NEW DRUGS IN HEMATOLOGY BOLOGNA, 15-17 April 2013 TYROSINE KINASE INHIBITORS IN CHRONIC MYELOID LEUKEMIA MICHELE BACCARANI michele.baccarani@unibo.it
Historic Development of CML Therapy Palliative Therapy Curative Therapy Arsenic Spleen irradiation No Therapy Busulfan Hydroxyurea Stem cell transplantation Interferon alpha Imatinib Nilotinib, Dasatinib Bosutinib, Ponatinib 1865 1903 1953 1964 1975 1983 1999 2005 2
SURVIVAL WITH CML RANDOMIZED STUDIES 1983-2008 Primary imatinib, 2002-2008 (CML IV) Survival probability IFN or SCT + 2nd line imatinib, 1997-2008 (CML IIIA) IFN or SCT, 1995-2008 (CML III) (CML I, II) IFN, 1986-2003 Hydroxyurea, 1983-1994 Busulfan, 1983-1994 YEARS AFTER DIAGNOSIS COURTESY OF THE GERMAN CML STUDY GROUP 3
CHRONIC MYELOID LEUKEMIA, 10 YEARS OF FIRSTLINE THERAPY WITH IMATINIB 400 mg DAILY SUMMARY OF 10 PROSPECTIVE STUDIES (*) IN 2895 PATIENTS - median of the results - CCgR at 1 YEAR 68% (49-88%) - MMR at 1 YEAR 40% (18-58%) - PFS at 5 YEARS 90% (83-94%) - OS at 5 YEARS 88% (83-97%) (*) IRIS, HAMMERSMITH, TOPS, FRENCH SPIRIT, ENESTnd, DASISION, GIMEMA, GERMAN CML STUDY IV, SWOG SO325, BELA
HIGH-DOSE IMATINIB vs. STANDARD-DOSE IMATINIB FASTER RESPONSES MORE RESPONSES EFFECT ON PFS TOXICITY and COST TOPS YES NO NO MORE FRENCH SPIRIT (yes) (yes) NO MORE GERMAN STUDY IV YES YES NO MORE ELN/GIMEMA (ONLY HIGH RISK) NO NO NO MORE PFS = progression-free survival; ELN = European LeukemiaNet
IMATINIB + IFNα vs. IMATINIB ALONE (400 mg) FASTER RESPONSES MORE RESPONSES EFFECT ON PFS TOXICITY and COST FRENCH SPIRIT YES YES NO MORE* GERMAN STUDY IV NO NO NO MORE* NORDIC STUDY (LOW + INTERMEDIATE RISK) YES YES NO MORE* *IFNα WAS DISCONTINUED IN 50% OF PATIENTS WITHIN 1 YEAR
SUMMARY OF BELA, DASISION and ENESTnd (3 YEARS) 2 nd GENERATION TKI vs. IMATINIB BOSUTINIB DASATINIB NILOTINIB CCgR SAME FASTER FASTER and MORE BCR-ABL 10% AT 3 mo MORE MORE MORE MMR FASTER and MORE FASTER and MORE FASTER and MORE > MMR FASTER and MORE FASTER and MORE FASTER and MORE FAILURE SLIGHTLY LESS SLIGHTLY LESS SLIGHTLY LESS AP / BP SLIGHTLY LESS SLIGHTLY LESS SLIGHTLY LESS PFS SLIGHTLY BETTER SLIGHTLY BETTER SLIGHTLY BETTER OS SAME SAME SAME SIDE EFFECTS (AE) ON TREATMENT AT 3 YEARS MORE and DIFFERENT DIFFERENT DIFFERENT 60% 70% 70%
PONATINIB A PAN-BCR-ABL INHIBITOR Rationally designed inhibitor of BCR- ABL Active against T315I mutant Unique approach to accommodating gatekeeper residue Potent activity against an array of BCR- ABL variants Also targets other therapeutically relevant kinases Inhibits FLT3, FGFR, VEGFR and PDGFR, and c-kit Once-daily oral activity in murine models Ile315 Ponatinib Avoids T315I FLT3 = FMS-like tyrosine kinase receptor-3; FGFR = fibroblast growth factor receptor; VEGFR = vascular endothelial growth factor receptor O Hare T, et al. Cancer Cell 2009;16:401-412 Imatinib Ponatinib
