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Introduction. The option of observation without therapy with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients is already included in Russian and international clinical guidelines. Evaluation of long-term follow-up results of treatment free remission (TFR) in CML patients is relevant for the introduction of this approach into routine clinical practice. Aim — to demonstrate the outcomes in a long-term follow-up of CML patients who discontinued TKI therapy in the RU-SKI trial. Patients and methods. The prospective study included 98 CML patients with TKI therapy duration ≥ 3 years and a deep molecular response (DMR, BCR::ABL1 ≤ 0.01 %) duration ≥ 2 years. TKI therapy was resumed with the loss of a major MR (MMR, BCR::ABL1 > 0,1 %). Results. Median time of follow-up after TKI discontinuation was 64 months (range of 51–86 months). Survival without MMR loss at 3 and 5 years after TKI discontinuation was 51 % (CI 41–61 %) and 46 % (CI 36–57 %) respectively. From 3 to 5 years of follow-up without therapy, the loss of MMR occurred in 2 (4 %) patients. There was no MMR loss observed after 5 years of follow-up. In patients with first and second treatment discontinuation, survival without MMR loss was 50 % versus 12,5 %(р = 0,039). All 50 patients with molecular relapses regained MMR and MR4 after TKI therapy resumption. BCR::ABL1 level fluctuations 0,01–0,1 % were in 62 % (n = 29) patients, who were in TFR at the time of analysis. Loss of MR4 was observed in 38 (42 %) from 90 patients with first TKI discontinuation. Survival without MMR loss from MO4 loss was 24 % at 5 years after TKI discontinuation. Loss of MO4 in the first 3 months after TKI cessation was associated with a high probability of further MMR loss (8 % versus 54 % in patients with loss of MO4 for > 3 months, p = 0.00015). Conclusion. The low frequency of late relapses (4 % after 3 years of follow-up) and the possibility of long-term persistence of minimal residual disease (MRD) after discontinuation of therapy determine the need to optimize the timing of molecular monitoring, taking into account the MRD status of patients.

Introduction. Given the possibility of preserving molecular remission in 40–60 % of patients with chronic myeloid leukemia (CML) with a stable deep molecular response (MR) after discontinuation of tyrosine kinase inhibitors (TKI), it is important to determine the number of candidates for observation in a treatment-free remission (TFR) and terms of treatment cancellation.Aim — to evaluate the probability of stable deep MR and the rate of patients who meet the criteria for TFR observation in the Russian part of the international multicenter prospective population study EUTOS PBS (European Treatment and Outcome Study — Population-Based Study).Materials and methods. Registration of all CML cases in the EUTOS PBS was conducted in 6 regions of Russia from September 2009 to December 2012. The main inclusion criterion was the diagnosis of CML confirmed by cytogenetic or molecular study in patients aged over 18 years. In total, 197 CML patients were included: 181 (92 %) with chronic phase (CP) CML, 14 (7 %) with accelerated phase (AP) and 2 (1 %) with blast crisis (BC) at diagnosis. Data on therapy and results was updated annually.Results. Deep MR (at least MR4 or BCR::ABL1 level less than 0.01 % IS) was achieved in 104 (54 %) of 192 patients receiving TKI therapy, with a median observation period of 7 years (range from 3 months to 10 years). The probability of a deep MR after 5 years of treatment was 48 % (95 % confidence interval (95% CI): 40–55 %) in patients with CP. The cumulative incidence of a stable deep MR with duration of more than 2 years in CML CP patients was 16 % (95% CI: 11–22 %) after 5 years of therapy, 29 % (95% CI: 22–37 %) after 7 years of therapy and 50 % (95% CI: 38–60 %) after 9 years of therapy. The cumulative incidence of a stable deep MR was significantly higher in those patients who had achieved a deep MR at 36 months of therapy compared to patients with only MMR: 40 % (95% CI: 28–53 %) vs. 3 % (95% CI: 0–13 %) at 5 year of therapy; 66 % (95% CI: 52–77 %) vs. 15 % (95% CI: 5–30 %) at 7 year and 89 % (95% CI: 64–97 %) vs. 48 % (95% CI: 25–67 %) at 9 year (p < 0.0001) in patients without MMR by 36 months. No patients without MMR at 36 months of therapy subsequently gained a stable deep MR. Fifty four patients met the TKI discontinuation criteria for transition into TFR phase: CP CML with a typical BCR::ABL1 p210 transcript, TKI therapy for more than 3 years and a stable deep MR for over 2 years. The rate of possible candidates for cancellation of therapy was 28 % of all 192 patients who received TKI in the study or 31 % in terms of patients with CP CML. Predominantly, patients with low-risk by Sokal or ELTS score were among the potential TFR candidates 26 (48 %) and 33 (61 %), respectively. No patients with long-term resistance to therapy were the TFR candidates.Conclusion. In the Russian portion of the prospective observational multicenter study EUTOS PBS, it was found that with a median duration of TKI therapy of 7 years, about a third of patients with CP CML may be candidates for the controlled therapy discontinuation. If half of these patients remain in molecular remission, up to 15 % of the initial number of patients will be able to continue observation in the TFR. Achievement of MMR and deep MR at 36 months of therapy is associated with a significantly greater likelihood of meeting the criteria for follow-up in the TFR phase in the future.

Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant/intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes because of disease biology and inadequate efficacy and/or safety of current therapies. Asciminib, a first-in-class BCR-ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), has the potential to overcome resistance/intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previously treated with ≥2 TKIs were randomized (2:1) to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. Randomization was stratified by major cytogenetic response (MCyR) status at baseline. The primary objective was to compare the major molecular response (MMR) rate at week 24 for asciminib vs bosutinib. A total of 233 patients were randomized to asciminib (n = 157) or bosutinib (n = 76). Median follow-up was 14.9 months. The MMR rate at week 24 was 25.5% with asciminib and 13.2% with bosutinib. The difference in MMR rate between treatment arms, after adjusting for MCyR at baseline, was 12.2% (95% confidence interval, 2.19-22.30; 2-sided P = .029). Fewer grade ≥3 adverse events (50.6% vs 60.5%) and adverse events leading to treatment discontinuation (5.8% vs 21.1%) occurred with asciminib than with bosutinib. The study showed a superior efficacy of asciminib compared with that of bosutinib, together with a favorable safety profile. These results support the use of asciminib as a new therapy in patients with CML-CP who are resistant/intolerant to ≥2 prior TKIs. This trial was registered at www.clinicaltrials.gov as #NCT03106779.

Multipotent mesenchymal stromal cells (MSC) are the key regulators of hematopoiesis. We studied changes in MSC characteristics in patients with myeloid leukemia and patients with lymphoproliferative diseases. MSC were obtained from the bone marrow of patients at the time of diagnostic puncture using a standard technique. Their proliferative potential and expression of genes associated with differentiation and regulation of hematopoiesis were studied. The total cell production of MSC in patients with leukemia at the onset of the disease did not differ from that in the group of healthy donors. The relative expression of the IL6, TGFb1 and TGFb2, PPARG genes was similar in all patients. The relative expression of the JAG1, LIF, IGF1, CSF1, IL1b, and IL1bR1 genes in MSC of patients with leukemia was enhanced and the relative expression of SDF1 was unchanged in comparison with MSC from donors. MSC from patients with leukemia were characterized by enhanced relative expression of PDGFRA and PDGFRB, and reduced expression of SOX9. Changes functions of the stromal microenvironment in patients with hemoblastoses attested to the role of stromal cells in the maintenance and spread of tumor cells.

Withdrawal syndrome (WS) a musculoskeletal pain after discontinuation of tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML) has been described in the treatment-free remission (TFR) studies. The pathophysiological mechanisms and predisposing factors of WS have not been well established.Our aim was to evaluate clinical features and factors associated with WS in the Russian cohort of CML patients who discontinued TKI therapy.WS was evaluated in total of 183 CML patients with chronic phase and sustained deep molecular response (DMR). WS was defined as a musculoskeletal pain newly observed after TKI cessation or as a worsening of previously observed symptoms.DMR loss free survival at 36 months was 49% and 43% in prospective and retrospective groups respectively (p=0.96) with mеdian (Me) time of observation 33 months (range 1136). WS was observed in 49 (27%) patients: grade 12 was in 45 (92%) patients, grade 3 in 4 (8%) patients. Me time to WS occurrence was 2 months (range 17), Ме duration of WS was 5 months (range 135). WS was resolved in 14 of 15 patients with molecular relapse after 13 months of TKI re-initiation and was decreased in 1 patient. WS was completely resolved in 31 of 34 patients who continued remained in TFR and decreased in 3 patients. WS was resolved spontaneously or with nonsteroidal anti-inflammatory drugs in 14 (45%) and 17 (55%) patients accordingly. Older age (p0.0001), longer duration of TKI therapy (p0.0001) and presence of locomotion system diseases (p=0.022) were observed in patients with WS. No WS was observed in pregnant patients (р0.001). Survival without DMR loss at 12 months after TKI stop was 66 and 42% in patients with and without WS accordingly (р=0.095).The rate of WS was 27% that is in a good concordance with the data of the other TFR studies. A longer period of TKI exposure, older age and the history of locomotion system diseases were associated with the development of the WS. We found for the first time that WS was not observed in patients with pregnancy. There was no association of WS development and the rate of molecular relapses.Обоснование. Синдром отмены (СО) после прекращения приема ингибиторов тирозинкиназ (ИТК) у пациентов с хроническим миелоидным лейкозом (ХМЛ) описан в исследованиях ремиссии без лечения (РБЛ). Патофизиологические механизмы и факторы развития СО точно не установлены. Цель. Определить клинические особенности СО и факторы его развития у больных ХМЛ после отмены терапии ИТК в российской когорте пациентов. Материалы и методы. Анализ выполнен в группе 183 больных ХМЛ со стабильным большим молекулярным ответом (БМО). СО определяли как впервые возникший после отмены ИТК скелетно-мышечный болевой синдром или увеличение степени выраженности ранее имевшихся симптомов. Результаты. Выживаемость без потери БМО через 36 мес после отмены ИТК составила 49 и 43% в проспективной и ретроспективной группах пациентов соответственно (p=0,96) при медиане (Me) наблюдения 33 (от 1 до 136) мес. СО наблюдался у 49 (27%) больных: 12-й степени у 45 (92%) человек, 3-й степени у 4 (8%) пациентов. Ме времени до появления СО составила 2 (от 1 до 7) мес, Ме длительности СО 5 (от 1 до 35) мес. После возобновления терапии в связи с молекулярным рецидивом СО полностью разрешился у 14 из 15 пациентов в течение 13 мес, выраженность проявлений уменьшилась у 1 пациента. СО полностью разрешился у 31 из 34 пациентов с продолжением наблюдения в РБЛ; у 3 больных уменьшилась выраженность его симптомов. СО купировался самостоятельно либо на фоне применения нестероидных противовоспалительных препаратов у 14 (45%) и 17 (55%) пациентов соответственно. У больных с СО статистически значимо чаще отмечены более старший возраст (р0,0001), длительный срок терапии ИТК (р0,0001) и наличие заболеваний опорно-двигательного аппарата (р=0,022). Развитие СО не зарегистрировано у беременных пациенток (p0,001). Выживаемость без потери БМО к 12 мес без терапии составила 66 и 42% в группах больных с наличием СО и без него соответственно (р=0,095). Заключение. Доля больных ХМЛ с СО после отмены ИТК составила 27%, что сопоставимо с данными других исследователей по наблюдению в РБЛ. Более длительный период терапии ИТК, старший возраст и наличие заболеваний опорно-двигательного аппарата ассоциированы с развитием СО. Впервые отмечено, что развитие СО не характерно для пациенток с беременностью. Взаимосвязи между развитием СО и молекулярными рецидивами не установлено.

