Renault IZ, Scholl V, Hassan R, Capelleti P, Lima M, Cortes J The group of patients with CCyR was heterogeneous, consisting of those who had CCyR associated to MMR or not. The individual value of MMR was demonstrated in several studies.(16-20) A recent work established an association between MMR and loosing CCyR. After 18 months of IM treatment, the probability of loosing CCyR when associated to MMR was 0% compared to 25% for patients with a CCyR but no MMR.(21) Patients who achieve MMR at 6, 12 or 18 months after initiating IM treatment have a probabilities of 93%, 69% and 37%, respectively, to evolve with a lasting CCyR.(22) Thus, achievement (and speed to achieve) MMR is a predictive factor for a durable CCyR. Rapidity in obtaining a MMR correlates with a higher probability of achieving a CMR. Patients achieving a MMR at 9 months have a 93% of probability of evolving towards a CMR. Also, achievement of a MMR within 12 months of starting the IM regimen was associated with a better PFS.(17,18) However, other studies have not confirmed significant differences in OS and PFS in CCy responders in respect to the level of molecular response achieved.(23) The additive effect of MMR associated to CCyR highlights the importance of a better understanding of the role of duration, extension and stability of a MMR in respect to clinical evolution. Once achieved, does the major molecular response become more stable over time? Besides the prognostic value of an early MMR, whether a stable MMR occurring during the course of a stable CCyR is an additive parameter to predict a better clinical evolution is a matter of discussion. A stable molecular response is associated with a lasting CCyR.(24) MMR has been subdivided as stable (persistent MMR), unstable (occasionally less than MMR) and never reached MMR. A significant difference was observed, in terms of duration of CCyR and PFS between patients with stable versus unstable MMR and patients who never reached MMR. After a long follow-up from the first assessment of a cytogenetic response, 96% of patients with stable MMR maintain a CCyR compared with 79% of patients with unstable molecular response. Similar results were reported by the MD Anderson Cancer Center (MDACC) group of 276 CML patients treated with high-dose IM therapy; a durable and stable MMR (continuous MMR lasting for a period > 12 months) was associated with a longer PFS. What is the meaning of fluctuating BCR-ABL levels? Clinicians should be aware of inherent assay variations within a laboratory. Therefore, values may fluctuate, but without clinical significance, on occasions. What constitutes a significant change varies between laboratories. Different patterns of molecular responses based in fluctuations of BCR-ABL levels have been reported in the 458 literature. Molecular monitoring may allow early recognition of acquired resistance. Increasing levels of BCR-ABL transcripts or suboptimal molecular responses (fluctuations at high BCR-ABL levels, i.e. 10%-1% on the IS at 18 months) are associated with increased risk of resistance due to mutations and loss of CCyR. In our experience, an increase of the BCR-ABL load to higher than 1% on any occasion is correlated with a loss of CCyR. In contrast, fluctuations at low BCR-ABL levels of from ≤ 0.1% IS values to undetectable levels, were associated with maintenance of the molecular response. Whether the stability and clinical value of an absolute clearance of BCR-ABL+ cells as detected by the most sensitive methodology (4.5 log by RT-qPCR) is the same as fluctuations of BCR-ABL at lower levels is still to be seen. Are molecular remissions all the same? MMR comprises those patients with tumor burden decreases to the range of 0.1% - 0.001% on the IS. The latter (MMR ≤ 0.001%) includes patients with undetectable levels by the most sensitive techniques available today (Nested- PCR and RT-qPCR) which are controversially classified as CMR. This difference between MMR and CMR is important because there is still a debate regarding the possibility of stopping IM in patients with a stable CMR. A French study showed that half of the patients who achieved and maintained CMR for a period of 2 years remained in CMR after IM discontinuation.(25) The primary endpoint of the Stop Imatinib Trial (STIM study) is the evaluation of the persistence of molecular remission after IM discontinuation. Although 50% of patients who suspended IM are reported in CMR, the discontinuation of the drug is not recommended outside clinical trials. Resistance to tyrosine kinase inhibitors Selection or evolution of resistant clones is a major cause of treatment failure in targeted therapy for CML. The most common identified cause of resistance in TKI-treated patients is the acquisition of point mutations in the tyrosine kinase domain of BCR-ABL that could (i) interfere with binding of IM to the ATP pocket;(26) (ii) prevent the adoption of the conformation required for optimal TKI binding or (iii) stabilize the enzyme in a conformation that is inaccessible to the action of TKI. Mutation analysis remains an important tool in TKI resistance assessment. The current recommendation for mutation analysis is on IM failure or suboptimal response. The latter includes failure to achieve a CHR or cytogenetic response (CyR) (95% Ph+) by 3 months; major cytogenetic response (MCyR) by 6 months; CCyR by 12 months, and MMR by 18 months. Among these parameters, the association between MMR at 18 months and acquisition of a resistant phenotype due to a point mutation in the BCR-ABL kinase domain is the least well defined. Rev Bras Hematol Hemoter. 2011;33(6):455-60