Retrospective Application of European LeukemiaNet Provisional Criteria for Second-Generation TKI Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2270-2270
Author(s):  
Massimo Breccia ◽  
Roberto Latagliata ◽  
Fabio Stagno ◽  
Antonella Gozzini ◽  
Elisabetta Abruzzese ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Conflicts Of Interest ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Primary Resistance ◽  
Free Survival ◽  
Optimal Response ◽  
Monitoring Response

Abstract Abstract 2270 An update of the European LeukemiaNet criteria for monitoring response of chronic myeloid leukemia patients was recently published and provisional criteria to evaluate patients during second generation TKI therapy after resistance to imatinib were proposed. In our study we retrospectively tested these criteria in a large series of CML patients resistant to imatinib further treated with second generation TKIs with the aim to analyze the outcome of suboptimal response and failure patients compared to those with optimal response and to validate the provisional criteria for monitoring response. One hundred twenty-seven CML patients resistant to imatinib were collected from 6 different Italian hematologic centers. There were 66 males and 61 females, median age 54 years (range 25–80). Twenty-seven patients were in late chronic phase after IFN resistance. Ninety-seven patients received second-generation TKI after acquired resistance, whereas 30 patients had primary resistance. We found that at different time points (3, 6 and 12 months), patients classified as failure showed significantly worse 2-year overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) than sub-optimal and optimal response patients. At 3 months, “failure” patients, had an OS of 83% compared to 86% of sub-optimal and 97% of optimal response patients (p=0.001); PFS was 77% for failure patients compared to 92% and 99% for sub-optimal and optimal response patients, respectively (p=0.001), whereas EFS was 41% for failure vs 59% for sub-optimal (p=0.001) and 85% and optimal response patients, respectively (sub-optimal vs optimal p<0.001). At 6 months, OS was 82%, 88% and 99% for failure, sub-optimal and optimal response patients (p=0.05), respectively; PFS was 82% for failure compared to 94% and 99% for sub-optimal and optimal response patients, respectively (p=0.001); EFS was 47% vs 69% for failure and sub-optimal response (p=0.001) and 86% for optimal response patients (sub-optimal vs optimal, p<0.001). At 12 months again OS was 84% for failure patients compared to 95% and 99% for sub-optimal and optimal response patients (p=0.04); PFS was 86%, 95% and 99% for failure, sub-optimal and optimal response patients, respectively (p=0.001) and EFS was 48% for failure, 67% for sub-optimal response patients (p=0.002) and 89% for optimal response patients (sub-optimal vs optimal, p<0.001). We found that ELN provisional criteria identified at any times worse EFS for sub-optimal response patients, similar to that of failure patients, and failure criteria at 3 months identified patients who had worse PFS and EFS. ELN provisional criteria for second-generation TKIs treated patients appear to clearly predict outcome and can be useful to identify patients at high risk of progression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Chronic myeloid leukemia: successful therapy with nilotinib in a young patient with high Sokal risk and in sub-optimal response with imatinib

2015 ◽  
Vol 4 (6S) ◽  
pp. 13-16
Author(s):  
Fausto Palmieri
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Young Patient ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Chronic Phase ◽  
Molecular Response ◽  
Optimal Response ◽  
Increased Risk

Here we describe a case of a young patient with chronic myeloid leukemia, at high-risk according to the Sokal index, who started imatinib at standard dose and obtained a sub-optimal response at 12 months. This condition was not automatically an indication to change therapy, but considering the patient as suboptimal, we decided to switch to a second-generation tyrosine kinase inhibitor (TKI), nilotinib 800 mg/die, obtaining soon a complete cytogenetic response (CCYR), thereafter a major molecular response (MMolR). Delayed achievement of cytogenetic and molecular is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving imatinib therapy. Therefore we can hypothesise that this kind of patient could be elegible for an early switch to second-generation TKI.

