European Treatment And Outcome Study Research Articles

To Study Demographic Profile, Risk Stratification, and Response to Treatment in Chronic Myeloid Leukemia Patients

Abstract Background: Chronic myeloid leukemia (CML) is the most common leukemia in India. The annual incidence of CML in India was originally reported to be 0.82.2 per 100,000 population. CML is a clonal disorder that is usually easily diagnosed by the Philadelphia chromosome. The approval of tyrosine kinase inhibitors has significantly reduced the mortality rate associated with CML and revolutionized treatment. Materials and Methods: Eighty patients diagnosed with CML were studied. Investigations were done and with European Treatment and Outcome Study (EUTOS) patients were stratified into low- and high-risk group and then treatment with Imatinib was given to all patients and molecular response was evaluated. Results: In the study population, out of 80 patients, 40 were female and 40 were male with M: F is 1:1. Out of total 80 patients’, maximum patients (54) were in 31-60 years age group. Our study showed that the most common symptom of presentation is abdominal discomfort followed by fever. Out of total 80 patients, 25 (31.3%) patients had high EUTOS score and 55 (68.8%) patients had low EUTOS score. On 6 months’ follow-up, 36.3% patients had complete molecular response, 16.3% patients had major molecular response and 47.5% patients had no molecular response, but on 12 months’ follow-up, 71.3% patients had complete molecular response, 16.25% patients had major molecular response, and 12.5% patients had no molecular response. Conclusion: In this observational study, we found a significant correlation between EUTOS score and molecular response at 6 months and 12 months follow-up after Imatinib therapy. Chronic myeloid leukemia, European treatment and outcome study score, response, tyrosine kinase inhibitor

Impact of BCR::ABL1 transcript type on RT-qPCR amplification performance and molecular response to therapy

Several studies have reported that chronic myeloid leukaemia (CML) patients expressing e14a2 BCR::ABL1 have a faster molecular response to therapy compared to patients expressing e13a2. To explore the reason for this difference we undertook a detailed technical comparison of the commonly used Europe Against Cancer (EAC) BCR::ABL1 reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) assay in European Treatment and Outcome Study (EUTOS) reference laboratories (n = 10). We found the amplification ratio of the e13a2 amplicon was 38% greater than e14a2 (p = 0.015), and the amplification efficiency was 2% greater (P = 0.17). This subtle difference led to measurable transcript-type dependent variation in estimates of residual disease which could be corrected by (i) taking the qPCR amplification efficiency into account, (ii) using alternative RT-qPCR approaches or (iii) droplet digital PCR (ddPCR), a technique which is relatively insensitive to differences in amplification kinetics. In CML patients, higher levels of BCR::ABL1/GUSB were identified at diagnosis for patients expressing e13a2 (n = 67) compared to e14a2 (n = 78) when analysed by RT-qPCR (P = 0.0005) but not ddPCR (P = 0.5). These data indicate that widely used RT-qPCR assays result in subtly different estimates of disease depending on BCR::ABL1 transcript type; these differences are small but may need to be considered for optimal patient management.

Trial in Progress: A Multicenter, Open Label, Randomized, Phase III Study of Asciminib (80 mg Once Daily) Vs Investigator-Selected TKI in Newly Diagnosed Adult Patients with Chronic Myeloid Leukemia in Chronic Phase

Trial in Progress: A Multicenter, Open Label, Randomized, Phase III Study of Asciminib (80 mg Once Daily) Vs Investigator-Selected TKI in Newly Diagnosed Adult Patients with Chronic Myeloid Leukemia in Chronic Phase

Sample Exchange to Standardize Molecular Monitoring for CML: The EUTOS Experience

