EUTOS Long-term Survival Score Research Articles

Is the Eutos Long Term Survival (ELTS) Score a Useful Marker to Predict Outcome in Children with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase (CP)? the Experience of the International Registry of Childhood CML

Aims. CML is a very rare disease in children. The present work aims to describe the characteristics of children with CML in chronic phase (CP) and to determine the outcome of this pediatric population. Methods. We retrospectively analyzed children with CML in CP registered in The International Registry of Childhood Chronic Myeloid Leukemia (I-CML-Ped Study; www.clinicaltrials.gov NCT01281735) which represents the largest cohort of children with CML. Results. Between January 2011 and March 2021, 576 CML patients less than 18 years of age at diagnosis were registered. We retrospectively selected 535 (92.8 %) children in CP according to the European leukemia net (ELN) criteria at diagnosis. Boys accounted for 58% of all patients with a boy to girl ratio of 1.25. The median age at diagnosis was 12.4 years (range, 8 months to 18 years). The most common symptoms at presentation were asthenia, weight loss and abdominal pain in 46%, 25% and 23% of the patients, respectively. CML in CP was diagnosed incidentally in 80 (16%) children when a blood assessment was performed for medical reasons. At diagnosis, thrombosis was observed in only one patient whilst 20% of the children presented with bleeding. Bleeding signs were associated with a higher frequency of palpable spleen (p=0.0007), higher leukocyte (p<0.0001) and platelets (p=0.02) counts, and a lower hemoglobin level (p=0.02). Clinical signs of leukostasis were observed in 88 (16.5%) patients. At diagnosis, spleen was palpable in 76% of the patients with a median of 9 cm (range, 1 to 32) below the costal margin. The median leukocyte count was 222 G/L (quartile 95-353). There is no statistical difference between boys and girls in terms of frequency of signs of leukostasis, frequency of splenomegaly, spleen size, median of the leucocyte count and hemoglobin level but the median of the platelet count was significantly higher in girls (p<0.0001). The majority (67%) of the children was allocated to the low-risk group according to the Eutos Long Term Survival (ELTS) score. First line therapy consisted of imatinib in 482 children with a median follow up of 4.6 years (IQR. 2.2-8.4). Among them, 208 (43%) children remained on imatinib with a median follow up of 2.9 years (IQR. 1.5-5.6). The main reason for switching (38.7% of the switches) was failure to achieve hematologic, cytogenetic or molecular response. Among the patients treated with imatinib first line, 15 (3.1%) children died and the probability of overall survival at 36 months was 97.4% (95% CI: 95-99%) (Figure 1). ELTS score was calculated for 406 of these patients: the 3-year survival rate was 98.1.% (95% CI: 96.3-100%), 94.4% (95% CI: 89.1-99.9%) and 95% (95% CI: 88.5-100%) in the low-, intermediate- and high-risk group, respectively (p logrank=0.009). Nineteen of these patients (3.9%) switched from imatinib to another treatment due to progression (accelerated or blastic phase). Progression free survival (PFS) rate at 3-years was 97.1% (95% CI: 94.9-99.2%), 91.7% (95% CI:84.5-98.3%) and 72.0% (95% CI: 59-87.9%) in the ELTS low-, intermediate- and high-risk group, respectively (p logrank<0.001) (Figure 2). Conclusion. The analysis of clinical and biological parameters of the largest cohort of children with CML in CP demonstrated that pediatric CML is characterized by a bulky disease (large splenomegaly, high leucocyte counts). However, these characteristics did not translate in a low rate of response and the outcome was similar to adults. While the ELTS score can identify children with the poorest outcome, a refined prognostic score specific for the pediatric population needs to be established and validated.

Efficacy and Safety of Flumatinib in Treatment of Patients with Chronic Myeloid Leukemia

To analyze the efficacy and safety of flumatinib in the treatment of patients with chronic myeloid leukemia (CML). The clinical data of 56 CML patients treated with flumatinib from January 2020 to December 2021 in the First Affiliated Hospital of Nanchang University were retrospectively analyzed. Patients were divided into three groups: 35 new diagnosed CML patients treated with flumatinib (group A), 10 patients with imatinib/dasatinib intolerance (group B) and 11 patients with imatinib/dasatinib resistance (group C) switched to flumatinib treatment, respectively. The molecular response and adverse effects of flumatinib treatment were evaluated. In group A, the early molecular response (EMR) at 3 months was 40.0%, and the major molecular response (MMR) at 6 and 12 months was 43.7% and 46.2%, respectively. In group B, the EMR was 50.0% at 3 months, and the MMR was 70.0% and 66.2% at 6 and 12 months, respectively. Among evaluable patients, 6 cases in group B achieved molecular response of 4.5 (MR4.5) at 12 months after switching to flumatinib treatment. In group C, 3 cases who switched from imatinib resistance to flumatinib achieved MR4.5 at 12 months, but 2 cases who switched from dasatinib resistance to flumatinib failed. Subgroup analysis showed significant differences in EUTOS long-term survival (ELTS) scores for patients in the medium-risk/high-risk group compared with those in the low-risk group for 3-month EMR (18.8% vs 57.9%), 6-month MMR (15.4% vs 63.2%) and 12-month MR4.5 (15.4% vs 69.2%) (P =0.036, P =0.012,P =0.015). The most common adverse effect in group A was thrombocytopenia, accounting for 54.5%, and 22.8% (8/35) patients discontinued the drug due to haematological adverse effects. Compared with patients who did not discontinue the drug or whose recovery time from discontinuation due to haematological toxicity was <1 month, patients whose recovery time from discontinuation was ≥1 month had a significantly worse 3-month EMR, 6-month MMR and 12-month MR4.5 (P =0.028, P =0.021, P =0.002). Flumatinib has better molecular response and tolerance in patients with primary, imatinib/dasatinib-intolerant or resistant CML. Medium-risk/high-risk in ELTS score and time to recovery from discontinuation due to haematological toxicity ≥1 month are important factors influencing achievement of better molecular response in flumatinib treatment.

