Leukemia Patients In Chronic Phase Research Articles

Risk Stratification of Chronic Myeloid Leukaemia Patients with ELTS Risk Score at a Tertiary Care Hospital in Bangladesh

Introduction: Chronic Myeloid Leukaemia (CML) is a myeloproliferative neoplasm characterised by uncontrolled proliferation of white blood cells and its precursors. At diagnosis, various risk scoring systems have been formulated for risk stratification. In 2016, European Treatment Outcome Study (EUTOS) Long Term Survival (ELTS) score has been formulated most recently. This score was recommended by European LeukaemiaNet in 2020. Objective: The objective of the study was to estimate the frequency of high-risk patients among Chronic Myeloid Leukaemia patients in chronic phase using ELTS scoring system. Materials and Methods: This observational study was conducted among patients at Bangabandhu Sheikh Mujib Medical University (BSMMU) between September 2020 and October 2021. A total of fifty chronic myeloid leukaemia patients were enrolled using purposive sampling technique. Clinical information and haematological parameters were recorded. Bone marrow study was conducted to confirm phase of the disease. ELTS risk score was calculated, and risk stratification was done. Chi-square test was done to find out statistical association between variables. Results: Among study participants, 14% were identified as high-risk cases using ELTS score. 40% of patients were intermediate-risk and 46% were low-risk disease. Presence of hepatomegaly or splenomegaly were significantly more common among high-risk patients. Significantly increased eosinophil and blast percentages and significantly lower haemoglobin level were found in high-risk patients. Conclusion: A fair proportion of the CML patients were identified as high-risk patients. Hepatomegaly, splenomegaly, lower haemoglobin, higher eosinophil and higher blast percentages were identified to be independently associated with higher risk stratification of patients.

An Observational Prospective Study of Dasatinib 50mg Daily As Frontline Therapy in Newly Diagnosed Chronic Myeloid Leukemia Patients in Chronic Phase

Study Title: An observational prospective study of Dasatinib 50mg Daily as Frontline Therapy in newly diagnosed Chronic Myeloid Leukemia patients in Chronic Phase Background: BCR-ABL Tyrosine kinase inhibitors (TKI's) are most successful of targeted therapies and are currently considered cornerstone in the management of patients with chronic myeloid leukemia (CML). TKIs approved for first line therapy in CML are Imatinib, Nilotinib, Dasatinib and Bosutinib. Data suggests that Dasatinib, a second generation TKI is 325 times more potent than Imatinib. [1, 2] A five-year follow-up of DASISION study showed that Dasatinib 100mg as a frontline lead to more rapid and deeper responses at early time points when compared with Imatinib, with estimated 5 years OS & PFS as 91% and 85%, also 5-year MMR rate as 76% respectively. [3] Talpaz. M. et al study showed that Dasatinib is active in lower dose and have better safety profile when evaluated as a second line treatment after Imatinib failure. [4] Naqvi et al. results showed that Dasatinib 50mg is active and well tolerated and also have the better 3- and 6-month rate of molecular response (BCR-ABL1 transcripts (IS) ≤1%) i.e., 72% and 84%, compared with 48% and 69% with Dasatinib 100mg, and 13% and 49% with imatinib 400mg, respectively. [5, 6]. Therefore, we aim to evaluate the molecular responses and safety of Dasatinib 50mg daily as a frontline therapy in Indian CML-CP patients. Material & Methods: It is an observational prospective study. All CML-CP patients started on Dasatinib 50mg daily will be offered to participate in this study. The data of demography, baseline characteristics, molecular response, toxicity, deaths, progression will be collected and the same will be entered in case record form/excel sheet. We retrospectively collected the data of Imatinib to compare the response outcome with lower dose dasatinib 50mg daily. Patients who received frontline dasatinib 50mg for less than 3 months for reasons other than toxic effects or intolerance to dasatinib were discontinued from the study. Informed consent form has been taken from patients who participated in the study. Objectives:To evaluate and compare the efficacy of lower dose dasatinib 50mg daily and Imatinib in Indian patients with CML-CP.To assess toxicities of lower dose dasatinib 50mg daily according to the CTCAE v 5.0 Results: Between June 2020 to Feb 2022, total 50 patients were included in the dasatinib 50mg once daily. Median age is 40 yrs. ranging from (19-73) yrs. Median spleen and liver size is 8cm (2 - 22) cm and 2cm (0 - 16.8) cm respectively. Duration of symptoms are 60 days (4 - 547) days. Median Hb, TLC and Platelets are 10.25gm/dL (5.1 - 14.9) gm/dL, 158980/cumm (30400 - 572880)/cumm and 327 × 109/L (83 - 789) × 109/L. Median time from diagnosis to treatment was 6 days (0 - 20) days. At a median follow up of 9.2 months, 49 patients completed 3 months and out of which 48 patients were evaluated as one patient stopped medication after a month due to financial constraint. The response rate at 3 months of lower dose of dasatinib 50mg daily and Imatinib were 68.75% and 69.7% respectively. At 12 months 68% and 66.6% patients achieved major molecular response [BCR-ABL≤0.1%] in dasatinib 50mg and imatinib group respectively. Dasatinib 50mg is showed somewhat similar profile in comparison to early molecular response [EMR], but patient on lower dose dasatinib achieved a good percentage of deep molecular response [MR4.0: BCR-ABL ≤ 0.01% and MR4.5: BCR-ABL ≤ 0.0032%] even at 6 months i.e., 05 (16.1%) and 02 (6.45%) respectively. Six (12%) patients switched to other TKI (Toxicity: 02 & Suboptimal Response/Failure: 04) and 10 (20%) of patients required dose escalation in view of suboptimal response/failure with low dose dasatinib 50mg daily group. Treatment was well tolerated in lower dose dasatinib 50mg daily group. Weight gain (04), Constipation (02), Thrombocytopenia (05), Elevated Liver Enzymes (02). Diarrhoea (03), Oral mucositis (01) and Skin Hypopigmentation (01) was observed in dasatinib 50mg daily group. All patients were alive in low dose dasatinib 50mg daily group whereas 2 patients expired in imatinib group and the cause is unknown. Conclusion: Lower dose dasatinib is safe and effective as an upfront therapy in CML-CP. Lower dose dasatinib showed faster and deeper molecular response as compared to Imatinib. Dasatinib, taken daily at a dose of 50 mg, may offer a new, cost-effective choice for frontline therapy in CML-CP. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mortality rate in patients with chronic myeloid leukemia in chronic phase treated with frontline second generation tyrosine kinase inhibitors: a retrospective analysis by the monitoring registries of the Italian Medicines Agency (AIFA).