Results of Imatinib Dose Escalation After 36 Months of Follow-up in Chronic Myeloid Leukemia Patients with Failure or Sub-Optimal Response According to 2006 EuropeanLeukemia Net (ELN) Criteria.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3302-3302
Author(s):  
Massimo Breccia ◽  
Fabio Stagno ◽  
Roberto Latagliata ◽  
Paolo Vigneri ◽  
Laura Cannella ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Standard Dose ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response

Abstract Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Early Molecular Response in Chronic Myeloid Leukemia Patients Predicts Future Response Status

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5529-5529
Author(s):  
Irina Martynkevich ◽  
Vasily Shuvaev ◽  
Ekaterina Petrova ◽  
Lyubov Polushkina ◽  
Lyudmila Martynenko ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Molecular Response ◽  
Prognostic Impact ◽  
Long Term Outcome ◽  
Transcript Levels ◽  
Optimal Response

Abstract Objectives and background: The level of early MR is important for the optimization of therapy and making a decision to a switch to 2nd line therapy in patients (pts) who have not achieved an optimal response (OR). According to the recent recommendations at definition of OR on CML therapy, pts must have the level of BCR-ABL transcript gene at 10% or less and Ph-positive cells 35% or less at 3 months. But, in half of all cases of pts with BCR-ABL >10% at 3 months progression events happen between 3 and 6 months. The goal of our research was to investigate the prognostic impact of a large BCR-ABL transcript amount at 3 months on the subsequent response and the long-term outcome of CML pts treated frontline with IM. Methods: We have examined 185 pts, who have got IM from January 2010 up to the present. Molecular monitoring has been done regularly in all patients according to ELN recommendations. Median age was 49 years. All pts were in CP. BCR-ABL transcript levels were assessed by real-time quantitative PCR. Results: In our study 54% (100/185 cases) of pts achieved the optimal response with BCR-ABL transcript levels ≤10% at 3 months, 50,3% (93/185 cases) did it - with BCR-ABL transcript levels ≤1% at 6 months, and only 18% achieved the optimal response at 12 months. The comparative analysis has shown statistical differences in all characteristics in 2 groups of pts, who either achieved or not the optimal response at 3 months. Pts with BCR-ABL transcript levels ≤10% more often achieved CCgR at 6 months (g=0,0000), CCgR during all period (g=0,0004), MMR at 12 months (g=0,0000), MMR during all period (g=0,0012) and MR4 during all period (g=0,0000), pts had londer event-free (g=0,0432) and overall (g=0,0279) 4-year survival. Figure 1 Figure 1. In our center we have switched 6 patients to the 2nd TKI - those who didn't achieve the optimal response at 3 months. The switching showed the positive influence on loss level expression of BCR-ABL gene in 5 out of 6 patients. After that all patients achieved the optimal response in the future. For example, we had one patient with failure of IM at 3 months. We switched him the therapy to NI in 5 months after the diagnosis. As a result the patient achieved CCgR at 1,5 months, and the deep molecular response 4,5 log at 3 months. Conclusions: Early and deep responses to TKIs are predictive of long-term response and favorable survival outcomes. 3-month reduction in BCR-ABL transcript levels to >10% is a factor of bad effectiveness of TKI therapy and requires switching to the 2nd TKI. Timely switching to the 2nd TKIs allows us to achieve an optimal response in CML patients with level BCR-ABL >10% at 3 months. References: Timothy P. Hughes, Giuseppe Saglio, Hagop M. Kantarjian et al. Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood, 27 February 2014 x Volume 123, Number 9. Disclosures No relevant conflicts of interest to declare.

Chronic Myeloid Leukemia (CML) Patients with “Suboptimal” Response to Imatinib (IM) According to European LeukemiaNet Criteria Have a Poorer Outcome with Respect to “Optimal” Responders: A GIMEMA CML WORKING PARTY Analysis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2196-2196 ◽  
Author(s):  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Francesca Palandri ◽  
Massimo Breccia ◽  
Marilina Amabile ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Working Party ◽  
Lower Probability ◽  
Molecular Response ◽  
Grey Zone ◽  
Long Term Outcome ◽  
Free Survival

