Christos Paliompeis

Adherence Is the Critical Factor for Achieving Molecular Responses in Patients With Chronic Myeloid Leukemia Who Achieve Complete Cytogenetic Responses on Imatinib

PURPOSE There is a considerable variability in the level of molecular responses achieved with imatinib therapy in patients with chronic myeloid leukemia (CML). These differences could result from variable therapy adherence. METHODS Eighty-seven patients with chronic-phase CML treated with imatinib 400 mg/d for a median of 59.7 months (range, 25 to 104 months) who had achieved complete cytogenetic response had adherence monitored during a 3-month period by using a microelectronic monitoring device. Adherence was correlated with levels of molecular response. Other factors that could influence outcome were also analyzed. RESULTS Median adherence rate was 98% (range, 24% to 104%). Twenty-three patients (26.4%) had adherence <or= 90%; in 12 of these patients (14%), adherence was <or= 80%. There was a strong correlation between adherence rate (<or= 90% or > 90%) and the 6-year probability of a 3-log reduction (also known as major molecular response [MMR]) in BCR-ABL1 transcripts (28.4% v 94.5%; P < .001) and also complete molecular response (CMR; 0% v 43.8%; P = .002). Multivariate analysis identified adherence (relative risk [RR], 11.7; P = .001) and expression of the molecular human organic cation transporter-1 (RR, 1.79; P = .038) as the only independent predictors for MMR. Adherence was the only independent predictor for CMR. No molecular responses were observed when adherence was <or= 80% (P < .001). Patients whose imatinib doses were increased had poor adherence (86.4%). In this latter population, adherence was the only independent predictor for inability to achieve an MMR (RR, 17.66; P = .006). CONCLUSION In patients with CML treated with imatinib for some years, poor adherence may be the predominant reason for inability to obtain adequate molecular responses.

Assessment of BCR-ABL1 Transcript Levels at 3 Months Is the Only Requirement for Predicting Outcome for Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors

PURPOSE We studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics. PATIENTS AND METHODS We analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere. RESULTS Patients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P < .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P < .001 and relative risk, 0.158; P < .001, respectively). CONCLUSION 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.

Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy.

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.

Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia

Background Second-generation tyrosine kinase inhibitors induce cytogenetic responses in approximately 50% of patients with chronic myeloid leukemia in chronic phase in whom imatinib treatment has failed. However, it has not yet been established which of the patients in whom imatinib treatment fails are likely to benefit from therapy with second-generation tyrosine kinase inhibitors. Design and Methods We analyzed a cohort of 80 patients with chronic myeloid leukemia who were resistant to imatinib and who were treated with dasatinib or nilotinib while still in first chronic phase. We devised a scoring system to predict the probability of these patients achieving complete cytogenetic response when treated with second-generation tyrosine kinase inhibitors. Results The system was based on three factors: cytogenetic response to imatinib, Sokal score and recurrent neutropenia during imatinib treatment. We validated the score in an independent group of 28 Scottish patients. We also studied the relationship between cytogenetic responses at 3, 6 and 12 months and subsequent outcome. We classified the 80 patients into three categories, those with good risk (n=24), intermediate risk (n=27) and poor risk (n=29) with 2.5-year cumulative incidences of complete cytogenetic response of 100%, 52.2% and 13.8%, respectively (P<0.0001). Moreover, patients who had less than 95% Philadelphia chromosome-positive metaphases at 3 months, those with 35% or less Philadelphia chromosome-positive metaphases at 6 months and patients in complete cytogenetic response at 12 months all had significantly better outcomes than patients with lesser degrees of cytogenetic response. Conclusions Factors measurable before starting treatment can accurately predict response to second-generation tyrosine kinase inhibitors. Cytogenetic responses at 3, 6 and 12 months may influence the decision to continue treatment with second-generation tyrosine kinase inhibitors.

Combining BCR-ABL1 transcript levels at 3 and 6 months in chronic myeloid leukemia: implications for early intervention strategies

Several groups have shown that that the BCR-ABL1 transcript level measured at 3 or 6 months after starting treatment with tyrosine kinase inhibitors strongly predicts clinical outcomes for patients with chronic myeloid leukemia. In this work, we asked whether the prognostic value of the 3-month transcript level could be improved by combining the 3- and 6-month results. We classified patients treated with imatinib and patients treated with dasatinib according to their transcript levels at 3 months and 6 months. The patients who met the 3-month landmark but failed the 6-month one had outcomes identical to those of patients who met both landmarks, whereas the patients who failed the first landmark but met the second one had prognoses similar to those who failed both landmarks. In summary, early intervention strategies can be based robustly just on the transcript level at 3 months. This trial was registered at www.clinicaltrials.gov as # NCT01460693.

Efficacy of tyrosine kinase inhibitors (TKIs) as third-line therapy in patients with chronic myeloid leukemia in chronic phase who have failed 2 prior lines of TKI therapy

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. Factors measurable before starting treatment with third line therapy and cytogenetic responses at 3 months can accurately predict subsequent outcome and thus guide clinical decisions.

