ALBERT

Description: Background: PF-114 is a 4th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCR-ABL1 isoforms including BCR-ABL1T315I. We present data from a phase-1 study in patients with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or with BCR-ABL1T315I (NCT02885766) with ≥6 months therapy. 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 criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03. Results: 51 patients were enrolled. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given continuously. Median age was 50 years (range, 29-82 years). Median CML duration pre-study was 10 years (range, 0.3-23 years). All patients had baseline ECOG performance scores 0-1. Twelve patients had BCR-ABL1T315I. Patients were heavily pre-treated: 25 received ≥3 prior TKIs; 5 patients with BCR-ABL1T315I received 1 prior TKI. Interim analysis was conducted at follow-up of ≥6 months (cut-off date January 16th 2019). Therapy was ongoing in 17 patients at doses 200 mg (n=4), 300 mg (n=9), 400 mg (n=3) and 600 mg (n=1) with median duration of exposure of 7,4 (range, 4,6-26), 9,2 (range, 7,4-26), 9,2 (range, 8,3-9,2) and 9,2 months. Other patients discontinued because of progression (n=18), adverse events (n=6), consent withdrawal (n=4), participation in another study (n=3) or other reasons (n=3). The MTD was 600 mg with the grade-3 psoriasis-like skin lesions the DLT, which occurred during the first 28 days of treatment. Reversible grade-3 skin toxicity occurred in 11 patients at doses ≥400 mg. There were no other drug-related non-hematologic grade-3 toxicities except 1 grade-3 toxic hepatitis at 400 mg and there were no detectable effects on ankle-brachial index or vascular occlusive events. The best safety/efficacy dose was 300 mg/d with 6 of 11 patients achieving a major cytogenetic response (MCyR) and 4 of them - a major molecular response (MMR). Higher doses were less effective probably because of toxicity-related therapy interruptions and discontinuations. Five of 12 patients with BCR-ABL1T315I responded, 3 of which achieved a complete hematologic response and 4 achieved MCyR. Conclusion: PF-114 was safe and effective in patients with CML failing ≥2 TKIs or with BCR-ABL1T315I. The most effective dose was 300 mg/d. Five of 12 patients with BCR-ABL1T315I responded. A pivotal study is beginning. Disclosures Turkina: Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau. Vinogradova:Novartis: Consultancy; Fusion Pharma: Consultancy. Lomaia:Novartis: Other: Travel Grant;Lecture fee; Pfizer: Other: Travel Grant. Shukhov:Pfizer: Consultancy; Novartis: Consultancy. Chelysheva:Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shikhbabaeva:Novartis: Consultancy; Fusion Pharma: Consultancy. Shuvaev:Fusion Pharma: Consultancy; Novartis: Consultancy; Pfize: Honoraria; BMS: Consultancy. Cortes:Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Ottmann:Roche: Honoraria; Pfizer: Honoraria; Fusion Pharma: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Mikhailov:Fusion Pharma: Employment. Novikov:Fusion Pharma: Employment. Shulgina:Fusion Pharma: Employment. Chilov:Fusion Pharma: Consultancy.

Description: Background The experience of usage of second line tyrosine kinase inhibitors (TKI2) in chronic myeloid leukemia (CML) patients in routine clinical practice in Russian Federation is still limited. Therefore the information about long-term therapy results and adverse events (AEs) is very important. Aim To provide information about the results of TKI2 nilotinib treatment in patients with chronic phase (CP) CML. To evaluate the long-term hematological and non-hematological AEs. Materialsandmethods Follow-up data of 37 CML CP patients treated by nilotinib 2nd line after imatinib failure due to resistance (28 [76%]) or intolerance (9 [24%]) were obtained and analyzed. The patients formerly participated in clinical trial ENACT after which continued treatment in routine clinical practice. A median CML observation prior to the nilotinib treatment was 66 months (range 7.9 to 148.1). Hematological, cytogenetic and molecular responses and AEs were evaluated with a median follow-up of 40 months (range 1.2 to 76.7). Results At the moment of evaluation 15 (41%) of 37 patients continue nilotinib treatment, 12 of 15 have been treated by nilotinib for more than 5 years. Nilotinib dose is 800 mg daily for all but one patient with 400 mg dose daily reduced due to constitutional hyperbilirubinemia. Nilotinib was discontinued in 22 (59%) of 37 patients: in 4 of 22 due to cytogenetic resistance, in 9 of 22 due to hematologic relapse, in 7 of 22 due to AEs. Two of 22 patients with concomitant atherosclerosis and diabetes diagnosed before nilotinib treatment died because of cardiovascular events. Efficacy Complete hematological remission (CHR), major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were obtained in 34 (92%), 26 (70%) and 18 (48%) consequently. Major molecular response (MMR) and complete molecular response (CMR) was achieved in 16 (43%) and 9 (24%) consequently. Currently 10 (27%) patients have stable CCyR, 5 of those 10 have stable CMR lasting more than 5 years in 2 of these 5. Disease progression No cases of progression to accelerated phase (AP) and blast crisis (BC) before treatment discontinuation were observed. Hematologic relapses were within CP. Deaths due to CML progression were not observed on nilotinib treatment. Hematological AEs Grade 3-4 thrombocytopenia was observed in 8 (22%) patients, grade 3-4 neutropenia was observed in 5 (14%) and grade 3 anemia was observed in 1 (3%) patient. Non-hematological AEs The most common AE was rash (12 [32%] patients), in some cases with pruritus and xerodermia. The hemorrhagic syndrome was observed in 4 (11%) patients, associated with grade 3-4 thrombocytopenia only in 2 patients. The other 2 patients had uterine bleeding with questionable connection to therapy. Neither QT prolongation nor other abnormalities were revealed by ECG. As to laboratory findings: hyperbilirubinemia occurred in 33 (89%) patients, mostly due to indirect fraction, 5 of those 33 had hyperbilirubinemia grade 3. ÀL” and AST elevation (all grades) was observed in 26 (70%) and in 20 (54%) patients respectively, grade 3-4 was observed in 3 (8%) patients. Grade 1 hyperglycemia occurred in 7 (19%) patients, grade 3 hyperglycemia was observed in 1 (3%) patient with concomitant type 2 diabetes. All AEs were manageable according to general rules. No life-threatening AEs were diagnosed. Summary The results of long-term nilotinib 2nd line therapy are satisfactory for patients who achieved stable CCyR. Low level of high grade toxicity AEs was observed on nilotinib treatment, no new kinds of AEs appeared during long-term treatment. Disclosures: Bykova: Federal State Budgetary Institution Hematology Research Center of Health Ministry of Russia, Moscow, Russian Federation : Employment. Gusarova:Novartis International AG : Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Federal State Budgetary Institution Hematology Research Center of Health Ministry of Russia, Moscow, Russian Federation : Employment. Chelysheva:Novartis International AG : Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Federal State Budgetary Institution Hematology Research Center of Health Ministry of Russia, Moscow, Russian Federation : Employment. Turkina: Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Description: Background: Clinical trials demonstrate a safe discontinuation possibility of tyrosine kinase inhibitors (TKI) in patients with deep molecular response (MR). However reasons and indications for TKI cessation as a part of treatment process have not been studied. Aims: To evaluate the eligibility of long term TKI cessation in CML patients with