Abstract 3414
We have previously shown that adherence to imatinib therapy is the single most important factor determining the degree of molecular response achieved by CML patients (Marin et al, JCO ...2010). We now study the relation between adherence to imatinib and the probabilities of losing CCyR and of imatinib failure in patients receiving long term therapy.
We measured the adherence to imatinib in 87 consecutive chronic phase CML patients who had received imatinib 400 mg day as first line therapy for a median of 59.7 months before enrolment, all of whom were in complete cytogenetic response (CCyR). Adherence levels were monitored during a 3-month period using microelectronic monitoring devices (MEMS, see below) and patients were followed subsequently for a median of 15 months. Data from the patients were censored in March 2010, when our previous work was published, to ensure that the results of this study were not influenced by possible changes in a patient's behavior.
MEMS is an electronic device fitted into the cap of a normal looking medication bottle that automatically records each time the bottle is opened. MEMS are considered as the ‘gold standard’ for measuring adherence. We also measured the imatinib plasma level, the presence of kinase domain mutations and the following factors assessed at diagnosis: demographic data, hemoglobin, leukocytes, Sokal risk group, BCR-ABL1 transcript type, hOCT1 transcript levels, and the presence of the 1236C>T polymorphism in ABCB1. The study protocol was approved by the Research Ethics Committee and patients gave written informed consent to participate.
Adherence was defined as the quantity of imatinib actually taken divided by the amount prescribed expressed at a percentage. The median adherence was 97.6% range 24–100%). In 23 (26.4%) patients adherence was ≤90% (median 76%) and in 12 (13.8%) ≤80% (median 63%). During the follow up 7 (8%) patients lost their CCyR, and 12 (13.8%) discontinued the imatinib therapy (7 because of loss of CCyR, 2 because of failure to achieve MMR and 3 because of side effects). In multivariate analysis the adherence rate was the only independent predictor for loss of cytogenetic response (RR=0.95, p=0.0001) and discontinuation of imatinib therapy (RR= 0.97, p=0.009). When we categorized the adherence rate as (≤90% or >90%) we found that at 18 months the 23 patients with an adherence rate ≤90% had a higher probability of losing the CCyR (26.8% vs 1.5%, p=0.0002) and a lower probability of remaining on imatinib (64.5% vs 90.6%, p=0.006) than the 64 patients with an adherence rate >90% (Figure). In summary we have shown that poor adherence to imatinib is the principal factor contributing to the loss of cytogenetic responses and treatment failure in Patients on long term therapy.
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Marin:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding.
Abstract 2274
Patients with CML in chronic phase who have failed imatinib therapy are commonly treated with dasatinib or nilotinib, but a significant proportion fail to respond or relapse in which ...case they are often treated with the other tyrosine kinase inhibitor (TKI) that they had not yet received. We report here the largest series of CML patients in CP treated with a third line TKI after failing both imatinib and another TKI.
We enrolled 26 patients. The median age was 64 years and 54% were male. 20 patients had received dasatinib and 6 nilotinib as second line therapy. All patients were still in first CP at the moment of commencing third line therapy, and none was harboring a T315I mutation. Failure to second line therapy was defined as no CHR at 3 months, no major cytogenetic response (MCyR) at 12 months or loss of a hematological or cytogenetic response. Patients who were unable to continue therapy on account of toxicity were also considered as having failed therapy. The median follow up for the surviving patients after starting third line therapy was 21.5 months (range, 6 – 46.5 months).
The 2.5 years (30 months) cumulative incidences of MCyR, CCyR and MMR were 48.2%, 32.4%, 21.1% respectively. Multivariate analysis showed that the achievement of at least MiCyR (<95% Ph-positive) on imatinib (RR=5.6, p=0.03) or on second line therapy (RR=11.8, p=0.006) were the only independent predictors for the achievement of CCyR. When combining both variables we found that patients who had achieved MiCyR on one of the two prior therapies had a significantly better OS and higher probability of achieving cytogenetic response on third line therapy, i.e. the 30 month probability of OS and CCyR were 72.7% vs 20.4% (p=0.03) and of 71.4% vs 0% (p=0.0005) respectively (Figure).
