A Video Viewpoint: Expert Discussions on CML Clinical Debates

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Roundtable Expert Discussions on CML Clinical Debates: A Collaborative Video Viewpoint Series With Medscape

This video viewpoint in its original and unaltered format is for educational purposes and is current as of May 31, 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at the user’s own risk, and all users should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.

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  • Physician and patient agree on course of therapy and monitoring 400 mg daily of Gleevec The patient is in stable phase and is not high-risk for transformation to accelerated phase CBC weekly for the first month then bi-weekly, bone marrow biopsy and cytogenetic testing at 6 months At 6 weeks The patient is in complete hematologic remission Splenomegaly has been resolved No evidence of myeloid precursors in peripheral blood Patient has superficial edema and complains of occasional muscle cramps In the IRIS clinical trials superficial edema and muscle cramps occurred in 58% and 43% of patients respectively, on Gleevec ANC 1.3 × 10 9 /L, platelets 120 × 10 9 /L
  • Time to progression to AP/BC is defined as the time from the date of randomization to the first documented disease progression to AP/BC or CML-related death On treatment (without clonal evolution): includes as event any progression to AP/BC (where definition of AP/BC does not include clonal evolution) or CML-related deaths occurring on treatment On treatment (with clonal evolution): includes as event any progression to AP/BC (where definition of AP/BC includes clonal evolution) or CML-related deaths occurring on treatment
  • SURVIVAL CURVES (OS [4 DEATHS IN THE B GROUP AND 12 IN THE I ARM], PFS) PLEASE
  • Probability of primary or acquired imatinib resistance dependent on the log reduction of BCR–ABL from the standardised baseline at 3 months of imatinib. The level of BCR–ABL reduction achieved early after commencing imatinib therapy is a good indicator of subsequent resistance.
  • In summary, the outcome of patients with CML in chronic phase post imatinib failure treated with second generation TKIs is mainly dependent on the previous cytogenetic response to imatinib therapy and performance status. Patients with poor performance status and no previous cytogenetic response to imatinib therapy have a low likelihood of responding to second generation TKI with poor event-free survival, and therefore should be offered additional treatment options. The achievement of a 12-month MCyR after therapy with second generation TKI may compensate for the presence of one or two unfavorable baseline factors. Thank you for your attention
  • Introducing dasatinib in patients with CML CP failing imatinib after loss of MCyR was associated with improved CCyR rates as well as EFS, PFS, and OS, compared with introducing dasatinib after loss of CHR or loss of CHR and CCyR, thus supporting the notion that switching therapy from imatinib to dasatinib early during the course of failure increases the chances of a favorable long-term outcome.
  • We then looked at the specific mutations that were identified after therapy with the different TKI, whether they were present before the start of therapy or not. As you can see, failure to dasatinib was preferentially associated with development of mutations at V299 and F317. In contrast, in patients treated with nilotinib , the most frequent mutations were seen in the P-loop, especially in Y253 and E255, as well as F311 and F359.
  • This slide shows the responses achieved among the 38 evaluable patients in chronic phase CML. A CHR was achieved or maintained in 95%. More importantly, a major cytogenetic response was achieved in two thirds of all patients who have had cytogenetic assessment, with a complete cytogenetic response in more than half of all patients. All 9 patients with T315I confirmed at baseline achieved a major cytogenetic response, and it was complete in 8 of them. Responses were somewhat lower among patients without T315I but still more than half achieved a major cytogenetic response and 40% a complete cytogenetic response. ____________________________________ Evaluable patients = There were 55 Evaluable Patients. Definition of the response evaluable population as follows: - Patient has at least one cyto, heme and MMR assessment OR - Patient has discontinued Using the above definition, there are a total of 55 evaluable CML/Ph+ ALL patients in the dataset. Of these 55, 38 are CP CML. Therefore the denominator for response (cyto, heme and MMR) summaries in CP CML would be 38.
  • A Video Viewpoint: Expert Discussions on CML Clinical Debates

    1. 1. DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of March 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice,diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
    2. 2. DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline forpatient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USE This activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. PIM and IMER do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of PIM and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
    3. 3. Disclosure of Conflicts of Interest Jorge E. Cortes, MD, has no real or apparent conflicts of interest to report. Michael W.N. Deininger, MD, PhD, reported a financial interest/relationship or affiliation in the form of: Consultant, Ariad Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Novartis Pharmaceuticals Corporation; Contracted Research, Bristol-Myers Squibb Company, Celgene Corporation, Genzyme, Inc. Jerald P. Radich, MD, reported a financial interest/relationship or affiliation in the form of: Consultant, Ariad Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Incyte Corporation, Novartis Pharmaceuticals Corporation, Pfizer, Inc.; Contracted Research, Novartis Pharmaceuticals Corporation.
    4. 4. Learning Objectives L Upon completion of this activity, participants should be better able to: Describe the laboratory tests needed to accurately diagnose/monitor CML Employ strategies for selecting optimal frontline therapies based on individual patient characteristics Explain how to define and identify a relapse Describe the role of mutational analysis in individualizing second-line treatment List investigational agents in clinical development for patients with relapsed/refractory disease Provide accurate and appropriate counsel as part of the treatment team
    5. 5. Introduction to Faculty Panel Jorge E. Cortes, MD – Professor, Leukemia – The University of Texas M. D. Anderson Cancer Center Michael W. N. Deininger, MD, PhD – Chief – Division of Hematology and Hematologic Malignancies – Huntsman Cancer Institute University of Utah Jerald P. Radich, MD – Professor – Fred Hutchinson Cancer Research Center
    6. 6. Activity Agenda Roundtable Expert Discussions on CML Clinical Debates: A Collaborative Video Viewpoint Series with Medscape Pre-Assessment Panel Introduction Clinical Debate 1: What Is the Optimal Frontline Therapy for Patients With CML? (30 mins) Case study – What laboratory tests should be ordered and how should the results be interpreted to make an accurate diagnosis? If CML is confirmed, how should first-line therapy be chosen based on patient characteristics? How should patients be monitored? – Avoiding diagnosis pitfalls: RT-PCR vs. FISH vs. bone marrow biopsyInterpreting PCR resultsHow do patient comorbidities influence choice of first-line therapy?The latest trial data on alternatives to frontline imatinib: Second-generation TKIs
    7. 7. Activity Agenda (cont.) Clinical Debate 2: What Constitutes a Relapse and How Should the Relapsed/Refractory Patient Be Treated? (30 mins) Case study: – How can a relapse be confirmed? What is the role of mutational analysis in choosing between an imatinib dose increase, second-line TKI, novel agent in a clinical trial, or stem cell transplant? – Defining hematologic, cytogenetic, and molecular response: What constitutes an optimal response? A relapse? – When should first-line therapy with imatinib be stopped and a new agent administered? – What is the role of cytogenetic testing in treatment choice for the relapsed/refractory patient? – What are the investigational novel agents in clinical development available to patients with T315I mutations and/or relapsed/refractory disease? Post-Assessment
    8. 8. Roundtable Expert Discussions on CML Clinical Debates:A Collaborative Video Viewpoint Series With Medscape
    9. 9. Clinical Debate 1: What Is the Optimal FrontlineTherapy for Patients With CML?
