NEWS FROM EHA Leucemia mieloide cronica

NEWS FROM EHA Leucemia mieloide cronica Giovanni Mar*nelli Is*tuto di Ematologia “ L. e A. Seràgnoli” University of Bologna • 
Some interes*ng abstracts for CML PREGNANCY OUTCOMES AND TREATMENT REGIMENS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA • 
EFFICACY AND SAFETY OF BOSUTINIB FOR PHILADELPHIA CHROMOSOME–POSITIVE LEUKEMIA IN OLDER VERSUS YOUNGER PATIENTS • 
BOSUTINIB VERSUS IMATINIB IN NEWLY DIAGNOSED CHRONIC PHASE CHRONIC MYELOID LEUKEMIA: 30-­‐MONTH UPDATE OF THE BELA TRIAL • 
DEFINITIONS AND STANDARDISATION OF ‘COMPLETE’ MOLECULAR RESPONSE IN CHRONIC MYELOID LEUKEMIA • 
CLINICAL AND BIOLOGICAL FEATURES OF PH CHRONIC MYELOID LEUKEMIA (CML) LONG SURVIVOR PATIENTS (MORE THAN 15 YEARS) • 
SUPERIOR EFFICACY OF NILOTINIB COMPARED WITH IMATINIB IN NEWLY DIAGNOSED PATIENTS WITH PH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-­‐CP): ENESTND 3-­‐YEAR FOLLOW-­‐UP • 
NILOTINIB INDUCES DEEPER MOLECULAR RESPONSES VS CONTINUED IMATINIB IN PATIENTS WITH PH CHRONIC MYELOID LEUKEMIA (CML) WITH DETECTABLE DISEASE AFTER = 2 YEARS ON IMATINIB: ENESTCMR 12-­‐MONTH RESULTS • 
FRONTLINE TREATMENT OF PHILADELPHIA POSITIVE CHRONIC MYELOID LEUKEMIA WITH SEQUENTIAL ADMINISTRATION OF NILOTINIB 400 MG TWICE DAILY AND IMATINIB 400 MG ONCE DAILY: A PHASE 2 MULTICENTRIC STUDY • 
EARLY BCR-­‐ABL TRANSCRIPT LEVELS PREDICT FUTURE MOLECULAR RESPONSE AND LONG-­‐TERM OUTCOMES IN NEWLY-­‐
DIAGNOSED PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE: ANALYSIS OF ENESTND 3-­‐YEAR DATA • 
PACE: A PIVOTAL PHASE 2 TRIAL OF PONATINIB IN PATIENTS WITH CML AND PH ALL RESISTANT OR INTOLERANT TO DASATINIB OR NILOTINIB, OR WITH THE T315I MUTATION Therapy Giovanni Mar*nelli Is*tuto di Ematologia “ L. e A. Seràgnoli” University of Bologna First line trials in chronic myeloid leukemia: sabato, 16 giugno 2012 SUPERIOR EFFICACY OF NILOTINIB COMPARED WITH IMATINIB IN NEWLY DIAGNOSED PATIENTS WITH PH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-­‐CP): ENESTND 3-­‐YEAR FOLLOW-­‐UP Author: F Clark, Richard E., Royal Liverpool University Hospital, Liverpool, United Kingdom Background: At 2 years of follow-­‐up from the landmark ENESTnd study, nilo`nib significantly reduced progression to accelerated phase/blast crisis (AP/BC) and demonstrated superior rates of major molecular response vs ima`nib. Aims: follow-­‐up of 3 years. Methods: 846 pa`ents with newly diagnosed Ph+ CML-­‐CP were randomized to nilo`nib 300 mg twice daily (BID) (n = 282), nilo`nib 400 mg BID (n = 281), or ima`nib 400 mg once daily (QD) (n = 283). Results: Significantly higher rates of MMR, MR4, and MR4.5 were observed for both doses of nilo`nib vs ima`nib The difference in rates of MR4 and MR4.5 between nilo`nib and ima`nib increased over `me. Rates of molecular response were superior for nilo`nib, regardless of Sokal risk score. No new progressions occurred on treatment since the 2-­‐year analysis. There was a significantly lower rate of progression to AP/BC on treatment for both nilo`nib arms compared with the ima`nib arm the rate of progression to AP/BC remained significantly lower for both nilo`nib arms compared with ima`nib (n = 9, 6, and 19 At 3 years, OS was 95.1%, 97.0%, and 94.0% for nilo`nib 300 mg BID, nilo`nib 400 mg BID, and ima`nib, respec`vely. There were significantly fewer CML-­‐related deaths in the nilo`nib 300 mg BID (n = 5) and nilo`nib 400 mg BID arms (n = 4) vs ima`nib (n = 14). Muta`ons were more frequent in pa`ents with high or intermediate Sokal risk, and most of these pa`ents had subop`mal response or treatment failure. The incidence of T315I muta`ons was similar for the nilo`nib (n = 3, nilo`nib 300 mg BID; n = 2, nilo`nib 400 mg BID) and ima`nib (n = 3) arms. Both drugs were well tolerated Conclusions: With a minimum follow-­‐up of 3 years, nilo`nib con`nues to demonstrate a significantly lower rate of progression to AP/
