Cumulative Incidence Of Complete Cytogenetic Response Research Articles

PF422 THE LONG‐TERM TREATMENT RESULTS OF THE MULTICENTER EUTOS ELN POPULATION‐BASED STUDY (EUTOS‐PBS) IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN RUSSIAN FEDERATION

Background:The data of 2904 adult patients (pts) with newly diagnosed chronic myeloid leukemia (CML) from 20 European countries were included into the multicenter EUTOS ELN population‐based Study (EUTOS PBS) from 2008 to December 2012 (Hoffman V et al. 2016). Russia took part in the EUTOS PBS and included 6.8% of the total number of pts. The EUTOS PBS in Russian Federation was prolonged and the results were updated at a long‐term follow‐up.Aims:To evaluate the long‐term results of treatment in pts with newly diagnosed CML in EUTOS PBS in Russia.Methods:The analyzed cohort of 197 pts (18 years) with Ph’+ /BCR‐ABL1+CML diagnosed in period 10/01/2009 ‐ 31/12/2012 from 6 regions of Russia was included into EUTOS PBS. CML was diagnosed in chronic phase (CP), accelerated phase (AP) and blast crisis (BC) in93,4%, 6% and 0,6%pts respectively. The ELTS low, intermediate and high score(n = 179)was in 86 (48%), 50 (28%) and 43 (24%) pts accordingly. Median (Me) age was 50 (18–82) years, the male/female ratio was equal. The overall survival (OS) considering CML phase, cumulative incidence (CI) of deaths depending on death reasons was analysed. The CI of complete cytogenetic response (CCyR) and major molecular response (MMR) was evaluated. All calculations were done using the SAS Version 9.4 package of procedures program.Results:Me follow‐up in the Russian part of EUTOS PBS was 69 (0,7 – 96) months (mo). Imatinib (IM) and 2ndgeneration tyrosine kinase inhibitors (TKI2) were used as 1stline therapy in 97% and 3% pts accordingly. The 5 years CI of CCyR and MMR at the 1stline TKI therapy was 83% and 67% accordingly. The switch to the 2ndand 3rdline of TKI2 therapy was in 22 (12%) of 193 pts, the main reason was IM failure.The OS by 5, 6 and 7 years was 80% (95% CI 72% ‐ 86%), 78% (95% CI 65% ‐ 80%) and 73% (95% CI 65% ‐ 80%) respectively in total cohort (p < 0,001). The OS of pts with low and high ELTS score was 88% and 56% (p < 0,0023) respectively by the 80 mo of follow‐up. The 5‐year OS in pts with AP+BC phase was 39%.In total 47 (23,8%) pts died during the whole observation period. The largest number of deaths was observed in the 1styear after the CML diagnosis: 17 (36%) of 47 cases. The death reasons were as follows: 1) progression of CML to AP/BC in 20 (43%) pts, 2) death in remission (pts with CCyR and /or MMR within 6 months before death) in 5 (11%) pts, 3) death without progression to AP/BC but with signs of leukemia and without CCyR in 22 (46%) patients. The 5 years CI of death from all reasons was 20%, CI of CML‐related and CML non‐related death at 5thyear was 18% and 11% respectively (figure1).Summary/Conclusion:In general, the results of therapy in CML pts of the Russian non‐selected population sample were comparable to the data of the whole European cohort. A higher proportion of pts with ELTS high ELTS scoreand a lower proportion of pts switched to 2nd/3rdline TKI therapy in comparison with Europe was identified. These issues could have an impact on the number of CML‐related deaths and their high proportion in the 1styear of therapy. Therefore, the early therapy interventions within the 1styear of therapy in CML pts are apparently important for the long‐term treatment results.image

European Treatment and Outcome Study score does not predict imatinib treatment response and outcome in chronic myeloid leukemia patients

