Jorge Cortes - Optimising CML Therapy - COLT Session 2

Views:
 
Category: Others/ Misc
     
 

Presentation Description

No description available.

Comments

Presentation Transcript

Optimizing Therapy in CML in 2014:

Optimizing Therapy in CML in 2014 Jorge Cortes, MD Chief, CML and AML Sections Department of Leukemia MD Anderson Cancer Center Houston, Texas

Signal Transduction Inhibition in CML – The Beginning:

Signal Transduction Inhibition in CML – The Beginning Nowell PC & Hungerford DA. Science 1960, 132: 1497

History Lesson #1: SCT is Curative (For Some):

History Lesson #1: SCT is Curative (For Some) Overall Survival Leukemia-Free Survival Arora et al. JCO 2009; 27: 1644-52 58% 50%

History Lesson #2: CCyR Correlates with Improved Survival:

History Lesson #2: CCyR Correlates with Improved Survival Kantarjian et al. Cancer 2003; 97: 1033

PowerPoint Presentation:

History Lesson #3: SCT is NOT the Only Curative Treatment for CML Kantarjian et al. Cancer 2003; 97: 1033

Cumulative Relative Survival by Time Period and Age - SEER:

<15 15 - 29 30 - 49 50 - 64 65 – 74 ≥ 75 Time since diagnosis (year) Relative survival ratio 1.0 0.8 0.6 0.4 0.2 0.0 10 8 6 4 2 0 Time since diagnosis (year) Relative survival ratio 1.0 0.8 0.6 0.4 0.2 0.0 10 8 6 4 2 0 Time since diagnosis (year) Relative survival ratio 1.0 0.8 0.6 0.4 0.2 0.0 10 8 6 4 2 0 Cumulative Relative Survival by Time Period and Age - SEER Chen et al. Leuk Lymphoma 2013; 54: 1411-7 1975-1989 2001-2009 1990-2000 <15 15 - 29 30 - 49 50 - 64 65 – 74 ≥ 75 <15 15 - 29 30 - 49 50 - 64 65 – 74 ≥ 75

Life Expectancy for CML Patients:

Life Expectancy for CML Patients 483 pts with CMP-CP treated with TKI General population data: US Vital Statistics Report 2009   Percent 5-yr OS Absolute (Pts) Relative (Pts) General Population Age Group 15-45 96.2 96.9 99.3 45-65 93.5 97.1 96.3 65-85 80.1 97.1 82.5 15-85 92.7 98.2 94.4 All Ages by Response at 1-Year CCyR 97.3 103.1 94.4 MMR 97.9 103.7 94.4 MR4.5 97.1 102.9 94.4 CMR 96.7 102.4 94.4 MDACC 2014

Results With Imatinib in Early CP CML – The IRIS Trial at 8-Years:

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 M, et al. Blood 2009; 114(22): 1126 .

Evolution of Frontline Therapy at MDACC:

Evolution of Frontline Therapy at MDACC 1990’s: IFN (± ara -C, ±HHT) 2000: Imatinib 400mg 2001: Imatinib 800mg 2005: Nilotinib, dasatinib 2012: Ponatinib

What was Happening in 2005:

What was Happening in 2005 Hurricane Katrina destroys New Orleans 2013: 1 st season since 1968 with no category ≥2 hurricanes A bomb explodes in a large metropolitan city London A new Pope Benedict XVI Oscar to the best movie: Million Dollar Baby (?!) World series: Chicago White Sox vs Houston Astros Astros 2013: Lost >100 games 3 seasons in a row (51-111 in 2013) Tour de France Champion Lance Armstrong (try to look him up now!)