BC (both on treatment and including events amer discon`nua`on), lower rates of muta`ons, and superior rates of MRs vs ima`nib. ENESTnd 3-Year Update
Incidenza cumulativa di MMR
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
100
90
n
282
281
283
% With MMR
80
By 3 Years
73%, P < .0001
By 1 Year
70
55%, P < .0001
70%, P < .0001
60
Δ 17%-20%
50
53%
51%, P < .0001
40
Δ 24%-28%
30
27%
20
10
0
0
3
6
9
12
15
18
21
Months Since Randomization
24
27
30
33
36
ENESTnd 3-Year Update
MMR per Sokal Risk a 3 anni
P = .0264
80
77
% With MMR
70
P = .0020
P = .0004
75
67
63
60
54
50
39
40
30
20
10
0n =
103
104
Low
Nilotinib 300 mg BID
• 
101
101
Intermediate
78
High
78
Imatinib 400 mg QD
L’incidenza di MMR è consistentemente alta nei pazienti trattati con nilotinib
vs imatinib in tutti gli score Sokal
Incidenza cumulativa di MR4*
50
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
% With MR4
40
ENESTnd 3-Year Update
By 3 Years
50%, P < .0001
n
282
281
283
44%, P < .0001
By 1 Year
30
Δ 18%-24%
20%, P < .0001
26%
20
15%, P = .0004
Δ 9%-14%
10
6%
0
0
3
6
9
12
15
18
21
24
Months Since Randomization
* Equivalente ad un livello di trascritto BCR-ABL ≤ 0.01% (IS).
27
30
33
36
ENESTnd 3-Year Update
Incidenza cumulativa di MR4.5*
% With MR4.5
40
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
30
n
282
281
283
By 3 Years
32%, P < .0001
By 1 Year
11%, P < .0001
28%, P = .0003
20
Δ 13%-17%
15%
10
7%, P < .0001
Δ 6%-10%
0
1%
0
3
6
9
12
15
18
21
24
27
30
33
36
Months Since Randomization
* Equivalente ad un livello di trascritto BCR-ABL ≤ 0.0032% (IS).
Data cut-off: 27Jul2011.
8
Saglio G, et al. Blood. 2011;118(21):208-209 [abstract 452].
ENESTnd 3-Year Update
% With MR4.5
MR4.5 per Sokal Risk a 3 anni
50
45
40
35
30
25
20
15
10
5
0
P = .0003
P = .0468
40
P = .0099
30
24
18
17
9
n=
103
Low
104
101
Intermediate
Nilotinib 300 mg BID
• 
101
78
High
78
Imatinib 400 mg QD
L’incidenza di MR4.5 è consistentemente alta nei pazienti trattati con nilotinib
vs imatinib in tutti gli score Sokal
Data cut-off: 27Jul2011.
9
Saglio G, et al. Blood. 2011;118(21):208-209 [abstract 452].
ENESTnd 3-Year Update
Progressione a AP/BC* nel Core Treatment
P = .0003
Number of Patients, n
P = .0085
P = .0059
17
P = .0185
12
2
0.7%
5
3
1.1%
2
4.2%
Nilotinib 300 mg BID
0.7%
1.8%
6.0%
Including Clonal Evolution
Nilotinib 400 mg BID
Imatinib 400 mg QD
•  Nessuna nuova progressione è avvenuta dall’ultimo
follow-up dei 2 anni
* Progression to AP/BC or death following progression.
ENESTnd 3-Year Update
Number of Patients, n
Progressione a AP/BC: inclusi gli eventi
dopo la sospensione (ITT Analysis)*
P = .0496
HR = 0.5 [0.2, 1.0]
P = .0076
HR = 0.3 [0.1, 0.8]
19
9
6
3.2%
2.1%
6.7%
On Core Treatment and After Discontinuation
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
§ 
Le informazioni sulle progressioni off treatment sono state collezionate
prospetticamente ogni 3 mesi dopo la sopensione
§ 
Nello studio IRIS, l’incidenza cumulativa di progressioni nei primi 3 anni sono
state approssimativamente 6% con imatinib1
* Progression to AP/BC or death following progression.
