IMATINIB RESISTANT CML

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IMATINIB RESISTANT CML

  1. 1. Elias Jabbour, MD University of Texas – M. D. Anderson Cancer Center CML and Imatinib Resistance: Which TKI and When?
  2. 2. CML and Imatinib Resistance: Which TKI and When? Marcos de Lima, MD Stem Cell Transplantation Program Case Western Reserve University University Hospitals Seidman Cancer Center Cleveland - OH
  3. 3. 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 et al; Blood 2009; 114: Abst# 1126
  4. 4. IRIS 8-Year Update 37% Unacceptable Outcome Deininger et al; Blood 2009; 114: Abst# 1126
  5. 5. 5 IRIS. Survival Without AP/BC Worse If No Major CG Response at 12 mos Estimated rate at 60 months n= 86 93% n= 73 81% n= 350 97% } p<0.001} p=0.20CCyR PCyR No MCyR Response at 12 months %withoutAP/BC 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 M o n th s s in c e r a n d o m iz a tio n 0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 6 Rx aim: major CG response (Ph ≤ 35%)
  6. 6. Criteria for Failure and Suboptimal Response to Imatinib Time (mo) Response Failure Suboptimal Optimal 3 No CHR No CG Response < 65% Ph+ 6 No CHR >95% Ph+ ≥35% Ph+ ≤35% Ph+ 12 ≥35% Ph+ 1-35% Ph+ 0% Ph+ 18 ≥5% Ph+ No MMR MMR Any Loss of CHR Loss of CCgR Mutation CE Loss of MMR Mutation Stable or improving MMR Baccarani. JCO 2009; 27: 6041-51
  7. 7. NCCN Treatment Recommendations 3-Month Follow-up Therapy BCR-ABL transcript levels ≤10% by QPCR International Scale (IS) or PCyR on bone marrow cytogenetics BCR-ABL transcript levels >10% by QPCR using the IS or <PCyR on bone marrow cytogenetics Continue same dose of IM, DAS, or NIL • Evaluate patient compliance and drug-drug interactions • Mutational analysis Monitor with QPCR every 3 mo DAS 100 mg daily NIL 400 mg BID Evaluation and discussion of HSCT Clinical trial 3-mo evaluation National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Revised September 13, 2012. No relapse Relapse
  8. 8. Adherence Is the Most Important Factor Contributing to Molecular Responses Marin D et al. J Clin Oncol. 2010;28(14):2381-2388. Adherence monitored over a period of 3 months using a microelectronic monitoring device in the imatinib bottle cap. Patients were not aware of the device. 0.1 12 Time Since Start of Imatinib Therapy (months) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0 6 18 24 30 36 42 48 54 60 66 72 ProbabilityofMMR Adherence >90% (n = 64) Adherence ≤90% (n = 23) P<0.001
  9. 9. EFS by Response to IM at 6 and 12 Mos 0 12 24 36 48 60 72 Months 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Failure Suboptimal Optimal p<0.0001 No. 9 10 240 Events (%) 6 (67) 5 (50) 14 (6) 0 12 24 36 48 60 72 Months 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Failure Suboptimal Optimal p<0.0001 No. 14 19 213 Evaluable (%) 8 (57) 3 (16) 8 (4) 6 month response 12 month response •281 pts; imatinib frontline (400mg in 73, 800mg in 208) •Suboptimal response at 6-12 months: 12-17% with 400mg, 1-4% with 800mg (p=0.002) Alvarado. Cancer. 2009;115:3709-18.
  10. 10. MDACC Retrospective Analysis: MCyR at 6 Months Associated With OS Patients with MCyR have better OS than patients that do not Landmark analysis at 6 mos 0 12 24 36 48 60 72 Cytogenetic response at 6 mos Total Dead P-value Complete 201 5 Partial 39 1 Minor 10 3 Othersa 9 3 0.85 0.01 0.62 1.0 0.8 0.6 0.4 0.2 0 Proportionalive Months Kantarjian H. Cancer. 2008;112:837–845.
  11. 11. MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS Patients with CCyR have better PFS than patients that do not. Similar results were observed in patients achieving CCyR at 18 and 24 mos. Landmark analysis at 12 mos ProportionPFS 1.0 0.8 0.6 0.4 0.2 0 0 12 24 36 48 60 72 Months Cytogenetic response at 12 mos Total Failure P-value Complete 214 7 Partial 19 3 Minor 5 2 Others 8 5 0.02 0.2 0.22 Kantarjian H. Cancer. 2008;112:837–845.
  12. 12. EFS and Survival by 12-month Response-CCyR with vs without MMR with TKI Frontline Rx Jabbour E et al. Blood. 2011.
