Welcome to Master Class for Oncologists Session 2: 8:15 AM - 9: AM Miami, FL December 18, 29 Chronic Myelocytic Leukemia: Imatinib and Beyond Speaker: Daniel J. DeAngelo, MD, PhD Dana-Farber Cancer Institute Brigham and Women s Hospital Harvard Medical School Presenter Disclosure Information CML Case Presentation The following relationships exist related to this presentation: Dr DeAngelo serves on the speakers bureaus for Bristol-Myers Squibb, Celgene, Enzon Pharmaceuticals, and Novartis Pharmaceuticals Corporation. Off Label/Investigational Discussion In accordance with Pri-Med Institute policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. 55-year-old female presents with complaints of occasional night sweats, fatigue, and bruising Physical exam significant for splenomegaly (8 cm) WBC 12, (3% blasts, 5% metas, 3 % basos), Hct 36%, platelets 65, Bone marrow exam shows CML in CP Cytogenetic studies reveal 2/2 Ph+ metaphases The patient is the eldest of 5 children. 3 4 CML Case Presentation (cont)? What is the Most Appropriate Frontline Treatment for this Patient? 1. Hydroxyurea 2. Imatinib at 4 mg per day 3. Imatinib at 4 mg twice daily 4. Dasatinib at 1 mg per day 5. Dasatinib at 7 mg twice daily 6. Nilotinib at 4 mg twice daily 7. Interferon-α 8. Upfront allogeneic stem cell transplant What Can We Expect from Imatinib? 5 1
What is Needed at Initial Diagnosis? CML Prevalence CBC + diff, complete metabolic profile, and LFTs Bone marrow aspirate and biopsy Cytogenetics (2 metaphases)?fish,?qpcr Why? Need to exclude AP/BP-CML. Sokal score predictive of response FISH important for cytogenetic negative CML (<5%). Would not base Dx solely on PCR. FISH may have some role in prognosis, e.g., del9q+ US prevalence is currently 4-5, patients with about 46 new cases per year. Anticipated increase of >1% in 28 7 NCCN Guidelines 29. 8 Survival in Early Chronic Phase CML IRIS Study in CP-CML: 7-year Update 9 Proportion surviving 1..8.6.4.2 95% Year Total Dead Imatinib 23 7 199-2 96 334 1982-1989 365 265 1975-1981 132 127 1965-1974 123 122 2 4 6 8 1 12 14 Years from referral 1 116 Patients originally enrolled in IRIS, 553 per arm Late-progression events KM estimate of EFS at 7 years: 81% KM estimated rate without AP/BC at 7 years: 93% Safety Grade 3/4 events decreased in incidence after years 1-2 No unique, previously unreported AEs emerged AP/BC: accelerated phase/blast crisis; EFS: event-free survival; KM: Kaplan-Meier. O Brien SG, et al. ASH 28. Abstract 186. IRIS Overall Survival (ITT Principle): Imatinib Arm What Happened To The Patients After 7 Years? 1 9 All randomized to imatinib (n = 553; 1%) 11 Probability of survival 8 7 6 5 4 3 2 1 Estimated overall survival at 7 years is 86% (94% considering only CML-related deaths) Survival: deaths associated with CML Overall survival 12 24 36 48 6 72 84 96 Months since randomization O Brien SG, et al. ASH 28. Abstract 186. Still receiving study imatinib (n = 332; 6%) In CCR (n = 317; 57%) No CCR (n = 15; 3%) Alive (n = 17; 4%) *Patients may have continued imatinib off study. **Including primary discontinuation reason Death (n=13) 12 Safety (n = 43; 8%) Dead** (n = 26; 6%) Discontinued study imatinib* (n = 221; 4%) Alive (n = 52; 63%) Efficacy (n = 82; 15%) Dead (n = 3; 37%) Alive (n = 81; 84%) Other (n = 96; 17%) Dead (n = 15; 16%) O Brien S et al. Blood 28;112(11): Abstract 186 (Oral). 2