1. Hochhaus A, et al. Leukemia. 2009;23(6):1054-1061.
First line trials in chronic myeloid leukemia sabato, 16 giugno 2012 FRONTLINE TREATMENT OF PHILADELPHIA POSITIVE CHRONIC MYELOID LEUKEMIA WITH SEQUENTIAL ADMINISTRATION OF NILOTINIB 400 MG TWICE DAILY AND IMATINIB 400 MG ONCE DAILY: A PHASE 2 MULTICENTRIC STUDY
Author: MD, PhD Castagnen, Fausto, Bologna for Gimema Background: The use of more than one TKI may decrease the frequency of drug-­‐resistance. Aims: To evaluate the response and the outcome of ECP Ph+ CML pa`ents treated with the sequen`al administra`on of NIL and IM. Methods: NIL was administered first because of faster therapeu`c effect. Schedule: alterna`ng administra`on every 3 months of NIL 400 mg twice daily and IM 400 mg daily; Results: 123 pa`ents have been enrolled CCgR rates were: 72%, 79% and 75% at 3, 6 and 12 months, respec`vely; the cumula`ve CCgR rate by 12 months was 87%. MMR rates at 3, 6 and 12 months were 58%, 63% and 65%, respec`vely; the cumula`ve MMR rate by 12 months was 82%. The median `me to CCgR and MMR was 3 months. At the last contact, 84% of pa`ents were s`ll on treatment with the study drugs, 61% with the alterna`ng schedule, 9% on NIL alone and 13% on IM alone. The overall survival was 94%, the progression-­‐free survival was 93%. The events leading to study discon`nua`on were: treatment failure 11%, Conclusions: The response rates with the sequen`al administra`on of NIL and IM are in the range of the results reported in studies of 2nd genera`on TKIs as single agents. Chronic myeloid leukemia -­‐ Biology and predic*on of response Date: domenica, 17 giugno 2012 AN EXPLORATORY ANALYSIS FROM 3-­‐YEAR DASISION FOLLOW-­‐UP EXAMINING THE IMPACT ON PATIENT OUTCOMES OF EARLY COMPLETE CYTOGENETIC RESPONSE AT 3 MONTHS AND MAJOR MOLECULAR RESPONSE AT 12 MONTHS
1106 Author: Jabbour, Elias, (Houston, United States of America) DASISION (CA180-056) Study Design
§  Treatmentnaïve CML-CP
patients
(N=519)
Dasatinib 100 mg QD (N=259)
Randomized*
§  108 centers
§  26 countries
Follow-up
5 years
Imatinib 400 mg QD (N=260)
*Stratified by EURO/Hasford risk score
n  Primary endpoint
Confirmed CCyR rate by 12 months
n  Other key endpoints
Rates of and times to CCyR and MMR,
duration of CCyR, progression-free survival,
overall survival
MMR Rates (ITT) by Month of Treatment
100
80
Dasatinib 100 mg QD
P=0.0002
Imatinib 400 mg QD
P<0.0001
57
60
%
39
40
20
0
46
41
28
27
18
8
0,4
Mo 3
13
8
Mo 6
Mo 9
Mo 12
MMR, BCR-ABL ≤0.1%
Any time
7
Any time
BCR-ABL
≤0.0032%
n  Based on time-to MMR analysis, likelihood of achieving a MMR was 1.8-fold
higher with dasatinib vs imatinib (stratified log-rank P<0.0001; HR=1.8)
n  Among patients who achieved a MMR, median time to MMR was 8.3 mos for
dasatinib and 11.8 mos for imatinib
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP
Cumulative Incidence of MMR
100
Dasatinib 100 mg QD
Imatinib 400 mg QD
80
34% no MMR
By 12 months
46%
60
By 24 months
64%
P<0.0001
%
46%
40
28%
20
0
0
10
20
Months
30
40
n  Median time to MMR in all patients calculated by competing risk
analysis was 15 months for dasatinib and 36 months for imatinib
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP
Cumulative Incidence of MR 4.5
(BCR-ABLIS ≤0.0032%*)
100
Dasatinib 100 mg QD
76 % no MR4.5
Imatinib 400 mg QD
By 24 months
17%
% 20
P=0.002
10
8%
0
0
* ≥4.5-log reduction (CMR4.5)
10
20
Months
30
40
Transformation to Accelerated/Blast Phase (ITT)
20
Dasatinib 100 mg QD
15
15
n
13
5.0%
10
6
5
0
n 
n 
n 
Imatinib 400 mg QD
5.8%
9
3.5%
2.3%
On study
Including follow-up
beyond discontinuation*
9 patients who achieved a CCyR transformed to AP/BP on study (3 dasatinib, 6 imatinib)
No patient who achieved MMR transformed to AP/BP by data cut-off
ELN 2006 criteria for transformation
* Yearly evaluations after discontinuation are currently stipulated by the protocol;
additional information on patient status may be provided by investigators at other times
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP
Kaplan-Meier Analyses
Failure-free survival*
(ELN 2006 criteria)
100
100
% not progressed
80
% without failure
Progression-free survival*
(no AP/BP or loss of response and
no death for any other reason)
60
24 months
Dasatinib: 91.2%
Imatinib: 87.8%
40
20
0
0
10
20
Months
30
40
80
60
24 months
Dasatinib: 93.7%
Imatinib: 92.1%
40
20
0
0
10
20
Months
30
40
Overall survival†
100
% alive
80
60
* Patients who discontinued for other
reasons were censored at last
hematologic or cytogenetic evaluation
24 months
Dasatinib: 95.3%
Imatinib: 95.2%
40
20
† Surviving
0
0
10
20
Months
30
40
patients were followed after
discontinuation and were censored on the
last date known to be alive