The Sokal and Hasford scores were developed in the chemotherapy and interferon era and are widely used as prognostic indicators in patients with chronic myeloid leukemia (CML). Recently, a new European Treatment and Outcome Study (EUTOS) scoring system was developed. We performed a multicenter retrospective study to validate the effectiveness of each of the three scoring systems. The study cohort included 145 patients diagnosed with CML in chronic phase who were treated with imatinib. In the EUTOS low- and high-risk groups, the cumulative incidence of complete cytogenetic response (CCyR) at 18 months was 86.9% and 87.5% (P = 0.797) and the 5-year overall survival rate was 92.6% and 93.3% (P = 0.871), respectively. The cumulative incidence of CCyR at 12 months, 5-year event-free survival and 5-year progression-free survival were not predicted using the EUTOS scoring system. However, there were significant differences in both the Sokal score and Hasford score risk groups. In our retrospective validation study, the EUTOS score did not predict the prognosis of patients with CML in chronic phase treated with imatinib.

Comparison of Sokal, Hasford and EUTOS Scores in Terms of Long-Term Treatment Outcome According to the Risks in Each Prognostic Model: A Single Center Data Analyzed in 255 Early Chronic Phase Chronic Myeloid Leukemia Patients Treated with Frontline Imatinib Mesylate.

AbstractAbstract 2794 BackgroundThe main difference of recently developed new prognostic classification, EUTOS score, from the conventionally used Sokal and Hasford scores is the simplicity of adopting only 2 clinical parameters, basophil counts and size of spleen, to discriminate high vs. low risks in chronic myeloid leukemia (CML). Concerns may rise from possible inter-observer gap when measuring the size of spleen. While there is currently controversial debate on its prognostic power, we present our single center results of comparing EUTOS score with other two scores. Patients and MethodsAmong 380 adult patients, consecutively registered as early chronic phase (CP) CML at Seoul St. Mary’s Hospital (Jan. 2004 – Apr. 2010), who received imatinib (IM) as frontline therapy, 255 were evaluable for analysis: subjects were strictly limited to those with documented clinical parameters measured at very early time of diagnosis by a single doctor, before any cytoreduction therapies. The median age was 42 years (range, 19–77) with a slight male predominance (57%). Cytogenetic and molecular responses were calculated at specific time points and cumulative rates of response were compared according to risk scores. Event-free survival (EFS) was analyzed by time from start of IM to the time of events, defined by death from any cause, primary or secondary resistance to IM, progression to advanced phases, intolerance to IM and switch to second line tyrosine kinase inhibitor (TKI) or allografting. Response assessment followed current European Leukemia Net recommendation. ResultsMedian time from diagnosis to IM start was 14 days (range, 1–183). After a median follow-up duration of 56.6 months (range, 13.0–102.2) in survivors, there were 10 deaths and 3 patients with disease progression to accelerated phase of blastic crisis. Sixty-four patients had switched IM to second TKI due to either IM resistance or intolerance.Overall comparisons are described in Table 1. Of 42 EUTOS high risk patients, only 25 high risk patients by Sokal and 15 by Hasford were included. Almost 90% of either low or intermediate (INT) risk patients by all risk models achieved complete cytogenetic response (CCyR) at 12 months after IM, whereas high risk groups had lower rates, especially in EUTOS high risk (57%, p = <0.0001). Regarding major molecular response (MMR) at 18 months, significant differences were observed according to risk stratifications by Sokal and EUTOS, but not in Hasford risks, in which the same proportion of low and INT risks achieved MMR (48%, P = 0.308). This seemingly less prominent prognostic difference of low vs. INT groups of Sokal and Hasford scores were further demonstrated by insignificant difference between these groups in cumulative incidence (CI) of CCyR and MMR. All 3 high risk groups showed significantly lower incidence of both CCyR and MMR compared to low risk groups. INT risk groups by Sokal and Hasford models failed to show statistical significance in all three outcomes: CI of CCyR and MMR, and 5-year EFS. Of note, high risk stratified by EUTOS score demonstrated the least favorable outcomes with strongest p-values (Table 1). ConclusionBy simply comparing the p-values, our data may implicate that high risk group discriminated by the EUTOS score is predicted with more unfavorable outcomes in achieving CCyR, MMR and survival after IM frontline therapy. Furthermore, the lack of statistically significant difference between outcomes of low and INT risk groups by conventional risk models may challenge the need for future classification of INT from low risk in this era of TKI.Table 1Comparison of Sokal, Hasford and EUTOS scoresSokalHasfordEUTOSn (%)Low 118 (46)INT 92 (36)High 45 (18)Low 135 (53)INT 100 (39)High 20(8)Low 213(84)High 42(16)CCyR rate at 12 months (%, n=245)9084698883638957P0.0080.020<0.0001MMR rate at 18 months (%, n=250)5249274848305124P0.0120.3080.002Median months to CCyR5.95.96.15.95.96.35.97.3HR (95% CI) for CI of CCyR10.8 (0.6–1.1)0.6 (0.4–0.9)10.9 (0.7–1.2)0.5 (0.3–0.8)10.4 (0.3–0.7)P0.1470.0040.7820.0180.0002Median months to MMR14.514.017.215.213.322.514.018.8HR (95% CI) for CI of MMR10.9 (0.7–1.3)0.5 (0.3–0.9)10.9 (0.6–1.2)0.5 (0.2–1.0)10.4 (0.2–0.7)P0.8980.0200.5430.0610.0015–year EFS (%¡¾SD)76.7 ± 4.169.0 ± 5.150.8 ± 7.975.5¡¾3.967.1 ± 4.840.7 ±73.9¡¾3.247.0 ± 8.2HR (95% CI)11.4 (0.8–2.5)2.5 (1.4–4.4)11.6 (0.9–2.6)2.8 (1.4–5.6)12.4 (1.50–4.04)P0.1610.0020.0600.003<0.0001 Disclosures:No relevant conflicts of interest to declare.