Aim. To study the impact of different clinical and biological factors on sustaining molecular remission after discontinuation of tyrosine kinase inhibitors (TKI) therapy in chronic myeloid leukemia (CML) patients with a stable deep molecular response (MR). Materials & Methods. The prospective multi-center trial on molecular remission sustainability after TKIs withdrawal, held from 2015 to 2019, enrolled 98 CML patients. The trial included patients with chronic phase CML treated with TKIs at least during 3 years and having a stable deep MR (< МО4; BCR-ABL < 0.01 %) during at least 2 years. Molecular monitoring was carried out every month during first 6 months after TKIs withdrawal, every 2 months during 0.5-1 year, and every 3 months after 1-year follow-up. In case of the loss of major MR (BCR-ABL > 0.1 %) therapy was reinitiated. Results. Three-year molecular relapse-free survival was 51 % (95% confidence interval 41-61 %) in all patients, 25 % in patients with the failure of prior treatment discontinuation, and 53 % in patients who discontinued TKI therapy for the first time. According to univariate analysis, the following factors proved to be significant: persistance of deep MR, duration of therapy, and depth of MR. It was shown that TKI therapy duration, but not deep MR persistance, has independent prognostic value for the Russian population of CML patients. No significant differences were identified in 3-year molecular relapse-free survival in the groups of patients treated only with imatinib (55 %) compared with patients who received 2nd generation TKI (TKI2) as first-line (70 %; p = 0.26) and second-line (39 %; p = 0.09) therapy. However, duration of therapy in patients treated with TKI2 as first-line therapy was more than twice as short as in patients treated with imatinib as first-line therapy (median 41.5 vs. 96.4 months, respectively; p < 0.0001). Conclusion. Longer therapy duration and MR depth (< M04.5) before TKI withdrawal raise the probability of sustaining off-treatment remission. The study showed that molecular relapse-free survival does not significantly increase with the use of TKI2 as first-line treatment compared to imatinib. Nevertheless, TKI2 as first-line treatment enables to halve the duration of therapy needed to achieve comparable molecular relapse-free survival, as compared with imatinib.

The development of National clinical guidelines on diagnosis and treatment of Ph-negative myeloproliferative neoplasms comes in response to the need to standardize the approach to diagnosis and treatment. The availability of clinical guidelines can facilitate the choice of adequate treatment strategy, provides practicing physicians with exhaustive and up-to-date information on advantages and shortcomings of different treatment methods as well as lets health professionals better assess expected extents of treatment required by patients. In 2013 a working group was formed to develop and formulate clinical guidelines on the treatment of myeloproliferative neoplasms. These guidelines were first published in 2014, afterwards they were revised and republished. The dynamic development of current hematology presupposes constant updating of knowledge and implementation of new diagnosis and treatment methods in clinical practice. In this context clinical guidelines present a dynamic document to be continuously amended, expanded, and updated in accordance with scientific findings and new requirements of specialists who deal directly with this category of patients. The present edition is an upgraded version of clinical guidelines with updated information on the unification of constitutional symptoms assessment using MPN-SAF TSS questionnaire (MPN10), on applying prognostic scales in primary myelofibrosis, assessing therapy efficacy in myeloproliferative neoplasms, revising indications for prescription, on dose correction, and discontinuation of targeted drugs (ruxolitinib). The guidelines are intended for oncologists, hematologists, healthcare executives, and medical students.

Tyrosine kinase inhibitor (TKI) therapy results in deep molecular response (MR) in 60-70 % of chronic myeloid leukemia (CML) patients. However, despite high efficacy of TKIs, many patients experience drug toxicity during the treatment. According to clinical studies, the probability of sustaining off-treatment remission in CML patients with deep MR is about 40-60 %. Great attention has recently been paid to personalized therapy of chronic phase CML. It consists in TKI dose modification to reduce or prevent adverse events. Major retrospective studies proved that in patients with optimal response TKI reduced doses can be considered safe from the point of view of sustaining major and deep MRs achieved with standard TKI doses. Also, prospective clinical trials deal with the follow-up using TKI reduced doses as pre-withdrawal period. But up to now, the results of only 4 of such studies have been available. To take a closer look at long-term follow-up of CML patients receiving reduced doses of TKIs, prospective clinical trials need to be carried out. The present article reviews the results of main studies dealing with management of CML patients treated with TKI reduced doses.

Introduction. BCR-ABL tyrosine kinase inhibitors are currently used to successfully treat chronic myeloid leukemia (CML). Drug therapy is carried out in a continuous daily mode throughout the patient’s life. Treatment with this group of drugs is associated with specific dermatological adverse events (dAE), which can lead to a change in the regimen of effective, vital therapy for CML patients.Purpose. To study the characteristics of dermatological adverse events, the severity and influence on the quality of life of BCR-ABL tyrosine kinase inhibitors.Patients and methods. The observational study included 93 patients. The clinical manifestations of dAE, their severity were evaluated, their photographs and pathomorphological studies of skin biopsy samples were performed, cases of dose reduction or drug withdrawal due to dAE were recorded. The quality of life of patients with dAE was determined based on the assessment of the dermatological index of quality of life.Results. Imatinib therapy was accompanied by a maculopapular rash in 43.3 % of patients, nilotinib caused follicular keratosis in 12.9 % of patients. In 3.2 % of patients, dasatinib caused hyperpigmentation, in 2.2 % of patients lichenoid rashes of the II degree occurred during treatment with bosutinib. Ponatinib treatment was followed by dAE in 9.7 % of patients. All dAE have an impact on the quality of life of patients, but the maculopapular rash and dyskeratotic changes are most pronounced. In a pathomorphological study, these dAE have specific features corresponding to immuno-mediated dermatitis.Conclusions. The most frequent and pronounced dAE that significantly affect the quality of life of patients with CML are a maculopapular rash and dyskeratotic skin changes: psoriasiform and lichenoid dermatitis. Clinical and pathomorphological characteristics of skin reactions make it possible in the future to determine effective methods of supportive therapy for dAE.

Russia took part in the multicenter population-based study (Europe) and included 6.8% adult patients with newly diagnosed chronic myeloid leukemia (CML). The objective of this study was to analyze the mortality in the Russian cohort of patients with newly diagnosed CML in the EUTOS PBS observational study.The analyzed cohort consisted of 197 patients (18 years) with Ph+/BCR-ABL1+ CML diagnosed in the period from October 1, 2009 through December 31, 2012 from 6 regions of Russia. The distribution of the phases of CML were: chronic phase (CP), 93.4% and accelerated phase (AP) + blast crisis (BC), 6% + 0.6%. The median age was 50 years (range, 18-82 years); the male/female ratio was equal.The overall survival (OS) at 5, 6, and 7 years was 80% (95% confidence interval [CI], 72%-86%), 78% (95% CI, 65%-80%), and 73% (95% CI, 65%-80%), respectively (P .001). The 5-year OS in patients with AP and BC was 39%. In Russia, the study was prolonged, with a median follow-up of 77 months (range, 0.7-108 months): 141 (71.5%) patients were alive, 47 (24%) patients died, and the status of 9 (4.5%) patients is was unknown. Forty-seven (23.8%) patients died during the follow-up period. The largest number of deaths was observed in the first year after the CML diagnosis: 17 (36%) of 47 cases, 3 of 17 died refusing the CML treatment. At the seventh year of CML therapy, 1 patient died after allogenic hematopoietic stem cell transplantation. The causes of death were: (1) progression of CML to AP/BC in 20 (43%) patients; (2) death in remission in 5 (11%) patients with complete cytogenetic response (CCyR) and/or major molecular response; and (3) death without progression to AP/BC but with signs of leukemia in 22 (46%) patients. The 5-year cumulative incidence of death from all reasons was 20%; the cumulative incidence of CML-related and non-CML-related death at the fifth year was 18% and 11%, respectively.In general, the results of treatment in the Russian population sample of non-selected patients with CML were comparable with the data of the total European cohort. The CML-related deaths prevailed in the first year of CML therapy. The appropriate monitoring and therapy interventions during the first year of CML treatment are apparently important for the long-term treatment results.

