Loss Of Complete Cytogenetic Response Research Articles

Phase 2 Study of Dasatinib with and without Venetoclax in Patients with Early Chronic Phase Chronic Myeloid Leukemia (ECP-CML)

Background Treatment-free remission (TFR) is a therapeutic goal for patients with ECP-CML once patients maintain a deep molecular remission (DMR) on tyrosine kinase inhibitors (TKIs). Only a fraction of patients (pts) achieved sustained (3+ years) molecular remission with 4.0- to 4.5-log reduction (MR4.5). Preclinical studies showed that BCL-2 is a key survival factor for CML stem/progenitor cells. Therefore, the combination of TKIs and venetoclax, targeting BCR::ABL1 and BCL-2, has the potential to significantly improve DMR and subsequently the rates of TFR. The aim of this study is to evaluate the safety and efficacy of the combination. Methods Patients with ECP-CML or accelerated phase (AP; defined by clonal evolution only) were eligible; pts with < 1 month of prior TKI therapy were eligible. Pts received single-agent dasatinib 50 mg/d for the first 3 months. From Month 4 and onwards, venetoclax was administered from Days 1 to 14 each month concomitantly with dasatinib for a total of 3 years. The first 16 patients received venetoclax 200 mg/d, with a rapid ramp-up starting 50 mg on Day 1, then 100 mg on Day 2, then 200 mg daily on Day 3 and onwards. Due to neutropenia observed with continuous dose of venetoclax 200 mg/d, the protocol was ameded: from patient #17 and onwards, venetoclax was administered at 200 mg/d for 14 days per month and upon achievement of MR4.5, venetoclax was reduced to 100 mg/d for 7 days per month. After 3 years of combination, patients received single-agent dasatinib. TFR was offered after ≥ 3 years of DMR. The primary endpoint was the rate of major molecular response (MMR) by 12 months of the combination. The secondary endpoints were the 12-month rate of MR4.5 and the cumulative overall rate of MR4.5; the rates of MR4.5 at 6-, 12-, 18-, 24, and 36-months of the combination; the proportion of patients with sustained MR4.5 of 3 years and more; the TFR rate; overall survival; and the safety of the combination. Cumulative response rates were calculated with treatment failure as a competing event. Failure-free survival (FFS) was calculated from the initiation of therapy to loss of major cytogenetic response (MCyR), transformation to AP or blast phase, discontinuation of therapy for any reason except of TFR, or death. Results Sixty-five pts were enrolled and treated between April 2018 and August 2021. The median age at treatment initation was 46 years (range, 23-73) and 57% of the pts were females. Twenty-one (32%) pts had splenomegaly, 46 (71%) had low Sokal risk disease and 3 (5%) had high Sokal risk disease (Table 1). By 12 months of the combination, 85% of the pts had achieved MMR or deeper response. The median time to MMR, MR4, and MR4.5 were 6.2 months, 13 months, and 23.9 months from the time of TKI start, respectively. After a median follow-up of 25.7 months (range, 8.7-48.1), two pts discontinued therapy due to adverse events (GI intolerance, and pleural effusion); the 2 -year FFS was 96%. One pt switched TKI therapy due to the lack of 18-month complete cytogenetic response (CCyR); no loss of CCyR, transformation, or death was observed. We then compared the outcomes with the combination to the outcomes of 85 pts treated with single-agent dasatinib. From the start of TKI therapy, the 12-month cumulative MMR rates were 78% and 79% in the dasatinib single-agent and dasatinib + venetoclax groups, respectively. The cumulative 24-month rates of CCyR, MMR, MR4, and MR4.5 are summarized in Table 2. In the dasatinib single-agent group, 3 pts switched TKI therapy due to the lack of 12-month MCyR, 18-month CCyR, and the acquisition of ABL1 mutation (1 each); 3 pts switched TKI therapy due to loss of CCyR; 2 pts died during therapy (deaths unrelated to CML). Within one year of therapy, the incidence of grade 1/2 neutropenia (absolute neutrophil count, below lower range of normal to 1,000 x10 9/L) was 21% and 52% in the dasatinib single agent and dasatinib + venetoclax groups, respectively ( P<0.001); the incidence of grade 3/4 neutropenia (absolute neutrophil count, below 1,000 x10 9/L) was 8% and 17%, respectively ( P<0.001). There was no incidence of neutropenic fever in the dasatinib + venetoclax. Conclusion The combination of dasatinib 50 mg/d and venetoclax is safe and effective in pts with ECP-CML. With a median follow-up of 2 years, the cumulative resposne of dasatinib + venetoclax is similar to that of dasatinib single-agent without adding significant toxicities. Further follow-up is needed for the evaluation of TFR.

Prospective Assessment of Co-Morbidities and Framingham Risk Score in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients and Its Impact on Clinical Outcomes Following Frontline TKI Therapy: Toronto CML Genomic Alliance in Greater Toronto Area & Ontario (TCGA-GTA)

Introduction Front-line (1L) tyrosine kinase inhibitor (TKI) drug selection is a pearl of clinical practice in CML. It requires consideration of multiple aspects including the goal of therapy, potency of the drug as well as comorbidity of the patient (pt). Contemporary CML practice emphasizes the importance of comorbidity for TKI selection. However, such data is scarce particularly the prevalence of comorbidity and its impact on 1L drug selection. We are developing a shared care model with community hematologists in Greater Toronto Area (TCGA-GTA). Newly diagnosed CML pts in the community will be referred to the study core center for prospective enrolment into the CML registry, informed consenting for genetic testing/future research, and evaluation of baseline comorbidity. Pt will return to referring hematologists for management of CML, including 1L TKI treatment as per standard of care, and is scheduled to visit the study center at 6 and 12 months, then annually for 10 years. It gives us a unique opportunity to evaluate the impact of comorbidity on 1L TKI drug selection. Patients and method Adult pts with newly diagnosed CML of any phase within 2 months of diagnosis are eligible for the study unless they are not able to visit study core center. Comorbidities and Framingham risk score (FRS) were assessed at the time of initial evaluation. Mutation profile testing is done by a bar-coded error-corrected sequencing platform for 40 genes developed at the Ontario Institute for Cancer Research. Cumulative incidence of molecular response with 2 log (MR2), 3 log (MR3), 4 log reduction or deeper (MR4), and treatment failure (TF) were calculated using cumulative incidence method considering competing risk. Event-free survival (EFS) was defined as time from start of TKI until TKI stop/switch, TF or death. Failure-free survival (FFS) was defined as time from start of TKI to TF [primary resistance, loss of complete cytogenetic response, new additional cytogenetic abnormalities (ACAs), and progression to accelerated or blasts phase (AP/BP)] or death. Results From November 2020 until June 31, 2023 (data cutoff), a total of 77 pts were enrolled in the study. The median follow-up time was 12 months. The frequency of 1L TKI selection was as follows: IMATINIB (IM) (n=23, 30%), DASATINIB (n=25, 32%), NILOTINIB (n=22, 29%), BOSUTINIB (n=1, 1%), ASCIMINIB (n=6, 8%). Majority of the pts were male (n=51, 66%). Ninety-three percent of pts were in chronic phase at diagnosis, while 4% and 3% were in AP and BP, respectively. Presence of ACAs was detected in 18 pts (23%), 10 of which were high risk, while 6% (n=5) were not evaluable. The baseline clinical and disease characteristics of pts on 1L IM vs other TKIs (2G-TKI) are summarised in Table 1. Of note, pts on IM were significantly older with higher FRS and comorbidities, including coronary artery disease, diabetes mellitus, and hypertension. The OS of all pts at 1 year was 98.5% (95% confidence interval 90%-99.8%). At 1 year, pts with intermediate to high risk FRS had lower FFS (73.2% vs 86.5%, p=0.037) while history of hyperlipidemia was associated with lower EFS (59.3% vs 81.5%, p=0.023) and 6 times more likely to stop or switch therapy due to intolerance or resistance (HR 5.9, p=0.002). Baseline comorbidities did not demonstrate signifincant impact on MR2 and MR3 at 1 year but pts with low FRS were more likely to achieve MR4 within 1 year (22.3% vs 0%, p=0.023). Age did not affect any of the clinical and molecular endpoints. Compared to 2G-TKI, IM had worse EFS (HR 3.93, p=0.003), FFS (HR 5.66, p=0.011), and MR2 (47.3% vs 84.4%, p=0.003) at 1 year. Further, IM pts experienced higher rate of any side effects compared to those on 2G-TKI (69.6% vs 31.5%, p=0.003). Conclusion The TCGA-GTA study provides valuable insights into the impact of comorbidity on selection of 1L TKI and its outcome in a real-world setting. Pts who are older and with higher FRS and comorbidities tend to receive 1L IM. However, pts on 1L 2G TKIs are more likely to reach treatment goals faster with lower probability of TF. The present study did not reach a clear conclusion whether the worse outcomes in the pts receiving IM are from IM treatment or concurrent risk factors such as age and comorbidities, thus further study with an expanded cohort and longer follow-up is required. Elderly pts or those with comorbidities would need alternative treatment with better efficacy and tolerability, such as Asciminib, that can overcome comorbidity issues in the future.