International management recommendations for chronic myeloid leukemia (CML) patients undergoing tyrosine kinase inhibitor therapy emphasise the importance of frequent molecular monitoring to determine the degree of response. Achievement or non-achievement of time-dependent molecular milestones helps to identify individuals who may or may not benefit from a change in treatment. Sequential monitoring enables the timely detection of relapse and may help to highlight other issues influencing response such as compliance.Molecular monitoring is performed by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) for BCR-ABL1 mRNA, and the use of a reference gene helps to control for variation in quality from sample to sample. Guidelines specify that results should be expressed on the International Scale (IS) for BCR-ABL1 measurement, which is essentially the same scale used in the International Randomized Study of Interferon and STI571 (IRIS) study. The ‘gold standard’ method for testing laboratories to generate results on the IS is to apply a laboratory-specific conversion factor (CF) to their local results, with the CF derived by patient sample exchange with an established reference laboratory (Branford et al., Blood 2008). We report here the experience of the European Treatment and Outcome Study (EUTOS) to standardise molecular monitoring in Europe by an expanded programme of sample exchange.The laboratory in Mannheim initially established itself as a European reference laboratory following derivation and validation of their own CF by patient sample exchange with the reference laboratory in Adelaide. Samples exchanges between Mannheim and Adelaide were repeated on a further 5 occasions and confirmed stability of the Mannheim CF. The Mannheim laboratory then undertook further patient sample exchanges with testing laboratories in Europe. Patient samples, typically up to 30 per round, were lysed in Trizol or guanidinium isothiocyanate solution and were provided by both the reference laboratory and the test laboratory. Samples were selected to span the range of detectable disease from approximately 10% BCR-ABLIS to MR4 and were transported on dry ice. Samples were extracted and analyzed in both centres, and results compared. Any consistent bias in the results between the reference laboratory IS values and the test laboratory values was identified by Bland-Altman analysis and a CF defined as the antilog of the mean bias. Multiple rounds of sample exchange were performed to confirm the validity of individual CFs and to help identify changes in test laboratory assay performance over time.The study was performed over a 10 year period (2006-2016) with the participation of 58 laboratories (defined as EUTOS reference centres) from 22 countries. A total of 291 sample exchanges were performed (median = 5; range 1-8), comprising 8396 samples of which 6956 were evaluable (mean 24 successful samples/exchange). Of the 291 sample exchanges, 7 were considered unsatisfactory due to poor concordance (<50% of samples within 2 fold), resulting in the issuance of 284 CF certificates. Of these, 244 (86%) were for laboratories using ABL1 as a reference gene and 44 for those using GUSB. For ABL1 laboratories the median CF was 0.56 (range 0.097-2.87) and for those using GUSB the median was 0.96 (0.32-3.82). Despite the wide range of CF values, 81% and 73% were within 2-fold of the median for ABL1 and GUSB, respectively, and the interquartile ranges were 0.37-0.81 for ABL1 and 0.68-1.34 for GUSB. Using previously described criteria for concordance (Branford et al., Blood 2008; Cross et al. Leukemia 2016), we defined a stable CF as CFn/CFn+1 = 0.63-1.58, with an optimal ratio of 0.83-1.2. Using these criteria, 124 CFs were stable on sequential analysis and 72 were unstable.Overall our study demonstrates the feasibility of large scale sample exchanges to promulgate laboratory-specific CFs to the IS, but the process is onerous, challenging and expensive. We anticipate that sample exchange will remain an option for laboratories to calibrate their assays but is likely to be largely superseded by approaches that use IS-calibrated secondary reference reagents. DisclosuresMüller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Institute for Hematology and Oncology (IHO GmbH): Employment, Equity Ownership. Dietz:Institute for Hematology and Oncology (IHO GmbH): Equity Ownership. Saglio:Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Mahon:NOVARTIS PHARMA: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; PFIZER: Consultancy, Honoraria; INCYTE: Honoraria. Pane:Novartis: Honoraria, Speakers Bureau. Hochhaus:Incyte: Research Funding; Novartis: Research Funding; MSD: Research Funding; BMS: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding. Cross:Incyte: Consultancy, Honoraria; Qiagen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria.

Validation of CIP2A as a Biomarker of Subsequent Disease Progression and Treatment Failure in Chronic Myeloid Leukaemia.

Simple SummaryTyrosine kinase inhibitor treatment has greatly improved the prognosis for many chronic myeloid leukaemia patients; however, disease progression is usually fatal for patients and remains a significant clinical challenge today. Using the UK SPIRIT 2 (STI571 Prospective International RandomIsed Trial 2) clinical trial, we have validated cancerous inhibitor of protein phosphatase 2A (PP2A) (CIP2A) as a diagnostic biomarker to identify patients at risk of disease progression and treatment failure. CIP2A is a simple diagnostic biomarker that may be a useful diagnostic tool in planning treatment strategies.Background: It would be clinically useful to prospectively identify the risk of disease progression in chronic myeloid leukaemia (CML). Overexpression of cancerous inhibitor of protein phosphatase 2A (PP2A) (CIP2A) protein is an adverse prognostic indicator in many cancers. Methods: We examined CIP2A protein levels in diagnostic samples from the SPIRIT2 trial in 172 unselected patients, of whom 90 received imatinib and 82 dasatinib as first-line treatment. Results: High CIP2A levels correlated with inferior progression-free survival (p = 0.04) and with worse freedom from progression (p = 0.03), and these effects were confined to dasatinib recipients. High CIP2A levels were associated with a six-fold higher five-year treatment failure rate than low CIP2A levels (41% vs. 7.5%; p = 0.0002), in both imatinib (45% vs. 11%; p = 0.02) and dasatinib recipients (36% vs. 4%; p = 0.007). Imatinib recipients with low CIP2A levels had a greater risk of treatment failure (p = 0.0008). CIP2A levels were independent of Sokal, Hasford, EUTOS (EUropean Treatment and Outcome Study), or EUTOS long-term survival scores (ELTS) or the presence of major route cytogenetic abnormalities. No association was seen between CIP2A levels and time to molecular response or the levels of the CIP2A-related proteins PP2A, SET, SET binding protein 1 (SETBP1), or AKT. Conclusions: These data confirm that high diagnostic CIP2A levels correlate with subsequent disease progression and treatment failure. CIP2A is a simple diagnostic biomarker that may be useful in planning treatment strategies.

