CML Update 2016
Chronic Myeloid Leukemia Splenomegaly CML (3 phase disease) Increased white cells Malignant proliferation of myeloid white cells Initially mature cells a) chronic phase of disease Evolution to immature cells b) accelerated and then c) blastic or acute phase Death due to effects of acute leukemia Median survival 3-4 yrs (pre TKI era) Philadelphia Chromosome (bcr-abl gene mutation)
CML Presenting features No symptoms or signs Routine blood test Symptoms of anemia, constitutional symptoms Abdominal discomfort, easy bruising, headaches, etc
CML laboratory Elevated WCC, myeloid series, left shift, often platelets high, Bone marrow myeloid proliferation Cytogenetics Philadelphia chromosome Molecular BCR-ABL gene re-arrangement, measured by quantitative PCR
ENESTcmr Definition of Molecular Endpoints Absolute values 1 2 log BCR-ABL % IS 0.1 0.01 0.001 CCyR MMR MR 4.5 3 log 4 log 5 log 0.0001 6 log 0.00001 7 log Undetectable BCR-ABL (With a sample sensitivity of 4.5 logs) Hughes TP, et al. Blood. 2012;120(21):[abstract 0694].
The Philadelphia Chromosome and BCR-ABL 9 9 q+ Chromosome 22 c-bcr 1 Chromosome 9 2-11 c-abl 22 Ph (or 22q-) 2-11 P210 BCR-ABLl ABL BCR BCR-ABL Fusion protein with tyrosine kinase activity 2-11 Exons Introns CML breakpoints ALL breakpoints P185 BCR-ABL t (9;22) translocation BCR-ABL gene structure Faderl et al.,1999; Melo, 1996.
Levels of Molecular Response in CML BCR- ABL (%IS) 100 Log Reduction in BCR- ABL Reduction in BCR-ABL Baseline 10 1 1:10 Approximates MCyR 1 2 1:100 Approximates CCyR 0.1 3 1:1,000 MMR 0 01 4 0 0032 4.5 0 001 5 1:10,000 1:32,000 1:100,000 MR 4 MR 4.5 MR 5 Deep molecular response 0 0001 6 1:1,000,000 MR 6 (with currently available technology, this level of response cannot be assessed) Level of Response Mahon and Etienne. Manuscript in preparation.
CML disease outlook Chonic phase minimal impact on wellbeing, controllable with hydroxyurea, average time in CP 3 yrs Accelerated and blastic phase due to increasing proliferation and increasing blasts in marrow. Fatal within 12-18 months. Pre 2000 treatment hydroxyurea and BMT
Proportion Surviving Survival trends - Chronic Myeloid Leukemia 1.0 0.8 0.6 Imatinib 90% Year Total Dead Imatinib 276 14 1990-2000 960 357 1982-1989 365 266 1975-1981 132 127 1965-1975 123 122 0.4 0.2 0.0 allogeneic transplant hydroxyurea interferon busulfan 0 3 6 9 12 15 Years From Referral The University of Texas M. D. Anderson Cancer Center database.
Survival CML survival is close to the healthy population Goldman JM ; pers.communication 1.0.9.8.7 Survival of 224 patients who received first line imatinib therapy therapy in Hammersmith Hospital (2000-2008).6.5.4 Survival for 246 patients treated with IFNa (1986-1994).3.2.1 0.0 0 2 4 6 8 10 12 14 16 18 20 Time from diagnosis (years) Gambacorti-Passerini C, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 2011 (7):553-61.
Epidemiology Estimated New Cases (USA) Estimated Deaths CML Both Men Women Both Men Women 1997 4,300 2,400 1,900 2,400 1,400 1,000 2007 4,570 2,570 2,000 490 240 250 The annual mortality rate has been reduced from 15% to 20% to ~2% and median survival is expected to exceed 15 to 20 years based on current data. Parker et al., 1997. Jemal et al., 2007. Alvarez et al., 2007.