Safety and Efficacy of Elective Switch from Nilotinib to Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

The treatment of newly diagnosed chronic phase chronic myeloid leukemia (CML) with nilotinib has resulted in a higher rate of major molecular (MMR) and complete cytogenetic response (CCyR) at 12 months compared to imatinib but at a higher cumulative cost and increased risk of serious adverse events. To maintain long-term efficacy and minimize both toxicity and costs, we aimed at evaluating in a prospective single-center trial the efficacy and safety of a response-directed switch from nilotinib to imatinib after 12 months in patients newly diagnosed with chronic phase CML. Thirteen adult patients were enrolled. Twelve patients started on nilotinib 300 mg twice daily. Eleven patients completed one year of nilotinib and were switched to imatinib 400 mg daily as per protocol. At 3 months, all patients achieved a complete hematologic response, with 7 (58%) patients had early molecular response. At 12 months, all patients achieved CCyR, of whom 5 (42%) and 4 (33%) patients achieved MMR and MR4.5, respectively. Three (27%) patients switched back to nilotinib after 18, 24, and 51 months respectively: 1 patient because of loss of CCyR after 18 months, and 2 patients because of imatinib intolerance. At last follow-up, all patients (n = 12) were alive and in MMR, 6 (50%) of them in continuous MR4.5. These findings suggest that response directed switch from nilotinib to imatinib at 12 months is capable of maintaining long-term response, with manageable side effects. This approach warrants further exploration with larger prospective trials. Clinical trial registration: Clinicaltrials.gov identifier: NCT01316250, https://clinicaltrials.gov/ct2/results?cond=&term=NCT01316250&cntry=&state=&city=&dist=.

Impact of metformin on tyrosine kinase inhibitor response in chronic myeloid leukemia.

ObjectiveOral tyrosine kinase inhibitors (TKIs) are first line therapy for chronic myeloid leukemia (CML). A complete cytogenetic response (CCyR) correlates with increased overall survival, however only 66%–88% of patients achieve CCyR after one year of TKI treatment. Because TKI therapy alone cannot eliminate CML stem cells, strategies aimed at achieving faster and deeper responses are needed to improve long-term survival. Metformin is a widely prescribed glucose-lowering agent for patients with diabetes and in preclinical studies, has been shown to suppress cell viability, induce apoptosis, and downregulate the mTORC1 signaling pathway in imatinib resistant CML cell lines (K562R). This study aims to investigate the utility of metformin added to TKI therapy in patients with CML.Data SourcesAn observational study at an academic medical center (Salt Lake City, UT) was performed for adults with newly diagnosed, chronic-phase CML to evaluate attainment of CCyR from TKI therapy with or without concomitant metformin use. Descriptive analyses were used to describe baseline characteristics and attainment of response to TKI therapy.Data SummaryFifty-nine patients were evaluated. One hundred percent (5 of 5) in the metformin group and 73.6% (39 of 54) in the non-metformin group achieved CCyR. Approximately 20% of patients in both groups relapsed (defined by a loss of CCyR during study) after a median 34.5 months of follow-up.ConclusionsFuture research is warranted to validate these findings and determine the utility of metformin added to TKI therapy.

E14a2 and e14a2+e13a2 BCR-ABL Transcripts Are Associated with Earlier Cytogenetic and Molecular Response Rates in CML-CP Treated with Imatinib

Background: The prognostic significance of BCR-ABL1 transcripts in chronic myeloid leukemia (CML) is still controversial. Methods: All consecutive CML patients in chronic phase treated with Glivec between January 2010 and December 2011 and generic imatinib between January 2015 and February 2017 from 8 Brazilian centers were analyzed. BCR-ABL1 transcripts were evaluated by multiplex qualitative RT-PCR. Only patients with BCR-ABL transcripts e13a2 and/or e14a2 were included in this analysis. All patients started imatinib less than six months from diagnosis. Study data were collected and managed using REDCap electronic data capture tools. Demographic data were collected at diagnosis: age, gender, blood cell counts, Sokal, Hasford and EUTOS score, cytogenetics and BCR-ABL transcript type. The definition of the responses followed the European Leukemia Net 2013 criteria. Event-free survival (EFS) was measured from starting of treatment until loss of complete hematologic remission, loss of complete cytogenetic response (CCyR), loss of major (MMR), progression to accelerated (AP) or blast phase (BC), or death from any cause at any time after initial therapy. Overall survival (OS) was measured from starting of imatinib until last follow-up or date of death from any cause at any time. Progression-free survival (PFS) was measured from date of imatinib starting to transformation to AP or BC or deaths while on therapy. SPSS 21.0 software (IBM Corp., Armonk, NY, USA) was used for chi-square, t-test, ANOVA, when adequate, considering p-value <0.05 as significant.Results191 CML-CP patients treated with imatinib (121 Glivec and 70 generic imatinib) were analyzed. Patient's characteristics are described in Table 1. The median age of patients was 46 (18-89) years. Sokal score: 52.1% low; 33.8% intermediate and 14.1% high risk. BCR-ABL transcripts: 109 (57%) presented e14a2 transcripts, 74 (38.8%) e13a2 and 8 (4.2%) both transcripts. There was no difference between the groups concerning age, gender, Hasford, EUTOS scores, whereas white blood cell counts at diagnosis was higher in patients with e13a2 transcripts (P=0.009). Higher rates of CCyR at 6 months were observed in e14a2 and both transcripts group, compared to e13a2 (58.4%, 60% and 30%, respectively - P=0.003); e14a2 group had higher rates of BCR-ABL transcripts <10% measured by real-time quantitative polymerase chain reaction (RQ-PCR) at 3 months (82.9%, 85.7% and 59.3%; P=0.007) and BCR-ABL <1% at 6 months (78.4% e14a2; 61.7% e13a2 and 43% both transcripts; P=0.039). The groups presented similar OS (89 %, 87% and 83%, P=0.49) and PFS (88%, 84% and 71%, P=0.08). EFS was inferior in the e13a2 group (45% vs. 65% e14a2 vs. 54% both transcripts; P=0.02).Conclusion: Patients with BCR-ABL transcripts e14a2 presented higher rates of CCyR at 6 months and higher rates of optimal molecular response at 3 and 6 months when compared to e13a2 transcripts, but there was no difference in overall and progression-free survival by 5 years. DisclosuresPagnano:Bristol-Meirs Squibb: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy.