The introduction of tyrosine kinase inhibitors (TKIs) has improved the overall survival of chronic myeloid leukemia patients in chronic phase (CP-CML) and reduced the rate of disease-related mortality. Conflicting results have been however reported between data emerged from sponsored clinical trials and from population-based registries. Moreover, no data are so far available for patients treated with frontline second-generation TKIs, excluding those from sponsored studies. We analyzed the mortality rate of 2315 CP-CML patients treated with frontline second-generation TKIs through the Italian Medicines Agency (AIFA) registries and compared it with the ISTAT mortality rate of the general population. The estimated differences show that the increased rate of mortality in CP-CML patients is less than 1% for the class 0-29years, stable around 2% for the intervals 30-44years and 45-59years, and 1.4% for the interval 60-74years; interestingly this rate is reduced for patients aged 75years and more as compared to the general population (- 0.65%). The difference between potential and estimated deaths is higher among women in the age classes between 30 and 74years.

Nilotinib Vs Nilotinib Plus Pegylated Interferon α (Peg-IFN) Induction and Nilotinib or Peg-IFN Maintenance Therapy for Newly Diagnosed BCR-ABL1 Positive Chronic Myeloid Leukemia Patients in Chronic Phase (TIGER Study): The Addition of Peg-IFN Is Associated with Higher Rates of Deep Molecular Response

Introduction: The TIGER (CML V)-study* (NCT01657604) is a multicenter, randomized phase III trial to evaluate efficacy and tolerability of nilotinib (NIL) 2*300mg/d monotherapy vs NIL 2*300mg/d + pegylated interferon α2b (Peg-IFN) 30-50μg/week as first line therapy for chronic myeloid leukemia (CML) patients (pts) in chronic phase and discontinuation of therapy after Peg-IFN maintenance (Figure). Methods: In August 2012, recruitment started with a pilot phase, aiming to validate the recommended dose of Peg-IFN. 25 pilot phase patients were treated with the combination of NIL 2*300 mg daily and Peg-IFN (30-50μg/week according to tolerability and commenced after ≥6 weeks NIL monotherapy). During the main phase of the study, 692 newly diagnosed pts were randomized between NIL 2*300 mg/d and NIL/Peg-IFN combination according to the outcome of the pilot phase. Results: Within 5 years, a total of 717 pts (429 male; median age 51 years, range 18-85; 12.9% EUTOS high risk) were recruited from 109 sites in Germany, Switzerland, and the Czech Republic. 702 pts with typical BCR-ABL1 transcripts (97.9%) were eligible for molecular follow-up assessments according to the international scale (IS). Fifteen pts (2.1%) expressed atypical BCR-ABL1 transcripts. 692 pts were randomized after EUTOS risk stratification to receive NIL monotherapy (n=353) or NIL/PEG-IFN combination therapy (n=339). Median observation time since recruitment was 41 months. Up to now, 477 pts concluded the induction phase by achieving a confirmed major molecular response, MMR (BCR-ABL1 transcript levels ≤0.1% IS, which qualified for entering the maintenance phase of the study using NIL or Peg-IFN monotherapy. During the maintenance phase, 199 pts achieved or sustained MR4 (BCR-ABL1 ≤0.01% IS) for at least one year and then discontinued all therapy. While the rate of MMR at 12 and 18 mo - the first primary endpoint of the study - was not different between the treatment arms, adding Peg-IFN to upfront NIL significantly improved rates of MR4 and MR4.5, BCR-ABL1 ≤0.0032% IS) (Table). In competing risk analysis, median time to MMR was 5.7 vs 5.4 mo, to MR4 20.9 vs 12.5 mo, and to MR4.5 33.8 vs 23.2 mo for NIL vs NIL/Peg-IFN, respectively. After NIL discontinuation, during Peg-IFN maintenance therapy, rate of molecular recurrence (BCR-ABL1 >1% IS) after 18 mo was 28%. From 199 pts who discontinued all therapy, 63 experienced a molecular relapse (BCR-ABL1 >0.1%). Relapse free survival by 18 mo after treatment discontinuation was 61% in the total cohort. By protocol, it is too early to assign relapse rates to the randomized treatment arm. Frequencies of adverse events after 24 mo of therapy were 90 and 92% (grade 1-5) and 36 and 42% (grade 3-5) for NIL vs NIL/Peg-IFN, respectively. Adverse events of special interest (all grades) were fatigue in 34.6 vs 40.4%, thrombocytopenia in 13.3 vs 18.9% and elevation of the alanin aminotransferase (ALAT) in 11.0 vs 18.9% of pts in the NIL vs NIL/Peg-IFN arms, respectively. Fifteen pts (2.1%) progressed to accelerated phase or blast crisis; 22 pts (3.1%) received an allogeneic stem cell transplantation, 10 of them after disease progression. In total, 22 pts (3.1%) died, 16 during the induction phase, 4 in the maintenance phase and 2 in treatment free remission. Four deaths were related to CML, 3 to vascular complications. Conclusions: This per protocol interim analysis demonstrates feasibility of the first-line treatment with NIL 2*300 mg/d combined with PEG-IFN 30-50 μg/week. Peg-IFN, when added upfront to NIL further increases the rates of MR4 and MR4.5, which may translate into higher rates oftreatment free remission. *The study is being conducted on behalf of the German CML Study Group, the Swiss Group for Clinical Cancer Research (SAKK) and the East German Study Group on Hematology and Oncology (OSHO). Disclosures Hochhaus: Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Burchert:Novartis: Research Funding. Saussele:Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria. Baerlocher:Novartis: Research Funding. Brümmendorf:Janssen: Consultancy; Ariad: Consultancy; University Hospital of the RWTH Aachen: Employment; Pfizer: Consultancy, Research Funding; Merck: Consultancy; Novartis: Consultancy, Research Funding. La Rosée:Novartis: Research Funding; Bristol-Myers-Squibb: Consultancy, Other: Travel support, Speakers Bureau. Heim:Novartis: Research Funding. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. le Coutre:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Lange:Novartis: Research Funding. Fabarius:Novartis: Research Funding. Hänel:Novartis: Honoraria; Amgen: Honoraria; Takeda: Other: advisory board; Celgene: Other: advisory board; Roche: Honoraria. Stegelmann:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Hasford:Novartis: Research Funding. Hehlmann:Novartis: Research Funding. Ernst:Novartis: Research Funding. OffLabel Disclosure: Combination of Nilotinib and PEG-IFN alpha is being tested is off-label and being tested in the TIGER study.