Long-Term Outcomes with Sequential Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients

Tyrosine kinase inhibitor (TKI) is the standard treatment for chronic myeloid leukemia (CML). In the national list of essential medicines in Thailand, the first, second, and third-line treatments are imatinib, nilotinib, and dasatinib, sequentially, different from the European Leukemia Net guidelines. This study aimed to evaluate the outcomes of CML patients who received sequential treatment with TKI. This study enrolled CML patients diagnosed between 2008 and 2020 at Chiang Mai University Hospital who received TKI. Medical records were reviewed for demographic data, risk score, treatment response, event-free survival (EFS), and overall survival (OS). One hundred and fifty patients were included in the study, 68 patients (45.3%) were female. The mean age is 45.9 ± 15.8 years. Most patients (88.6%) had good ECOG status (0-1). The CML diagnosis was in the chronic phase in 136 patients (90.6%). The EUTOS long-term survival (ELTS) score revealed a high of 36.7%. At the median follow-up of 8.3 years, 88.6% of patients were in complete cytogenetic response (CCyR), whereas 58.0% were in major molecular response (MMR). The 10-year OS and EFS were 81.33% and 79.33%, respectively. The factors associated with poor OS were high ELTS score (P = 0.01), poor ECOG performance status (P < 0.001), not achieved MMR within 15 months (P = 0.014), and not achieved CCyR within 12 months (P < 0.001). The sequential treatment for CML patients had a good response. Factors predicting survival were ELTS score, ECOG performance status, and early achieving MMR and CCyR.

The Impact of EUTOS Long-Term Survival (ELTS) Score on Predicting Progression and Survival Among Turkish Patients with Chronic Myeloid Leukemia

Introduction and Objectives: For patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP), four baseline prognostic scores are commonly used including the Sokal score and the most recently introduced EUTOS long-term survival (ELTS) score. The ELTS score was shown to be superior to the Sokal score for predicting survival. The aim of the study is to evaluate the value of ELTS score on predicting disease progression and survival in Turkish pts with CML-CP.Material and Method: Demographic, laboratory and clinical features, disease responses to tyrosine kinase inhibitor (TKI) therapy and survival of CML-CP pts, who received upfront imatinib (IM) between 2003 and 2018 were analyzed retrospectively. Treatment responses were reevaluated according to European LeukemiaNet 2013 recommendations. Risk groups analysis, discrimination and hazard ratios (HRs) were evaluated with Cox regression and Kaplan-Meier survival analysis. Receiver operating characteristic (ROC) analysis was performed to examine the effects of scores on predicting overall survival (OS) and progression-free survival (PFS).Results: A total of 185 pts were included, of which 103 (55.7%) were male and median age was 47 years (range, 16 - 81 years) (Table 1). The percentages of pts with low-, intermediate-, and high-risk ELTS scores were 60.5%, 25.9%, and 13.5%, respectively. For the Sokal score, these percentages were 37.3%, 40.5%, and 22.2% respectively. For Sokal high-risk pts, only 46.3% were classified as high-risk according to the ELTS score. Similarly, 44% of pts with intermediate Sokal risk had low-risk ELTS score (Fig. 1). Seventy-seven pts (41.6%) had at least one comorbidity, and the most common comorbidities were hypertension (21.6%), diabetes mellitus (13%), and ischemic heart disease (12.4%) (Table 1). The median durations of IM therapy and follow-up were 2728 (range, 14 - 6320 days) and 3473 (range, 71 - 6320 days) days, respectively. Complete hematologic and early molecular (BCR-ABL1 IS <10% at 3 months) responses at 3 months were 95.6% and 75.9%, respectively. Complete cytogenetic and major molecular response rates at 6 and 12 months were 72.3% and 86.1% and 45.4% and 54%, respectively. Thirty-five pts (18.9%) switched to second-generation TKI therapy and 6 pts (3.2%) progressed to advanced-phase disease during the follow-up (Table 1). For PFS, with reference to the low-risk Sokal score, the HR of high-risk groups was 9.301 (95% CI: 1.086-79.656, p=0.042) (Fig. 2A). Similarly, with reference to the low-risk ELTS score, the HR of intermediate- and high-risk groups were 4.744 (95% CI: 0.43-52.314, p=0.204) and 14.642 (95% CI: 1.523-140.791, p=0.020) (Fig. 2B). Regarding OS, with reference to the low-risk Sokal score, the HR of the intermediate- and high-risk groups were 1.835 (95% CI: 0.564-5.964, p=0.313) and 6.412 (95% CI: 2.11-19.489, p=0.001), respectively (Fig. 2C). With reference to the low-risk ELTS score, the HR of the intermediate- and high-risk groups were, 3.263 (95% CI: 1.242-8.576, p=0.016) and 7.258 (95% CI: 2.762-19.074, p<0.001) respectively (Fig. 2D). In the ROC analysis, the ELTS score was superior than the Sokal risk score for both predicting PFS (AUC=0.820 vs. AUC=0.818) and OS (AUC=0.762 vs. AUC=0.744). During the follow-up, 27 (14.6%) pts died, of which 6 died due to CML progression and causes of death were unrelated to CML in 21.Conclusion: In our study, we showed that the ELTS score could successfully predict high-risk pts compatible with the literature. With higher hazard ratios and better risk group stratifications, the ELTS score outperformed the Sokal score. The ELTS score can help clinicians to better discriminate poor prognostic pts and can promote optimal treatment strategies for these pts with potentially worse prognosis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Is the Sokal or EUTOS long-term survival (ELTS) score a better predictor of responses and outcomes in persons with chronic myeloid leukemia receiving tyrosine-kinase inhibitors?