CHRONIC MYELOID LEUKEMIA COURSE IN PERSONS EXPOSED TO IONIZING RADIATION AS A RESULT OF THE CHORNOBYL ACCIDENT.

Describe and characterize the peculiarities of the chronic myeloid leukemia (CML) course and responseto treatment in patients irradiated as a result of the Chornobyl nuclear power plant (ChNPP) accident based on theassessment of clinical-laboratory and clinical parameters. The CML patients (n = 33) exposed to ionizing radiation as a result of the ChNPP accidentwere enrolled. The comparison group consisted of CML patients (n = 725) with no history of radiation exposure. Allpatients were in the chronic phase of the disease. Clinical, hematological and molecular genetic research methodswere applied. Patients exposed to ionizing radiation as a result of the ChNPP accident had no differences in CML manifestation, as well as in classical genetic markers at the onset of the disease compared with patients with no historyof radiation exposure. Reduction of tumor clone on imatinib therapy was significantly less effective in the patientsexposed to ionizing radiation than in cases of no history of radiation exposure. Cases of primary resistance were statistically significantly prevalent in the ChNPP accident consequences clean-up workers while in the residents ofradiologically contaminated areas a statistically significant increase in probability of loss of complete cytogeneticresponse (development of secondary resistance) to imatinib therapy was found. An association was found betweenthe radiation exposure and probability of loss of complete cytogenetic response to imatinib therapy in this group ofpatients. The radiation exposure in the history even many years before the onset of CML is an unfavorable exogenous factor responsible for the development of resistance to imatinib therapy.

Comparison of the Clinical Outcomes of Nilotinib and Dasatinib Therapies in Newly Diagnosed Patients in the Chronic Phase of Chronic Myeloid Leukemia: A Retrospective Analysis

Background and Aim: Treatment with a tyrosine kinase inhibitor (TKI) is the standard of care for patients with chronic myeloid leukemia (CML). Based on the results of the ENESTnd and DASISION studies, the European LeukemiaNet 2013 guidelines now recommend the use of TKIs, imatinib (400 mg once daily), nilotinib (300 mg twice daily), and dasatinib (100 mg once daily) as first-line treatment for patients with CML in the chronic phase (CML-CP). Compared to imatinib, the new generation TKIs, nilotinib and dasatinib, were found to have deeper and faster treatment response rates with acceptable toxicities. However, a direct comparison between nilotinib and dasatinib has never been reported previously. Our study aims to compare the outcomes and molecular responses achieved following the first-line use of these two agents in patients with CML-CP.Patients and Methods: The database of the CML Cooperative Study Group, which includes patients who were initially diagnosed with CML after the introduction of imatinib (April 2001), was reviewed, and patients who were given nilotinib or dasatinib as first-line therapy were identified. The event-free survival (EFS, defined as the loss of treatment efficacy, disease progression, or any cause of death), and rates of cumulative major molecular response (MMR), and deep molecular response (DMR, defined as the depth of MR 4.5) were compared between the nilotinib and dasatinib groups. Further, the predictive ability of the Sokal, Hasford, and European Treatment and Outcome Study (EUTOS) scoring systems for the achievement of molecular responses was also evaluated. For the analysis of molecular responses, patients who switched from their initial treatment agent to another TKI before achievement of MMR or DMR were considered to have no MMR or DMR.Results and Discussion: Out of 361 patients with CML-CP enrolled in our database, 58 and 63 were treated with conventional doses of nilotinib (300 mg twice daily) and dasatinib (100 mg once daily), respectively, as first-line therapy. Patients who had been started on a low dose TKI therapy were excluded from this analysis. The patient demographics, including age, sex, observation periods, and the Sokal, Hasford, and EUTOS scores did not show significant differences between the groups. In total, there were five events during the observation period (1 in the nilotinib group and 4 in the dasatinib group), and all events were deaths unrelated to CML, except for one in a patient in the dasatinib group who showed loss of complete cytogenetic response. The disease did not progress to the accelerated or blastic phase in any of the cases. The EFS did not differ between these two groups (p = 0.214). The MMR rates by 6, 12, 18, and 24 months were 59%, 72%, 74%, and 81%, respectively, in the nilotinib group and 52%, 73%, 81%, and 86%, respectively, in the dasatinib group. The DMR rates by 6, 12, 18, and 24 months was 7%, 17%, 24%, and 28%, respectively, in the nilotinib group and 3%, 16%, 25%, and 29%, respectively, in the dasatinib group. During the first 24 months of treatment, 4 (7%) patients in the nilotinib group and 11 (17%) in the dasatinib group had been switched to other TKIs (p = 0.0983). Among the three scoring systems, only the Hasford score could predict the achievement of DMR, and all of them failed to predict the achievement of MMR in the entire cohort. Our data suggest that both nilotinib and dasatinib have comparable efficacies, with high molecular response rates and promising outcomes. The validity of our findings should be tested in a randomized study, which is currently underway in Japan. DisclosuresTakaku:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Novartis Pharma K.K.: Honoraria, Speakers Bureau. Tokuhira:Mitsubishi Tanabe Pharma Corporation: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; AYUMI Pharmaceutical Corporation: Speakers Bureau; Chugai: Speakers Bureau. Asou:Eisai Co., Ltd.: Research Funding; SRL Inc.: Consultancy; Yakult Honsha Co., Ltd.: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Asahi Kasei Pharma Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Kizaki:Nippon Shinyaku,: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Speakers Bureau. Kawaguchi:Novartis Pharma K.K.: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Alexion: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau.

Adolescent and Young Adult Chronic Myeloid Leukemia in Real-World Settings: Experience from a Tertiary Care Institute in Northern India.

The data on adolescent and young adult chronic myeloid leukemia (AYA-CML) from the Indian subcontinent are scarce. We studied characteristics of AYA-CML through a retrospective analysis of 1950 CML patients registered to a tertiary care hospital in Northern India. AYA-CML represented 22.1% of all CML patients, with cumulative overall survival (OS) of 84%, and 1 and 8 years OS of 94.2% and 74.2%, respectively. Of all cases, 8.91% patients had advanced disease at the time of diagnosis, and 13.95% had myelofibrosis in the diagnostic marrow, 79.6% had complete cytogenetic response (CCyR), and 84.5% had major molecular response (MMR). Loss of CCyR and MMR was noted in 37.2% and 28.4%, respectively. The cumulative OS was significantly better in patients on patient assistance program, and they were initiated on therapy within 3 months of symptom onset.