Assessment of individual molecular response in chronic myeloid leukemia patients with atypical BCR-ABL1 fusion transcripts: recommendations by the EUTOS cooperative network

PurposeApproximately 1–2% of chronic myeloid leukemia (CML) patients harbor atypical BCR-ABL1 transcripts that cannot be monitored by real-time quantitative PCR (RT-qPCR) using standard methodologies. Within the European Treatment and Outcome Study (EUTOS) for CML we established and validated robust RT-qPCR methods for these patients.MethodsBCR-ABL1 transcripts were amplified and sequenced to characterize the underlying fusion. Residual disease monitoring was carried out by RT-qPCR with specific primers and probes using serial dilutions of appropriate BCR-ABL1 and GUSB plasmid DNA calibrators. Results were expressed as log reduction of the BCR-ABL1/GUSB ratio relative to the patient-specific baseline value and evaluated as an individual molecular response (IMR).ResultsIn total, 330 blood samples (2–34 per patient, median 8) from 33 CML patients (19 male, median age 62 years) were analyzed. Patients expressed seven different atypical BCR-ABL1 transcripts (e1a2, n = 6; e6a2, n = 1; e8a2, n = 2; e13a3, n = 4; e14a3, n = 6; e13a3/e14a3, n = 2; e19a2, n = 12). Most patients (61%) responded well to TKI therapy and achieved an IMR of at least one log reduction 3 months after diagnosis. Four patients relapsed with a significant increase of BCR-ABL1/GUSB ratios.ConclusionsCharacterization of atypical BCR-ABL1 transcripts is essential for adequate patient monitoring and to avoid false-negative results. The results cannot be expressed on the International Scale (IS) and thus the common molecular milestones and guidelines for treatment are difficult to apply. We, therefore, suggest reporting IMR levels in these cases as a time-dependent log reduction of BCR-ABL1 transcript levels compared to baseline prior to therapy.

Point: Is there a best duration of deep molecular response to achieve therapy-free remission in chronic myeloid leukaemia?

Point: Is there a best duration of deep molecular response to achieve therapy-free remission in chronic myeloid leukaemia?

The EUTOS long-term survival score predicts disease-specific mortality and molecular responses among patients with chronic myeloid leukemia in a practice-based cohort.

The European Treatment and Outcome Study (EUTOS) long‐term survival (ELTS) score predicts disease‐specific death in patients with chronic myeloid leukemia (CML) being treated with imatinib during the chronic phase (CP) of the disease. However, it is unclear whether the ELTS score predicts CML‐related events or treatment responses. This study evaluated the predictive value of the ELTS score regarding prognosis and treatment response in patients with CML‐CP. Clinical data were retrospectively obtained from patients enrolled in the CML Cooperative Study Group (CML‐CSG), which included patients diagnosed with CML‐CP from April 2001 to January 2016, and treated with any tyrosine kinase inhibitor (TKI) as first‐line therapy. Among 342 eligible patients, the ELTS scores indicated low‐, intermediate‐, and high‐risk in 74%, 21%, and 5% of patients, respectively. Patients with high ELTS scores had significantly higher disease‐specific mortality and worse event‐free survival, progression‐free survival, and overall survival. Among four risk scores, including the Sokal, Hasford, EUTOS, and ELTS scores, risk stratification by the ELTS score had the highest predictive value in assessing patient prognosis, and also in treatment responses. In fact, the EUTOS and ELTS scores were able to predict the major molecular response within 12 months. Most importantly, the ELTS score was the only scoring system that predicted deep molecular response at any time, regardless of risk level (65.0%, 43.7%, and 23.5% in low‐, intermediate‐, and high‐risk groups, respectively). Compared to other risk scores, the ELTS score was the most sensitive risk classification tool for the four endpoints of interest in this study, as well as molecular responses in patients with CML‐CP.