Evaluation of anemia after long-term treatment with imatinib in chronic myeloid leukemia patients in chronic phase

IntroductionThe incidence of grade 3–4 anemia was reported to be 3% with imatinib therapy for newly diagnosed chronic myeloid leukemia (CML) in the chronic phase (CP). However, there are few data regarding the causes and the development of anemia after long-term treatment. This study aimed to evaluate the incidence of anemia after at least two years of imatinib treatment of CML patients in the CP and to identify other contributing causes of anemia in this population. Patients and methodsWe performed a retrospective analysis of 97 CML patients in the CP treated with imatinib for at least two years. We analyzed the hemoglobin (Hb) levels of CML patients at diagnosis, upon initiation of treatment with imatinib and after two years of imatinib treatment, and investigated other causes of anemia in this population. ResultsMost of the patients presented Hb levels below the normal range (80.4%) after the second year of treatment, 17.9% grade 2 and 1.3% grade 3. In 13 cases (16.7%), anemia was attributed to resistance and in 13 cases (16.7%) the following causes were identified: iron deficiency (n=5), hypothyroidism (n=2), vitamin B12 deficiency (n=3), acquired immune deficiency syndrome (AIDS) (n=1), pulmonary tuberculosis (n=1) and renal toxicity (n=1). In 52 patients (66.6%), there were no other factors contributing to anemia, except imatinib treatment. ConclusionRegular follow-up is required to identify the causes of anemia not related to CML or imatinib toxicity. The importance of investigating secondary causes of anemia should be emphasized, especially in patients with good adherence to treatment and satisfactory therapeutic response.

De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways.

Despite the advent of tyrosine kinase inhibitors, a proportion of chronic myeloid leukemia patients in chronic phase fail to respond to imatinib or to second-generation inhibitors and progress to blast crisis. Until now, improvements in the understanding of the molecular mechanisms responsible for chronic myeloid leukemia transformation from chronic phase to the aggressive blast crisis remain limited. Here we present a large parallel sequencing analysis of 10 blast crisis samples and of the corresponding autologous chronic phase controls that reveals, for the first time, recurrent mutations affecting the ubiquitin-conjugating enzyme E2A gene (UBE2A, formerly RAD6A). Additional analyses on a cohort of 24 blast crisis, 41 chronic phase as well as 40 acute myeloid leukemia and 38 atypical chronic myeloid leukemia patients at onset confirmed that UBE2A mutations are specifically acquired during chronic myeloid leukemia progression, with a frequency of 16.7% in advanced phases. In vitro studies show that the mutations here described cause a decrease in UBE2A activity, leading to an impairment of myeloid differentiation in chronic myeloid leukemia cells.

Overall Survival and Response Rates after a 10-Year Follow-up of Chronic Myeloid Leukemia Patients in Chronic Phase Treated with Imatinib in a Real-Life Practice

Background. Imatinib, the first BCR/ABL kinase inhibitor, has drastically changed the chronic myeloid leukemia (CML) scenario improving the rate of responses and long-term outcome. The aim of our analysis was to assess, after a median follow-up of 10.2 years (range 5.8-14.8), the long-term efficacy and safety of imatinib treatment in a monocentric cohort of CML patients treated outside of clinical trials.Methods. We retrospectively analyzed a series of 458 CML patients treated with imatinib frontline or after interferon (IFN) failure at a single center between 2000 and 2016. Long-term analysis included overall survival (OS), progression-free survival (PFS), event-free survival (EFS), response to treatment and adverse events.Results. The median age was 55.1 years (range 18.8-91.2). Seventy-one % of patients received imatinib frontline and 29% after IFN failure. Median time of prior IFN treatment was 5.6 years (range 2.4-8.9); the 10-year OS of patients treated with imatinib after IFN and with imatinib frontline was 75.3% (CI 95%: 66.9-81.9) and 77.8% (CI 95%: 72.2-82.5) (p=0.468), respectively. The 10-year-OS of the whole cohort was 77.1% (CI 95%: 73.1-81.5); the 10-year probability of dying due to CML and of other causes was 7.8% (CI 95%: 5.1-10.3) and 16% (CI 95%: 11.5-18.8), respectively (Figure 1). When patients were stratified into 4 groups according to age (18-35, >35-<50, >50-<65 and >65 years), no difference was found in the 10-year OS considering only the CML-related deaths (p=0.472), whereas a difference was observed when all other causes of death were considered (p<0.001) (Figure 2). The b2a2 transcript (detected in 34% of patients) at baseline had a negative impact on the 10-year PFS (p=0.035), but not on the 10-year OS (p=0.151). The Eutos long-term survival (ELTS) better stratified the baseline risk of patients in terms of 10-year OS compared to the Sokal and Hasford scores. The 10-year PFS was 77.1% (CI 95%: 72.6-81), while the 10-year EFS was 55% (CI 95%: 50-59.6), considering as event anything that could lead to treatment discontinuation: intolerance (10.4%), lack of cytogenetic response (17.5%), no major molecular response over time (MMR, 22.6%), lack of molecular response (6.1%), evolution into blast phase (13.7%), death (29.7%). After a median time of 10.2 years, 83 patients (18.1%) achieved as their best molecular response a MMR after a median time of 2.4 years (range IQ 1.36-4.01), 74 patients (16.1%) a MR4.0 after a median time of 4.57 years (range IQ 2.08-7.33), 162 (35.3%) a MR4.5 after a median time of 8.23 years (range IQ 4.14-11.53) and 60 (13.1%) never achieved a MMR during treatment. The achievement of an early molecular response (EMR) at 3-months (BCR/ABL1 <10%) and a MMR at 12-months was associated with a significant advantage in terms of 10-year OS (p=0.006 and p=0.032, respectively) and of 10-year PFS (p=0.004 and p=0.009, respectively). One-hundred and twenty eight patients (27.9%) switched to a second generation inhibitor (2TKI) after a median time of treatment of 3.48 years (range IQ 1.47-5.89); 23 patients (17.9%) were intolerant, while 105 (82.1%) were resistant. Among resistant patients, 81 (77.1%) never achieved a MMR during imatinib, while 24 who had achieved at least a MMR lost it after a median of 14 months (range 6-22). Furthermore, 11 patients (10.4%) experienced a blast phase evolution. The 5-year OS after starting a 2TKI was 85.2% (CI 95%: 73.5-94.3). We collected also the long-term safety with a particular attention to cardiovascular (CV) events and development of solid tumors. In 27 patients (5.8%), a grade 3 CV event occurred during treatment. Eight (29.6%) experienced a myocardial infarction and 3 patients died, 4 (14.8%) a heart failure that required hospitalization, 4 (14.8%) a stroke with 3 deaths, 5 (18.6%) an atrial fibrillation controlled with specific therapy, 3 (11.1%) a venous thrombotic event that required anticoagulant treatment and 3 (11.1%) a peripheral arterial occlusive event with 1 pulmonary embolism. Thirty-nine patients (8.5%) developed a solid tumor during the course of treatment: the most frequent sites involved were the prostate (20.5%), gastrointestinal (15.3%), bladder (12.8%), lung (10.2%) and breast (10.2%).Conclusions. A 10-year real-life follow-up of CML patients demonstrates that imatinib maintains efficacy over time and is associated with a low rate of CV events and second neoplasias. [Display omitted] DisclosuresRizzo:Sapienza University, Rome: Other: Resident in Hematology. Foà:GILEAD: Speakers Bureau; INCYTE: Other: ADVISORY BOARD; AMGEN: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau. Breccia:Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria; Pfizer: Honoraria.