First line trials in chronic myeloid leukemia Sabato, 16 giugno 2012 BOSUTINIB VERSUS IMATINIB IN NEWLY DIAGNOSED CHRONIC PHASE CHRONIC MYELOID LEUKEMIA: 30-­‐MONTH UPDATE OF THE BELA TRIAL Author: Brummendorf, Tim H, Hamburg, Germany (Presen`ng author) Background: The BELA study compared the efficacy and safety of bosu`nib, a dual Src/Abl kinase inhibitor, with ima`nib in newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML). Aims: The current analysis reports data amer ≥24 months of follow-­‐up; updated data including ≥30 months of follow-­‐up Methods: A total of 502 pa`ents with newly diagnosed CP CML were randomized to bosu`nib 500 mg/day or ima`nib 400 mg/
day and stra`fied by Sokal risk group and geographic region. Results: The median treatment dura`on was 27.5 months in both cohorts; 63% of bosu`nib pa`ents and 71% of ima`nib pa`ents were s`ll receiving treatment at the `me of this analysis. The primary reason for bosu`nib discon`nua`on was a treatment-­‐emergent adverse event (TEAE; 24% vs 7% with ima`nib), while the primary reason for ima`nib discon`nua`on was disease progression (13% vs 4% with bosu`nib). Cumula`ve complete cytogene`c response rates by 24 months were 87% versus 81% in the evaluable popula`on (P = 0.046). Cumula`ve major molecular response (MMR) rates by 24 months were 59% for bosu`nib and 49% for ima`nib (P = 0.019). Cumula`ve MMR rates by 24 months were 65% for bosu`nib versus 51% for ima`nib (P = 0.002). Kaplan-­‐Meier es`mates of event-­‐free survival at 24 months were 92% for bosu`nib and 87% for ima`nib. Conclusions: Bosu`nib was effec`ve for treatment of newly diagnosed CP CML, with higher rates of MMR and CMR than ima`nib • 
Chronic myeloid leukemia -­‐ Biology and predic*on of response Date: domenica, 17 giugno 2012 PACE: A PIVOTAL PHASE 2 TRIAL OF PONATINIB IN PATIENTS WITH CML AND PH ALL RESISTANT OR INTOLERANT TO DASATINIB OR NILOTINIB, OR WITH THE T315I MUTATION 1104 Author: MD Cortes, J, (Houston, United States of America) Ponatinib
• 
Oral pan-BCR ABL TKI with potent activity against
native and mutated BCR-ABL and other kinases
• 
Rationally designed with
extensive network of
optimized molecular contacts
and triple bond to
accommodate T315I
I315 triple bond pona*nib • 
Phase 1 trial
•  Recommended dose: 45 mg/day
•  Well-tolerated
•  Early and durable responses in refractory patients
• 
This is the initial report of the pivotal phase 2 PACE trial
Best Response
Ph+ N=48 evaluable patients
No. (%)
Overall
Best Response
T315I mutation*
CP
AP, BP, ALL
CP
AP, BP, ALL
N=32
N=16
N=11
N=9
CHR
30 (94)**
-
11 (100)**
-
MHR
-
5 (31)
-
3 (33)
N=32
N=16
N=11
N=9
20 (63)
3 (19)
9 (82)
2 (22)
12 (38)
1 (6)
8 (73)
1 (11)
Hematologic
Cytogenetic
MCyR
CCyR
20 MCyR in patients with CML CP
•  18 remain on therapy without progression (mean: 326 days [142-599])
•  2 PD after a PCyR in the 4 mg and 15 mg cohorts, respectively
* T315I category includes patients by past history or confirmed at baseline. **Includes new CHRs and baseline CHRs.
Phase 1 Study of Ponatinib
Best Response to Therapy
Advanced Phases
Best
Response
Hematologic
MHR
Cytogenetic
MCyR
CCyR
Overall
N=17
N (%)
T315I*
N=5
Non-T315I
N=12
6 (35)
1 (20)
5 (42)
4 (24)
2 (12)
1 (20)
0 (0)
3 (25)
2 (17)
*Includes only those with T315I status confirmed at study entry.
Updated at ASH 2011
Monitoring Giovanni Mar*nelli Is*tuto di Ematologia “ L. e A. Seràgnoli” University of Bologna First line trials in chronic myeloid leukemia sabato, 16 giugno 2012 EARLY BCR-­‐ABL TRANSCRIPT LEVELS PREDICT FUTURE MOLECULAR RESPONSE AND LONG-­‐TERM OUTCOMES IN NEWLY-­‐DIAGNOSED PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE: ANALYSIS OF ENESTND 3-­‐
YEAR DATA Author: Hochhaus, A, Universitätsklinikum Jena Background: Several independent groups have conducted analyses sugges*ng that achievement of BCR-­‐ABL transcript levels according to the interna*onal scale (IS) of <10% and <1 at 3 months were associated with improved outcomes. Methods: The nilo*nib 300 mg BID (n = 282) and ima*nib (n = 283) arms from ENESTnd were used for this analysis. Results: Among evaluable pa*ents at 3 months, 91% of pa*ents in the nilo*nib arm vs 67% in the ima*nib arm achieved BCR-­‐ABL transcript levels of ≤10%; 56% vs 16% of pa*ents achieved BCR-­‐ABL transcript levels of ≤1%. The ini*al molecular response also correlated with progression to AP/BC and with OS. Of the 187 pa*ents who achieved ≤1% BCR-­‐ABL at 3 months, only 1 progressed on treatment 2 of 222 pa*ents who achieved >1% to 10% progressed (both on ima*nib) 9 of 111 pa*ents who achieved >10% at 3 months progressed (1 on nilo*nib and 8 on ima*nib). Pa*ents who achieved ≤1% BCR-­‐ABL transcript levels at 3 months had a higher OS rate than pa*ents who achieved >10% BCR-­‐ABL transcript levels at 3 months (3-­‐year OS 97% and 87%, respec*vely, in the nilo*nib arm and 95% and 85%, respec*vely, in the ima*nib arm). Conclusions: More pa*ents in the nilo*nib arm vs the ima*nib arm achieved BCR-­‐ABL transcript levels ≤1% (56% vs 16%) and ≤10% (91% vs 67%) at 3 months. Early molecular response at 3 months correlated with an increased probability of freedom from progression and OS.
