The management of CML: current treatment paradigms and future perspectives
NAPLES 18 – 19 MAY 2009
First line treatment of CML with Imatinib: the IRIS trial and the GIMEMA trials
Michele Baccarani
IRIS IRIS ProtocolProtocol: : StudyStudy DesignDesign
IFNIFN--a a + +
AraAra--CC
ImatinibImatinib
CrossoverCrossover forfor::•• LackLack ofof responseresponse•• LossLoss ofof responseresponse•• IntoleranceIntolerance ofof treatmenttreatment•• ReluctanceReluctance toto continuecontinue IFNIFN
CrossoverCrossover
RRAANNDDOOMMIIZZEE
n = 553n = 553
n = 553n = 553
O’BRIEN et al, NEJM, 2003
IRIS 7 Year Update: Main Points
• What happened to all the patients?- Discontinuation- Survival
• Late progression events• Durability of complete cytogenetic response (CCR)
- Is CCR a ‘safe haven’?• PCR data• Adverse Events• Conclusions
What Happened To The Patients After 7 Years?
All randomized to imatinib(n= 553; 100%)
All randomized to All randomized to imatinibimatinib(n= 553; 100%)(n= 553; 100%)
Discontinued study imatinib*(n = 221; 40%)
Discontinued study Discontinued study imatinibimatinib**(n = 221; 40%)(n = 221; 40%)
Still receiving study imatinib(n = 332; 60%)
Still receiving study Still receiving study imatinibimatinib(n = 332; 60%)(n = 332; 60%)
In CCR (n = 317;
57%)
In CCR In CCR (n = 317; (n = 317;
57%)57%)
No CCR (n = 15;
3%)
No CCR No CCR (n = 15; (n = 15;
3%)3%) Safety(n = 43;
8%)
SafetySafety(n = 43; (n = 43;
8%)8%)
Efficacy (n = 82;
15%)
Efficacy Efficacy (n = 82; (n = 82;
15%)15%)
Other (n = 96;
17%)
Other Other (n = 96; (n = 96;
17%)17%)
Alive(n = 17;
40%)
AliveAlive(n = 17; (n = 17;
40%)40%)
Dead**(n = 26;
60%)
Dead**Dead**(n = 26; (n = 26;
60%)60%)
Alive(n = 52;
63%)
AliveAlive(n = 52; (n = 52;
63%)63%)
Dead(n = 30;
37%)
DeadDead(n = 30; (n = 30;
37%)37%)
Alive(n = 81;
84%)
AliveAlive(n = 81; (n = 81;
84%)84%)
Dead(n = 15;
16%)
DeadDead(n = 15; (n = 15;
16%)16%)
**Including primary discontinuation reason ‘Death’ (n=13)
*Patients may have continued imatinib off study.IRIS 7 year update
O’BRIEN et al, ASH 2008, Blood 2008; 112(11): 76, Abstract 186
Overall Survival (ITT Principle): Imatinib Arm
Estimated overall survival at 7 years is 86%
(94% considering only CML-related deaths)
Survival: deaths associated with CMLOverall Survival
% W
ithou
t Eve
nt
0102030405060708090
100
Months Since Randomization0 12 24 36 48 60 72 84 96
IRIS 7 year updateO’BRIEN et al, ASH 2008, Blood 2008; 112(11): 76, Abstract 186
Annual Event Rates: Imatinib Arm
0
1
2
3
4
5
6
7
8
1 2 3 4 5 6 7Year
% W
ith E
vent
EventLoss of CHR,Loss of MCR,AP/BC,Death during treatment
AP/BC3.3
7.5
4.8
1.71.5
2.8
1.60.9 0.8
0.30.50
2.0
0.4
• KM estimated EFS at 7 years = 81%• KM estimated rate without AP/BC at 7 years = 93%
*Total events (n=5) including loss of MCR (n=3) and deaths (n=2, one of which was coded as progression to AP/BC in a patient in CMR 6 months prior to death).
