Late Responders to Imatinib: Is Timing of Achievement of Complete Cytogenetic and Molecular Responses the Same in Previously Treated as Compared to the Newly Diagnosed CML Patients?

Appropriate monitoring of the effect of tyrosine kinase (TK) therapy is a relevant issue for CML therapeutic strategy. Although cytogenetics is the gold-standard method for response evaluation, serial quantification of BCR-ABL levels by real time PCR (RQ-PCR) has shown accuracy in predicting therapeutic response. Optimal cytogenetic (CCyR) and molecular (MMR) responses for newly diagnosed chronic phase (CP) CML patients were defined within 12 and 18 months of Imatinib (IM) therapy. However, patients not achieving optimal responses (OpRes) within these times are classified as “late responders”. We evaluated a group of 142 patients (4 year follow up) treated with IM as 2^nd line. Patients were classified in 3 groups according to previous treatment: IFN (n=90), SCT (n=11) and HU/IFN ≤3 months (n=41, considered as without treatment). BCR–ABL levels were measured every 3 months, at least 5 times/patient during follow-up. A laboratory-specific conversion factor of 1.33 was generated to convert the BCR-ABL/ABL% values to an International Scale (IS). At the moment, 90 patients are being followed (69 CP, 11 AP). Cytogenetics results were available in 80/90 cases, and 63/80 (79%) (55 CP, 8 AP) achieved CCyR. After 12 months of IM treatment, 30/63 cases (48%) obtained CCyR (early responders), and 33/63 (52%) were late responders. When 18 months were considered as a cut-off time to achieved OpRes, 46 (73%) were considered early and 17 (27%) late responders. Molecular data were available for 74 patients; 45/74 (61%) (40 CP, 5 AP) achieved MMR, and 20 (27%) also showed Complete MR. 10/45 cases (22%) were early responders, and 35/45 (78%) late at 18 months of IM. When evaluating at 24 months, 17 (38%) were early and 28 (62%) were late responders. When only CP patients that achieved CCyR (n=55) and MMR (n=40) were considered, these proportions were maintained. Attainment of CCyR/MMR was similar between patients with and without previous treatment (p=0,26;p=0,09). However, we found a delay in the timing of OpRes achievement in comparison with previous related work analyzing patients in 1^st line IM. Thus, to achieve similar frequencies of CCyR/MMR obtained from the use of 1^st line IM, previously treated patients needed an extension time of 6 months. Thus we suggest for the patients treated with IM as 2^nd line a threshold of 18 months for CCyR and 24 for MMR for the establishment of the OpRes. This swap concept might be important in countries such as Brazil that postponed the introduction of IM as 1^st line therapy for CML.