ENEST1st: EUTOS Collaboration
Incidenza cumulativa di MMR e MR4*
100
By 6 months
By 3 months
90
Patients, %
80
70
60
50%
50
40
30
23%
20
20%
10
5%
0
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7 7.5
8 8.5
9 9.5
10
Time Since Study Entry, months
MMR
MR4
* n = 191 pazienti trattati con risposta molecolare valutabile e trascritto tipico.
MMR, major molecular response; MR4, molecular remission with a sensitivity of 4 logs.
27
Giles FJ, et al. Blood. 2011;118(21):1186-1187 [abstract 2759].
ENEST1st: EUTOS Collaboration
Incidenza cumulativa di MMR e MR4
In base all’ EUTOS Score*
100
By 6 months
By 3 months
90
Patients, %
80
70
60
54%
50
40
30
27%
20
27%
21%
5%
10
7%
5%
0%
0
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7
7.5
8
8.5
9 9.5
10
Time Since Study Entry, months
MMR - high risk
MMR - low risk
MR4 - high risk
MR4 - low risk
EUTOS, European Treatment and Outcomes Study; MMR, major molecular response; MR4, molecular remission with a
sensitivity of 4 logs.
28
Giles FJ, et al. Blood. 2011;118(21):1186-1187 [abstract 2759].
TIDEL-II, ASH 2011
Molecular Response at 3 months
Predicts MMR at 12 months:
Evaluable patients (n=174)
BCR-ABL at
3 months
n
<1%
1% to <10%
≥10%
105 (60%)
50 (29%)
19 (11%)^
MMR at 12 Transformation
months
to BC
83%
52%
21%
p<0.0001*
1%
2%
10.5%
p=0.011*
^Excludes 1 patient who transformed before 3 months
*Fisher’s Exact Test
Chronic myeloid leukemia -­‐ Biology and predic*on of response Date: domenica, 17 giugno 2012 HIGH SENSITIVITY MUTATION SCREENING AND CLONAL ANALYSIS ALLOWED BY ULTRA-­‐DEEP AMPLICON SEQUENCING UNCOVER THE COMPLEXITY OF BCR-­‐ABL MUTATION STATUS IN PATIENTS TREATED WITH TYROSINE KINASE INHIBITORS 1103 PhD SOVERINI, SIMONA, (Bologna, Italy) Discon*nua*on Eradica*on Giovanni Mar*nelli Is*tuto di Ematologia “ L. e A. Seràgnoli” University of Bologna Long term management of CML patients:
• 
• 
• 
• 
Prevalence increasing
First line therapy improving
Tailoring treatment according to molecular milestones feasible
Selection of second line therapies based on patient history and
molecular parameters
•  Option for discontinuation of TKI
•  Life long surveillance needed
Diagnosis
>2 years
Response induction
•  Most active BCR-ABL
inhibitor
•  Combinations
MR4-4.5
TKI discontinuation
>1 year
Follow up
Response consolidation
Continuous MR
•  Targeting detectable or
undetectable residual
disease with acceptable
toxicity profile.
•  IFN ?
STIM Study: Kaplan-Meier Estimates of
CMR after Discontinuation of Imatinib
• 
The overall probability of maintenance of CMR at 24 and 36
months was 39% (95% CI 29-48).
Molecular relapse occurred in 61 pts with 58
relapses occurring during the first 7 months 3 late
relapses at month 19, 20 and 22, respectively
Mahon et al. Blood (ASH) 2011;118: Abstract 603
Chance of CMR after imatinib discontinuation in
100 patients with CML according to Sokal score
Among the 11 patients with high Sokal risk score 9 patients relapsed
Hypothetical Model of CML persistence and recurrence
versus extinction
The eradication of the leukemic clone may depend on inherent features of
the disease or on the duration of therapy, or both.