deep and long lasting MR. To describe the reasons of stopping therapy, principles and terms of observation without treatment, preserving and restoring of MR. Methods: We summarized retrospectively and prospectively 25 TKI discontinuation cases in 2 clinics of Russian Federation (Moscow, St.Petersburg, 2008-2014). Inclusion criteria were: 1) Ph+CML 2) MR4 (BCR-ABL12 months confirmed by 〉2 consecutive analyses 3) discontinuation of TKI treatment. Chronic phase (CP)/accelerated phase (AP) at diagnosis was 24/1. Sokal score for CP patients was 15/8/1 for low/intermediate/high risl group. Therapy before discontinuation was the following: imatinib 1st line (n=16), 2nd generation TKI (TKI2) 2nd-3rd line (n=9): 5 dasatinib/ 4 nilotinib. Me TKI duration was 7,2 (range 2,5-13) years, Me MR4 duration was 50 (range 12-97) months. IFN before TKI was received by 13(52%) of 25 patients for Me 18 months (2-60 months). Results: We specify 2 reasons of TKI discontinuation: 1) adverse events (AE) of TKI (Toxicity Group), n=18 2) self decision of patients (Active Group), n=7 (Table 1). Table 1. Characteristics of CML patients according to reason of stopping TKI (n=25) Toxicity Group (n=18) Active Group (n=7) Ме of age, years (min-max) 55 (27-74) 36 (23-58) Ratio male/female (m:f) 9m:9f 3m:4f Ме duration of TKI therapy, years (min-max) 5,9 (2,5-13) 8,6 (4,4-10,1) Ме duration of МО4 at treatment cessation, months (min-max) 41 (12-97) 67 (33-79) In Toxicity Group therapy was stopped for 1) AE grade 1-3 in 5 of 18 patients: unstable angina (2), hepatotoxicity (1), acute renal failure (1), menstrual dysfunction and infections (1); 2) AE grade 1-2 in 13 of 18 patients including recurrent or long lasting: fatigue, edema, arthralgia, muscle cramps, diarrhea, recurrent pleural effusion. The key clinical decision was not to restart TKI after AE termination and to continue monitoring of BCR-ABL transcript levels by RQ-PCR. For Active Group self-made discontinuation was in 7 patients with long lasting MR4 due to knowledge of safe discontinuation (4) and for conception (3). In 6 of 7 patients BCR-ABL monitoring was performed, 1 patient refused from monitoring. Treatment was restarted at major molecular response (MMR) loss (BCR-ABL〉0,1%) or by decision of physician. In case of severe AE the patients were switched to alternative TKI. Thirteen (52%) of 25 patients were observed without treatment for Me 23 months (6-77 months), in 12 MR4 was maintained, 1 patient being off treatment for 54 months refused from monitoring (Active Group). Therapy was resumed in 10 patients with MMR loss and in 2 without MMR loss, by physician decision. All MMR loss cases occurred within first 6 months, no CML progression observed. Response restoration to MR4 was in 8 of 10 patients in 3-16 months, in other 2 it is early to estimate Summary/Conclusion: Observation without therapy may become an option in CML patients with mostly low/intermediate Sokal risk group, stable MR4 and recurrent/severe TKI toxicity. Self declared decisions of young patients with durable deep MR should be accompanied by regular RQ-PCR especially within first 6 months after TKI discontinuation. Resuming therapy at MMR loss shows to be safe. Disclosures No relevant conflicts of interest to declare.

Description: Background The data on quality of life (QoL) in chronic myeloid leukemia (CML) patients (pts) with deep molecular response (DMR) in the treatment-free remission (TFR) studies are limited. The influence of comorbidities on QoL in CML pts before and after tyrosine kinase inhibitors (TKIs) discontinuation has not been studied. Aim We aimed to study the impact of comorbidities on QoL in CML pts before and after the stop therapy by TKIs. Patients and methods The chronic phase (CP) CML pts who had received therapy by any TKI ≥3 years (yrs) with sustained DMR (BCR-ABL ≤0.01% IS) during ≥2 yrs were enrolled into the prospective TFR study RU-SKI. A regular qPCR with BCR-ABL IS evaluation was performed after TKI cessation. TKI were resumed in pts with major molecular response loss (MMR loss, BCR-ABL〉0,1%). The QoL was evaluated by RAND SF-36 questionnaire at baseline before TKI stop and at 1, 3, 6, 12 mo during TFR. Eight functional scales were assessed: physical functioning, role limitations physical, bodily pain, general health perceptions, energy/vitality, social functioning, role limitations emotional, mental health. The Integral QoL Index (IQoLI) was calculated based on the scales. Mann-Whitney test, paired Wilcoxon test χ2 were used for the statistical analysis. Molecular relapse free survival (MRFS) was evaluated by Kaplan-Meier