Data from 1661 consecutive subjects with chronic-phase chronic myeloid leukemia (CML) receiving initial imatinib (n = 1379) or a 2nd-generation tyrosine-kinase inhibitor (2G-TKI; n = 282) were interrogated to determine whether the Sokal or European Treatment and Outcome Study for CML (EUTOS) long-term survival (ELTS) scores were more accurate responses and outcome predictors. Both scores predicted probabilities of achieving complete cytogenetic response (CCyR), major molecular response (MMR), failure- and progression-free survivals (FFS, PFS), and survival in all subjects and those receiving imatinib therapy. However, the ELTS score was a better predictor of MR4, MR4.5, and CML-related survival than the Sokal score. In subjects receiving 2G-TKI therapy, only the ELTS score accurately predicted probabilities of CCyR, MMR, MR4, FFS, and PFS. In the propensity score matching, subjects classified as intermediate risk by the ELTS score receiving a 2G-TKI had better responses (p < 0.001~0.061), FFS (p = 0.002), and PFS (p = 0.03) but not survival. Our data suggest better overall prediction accuracy for the ELTS score compared with the Sokal score in CML patients, especially those receiving 2G-TKIs. People identified as intermediate risk by the ELTS score may benefit more from initial 2G-TKI therapy in achieving surrogate endpoints but not survival, especially when a briefer interval to stopping TKI therapy is the therapy objective.

The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.

Validation of the EUTOS Long-Term Survival Score in Chinese Chronic Myeloid Leukemia Patients Treated with Imatinib: A Multicenter Real-World Study.

PurposeTo validate the clinical efficacy of the recently developed EUTOS long-term survival (ELTS) score in a real-world setting.Patients and MethodsA total of 479 chronic myeloid leukemia (CML) patients treated with frontline imatinib between January 2010 and December 2017 were enrolled in this retrospective study. The ELTS score was evaluated on the end-points including complete cytogenetic response (CCyR), progression-free survival (PFS), overall survival (OS) and CML-related death, and the efficiency of the ELTS score was further compared with the historical Sokal, Hasford, EUTOS scores.ResultsWith a median follow-up of 69 months (range, 9–112 months), 462 evaluable patients were stratified into the ELTS low-risk (n = 230), ELTS intermediate-risk (n = 168) and ELTS high-risk (n = 64) groups. For the regular assessment indicators like CCyR, PFS and OS, the ELTS scoring system could effectively identify the corresponding risk groups, similarly with the results provided by previous scoring systems. With respect to the CML-related death, the ELTS score could accurately identify a high-risk group with a significantly higher risk of dying of CML, and the 5-year cumulative incidence occurred in the ELTS high-, intermediate-, and low-risk groups was 11% (95% CI: 3–19%), 5% (95% CI: 1–9%) and 2% (95% CI: 0–4%), respectively. Most notably, the ELTS score outperformed the Sokal, Hasford and EUTOS scores without statistical difference among different risk groups.ConclusionThe ELTS score could effectively predict the prognosis of imatinib-treated CML patients in real-life settings.

On a Long Way to the Treatment Free Remisson: The Results of the Long-Term Observation of the Chronic Myeloid Leukemia Patients in Russian Part of EUTOS Population-Based Study

