Introduction. The advent of tyrosine kinase inhibitors (TKIs) in clinical practice drastically improved prognosis in patients with chronic myeloid leukaemia (CML). Adverse events of the TKI therapy and its high financial burden warrant the trend to gradually abandon this treatment.Aim. To assess the results of CML patient monitoring after the withdrawal of TKI therapy.Patients and methods. This prospective study included 98 chronic phase CML patients satisfying the criteria: any receiving of TKI therapy for ≥3 years; deep molecular response (DMR, BCR-ABL ≤ 0.01 % IS) during ≥ 2 years. The withdrawal was followed by quantitative BCR-ABL estimation performed monthly for the first 6 months of the survey, bimonthly for 1 year and every 3 months from the second year onwards. Therapy was resumed at a loss of major molecular response (MMR, BCR-ABL ≥ 0.1 % IS).Results. The MMR loss upon the TKI withdrawal was observed in 48 (49 %) patients. Survival without MMR loss was 52 % past 24 months since withdrawal, with a median of 35 months (23–52). The duration of therapy, MR and the MR depth at the time of withdrawal significantly correlated with a conserved post-therapy MMR. Gender, age, a Sokal risk group, type and line of TKI therapy at withdrawal, and imatinib resistance in history were not observed to significantly impact molecular relapse-free remission. MMR was recovered in all 48 patients with TKI therapy resumed in molecular relapse. In 65 % of the patients, adverse therapy events observed during treatment completely resolved by 6 months of post-therapy monitoring. Musculoskeletal pain (withdrawal syndrome, WS) was reported in 42 % patients in the post-therapeutic period, which did not lead to TKI resumption. The WS development correlated with an elder age and longer therapy prior to withdrawal.Conclusion. Molecular relapse-free survival in CML patients with treatment-free remission (TFR) is comparable to other published evidence. Monitoring safety during TFR is attested by the lack of disease progression and MMR recovery upon TKI resumption in all patients.

Background.The European Population Register EUTOS for CML includes data on adult patients (n = 2904) diagnosed with Ph-positive (Ph+) and/or BCR-ABL1-positive (BCR-ABL1+) chronic myeloid leukemia (CML) in 20 European countries during the period from 2008 to December 2012. Russia took part in this study, having contributed 6.8 % of CML patients to the total number of patients in the Register.Aim.To estimate long-term treatment outcomes in patients with newly diagnosed CML in the Russian Federation in comparison with the data obtained for a pan-European population cohort of patients.Patients and methods.The cohort under study consisted of 197 patients from 6 Russia regions, all of whom were diagnosed with a Ph+ / BCR-ABL1 + CML during the period from October, 1, 2009 to December, 31, 2012. The patients’ median age was 50 (18–82) years, with men and women being represented in approximately equal proportions.Results.In the first line, 97 % and 3 % of the patients received Imatinib and 2nd generation tyrosine kinase (TKI) inhibitors, respectively. The response dynamics was as follows: 12 months after the treatment, a complete cytogenetic response and a major molecular response were achieved in 40 % and 20 % of the patients. The overall survival (OS) and progression-free survival rates in patients in Russia following 12, 24 and 30 months were 93 %, 87 % and 84 %, and 92 %, 87 % and 87 %, respectively. In Russia, the study was prolonged. By 80 months of observation, the OS of patients in the chronic CML phase with a low and high risk of the disease progression had been 88 % and 56 %, respectively. In the acceleration phase, the 5-year overall survival rate was 39 %.Conclusion.An analysis of treatment outcomes in CML patients in a population-based non-selected sample indicates an increase in the survival of CML patients. However, problematic aspects of the therapy have been identified, along with a need for intensification of the treatment in patients with an unfavourable CML prognosis.

Introduction. The properties of progenitor cells in the stromal microenvironment, i.e. multipotent mesenchymal stromal cells (MMSC) and fi broblast colony-forming units (CFU-F), undergo changes in patients with chronic myelogenous leukaemia (CML).Aim. To compare the progenitor cells of the stromal microenvironment (MMSCs and CFU-Fs) obtained from the bone marrow of CML patients at the onset of the disease, one year after the start of the treatment and during the long-term treatment with tyrosine kinase inhibitors (TKI).Materials and methods. The study involved an analysis of the characteristics of MMSCs, the concentration of CFU-Fs in the bone marrow of CML patients, as well as the relative expression level of genes (REL) associated with differentiation and involved in the regulation of haematopoiesis. The analysis was performed at the onset of the disease, one year after the start of the treatment, as well as 3–8 and 9–16 years after the TKI therapy. MMSCs and CFU-Fs of healthy donors were used for control purposes.Results. The concentration of CFU-Fs at the onset of the disease did not differ from that in donors; however, the relative expression level of genes associated with differentiation was increased in the CFU-F colonies. A year after the start of TKI treatment, the concentration of CFU-Fs decreased by four times. Subsequently, the concentration increased to reach normal values following 8 years of TKI treatment. The total production of MMSCs was not changed at the onset of the disease; however, it decreased after a year of TKI treatment, subsequently returning to normal. The expression of many genes was altered in the MMSCs of patients, i.e. the REL of LIF and JAG1 increased by 10 and 2 times, respectively; in the course of treatment, the REL of LIF in MMSCs decreased, always remaining higher than in those of the donors, whereas the expression of JAG1 returned to normal. At the onset of the disease, the REL of LIF in the MMSCs of patients, who achieved a deep molecular response (DMR) within 17 months of the treatment, was three times lower than in the MMSCs of those patients who did not reach DMR within 50 months, with JAG1 not differing from that of donors.Conclusion. Changes in stromal progenitor cells are associated with the influence of tumour cells, as well as with TKI therapy. A normal expression level of JAG1 and a decreased expression level of LIF in the MMSCs of CML patients at the onset of the disease may be predictive of DMR achievement.Conflict of interest: the authors declare no conflict of interest.Financial disclosure: the study had no sponsorship.

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