EVI-1 oncogene expression predicts survival in chronic-phase CML patients resistant to imatinib treated with second-generation tyrosine kinase inhibitors

Activation of the EVI-1 oncogene has been reported in acute myeloid leukemia, chronic myeloid leukemia (CML) in blast crisis, and less commonly, in chronic-phase CML patients. We screened an unselected cohort of 75 chronic-phase CML patients who had failed imatinib for expression of EVI-1 and sought a correlation with subsequent outcome on the second-generation tyrosine kinase inhibitors dasatinib (n = 61) or nilotinib (n = 14). The 8 patients (10.7%) who expressed EVI-1 transcripts detectable by real-time polymerase chain reaction had significantly lower event-free survival, progression-free survival, and overall survival than patients with undetectable transcript. The predictive value of EVI-1 expression was validated in an independent cohort. In a multivariate analysis, EVI-1 expression status and the best cytogenetic response obtained on imatinib were the only independent predictors for overall survival, progression-free survival, and event-free survival. Our data suggest that screening for EVI-1 expression at the time of imatinib failure may predict for response to second-line TKI therapy and consequently aid clinical management.

Excellent outcome after repeated changes of tyrosine kinase inhibitor therapy for chronic myeloid leukaemia in complete cytogenetic response due to minor side effects

Imatinib induces durable responses in the majority of chronic myeloid leukaemia (CML) patients (de Lavallade et al, 2008), however a substantial proportion of patients have persistent lowgrade side effects that impair quality of life (Marin et al, 2010; Eliasson et al, 2011). Furthermore, side effects have been identified as one of the possible reasons for poor adherence (Marin et al, 2010; Eliasson et al, 2011; Ibrahim et al, 2011; Breccia et al, 2012). A possible strategy to minimize side effects is to take advantage of low cross-intolerance between different tyrosine kinase inhibitors (TKIs) and change therapy in presence of low-grade side effects. However it is not clear whether such changes can affect response, induce resistance or eliminate the side effects. We report our experience in 57 patients who achieved complete cytogenetic response (CCyR) on imatinib as first line therapy (de Lavallade et al, 2008) and had their TKI changed solely on account of minor persistent side effects. The median age of the patients was 54 years (range 36–69). Thirty-seven patients received dasatinib, 19 nilotinib and one bosutinib as second line therapy. Seventeen patients subsequently changed to third line TKI (14 patients to nilotinib, three to dasatinib) due to intolerance and finally, two of these 17 patients changed to a fourth line TKI. Dasatinib, nilotinib and bosutinib were administered as previously described (Milojkovic et al, 2012). Patients gave informed consent. Minor side effects were defined as side effect caused by the TKI therapy that persisted at grade I despite optimal care. Common toxicity criteria (CTC; http://ctep.cancer.gov/ protocoldevelopment/electronic_applications/docs/ctcaev3.pdf) were used to grade the side effects. BCR-ABL1 transcripts were measured as described previously (Foroni et al, 2011). We used standard definitions of CCyR, MR3 (3 log reduction in the transcript level), 4 5-log reduction (MR4 5), and complete molecular response (CMR; Cross et al, 2008). Kinase domain (KD) mutations were analysed using direct sequencing (Alikian et al, 2012). The probabilities of molecular responses were calculated using the cumulative incidence (CI) procedure, whereby molecular response was the event of interest and death and therapy discontinuation were the competitors. Patients received imatinib for median of 44 months (range 16–135). Median duration on second line TKI was 48 months (range 10–50). Median duration on third line was 30 months (range 7–42). Two patients changed to a fourth TKI (bosutinib n = 1, nilotinib n = 1) due to side effects. At the time of starting second line TKI, two patients were in CMR, three in MR4 5, 25 in MR3 and 27 in CCyR. Two patients died from non-CML related causes. Table I shows the side effects that motivated change of therapy and their outcomes; the most common side effects on imatinib were arthralgia (16%), rash and pruritus (16%), and headache (14%). Twenty-five (44%) patients developed side effects on second TKI, with the most common being pleural effusion (n = 9, 36%) and headache (n = 2, 8%). Twenty patients had a grade I side effect, and five were grade II to IV (Table I). Eight patients who had grade I side effects on second line TKI elected not to change therapy as the side effects (Table I) were mild. As explained above, 17 patients changed to a third line TKI; 12 of these 17 patients (71%) become totally free of side effects. Two of the remaining five patients who changed to a fourth line drug (pleural effusion, peripheral occlusive arterial disease) are now asymptomatic. The remaining three patients elected not to change treatment with minor side effects. All 57 patients had further reduction in BCR-ABL1 transcript levels following change of therapy. Median transcript level at time of changing was 0 29% (range 0 09–3 5%) and the median reduction in 12-month BCR-ABL1 transcript level after TKI change was half-log (range 0 2–1 5). The 1and 4-year cumulative incidence (CI) of MR3 for the 38 who had not achieved MR3 at point of change was 78% and 94%, respectively. Similarly, 1-and 4-year CI of MR4 5 was 30% and 48%, respectively, and 1and 4-year CI of CMR was 8% and 24%, respectively. Seventeen patients who changed to third line TKI also attained further reduction in their BCR-ABL1 transcript numbers and median reduction in transcript level 12 months after change was 1 log (range 0 1–2). Two patients who subsequently changed to a fourth TKI due to side effects (bosutinib, nilotinib) had further reduction in their transcript levels. Analysis performed at the time of changing therapy unexpectedly identified one KD mutation (D276G) in a patient on imatinib, which disappeared with change of therapy. No other mutations were detected during an additional 143 mutation analyses during TKI changes.