Medical profession is notable for its enormous social value and associated with no less responsibility. At the same time, society’s requirements for doctors constantly increase. The regulation of medical activities in various disciplines becomes more and more stringent. The aim of the present article was to study the quality of life of 104 hematologists working in different regions of the Russian Federation. For this purpose, the Russian-language version of RAND SF-36 health survey questionnaire was used. Young doctors aged 35-44 years showed lowest scores on mental health inventory which may indicate negative emotional status and a low level of positive emotions. Compared to relatively healthy respondents, hematologists show a low level of emotional role functioning that may also indicate negative emotional status which in turn negatively affects the quality of health care delivery and appears to be a contributing factor in burnout syndrome. Compared to relatively healthy respondents, hematologists show higher pain scores which may indicate a specific attitude of doctors to pain due to their professional approach. Similar quality of life indicators indirectly suggest that hematologists in different regions of the Russian Federation regard their professional activities as a priority, and it affects their quality of life. Both the results obtained and the literature review prove the relevance of the study of human resources and development of programs aimed at continuity of personnel in the health care system. The quality of life of doctors in different disciplines should become the object of comprehensive sociological, clinical, and sanitation studies which will permit to design a program to improve the quality of life of the medical professionals.

Aim. To analyze adverse cardiovascular events in chronic myeloid leukemia (CML) patients who received various tyrosine kinase inhibitors (TKI). Materials & Methods. The trial included 97 CML patients with nilotinib, dasatinib or imatinib indications. By the time of examination the patients had undergone TKI therapy for 1-138 months. The three of them were sequentially treated with 2 drugs over the monitoring period. All CML patients were aged 22-79 years (median 53.5 years): 55 women were aged 22-71 years (median 53.5 years) and 42 men were aged 24-79 years (median 53 years). Results. The comparative analysis demonstrated significantly higher impact of nilotinib on daily maximum QTc duration compared with other TKIs. The patients who received nilotinib (n = 15) throughout 38 months had QTc of 0.47 s (interquartile range [IQR] 0.46-0.47 s), in imatinib group (n = 17) QTc was 0.43 s (IQR 0.43-0.44 s), and in dasatinib group (n = 4) QTc was 0.43 s (IQR 0.42-0.44 s) (p = 0.0008). Among all patients treated with nilotinib there were 62 % (31/50) with QTc > 0.46 s, in imatinib (6/41) and dasatinib (2/18) groups it was detected in 14.6 % and 11.1 % of patients, respectively (p = 0.0008). Five patients had QTc > 0.48 s, which is the criterion for discontinuation of treatment or dose reduction. In two patients the identified changes of QTc duration required TKI temporary suspension. After nilotinib dose reduction or discontinuation QTc duration normalized in all cases within 2 weeks. Decreased ankle-brachial index (ABI) < 0.9 without pronounced clinical symptoms was identified in two patients who received nilotinib. Afterwards they showed peripheral occlusive disease of lower extremities, and nilotinib treatment was discontinued. In patients treated with other TKIs no occlusive vascular lesions were observed. A case of chronic heart failure with reduced left ventricular ejection fraction developing on nilotinib therapy was revealed and described. Conclusion. Despite high specificity for BCR-ABL tyrosine kinase, new TKIs can, although rarely, induce cardiovascular adverse events. Prior to TKI treatment assignment CML patients should be examined with ECG and EchoCG with systolic function evaluation, and the measurement of pulmonary artery pressure as well as ABI. The examination should be repeated in the end of the 1st year TKI treatment if there is no reason for extra examinations. It is recommended to hold 24-hour ECG monitoring with QTc max measurement prior to nilotinib assignment, then once a year within 2 years of nilotinib treatment, and once in 6 months after 3 years of therapy.

Aim. Based on our own materials to characterize the clinical manifestations of hypereosinophilic states distinguishing between reactive eosinophilia (RE), clonal myeloproliferative neoplasms with eosinophilia (MPN-eo), and myeloproliferative variant of hypereosinophilic syndrome (MP-HES); to evaluate treatment results. Materials & Methods. The trial included 188 patients with primary HES (132 men and 56 women, aged 19-72 years) having been followed-up at the National Research Center for Hematology since 2001. The main entry criteria were blood eosinophilia > 1.5 x 109/L and clinical symptoms resulting sometimes from hypereosinophilia. All patients received complete physical examination, immunomorphological, standard cytogenetic, and molecular genetic testing. Treatment was provided to 73 patients (63 men and 10 women) including those with MPN-eo PDGFRA+ (п = 39), PDGFRB+ (п = 2), FGFR1+ (п = 1), chronic eosinophilic leukemia not otherwise specified (п = 8), systemic mastocytosis (п = 1), and MP-HES (п = 22). Complete hematological response (CHR) was the criterion for treatment efficacy. In the MPN-eo PDGFRA+ and PDGFRB+ groups molecular response (MR) rate was also estimated in cases of imatinib treatment. MR was considered as no expression of the FIP1L1-PDGFRA and ETV6-PDGFRB transcripts in RT-PCR. Results. The trial yielded the cause of eosinophilia in 117 (62.2 %) out of 188 patients. RE was diagnosed in 60 (32 %) out of 117 patients, various types of clonal MPNs were reported in 57 (30 %) patients. In 71 (38 %) out of 188 patients HES was still present at the first trial stages. Later within this group MP-HES was identified in 22 (30.9 %) out of 71 patients. Among imatinib recipients CHR was achieved in 37 (90 %) out of 41 patients within 1-3 months: in 36 patients with MPN-eo FIP1L1-PDGFRA+ and in 1 patient with MPN-eo ETV6-PDGFRB+. MR was achieved in 88 % of cases. In the absence of molecular markers characteristic of MPN-eo CHR was achieved in 26 % of cases. Among the recipients of treatments other than imatinib nobody achieved CHR. Conclusion. The diagnosis approach in patients with HES should be complex and individualized. Development and enhancement of molecular genetic diagnostic techniques are regarded as ones of the highest priority areas in modern hematology. The use of imatinib mesylate in MPN-eo therapy commonly results in long-term hematological and molecular remissions. On achieving CHR to imatinib treatment of patients without molecular markers characteristic of MPN-eo early use of this drug (or other tyrosine kinase inhibitors) can be recommended in acute forms of HES.

Tyrosine kinase inhibitors have radically changed the course of chronic myeloid leukemia, significantly increasing survival and reducing the risk of disease progression. Nearly 50–70 % of patients achieve a consistently low or undetectable level of minimal residual disease – a deep molecular response. The long-term tyrosine kinase inhibitors treatment in about one-third of patients is accompanied by toxicity which impairs the quality of life. Therefore, the safe treatment discontinuation is relevant. The results of clinical trials have shown 40-60% possibility of maintaining treatment-free remission in patients with long-term deep molecular respons; however, all patients with molecular relapse regain molecular remission after the resumption of tyrosine kinase inhibitors therapy. Currently, clinical and biological factors associated with maintaining treatment-free remission are being studied. It is assumed that cessation of tyrosine kinase inhibitors therapy can improve the quality of life, but approximately 30 % of patients are reporting musculoskeletal pain – so called “withdrawal syndrome” – that begins or worsens after stopping tyrosine kinase inhibitors therapy. The mechanisms for the development of this phenomenon are currently unclear. Thus, many aspects concerning treatment-free remission require to be studied, which determines the importance of clinical trials in this area.

Background Approximately 5–20% of chronic myeloid leukemia (CML) patients demonstrate primary resistance or intolerance to imatinib. None of the existing predictive scores gives a good prognosis of TKI efficacy. Gene polymorphisms, expression and microRNAs are known to be involved in the pathogenesis of TKI resistance in CML. The aim of our study is to find new molecular markers of TKI therapy efficacy in CML patients. Methods Newly diagnosed patients with Ph+ CML in chronic phase were included in this study. Optimal and non-optimal responses to TKI were estimated according to ELN 2013 recommendation. We performed genotyping of selected polymorphisms in 62 blood samples of CML patients, expression profiling of 33 RNA samples extracted from blood and miRNA profiling of 800 miRNA in 12 blood samples of CML patients. Results The frequencies of genotypes at the studied loci did not differ between groups of patients with an optimal and non-optimal response to TKI therapy. Analysis of the expression of 34,681 genes revealed 26 differently expressed genes (p

Background. Current clinical guidelines on diagnosis and treatment of chronic myeloid leukemia (CML) define indications for substitution of first-line tyrosine kinase inhibitor (TKI) at therapy failure during different phases of disease progression. Aim. To assess the efficacy of CML treatment with implementing the protocol of timely monitoring and switching to another TKI. Materials & Methods. Patients were included into pilot prospective study РИТМ during 5 years. Data on 100 CML patients were analyzed. Therapy and monitoring were conducted according to the Federal clinical guidelines on CML diagnosis and therapy, 2013. Results. Median follow-up after initiation of treatment was 46 months (range 12-74). Imatinib mesylate was administered as first-line therapy to 91 (91 %) patients, 9 (9 %) patients received 2nd generation TKI (TKI2). Therapy failure was registered in 31 (31 %) patients; 26 (84 %) of them were switched to TKI2. At the time of analysis 95 (95 %) patients were followed-up. Cumulative incidence of CML-associated mortality was 2 %. By the fifth year of follow-up cumulative probability of complete cytogenetic, major and deep molecular responses was 93 %, 88 % and 66 %, respectively. Conclusion. CML treatment according to current guidelines yields the results comparable with those achieved by first-line TKI2 therapy. This approach reduces CML treatment costs and lowers the risk of TKI2-associated adverse events. Due to a high rate of deep molecular response the proportion of CML patients in remission without treatment can be increased in the future.

Background. The tyrosine kinase inhibitors (TKI) era is marked by a long-term favorable prognosis of chronic myeloid leukemia (CML). In this context CML patients of reproductive age are faced with major issues of family planning with due regard to the risk of TKI treatment interruption during pregnancy. Additionally, TKI impact is another potential risk to the fetus. Aim. To develop differentiated approach to CML treatment during pregnancy. Materials & Methods. Analysis includes literature data and clinical experience based on 166 pregnancies of 120 CML patients from CML Pregnancy Registry. Results. Pregnancy planning is recommended after achieving stable and deep molecular response (with BCR-ABL > 0.01 %, IS) within the period of at least 2 years. At conception TKI therapy does not have to be interrupted. However, early pregnancy detection and TKI treatment interruption after pregnancy confirmation are of vital importance due to teratogenic risks. Furthermore, no TKI may be administered during organogenetic period, i.e. up to the 15th week of gestation. In the absence or loss of complete hematologic response and growth of BCR-ABL > 1 % after the 15th week of gestation imatinib or nilotinib administration is justified in the interest of pregnant patients taking into account limited transfer of these drugs through placenta. In the absence of complete hematologic response before the 15th week of gestation interferon-а can be administered. With BCR-ABL < 1 % patients can be either followed-up without therapy or they can receive interferon-а throughout pregnancy. Dasatinib, bosutinib, and other TKI are contraindicated at any stage of pregnancy. There are no special recommendations for childbirth, delivery is to be adapted to obstetric conditions. Breast feeding is not recommended because of the lack of practical evidence for its safety. Conclusion. A regular molecular monitoring of BCR-ABL and hematologic status is indispensable, health condition of fetus should be continuously monitored as well. CML patient management should be conducted by cooperating hematologists and gynecologists.