Nilotinib Vs Nilotinib Plus Pegylated Interferon-alpha2b Induction and Nilotinib or Pegylated Interferon-alpha2b Maintenance Therapy for Newly Diagnosed BCR-ABL+ Chronic Myeloid Leukemia Patients in Chronic Phase: Interim Analysis of the Tiger (CML V)-Study

Introduction: The TIGER (CML V)-study (NCT01657604) is a multicenter, randomized phase III trial to evaluate efficacy and tolerability of nilotinib (NIL) 2*300mg/d monotherapy vs NIL 2*300mg/d + pegylated interferon alpha2b (Peg-IFN) and the option to discontinue therapy after Peg-IFN maintenance as first line therapy for chronic myeloid leukemia (CML) patients in chronic phase.Methods: Recruitment started in August 2012 with a pilot phase, aiming to validate the recommended dose of PEG-IFN. 25 pilot phase patients (pts) were treated with the combination of NIL 2*300 mg daily and PEG-IFN (30-50μg/week according to tolerability and commenced after >6 weeks NIL monotherapy). During the main phase of the study, newly diagnosed pts were randomized between NIL 2*300 mg/d and NIL/PEG-IFN combination in accordance with the approach which was confirmed to be feasible during the pilot phase. After at least 2 years NIL based induction therapy and achievement of major molecular remission (MMR, BCR-ABL transcript level ≤0.1% according to the international scale, IS), maintenance therapy (NIL vs PEG-IFN) started. Requirements for treatment discontinuation were treatment duration of at least 3 years with stable MR4 (BCR-ABL ≤0.01%) for at least one year. NIL therapy was reinitiated in case of molecular recurrence, defined as loss of MMR. The major co-endpoints of the study are (i) rate of MMR at 18 months (NIL vs NIL+PEG-IFN), and (ii) rate of continuous MMR 12 and 24 months after discontinuation of NIL vs PEG-IFN. Efficacy and safety data are presented without specification of the randomized therapy during the ongoing study.Results: Within 5 years, a total of 717 pts (429 male; median age 51, range 18-85 years; 13.3% EUTOS high risk) were recruited from 111 sites in Germany, Switzerland, and the Czech Republic. Median observation time since recruitment was 30.3 months. 396 pts concluded the induction phase and reached the maintenance phase of the study. 138 pts achieved and maintained MR4 (BCR-ABL ≤0.01% IS) for at least one year during the maintenance phase and discontinued all therapy. With regard to efficacy in the two treatment arms, 79.5% reached MMR at 12 mo. (95% confidence interval (CI): [76.1-82.7%]), 84.9% at 18 mo. (95% CI: [81.4-88.0%]), and 89.4% at 24 mo. (95% CI: [86.0-92.2%]) after randomization. Probabilities of adverse events of grade 1-5 after 12 mo. of therapy were 83.7 (95% CI: [79.2-87.3%]) and 90.0% (95% CI: [85.8-93.0%]), and of grade 3-5 after 3 years 39.6 (95% CI: [33.4-45.7%]) and 49.5% (95% CI: [42.7-56.0%]) for the two treatment arms. Twelve pts progressed to accelerated phase or blast crisis; four of them died from blast crisis. A total of 13 patients received 14 allogeneic stem cell transplantations in chronic phase (n=7) or blast crisis (n=7). In total, 19 pts died, five related to CML, three from vascular complications.Conclusions: This interim analysis demonstrates feasibility of 1st-line treatment with NIL 2*300 mg/d combined with PEG-IFN 30-50 μg/week. Molecular response during the first 24 mo. favourably compares with data from recent NIL based studies (ENESTnd, NCT00471497; ENEST1st, NCT01061177) and permits access to the maintenance phase (NIL vs PEG-IFN monotherapies) for the majority of patients - with the potential of treatment-free remission.The study was conducted by the German CML Study Group in cooperation with the Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) and the Ostdeutsche Studiengruppe Hämatologie und Onkologie (OSHO). DisclosuresHochhaus:Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Saussele:Novartis: Research Funding; BMS: Research Funding; MSD: Research Funding. Baerlocher:Novartis: Research Funding. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy; Janssen: Consultancy. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Research Funding. La Rosée:Novartis: Research Funding. Hasford:Novartis: Research Funding. Heim:Novartis: Research Funding. Krause:Novartis: Research Funding. le Coutre:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Niederwieser:Miltenyi: Speakers Bureau; Novartis: Research Funding. Mayer:Novartis: Research Funding; Amgen: Research Funding. Lange:Novartis: Research Funding. Haenel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Stegelmann:Novartis: Consultancy, Honoraria. Gil:Novartis: Research Funding. Ernst:Novartis: Research Funding. Fabisch:Novartis: Research Funding. Pfirrmann:Novartis: Research Funding.

PTCH1 is a reliable marker for predicting imatinib response in chronic myeloid leukemia patients in chronic phase.

