87
6
10
0
Chronic Phase,
Phase II Study
28
400mg, n=454
• Starting dose in
advanced phases:
600mg once daily
60
Patients achieving MCR (%)
• Starting dose in
chronic phase:
400mg once daily
Kantarjian H. et al. New Engl J Med 2002,346:645-652.
Talpaz M. et al. Blood 2002,99:1928-1937;Wyers C, et al. Blood. 2002;99:3530-3539
The European Group for Blood and Marrow Transplantation
Cautionary Note
However, a study by Lucas et al of a “community experience”
of primary imatinib therapy at 18 months showed:
• A CCyR rate of only 49%
• A real world primary resistance rate of 51%
• This, said the authors, demonstrates that resistance can
occur in a significant number of patients and that
therapeutic monitoring is essential
Lucas C.M.et al. Leukemia 2008, 22 :1963-1966
The European Group for Blood and Marrow Transplantation
CML Mutations Background
• Despite the success of targeted therapy, resistance to
imatinib occurs in approximately 15% of patients with
CML-CP, mostly in the first 3 years
Druker B.J.et al. N Engl J Medicine 2006, 335: 2408-2417
• Mutations in the BCR-ABL kinase domain are associated
with 50% of secondary imatinib resistance
Jabbour E. et al. Blood 2009, 114: 2037-2043
The European Group for Blood and Marrow Transplantation
CML Mutations Background
• Mutations in the BCR-ABL kinase domain affect the binding of
the protein with TKIs
Nardi V. et al. Curr Opin Hematol 2004, 11: 35-43
• More than 100 mutations have been reported
• It has been proposed to use in vitro data to guide selection of
TKIs for CML patients
Radelli S. et al. J Clin Oncol 2009, 27:469-471
The European Group for Blood and Marrow Transplantation
Imatinib resistance
Resistance to imatinib in CML is defined as either:
• Primary (intrinsic)
• Secondary (acquired)
The European Group for Blood and Marrow Transplantation
Primary imatinib resistance
• Indicates a lack of efficacy at the onset of treatment
• It is identified based on failure to achieve time-based
landmark responses, outlined by the National
Comprehensive Cancer Network (NCCN)
• An estimated one quarter of newly diagnosed
patients had primary resistance to first line imatinib
Hughes+Bradford. Blood Reviews, 2006: 20, 29-41
The European Group for Blood and Marrow Transplantation
Secondary imatinib resistance
• Acquired resistance develops after an initial
response to imatinib therapy and is defined
as a loss of a previously achieved response
(hematologic or cytogenetic) or disease
progression during imatinib treatment
• Secondary imatinib resistance should
prompt an immediate change in treatment
(NCCN, 2008)
The European Group for Blood and Marrow Transplantation
Secondary imatinib resistance
• Acquired resistance often is associated with the
emergence of BCR-ABL mutations that prevent
imatinib from binding to its target
Nardi, Azam, & Daley, 2004
• It is important for patients to be continuously
monitored during imatinib treatment to detect
secondary resistance as early as possible
European LeukemiaNet Guidelines on monitoring patients. Baccarani M.et al.
J Clin Oncol 2009, 27:6041-51
The European Group for Blood and Marrow Transplantation
Secondary imatinib resistance
• It is important for patients to be continuously
monitored during imatinib treatment to detect
secondary resistance as early as possible
European LeukemiaNet Guidelines on monitoring patients. Baccarani M . et al.