PCN37 IMATINIB AND ITS CLINICAL ASSOCIATED OUTCOME IN CHRONIC MYELOID LEUKAEMIA PATIENTS

Imatinib, a signal transduction inhibitor useful in the management of chronic myeloid leukemia (CML). There is a dearth of evidence available concerning the Imatinib and its associated outcomes in Indian CML patients. So, this study is aimed to assess the clinical outcomes associated with Imatinib. This study was conducted at Mahavir Cancer Sansthan & Research center Patna, India over a period of 10 months. Patients with confirmed CML diagnosis and were receiving Imatinib therapy were included. The toxicity was evaluated through CTCAE v 4.0 (common terminology criteria for adverse events) and compared with clinical outcomes. The EUTOS (European Treatment and Outcome Study) score was used to assess the complete cytogenetic response after 10 months. The data were analyzed through SPSS v 22. A total of 81 patients completed the study. The mean age of the patients was 38.8 ± 6.4 years and 35.80% were female. The majority of the patients belong to the age group of 41 – 60 years. Among BCR-ABL group patients, P210 kD (kilo Dalton) protein was found among 69 patients, P190 kD protein was found in 9 patients while dual fusion transcript of P210 kD and P190 kD protein was found in only 3 patients. Neutropenia was the most common adverse event associated with P210 kD protein determined through CTCAE v 4.0. The blast cell's content was more in the blast crisis phase as compared to the chronic and accelerated phase. The CML patients with P210 kD protein were at higher risk while P190 kD and coexistence were at a lower risk of progression to blastic and further to accelerated phase based on EUTOS score. It might be advisable to identify the BCR-ABL fusion transcript in CML patients when the patient started receiving Imatinib therapy in order to link the detected transcript with their clinical findings.

Risk Stratification of Chronic Myeloid Leukemia According to Different Prognostic Scores.

IntroductionSeveral prognostic indices are in use to stratify chronic myeloid leukemia (CML) patients: Sokal, Hasford, and the European Treatment and Outcome Study (EUTOS) being the most commonly reported ones. The application of different scores may cause variability in the determination of disease prognosis. This study was conducted to stratify patients of CML in accordance with Sokal, Hasford, and EUTOS scoring systems and to determine the concordance rate of risk categories, calculated by using all three scoring systems.MethodsThis study was conducted at King Edward Medical University from January 2013 to May 2019. A total of 114 patients were diagnosed with CML in the chronic phase during the study period and included in the analysis. Variables of interest were computed using Microsoft Excel. These variables include age, spleen size, platelet count, the percentage of myeloblasts in the peripheral blood, as well as the percentage of basophils and eosinophils in the peripheral blood. Using these baseline variables, the prognostic category of each patient was calculated using Sokal, Hasford, and EUTOS scores.ResultsThe male to female ratio of patients included in the study was 1.43. The mean age was 39.3±1.58 years, with an age range of 13 to 95 years. A total of only 4 out of 73 patients were categorized as a low-risk category, whereas 23 out of 80 patients were categorized into a high-risk category by all three scoring systems. The assignment of prognostic categories was variable, depending on which prognostic score was applied. The concordance rate of Sokal vs Hasford was 53%, Sokal vs EUTOS 64%, and Hasford vs EUTOS 98%.ConclusionThere is considerable inter-variability between the various prognostic indicators. In general, the Hasford and EUTOS scores assign some patients to a lower risk category when compared to Sokal score.

The Impact of Treatment Recommendation By Leukemia Artificial Intelligence Program (LEAP) on Survival in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

The Impact of Treatment Recommendation By Leukemia Artificial Intelligence Program (LEAP) on Survival in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Halving Time of BCR-ABL1 in Chronic Myeloid Leukemia: Is It Better Than Day-90 Value—A Multicenter Study From South India