PACE Results RESPONSE TO PONATINIB 45 mg daily IN CHRONIC PHASE CML PATIENTS RESISTANT TO 2 OR 3 TKI Cortes et al, ASH 2012 n Response (%) Response Overall # (n=267) R/I Cohort (n=203) T315I Cohort (n=64) CHR* 249 (93) 191 (94) 58 (91) MCyR** 144 (54) 99 (49) 45 (70) CCyR 118 (44) 76 (37) 42 (66) MMR*** 79 (30) 47 (23) 32 (50) *CHR maintained or achieved during study; 103 patients had CHR at baseline **MCyR = primary endpoint ***Patients without a valid baseline MMR assessment, or who meet the criteria for MMR at baseline, counted as non-responders # Excludes three patients who were unassigned (post-imatinib, non-t315i), but treated CHR = complete hematologic response; MCyR = major cytogenetic response Data as of 27 Apr 2012
CLINICALLY IMPORTANT ENDPOINTS OVERALL SURVIVAL? PROGRESSION-FREE SURVIVAL? - IS ALWAYS INFLUENCED BY 2 ND AND 3 RD LINE TREATMENTS - COMPETITION WITH DEATHS FROM OTHER CAUSES - THE DATE OF PROGRESSION, PARTUCULARLY OF AP MAY BE DIFFICULT TO DETERMINE - IS ALWAYS INFLUENCED BY 2 ND LINE TREATMENTS FAILURE FREE SURVIVAL? EVENT-FREE SURVIVAL - BEST ASSESSMENT OF EFFICACY OF 1 ST LINE TREATMENT - REQUIRES A SHARED DEFINITION OF FAILURE, AND THE USE OF EARLY SURROGATE MARKERS (e.g. ELN JCO 2009) - BEST ASSESSMENT OF THE CLINICAL VALUE (EFFICACY, TOLERABILITY, COMPLIANCE) OF A TREATMENT EVENT IS TREATMENT DISCONTINUATION FOR ANY CAUSE
REVIEWING RESPONSE - RELATED PROGNOSTIC FACTORS THE SAGA OF MOLECULAR RESPONSE MEASURING BCR-ABL TRANSCRIPT LEVEL - METHODS, STANDARDIZATION - WHICH LEVELS ARE IMPORTANT? - AT WHAT TIME ARE IMPORTANT?
THE BCR-ABL TRANSCRIPTS LEVEL AT 3 MONTHS (10%) AND 6 MONTHS (10% AND 1%) MAY HAVE A PROGNOSTIC VALUE GREATER THAN THE MAJOR MOLECULAR RESPONSE WITH IMATINIB: GERMAN CML STUDY IV (1) HAMMERSMITH (2) DASISION (3) ENESTnd (4) WITH DASATINIB: DASISION (3) WITH NILOTINIB: ENESTnd (4) (1)Hanfstein et al Leukemia 2012 (3)Saglio et al ASH 2012 (2)Marin et al JCO 2011 (4)Hochhaus et al ASH 2012
PROGRESSION-FREE SURVIVAL BCR-ABL TRANSCRIPTS LEVEL AT 3 mo 10% > 10% 10% > 10% IMATINIB - ENESTnd, 2 y 97% <0.0001 84% 97% < 0.0001 85% - DASISION, 3 y 96% 0.0001 75% 96% 0.036 88% - GERMAN CML STUDY IV, 5 y 94% 0.037 87% 96% 0.012 87% - GIMEMA, 6 y 85% NS 90% 87% NS 87% - HAMMERSMITH, 8 y 93% < 0.001 57% 93% < 0.001 57% DASATINIB - DASISION, 3 y 96% 0.0003 68% 96% 0.034 86% NILOTINIB - ENESTnd 96% 0.01 83% 97% 0.059 87% - MEDIAN 96% 83% 96% 87%
EARLY SWITCH FROM IMATINIB TO 2nd GENERATION TKI PROS : CONS : - THE DATA FROM ALMOST ALL THE STUDIES OF IMATINIB, NILOTINIB AND DASATINIB SUPPORT THE PROBABILITY OF ACHIEVING A BETTER RESPONSE, AND A BETTER PROGRESSION FREE AND OVERALL SURVIVAL, IF BCR-ABL AT 3 MONTHS IS < 10% - THERE ARE NO DATA FROM PROSPECTIVE STUDIES OF EARLY SWITCH (WILL SWITCHING HELP?) - RETROSPECTIVE ANALYSIS OF SUBGROUPS - DIFFERENCES ARE MUCH MORE SIGNIFICANT FOR RESPONSES THAN FOR OUTCOMES - SWITCHING MAY BE USEFUL IN FEW PATIENTS (SWITCH MANY TO BENEFIT FEW) - WORRY OF LATE, OFF-TARGET SIDE EFFECTS - COST OF 2nd GEN TKI
MODELLING THE TREATMENT THE GOALS SURVIVAL, QUALITY OF LIFE, CURE Still, the best, simplest and confirmed early surrogate markers of survival are the CCgR and the MMR at 12 months Some critical points - The relationship between initial treatment and survival may be confused by subsequent treatments - Distinguishing the deaths by other causes from the deaths caused by leukemia or by treatment, or related to leukemia or treatment, is difficult.