J Clin Oncol, 2009, 27:6041-51
The European Group for Blood and Marrow Transplantation
Need for alternative TKI treatments
primary and secondary resistance in
IRIS study
• Primary resistance was observed in 24% of
patients 18 months after the start of treatment
O’Brien S.G. et al. N Engl J Med 2003, 348:994-1004
The European Group for Blood and Marrow Transplantation
Need for alternative TKI treatments
primary and secondary resistance in
IRIS study
• Secondary resistance was observed at a median
follow-up of 60 months as relapsed disease in
approximately 17% of patients
An additional 7% of patients experienced disease
progression
Druker B.et al. NEJM 2006,355:2408-2417
The European Group for Blood and Marrow Transplantation
Need for alternative TKI treatments
primary and secondary resistance in
IRIS study
• After six years altogether 32% of patients had
discontinued imatinib
• 12% due to insufficient therapeutic effects
•
4% as a result of adverse effects
Hochhaus A.et al. Blood 2007, 110:15a-16a
The European Group for Blood and Marrow Transplantation
Methods of acquired
imatinib resistance
•
•
•
•
Mutations of BCR-ABL
Increased production of BCR-ABL
Increased activity of drug transporter proteins
Activation of BCR-ABL independent signalling
pathways
Bauer S. Clinical Journal of Oncology Nursing 2009, 13:523-534
The European Group for Blood and Marrow Transplantation
Philipp le Coutre, Michaela Schwarz, and Theo D. Kim: New Developments in Tyrosine Kinase Inhibitor Therapy
for Newly Diagnosed Chronic Myeloid Leukemia
The European Group for Blood and Marrow Transplantation
Options for CML patients
experiencing progression on imatinib
• Escalating dose of imatinib (from 400-600mg/day in
Chronic Phase CML or 600 -800 mg/day in AP/BC CML)
• Switching treatment to second generation TKI:
• I. Dasatinib (Sprycel®) or
• II. Nilotinib (Tasigna®)
• Entering clinical trial for emerging TKI treatments
• Haematopoietic Stem Cell Transplantation (HSTC)
The European Group for Blood and Marrow Transplantation
Treatment Recommendations
Expert Panel: European LeukemiaNet
• New diagnosis imatinib 400 mg/day
• Consider HSCT, dose increase or second generation
TKI or experimental therapy if:
• 3 months - no haematologic response at 3 months
• 6 months - incomplete haematologic response or no
cytogenetic response
The European Group for Blood and Marrow Transplantation
Treatment Recommendations
Expert Panel: European LeukemiaNet
• 12 months – Less than partial (PH>35%) cytogenetic
response
• 18 months - Less than a complete cytogenetic
response
European LeukemiaNet Guidelines on monitoring patients. Baccarani M. et al. J Clin Oncol 2009, 27:6041-51
The European Group for Blood and Marrow Transplantation
NCCN (2009) guidelines
According to NCCN (2009) guidelines, patients
on standard-dose imatinib who do not reach time
based milestones are considered to have primary
resistance and should be switched to alternative
therapies
The European Group for Blood and Marrow Transplantation
NCCN (2009) guidelines
In addition, for patients who did reach those
milestones, loss of CHR or CCyR or the
development of BCR-ABL mutations with
a high insensitivity to imatinib constitute
secondary resistance and also justify a change
in treatment (NCCN)
The European Group for Blood and Marrow Transplantation
Monitoring Guidelines for imatinib in CML according to the
National Comprehensive Cancer Network (NCCN)
Imatinib
3-month evaluation
Hematologic response No hematologic response
12-month evaluation
Continue imatinib,
Monitor cytogenetics
every 3 to 6 months
Increase dose of imatinib,
or IFN-a ± ara-C,
or SCT if feasible
Complete cytogenetic
Partial cytogenetic response
response
or no cytogenetic response
Continue imatinib
National Comprehensive Cancer Network.
Available at: http://www.nccn.org/physiciangls/f_guidelines.html.
Increase dose of imatinib
or continue same dose,
IFN-a ± ara-C;
SCT if feasible, or clinical trial
The European Group for Blood and Marrow Transplantation
Second Generation TKIs
• Nilotinib and dasatinib have been rationally designed to
improve binding affinity against BCR-ABL
• Each agent differs in its molecular structure, how it binds
to the BCR-ABL protein, and the other TKIs that it inhibits
These differences have led to different patterns of
activity and patterns of activity and resistance
The European Group for Blood and Marrow Transplantation
Second Generation TKIs
• Because both nilotinib and dasatinib have a different
spectrum of side effects they can work well in imatinib
intolerant patients
• Researchers have identified up to 50 mutations in the
BCR-ABL protein that cause imatinib resistance.
