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.
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.
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).
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.
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.
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.
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).
In patients with CML treated with imatinib for some years, poor adherence may be the predominant reason for inability to obtain adequate molecular responses.
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.
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.
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.
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.
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.
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 http://www.clinicaltrials.gov as # NCT01460693.
•Response to TKIs can be accurately established by measuring the 3-month transcript level.•An additional measurement of the transcript level at 6 months adds very little useful clinical information to the 3-month result.
Abstract 3290
Poster Board III-1▪▪This icon denotes an abstract that is clinically relevant.
There is a great variability in the degree of molecular responses achieved by chronic myeloid leukemia ...(CML) patients treated with imatinib. These different levels of molecular response could reflect different degrees of adherence to therapy. We measured the adherence to imatinib therapy in 87 consecutive CML chronic phase patients who had received imatinib 400 mg day as first line therapy for a median of 59.7 months before enrolment (range 25–104) and therefore all them were in complete cytogenetic response. Adherence levels were monitored during a 3-month period using microelectronic monitoring devices (MEMS) and were related to levels of molecular response. MEMS consist of an electronic device fitted in 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 TKD mutations and the following prognostic factors measured at diagnosis: hOCT1 transcripts level, polymorphism 1236C>T in ABCB1, Sokal risk group, hemoglobin, leukocytes , BCR-ABL1 transcript type and BCR1-ABL1 ratio and demographic data. The study protocol was approved by the Research Ethics Committee and patients gave written informed consent to participate.
The median adherence rate was 97.6% (range 22.6–103.8%). In 23 (26.4%) patients adherence was ≤90% (median 76%) and in 12 (13.8%) ≤80% (median 63%). We found a strong association between adherence rate (≤90% or >90%) and the 6-year probability of major molecular response (MMR) (28.4% vs 94.5%, p<0.0001) and complete molecular response (CMR) (0% vs 43.8%, p=0.002) (Fig 1). Multivariate analysis identified adherence (RR=11.7, p=0.001) and expression of the molecular transporter hOCT1, (RR=1.79, p=0.038) as the only independent predictors for MMR. Adherence was the sole independent predictor for CMR. No molecular responses were observed when the adherence was ≤20% (p=0.0001). In patients whose imatinib dose had been increased (n=32) the adherence was poor (median 86.4%). Adherence was the only independent predictor for failure to achieve a 3-log transcript reduction (RR=17.66, p=0.006) in this subgroup of patients. Patients with CML vary greatly in their response, as demonstrated originally by Sokal et al. in 1984, and the same variation is seen in patients treated with imatinib in the modern era. The basis for this variation is unknown but it has been attributed to the intrinsic biological heterogeneity of the leukemia. In contrast we show here that adherence to therapy is the major factor determining the degree of response that a CML patient treated with imatinib will achieve.
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Mahon:Novartis: Consultancy, Research Funding. Apperley:Novartis: Consultancy, Honoraria. Rezvani:Novartis: Consultancy, Honoraria, Research Funding. Marin:Novartis: Consultancy, Research Funding.
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.
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.
Abstract 605
Variations in RTQ-PCR estimations of BCR-ABL1 transcript numbers between laboratories have resulted in recognised difficulties in interpreting results and have led to a global effort of ...harmonisation via an international reporting scale (IS). Currently this is achieved in a limited number of laboratories worldwide by exchange of samples and will hopefully be replaced by the production of internationally accredited reference reagents. Differences in the limits of sensitivity of assays in different laboratories pose particular problems in the definition and interpretation of molecular negativity, so-called complete molecular remission (CMR), leading some investigators to suggest distinctions between assays capable of detecting 4, 4.5 and 5 log reductions in tumour load and introducing the terms CMR4, CMR4.5 and CMR5. These definitions take on particular relevance when designing studies of de-escalation and/or stopping tyrosine kinase inhibitor (TKI) therapy. In the French STIM trial, criteria for stopping were relatively stringent in that patients were required to have at least 5 results of RTQ-PCR negativity in their local laboratory sustained over at least 2 years and confirmed on one further occasion in the centralised laboratory. Negative results of BCR–ABL 1 amplification were reported only if the RNA was of good quality and quantity (50 000 copies of normal ABL1). Subsequently several groups are designing similar studies. As our ability to stop treatment must in large part be determined by the level of residual disease at the time of cessation, it is important to have robust definitions of CMR.
We maintain a comprehensive database of all our CML patients on TKI. For chronic phase this database now contains 521 patients (273 52% male) of median age 48 yrs (range 13–86). 212 patients received interferon prior to TKI therapy. The median follow up for surviving patients is 76 mths (range15-137). 88 (37 42% male) of these patients have achieved RTQ-PCR molecular negativity on more than one occasion and prompted us to identify the proportion that would satisfy entry criteria for a stopping study and hence the natural history of RTQ-PCR results in such patients. Confirmed complete molecular response (cCMR) was defined as two consecutive samples with no detectable transcripts at least 4 weeks apart with an ABL1 control >40,000 copies (median ABL1 control in the CMR samples was 84,000 copies). 64 patients met our criteria for cCMR, the remaining 24 patients had at least two negative results but never consecutively. 56 patients achieved cCMR on their first line TKI (imatinib in all but 2). Times from diagnosis to MMR and cCMR in this cohort were a median of 24 (range 3–77) and 46 mths (range 5–118) respectively. The median time from MMR to cCMR was 26 mths (range 0–89). Excluding 8 patients in whom follow-up since cCMR is less than 24 months the median duration from cCMR is 53 mths (range 24–113), Only one patient has subsequently lost MMR confirming the excellent prognosis of this cohort. However, only 10 patients (21%) have sustained RTQ-PCR negativity over a 2 year period that would deem them eligible for a STIM-equivalent study. If we were to define a less stringent CMR4.5 as a BCR-ABL ratio of 0.0032 in the international scale the number of eligible patients increases to 18/48 (37.5%). If we applied CMR4.5 to the 24 patients without consecutive RTQ-PCR results a further 3 patients would meet the criteria for a stopping study, total 21/88 (24%).
In conclusion the numbers of patients eligible for stopping studies confined to sustained cCMR is relatively few although we cannot exclude the possibility that some patients were not entirely compliant. Although not proven, reducing the stringency of the definition of CMR is likely to lead to higher relapse rates in subsequent stopping studies than in the original STIM trial. This must be considered when interpreting the results of first-line second generation TKI where the rates of achievement of MMR and CMR may be higher than with imatinib. In these studies CMR may not be synonymous with a 50% chance of discontinuing treatment permanently and future studies might more appropriately consider strategies of de-escalation rather than cessation.
Apperley:Novartis: Honoraria, Research Funding; Bristol Myers Sqibb: Honoraria; Ariad: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria.
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