Durability of Cytogenetic Response 456 of 553 (82%) of first-line imatinib patients achieved CCR 317 (57%) patients randomized to imatinib remained on protocol and were in complete cytogenetic response (CCR) Remained on imatinib (n = 298; 65%) In CCR (n = 377 of 456: 83%) Patients who achieved CCR (n = 456; 1%) Off imatinib (n = 79; 17%) Regained CCR (n = 19; 4%) Lost CCR (n = 79 of 456: 17%) Remained on imatinib (n = 25; 5%) In MCR (n = 6; 1%) Regained CCR after dose increase (n = 6) 13O Brien S et al. Blood 28;112(11): Abstract 186 (Oral). 14 IRIS Rates of Progression in Patients After CCR Progression to AP/BC occurred in 15 (3%) of 456 patients who achieved CCR. Of 456 patients who achieved CCR, 1 (2%) died from CML. Number progressing after CCR 1 9 8 7 6 5 4 3 2 1 2 7 1 3 1 Time to CCR 12 months (n = 373) >12-24 months (n = 5) >24 months (n = 33) Not shown: 1 event in seventh year after CCR cause of death uncertain but suspected to be related to CML 1st 2nd 3rd 4th 5th Year after achievement of CCR O Brien SG, et al. ASH 28. Abstract 186. IRIS PCR Studies Sample Collection and Analysis: Methodology The IRIS protocol mandated measurement of molecular responses once patients achieved CCR. Additional samples were submitted by some sites at intervals independent of cytogenetic response status. Preplanned sub-studies at sites in Australia and Germany conducted PCR measurements at intervals independent of cytogenetic response status (n =1). - By 7 years, > 85% of patients had at least one PCR measurement submitted with a large number of samples available at baseline and every follow-up point. All results are expressed as BCR-ABL/control gene ratio and in the international scale (IS). BCR-ABL% (IS) 1 1 1..1.1.1 MMR (.1%) Baseline -1 log -2 log -3 log -4 log -5 log MMR, major molecular response. 15 O Brien S et al. Blood 28;112(11): Abstract 186 (Oral). 16 Hughes T et al. Blood 28;112(11): Abstract 334 (Oral). Molecular Response Rates Optimal Duration of Imatinib: Key Findings % of available samples 1 9 8 7 6 5 4 3 2 Major molecular response (MMR) and the depth of molecular response increase over time BCR-ABL% (International Scale).1% (MMR).1% IRIS showed that MMR rates and depth of molecular response increased over time. 1 Overall EFS: 81% Few patients (17%) who achieve CCR subsequently lose CCR during imatinib. A small percentage of patients (3%) who achieve CCR progress during imatinib therapy. After 7 years, imatinib continues to provide clinical benefit. Will there be patients who experience functional cures? 1 3 6 9 12 15 18 21 24 3 36 42 48 54 6 66 72 78 84 17 Sample Analysis Timepoints (months) O Brien S et al. Blood 28;112(11): Abstract 186 (Oral). 18 EFS: event-free survival. 1. O Brien SG, et al. ASH 28. Abstract 186. 3
Imatinib Dosing: Does Increasing the Dose Improve Outcomes? Study Patients Imatinib Dosing Outcomes (4 mg vs 6 mg or 8 mg) SPIRIT 1 N = 636 newly diagnosed 4 mg (n = 159) CCyR 6 mo: 49% vs 68%, P <.1 63% intermediate- to high-risk Sokal 6 mg (n = 16) CCyR 12 mo: 55% vs 62%, NS MMR 6 mo: 2% vs 31%, NS MMR 12 mo: 38% vs 49%, NS Overall D/C rate: 21% vs 23%, NS Can We Do Better Than Standard Dose Imatinib? European Leukemianet 2 N = 216, high risk 4 mg (n = 18) 6 mg (n = 18) TOPS 3 N = 476 61% intermediate- to high-risk Sokal (4 mg) 58% intermediate- to high-risk Sokal (8 mg) 4 mg (n = 157) 8 mg (n = 319) CCyR 6 mo: 5% vs 52%, NS CCyR at 12 mo: 58% vs 65%, NS MMR at 6 mo: 25% vs 31%, NS MMR at 12 mo: 33% vs 4%, NS Projected 4-yr OS: 84% vs 91%, NS CCyR 6 mo: 45% vs 57%, P =.146 CCyR 12 mo: 66% vs 7%, NS Time to MMR: 13.6 vs 8.4 mos, P =.38 On treatment at 1 yr: 92% vs 9%, NS German CML Study IV 4 N = 1242 4 mg (n = 312) 8 mg (n = 33, 1% high-risk) Responses comparable, data not reported CCyR: complete cytogenetic response; DC: discontinuation; MMR: major molecular response; OS: overall survival; SPIRIT: randomized comparison of imatinib vs imatinib combination therapies in newly diagnosed CML; TOPS: tyrosine kinase inhibitor optimization and selectivity. 2 1. Guilhot G, et al. ASH 28. Abstr 183. 2. Baccarani M, et al. ASH 28. Abstr 185. 3. Cortes J, et al. ASH 28. Abstr 335. 4. Hehlmann R, et al. ASH 28. Abstr 184. 