Chronic Myeloid Leukemia Key Points 1) CML is the success story of targeted therapy 10 yr survival from 10% to 85% in past decade 2) Current therapy (imatinib, nilotinib and dasatinib) is good for majority who tolerate it and respond well. But an unmet need for the 10-20% of patients have to change therapy because of intolerance or resistance to treatment. 3) Alternative Options? Allogeneic stem cell transplant (If suitable donor), mortality 20-30% Hydroxyurea and wait for disease progression
% Alive Survival (ASH 2009): Imatinib Arm Deininger et al, ASH 2009 100 90 80 70 60 50 40 30 20 10 0 Estimated overall survival at 8 years was 85% (93% considering only CML-related deaths) Survival: deaths associated with CML Overall Survival 0 12 24 36 48 60 72 84 96 Months Since Randomization
IRIS STUDY Event Free Survival - Imatinib vs Inteferon 6 yr outcome according to response at 18 mths So poor response in about 15% and half of these patients show progression at 5 years Long term depends on depth of response, getting to less than 1% or better on Bcr-Abl 18
CML Goals of therapy 2016 Stop or reduce transformation to acute leukemia Achieve deep remission quickly Achieve sustained remission after treatment discontinuation (treatment free remission) Minimise drug toxicity/improve Quality of Life
% Alive Survival after progression advanced phase CML Most are dead within 3 yrs 100 90 ENESTnd IRIS 80 70 60 50 40 30 20 10 0 Median survival ~10.5 months 0 6 12 18 24 30 36 42 48 Months Since Progression Clark RE, et al. Haematologica. 2012;97(s1):237 [abstract 0583].
Tyrosine kinase inhibitors for CML Date of FDA approval 2 nd 1 st Administration convenience Adverse effects Imatinib 2001 2002 Dasatinib 2006 2010 Nilotinib 2007 2010 Bosutinib 2012 Ponatinib 2012 Once a day, taken with food Once a day, no food effect Twice a day, Taken fasting Once a day, no food effect Once a day, no food effect Cramps, fatigue, gastrointestinal Pleural effusion, pulmonary hypertension Hyperglycemia, pruritus, accelerated vascular disease (PAOD) Gastrointestinal Rash, accelerated cardiovascular disease
3 Randomised trials in newly diagnosed CML
Do current TKIs have a good record for sustained usage? Comparison of 3 randomized trials Percentage Nilotinib Imatinib Dasatinib Imatinib Bosutinib Imatinib Discontinued ALL 27 38 23 25 37 29 Discontinued AE 12 11 9 6 24 7 MMR by 12 months 53 27 46 28 Discontinuation rate = 23% - 38% MMR by 24 months 69 44 64 46 61 50 MR 4.5 by 24 months 23 10 17 8 25 17 (due to intolerance, disease progression) Transformation 2.6 6.7 3.5 5.8 2 5 Deaths 3.7 6 6 5 3 5 still an unmet need for 1 in 3 patients
Molecular responses in the three trials 73% vs 53% Yes discriminating! 64% vs 46% 61% vs 50% DASISION BELA
ENESTcmr - Cumulative Incidence of MR 4.5* n % With MR 4.5 40 30 20 10 Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD 282 281 283 By 1 Year 11%, P <.0001 7%, P <.0001 Δ 6%-10% By 3 Years 32%, P <.0001 28%, P =.0003 Δ 13%-17% 15% 0 1% 0 3 6 9 12 15 18 21 24 27 30 33 Months Since Randomization 36 * Equivalent to BCR-ABL transcript levels of 0.0032% (IS). 25 Data cut-off: 27Jul2011.
Reduction in transformation by all 2 nd generation TKIs Remarkable consistency Expect ~ 50% reduction in transformation from 5-6% 2-3% at 3 yrs
Overall Survival on Study Nilotinib 300 mg BID n = 282 Nilotinib 400 mg BID n = 281 Imatinib 400 mg QD n = 283 Total number of deaths 15 9 19 Estimated 4-year OS, % 94.3 96.7 93.3 Hazard ratio (95% CI) 0.78 (0.39-1.53) 0.46 (0.21-1.02) P value 0.4636 0.0498 CML-related deaths a 5 4 13 Estimated 4-year survival considering only CML-related deaths, % Hazard ratio (95% CI) 98.1 98.5 95.4 0.38 (0.13-1.06) 0.30 (0.1-0.92) P value 0.0547 0.0250 a The definition of CML-related death was revised in 2012 to include only those patients for whom the principle cause of death was either study indication or was unknown or not reported but occurred subsequent to a documented progression to AP/BC. As a result of this change, 3 deaths in the imatinib arm, previously considered CML related, no longer fit the criteria and were removed from the 4-year totals. Since the 3-year analysis, there were 5 additional deaths reported 2 CML-related deaths occurred on the imatinib arm, both after treatment discontinuation 2 deaths occurred on treatment in the nilotinib 300 mg BID arm (cerebrovascular accident and unknown cause) 1 patient in the nilotinib 400 mg BID arm died after treatment discontinuation from subdural hematoma Data cutoff: July 27 2012. Kantarjian HM, et al. Blood. 2012;120(21):[abstract 1676].