Background: A success of the tyrosine kinase inhibitors (TKI) therapy in patients (pts) with chronic myeloid leukemia (CML) allowed to set a new goal: a treatment-free remission (TFR). A stable and long-lasting deep molecular response (DMR) is required for a successful TKI discontinuation. The number of CML pts with stable DMR increases on late terms of TKI therapy. With the relationship to this new goal it is relevant to evaluate the proportion of the potential candidates for TKI discontinuation in accordance with the country-specific features of the CML pts population in routine clinical practice. Aim :To characterize the cohort of CML pts treated in routine clinical practice in Russian Federation and to evaluate the proportion of CML pts eligible for TFR. Methods: The analyzed cohort consisted of 197 pts from 6 regions of Russia covering the population of 10 million inhabitants. All pts with CML diagnosed from 01.10.2009 to 31.12.2012 were included into the prospective multicenter EUTOS Population Based Study (EUTOS PBS). Median (Me) age was 50 (18-82)years, 49% were males. Chronic phase, accelerated phase and blast crisis was diagnosed in 93,4%, 6% and 0,6% pts respectively. Imatinib as a 1st line was used in 97% pts. The 2nd generation TKIs (TKI2) were used as 1st and 2nd -3rd line in 3% and 12% pts respectively; imatinib failure was the main reason of switch to TKI2. Overall survival (OS) and cumulative (CI) of DMR were evaluated and adjusted to the new ELTS (EUTOS long-term-survival) score. A proportion of pts with sustained DMR eligible for TFR was calculated. DMR was considered as BCR-ABL&lt;0,01% IS. A TFR eligibility was considered as a sustained DMR lasting for &gt;2 years and TKI therapy &gt;3 years. Results:Me follow-up in Russian CML pts cohort of EUTOS PBS was 77 (0,7 - 107) months (mo). The ELTS score available in 179 pts was low, intermediate and high in 86(48%), 50(28%) and 43(24%) pts accordingly. The 7-year OS was 76% in total cohort (figure 1a). The 7-year OS in low, intermediate and high ELTS group was 87%, 68% and 55% respectively (p=0,001). Me time of DMR achievement was 38mo (11,2 - 89 mo). The 7-year CI of DMR was 62%. The CI of 7-year DMR achievement in ELTS low, intermediate and high group was 62%, 42% and 38% respectively with significant difference between low and non-low score pts (p= 0,001) (figure 1b). The data for the molecular response at data cut-off April 2019 were available in 114/123 pts who were alive and treated by TKIs with Me time 85 (range 65 - 105) mo. DMR, major molecular response (MMR, (BCR-ABL &gt;0,01%- 0,1% IS) and no MMR (BCR-ABL&gt; 0,1% IS) was in 76 (66,7%), 8 (7%) and 30 (26,3%) pts respectively. A sustained DMR was in 38 (50%) of 76 pts or 19% of the total cohort of 197 pts. Conclusion: A significant proportion of CML pts reach a sustained DMR on late terms of TKI therapy. In total 19% of CML pts in Russian part of the EUTOS PBS study can be eligible to treatment-free observation after 7 years of TKI therapy. The low ELTS score predicts better survival and better chance of DMR achievement. The evaluation of the TFR perspective in routine clinical practicein important from diagnosis to late terms of treatment. Disclosures Chelysheva: Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Vinogradova:Novartis: Consultancy; Fusion Pharma: Consultancy. Turkina:Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy.

Prognostic Effects of Pretreatment Statuses at Diagnosis in Patients with Chronic Myeloid Leukemia: Results of the New Target Observational Study 1

Prognostic Effects of Pretreatment Statuses at Diagnosis in Patients with Chronic Myeloid Leukemia: Results of the New Target Observational Study 1

Second-Generation Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia with Additional Chromosomal Abnormalities

Second-Generation Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia with Additional Chromosomal Abnormalities

Ten-year outcome of chronic-phase chronic myeloid leukemia patients treated with imatinib in real life.

Imatinib, the first BCR/ABL kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML), has changed the long-term outcome of patients affected by this disease. The aim of our analysis was to report, after a median follow-up of 10.2years (range 5.8-14.8), the long-term outcome, efficacy, and safety of imatinib treatment (frontline and after interferon failure) in a single institution cohort of 459 patients with CML in chronic phase treated outside of clinical trials. The 10-year overall survival of the whole cohort was 77.1%, while the 10-year probability of dying due to CML and other causes was 7.8% and 16%, respectively. The prognostic value of the BCR-ABL1 ratio at 3months (⩽10%) and of complete cytogenetic response and major molecular response at 1year was confirmed also in the real-life practice. The EUTOS long-term survival score better stratified the baseline risk of dying of CML compared with other risk scores. Two hundred thirty-six (51.4%) patients achieved a deep molecular response during imatinib treatment after a median time of 4.57years, and 95 (20.6%) had a stable deep molecular response maintained for at least 2 consecutive years. Imatinib was associated with a low rate of serious cardiovascular events and second neoplasia. This 10-year real-life follow-up study shows that imatinib maintains efficacy over time and that long-term administration of imatinib is not associated with notable cumulative or late toxic effects.

The Use of EUTOS Long-Term Survival Score Instead of Sokal Score Is Strongly Advised in Elderly Chronic Myeloid Leukemia Patients

Background. Many prognostic scores have been proposed for risk stratification of chronic myeloid leukemia (CML) patients: the Sokal is the oldest and the most widely used score; the EUTOS long-term survival (ELTS), based on a large cohort of patients treated frontline with imatinib (IM), is the most recent score. The ELTS score, compared to Sokal score, showed superior ability to predict overall and leukemia-related survival, but data are limited and differences were small. Further evidence is required to support and to implement the clinical use of ELTS score. Aims. Given the different weight of the variable "age" in ELTS and Sokal score formulations, we hypothesized a different predictive value in specific age groups. Consequently, the aim of our study was to compare the prognostic value of ELTS and Sokal scores in a cohort of CML patients treated frontline with tyrosine kinase inhibitors (TKIs), according to the age, Methods. Nine hundred and four adult patients were included, 559 treated with IM and 345 treated with nilotinib (NIL). Patients were enrolled in six multicenter studies (NCT00481052, NCT00769327, NCT01535391, NCT00514488, NCT00510926, observational trial CML/023) conducted by the GIMEMA CML WP. The intention-to-treat population of each study was analyzed. Definitions: major molecular response (MR3 or MMR), BCR-ABL IS IS 10.000 copies; progression, transformation according to ELN criteria; leukemia related death (LRD): death after progression. Results. Median age, 52 years (range 18-86). Age distribution: 65 years) only the ELTS score was able to predict the achievement of MR3 (99%, 87% and 75% in low, intermediate and high-risk patients, respectively; p=0.001) and MR4 (82%, 61% and 50% in low, intermediate and high ELTS score patients, respectively; p=0.005). Interestingly, in elderly patients both scores predicted the OS, while only the ELTS score predicted a significantly different LRD probability (cumulative incidence 2%, 6% and 14% in low, intermediate and high-risk patients, respectively; p=0.049). The results were similar considering patients Summary/Conclusion. The risk distribution according to ELTS and Sokal score and the concordance between the two scores was different in young adults ( Disclosures Castagnetti: Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta: Pfizer: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Breccia: Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Levato: Novartis: Other: Advisory board. Abruzzese: Ariad: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Soverini: Incyte Biosciences: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy. Foa: GILEAD: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; AMGEN: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau. Martinelli: Abbvie: Consultancy; Novartis: Speakers Bureau; Janssen: Consultancy; Roche: Consultancy; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; Ariad/Incyte: Consultancy; Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Cavo: AbbVie: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Pane: Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; AMGEN: Speakers Bureau.