method, log-rank test was used for comparison. Results The analysis was performed in the group of 97 CML pts. Median (Me) age was 47±14.5 (yrs), 48.5% were males. The TKI before treatment cessation were as follows: imatinib and second-generation (2G) TKIs in 67 (70%) and 30 (30%) pts accordingly; 9 (30%) pts received 2G TKIs in 1st line and 21 (70%) pts in 2nd line. Me time of observation was 25 mo (range 12-42). Comorbidities were present in 81 pts (82%) at baseline. The most frequent comorbidities were cardiovascular (38.4%), gastroenterological (29.3%) and musculoskeletal disorders (27.3%). First we compared baseline QoL in 2 pts groups: group 1 - pts with acute comorbidity status at baseline (n=42), group 2 - pts with stable comorbidity status (n=29) and with no comorbidity (n=16). QoL in group 1 was significantly worse by all functional scales, except mental health (p

Description: Abstract 4431 The European Treatment Outcome Study (EUTOS) is register based international investigation started in June 2007. [1] The aim is to study the epidemiology of CML and to gain insight into the ‘real world’ treatment of patients with CML. Population base section (EUTOS-PBS) is the prospective study directed mostly to epidemiology aims. Russian part of the EUTOS-PBS registry collect data of newly diagnosed patients lived in 7 large regions of about 10 millions of population totally. EUTOS-PBS inclusion criteria are following: newly diagnosed CML (Ph +/BCR-ABL) started form 1st October 2009, age: older than 18. Russian CML group includes additional protocol for collection data for patients with clinical symptoms of CML. These patients are included into the roster table and after laboratory confirmation are enrolled into the main phase of the study. Thus, 174 patients were included in pre-phase, 142 (82%) had the diagnosis of CML which was confirmed by cytogenetic/molecular-genetic tests (Ph +/BCR-ABL +), 32 (18%) was not confirmed as CML. Among them 87% (n = 20) - have other Ph–negative chronic myeloproliferative diseases, and also acute leukemia (n = 1), cancer (n = 1), chronic inflammatory processes (n = 1). 142 patients with CML are 73 men, 69 women have the age from 18 to 82 (Me 49) years. 136 (96%) of patients are in the chronic phase, 6 (4%) -in the phase of acceleration, nobody in a blast ñrisis. The standard frequency analysis with adjustment to the standard population of WHO was carried out to estimate distribution. The results was presented in the table 1. As shown registered morbidity in 6 regions is not varied so much: source incidence is 0,58 (0,44–0,69); standardized on WHO incidence is: 0,7 (0,57 – 0,85); per 100 thousands per year. Estimated registered morbidity of CML in Russian regions are in 1.5–2 times less, than published morbidity in western countries. The analysis of the incidence in age stratums (table 2) shows that there is no much growth of age morbidity as expected. It obviously points to low detectability of new CML incidents in senior age categories (are more senior 60 years). This fact is probably the main reason of low total registered morbidity. Tabl.1. Incidence rate of new CML cases in 6 regions of Russia Region population (mln.) N CML for 100000. in year Standard of WHO Mordovia Republic 0.87 14 0.69 0.85 Kirov region 1.46 18 0.53 0.6 Perm territory 2.77 45 0.68 0.8 Bryansk region 1.35 17 0.53 0.65 Irkutsk region 2.55 36 0.56 0.68 Zabaikal's territory 1.36 12 0.44 0.57 Total 10.13 142 0.58 0.7 Table 2.CML incidence in age groups Age groups Male Female Maleandfemale 18–29 0.65 0.57 0.61 30–39 0.86 0.39 0.62 40–49 0.50 0.57 0.54 Conclusion: The CML incidence in Russia regions is underestimated. The main reason is an insufficient CML diagnostic screening in the senior age groups of population. References. 1. http://www.eutos.org/content/registry/documents/documents/e940/infoboxContent941/CML-Registry_February09.pdf Disclosures: Vinogradova: BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Chelysheva:Novartis Pharma: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; MSD: Speakers Bureau. Senderova:Novartis: Consultancy. Turkina:Novartis Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Pregnancy in CML patients (pts) is becoming a reality due to the increase in information from published cases or larger multicentric database (GIMEMA and ELN). Interferon (IFN) has been used during pregnancy, but little is known about the use of tyrosine kinase inhibitors (TKIs), which should be stopped early due to their teratogenic effects. Female pts can ideally plan a pregnancy if they are in a deep, stable, molecular response (DMR=MR≥ 