% With MMR MMR by 3 Years ENESTnd According to Sokal Risk 80 77 75 70 63 60 54 50 40 30 20 10 0 P =.0264 P =.0020 P =.0004 67 39 n = 103 104 101 101 78 78 Low Intermediate High Nilotinib 300 mg BID 28 Imatinib 400 mg QD Rates of MMR were consistently higher in patients treated with nilotinib vs imatinib across Low, Intermediate, or High Sokal risk scores Data cut-off: 27Jul2011.
Comparison of 3 randomized trials Percentage NIL IM DAS IM BOS IM Discontinued ALL 27 38 23 25 37 29 Discontinued AE 12 11 9 6 24 7 MMR by 12 months 53 27 46 28 MMR by 24 months 69 44 64 46 61 50 MR 4.5 by 24 months 23 10 17 8 25 17 Transformation 2.6 6.7 3.5 5.8 2 5 Deaths 3.7 6 6 5 3 5 More Similarities than differences
So 2 nd generation TKIs Faster, deeper responses 50% reduction in transformation Favourable toxicity profile?? No survival advantage (yet) but CML related deaths are less = Imatinib is finished? BUT imatinib has history and > 10yrs experience
Predicting long term outcome from early results If long term poor responders are identified early then possible interventions may be applied before transformation (needs to be proven in clinical trial) NEW GOAL: BCR-ABL < 10% at 3 months
PFS (%) IRIS Imatinib - Progression-free survival according to BCR-ABL IS after 3 months 100 80 < 10% 10% 96 % estimated rate after 8 years 83 % 60 p= 0.0156 0 12 24 36 48 60 72 84 96 months Definition of Progression: AP, BC, death from any reason
Dragana Milojkovic,.. John M Goldman, David Marin. Department of Haematology, Hammersmith Hospital, Imperial College London, Good Risk OS = 93.3% BCR-ABL 3mth < 9.84% OS = 93.3% Good Risk c-ccyrs = 91.1% Poor Risk OS = 56.9% Poor Risk c-ccyrs = 47% BCR-ABL 3mth > 9.84% OS = 56.9% OS Comparison p<0.0001 C-CCyRS comparison p=0.0002 36
Molecular evaluation performed at 3 months is also very relevant to predict the clinical evolution The German CML Study IV: Overall Survival (OS) BCR-ABL IS at 3 months 10% vs. >10% 10% >10% BCR-ABL IS n 5Y-OS 10% 501 95% p-value <0.001 >10% 191 87% Hanfstein et al. Leukemia 2012 Mar 26. doi: 10.1038/leu.2012.85.
>10% BCR-ABL at 3 months new definition of early failure BUT no evidence that these patients benefit from a switch to nilotinib (TIDEL II) Other salvage strategies yet to be proven Has the boat been missed at 3 mths?
Toxicity
What is the toxicity profile of 2 nd gen TKIs?? Do the benefits outweigh the risks?
Selecting TKI according to frequent adverse reactions Adverse Event Imatinib Nilotinib Dasatinib Arterial Occlusive Disease < 1% 10-20% 1-5% Pleural Effusion < 1% < 1% 20% Hyperglycaemia 5-10% 30% < 1% Pulmonary HT < 1% < 1% 1-5% Skin Rash 5-20% 20-30% 5-10% Muscle Cramps 20-30% 5-10% 5-10% Diarrhoea 10-20% 5-10 5-10% Increase Lipase/Amylase 5% 5-10% < 1% BUT DO PATIENT FACTORS AFFECT RISK?