*
IRIS 7 year updateO’BRIEN et al, ASH 2008, Blood 2008; 112(11): 76, Abstract 186
Durability of Cytogenetic Response• 456 of 553 (82%) of first-line imatinib patients achieved CCR• 317 (57%) patients randomized to imatinib remained on protocol and were in
complete cytogenetic response (CCR)
Patients who achieved CCR (n = 456; 100%)
Patients who achieved Patients who achieved CCR (n = 456; 100%)CCR (n = 456; 100%)
Lost CCR(n = 79 of 456: 17%)
Lost CCRLost CCR(n = 79 of 456: 17%)(n = 79 of 456: 17%)
In CCR (n = 377 of 456: 83%)
In CCR In CCR (n = 377 of 456: 83%)(n = 377 of 456: 83%)
Remained on imatinib(n = 25; 5%)
Remained on Remained on imatinibimatinib(n = 25; 5%)(n = 25; 5%)
Regained CCR(n = 19; 4%)
Regained CCRRegained CCR(n = 19; 4%)(n = 19; 4%)
In MCR(n = 6; 1%)In MCRIn MCR
(n = 6; 1%)(n = 6; 1%)
Remained on imatinib(n=298; 65%)
Remained on Remained on imatinibimatinib(n=298; 65%)(n=298; 65%)
Off imatinib(n = 79; 17%)Off Off imatinibimatinib(n = 79; 17%)(n = 79; 17%)
Regained CCRafter dose increase (n = 6)
Regained CCRRegained CCRafter dose increase (n = 6)after dose increase (n = 6)
IRIS 7 year updateO’BRIEN et al, ASH 2008, Blood 2008; 112(11): 76, Abstract 186
7
3
1
2
1
0123456789
10
1st 2nd 3rd 4th 5th
Rates of Progression in Patients After CCR
• Progression to AP/BC occurred in 15 (3%) of the 456 patients whohad achieved a CCR
• Of 456 patients who achieved CCR, 10 (2%) died from CML
Not shown: 1 event in seventh year after CCR - cause of death uncertain but suspected to be related to CML
>24 months (n = 33)>12- ≤24 months (n = 50)≤12 months (n = 373)
Num
ber P
rogr
essi
ng A
fter C
CR
Year After Achievement of CCR
Time to CCR
IRIS 7 year update
O’BRIEN et al, ASH 2008, Blood 2008; 112(11): 76, Abstract 186
• Major molecular response (MMR) and the depth of molecular response increase over time
Molecular Response Rates
BCR-ABL% (International Scale)
Sample Analysis Timepoints (months)
≤0.1% (MMR)≤0.01%
0
10
20
30
40
50
60
70
80
90
100
% o
f ava
ilabl
e sa
mpl
es
0 3 6 9 12 15 18 21 24 30 36 42 48 54 60 66 72 78 84
IRIS 7 year updateSee abstract 334 for complete data
O’BRIEN et al, ASH 2008, Blood 2008; 112(11): 76, Abstract 186
IRIS SAEs in Years 6 and 7
• No unique, previously unreported AEs attributed to imatinibobserved over the past 24 months
• In years 6 and 7, 13 SAEs with suspected relationship to imatinib were reported: • Congestive Heart Failure (n=3): all of the patients had pre-
existing cardiac disease prior to study entry• Second malignancy (n=3)*• Myositis (n=1); elevated CK (n=1); multiple sclerosis (n=1)• Pancreatitis (n=1); vomiting (n=1) • Renal failure (n=1)• Dermatitis (n=1)
*With >400,000 patient years of estimated imatinib exposure, the analysis of clinical safety data from clinical trials and spontaneous reports did not provide evidence for an increased incidence of malignancies for patients treated with imatinib compared to that of the general population
IRIS 7 year updateO’BRIEN et al, ASH 2008, Blood 2008; 112(11): 76, Abstract 186
IRIS 7-Year Update: Conclusions
• Overall Survival 86%• Event Free Survival 81%; 7% progressed to AP/BC on imatinib• 40% patients discontinued study imatinib• CCR achieved by 456 of 553 (82%) of patients
- 17% of those achieving CCR subsequently lost CCR- 3% of those achieving CCR progressed to AP/BC- Of 456 patients who achieved CCR, 10 (2%) died from CML- Time taken to achieve CCR did not correlate with rates of