4, ≤0.01%IS) and treatment free remission (TFR) parameters are satisfied. Molecular remission can be maintained throughout the pregnancy, but how to proceed if the remission is rapidly lost, or if the patient is not in DMR, or when CML is discovered during pregnancy? To address these questions, we analyzed more than 300 pregnancies registered through the ELN database. Pts completing pregnancy were grouped as follow: 1) pts diagnosed with CML while pregnant 2) pts in DMR 3) pts with ≤MR3 (≥ 0.1%IS) In 47 patients CML was diagnosed during pregnancy, 21 during the 1st trimester, 15 in the 2nd , and 11 in the 3rd (range 3-38 wk). Sixteen patients were not treated until delivery, 15 were treated with IFN; 19 with Imatinib (IM), 12 in the 2nd trimester (〉16 wk), and 7 in the 3rd. Forty-eight children were born (one set of twins). Three were preterm (35-37 wk), and one pregnancy is ongoing. No births defects were observed. Seven newborns had a low birth weight (〈 2.5 Kg) 6 of them were exposed to IM at late pregnancy and 3 were preterm. Follow-up was uneventful. The majority of pts achieved ≥ MR3 after starting TKI. Two pts died: 1 in blast crisis (BC) after 9 years, but she was not adherent to treatment; 1 of transplant complication (resistant to〉2TKI). Seventy five pts had 80 pregnancies in DMR. Six were in TFR (no therapy) for more than 12 mo, while 8 stopped TKI in order to conceive (2-8 mo before conception). Twenty two pts were treated during pregnancy: 12 with TKI (8 IM, 4 nilotinib, NIL) 1 in the 1st trimester (never stopped IM), 7 in the 2nd and 4 in the 3rd; 10 pts received IFN. Eighty one children were born (6 patients had 2 pregnancies, 1 had twins) with one baby born preterm (wk 35). No births defects were observed and two pregnancies are ongoing. Fifty eight pregnancies were carried without any CML treatment. Twenty six maintained DMR, 28 ≤ MR3 and considered in "treatment free pregnancy" (TFP), and 5 had 〉10% transcript levels at delivery, considered as high tumor burden (HTB). None of the patients progressed after pregnancy, 4 patients maintained TFR. Four patients did not return to MR3

Description: Introduction: Most surrogate endpoints are based on periodical measurement and the assessment of event time uses data censored by both sides. Kaplan-Maier (KM) estimators are calculated from right censored data and as result they are biased and sensitive to irregularity in measurements. High rate of missing data and irregularity is a common problem for registries. Interval Censorship Estimators (ICE) are relative complex but more reliable and robust than KM. Cytogenetic response is a major prognostic factor for long-term results of therapy of chronic myeloid leukemia (CML) and is often used as surrogate endpoint. The challenge of ICE usage instead of KM’s for cytogenetic response estimation is illustrated on real data from the registry of patients with CML. Methods and data source: We compare data in 2 studies of similar population of CML patients. The studies are distinguished by the design and completeness of data. First one is retrospective, second is prospective controlled registry population study. For evaluation of time to event characteristics two estimators were used and compared: classical KM estimators and ICE estimators based on Turnbul’s algorithm, realized as SAS Macro [1]. The EUropean Treatment Outcome Study (EUTOS) is a registry based international investigation started in June 2007 running for 3 years. The aim is to study the epidemiology of CML. The first part of the study is OUT Study section (EUTOS-OSP) with retrospectively collect data form patients who are not included into the local or international clinical trials. The second part of EUTOS study is online registry so called Population Based Sections (PBS EUTOS) aimed to estimate incidence of CML in EUROPE. Results: For the analysis we made 2 data sets. First one includes data of 508 patients with 2005-2008 years of diagnosis from study EUTOS-OSP collected retrospectively from 36 regions of Russian. Median age at diagnosis was 49,3 years, range from 18 to 82, 47,6% of men, 6.7% in AC,BC phase, 29,3% at high risk by Sokal. Second set includes data of all 200 patients of PBS EUTOS study prospectively collected form 6 regions of Russia in 2008-2012 years. Median age at diagnosis was 50,4 years, range from 16 to 82, 50,8% of men, 6.0% in AC,BC phase, 31,7% at high risk by Sokal. Progression free survival (PFS) and complete cytogenetic responds (CCyR) probability were calculated by traditional KM method in OSP and PBS data sets. Also ICE estimations of the CCyR was done in