BackgroundThe 90-day BCR-ABL1 (breakpoint cluster region-Abelson 1) level has been one of the accepted milestones for predicting the molecular response in patients with chronic myeloid leukemia (CML). The rate of decline in BCR-ABL1 has been considered a better predictor of the response but has not been uniformly accepted. A paucity of evidence is available to predict the accuracy of the rate of decline in the Indian context. Therefore, we tested the accuracy of the rate of decline of BCR-ABL1 in predicting the molecular response compared with the single 90-day values in a retrospective cohort study of selected cancer centers in south India. Methods and MaterialsPatients with chronic-phase CML diagnosed from January 2013 to December 2018, the serial BCR-ABL1 levels were estimated at 0, 45, and 90 days, 6 months, and 1 year. Data on patient demographics, risk stratification assessed using the Sokal and EUTOS (European Treatment and Outcome Study) scores were extracted using a mobile-based data capture tool from the medical records of the enrolled patients. The halving time, determined by log reduction, was compared with the 90-day BCR-ABL1 values using the receiver operating characteristic curve for the major and complete molecular response at 6 months and 1 year as standards. Accuracy was determined from the area under the curve. The cutoff for the halving time was chosen to balance the sensitivity and specificity. ResultsThe rate of decline had more predictive accuracy compared with the 90-day BCR-ABL1 values (area under the curve for rate of decline, 0.83; 90-day, 0.80). A halving time of < 20 days identified 95% of the patients who had achieved major molecular response at 12 months compared with 80% using the single 90-day BCR-ABL1 response. ConclusionsThe halving time of BCR-ABL1 appears promising as a predictor of the outcomes for patients with CML.

Comparison of the Clinical Outcomes of Nilotinib and Dasatinib Therapies in Newly Diagnosed Patients in the Chronic Phase of Chronic Myeloid Leukemia: A Retrospective Analysis

Background and Aim: Treatment with a tyrosine kinase inhibitor (TKI) is the standard of care for patients with chronic myeloid leukemia (CML). Based on the results of the ENESTnd and DASISION studies, the European LeukemiaNet 2013 guidelines now recommend the use of TKIs, imatinib (400 mg once daily), nilotinib (300 mg twice daily), and dasatinib (100 mg once daily) as first-line treatment for patients with CML in the chronic phase (CML-CP). Compared to imatinib, the new generation TKIs, nilotinib and dasatinib, were found to have deeper and faster treatment response rates with acceptable toxicities. However, a direct comparison between nilotinib and dasatinib has never been reported previously. Our study aims to compare the outcomes and molecular responses achieved following the first-line use of these two agents in patients with CML-CP.Patients and Methods: The database of the CML Cooperative Study Group, which includes patients who were initially diagnosed with CML after the introduction of imatinib (April 2001), was reviewed, and patients who were given nilotinib or dasatinib as first-line therapy were identified. The event-free survival (EFS, defined as the loss of treatment efficacy, disease progression, or any cause of death), and rates of cumulative major molecular response (MMR), and deep molecular response (DMR, defined as the depth of MR 4.5) were compared between the nilotinib and dasatinib groups. Further, the predictive ability of the Sokal, Hasford, and European Treatment and Outcome Study (EUTOS) scoring systems for the achievement of molecular responses was also evaluated. For the analysis of molecular responses, patients who switched from their initial treatment agent to another TKI before achievement of MMR or DMR were considered to have no MMR or DMR.Results and Discussion: Out of 361 patients with CML-CP enrolled in our database, 58 and 63 were treated with conventional doses of nilotinib (300 mg twice daily) and dasatinib (100 mg once daily), respectively, as first-line therapy. Patients who had been started on a low dose TKI therapy were excluded from this analysis. The patient demographics, including age, sex, observation periods, and the Sokal, Hasford, and EUTOS scores did not show significant differences between the groups. In total, there were five events during the observation period (1 in the nilotinib group and 4 in the dasatinib group), and all events were deaths unrelated to CML, except for one in a patient in the dasatinib group who showed loss of complete cytogenetic response. The disease did not progress to the accelerated or blastic phase in any of the cases. The EFS did not differ between these two groups (p = 0.214). The MMR rates by 6, 12, 18, and 24 months were 59%, 72%, 74%, and 81%, respectively, in the nilotinib group and 52%, 73%, 81%, and 86%, respectively, in the dasatinib group. The DMR rates by 6, 12, 18, and 24 months was 7%, 17%, 24%, and 28%, respectively, in the nilotinib group and 3%, 16%, 25%, and 29%, respectively, in the dasatinib group. During the first 24 months of treatment, 4 (7%) patients in the nilotinib group and 11 (17%) in the dasatinib group had been switched to other TKIs (p = 0.0983). Among the three scoring systems, only the Hasford score could predict the achievement of DMR, and all of them failed to predict the achievement of MMR in the entire cohort. Our data suggest that both nilotinib and dasatinib have comparable efficacies, with high molecular response rates and promising outcomes. The validity of our findings should be tested in a randomized study, which is currently underway in Japan. DisclosuresTakaku:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Novartis Pharma K.K.: Honoraria, Speakers Bureau. Tokuhira:Mitsubishi Tanabe Pharma Corporation: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; AYUMI Pharmaceutical Corporation: Speakers Bureau; Chugai: Speakers Bureau. Asou:Eisai Co., Ltd.: Research Funding; SRL Inc.: Consultancy; Yakult Honsha Co., Ltd.: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Asahi Kasei Pharma Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Kizaki:Nippon Shinyaku,: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Speakers Bureau. Kawaguchi:Novartis Pharma K.K.: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Alexion: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau.