Limfocytoza CD4+CD8+ oraz wysięki osierdziowy i opłucnowy u chorego na przewlekłą białaczkę szpikową w fazie przewlekłej leczonego dazatynibem z powodu niepowodzenia terapii imatynibem

Using tyrosine kinase inhibitors in chronic myelogenous leukemia (CML) patients may have resulted in abnormalities of the immune system. The paper is showing disease outcome in a patient with CML in chronic phase treated with interpheron a, and thereafter with imatinib (IM) due to loss of major cytogenetic response. After 4 years of IM treatment, despite previous major molecular response (MMR) obtained, loss of complete cytogenetic response was documented (mutational resistance, M244V BCR/ABL1). Administering 100 mg dasatinib daily in consecutive treatment line allowed obtaining deep molecular response (DMR). During initial 9 months of the treatment, tolerance was good. Thereafter, the general symptoms could be observed (subfebrile states, excessive sweets), rhinitis and leukocytosis with absolute lymphocytosis CD3+, CD8+, HLA-DR in the peripheral blood. After two years, due to an increase in symptoms intensity, the dose of the drug was reduced to 80 mg daily. It was related with symptoms release and normalization of leuko- and lymphocyte count in the blood. Drug dose reduction, however, resulted in loss of MMR. Increasing the dose to the initial one allowed re-obtaining DMR. Improvement in molecular response quality was associated with reccurrence of general symptoms and lymphocytosis in the peripheral blood. After a few months, pleural/pericardial effusion symptoms were noted. Patient required hospitalization and therapeutic paracentesis. After normalization of the general patient status, the decision about nilotinib treatment was taken. During 12 months follow-up, the drug tolerance was good. Nilotinib treatment resulted in fast disappearance of general symptoms and lymphocytosis, and achievement of DMR.

Does the Achievement of MR4.5 Improve the Outcome of Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Treated with Front Line Tyrosine Kinase Inhibitors (TKI)?

Background: Aside from the possibility of treatment discontinuation, the prognostic significance of deep molecular responses regarding survival endpoints in pts with CP-CML treated with TKI remains controversial. Achievement of complete cytogenetic response (CCyR) correlates with improved overall survival (OS). Among pts with CCyR, achievement of major molecular response (MMR) correlates with improved event-free survival (EFS). We have previously shown that among pts in sustained CCyR, those who achieve deeper molecular responses at 18 or 24 months may have longer EFS and failure-free survival (FFS) but not transformation-free survival (TFS) or OS. In this analysis, we sought to determine whether the achievement of a MR4.5 might correlate with improved long-term outcome in CP-CML pts who achieve CCyR after frontline TKI therapy.Methods: Pts with CP-CML treated with front line TKI, including imatinib 400 mg daily (IM400), imatinib 800 mg daily (IM800), nilotinib (NILO), or dasatinib (DASA), were included in the analysis. Landmark analyses were conducted at various time points to identify the association between achieving MR4.5 and various survival outcomes. Since the benefit of achieving CCyR is well established, only pts who were in CCyR were considered at each time point. The probabilities of OS, EFS, FFS and TFS were estimated using the Kaplan-Meier method and Cox proportional hazards regression models were fit to assess the association between OS, EFS, FFS, TFS and response. All outcomes were measured from the date treatment was started. OS was measured until death from any cause; TFS until death or transformation to accelerated (AP) or blast phase (BP) during study; EFS until loss of complete hematologic response or major cytogenetic response, transformation to AP or BP, or death from any cause; FFS until any event (as per EFS definition), failure (as defined by the ELN criteria), loss of CCyR, discontinuation or change of therapy for any reason.Results: The study population consisted of 478 pts. 59% of them were males and 9% had high Sokal score at diagnosis. 71 pts received IM400, 204 IM800, 105 NILO, and 98 DASA. Median follow-up is 106 (4-177) months (163 for IM400, 133 for IM800, 61 for NILO and 71 for DASA). The overall cumulative rate of CCyR was 92% (85% for IM400, 90% for IM800, 99% for NILO, and 97% for DASA). The overall cumulative rate of MR4.5 was 73% (56%, 74%, 80% and 78%, respectively for the 4 treatment cohorts). Among pts with CCyR, corresponding rates of MR4.5 were 79% overall and 66%, 81%, 83% and 80%, respectively, for the 4 treatment cohorts. For the entire population, the 5-year OS was 92.7%, TFS 86.0%, EFS 80.7%, and FFS 69.1%. In pts who were in CCyR at 12, 18, 24, 30, 36 or 48 months after initiation of TKI therapy there was no significant difference in terms of EFS, FFS, TFS or OS between pts who achieved a MR4.5 and those who did not (Table).Conclusion: Our analysis suggests that the achievement of MR4.5 does not provide a meaningful improvement in EFS, FFS, TFS, or OS for CP-CML pts who have achieved CCyR after being treated with frontline TKI. While obtaining a MR4.5 may enable the option of TKI discontinuation, our results suggest that failure to do so should not be considered failure or suboptimal response and thus should not prompt a change in TKI in pts who are in CCyR. Change of therapy to achieve MR4.5 with the goal of treatment discontinuation should be considered only within clinical trials.Table 1Cox proportional hazards models for EFS, FFS, TFS, and OS at various time points.Time pointEFSFFSTFSOSHR95% CIp-valueHR95% CIp-valueHR95% CIp-valueHR95% CIp-value12 months0.820.42-1.610.570.940.58-1.530.810.990.46-2.120.981.060.47-2.390.8918 months0.960.51-1.820.90.750.45-1.250.271.340.69-2.810.361.410.68-2.940.3524 months0.850.44-1.650.630.80.49-1.330.390.90.41-2.010.80.990.43-2.250.9730 months0.750.35-1.620.470.640.36-1.150.140.820.34-1.960.650.980.40-2.390.9736 months0.980.46-2.090.960.550.30-1.020.061.110.47-2.650.811.240.52-2.950.6348 months0.860.35-2.100.730.70.35-1.400.310.840.29-2.430.750.860.30-2.480.78 DisclosuresPemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Consultancy, Research Funding.

Impact of Finding of Low Level Kinase Domain Mutations Using Ultra Deep Next Generation Sequencing in Patients with Chronic Phase CML