    10. 10. Case Study 1: Newly Diagnosed CML  47-yr-old teacher found to have elevated WBC (53 x 109/L) on routine blood work while trying to purchase life insurance policy  Initial work-up – WBC (53 x 109/L), platelets (583 x 109/L), peripheral blood blasts (6%), basophils (2%) – Spleen palpable 7 cm below costal margin  PMH includes diabetes mellitus well controlled with insulinCML = chronic myeloid leukemia; WBC = white blood count; PMH = past medical history.
    11. 11. Case Study 1 Laboratory Testing  You suspect a diagnosis of CML  What is your recommendation for initial work-up of this patient? – Bone marrow aspiration with differential – Cytogenetic analysis – Peripheral blood FISH – Real-time PCR in peripheral blood – Mutations analysis – Leukocyte alkaline phosphatase – Vitamin B12 levelsFISH = fluorescent in situ hybridization; PCR = polymerase chain reaction.
    12. 12. Case Study 1: Diagnosis and Result Interpretation  Bone marrow with 8% blasts, 3% basophils  Cytogenetics: 46XY, t(9;22;11) in 20/20 metaphases  FISH shows 98% interphases with a BCR-ABL fusion signal and deletion of the derivative 9 genePh = Philadelphia; ACA = additional chromosomal abnormalities.
    13. 13. Case Study 1: Diagnosis and Result Interpretation (cont.)  How would you interpret these results? – Classic Ph chromosome – Varian Ph chromosome – Clonal evolution – ACA – Blast phase – An error in reportingPh = Philadelphia; ACA = additional chromosomal abnormalities.
    14. 14. What Is Clonal Evolution Clonal evolution XxXx9 22 x Xx DiploidXx Xx x ACA x (Clonal “selection”) Variant Ph
    15. 15. Case Study 1: Diagnosis Basedon these results what phase do you consider this patient to be in? – Chronic phase – Late chronic phase – Second chronic phase – Accelerated phase – Blast phase
    16. 16. CML Phases Chronic Accelerated BlasticPast 3-5 years 12-18 months 3-9 monthsPresent 25+ years 4-5 years 6-12 months • Asymptomatic • Blasts ≥ 15% • Blasts ≥ 30% (if treated) • Bl + pros ≥ 30% • Basophils ≥ 20% • Extramedullary • None of criteria for accelerated or blast • Plts < 100,000/mcl disease with localized blast phase • Clonal evolution immature blasts 17
    17. 17. Choosing First-Line Therapy  If the patient has a healthy brother and sister, what are the options for first-line treatment? – Imatinib 400 mg – Imatinib 800 mg – Dasatinib 100 mg daily – Nilotinib 300 mg bid – Nilotinib 400 mg bid – SCTbid = twice daily; SCT = stem cell transplant.
    18. 18. Patient Characteristics: Influencing Therapy  How do patient comorbidities influence choice of first-line therapy?bid = twice daily; SCT = stem cell transplant.
    19. 19. Improving Frontline Therapy in CML  Standard-dose imatinib  High-dose imatinib  Imatinib-based combinations  Second generation TKI – Dasatinib – Nilotinib – BosutinibTKI = tyrosine-kinase inhibitor.NCCN, 2011.
    20. 20. Results With Imatinib in Early CP-CML: IRIS Trial at 8 Yrs  304 (55%) patients on imatinib on study  Projected results at 8 yrs – CCyR: 83% • 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP – EFS: 81% – TFS: 92% • If MMR at 12 mos: 100% – Survival: 85% (93% CML-related)  Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, 0.4%CP-CML = chronic-phase CML; CCyR = complete cytogenic response; AP = accelerated phase; BP = blast phase; EFS= event-free survival; TFS = transformation-free survival; MMR = major molecular response; IRIS = InternationalRandomized Study of Interferon and STI571.Deininger et al, 2009.
    21. 21. Survival in Early CP-CMLKantarjian et al, 2011.
    22. 22. Long-Term Outcome With Imatinib in Early CP-CML (ITT) 1.0 0.9 0.8 Probability (%) 0.7 0.6 0.5 Survival 63% PFS 0.4 CHR 0.3 EFS Loss of MCyR 0.2 0.1 0 6 12 18 24 30 36 42 48 54 60 Time From Start of Imatinib Therapy (mos)de Lavallade et al, 2008.
    23. 23. TOPS: Rate of MMR Over Time by Imatinib Dose (ITT) 476 patients with early CP-CML randomized to imatinib 400 mg daily vs. 800 mg daily Percent (%) Outcome at 24 mos 400 mg 800 mg CCyR 76 76 MMR 54 51 EFS 95 95 PFS 97 98  Significant impact of dose intensity/treatment interruptions on MMR rateTOPS = tyrosine kinase inhibitor optimization and selectivity: ITT = intent-to-treat; PFS = progression-free survival.Baccarani, Druker, et al, 2009.
