An NCRI randomised study comparing dasatinib with imatinib in patients with newly diagnosed CML Stephen O’Brien, Corinne Hedgley, Sarah Adams, Richard Clark, Jane Apperley, Letizia Foroni, Chris Pocock, Tessa Holyoake, Jenny Byrne, Caroline Hodgson, Wendy Osborne, Mhairi Copland, John Goldman The Newcastle Hospitals www.spirit-cml.org NHS Foundation Trust
814 patients recruited Recruitment closed Feb 2013 172 hospitals set up 145 recruited patients
Acknowledgements Stephen O’Brien, Corinne Hedgley, Sarah Adams Data analysis and presentation Trial management and Corinne Hedgley, Lynn Seeley, Caroline Hodgson, Ruth Bescoby, data collection Carrie Page, Angela Fallows, Laura Brown, Wendy Banks, Meg Newcastle Buckley, Leanne Woolmer, Wendy Osborne PCR & DNA/RNA biobanking Letizia Foroni, Gareth Gerrard, Hammersmith Cell biobanking Tessa Holyoake, Alan Hair, Glasgow SO’B, CH, Richard Clark, Liverpool; Jane Apperley, Hammersmith, Study Management Committee Mhairi Copeland (Chair of CML WG) Data Monitoring Committee John Goldman , Keith Wheatley, Graham Dark Sponsor Newcastle Hospitals NHS Foundation Trust Funder Bristol Myers Squibb Stephen O’Brien Chief Investigator Sites n=172. Thanks to all our investigators and site staff. Patients n=814. A huge thank you to all participating patients.
TKIs in CML Off patent 2016 Imatinib Development License NICE approved Dasatinib Nilotinib Bosutinib Ponatinib (radotinib) CDF 2000 2005 2010 2015
Background • Imatinib still used as first line therapy • 2 nd generation TKIs generally produce higher rates of major molecular response • Dasision study* (n= 519) MR 3 (MMR) at 3 years: • Imatinib 55% 69% still on treatment • Dasatinib 69% 71% still on treatment • No differences in OS at 3 years • Some concerns about long term safety of 2 nd gen • SPIRIT 2 (n=814) is largest comparative dasatinib trial *Jabbour et al . Blood (2014); 123: 494-500
SPIRIT 2: study design Arm A Imatinib 400 Chronic phase CML N=407 R within 3 months of diagnosis n=814 Arm B Dasatinib 100 N=407 Randomised, open label Primary endpoint: 5 year EFS Secondary: cytogenetic, PCR response, toxicity
Inclusion criteria 1. Male or female patients ≥ 18 years of age. 2. Patients must have all of the following: i) be enrolled within 3 months of initial diagnosis of chronic phase CML ii) confirmation of the Philadelphia chromosome or variants of (9;22) translocations; iii) (a) < 15% blasts in peripheral blood and bone marrow; (b) < 30% blasts plus promyelocytes in peripheral blood and bone marrow; (c) < 20% basophils in peripheral blood, (d) ≥ 100 x 109/L platelets iv) no evidence of extramedullary leukaemic involvement, with the exception of hepatosplenomegaly. 3. Written voluntary informed consent.
Exclusion criteria 1. Ph-negative, BCR-ABL-positive, disease not eligible 2. Any prior treatment for CML (hydroxycarbamide and anagrelide permitted) 3. Prior chemotherapy, including PBSC mobilisation 4. Prior autograft or allograft 5. ECOG Performance Status Score ≥ 3 6. >2x ULN liver, renal function; >1.5x ULN coag; warfarin OK 7. Uncontrolled medical disease; known HIV pos; major surgery within 4 weeks 8. Patients who are: pregnant; breast feeding; not on appropriate contraception 9. Other malignancy within the past five years (except BCC)
Endpoints Primary : • 5 year event free survival (EFS) – Assessed for all patients March 2018 Secondary : • Rate of complete cytogenetic response (CCR) • Rate of Major Molecular Response – (MMR, MR 3 , BCR-ABL/ABL ratio<0.1%) • Toxicity • Treatment failure rates (TFR) after 5 years • Rates of complete haematologic response (CHR) • Overall survival at two and 5 years
Patients enroled Aug 2008 to Feb 2013 814 in 54 months: 15 per month Imatinib Dasatinib Total Characteristic n=407 (%) n=407 (%) n=814 (%) Age Median 53.0 53.0 53.0 Range 18.0-87.0 18.0-89.0 18.0-89.0 Gender Female 165 (40.5) 157 (38.6) 322 (39.6) Male 241 (59.2) 249 (61.2) 490 (60.2) NK 1 (0.2) 1 (0.2) 2 (0.2) Available data for Sokal 242 (59.6) 246 (60.6) 488 (60.1) Follow up (months) Median 35.0 35.0 35.0 7 – 65 8 – 68 Range 7 - 69