Predictive factors for pleural effusions and arterial occlusive disease Reported risk factors Pleural Effusion with Dasatinib Higher dose of Dasatinib * Twice daily schedule * Duration of treatment Duration of CML Advanced CML (AP/BP) Age >55 * Charlsen comorbidity score Cardiac history Arterial Hypertension Autoimmune Disease Hypercholesterolemia Skin rash during Dasatinib Arterial occlusive disease - Nilotinib Higher dose of Nilotinib (300 vs 400) * Known atherosclerosis * Cardiovascular risk score * Pre-existing risk factors for PAOD development: * (Advanced Age, Diabetes, Cardiac history, Hypertension, Obesity, Hypercholesterolemia, Smoking) *= potential decision making factor Potential Risk factors Pulmonary disorders Pulmonary hypertension Respiratory infections Viral (CMV) re-activation Immune cell activation (NK cell expansion) Advanced CML (AP/BP) Duration of treatment Increased fasting glucose during Nilotinib Prior Imatinib Switch to Ponatinib
31 patients switching from Imatinib to Nilotinib 50% developed dislipidemia with cholesterol level above ULN 35% required statin therapy on NIL compared with 3% on Imatinib
Cardiac and Vascular Events by 4 Years (All Grades) Patients With an Event, n (%) Nilotinib 300 mg BID n = 279 Nilotinib 400 mg BID n = 277 Imatinib 400 mg QD n = 280 IHD 11 (3.9) 14 (5.1) 3 (1.1) PAOD 4 (1.4) 5 (1.8) 0 (0) IHD, ischaemic heart disease; PAOD, peripheral arterial occlusive disease. Between years 3 and 4, five new patients had an IHD event (2 in the nilotinib 300 mg BID arm and 3 in the nilotinib 400 mg BID arm), and 2 new patients had a PAOD event (both in the nilotinib 400 mg BID arm; Table 5) 1 patient in the nilotinib 400 mg BID arm with previously reported PAOD had a newly reported drug-related serious AE (arterial stenosis limb) leading to treatment discontinuation Data cutoff: July 27 2012. Kantarjian HM, et al. Blood. 2012;120(21):[abstract 1676].
Dasatinib safety concerns Pulmonary hypertension in 5-20% Pleural effusions - 5% per year, doesn t seem to be slowing down. - Approx 50% in pts > age 70
Note: different patterns of pleural effusion A) R pleural effusion B) ground glass opacities C) Septal thickening D) Alveolar consolidation + pleural effusion
Monitoring Response
Treatment Guidelines for CML Baccarani M et al. Blood. 2013;122:872-84
ELN 2013 response to firstline treatment imatinib, nilotinib, and dasatinib OPTIMAL WARNING FAILURE BASELINE NA -HIGH RISK, -CCA/Ph+ (Major route) NA 3 mo Ph+ 35% and/or BCR-ABL 10% 6 mo Ph+ 0 and/or BCR-ABL < 1% Ph + 36-95% and/or BCR-ABL 10% Ph + 1-35% and/or BCR-ABL 1-10% No CHR and/or Ph + > 95% Ph + > 35% and/or BCR-ABL > 10% 12 mo BCR-ABL 0.1% BCR-ABL 0.1-1 % Ph + 1%, and/or BCR-ABL > 1% 24 mo BCR-ABL 0.1% BCR-ABL 0.1-1% BCR-ABL > 1% Baccarani M et al. Blood. 2013
Resistance to TKI treatment
Clinical Resistance to Imatinib Mechanisms Primary Resistance Insufficient inhibition of BCR-ABL Can be due to low plasma levels, activity of drug pumps, etc Individual variation in normal bone marrow reserve (low levels of normal hematopoietic stem cells in some patients) Secondary resistance Outgrowth of one or more clones harboring an imatinib-resistant BCR-ABL kinase domain mutation (most common) Overproduction of BCR-ABL (e.g. via genomic amplification) BCR-ABL-independent mechanisms (poorly understood)
BCR-ABL Kinase Domain Mutations Associated with Clinical Resistance to Imatinib (Incomplete Map) L298V E292V x P C A Gorre et al, 2001; von Bubnoff et al, 2002; Branford et al, 2002; Hofmann et al, 2002; Roche-L Estienne et al, 2002; Shah et al, 2002; Hochhaus et al, 2002; Al-Ali et al, 2004 Courtesy Tim Hughes
Nilotinib has a Better Fit to the Binding Pocket Imatinib (Glivec ) IC 50 669 nm Nilotinib (Tasigna ) IC 50 25nM Rationally designed highly specific inhibitor of BCR-ABL 30x more potent than imatinib; maintains target specificity No significant effect on other kinases (Src, FLT3, VEGFR, EGFR, InsR, RET, MET, IGFR, etc)
Discontinuation of Therapy
The new goal Achieving complete molecular remission Also called MR 4.5 or BCR-ABL IS 0.0032 2 nd Generation TKIs superior to imatinib up-front, but do 2 nd gen TKIs achieve CMR for imatinib good responders? Not for survival but for treatment cessation strategies
Discontinuation of Imatinib in Patients With Sustained CMR: STIM Trial Update 100 patients, CMR on imatinib for 2 yrs Median F/U: 30 mths (range 9-45) 39% cumulative probability of maintaining CMR at 36 mths after stopping imatinib - 58 relapses within 7 mos, 3 late relapses (19-22 mos) - No relapses between 24 and 36 mos - All relapsed patients sensitive to imatinib rechallenge - 56 regained CMR after imatinib re-treatment (after 0-21 mths) Prognostic factors: - Sokal score & shorter imatinib duration predict molecular relapse - Low Sokal + duration > 5 yrs: 68% CMR at 24 mos Mahon FX, et al. ASH 2011. Abstract 603.