Abstract Abstract 2196 Poster Board II-173 BACKGROUND: Imatinib (IM) 400 mg daily is the standard treatment for Chronic Myeloid Leukemia (CML) in early chronic phase (ECP). The European LeukemiaNet (ELN) recommendations were designed to help identify ECP CML patients responding poorly to front-line IM, suggesting, at given time points, when the treatment strategy should be changed (”failure”), or when “the long-term outcome of the treatment would not likely be as favourable” (“suboptimal response”). Suboptimal response is a “grey zone”: the patient may still have substantial benefit from continuing IM, but other therapies should be considered. AIM: To assess the outcome of “failure” and “suboptimal responders” Philadelphia-positive (Ph+) CML patients in a large multicentric, nationwide experience. METHODS: Between January 2004 and April 2007, 559 patients were enrolled in an observational study and in 2 independent intervention studies of the GIMEMA CML WP (Clin Trials Gov. NCT00514488 and NCT00510926). Response monitoring was based on conventional cytogenetic examination of bone marrow cell metaphases every 6 months and RT Q-PCR evaluations of blood cells after 3, 6, 12 months, and every 6 months thereafter. Definitions: major molecular response (MMR): BCR-ABL/ABL ratio < 0,1%IS; failure (according to ELN criteria): no hematologic response (HR) at 3 months, no complete HR (CHR) at 6 months, no cytogenetic response (CgR) at 6 months, no partial CgR (PCgR) at 1 year, no complete CgR (CCgR) at 18 months, loss CHR or CCgR, progression or death; suboptimal response (according to ELN criteria): no CHR at 3 months, no PCgR at 6 months, no CCgR at 12 months, no MMR at 18 months ; optimal response: non-suboptimal and non-failure at each time-point; event: failure or treatment discontinuation for any reason. All the calculations have been made according to the intention-to-treat principle. RESULTS: The patients who fitted the ELN criteria for failure had a significantly lower probability of subsequently achieving a CCgR and a MMR, and had a significantly lower overall survival (OS), failure-free survival (FFS) and event-free survival (EFS). The patients who fitted the ELN definitions of suboptimal response at 6 months (data not shown) and at 12 months (figure 1) had a significantly lower probability than “optimal” responders of subsequently achieving a CCgR and a MMR, and a significantly poorer FFS and EFS (figure 1), while the OS was not different in the two groups (90% and 95%, p= 0.35). CONCLUSIONS Our data confirms that suboptimal responders at 6 and at 12 months have a poorer outcome with respect to “optimal” responders, comparable to the outcome of failure patients. Acknowledgments: European LeukemiaNet, COFIN, University of Bologna and BolognAIL. Disclosures: No relevant conflicts of interest to declare.

Sustained Responses and Resistance to Imatinib Mesylate in the First 173 Chronic Myeloid Leukemia Patients Accrued by the SCREEN Multicenter Study: First Interim Report.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4276-4276
Author(s):  
Paolo Vigneri ◽  
Fabio Stagno ◽  
Stefania Stella ◽  
Alessandra Cupri ◽  
Michele Massimino ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance

Abstract Abstract 4276 Introduction Imatinib mesylate (IM) has shown unprecedented effectiveness in the treatment of Chronic Myeloid Leukemia (CML) patients (pts) in the chronic phase of the disease. As most of the data concerning the efficacy of the drug derive either from a single sponsored trial or from single institution reports, we decided to accrue all CML pts diagnosed in the Italian region of Sicily to the observational SCREEN (Siciliy CML Regional Enterprise) study, to evaluate the hematological, cytogenetic and molecular responses of this unselected population to IM. Patients and Methods Although the study is still ongoing, 173 consecutive CML pts have been enrolled between January 2005 and June 2009 (cutoff time for the first interim analysis) by one of the 12 institutions involved. Each center was responsible for the diagnosis, treatment (IM 400 mg qd) and follow-up of the pts accrued, while all molecular analyses were centralized in Catania. Median follow-up time was 31 months. Eleven pts (6.3%) are currently off study. Results Pts characteristics were as follows: 95 males (54.9%) and 78 females (45.1%) were enrolled with a median age of 53 years (range 24-90). Eighty-nine pts (51.4%) were low Sokal risk, 62 (35.8%) were intermediate risk and 22 (12.8%) were high risk. Nine pts (5.2%) displayed additional chromosomal abnormalities. Median leukocyte counts (1×109L) were 67.6 (range 3.4-718), median hemoglobin (g/L) was 122 (range 75-170) while median platelet counts (1×109L) were 317 (range 67-2620). Cumulative incidences of complete hematologic response (CHR) and complete cytogenetic response (CCyR) were 98.3% and 85% respectively, while 59.2% of pts obtained a major molecular response (MMR). At 54 months, estimated overall survival was 95.6%. Estimated progression free survival (accounting for all pts that failed IM according to the European Leukemia Net criteria) was 75.1%. Thirty pts (17.3%) presented resistance to IM, either because of failure to obtain a satisfactory response (primary resistance, 21 pts) or because of loss of previously obtained responses (secondary resistance, 9 pts). Thirty-three pts (19%) presented a suboptimal response, 8 because of failure to achieve a CCyR by 12 months of therapy and the remaining 25 because of lack of a MMR after 18 months of IM. Only 3 pts (1.7%) were intolerant to IM. Interestingly, the median amount of BCR-ABL transcript at diagnosis (measured according to the International standardized Scale) displayed by pts that failed IM or achieved a suboptimal response (106.5IS) was significantly higher than that of pts obtaining an optimal response (61.9 IS p=0.0031). Conclusions IM is a highly effective and well-tolerated treatment for most chronic phase CML pts, producing high rates of CHR and CCyR. Approximately 60% of cases will also achieve a MMR. 35-40% of pts will either fail IM or obtain only partially satisfying results (suboptimal response). High levels of BCR-ABL transcript at diagnosis might allow a rapid identification of this less responsive pt population. Disclosures: No relevant conflicts of interest to declare.

The Outcome of Unselected Patients with Chronic Myeloid Leukemia (CML) In Chronic Phase (CP) Treated with Imatinib In the First Line and the Prognostic Value of ELN Defined Responses – Population Based Analysis of 458 Patients Treated Between 2003–2009.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1239-1239 ◽  
Author(s):  
Hana Klamova ◽  
Daniela Zackova ◽  
Edgar Faber ◽  
Katerina Steinerova ◽  
Michal Karas ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Treatment Response ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
Response Evaluation ◽  
Free Survival ◽  
Optimal Response