EUROPEAN LEUKEMIANET 2013 RESPONSE TO TREATMENT FIRSTLINE, IMATINIB, NILOTINIB, and DASATINIB OPTIMAL WARNING FAILURE BASELINE NA -HIGH RISK, -CCA/Ph+ (Major route) NA 3 mo BCR-ABL 10% and/ or Ph+ 35% BCR-ABL 10% and/or Ph + 36-95% No CHR and/or Ph + > 95% 6 mo BCR-ABL < 1% and/ or Ph+ 0 BCR-ABL 1-10% and/ or Ph + 1-35% BCR-ABL > 10% and/or Ph + > 35% 12 mo BCR-ABL 0.1% BCR-ABL 0.1-1 % BCR-ABL > 1% and/or Ph + 1% Then BCR-ABL 0.1% BCR-ABL 0.1-1% BCR-ABL > 1%
MODELLING THE TREATMENT THE GOALS: SURVIVAL, QUALITY OF LIFE, CURE Side-effects, even mild, particularly when they are chronic or recurrent, affect significantly the quality of life. Side effects may become the most frequent and important reason for switching from one TKI to another, or for discontinuing a combination treatment (like TKI+IFNa). The availability of more TKI, allows making a choice of the better tolerated drug. However, the quality of life does not depend only on sideeffects. Living with leukemia and taking drugs lifelong may affect very significantly the quality of life even in the absence of side-effects.
MODELLING THE TREATMENT THE GOALS: SURVIVAL, QUALITY OF LIFE, CURE Freedom from leukemia and from treatment is the ultimate goal of any treatment. But currently it can be achieved in (very) few patients. The best policy for cure is not yet clear. - Intensive, then consolidation? - Which TKI frontline? - Early vs. late switch? - TKI alone or in combination?
THE STIM STUDY, A PROOF OF PRINCIPLE Imatinib was discontinued in 100 pts who were in MR 4.5 for at least 2 years. The overall probability of molecular recurrence at 3 years was 61% (95% CI 52-71%). Molecular relapse occurred in 61 pts with 58 relapses occurring during the first 7 months 3 late relapses at month 19, 20 and 22, respectively Mahon FX, et al. Blood 2011;118:abstract 603
What did we learn from the STIM study? - 100 PTS ON IMATINIB IN STABLE MR 4.5 OR BETTER FOR MORE THAN 2 YEARS - WHAT FRACTION OF ALL PATIENTS DO THEY REPRESENT? LESS THAN 10%? - 40% OF THEM REMAINED MOLECULARLY NEGATIVE ACCOUNTING FOR LESS THAN 4% OF ALL PATIENTS * Mahon FX et al, Lancet Oncol 2010; 11: 1029-1035
HOW CAN WE IMPROVE THE PROPORTION OF PATIENTS WHO CAN BE ELIGIBLE FOR TREATMENT DISCONTINUATION WITHOUT MOLECULAR RECURRENCE? 1. PROLONGING THE TIME ON TREATMENT WITH IMATINIB? FOR MORE THAN 4 YEARS? 1. COMBINING IMATINIB (OR OTHER TKI?) WITH INTERFERON? 3. USING 2nd GENERATION TKI FIRSTLINE OR SECONDLINE? TO ACHIEVE MORE AND DEEPER MOLECULAR RESPONSES? 1. COMBINING TKI WITH INVESTIGATIONAL AGENTS?
