CHRONIC MYELOGENOUS LEUKEMIA - 2012 Charles A. Schiffer, M.D. Karmanos Cancer Institute Wayne State University School of Medicine Detroit, MI DISCLOSURES •  Consultant – Novartis, BMS, Pfizer, Chemgenix •  Grant support – Novartis, BMS, Ambit A minute chromosome in human granulocytic leukemia. Science 132, 1960, 1497. P.C. Nowell, D.A. Hungerford, University of Pennsylvania in Philadelphia …the findings suggest a causal relationship between the chromosome abnormality observed and chronic granulocytic leukemia… Chromosome 9 Chromosome 22 Philadelphia Chromosome t(9;22) (q34;q11) q11 c-BCR BCR/ABL reciprocal translocation q34 c-ABL BCR/ABL (210 kDa) c-ABL c-BCR 1294 Y 177 Y OD Ser/Thr kinase DBL SH3 SH2 Tyr kinase NLS DNA BD actin BD CML CASE •  A 32 year old woman had CML diagnosed after she was found to have a WBC of 130,000/mm3 with platelets of 722,000/ mm3 during a routine physical examination •  Peripheral blood cytogenetics showed a t(9;22) without additional changes •  She was begin on imatinib, 400 mg daily Nilotinib Versus Imatinib in Patients With Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 3-Year Follow-up Giuseppe Saglio, Philipp D. le Coutre, Ricardo Pasquini, Saengsuree Jootar, Hirohisa Nakamae, Ian W. Flinn, Andreas Hochhaus, Timothy P. Hughes, Richard A. Larson, Albert Hoenekopp, Neil J. Gallagher, Richard Yu, Rick E. Blakesley, Dong-Wook Kim, Hagop M. Kantarjian on behalf of the ENESTnd Investigators ‹#› 6 Study Design R A Nilotinib 300 mg BID (n = 282) N •  N = 846 •  217 centers •  35 countries D O M I Z E D Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) *Stratification by Sokal risk score * Follow-up 5 years 7 Cumulative Incidence of MMR Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD 100 90 n 282 281 283 % With MMR 80 By 3 Years 73%, P < .0001 By 1 Year 70 55%, P < .0001 70%, P < .0001 60 Δ 17%-20% 50 53% 51%, P < .0001 40 Δ 24%-28% 30 27% 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Since Randomization Data cut-off: 27Jul2011. Number of Patients, n Progression to AP/BC: Including Events After Discontinuation (ITT Analysis)* P = .0496 HR = 0.5 [0.2, 1.0] P = .0076 HR = 0.3 [0.1, 0.8] 19 9 6 3.2% 2.1% 6.7% On Core Treatment and After Discontinuation Nilotinib 300 mg BID     Nilotinib 400 mg BID Imatinib 400 mg QD Off treatment progression information was prospectively collected for all patients every 3 months after discontinuation In the IRIS study, cumulative progression rates in the first 3 years of therapy were approximately 6% on imatinib1 * Progression to AP/BC or death following progression. 1. Hochhaus A, et al. Leukemia. 2009;23(6):1054-1061. 9 Data cut-off: 27Jul2011. Overall Survival Patients Receiving Initial Treatment Total Number of Deaths Estimated 3-year overall survival (OS) Still on Core Treatment Nilotinib 300 mg BID n = 282 Nilotinib 400 mg BID n = 281 Imatinib 400 mg QD n = 283 13 8 17 95.1% 97.0% 94.0% 71% 74% 62% •  Of 38 total deaths on study, 23 were following progression to AP/BC Data cut-off: 27Jul2011. 2764 Safety and Efficacy of Frontline Nilotinib (Nb) for Chronic Phase (CP) Chronic Myeloid Leukemia (CML) in Diabetic Patients (pts) •  Can make control of diabetes more difficult •  Hyperglycemia is manageable with conventional approaches/medications SUMMARY OF THE DASISION and ENEST STUDIES I CyCR MMR D* 80% 41 ON THERAPY 81 AP/BC 3.5 N** I 85% 57 87% 62 77% 80 2.3 74 0.7 67 37 4.2 *DASISION – 18 months F/U; **ENESTnd 24 months, 300 mg ARM Hmmm…. •  Higher response rates •  “Deeper” responses •  Less early progression? •  Good tolerabilty •  And, imatinib is wonderful, but not perfect ~ 60% of chronic phase patients remain in CyCR on imatinib at 5 years Why would anyone use imatinib? TRIAL DESIGNS USING SECOND GENERATION TKIS “UP FRONT” IMATINIB $“X”vsvs$$ $ vs $$ MORE “REAL WORLD” DESIGN “X” vs IMATINIB “X” IMATINIB vs “X” ?? MY PREFERRED ENDPOINT The fraction of patients in a minimum of CyCR at 2 years with a normal PS and a