Integration of Multiple Bioassays Using Machine Learning to Identify High-Risk CP-CML Patients Treated with Frontline Imatinib

Introduction. Imatinib has revolutionised the treatment of chronic phase-chronic myeloid leukemia (CP-CML), with up to 70% of patients (pts) achieving major molecular response (MMR, BCR-ABL1 < 0.1% IS). Achievement of MMR by 2 years (yrs) is associated with an excellent prospect of long term survival. Currently, three baseline prognostic scoring systems - the Sokal, Hasford (Euro) and EUTOS risk scores - have all been used to identify pts with a poor response and/or an adverse prognosis in CP-CML. Recently, the EUTOS long-term survival (ELTS) score is shown to have strong predictive power for overall survival in CML pts. We have previously reported bioassays that have significant value for predicting MMR. Combinations of these biomarkers, together with clinical risk score, may provide a better indicator of high risk pts at the time of diagnosis.Aim. To identify high-risk pts by combining selected predictive bioassay, determine whether the ELTS score is more discriminating, and determine whether it provides additional predictive value when combined with the biomarker score.Methods. Bioassays including CRKL IC50 imatinib (White, Blood, 2005), OCT-1 Activity (OA)(White, JCO, 2010), leves of 39 plasma cytokines (Nievergall, Leukemia, 2016), expression of 20 most prognostic gene by qPCR TLDA (Kok, ASH abstract, 2015), ABCB1 gene expression (Eadie, Leukemia, 2016), KIR2DL5B genotype (Yeung, Blood, 2015), BIM and ASXL1 polymorphisms (Marum, Blood advances, 2017) were used in this study. High-risk by biomarker score (HR) was defined as pts who did not achieve MMR by 2 yrs. 210 TIDEL-II pts (frontline imatinib with early switch to nilotinib for failure to meet optimal time-dependent molecular targets) were used in this study (Yeung, Blood, 2015). Only 201 pts had ELTS scores. The Recursive Partitioning and Regression Trees (rpart) algorithm was used to identify important bioassays in predicting high-risk pts. Fisher's-exact test was used for statistical analysis.Results. In the TIDEL-II cohort, there were 21 high ELTS and 180 low/intermediate ELTS pts. Pts with high ELTS had significantly lower rates of MMR by 2 yrs compared to those pts with low/intermediate ELTS (57% vs 81%, p=0.02). We constructed a predictive model using multiple different bioassays as variables to predict high-risk pts. The rpart based model used in this analysis yielded four variables (IGFBP2 gene expression, KIR2DL5B genotype, OA, and MCP-1 cytokine plasma level) as most important for predicting high-risk pts. The accuracy of the model was 84%. Pts predicted as high-risk (HR, n=27) had significantly lower MMR achievement rate compared to those predicted as low-risk (LR), (26% vs 86%, n=183, p<0.0001, OR:17.3). Importantly, pts with HR had significantly higher rate of blast-crisis progression (15%, n=4/27) compared to those with LR (1.6%, n=3/183, p=0.006, OR:10.4) and pts with high ELTS (5%, n=1/21). Interestingly, there were two categories of HR patient groups based on the model: 1) Patient with high IGFBP2 gene expression and low OA, and 2) pts with low IGFBP2, KIR2DL5B positive genotype and high MCP-1 cytokine level. When combined with ELTS, the bioassays model improved ELTS performance in predicting HR pts. For instance, within the low/intermediate ELTS pts group, our assays could futher distinguish HR pts with inferior MMR (n=20, 2 yrs MMR of 30%) versus LR pts (n=160, 2 yrs MMR 87%). Similarly, pts with high ELTS in combination with HR also had lower MMR rate (n=1/5, 20%) compared to pts with high ELTS in combination with LR (n=11/16, 69%, p=0.11, OR:8.8).Conclusion. We developed a combined bioassays model that is predictive of MMR failure and adverse clinical outcomes for pts who receive optimised frontline imatinib therapy. This model performs well even without adding clinical parameters. Our model has additional predictive value when used together with the ELTS score, and can distinuguish HR pts within the low/intermediate ELTS group, as well as LR patients within the high ELTS category. Further confirmation of the predictive performance of this model, using a large independent patient cohort is now indicated. We postulate that this bioassay-based model could be used, in combination with ELTS, for identifying HR pts who would benefit from intensified therapeutic approaches to obtain optimal clinical outcome. [Display omitted] DisclosuresYeung:Amgen: Honoraria; Pfizer: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Specialised Therapeutics Australia: Honoraria. Yong:Celgene: Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. White:BMS: Research Funding; Novartis: Honoraria, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees.