    24. 24. High-Dose Imatinib as Initial Therapy in CML  281 patients Rx’d with imatinib 400 mg (n = 73) or 800 mg (n = 208) Overall Response (%) 400 mg 800 mg p Value CCyR 87 91 .49 MMR 78 87 .06 CMR 39 49 .21 Time to CMR EFS 1 1.0 Total CMR 800 mg 206 100 p = 0.04 0.8 400 mg 71 28 0.8 0.6 0.6 0.4 0.4 Total No.event 400mg 73 15 p = 0.01 800mg 208 22 0.2 0.2 0 0.0 0 12 24 36 48 60 72 84 96 108 120 0 12 24 36 48 60 72 84 96 108 120CMR = complete molecular response.Pemmaraju et al, 2010.
    25. 25. Significance of OCT-1 Activity in Response to Imatinib  Transporter responsible for imatinib cell influx  Not required for second generation TKI Percent (%) Outcome Dose p Value Low OCT-1 High OCT-1 MMR < 600 mg 27 92 .021 600 mg 72 87 .093 EFS < 600 mg 27 67 .018 600 mg 61 80 .241 TFS < 600 mg 73 100 .048 600 mg 100 100 NSOCT-1 = organic cation transporter-1; NS = not significant.White, Dang, et al, 2010.
    26. 26. Imatinib + IFN as Frontline Therapy for CML  CML-IV – 1,014 patients randomized to IM 400 mg, IM 800 mg, or IM 400 mg + IFN-α (median dose: 1.7 MU/d) – No improvement in response rate of 5-yr PFS with IFN  SPIRIT – 636 patients randomized to IM 400 mg, IM 600 mg, IM + ara-C, and IM 400 mg + Peg-IFNα-2a – Higher rate of MMR, SMRa, and CMR at 24 mos – No difference in 4-yr EFS  MDACC – 91 patients randomized to IM 800 mg ± Peg-IFN-2b – No difference in response, EFS, PFSa ≤ 0.01%.IM = intramuscular prospective randomized trial; SPIRIT = STI571; ara-C = cytarabine; SMR = superior molecular response;MDACC = The University of Texas M. D. Anderson Cancer Center.Hehlmann et al, 2011; Preudhomme et al, 2010; Cortes et al, 2011.
    27. 27. EFS by Treatment in Early CP-CML 1.0 0.8 Probability EFS (%) 0.6 0.4 Total Events Imatinib 400 mg 73 15 Imatinib 800 mg 208 22 Dasatinib 76 2 0.2 Nilotinib 1 p = 0.01 78 0.0 0 12 24 36 48 60 72 84 96 108 120 Time (mos)Cortes, O’Brien, et al, 2009.
    28. 28. Nilotinib Vs. Imatinib in Newly Diagnosed CML (ENESTnd) R A Nilotinib 300 mg bid (n = 282) N D  N = 846 O  217 centers M Nilotinib 400 mg bid (n = 281) I  35 countries Z E D a Imatinib 400 mg QD (n = 283) Follow-Up 5 yrs  Primary end point: MMR at 12 mos  Key secondary end point: Durable MMR at 24 mos  Other end points: CCyR by 12 mos, time to MMR and CCyR, EFS, PFS, time to AP/BC on study treatment, OS including follow-upa Stratification by Sokal risk score.ENESTnd = evaluating nilotinib efficacy and safety in clinical trials - newly diagnosed patients; OS = overall survival.Larson et al, 2010.
    29. 29. Nilotinib Vs. Imatinib in Newly Diagnosed CP-CML 846 patients randomized to nilotinib 300 mg bid (n = 282), nilotinib 400 mg bid (n = 281), or imatinib 400 mg QD (n = 283) Minimum follow-up: 24 mos Outcome Nil 300 Nil 400 IM 400 % CCyRa 87 85 77 % MMRa 71 67 44 % BCR-ABL ≤ 0.0032%a 26 21 10 % Discontinued Treatment 18 21 22 New Mutation (No.) 10 8 20a By 24 mos.Larson et al, 2011; Kantarjian, Hochhaus, et al, 2011.
    30. 30. ENESTnd: Progression to AP/BC Nilotinib 300 mg bid Nilotinib 400 mg bid Imatinib 400 mg QD p = .0059 p = .0003 p = .0196 p = .0089 No. Patients 0.7% 1.1% 4.2% 0.7% 1.8% 6.0% Including Clonal Evolution  Progression events after discontinuation of treatment occurred in an additional 7, 2, and 6 patients (excluding clonal evolution) in nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively; progression within 60 days of discontinuation occurred in 1, 1, and 2 of these patients across respective armsLarson et al, 2011; Kantarjian, Hochhaus, et al, 2011.
    31. 31. Dasatinib Vs. Imatinib Study in Treatment-Naïve CML (DASISION) Trial Design Dasatinib 100 mg QD (n = 259)  N = 519 Follow-Up  108 centers Randomized a 5 yrs  26 countries Imatinib 400 mg QD (n = 260)  Primary end point: Confirmed CCyR by 12 mos  Secondary/other end points: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; OSStratified by Hasford risk score.aDASISION = dasatinib vs. imatinib study in treatment-naive CML patients.Kantarjian, Shah, et al, 2011.
    32. 32. Dasatinib Vs. Imatinib in Newly Diagnosed CP-CML 519 patients randomized to dasatinib 100 mg QD (n = 259) or imatinib 400 mg QD (n = 260) Median follow-up: 24 mos Outcome Das 100 IM 400 % CCyR 86 82 % MMR 64 46 % BCR-ABL ≤ 0.0032% 17 8 % Discontinued Therapy 23 25 New Mutations (No.) 10 10Kantarjian, Shah, et al, 2011.
    33. 33. DASISION: Transformation to AP/BP CML (ITT) 100 Dasatinib 100 mg QD Imatinib 400 mg QD (%) n/N 6/259 13/260 9/259 15/260 On Study Including Follow-Up Beyond DiscontinuationKantarjian, Shah, et al, 2011.