  13. 13. Outcome by 12-Month Response in CML CP •848 pts randomized to IM 400mg, IM 800mg, or IM 400 + IFN •Median FU: 40 months 12-month BCR-ABL/ABL (IS) N Percentage PFS OS <0.1% 341 99 99 0.1-1% 240 97 98 >1% 267 94 93 P value 0.0023 0.0011 •Outcome independent of treatment arm Hehlman et al. JCO 2011;29:1634-42 CCyR
  14. 14. Probabilityofsurvival Time from onset of imatinib therapy (years) BCR-ABL/ABL<9.8% OS= 93.3% BCR-ABL/ABL>9.8% OS= 54% p<0.0001 Survival After Imatinib Therapy by Molecular Response Achieved at 3 Months Marin et al, JCO 2011; [Epub ahead of print • Optimal PCR value determined by Receiver operating characteristic (ROC) curve
  15. 15. CML IV: Long-Term Impact of Response at 3 Months •1223 pts randomized to imatinib 400, imatinib + IFN, imatinib + ara-C, imatinib 800 •3 month analysis: PCR in 692 pts, cytogenetics in 460 •3 mo transcript levels predictive of achievement of CCyR and MMR % 5-year outcome Cytogenetics (% Ph+) Molecular [BCR-ABL/ABL (IS)] ≤35% >35% ≤10% >10% PFS 94 87 93 87 OS 95 87 95 87 Hanfstein et al. ASH 2011; Abstract #783
  16. 16. OS by Response to TKI at 3 Months at MDACC Naqvi et al. ASH 2011; Abstract #3784
  17. 17. EFS by Response to TKI at 3 Months at MDACC Naqvi et al. ASH 2011; Abstract #3784
  18. 18. Failure On Imatinib And Strategies Imatinib Failure ↑ Imatinib Second Generation TKI • Ph 100% at 6 mos _ + • Ph ≥ 35% at 12 mos + + • No CGCR in yr 2 + + • CG relapse + + • Hematologic relapse _ +
  19. 19. Imatinib Dose Escalations % 2-yr Resistance1,2 No. % CG CR TFS OS Cytogenetic 63 52 80 90 Hematologic 21 5 51 67 • Similar results from IRIS 3 1 Kantarjian Blood 101:473, 2003 2 Jabbour Blood 113:2154, 2008 3 Kantarjian Cancer 115:551, 2008
  20. 20. 2nd Generation TKI in CML Parameter Dasatinib Nilotinib Bosutinib Potency (fold vs IM) 325 30 20-50 Target Src & Abl Abl Src & ABL BCR-ABL binding Active + Inactive Inactive Intermediate Resistant mutations T315I T315I T315I Mutations with intermediate sensitivity E255K/V, V299L, F317L E255K/V, Y253F/H, Q252H, F359V E255V/K, V299L, F317L Standard dose (CP) 100mg QD 400mg BID 500mg QD Grade 3-4 neutropenia & thrombocytopenia 33% / 22% 31% / 33% 12% / 21% Other notable toxicities Pleural effusion, bleeding Bilirubin, lipase elevation Diarrhea, rash C-kit inhibition (vs imatinib) Increased Similar None PDGFR inhibition (vs imatinib) Increased Similar None Clinical activity Highly active Highly active Highly active
  21. 21. Phase II Studies of Dasatinib After Imatinib Failure Response Percent by Disease Stage CP n=387 AP n=174 MyBP n=109 LyBP n=48 ALL n=46 Hematologic 91 64 50 39 49 CHR 91 50 26 29 35 NEL - 14 7 6 7 Cytogenetic 62 40 47 58 62 Complete 53 33 27 46 54 Partial 9 7 7 6 2 Blood 110:abst 470 and 734, 2007.
  22. 22. Baccarani. Blood 112:abst 450, 2008 Optimal Dose and Schedule of Dasatinib IN CML CP after Imatinib Failure % Parameter 100mg QD N=166 50mg BID N=166 140mg QD N=163 70mg BID N=167 MCyR 63 61 63 61 CGCR 50 50 50 54 24-months PFS 80 76 75 76 Neutropenia, G3-4 35 47 44 45 Thrombocytopenia, G3-4 23 36 41 38 Pleural effusion, G3-4 2 4 5 5 Interruption 58 66 69 71 Reduction 33 45 54 57 Shah. Blood 112:abst 3225, 2008
  23. 23. Phase II Studies of Nilotinib After Imatinib Failure Response Percentage CP n =321 AP n =137 MyBP n =106 LyBP n =30 •HR 77 54 24 20 CHR 76 26 12 13 •Cytogenetic Major 59 31 38 50 Complete 44 19 28 33 Blood 112:abst 3229, 3238, 2008.