All but one - T315I remain sensitive to dasatinib and
nilotinib
The European Group for Blood and Marrow Transplantation
Nilotinib (Tasigna®)
• Similar in structure to imatinib
Designed to achieve a better fit into the binding pocket
• Shown to be 10 to 50 fold more potent at BCR-ABL
inhibition in invitro studies than imatinib
Weisberg E. et al. Cancer Cell 2005, 7: 129-141
• Activity against most common mutations except T315I
The European Group for Blood and Marrow Transplantation
Nilotinib rationally designed for a more effective binding to
the inactive conformation of the ABL kinase domain and
can overcome most imatinib-resistant mutations
Hydrogen bonds form with specific amino
acids lining the binding site
Imatinib
Auxiliary binding
pocket
Hydrogen bonds with
Ile360 & His361
Only maintains 4 hydrogen bonds
Nilotinib
Improved fit to auxiliary pocket, via lipophilic
interactions, making it less susceptible to
point mutations
Weisberg E, et al. Cancer Cell. 2005;7:129–141
The European Group for Blood and Marrow Transplantation
Dasatinib (Sprycel®)
• Inhibits BCR-ABL and the SRC family of kinases
• The SRC family of kinases are involved in cell growth,
differentiation, migration, survival, tumour metastasis and
angiogenesis
• 325 times more potent at BCR-ABL inhibition than imatinib
O’Hare T. et al. Cancer Research 2005, 65:4500-4505
The European Group for Blood and Marrow Transplantation
Dasatinib (Sprycel®)
• Structurally different from imatinib and nilotinib
• Can bind to both active and inactive conformations of
the ABL kinase domain
• Activity against most common mutations except T315I
The European Group for Blood and Marrow Transplantation
Nilotinib 800mg/day was approved by the FDA for patients with CP or AP
(but not BC) who are resistant or intolerant of first line treatment including
imatinib on the basis of an open label phase 2 study
• After 18 months of follow-up in Chronic Phase CML
•
•
•
•
MCyR
57%
CCyR 41 %
Overall survival 91%
Discontinuation of treatment 48%
(20% due to disease progression,
14% drug related adverse effects)
The European Group for Blood and Marrow Transplantation
Nilotinib 800mg/day was approved by the FDA for patients with CP or AP
(but not BC) who are resistant or intolerant of first line treatment including
imatinib on the basis of an open label phase 2 study
After 2 years:
• MCyR 59%
• CCyr 44%
Kantarjian H. et al. Blood 2008, 112. 3238 (abstract)
Kantarjian H.et al. Blood 2007, 110 :3540-3546
The European Group for Blood and Marrow Transplantation
START trials for second
line dasatinib
Dasatinib was approved in patients with resistant or
intolerant CML based on a series of phase 2 clinical
studies known as the SRC/ABL Tyrosine Kinase
Inhibition Activity: Research Trials of dasatinib
(START) trials:
START–C trial, patients with imatinib-resistance or
intolerant chronic phase CML treated with dasatinib
(70 mg twice daily)
The European Group for Blood and Marrow Transplantation
START trials for second
line dasatinib
• START-A trial, patients with imatinib resistant or
intolerant accelerated phase CML treated with 70
mg dasatinib twice daily
• START-B trial, patients with imatinib resistant or
intolerant CML in myeloid blast crisis or lymphoid
blast crisis
• START-L trial, patients with lymphoid CML– BP and
Ph+ ALL
The European Group for Blood and Marrow Transplantation
START–Phase II clinical trials
The European Group for Blood and Marrow Transplantation
Should second generation TKIs nilotinib and dasatinib
be saved only for relapse or used front line?
• ENESTnd: Nilotinib as front line treatment
• ENESTnd Study comparing twice daily nilotinib
(300mg BID + 400 mg BID ) to a standard
imatinib arm (400mg once daily) in a randomised
design 1:1:1 in 846 patients with newly
diagnosed CML
The European Group for Blood and Marrow Transplantation
Should second generation TKIs nilotinib and dasatinib
be saved only for relapse or used front line?
• DASISION: Dasatinib as first line treatment
• An open label phase 3 study comparing dasatinib
(n=259), administered at a dose of 100 mg once
daily, with imatinib, (n=260) administered at a dose
of 400 mg once daily, among patients with newly
diagnosed chronic-phase CML
The European Group for Blood and Marrow Transplantation
Study Design and Endpoints
• N = 846
• 217 centers
• 35 countries
R
A
N
D
O
M
I
Z
E
D
*
• Primary endpoint:
• Key secondary endpoint:
• Other endpoints:
Nilotinib 300 mg BID (n = 282)