▪Kinase domain (KD) mutations in the BCR-ABL1 gene are associated with resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML). Next-generation Sequencing (NGS) allows detection of low-level KD mutations but its relevance in clinical practice remains debated, and the incidence and prognostic significance of finding of low-level KD mutation in chronic phase (CP) patients is unknown.We analyzed the outcome for 121 newly diagnosed CP-CML patients treated with TKIs (imatinib 111, nilotinib 7 and dasatinib 3) who we routinely screened for KD mutations using ultra-deep NGS regardless of response to TKI. When a mutation was found by ultra-deep NGS (using Illumina NexteraXT and MiSeq platform) all available previous cDNA samples were analyzed to establish the date of its first occurrence and subsequent kinetics. ABL1 transcripts from 27 healthy donors were sequenced and used as a control. Sequencing for both single and nested PCR products were compared, and samples were re-sequenced in two independent runs in order to analyze reproducibility of variants detection.Median age of patients was 56 years and the Sokal risk score was 'low' in 38% patients, 'intermediate' in 15.5% and 'high' in 46.5%.A mutation was detected in 25 of the 121 patients (20.6%) at a median time of 14 months from starting TKI. 19 different mutations were identified, the most frequents being F317L (n=17), Y253H (n=15), M244V (n=14) and T315I (n=10).All mutations previously detected by Sanger sequencing were also found using ultra-deep NGS. In addition low-level mutations (<20%) were found using ultra-deep NGS in 23 samples (16 patients), while not being detected using Sanger sequencing. Multiple mutations were found in 14 samples (10 patients).Eighteen patients discontinued imatinib while still in CP and received dasatinib, nilotinib or an allogeneic stem cell transplantation. The overall progression-free survival (absence of advanced phase) at 5 years was 85%. Complete cytogenetic responses (CCyR) and major molecular responses (MMR) with front-line TKI therapy were achieved in 74 (61%) and 52 (43%) patients respectively.We stratified patients according to response to TKI therapy as per 2009 ELN guidelines (Baccarani et al., 2009): patients with optimal response ('responders', R), failure at any time ('non-responders', NR) and sub-optimal response (SR). Patients with known TKI dose-interruption were analyzed separately. Mutations were classified and analyzed according to clinical relevance (clinically relevant versus clinically non relevant mutations, Branford et al., 2009).Among non-responders (NR), 37% of patients developed a mutation (29% among patients who lost CCyR), compared to only 5% among responders (2 patients, both with KD mutations sensitive to imatinib). Among patients with suboptimal response (SR), 19% developed a mutation while being in CCyR but not in MMR with all clinically relevant mutated clone percentages increasing in patients being treated with a TKI to which the KD mutation was conferring resistance. Similarly in all NR patients the mutated clone percentage rose in sequential samples if a clinically relevant mutation was detected.Patients harboring a mutant clone had a poorer PFS at 5 years compared to patients without mutation (67% versus 92%, p<.001). By multivariate analysis, factors associated with worse EFS (progression to AP/BP, death or loss of CCyR) were the presence of a KD mutation and failure to achieve CCyR at 12 months (relative risks 5.4 and 3.6, p=.003 and p=.015, respectively).We next evaluated the incidence and impact of finding of KD mutations at the early molecular response time point (3-months BCR-ABL1 transcript level). Samples from 41 patients were analyzed at 3 months of which 20 with a BCR-ABL1 transcript level > 10%. A KD mutation was found at 3 months in 4/41 patients (9.7%) all of whom progressed subsequently to advanced phase compared to only 3/37 in patients without mutation (p<0.001). Of note 3/4 patients with a KD mutation had a 3-months BCR-ABL1 transcript level >10%, while only one patient had a 3-months BCR-ABL transcript level <10%.In conclusion, ultra-deep NGS can reliably and consistently detect early appearance of KD mutation in patients who fail to achieve early molecular response at 3 months as well as in non responder patients or patients who are in CCyR but not in MMR, thus allowing potential early clinical intervention. DisclosuresBest:Onconova Therapeutics Inc: Research Funding. Pocock:Janssen: Honoraria. McLornan:Novartis: Research Funding, Speakers Bureau. Mufti:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de Lavallade:Ariad: Research Funding; Novartis: Consultancy.

Complete Molecular Response due to nilotinib as III line treatment in a patient with CML and F317L point mutation of the Bcr-Abl kinase domain

In 1997, a forty-three years old woman was diagnosed with CML and treated with alfa-Interferon, achieving complete haematological response (CHR). Three years later, patient was switched to hydroxiurea due to thyroid toxicity. For logistic reasons, therapy with imatinib 400 mg/die was initiated only in 2003, obtaining complete cytogenetic response (CCyR) and suboptimal molecular response in twelve months. CCyR and CHR were then lost three years later. Doubling imatinib dose to 800 mg/die gave no positive results. Mutational analysis performed in September 2007 showed F317L point mutation of the Bcr-Abl kinase domain. In October 2007 dasatinib was started and in April 2008 CCyR was reached with suboptimal molecular response. In March 2009 Bcr-Abl transcript progressively increased, and in August 2009 cytogenetic analysis showed loss of CCyR. Therapy with nilotinib 800 mg/die was started, and in October 2009 the patient obtained complete molecular response (CMR). Bcr-Abl kinase-domain point mutations, acquired during first line therapy, are a common cause of resistance to tyrosine kinase inhibitors. While several Bcr-Abl mutations have been identified, involvement of codon 317 has been reported in the literature following treatment with imatinib and dasatinib.

Comparison of the utility and applicability of the Sokal, Hasford, and EUTOS scores in a population of Chinese patients with chronic-phase chronic myeloid leukemia undergoing imatinib therapy.

BackgroundTyrosine kinase inhibitors are increasingly used to treat chronic myeloid leukemia (CML), but loss of complete cytogenetic response (CCyR) indicates treatment failure.AimTo compare the efficacy of Sokal, European Treatment Outcome Study (EUTOS), and Hasford prognostic scores with 3-month and 12-month CCyR, event-free survival (EFS) and progression-free survival (PFS) in patients with chronic-phase CML (CP-CML) undergoing imatinib therapy.MethodsWe retrospectively analyzed the outcome of 210 patients with CP-CML treated at the First Affiliated Hospital of Anhui Medical University treated between January 2006 and December 2013. Sokal, EUTOS, and Hasford scores were compared with 3-month and 12-month CCyR, EFS, and PFS.ResultsKaplan–Meier analyses revealed that 3-month and 12-month CCyR and PFS were lower in patients with high EUTOS scores, and intermediate or high Sokal and Hasford scores (all P<0.05). Furthermore, EFS was lower in patients with intermediate or high Sokal and Hasford scores (both P<0.05). Hasford score (hazard ratio =2.608, 95% confidence interval: 1.473–4.617, P=0.001) was independently associated with 3-month CCyR.ConclusionAlthough all three scoring systems were associated with EFS, PFS, and 3-month and 12-month CCyR in the Kaplan–Meier analyses (except EFS with EUTOS), only the Hasford score was independently associated with 3m-CCyR, while EUTOS score and Sokal score were not independently associated with any of these outcomes.

Five-Year Outcome of 215 Newly Diagnosed Chronic Myeloid Leukemia Patients Treated Frontline with Nilotinib-Based Regimens: A Gimema CML Working Party Analysis