ENESTnd Cumulative Incidence of MR 4.5 by BCR-ABL Levels at 3 Months (Nilotinib 300 mg BID)* % With MR 4.5 100 90 80 70 60 50 40 30 20 10 0 * These data exclude 1 patient in the nilotinib arm who achieved MR 4.5 at or before 3 months. 83 patients with 1% BCR-ABL levels at 3 months who later achieved MR 4.5 represents 32% of the 257 patients with BCR-ABL levels available at 3 months. 1% >1% 10% >10% Pat 144 89 24 MR 4.5 by 4 years for 10% vs >10% BCR-ABL (47% vs 4%; P <.0001) MR 4.5 by 3 years 50% 18% 4% 58% (32% overall ) 28% 4% P =.0001 P =.0135 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Time Since Randomization (Months) MR 4.5 by 4 years HOCHHAUS et al, ASH 2012 Data cut-off: 27Jul2012.
TOWARDS CURE IN HOW MANY PATIENTS CAN WE DISCONTINUE TKI THERAPY SUCCESSFULLY, NOW AND IN THE FUTURE? - NOW, LESS THAN 10% - IN THE FUTURE, MORE THAN 20%? - MOSTLY BASED ON THE USE OF 2nd GENERATION TKI FIRSTLINE AND SECONDLINE - NOT FORGETTING ALLOGENEIC SCT - MOST IMPORTANT FOR YOUNG PATIENTS - THE PATH TO CURE IS TRACED, BUT REQUIRES TRAINING, EDUCATION AND DEDICATION
EUROPEAN LEUKEMIANET 2013 TREATMENT RECOMMENDATIONS, CHRONIC PHASE, FIRST LINE IMATINIB 400 or NILOTINIB 300 x 2 or DASATINIB 100, FOR ALL PATIENTS A higher dose of Imatinib (600 to 800 mg) and the combination of a standard, 400 mg, dose of Imatinib with different formulations of Interferon alfa have been shown to be highly effective (or to be competitive ), in some but not in all studies.
ELN TREATMENT RECOMMENDATIONS, CHRONIC PHASE, FIRST LINE 2nd GENERATION TKI HAVE BEEN THE WINNER (vs. IMATINIB) IN TWO PHASE 3 PROSPECTIVE RANDOMIZED STUDIES (ENESTnd AND DASISION). WHY IMATINIB CONTINUES TO BE INCLUDED IN THE RECOMMENDATIONS FOR 1st LINE TREATMENT? - ONLY COMPANY-SPONSORED STUDIES - NO CONFIRMATION AS YET - BIG DIFFERENCES IN SURROGATE MARKERS (PARTICULARLY MOLECULAR RESPONSE) BUT SMALL OR NOT SIGNIFICANT DIFFERENCES IN OUTCOMES (PFS AND OS AT 4 YEARS) - SHORTER FOLLOW-UP - ISSUES OF LATE, OFF-TARGET, SIDE EFFECTS - COST, REIMBURSABILITY * SAGLIO G. et al, NEJM 2010 + KANTARJIAN H. et al, NEJM 2010
EUROPEAN LEUKEMIANET 2013 TREATMENT RECOMMENDATIONS 1st LINE: IMATINIB 400 x 1, NILOTINIB 300 x 2, DASATINIB 100 x 1 2nd LINE - INTOLERANCE - SWITCH TO ONE OF THE OTHER TKI, taking into account comorbidities and side effects - FAILURE - SWITCH IMATINIB TO OTHER TKI, taking into account mutations, comorbidities and side effects 3rd LINE - SWITCH NILO TO DASA, BOS or PONA - SWITCH DASA TO NILO, BOS or PONA - ALLOGENEIC SCT - SWITCH TO ANOTHER TKI (PONA) - ALLOGENEIC SCT - EXPERIMENTAL TREATMENT