progression to AP/BC• MMR rates and the depth of molecular responses in patients
increase over time • No new safety issues observed• Imatinib 400 mg daily confirmed as the standard of care for the
initial therapy of chronic-phase CML
O’BRIEN et al, ASH 2008, Blood 2008; 112(11): 76, Abstract 186
LONG-TERM OUTCOME OF 559 PH+ CML PATIENTS TREATED WITH IMATINIB
IN EARLY CHRONIC PHASE
GIMEMA CML WP
559 Early Chronic Phase patients accrued betweenJan 2004 and Apr 2007 in 3 multicentric studies:
• CML/021, phase II 82 ptsimatinib 800 mg in intermediate Sokal risk
• CML/022, phase III, randomized 112 ptsimatinib 400 vs 800 mg in high Sokal risk
• CML/023, observational 365 ptsimatinib 400 mg, all risks
ANALYSIS
PATIENTS
52 (18-84)115 (21)1 (0-24)
352 (74-4553)1.0 (0-10.0)3.0 (0-15.0)2.0 (0-19.0)
Sokal Hasford219 (39) 243 (43)216 (39) 277 (50)124 (22) 39 (7)
30 (5)21 (4)60 (11)
423 (76)136 (24)42 (1-64)
Age, years; median (range)65 years or older; n (%)Splenomegaly, cm; median (range)Platelet count, 10^9/L; median (range)Peripheral blasts, %; median (range)Eosinophils, %; median (range)Basophils, %; median (range)Relative Risk; n (%)• Low• Intermediate• HighVariant Translocations; n (%) CCA Ph+; n (%) Der(9) deletions; n (%) 400 mg; n (%)800 mg; n (%)Follow-up, months; median (range)
N = 559
RESPONSE TO TREATMENT (ITT)
41 (7.3)
441 (79)35 (6)6 (1)6 (1)28 (5)43 (8)
12 months
63 (11.3)
439 (79)15 (3)3 (1)1 (0)42 (8)
59 (11)
18 months
381 (68)67 (12)14 (3)15 (3)16 (3)
66 (12)
Cytogenetic Response
Complete, n (%)Partial, n (%)Minor, n (%)Minimal, n (%)Absent, n (%)Not evaluable, n (%)
21 (3.8)Failures (cumulative), n (%)
6 months
80
146
81
109
85
78
86
59
0
20
40
60
80
100
6 mos>65
6 mos<65
12mos>65
12mos<65
CCyR PCyR < MCyR
GIMEMA CML WP EARLY CHRONIC PHASE - RESPONSE TO IMATINIB AND AGE
CYTOGENETIC RESPONSE
105 PATIENTS MORE THAN 65 YEARS OLD(MEDIAN 71, INTERVAL 65-84) vs382 PATIENTS LESS THAN 65 YEARS OLD(MEDIAN 56, INTERVAL 18-64)ROSTI G et al, Haematologica 2007; 92: 101-105
Overall responses andlong-term outcome
79
54
68
93
92
82
74
CCgR at 12 months; %
MMolR at 12 months; %
MMolR % of CCg responders
Overall Survival; %
Progression-Free Survival; %
Failure Free-Survival; %
Event-Free Survival; %
Failures (ELN criteria): no CHR at 6 mos, no CgR at 6 mos, no PCgR at 12 mos, no CCgR at 18 mos, loss CHR or CCgR, progression to accelerated/blasticphase and death. Events: failures, off-treatment for toxicity, refusal and lost to follow-up.
CCgR durability
491 patients (88%): CCgR as best CgR
26 patients (5%): CCgR not confirmed 465 patients (83%): confirmed CCgR(2 or more times)
441 patients (79%): stable CCgR
CCgR duration (months) median (range): 35 (4 - 55)
384 patients > 24 months211 patients > 36 months
24 patients (4%): lost CCgR
CCgR duration (months) median (range): 13 (3 - 42)
On imatinib study treatment, n (%) 415 (74.2)
Discontinuation, n (%) 144 (25.8)
- Side effects/SAEs 25 (4.5)- Deaths (unrelated to CML) 9 (1.6)- Lack of efficacy / progression 83 (14.8)- Other reason (refusal, lost to follow-up) 27 (4.8)
Patients on Study / Discontinuations
TOTAL N = 559Follow-up, months; median (range) 42 (1 - 64)
SUMMARY OF THE RESULTS OF IMATINIB SUMMARY OF THE RESULTS OF IMATINIB TREATMENT (STANDARD DOSE 400 MG, FRONTTREATMENT (STANDARD DOSE 400 MG, FRONT--LINE) IN LINE) IN PhPh POS CHRONIC MYELOID LEUKEMIAPOS CHRONIC MYELOID LEUKEMIA
COMPLETE HEMATOLOGIC RESPONSE COMPLETE HEMATOLOGIC RESPONSE ≥≥ 95%95%