Multipotent mesenchymal stromal cells (MSC) are the key regulators of hematopoiesis. We studied changes in MSC characteristics in patients with myeloid leukemia and patients with lymphoproliferative diseases. MSC were obtained from the bone marrow of patients at the time of diagnostic puncture using a standard technique. Their proliferative potential and expression of genes associated with differentiation and regulation of hematopoiesis were studied. The total cell production of MSC in patients with leukemia at the onset of the disease did not differ from that in the group of healthy donors. The relative expression of the IL6, TGFb1 and TGFb2, PPARG genes was similar in all patients. The relative expression of the JAG1, LIF, IGF1, CSF1, IL1b, and IL1bR1 genes in MSC of patients with leukemia was enhanced and the relative expression of SDF1 was unchanged in comparison with MSC from donors. MSC from patients with leukemia were characterized by enhanced relative expression of PDGFRA and PDGFRB, and reduced expression of SOX9. Changes functions of the stromal microenvironment in patients with hemoblastoses attested to the role of stromal cells in the maintenance and spread of tumor cells.

The ENESTop study evaluated treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) in chronic phase who had received ≥3 years of tyrosine kinase inhibitor therapy and achieved sustained deep molecular response only after switching from imatinib to nilotinib. After 1-year nilotinib consolidation, 126 patients attempted TFR. At 48 weeks (primary analysis), 57.9% (73/126) were in TFR. In the present analysis at 5 years, 42.9% (54/126) were in TFR. Since the 48-week analysis, among patients who left the TFR phase, 58% (11/19) did not have a loss of molecular response and discontinued for other reasons. Of the 59 patients who reinitiated nilotinib upon loss of major molecular response (MMR) or confirmed loss of MR4, 98.3% regained MMR, 94.9% regained MR4, and 93.2% regained MR4.5. Overall adverse event rates decreased over the 5 years of TFR. In patients reinitiating nilotinib, there was a cumulative increase in cardiovascular events with longer nilotinib exposure. No disease progression or CML-related deaths were reported. Overall, these results confirm the durability and safety of TFR for patients receiving second-line nilotinib. Cardiovascular risk should be carefully managed, particularly when reinitiating treatment after TFR.

In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.

7004 Background: Asciminib is the first BCR::ABL1 inhibitor to specifically target the ABL Myristoyl Pocket (STAMP). In the ASCEMBL primary analysis, asciminib had superior efficacy and better safety/tolerability than BOS in pts with CML-CP after ≥2 prior TKIs. After a median follow-up of 2.3 years (16.5 months’ additional follow-up since primary analysis), we report efficacy and safety results (cutoff: October 6, 2021). Methods: Eligible pts were adults with CML-CP after ≥2 prior TKIs, with intolerance or lack of efficacy per 2013 European LeukemiaNet. Pts were randomized 2:1 to asciminib 40 mg twice daily or BOS 500 mg once daily, stratified by major cytogenetic response (MCyR) status (Ph+ metaphases ≤35%) at baseline. The key secondary endpoint was major molecular response (MMR) rate at wk 96. Results: 233 pts were randomized to asciminib (n=157) or BOS (n=76). At cutoff, treatment was ongoing in 84 (53.5%) and 15 (19.7%) pts, respectively; the most common reason for discontinuation was lack of efficacy in 38 (24.2%) and 27 (35.5%) pts, respectively. MMR rate at wk 96 (per ITT) was higher on asciminib (37.6%) than BOS (15.8%). The difference, adjusting for baseline MCyR, was 21.7% (95% CI, 10.5%-33.0%; 2-sided P=.001). More pts on asciminib than BOS, respectively, had BCR::ABL1IS ≤1% (45.1% vs 19.4%) at wk 96. The probability of maintaining MMR and BCR::ABL1IS ≤1% for ≥72 wk was 96.7% (95% CI, 87.4%-99.2%) and 94.6% (95% CI, 86.2%-97.9%), respectively, on asciminib and 92.9% (95% CI, 59.1%-99.0%) and 95.0% (95% CI, 69.5%-99.3%), respectively, on BOS. Median duration of exposure was 103.1 (range, 0.1-201.1) wk on asciminib and 30.5 (range, 1.0-188.3) wk on BOS. Despite the longer duration of asciminib exposure, safety/tolerability of asciminib continued to be better than that of BOS (Table). No new on-treatment deaths were reported since the primary analysis. Most frequent (>10%) grade ≥3 adverse events (AEs) on asciminib vs BOS were thrombocytopenia (22.4%, 9.2%), neutropenia (18.6%, 14.5%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). Conclusions: After >2 years of follow-up, asciminib continued to show superior efficacy and better safety/tolerability vs BOS. Responses were durable, with more pts on asciminib in MMR. Additionally, more pts on asciminib had BCR::ABL1IS ≤1%, a milestone response in later lines associated with improved survival. These results continue to support the use of asciminib as a new CML therapy, with the potential to transform standard of care. Clinical trial information: NCT03106779. [Table: see text]

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.

Despite the availability of guidelines for the management of chronic myeloid leukaemia (CML), various issues may prevent their successful implementation. the TARGET survey examined real-world management of CML patients compared with international recommendations. This online survey was completed in 2017. Results were discussed by a Steering Committee (SC) of eight international haematologists, challenges were identified and practical solutions developed. of the 1008 haematologists invited (33 countries), 614 completed the survey. Gaps regarding treatment efficacy and molecular monitoring were identified. Half of the physicians did not perform three-monthly testing of during the initial 12 months of treatment, citing cost as the major barrier, although they know it should be done. Treatment-free remission was not considered a primary treatment goal or as a priority factor influencing treatment decisions. European Leukemia Net guidelines interpretation was generally acceptable, but awareness regarding management of persistent adverse events was poor. Practical solutions proposed by the SC were mostly focused on enhancing physician education and awareness, or encouraging hospitals to work with the government, in order to improve the quality of BCR-ABL testing. Gaps in current CML management were identified compared with international recommendations, which the proposed practical solutions would help to address., NovartisNovartis, This study was funded by Novartis and set up by KPL. Medical writing assistance with the preparation of this manuscript was provided by KPL and Galien Health Publishing, with funding provided by Novartis.

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.

Chronic myeloid leukemia (CML) is a myeloproliferative disease, caused by BCR/ABL protein with high tyrosine kinase activity. Since 2001, CML has been effectively treated with tyrosine kinase inhib...

The results of long-term follow-up of patients (pts) with chronic myeloid leukemia (CML) do not lose their importance. Data from routine clinical practice are of particular interest. The use of 1 st (imatinib, IM) and 2nd generation TKI (2G TKI) led to a significant increase in survival, so the probability of death associated with CML could be significantly lower than the probability of death due to common causes of death other than CML. To analyze the overall survival (OS) and causes of mortality in CML pts treated in routine clinical practice in Russian Federation for a long period (>15 years) of time. The long-term follow-up data of the Russian part of the European LeukemiaNet (ELN) OSP EUTOS multicenter observational study were evaluated. The analyzed cohort consisted of 678 Ph/BCR-ABL-positive CML pts from 35 regions of Russia diagnosed in 2002-2006 with IM therapy initiation ≤6 months (mo) after diagnosis. Median (Me) age was 47(range 18-81) years (y), 47% males. Chronic phase, accelerated phase and blast crisis at diagnosis was in 631 (93%), 41(6%) and 6(1%) pts, respectively. The annual number of newly diagnosed pts was as follows: 2002 - 15 pts, 2003 - 38 pts, 2004 - 46 pts, 2005 - 206 pts, 2006 - 302 pts. The last update for 209 pts was done in Jun. 2021; last contact for 100 pts - in 2020, for 39pts - in 2019, for the other - before 2018. The date of the last contact/death could not be established for 14 pts. Statistical analysis included 661 pts, the OS was evaluated by Kaplan-Mayer method using the SAS 9.4 package. In total, 331 (50%) pts of the analyzed cohort were alive with the Me follow-up of 180 (range 2-232) mo or 15 y (range 2 mo-19,3 y). All pts started therapy with IM with 25% switched to 2G TKI in subsequent therapy lines. In total, 218 (66%) pts achieved MR4, 183 (55%) pts got MMR; 46 (21%) of these pts with deep molecular response (DMR) were observed in hematology centers of Moscow. The 15-y OS in the total cohort was 63% (CI 59-70%)(fig.1). The OS by age groups was as follows: 18-40yy-75% (CI 73-82%), 40-60yy- 63% (CI 59-70%), 60-80yy- 37% (CI 30-45%). The most complete information was provided by Moscow centers (2 centers, 113 pts). The 15-y OS of pts receiving treatment in Moscow was significantly higher vs pts from other regions (32 centers, 548 pts): 75% vs 60%, p=0,0030 (fig.2). The mortality in the whole cohort of 661 pts was 35% (233 pts). Of these 233 pts, 112(48%) pts deaths were due to CML progression to AP or BP (including non-compliant cases); 3pts (1,5%) died after allogenic stem cell transplantation (infection complications); the cause of death was unknown in 50 (21,5%) pts. The highest death rate from CML progression was at 4-9 y of follow-up. Deaths caused by concomitant diseases were in 68 (29%) pts: coronary artery disease/myocardial infarction/heart failure in 42 (62%) of 68 pts, acute ischemic stroke in 10 (15%) pts, second malignancies (Cr- cancer) in 10 (15%) pts (lung tumor, metastatic esophageal Cr, stomach Cr, brain tumor, sigmoid colon Cr, rectal colon Cr, melanoma, renal Cr, breast tumor, other hematological malignancies), accidents - 1 pt, liver cirrhosis - 2 pts, in 2 cases - respiratory virus infections complicated with pneumonia, 1 pt died due to Covid-19. Conclusions. The long-term follow-up of the multicenter study EUTOS OSP in 35 regions of Russian Federation allows not only to characterize the 15-y OS in CML pts but also provides the long-term outlook of the routine clinical practice. Probably, better OS of CML patients receiving treatment in Moscow (2 centers) may be related to organizational issues of interaction with the federal center, better monitoring and timely switching to 2G TKI therapy. The organization and support of multicenter studies may improve the situation with the treatment of diseases of the blood system. Figure 1 Figure 1. Disclosures Chelysheva: Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Vinogradova: Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Voloshin: Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Pfizer: Consultancy; Biacad: Consultancy, Speakers Bureau. Turkina: Pharmstandart: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Novartis Pharma: Speakers Bureau.