The Evaluation of Residual Disease By Digital PCR, and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after for Stopping Imatinib First-Line in Chronic Phase CML Patients: Results of the STIM2 Study.

BackgroundTKI discontinuation is now a critical goal of CML management and several studies have demonstrated the feasibility of stopping safely imatinib (IM). A sustained deep molecular response (DMR) on long-term TKI therapy seems critical prior to attempting treatment-free remission (TFR). Results from different studies have been reported recently, but they failed to identify robust and reproducible predictive factors allowing a better selection of candidate patients for successful TFR.AimsWe prospectively asked whether the use of IM first-line in de novo CP-CML patients and a systematic screen of patients with digital droplet quantitative PCR (ddPCR) for BCR-ABL1 would impact on the TFR rates.MethodsIn a national prospective phase II trial (Eudract # NCT01343173), we enrolled newly diagnosed CP-CML patients, in sustained MR4.5 (≥2 yrs on at least 5 consecutive points) according to the ELN criteria, checked centrally. Further molecular follow-up was performed in local laboratories, all ELN standardized and aligned on the international scale (IS). Molecular recurrence was defined as the positivity of BCR-ABL1/ABL1 transcripts with at least 1-log increase between 2 consecutive assessments or as loss of MMR on a single assessment. Duplex ddPCR was performed on screening samples after RT, using EAC primers and probes. Pre-mixes were transferred in aDG8 cartridge, and generation of droplets was made on the QX200 droplet generator. Each emulsion was transferred into a 96 wells ddPCR plate and amplified on the Biorad-C1000 Touch Thermocycler. Each patient was analyzed in duplicate. ddPCR was considered positive when the BCR-ABL1/ABL1 % was ≥3 SD. BCR-ABL1/ABL1 ratios were aligned on the IS, a conversion factor was calculated for the RT-ddPCR as previously described (S. Branford et al., Blood 2008). Impact of variables on the risk of relapse were assessed through univariate and multivariate analyses using SAS program.ResultsThe median follow-up after IM cessation was 23.5 (1-64) Mo. One patient died from unrelated cause, and 107 experienced a loss of MMR. The molecular recurrence-free survival (RFS) was 52% (95%CI: 45-59%) at 6 months, and 50% (95%CI: 43-57%) at 24 months. The Sokal and the EUTOS long-term survival (ELTS) scores failed to discriminate patients but a trend was observed for ELTS score (p=0.0547). Other variables analysed such as gender (p=0.6246), age at diagnosis (p=0.966), age at IM cessation (p=0.6197), interval diagnosis-IM (p=0.9621), interval IM initiation-DMR (p=0.9978) did not impact on the rate of relapse. In contrast, IM and DMR duration before IM cessation significantly impacted on the rate of relapse, as this interval is redundant with IM duration (p=0.008). ddPCR was applied to 174 out of 218 patients at IM cessation. A cut-off of 0.0023%IS ratio (= median of positive ratios) was also associated with a higher risk of relapse. The RFS estimate according to this cut-off is shown in Figure 1. In a multivariate analysis, the duration of IM (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified significant predictive factors with respectively p=0.0366 [HR=0.635, 95%CI: 0.415-0.972] and p=0.0081 [HR=0.635, 95%CI: 0.415-0.972)].No association was observed between a ddPCR ≥0.0023%IS and gender, Sokal or ELTS score, age at diagnosis, age at IM discontinuation, duration of IM treatment, DMR duration or the time-lapse for obtaining DMR.ConclusionWe conclude that the duration of IM and the residual leukemic cell load as determined by a sensitive technique such as ddPCR are key factors for predicting TFR for de novo CP-CML patients who have been treated with IM front-line. DisclosuresNicolini:Sun Pharma Ltd: Consultancy; BMS: Consultancy, Speakers Bureau; Incyte Biosciences: Consultancy, Speakers Bureau. Dulucq:Incyte: Consultancy; BMS: Consultancy. Etienne:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mahon:Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; BMS: Speakers Bureau.

Prognostic discrimination based on the EUTOS long-term survival score within the International Registry for Chronic Myeloid Leukemia in children and adolescents.

The EUTOS Long-Term Survival score was tested in 350 children with chronic myeloid leukemia in first chronic phase treated with imatinib and registered in the International Registry for Childhood Chronic Myeloid Leukemia. With a median follow up of 3 years (range, 1 month to 6 years) progression and/or death (whichever came first) occurred in 23 patients. For the entire cohort of patients the 5-year progression-free survival rate was 92% (95% CI: 87%–94%) and the 5-year survival accounting for chronic myeloid leukemia deaths was 97% (95% CI: 94%–99%). Of the 309 patients allocated to low (n=199), intermediate (n=68) and high (n=42) risk groups by the EUTOS Long-Term Survival score, events (progression and/or death) occurred in 6.0%, 8.8% and 26.2%, respectively. Estimates of the 5-year progression-free survival rates according to these three risk groups were 96% (95% CI: 92%–98%), 88% (95% CI: 76%–95%) and 67% (95% CI: 48%–81%), respectively. Differences in progression-free survival according to these risk groups were highly significant (P<0.0001, overall). The EUTOS Long-Term Survival score showed better differentiation of progression-free survival than the Sokal (<45 years), Euro and EUTOS scores in children and adolescents with chronic myeloid leukemia and should be considered in therapeutic algorithms. (Trial registered at: www.clinicaltrials.gov NCT01281735)