  24. 24. Nilotinib in Chronic Phase CML Post Imatinib Failure • 321 pts; nilotinib 400 mg BID; median FU 19 mos; median nilotinib 788 mg/D; median days off 20 • Outcome Percent - CGCR 46 - MMR 28 (56% of CGCR) - 24-mos PFS 64 - 24-mos OS 87 Kantarjian. Blood 114:abst 1129; 2009
  25. 25. Nilotinib in CML Chronic Phase. Survival and PFS 0 10 20 30 40 50 60 70 80 90 100 0 3 6 9 12 15 18 21 24 27 30 33 Time in mos 84% 73% 64% 95% 91% 88% Kantarjian. Blood 112:abst 3238, 2008 %Progression-freesurvival
  26. 26. Bosutinib in CML-CP post imatinib failure • 288 pts Rx with bosutinib 500 mg/D: Imatinib resistant 200; intolerant 88 • Parameter Percent -CHR 86 -MCyR 53 -CCyR 41 -MMR if CCyR 64 -2-yr PFS 79 2-yr OS 92 • Side effects: diarrhea 9%, rash 9% Cortes. Blood 118: 4567;2012
  27. 27. Response to Bosutinib 3rd Line Therapy • Dual Src & Abl inhibitor, no effect over c-kit or PDGFR • 118 pts who failed imatinib (600mg) & dasatinib or nilotinib Response, % IM + D resistant (n = 37) IM + D intolerant (n = 50) IM + NI resistant (n = 27) CHR 50 80 77 MCyR 31 30 32 CCyR 14 28 27 PCyR 17 2 8 MMR 3 35 11 2-yr PFS 22 61 50 2-yr OS 66 85 100 IM, imatinib; D, dasatinib; NI, nilotinib. Khoury. Blood 119:3403;2012
  28. 28. 2nd Generation TKI in CML CP Post-Imatinib Resistance Response Percentage Dasatinib Nilotinib Bosutinib FU (mo) >24 >24 24* CHR 89 77 86 MCyR 59 56 54 CCyR 44 41 41 24 mo PFS** 80% 64% 79% 24 mo OS** 91% 87% 92% * Median ** All patients Shah et al. Haematologica 2010; 95: 232-40 Kantarjian et al. Blood 2011; 117: 1141-45 Cortes et al. Blood 2011; 118; 4567-76
  29. 29. 2nd -Generation TKI in CML CP Post- Imatinib Failure Toxicity Dasatinib Nilotinib Bosutinib Pleural effusion ++ - - Liver + + + Transaminases + + ++ Bilirubin - ++ - Rash + + ++ Diarrhea - - ++ Lipase - (+) ++ - Glucose - ++ - Hypophosphatemia ++ ++ + Bleeding + - - QTc ++ ++ -
  30. 30. 2nd -Generation TKI in CML CP Post- Imatinib Failure Toxicity Dasatinib Nilotinib Bosutinib Anemia 13 11 13 Neutropenia 35 31 18 Thrombocytopenia 23 30 24 Shah et al. Haematologica 2010; 95: 232-40 Kantarjian et al. Blood 2011; 117: 1141-45 Cortes et al. Blood 2011; 118; 4567-76
  31. 31. Better Outcome on Dasatinib with Earlier Intervention • Patients on dasatinib studies analyzed by failure status on imatinib: loss of MCyR vs loss of CHR • Status at IM Failure No. Percentage CCyR MMR Loss of MCyR 151 72 60 Loss of CHR & MCyR 33 42 29 Loss of CHR (never MCyR) 109 26 26 Quintás-Cardama. Cancer 115: 2912-21, 2009
  32. 32. Dasatinib Early Intervention EFS & OS Quintás-Cardama. Cancer 115: 2912-21, 2009 Event-Free Survival Overall Survival Time to intervene: Loss of MCyR
  33. 33. Prognosis with 2nd TKIs. Survival •Adverse factors: PS ≥1 and lack of CyR to imatinib Jabbour. Blood 117: 1822-7, 2011
  34. 34. No MCyR (27) MCyR (59) 0 0.2 0.4 0.6 0.8 1 0 12 24 36 Months on second TKI PFS(%) PFS and Response to 2nd TKI Response @ 12 mo % AP/BP/Death/CHR loss Next Year MCyR 3% No MCyR 17% • 113 CML CP pts receiving nilotinib (n=43) or dasatinib (n=70) after imatinib failure Tam. Blood 112: 516-8, 2008 p = 0.003
  35. 35. Optimal Response to 2nd TKIs. Survival 3-year survival (%) Parameter Event-free Overall CCyR by 3 months Yes 74 98 No 43 79
  36. 36. How Do You Choose The Second Generation TKIs • Disease characteristics - AP/BP: favor dasatinib (?) and combinations - chronic: see below • Mutations -T315I → none - nilotinib IC50 > 150nM → avoid - dasatinib IC50 > 3nM → avoid • Patient Hx - Hypertension, CHF, lung problems, COPD → avoid dasatinib, consider bosutinib/nilotinib - Severe diabetes, pancreatitis Hx, atherosclerosis → avoid nilotinib, consider bosutinib/dasatinib - QTc problems → be cautious with all (?)
