TY - JOUR

T1 - The Rate of Individual BCR-ABL Decline As an Optimized Predictor of Tyrosine Kinase Inhibitors Treatment Outcome in Chronic Phase CML Patients, Comparison with CML Prognostic Scores and Early Molecular Response Achievement

AU - Fominykh, Mikhail

AU - Shuvaev, Vasily

AU - Martynkevich, Irina

AU - Tsaur, Grigory

AU - Bederak, Natalya

AU - Chelysheva, Ekaterina

AU - Shukhov, Oleg

AU - Abdullaev, Adhamjon

AU - Udaleva, Vera

AU - Golovchenko, Regina

AU - Zotova, Irina

AU - Shikhbabaeva, Dzhariyat

AU - Polushkina, Lyubov

AU - Petrova, Ekaterina

AU - Ivanova, Marina

AU - Martynenko, Lyudmila

AU - Kleina, Elizaveta

AU - Cybakova, Natalya

AU - Turkina, Anna

AU - Abdulkadyrov, Kudrat

PY - 2015

Y1 - 2015

N2 - Background. About 70% of chronic myeloid leukemia (CML) patients achieve early molecular response (BCR-ABL IS2 10% at 3-months) that lead to 5-years overall survival close to 95 However, CML patients remain heterogeneous group and several studies in recent years were aimed to personalize treatment based on individual patients' characteristics. Our group previously put forward a hypothesis about the prognostic value of individual BCR-ABL declinerate in the first three months of CML therapy1,2. The ratio BCR-ABL at 3 months to baseline had chosen as 0.1 as best cut-off value to predict MMR at 12 months. The aims of this study were to validate our prognostic method in larger group of patients and compare these results according to CML prognostic scores. Patients and methods. Fifty-five patients (median age, 52 years; range 19-84; 24 male and 31 female) with chronic phase CML were included in the study. Patients' distribution for Sokal risk groups were as follows: low-30 / intermediate-15 / high-10. Six patients had EUTOS high-risk. Forty-two patients started treatment with Imatinib 400 mg/day, 12 patients started with Nilotinib 600 mg/day and 1 patient started with Dasatinib 100 mg/day. Median BCR-ABL transcript levels was 41.38% at diagnosis, range 3.39-3185.36% (IS). The ratio of BCR-ABL levels at 3 months to baseline for each patient was calculated. In addition, we calculated ratio of BCR-ABL levels at 3 months to BCR-ABL levels at 1 month for 13 patients. Comparison was made of the predictive sensitivity to achieve early molecular response at 3 months (10% by IS) and according to prognostic CML scores (Sokal and EUTOS). We also assessed positive likelihood ratio (LR) value for the probability of achieving MMR between patients' stratification methods. Statistical analysis was conducted with Fisher exact test and sensitivity-specificity analyses. Results. Twenty-six out of 34 patients (76.5 with ratio of BCR-ABL levels at 3 months to baseline below than 0.1 achieved MMR at 12 months, while only 9 of 21 patients (42.9 with ratio more than 0.1 had optimal response (LR = 1.86 (1.05 - 3.29); p=0.003). Ratio of BCR-ABL levels at 3 months to 1 month showed much better results with the same (0.1) cut-off value - 5 out of 6 patients (83.3 with ratio BCR-ABL at 3 months to 1 month below than 0.1, while only 1 patient (14.3 with ratio more than 0.1 achieved optimal response (LR = 5.83 (0.92 - 37.08); p=0.05), respectively. Application of early molecular response at 3 months (10% by IS) yielded worse discrimination results: 34 of 47 (72.3 patients with BCR-ABL level texttwosuperior10% at 3 months, whereas 2 of 8 (25 patients with BCR-ABL gt;10% had MMR at 1 year (LR = 1.38 (1.01 - 1.89); p=0.78), respectively. CML prognostic scores results had the following sensitivity-specificity results: for Sokal - low-risk 23 of 30 (76.7, intermediate-risk 9 of 15 (60 and 3 of 10 (30 high-risk patients achieved MMR at 1 year (LR (low+intermediate)/high = 1.41 (1.00 - 1.97); p=0.03); for EUTOS-score - low-risk 34 of 49 (69.4 and only 1 of 6 (16.7 high-risk patients had achieved MMR at 12 months (LR = 1.30 (1.00 - 1.68); p=0.02). Furthermore, application of our ratio cut-off value among patients with BCR-ABL level texttwosuperior10% at 3 months allowed us to revealed additional 6 high-risk patients have not reached MMR at 1 year of therapy (Table 1).Conclusion. Our study showed that individual rates of BCR-ABL decline from baseline to 3 months and to 1 month had better LR than CML prognostic scores (Sokal, EUTOS) or early molecular response achievement (BCR-ABL levels texttwosuperior10% at 3 months) and might be useful as an optimized predictors of outcome for CML patients (MMR at 1 year of treatment).1 Fominykh M., ShuvaevV., Martynkevich I. et al. ELN Frontiers Meeting c CWhere science meets clinical practiceÈ 16-19 October, 2014, Berlin, Germany. Abstract book: 11.2 Shuvaev V., Fominykh M., Martynkevich I. et al. Blood (56th ASH Annual Meeting Abstracts), 2014; 124 (21): 5529.Figure 1. The patient numbers of achieving MMR at 12 months of therapy in various stratification groups with sensitivity-specificity characteristicsDisclosures Chelysheva: Novartis Pharma: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria. Turkina: Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis Pharma: Consultancy.↵* Asterisk with author names denotes non-ASH members. This icon denotes a clinically relevant abstract