During follow up 9 (34.6%) patients died. The probability of OS at 30 months was 46.7%. The achievement of a cytogenetic response on second line and age younger than 64 (possibly reflecting eligibility for transplantation) were the only independent predictors for OS (RR=6.5, p=0.02 and RR=0.13, p= 0.02).
Seventeen patients (65%) were classified as intolerant to previous therapies (imatinib or second line TKI). Intolerant patients had a probability of responding to the third line therapy similar to those of the resistant patients, but when this cohort was subdivided according to the type of intolerance we found that 11 patients who had hematologic toxicity with either therapy had a probability of CCyR at 30 months lower than that of the remaining 15 patients (11.1% vs 47.5 %, p=0.03), while the 8 patients with non-hematologic intolerance to the imatinib or to the second line had a probability of 30-month CCyR greater than that of the remaining 18 patients (87.5% vs 5.6%, p<0.001).
At 3 months 26 patients remained on follow up, of whom 9 patients had achieved at least MiCyR. These 9 patients had better 30-month probabilities of CCyR and OS than the patients who had failed to achieve MiCyR, namely 88.9% vs 13.3% (p<0.0001), and 87.5% vs. 35.0% (p=0.1). When we excluded the only patient who died of non-leukemia related causes while in CCyR, the probabilities of OS was 100% vs 35.0% (p=0.04)
Which patients should be offered third line TKI therapy? Patients who achieved cytogenetic response on first or second line therapy and patients with a history of non-hematologic intolerance to the prior TKI benefited from a third TKI. Patients with primary cytogenetic resistance to two TKIs or with a history of hematologic intolerance should receive an allogeneic stem cell transplant when possible. For patients in this situation who lack a transplant option we would recommend only a short course (3 months) of the third line therapy to identify responders. Non-responders should be offered experimental studies.
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Marin: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding.
The use of real time quantitative PCR (RQ-PCR) is now established for monitoring minimal residual disease (MRD) in patients with leukemia responding well to therapy. The level of the target gene is ...usually expressed as a percentage ratio normalised to the control gene. Measurement of a control gene is needed to exclude the possibility of false negative values due to sample (RNA) deterioration. The ideal control gene should be expressed in blood and/or bone marrow at intermediate level without significant variation between different patients; its RNA should have stability similar to that of the gene of interest; and it should not have a processed pseudogene. For monitoring the low levels of BCR-ABL transcripts characteristic of Ph-positive CML during treatment, different laboratories have quantified as controls (amongst others) ABL, BCR, G6PD, GAPDH,β-actin and β2-microglobulin. Despite the ABL gene being a component of the BCR-ABL fusion gene, it fulfils the criteria for a good control. Moreover as it is expressed at relatively low levels it is sensitive to sample deterioration. Analysis of 10,021 CML blood samples revealed that ABL transcript numbers were consistent when BCR-ABL transcript numbers were less than 20,000 (median 50,200), but above this level ABL quantification was influenced by BCR-ABL copy number (median 110,500). In MRD studies designed specifically to detect small numbers of residual transcripts, the contribution of amplifying BCR-ABL to the control value is not critical to the assessment of tumour load. A contemporaneous comparison of levels of BCR and ABL transcript levels in 831 blood samples taken from patients with CML at various stages of treatment showed a linear relationship (p=0.0001), but the median BCR expression was 0.7 log greater than the median ABL expression. In practice an assay using ABL as control gene for measuring the log reduction in BCR-ABL transcript levels following effective treatment compared with a BCR-ABL baseline value obtained before treatment yields values approximately equivalent to the log reduction obtained with an assay based on BCR as control gene. Nonetheless the variable expression of the commonly used control genes means that log reduction values may differ between centers. Thus we believe that the best method for reporting MRD values in CML patients undergoing treatment is as a percent ratio compared with previous values, i.e. the serial samples post treatment. Log reductions may be a useful ancillary for use within individual centres.
