© F e r r a t a S t o r t i F o u n d a t i o nreported that sustained CMR for more than two consecutive years can lead to cessation of IM treatment without molecular relapse in almost 40% of cases. 12 We set out to assess the frequency of CMR in CP-CML patients treated with IM as front-line therapy, identify both base-line and under-treatment predictive factors of CMR in patients who achieved CCyR on IM therapy, and determine whether achieving a CMR was associated with a better outcome. MethodsPatients with diagnosed Philadelphia chromosome-positive (Ph-positive) CML referred to the two participating centers (University Hospitals of Bordeaux and Lyon) from January 2000 to March 2010 who were in chronic phase at diagnosis, treated with front-line IM, were considered for inclusion in this study.All patients provided informed consent to participate in the study. The study was approved by the local ethics committee and by the French Data Protection Authority (Commission Nationale Informatique et Libertés, CNIL, Paris, France).Cytogenetic responses were evaluated at least every six months during the first year of therapy and then every 3-6 months until CCyR. During follow up and after a first CCyR documented on cytogenetic analysis, a BCR-ABL transcript level below 1% (IS) was considered as equivalent to CCyR.Molecular response was assessed according to previously reported recommendations. 13 MMR was defined as a reduction of BCR-ABL/ABL level of at least 3 logs from a standardized base-line value and confirmed on two consecutive analyses at least two months apart. In the current work, CMR was defined as MR4.5 with undetectable BCR-ABL transcript on two consecutive analyses at least two months apart. Loss of MMR and of CMR were defined as BCR-ABL/ABL transcripts of 0.1% or over and detectable BCR-ABL transcript, respectively, both on two consecutive analyses at least two months apart.Univariate and multivariate analyses were performed with Cox regressions. Fine and Gray models were used to analyze the cumulative incidence of molecular responses.EFS, failure-free survival (FFS) and OS were measured from the date of the first CCyR on therapy to the date of event or death. Survival differences, estimated by KaplanMeier analysis for patients of the different groups, were assessed using a log rank test.Times to event were measured as the time between date of CCyR and the event of interest. For censored cases, it corresponded to time between date of CCyR and the last observational period under IM. EFS referred to survival without loss of complete hematologic response, loss of CCyR, detection of a BCR-ABL domain kinase point mutation associated with a high level of IM resistance, progression to accelerated or blastic phase, death from any cause on or off therapy, treatment cessation for toxicity. FFS referred to survival without events previously described with the exception of treatment cessation for toxicity according to the ELN recommendations. 14 Only the first event for an individual patient was considered.Pa...

In chronic myeloid leukemia (CML), cytogenetic abnormalities found in addition to the t(9;22) translocation may impact the response to therapy. Loss of the Y chromosome is generally overlooked in this context, owing to its relatively frequent occurrence in healthy elderly patients. In this multicenter retrospective study, the outcome after imatinib treatment of 30 CML patients with karyotype showing Y chromosome loss (Y-) was compared to 30 Y+ control males diagnosed and treated at the same time in the same institutions. Y-patients had significantly delayed cytogenetic and molecular responses, lower event-free survival and shorter overall survival than Y+ patients. The negative impact of this abnormality was particularly marked when it occurred in a sub-clone (clonal evolution) rather than in all mitoses. These data indicate that loss of the Y chromosome should be taken into account in the prognostic evaluation of chronic myelogenous leukemia patients.

Purpose To assess the incidence of BCR‐ABL kinase domain (KD) mutation detection and its prognostic significance in chronic phase chronic myeloid leukemia (CP‐CML) patients treated with tyrosine kinase inhibitors (TKIs). Patients and Methods We analyzed characteristics and outcome of 253 CP‐CML patients who had at least one mutation analysis performed using direct sequencing. Of them, 187 patients were early CP (ECP) and 66 were late CP late chronic phase (LCP) and 88% were treated with Imatinib as first‐line TKI. Results Overall, 80 (32%) patients harbored BCR‐ABL KD mutations. A BCR‐ABL KD mutation was identified in 57% of patients, who progressed to accelerated or blastic phases (AP‐BP), and 47%, 29%, 35%, 16% and 26% in patients in CP‐CML at the time of mutation analysis who lost a complete hematologic response, failed to achieve or loss of a prior complete cytogenetic and major molecular response, respectively. Overall survival and cumulative incidence of CML‐related death were significantly correlated with the disease phase whatever the absence or presence of a mutation was and for the latter the mutation subgroup (T315I vs P‐loop vs non‐T315I non‐P‐loop) ( P <.001). Considering patients who were in CP at the time of mutation analysis, LCP mutated patients had a significantly worse outcome than ECP‐mutated patients despite a lower incidence of T315I and P‐loop mutations ( P <.001). With a median follow‐up from mutation analysis to last follow‐up of 5 years, T315I and P‐loop mutations were not associated with a worse outcome in ECP patients ( P = .817). Conclusion Our results suggest that early mutation detection together with accessibility to 2nd and 3rd generation TKIs have reversed the worst outcome associated with BCR‐ABL KD mutations whatever the mutation subgroup in CP‐CML patients.

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Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2–3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2–3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2–3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.