AB - Background. About 70% of chronic myeloid leukemia (CML) patients achieve early molecular response (BCR-ABL IS2 10% at 3-months) that lead to 5-years overall survival close to 95 However, CML patients remain heterogeneous group and several studies in recent years were aimed to personalize treatment based on individual patients' characteristics. Our group previously put forward a hypothesis about the prognostic value of individual BCR-ABL declinerate in the first three months of CML therapy1,2. The ratio BCR-ABL at 3 months to baseline had chosen as 0.1 as best cut-off value to predict MMR at 12 months. The aims of this study were to validate our prognostic method in larger group of patients and compare these results according to CML prognostic scores. Patients and methods. Fifty-five patients (median age, 52 years; range 19-84; 24 male and 31 female) with chronic phase CML were included in the study. Patients' distribution for Sokal risk groups were as follows: low-30 / intermediate-15 / high-10. Six patients had EUTOS high-risk. Forty-two patients started treatment with Imatinib 400 mg/day, 12 patients started with Nilotinib 600 mg/day and 1 patient started with Dasatinib 100 mg/day. Median BCR-ABL transcript levels was 41.38% at diagnosis, range 3.39-3185.36% (IS). The ratio of BCR-ABL levels at 3 months to baseline for each patient was calculated. In addition, we calculated ratio of BCR-ABL levels at 3 months to BCR-ABL levels at 1 month for 13 patients. Comparison was made of the predictive sensitivity to achieve early molecular response at 3 months (10% by IS) and according to prognostic CML scores (Sokal and EUTOS). We also assessed positive likelihood ratio (LR) value for the probability of achieving MMR between patients' stratification methods. Statistical analysis was conducted with Fisher exact test and sensitivity-specificity analyses. Results. Twenty-six out of 34 patients (76.5 with ratio of BCR-ABL levels at 3 months to baseline below than 0.1 achieved MMR at 12 months, while only 9 of 21 patients (42.9 with ratio more than 0.1 had optimal response (LR = 1.86 (1.05 - 3.29); p=0.003). Ratio of BCR-ABL levels at 3 months to 1 month showed much better results with the same (0.1) cut-off value - 5 out of 6 patients (83.3 with ratio BCR-ABL at 3 months to 1 month below than 0.1, while only 1 patient (14.3 with ratio more than 0.1 achieved optimal response (LR = 5.83 (0.92 - 37.08); p=0.05), respectively. Application of early molecular response at 3 months (10% by IS) yielded worse discrimination results: 34 of 47 (72.3 patients with BCR-ABL level texttwosuperior10% at 3 months, whereas 2 of 8 (25 patients with BCR-ABL gt;10% had MMR at 1 year (LR = 1.38 (1.01 - 1.89); p=0.78), respectively. CML prognostic scores results had the following sensitivity-specificity results: for Sokal - low-risk 23 of 30 (76.7, intermediate-risk 9 of 15 (60 and 3 of 10 (30 high-risk patients achieved MMR at 1 year (LR (low+intermediate)/high = 1.41 (1.00 - 1.97); p=0.03); for EUTOS-score - low-risk 34 of 49 (69.4 and only 1 of 6 (16.7 high-risk patients had achieved MMR at 12 months (LR = 1.30 (1.00 - 1.68); p=0.02). Furthermore, application of our ratio cut-off value among patients with BCR-ABL level texttwosuperior10% at 3 months allowed us to revealed additional 6 high-risk patients have not reached MMR at 1 year of therapy (Table 1).Conclusion. Our study showed that individual rates of BCR-ABL decline from baseline to 3 months and to 1 month had better LR than CML prognostic scores (Sokal, EUTOS) or early molecular response achievement (BCR-ABL levels texttwosuperior10% at 3 months) and might be useful as an optimized predictors of outcome for CML patients (MMR at 1 year of treatment).1 Fominykh M., ShuvaevV., Martynkevich I. et al. ELN Frontiers Meeting c CWhere science meets clinical practiceÈ 16-19 October, 2014, Berlin, Germany. Abstract book: 11.2 Shuvaev V., Fominykh M., Martynkevich I. et al. Blood (56th ASH Annual Meeting Abstracts), 2014; 124 (21): 5529.Figure 1. The patient numbers of achieving MMR at 12 months of therapy in various stratification groups with sensitivity-specificity characteristicsDisclosures Chelysheva: Novartis Pharma: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria. Turkina: Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis Pharma: Consultancy.↵* Asterisk with author names denotes non-ASH members. This icon denotes a clinically relevant abstract

M3 - тезисы

VL - 126

SP - 5150

EP - 5150

JO - Blood

JF - Blood

SN - 0006-4971

IS - 23

Y2 - 5 December 2015 through 8 December 2015

ER -