What is New in CML in 2011 Hagop Kantarjian, M.D. February 2011 1
CML. Historical vs. Modern Perspective Parameter Historical Modern Course Fatal Indolent Prognosis Poor Excellent 10-yr survival 10% 84-90% Frontline Rx Allo SCT; Imatinib; IFN-α nilotinib; dasatinib Second line Rx? New TKIs; 2 allo SCT
Today, CML is an indolent disease. Patients can be functionally cured and live their normal expected life span, provided they continue treatment with oral TKIs (imatinib). CML is now a condition like diabetes, hypertension, CASHD, which, treated appropriately, should result in a normal life Hagop Kantarjian; Somewhere, 2006 3
CML in US. Incidence vs. Prevalence The Changing Demographics of CML Incidence 5,000 cases/yr Prevalence plateaus when incidence = annual mortality 2% Annual Mortality X Incidence of 5000 cases = 100 Prevalence of 5000 X 100 2 = Kantarjian. CML Chapter. Abeloff s Clinical Oncology 4 th Edition, 2279, 2008. 250,000 cases
CML in US. Incidence vs Pervalence Kantarjian. CML Chapter. Abeloff s Clinical Oncology 4 th Edition, 2279, 2008.
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BCR-ABL Expression Sufficient for CML Induction LTR BCR/ABL LTR STEM CELL (Daley et al., Science 1990) CML 8
H Neves. Blood 93:1197, 1999 9
Do We Need Bone Marrow At Dx? Assess % of blasts and basos (10-15% have CML transformation at Dx) Confirm Ph by CG; detect clonal evolution FISH can be falsely positive QPCR can be falsely positive or negative 10
Monitoring CML Course Cytogenetics Fluorescent in situ hybridization (FISH) Quantitative PCR (QPCR):real time, competitive Abl mutations 11
Monitoring Procedures in CML CG: tedious; only 20 metaphases (SD ± 15%); painful BM FISH: faster; 200 cells; PB; but false + up to 5-10% QPCR: best use in CGCR; predicts for relapse; variability up to 0.5 log; use 1 source (PB) and 1 reliable lab 12
Monitoring CML in Stable CGCR. My (Simple) Approach FISH and QPCR q 6 mos (ensure concordance and stability of high quality CGCR; both tests can be false positive or false negative) Marrow CG q 2-3 yrs; more often if abnormalities in Ph-negative diploid cells (eg chromosome 5 or 7 abn) Mutation analysis only if imatinib failure or change of Rx Do not order imatinib plasma levels
How Do I Use FISH and QPCR Monitoring in CGCR? FISH QPCR Interpretation Neg <0.1% Excellent response; FU 6 mos Pos <0.1% FISH and QPCR false + or Neg >1% false -; FU 3 mos Neg 0.1-1% FU 6 mos, FU 3 mos if one log Pos >1% Check marrow + CG;? relapse
Course of CML in CGCR on Imatinib Highly Stable and Predictable Historical fear of sudden blastic transformation On imatinib, sudden transformation may still occur, but: rare, usually in first 2 yrs, usually lymphoid BP in younger pts, usually responsive to HCVAD + TKI Closer monitoring in first 2 yrs Monitoring in stable durable CGCR Q 6 mo (I like FISH + QPCR check for concordance)
Analysis of Mutations in CML If CG or hematologic relapse, mutations studies help No role for mutation studies pre-rx or in imatinib responding patients T315I: no role for new TKIs; allo SCT or others (HU, ara-c, HHT, T315I inhibitors ) Nilotinib IC50>150nM :use dasatinib (e.g. P- loop,y253h,e255v) Dasatinib IC50>3nM :use nilotinib (e.g.f317l) Kantarjian. Blood 111:1774-1780, 2007 16