Introduction Data on the effectiveness and safety of new vaccines against COVID-19 in patients (pts) with hematological diseases are just beginning to accumulate. We planned to obtain such information for pts with chronic myeloid leukemia (CML) during vaccination. Objective. To evaluate the antibodies formation and adverse events (AEs) after vaccination against COVID-19 in pts with CML Materials and methods. All pts with CML diagnosis who applied to the National Research Center for Hematology (NRCH, Moscow, Russia) for outpatient or remote consultations were suggested to prospectively report the AEs after getting a vaccination against COVID-19 by the most frequently used vector-based vaccine GamCovidVac (Sputnik V). Two vaccine components with the interval of 21 days were given at the vaccination facilities, as prescribed. At least after 3 weeks after the 2 nd injection, pts were advised to perform a blood test for the specific antibodies against spike (S) protein of SARS-CoV-2. A semi-quantitative test detecting the SARS-CoV-2 S1 subunit (RBD) IgG antibodies by enzyme-linked immunoassay (ELISA) kit was used in the clinic. The results were considered positive with the cutoff index >1,1. The use of any other lab tests detecting antibodies to S protein of SARS-CoV-2 was acceptable as well. Results. In total, 66 pts with chronic phase of CML received a vaccination by Sputnik V in the 7 months period (from 18.12.2020 to 20.07.2021). Me age was 54 years (range 29 - 89 years), 34 (52%) were males. Median (Me) CML duration was 8 years (from the moment of diagnostics up to 20 years). Fifty one (77%) pt received TKI therapy and 15 (23%) were off-therapy at the time of vaccination, including 12 (18%) in a treatment-free remission and 3 (4,5%) pts in the process of diagnosis. Deep and major molecular response (MMR) was in 46 (70%) and 7 (11%) pts, respectively. Two (3%) pts had a molecular response MR2, 11 (17%) had no MR2. Eight (12%) pts had a history of COVID-19 manifestation prior to vaccination. Me time for testing for the antibodies was 27 days (range 5-77) after the 2 nd vaccine injection. The tests were done in 44 (67%) of pts and revealed positive by any of the test systems in 42 (95%) pts. ELISA test was used in 30 (45%) pts and was positive in 25 (83%) of 30 pts. Me cutoff index in the positive samples was 7,7 (range 1,1 - 12) and corresponded to the value observed in healthy people after vaccination (medical stuff, data not shown). In all 3 pts with the history COVID 19, the index of positivity was above the Me value (Fig. 1, 2). Other test systems were used in 14 (21%) pts, in all 14 (100%) the antibodies were found. In 3 of 5 patients with the cutoff index A weak reverse correlation of the antibody levels with the time after vaccination was noted ( r = - 0,39, p = 0,033). A very weak reverse correlation with age was observed ( r = - 0,28, p = 0,127) (Fig. 1, 2). No AEs after the vaccination were observed in 25 (38%) pts while 41 (62%) pts reported the AEs and 7 (10%) pts did not report their reactions. The AEs were as follows: local pain/discomfort in the injection site in 19 (29%) pts, weakness and/or drowsiness in 20 (30%), fever and/or chills in 16 (24%), other reactions in 8 (12%) including headache, heartbeat, lower back pain, pain in limbs, activation of herpes infection. Conclusion: The single center study revealed no unusual or unexpected AEs in CML pts after the vaccination against COVID-19 by Sputnik V vaccine. The proportion of CML pts with specific antibodies after was 95% which is close to the published results of the 3rd phase study. No significant correlation was found with age (r = -0,28, p = 0,127), however, the absence or very low antibody levels were detected in individual patients aged about 60-70 years. This data raise a question of a necessity for a non-specific protection (masks, respirators, distance etc) and probably considering additional vaccination in some elderly persons. The duration of a humoral response against COVID-19, protective antibody titer and connection with clinical outcomes in CML pts need further evaluation in parallel with a common population. Figure 1 Figure 1. Disclosures Chelysheva: Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Novartis Pharma: Speakers Bureau. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Gurianova: Pfizer: Speakers Bureau. Turkina: Pharmstandart: Speakers Bureau; Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

INTRODUCTION: Asciminib is the first BCR-ABL1 inhibitor that potently inhibits kinase activity of the BCR-ABL1 oncoprotein by Specifically Targeting the ABL Myristoyl Pocket (STAMP). The primary analysis from ASCEMBL, a randomized, phase 3 trial, demonstrated that asciminib has superior efficacy and a better safety and tolerability profile than bosutinib (BOS) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after ≥2 prior ATP-binding tyrosine kinase inhibitors (TKIs). The major molecular response (MMR) rate at wk 24 was 25.5% with asciminib vs 13.2% with BOS; the difference in MMR rates, after adjusting for major cytogenetic response status at baseline, was 12.2% (95% CI, 2.19-22.30; 2-sided P=.029). Grade ≥3 adverse events (AEs) were reported in 50.6% and 60.5% of pts receiving asciminib and BOS, respectively, and AEs leading to discontinuation in 5.8% and 21.1%, respectively. After a median follow-up of 19.2 months (or 7.5 months' additional follow-up since the primary analysis), we report updated efficacy and safety results from ASCEMBL. METHODS: Adults with CML-CP treated with ≥2 prior TKIs were randomized 2:1 to asciminib 40 mg twice daily (BID) or BOS 500 mg once daily (QD). Eligible pts must have experienced treatment failure (lack of efficacy) per 2013 European LeukemiaNet recommendations for second-line TKI therapy or intolerance of the most recent TKI at screening. Pts intolerant of their most recent TKI were eligible only if they had BCR-ABL1 on the International Scale >0.1% at screening. Pts with known BOS-resistant T315I or V299L mutations were ineligible. The cutoff date for the current analysis was January 6, 2021. RESULTS: A total of 233 pts were randomized to receive either asciminib (n=157) or BOS (n=76). At cutoff, all randomized pts had completed their wk 48 visit or had discontinued earlier. Treatment was ongoing in 89 (56.7%) and 17 (22.4%) pts on asciminib and BOS, respectively; the most common reason for treatment discontinuation was lack of efficacy in 37 (23.6%) and 27 (35.5%) pts, respectively (Table 1). By wk 48, the cumulative incidence of MMR was 33.2% with asciminib and 18.6% with BOS, showing that the difference between the 2 treatment arms observed by wk 24 in the primary analysis was maintained with longer follow-up (Figure 1). The cumulative incidence of BCR-ABL1IS ≤1% by wk 48 in patients without this level of response at baseline was 50.8% with asciminib and 33.7% with BOS. The difference in deep molecular responses (MRs) favoring asciminib vs BOS persisted by wk 48: MR 4 (BCR-ABL1IS ≤0.01%) and MR 4.5 (BCR-ABL1IS ≤0.0032%) rates were 14.0% and 9.6% with asciminib and 6.6% and 2.6% with BOS, respectively. With a longer duration of exposure in the asciminib arm, the safety and tolerability profile in the current analysis remains similar to that at the primary analysis. Median duration of exposure was 67.1 wk (range, 0.1-162.1 wk) for asciminib and 29.7 wk (range, 1.0-149.3 wk) for BOS. By the cutoff date, 91.0% of pts on asciminib and 97.4% of pts on BOS reported ≥1 all-grade AE; 54.5% and 67.1% of pts, respectively, reported ≥1 grade ≥3 AE. No additional fatal events were reported since the primary analysis. Fewer pts in the asciminib (7.1%) than BOS (25.0%) arm experienced AEs leading to treatment discontinuation (Table 2). The most common AEs leading to treatment discontinuation included thrombocytopenia (3.2%) and neutropenia (2.6%) in the asciminib arm and increased alanine aminotransferase (5.3%) and neutropenia (3.9%) in the BOS arm. CONCLUSIONS: Resistant/intolerant CML-CP after 2 lines of TKI treatment remains BCR-ABL1 dependent. The novel STAMP inhibitor asciminib demonstrates continued superior efficacy and a limited adverse event profile; myelosuppression, while more prominent, appears to be early and disease related. Secondary resistance based on loss of MMR is rare. Overall, after a median follow-up of 19.2 months, the positive benefit-risk profile of asciminib vs BOS continues to support the use of asciminib as a new therapy in this heavily pretreated pt population. This study is sponsored by Novartis. Figure 1 Figure 1. Disclosures Mauro: Sun Pharma / SPARC: Research Funding; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy. Minami: Takeda: Honoraria; CMIC: Research Funding; Astellas: Honoraria; Ono: Research Funding; Pfizer Japan Inc.: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria. Rea: Novartis: Consultancy, 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Voloshin: Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Pfizer: Consultancy; Biacad: Consultancy, Speakers Bureau. Turkina: Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Kim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Apperley: Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau; Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau. Cortes: Sun Pharma: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Fogliatto: AstraZeneca: Speakers Bureau. Kim: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Paladin: Honoraria, Research Funding; Bristol-Meier Squibb: Research Funding. le Coutre: Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Bristol Myers Squibb: Honoraria. Saussele: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Pfizer: Honoraria; Roche: Honoraria. Hughes: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte: Honoraria. Chaudhri: Abbvie: Honoraria; Novartis: Honoraria; Astra Zeneca: Honoraria. Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Garcia Gutierrez: Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Kapoor: Novartis: Current Employment, Current equity holder in publicly-traded company. Allepuz: Novartis: Current Employment, Current equity holder in publicly-traded company. Quenet: Novartis: Current Employment. Bédoucha: Novartis: Current Employment. Boquimpani: Pinth Pharma: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jansen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction Despite the availability of vaccination against COVID 19 for all population categories since January 2021, it is moving slowly in Russia. Patients (pts) with chronic myeloid leukemia (CML) usually lead a normal life with social interactions. In the context of the COVID 19 pandemic, we find it important to identify the factors of adherence to vaccination and clarify the concerns. Objective: To determine the proportion of CML pts willing to consider vaccination against COVID 19, adherence factors and reasons for not vaccinating. Materials and methods. A survey on the attitude to vaccination against COVID 19 was prospectively carried out among all pts with CML consulted at the outpatient department of National Research Center for Hematology (Moscow, Russia) who agreed to participate. The key questions included considerations for and against vaccination, socio-demographic and clinical characteristics, lifestyle, comorbidities and history of COVID 19. Results. Within 4 months (from March 15 to July 19, 2021), 172 CML pts completed the questionnaire. CML chronic phase, advanced phase and blast crisis were in 167 (97%), 4 (2%) and 1(1%) respectively. In total, 141 (82%) pts were on therapy with 1 st, 2 nd and >3 rd therapy line in 77 (55%), 33 (23%) and 31 (22%) pts, respectively. Thirty one (18%) had no therapy: 6 (3.5%) newly diagnozed, 25 (14.5%) in a treatment-free remission. A deep and major molecular response was in 77 (45%) and 30 (17%) pts, respectively. Presence and absence of molecular response MR2 was in 20 (12%) and 45 (26%) pts respectively. The median age of pts was 46 years (range 19-82), 75(44%) were males. Married 108 (63%), 70 (41%) lived with elderly relatives, 35 (20%) with children. A higher education was in 123 (72%) pts, 123 (72%) could not work remotely and 46 (27%) had interactions to people by work. Any comorbidity was in 89 (52%) pts, 42(24%) had >1 concomitant disease, 48 (28%) had cardiovascular diseases, 44 (26%) had an obesity. A history of COVID 19 was in 41 (24%) pts and in the close circle of 74 (43%) pts. Vaccination was supported by 94(55%) pts (with 29 (17%) already vaccinated) and not supported by 76 (44%) pts, 2 (1%) pts did not answer. Among those supporting vaccination vs not supporting there was significantly more males (52% vs 33%, p=0,012), married pts (73% vs 49%, p The two most common reasons to avoid vaccination were the fear of complications in 37(49%) pts and waiting for additional data in 19(25%) (Fig.1). Notably, 7 (9%) pts considered CML as a contraindication to vaccination. Among those supporting vaccination, 55(59%) preferred to choose the GamCovidVac (Sputnik V) vaccine, 20(21%) had no preference (Fig.2). Out of 32 pts who gave the rationale for the Sputnik V choice 19(59%) noted its best availability, study or popularity (Fig.3). Among 23 pts with additional questions 12 (52%) wondered about the possibility of vaccination with CML diagnosis and 6 (26%) asked help with a vaccine choice. Conclusion: Despite access to vaccines against COVID 19 with proven efficacy and safety, almost half of CML pts (44%) do not support vaccination. Socio-demographic factors such as gender, education, marriage status appeared to be significant for this decision. Considering the frequent concerns of the possibility of vaccination with CML diagnosis as well as the fear of complications, hematologists should provide a relevant clarifying information on these issues. Figure 1 Figure 1. Disclosures Chelysheva: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Gurianova: Pfizer: Speakers Bureau. Kokhno: Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Turkina: Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

Background: The problem of resistance and intolerance to 2nd generation tyrosine kinase inhibitors (2G TKIs) in patients (pts) with chronic myeloid leukemia (CML) currently remains relevant. Ponatinib has demonstrated a high effectiveness and may be an option in CML pts with resistance or intolerance to available TKIs but the high incidence of vascular adverse events (AEs) limits its broad use. A STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor asciminib has demonstrated a superiority over bosutinib in CML pts previously treated with 2 or more TKIs (Phase III Study). Asciminib is available in Russia under the Managed Access Program (MAP) approved by Novartis. Aim: to present the first results of the use of asciminib in clinical practice under the MAP program in Russia. Methods: In total 46 CML pts from 3 Russian clinics were enrolled into the MAP program and received asciminib from September 2019 to June 2021 (1 pt started asciminib in a cinical trial and was transferred to MAP later). We analyzed therapy results of 32 pts who received asciminib for at least 3 months. Patient recruitment, dosing regimen, response monitoring, and toxicity control were performed according to the MAP treatment plan. Complete cytogenetic response (CCyR), major molecular response (MMR) and deep molecular response (MR4) rates were assessed by cumulative incident function (CIF). Differences between the subgroups were considered significant with p value ≤ 0.05 by the Gray's test. Results: Baseline characteristics: male: 41%; Меdian (Me) age 54 years (range 26-81); Me duration of CML before asciminib was 8 years (range 2-24); 23 pts were in chronic phase (CP) CML, 7 and 2 pts had a history of accelerated phase (AP) and blast crisis (BC), respectively, but were in a second CP at baseline. Nineteen (59%) pts had BCR-ABL mutations, 10 pts (31%) had BCR-ABLt315i clones, 7 (22%) pts had at least two mutations. Eight (25%) pts had additional chromosomal abnormalities (ACAs). Twenty one (66%) pts received ≥4 TKIs, 14 (44%) pts had a history of ponatinib treatment. Me duration of asciminib treatment at the time of analysis was 7 months (range 4-24), 4 (12.5%) pts discontinued asciminib due to lack of efficacy; all pts were alive. The initial asciminib dose was 40 BID in 22 (69%) pts and 200 mg BID in 10 (31%) pts. CCyR, MMR and MR4 at the time of analysis was achieved in 32% (8/25), 34% (10/29) and 17% (5/30) pts, respectively (considering pts without this kind of response at baseline). The 6 month CIF of CCyR, MMR and MR4 was 27%, 24% and 19%, respectively. Univariate analysis was performed in 29 pts without MMR at baseline evaluating the following factors of 6 month MMR achievement: initial dose of asciminib, CML phase, presence of BCR-ABL mutations and ACAs, best molecular response on previous TKIs, molecular response at the time of asciminib starting, history of ponatinib treatment, number of TKIs and duration of TKI therapy before asciminib. The duration and number of TKIs, the history of advanced phases, BCR-ABL kinase domain mutations and ACAs did not significantly effect on MMR rate (tab.1). BCR-ABL Fourteen (44%) of 32 pts had AEs of any grade and 7 (22%) had AEs of grade 3-4 (hematological AEs -6 (19%), non-hematological AE- 1 (3%)) (tab.2). Conclusion: Asciminib has shown promising efficacy and a good toxicity profile in a cohort of highly pre-treated CML pts and should be considered as a therapeutic option for CML pts resistant or intolerant to other TKIs. Figure 1 Figure 1. Disclosures Turkina: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Chelysheva: Novartis Pharma: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Gurianova: Pfizer: Speakers Bureau.

Background: Not everyone with CML responds optimally to TKI-therapy, especially those with BCR::ABL1T315I. PF-114 is a 4 th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCR::ABL1 isoforms including BCR::ABL1T315I. We present final results of a phase-1 study (NCT02885766). Methods: 3+3 dose-escalation study to determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included safety and efficacy based on haematological, cytogenetic and molecular response criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03. Results: 51 subjects (5 with accelerated phase CML, 46 - with chronic CML), 23 males, were studied. Daily doses were 50-600 mg/d given once daily continuously. Median age was 50 y (range, 29-82 y). Median CML duration pre-study was 10 y (range, 0.3-23 y). 16 subjects had BCR::ABL1T315I. 25 subjects received ≥ 3 prior TKIs. Median follow-up was ≥ 31 mo and median exposure, 6 mo (range, 0.4-52). Therapy was ongoing in 7 subjects at study termination. Others discontinued because of progression (n = 20), AEs (n = 2), consent withdrawal (n = 5), entry into another study (n = 3) or other reasons (n = 14). The MTD was 600 mg with the grade-3 psoriasis-like skin AE as the DLT. There were no vascular occlusive events or deviations of ankle-brachial index. Complete haematologic response (CHR) was achieved in 14 of 30 subjects, major cytogenetic response (MCyR) in 15 of 44 subjects, complete cytogenetic response (CCyR) in 11 of 50 subjects and major molecular response (MMR) in 8 of 51 subjects. Median duration of CHR was 12 mo and has not been reached for MCyR, CCyR and MMR. The best safety/efficacy dose was 300 mg/d with 6 of 9 subjects achieving a MCyR, 5, a CCyR and 4, MMR. 5 of 16 subjects with BCR::ABL1T315I responded, including 4 achieving a MCyR, 2, a CCyR and 1, a MMR. 2 of 6 subjects failing ponatinib achieved a CHR. Conclusion: PF-114 was safe and effective in subjects failing ≥ 2 TKIs and those with BCR::ABL1T315I including those failing ponatinib. The PF-114 dose for further study is 300 mg/d. Disclosures Turkina: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau. Vinogradova: Bristol Myers Squibb: Speakers Bureau; Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Chelysheva: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pharmstandart: Speakers Bureau. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Cortes: Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Baccarani: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ottmann: Fusion: Honoraria; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria. Mikhailov: Fusion Pharma: Current Employment. Novikov: Fusion Pharma: Current Employment. Shulgina: Fusion Pharma: Current Employment. Chilov: Fusion Pharma: Current Employment.

To assess the results of following up patients with chronic myeloid leukemia (CML) and a deep molecular response (MR) without tyrosine kinase inhibitor (TKI) therapy.The reasons for TKI discontinuation in 70 patients with CML and a deep MR of more than 1 year's duration were adverse events, pregnancy, and patients' decision. Information was collected retrospectively and prospectively in 2008-2016.The median follow-up after TKI therapy discontinuation was 23 months (2 to 100 months). At 6, 12 and 24 months after TKI therapy discontinuation, the cumulative incidence of major MR (MMR) loss was 28, 41 and 48%, respectively; the survival rates without TKI therapy were 69, 50, and 39%, respectively. MMR loss was noted in 28 (88%) patients at 12 months; it was not seen without TKI therapy at 2-year follow-up. Deaths due to CML progression were absent. The Sokal risk group was a reliable factor influencing MMR loss (p ≤ 0.05). The cumulative recovery rate for deep MR after resumption of TKI use was 73 and 100% at 12 and 24 months, respectively, with a median follow-up of 24 months (1 to 116 months). Deep MR recovered at a later time when the therapy was resumed more than 30 days after MMR loss.Safe follow-up is possible in about 50% of the patients with CML and stable deep MRs without TKI therapy. The introduction of this approach into clinical practice requires regular molecular genetic monitoring and organizational activities. Biological factors in maintaining remission after TKI discontinuation need to be separately studied.Цель исследования. Оценка результатов наблюдения больных хроническим миелолейкозом (ХМЛ) с глубоким молекулярным ответом (МО) без терапии ингибиторами тирозинкиназ (ИТК). Материалы и методы. Причинами отмены ИТК у 70 больных ХМЛ с длительностью глубокого МО более 1 года служили нежелательные явления, беременность, собственное решение больных. Сбор информации осуществлялся ретроспективно и проспективно в 2008-2016 гг. Результаты. Медиана времени наблюдения после отмены терапии ИТК составила 23 мес (от 2 до 100 мес). Кумулятивная частота потери большого молекулярного ответа (БМО) после прекращения терапии ИТК через 6, 12 и 24 мес составила 28, 41 и 48% соответственно, выживаемость без терапии ИТК - 69, 50 и 39% соответственно. У 28 (88%) пациентов потеря БМО отмечена в течение 12 мес; после 2 лет наблюдения без терапии ИТК потери БМО не отмечалось. Летальные исходы от прогрессии ХМЛ отсутствовали. Группа риска по Sokal являлась достоверным фактором, влияющим на потерю БМО (p≤0,05). Кумулятивная частота восстановления глубокого МО после возобновления приема ИТК составляла 73 и 100% через 12 и 24 мес соответственно при медиане наблюдения 24 мес (от 1 до 116 мес). Восстановление глубокого МО наблюдалось позднее при возобновлении терапии более, чем через 30 дней после потери БМО. Заключение. Примерно у 50% больных ХМЛ со стабильным глубоким МО возможно безопасное наблюдение без терапии ИТК. Для внедрения этого подхода в клиническую практику необходимы обеспечение регулярного молекулярно-генетического контроля и организационные меры. Биологические факторы сохранения ремиссии после отмены ИТК нуждаются в отдельном изучении.

Summary The Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose-optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re-escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2–75·1%) achieved major molecular response (BCR-ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re-escalation). The safety profile of nilotinib was consistent with prior studies. The most common non-haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188).

Background. Much attention has been paid to molecule-genetic diagnostics of chronic myeloid leukemia (CML) and its treatment using new highly effective methods of therapy. The baseline characteristics of patients at primary CML diagnosis are hardly discussed in literature. Aim. To provide clinical, hematological, molecular genetic and demographic characteristics of patients obtained at primary diagnosis of CML. Patients & Methods. Characteristics of CML patients are based on data gathered by the Russian Investigational Group for CML within the international project European Treatment and Outcome Study of CML in Europe (EUTOS, the European Treatment and Outcomes Study). The study included 197 patients with newly diagnosed CML in 6 regions of the Russian Federation (Mordovia, Kirov, Perm (2 sites), Bryansk, Irkutsk, and Chita) over the period from 2009 till 2012. Results. The study demonstrated that 94 % of CML cases were diagnosed in the chronic phase (CP) and 6 % of cases in the acceleration phase (AP) and the blast crisis phase (BC). In 40 % of patients there were no clinical symptoms, and CML was suspected only due to changes in the CBC test. Fatigue was the main subjective complaint presented by 77 % of patients in the CP and 100 % of patients with the AP and BC. Peripheral blood leukocytosis, left shift to immature myeloid cells and increased granulocytic lineage in bone marrow were typical for the patients. In all patients, the CML diagnosis was confirmed by cytogenetic or molecular tests. The social and demographic characteristics of CML patients and comorbidities at diagnosis were analyzed. Conclusion. Based on the results of the study, a modern «portrait of a CML patient» was obtained. The study demonstrated that cytogenetic and molecular methods allow to diagnose CML in most patients at early stages of the disease in the absence of clinical signs of progression. The data on comorbidities require a special attention while choosing a therapy considering its duration. Demographic and social characteristics of CML patients demonstrate that they are socially active, particularly interested in retaining the working capacity and quality of life.

Background: The ENESTop study (NCT01698905) evaluates treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with sustained deep molecular response following second-line (2L) treatment with nilotinib (NIL). In the primary analysis, 57.9% of pts remained in TFR 48 weeks after stopping NIL and previous analysis at ≥3.7 years showed durability of TFR. The present analysis first assessed long-term TFR outcomes at ≥5 years and then a post-hoc analysis evaluated rates of regain of molecular response following NIL re-initiation in pts with loss of major molecular response (MMR) or confirmed loss of MR4.0 at a follow-up of 5 years. Methods: Eligible pts had received ≥3 years of treatment (including >4 weeks of imatinib followed by ≥2 years of NIL) and had achieved MR4.5 (BCR-ABL1IS ≤0.0032%) on NIL. Pts without confirmed loss of MR4.5 after 1 year of consolidation treatment (CONS) could attempt TFR. NIL was re-initiated upon loss of MMR (BCR-ABL1IS >0.1%) or confirmed loss of MR4.0 (BCR-ABL1IS >0.01% in 2 consecutive assessments). By data cut-off (29 Jan 2020) pts had completed ≥5 years of TFR, resumed NIL, or discontinued the study. Results: At the data cut-off, of the 126 pts who entered TFR, 52 remained in TFR, 59 had resumed NIL and 15 had discontinued the study. At 5 years, the TFR rate was 42.9% (54/126; 95% CI, 34.1-52.0). Compared with pts in TFR at the end of the 3.7-year follow-up, an additional 4 pts were not in TFR at the 5-year follow-up, none due to loss of response: 2 pts discontinued TFR due to pt/guardian decision, 1 pt had an ischemic stroke and died in the post-treatment follow-up phase, and 1 pt was lost to follow-up. The MR4.5 rate at 5 years after starting TFR was 37.3% (47/126, 95% CI: 28.9-46.4). 11 pts with MR4.5 at 5 years had a temporary loss of MR4.5 while 36/126 (28.6%) maintained stable MR4.5 for 5 years. The estimated treatment-free survival (TFS) rate at 5 years was 49.4% (95% CI: 40.3-57.9). Of the 59 pts who resumed NIL, 58 (98.3%) regained MMR. The only pt who did not regain MMR stopped retreatment at 20 weeks and withdrew from the study. 56 (94.9%) pts regained MR4.0 and 55 (93.2%) regained MR4.5 (Figure). The median time to regain MR4.5 was 2.9 months (range: 0.9-22.5). Baseline characteristics between pts who resumed NIL due to loss of MMR (n=34) or confirmed loss of MR4.0 (n=25)were similar; more pts with loss of MMR had a low Sokal relative risk score at diagnosis (44.1% vs 16.0%) and pts with loss of MMR had a shorter median time from achievement of MR4.5 until TFR entry (27.9 vs 40.1 months). In pts with confirmed loss of MR4.0, 25/25 (100.0%) and 24/25 (96.0%) regained MR4.0 and MR4.5 within the first 48 weeks of NIL re-initiation, respectively. In pts with loss of MMR, 33/34 (97.1%), 31/34 (91.2%) and 30/34 (88.2%) regained MMR, MR4.0 and MR4.5 within the first 48 weeks of NIL re-initiation, respectively. The median time to regain MR4.5 for pts who resumed NIL due to confirmed loss of MR4.0 or loss of MMR was 2.0 months (range: 0.9-4.6) and 3.6 months (range: 1.6-22.5), respectively. There were no cases of disease progression or death due to underlying CML. For pts remaining in TFR >3.7 years (n=58), the rates of all-grade adverse events (AEs) were 50.0% in the fifth 48 weeks of TFR compared with 55.2% in the fourth 48 weeks. The musculoskeletal pain AE rate was high during the first 48 weeks of TFR (53.4%) but by the fifth 48 weeks of TFR was lower (6.9%) than during CONS (10.3%). In pts who resumed NIL (n=59), the rate of all-grade AEs was higher (94.9%) than during CONS (77.9%, n=163). Overall all-grade AE rates were similar between pts re-initiating NIL due to loss of MMR (94.1%) or confirmed loss of MR4.0 (96.0%), with the most common AEs being hypertension (26.5% vs 32.0%), arthralgia (20.6% vs 8.0%), constipation (11.8% vs 20.0%) and hyperglycemia (26.5% vs 0%). Conclusions: These results illustrate the long-term (up to 5 years) durability and safety of TFR in pts with CML-CP following 2L NIL. The majority of pts requiring NIL re-treatment rapidly regained MMR, MR4.0 or MR4.5. The faster rate of regain in pts resuming NIL due to confirmed loss of MR4.0 likely reflects earlier intervention but could also suggest a slower tempo of relapse and possibly more favorable biology. Subgroup analysis should be interpreted with caution due to small base sizes. No new or unexpected safety signals were observed. Disclosures Mahon: ARIAD: Honoraria; Novartis Pharma: Honoraria, Research Funding; Pfizer: Honoraria; BMS: Honoraria. Clementino:EMS: Other: Financial support for congress. Fominykh:Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Lipton:Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Moiraghi:Novartis: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Sun Pharma Ltd: Consultancy; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Takahashi:Pfizer Japan Inc.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria, Research Funding; Bristol-Myers Squibb Company: Honoraria. Sacha:Incyte: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Kim:Sun Pharma.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Fellague-Chebra:Novartis: Current Employment, Current equity holder in publicly-traded company, Research Funding. Tiwari:Novartis: Current Employment. Bouard:Novartis: Current Employment. Hughes:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background The criteria of molecular relapse in different treatment-free remission (TFR) trials in patients (pts) with chronic myeloid leukemia (CML) varied. In the early trials molecular relapse was defined as loss of deep molecular response (DMR) including MR4 loss. In recent ELN guideline (Hochhaus et al, 2020) major molecular response (MMR) loss was a criterion of molecular relapse. We consider it reasonable to evaluate the role of MR4 loss in connection with MMR loss and time of treatment-free observation and to describe the pattern of minimal residual disease (MRD) in this context. Aim To evaluate the role of MR4 loss on further MMR loss in CML pts during early and late period after TKI cessation and to describe the pattern of MRD during TFR. Patients and methods In total 98 CML pts with chronic phase who had received therapy by any TKI ≥3 years (yrs) with sustained DMR (at least MR4 or BCR-ABL ≤0.01% by international scale (IS)) during ≥2 yrs) were enrolled into the prospective TFR study RU-SKI. The BCR-ABL level (IS) was evaluated by RQ-PCR monthly during the first 6 months (mo) after TKI cessation, every 2 mo from 6 to 12 mo and every 3 mo thereafter. MR4 loss was considered if BCR-ABL was >0,01% and 0,1%). Molecular relapse free survival (MRFS) was evaluated by Kaplan-Meier method, log-rank test was used for comparison. Results Меdian (Me) time after TKI discontinuation was 40 mo (range 28-57). MMR loss and MR4 loss was observed in 48(49%) and 38(39%) pts respectively. In 42(87%) pts MMR loss was observed within first 6 mo after treatment cessation. MRFS at 36 mo was 51% (95% CI 41 - 61%). No MMR loss occurred in 10(26%) pts with MR4 loss while 28(74%) pts with MR4 loss subsequently lost MMR. The MRFS after the first documented MR4 loss was 29% (95% CI 15 - 44%) and 24% (95% CI 10,5 - 38%) at 12 and 24 mo respectively. MRFS at 24 mo was significantly higher in pts with late MR4 loss (>3 mo) than in pts with early MR4 loss ( The pattern of MRD in 50 pts who continued a treatment-free observation after TKI cessation was represented by 3 main variants: 1) stable undetected MRD in 17(34%) pts; 2) transient short-term or long-term fluctuations without MR4 loss in 23(46%) pts; 3) fluctuations with transient MR4 loss but without MMR loss in 10(20%) pts (figure 2). Interestingly, 8 of 10 pts with MR4 fluctuations subsequently achieved MRD-negative status. Conclusion We confirmed that MR4 loss after TKI cessation in most cases (74%) preceded the molecular relapse which was considered as MMR loss. However, the MRFS was significantly higher in pts with late MR4 loss than in those with early MR4 loss during the first 3 mo of TKI cessation and comparable with MRFS in the whole pts cohort. We found that only 34% pts who maintained a molecular remission had stable undetected MRD while 66% of pts had fluctuations of MRD during TFR. About a quarter of pts (26%) with MR4 loss could remain in TFR and achieve the MRD-negative status. We support the importance of regular MRD monitoring both in early and late terms during TFR observation to benefit for the safety of the pts. Disclosures Chelysheva: Novartis: Other: performed lectures; Fusion Pharma: Consultancy. Shukhov:Novartis: Consultancy, Other: performed lectures; Pfizer: Consultancy, Other: performed lectures. Ionova:BMS: Other: principal investigator of the observational studies sponsored by BMS; Takeda: Other: principal investigator of the observational studies sponsored by Takeda. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria.