COMPLETE CYTOGENETIC RESPONSECOMPLETE CYTOGENETIC RESPONSE 7575--90%90%
MAJOR MOLECULAR RESPONSEMAJOR MOLECULAR RESPONSE 5050--70%70%
““COMPLETECOMPLETE”” MOLECULAR RESPONSEMOLECULAR RESPONSE 1010--40%40%
66--YEARS EVENTYEARS EVENT--FREE SURVIVAL AND ON FREE SURVIVAL AND ON
IMATINIBIMATINIB 6060--70%70%
66--YEARS PROGRESSIONYEARS PROGRESSION--FREE SURVIVALFREE SURVIVAL 8585--90%90%
66--YEARS OVERALL SURVIVALYEARS OVERALL SURVIVAL 9090--95%95%
BACCARANI M, personal
Molecular biologyMarilina Amabile Ilaria IacobucciAngela Poerio
Simona Soverini
CytogeneticsNicoletta Testoni
Simona LuattiGiulia Marzocchi
Clinical teamGianantonio RostiGiovanni Martinelli Francesca PalandriFausto CastagnettiGabriele Gugliotta
Michele BaccaraniSecretariatKatia Vecchi
Department of Hematology and Oncology
“L. e A. Seràgnoli”
GIMEMA CML Working Party
• G. Lucarelli and G. Polimeno (Acquaviva delle Fonti); P. Galieni and C. Bigazzi (Ascoli Piceno); V. Liso and G. Specchia (Bari); V. Zampaglione (Biella); P. Coser, and R. Quaini(Bolzano); E. Abruzzese (Roma); M. Gobbi and M. Miglino (Genova); E. Pogliani, C. Gambacorti Passerini and M. Miccolis (Monza); M. Lazzarino and E. Orlandi (Pavia); P. Bernasconi and R. Invernizzi (Pavia); R. Fanin and M. Tiribelli (Udine); D. Russo and M. Malagola (Brescia); G. Alimena (Roma); G. Rossi and A. Capucci (Brescia); F. Nobile, M. Martino and E. Oliva (Reggio Calabria); L. Gugliotta and P. Avanzini (Reggio Emilia); P. Fattori (Rimini); G. Leone and S. Sica (Roma); L. Annino (Roma); M. C. Petti (Roma); E. Conte (Roma); A. M. Carella (Genova and San Giovanni Rotondo); M. Longinotti and S. Pardini (Sassari); E. Gottardi , M. Fava (Orbassano); L. Cavanna, D. Vallisa and E. Trabacchi(Piacenza); A. Bacigalupo (Genova); B. Rotoli, and L. Luciano (Napoli); F. Ferrara and E. Schiavone (Napoli); V. Mettivier (Napoli); A. Tabilio, C. Mecucci and D. Falzetti (Perugia); G.Visani and G. Nicolini (Pesaro); T. Barbui, U. Giussani (Bergamo); V. Rizzoli and M. Crugnola (Parma); M. Bocchia (Siena); E. Volpe and F. Palmieri and N. Cantore (Avellino); M.C. Michieli (Aviano); S. Amadori and A. Cantonetti (Roma); A. Levis, and M. Pini (Alessandria); E. Angelucci and E. Usala (Cagliari); A. Cuneo and G.L. Scapoli (Ferrara); E. Curioni and F. Radaelli (Milano); R. Marasca and G. Leonardi (Modena); E. Morra and E. Pungolino (Milano); V. Montefusco (Milano); A. Peta and F. Iuliano (Catanzaro); P Leoni and S. Rupoli (Ancona); A. Bosi and S. Santini (Firenze); R. Giustolisi and F. Stagno and P. Guglielmo (Catania); F. Porretto (Palermo); A. Liberati and E. Donti (Perugia); A. Zaccaria, E. Zuffa (Ravenna); P. Mazza and M. Cervellera (Taranto); D. Ferrero and C. Della Casa (Torino); M. Candela and G. Danieli (Ancona); S. Morandi and C. Bergonzi (Cremona); A. Gabbas and D. Noli (Nuoro); G Semanzato and L. Trentin (Padova); S. Mirto, S. Tringali and D. Turri (Palermo); V. Abbadessa, G. Marini and Caracciolo (Palermo); M. Musso and F.Porretto (Palermo); A. D’ Emilio (Vicenza); A. Bonati (Parma); M. Petrini, F. Parineschi and R. Fazzi (Pisa); F. Ricciuti and M. Pizzuti (Potenza); E. Gallo and P. Pregno (Torino); F.Gherlinzoni and C. Tecchio (Treviso); A. Ambrosetti and V. Meneghini (Verona); R. Di Lorenzo and G. Fioritoni (Pescara); G. Quarta, and M. Girasoli (Brindisi); E. De Biasi(Castelfranco Veneto); M. Monaco and E. Capussela (Foggia); A. Gallamini (Cuneo); A. De Blasio (Latina); C. Musolino (Messina)
