A single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.

We studied the relation between adherence to imatinib measured with microelectronic monitoring systems and the probabilities of losing a complete cytogenetic response (CCyR) and of imatinib failure in 87 CCyR chronic myeloid leukemia patients receiving long-term therapy. We included in our analysis the most relevant prognostic factors described to date. On multivariate analysis, the adherence rate and having failed to achieve a major molecular response were the only independent predictors for loss of CCyR and discontinuation of imatinib therapy. The 23 patients with an adherence rate less than or equal to 85% had a higher probability of losing their CCyR at 2 years (26.8% vs 1.5%, P ‫؍‬ .0002) and a lower probability of remaining on imatinib (64.5% vs 90.6%, P ‫؍‬ .006) than the 64 patients with an adherence rate more than 85%. In summary, we have shown that poor adherence is the principal factor contributing to the loss of cytogenetic responses and treatment failure in patients on long-term therapy. (Blood. 2011; 117(14):3733-3736)

We analyzed a cohort of 26 patients with chronic myeloid leukemia who had failed imatinib and a second tyrosine kinase inhibitor but were still in first chronic phase and identified prognostic factors for response and outcomes. The achievement of a prior cytogenetic response on imatinib or on second-line therapy were the only independent predictors for the achievement of complete cytogenetic responses on third-line therapy. Younger age and the achievement of a cytogenetic response on second line were the only independent predictors for overall survival (OS). At 3 months, the 9 patients who had achieved a cytogenetic response had better 30-month probabilities of complete cytogenetic responses and OS than the patients who had failed to do so.

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The BCR-ABL T315I mutation confers resistance to currently licensed tyrosine kinase inhibitors in chronic myelogenous leukemia. However, the impact of this mutation on survival in early stages of disease, in chronic phase, has never been detailed. Using matched pair analysis, a cohort of 64 patients with chronic phase chronic myelogenous leukemia harboring a T315I mutation and resistant to imatinib mesylate was compared to a similar cohort of 53 chronic phase patients resistant to imatinib, but with no detectable T315I mutation, in the pre-ponatinib era. These patients were matched according to age at diagnosis, interval between disease diagnosis and start of imatinib treatment, and duration of imatinib therapy. Kaplan-Meier survival analyses demonstrated the significant negative impact of the presence of the T315I mutation on overall survival (since imatinib-resistance: 48.4 months for T315I + patients versus not reached for T315I -ones; P=0.006) and failure-free survival (since imatinib-resistance: 34.7 months for T315I + patients versus not reached for T315I -patients; P=0.003). In addition, Cox proportional hazard models adjusted on overall survival demonstrated the negative influence of the T315I mutation (P=0.02, HR=2.54). These results confirm early assumptions concerning the poor prognosis of chronic phase chronic myelogenous leukemia patients with the T315I mutation who are not eligible for allogeneic transplantation, and demonstrate the need for more therapeutic options.The BCR-ABLT315I mutation compromises survival in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors, in a matched pair analysis

Second-generation tyrosine kinase inhibitors (2G-TKIs) are effective at inducing complete cytogenetic responses (CCyRs) in approximately half of chronic myeloid leukemia patients treated while still in the chronic phase and after failing imatinib. It is less clear whether these responses are durable. In the present study, we report the clinical outcome of 119 patients who received a 2G-TKI as second-line treatment while still in the chronic phase. In an intention-to-treat analysis, the 4-year probabilities of overall and event-free survival were 81.9% and 35.3%, respectively. Sixty-two patients discontinued the initial 2G-TKI because of resistance or intolerance. To further explore the durability of cytogenetic responses, irrespective of the need for a third-line TKI, we used the concept of "current CCyR-survival" (c-CCyRS). The c-CCyRS at 4 years was 54.4%. After introduction of a 2G-TKI, 77 patients had a 3-month BCR-ABL1/ ABL1 transcript ratio of < 10% and had significantly superior overall survival (91.3% vs 72.1%, P ‫؍‬ .02), event-free survival (49.3% vs 13.0%, P < .001), and cCCyRS (67.2% vs 11.2%, P ‫؍‬ .0001) compared with the 33 patients with ratios > 10%. The 3-month molecular response was the only independent predictor for overall survival. Using an intentionto-treat analysis, we have shown that the responses to second-line therapies are durable. Patients destined to fare poorly can be identified early during therapy.

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using the HbA2 value of 3.4% as cut off. 8 Using the value of 30 mg/L for serum ferritin as cut off, 861 samples showed iron deficiency (ID) (group A) and 271 were without ID (group B) (Figure 1). The mean HbA2 value was 2.8%±0.79 in group A and 3.50%±1.23 in group B, with a significant difference (P=0.00001) among between the two groups. The distribution of the 253 samples with molecular analysis between groups A and B showed that 170 samples were part of group A and 83 of group B (Figure 1). From 170 samples of group A, 21 resulted positive for a b-globin gene mutation with a mean of HbA2 value of 4.90%±1.29. From 83 samples of group B, 29 resulted positive for a b-mutation (mean of HbA2 value: 5.37%±0.87). The comparison between the HbA2 mean value of b-thalassemia carriers with (group A) or without (group B) ID, using the value of 30 mg/L as serum ferritin cut off, does not show a significant difference (P=0.060) and in both groups HbA2 levels are more than 3.4%. Reduction of HbA2 has been reported to be linked to the severity of anemia 9 so that it is possible that the value of 30 mg/L for serum ferritin defines an ID not sufficiently severe or not sufficiently prolonged to significantly reduce the level of HbA2. The ROC analysis, performed with samples of group A, at the 3.4% HbA2 cutoff value, showed sensitivity and specificity of 74.19% and 95.8%, respectively. The false negative samples were 8 of 30 (26,6%): 3 presented Hb b variants, co-eluting with HbA, (Hb Valletta, Hb Ernz and Hb City of Hope) that do not require prenatal diagnosis, one showed an undefined single nucleotide polymorphism (SNP) in the b-globin gene of ambiguous diagnostic significance, 8 2 samples presented, respectively, the α-globin gene triplication (ααα anti3.7), and the b-globin gene promoter mutation,-101 (HBB c.-151C→T), and finally, 2 samples showed co-heredity of b + and d + mutation. The samples with ααα anti3.7 and the-101 beta mutation showed, respectively, HbA2 values of 3.0% and 3.2% with a lower value of Hb (<12 g/dL) and MCV (<75 fL). The contemporary analysis of hematologic and hemoglobin data enable us to identify these subjects as samples that must be submitted to molecular analysis if their partners are carriers of b thalassemia. 6 While, in other cases, it is recommended to remeasure HbA2 after ID treatment. In the 2 samples showing co-heredity of b + and d + mutation, the large reduction is principally associated with the presence of delta mutation rather than serum ferritin value. Our results show that the presence of iron deficiency did not preclude the detection of classical b carrier in our population. There could be some problems in the presence of silent b mutation or α gene triplication with ID, because HbA2 shows almost normal levels. However, the reduction in total Hb and MCV, and possible persistently low MCV and MCH after iron suppletion, should suggest greater attention is needed and molecular analysis exploring both the α and the b genes should be carried out, especially if the subject is a partner of...