Patched homolog 1 gene (PTCH1) expression and the ratio of PTCH1 to Smoothened (SMO) expression have been proposed as prognostic markers of the response of chronic myeloid leukemia (CML) patients to imatinib. We compared these measurements in a realistic cohort of 101 patients with CML in chronic phase (CP) using a simplified qPCR method, and confirmed the prognostic power of each in a competing risk analysis. Gene expression levels were measured in peripheral blood samples at diagnosis. The PTCH1/SMO ratio did not improve PTCH1 prognostic power (area under the receiver operating characteristic curve 0.71 vs. 0.72). In order to reduce the number of genes to be analyzed, PTCH1 was the selected measurement. High and low PTCH1 expression groups had significantly different cumulative incidences of imatinib failure (IF), which was defined as discontinuation of imatinib due to lack of efficacy (5% vs. 25% at 4 years, P = 0.013), probabilities of achieving a major molecular response (81% vs. 53% at first year, P = 0.02), and proportions of early molecular failure (14% vs. 43%, P = 0.015). Every progression to an advanced phase (n = 3) and CML-related death (n = 2) occurred in the low PTCH1 group (P<0.001 for both comparisons). PTCH1 was an independent prognostic factor for the prediction of IF. We also validated previously published thresholds for PTCH1 expression. Therefore, we confirmed that PTCH1 expression can predict the imatinib response in CML patients in CP by applying a more rigorous statistical analysis. Thus, PTCH1 expression is a promising molecular marker for predicting the imatinib response in CML patients in CP.

An analysis of the kinetics of molecular response during the first trimester of treatment with nilotinib in newly diagnosed chronic myeloid leukemia patients in chronic phase

PurposeThis study was aimed to analyze the association of very early molecular response to nilotinib with the achievement of deep molecular response (MR4) at 18 months. We hypothesized that the BCR-ABL1 levels during the first 3 months of therapy, and the kinetics of their descent in this period, could be predictive of deep molecular response thereafter.MethodsThis substudy of the ENEST1st trial included 60 patients with chronic myeloid leukemia in chronic phase treated with front-line nilotinib, and BCR-ABL1IS levels were measured using GUS as the control gene. The analysis included seven time points during the first trimester of treatment (baseline and fortnightly thereafter).ResultsThe rates of MMR at 12 months, and of MR4 at 18 months (primary variable of the study), were 70 and 41%, respectively, similar to those obtained in the core study. BCR-ABL1IS ≤10% was achieved at 1, 1.5, 2 and 3 months in 50, 70, 83 and 93% of the patients, respectively. The observed shape of the BCR-ABL1IS descent was biphasic, with a faster slope during the first trimester and a median halving time (HT) of 11 days, the shortest reported in the literature. An HT ≤13 days was predictive of MMR at 12 months and MR4 at 18 months.ConclusionsThe association of a shorter HT with response provides a rationale for exploring very early kinetics patterns in all patients treated with potent TKIs such as nilotinib.

Proposal for a tailored stratification at baseline and monitoring of cardiovascular effects during follow-up in chronic phase chronic myeloid leukemia patients treated with nilotinib frontline

Nilotinib was approved for chronic myeloid leukemia patients in chronic phase or accelerated phase after resistance to imatinib or as frontline treatment. The drug, as other tyrosine kinase inhibitor has a specific safety profile with possible occurring metabolic side effects, such as increased glycaemia and cholesterol level, that may result, in predisposed patients, in an increased rate of cardiac and vascular disorders. The objectives of this paper were to focus on the optimal procedures to perform at diagnosis in order to identify patients at risk of possible events and the correct monitoring procedures in order to prevent and manage metabolic and cardiovascular adverse events. Several national haematologist and cardiologist reviewed the literature, analysed levels of evidence for each topic and, after extensive discussions presented their proposals based on current international guidelines.

Effects of Deeper Molecular Responses on Outcomes in Chronic Myeloid Leukemia Patients in Chronic Phase Treated With Imatinib Mesylate.

The prognostic significance of complete cytogenetic response (CCyR) is well defined in patients with chronic phase chronic myeloid leukemia treated with imatinib as first-line therapy. However, the effect on outcomes of obtaining molecular response itself and the depth of it is not clear. In this study we aimed to determine the frequency of complete molecular response (CMR) during long-term follow-up and the clinical significance of CMR on patient outcomes and survival. We retrospectively evaluated the files of 178 chronic phase chronic myeloid leukemia patients using imatinib therapy. Forty-seven patients with missing data were excluded from the study and the assessment was done in 131 patients. CMR was defined as undetectable BCR-ABL transcripts using real-time quantitative polymerase chain reaction with a sensitivity level of≥ 104 in 2 consecutive analyses at least 3months apart. Cytogenetic and molecular monitoring during treatment was performed according to the European LeukemiaNet recommendations criteria. Our primary objective was to analyze the association of deeper molecular response with differences in progression-free survival (PFS). Eighty-eight patients (67%) achieved CMR at any time in a median of 65 months of follow-up. The rate of CMR was higher in patients who achieved CCyR at 12months and major molecular response (MMR) at 18 months. Fewer events occurred in the CMR group than the MMR group (26.1% vs. 50.0%). Overall survival was not different in both groups. CMR was associated with longer PFS with borderline significance. Prolonged imatinib therapy helps to achieve a deeper molecular response in the long-term. Achieving deeper molecular response at any time positively affects maintaining the cytogenetic and molecular responses, and decreases the transformation to accelerated and/or blastic phase. The slight prolongation in PFS did not reach statistical significance.

‘Real-life’ study of imatinib therapy in chronic phase-chronic myeloid leukemia: A novel retrospective observational longitudinal analysis

Objectives: Imatinib is a cornerstone of treatment of chronic myeloid leukemia. It remains unclear whether transient treatment discontinuation or dose changes affect outcome and this approach has not yet been approved for use outside clinical trials.Methods: We conducted a retrospective single-institution observational study to evaluate factors affecting response in ‘real-life’ clinical practice in 138 chronic myeloid leukemia patients in chronic phase treated with imatinib. We used a novel longitudinal data analytical model, with a generalized estimating equation model, to study BCR–ABL variation according to continuous standard dose, change in dose or discontinuation; BCR–ABL transcript levels were recorded. Treatment history was subdivided into time periods for which treatment was given at constant dosage (total 483 time periods). Molecular and cytogenetic complete response was observed after 154 (32%) and 358 (74%) time periods, respectively.Results: After adjusting for length of time period, no association between dose and cytogenetic complete response rate was observed. There was a significantly lower molecular complete response rate after time periods at a high imatinib dosage.Discussion: This statistical approach can identify individual patient variation in longitudinal data collected over time and suggests that changes in dose or discontinuation of therapy could be considered in patients with appropriate biological characteristics.