21 Imatinib Dosing: Key Findings All dosing regimens are safe and generally well tolerated. Dosing intensity for higher doses is maintained in most patients. Faster cytogenetic responses observed in patients able to adhere to high-dose therapy compared with those receiving lower doses Rates of discontinuation generally similar between standard- and highdose imatinib arms Overall responses comparable Higher doses reach MMR more quickly By 1 year, CCyR, MMR, and survival outcomes comparable Frequency and severity of AEs comparable High-dose imatinib offers no clear-cut benefit, but longer follow-up is needed 22 SPIRIT Interim Analysis: Open-label, Randomized Phase III in Newly Diagnosed CP-CML Patients with newly diagnosed chronic-phase CML (N = 636) Imatinib 4 mg/d for 14 days Guilhot F, et al. ASH 28. Abstract 183. Stratified by Sokal risk group Imatinib 4 mg/d (n = 159) Imatinib 6 mg/d (n = 16) Imatinib 4 mg/d + cytarabine 2 mg/m 2 /d on days 15-28 every 28 days (n = 159) Imatinib 4 mg/d + peginterferon alfa-2a 9 μg/wk (n = 159) German CML Study IV Results with Imatinib plus IFN or High-dose Imatinib Standard imatinib 4 mg/d (n = 312) Results are interesting Longer follow-up is needed Study Outcome Imatinib 4 mg/d Imatinib + Ara-C Imatinib + IFN Imatinib 6 mg/d IFN f/b Imatinib Patients with newly diagnosed chronic-phase BCR/ABLpositive CML (N = 1242) *Recruitment terminated in 25. Low- or intermediate-risk patients only. Hehlmann R, et al. ASH 28. Abstract 184. 23 Imatinib 4 mg/d + interferon alfa (n = 338) Imatinib 4 mg/d + cytarabine (n = 158) Interferon alfa followed by imatinib 4 mg/d * (n = 131) Imatinib 8 mg/d (n = 33) 24 SPIRIT 1 CCyR 6 months 12 months MMR 6 months 12 months Optimal Molecular Response 12 months N = 159 49% 55% 2% 38% 15% N = 158 56% 63% 23% 46% 15% German CML Study IV 2 5-yr OS N/A N = 153 91% N = 159 56% 65% 39% 57% 3% N = 192 94% N = 16 68%* 62% 31% 49% 18% N = 173 89% N/A <.1 NS.24.85.19 N = 124 92% Ara-C: cytarabine; MMR: BCR-ABL:ABL ratio.1%; NS: not significant; optimal molecular response: BCR-ABL:ABL ratio.1%. *P <.1 vs imatinib 4 mg/d; P =.3 vs 2 combination therapy arms P =.5 vs imatinib 4 mg/d P =.8 vs imatinib 4 mg/d 1. Guilhot F, et al. ASH 28. Abstract 183. P =.2 vs imatinib 4 mg/d 2. Hehlmann R, et al. ASH 28. Abstract 184. 4
Combination Therapy: Key Findings SPIRIT showed that MMR rates are superior with imatinib/ifn vs standard-dose imatinib after 1 year. 1 Longer-term follow-up is needed Arm with cytarabine had highest discontinuation rate Higher incidence of grade 3/4 toxicities with higher-dose imatinib and imatinib combination therapies German CML Study IV showed comparable response rates. 2 Response tended to lag in the IFN-followed-by-imatinib arm Role of IFN could expand in the future IFN stimulation of immune response may provide benefit Rationale for and Current Status of Front-line Second-generation TKIs Dasatinib and nilotinib more potent than imatinib against unmutated BCR-ABL Clinical relevance unclear Efficacy and safety demonstrated in second-line setting Studies in front-line setting small Similar study designs: open-label, phase II Similar patient populations Previously untreated CP-CML No head-to-head comparison trials have been conducted 25 1. Guilhot F, et al. ASH 28. Abstract 183. 2. Hehlmann R, et al. ASH 28. Abstract 184. 26 Dasatinib and Nilotinib in Front-line Therapy: Baseline Characteristics and CCyR Front-line Second-generation TKIs: Key Findings Dasatinib 1 mg/d* Nilotinib 4 mg BID (N = 52) 1 (N = 73) 2 Median age, yrs (range) 46 (19-77) 51 (18-83) Sokal risk Low Intermediate High 52% 38% 1% 45% 41% 14% Follow-up (f/u) Median: 23 months (1-34) Minimum f/u 6 months: 1% Minimum f/u 12 months: 44% Mutations Clonal evolution: 6% Del der(9): 12% CCyR 3 months: 79% 6 months: 83% Chromosomal abnormality: 4% Del der(9): 1% -3 months: 78% 4-6 months: 96% Rapid CCyR occurs in most patients Responses significantly higher than imatinib historical controls at months 3, 6, and 12 Responses continue to increase over time Toxicity profile needs further evaluation (eg, pleural effusion occurrence and management) Findings encouraging but clinical benefit unclear Use in front-line setting not approved Longer follow-up in larger trials needed 27 *5 mg BID (n = 26) or 1 mg daily (n = 26) Del der(9): deletions of derivative chromosome 9 1. Cortes J, et al. ASH 28. Abstract 182. 