▪Background. Nilotinib (NIL) is a potent and selective BCR-ABL inhibitor approved for the frontline treatment of chronic myeloid leukemia (CML) based on the results of the ENESTnd study. The sustained superiority of NIL vs. imatinib (IM) was confirmed after 5 years of follow-up (Hughes et al, abs. 677, EHA 2014). However, few data are available on patients (pts) treated frontline with NIL outside of Company-initiated trials.Objectives. To analyze the long-term outcome in a large, independent cohort of newly diagnosed CML pts treated frontline with NIL-based regimens.Methods. We analyzed 215 pts, enrolled in 2 multicenter phase II studies conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00481052 and NCT00769327) or treated at the Bologna University Hospital, with NIL 300 mg or 400 mg BID as initial treatment; 123 pts received a sequential treatment with NIL and IM (NIL-IM), with a 3-months (mos) rotation period (all patients received NIL in the first 3 mos). The median age was 53 years (range 18–86). Ten out of 215 pts (5%) had a high EUTOS score. The median follow-up was 57 mos (range 36–81 mos). We assessed: the rates of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR); the rates of optimal responders at each milestone according to ELN 2013 recommendations; the overall survival (OS; any death included), progression-free survival (PFS; progression to accelerated/blast phase [AP/BP] and deaths for any cause), failure-free survival (FFS; failures according to ELN 2013 recommendations and deaths for any cause), and event-free survival (EFS; events: failures, permanent discontinuation of NIL for any cause, including deaths). All analysis was made according to the intention-to-treat principle.Results. The cumulative rates of CCyR and MMR were 93% and 88%, respectively. At 3 mos, 82% of the pts were in Partial Cytogenetic Response and 90% had a BCR-ABL/ABL (IS) < 10%; at 6 mos, 86% were in CCyR and 83% had a BCR-ABL/ABL (IS) < 1%; at 12 mos, 72% were in MMR; all these pts were optimal responders according to ELN 2013 recommendations. Overall, 80 (37%) pts permanently discontinued NIL: 45 (21%) for adverse events or intolerance; 25 (12%) for failures; 7 (3%) while in stable MR4; 3 (1%) for other reasons. Cardiovascular adverse events (CVAE) were cause of permanent NIL discontinuation, after a median time of 37 mos, in 13 (6%) pts, and included 4 peripheral arterial occlusive diseases and 3 ischemic coronary diseases; only one pt died for CVAE. Nine (4.1%) pts progressed to AP/BP, 8/9 during the 1st year of therapy and one after 25 mos; all pts subsequently died (after a median of 13 mos, range 1-34 mos). NIL-resistant mutations were identified in 6 of these pts (4 T315I; 1 Y253H; 1 F359V); 7/9 progressions occurred in patients receiving NIL-IM. In addition, 6 pts were classified as failures at 3,6, or 12 mos according to ELN 2013 recommendations; afterwards, 10 pts developed a secondary resistance (3 loss of CHR, 3 loss of CCyR, and 4 confirmed loss of MMR). Overall, 17 (8%) pts died, in 7 cases for reasons unrelated to CML progression. The estimated 6-year OS, PFS, FFS, and EFS were 91%, 91%, 83%, and 59%, respectively.Conclusions. Our National experience showed that most pts treated frontline with NIL-based regimens were optimal responders according to ELN recommendations and that 91% of the patients were estimated to be alive and progression-free at 6 years. In particular, NIL alone was highly effective in the prevention of AP/BP. Considering that AP/BP had in most cases an early onset and an extremely poor prognosis, its prevention should be the priority of CML treatment, especially in the firsts 2-3 years. However, afterwards, the relatively high number of CVAE observed, suggests to focus, at least in selected patients, on strategies aimed at the prevention of CVAE (NIL dose reduction? switch to IM?).Acknowledgments. European LeukemiaNet, COFIN, Bologna University, BolognAIL DisclosuresGugliotta:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy. Castagnetti:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy. Abruzzese:Novartis: Consultancy. Martinelli:ARIAD: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Saglio:BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other. Baccarani:Novartis, BMS, Pfizer, Ariad: Consultancy, Honoraria, Speakers Bureau. Rosti:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy; Ariad: Consultancy; Pfizer: Consultancy.

The Impact of Early Molecular Response in Event Free Survival in Patients with Chronic Myeloid Leukemia Treated with Imatinib

BackgroundMonitoring response to TKI therapy is one of the key management strategies of chronic myeloid leukemia (CML). Early molecular response to first-line TKI therapy is emerging as an effective prognostic factor indicator of long-term durable response and survival.ObjectivesWe conducted a study to evaluate the importance of the early molecular response (EMR) at 3, 6 and 12 months (mo), and 3-year event free survival (EFS).MethodsThis is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) enrolled in 14 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN recommendations. EFS was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase.ResultsWe analyzed data from 517 pts with CML-CP diagnosed since 1990. After a median observation time of 46 months, 5-year overall survival (OS) was 86% and 5-year event-free-survival was 53%. At 3 mo, EFS was 72,5% for 46 pts with BCR-ABLIS ≤10% compared to 58% for 14 pts with BCR-ABLIS >10% (p<0,07). Similarly, when EMR was analysed at 6 mo, the EFS was 81% for 75 pts with BCR-ABLIS ≤1%, while 31% of EFS was achieved for 38 pts with BCR-ABLIS >1% (p<0,001). At 12 mo, the 3-year EFS was 86% for 65 pts with with BCR-ABLIS ≤0,1% compared to 54% for pts with BCR-ABLIS>0,1% (p<0,001).ConclusionsA significant proportion of pts achieve ERM after 3,6 and 12 mo of imatinib therapy with better 3-year EFS. ERM may could identify those pts more likely to have a favorable outcome. DisclosuresNo relevant conflicts of interest to declare.

Phase II Clinical Trial Results of Dasatinib for Frontline Therapy in Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP)

▪Background: Dasatinib is approximately 300 times more potent than imatinib (IM) in vitro and has significant activity in patients (pts) with CML-CP resistant to or intolerant of IM. In 2005, we initiated a phase II trial to study the efficacy and safety of dasatinib in pts with previously untreated CML-CP.Objective: To determine the long-term outcome of pts with CML-CP treated with front-line dasatinib. The primary endpoint was achievement of major molecular response (MMR) at 12 months (mos).Methods: Pts with previously untreated CML-CP within 6 mos from diagnosis were eligible and received dasatinib 100 mg/day, randomized to either 50 mg twice daily (BID) or 100 mg once daily (QD). After 66 pts were accrued, the BID arm was closed and all subsequent pts were treated with 100 mg QD. No prior therapy was allowed except for IM for <1 month, or hydroxyurea.Results: From November 2005 to August 2014, a total of 155 pts have been enrolled. For this analysis, we included only those pts with a minimum of 12 mos follow-up: 107 pts (77 QD, 30 BID). Median age was 48 years (yrs) (range 16–83 yrs). Median baseline counts: WBC 26.4 K/uL, peripheral blood blasts 0%, bone marrow blasts 2%, and platelets 333 K/uL. Twenty-seven pts (25%) had brief prior exposure to IM. Sokal score by distribution: Low (76%), Intermediate (21%), High (4%). Median follow-up is 62.9 mos (11.7 - 104.1 mos). Of the 99 evaluable pts who were not in CHR at the start of therapy, 99 (100%) achieved CHR. Of 105 evaluable pts (ie, followed for at least 3 mos), 105 (100%) achieved complete cytogenetic response (CCyR). MMR has been achieved in 94 pts (90%), including 59 pts (56%) with complete molecular response (CMR; minimum 100,000 ABL copies). BCR-ABL/ABL <10% at 3 mos occurred in 100/106 evaluable (94%) and at 6 mos in 98/104 evaluable (94%). At 6 mos, 93/102 evaluable (91%) pts had achieved a CCyR and 69/101 evaluable (68%) an MMR; corresponding figures at 12 mos are 92/97 pts evaluable (95%) and 73/95 pts evaluable (77%), respectively. Fifty-eight pts (54%) have required at least one dose reduction (most common reasons: 22 pts had dose reductions due to pleural effusions, 8 due to neurologic/headaches, 4 due to thrombocytopenia). The actual median daily dose for all pts was 80mg (20–140mg). Five pts lost CCyR: (2/5 of these pts who lost CCyR ultimately progressed to accelerated phase (CML-AP)). The 3-yr and 5-yr overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS) are shown in the Table. There have been two deaths on study (1 pt: 74 yr-old woman with sepsis/infection; 1 pt: 53 yr-old man with morbid obesity and hypertension who died of unknown causes). Twenty-six (24%) pts have discontinued therapy: 11 due to toxicity (most commonly due to pleural effusion in 7 pts), 5 pt choice, 5 lost CCyR, 2 died on study, 2 pt non-adherence, 1 due to development of T315I mutation.Conclusion: Rapid CCyR occurs in nearly all pts, and MMR was achieved in 90% of pts with previously untreated CML-CP treated with frontline dasatinib therapy with a favorable toxicity profile. Deep responses occur early. Only two patients experienced transformation to CML-AP, and only one patient developed T315I mutation. These results confirm the sustained efficacy of dasatinib as initial therapy for CML-CP.Table:Outcomes at 3-year and 5-year timepoints in patients with CML treated with frontline dasatinibTotalEvents3-Year5-YearOS107598%95%EFS107895%92%TFS107499%95%FFS1072484%76%*Definitions:EFS: includes, at any time on study: International Randomized Study of Interferon and STI571 trial (IRIS)-defined events, which includes loss of major cytogenetic response, loss of complete hematologic response, transformation to accelerated or blast phase, death from any cause while on study. FFS: includes loss of complete cytogenetic response, failure to achieve response at set times as defined by European Leukemia Net, treatment intolerance, or treatment discontinuation for any reason while on study. TFS: measured from start of therapy to date of transformation to accelerated or blast phases while on therapy or to date of last follow-up. DisclosuresKantarjian:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Research Funding. O’Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity’s Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Ravandi:BMS: Honoraria, Research Funding. Verstovsek:Incyte Corporation: Research Funding. Jabbour:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