Evolution of Frontline Therapy at MDACC:

Evolution of Frontline Therapy at MDACC 1990’s: IFN (± ara -C, ±HHT) 2000: Imatinib 400mg 2001: Imatinib 800mg 2005: Nilotinib, dasatinib 2012: Ponatinib

TKI Frontline Therapy in CML CCyR AT Time Periods (ITT):

TKI Frontline Therapy in CML CCyR AT Time Periods (ITT) 487 patients with CML frontline therapy: imatinib 400 mg (n=71), imatinib 800 mg (n=201), nilotinib ( n=109), dasatinib ( n=107) Jain et al. ASH 2013

TKI Frontline Therapy in CML MMR AT Time Periods (ITT):

TKI Frontline Therapy in CML MMR AT Time Periods (ITT) Jain et al. ASH 2013

TKI Frontline Therapy in CML MR4.5 AT Time Periods (ITT):

TKI Frontline Therapy in CML MR4.5 AT Time Periods (ITT) Jain et al. ASH 2013

TKI Frontline Therapy in CML Long-Term Outcome By Response Time:

TKI Frontline Therapy in CML Long-Term Outcome By Response Time Event-Free Survival Transformation-Free Survival p<0.001 Jain et al. ASH 2013

TKI Frontline Therapy in CML Long-Term Outcome By Response Time:

TKI Frontline Therapy in CML Long-Term Outcome By Response Time Failure-Free Survival Overall Survival p<0.001 Alattar et al. ASH 2011; Abstract #745

Nilotinib vs Imatinib in Newly Diagnosed Chronic Phase CML:

Nilotinib vs Imatinib in Newly Diagnosed Chronic Phase CML 846 pts randomized to nilotinib 300 mg BID (n=282), nilotinib 400 mg BID (n=281), or imatinib 400 mg QD (n=283) Minimum follow-up 5 years Outcome Nil 300 Nil 400 IM 400 % CCyR* 87 85 77 % MMR** 77 77 60 % BCR-ABL ≤0.0032%** 54 52 31 % Transformed AP/BP 3.5 2.1 7.1 % 5-yr EFS 92 95 91 % 5-yr OS 94 96 92 * by 24 months, ** by 60 months (K-M) Saglio G, et al. ASH 2013; 92

Dasatinib vs Imatinib in Newly Diagnosed Chronic Phase CML:

Dasatinib vs Imatinib in Newly Diagnosed Chronic Phase CML 519 pts randomized to dasatinib 100 mg QD (n=259) or imatinib 400 mg QD (n=260) Minimum follow-up 48 mo Outcome Das 100 IM 400 % CCyR * 86 82 % MMR** 74 60 % BCR-ABL ≤0.0032%** 34 21 % Transformed AP/BP 5 7 % 4-yr PFS 90 90 % 4-yr OS 93 92 Cortes et al. ASH 2013; 653 * by 24 months, ** by 48 months (K-M)

Bosutinib vs Imatinib in Newly Diagnosed Chronic Phase CML:

Bosutinib vs Imatinib in Newly Diagnosed Chronic Phase CML 502 pts randomized to bosutinib 500 mg QD (n=250) or imatinib 400 mg QD (n=252) Minimum follow-up 24 mo Response* Bos 500 IM 400 % CCyR 79 80 % MMR 61 50 % CMR 23 16 % Transformed AP/BP 2 5 % 2-yr EFS 92 88 % 2-yr OS 97 95 Cortes et al. JCO 2012; 30: 3486-92 * by 24months

Propensity Score-Matched Comparison of Dasatinib and Nilotinib as Frontline CML Therapy:

Propensity Score-Matched Comparison of Dasatinib and Nilotinib as Frontline CML Therapy Pts treated with dasatinib (N=102) or nilotinib (N=104) matched by propensity score Percentage P value Dasatinib N=87 Nilotinib N=87 Response at 3 months   MMR 47 56 0.18 BCR/ABL (IS) < 10% 93 94 0.50 CCyR 77 84 0.15 MCyR 91 93 0.25 Cumulative (Best) response   CMR 51 48 0.82 MMR 72 75 0.61 CCyR 94 93 1.00 MCyR 95 93 1.00 MDACC 2014

Propensity Score-Matched Comparison of Dasatinib and Nilotinib as Frontline CML Therapy:

Propensity Score-Matched Comparison of Dasatinib and Nilotinib as Frontline CML Therapy Pts treated with dasatinib (N=102) or nilotinib (N=104) matched by propensity score 3-year Survival Endpoints  Percentage P value Dasatinib N=87 Nilotinib N=87 Overall 99 93 0.95 Event-free 89 87 0.99 Failure-free 74 63 0.71 Transformation-free 95 89 0.28 MDACC 2014

TKI Frontline Therapy in CML Treatment Discontinuation:

TKI Frontline Therapy in CML Treatment Discontinuation Percentage F/U ( mo ) IM400 Nilotinib Dasatinib Bosutinib ENESTnd * ¥ >50 49 38 DASISION >48 35 33 BELA >24 29 37 * Nilotinib 300mg BID shown. ¥ Includes patients who discontinued into extension study; rates are 34% imatinib and 29% nilotinib if all excluded Saglio G, et al. ASH 2013; 92; Cortes et al. ASH 2013; 653; Cortes et al. ASH 2011; Abstract # 455 Less than 70% have successful outcome

PowerPoint Presentation:

Probability of survival 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 2012; 30: 232-8 Optimal PCR value determined by Receiver operating characteristic (ROC) curve

What if you have >10% BCR-ABL (i.e., no MCyR) at 3 months?:

What if you have >10% BCR-ABL (i.e., no MCyR ) at 3 months? BCR-ABL/ABL <10% BCR-ABL/ABL >10%

NCCN Treatment Recommendations 3-Month Follow-up Therapy:

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

Molecular Response at 3 Months Predicts for Progression-Free Survival:

Molecular Response at 3 Months Predicts for Progression-Free Survival Wang et al. BJH 2003; 120: 990-9

Probability of MMR and Progression by Molecular Response at Fixed Times:

Probability of MMR and Progression by Molecular Response at Fixed Times Bcr-Abl / Abl Transcript Levels % Probability Outcome by Transcript Levels at Specified Months MMR Progression 3mo 6mo 12mo 3mo 6mo 12mo ≤ 0.1 100 100 100 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<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 Quintas-Cardama et al. Blood 2009; 113: 6315-21

The Tortoise and The Hare:

The Tortoise and The Hare Aesop; c. 560 BC The fable was not about speed but about perseverance

3-Year EFS by Molecular Response at 3 Months:

3-Year EFS by Molecular Response at 3 Months * Estimated Hochhaus A, et al. Blood. 2012; 120:Abstract 167 . Saglio G, et al. Blood. 2012; 120:Abstract 1675. Brummendorf TH, et al. Blood. 2012;120: Abstract 69.

3-Year OS by Molecular Response at 3 Months:

3-Year OS by Molecular Response at 3 Months * Estimated Hochhaus A, et al. Blood. 2012; 120:Abstract 167 . Saglio G, et al. Blood. 2012; 120:Abstract 1675. Brummendorf TH, et al. Blood. 2012;120: Abstract 69.

PowerPoint Presentation:

Factors Predicting Optimal Response at 3 Months - Multivariate Analysis Favorable risk factor P-value OR [95 CI] Older age <0.001 0.96 [0.93-0.98] Low-Intermediate Sokal score <0.001 2.88 [1.65-5.02] Imatinib 800, dasatinib or nilotinib <0.001 0.17 [0.07-0.39]* 0.06 [0.02-0.18]^ * Imatinib 800 mg (vs imatinib 400 mg) ^ Dasatinib or nilotinib (vs imatinib 400 mg) Jain P, et al. Blood 2013; 121: 4867-74

The Problem with the 3 Months Response:

The Problem with the 3 Months Response Transcripts Time 3 mo 10% Are these the same? Myelosuppression Rash Non-adherence

Change Therapy at 3 Months?:

Change Therapy at 3 Months? 80% 20% 95% 5% ≤10% > 10% EFS Change therapy to all of these? Only 15-20% need help At most 10-15% would benefit

Change Therapy at 3 Months?:

Change Therapy at 3 Months? 80% 20% 95% 5% ≤10% > 10% EFS Or better identify the 20% who may need help? Small difference in survival (88% vs 98%) Some deaths not-related to CML Effective salvage therapy

PowerPoint Presentation:

What is the dog doing? Coming out Sinking Not moving Perro semihundido . Goya.