Discontinuation of Imatinib in Patients With Sustained CMR: STIM Trial Update No relapses after 24 mths Mahon FX, et al. Lancet Oncol. 2010;11:1029-1135.
FREQUENT AND SUSTAINED DRUG-FREE REMISSION IN THE AUSTRALASIAN CML8 TRIAL OF IMATINIB WITHDRAWAL Median follow-up of 42 months (range 15 72 months) Ross DM et al. Blood. 2013 Jul 25;122(4):515-22.
ENESTcmr Preliminary Results Complete Molecular Response (CMR) Rate With Nilotinib in Patients With CML-CP Without CMR After 2 Years on Imatinib: Preliminary Results From the Randomized ENESTcmr Trial Timothy P. Hughes, Jeffrey H. Lipton, Brian Leber, Nelson Spector, Francisco Cervantes, Ricardo Pasquini, Nelma Cristina D. Clementino, Anthony P. Schwarer, Francois-Xavier Mahon, Delphine Réa, David T. Yeung, Suzanne Kamel-Reid, Israel Bendit, John Reynolds, Lisa Williams, Tomasz Szczudlo, Susan Branford Hughes TP, et al. Blood. 2011;118(21):1184-1185 [abstract 2755].
ENESTcmr Preliminary Results Study Design and Endpoints R A N D O M I Z E END POINTS Primary Nilotinib 400 mg BID N = 207 1:1 randomization stratified by: Prior imatinib ( 36 mos, > 36 mos) AND Prior interferon (None, 12 mos, > 12 mos) Imatinib continue same dose 4-year study Confirmed CMR (undetectable BCR-ABL) by 12 months Secondary Kinetics of molecular response (undetectable BCR-ABL levels, MR 4 and MR 4.5 over time RQ-PCR for primary and secondary endpoints was performed every 3 months and assessed at a central laboratory in Adelaide, Australia Safety profile RQ-PCR, real-time quantitative polymerase chain reaction; CCyR, complete cytogenetic response Hughes TP, et al. Blood. 2011;118(21):1184-1185 [abstract 2755].
% Patients ENESTcmr Preliminary Results Molecular Response Rates by 12 Months (in patients without indicated response at baseline) P =.006 P =.008 P =.03 74 78 94 91 101 100 MR 4 MR 4.5 CMR (Undetectable BCR-ABL)* * With 4.5-log assay sensitivity. 12 month follow-up Hughes TP, et al. Blood. 2011;118(21):1184-1185 [abstract 2755].
3 rd Generation TKI Ponatinib
Where does Ponatinib fit in all this? Ponatinib use in Chronic Myeloid Leukemia Several trials, Phase I, II, III. 5 yrs follow up Ponatinib is the most active agent in CML. High response rates seen in 1 st line High response rates in 2 nd /3 rd line chronic phase, accelerated phase, blastic phase and Philadelphia chromosome +ve acute lymphoblastic leukemia. Active against all resistance mutations
Long term follow up of PACE in the T315I subgroup Durable response
PACE Trial: Conclusions Ponatinib is active in heavily pretreated and multidrug-resistant CML or Ph-positive ALL 94% of patients previously treated with 2 TKIs 59% of patients previously treated with 3 TKIs Responses seen in patients with T315I mutation Ponatinib well tolerated Grade 3 adverse events in > 10% of patients: thrombocytopenia (25%), neutropenia (14%) Cortes JE, et al. ASH 2011. Abstract 109.
Despite early termination of the EPIC trial, preliminary analyses suggest improved efficacy of ponatinib over imatinib in newly diagnosed patients Best Overall Molecular Response (at any time) Failure to Achieve <10% BCR-ABL Transcripts at 3 Months Major Molecular response (safe haven) 41% vs 18% Molecular Response at 3, 6, 9, and 12 Months Early deep response Bcr-Abl < 10% at 3 mths: 94% vs 68% 68 Median follow-up=5.1 months
Incidence of arterial and venous vascular events in PACE study 3 deaths attributed to ponatinib related vascular events: acute myocardial infarction (1), cardiac arrest (1), Mesenteric arterial occlusion (1)
Skin rash in ponatinib patient Ponatinib rash
What to do with CML patients on ponatinib? A) Stay on Ponatinib OR B) Allogeneic transplant
Retrospective pooled data of ponatinib trials of T315I patients (n=128) Comparison with EBMT Registry (n = 222) Primary endpoint: OS
Adjusted OS Ponatinib Allo-SCT P Value CP-CML, n OS, median mos 64 NR (45.9-NR) 26 103.3 (6.6-103.3).013 AP-CML, n OS, median mos 18 NR (24.6-NR) 8 55.6 (11.4-NR).889 BP-CML, n OS, median mos 24 7.0 (3.5-11.0) 17 10.5 (5.8-49.9).026 Ph+ ALL, n OS, median mos 22 6.7 (4.0-15.3) 5 32.4 (7.8-NR).119 For CP-CML, ponatinib achieved significantly longer OS vs allo-sct For BP-CML, allo-sct achieved significantly longer OS vs ponatinib Although not significant, OS for Ph+ ALL was longer for allo-sct vs ponatinib
Should we be doing therapeutic drug monitoring for imatinib 15 years down the track?
Aim to evaluate whether the dosage of imatinib could be optimized for each patient with newly diagnosed CP-CML based on their imatinib [C]min levels
CML Chronic phase, 133 patients Measure imatinib trough at day 15 of treatment Group 1: If IM < 1000 ng/ml dose escalation to IM level > 1000 Group 2: If IM < 1000 ng/ml standard management Group 3: If IM > 1000 ng/ml observation Primary study endpoint: Major MR rate at 12 months
Results: IM trough < 1000 ng/ml in 86/133 pts (65%), assigned to group 1 or 2 Group 1 63% Group 2 37% Major MR rate at 12 mths Group 3? NS No significant difference in adverse events. P value <.001 Conclusion: 2/3 rd of patients are underdosed on IM 400 mg Strong case for personalised dosing to optimise outcome
Resurrecting alpha interferon
Abs 456. Pegylated Interferon a2a (PegIFN) At the Dose of 45µg Per Week in Combination with Imatinib 400mg Is the Recommended Initial Dose for Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CML-CP): Results From the French SPIRIT Trial of the French CML Group (FI LMC) Hyacinthe Johnson-Ansah,. & Francois Guilhot Imatinib 400mg + PegIFN 90ug/wk had superior molecular response but 45% cessation by 12mths Response correlated with duration, < 4mths vs >12 mths Dose adjustment to 45ug/week Preudhomme NEJM 2010
Abs 456. Pegylated Interferon a2a (PegIFN) At the Dose of 45µg Per Week in Combination with Imatinib 400mg Is the Recommended Initial Dose for Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CML-CP): Results From the French SPIRIT Trial of the French CML Group (FI LMC) Hyacinthe Johnson-Ansah,. & Francois Guilhot AE before the amendment (n=171) AE after the amendment (n=50) Hematologic toxicity Grade 3-4, % 54 27 % receiving > 12 mths pegifn 65 90 % reaching < 4 log MMR 25 28 Neuropsychiatric syndrome 4 4 Imatinib Imatinib /pegifn PFS at 60 mths 92% 94% Blast crisis 11% 6% Death in chronic phase 2 5 Verbal comment by Dr. Guilhot - trend in survival favouring pegifn is appearing Trials in progress with 2 nd generation TKIs
Allogeneic Stem Cell Transplantation
Influence of Age on Survival Post-HSCT in Chronic Phase (CP) CML 1.0 < 20 years (N = 14) Probability of Survival 0.8 0.6 0.4 0.2 20 and < 30 years (N = 50) 30 and < 40 years (N = 81) 50 years (N = 19) 40 and < 50 years (N = 51) 0 0 5 10 15 20 Years N = 215, 1982-1997. Thomas ED et al. Ann Intern Med. 1986;104:155-163 and findings noted by Radich J, MD (written communication, January 2007). Findings noted by Radich J, MD (written communication, January 2007).
Related Transplants ( 1992)