PTCH1 Expression At Diagnosis Reliably Predicts Treatment Failure in Imatinib-Treated Chronic Myeloid Leukaemia Patients

AbstractAbstract ▪875▪This icon denotes a clinically relevant abstractImatinib treatment has radically changed the prognosis of patients with chronic myeloid leukaemia (CML). However, around 23–32% of patients discontinue this therapy due to lack of efficacy, so there is scope to further improve the management of CML patients. We sought to identify a biomarker, or biomarkers that could be used to predict at diagnosis which patients will respond to first line treatment using routinely accessible material.TaqMan Low Density Array (TLDA) technology was used to measure the expression of 29 genes that have been previously implicated in CML pathogenesis, normalized against 3 control genes (GUSB, B2M and 18S). RNA was extracted from archived white cell lysates from the peripheral blood of 73 patients (with appropriate ethical approval), converted to cDNA via first-strand synthesis and these were then analyzed as the learning cohort. ROC curves were plotted in order to find the optimal thresholds for each gene to divide patients into low and high expression groups; in the case of a low area under curve, the median expression value was used. Imatinib failure (IF) was defined as loss of complete hematologic response (CHR) or of complete cytogenetic response (CCyR), progression to advanced phase disease, death or change in treatment from imatinib due to lack of efficacy. Imatinib failure free survival (IFFS), cumulative incidence of CCyR and overall survival related to CML (CML OS) were analyzed by Kaplan-Meier and log-rank test for each gene. Results were validated in an independent cohort composed of 56 patients enrolled in the SPIRIT-1 trial.Of the 29 genes, only PTCH1 (inhibitor of Smoothed (SMO), member of the Hedgehog (Hh) signalling pathway and tumour suppressor gene involved in different cancers) and XIAP (X-linked inhibitor of apoptosis) were significant across multiple endpoints across both cohorts. Using a consistent PTCH1 expression threshold, significant differences in IFFS, CCyR and CML OS were seen, while XIAP predicted only for IFFS and CCyR.In order to corroborate our results, RT-qPCR using a different set of primers and probes (designed in-house) was performed on a subset of 37 patient diagnostic samples from the initial cohort and a further 20 samples taken on treatment, once patients had achieved CCyR, were also analysed for comparison. PTCH1 was successfully validated, and there was good correlation (r=0.823, p<0.001) between both techniques; however, the RT-qPCR results for XIAP did not recapitulate the TLDA data. Low and high PTCH1 expression groups (measured by RT-qPCR) had a 5 year rates of IFFS of 18% vs 94% (p<0.001), CCyR of 46.1% vs 100% (p=0.005) and OS CML 74% vs 100% (p=0.017). Cox regression using PTCH1 expression (categorised into high/low using the ROC), age and Sokal score demonstrated that PTCH1 expression was an independent predictor of IFFS and CCyR, irrespective of the method used for quantification. PTCH1 measurement by RT-qPCR using the second primer-probe set, showed a sensitivity for detecting IF (at any point) of 93.8%, specificity of 81% and negative predictive value of 94.4%. Finally, the median expression of PTCH1 was found to be significantly higher in remission samples compared to those taken at presentation which supports the hypothesis that the distinct PTCH1 signal detected in diagnostic samples reflects the presence of leukemic cells with a reduced expression of this tumour suppressor gene.These results are consistent with current hypotheses regarding Hh signaling and highlight its importance in CML pathogenesis. Given the high negative predictive value of high PTCH1 expression for imatinib failure, we propose that its measurement at diagnosis be used to help identify those patients that may require second generation TKIs or other therapies, which may, in future, include Smoothened inhibitors. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