Evaluation of chronic myeloid leukemia patients and their molecular responses to tyrosine kinase inhibitors in Erbil city, Iraq

Background: Chronic myeloid leukemia (CML) is one of the indolent myeloproliferative neoplasms. It is characterized by the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22 or BCR-ABL1 gene. Objectives: The aims of this study were to evaluate characteristics of CML patients and their molecular response to tyrosine kinase inhibitors (TKI) in Erbil city in Iraq. Patients and Methods: Seventy-six patients with CML were recruited in this retrospective and prospective study from February 2014 to March 2016, at Nanakaly Hospital for Blood Diseases in Erbil city – Kurdistan region of Iraq. They were evaluated from clinical point of view and their laboratory data, and molecular responses to TKI based on polymerase chain reaction were analyzed. Results: The median age of participants was 45 years; the male: female ratio was 1:0.9. The main presenting features were abdominal fullness in 66% and splenomegaly in 95% of patients. Nearly 66% of them had low European Treatment and Outcome Study (EUTOS) score; 70% of patient had major or complete molecular responses (MMR/CMR). There was a significant difference between patients who did versus who did not achieve MMR/CMR in hemoglobin level, promyelocyte, and myelocyte percent, EUTOS, and Sokal scores (P = 0.02, 0.006, 0.03, 0.001, and 0.02, respectively). Conclusion: In the current study, CML patients were at a younger age of onset, and more high EUTOS score. The majority of patients achieved MMR with frontline Imatinib or Nilotinib and those who switched from Imatinib to Nilotinib as well.

Analysis of clinical characteristics and efficacy of chronic myeloid leukemia onset with extreme thrombocytosis in the era of tyrosine kinase inhibitors

The aim of this study was to investigate the clinical characteristics and efficacy of chronic myeloid leukemia (CML) onset with extreme thrombocytosis. A total of 121 newly diagnosed and untreated CML patients in chronic phase with complete clinical information from the First Hospital of Jilin University, from January 2010 to December 2014 were retrospectively recruited. Based on the platelet (PLT) count, 22 patients were assigned into CML with thrombocytosis (CML-T) group (PLT >1,000×109/L) and 65 patients were classified into CML without extreme thrombocytosis (CML-N) group (PLT ≤1,000×109/L). Fifty-four point five percent of patients in the CML-T group were female, which was higher than that in the CML-N group (27.7%) (P=0.022). Except for gender, there was no significant difference for clinical information of patients between the two groups. For Sokal and Hasford scoring systems, the percentage of patients at high risk in the CML-T group were higher than those in the CML-N group, 95.5% vs 52.3% (P=0.000) and 68.2% vs 41.5% (P=0.031), respectively; however, there was no significant difference for European Treatment and Outcome Study (EUTOS) score system between the two groups (P=0.213). In terms of major molecular response (MMR) rate, the percent of patients with MMR in CML-T group was lower than that in CML-N group at 36 months after tyrosine kinase inhibitor therapy (P=0.037). Up until December 2016, the median of event-free survival was 21 months in the CML-T group, however, that was not reached in the CML-N group (P=0.027). The majority of CML patients with extreme thrombocytosis were females, and compared to patients in the CML-N group, the percentage of high risk patients based on the Sokal and Hasford scoring systems was higher in the CML-T group, and the median event-free survival of patients was shorter.

Can the Use of Bone Marrow Parameters Improve the Efficacy of Risk Prediction Scores in Chronic Myeloid Leukemia in Imatinib Era?

