How will I know if I’m doing OK on treatment and when might you consider changing my treatment?

1. How will I know if I’m doing OK on treatment and when might you consider changing my treatment? Dr Andy Goringe

2. How will I know? • How should I feel? • What should I watch out for? • What can I do to help myself?

3. IRIS 8-Year UpdateResults: Overall Survival (Intent-to-Treat) – Imatinib Arm 1 0 0 9 0 8 0 7 0 E s t i m a t e d o v e r a l l s u r v i v a l 6 0 a t 8 y e a r s w a s 8 5 % (93%, considering onlyCML related deaths) % 5 0 , e v i l 4 0 A 3 0 2 0 S u r v i v a l : d e a t h s a s s o c i a t e d w i t h C M L 1 0 O v e r a l l S u r v i v a l 0 0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 M o n t h s S i n c e R a n d o m i z a t i o n % Alive Deininger M, et al. Blood. 2009;114(22):462. Abstract # 1126.

4. How can we monitor your progress? • Clinical examination • spleen • Peripheral blood count • Complete Haematological Response (CHR) • Platelets <450, WBC within normal range and with no immature cells, <5% basophils • BM examination • Cytogenetics and FISH • PCR testing

5. The Philadelphia Chromosome: t(9;22) Translocation 9 9+ 22 Ph bcr bcr-abl abl FUSION PROTEINWITH TYROSINEKINASE ACTIVITY

6. European LeukaemiaNet Guidelines

7. 3 months • Optimal • BCR-ABL1 ≤ 10% and/or • Ph+ ≤ 35% • Warning • BCR-ABL1 > 10% and/or • Ph+ 36-95% • Failure (Change Treatment) • Non CHR and/or • Ph+ > 95%

8. PCR at 3 months • German CML IV study • 1303 newly diagnosed imatinib-treated patients • BCR/ABL levels at 3 months (IS) • >10% 28% patients 5yr OS 87% • >1-10% 41% patients 5yr OS 94% • ≤ 1% 31% patients 5yr OS 97% • Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia. 2012 Sep;26(9):2096-102. Hanfstein B et AL • Hammersmith Study • 282 patients treated with Imatinib front-line • BCR/ABL levels at 3 months (IS) • >9.84% 8yr OS 56.9% • <9.84% 8yr OS 93.3% • Assessment of BCR-ABL1transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukaemia treated with tyrosine kinase inhibitors. J Clin Oncol 30(3):232-238 Marin D et al

9. Should I consider changing treatments if my PCR >10% at 3 months? • Yes, though we’re not entirely sure • Variability in PCR results • Co-morbidities • Side effects / compliance • Initial risk score • Lack of trial data

10. 6 months • Optimal • BCR-ABL1 < 1% and/or • Ph+ 0 • Warning • BCR-ABL1 1-10% and/or • Ph + 1-35% • Failure • BCR-ABL1 > 10% and/or • Ph + >35%

11. 12 months • Optimal • BCR-ABL1 ≤ 0.1% • Major Molecular Response (MMR) • Warning • BCR-ABL1 0.1-1% • Failure • BCR-ABL1 > 1% and/or • Ph+ >0 • Failure to achieve a Complete Cytogenetic Response (CCyR)

12. Should I consider changing my treatment? • Warning • CCyR may have been achieved with a BCR-ABL level 0.1-1%. • If it has I would be reluctant to change • Failure • Should consider changing • ? trend of PCR level

13. After 12 months • Optimal • BCR-ABL1 ≤ 0.1% • Warning • CCA Ph- (-7, or 7q-) • Failure • Loss of CHR • Loss of CCyR • Confirmed loss of MMR • Mutations • CCA Ph+ PCR monitoring every 3-6 months after MMR

14. Will I need another BM? • Achievement of CCyR is an important milestone • OS is similar between patients achieving CCyR and MMR in most studies • Though patients achieving MMR are less likely to lose CCyR at any stage in the future • BM picks up CCA Ph- cells • Not always helpful • PCR level 0.1-1% correspond to CCyR? • In practice I would prefer confirmation of CCyR but often do not repeat BM in patients clearly achieving a MMR • I would want confirmation of CCyR in patients not achieving MMR

15. Thank you • Any Questions?