minimum of symptoms who are either - still taking the assigned drug - or have switched to an alternative drug per protocol ISSUES •  Large numbers of patients are no longer receiving their assigned drug •  Data as presented are not strictly intention to treat - incomplete information about patients who went “off study” for reasons other than treatment failure or progression - this makes the curves “look better” (Fleming, T. Addressing Missing Data in Clinical Trials. Ann Int Med 154:113, 2011) •  Emerging data about long term side effects from dasatinib and nilotinib •  Inadequate effect in patients in more advanced stages of chronic phase DASATINIB ≠ NILOTINIB •  Long term side effect profile •  •  •  - Pleuro/pericardial effusions, pulmonary hypertension – dasatinib - Hyperglycemia, peripheral arterial occlusive disease, chronic effects on pancreas or bone metabolism (??) - nilotinib Activity vs. other kinases differ T/NK lymphocytosis with dasatinib (good or bad??) Compliance?? (daily vs bid) GOALS OF THERAPY FOR CML CHRONIC PHASE IMAT RAPIDITY OF RESPONSE SUSTAINED RESPONSE SHORT TERM TOLERANCE LONG TERM TOLERANCE BENEFIT IN HIGH RISK PTS PFS OVERALL SURVIVAL OVERALL COST STOP THERAPY D,N XX ?? XX ?? X X? ??? XXX ??? A CLINICIAN’S DILEMMA When to adopt “promising” results presented at ASH, ASCO or even after receiving the blessing of the FDA when follow-up or other data are incomplete Remembering the high degree of patient selection/exclusion inherent in most clinical trials Other people’s money! What if it was your own money? ALTERNATIVE APPROACHES •  Imatinib initially with switching to second generation if inadequate response with early endpoints - lower risk patients •  Second line initially with switch to imatinib after MMR AH….BUT WHICH DRUG? HOW TO CHOOSE BETWEEN (AMONGST) THEM? •  Marketing •  Comparative trials •  Side effect profile •  Evidence that effects other than bcr/abl inhibition are important •  Convenience – once vs. twice daily without food •  REMS for nilotinib •  Cost Progression to AP/BC* on Core Treatment P = .0003 Number of Patients, n P = .0085 P = .0059 17 P = .0185 12 2 0.7% 5 3 1.1% Nilotinib 300 mg BID 2 4.2% 0.7% 1.8% 6.0% Including Clonal Evolution Nilotinib 400 mg BID Imatinib 400 mg QD •  No new progressions occurred on core treatment since the 2-year analysis * Progression to AP/BC or death following progression. 23 Data cut-off: 27Jul2011. •  Six months later, a peripheral blood FISH detected bcr/abl in 18% of cells You would recommend: 1.  A bone marrow aspirate for cytogenetics 2.  Switch to dasatinib or nilotinib 3.  Referral for allogeneic transplantation 4.  Testing for imatinib blood levels 5.  Continuation of imatinib with repeat FISH in 3 months Survival Without AP/BC by Level of CyR at 12 months on First-line Imatinib ~ 2/3 of patients Response at 12 months CCyR PCyR No MCyR n= 350 n= 86 n= 73 Estimated rate at 60 months 97% 93% 81% ! p<0.001 p=0.20 ! •  Six months later a bone marrow was done which showed a normal female karyotype. •  Pcr for bcr/abl did not demonstrate a major molecular response (0.18% on the International scale) You would recommend: 1.  Switch to dasatinib or nilotinib 2.  Referral for allogeneic transplantation 3.  Continuation of imatinib with repeat bone marrow pcr in 3 months 4.  Continuation of imatinib with peripheral blood pcr in 3 months 27 0 1.0 2.0 3.0 4.0 5.0 Leukocytosis 13 12 Ph-chromosome pos 11 Ph-negative but.. 10 RQ-PCR positive 9 RQ-PCR negative 6.0 8 7 6 5 4 3 2 0 Cure ? 