Background Frequency of BCR-ABL1 translocation and JAK2V617F or CALRtype-1,2 mutation co-occurrence in chronic myeloid leukemia (CML) patients varies in different populations. According to Soderquist et al., it amounts to 0.4% of cases in USA; Martin-Cabrera et al. – 0.2% in Germany; Lewandowski et al. – 0.7% in Poland. Combination of BCR-ABL1 translocation with CALRtype-1,2 mutations in CML patients during tyrosine kinase inhibitor (TKI) therapy has not been reported yet. Prognostic value of the BCR-ABL1 transcript level kinetics and of JAK2V617F or CALRtype-1,2 mutations allele burden (AB) in Russian CML patients undergoing TKI therapy has not been assessed so far. Aims To evaluate frequency of coexistence and kinetics of the BCR-ABL1 transcript level and AB of JAK2V617Fand CALRtype-1,2 mutations in CML patients undergoing TKI therapy. Materials and Methods mRNA and DNA samples isolated from blood and bone marrow cells of 683 CML patients, who underwent periodic monitoring of the BCR-ABL1 transcript level over the 2012–2020 period were included in the study. The BCR-ABL1 transcript level and AB of JAK2V617F mutation were determined using a highly sensitive (Log-5) quantitative real-time polymerase chain reaction. CALRtype-1,2 mutations were investigated using fragment analysis followed by Sanger sequencing. Results The combination of the BCR-ABL1, JAK2V617F, and CALRtype-1,2 mutations among CML patients receiving TKIs occurred in 8 of 683 cases (1.17%). Out of these, the combination of BCR-ABL1 with JAK2V617F, and the combination of BCR-ABL1 with CALRtype-1,2 mutations were detected in 0.88% (6/683) and 0.29% (2/683) of cases, respectively. During TKI therapy, in 6 out of 8 cases, the level of BCR-ABL1 reached major molecular response (MR). In 4 of these cases, the therapy was discontinued. These patients are currently in molecular remission. In the remaining 2 patients, major MR was not achieved, despite the use of second generation TKIs. Conclusions The combination of the BCR-ABL1 translocation with JAK2V617F or CALRtype-1,2 mutations is a rare event in our cohort of patients and occurred in 0.88 and 0.29% of cases, respectively. The combination of the BCR-ABL1, JAK2V617F, and CALRtype-1,2 mutations may not interfere with the achievement of major MR under TKI treatment.

Context Chronic myeloid leukemia (CML) patients (pts) receive a long-term treatment with tyrosine kinase inhibitors (TKI) in standard doses. A new approach with reduced dose TKI use is desirable for the CML pts with adverse effects (AE) or with a high risk of AE, particularly in pts with major molecular response (MMR) and deep molecular response (DMR) receiving second generation TKI (2GTKI). Objective To evaluate the stability of MMR in CML pts after dose reduction of 2GTKI. Patients We included 36 pts taking 2GTKI, all in chronic phase, in retrospective analyses. Median (Me) age was 47 years (range 22-71). Me therapy duration was 42.5 months (mo). MMR was in 7 (19%) pts, DMR in 29 (81%) pts. Me duration of MMR was 21.5 mo at the time of dose reduction. The AEs were in 21 (58%) pts before the dose reduction. Interventions The dose reduction of nilotinib and dasatinib was done in 28 (78%) and 8 (22%) pts. Initial dose of nilotinib was 800, 600 and 400 mg in 18 (64%), 8 (28%) and 2 (7%) pts. The dose of nilotinib was reduced to 600, 400, 300, and 200 mg in 1 (4%), 21 (75%), 2 (7%) and 4 (14%) pts. The initial dose of dasatinib was 140 mg in 1 (12.5%) and 100 mg in 7 (87.5%) pts, and the reduced dose was 70 and 50 mg in 2 (25%) and 6 (75%) pts. Results Me follow-up after 2GTKI dose reduction was 13 mo. The MMR loss occurred in 3 pts with MMR duration 3, 6 and 8 mo at the time of dose reduction. Survival without MMR loss at 12 mo was 96% (CI 89% -100%) and 64% (CI 23-100%) in the DMR and MMR cohort. MMR was regained in all pts after the standard dose therapy was recommenced. The toxicity after dose reduction was resolved in 19 (90%) of 21 pts with the previously observed AE. Conclusions This option allows reduction of the drug toxicities and prevents the potential AE of TKI therapy. In January 2020 in Russia, the prospective clinical trial was started in order to evaluate a relapse-free survival after discontinuation of therapy with the previous 12-months two-stage phase of TKI dose reduction.

We aimed to characterize withdrawal syndrome (WS) and evaluate factors associated with its development in the prospective clinical study RU-SKI in patients with chronic myeloid leukemia with deep molecular response who discontinued tyrosine kinase inhibitor (TKI) therapy. In total, 98 adult patients with chronic myeloid leukemia chronic phase, TKI therapy ≥ 3 years, and deep molecular response (BCR-ABL ≤ 0.01%) ≥ 2 years were enrolled and observed without treatment. WS was defined as newly observed or worsening musculoskeletal pain after TKI cessation. WS symptoms were found in 41 (42%) of 98 patients with a median time of observation of 25 months (range, 12-42 months). WS grades 1 to 2 and grade 3 were observed in 39 (95%) and in 2 (5%) patients, respectively. The median duration of WS was 5 months (range, 1-25 months). WS was resolved in 37 (90%) patients. Anti-inflammatory therapy was used in 21 (51%) patients. Older age (P = .039) and longer TKI therapy (P = .001) were associated with WS. The 2-month landmark analysis found no association of WS development and the rate of molecular relapses. In total, 42% of the patients experienced WS after TKI therapy discontinuation in the RU-SKI study. Physicians should be warned about the possibility of WS development, and patients of older age and with longer TKI treatment need special attention.

We analyzed changes in multipotent mesenchymal stromal cells of patients with chronic myeloid leukemia before discontinuation of tyrosine kinase inhibitors. Withdrawal syndrome was significantly more common in patients who have been taking tyrosine kinase inhibitors for a longer time and in patients of older age and with lower body weight. In patients with withdrawal syndrome, the total production of mesenchymal stromal cells and expression of FGFR2 and MMP2 genes were significantly lower; loss of deep molecular response was also less frequent in this group of patients. At the same time, the expression of genes important for the maintenance of stem cells (SOX9, PDGFRa, and LIF) was significantly lower in the mesenchymal stromal cells of patients with withdrawal syndrome and loss of deep molecular response. We observed a clear-cut relationship between the development of withdrawal syndrome and the loss of deep molecular response. The decrease in the expression of FGFR2 and MMP2 genes in the mesenchymal stromal cells of patients with chronic myeloid leukemia before discontinuation of treatment can be a predictor of withdrawal syndrome, while simultaneous decrease in the expression of SOX9, PDGFRa, and LIF in these cells attests to undesirability of therapy discontinuation at the moment.