2. Rosti G, et al. ASH 28. Abstract 181. 28 Allo HSCT vs Best Available Drug in Newly Diagnosed CP-CML ( genetic randomization ) Is There a role for SCT? Randomization if eligible for HSCT Patients with newly diagnosed CP-CML (N = 621) Allo HSCT through matched related donor (n = 123) Best Available Drug* (n = 219) Patients ineligible for HSCT received best available drug (n = 265) HSCT in CP (n = 97) No HSCT (n = 122) *Patients initially received interferon alfa-based treatment; 197 patients switched to imatinib after failure of interferon-based regimen. 3 Hehlmann R, et al. Blood. 27;19:4686-4692. 5
Allo HSCT vs Optimal Rx in Newly Diagnosed CP-CML CML Case Presentation Better overall OS, drug treatment vs HSCT; P =.49 Increased 8-year survival, drug treatment vs HSCT; P =.41 No survival difference in intermediate, high risk groups First-line drug treatment recommended in CP-CML Survival Probability, % All (n = 135) Related Donor Low risk Int/High risk (n = 85) (n = 5) No Related Donor All Low risk Int/High risk (n = 219) (n =129) (n = 9) After 2 years 76 78 74 89 93 84 After 5 years 62 68 52 73 85 56 After 1 years 53 59 43 52 62 4 55-year-old female presents with complaints of occasional night sweats, fatigue, and bruising Physical exam significant for splenomegaly (8 cm) WBC 12, (3% blasts, 5% metas, 3 % basos), Hct 36%, platelets 65, Bone marrow exam shows CML in CP Cytogenetic studies reveals 2/2 Ph+ metaphases The patient is the eldest of 5 children. 31 Hehlmann R, et al. Blood. 27;19:4686-4692. 32 CML Case Presentation (cont)? What is the Most Appropriate Frontline Treatment for this Patient? 1. Hydroxyurea 2. Imatinib at 4 mg per day 3. Imatinib at 4 mg twice daily 4. Dasatinib at 1 mg per day 5. Dasatinib at 7 mg twice daily 6. Nilotinib at 4 mg twice daily 7. Interferon-a 8. Upfront allogeneic stem cell transplant Can We Ever Stop Imatinib Therapy? 33 Responses Following Imatinib Discontinuation: STIM Study Patients (N = 69) with CMR 2 years 52% feceived prior IFN 41% of patients had molecular relapse within 6 months Probability of maintaining molecular remission slightly better with IFN pretreatment (53% vs 39%; P =.54) 5/7 patients maintaining CMR after 14 months received IFN 1% patients responded to imatinib retreatment Using Initial Molecular Response to Guide Treatment 35 CMR: complete molecular response. Mahon F, et al. ASH 28. Abstract 187. 6
Monitoring During Front-Line Imatinib EFS: 6-Month Landmark Analysis 37 Current consensus is to perform mutational analysis in patients who fail to respond or lose response. Not currently known if early identification of mutation prevents relapse Patients routinely monitored by BCR-ABL Q-PCR One study suggests a rise in transcript > 2.6-fold should trigger screening for mutations. 1 The actual fold-rise may vary by institution. General consensus regarding monitoring still needs to be obtained as variation exists across institutions and in the community. Q-PCR: quantitative polymerase chain reaction; RNA: ribonucleic acid. 1. Press RD, et al. ASH 28. Abstract 118. 38 % Without Event 1 9 8 7 6 5 4 3 2 1 BCR-ABL % (IS).1% (n = 86) >.1-1% (n = 89) > 1-1% (n = 43) > 1% (n = 38) 12 24 36 48 6 72 84 Months Since Start of Treatment 93% 85% 85% 58% P =.25 Hughes T, et al. ASH 28. Abstract 334. EFS: 12-Month Landmark Analysis EFS: 18-Month Landmark Analysis 1 9 8 92% 91% P =.25 1 9 8 95% 86% P =.1 % Without Event 7 6 5 4 3 2 1 BCR-ABL % (IS).1% (n = 153) >.1-1% (n = 9) > 1-1% (n = 36) > 1% (n = 22) 84% 53% % Without Event 7 6 5 4 3 2 1 BCR-ABL % (IS).1% (n = 164) >.1-1% (n = 47) > 1-1% (n = 25) > 1% (n = 13) 62% 58% 12 24 36 48 6 72 84 12 24 36 48 6 72 84 39 Months Since Start of Treatment Hughes T, et al. ASH 28. Abstract 334. 