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Context Tyrosine kinase inhibitors in third-line therapy (TKI-3L) in chronic-phase chronic myelogenous leukemia (CP CML) is effective in a portion of patients. Meanwhile, it is unclear which patients may benefit from TKI-3L. Objective To identify the factors affecting the outcome of TKI-3L therapy in CP CML. Design A retrospective study was conducted in five centers of St. Petersburg and Leningrad Region in 2019. All CP CML patients who ever obtained TKI-3L in these centers were included, except patients (pts) with complete cytogenetic response (CCyR). Results Seventy-three pts (male=26) with baseline median age 51 (25–88) were included in the study. There were 51 (70%) pts without any CyR, including 27 (37%) cases without complete hematologic response in baseline. For other patients, the best baseline cytogenetic response was minimal or minor (mmCyR) in 12 (16%) and partial (PCyR) in 10 (14%). BCR-ABL mutations were detected in 30/73 (42%) cases at any time before TKI-3L. Reasons for switching to TKI-3L were resistance in 56 (77%) or intolerance in 17 (23%). Dasatinib, Nilotinib, Bosutinib, or Ponatinib were used as TKI-3L in 43 (59%), 18 (25%), 9 (12%), and 3 (4%) pts, respectively. The median time of TKI-3L treatment duration was 15 (1–120) months. CCyR was achieved in 8/51 (16%) and 14/22 (64%) pts without CyR and with mmCyR/PCyR, respectively(p=0.001). CCyR subsequently had been lost 5/8 (62.5%) and 5/14 (29%) pts initially without or with any CyR (p=0.01). MMR was achieved in 3/51 (6%) and 6/22 (27%) pts without or with any CyR (p>0.05). Estimated overall 1-year, 3-year, and 5-year OS were 95%, 81%, and 65%, respectively. The median follow-up was 26 (3–136) months. There were 14 (19%) death: 11 due to CML progression and 3 after allo-SCT. All deaths occurred in pts without any CyR at baseline. Transformation to accelerated phase and blast crisis was occurred in 13 (18%) pts only in pts group without any CyR initially. The median time to progression was 15 (6–102) months. The only relevant baseline factor for CCyR, OS, and PFS probability in multivariant analysis was the presence of any CyR at baseline (p Conclusion Initial presence of any CyR was a favorable factor for long-term results of TKI third-line treatment in CP CML. TKI-3L should be considered as an appropriate tool in CML treatment for this group.

Background: Thrombosis in Primary Myelofibrosis (PMF) is one of the main but not fully covered problem. Thrombotic complications in PMF occur more frequently than in general population and could result to morbidity and lethality of patients. Several previous studies have demonstrated different thrombotic rates related to type molecular driver mutation (JAK2V617F, CALR, MPL) in myeloproliferative neoplasms, but this fact now is not fully understood. The standard clotting tests cover only initial stages of coagulation and could not evaluate anticoagulant system. Its results are not varied in PMF patients with different mutations. We have interested and initiated study of the coagulation system in PMF patients with integral hemostasis test - Calibrated Automated Thrombography (CAT). Here we present the results of pilot study group assessment. Aim: to investigate of the coagulation system in PMF patients with different molecular driver mutations (JAK2V617F, CALR, MPL) using thrombin generation test. Methods: The study included 13 MF patients (26 - 71 years, median = 40). There were 11 females and 2 males. Nine patients were JAK2V617F positive, 3 had CALR mutations and one patient was MPL-mutated. Thrombin generation was assessed by calibrated automated thrombinography (CAT) according to Hemker et al. Assessments were conducted in platelet poor plasma (PPP) with or without presence of thrombomodulin (PPP reagent +/- TM) as an activator of protein C system. The following parameters were evaluated: endogenous thrombin potential (ETP, nM*min), peak thrombin (Peak, nM), lag-time (Lag, min), and time to peak (TTP, min). Sensitivity ETP and Peak for TM were calculated as percent of decreasing of these parameters after adding to assay of TM (S ETP, % and S Peak, % respectively). STATISTICA 6.0 package was used in data analysis. Results were presented as median (Me) with 95% confidence intervals (CI). Results: ETP was highest in JAK2V617F patients (1213.57; min 781.60-max 1781.26 nM*min), intermediate in CALR (1058.47; min 933.14-max 1190.79 nM*min) and lowest in MPL group (972.49 nM*min). However, the Peak was higher in CALR (207.57; min 165.63-max 235.36 nM) than in JAK2V617F (160.9; (min 94.38-max 317.11 nM) and MPL (136.19 nM). We have observed disruption of protein C functioning in JAK2V617F (S-ETP 34%, min 8.65%-max 68.73%; S-Peak 20%, min 0.01%-max 44.64%) and MPL (S-ETP 46%; S-Peak 24%) groups compared to CALR patients (S-ETP 6.4%, min 2.5%-max 9.2%; S-Peak 1.8%, min 0.87%-max 1.8%). Conclusion: The results of thrombin production were differed in relation to driver mutation type. JAK2V617F-patients produced more thrombin and have protein C system dysfunction. It could be serve as an explanation of higher risk of thrombosis in MF patients with JAK2V617F mutation. The yielded results force us to continue research to confirm our findings on representative sample of PMF patients. Disclosures No relevant conflicts of interest to declare.