TKI Treatment Discontinuation: How Many Patients Could Stop Tyrosine Kinase Treatment According to Discontinuation Trials Criteria? Incidence and Prognostic Impact of Deep Molecular Response in a Cohort of Chronic Myeloid Leukemia Patients of South Brazil’s Hematology Centers

Sustained deep molecular response (MR4.5) after imatinib treatment defines a subgroup of patients with chronic myeloid leukemia (CML) with better outcome and that probably would be able to stop treatment in the future, according to results of clinical TKI discontinuation trials. Most of these trials showed that patients with a long-term imatinib treatment and low Sokal risk have a higher probability of maintain a deep molecular remission after stopping treatment.OBJECTIVESThe main objective is to review the molecular responses, overall survival and event free survival of CP CML patients that have been treated with imatinib in 14 hematology centers in South Brazil. Using our data basis we also would like to see how many of them present long-term imatinib treatment, sustained deep molecular remission and correlate these findings with the Sokal risk groups. These data would allow us to predict patient profile that could be able to discontinue the treatment in the future in a prospective clinical trial.PATIENTS AND METHODSThis is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) that have been treated in 14 hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN recommendations. MR(4.5) was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction. All tests were performed at a central standardized according to ELN. Event-free-survival (EFS) was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Overall survival (OS) was measured from the start of imatinib until death of any cause or to the date patient was last known to be alive.RESULTSData from 474 patients was analyzed. After a median observation time of 46 months, 5-year overall survival (OS) was 86%, 5-year event-free-survival was 53%. Of the 474 patients, 258 had adequate PCR evaluations during treatment. 118 of 258 (45,7%) patients achieved MR(4.5) and 69 of 258 (27%) had sustained response for at least two years after a minimum time of treatment of 3 years. The cumulative incidence of MR(4.5) after 9 years was 76% (median, 3 years). In the group that achieved MR(4.5), there was only 1 (0,8%) death and 1 (1,1%) progression compared to 8 deaths (5,7%) and 8 progressions (7,5%) in the group without MR(4.5); these differences were significant with p=0,03 and 0,02 respectively. In the subgroup of 69 patients that had had been treated with imatinib for 3 year or more and sustained deep response (RM4,5) for at least two years, 21 pts had low Sokal risk, 7 pts intermediate Sokal risk and only 4 pts a high Sokal risk. Unfortunately, in 37 pts the Sokal risk could not be accessed due to missing information.CONCLUSIONIn our series MR(4.5) is reached in the majority of patients with long-term imatinib treatment. MR(4.5) is a predictor of outcome with only one disease progression and one death due to CML in this group of patients. Unfortunatly PCR are not available for all patients in our clinical practice, but this situation are improving. Regarding the 69 patients with TKI discontinuation trial criteria, we find out that 21 patients fulfill such criteria. In the future, according to the results of current stop trials it could be possible include this selected group of CP CML patients in a prospective clinical trial. DisclosuresNo relevant conflicts of interest to declare.

The Risk of Relapse in CML Patients Who Discontinued imatinib Can Be Predicted Based on Patients Age and the Results of dPCR Analysis

▪Introduction. Chronic myeloid leukemia (CML) patients (pts) treated with imatinib first line achieve complete cytogenetic response (CCyR) in > 70% of cases and major molecular response (MMR) in 18-58%. These pts have a life expectancy similar to the general population. However even undetectable BCR-ABL may not equate to eradication of the disease because of the sensitivity of Q-RT-PCR. A new diagnostic method, the digital-PCR (dPCR), able to detect 1 BCR-ABL+ cell out of 107 cells, has been recently developed (Goh HG et al., 2011). dPCR corresponds to a 100 fold increase in sensitivity as compared to Q-RT-PCR. Therefore, dPCR by assessing the presence of minimal residual disease with higher sensitivity, could potentially identify pts in whom CML has been eradicated.Aims. The Imatinib Suspension And Validation (ISAV) study is aimed at validating the capability of dPCR to predict relapses after imatinib discontinuation in CML pts with negative Q-RT-PCR results.Methods. This study involves 15 sites, 10 in Italy and 1 in each of the following countries: Germany, Spain, The Netherlands, Canada and Israel. CML pts (Chronic or Accelerated Phase) under imatinib therapy since more than 2 years and in complete molecular remission (CMR) were eligible for this study. Patients had to be in CMR for at least 18 months (mts), with a minimum of 3 Q-RT-PCR performed at their own sites. After signing the informed consent, blood samples are obtained for dPCR and the pts discontinue imatinib therapy. Standard Q-RT-PCR is performed monthly (mts 1-6) and then bimonthly for 36 mts to assess the maintenance of the molecular remission. The loss of molecular remission is defined as two consecutive positive Q-RT-PCR tests with at least one BCR-ABL/ABL value above 0.1%. Patients losing molecular remission resume imatinib treatment at the same dosage used before interruption. Patients’ quality of life during imatinib discontinuation/resumption is evaluated through the EORTC – C30 Quality of Life questionnaire.Results. The enrolment in ISAV began in November 2011 and ended in July 2013. The study enrolled 112 pts: Italy 69.6%, Germany 21.4%, Canada 5.3%, Spain 2.6% and Israel 0.9%. Among the 112 pts, 59.3% were male and 37.0% were aged 65 or older; median duration of imatinib treatment was 103.1 mts with median duration of CMR of 25.8 mts before imatinib discontinuation. To date, the median follow-up (FUP) time is 16.6 mts [95% CI: 14.9-18.2]. Forty-seven pts (43.5%, 95% CI: 34.0-53.4) of the 108 eligible pts relapsed and resumed imatinib; 38/47 (80.9%) of them relapsed in the first 9 mts and the last relapse occurred 19.6 mts after imatinib discontinuation. A loss of CCyR occurred in 11 pts (23.4%): 10/11 CCyR losses were recovered; 1 patient withdrew the consent shortly after obtaining a partial cytogenetic response. No case of CML progression was observed. After the resumption of imatinib the median time to either MMR or CMR was 1.9 [95% CI: 1.2-2.4] mts. Of the 61 not-relapsed pts, 43 (39.8% of the total) regained Q-RT-PCR positivity but never lost MMR. The median time to Q-RT-PCR positivity was 3.6 mts [95% CI: 3.0-4.8] and the range of duration of Q-RT-PCR positivity (below 0.1%) was between 5.7 and 29.2 mts. No significant correlation between relapse and previous duration of imatinib treatment, use of interferon, time to CCyR or duration of CMR was identified. An inverse relationship between pts age and risk of relapse is evident: 90% of pts < 45 years relapsed vs 37.5% in the class ≥ 45 - < 65 years and 27.5% of pts ≥ 65 years, p(χ2)<0.0001. dPCR results showed that 23.4% of pts were positive and 76.6% negative, with a dPCR Negative Predictive Value (NPV) of 63.4% (Tab.1) and a significant NPV ratio (dPCR/Q-RT-PCR) of 1.131 [95% CI: 1.032-1.239]. Age and dPCR results predicted the risk of relapse: pts with less than 45 years and with a positive dPCR had the highest risk of relapse (100%) as opposed to pts ≥ 45 years and with negative dPCR (30.6%; Fig.1).Conclusions. After 32 mts from the beginning of the study, with a median FUP of 16.6 mts, 43.5% of pts relapsed; the majority of relapses developed in the first 9 months after imatinib discontinuation. Age < 45 years and dPCR positivity are significantly associated with relapses. Funded by Regione Lombardia. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Warning As Defiened By European Leukemia Net 2013 (ELN 2013) In Chronic Phase Chronic Myeloid Leukemia (CP-CML) Corresponds To Warning In The Clinical Practice?