this data sets. The 3-year PFS was estimated as 89.6% in OSP set and 88.8% in PBS set (fig. 1). KM estimations gives median time to CCyR =17.5 months in OSP and 12 months in PBS group, delta=5.5 moths (fig.2), if ICE estimations is used median time to CCyR =12 month in OSP, 8.5 month in PBS group, delta=3.5 moths (fig.3). The difference of CCyR between OSP and PBS was much less on fig.3 than on fig.2. The completeness of cytogenetic data in both studies was quite distinguishing. Percentages of patients with reported cytogenetic tests were following: in 6±3 month – 333/497 (67%) in OSP and 151/174 (87%) in PBS, in 24±3 month – 254/470 (54%) in OSP and 52/79 (66%) in PBS. Figure 1. KM estimations PFS in OSP (dash line) and PBS (solid line) sets Figure 1. KM estimations PFS in OSP (dash line) and PBS (solid line) sets Figure 2. KM estimations of CCyR in OSP (dash line) and PBS (solid line) sets. Figure 2. KM estimations of CCyR in OSP (dash line) and PBS (solid line) sets. Figure 3. ICE estimations of CCyR in OSP (dash line) and PBS (solid line) sets. Figure 3. ICE estimations of CCyR in OSP (dash line) and PBS (solid line) sets. Long term results of studies are almost identical (p=0.3, fig.1) although the KM estimations of response rates are essentially different (p

Description: Background: A success of the tyrosine kinase inhibitors (TKI) therapy in patients (pts) with chronic myeloid leukemia (CML) allowed to set a new goal: a treatment-free remission (TFR). A stable and long-lasting deep molecular response (DMR) is required for a successful TKI discontinuation. The number of CML pts with stable DMR increases on late terms of TKI therapy. With the relationship to this new goal it is relevant to evaluate the proportion of the potential candidates for TKI discontinuation in accordance with the country-specific features of the CML pts population in routine clinical practice. Aim :To characterize the cohort of CML pts treated in routine clinical practice in Russian Federation and to evaluate the proportion of CML pts eligible for TFR. Methods: The analyzed cohort consisted of 197 pts from 6 regions of Russia covering the population of 10 million inhabitants. All pts with CML diagnosed from 01.10.2009 to 31.12.2012 were included into the prospective multicenter EUTOS Population Based Study (EUTOS PBS). Median (Me) age was 50 (18-82)years, 49% were males. Chronic phase, accelerated phase and blast crisis was diagnosed in 93,4%, 6% and 0,6% pts respectively. Imatinib as a 1st line was used in 97% pts. The 2nd generation TKIs (TKI2) were used as 1st and 2nd -3rd line in 3% and 12% pts respectively; imatinib failure was the main reason of switch to TKI2. Overall survival (OS) and cumulative (CI) of DMR were evaluated and adjusted to the new ELTS (EUTOS long-term-survival) score. A proportion of pts with sustained DMR eligible for TFR was calculated. DMR was considered as BCR-ABL2 years and TKI therapy 〉3 years. Results:Me follow-up in Russian CML pts cohort of EUTOS PBS was 77 (0,7 - 107) months (mo). The ELTS score available in 179 pts was low, intermediate and high in 86(48%), 50(28%) and 43(24%) pts accordingly. The 7-year OS was 76% in total cohort (figure 1a). The 7-year OS in low, intermediate and high ELTS group was 87%, 68% and 55% respectively (p=0,001). Me time of DMR achievement was 38mo (11,2 - 89 mo). The 7-year CI of DMR was 62%. The CI of 7-year DMR achievement in ELTS low, intermediate and high group was 62%, 42% and 38% respectively with significant difference between low and non-low score pts (p= 0,001) (figure 1b). The data for the molecular response at data cut-off April 2019 were available in 114/123 pts who were alive and treated by TKIs with Me time 85 (range 65 - 105) mo. DMR, major molecular response (MMR, (BCR-ABL 〉0,01%- 0,1% IS) and no MMR (BCR-ABL〉 0,1% IS) was in 76 (66,7%), 8 (7%) and 30 (26,3%) pts respectively. A sustained DMR was in 38 (50%) of 76 pts or 19% of the total cohort of 197 pts. Conclusion: A significant proportion of CML pts reach a sustained DMR on late terms of TKI therapy. In total 19% of CML pts in Russian part of the EUTOS PBS study can be eligible to treatment-free observation after 7 years of TKI therapy. The low ELTS score predicts better survival and better chance of DMR achievement. The evaluation of the TFR perspective in routine clinical practicein important from diagnosis to late terms of treatment. Disclosures Chelysheva: Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Vinogradova:Novartis: Consultancy; Fusion Pharma: Consultancy. Turkina:Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy.