1 0 Number of leukemia cells (log10) Decreasing residual leukemia Log reduction from baseline BCR-ABL transcript numbers expressed as log reduction in responding CML patients HOW TO MONITOR RESPONSE •  Marrow with cytogenetics at diagnosis •  Peripheral blood FISH or serial pcr every 3 months •  Marrow to confirm cytogenetic remission •  Peripheral blood pcr thereafter MAJOR MOLECULAR RESPONSE (MMR) •  Samples from a subgroup of ~ 40 patients •  •  •  •  from the IRIS trial were used to establish an average baseline of transcripts at the time of diagnosis It is NOT calculated from the baseline value in an individual patient International Scale – Baseline is 100% – MMR (3 log reduction) is < 0.1% – CyCR is ~ 1% (2 log reduction) Initial analyses suggested an improved outcome in patients in whom a 3 log reduction in transcripts was achieved And it took on a life of it own But, you have to be able to measure it….. CAVEATS Therefore, reporting BCR-ABL values on the IS will allow accurate comparison of response rates for clinical trials, providing, however, that laboratories maintain the consistent performance of their RQ-PCR analytical system. This can be monitored by the inclusion of QC samples in every run to recognize shifts in data, which should be corrected before results are deemed acceptable. Otherwise, the laboratory-specific conversion factor may be invalid. Branford S et al. Blood 112:3330, 2008 MORE CAVEATS •  Furthermore, assessment of precision should ideally be performed using stable QC samples with defined BCR-ABL values that are analyzed at least 10 times over several runs. Such material has currently not been tested and is not available. Therefore, the procedures used in this study require refinement to appropriately assess the performance of each laboratory. •  Therefore, there will be a need to continue the conversion factor process for some time to achieve standardization. This may be a formidable task for laboratories where BCR -ABL analysis is a minor component of their testing procedures. Branford S et al. Blood 112:3330, 2008. TECHNICAL ISSUES •  Duplicate results have more variability at lower ranges - CAP survey: ~ 50% of labs perform duplicates; few report duplicate values - pipetting variability - RNA quality •  As an example, I frequently see duplicate results of 0/.001% •  ~ $550/test QUANTITATIVE PCR FOR BCR/ABL •  The test can be fickle with some variability •  Use the same laboratory for serial monitoring •  Never change therapy based on a single result – repeat in 4-6 weeks •  If there is a clear-cut pattern of increase: bone marrow for cytogenetics, bcr/abl kinase mutational analysis •  It is very helpful to know what pcr “level” corresponds to CyCR in your laboratory PCRITIS Side effects Confused physicians Inappropriate dose increase Inappropriate referral for transplantation Inappropriate switch to new TKI Patient anxiety 38 •  As a CML patient for almost 5 years, and someone who is in regular contact with other CML patients from around the world, I continually see the confusion that surrounds this very important issue. We hang on every PCR test result,… •  So PCR numbers from different labs cannot be directly compared. This is a source of confusion when an oncologist uses different labs, when we change physicians, or when we see a specialist who uses a different lab. •  …..her PCRs had been done by different labs, and only the more recent PCR result was on the International Scale…. But the oncologist did not understand this change in PCR methodology and instead of providing a log reduction comparison simply compared the PCR numbers, and assumed she was failing drug therapy •  Other sources of PCR confusion continue unabated. 39 LONG TERM MOLECULAR MONITORING •  Know your lab •  Know which levels in that lab = CCyR •  Use the same lab for serial samples in individual patients •  Repeat the test before changing therapy •  With few exceptions, it’s a marathon, not a sprint If the relapse rate is so low, why bother to monitor after the first couple of years?? • It is fun to see these patients doing so well • REINFORCE COMPLIANCE!! • Stop therapy someday?? B. Hanfstein, M. C. Müller, P. Erben, M. Lauseker, S. Saussele, U. Proetel, S. Schnittger, C. Haferlach, H. J. Kolb, S. W. Krause, C. Nerl, D. Heim, G. M. Baerlocher, J. E. A. Schubert, H. Einsele, M. Hänel, J. Dengler, C. Falge, L. Kanz, A. Neubauer, M. Kneba, F. Stegelmann, M. Pfreundschuh, C. Waller, M. Pfirrmann, J. Hasford, W.