Deininger, M. Nat. Rev. Clin. Oncol. advance online publication 1 February 2011;
doi:10.1038/nrclinonc.2011.17
First line trials in chronic myeloid leukemia sabato, 16 giugno 2012 •  INTERMITTENT IMATINIB (INTERIM) TREATMENT IN PH -­‐CML ELDERLY PATIENTS IN STABLE COMPLETE CYTOGENETIC RESPONSE 0187 •  Author : Russo, Domenico, Univ. of Brescia One year of Intermittent Imatinib (IM) treatment (InterIM) maintains the complete
cytogenetic response (CCgR) previously achieved with standard IM therapy in
elderly (≥ 65 years) Ph+ CML patients
Fig.3 Distribution of patients according to Molecular Biology
Futhermore
did notwith
observe
• 83 pts werewe
treatment
InterIM
• A
dditional
Cytogenetic
Abnormalities
94%
pts mantained
a CCgR
• B
CR/ABL
6%
pts lostMutations
CCgR
• N
o progression
to ABP
75%
pts mantained
a MMR
• 25% pts lost MMR
There are no relevant conflicts of interest to disclose
LOSS OF MAJOR MOLECULAR RESPONSE IS ACCURATE FOR RESTARTING IMATINIB AFTER IMATINIB DISCONTINUATION IN CP-­‐CML PATIENTS WITH LONG LASTING CMR: IMPORTANCE OF FLUCTUATING VALUES OF MRD AND INTERFERON 0194 MD/PhD Rousselot, Philippe, Charbonnier, A, Cony-­‐
Makhoul, P, Agape, P, Nicolini, F, Varet, B, Réa, D, Legros, L, Tulliez, M, Roy, L, Guilhot, F, Mahon, FX (Le Chesnay, France) CML Stem cell research Giovanni Mar*nelli Is*tuto di Ematologia “ L. e A. Seràgnoli” University of Bologna Proper*es and targets of the CML Leukemia Stem Cell Self-­‐renewal Inhibition of
ü  Hedgehog
ü  Wnt/b-cathenin
ü  mTOR pathway
ü  5-LO pathway
Resistance to apoptosis •  Inhibition of
ü  Histone deacetylase
ü  Farnesyltransferase/PKCb
activation
ü  Autophagy
BCR-­‐ABL+ CD34+ CD38-­‐ Lin-­‐ cell •  Omacetaxine
•  Sesquiterpene oils
•  Fingolimod
Quiescence Inhibition Of:
ü  SDF-1/CXCR4
ü  PML (As2O3)
•  Interferon-a
Immunotolerance •  Interferon-a
•  Vaccines •  SCT Courtesy of M. Bonifacio
Acknowledgments Dpt. of Hematology/Oncology “Seràgnoli”, Bologna Michele Baccarani Ilaria Iacobucci, Maria Teresa Bochicchio, Simona Soverini, Emanuela Omaviani, Viviana Guadagnuolo, Nicolema Testoni, Anna Ferrari Gianantonio Ros*, Gabriele Guglioma, Fausto Castagnen, Francesca Palandri Cris*na Papayannidis, Stefania Paolini, Antonio Cur*, Sarah Parisi, Maria Chiara Abbenante Stem cell biology: domenica, 17 giugno 2012
•  STAT1-­‐DEFICIENT MICE DEVELOP A MYELOPROLIFERATIVE SYNDROME RESEMBLING HUMAN CML 1148 •  Chris`ne , Schneckenleithner, Hölbl, Andrea, Müller, Mathias, Kolbe, Thomas, Decker, Thomas, Sexl, Veronika (Vienna, Austria) Stem cell biology: domenica, 17 giugno 2012 NERVE GROWTH FACTOR AND COLLAGEN 1 PREVENT APOPTOSIS AND MAINTAIN DURABLE SELF-­‐RENEWAL OF ADULT MOUSE HEMATOPOIETIC STEM CELLS STIMULATED WITH PROLIFERATIVE CYTOKINES 1151 Author: Wohrer, Stefan, (Vienna, Austria) Stem cell biology: domenica, 17 giugno 2012
ROLE OF JAM-­‐B/JAM-­‐C INTERACTION IN THE CIRCULATION OF HEMATOPOIETIC STEM CELLS AND THEIR RETENTION IN THE BONE MARROW
1149 Author: PhD ARCANGELI (Marseille, France) Stem cell biology: domenica, 17 giugno 2012 THE TRANSCRIPTION FACTOR MEIS1 REGULATES COMMITMENT TOWARDS THE MEGAKARYOCYTE-­‐ERYTHROCYTE LINEAGE BY REGULATING GATA1 EXPRESSION 1150 Author: Zeddies, Sabrina, Amsterdam, NDL