Abstract Abstract 1239 Background. Imatinib (IM), a selective BCR-ABL tyrosine kinase inhibitor (TKI), is a treatment of choice for newly diagnosed chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP) as it was shown in the IRIS trial. The treatment strategy and response evaluation is based on NCCN or ELN guidelines. Only limited “real life” data of IM impact on pts outcome as well as ELN (European LeukemiaNet) recommendations applicability in daily practice has been published. In the Czech as well as in the Slovak Republic (15 million inhabitants), the treatment of CML patients is centralized in overall 13 centers, capable carrying on both the treatment and laboratory monitoring. There are two CML prospective projects CAMELIA and INFINITY focused on CML pts analysis. Aims. To analyze the treatment response and long-term outcome in consecutive, unselected patients with CP-CML treated with IM and to evaluate the prognostic role of ELN 2006 and 2009 response evaluation. To analyze molecular response in more detail. Methods. Altogether 458 consecutively included patients in INFINITY (152 pts) and CAMELIA projects (306 pts) were assessed. For the treatment response evaluation the ELN 2006 and ELN 2009 definitions were used. We assessed rates and the cumulative incidences of complete hematologic responses (CHR), complete cytogenetic responses (CCyR), major (MMoR) and complete molecular responses (CMoR). Overall survival (OS) was defined as the time from the start of IM to death from any cause, overall survival CML-related death (OSCML), transformation-free survival (TFS) as survival without evidence of AP or BP or death from any cause, progression-free survival (PFS) as survival without evidence of AP or BP, loss of CHR, MCyR, increasing white blood cell count or death fron any cause while on IM treatment and event-free survival (EFS) –events defined as a progression (the same as in PFS, as described above), loss of CCyR, failure to achieve CHR at 6 months, MCyR at 12 months and CCyR at 18 months, or intolerance of IM as the cause its discontinution. The patient survival according to MMoR achievement and the cumulative incidence of MMoR according to different BCR-ABL ratio within the first 3 months of IM therapy was analysed. Kaplan-Meier cumulative incidence methods and log rank test were used for survival statistic analysis. Results. A total of 458 patients (median age 52 year;17-81) treated with IM between 2003–2009 were analysed.The median follow-up was 33.1 months (1.4-82.1). At 2 and 4 years the cumulative incidence of CHR was 90.9% and 94.7%, CCyR 64.9% and 76%, MMR 52.4% and 68.1% and CMR 24.5% and 43%, respectively. In 4 years estimated OS was 91.1%, OSCML 96.6%, TFS 93.9%, PFS 83.2% and EFS 66%. According to ELN 2006 criteria the optimal response (OR) by 6 months (defined as PCyR) and by 12 months (defined as CCyR) resp. had significant impact on PFS (p=0.04 and p<0.001 resp.). The optimal reponse by 3 months (defined as CHR) had significant impact on TFS (p<0.001). According to actualized criteria in ELN 2009, the new definition of optimal response in the 3rd month - at least minor cytogenetic response (mCyR), did not show any prognostic impact on PFS. The achievement of MMoR was correlated with the significant improvement in PFS in the 3rd month (p=0.039) as well as in the 12th month (p<0.049). There was significant improvement in EFS for patients in MMoR in all timepoints (p<0.003, <0.001, <0.001, <0.005). The BCR-ABL ratio lower than 1% within the first 3 months was associated with MMoR achievement in higher number of patients in comparison to patients with higher BCR-ABL levels (p<0.001) Conclusion. The excellent and long-lasting efficacy of imatinib in the treatment of CP-CML in non-selected group of patients treated in the defined region was confirmed. Our results are comparable to those achieved in IRIS trial. Response criteria and their predictive role defined by ELN 2006 and 2009 seems to be helpful at some time points, but the ELN 2009 modification does not seem to represent significant improvement compared to ELN 2006. On the other hand based on the present analysis the earlier incorporation of molecular response into the evaluation scheme may be beneficial. Supported by: CELL-The Czech Leukemia Study Group for Life, Project INFINITY; Project CAMELIA. Disclosures: Faber: BMS, Novartis: Consultancy, Honoraria.

Early Assessment of Molecular Response in Chronic Myeloid Leukemia Patients On Dasatinib After Imatinib Failure Identify Patients with Poor Cytogenetic and Molecular Responses

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3787-3787
Author(s):  
Katia B. Pagnano ◽  
Beatriz F Ribeiro ◽  
Eliana C M Miranda ◽  
Marcia T Delamain ◽  
Carmino Antonio De Souza ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Internal Control ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Molecular Response ◽  
Early Assessment ◽  
Molecular Responses ◽  
Free Survival ◽  
Dasatinib Treatment