-K. Hofmann, R. Hehlmann, A. Hochhaus for the SAKK and the German CML Study Group Thank You! over 200 participating centers including Switzerland and Czech Republic Progression-free Survival (PFS) BCR-ABLIS at 3 months ≤1% vs. 1-10% vs. >10% ≤1% 1-10% >10% BCR-ABLIS n 5Y-PFS ≤1% 218 96% p-value 1-10% 281 92% >10% 189 87% n.s. 0.037 Overall Survival (OS) BCR-ABLIS at 3 months ≤10% vs. >10% ≤10% >10% BCR-ABLIS n 5Y-OS p-value ≤10% 501 95% >10% 191 87% <0.001 Overall Survival (OS) BCR-ABLIS at 3 months ≤1% vs. 1-10% vs. >10% ≤1% 1-10% >10% BCR-ABLIS n 5Y-OS ≤1% 218 97% p-value 1-10% 283 94% >10% 191 87% n.s. 0.012 Overall Survival (OS) Ph+ at 3 months ≤35% vs. >35% ≤35% >35% Ph+ n 5Y-OS p-value ≤35% 336 95% >35% 124 87% 0.036 (Their) Conclusions   The levels of molecular or cytogenetic response at 3 months allow for a risk stratification of patients‘ outcome in terms of PFS and OS.   Missing the 10% BCR-ABLIS landmark at 3 months predicts inferior survival: 5-year OS with BCR-ABLIS >10% at 3 months is 87% (28% of pts.) 5-year OS with BCR-ABLIS <1% at 3 months is 97% (31% of pts.)   Treatment intervention is suggested for slow responders as indicated by inferior survival. LESSONS FROM THESE AND THE OTHER ABSTRACTS INCLUDED IN THE HANDOUT (and this week’s JCO) •  Rapid response is predictive of excellent •  •  •  •  long term outcome The OS in “failures” is still very good It is not known whether switching “early” will help – poor initial response may be a marker of overall resistance Is this supportive of using new TKIs front line? New ELN guidelines are being developed /debated "Not everything that counts can be counted, and not everything that can be counted, counts." Albert Einstein Initial Findings from the PACE Trial: A Pivotal Phase 2 Study of PONATINIB in Patients with CML and Ph+ ALL Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I Mutation J Cortes, D-W Kim, J Pinilla, P le Coutre, C Chuah, F Nicolini, R Paquette, J Apperley, J DiPersio, HJ Khoury, D Rea, M Talpaz, DJ DeAngelo, E Abruzzese, M Baccarani, MC Mueller, C Gambacorti-Passerini, S Wong, S Lustgarten, CD Turner, V Rivera, T Clackson, F Haluska, and HM Kantarjian On behalf of the PACE Investigators Ponatinib •  Oral pan-BCR ABL TKI with potent activity against native and mutated BCR-ABL and other kinases •  Rationally designed with extensive network of optimized molecular contacts and triple bond to accommodate T315I I315 triple bond pona*nib •  Phase 1 trial •  Recommended dose: 45 mg/day •  Well-tolerated •  Early and durable responses in refractory patients •  This is the initial report of the pivotal phase 2 PACE trial PACE Initial Results Prior Treatments N (%) Prior TKIs Imatinib only* CP-CML R/I N=207 T315I N=64 0 (0) 10 (16) Overall N=444 16 (4) Imatinib + (dasatinib OR nilotinib)* 76 (37) Imatinib + dasatinib + nilotinib* 124 (60) 21 (33) 237 (53) ≥ 2 prior TKIs** ≥ 3 prior TKIs** 31 (48) 172 (39) 98% 83% 94% 66% 41% 59% Data as of 02 Dec 2011 PACE Initial Results Best Response to Most Recent Dasatinib or Nilotinib % Attaining Endpoint Endpoint CP-CML AP-CML BP-CML Ph+ALL MCyR (primary CP endpoint) 25% N/A N/A MaHR (primary AP, BP/ALL endpoint) N/A 33% 25% MMR 3% 6% 4% Data as of 02 Dec 2011 PACE Initial Results Response CP-CML Cohorts n Response / N Evaluable (%) Response Overall R/I Cohort T315I Cohort CHR 248/271 (92) 193/207 (93) 55/64 (86) MCyR* 116/248 (47) 79/191 (41) 37/57 (65) 96/248 (39%) 63/191 (33%) 33/57 (58%) 51/265 (19) 31/205 (15) 20/60 (33) CCyR MMR *MCyR is the primary endpoint Data as of 02 Dec 2011 PACE Initial Results Response by Mutation Status CP-CML Mutation Status at Entry CP-CML n Response / N Evaluable (%) MCyR CCyR MMR Any mutation 30/66 (46) 24/66 (36) 16/69 (23) No mutation 49/125 (39) 40/125 (32) 15/136 (11) R/I Cohort T315I Cohort T315I only 28/43 (65) 24/43 (56) 16/48 (33) T315I + additional mutation(s) 9/14 (64) 9/14 (64) 4/12 (33) Data