    34. 34. DASISION: Cumulative Incidence of MMR 100 Dasatinib 100 mg QD Imatinib 400 mg QD 80 By 24 mos 64% By 12 mos 60 46% p < .0001 MMR (%) 40 46% 28% 20 0 0 10 20 30 40 Time (mos)Kantarjian, Shah, et al, 2011.
    35. 35. DASISION: CMR4.5 Rates (ITT) by Month of Treatment 100 Dasatinib 100 mg QD Imatinib 400 mg QD (%) 6 mos 12 mos 18 mos 24 mosKantarjian, Shah, et al, 2011.
    36. 36. Bosutinib Efficacy and Safely in Newly Diagnosed CML (BELA): Study Design Phase III Open-Label Trial R Bosutinib in Newly Diagnosed A 500 mg/day 5-yr follow-up CP-CML N (n = 250) D N = 502 O M 139 Sites, 31 Countries I Imatinib Stratification Factors: Z 5-yr follow-up 400 mg/day Geographical Region E (3 regions), Sokal score (n = 252) 1-yr analysis  Eligibility criteria: Cytogenetic diagnosis of Ph+ CP-CML ≤ 6 mos prior; No prior therapy other than hydroxyurea or anagrelide  Primary end point: CCyR rate at 12 mos  Secondary end points: – MMR rate at 12 mos – Time to CCyR and MMR – Time to and rate of transformation to AP/BP CML, survival – Safety and tolerabilityBELA = bosutinib efficacy and safety in CML.Gambacorti-Passerini et al, 2011.
    37. 37. Bosutinib Vs. Imatinib in Newly Diagnosed CP-CML  502 patients randomized to bosutinib 500 mg QD (n = 250) or imatinib 400 mg QD (n = 252)  Minimum follow-up: 18 mos Response at 12 mos Bos 500 IM 400 % CCyRa 79 79 % MMRa 55 45 % CMRa 18 10 % Discontinued Therapya 33 26By 18 mos.aGambacorti-Passerini et al, 2011.
    38. 38. Outcome by Frontline Therapy in CP-CML: BELA 9 33 4 13 5 9Gambacorti-Passerini et al, 2011.
    39. 39. Selective Dose Escalation and Early Switch for CML Therapy  105 patients, median follow-up: 21 mos (12–36 mos)  Still on Rx: 88% (65% imatinib, 23% nilotinib) Day 22 IM IM < 1,000 ng/mL 800 IM 800 10% IM 1% 800 Nilotinib CCyR IM 0.1% 800 IM600 MMR 1 3 6 9 12 15 18 21 24Yeung et al, 2010.
    40. 40. TIDEL II Primary End Point: 12-mos MMR 101 103 103 105 76 59 48 33 80% 82% 80% 77% 71% 70% 67% 61% 60% MMR 50% 48% 40% 30% 20% 18% 30% 10% 22% 21% CMR 13% 12% IS ≤ 0.0032% 0% 3 6 9 12 15 18 21 24 Time Points (mos)  MMR after switch to nilotinib: For intolerance 91%, for suboptimal response 9%TIDEL = trial of imatinib with dose escalation in CML.Yeung et al, 2010.
    41. 41. Impact of OCT-1 Activity on Response to Dose Increase or Change to Nilotinib  63 patients with ≥ 12-mos follow-up and OCT-1 activity assessed MMR 12-mos ⇑IM to Switched MMR Mutations on IM MMR 800 mg to Nil on Nil 800 mg Low OCT-1 37% 19% 23% 17% 42% 10% (n = 26) High OCT-1 81% 0% 8% 100% 14% 100% (n = 37)White, Saunders, et al, 2010.
    42. 42. Probability of Resistance by Molecular Response at 3 Mos 95 Probability of Resistance (%) 0–1 log (n = 10) 83% > 1–2 log (n = 22) P <0.001 75 > 2 log (n = 20) 55 35 15 5% 0% -5 0 5 10 15 20 25 30 Time on Imatinib (mos)Hughes et al, 2006.
    43. 43. Probability of MMR and Progression by Early Molecular Response to Imatinib % Probability Outcome by Transcript Levels BCR-ABL/ at Specified Mos ABL Transcript MMR (mos) Progression (mos) Levels 3 6 12 3 6 12 ≤ 0.1 100 96 97 4 1 3 > 0.1–1 84 69 61 3 7 2 > 1–10 53 44 20 11 9 8 > 10 33 15 7 13 23 50 p < .001 p < .001 p < .001 p < .001 p < .001 p < .001Quintas-Cardama, Kantarjian, et al, 2009.
    44. 44. 7-Yr Outcome by Molecular Response: All Patients Percent (%) Landmark MMR No MMR EFS 85 84 6 mos TFS 96 93 OS 90 89 EFS 91 79 12 mos TFS 99 90 OS 93 89 EFS 95 75 18 mos TFS 99 90 OS 95 90Hughes et al, 2010.
    45. 45. 7-Yr Outcome by Molecular Response: Only Patients With CCyR Percent (%) Landmark MMR No MMR EFS 85 93 6 mos TFS 96 98 OS 90 93 EFS 91 92 12 mos TFS 99 96 OS 93 97 EFS 95 86 18 mos TFS 99 96 OS 95 96Hughes et al, 2010.
    46. 46. OS by 12-Mos Response in CP-CML  848 patients randomized to IM 400 mg, IM 800 mg, or IM 400 mg + IFN  Median follow-up: 40 mosHehlmann et al, 2011.
    47. 47. Time to Loss of CCyR by Molecular Response at 18 MosHughes et al, 2010.
    48. 48. Optimal Response to Second TKIs: Frontline Response (N = 167)  167 patients with CP-CML treated with frontline dasatinib or nilotinib  Median follow-up: 33 mos (range: 3–66 mos) Mos on Therapy Response Total (%) Optimal 160 (100) 3 (N = 160) Sub-optimal 0 Failure 0 Optimal 152 (98) 6 (N = 155) Sub-optimal 3 (2) Failure 0 Optimal 128 (99) 12 (N = 129) Sub-optimal 1 (1) Failure 0 Optimal 99 (84) 18 (N = 119) Sub-optimal 14 (12) Failure 5 (4)Jabbour et al, 2011a.
    49. 49. Long-Term Outcome by Response at 6 Mos From Start of Therapy  435 CP-CML patients treated with frontline imatinib 400 (n = 73), imatinib 800 (n = 208), dasatinib (n = 76), or nilotinib (n = 78) EFS OSJabbour et al, 2011b.
    50. 50. CML Frontline Therapy – 2011 Frontline therapy: New standard – Imatinib is good – Second generation TKI (dasatinib, nilotinib, bosutinib) are better – Sequential therapy? – Adequate monitoring and management of AEs Failure to therapy – New definitions (no CCyR at 6 mos)? – Prompt identification and action of suboptimal response if imatinib therapy No need to change if responding to imatinib
    51. 51. How Should Patients Be Monitored? Whichof the following tests would you use to monitor your patient? 1) Cytogenetic analysis 2) FISH 3) PCR 4) Mutation analysis 5) Imatinib plasma levels 6) All of the above
    52. 52. Monitoring Procedures in CML CG: looks at all chromosomes; but: tedious; needs metaphases; only 20 cells counted (SD ± 15%); painful BM FISH: faster; 200 cells; PB; but: false + up to 5-10%; no information on other chromosomes PCR: most sensitive; PB; evaluable in CCyR; predicts for relapse; but: not standardized; no information on other chromosomes; variability up to 0.5 log; use 1 source (PB) and 1 reliable lab 53
    53. 53. Monitoring Recommendations for CML According to the ELN 2009 Objective Recommended frequency Every 2 wk until CHR, then at least every 3 mo or as Hematologic required At diagnosis, 3 mo, 6 mo and every 6 mo until confirmed CCyR, then every 12 mo if molecular monitoring not Cytogenetic assured At failure or unexplained myelosuppression Molecular Every 3 mo until MMR confirmed, then every 6 mo In case of failure or suboptimal response, or before Mutations change to 2nd TKIBaccarani et al. JCO 2009; 27: 6041-51
    54. 54. 7-Year Outcome by Molecular Response – Patients with CCyR Percentage Landmark MMR No MMR EFS 85 93 6 mo TFS 96 98 OS 90 93 EFS 91 92 12 mo TFS 99 96 OS 93 97 EFS 95 86 18 mo TFS 99 96 OS 95 96Hughes T, et al. 2010.
    55. 55. Clinical Debate 2: What Constitutes a Relapse andHow Should the Relapsed/Refractory Patient Be Treated?
    56. 56. Case Study 2: CML Post Imatinib Therapy A 52-yr-old woman with an HLA-identical sibling started therapy with imatinib 400 mg daily upon diagnosis of CP-CML.  She has now received imatinib 400 mg daily for 6 mos.  CG at 12 mos shows Ph+ 50%.HLA = human leukocyte antigen.
    57. 57. Confirming Relapse How can relapse be confirmed? Howcan you define hematologic, cytogenetic and molecular response? What constitutes an optimal response?
    58. 58. Case Study 2: Response Post Imatinib Therapy How would this response be labeled? – Failure – Secondary resistance – Suboptimal response – Optimal response
    59. 59. Criteria for Failure and Suboptimal Response to Imatinib Response Time (mos) Failure Suboptimal Optimal 3 No CHR No CG Response < 65% Ph+ No CHR 6 ≥ 35% Ph+ ≤ 35% Ph+ > 95% Ph+ 12 ≥ 35% Ph+ 1%–35% Ph+ 0% Ph+ 18 ≥ 5% Ph+ No MMR MMR Loss of CHR Loss of CCyR Loss of MMR Stable or Any Mutation Mutation Improving MMR CEBaccarani, Cortes, et al, 2009.
    60. 60. CML Post Imatinib Therapy: Management  How would you manage this patient now? – Continue imatinib 400 mg QD – Increase imatinib dose – Change to dasatinib 100 mg QD – Change to nilotinib 400 mg bid – Allogeneic BMTBMT = bone marrow transplant.
    61. 61. CML Post Imatinib Therapy (cont.) Thepatient has now received imatinib 400 mg daily for 12 mos with good tolerance. You repeat a cytogenetic analysis and it shows 10% Ph+ metaphases. How would you label this response now? – Failure – Secondary resistance – Suboptimal response – Optimal response
    62. 62. CML Post Imatinib Therapy: Management (cont.) How would you manage this patient now: – Continue imatinib 400 mg QD – Increase imatinib dose – Change to dasatinib 100 mg QD – Change to nilotinib 400 mg bid – Allogeneic BMT
    63. 63. Response Post Imatinib Therapy (cont.) The patient has now received imatinib for 18 mos, the last 6 mos at 800 mg/d. The patient has a sustained CCyR but has not achieved an MMR. How would you label this response: – Failure – Secondary resistance – Suboptimal response – Optimal response
    64. 64. CML Post Imatinib Therapy (cont.) How would you manage this patient now: – Continue imatinib 400 mg bid – Change to dasatinib 100 mg QD – Change to nilotinib 400 mg bid – Start an investigational option – Allogeneic BMT
    65. 65. Cytogenetic Testing What is the role of cytogenetic testing in treatment choice for the relapsed/refractory patient?
    66. 66. Long-Term Outcome With Imatinib in Early CP-CML (ITT) 1.0 0.9 0.8 Probability (%) 0.7 0.6 0.5 Survival 63% PFS 0.4 CHR 0.3 EFS Loss of MCyR 0.2 0.1 0 6 12 18 24 30 36 42 48 54 60 Time From Start of Imatinib Therapy (mos)de Lavallade et al, 2008.
    67. 67. Frequency of Suboptimal Response With Imatinib Therapy Time on Rx % With Response Response p Value (mos) 400 mg 800 mg Optimal 100 99 3 Suboptimal 0 0 NS Failure 0 1 Optimal 83 96 6 Suboptimal 12 1 .002 Failure 6 3 Optimal 70 92 12 Suboptimal 17 4 < .001 Failure 13 3 Optimal 44 52 18 Suboptimal 33 43 .005 Failure 23 5Alvarado et al, 2009.
    68. 68. EFS by Response to Imatinib at 18 Mos Time (mos)Alvarado et al, 2009.
    69. 69. Treatment Options for Imatinib Resistant CML  Higher doses of imatinib  Second generation TKIs  Allogeneic SCT  Third generation TKIs (ie, T315I inhibitors)  Others: Omacetaxine, decitabine, hedgehog inhibitorsNCCN, 2011; Cortes, Khoury, Nicolini, et al, 2009; Kantarjian et al, 2003; Zhao et al, 2009.
    70. 70. Treatment Recommendations for CP-CML According to ELN Status Recommendation First-line All Imatinib 400 mg Second-line IM Intolerant Dasatinib or nilotinib Suboptimal Imatinib same dose, or ⇑ dose, or dasatinib or niloitnib Failure Dasatinib or nilotinib; SCT if AP/BP or T315I Third-line Second TKI Suboptimal Conitnue same; SCT if warnings and EBMT score ≤2 Second TKI Failure SCTELN = European LeukemiaNet; SCT = stem cell transplant; EBMT = European Group for Blood and Marrow Transplantation.Baccarani, Cortes, et al, 2009.
    71. 71. Is There a Role for Imatinib Dose Escalation?  CCyR 50% if cytogenetic failure to imatinib 400 mg, 5% if hematologic failure  Uses – Suboptimal response: Long-term benefit unclear – Failure • Second generation TKI unavailable or impractical • Loss of CyR • Sensitive mutationsBreccia et al, 2011.
    72. 72. Dasatinib in CP-CML After Imatinib Failure  60-mos follow-up of dose optimization study  35% still on treatment: 46% still at 100 mg QD (35% < 100 mg QD) Parameter (%) N = 167 MCyR (2-yr) 63 CCyR (2-yr) 50 5-yr MMR 44 5-yr PFS 57 5-yr OS 78 Pleural Effusion 24 Grade 3–4 4  Mutations persisting or developing after dasatinib discontinuation for loss of response: V299L, T315I, and F317LShah et al, 2011.
    73. 73. PFS With Dasatinib After Imatinib Failure 1.0 0.8 Not Progressed (%) 0.6 PFS rate (95% CI) 0.4 n 12 mos 24 mos 36 mos 48 mos 60 mos 100 mg QD 167 91% 81% 72% 63% 57% (48–67) 70 mg bid 168 87% 76% 68% 66% 61% (52–70) 0.2 140 mg QD 167 87% 75% 61% 56% 51% (40–62) 50 mg bid 168 86% 76% 73% 69% 67% (58–75) 0.0 0 6 12 18 24 30 36 42 48 54 60 66 Time (mos) Progression was defined as increasing WBC count, loss of CHR or MCyR, ≥ 30% increase in Ph+ metaphases, confirmed AP/BP disease, or deathCI = confidence interval; CHR = complete hematologic response.Shah et al, 2011.
    74. 74. OS With Dasatinib After Imatinib Failure 1.0 0.8 0.6 Alive (%) OS rate (95% CI) 0.4 n 12 mos 24 mos 36 mos 48 mos 60 mos 100 mg QD 167 96% 91% 88% 82% 78% (72–85) 70 mg bid 168 94% 88% 81% 75% 73% (66–80) 0.2 140 mg QD 167 96% 94% 86% 83% 79% (72–86) 50 mg bid 168 96% 91% 85% 82% 75% (68–82) 0.0 0 6 12 18 24 30 36 42 48 54 60 66 Time (mos)Shah et al, 2011.
    75. 75. Nilotinib in CP-CML Post Imatinib Failure  321 patients with imatinib resistance (71%) or intolerance (29%)  Median age – 58 yrs; median exposure – 19 mos  Nilotinib 400 mg po bid ≥ 6 mos Outcome Percent (%) CHR 85 MCyR/CCyR 59/44 Resistant 56/41 Intolerant 66/51 24-mos OS/PFS 87/64  Median dose intensity 789 mg/d  Grade 3–4 ↓ platelets 31%, neutrophils 31%; lipase elevation 17% (pancreatitis < 1%), bilirubin 8%Kantarjian, Giles, et al, 2011.
    76. 76. EFS With Nilotinib After Imatinib Failure in CP-CML 64% at 24 mosKantarjian, Giles, et al, 2011.
    77. 77. OS With Nilotinib After Imatinib Failure in CP-CMLKantarjian, Giles, et al, 2011.
    78. 78. Bosutinib (SKI–606) in CML and Ph+ ALL  Src-Abl inhibitor 30x more potent than IM – No inhibition of PDGFR, c-kit  321 CP patients; median time from diagnosis 52 mos  Bosutinib 400–600 mg/d; phase II 500 mg/d  Median follow-up: 7 mos Response (%) in CP, prior imatinib only (N = 102) Resistant Intolerant (n = 69) (n = 33) CHR 81 82 MCyR 45 51 CCyR 32 40 MMR 42 39 CMR 22 32  Grade 3–4 toxicity: Thrombocytopenia 21%, neutropenia 12%, diarrhea 8%, rash 7%PDGFR = platelet-derived growth factor receptor; ALL = acute lymphocytic leukemia.Cortes et al, 2008.
    79. 79. Better Outcome on Dasatinib With Earlier Intervention  Patients on dasatinib studies analyzed by failure status on imatinib: loss of MCyR vs. loss of CHR Percent (%) Status at IM Failure No. CCyR MMR Loss of MCyR 151 72 60 Loss of CHR and MCyR 33 42 29 Loss of CHR (never MCyR) 109 26 26Quintás-Cardama, Cortes, et al, 2009.
    80. 80. Dasatinib Early Intervention EFS and OS EFS OS Loss of MCyR Loss of CHR Loss of MCyR and CHRQuintás-Cardama, Cortes, et al, 2009.
    81. 81. Mechanisms of Resistance to Imatinib  BCR-ABL dependent – Mutations in ABL – Amplification/overexpression – Remigration of BCR-ABL to cytoplasm  BCR-ABL independent – Decreased hOCT1 expression – Increased MDR expression – Increased alpha-1 acid glycoprotein – Overexpression of Src-related kinases  Quiescent stem cells (persistence)le Coutre et al, 2000; Weisberg et al, 2000; Mahon et al, 2000; Gamacorti-Passerini et al, 2000; Vigneri et al, 2001.
    82. 82. Sensitivity of Mutations to TKI Ba/F3 cell proliferation IC50 (nM) Imatinib Nilotinib Dasatinib WT 260 13 0.8 M244V 2,000 38 1.3 G250E 1,350 48 1.8 Q252H 1,325 70 3.4 Y253F 3,475 125 1.4 Y253H > 6,400 450 1.3 E255K 5,200 200 5.6 E255V > 6,400 430 11 V299L 540 ND 18 T315A 971 61 125 T315I > 6,400 > 2,000 > 200 F317L 1,050 50 7.4 F31TV 350 ND 53 E355G 2,300 ND 1.8 F359V 1,825 175 2.2 V379I 1,630 51 0.8 H396P 850 41 0.6 H396R 1,750 41 1.3Resistant / Moderately Sensitive / Sensitive O’Hare et al, 2007.
    83. 83. CCyR by Mutations in CML Treated with Second Generation TKI After IM Failure  86/169 (51%) patients treated had mutation – CP 30/59 (51%), AP 41/71 (58%), BP 15/39 (38%)  Mutations classified into high, intermediate, and low sensitivity to dasatinib or nilotinib based on IC50 Chronic Phase Accelerated PhaseJabbour et al, 2009.
    84. 84. Spectrum and Frequency of BCR-ABL KD Mutations Recovered After TKI Therapy  T315I and F359V recovered after treatment with SKI-606Cortes et al, 2007.
    85. 85. Time to Response to Second Generation TKI 113 CP-CML patients receiving nilotinib (n = 43) or dasatinib (n = 70) after imatinib failure 1 Response % AP/BP/Death/CHR Probability of Resistance (%) at 12 mos Loss Next Year 0.8 MCyR 3% No MCyR 17% 0.6 No MCyR (27) 0.4 p = .003 0.2 MCyR (59) 0 0 12 24 36 Time (mos on imatinib) CG Response at 3–6 mos Probability MCyR at 12 mos None 3%–7% ≥ mCyR > 50%Tam et al, 2008.
    86. 86. MSD and MUD SCT in CP-CML  3,514 MDS and 1,052 URD SCT from CIBMTR from 1988–2003  All in CP1; median age: 35–37 OS LFSLFS = leukemia-free survival.Arora et al, 2009.
    87. 87. Allo-SCT for CML in the Imatinib Era Probablity of survival n=84 Median age: 38 yrs (21–56 yrs) Median time from Dx: 18 mo (5–54 mos) HSCT in advanced phase, n= 28, 3 year survival 59% HSCT after IM failure in 1st CP, n= 37, 3 year survival 94% Elective HSCT, n=19, 3 year survival 88% Months after transplantationSaussele et al, 2010.
    88. 88. Allo-SCT After Imatinib Resistance  47 patients with imatinib resistant CML  34 CP, 9 AP, 4 BP  19 (40%) with ABL1 mutations (4 with T315I)  15/19 had AP, BP, or second CPJabbour, Cortes, et al, 2011.
    89. 89. Allo-SCT After Imatinib Resistance EFS by Mutational Status 2-yr EFS, % 2-yr OS, % Group No. (95% CI) (95% CI) All patients 47 49 (35–64) 63 (49-78)   ABL1 mutation 19 36 (14–58) 44 (20-67)   No mutation 28 58 (39-77) 76 (59-93)     p value .05 .02 Phase   CP 16 62 (39-86) 72 (49-96)   AP 31 44 (25-61) 59 (41-77)     p value .27 .30 OS by Mutational Status CP only   ABL1 mutation 4 25 (0-67) 33 (0-87)   No mutation 12 75 (50-99) 81 (58-100)     p value .20 .13 AP/BP only   ABL1 mutation 15 40 (15-65) 46 (20-71)   No mutation 16 45 (18-72) 72 (48-96)     p value .20 .12Jabbour, Cortes, et al, 2011.
    90. 90. SCT in CML According to ELN 2009 Searching for family donor At diagnosis Patients in AP/BP Patients < 20 yrs Patients with warning factors At imatinib failure All patients Searching for unrelated donor At diagnosis Patients in AP/BP At imatinib failure Patients who progressed to AP/BP, or with T315I, or with hematologic resistance During/after second TKI Patients with TKI failure Patients with a suboptimal response and EBMT risk 0–2 Performing allo-SCT At diagnosis Patients in AP/BP (pretreatment with TKI recommended) At imatinib failure Patients in AP/BP (pretreatment with second generation TKI recommended), or with T315I Failure to second TKI All patientsBaccarani, Cortes, et al, 2009.
    91. 91. Criteria for Failure to Second Generation TKI (ELN) Time (mos) Suboptimal Failure Warning Baseline NA NA Imatinib Heme Resistance CE Mutations 3 Ph+ 36%–65% Ph+ > 95% Ph+ 66%–95% New mutation 6 Ph+ 1%–35% Ph+ 66%–95% Ph+ 36%–65% New mutation 12 No MMR Ph+ > 35% New mutationBaccarani, Cortes, et al, 2009.
    92. 92. Dasatinib and Nilotinib in Advanced Phase CML After Imatinib Failure  Accelerated phase (dasatinib, nilotinib) – MaHR: 50%–60% – MCyR: 30%–40% • CCyR: 19%–30% – PFS: 40%–50% at 24 mos  Blast phase (dasatinib) – MaHR: 30%–40% – MCyR: 30%–50% – Median PFS: 3–5 mosMaHR = major hematologic response.Kantarjian et al, 2010; Kantarjian, Hochhaus, et al, 2011; Kantarjian, Giles, et al, 2011b.
    93. 93. Survival of Patients With T315I CML AP (n=38, dead=16) CML CP (n=82, dead=37) Ph+ ALL (n=46, dead=32)CML BP (n=56, dead=48) Nicolini et al, 2009. Jabbour et al, 2008.
    94. 94. Use of Second Generation TKI as Third-Line Therapy  37 patients treated with dasatinib (n = 29) or nilotinib (n = 8) after 2 TKI failure  MCyR: CP 25%, AP 33%, BP 25% Failure-Free Survival 1.0 0.9 Failure No. No. Failure •Loss CHR 0.8 CP 16 10 •Loss MCyR AP 9 9 BP 12 12 •Loss of CCyR 0.7 •Discontinuation for toxicity •Transformation to AP/BP 0.6 •Death 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 T imeGarg et al, 2009.
    95. 95. CML Resistance to Therapy Goal of therapy in CML: Improve long-term outcome Current results could be improved Definition of resistance evolving Early end points critical for long-term benefit Early treatment intervention required for optimal long-term benefit Good treatment options available – Better treatment options needed
    96. 96. What Is The Role of Mutational Analysis? When would you test for mutations on a patient like this: – At the time imatinib is started – At the time suboptimal response is detected – At the time resistance to imatinib is documented – At regular intervals during therapy – I would not check for mutations
    97. 97. Investigational Agents for Relapsed/Refractory Disease What are the investigational novel agents in clinical development available to patients with T315I and/or relapsed/refractory disease?
    98. 98. Treatment Options for CML With T315I or After ≥ 2 TKI  Multi-kinase inhibitors – MK-0457 (RIP) – AP24534 (Ponatinib) – DCC-2036 – PHA-739358 – XL-228 – KW-2449  Omacetaxine (homoharringtonine)  Other approaches (eg, HSP-90 inhibitors, histone deacetylase inhibitors, etc.)  Combination therapyXu et al, 2011; Eiring et al, 2011; King et al, 2011; Nguyen et al, 2011; Kim et al, 2011.
    99. 99. Ponatinib (AP24534) in Refractory CML  Orally administered multikinase inhibitor with activity against all mutants including T315I  At 40nM inhibits emergence of resistant clones  Phase I study in 74 patients: 60 CML (44 CP, 7 AP, 9 BP), 4 Ph+ ALL, 6 AML FLT3 ITD, 4 Other  Prior TKI (Ph+ diseases): 2 in 95%, 3 in 65%  Mutations in 63%, T315I in 28%  MTD 45 mg, DLT pancreatitisMTD = maximum tolerated dose; DLT = dose-limiting toxicity; ITD = internal tandem duplication.Cortes et al, 2010.
    100. 100. Phase I Study of Ponatinib (AP24534) Best Response to Therapy CP-CML N (%) Best Overall T315Ia Non-T315I Response (N = 38) (n = 9) (n = 29) Hematologic CHRb 36 (95) 9 (100) 27 (93) Cytogenetic MCyR 25 (66) 9 (100) 16 (55) CCyR 20 (53) 8 (89) 12 (41)Includes only those with T315I status confirmed at study entry.aIncludes new CHRs and baseline CHRs.bCortes et al, 2010.
    101. 101. Omacetaxine for CML With T315I Response to Therapy  81 patients with T315I CML  Omacetaxine 1.25 mg/m2 bid x 14 days, then x 7 days  Prior TKI: 1 in 21%, 2 in 53%, and 3 in 26% No. (%) Response CP AP BP N = 49 N = 17 N = 15 Hematologic 42 (86) 6 (35) 7 (47) CHR 42 (86) 5 (29) 3 (20) HI NA 3 (18) 1 (7) RCP NA 1 (6) 4 (27) Cytogenetic 20 (41) 1 (6) – MCyR 13 (27) 1 (6) – CCyR 9 (18) 1 (6) – Minimal 7 (14) – –  Median survival: CP = NR (65% at 24 mos); AP = 19 mos; BP 2 mosCortes, Khoury, et al, 2009.
    102. 102. Response to Bosutinib Third-Line Therapy  Dual Src and Abl inhibitor, no effect over c-kit or PDGFR  114 patients who failed imatinib (600 mg) and dasatinib or nilotinib IM + D IM + D IM + NI resistant intolerant resistant Response (%) (n = 36) (n = 51) (n = 27) CHR 61 80 78 MCyR 29 37 29 CCyR 9 34 17 PCyR 21 3 13 MMR 8 36 6Khoury et al, 2010.
    103. 103. SCT for CML With T315I  8 patients received 9 SCT – 7 MUD, 2 CB  Stage: 2 CP (in PCyR), 3 AP (active disease), 4 second CP from LyBP (1 mCyR, 2 MMR, 1 CMR with extramedullary disease)  Best response: 4 CMR (2 CP, 2 second CP), 3 CCyR (2 AP, 1 BP), 1 CHR (AP), 1 early death  Median follow-up: 13 mos – 3 died (5, 8, and 10 mos post SCT) with relapse – 5 alive: • 2 CP in CMR (14 and 42 mos post SCT) • 1 AP in CCyR (26 mos) with persistent T315I • 1 AP in CHR (39 mos) with persistent T315I • 1 BP in CMR (10 mos post second SCT)MUD = matched unrelated donor; CB = cord blood; LyBP = lymphoid blast phase; CMR = complete molecular response.Velev et al, 2010.
    104. 104. Take Home Message – CML 2011• Frontline therapy: new standard – Imatinib is good – 2nd generation TKI (dasatinib, nilotinib , bosutinib?) are better – Sequential therapy?• Failure to therapy: – New definitions (no CCyR at 6 months)? – Change quickly if imatinib therapy• No need to change if responding to imatinib• Good (but not great) 2nd line therapy• Future needs: – 3rd line (Ponatinib ⇒ 2nd and 1st line?) – Treatment discontinuation

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