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
Follow-up
5 years
MMR at 12 months
Durable MMR at 24 months
CCyR, time to MMR and CCyR, EFS, PFS,
time to AP/BC, OS
*Stratification by Sokal risk score
The European Group for Blood and Marrow Transplantation
MMR AT 12 and 24 Months*
P < . 0001
70
P < .0001
60
Percentage
% With MMR
P < . 0001
P < .0001
50
44
62
59
43
37
40
30
22
20
10
n = 282
0
n = 281
n = 283
MMR at 12 months1
Nilotinib 300 mg BID
n = 282
n = 281
n = 283
MMR at 24 months
Nilotinib 400 mg BID
Imatinib 400 mg QD
Durable MMR at 24 months: Less than 2% of patients in each treatment arm lost
MMR between 12 and 24 months
1. Saglio G. et al. NEJM. 2010;362:2251-2259.
*ITT population
The European Group for Blood and Marrow Transplantation
Data cut-off: 20Aug2010
CCyR Rates by 24 Months*
P = .0018
% With CCyR
P = .016
n = 282
*ITT population
n = 281
n = 283
The European Group for Blood and Marrow Transplantation
Data cut-off: 20Aug2010
Overall
†
Survival*
Nilotinib
300 mg BID
n = 282
Nilotinib
400 mg BID
n = 281
Imatinib
400 mg QD
n = 283
9
6
11
Estimated 24-month
rate of OS
97.4%
97.8%
96.3%
P-value (OS)
0.6485
0.2125
–
CML-unrelated
4
3
1
CML-related
5
3
10
Estimated 24-month
rate of CML deaths
98.9%
98.9%
96.7%
P-value (CML deaths)
0.1930
0.0485
–
Total number of deaths
*ITT population
†Including deaths after discontinuation of core treatment
Data cut-off: 20.8. 2010
The European Group for Blood and Marrow Transplantation
ENESTnd 24-Month Update
• Nilotinib continues to demonstrate:
– Superior CCyR, MMR, and CMR4.5
– Significantly fewer progressions to AP/BC
– Lower rates of suboptimal response and treatment failure
• Nilotinib at both doses was generally well-tolerated, and fewer
adverse events lead to discontinuation in the nilotinib 300 mg
BID arm
• Longer follow-up supports the superiority of nilotinib for the
treatment of patients with newly diagnosed CML-CP
The European Group for Blood and Marrow Transplantation
Dasatinib versus imatinib Study in TreatmentNaive CML Patients (DASISION) study
• Compared the efficacy and safety of dasatinib, administered
at a dose of 100 mg once daily, with those of imatinib,
administered at a dose of 400 mg once daily, among
patients with newly diagnosed chronic-phase CML
• Open label randomised phase 3 study
• The study enrolled 519 patients: 259 patients were
randomised to dasatinib and 260 patients were randomised
to imatinib
The European Group for Blood and Marrow Transplantation
Dasatinib versus imatinib Study in TreatmentNaive CML Patients (DASISION) study
12 month follow-up results:
• CCyr – 77% treated with dasatinib versus 66% treated with
imatinib (P=0.007)
• MMR- 52% for patients treated with dasatinib versus 34%
with imatinib (P<0.001)
• The time to a confirmed CCyR was significantly shorter with
dasatinib than imatinib (P<0.0001)
• Transformation to accelerated or blast phase occurred in 5
patients receiving dasatinib versus 9 receiving imatinib
Kantarjian H. et al, NEJM 2010, 362:2260-70
The European Group for Blood and Marrow Transplantation
Dasatinib versus imatinib Study in TreatmentNaive CML Patients (DASISION) study
18 month follow-up results:
• CCyR – 78% patients treated with dasatinib versus
70%treated with imatinib (p=0.0366)
• MMR 57% for patients treated with dasatinib versus 41 %
with Iiatinib (p=0.0002)
• Transformation to accelerated or blast phase occurred in 6
patients receiving dasatinib versus 9 receiving imatinib
Shah. ASH 2010
The European Group for Blood and Marrow Transplantation
Dasatinib versus Imatinib Study in TreatmentNaive CML Patients (DASISION) study
24 month follow-up results:
• cCCyR –80 patients treated with dasatinib versus 74%treated with
imatinib (p=0.0366)
• CCyR – 86 patients treated with dasatinib versus 82% with imatinib
(P=.0932)
• MMR -64% for patients treated with dasatinib versus 46 % with imatinib
(p<0.001)
• Transformation to accelerated or blast phase occurred in 6 patients
receiving dasatinib versus 13 receiving imatinib
Hochhaus A. et al. Haematologica 2011,96(Suppl 2):422. (abst 1011)
The European Group for Blood and Marrow Transplantation
Should second generation
treatments now be used front line?