as of 02 Dec 2011 PACE Initial Results Response Advanced Phase Cohorts n Response / N Evaluable (%) Response AP-CML R/I MaHR* MCyR 31/42 (74) 17/54 (32) 6/54 CCyR (11%) MMR 4/59 (7) BP-CML/Ph+ALL T315I R/I T315I 6/13 (46) 17/46 (37) 16/43 (37) 9/17 (53) 14/41 (34) 15/41 (37) 4/17 (24%) 11/41 (27%) 11/41 (27%) 1/15 (7) 9/41 (22) 2/29 (7) *MaHR is the primary endpoint (excludes 15 patients with baseline MaHR) Data as of 02 Dec 2011 PACE Initial Results Treatment-Related Adverse Events Treatment-Related Adverse Events (≥ 10% any grade) Rash* Dry skin Abdominal pain Headache Fatigue Myalgia Arthralgia Lipase increased Constipation Nausea Asthenia Pancreatitis Thrombocytopenia Neutropenia Anemia CP-CML (N=271) Any Grade Grade ≥ 3 n (%) n (%) Entire Study (N=449) Any Grade Grade ≥ 3 n (%) n (%) 102 (38) 78 (29) 59 (22) 55 (20) 45 (17) 41 (15) 43 (16) 43 (16) 40 (15) 28 (10) 27 (10) 18 (7) 10 (4) 4 (2) 17 (6) 4 (2) 2 (1) 3 (1) 5 (2) 20 (7) 3 (1) 0 (0) 2 (1) 16 (6) 144 (32) 107 (24) 83 (19) 75 (17) 65 (15) 63 (14) 61 (14) 61 (14) 55 (12) 47 (11) 35 (8) 26 (6) 14 (3) 5 (1) 23 (5) 5 (1) 4 (1) 3 (1) 5 (1) 35 (8) 4 (1) 0 (0) 4 (1) 21 (5) 99 (37) 36 (13) 21 (8) 76 (28) 32 (12) 11 (4) 140 (31) 68 (15) 52 (12) 110 (25) 61 (14) 31 (7) *Combines the terms erythematous, macular and papular rash Data as of 02 Dec 2011 What’s next for Ponatinib? •  NDA for patients refractory/intolerant of second nilotinib and/or dasatinib with or without the T315I •  Consideration of a randomized comparison with imatinib in newly diagnosed patients with chronic phase CML •  The pcr for bcr/abl became undetectable. After 4 additional years of continued imatinib treatment, it remains negative. •  The patient would like to become pregnant You would tell her: 1.  Imatinib is teratogeneic and you counsel against pregnancy 2.  Relapse is universal after discontinuation of successful TKI therapy 3.  If relapse occurs after imatinib discontinuation, reinduction therapy is usually not successful 4.  You would consider discontinuation with close monitoring and if it remains negative, pregnancy could be considered IMATINIB PACKAGE INSERT Pregnancy Category D Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec. Sexually active female patients taking Gleevec should use adequate contraception. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day. Discontinuation of Imatinib in Patients with Chronic Myeloid Leukemia WHO HAVE MAINTAINED COMPLETE MOLECULAR RESPONSE: Update Results of the STIM François-Xavier Mahon, Delphine Réa, Joëlle Guilhot, François Guilhot, Françoise Huguet, Franck Nicolini, Laurence Legros, Aude Charbonnier, Agnès Guerci, Bruno Varet, Gabriel Etienne, Josy Reiffers, Philippe Rousselot, on behalf of the Intergroupe Français des Leucémies Myéloïdes Chroniques (FILMC) on behalf of the STIM Investigators ‹#› 64 Kaplan-Meier estimates of CMR after discontinuation of imatinib The overall probability of maintenance of CMR at 24 and 36 months was 39% (95% CI 29-48). Molecular relapse occurred in 61 pts with 58 relapses occurring during the first 7 months -- 3 late relapses at months 19, 20 and 22 ‹#› 65 Fluctuation of BCR-ABL detection after discontinuation % BCR-ABL/ABL 10 1 STOP 0.1 0.01 0.001 Among the 39 pts without confirmed molecular relapse, 5 exhibited a fluctuation in BCR-ABL transcript detection Multivariate Analysis Cox model: all patients and all relapses Multivariate analysis Cox model Hazard ratio (95% CI) Sokal score 2.555 (1.278 -5.119) IM duration >60 months vs <60 months 0.582 (0.340 -0.995) p value 0.008 0.047 Final Model => 2 independent prognostic factors ‹#› 67 Kaplan-Meier estimates of CMR after discontinuation of imatinib in 100 pts according to combined factors MANY REMAINING ISSUES - minimal understanding of non bcr/abl mutation mechanisms of resistance - poor outcomes in AP, myeloid BP : new trials -  clonal changes in Ph- cells -  Effect of T/NK proliferation with dasatinib - are patients “cured” and why?