4 Months Since Start of Treatment Hughes T, et al. ASH 28. Abstract 334. Factors Predictive of Response During Imatinib Therapy Significance of Rising QPCR Levels in Patients Receiving Imatinib BCR-ABL% IS values at 6, 12, and 18 months are predictive of long-term EFS and transformationalfree survival. 1 Cytogenetic evaluations should guide treatment until CCyR is achieved. Molecular assessments are utilized thereafter. MMR obtained at any time point is a favorable event. Most patients in CCyR with rising QPCR remain in CCyR 11/116 patients (9%) with increasing QPCR progressed No patients in MMR (N = 28) with increasing QPCR (any log) progressed Warning signs requiring closer monitoring (risk of relapse 23%) Loss of MMR and >1 log increase QPCR Never in MMR and >1 log increase QPCR Awaiting evidence of cytogenetic loss of response before intervention is reasonable These patients are candidates for clinical trials. Prognosis is too favorable to consider allo-sct Await cytogenetic relapse or CML progression 41 Event defined as death during study treatment, loss of complete hematologic response, loss of MCyR, progression to accelerated phase (AP) or blast crisis (BC), or an increasing white blood cell count to > 2 x 1 9 /L. EFS: event-free survival; NR: not reached; NS: not significant. 1. Hughes T, et al. ASH 28. Abstract 334. 42 SCT: stem-cell transplant. Kantarjian H, et al. ASH 28. Abstract 445. 7
CML Case: Treatment Course Managing Patients Resistant or Intolerant to Imatinib The patient continues therapy with imatinib 4 mg per day. After 2 years of therapy her qpcr rises from.1% (nadir) to 5.%. A repeat qpcr 1 month later is performed, which confirms the increase and is now 18.%. A bone marrow examination is performed and cytogenetic analysis shows loss of cytogenetic remission with 8/2 Ph+ metaphases. A mutational analysis is sent and no TK domain mutations are detected. 44 CML Case: Treatment Course CML Case: Treatment Course? The patient is switched to dasatinib 1 mg once daily. She initially does well and enters a CyCR and achieves a major molecular remission. qpcr is.1%. After 2 years on dasatinb, her qpcr rises to 8%. A mutational analysis is sent and a F317L TK domain is detected. What is the Most Appropriate Treatment for this Patient? 1. Switch back to imatinib, but at a dose of 4 mg twice daily. 2. Increase the dose of dasatinib to 7 mg twice daily. 3. Increase the dose of dasatinib to 9 mg twice daily 4. Switch her to nilotinib at 4 mg twice daily 5. Switch her to Interferon-a. 6. Enroll her on a clinical trial. 7. Pursue allogeneic stem cell transplant. 45 46 The Lexicon of Imatinib Resistance Efficacy of Nilotinib in Imatinib Resistant or Intolerant CML 47 Failure: Inadequacy of imatinib at current dose Primary failure: hitting the wall Secondary failure: falling off the wagon Suboptimal response: Ongoing benefit of imatinib at current dose remains but is less than ideal / maximal Resistance: encompasses both groups; best used to describe clinical status Intolerance: High grade toxicity at doses required for adequate response; an additional population at risk 48 CHR N (CHR+NEL*) MCyR (complete) CML-CP 321 77% 57% (41%) CML-AP 136 26% (54%*) 31% (19%) CML-BC myeloid 13 11% 38% (29%) CML-BC lymphoid 6 13% 48% (32%) Ph+ ALL 41 26% 51% (34%) Kantarjian H, et al. Blood. 27,11;11:#735. ASH 27. le Coutre P, Giles FJ, Apperley J, et al. ASH 27. Abstract 471. Giles FJ, Larson RA, Kantarjian HM, et al. ASH 27. Abstract 125. Ottmann OG, Larson RA, Kantarjian HM, et al. ASH 27. Abstract 2815. Disease Progression 2% 29% 52% (52%) 63% 8