EUTOS Score Identifies Cases with Poor Outcome in Patients with Early Chronic Phase Chronic Myeloid Leukemia, Though Not Predictive for Optimal Response to Imatinib

AbstractAbstract 3778 Introduction.The EUTOS score has recently been developed by the European Leukemia-Net (ELN) to predict the achievement of an 18-month complete cytogenetic response (CCyR) and progression-free survival in imatinib-treated early chronic phase (ECP) chronic myeloid leukemia (CML) patients. The score uses the percentage of basophils and spleen size to divide patients in 2 groups of low- and high-risk. Since its publication in 2011, however, there have been conflicting reports about the efficacy of EUTOS score. Moreover, scanty data are available on the power of this scoring system to foresee optimal response to imatinib, as defined by ELN recommendations. Aims and Methods.To test the power of EUTOS score in predicting achievement of optimal response to imatinib, as defined by ELN, time to imatinib failure (TTF) and progression-free survival (PFS), we evaluated 265 ECP CML patients treated with front-line standard dose imatinib (400 mg daily) at 5 major hematology centres in the north-eastern area of Italy. Partial cytogenetic response (PCyR) and CCyR were defined as 1–35% and 0% Ph+ metaphases, respectively; major molecular response (MMR) was defined as BCR-ABL <0.1%IS. TTF was measured from the start of imatinib to the date of any of the following events: progression to accelerated or blastic phase, death for any cause at any time, imatinib dose increase (≥ 600 mg/day) for primary or secondary hematologic or cytogenetic resistance. PFS was measured from the start of imatinib to the date of progression to accelerated or blastic phase or death for any cause at any time. Survival probabilities were estimated by the Kaplan-Meier method and compared by log rank test; differences among variables were evaluated by the Fisher’s exact test or by Student’s t-distribution. Results.A total of 265 consecutive patients with ECP CML were included in this study. The median age was 55 years (range 19–84), with 149 males and 116 females. The median follow-up was 61 months (range 6–136). The median time from diagnosis to imatinib therapy was 0.7 months (range 0 – 7.6). The distribution according to the EUTOS score was: 248 patients (93.6%) in the low risk group and 17 patients (6.4%) in the high risk group. The “optimal response” endpoints to imatinib (i.e. PCyR at 6th months, CCyR at 12th months and MMR at 18th months) were higher in low-risk patients, but did not achieve statistical significance. Specifically, the values were as following: PCyR 86% vs 67% (p=0.055), CCyR 80% vs 63% (p=0.117) and MMR 61% vs 36% (p=0.126). Cumulative incidence of CCyR was comparable in the two groups (88%% in low-risk and 80% in high risk), but time to CCyR was shorter in low-risk patients (6 months) compared to the one in high-risk patients (9 months) (p=0.048) [figure 1]. More importantly, EUTOS score was able to predict long term response to therapy. Indeed, 59% of patients in the high-risk group experienced imatinib failure, compared to 30% in the low-risk group (p=0.027). Moreover also TTF was significant shorter in the high-risk group [figure 2]. Fifty-three patients in the low-risk group (21%) were switched to 2nd-generation TKIs (29 dasatinib, 22 nilotinib, 1 bosutinib, 1 ponatinib), compared to six (35%) in the high-risk group (4 dasatinib, 2 nilotinib). Also PFS rate was significantly worse in patients with high EUTOS score, with 11/248 events (4%) in the low-risk group and 4/17 (23%) in the high-risk cases (p=0.01) [figure 3]. Conclusions.In our study group, the EUTOS score was predictive for long-term outcome of imatinib therapy, both in terms of treatment failure and of progression-free survival. Taking into consideration the ELN definitions of optimal response, there was a trend toward better cytogenetic and molecular response in low-risk patients; the lack of statistical significance could be due to the relatively small number of high-risk cases. [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