Velocity of Early BCR-ABL Transcript Elimination As an Optimized Predictor of Deep Molecular Response in Chronic Myeloid Leukemia Patients in Chronic Phase on Treatment with Dasatinib

▪Background: We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan (IMIDAS PART2 study; UMIN000006358). Several groups reported that some of CML patients who achieved stable deep molecular response (DMR) level or deeper could stop Tyrosine Kinase Inhibitor (TKI) and approximately 40% of these patients could keep therapy free survival by cessation of TKI. Discontinuation of TKI has emerged as a new goal of treatment in CML. Achievement of DMR is necessary for discontinuation of TKI. The aim of the present study was to analyze the prognostic significance of (i) BCR-ABL transcript International Scale (BCR-ABL IS) levels, (ii) the halving time and (iii) velocity of BCR-ABL transcript elimination using an optimized cutoff according to receiver operating characteristic (ROC) analysis.Methods: Eighty newly diagnosed CML-CP patients were included in this study. Patients received dasatinib 100mg once daily. Treatment has continued until disease progression or unacceptable toxicity. Clinical efficacy and safety was partially reported in 55th ASH Meeting. We sought to investigate the impacts of above 3 parameters within the initial 1 or 3 months of therapy. Halving time was calculated by the method, described by Branford et al. Velocity of BCR-ABL transcript elimination at 1 or 3 months (V-BCR-ABL1m or 3m respectively) was calculated as BCR-ABL IS at 1 or 3 months (BCR-ABL IS1m or 3m respectively) divided by that at diagnosis.Results: One patient was withdrawal before administration of dasatinib. Seventy-nine patients administered dasatinib 100 mg once daily. The estimated MMR and DMR rates were 92.1 % (95%CI, 76.8-97.3 %) and 60.9% (95%CI; 42.3-73.4 %) by 12 months respectively. The patients who had already achieved DMR at 3 months were excluded from landmark analysis. The cut off values for prediction of DMR at 12 months were obtained by ROC analysis. Those of BCR-ABL IS1m and BCR-ABL IS3m were 11.7% and 0.284% respectively. Those of halving times on 0-1 month and 0-3months (halving time1m and 3m) were 17.8 and 13.6 days respectively. Those of V-BCR-ABL1m and V-BCR-ABL3m were 0.321 and 0.018 respectively. The estimated DMR at 12 months, 95% CI and probability (P), obtained by Kaplan-Myer analysis, were shown in Figure 1. Odd' ratio, obtained by Chi-square test, was shown in Table 1. The patients with less than 0.321 at V-BCR-ABL1m showed the highest DMR at 12 months (80%), the least probability (P=0.009) and the least odd' ratio (0.175). At 3 months, there were similar data in these parameters among BCR-ABL IS3m, halving time3m and V-BCR-ABL3m. Figure 1 showed the cumulative DMR rate according to the cutoff values in V-BCR-ABL1m and V-BCR-ABL3m. V-BCR-ABL1m 0.321 and V-BCR-ABL3m 0.018 separated best.Conclusion: These data strongly suggested that V-BCR-ABL1m,3m would be a significant landmark to predict DMR at 12 months as well as BCR-ABL IS1m,3m, halving time1m,3m. Among them, less than 0.321 in V-BCR-ABL1m was identified as an optimized predictive cutoff value of DMR at 12 months. [Display omitted] [Display omitted] DisclosuresIshida:Bristol-Myers Squibb: Honoraria.

Propensity Score Matching Analysis Demonstrates the Use of Statin Enhances Chance of Achieving MR4.5 in Chronic Myeloid Leukemia Patients in Chronic Phase Following Imatinib Therapy Regardless of Other Clinical Features Including Age of the Patients

▪BACKGROUND: HMG-CoAreducatase inhibitor, or statin was suggested to increase therapeutic efficacy of anti-cancer therapy, to improve response rate of chemotherapy and to improve survival of cancer patients. Statin family of drugs is known to trigger tumor specific apoptosis and to result in growth arrest in leukemias (Penn, Leukemia 2002). Our previous study (Kim, ASH 2014) suggested the use of statin could enhance chance of achieving MR4.5 with imatinib therapy by 78.5% in 503 chronic myeloid leukemia (CML) patients in chronic phase.A concern has remained regarding that the clinical features of patients receiving statins are more related to the adherence to medication including age. For example, elderly patient who is known to be more adherent to medication dosing, is more likely to take statins. Thus clinical and demographic characteristics of patients should be taken account into the interpretation of enhancing therapeutic effect of statin in combination with imatinib.Propensity score matching (PSM) analysis is a statistical method to adjust for the clinical factors which affect the choice of treatment between different treatment options. Using PSM analysis, clinical and demographic characteristics between the groups with vs without statin can be balanced out, thus mimicking randomized controlled prospective trial.METHODS: Out of 408 patients treated with imatinib at 400mg daily dose as a frontline for CML in CP, 88 patients was identified as "statin" group, while remaining 320 as "non-statin" group. The statin group was defined as those on statin for cholesterol control at the time of imatinib commencement and remaining on statin while on at least 3 years or longer. There was significant difference in age between the statin vs non-statin group (median 62 vs 49, p<0.001). Other clinical factors did not show an difference between the 2 groups including gender, sokal risk group or additional cytogenetic abnormalities at the time of imatinib commencement.Using PSM analysis, we performed a case-control study with well-balanced pairs of patients treated with vs without statin. Pre-treatment variables included in the PSM were age, gender, Sokal risk group and additional cytogenetic abnormalities. A total of 84 case-control pairs were selected within 0.05 of a difference in propensity score. Paired analysis was adopted throughout the PSM analysis.Treatment outcomes were evaluated for the response to TKI therapy with respect to complete cytogenetic response (CCyR), major molecular response (MMR), molecular response at 4.5 (MR4.5) and for long-term outcomes including treatment failure, progression free- (PFS) and overall survival (OS). Cumulative incidence method considering competing risk was adopted to calculate the incidences of MCyR, CCyR, MMR and MR4.5. Discontinuation of imatinib was accounted as competing risk in the analysis. Treatment failure, PFS and OS was also evaluated.RESULT: After the PSM matching, each of 84 patients was selected, thus a total of 168 patients were included in the final analysis. With a median follow-up duration of 6 years (range 3 months to 14 years), clinical and demographic characteristics between the 2 groups did not show any differences including age (p=0.813), gender (p=0.440), Sokal risk group (p=0.888), and additional cytogenetic abnormalities (p=0.682), thus balancing all the confounding factors related to the use of statin.The statin group showed a higher MR4.5 rate than non-statin groups (p=0.019): 56.8±11.9% vs 47.0±11.6%, MR4.5 at 5 years. The use of statin increased the chance of achieving MR4.5 by 64.3% (hazard ratio 1.643 [1.080-2.501]). There is a trend of better MMR at 18 months in statin group compared to non-statin group: 68.2±10.7% vs 53.1±11.1% (p=0.072). However, the use of statin was not found to be associated with improvement in treatment failure (p=0.953), PFS (p=0.938) or OS (p=0.734).CONCLUSION: The use of statin is suggested to improve deeper molecular response following imatinib therapy in CML-CP patients. After taking account for potential confounding clinical variables using PSM analysis, we confirmed that independent of age or other clinical variables, the use of statin could enhance deeper molecular response following imatinib therapy in CML-CP patients. This approach of adopting statin in CML treatment could potentially increase the proportion of patients eligible for TKI discontinuation attempt. DisclosuresKim:Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Lipton:Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding.