Efficacy of Dasatinib in Imatinib Resistant or Intolerant CML The ABL Kinase Mutation Spectrum 49 N CHR (CHR+NEL*) MCyR (complete) CML-CP 321 9% 62% (53%) CML-AP 136 5% (64%*) 4% (33%) CML-BC myeloid 13 11% 38% (29%) CML-BC lymphoid 6 13% 48% (32%) Ph+ ALL 41 35% (42%*) Stone RM, Kantarjian HM, Baccarani M, et al. ASH 27. Abstract 734. Guilhot F, Apperley JF, Kim DW, et al. ASH 27. Abstract 47. Gambacorti C, Cortes J, Kim DW, et al. ASH 27. Abstract 472. Porkka K, Simonsson B, Dombret H, et al. ASH 27. Abstract 281. 56% (54%) Disease Progression 2% 54% 47% (47%) 57% G25E/A/F V289A/I Q252H/R G236E Y253H/F 5 L248V P-loop E255K/V T315I/D F311L/I/V F317L/L L324Q V299L L298V E292V M343T A344V S348L A35V K357R F382L G383D L387F/M M388L M244V E275K D276G M351T/L V379I T277A/N E355G/D L364I D241G E279K F359V/C/D/I E281A M237I K285N A397P H396R/P Activation loop E45G/Q/K Q447R S417Y E453G/K/A/V M472I F486S I418V S438C E459K/Q Red indicates mutations detected in >1% of patients with mutations Green indicates mutations detected in 2-1% of patients with mutations Nilotinib Efficacy According to Baseline BCR-ABL Mutations in CML-CP Frequency of Baseline BCR-ABL Mutations by in vitro IC 5 to Dasatinib T315I F359C/V E255K/V Y253H 3% 5% 4% 4% IC 5 15 nm Others* 15% 24% No Mutation 45% IC 5 -based grouping 1 IC 5 15 nm M244V, L248V, G25E, Q252H, E275K, D276G, F317L, M351T, E355A, E355G, L387F, F486S IC 5 > 15 nm Y253H, E255K/V, F359C/V IC 5 > 1, nm T315I * Mutations 1 without available IC 5 data Nilotinib IC 5 data cited were established in Ba/F3 in vitro proliferation assay (Weisberg E, Br J Cancer. 26;94:1765-1769.) 51 Hochhaus A, et al. Blood. 28;112(11):Abstract 3216. 52 Patients with resistance or suboptimal response to imatinib No BCR-ABL mutation (n = 421) 52% Mueller et. al., ASH 28. 9% 31% Unknown IC 5 to dasatinib (n = 74) 38 different BCR-ABL mutations IC 5 3 nm (n = 248) M244V, G25E, Y253F/H/K, F311L, M351T, E355G, F359C/I/V, V379I, L387M, H396P/R <1% V299L (n = 1) 1% Q252H (n = 6) 2% F317L (n = 13) 3% E255K/V (n = 25) 2% T315I (n = 2) IC 5 > 2 nm IC 5 >3 nm (n = 42) 5% Patients With Resistance or Suboptimal Response to Imatinib: Dasatinib Response Rates After 24 Months Nilotinib Efficacy According to Baseline BCR-ABL Mutations in CML-CP 1 8 93 9 All dasatinib doses No mutation (n = 421) Any mutation (n = 384) Mutation* Duration of MCyR by Mutation Type. * N 12-Month Rate of Continuing MCyR (%) No mutation 58 9 % 6 4 58 55 47 43 36 31 Any mutations 51 78 -IC 5 15 nm 26 84 -IC 5 > 15 nm 6 5 2 - Unknown IC 5 18 77 *Results are from patients with at least 12 months of follow-up; patients with T315I were excluded. 53 CHR MCyR CCyR MMR Overall MMR rate in patients with samples available MMR: BCR-ABL ratio.1% on the international scale by RO-PCR. Müller MC, et al. ASH 28. Abstract 449. 54 MCyR was durable at 12 months in patients with and without mutations. Duration of MCyR at 12 months was similar for patients without mutations and those with mutations with high sensitivity to nilotinib. MCyR was maintained 5% of patients in the > 15nM group (Y253H, E255K/V, F359C/V) based on 6 MCyRs. 9
BCR-ABL Mutations in Patients Treated With Second- Generation TKIs After Imatinib Failures Dasatinib Efficacy in CP-CML and Preexisting BCR-ABL Mutations Newly acquired mutations leading to relapse in patients receiving dasatinib (N = 78) or nilotinib (N = 43) arise rapidly. 1 Likelihood of mutations diminishes over time. Newly acquired mutations seem confined to advanced phase or patients not achieving a cytogenetic response. Newly acquired mutations in patients relapsed on dasatinib: T315I (n = 12), F317L (n = 8), T315A (n = 3), V299L (n = 3), F317I (n = 2) Newly acquired mutations in patients relapsed on nilotinib: E255K (n = 3), E255V (n = 2), Y253H (n = 2), T315I (n = 1), F359V (n = 1), F359C (n = 1) Sixteen patients (none with T315I) switched to dasatinib, nilotinib, or highdose imatinib as third TKI with rescued hematologic or cytogenetic responses in a proportion of cases* 55 *Not quantified Soverini S, et al. ASH 28. Abstract 2118. 56 Pooled analysis of 115 patients with CP-CML treated with dasatinib during Phase II/III trials Of 143 patients with a mutational assessment before treatment, 174 had a mutational assessment at the time of dasatinib discontinuation. Dasatinib produced high rates of durable responses in 143 patients with and without BCR-ABL mutations. 