Description: Introduction. Stromal microenvironment of the bone marrow (BM) is essential for normal hematopoiesis; the very same cells are involved in the interaction with the leukemic stem cells. The aim of the study was to reveal the alterations in stromal microenvironment of patients in debut and after the therapy using multipotent mesenchymal stromal cells (MSC) as a model. Methods. MSC of patients with acute myeloid leukemia (AML, N=32), acute lymphoblastic leukemia (ALL, N=20), chronic myeloid leukemia (CML, N=19), and diffuse large B-cell lymphoma without BM involvement (DLBCL, N=17) were isolated by standard method from the patients' BM. Each BM sample was acquired during diagnostic aspiration after the informed signed consent was obtained from the patient. Groups of BM donors comparable by age and gender were used as controls for each nosology. Gene expression was analyzed with real-time RT-PCR. The significance of differences was evaluated with Mann-Whitney U-test. Results. The results of gene expression analysis are summarized in Table. The expression of genes regulating hematopoietic stem and precursor cells (JAG1, LIF, IL6) was significantly upregulated in MSC of the patients in debut, except for DLBCL. The latter was characterized with upregulation of osteogenic marker gene SPP1 and downregulation of FGFR1 gene. The upregulation of the expression of genes regulating proliferation of stromal cells (PDGFRA, FGFR1) and adipogenic marker gene (PPARG) was common for AML and CML. Both acute leukemias were characterized by the upregulation of genes associated with inflammation and regulation of hematopoietic precursors (CSF1, IL1B, IL1BR1) and by the downregulation of chondrogenic differentiation marker gene (SOX9). CML and DLBCL demonstrated the upregulation of FGFR2. BM of the DLBCL patients did not contain any malignant cells; nevertheless, stromal precursors from the BM were significantly affected. This indicates the distant effects of DLBCL malignant cells on the patients' BM. Myeloid malignancies seem to affect MSC more profoundly then lymphoid ones. Effect of leukemic cells on stromal microenvironment in case of myeloid leukemia was more pronounced. The treatment significantly affected gene expression in MSC of patients. In all studied nosologies the IL6 gene expression was upregulated, which may reflect the inflammation processes ongoing in the organism. The expression of LIF was upregulated and ICAM1, downregulated in MSCs of AML, ALL, and CML patients. In the MSC of patients with AML, who had received the highest doses of cytostatic drugs to achieve remission, a significant decrease in the expression of most studied genes was found. In patients with ALL with long-term continuing treatment in combination with lower doses of drugs, IL1B expression was increased, while the decrease in expression was detected for a number of genes regulating hematopoietic stem cells (SDF1, TGFB1), differentiation and proliferation (SOX9, FGFR1, FGFR2). Treatment of CML patients is based on tyrosine kinase inhibitors in doses designed for long-term use, and is less damaging for MSC. The upregulation of TGFB1, SOX9, PDGFRA genes and downregulation of IL1B gene was revealed. MCS of DLBCL patients, unlike the other samples, were analyzed after the end of treatment. Nevertheless, significant upregulation of IL8 and FGFR2 genes was found. Thus, both the malignant cells and chemotherapy affect stromal precursor cells. The changes are not transient; they are preserved for a few months at least. MSCs comprise only a minor subpopulation in the BM in vivo. When expanded in vitro, they demonstrate significant changes between groups of patients and healthy donors. Conclusions. Leukemia cells adapt the stromal microenvironment. With different leukemia, the same changes are observed in the expression of genes in MSC. MSC of patients with acute forms have a lot of changes which coincide among these two diseases. MSC of AML patients are most affected both in debut and after the therapy. Treatment depends on the nosology and in varying degrees changes the MSC. This work was supported by the Russian Foundation for Basic Research, project no. 17-00-00170. Disclosures Chelysheva: Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shukhov:Novartis: Consultancy; Pfizer: Consultancy. Turkina:Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; fusion pharma: Consultancy.

Description: 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 (