Measurement of PTCH1 Expression at Diagnosis Is an Appropriate Tool for Tyrosine Kinase Inhibitors Selection in Chronic Myeloid Leukemia Patients in Chronic Phase

Imatinib treatment has radically changed the prognosis of patients with CML. However, around 23-32% of patients discontinue this therapy due to lack of efficacy. Second generation TKI are available, which exhibit greater potency, so there is scope to further improve the strategy of selection of the appropriate TKI in the first line setting. Measurement of PTCH1 expression at diagnosis has been proposed as a useful strategy to tailor first line therapy as patients with low PTCH1 expression showed a worse outcome. Signalling via SMO is inhibited by non-Hedgehog ligated PTCH1 in Hedgehog pathway. SMO and PTCH1/SMO expression ratio has also been related to response to imatinib. Our aim was to corroborate imatinib outcome prediction in a different cohort and compare the prognostic power of PTCH1, SMO and PTCH1/SMO.We have retrospectively studied 101 pre-treatment samples of patients who received first-line imatinib from 14 Spanish centres. Clinical data were recorded in the Spanish CML Registry (RELMC). Informed consent was signed by every patient. Predesigned assays for PTCH1, SMO and GUSB (control gene) were used in single qPCR reactions in duplicates and run in an ABI 7900. Receiver operating characteristic (ROC) curves were plotted for PTCH1, SMO and PTCH1/SMO expression ratio and the area under curve (AUC) was used to compare its capacity to predict imatinib failure free survival (IFFS). For the measurement with higher AUC a threshold was set to divide patients with high and low expression. TKI failure was defined as loss of CCyR, progression to advanced phase disease, death or change in treatment from imatinib due to lack of efficacy. Secondary endpoints were: probability of achieving <10% BCRABL/ABL at 3 months, probability of achieving CCyR; probability of achieving MMR, progression free survival (PFS) and overall survival related to CML (CML OS). TFFS, CCyR, MMR and CML OS were analyzed by Kaplan-Meier analysis and log-rank test. Fishers exact test was employed to analyze the relationship with <10% BCRABL/ABL at 3 months and PFS. All analysis were carried out in an intention-to-treat basis. Age, Sokal, and EUTOS scores were introduced with categorised PTCH1 expression in a forward stepping Cox regression analysis for prediction of IFFS. Sensitivity, specificity and negative predictive values for prediction of IFFS were calculated.Patient median follow-up was 33 months (2-151). 13 patients (12.9%) showed imatinib failure. The AUC of PTCH1, SMO and PTCH1/SMO expression ratio were 0.72, 0.55 and 0.71. A PTCH1 expression of 0.026 was used as cut-off. Low and high PTCH1 expression groups had a 10 year rates of IFFS of 64% vs 95% (p=0.01), CCyR at 1 year of 91% vs 93% (p=0.261) and MMR at 12 months of 53% vs 81% (p=0.022). Median time of the entire cohort of achievement of CCyR was 6 months. Fishers exact test for achievement of <10% BCRABL/ABL at 3 months was significant (p=0.021). Three patients who progressed to accelerated or blastic phase and two of them who died from CML were included in the low expression group but no significant results were obtained due to the low number of events. PTCH1 expression was the unique independent predictor of IFFS in the multivariate analysis (p=0.023, HR=5.8(1.3-26)). Sensitivity, specificity and negative predictive values were 84.6%, 55.7 and 96.1%.We have confirmed PTCH1 expression prognostic power and found a greater predictive capacity than SMO and PTCH1/SMO expression ratio. Compared to previous PTCH1 studies this is a more real-to-life cohort, extracted from tertiary and secondary hospitals and the results confirm PTCH1 expression can be applied to very different clinical settings (previous studies had been performed in a cohort from a national CML reference hospital). Maybe the greater prognostic power of PTCH1 expression reflects its biological role in CML expands further than controlling SMO activity. Therefore PTCH1 could be used as a therapeutic target instead of SMO inhibitors which have shown poor results and high toxicity in early phase clinical trials. A reference standard, similarly as made for BCRABL/ABL1 measurement, could be developed with a level of PTCH1 expression equivalent to the cut-off established in this study. In this way PTCH1 expression could be implemented in the clinical setting. [Display omitted] DisclosuresGarcía-Gutierrez:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinez-Lopez:Janssen: Honoraria; Bristol-Meyer Squibb: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria.

