1. P Ferguson, R Hills, A Grech, L Kjeldsen, M Dennis, P Vyas, R Clark, N Russell, C Craddock, On behalf of the NCRI AML Working Group. An operational definition of primary refractory acute myeloid leukaemia which allows early identification of patients who may benefit from allogeneic stem cell transplantation

2. Introduction Up to 40% of adults with AML fail to achieve a complete remission (CR) after induction chemotherapy (IC). Currently there is no consensus definition of Primary Refractory AML (PREF AML). This lack of a diagnostic consensus has compromised the development of treatment strategies in PREF AML.

3. Current working definitions of PREF AML include: – International Working Group/European LeukaemiaNet “Patients surviving 7 days following completion of initial treatment, with evidence of persistent leukemia by blood and/or bone marrow examination” Cheson et al. Journal of Clinical Oncology. 2003. 21: 4642-4649. Dohner et al. Blood. 2010. 115: 453-474. Other studies define PREF AML as a failure to achieve CR with two courses of IC. Conjecture exists regarding whether the degree of response to the first cycle (C1) of IC is predictive of outcome Rowe et al. Cancer. 2010. 116: 5012-5021. Schlenk et al. Leukaemia. 2003. 17: 1521-1528. Wheatley et al. British Journal of Haematology. 1999. 107: 69-79.

4. Allogeneic stem cell transplant (AlloSCT) delivers long term survival in a proportion of patients with PREF AML. Duval et al. Journal of Clinical Oncology. 2010. 28;23:3730-3738. Craddock et al. Leukaemia. 2011. 25;5: 808-813. The advent of reduced intensity conditioning (RIC) has increased the availability of AlloSCT to patients with PREF AML. The optimal role of AlloSCT in the management of PREF AML is unknown due to: – Inconsistent criteria for defining PREF AML – selection bias of small registry based transplant reports

5. Aims Analyse the survival outcomes for patients not in CR after 1 or 2 courses of IC utilising different definitions of PREF AML in order to: – Derive a definition of PREF AML that allows early identification of patients who are predicted to have poor outcomes with IC. – To characterise more precisely the outcomes for patients with PREF AML. – To study the impact of AlloSCT on survival in PREF AML.

6. Methods Retrospective analysis of 8,907 patients with non APML AML treated with intensive chemotherapy on the UK MRC/NCRI AML 10 - 16 trials. Disease response was assessed by morphological bone marrow evaluation approximately 21 days after completion of IC. Applied four differing criteria for PREF AML following 1 or 2 cycles of IC and correlated these with patient outcome. Evaluated the impact of AlloSCT on long term survival of patients defined by each of the four definitions of PREF AML.

7. REF1A Not in CR post C1 N = 2548 REF1B Minor Response >15% blasts & <50% blast reduction N = 802 REF1C Major Response <15% blasts or >50% blast reduction N = 1746 REF2 Not in CR post C2 N = 473

8. Transplant characteristics 581 AlloSCT 413 MAC 168 RIC 251 SIB 162 MUD 73 SIB 95 MUD

9. Overall survival according to four definitions of PREF AML

10. Survival in PREF AML in patients under 60yrs

11. Survival in PREF AML of patients aged over 60yrs

12. Transplant outcomes in PREF AML according to definition REF 1A – 2356 total REF 1B – 721 total REF 1C – 1685 total REF 2 – 419 total ( Tx26 not 1B;NTx 146) REF 3 – 968 total

13. Transplant outcomes in the REF1B cohort: <50yrs

14. Transplant outcomes in the REF1B cohort: >50 yrs

15. Transplant outcomes in the REF2 cohort: <50 yrs

16. Transplant outcomes in the REF2 cohort: >50yrs

17. Conclusions Failure to achieve CR following one course of IC is associated with reduced survival compared to patients achieving CR. REF1B and REF2 criteria identify patients with PREF AML whose survival is extremely poor with chemotherapy alone- defining more clearly chemorefractoriness. Adoption of REF1B criteria allows early identification of PREF AML patients and represents a novel, operational disease definition.

18. This definition of PREF AML is valid for patients treated on IC protocols designed for older or younger patients. The REF1B definition of PREF AML requires validation in patients receiving high dose Ara-C containing IC. AlloSCT represents a curative strategy in patients with PREF AML defined according to either REF1 B or REF2 criteria. Outcomes after allografting may improve with earlier donor identification and improved supportive care Early identification of PREF AML, using the REF1B criteria, has the potential to improve transplant outcomes in PREF AML.

19. Acknowledgements Leukaemia and Lymphoma Research Medical Research Council Cancer Research UK Participating patients Research nurses Data co-ordinators Treating clinicians