• The possible superiority of nilotinib and dasatinib
to imatinib front-line is being evaluated in ongoing
trials
• There may be cost considerations, i.e. second
generation TKIs may be more expensive
The European Group for Blood and Marrow Transplantation
Stem cell transplants (SCT)
for CML in the imatinib era
• In the past allogeneic haematopoietic stem cell
transplantation (HSCT)was the curative option for CML
• But today imatinib, nilotinib and dasatinib have pushed
transplantation to the role of salvage therapy in CML
• However, approximately 20 to 30% of patients will fail
primary therapy, either from intolerance, relapse or
progression to advanced phase disease
• For these patients allogeneic transplantation remains an
option
The European Group for Blood and Marrow Transplantation
Stem cell transplantation (SCT)
is recommended for:
• Patients with T315I mutations
(who do not respond to imatinib, dasatinib or nilotinib)
• Patients who show an inadequate response to standard
dose imatinib (no hematologic remission or in hematologic
relapse at 3 months; no cytogenetic response at 6 months,
minor or no cytogenetic response or in cytogenetic relapse
at 12 months; partial a, minor or no cytogenetic response or
in cytogenetic relapse at 18 months)
The European Group for Blood and Marrow Transplantation
Stem cell transplantation (SCT)
is recommended for:
• Allogeneic HSCT is a consideration for patients with
disease progression on imatinib and for patients presenting
with accelerated phase or blast crisis CML
In patients with disease progression on imatinib therapy,
treatment with a course of dasatinib or nilotinib will be
beneficial as a “bridge” to transplantation
National Comprehensive Cancer Network Practice Guidelines in Oncology
The European Group for Blood and Marrow Transplantation
Study comparing Stem Cell
Transplantation (SCT ) to drug treatment
In a study 354 patients with chronic phase CML were
randomized to receive allogeneic stem cell transplantation
(HSCT) if they had a donor or best available treatment if they
did not (interferon and imatinib)
With an observation time up to 11.2 years (median 8.9 years)
survival was found to be superior for those with drug
treatment (P=.049)
The European Group for Blood and Marrow Transplantation
Study comparing Stem Cell
Transplantation (SCT ) to drug treatment
The authors concluded:
“The general recommendation of HSCT as first-line treatment
option in chronic phase CML can no longer be maintained.
It should be replaced by a trial with modern drug treatment.”
They added:
“HSCT is regarded as an important salvage therapy in
patients without optimal response to drug therapy or in early
relapse.”
Hehlmann R. et al. Blood 2007, 109: 4686-4692
The European Group for Blood and Marrow Transplantation
The Stem Cell Transplantation
(SCT) process
• The patient is injected with mobilisation agents that
stimulate the stem cells to move into the blood
stream from the bone marrow space
• Blood forming stem cell are collected from the
peripheral blood and frozen and stored
The European Group for Blood and Marrow Transplantation
The Stem Cell Transplantation
(SCT) process
• The patient receives high-dose chemotherapy and
sometimes radiation treatment to the entire body to
destroy any remaining cancer cells and make place for
new cells to live
• The frozen stem cells are thawed and given as an
intravenous infusion into the blood stream. They settle
into the patient’s bone marrow and start to grow and
make new blood cells
The European Group for Blood and Marrow Transplantation
Outcomes Stem Cell
Transplantation (SCT) in CML
“Today one should expect survival to be
greater than 80% for chronic phase patients,
40 to 50% for accelerated phase patients and
approximately 20% for blast crisis patients.”
Radich J et al.Semin Hematol 2010,47: 354-361
The European Group for Blood and Marrow Transplantation
Risks of Stem Cell Transplants
Short-term risks
- Sepsis
- Acute graft-versus host disease
- multi-organ failure or toxic death
Long-term risks
- Chronic graft-versus host disease (lung, gut, liver, skin)
- Relapse
- Infection
- Endocrine complications
- Ocular complications
The European Group for Blood and Marrow Transplantation
Factor influencing outcomes of
allogeneic HSCT
• Most studies show an inverse relation between
age and prognosis due to high transplant related
mortality in older patients
• Outcomes are superior for patients in the chronic
phase. Results for patients with accelerated phase
and blast crisis are less successful
The European Group for Blood and Marrow Transplantation
Factor influencing outcomes of
allogeneic HSCT
• Degree of donor-host match. Generally
patients with complete six antigen matches
(usually from HLA identical siblings) have the
best match
• Transplantation is more successful if neither
donor nor patient has evidence of prior
cytomegalovirus (CMV)
The European Group for Blood and Marrow Transplantation
Factor influencing outcomes of
allogeneic HSCT
• Preparative regimen.