  37. 37. Ponatinib Phase 2 Study - PACE Response Characteristics CP-CML • 93% failed ≥2 TKI, 58% failed ≥3 TKI Response Rate, n (%) N=267 Any Cytogenetic Response 180 (67) MCyR 149 (56) CCyR 124 (46) MMR 91 (34) MR4.5 39 (15) BCR-ABL ≤10% at 3 months, n/N(%) 142/240 (59) 1 prior approved TKI 14/16 (88) Median Time to Response* , months [range] MCyR 2.8 [1.6 – 11.3] MMR 5.5 [1.8 – 19.2] • 91% MCyR sustained at 12 months (K-M) Cortes J, et al. Blood. 2012;120: Abstract 163.
  38. 38. Ponatinib Phase 2 Study - PACE Response by Baseline Mutation CP-CML Baseline Mutations in at Least 2 Patients (Excluding T315I) P-Loop Non P-Loop NumberofPatients MCyR CP-CML N=267 n/N (%) R/I, no mutation 66/136 (49) R/I, any non-T315I mutation 38/67 (57) T315I mutation 45/64 (70) Cortes J, et al. Blood. 2012;120: Abstract 163.
  39. 39. Ponatinib Phase 2 Study - PACE Response in Advanced Phase n (%) AP-CML N=83 BP-CML N=62 Ph+ ALL N=32Myeloid N=52 Lymphoid N=10 MaHR* 47 (57) 15 (29) 4 (40) 13 (41) Any CyR** 46 (55) 19 (37) 5 (50) 15 (47) MCyR 32 (39) 10 (19) 4 (40) 15 (47) CCyR 20 (24) 8 (15) 3 (30) 12 (38) MMR# 13 (16) N/A N/A N/A *MaHR = primary endpoint; 14 AP-CML patients with baseline MaHR and 1 AP-CML patient with no baseline MaHR assessment counted as non-responders **CCyR + PCyR + minor CyR + minimal CyR # MMR was assessed on the International Scale using peripheral blood; Patients missing a valid baseline MMR assessment , or who met the criteria for MMR at baseline, were counted as non-responders Kantarjian HM, et al. Blood. 2012;120: Abstract 915.
  40. 40. Omacetaxine for CML CP After Failure to ≥2 TKI • 122 pts with CML CP (n=81) or AP (n=41) with ≥2 prior TKI • Omacetaxine 1.25 mg/m2 BID x14d, then x7d Response, % CP N=81 AP N=41 Primary endpoint MCyR 20% MaHR 27% CCyR 10% CHR 24% Median duration, mo 17.7 9 Median PFS, mo 9.6 4.7 Median OS, mo 33.9 16 • 11 pts (9 CP, 2 AP) ongoing response • Median 35 cycles over median 39 months • Median response duration: 14 mo CP, 24 mo AP Kantarjian HM, et al. Blood. 2012;120: Abstract 2767.
  41. 41. Allo SCT. Second or Third Salvage? • Imatinib failure in AP, BP: use new TKI as bridge to MRD, then alloSCT ASAP • T315I mutation in any CML phase: use AP 24534, other T315I inhibitors, HHT, HU, others as bridge to MRD, then allo SCT ASAP • Imatinib failure in CP: – if IC50 ↑, clonal evolution, or no major CG in 12 mos → allo SCT (risk should also 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; • Young patient (?) • Financial considerations
  42. 42. Monitoring Patients with CML While on TKI Therapy • Adequate monitoring required to optimize outcome / Not too much, not too little • CCyR is associated with survival benefit • MMR is associated with durable CCyR and may therefore decrease probability of relapse • CMR offers hope for treatment discontinuation (clinical trials only) • Results should be interpreted in the context of alternative options • Not failure criterion / QPCR ↑ in CCyR
  43. 43. CML in 2013 • 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: ponatinib, omacetaxine
  44. 44. Questions? ejabbour@mdanderson.org Marcos.delima@uhhospitals.org

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