1. The Challenge of Monitoring CML When Resources Are Limited Jorge Cortes, MD Chief, CML & AML Section Department of Leukemia MD Anderson Cancer Center

2. 1 Number of leukemic cells 10 12 10 6 10 8 10 10 2 10 4 CML Evaluating Response in CML 3 log reduction Limits of detection 4 log reduction Molecular response (Q-PCR) CCR (CG) MCR Cytogenetic response CCR (FISH) CHR Hematologic response

3. 1 Number of leukemic cells 10 12 10 6 10 8 10 10 2 10 4 CML Evaluating Response in CML 3 log reduction Limits of detection 4 log reduction TKIs CCR (CG) MCR Interferon CCR (FISH) CHR Hydroxyurea

4. IFN  in CML Survival by CG Response Kantarjian et al. Cancer 2003; 97: 1033

5. 5 Monitoring Procedures in CML CG: looks at all chromosomes; but: tedious; needs metaphases; only 20 cells counted (95% CI CCyR 15%); painful BM FISH: faster; 200 cells; PB; but: false (+) up to 5-10%; no information on other chromosomes PCR: most sensitive; PB; evaluable in CCyR; predicts for relapse; but: not standardized; no information on other chromosomes; variability up to 0.5 log; use 1 source (PB) and 1 reliable lab

6. Monitoring Recommendations for CML According to the ELN 2009 ObjectiveRecommended frequency Hematologic Every 2 wk until CHR, then at least every 3 mo or as required Cytogenetic At diagnosis, 3 mo, 6 mo and every 6 mo until confirmed CCyR, then every 12 mo if molecular monitoring not assured At failure or unexplained myelosuppression Molecular Every 3 mo until MMR confirmed, then every 6 mo Mutations In case of failure or suboptimal response, or before change to 2 nd TKI Baccarani et al. JCO 2009; 27: 6041-51

7. Why Do We Monitor? The number is not important! Identify good responses Predict long-term outcome Identify patients who need alternative therapy

8. So What Do We Get? ResponseTranslates into: CHRDecreased symptoms CCyR Significantly improved survival MMR Improvement in EFS, possible longer duration CCyR CMR Possibility of considering treatment discontinuation (clinical trials only)

9. Common Obstacles for Proper Monitoring Education – Patient: goals – Healthcare provider: significance Availability Reliability Lack of standardization Training Cost

10. Base: 435 respondents Q5 - When a patient of yours receives a preliminary diagnosis of CML, where do you typically obtain confirmatory testing by cytogenetics, FISH or PCR? Nearby labs in the country are the most commonly used. Physicians working in Academic settings use less commercial labs and have more accessibility to labs located in the hospitals where they work. Cytogenetics or FISHPCR

11. Q8 - In addition to peripheral blood counts, which of the following do you routinely use in monitoring response to imatinib therapy? Base: 435 respondents A majority of respondents routinely use cytogenetics to monitor the response to imatinib; 2/3 rds use quantitative PCR

12. Base: 435 respondents Q9 - How frequently do you typically repeat cytogenetic analysis studies for monitoring response to imatinib therapy? Q10 - How frequently do you typically repeat qRT-PCR for BCR-ABL when monitoring response to imatinib therapy? Base: 435 respondents Cytogenetics is performed every 6 months by half of respondents and every 3 months by 1/3 rd of them qRT-PCR is performed every 6 months for 41% of respondents and 13% of them never use this test

13. Base: 435 respondents Q11 - How frequently do you typically repeat BCR-ABL kinase domain mutation studies for monitoring response to Imatinib therapy? BCR-ABL kinase domain mutations analysis is not available for 40% of respondents. When available, 1/3 rd use it to evaluate the failure to achieve or the loss, of an hematologic response

14. What To Do In The Absence of Adequate Monitoring Tools Educate patients (and healthcare providers) Avoid unnecessary treatment interruptions and dose reductions Emphasize adherence to therapy – Help patients More frequent follow-up Most reliable and accessible monitoring tool at least every 12 months

15. Important Considerations Regarding Molecular Monitoring in CML Molecular monitoring can assess cytogenetic response Maintain same source Maintain same lab – IS to minimize this problem Consider variability of test Uniform reporting Needs: standardization, speed, access

16. The Goal of Universal Standardization One test Simple Automated Formal standardization (e.g., WHO) Inexpensive

17. The Evolution of Blood Counting

18. Improving Diagnostic/Monitoring Tools The Xpert BCR-ABL Assay ~2 hrs

19. Work for the Future Aim high Work towards centralization Train personnel Resources: – Authorities – Organizations (MAX, iCMLf, etc) – Corporations

20. The ERSAP Diagnosis and Testing Program is providing unprecedented access to CML diagnostics allowing access to treatment along with enhanced monitoring ensuring optimal outcomes for people with CML. Become an iCMLf member at - www.cml-foundation.org

21. Analysis of Mutations in CML Over emphasized; results produce more false therapeutic leads than benefits No role for mutation studies pre-Rx or in imatinib responding patients If CG or hematologic relapse, mutations studies may help – T315I: no role for new TKIs; allo SCT or others (HU, ara-C, HHT, “T315I inhibitors”) – Nilotinib IC 50 >150nM (e.g. Y253H, E255V, F359V)  Dasatinib – Dasatinib IC50>3nM (e.g. F317L, V299L)  Nilotinib But: ~50% have no mutations, and no difference or no information for most

22. Not everything that counts can be counted, and not everything that can be counted counts. Albert Einstein (1879-1955) (Sign hanging in Einstein's office at Princeton)

23. Questions? jcortes@mdanderson.org 713-794-5783