Prediciton for Future PFS at 18 Months:

Prediciton for Future PFS at 18 Months

Nomograms to Predict Outcome by BCR-ABL/ABL at 3, 6, 9 and 12 Months:

Nomograms to Predict Outcome by BCR-ABL/ABL at 3, 6, 9 and 12 Months 3 months after TKI start 12 months after TKI start 9 months after TKI start 6 months after TKI start Quintas-Cardama et al. CLML 2014; 14: 327-34

Early Response to TKI: 3 months or 6 months?:

Early Response to TKI: 3 months or 6 months? 58/489 (12%) pts on frontline TKI had no MCyR at 3 months 5-y EFS 77%, OS 88%, TFS 94% By 6 months, 52 (90%) still on TKI (4 intolerance, 1 loss CHR, 1 BP) 5-yr Outcome % by Response at 6 months MCyR No MCyR OS 100 79 EFS 85 66 TFS 95 94 Conclusion: Waiting for 6 month response better discriminates for poor outcome. Nazha A, et al. Haematologica 2013;98(11):1686-1688.

Outcome by Response at 3 and 6 Months:

Outcome by Response at 3 and 6 Months 528 patients treated with imatinib 89/483 (18%) had BCR-ABL >10% at 3 months Response No. % at 4 years 3 mo 6 mo Survival PFS FFS MMR ≤10% <1 342 97 97 87 88 ≤10% 1-10 42 100 97 79 71 ≤10% >10 10 89 90 51 56 >10% <1 18 100 100 76 88 >10% 1-10 36 100 94 79 69 >10% >10 35 74 69 11 3.3 Branford S , et al. Blood. 2013;122: Abstract 254.

PFS by Combined Absolute Transcript Levels and Slope of Decline:

PFS by Combined Absolute Transcript Levels and Slope of Decline 3-Month Response 6 -Month Response RR3 = (PCR at 0 mo -PCR at 3 mo )/PCR at 0 mo RR6 = (PCR at 3 mo -PCR at 6 mo )/PCR at 3 mo Quintás-Cardama A , et al. Blood. 2013;122: Abstract 3993. Both have ≥10 BCR-ABL/ABL at 3 months

CI of CMR at 8 years:

CI of CMR at 8 years p<0.001 L/L ( 13%) L/H ( 2%) H/H ( 70.5%) H/L ( 14.5%) (L/L) Low at 3 and low at 6 months (L/H) Low at 3 and high at 6 months (H/H) High at 3 and high at 6 months (H/L) High at 3 and low at 6 months Neelakantan P, et al. Blood. 2012;120: Abstract 68.

Adherence to Imatinib:

Adherence to Imatinib 87 pts on imatinib for ≥2 years Compliance measured by : self reporting, pill count and microelctronic monitoring system (MEMS) Response % Response at 6 yrs by Adherence Rate P value >90% N=64 ≤90% N=23 MMR 94 14 <0.0001 CMR 44 0 0.002 Poor correlation between 3 methods MVA for molecular response: adherence (MMR and CMR) and OCT1 (CMR) Bazeos et al. Blood 2009; 114: abst# 3290

Effect of reduced dosing on 3 mth RQ-PCR by total dose and by number of missed days:

Effect of reduced dosing on 3 mth RQ-PCR by total dose and by number of missed days Probability of achievement of RQ-PCR <10% decreases with increased numbers of missed doses and decreased total dosing Imatinib Dasatinib Percent prescribed dose No. (%) (N= 327) 3 mo PCR < 10% No. (%) (N= 315) 3 mo PCR < 10% 100% 272 (83) 78.3% 222 (71) 95.5% 80-99% 42 (13) 61.9% 48 (13) 85.4% <80% 13 (4) 46.2% 45 (4) 80.0% Total missed days median (range) 13.5 (1-48) 14 (1-58) 0 272 (83) 78.3% 222 (71) 95.5% 0-14 41 (13) 58.5% 48 (15) 85.4% > 14 14 (4) 57.1% 45 (14) 80.0% Apperley JF , et al. Blood. 2013;122: Abstract 93.