FROM RECOMMENDATIONS TO PRACTICE THE CHOICE OF THE TREATMENT DEPENDS ON MANY FACTORS EFFICACY - (EARLY) SURROGATE MARKERS OF THE OUTCOMES (RATE, DEPTH, AND TIME OF CgR AND MolR) - CLINICAL OUTCOMES, PFS and OS SIDE EFFECTS SAFETY - LONG TERM, OFF TARGET COMPLICATIONS PATIENT - ACUTE, SEVERE, causing treatment discontinuation - CHRONIC, MILD, affecting the quality of life 1. AGE 2. COMORBIDITIES 3. LIFESTYLE 4. EDUCATION 5. COMPLIANCE AND ALSO ON DRUG AVAILABILITY (NOT ALL DRUGS ARE AVAILABLE WORLDWIDE) AND COST (NOT ALL COUNTRIES AND ALL PATIENTS HAVE THE SAME FINANCIAL POSSIBILITIES; THE COST OF THE DRUGS IS NOT THE SAME IN ALL COUNTRIES)
ITALY (EMILIA-ROMAGNA and SICILY) AGE DISTRIBUTION OF NEWLY DIAGNOSED Ph+ BCR-ABL CML PATIENTS, 2008-2011 % Years
ACKNOWLEDGEMENTS - EUROPEAN LEUKEMIANET, WP 4 - EUTOS (EUROPEAN TREATMENT AND OUTCOME STUDY ON CML) - NOVARTIS ONCOLOGY, EUROPE and GLOBAL - CML PATIENTS ADVOCACY GROUPS - DPT. OF HEMATOLOGY L. and A. Seràgnoli (F. Castagnetti, G. Gugliotta, I. Iacobucci, F. Palandri, G. Rosti, S. Soverini ) GIMEMA CML WP - GIMEMA CML Working Party (M. Breccia, F.Pane, D. Russo, G.Saglio,..)
EUROPEAN LEUKEMIANET RECOMMENDATIONS FOR CHRONIC MYELOID LEUKEMIA SAN DIEGO, 11 DECEMBER 2011 AMSTERDAM, 14 JUNE 2012 BALTIMORE, 20 SEPTEMBER 2012 ATLANTA, 6 DECEMBER 2012 ELN, CML Panel Jane Apperley Michele Baccarani Francisco Cervantes Richard Clark Jorge Cortes Michael Deininger John Goldman François Guilhot Rüdiger Hehlmann Henrik Hjorth-Hansen Andreas Hochhaus Timothy Hughes Hagop Kantarjian Dong-Wook Kim Richard Larson Jeff Lipton François Xavier Mahon Giovanni Martinelli Jiri Mayer Martin Mueller Fabrizio Pane Jerald Radich Gianantonio Rosti Philippe Rousselot Giuseppe Saglio Susanne Saussele Charles Schiffer Richard Silver Bengt Simonsson Juan Luis Steegmann,
Some golden rules not only for CML Prediction is very difficult, especially if it's about the future. Niels Bohr Not everything that counts can be counted and not everything that can be counted counts Albert Einstein
PLANNING THE TREATMENT OF CML MAJOR CONTROVERSIAL ISSUES - SURVIVAL vs. CURE (COST, SIDE EFFECTS, LATE OFF- TARGET COMPLICATIONS, QUALITY OF LIFE) - FIRST LINE - IMATINIB vs. 2nd GEN TKI? - SECOND LINE - WHEN? EARLY vs. LATE SWITCH? - ALLO SCT - WHEN? - TARGETS - CCgR? MR 3.0? MR 4.0 or BETTER? - SAME STRATEGY FOR ALL PATIENTS?
ELN, SECONDARY FAILURES 2009* 2013 - LOSS OF CHR - LOSS OF CHR - LOSS OF CCgR - LOSS OF CCgR - MUTATIONS (1) - MUTATIONS (2) - CCA / Ph + (3) - CCA / Ph + (3) - CONFIRMED LOSS OF MMR (1) Imatinib-resistant mutations (2) Any mutations (3) Accelerated phase (4) Two consecutive tests > 0.1 of wich one must be > 1% * Baccarani et al, JCO 2009; 27: 6041-6051
MONITORING CML TREATMENT - THE COST OF MONITORING IS MUCH LOWER THAN THE COST OF THE DRUGS - MONITORING HELPS SELECTING THE GOOD DRUG, and TO OPTIMIZE TREATMENT - EXCESS MONITORING AFFECTS THE POCKET - TREATMENT OPTIMIZATION AFFECTS LIFE (and also the pocket!)