BCR-ABL Fusion Transcript Do Not Significantly Influence the Outcome of Chronic Myeloid Leukemia Patients In Early Chronic Phase Treated with Imatinib Mesylate: a GIMEMA CML WP Analysis.

AbstractAbstract 1230 Background:Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL fusion gene. Different types of BCR-ABL transcripts can be found, due to different genomic breakpoints and alternative splicing. The most frequent transcripts are the e13a2 (b2a2) and the e14a2 (b3a2), that codify for a p210 protein. Occasionally, both transcripts may be present. In the imatinib (IM) era, few data about the prognostic significance of the transcript type are available, particularly in the setting of early chronic phase (ECP): one study suggested that patients with the b2a2 transcript may be more sensitive to IM (de Lemos et al. Genet Mol Res 2005), while two larger studies suggested that patients with b3a2 transcript may have better responses to IM (Vega-Ruiz et al. ASH 2007; Lucas et al. Haematologica 2009). No systematic evaluations in the context of large prospective clinical trials have been performed. AIM: To investigate the influence of the type of BCR-ABL fusion transcript on the responses and the outcome of CML patients treated with IM in ECP. Methods:We performed an analysis of 3 concurrent clinical trials of the GIMEMA CML Working Party (Clin Trials Gov. NCT00514488, NCT00510926 and the observational trial CML/023). Response monitoring was based on conventional cytogenetic examination (bone marrow) and quantitative molecular (Q-PCR) evaluation (peripheral blood). Definitions: Complete Cytogenetic Response (CCgR): 0% Ph+; Major Molecular Response (MMR): BCR-ABL/ABL ratio <0.1% (International Scale); failures: according to the revised European LeukemiaNet criteria (Baccarani et al. J Clin Oncol 2009). Results:559 consecutive CML patients in early CP have been enrolled from January, 2004 to January, 2007. Patients expressing rare transcript types (e1a2 and e19a2) and patients with the presence of both b2a2 and b3a2 transcripts were excluded: 493 out of 559 patients were evaluable, 203 (41%) with a b2a2 transcript and 290 with a b3a2 transcript (59%). The 2 groups were comparable (no significant difference in sex, age, Sokal and Hasford scores, clonal chromosomal abnormalities in Ph+ cells before IM and imatinib dose). The median observation time is currently 60 (extremes 2–80) months. In patients with b2a2 and b3a2 transcript, the observed 12-months CCgR rates were 77% and 80%, respectively; the cumulative incidence of CCgR was 89% and 88%, respectively (no significant differences). The time to MMR was significantly shorter for patients with b3a2 transcript (fig.1), but the cumulative incidence of MMR was not significantly different (81% and 86% in patients with b2a2 and b3a2 transcript, respectively). The probabilities of Failure-Free Survival, Progression-Free Survival and Overall Survival were 69% and 75%, 83% and 89%, 87% and 92% in patients with b2a2 and b3a2 transcript, respectively (fig. 1); no difference was statistically significant. Conclusions:In our experience, based on 493 early CP CML patients treated frontline with IM, the type of BCR-ABL fusion transcript had no relevant prognostic impact and no outcome differences have been observed so far. Acknowledgments:Work supported by European LeukemiaNet, COFIN, University of Bologna and BolognAIL. [Display omitted] Disclosures:Castagnetti:Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Gugliotta:Novartis: Honoraria. Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy. Saglio:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baccarani:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; Wyeth: Consultancy, Research Funding. Rosti:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.