Chronic myeloid leukemia -­‐ Biology and predic*on of response Date: domenica, 17 giugno 2012 THE EUTOS HIGH RISK POPULATION DIFFERS SUBSTANTIALLY FROM THE EURO HIGH RISK GROUP; THE EUTOS SCORE PREDICTS MOLECULAR RESPONSE IN CHRONIC PHASE CML PATIENTS: RESULTS OF THE GERMAN CML-­‐
STUDY IV 1105 MD Saußele, (Mannheim, Germany) •  EUTOS SCORE IS PREDICTIVE FOR SURVIVAL AND OUTCOME IN PATIENTS WITH EARLY CHRONIC PHASE CHRONIC MYELOID LEUKEMIA TREATED WITH NILOTINIB-­‐BASED REGIMENS 0193 •  MD, PhD Castagnen Chronic myeloid leukemia -­‐ Biology and predic*on of response Date: domenica, 17 giugno 2012 REGULATION OF CHRONIC MYELOID LEUKEMIA STEM CELLS BY LEUKEMIA ONCOGENE EVI1 1102 MD PhD Sato, (Tokyo, Japan) DASATINIB MAY OVERCOME THE NEGATIVE PROGNOSTIC IMPACT OF KIR2DS1 IN NEWLY DIAGNOSED PATIENTS WITH CHRONIC MYELOID LEUKEMIA 0165 MD, PhD Rezvani, (London, United Kingdom) Acknowledgments Dpt. of Hematology/Oncology “Seràgnoli”, Bologna Michele Baccarani Ilaria Iacobucci, Maria Teresa Bochicchio, Simona Soverini, Emanuela Omaviani, Viviana Guadagnuolo, Nicolema Testoni, Anna Ferrari Gianantonio Ros*, Gabriele Guglioma, Fausto Castagnen, Francesca Palandri Cris*na Papayannidis, Stefania Paolini, Antonio Cur*, Sarah Parisi, Maria Chiara Abbenante “Dormant” Leukemia Ph+ Stem Cell
CD19+
SMO +
DNA repair +
Ikaros del
CDKn2A del
CD26
ABCG2+
ABCC4+
(Side population)
TIE2-ANG1+
NOTCH
AKT1
Istituto Seragnoli
CML CD34+ High Sokal’s risk vs Low GEP
Affy ID
Gene Symbol
Protein name
Signal
P_value
227499_at
FZD3
Frizzled-3
1,07964814 0,00040093
235457_at
MAML2
Mastermind-like protein 2
-0,8086432 0,00499238
213532_at
ADAM17
Disintegrin and metalloproteinase domain-containing protein 17
-0,3313421
227489_at
SMURF2
E3 ubiquitin-protein ligase SMURF2
-0,3342401 0,01846165
221609_s_at
WNT6
Protein Wnt-6
0,39941692 0,02027968
205698_s_at
MAP2K6
Dual specificity mitogen-activated protein kinase kinase 6
-0,3571502 0,02212064
210446_at
GATA1
Erythroid transcription factor
0,61870161
225927_at
MAP3K1
Mitogen-activated protein kinase kinase kinase 1
-0,3568996 0,04231478
0,0154189
Signal transduction_
NOTCH signaling
0,0416767
Carolina Terragna et Al . ASH 2010
Stem cell mobilitation markers
LSC markers
Abcg2
Abcb1
Nanog
Bmi1
Sox2
Oct3/4
Vegf
Hif
markers
CD25 CD58
CD32 CD99
CD44
CD47
CLL-1
CD96
CD26
CD123
CD114
TIM3
Multi Drug Resistant markers
Stemness
CD34+
CD38CD90+
CD133+
LinAldh1+
Gli 1
Gli 2
Gli 3
Smo
Cxcr4
Sdf1
Hypoxia markers
Stem Cell markers
Biomarkers of Hedgehog Patwhay
Immunologic escape markers
CD274 (PDL1)
CD273+
Beta-galectin
CIITA
CML CD34+ High Sokal’s risk vs Low GEP
Affy ID
Gene Symbol
Protein name
Signal
P_value
209696_at
FBP1
Fructose-1,6-bisphosphatase 1
0,76998605
201427_s_at
SEPP1
Selenoprotein P
-1,1592526 0,00680954
202554_s_at
GSTM3
Glutathione S-transferase Mu 3
0,75750473 0,01432935
203815_at
GSTT1
Glutathione S-transferase theta-1
0,83000157 0,03490554
39729_at
PRDX2
Peroxiredoxin-2
0,33795114 0,04421954
203949_at
MPO
Myeloperoxidase
-1,2060973 0,04902287
0,000023
Response to hypoxia
and oxidative stress
Glucose
metabolism
Glucose
Glycolysis
HIGH RISK CML
PATIENTS
Glucose 6-P
FBP1 (p = 0.04)
25
Fructose 6-P
20
15
10
Fructose 1,6-P2
5
0
HIGH
non-HIGH
Pyruvate kinase M2
(Spliced and mutated)
Warburg
effect
Pyruvate
Lactate
Pyruvate
TCA cycle “Seràgnoli” Institute of Hematology– Bologna, Italy
High risk CML glucose metabolism?