Abstract Abstract 3787 Dasatinib is effective at inducing complete cytogenetic response (CCyR) in approximately half of chronic myeloid leukemia (CML) patients treated in the chronic phase (CP) after failing imatinib. The aim of this work was to evaluate the role of molecular monitoring in predicting the outcome of patients treated with dasatinib after imatinib therapy. Between 2008 and 2012, it was analyzed 55 consecutive patients with CML with imatinib intolerance or resistance treated in a single center. Patients received dasatinib (50–140 mg) as second or third line therapy. Cytogenetic analysis was performed at 3, 6, 12 and 18 months after dasatinib introduction. BCR-ABL1 transcripts were measured in the blood at 3 months intervals using real-time quantitative PCR (RQ-PCR). Results were expressed as percent ratios relative to an ABL1 internal control. Major molecular response (MMR) was defined as a transcript level ≤ 0.1% on the international scale. Kinase domain (KD) mutations were performed before starting therapy and/or after dasatinib resistance. The probabilities of overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) were calculated using the Kaplan-Meier method. An event was defined as the loss of a CCyR or complete hematologic response, progression to AP and BP, death, or discontinuation of dasatinib. The probabilities of cytogenetic and molecular responses were calculated using cumulative incidence (CI) and x2method. Results: 33 patients were male (60%) and 22 female (40%), with median age of 48 years (15–81). At diagnosis Sokal scores were low for 11/34 (32.4%), intermediate for 6 (17.6%) and high for 17 (50%) (21 NA). Thirteen patients had a previous CCyR with imatinib. The median time between diagnosis and dasatinib treatment was 25 (2–223) months. The median follow-up was 12 months. Disease phase at beginning of dasatinib treatment: 32 (58%) CP, 13 (24%) accelerated phase (AP) e 10 (18%) blast phase (BP). Eight-seven percent achieved RHC, 55% CCyR and 38% MMR. At 3 months 67% (25/37) had BCR-ABL1/ABL1 transcript ratio '10%, at 6 months 48% (14/29) ≤ 1% and at 12 months 27% (6/22) RQ-PCR ≤ 0.1%. After introduction of dasatinib, patients with the 3-month BCR-ABL1/ABL1 transcript ratio of >10% had a lower chance of achieving CCyR (12.5% vs 81.5%, p= 0.001) and MMR (8.3% vs. 58.3%, p= 0.005). Patients with the 6-month BCR-ABL1/ABL1 transcript ratio of >1% had a lower chance of achieving CCyR (8% vs. 75%, p= 0.01) and MMR (26.6% vs. 64.2%, p=0.06) compared with patients with ratio ≤ 1%. The probability of OS, PFS and EFS in 48 months while on treatment was 83%, 70% and 29%, respectively. PFS was 88%, 76% e 11% in CP, AP and BP respectively (p< 0.0001). EFS was 36%, 32% e 10% in CP, AP and BP (P< 0.0001). Dasatinib was discontinued in 26/55 because of resistance (12), intolerance (5) or transplant (1). BCR-ABL KD mutations were detected in 13/38 cases, two before (L387M e M351T) and 11 during dasatinib treatment (T315I-6, M244V-2, E255V-1, E499E-1, M351T-1). Patients with mutations had an inferior EFS (p=0,05). In conclusion, this study indicates that evaluation of molecular response at 3 and 6 months can identify patients with less chance of response to dasatinib in patients with imatinib failure. The early identification of patients with poor outcome is important for planning future treatments. Disclosures: No relevant conflicts of interest to declare.

The Impact of Early Molecular Response in Event Free Survival in Patients with Chronic Myeloid Leukemia Treated with Imatinib

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5536-5536
Author(s):  
Laura Fogliatto ◽  
Marcelo Eduardo Zanella Capra ◽  
Mariza Shaan ◽  
Tito Vanelli Costa ◽  
Mayde Seadi Torriani ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Significant Proportion ◽  
Chronic Phase ◽  
Molecular Response ◽  
Event Free Survival ◽  
Durable Response ◽  
Free Survival ◽  
The Impact

Abstract Background Monitoring response to TKI therapy is one of the key management strategies of chronic myeloid leukemia (CML). Early molecular response to first-line TKI therapy is emerging as an effective prognostic factor indicator of long-term durable response and survival. Objectives We conducted a study to evaluate the importance of the early molecular response (EMR) at 3, 6 and 12 months (mo), and 3-year event free survival (EFS). Methods This is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) enrolled in 14 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN recommendations. EFS was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Results We analyzed data from 517 pts with CML-CP diagnosed since 1990. After a median observation time of 46 months, 5-year overall survival (OS) was 86% and 5-year event-free-survival was 53%. At 3 mo, EFS was 72,5% for 46 pts with BCR-ABLIS ≤10% compared to 58% for 14 pts with BCR-ABLIS >10% (p<0,07). Similarly, when EMR was analysed at 6 mo, the EFS was 81% for 75 pts with BCR-ABLIS ≤1%, while 31% of EFS was achieved for 38 pts with BCR-ABLIS >1% (p<0,001). At 12 mo, the 3-year EFS was 86% for 65 pts with with BCR-ABLIS ≤0,1% compared to 54% for pts with BCR-ABLIS>0,1% (p<0,001). Conclusions A significant proportion of pts achieve ERM after 3,6 and 12 mo of imatinib therapy with better 3-year EFS. ERM may could identify those pts more likely to have a favorable outcome. Disclosures No relevant conflicts of interest to declare.

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