ELN Definitions of Response 2009 & 2013:

ELN Definitions of Response 2009 & 2013 No HR No CyR No PCyR No CCyR No MMR 3 mo 6 mo 12 mo 18 mo N/A Failure Suboptimal Optimal ELN 2009 Failure Warning Optimal ELN 2013 Baccarani et al. JCO 2009; 27: 6041-51; Baccarani et al. Blood 2013; 122: 872-84

Switch to Nilotinib vs HD-Imatinib in CP-CML with Suboptimal Response - LASOR:

Switch to Nilotinib vs HD-Imatinib in CP-CML with Suboptimal Response - LASOR Primary endpoint not met: No difference in 6-mo CCyR rate (ITT analysis) Secondary endpoint: Higher MMR rates with nilotinib at 12 mo Response, % Nilotinib (n = 96) Imatinib (n = 95) 6-mo CCyR 49 42 Before crossover 49 36 Evaluable patients 55 39 12-mo MMR 36 25 Before crossover 35 16 Evaluable patients 49 22 Cortes J , et al. Blood. 2013;122: Abstract 95.

ENESTcmr: Results:

207 pts with CML CP treated with imatinib ≥2 years, in CCyR with persistent disease by PCR Randomized to continue imatinib 400-600 mg or change to nilotinib. Outcome (%) Nilotinib n = 104 Imatinib n = 103 Confirmed CMR 12 mo * 13** 6** Confirmed CMR 24 mo 22** 9** 12-mo MR 4.5 33 14 24-mo MR 4.5 43 21 36-mo MR 4.5 47 24 Discontinued Rx @1-y, % 16 9** Adverse event(s) 9 3** Cardiovascular events by 36-mo 12 2 IHD/CVE/PAD 4/3/7 1/1/0 ENESTcmr : Results * Primary endpoint ** Overall (not presented in 2013) Spector N, et al. JCO. 2014; [abstract 7025 ]

PowerPoint Presentation:

TKI IM 400 N=52 IM 800 N=148 NILO N=48 DASA N=56 CCyR (%) 46 (88) 144 (97) 46 (96) 55 (98) Best MR rates Median F/U, months (range) 124 (13-142) 100 (4-132) 31 (3-77) 36 (2-73) Molecular Response in CML MR Rates at 36 Months ( CCyR patients) MMR NO MR MR4 MR4.5 UND Falchi L, et al. Blood. 2012; 120:Abstract 164.

PowerPoint Presentation:

Molecular Response in CML F FS by MR at 18 and 24 months 18 months 24 months Response Total Failed P-value (vs. UND) 65 4 n/a 96 16 .02 42 7 .13 89 17 .01 37 8 .01 Time (months) Response Total Failed P-value (vs. UND) 65 5 n/a 113 15 .16 36 5 .52 70 13 .02 23 6 .02 p =.11 p =.07 Survival F ree from Failure (%) Falchi et al. Am J Hematol 2013 [ Epub ahead of print]

FFS by Achievement of CMR with Dasatinib or Nilotinib:

FFS by Achievement of CMR with Dasatinib or Nilotinib Nilotinib Dasatinib MDACC 2014

PowerPoint Presentation:

Time (months) TFS Response Total AP/BP P-value (vs. UND) 66 1 n/a 113 0 .25 37 0 .38 72 0 .33 25 0 .56 p =.50 Molecular Response in CML TFS and OS by MR at 24 months OS Response Total Died P-value (vs. UND) 66 3 n/a 113 4 .89 37 2 .94 72 2 .70 25 3 .22 p =.52 Survival (%) Falchi et al. Am J Hematol 2013 [ Epub ahead of print]

Imatinib Treatment Discontinuation STIM1 and STIM2:

Imatinib Treatment Discontinuation STIM1 and STIM2 STIM1 STIM2 100 pts Median follow-up 55 mo (range, 9-72) 127 pts Median follow-up 16 mo (range, 0-27) Mahon et al. ASH 2013; Abstracts #255 & 654

Loss of MMR as Trigger to Re-Start TKI:

Loss of MMR as Trigger to Re-Start TKI 80 pts discontinued imatinib after ≥2 yrs sustained MR 4.5 Probability of Relapse CMR After Re-Star of Imatinib* * All patients regained MMR Rousselot et al. ASH 2013; Abstract #381 45% sustained PCR(-) 24% occasional PCR(+) 31% ≥2 consecutive PCR(+)

Progression After Treatment Discontinuation:

Progression After Treatment Discontinuation CML low Sokal in CCyR Interferon : 9 years CMR Imatinib 3 years CMR MMR loss A-STIM 9 months MMR Imatinib 8 months LBC CHR Nilotinib Allo HSCT No mutation No ACA ALIVE We want patients in CMR (PCR 0) so we can put them back in MMR (PCR ≤ 0. 1)?!? How many patients transforming to AP/BP are we willing to accept after treatment discontinuation? Rousselot et al. ASH 2013; Abstract #381

TKI Re-Treatment after Treatment Discontinuation:

TKI Re-Treatment after Treatment Discontinuation Author N Re-Rx Response Mahon 42/42 26 CMR, 16 “↓ transcripts” Ross 22/22 16 sCMR , 1 iCMR , 2 D/ C→relapse * Takahashi 17/19 13 CMR, 4 MMR Yhim 10/10 7 CMR, 3 MMR Lee 9/9 7 CMR, 1 MMR (1 NR?) Benjamini 10/11 6 CMR, 3 MR 4.5 , 1 MMR * 19 with F/U ≥24 months reported Mahon et al. Lancet Oncol 2010; 11: 1029-35; Ross et al. Blood 2013 [ Epub ahead of print]; Takahashi et al. Haematologica 2012; 97: 903-6; Yhim et al. Leuk Res 2012; 36: 689-93; Lee et al. Am J Hematol 2013 { Epub ahead of print]; Benjamini et al. ASH 2012

Cumulative Incidence of Relapse after Allogeneic BMT for CML:

Cumulative Incidence of Relapse after Allogeneic BMT for CML YEARS 0 4 8 12 18 20 CUMULATIVE INCIDENCE 0.0 0.2 0.4 0.6 0.8 1.0 1: Sib + CP1 (N=3,319) 2: Sib + Not CP1 (N=1,115) 3: Other Donor + CP1 (N=1,261) 4: Other Donor + Not CP1 (N=690) 5: All Patients (N=6,391) 2444 pts with CML alive and in remission for at least 5 years after SCT Cumulative incidence relapse @ 15 yrs : 8% sibling donor, 2% MUD Goldman et al. JCO 2010; 28: 1888-95

Treatment Discontinuation at MDACC:

Treatment Discontinuation at MDACC

Treatment Discontinuation at MDACC:

Treatment Discontinuation at MDACC You do not discuss with your patients Need to be more convincing You project negative feelings to your patients It is important to have good rapport with the patients

Patient-Driven Treatment Discontinuation in CML:

Patient-Driven Treatment Discontinuation in CML 35 pts discontinued therapy 18 (51%) for AEs, 3 (9%) for pregnancy, 8 (23%) for prolonged CMR, 6 (17%) for financial reasons Median f/u after discontinuation 16 mo (2-106 mo ) Response at TKI discontinuation: CMR 27 (77%), MR 4.5 5 (14%), MMR 3 (9%) Benjamini et al. Leuk & Lymphoma 2013 [ Epub ahead of print]

Outcome of CML Patients After TKI Discontinuation - MDACC:

Outcome of CML Patients After TKI Discontinuation - MDACC Benjamini et al. Leuk & Lymphoma 2013 [ Epub ahead of print] By CMR Duration By TKI

PowerPoint Presentation:

Factors associated with sUND (multivariable analysis, N= 495) Older age Higher baseline platelets TKI modality (non-IM400) CCyR at 3 months Falchi et al. Am J Hematol 2013; 88: 1024-9

The Risks of Treatment Discontinuation (Today):

The Risks of Treatment Discontinuation (Today) PCR sensitivity not standardized Not all who relapse regain response Favor emergence of resistant clones? Lack of long term follow-up Send the wrong message (e.g., stopping therapy is OK)

2nd Generation TKI in CML CP Post-Imatinib Resistance:

2 nd 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

2nd-Generation TKI in CML CP Post- Imatinib Failure:

2 nd -Generation TKI in CML CP Post- Imatinib Failure Toxicity Dasatinib Nilotinib Bosutinib Pleural effusion ++ - - Liver + + + Transaminases + + ++ Bilirubin - ++ - Rash + + ++ Diarrhea - - ++ Lipase - (+) ++ - Glucose - ++ - Hypophosphatemia ++ ++ + Bleeding + - - QTc ++ ++ -

2nd-Generation TKI in CML CP Post- Imatinib Failure:

2 nd -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

CCyR by Mutations in CML Treated with 2nd Generation TKI after IM Failure:

CCyR by Mutations in CML Treated with 2 nd Generation TKI after IM Failure Jabbour et al, Blood 2009; 114: 2037-43 86/169 (51%) pts treated had mutation CP 30/59 (51%), AP 41/71 (58%), BP 15/39 (38%) IC50 for dasatinib, nilotinib predictive for cytogenetic response in CP, AP and BP Chronic Phase Accelerated Phase

Response to Bosutinib 3rd Line Therapy:

Response to Bosutinib 3 rd 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 68 76 76 MCyR 39 42 36 CCyR 22 40 28 PCyR 17 2 8 MMR 3 25 11 3-yr Transformation 8 0 4 IM, imatinib; D, dasatinib; NI, nilotinib. Cortes et al. ASH 2013; Asbtract #4025

Ponatinib Phase 2 Study Responses at Any Time:

Ponatinib Phase 2 Study Responses at Any Time   CP-CML AP-CML BP-CML Ph + ALL MCyR CCyR MMR MaHR* MaHR MaHR R/I to das/nil 56% 48% 31% 62% 32% 50% T315I 72% 70% 58% 61% 29% 36% Total ** 60% 54% 38% 61% 31% 41% Median time to response, months 2.8 2.9 5.5 0.7 1.0 0.7 *14 AP-CML patients with baseline MaHR and 1 AP-CML patient with no baseline MaHR assessment counted as non-responders **Total comprises all eligible patients treated with ponatinib. It excludes 5 patients (3 CP-CML, 2 AP-CML) who were non-cohort assigned (post-imatinib, non-T315I), but treated; all 5 achieved MCyR 67 Cortes et al. ASH 2013; 650

The Choice of Treatment in CML:

The Choice of Treatment in CML vs How we are thinking…. Imatinib 2 nd Generation TKI

The Choice of Treatment in CML:

The Choice of Treatment in CML The reality Imatinib Dasatinib Nilotinib Bosutinib Ponatinib SCT Omacetaxine

Treatment Choices in CML:

Treatment Choices in CML I D N

Treatment Choices in CML:

Treatment Choices in CML x 4 x 4 48 possible treatment options for each patient More considering SCT, clinical trials

PowerPoint Presentation:

Outcome with Two-Stage Regime Might Be Non-Intuitive Treatment Favorable Outcome Probabilities Frontline Salvage with C if Frontline Fails Overall (In 1 or 2 stages) A 60% 10% 64% B 50% 40% 70% 1 ) If salvage is ignored, it seems that A > B. 2 ) If getting a response in 1 or 2 stages is acceptable, then strategy ( B,C) > strategy (A,C )

The Real Outcome With TKI (Sequential):

The Real Outcome With TKI (Sequential) 281 pts Rx with imatinib as initial therapy (73 SD, 208 HD) CCyR 88%  75 stopped IM 41 events  23 received subsequent TKI  14 (67%) CCyR CEFS at 7 yrs = 88% EFS at 7 yrs = 81% Probability (%) 0.2 0.4 0.6 0.8 1.0 0.0 12 24 36 48 60 0 72 84 Al-Kali et al. Cancer 2011; 117: 327-35

Treating or Preventing Failure?:

Treating or Preventing Failure? Success with Imatinib Failure Success 2 nd TKI Frontline imatinib: CCyR 83% Loss CCyR 15% Intolerance ~5% EFS ~63% 2 nd TKI: CCyR ~50% Loss CCyR (2 yr) ~15% Frontline Imatinib

Treating or Preventing Failure?:

Treating or Preventing Failure? Success with Imatinib Failure Success 2 nd TKI Success with 2 nd TKI Failure ? Frontline Imatinib Frontline 2 nd TKI ?

Good Outcome: Just in Clinical Trials?:

Good Outcome: Just in Clinical Trials? 65 pts treated off protocol & 71 on protocols Imatinib 400 mg; Median f/u 51 mo Median [range], or Percentage On protocol Off protocol US Population Age, y 49 [15-79] 49 [15-84] High-risk Sokal 6 5 3-mo MCyR 71 69 12- mo CCyR 84 83 12-mo MMR 30 24 5-yr EFS 86 84 5-yr TFS 96 94 5-yr OS 90 96 Median income, $ 45,735 44,606 42,148 Education HS or less 42 43 48 Uninsured 10 8 14 Yilmaz M, et al. Clin Lymphoma Myeloma Leuk 2013; 13: 693-9

Monitoring Patterns in a Community Setting in the US:

Monitoring Patterns in a Community Setting in the US Cytogenetic Response Monitoring Testing status <6 mo 6 ≤ 12 mo 12 ≤ 18 mo 18+ mo Total N 418 360 284 242 Tested at milestone, % 32 31 16 27 CCyR , % 22 55 56 62 No CCyR , % 78 45 44 38 Switched TKI, % 9 36 20 88 Not tested at milestone, % 68 69 84 73 Molecular Response Monitoring Testing status @ mo 0-3 3 ≤ 6 6 ≤ 9 9 ≤ 12 12 ≤ 15 15 ≤ 18 ≥18 Total N 418 400 388 378 370 364 353 Tested at milestone, % 31 35 43 39 41 39 81 CMR, % 0 9 14 20 22 29 52 MMR, % 3 13 23 15 26 23 20 No CMR/MMR, % 85 60 52 55 43 41 27 Unknown 12 18 11 10 9 7 1 Not tested at milestone, % 69 65 57 61 59 61 19 Chen et al. 2014

OS and PFS of CML-CP Patients Treated with First-line TKI:

OS and PFS of CML-CP Patients Treated with First-line TKI After adjusting for confounding variables (age, gender, baseline KPS, payer type, co morbidities), annual MR testing remained the driving impact OS (HR=0.341; 95% CI, 0.162-0.717, P-value=0.0065) and PFS (HR=0.319; 95% CI, 0.161-0.632, P-value=0.0019). 0.00 0.25 0.50 0.75 1.00 0 10 20 30 40 50 60 Time to death (in months) No annual MR test MR test received Kaplan-Meier Estimates of OS † by Annual MR Testing Status Log Rank p < 0.0001 0.00 0.25 0.50 0.75 1.00 0 10 20 30 40 50 60 Time to AP/BC (in months) No annual MR test MR test receivedd Kaplan-Meier Estimates of PFS‡ by Annual MR Testing Status Log Rank p < 0.0001 Chen et al. 2014

Predictors of Outcome in CML:

Predictors of Outcome in CML Patient Disease Management Response Survival Endpoints Discontinuation

Optimizing Frontline CML Therapy in 2014:

Optimizing Frontline CML Therapy in 2014 Excellent therapy for CML available Optimizing therapy is much more than comparing drugs Progress in management lagging progress in treatment Clinical trials still very much needed CML not a disease of the past

Questions?:

Questions? [email protected] 713-794-5783

authorStream Live Help