The combination of busulfan and cyclophosphamide
seems to be as effective as cyclophosphamide and
total body irradiation, but has the advantage of less
toxicity
• Increasing the interval from diagnosis to transplant
was associated with worse outcomes, even for
patients with chronic disease
The European Group for Blood and Marrow Transplantation
Reduced intensity allogeneic
HSCT
• In this type of transplant patients get lower doses of
chemo and radiation that do not destroy all the cells in
the bone marrow
• The transplanted cells form a new immune system
which sees the leukaemia cells as foreign and attacks
them
• The primary goal of the approach is to increase the age
at which transplants can be performed
The European Group for Blood and Marrow Transplantation
Reduced-Intensity Conditioning
in CML
• The EBMT reported results on 186 patients with CML
(median age, 50 years) who received RIC:
- The 100-day non-relapse mortality was 6%
- The 2-year non-relapse mortality was 23%
- The 3-year overall and relapse-free survival rates were
58% and 37%, respectively
The European Group for Blood and Marrow Transplantation
Reduced-Intensity Conditioning
in CML
• Over 60% of patients enjoyed a complete cytogenetic
remission (CCyR), while 40% attained a complete
molecular response by PCR testing
Crawley C.et al. Blood. 2005,106:2969-76
• “Such studies suggest that RIC/NMA transplantation is
a promising approach for CML patients, and one can
imagine a combined approach of lower-intensity
transplantation followed by TKI prophylaxis.”
Radich J.et al Semin Hematol 2010, 47: 354-361
The European Group for Blood and Marrow Transplantation
Using TKI to treat or prevent
relapse following transplant
• Relapse is the main cause of treatment failure after
transplant
• Treatment with IFN can produce both clinical and
cytogenetic remissions in patients who have relapsed
after transplantation
Higano C.S. et al. Blood 1997, 90:2549-54
• Imatinib appears highly active as post-transplant
therapy for relapse
Kantarjian H.M.et al. Clin Cancer Res 2002, 8:2177-8
The European Group for Blood and Marrow Transplantation
Effect of prior TKI therapy
Concerns have been raised that previous TKI therapy
might have a detrimental effect on subsequent transplant
outcomes (such as occurred earlier with busulfan and
interferon)
In the IBMTR study, investigators analysed outcomes for
409 patients who had received imatinib prior to
transplantation and 900 who had not
The European Group for Blood and Marrow Transplantation
Effect of prior TKI therapy
Results show that in the chronic phase 3 year survival
rates were 72% for patients who received prior imatinib
versus 65% for those who did not; and that in the
advanced phase 3 year survival rates were 34% versus
36% respectively
The authors concluded that prior treatment with imatinib
does not adversely affect outcomes
Lee S.J. et al. Blood 2008, 112:3500-3507
The European Group for Blood and Marrow Transplantation
Issue of whether it is safe to
stop imatinib treatment?
Stop imatinib (STIM) study:
Imatinib treatment was halted in 100 French CML
patients from 19 treatment centres who had been
treated for at least 2 years and achieved complete
molecular remission during treatment
The European Group for Blood and Marrow Transplantation
Issue of whether it is safe to
stop imatinib treatment?
Results:
• 41 % of patients maintained complete molecular
remission for 2 years
• 38% of patients maintained complete molecular
remission for 2 years
• Low sokal score, male sex and imatinib treatment
duration were identified as factors of CMR
maintenance after imatinib withdrawal
Mahon F. X. et al. Lancet Oncology 2010, 11:1029-1035
The European Group for Blood and Marrow Transplantation
STIM implications
• The evidence suggests that a small percentage of
patients with an extremely good response might stop
imatinib treatment
• But candidates for discontinuation (who achieve
sustained deep molecular remission) only represent
10% of all CML patients
• TKI discontinuation should only be undertaken in the
context of a clinical trial
The European Group for Blood and Marrow Transplantation
Nursing take home messages
• Nurses must ensure that patients are educated
to understand the concept of imatinib resistance
and the second line treatment options that are
available
• Imatinib resistance needs to be identified as
early as possible through regular monitoring to
ensure the best chance of positive treatment
outcomes
The European Group for Blood and Marrow Transplantation
Nursing take home messages
• Second generation TKIs may be more
effective front-line
• There is still a role for stem cell
transplantation
• Patients should only stop TKI treatment
as part of a clinical trial
The European Group for Blood and Marrow Transplantation
Coming soon......
Module III:
• How to take the different TKI treatments
• Importance of adherence to treatment
• Management of special CML populations
The European Group for Blood and Marrow Transplantation