Many attempts have been made to develop risk prediction scores for chronic myeloid leukemia in chronic phase (CML-CP) to identify the subgroup with a poorer response to therapy to enable early intensification of treatment. Because the bone marrow (BM) provides a more sensitive reflection of the disease process, we hypothesized that using BM parameters in the Sokal and European Treatment and Outcome Study (EUTOS) risk scores could improve their efficacy in an imatinib-treated population. We analyzed cases of CML-CP for their response and survival outcomes with imatinib using risk groupings determined by the Sokal and EUTOS scores using peripheral blood (PB) or BM parameters (Sokal-PB, Sokal-BM, EUTOS-PB, and EUTOS-BM). A total of 371 cases were analyzed. The concordance for risk groups was greater for the EUTOS scores (81.9%) than for the Sokal scores (68.1%) using PB versus BM parameters. For all 4 risk scores, the predictive efficacy was statistically significant. EUTOS-PB and EUTOS-BM could better prognosticate for progression-free survival (PFS) and overall survival (OS) between the low- and high-risk groups (P< .0001). However, with the Sokal risk score, the use of BM parameters improved the prognostic capacity for PFS between the low- and intermediate-risk groups, with a statistically significant difference (P= .025), but not for OS (P= .88). The use of BM parameters, a simple method that is feasible in routine clinical practice could improve the prognostic efficacy of the Sokal score for PFS but not for OS in low- and intermediate-risk groups. Further research to improve the sensitivity of risk scores for CML-CP prognosis and attempts at risk-directed therapy is warranted.

Smokers with chronic myeloid leukemia are at a higher risk of disease progression and premature death.

Smoking is suspected to not only be a risk factor for chronic myeloid leukemia but an adverse prognostic factor for the disease as well. The objective of the current study was to investigate the impact of smoking on survival and progression to advanced phases of disease. Based on the data of the German CML Study IV, the authors analyzed the effect of smoking using a multivariate Cox model with the addition of the European Treatment and Outcome Study (EUTOS) long-term survival score variables of age, spleen size, thrombocytes, and peripheral blasts as well as sex, comorbidities, and type of treatment center. The 8-year survival probability was 87% for a nonsmoking patient and 83% for a patient who smoked. The authors noted a 2.08-times higher risk of death for smokers in comparison with nonsmokers and a 2.11-times higher cause-specific hazard of disease progression. An interaction between smoking and age was found in the model for survival. No significant difference with regard to molecular response was observed. Even when considering differences in socioeconomic status and lifestyle between patients who smoke and nonsmokers, the current analysis demonstrated that smoking also might affect disease biology. The results of the current study indicate that patients with chronic myeloid leukemia, in particular those aged <60 years, should be encouraged to quit smoking. Cancer 2017;123:2467-71. © 2017 American Cancer Society.

Cytogenetic and molecular response of EUTOS risk groups in children with chronic myeloid leukemia chronic phase on imatinib treatment

Introduction Recently (2011), the European Treatment and Outcome Study (EUTOS) scoring system was formulated to risk-stratify chronic myeloid leukemia (CML) chronic phase patients on imatinib treatment. CML during childhood is rare, making prognostication and management difficult. This study was conducted to investigate the cytogenetic and molecular response rates among EUTOS risk groups in pediatric CML patients on treatment with imatinib. Patients and methods Hospital records of pediatric CML chronic phase patients (age18 years) from 2009 to 2012 were analyzed retrospectively for demographic data, imatinib dose, date of initiation of treatment, EUTOS risk score, follow-up details, and cytogenetic and molecular response. Results A total of 57 children were included in this study, with a median age of 14.5 years (range: 5–18 years) and male preponderance (M:F, 1.19:1). The majority (67%) of them were in the low-risk group as per the EUTOS score and the remaining were in the high-risk group. Complete hematological response at 3 months was 100% in the low-risk and 94% in the high-risk group. Complete cytogenetic response at 12 months was 76 and 73% in the low-risk and high-risk groups, respectively. Major molecular response at 18 months was 85 and 79% in the low-risk and high-risk groups, respectively. Two-year event-free survival was 89 and 80% in the low-risk and high-risk groups, respectively. Conclusion The EUTOS low-risk cohort responded better than the high-risk cohort, but the difference was not statistically significant. Both groups had similar outcome at the end of 2 years. The EUTOS score did not predict the response and outcome in pediatric CML.

Effectiveness of Three Prognostic Scoring Systems in Predicting the Response and Outcome in Pediatric Chronic Myeloid Leukemia Chronic Phase on Frontline Imatinib.