Prognostic Discrimination of Children and Adolescents with Chronic Myeloid Leukemia Based on the EUTOS Long Term Survival (ELTS) Score

▪The Sokal score for patients less than 45 years can be used for the prognostic discrimination in the pediatric population. Limited data are available regarding the utility of the EUTOS score in the pediatric population (Gurrea Salas et al, Ann Hematol 2015). Recently, a new EUTOS score, the EUTOS Long Term Survival (ELTS) score was validated in the adult population (Pfirrmann et al, Leukemia 2016). The international registry for chronic myeloid leukemia (CML) in children and adolescents (I-CML- Ped Study registered at www.clinicaltrials.gov as NCT01281735) gave us the opportunity to test this score in this population.Aim: The aim of this analysis was the comparison of risk groups allocations and outcome between the Sokal (<45 years) score and the ELTS score in the pediatric population.Patients and Methods: As of June 1, 2016, 462 children and adolescents less than 18 years old were enrolled in the I-CML-Ped study between January 2011 and April 2016. Among them, 350 patients diagnosed with CML in chronic phase according to the ELN definition and treated with imatinib (+/- hydroxyurea or anagrelide) as first line treatment were eligible for analysis. For progression free survival (PFS) analyses, events of interest included progression to accelerated phase or blast crisis and deaths irrespective of its cause, whichever came first. For survival analyses, the event of interest was death from CML, deaths from other causes being considered as competing events, as initially designed in the ELTS score model. Estimates were compared by the log-rank test and Gray test respectively. Level of significance was 0.05.Results: The median follow up of the 350 patients was 3 years (range 1 month to 6 years). Progression and/or death (whichever came first) occurred in 23 patients. For the entire cohort of patients the 5-year PFS was 92% (95% CI: 88%-94%) and the 5-year survival accounting for CML death was 97% (95% CI: 94%-99%). Of the 308 patients allocated to low (n=54), intermediate (n=118) and high (n=136) risk groups by the Sokal (<45 years) score, events (progression and/or deaths) occurred in 5.5%, 5% and 9.5%, respectively. Estimation of the 5-year progression free survival accounting for CML death according to these 3 risk groups was 93% (95% CI:81%-98%), 94% (95% CI: 87%-97%) and 88% (95% CI: 80%-93%), respectively (p = 0.376, overall). Estimation of the 5- year survival accounting for CML death according to these 3 risk groups was 100%, 97% (95% CI: 92%-100%) and 96% (95% CI: 89%-100%), respectively, (p = 0.576, overall). Of the 308 patients allocated to low (n=199), intermediate (n=68) and high (n=41) risk groups by the ELTS score, events (progression and/or deaths) occurred in 6%, 8.8% and 24%, respectively. Differences in PFS according to these risk groups were highly significant (p < 0.0001, overall) (Figure 1). Estimation of the 5-year PFS according to these 3 risk groups was 96% (95% CI:92%-98%), 94% (95% CI: 76%-95%) and 67% (95% CI: 49%-82%), respectively. Estimation of the 5-year survival related with CML death according to these 3 risk groups was 99% (95% CI:95%-100%), 96% (95% CI: 88%-99%) and 89% (95% CI: 10%-98%), respectively (p = 0.107, overall).Conclusion: ELTS score showed better differentiation regarding progression free survival than Sokal (<45 years) score in children and adolescents with CML. However , ELTS score has failed to predict the survival accounting for CML death only. A specific prognostic score incorporating clinical, biological and molecular features is still needed for the pediatric population. [Display omitted] DisclosuresSuttorp:Novartis, Bristol Meyer Squib, Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Biondi:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Cellgene: Other: Advisory Board.

Genetic Profiling Augments Prognostic Value of the EUTOS Long-Term Survival Score for Disease-Specific Mortality in Imatinib-Treated Asian Chronic Myeloid Leukaemia Patients