What happened to the patients? Imatinib Dasatinib Total n=407 (%) n=407 (%) n=814 (%) Consent withdrawl/protocol 1 (0.2) 1 (0.2) 2 (0.2) violation Treated 406 (%) 406 (%) 812 (%) All deaths, 12 (3.0) 14 (3.4) 26 (3.2) any cause Ongoing 249 (61.3) 291 (71.7) 540 (66.5) Discontinued 157 (38.7) 115 (28.3) 272 (33.5)
Patients who discontinued Imatinib Dasatinib Total n=157 (%) n=115 (%) n=272(%) Consent withdrawn 4 (1.0) 9 (2.2) 13 (1.6) Death, any cause 7 (1.7) 4 (1.0) 11 (1.4) Accelerated phase 3 (0.7) 2 (0.5) 5 (0.6) Blast crisis 7 (1.7) 4 (1.0) 11 (1.4) Failure to achieve CCR after 24 months 3 (0.7) 1 (0.2) 4 (0.5) Failure to achieve MCR after 12 months 20 (4.9) 3 (0.7) 23 (2.8) Intolerance - non haem tox 48 (11.8) 67 (16.5) 115 (14.2) Intolerance - haem/lab tox 11 (2.7) 10 (2.5) 21 (2.6) Loss of CHR 4 (1.0) 0 4 (0.5) Loss of MCR 8 (2.0) 2 (0.5) 10 (1.2) Lost to follow up 1 (0.2) 0 1 (0.1) Other 4 (1.0) 10 (2.5) 14 (1.7) Suboptimal respose (cytogenetic, haematological, molecular, 37 (9.1) 3 (0.7) 40 (4.9) mutation detected)
Adverse events Imatinib Dasatinib All grades n=406 (%) n=406 (%) Fluid retention 12 (3.0) 11 (2.7) Oedema 7 (1.7) 4 (1.0) Pleural effusion 3 (0.7) 77 (19.0) 13 (3.2) Required chest drain 0 13 of 77 is 16.9% Myalgia 32 (7.9) 23 (5.7) Nausea 124 (30.5) 91 (22.4) Vomiting 49 (12.1) 46 (11.3) Diarrhoea 119 (29.3) 96 (23.6) Fatigue 102 (25.1) 119 (29.3) Headache 52 (12.8) 101 (24.9) Rash 69 (17.0) 97 (23.9) Dyspnoea, no pleural effusion 32 (7.9) 69 (17.0)
Comparative AEs Fluid retention Difference Oedema Pleural effusion Myalgia 95% CIs Nausea Vomiting Diarrhoea Fatigue Headache Rash Pulmonary (arterial) hypertention Dyspnoea (exertional) with no pleural effusion Favours dasatinib Favours imatinib
Lab AEs Imatinib Dasatinib Total 406 (%) 406 (%) 812 (%) All grades Grade 3/4 All grades Grade 3/4 All grades Grade 3/4 Anaemia 362 (89.2) 105 (25.9) 372 (91.6) 124 (30.5) 734 (90.4) 229 (28.2) Neutropenia 187 (46.1) 40 (9.9) 208 (51.2) 44 (10.8) 395 (48.6) 84 (10.3) Thrombocytopenia 194 (47.8) 17 (4.2) 280 (69.0) 51 (12.6) 474 (58.4) 68 (8.4) Elevated ALT 148 (36.5) 6 (1.5) 180 (44.3) 0 328 (40.4) 6 (0.7) Elevated creatinine 81 (20.0) 13 (3.2) 71 (17.5) 17 (4.2) 152 (18.7) 30 (3.7)
PCR milestones (used in SPIRIT 3) Imatinib Dasatanib Total (n=406) (n=406) (n=812) 3 month samples 305 (100%) 304 (100%) 609 (100%) PCR <10% (MR1) 147 (48.2) 235 (77.3) 382 (62.7) 12 month samples 340 (100%) 358 (100%) 698 (100%) PCR <1.0% (MR2) 240 (70.6) 301 (84.1) 541 (77.5) 18 month samples 274 (100%) 291 (100%) 565 (100%) PCR <0.1% (MR3) 137 (50.0) 163 (56.0) 300 (53.1)
PCR response and pleural effusion Imatinib Dasatinib Total n=406 n=406 n=812 Available 18 month PCR 274 (100%) 291 (100%) 565 (100%) PCR <0.1% (MR3) 137 (50.0) 163 (56.0) 300 (53.1) No pleural effusion Available 18 month PCR 272 (100%) 233 (100%) 505 (100%) PCR <0.1% (MR3) 137 (50.4) 125 (53.6) 262 (51.9) With pleural effusion Available 18 month PCR 2 58 60 PCR <0.1% (MR3) 0 38 (65.5) 38 (63.3)
Conclusions • Largest randomised trial of dasatinib vs imatinib – n=814 – median follow up 3 years • Both drugs generally well tolerated – 540 of 812 (66.5%) continue on study medication – GI tox, pleural effusions – No difference in cardiovascular events • 786/812 (96.8%) remain alive overall • Comparative response, survival to follow • Dasatinib might allow more patients to reduce dose, stop • Dasatinib supply free of charge until at least 2018
Key questions in CML 1. 10% at 3 months seems important. Can we improve outcome by switching drugs? 2. Imatinib is going to be around for a while. Can we work out how best to use it? 3. Can we give CML patients less treatment, minimise toxicity and stop treatment? – Quality of life, toxicity – Economics – Survival not compromised; ‘cure’ 4. What’s the most cost effective way to treat CML? 5. Can we personalise treatment?
www.spirit-cml.org
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An NCRI randomised study comparing dasatinib with imatinib in patients with newly diagnosed CML Stephen O’Brien, Corinne Hedgley, Sarah Adams, Richard Clark, Jane Apperley, Letizia Foroni, Chris Pocock, Tessa Holyoake, Jenny Byrne, Caroline Hodgson, Wendy Osborne, Mhairi Copland, John Goldman www.spirit-cml.org The Newcastle Hospitals Stephen.O’Brien@ncl.ac.uk NHS Foundation Trust
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