54 new mutations were identified in 47 patients 42 patients had new mutations with an IC 5 to dasatinib > 3 nm In patients with mutations with an IC 5 to dasatinib > 3 nm, CCyR and MMR were observed Müller MC, et al. ASH 28. Abstract 449. Dasatinib Time to and Durability of MCyR and CCyR in CP-CML Patients With Prior Imatinib Time to Cytogenetic Response With Dasatinib Dasatinib is associated with high rates of durable CHR, MCyR, and CCyR in patients resistant to or intolerant of imatinib. 1-3 Responses are achieved rapidly Pooled analysis of 2 phase II studies (START-C, START-R) and phase III dose-optimization study 2 MMR rates in patients with imatinib resistance/suboptimal response (n = 829) at 3, 6, 12, and 24 months: 1%, 18%, 29%, and 34%, respectively MMR rates in patients with imatinib intolerance (n = 238) at same time points: 22%, 37%, 55%, and 63%, respectively % of Patients with response 1 8 6 4 2 Months 3 6 9 12 24 N = 488 36% 47% 53% 57% 6% MCyR rate 24% 35% 42% 45% 51% CCyR rate CHR: complete hematologic response; MCyR: major cytogenetic response. 1. Baccarani M, et al. ASH 28. Abstract 45. 2. Hochhaus A, et al. ASH 28. Abstract 195. 57 3. Liu D, et al. ASH 28. Abstract 2128. 58 3 6 9 12 15 18 21 24 27 3 Months Baccarani M, et al. ASH 28. Abstract 45. Nilotinib in CML-CP Nilotinib in CML-CP Progression Free Survival (N = 321) 1 9 84% 73% 64% 8 7 6 5 4 3 2 1 = Censored 3 6 9 12 18 24 15 21 27 3 33 Months since Start of Treatment Progression = AP or BC, or discontinuation of therapy due to death or progression to AP/BC. AP, accelerated phasae; BC, blast crisis. Most patients on nilotinib remain free of progression at 24 months. Overall Survival (N = 321) 95% 91% 88% 1 9 8 7 6 5 4 3 2 Number of Patients = 321 Number failed = 37 1 = Censored observations 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 16 17 18 19 2 21 22 23 24 25 26 27 28 29 3 31 32 33 34 35 Months since Start of Treatment 88% of patients are estimated to be alive on nilotinib therapy at 24 months. 59 Kantarjian et al. Blood 28;112(11):Abstract 3238. 6 Kantarjian et al. Blood 28;112(11):Abstract 3238 1
Dasatinib in CML-CP: Landmark Analysis According to CCyR at 12 Months Dasatinib in CML-CP: Landmark Analysis According to CCyR at 12 Months Progression-free Survival Overall Survival 1 1 8 8 % Not progressed 6 4 2 PFS at 24 months % 95% CI CCyR at 12 months 95% 92%-99% 99% No MCyR at 12 months 82% 76%-89% P =.3 % Alive 6 4 2 OS at 24 months % 95% CI CCyR at 12 months 99% 98%-1% P =.19 No MCyR at 12 months 97% 93%-1% 3 6 9 12 15 18 21 24 27 3 Months 3 6 9 12 15 18 21 24 27 3 Months 61 Baccarani M, et al. ASH 28. Abstract 45. 62 Baccarani M, et al. ASH 28. Abstract 45. Second-generation TKIs After Failure of Two Prior TKIs 37 patients were sequentially treated with 3 different TKIs. Responses were not durable except for some patients in CP. New treatment options are needed for these patients. CP AP BP Overall Number 16 9 12 37 Median OS, months NR 19.6 4.8 18 Median EFS, months NR 4.7 4 8 New Agents Median FFS, months 2 4.7 2 4 63 FFS: failure-free survival. Garg RJ, et al. ASH 28. Abstract 2119. Novel Agents Under Evaluation Bosutinib (SKI-66) 1 Dual Src/Abl inhibitor, more potent than imatinib Phase I/II Omacetaxine mepesuccinate (homo-harringtonine) 2 MOA independent of TKI inhibition Activity in T315I-mutated CML XL228 3 BCR-ABL/IGF-1R/Src/aurora kinase inhibitor Activity in T315I-mutated CML Summary AUY922 4 Novel ATP-binding site heat shock protein 9 (HSP 9 ) inhibitor 65 MOA: mechanism of action. 1. Cortes J, et al. ASH 28. Abstract 198. 2. Nicolini F, et al. ASH 28. Abstract 113. 3. Cortes J, et al. ASH 28. Abstract 3232. 4. Tauchi T, et al. ASH 28. Abstract 724. 11
Overall Impressions and Recommendations Upfront therapy: Gold standard remains imatinib 4 mg daily Higher dose TKIs all yield faster MMR, but need to wait for randomized trials before standard of care will change IFN/TKI combinations are interesting but require additional follow-up Stopping imatinib not indicated now Monitoring: Rapid early molecular response has predictive value, but clinical utility still being explored Second-generation TKIs: Data similar for imatinib in that early response is generally predictive of longer duration response and may have clinical utility since only option for such patients is generally allo-sct or clinical trial Anti-T315I agents bear watching, not yet ready Analysis of Mutations in CML No role for mutation studies pre-imatinib or in responding patients Mutation studies are important on patients with a hematologic, cytogenetic or molecular relapse. T315I: no role for current TKIs, allo-sct or alternative therapy Y253H, E255V: dasatinib F317L, F317A: nilotinib Others or no mutation: dasatinib or nilotinib or clinical trial or all- SCT 67 68 How to Follow Your Patient? Monitoring Patients on Imatinib CBC + diff, complete metabolic profile, and LFTs Every 3 months Bone marrow aspirate and biopsy Cytogenetics (2 metaphases) Every 6 months until complete cytogenetic remission (CCR) Further bone marrow exams as needed QPCR Every 3 months. Can go to every 6 months after 2 years of major molecular response FISH not helpful Only follow in patients with cytogenetic negative CML (< 5%). NCCN Guidelines 29. 69 7 No CHR at 3 mos: switch to 2 nd TKI at 6 mos > 95% Ph+ : switch to 2 nd TKI at 6 mos 35 95% Ph+:? increase dose at 12 mos > 35% Ph+ : switch to 2 nd TKI at 12 mos 1-35% Ph+ :? Increase dose at 18 mos 1-35% Ph+ : switch to 2 nd TKI Cytogenetic Relapse : switch to 2 nd TKI Send mutation analysis Molecular relapse:?????????? Repeat in 1-2 months Send mutation analysis Consider repeating BM NCCN Guidelines 29. Treatment Pearls Maximize compliance by managing toxicities Never dose reduce below 3 mg daily Heme toxicities (ANC < 1; Plts < 75K): rare and easily managed Gleevec serum trough levels available Never change dose based solely on QPCR Repeat in 1 month Confirm with bone marrow exam before changing therapy Mutational analysis Not useful at initial diagnosis or in responding patients Send at time of any change in therapy (increase in dose or 2 nd TKI) Stem cell transplant Refer at time of 1 st failure (want to know donor status) Transplant in patients who fail 2 nd TKI, have a T315I or AP/BP- CML CML Case: Treatment Course The patient continues therapy with imatinib 4 mg per day. After 2 years of therapy her qpcr rises from.1% (nadir) to 5.%. A repeat qpcr 1 month later is performed, which confirms the increase and is now 18.%. A bone marrow examination is performed and cytogenetic analysis shows loss of cytogenetic remission with 8/2 Ph+ metaphases. A mutational analysis is sent and no TK domain mutations are detected. 71 NCCN Guidelines 29. 72 12
CML Case: Treatment Course CML Case: Treatment Course? The patient is switched to dasatinib 1 mg once daily. She initially does well and enters a CyCR and achieves a major molecular remission. qpcr is.1%. After 2 years on dasatinb, her qpcr rises to 8%. A mutational analysis is sent and a F317L TK domain is detected. What is the Most Appropriate Treatment for this Patient? 1. Switch back to imatinib, but at a dose of 4 mg twice daily. 2. Increase the dose of dasatinib to 7 mg twice daily. 3. Increase the dose of dasatinib to 9 mg twice daily 4. Switch her to nilotinib at 4 mg twice daily 5. Switch her to Interferon-a. 6. Enroll her on a clinical trial. 7. Pursue allogeneic stem cell transplant. 73 74 CML Case: Treatment Course The patient is switched to nilotinib 4 mg twice daily. She initially well and re-enters a CyCR and achieves another major molecular remission. qpcr is.1% The saga continues. Thank you for attending Master Class for Oncologists 75 Questions & Answers? 77 13