A Case Report of two Chronic Myeloid Leukemia Patients in Chronic Phase Exhibiting IgVH Gene Rearrangement

A Case Report of two Chronic Myeloid Leukemia Patients in Chronic Phase Exhibiting IgVH Gene Rearrangement

Monitoring of Disease Activity in Chronic Myeloid Leukemia-chronic Phase Patients Treated with Indian Generic Veenat (NATCO) Imatinib Mesylate: A Tertiary Care Experience

Aim: Real-time quantitative polymerase chain reaction (RT-PCR) is a sensitive technique to monitor treatment response in chronic myeloid leukemia (CML). Standardization of RT-PCR protocols and interpretation of results are important to maintain the reliability of this molecular test. Methods: We present the analysis of treatment monitoring after administration of Indian generic imatinib mesylate (IM) (Veenat) in 73 patients with CML-chronic phase using RT-PCR. Results: A consistent decrease in the median breakpoint cluster region-abelson1 (BCR-ABL1) percentage denoting a continued time-bound response to IM is observed. At 6 months, 87.5% patients showing ≥ 1-log reduction in BCR-ABL1 levels subsequently developed ≥ 3-log reduction as compared to 42.8% patients showing < 1-log reduction. All patients with ≥ 3-log reduction in BCR-ABL1 at 12 months maintained treatment response at 18 months. Conclusion: The efficacy of Veenat (NATCO) is comparable to Gleevac (Novartis). Patients who attain ≥ 1-log reduction at 6 months and ≥ 2-log reduction at 12 months are more likely to subsequently attain a major molecular response.

The Use of Statin Enhances Chance of Achieving MR4.5 in Chronic Myeloid Leukemia Patients in Chronic Phase Following Imatinib Therapy

Abstract BACKGROUND: HMG-CoA reducatase inhibitors, or statins, are commonly prescribed medications which improve life expectancy in general population. They are known to improve hypercholesterolemia and decrease the incidence of cardiovascular events including myocardial infarction or stroke, but also suggested for cancer prevention even though the mechanism is not fully elucidated. Recent studies emphasized the potential role of statins in the cancer treatment to increase response rate to chemotherapy and to improve survival of cancer patients. Statin family of drugs is known to trigger tumor specific apoptosis and to result in growth arrest in leukemias (Penn, Leukemia 2002). The promising result of STIM (STop Imatinb) trial suggested that successful discontinuation of tyrosine kinase inhibitor (TKI) in patients with chronic myeloid leukemia (CML) is possible when patients attain deeper molecular response (defined as 4.5 log reduction or deeper) for 2 years or longer. However, with our current knowledge, there is no known additive intervention facilitates the achievement of MR4.5. We hypothesized that the use of statin improves response rate to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML), thus increasing MR4.5 achievement and increasing the chance of being attempted TKI discontinuation. METHODS: A total of 503 patients treated with TKI for CML treatment were initially evaluated for the response to TKI therapy with respect to complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response at 4.5 (MR4.5) and statin use. The inclusion criteria confined the patients with chronic phase (CP) treated with imatinib at the dose of 400mg daily, thus excluding 95 patients. Finally, 408 patients were entered into the final analysis. The statin group was defined as those on statin for cholesterol control at the time of imatinib commencement and remaining on statin while on at least 3 years or longer. Cumulative incidence method considering competing risk was adopted to calculate the incidences of MCyR, CCyR, MMR and MR4.5. Discontinuation of imatinib was accounted as competing risk in the analysis. Treatment failure, progression free- and overall survival was also evaluated. RESULTS: With a median follow-up duration of 6 years (range 3 months to 14 years), 88 patients (21.3%) were defined as “statin” group. Types of statin includes atorvastatin (n=44, 50%), rosuvastatin (n=26, 30%), simvastatin (n=10, 11%), pravastatin (n=6, 7%) and fluvastatin (n=2, 2%). The MCyR and CCyR achievement was not significantly different between the 2 groups (p=0.769 for MCyR and p=0.091 for CCyR). No difference of CCyR at 12 months was noted: 70.1% in statin vs 62.8% in non-statin group. The statin group showed a higher response rate than non-statin group for MMR (p=0.005) and MR4.5 (p=0.001): 67.3% vs 49.2% for MMR at 18 months; 55.8% vs 41.0% for MR4.5 at 5 years (Figure). Multivariate analysis was successful to confirm the use of statin as an independent clinical factor for improving MR4.5 (HR 1.785, 95% CI [1.260-2.530], p=0.001), but other clinical factors were not identified such as Sokal risk, age, gender or additional cytogenetic abnormalities (ACAs) at presentation. For MMR, the use of statin was also confirmed as independent factor for MMR (HR 1.541 95% [1.015-2.341], p=0.043) in addition to ACAs (HR 0.381, p=0.0038) and high sokal risk (HR 0.687, p=0.042). The use of statin was not found to be associated with improvement in treatment failure (p=0.580), progression free survival (p=0.731) or overall survival (p=0.542) in the present study. CONCLUSION: The use of statin suggested to improve deeper molecular response following imatinib therapy in CML-CP patients, therefore is promising to increase chance of attempt to TKI discontinuation. Statin appears to improve the chance of MR4.5 achievement by 78.5%. Careful interpretation is required and replication study in an independent cohort is strongly warranted to reach a clear conclusion on this promising effect of statin. The use of statin to deepen the molecular response of TKI therapy should be evaluated in the context of clinical trial. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Next-generation deep sequencing improves detection of BCR-ABL1 kinase domain mutations emerging under tyrosine kinase inhibitor treatment of chronic myeloid leukemia patients in chronic phase.

Here, we studied whether amplicon next-generation deep sequencing (NGS) could improve the detection of emerging BCR-ABL1 kinase domain mutations in chronic phase chronic myeloid leukemia (CML) patients under tyrosine kinase inhibitor (TKI) treatment and discussed the clinical relevance of such sensitive mutational detection. For NGS data evaluation including extraction of biologically relevant low-level variants from background error noise, we established and applied a robust and versatile bioinformatics approach. Results from a retrospective longitudinal analysis of 135 samples of 15 CML patients showed that NGS could have revealed emerging resistant mutants 2-11 months earlier than conventional sequencing. Interestingly, in cases who later failed first-line imatinib treatment, NGS revealed that TKI-resistant mutations were already detectable at the time of major or deeper molecular response. Identification of emerging mutations by NGS was mirrored by BCR-ABL1 transcript level expressed either fluctuations around 0.1 %(IS) or by slight transcript level increase. NGS also allowed tracing mutations that emerged during second-line TKI therapy back to the time of switchover. Compound mutants could be detected in three cases, but were not found to outcompete single mutants. This work points out, that next-generation deep sequencing, coupled with a robust bioinformatics approach for mutation calling, may be just in place to ensure reliable detection of emerging BCR-ABL1 mutations, allowing early therapy switch and selection of the most appropriate therapy. Further, prospective assessment of how to best integrate NGS in the molecular monitoring and clinical decision algorithms is warranted.