What is New in CML in Hagop Kantarjian, M.D. February 2011

Transcription

1 What is New in CML in 2011 Hagop Kantarjian, M.D. February

2 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

3 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,

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5 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 = Kantarjian. CML Chapter. Abeloff s Clinical Oncology 4 th Edition, 2279, ,000 cases

6 CML in US. Incidence vs Pervalence Kantarjian. CML Chapter. Abeloff s Clinical Oncology 4 th Edition, 2279, 2008.

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8 BCR-ABL Expression Sufficient for CML Induction LTR BCR/ABL LTR STEM CELL (Daley et al., Science 1990) CML 8

9 H Neves. Blood 93:1197,

10 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

11 Monitoring CML Course Cytogenetics Fluorescent in situ hybridization (FISH) Quantitative PCR (QPCR):real time, competitive Abl mutations 11

12 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

13 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

14 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

15 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)

16 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: ,

17 CML Blastic Phase Morphology No %CR %OR Myeloid Lymphoid 129 (24%) Undiff/others Lymphoid BP Px ± (<10%), Tdt + CD10, 19+ CD13, 33+ in 80% often Rx as myeloid BP 17

18 Leukocytosis Hypercellular BM Splenomegaly Ph+ vs. Ph- Ph + (90%) Ph- BCR+ BCR- Ph- MPD Atypical CML CMML 18

19 Therapy of CML in 2010 Frontline Imatinib 400 mg/d 800(?); nilotinib 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

20 CML. Survival after Allogeneic BMT PROBABILITY : 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) YEARS 20 LTO03_5.ppt

21 CML. Survival after Allogeneic BMT 1.0 PROBABILITY % 45% 15% mortality over 15 yrs YEARS 21

22 CML Survival after Allogeneic BMT PROBABILITY 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% YEARS 22

23 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

24 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.

25 Population-Based CML Outcome in Sweden 3173 patients diagnosed between Median age 62 yrs 80% 54% 37% 23% 21% Bjorkholm, et al. Blood. 2010;116: Abstract 205.

26 Event-Free Survival by Treatment in ECP CML Probability Event-Free Months Cortes et al. Blood 2009; Abst# 338 & 341; Updated October 2010

27 Frontline CML Rx with IM 400, IM IFN, IM 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 IM IFN IM Conclusion higher CMR rates with HD imatinib Hehlmann. Blood 116: abst 357; 2010

28 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 SMR ( 0.01%) moCMR 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

29 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= % } } n= 86 93% p<0.001 p=0.20 n= 73 81% 29

30 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= % n= 54 98% n= 89 87% p<0.001 p=0.11

31 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

32 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,

33 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

34 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 RELAPSE CMR 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

35 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: ,

36 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

37 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 = 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,

38 Nilotinib vs. Imatinib in CML-CP. MMR at 12 and 24 Mo (ITT) P < P <.0001 P < 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

39 Nilotinib vs. Imatinib in CML-CP. CCyR Rates by 24 Mo (ITT) P = P =.016 % With CCyR n = 282 n = 281 n = 283 Hughes. Blood 116: abst 207; 2010

40 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

41 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

42 Nilotinib vs. Imatinib in CML-CP. PFS on Study Rx (ITT) Nilo 300 n = 282 Nilo 400 n = 281 Ima 400 n = 283 Events Estimated 24-mo PFS Stratified logrank test vs imatinib 98% 97.7% 95.2% Hughes. Blood 116: abst 207; 2010

43 Nilotinib vs. Imatinib in CML-CP. Grade 3/4 Myelosuppression 21 % of Patients Anemia Neutropenia Thrombocytopenia Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Hughes. Blood 116: abst 207; 2010

44 Nilotinib vs. Imatinib in CML-CP. Drug- Related Non-Lab AEs ( 10% in Any Group) % Pts Nilo Nilo Ima n = 279 n = 277 n = 280 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Nausea 14 < Muscle spasms < 1 27 < 1 Diarrhea 8 < Vomiting Peripheral edema Facial edema < < 1 Eyelid edema < < 1 16 < 1 Periorbital edema < Rash 32 < Headache < 1 Pruritus 16 < 1 13 < Alopecia Myalgia 10 < Fatigue < 1 10 < 1 Hughes. Blood 116: abst 207; 2010

45 Dasatinib Versus Imatinib Study In Treatmentnaïve CML: DASISION (CA ). Design N= 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.

46 DASISION. Confirmed CCyR (ITT) P= P= Shah. Blood 116: abst 206, 2010

47 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

48 DASISION. MMR (ITT) P< P= MMR, BCR-ABL 0.1% BCR-ABL % 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

49 DASISION. MMR BY Hasford Risk Shah. Blood 116: abst 206, 2010

50 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

51 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

52 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 Rate difference (dasatinib imatinib) with exact 95% CI *Myalgia = myalgia, muscle inflammation and MSK pains Favors dasatinib Favors imatinib Kantarjian. NEJM 362: 2260, 2010.

53 Bosutinib vs. Imatinib in CML Frontline Rx. Design Phase 3 open-label trial in newly diagnosed chronic phase CML N = 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 = year follow-up 5-year follow-up 1-year analysis Gambacorti-Passerini. Blood 116: abst 208; 2010

54 Bosutinib vs. Imatinib in CML Frontline Rx. Response at 12 Mos (ITT) P = P = n = 250 n = 252 n = 250 n = 252 Gambacorti-Passerini. Blood 116: abst 208; 2010

55 P <0.001 P = P = Gambacorti-Passerini. Blood 116: abst 208; 2010

56 100 Probability of overall survival (%) Time to death (wks) Bosutinib Imatinib P = Gambacorti-Passerini. Blood 116: abst 208; 2010

57 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.

58 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:

59 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

60 Phase 1 Ponatinib. Study Group (N=74) Median age 56 yrs - Range 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 XL Bosutinib 10 MK INNO Cortes. Blood 116: abst 210; 2010

61 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

62 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

63 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 ( ) IM + Das Response, % or Nil N = 48 IM + Das + Nil N = 37 Overall N = 61 CHR MCyR CCyR Median duration MCyR 7.4 mo ( mo) Median survival 30.1 mo Cortes J, et al. Blood. 2009;114: Abstract 644.

64 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

65 Leukemia Questions? Pager: Hagop Kantarjian, M.D.