Protein name
Glutathione S-transferase Mu 3
Glucose
NADP
NADPH
Glucose 6-P
Glucose-6phosphate 1dehydrogenase
Protein
Glucose-6-phosphate
1-dehydrogenase
GEP Signal
0,7575
P_value
0,0143
Glutathione peroxidase 7
0,3396
0,0335
Glutathione S-transferase theta-1
0,8300
0,0349
Glutathione peroxidase 1
0,3232
0,0416
Glutathione S-transferase theta-2
0,2635
0,1239
Phospholipid hydroperoxide glutathione peroxidase, mitochondrial
0,2738
0,1984
Glutathione S-transferase Mu 4
0,3224
0,2010
Glutathione S-transferase P
0,2969
0,2454
Glutathione S-transferase kappa 1
0,1796
0,4129
Glutathione S-transferase Mu 5
0,2259
0,6642
Glutathione S-transferase omega-1
0,0464
0,7687
Glutathione reductase, mitochondrial
0,0294
0,8691
6-P-glucolactone
NADP
GEP
Signal
P_value
0,3045
0,2358
Pentose
phosphat
e shunt
Fructose 6-P
NADPH
Ribose-5-phosphate
FBP1
Fructose 1,6-P2
6-P-gluconate
Tranketolase
Protein
GEP
Signal
Transketolase
0,282118
P_value
0,31618
Nucleotide
synthesis
Summary
1.  Comparison of gene profiles of HIGH and non-
HIGH Sokal risk CP-CML patients.
2.  Self-renewal, and cell metabolism are the most
significantly affected pathways.
3.  FBP1 over-expression: activation of survival
pathways?
“Seràgnoli” Institute of Hematology– Bologna, Italy
•  EARLY PREDICTORS OF PROGRESSION TO ACCELERATED-­‐BLASTIC PHASE IN EARLY CHRONIC PHASE CHRONIC MYELOID LEUKEMIA PATIENTS TREATED FRONTLINE WITH NILOTINIB-­‐BASED REGIMENS 0195 •  Guglioya, Gabriele, Castagnen, Fausto, Palandri, Francesca, Breccia, Massimo, Levato, Luciano, Stagno, Fabio, Rege Cambrin, Giovanna, Zaccaria, Alfonso, Specchia, Giorgina, Usala, Emilio, Gozzini, Antonella, Mar`no, Bruno, Capucci, Adele, Pierri, Ivana, Tiribelli, Mario, Bocchia, Monica, Abruzzese, Elisabeya, Soverini, Simona, Testoni, Nicoleya, Saglio, Giuseppe, Mar`nelli, Giovanni, Pane, Fabrizio, Alimena, Giuliana, Ros`, Gianantonio, Baccarani, Michele (Bologna, Italy) •  EARLY PREDICTORS OF PROGRESSION TO ACCELERATED-­‐BLASTIC PHASE IN EARLY CHRONIC PHASE CHRONIC MYELOID LEUKEMIA PATIENTS TREATED FRONTLINE WITH NILOTINIB-­‐BASED REGIMENS 0195 •  Guglioya, Gabriele, Castagnen, Fausto, Palandri, Francesca, Breccia, Massimo, Levato, Luciano, Stagno, Fabio, Rege Cambrin, Giovanna, Zaccaria, Alfonso, Specchia, Giorgina, Usala, Emilio, Gozzini, Antonella, Mar`no, Bruno, Capucci, Adele, Pierri, Ivana, Tiribelli, Mario, Bocchia, Monica, Abruzzese, Elisabeya, Soverini, Simona, Testoni, Nicoleya, Saglio, Giuseppe, Mar`nelli, Giovanni, Pane, Fabrizio, Alimena, Giuliana, Ros`, Gianantonio, Baccarani, Michele (Bologna, Italy) •  NILOTINIB 400 MG BID IN EARLY CHRONIC PHASE CHRONIC MYELOID LEUKEMIA: BEYOND 4 YEARS RESULTS REMAIN STABLE -­‐ THE GIMEMA CML WP TRIAL CML0307 0198 •  MD Ros`, Gianantonio, (Bologna, Italy) for Gimema •  SIX-­‐YEAR FOLLOW-­‐UP OF PATIENTS WITH IMATINIB-­‐RESISTANT OR IMATINIB-­‐INTOLERANT CHRONIC-­‐PHASE CHRONIC MYELOID LEUKEMIA (CP-­‐CML) RECEIVING DASATINIB 0199 •  Rea, Delphine , Vellenga, Edo, Junghanß, Chris`an, Baccarani, Michele, Kantarjian, Hagop, Lofgren, Chris`na, Dejardin, David, Hochhaus, Andreas (Paris, France) • 
17:45-­‐19:00
17:45-­‐19:00
BCR-­‐ABL KINETICS AFTER DISCONTINUATION OF IMATINIB IN CML PATIENTS WITH MR4.5 O
R UNDETECTABLE MOLECULAR RESIDUAL D ISEASE 0200 17:45-­‐19:00
•  MD Lee, Sung-­‐Eun, Choi, Soo Young , Bang, Ju-­‐Hee , Kim, Soo-­‐Hyun , Jang, Eun-­‐jung, Choi, Miyeon, Byeun, Ji-­‐Young , Park, Jin-­‐Eok , Jeon, Hye-­‐Rim , Kim, Hyeoung-­‐
Joon , Park, Joon Seong , Kim, Sung Hyun , Zang, Dae Young , Koo, Dong-­‐Hoe , Kim, Hawk, Kim, Dong-­‐Wook (Seoul , South-­‐Korea)