BackgroundTreatment of chronic myeloid leukemia with imatinib leads to disease remission in a majority of patients (pts), but in a subgroup of pts controlling the disease remains a challenge. One of the proposed prognostic factors for identifying this subset of pts is the treatment response in the first months of imatinib therapy. The definitions of response, warning signs and failure to treatment, with the identification of pts at greater risk of progression or failure, were revised and published in 2013 by the European Leukemia Net group. AimsTo apply the new recomendations of ELN2013 in order to verify the evolution of the patients according to the response criteria at 12 months (mo) of imatinib therapy. MethodsRetrospective study in a cohort of patients with CP-CML from a southern Brazilian database. All patients received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN2013 criteria and were classified in 3 groups according to the cytogenetic and molecular responses at 12 mo: optimal, warning and failure. An event was defined as any of the following while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. ResultsData from 98 pts with a median follow-up (FU) time of 40 mo was analysed. At 12 mo of imatinib therapy, 35 pts (36%) had optimal response according to the ELN2013 criteria. 26 (26,5%) were classified as warning and 37 (37,5%) as failure. Within the pts with optimal response, only 4 (11%) have had any event, with a median time-to-event (TTE) of 36 mo; in the warning group the event rate and TTE were 3 (12%) and 28 mo, respectively. There were no significant differences in the results between these two groups. On the other hand, within the pts with failure, 24 (65%) presented an event during FU with a TTE of 19 mo. This difference was significant compared to the two previous groups. Interestingly, within the warning group, 12 pts (46%) developed major molecular response (MMR) at any point during FU, while only 12 (32%) pts achieved RMM in the failure group. ConclusionIn this cohort of CP-CML pts is established the diference in the event rate between the pts who achieve optimal or warning responses at 12 mo of imatinib treatment when compared with those with failure criteria, according to the new ELN2013 recomendations. Despite having some late responders, atention must be paid in pts in the failure group as they are in greater risk of progression or failure. As demonstrated in this analysis, the ELN2013 criteria can be applied in this population in the clinical practice. Disclosures:No relevant conflicts of interest to declare.

Treatment Results With Dasatinib Or Nilotinib In Third Line Therapy Of Chronic Myeloid Leukemia After Failure Of Two Tyrosine Kinase Inhibitors

Chronic myeloid leukemia (CML) patients with imatinib failure are usually treated with second generation tyrosine kinase inhibitors (TKI). In case of dasatinib or nilotinib intolerance or resistance patients with HLA matched donor are submitted to allogeneic hematopoietic stem cell transplantation (HSCT) or switch treatment to a different TKI. Aimsto evaluate complete hematological response (CHR), cytogenetic and molecular responses, overall, progression free and event free survival (OS, FPS and EFS) in CML patients in third line therapy that previously used 2 TKI. BCR-ABL mutations was also evaluated in this population Patients and methodsbetween July 2008 and August 2012 26 CML patients were evaluated: 10 patients (pts) treated with dasatinib (38,5%) and 16 with nilotinib (61,5%) in third line therapy. OS, PFS and EFS were calculated with Kaplan-Meier method and Log-Rank was used for comparison, from the date of the third TKI start. The events for PFS were progression to accelerated phase (AP) or blast crisis (BC) and death. For EFS, were considered loss of CHR, loss of complete cytogenetic response (CCR), TKI discontinuation for failure or intolerance, progression or death. Patients were censored in HSCT date or TKI discontinuation for cytogenetic and molecular responses evaluation, but not for OS. Mutational analysis was done with Sanger sequencing. Results13 male (50%) and 13 female patients with median age 54 years (22-75) and median follow-up of 32 months were analyzed (1-59). Previous response to imatinib: only one patient has achieved CCR. Status before third TKI start: 19 (73%) less than partial cytogenetic response (PCyR); 2 (7,7%) PCyR; 4 (15,5%) CCR;and 1 (3,8%) clonal evolution. 8/18 (42%) patients presented the following mutations: F317L (2), E255V (1), Y253H (1), M351T (1), M244V (1) e F359V (2). The median time of the third TKI treatment was 171 days (15-1140). Responses to third line TKI: CHR 17/19 (89%) in CP; 3/3 AF; 0/4 BC; CCR: 3/19 in CP (2 pts at 3 months and one in the 12º month); 1/3 AP; 0/4 BC; MMR: 4/19 in CP; 1/3 AP; 0/4 in BC. Nine lost CHR (45%) (8 in CP and one in AP).At 3 months, 1/21 pts (4.5%) achieved MMR; 2/13 (15%) at 6 months, while at 12 months 1/11 (9%) had MMR. At 3 months 11/21 had a BCR-ABL/ABL(IS) >10% and at 6 months 10/13 >1%. Three patients progressed to advanced phases (11,5%) ; 6 (23%) died (4 due to LMC, 1 acute myocardial infarction and 1 from graft vs host disease after HSCT; one lost follow-up. Third line treatment was discontinued in 12 (46%) pts: 6 for resistance, 2 death; 2 intolerance and resistance; 1 intolerance and one loss of follow-up.OS, PFS and EFS were 69%, 68% e 30% respectively(figure 1). OS was inferior in AP and BC in comparison with CP (0% vs 50% vs 90% - p< 0,0001)(figure 2). In summaryresponses may be obtained with dasatinib or nilotinib after 2 TKI failure, but they are not durable in advanced phases. Besides the results, that is an alternative for disease stabilization until the identification of a suitable donor or for patients with no performance status for HSCT. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.