ALBERT

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: 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.