Introduction:The Sokal and Hasford (Euro) scores were developed in the chemotherapy and interferon eras and are widely used as prognostic indicators in patients with chronic myeloid leukemia (CML). Recently, European Treatment and Outcome Study (EUTOS) scoring system was introduced. Data on risk stratification in pediatric CML population was lacking due to its rarity (<3%).Objective:To study the effectiveness in predicting the response and outcome with three prognostic scores in pediatric CML-chronic phase patients on front line Imatinib. Materials and Methods: We retrospectively analyzed the hospital records of newly diagnosed CML CP patients (aged ≤18 years) from 2006 to 2010 for their risk score, cytogenetic response at 18 months and event free survival (EFS) at the end of 4 years. Events include loss of hematological response, loss of cytological response, progression to accelerated/blast phase (AP/BC). All received free Imatinib under Gleevac international patient assistance program.Results:Data of 106 children was analyzed with median age of 13.5 (ranged 5-18 years) and male preponderance (M:F = 1.14:1). The distribution of children was 63%, 32% and 5% in Sokal low, intermediate and high risk respectively, 50%, 43% and 5% in Hasford/Euro low, intermediate and high risk respectively, 71% and 29% in EUTOS low and high risk respectively. The overall cumulative complete hematological response at the end of 3 month was 94%, and complete cytogenetic response at 12 months was 75%. The CCyR at 18 month was seen in 90%,74% and 83% among Sokal low, intermediate and high risk groups respectively, 83%, 86% and 83% among Hasford/Euro low, intermediate and high risk groups respectively, 84% and 86% EUTOS low and high risk groups respectively. The EFS at the end of 48 months was seen in 87%,79% and 83% among Sokal low, intermediate and high risk groups respectively, 83%, 86% and 83% among Hasford/Euro low, intermediate and high risk groups respectively, 86% and 80% EUTOS low and high risk groups respectively.Conclusion:None of the scoring systems predicted the response and outcome effectively in children with CML CP on front line Imatinib.

Assessment of Molecular Response in CML Patients with Atypical BCR-ABL Tanscripts. Recommendations By the EUTOS Collaboration

▪Approximately 2‐3% of CML patients (pts) have variant BCR‐ABL fusions transcripts that cannot be monitored by RQ‐PCR using standard methodologies. Most rare variants are accounted for by seven variant fusions (e1a2/3, b2/3a3, e6a2, e8a2, e19a2). Within the European Treatment and Outcome Study (EUTOS) we sought to establish and validate robust RQ-PCR methods for each of these abnormalities. RNA was extracted from leukocytes obtained from 20 mL peripheral blood. Samples were received either locally or by mail and spent between 1 to 3 days in transit. Multiplex reverse transcription polymerase chain reaction (RT-PCR) experiments were performed to identify BCR-ABL1 transcripts (Cross et al., Leukemia 1994). In all cases, gel electrophoresis showed an unusual band. PCR products were then sequenced to characterize BCR-ABL1 rearrangements. Monitoring of residual disease was carried out by RQ-PCR with specific forward and/or reverse primers and probes using a serial dilution of individual BCR-ABL1 or GUSB plasmid DNA calibrators. GUSB transcripts were quantified as internal control and results were expressed as the BCR-ABL1/GUSB ratio with no conversion according to the international scale (IS) as it is recommended for only typical major (M) BCR-ABL1 and cannot be applied to other transcripts in CML. 43 pts from 8 prospective studies and pts outside of studies were investigated. A total of 435 samples (1-72 per patient, median 8) were analyzed. Pts expressed 6 different atypical BCR-ABL1 transcripts (e19a2, n=18; e1a2, n=10; b2a3, n=5; b3a3, n=5; b2a3&b3a3, n=2, e8a2, n=3). At the start of the observation period, ratios BCR-ABL1/GUSB ranged between 0.01% and 179.1% (median 13.75%). Follow-up results were determined in comparison to the starting level and expressed as relative log reduction. 9 pts were in deep molecular remission considering a minimum GUSB transcript level of 20,000/reaction. During the observation period, six pts relapsed with a significant increase of BCR-ABL1/GUSB ratios. We conclude that very few pts are diagnosed with unusual BCR-ABL1 transcripts, but their characterization is important for proper assessment of treatment response in affected patients, and to avoid false negative assessment of residual disease status. Based on the individual PCR strategies, results cannot be expressed with precision on the International Scale and thus the common molecular milestones and triggers for treatment discontinuation are difficult to apply. We suggest that residual disease in these cases should be assessed primarily by considering trends in BCR-ABL/reference gene ratios over time. DisclosuresSaussele:NOVARTIS PHARMA: Consultancy, Honoraria; BMS: Honoraria. Cross:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.