CML Blastic Phase Morphology No %CR %OR Myeloid 247 13 25 Lymphoid 129 (24%) 43 61 Undiff/others 167 14 25 Lymphoid BP Px ± (<10%), Tdt + CD10, 19+ CD13, 33+ in 80% often Rx as myeloid BP 17
Leukocytosis Hypercellular BM Splenomegaly Ph+ vs. Ph- Ph + (90%) Ph- BCR+ BCR- Ph- MPD Atypical CML CMML 18
Therapy of CML in 2010 Frontline Imatinib 400 mg/d 800(?); nilotinib 300-400 mg BID; dasatinib 100 mg/d Imatinib failure - Nilotinib, dasatinib, bosutinib Allogeneic SCT Investigational T315I inhibitors, (AP24534, DCC2036) omacetaxine, decitabine, TKIs combos Combining TKIs + old standards (HU, ara-c) 19
CML. Survival after Allogeneic BMT PROBABILITY 1.0 0.8 0.6 0.4 1: Sib + CP1 (N=3,372) 2: Sib + Not CP1 (N=1,141) 3: Other Donor + CP1 (N=1,302) 4: Other Donor + Not CP1 (N=725) 5: All Patients (N=6,548) 0.2 0.0 0 4 8 12 18 20 YEARS 20 LTO03_5.ppt
CML. Survival after Allogeneic BMT 1.0 PROBABILITY 0.8 0.6 0.4 60% 45% 15% mortality over 15 yrs 0.2 0.0 0 4 8 12 18 20 YEARS 21
CML Survival after Allogeneic BMT PROBABILITY 1.0 0.8 0.6 0.4 0.2 Imatinib 60% 1: Sib + CP1 (N=3,372) 2: Sib + Not CP1 (N=1,141) 3: Other Donor + CP1 (N=1,302) 4: Other Donor + Not CP1 (N=725) 5: All Patients (N=6,548) 45% 0.0 0 4 8 12 18 20 YEARS 22
Allo SCT. Second or Third Salvage? Imatinib failure in AP, BP: new TKI as bridge to MRD, then allo SCT ASAP T315I mutation in any CML phase: AP 24534, other T315I inhibitors, HHT, HU, others as bridge to MRD, then allo SCT ASAP Imatinib failure in CP: if IC50, CE, or no major CG in 12 mos allo SCT (risk should be reasonable: young, good match) If not TKI until failure Age 70 yrs or if poor match: may decide to forgo curative allo SCT option for several years of CML control
Results with Imatinib in Early CP CML The IRIS Trial at 8-Years 304 (55%) patients on imatinib on study Projected results at 8 years: - CCyR 83% - 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP - Event-free survival 81% - Transformation-free survival 92% - If MMR at 12 mo: 100% - Survival 85% (93% CML-related) Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4% Deininger. Blood. 2009;114: abst1126.
Population-Based CML Outcome in Sweden 3173 patients diagnosed between 1973-2008 - Median age 62 yrs 80% 54% 37% 23% 21% Bjorkholm, et al. Blood. 2010;116: Abstract 205.
Event-Free Survival by Treatment in ECP CML Probability Event-Free Months Cortes et al. Blood 2009; Abst# 338 & 341; Updated October 2010
Frontline CML Rx with IM 400, IM 400 + IFN, IM 800 1022 pt with CML randomized to IM 400 mg/d (n=324), IM 400 mg/d + IFN (n=350), IM 800 mg / D (n=338) % Cumulative Rate at 36 mo MMR CMR IM 400 79 45 IM 400 + IFN 71 40 IM 800 82 57 Conclusion higher CMR rates with HD imatinib Hehlmann. Blood 116: abst 357; 2010
Imatinib and Pegasys in Chronic Phase CML 636 pt randomized to IM 400 mg; IM 600 mg; IM 400 mg+ara- C; IM 400+Pegasys 90 mcg/wk Median pegasys dose 54 mcg/wk; 45% stopped pegasys in yr 1 IM 600 or % at 18 mos IM+IFN IM 400 IM+ara-C pvalue MMR 62 42 50-53.003 SMR ( 0.01%) 35 18 19-22.001 24-moCMR 16 9 8 0.01 12-mo CGCR rates similar in 4 arms % 12-mo SMR (Q PCR 0.01%) 30% with IM+ Pegasys vs. 14% with IM400 (p=0.001). % 24-mo rates 38% vs. 22% (p=0.01) No difference in PFS or survival Preudhomme. NEJM 363: 2511; 2010
IRIS. Survival Without AP/BC Worse If No Major CG Response at 12 mos Rx aim: major CG response (Ph 35%) Response at 12 months CCyR PCyR No MCyR Estimated rate at 60 months n= 350 97% } } n= 86 93% p<0.001 p=0.20 n= 73 81% 29
IRIS. Survival Without AP/BC Worse If No CGCR In Year 2 But Not Related To MMR Rx aim: CGCR in Year 2+; no need for MMR Response at 18 months CCyR with >=3 log red. CCyR with <3 log red. No CCyR Estimated rate at 60 months n= 139 100% n= 54 98% n= 89 87% p<0.001 p=0.11
CG Abnormalities in Ph-negative Metaphases with IM Frontline Therapy 21/258 (9%) patients developed CG abnormalities in Phmetaphases after median 36 mo Most common abnormalities: -Y (n=9; 43%), +8 (n=9; 43%), -7 (n=5; 17%) 1 (5%; 0.4% overall) developed AML [-7] Overall Survival Progression-Free Survival Warning? Warning? Jabbour. Blood 110:2991-5, 2007
Imatinib and Pregnancy 180 women, outcome available in 125 (69%) Outcomes: 50% normal infants 28% elective termination (3 abnormalities) 12 infants (9%) with abnormalities 3/12 similar complex malformations (exomphalos, kidneys, bones) Conclusion: Women on imatinib should be advised not to become pregnant Pye. Blood 111:5505, 2008. 32
Imatinib Treatment Discontinuations The French Experience 69 pts treated with imatinib for 3 yrs with CMR ( 5-log ) sustained for 2 yrs 34 prior IFN, 35 no prior IFN Median follow-up 21 mo (11-29 mo) 41 (59%) pts relapsed; all within 7 mo 53% prior IFN, 66% no prior IFN Probability of CMR 12 mo after stop: 47% post IFN, 34% no prior IFN Peripheral NK cells significantly lower in relapse pts at imatinib discontinuation All patients responded after imatinib re-start Mahon. Blood 114: abst 859, 2009
STIM Study. Relapses 40 pts relapsed (loss of CMR) within the first 6 mos; one pt relapsed at M7. STOP IMATINIB AND MOLECULAR RELAPSES 70 7 Number of patients 60 50 40 30 20 10 69 62 15 47 13 1 34 33 3 1 1 30 29 28 28 28 27 26 23 RELAPSE CMR 19 18 17 13 11 9 0 Selection M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 M14 M16 M18 M20 M22 M24 Follow-up Mahon. Blood 114:abst 859, 2009
CML. Criteria For Failure On Imatinib No CG response at 6 mos (Ph 100%) No major CG response at 12 mos (Ph>35%) No CGCR in Year 2+ CG relapse or hematologic relapse Not failure criteria - suboptimal CG response - QPCR in CGCR Baccarani. Blood 108:1809-20, 2006 35
Chemical Structures of Approved BCR-ABL Tyrosine Kinase Inhibitors C H 3 N N N N H 3 H N C H N O N N C H 3 N N H 3 H N C O N H F F F N Imatinib N Nilotinib Imatinib Dasatinib 36
Nilotinib vs Imatinib in Newly Dx CML. Endpoints and Design Primary: MMR at 12 mos Secondary: CCyR by 12 mos Other: time/duration of MMR and CGCR, EFS, PFS, time to AP/BP, OS Newly Diagnosed CML-CP: N = 846 217 centers;35 countries R A N D O M I Z E D Nilotinib 300 BID (n=282) Nilotinib 400 BID (n=281) Imatinib 400 QD (n=283) Stratification by Sokal risk; MMR defined as 0.1% BCR- ABL(/ABL ratio) on International Scale Saglio. NEJM 362: 2251, 2010. 37
Nilotinib vs. Imatinib in CML-CP. MMR at 12 and 24 Mo (ITT) P <. 0001 P <.0001 P <. 0001 P <.0001 % With MMR n = 282 n = 281 n = 283 n = 282 n = 281 n = 283 MMR at 12 months MMR at 24 months Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Hughes. Blood 116: abst 207; 2010
Nilotinib vs. Imatinib in CML-CP. CCyR Rates by 24 Mo (ITT) P =. 0018 P =.016 % With CCyR n = 282 n = 281 n = 283 Hughes. Blood 116: abst 207; 2010
Nilotinib vs. Imatinib in CML-CP. Suboptimal Response and Rx Failure by 18 Mo (ITT) % of Patients n = 282 n = 281 n = 283 n = 282 n = 281 n = 283 Hughes. Blood 116: abst 207; 2010
Nilotinib vs. Imatinib in CML-CP. Progression to AP/BC or Death on Study TKI P =.0059 P =.0196 P =.0003 P =.0089 Number of Patients 0.7% 1.1% 4.2% 0.7% 1.8% 6.0% Without Clonal Evolution With Clonal Evolution Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Hughes. Blood 116: abst 207; 2010
Nilotinib vs. Imatinib in CML-CP. PFS on Study Rx (ITT) Nilo 300 n = 282 Nilo 400 n = 281 Ima 400 n = 283 Events 5 4 12 Estimated 24-mo PFS Stratified logrank test vs imatinib 98% 97.7% 95.2% 0.07 0.04 -- Hughes. Blood 116: abst 207; 2010
Nilotinib vs. Imatinib in CML-CP. Grade 3/4 Myelosuppression 21 % of Patients 4 4 5 12 11 10 12 9 Anemia Neutropenia Thrombocytopenia Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Hughes. Blood 116: abst 207; 2010
Nilotinib vs. Imatinib in CML-CP. Drug- Related Non-Lab AEs ( 10% in Any Group) % Pts Nilo Nilo Ima 300 400 400 n = 279 n = 277 n = 280 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Nausea 14 < 1 21 1 34 0 Muscle spasms 8 0 7 < 1 27 < 1 Diarrhea 8 < 1 7 0 26 1 Vomiting 5 0 9 1 18 0 Peripheral edema 5 0 6 0 15 0 Facial edema < 1 0 2 0 11 < 1 Eyelid edema < 1 0 2 < 1 16 < 1 Periorbital edema < 1 0 1 0 14 0 Rash 32 < 1 37 3 13 2 Headache 14 1 22 1 9 < 1 Pruritus 16 < 1 13 < 1 6 0 Alopecia 9 0 13 0 5 0 Myalgia 10 < 1 10 0 11 0 Fatigue 11 0 9 < 1 10 < 1 Hughes. Blood 116: abst 207; 2010
Dasatinib Versus Imatinib Study In Treatmentnaïve CML: DASISION (CA180-056). Design N=519 108 centers 26 countries Dasatinib 100 mg QD (n=259) Randomized* Imatinib 400 mg QD (n=260) *Stratified by Hasford risk score Follow-up 5 years Primary endpoint: Confirmed CCyR by 12 months Secondary/other endpoints: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; overall survival Kantarjian. NEJM 362: 2260, 2010.
DASISION. Confirmed CCyR (ITT) P=0.0086 P=0.0366 Shah. Blood 116: abst 206, 2010
DASISION. Confirmed CCyR (ITT) Likelihood of achieving CCyR at any time 1.5-fold higher with dasatinib (stratified log-rank P<0.0001; HR=1.5) Shah. Blood 116: abst 206, 2010
DASISION. MMR (ITT) P<0.0001 P=0.0002 MMR, BCR-ABL 0.1% BCR-ABL 0.0032% Likelihood of achieving a MMR 1.8-fold higher with dasatinib (stratified logrank P<0.0001; HR=1.8) Shah. Blood 116: abst 206, 2010
DASISION. MMR BY Hasford Risk Shah. Blood 116: abst 206, 2010
DASISION. Progression to AP-BP (ITT) 100 n/n 6/259 9/260 No patient who achieved MMR progressed to AP/BP CML 5 patients who achieved a CCyR progressed to AP/BP CML (2 dasatinib, 3 imatinib) Rates of progression-free survival at 18 mos 94.9% for dasatinib and 93.7% for imatinib Shah. Blood 116: abst 206, 2010
DASISION. Grade 3/4 Cytopenia 100 Grade 3/4 bleeding occurred in 2 pts on dasatinib and 3 pts on imatinib 6 pts on dasatinib and 3 pts on imatinib D/C Rx due to cytopenia Shah. Blood 116: abst 206, 2010
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Forest Plots Comparing Differences in AE Rates Anemia, grade 3/4 Neutropenia, grade 3/4 Thrombocytopenia, grade 3/4 Myalgia* Nausea Vomiting Rash Diarrhea Fatigue Headache Fluid retention Superficial edema Pleural effusion 0.4 0.2 0 0.2 0.4 Rate difference (dasatinib imatinib) with exact 95% CI *Myalgia = myalgia, muscle inflammation and MSK pains Favors dasatinib Favors imatinib Kantarjian. NEJM 362: 2260, 2010.
Bosutinib vs. Imatinib in CML Frontline Rx. Design Phase 3 open-label trial in newly diagnosed chronic phase CML N = 502 139 sites 31 countries Randomization is stratified based on Sokal risk score and geographical regions. R A N D O M I Z E Primary endpoint: CCyR at 12 mos Secondary endpoints: MMR at 12 mos Duration of CCyR, MMR, and CHR Time to and rate of AP and BP Safety and tolerability Bosutinib 500 mg/day n = 250 Imatinib 400 mg/day n = 252 5-year follow-up 5-year follow-up 1-year analysis Gambacorti-Passerini. Blood 116: abst 208; 2010
Bosutinib vs. Imatinib in CML Frontline Rx. Response at 12 Mos (ITT) P = 0.601 P = 0.002 n = 250 n = 252 n = 250 n = 252 Gambacorti-Passerini. Blood 116: abst 208; 2010
P <0.001 P = 0.053 P = 0.065 55 Gambacorti-Passerini. Blood 116: abst 208; 2010
100 Probability of overall survival (%) 95 90 85 80 0 0 Time to death (wks) Bosutinib Imatinib P = 0.117 12 24 36 48 56 Gambacorti-Passerini. Blood 116: abst 208; 2010
Event-Free Survival by Treatment in ECP CML Probability Event-Free Months Cortes J, et al. Blood. 2009;114: Abstract 338 & 341. Updated October 2010.
Ponatinib (AP24534). Pan-BCR-ABL Inhibitor Rationally designed inhibitor of BCR-ABL Active against T315I mutant - Unique approach to accommodating gatekeeper residue Potent activity against an array of BCR-ABL variants Also targets other therapeutically relevant kinases: - Inhibits FLT3, FGFR, VEGFR and PDGFR, and c-kit Once-daily oral activity in murine models Ile315 Imatinib Ponatinib Avoids T315I Ponatinib O Hare T, et al. Cancer Cell. 2009;16:401-412
Phase 1 Ponatinib. Study Design Phase 1 dose escalation design Primary objective - MTD or recommended oral dose Secondary objectives - Safety and anti-tumor activity - PK, PD and pharmacogenomics Ponatinib daily oral administration - 2, 4, 8, 15, 30, 45 & 60 mg QD capsules - 45 & 60 mg QD tablets - Intra-patient dose escalation Expansion cohort at MTD Cortes. Blood 116: abst 210; 2010
Phase 1 Ponatinib. Study Group (N=74) Median age 56 yrs - Range 26-85 years Prior Rx Ph+ Pts (n=60) Percent Dx N=74 CML (CP, AP, BP) 60 (44, 7, 9) Ph+ ALL 4 AML 6 Other (MM, MDS, MF) Prior TKI Ph+ Pts (n=60) Resistant 2 TKIs 95% Resistant 3 TKIs 65% 4 Imatinib 97 Dasatinib 90 Nilotinib 57 Dasatinib & Nilotinib 52 Omacetaxine 18 XL228 12 Bosutinib 10 MK-0457 5 INNO-406 3 Cortes. Blood 116: abst 210; 2010
Phase 1 Ponatinib. Best Response in Best Response CP CML Overall N=38 N (%) T315I N=9 Non-T315I N=29 CHR 36 (95) 9 (100) 27 (93) MCyR 25 (66) 9 (100) 16 (55) CCyR 20 (53) 8 (89) 12 (41) Cortes. Blood 116: abst 210; 2010
Phase 1 Study of Ponatinib. Duration of CG response (CP) 25 pts with CML CP in MCyR; 23 pts still on Rx; 21 still in MCyR 3 pts lost response (1 at 4 mg; 2 at 15 mg) 1 pt D/C due to AE (30 mg) Duration 1 Yr Total n=25 78% T315I n=9 89% Other n=16 69% Cortes. Blood 116: abst 210; 2010
Omacetaxine for CML CP After Failure to 2 TKI 85 pts with CML with 2 (n = 48) or 3 (n = 37) TKI Omacetaxine 1.25 mg/m 2 BID x14d, then x7d Median follow-up 14.1 mo (0.3-42+) IM + Das Response, % or Nil N = 48 IM + Das + Nil N = 37 Overall N = 61 CHR 79 65 73 MCyR 25 14 20 CCyR 13 8 11 Median duration MCyR 7.4 mo (0.9-26+ mo) Median survival 30.1 mo Cortes J, et al. Blood. 2009;114: Abstract 644.
CML in 2010 Imatinib,nilotinib,dasatinib are standard frontline Rx (except p190 CML) Dose optimization and adequate monitoring Sub-optimal response dose imatinib (400mg 800mg) New TKI Failure Dasatinib, nilotinib, bosutinib Allogeneic SCT T315I: AP24534, DCC2036, omacetaxine
Leukemia Questions? Pager: 713-404-3387 Email: hkantarj@mdanderson.org Hagop Kantarjian, M.D.