Introduction:Long-term survival rates among patients with chronic-phase chronic myeloid leukaemia (CP-CML) have remarkably improved since the introduction of imatinib, a BCR-ABL1 tyrosine-kinase inhibitor (TKI), as the standard first-line therapy. Several prognostic scores have been employed to predict clinical response and survival of CP-CML patients treated with TKIs. The EUTOS long-term survival (ELTS) score was recently introduced and shown to predict the probability of CML-specific death in long-term surviving patients on imatinib therapy, more effectively than the existing scores. The ELTS score was calculated by a formula that included age at diagnosis, spleen size below costal margin, platelet count and blast percentage in peripheral blood as prognostic factors. In our study, we evaluated the ELTS score in predicting the probabilities of CML-specific death, long-term overall survival (OS) and progression-free survival (PFS) rates in Asian CML patients treated with imatinib. As genetic differences, particularly the BCL-2 like 11 (BIM) deletion polymorphism, have been shown to confer intrinsic resistance to imatinib in East-Asian patients, we also explored the role of BIM deletion polymorphism profiling as a prognostic biomarker for CML-specific death among different risk groups stratified by the ELTS score.Methods:A retrospective analysis was performed on CP-CML patients treated with first-line imatinib within one year of diagnosis in Singapore General Hospital from June 2001 to November 2014. The ELTS score was obtained with online calculator at www.leukemia-net.org. Low-risk group was defined as a score ≤1.568, intermediate-risk group as a score >1.568 but ≤2.2185, and high-risk group as a score >2.2185. Progression was defined as transformation to accelerated or blast phase or death from any cause. OS and PFS were calculated with the Kaplan-Meier method and compared by the log-rank test. Cumulative incidence probabilities of CML-specific death were compared by the Gray test.Findings:134 patients were included for analysis. 63% were Chinese, 17% were Malays, 8% were Indians and 12% were of mixed ethnic origin. Median age at diagnosis was 45 years and 60% were male. Median follow-up was 7.7 years (range: 0.4 to 13.2 years). 17 deaths out of 134 patients (13%) were recorded, of which 11 were CML-specific (65%). 54% of patients were categorised as low-risk, 36% as intermediate-risk and 10% as high-risk by the ELTS score. The cumulative incidence probabilities of CML-specific death at 10 years were 43% in high-risk (hazard ratio (HR): 11.76, 95% confidence interval (CI): (2.32, 59.71), p=0.003) and 9% in intermediate-risk (HR: 2.24, 95% CI: (0.37, 13.49), p=0.38) compared to 3% in low-risk groups.10-year OS probabilities were 50%, 82% and 93% in high-, intermediate- and low-risk ELTS groups respectively (p=0.001). 10-year PFS probabilities were 50%, 84% and 89% in high-, intermediate- and low-risk ELTS groups respectively (p=0.004).Among 103 East-Asian patients with low- and intermediate-risk ELTS sub-groups, 15% harboured BIM deletion polymorphism. The probability of CML-specific death at 10 years in this subset was 16% with BIM deletion polymorphism, but 4% without polymorphism (HR 4.30, 95% CI: (0.76, 24.35), p=0.099). 10-year OS probabilities in the subset were 75% and 89% in patients with and without BIM deletion polymorphism respectively (p=0.014).Conclusions:The ELTS score was able to predict the probability of CML-specific death and identify high-risk patients in our multi-racial Asian CML patients treated with imatinib. Genetic profiling using BIM deletion polymorphism provided further stratification by identifying a subset of inferior long-term survivors with high probability of CML-specific death among otherwise non high-risk patients. [Display omitted] DisclosuresChuah:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Chiltern: Honoraria.

A Population-Based Study of Chronic Myeloid Leukemia Treated with Imatinib in First Line

Background. Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapies. However these clinical trials included patients selected according to different inclusion and exclusion criteria, particularly age and comorbidities, and with specific treatment obligations. In daily clinical practice (real life), no inclusion and exclusion criteria do exist, and treatment outcomes depend not only on choice of the first-line TKI, but also on doctor- and patient-choice of second- and third-line TKIs. Aims. To investigate the response and the outcome on first-line imatinib, with switch to 2nd generation TKIs in case of failure or toxicity, in BCR-ABL1+ CML patients enrolled in a population-based registry (real-life setting). Methods. We report here the results from a prospective study, enrolling all newly diagnosed patients (N = 236, median age 60 years) living in two Italian regions, that were registered according to population-based criteria and treated front-line with imatinib. The decision to switch to second-line treatment was up to the Local Investigator (no predefined criteria) Definitions: major molecular response (MMR or MR3.0): BCR-ABL1IS ratio 10,000 ABL1 copies; failure and suboptimal response: according to 2009 European LeukemiaNet (ELN) criteria; progression: transformation to advanced phases according to ELN criteria; leukemia-related death (LRD): death after progression. Results. Median age was 60 years at diagnosis and 64 years at last contact, with a median follow up of 48 months (range 2-86 months). High risk patients according to Sokal score and new EUTOS long-term survival (ELTS) score were 23% and 18%, respectively. A switch from imatinib to a second generation TKI was reported in 14% of patients for side-effects, and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The median time to switch was 8 months for toxicity and 20 months for failure. At 12 months, 55% of all evaluable patients were in MR3.0 or better. At last contact, 75% of all evaluable patients were in MR3.0 or better and 48% were in MR4.0 or better. The molecular response of patients switching for failure or suboptimal response was evaluable in 61/63 patients: improved in 57%, not modified in 38%, worsened by at least 1 log in 5% of patients. Overall, the treatment switch was associated with a remarkable increase of MR3.0 rate: from 10% at the time of switching to 52% at last qPCR. Overall, 33% achieved a stable MR4.0, of whom 22% with imatinib alone, and 11% after switching to a second generation TKI (Table 1). The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively. Twenty-seven patients (11%) died, of whom 13 (6%) of leukemia, after disease progression and 14 (6%) of "other" causes, without any evidence of progression. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients who received nilotinib in second-line. OS was not affected by age in the interval between 18 and 69 years (5-year OS 92%, ranging from 89% to 95 % in the different decades), but 5-year OS probabilities of elderly (70-79 years) and very elderly patients (≥ 80 years) were significantly lower (78%, P = 0.003, and 34%, P Conclusions. The results of this prospective population-based study emphasize the importance of second-line treatment in the clinical practice: the CML management with the 3 available TKIs in the period 2008-2012, according to current treatment recommendations for switching and without any predefined obligation, resulted in response rates and outcomes, that are in the high range of prospective interventional studies investigating the efficacy and the safety of a single TKI in selected patients. This study provides a robust dataset on the results of CML treatment with TKI in clinical practice, that will be important for interpreting and evaluating the results of the next prospective studies, arguably limited to selected patients. Disclosures Castagnetti:Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Marasca:Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Honoraria; Roche: Honoraria. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Ariad: Consultancy. Martinelli:Genentech: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; MSD: Consultancy; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy. Cavo:Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Rosti:Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Baccarani:Ariad: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau.