Patients In Accelerated Phase Research Articles

Treatment status of tyrosine kinase inhibitor for newly-diagnosed chronic myeloid leukemia: a domestic multi-centre retrospective real-world study

Objective: To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China. Methods: Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed. Results: 6 893 patients in CP (n=6 453, 93.6%) or AP (n=440, 6.4%) receiving initial imatinib (n=4 906, 71.2%), nilotinib (n=1 157, 16.8%), dasatinib (n=298, 4.3%) or flumatinib (n=532, 7.2%) -therapy. With the median follow-up of 43 (IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance (n=1 055, 15.3%), intolerance (n=248, 3.6%), pursuit of better efficacy (n=168, 2.4%), economic or other reasons (n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph(+) ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph(+) ACA, poorer TFS; Ph(+) ACA, poorer OS. Conclusion: At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Real World Population- Based Data from Nationwide Registry Support the Existence of Accelerated Phase in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients Even in Tyrosine Kinase Inhibitors (TKIs) Era

Background For decades, CML has been considered to be a triphasic disease recognizing 3 distinct stages: chronic phase (CP), accelerated phase (AP), and blast crisis (BC). Since the discovery of TKIs, the prognosis of CML patients has rapidly improved and less than 10% of patients diagnosed in CP experience disease progression on the therapy. Based on low incidence of CML progression and the fact that CML biological behavior seems biphasic, the new WHO 2022 classification of CML deemed AP less relevant and suggested the omission of AP. Many experts, however, still advocate for its inclusion in CML classification (e.g. ELN 2020, ICC 2022, NCCN 2023), even though the universal definition of AP is not established and differs in between publications. Methods This retrospective, real-world study is based on the Czech nationwide CML registry INFINITY with the data of newly diagnosed CML patients who agreed and provided their written consent. Recruited subjects were adult patients diagnosed in years 2005 - 2022 with sufficient data to determine the phase of the disease at diagnosis and follow-ups to assess their overall survival (OS), disease specific survival (DSS) and progression-free survival (PFS). The phase of the disease at the time of diagnosis was determined using the classification according to ELN 2020, ICC 2022, WHO 2016, and WHO 2022. Whenever CP was established, EUTOS Long-Term Survival (ELTS) score was calculated, assigning the patient to low risk (LR), intermediate risk (IR) and high risk (HR) group. OS and PFS are defined according to published guidelines. DSS is defined as the time from diagnosis to death due to CML disease or CML treatment. Results During the studied time period, 1660 new cases of CML were reported in INIFINITY registry. Of them, 1500 patients had data sufficient to classify the phase of the disease at the time of the diagnosis according to ELN 2020 guidelines and WHO 2022 classification and 1395 patients had data to assess the phase according to WHO 2016 and ICC 2022 classifications. When using ELN 2020 guidelines, groups were assigned as follows: LR CP- 784 patients (52.3%), IR CP- 421 patients (28.1%), HR CP- 227 patients (15.1%), AP- 42 patients (2.8%), BC- 26 patients (1.7%). There were significant differences in representation by gender, age, comorbidities and performance score amongst patient groups. When comparing just HR CP and AP CML patients, there were no significant differences. Calculated estimates of 5- and 10- year OS, respectively, were 92.5% and 87.2% for LR CP, 83.5% and 65.9% for IR CP, 76.9% and 65.5% for HR CP, 59.2% and 45.9% for AP, and 32.9% for BC, p= 0.031 for HR CP versus AP (Figure 1). In the case of WHO 2016 and ICC 2022 classifications, 714 (51.2%) patients were diagnosed in LR CP, 374 (26.8%) in IR CP, 154 (11.0%) in HR CP, 125 (9.0%) in AP, and 28 (2.0%) in BC. Again, there were significant differences in representation by gender, age, comorbidities and performance score amongst patient groups. When comparing just HR CP and AP CML patients, only age at the time of diagnosis was significantly different. Calculated estimates of 5- and 10- year OS, respectively, were 93.2% and 87.5% for LR CP, 84.9% and 67.7% for IR CP, 80.0% and 69.5% for HR CP, 65.7% and 55.6% for AP, and 39.7% for BC. We also performed propensity score matching according to age for patients in HR CP and AP and calculated estimates of 5- and 10- year OS, respectively, were 85.4% and 74.4% for HR CP and 60.2%, and 52.0% for AP, p= 0.003 (Figure 2). Similar results were obtained when testing for PFS and DSS. Summary Real-world data obtained from 1500 patients diagnosed in Czechia over 17 years, in our opinion, support the need to recognize the existence of AP at the time of diagnosis, even though a singular definition of AP is not agreed upon. Patients in AP have worse survival scores (OS, DSS, PFS) compared to patients in CP and/or HR CP. Moreover, because ELTS risk score was calculated on patients in CP, it may not be suitable for patients in AP, which would be changed to CP according to the new WHO 2022 classification. In conclusion, based on the real-world data with long-term follow-up, we believe it would be reasonable to keep the AP as part of CML classification of newly diagnosed patients. This publication was supported by the grant number MUNI/A/1224/2022, Programme EXCELES, ID Project No. LX22NPO5102, and by the Ministry of Health of the Czech Republic grant number 00023736.

Characteristics and Survival of Patients with Chronic Phase Myelofibrosis and Elevated Blasts (5-9%), and the Effect of Therapy with JAK2 Inhibitor Ruxolitinib

Abstract Introduction: Patients with accelerated phase (AP) myelofibrosis (MF) (10-19% blasts in bone marrow [BM] or peripheral blood [PB]) have higher risk of leukemic transformation and shorter overall survival (OS) than those in the chronic phase ( Objective: We aimed to identify clinical characteristics, and survival, as well as evaluate effect of JAK2 inhibitor ruxolitinib (RUX) on outcome of patients with 5-9% PB / BM blasts seen at MD Anderson Cancer Center (MDACC). Methods: Medical charts of 1199 patients who presented to MDACC between years 1984 - 2015 with MF and available blast percentage in PB and BM, were retrospectively evaluated. All relevant clinical characteristics were collected at the time of referral. Chronic phase (CP) was defined as Results: Eighty five percent of patients (n=1020) were in CP; 10% (n=123) in CP-e, and 5% (n=56) in AP. Clinical characteristics and demographics are shown in Table 1. Patients with CP-e had similar clinical characteristics as patients in AP, and furthermore, both had higher white blood cell counts, lower hemoglobin and platelets, more frequent splenomegaly, systemic symptoms, and presence of abnormal and unfavorable karyotype (Caramazza, Leukemia 2011) than patients in CP. After median follow-up of 27 months (range, 1-251), 50% (n=594) of patients have died. Fourteen percent of patients (n=169) were untreated while being followed at MDACC. Among the remaining 1030 patients, 52% (n=533), 16% (n=162), and 12% (n=126) have received one, two, and ≥3 therapies. RUX was used in 30% of patients (n=328): in 289 (28%), 33 (27%) and 6 (11%) patients in CP, CP-e and AP, respectively. The median overall survival (OS) of the entire group was 48 months (range, 40-65). The median OS for patients in CP, CP-e and AP was 56, 34, and 23 months, respectively (p As the next step we analyzed the impact of RUX on OS in each of the groups. Patients who were exposed to RUX have superior overall survival within CP as well as CP-e groups, with respective OS of 61 vs 52 months in CP (with vs without RUX; p=0.002, HR 0.85, 95% CI 0.69-0.97), and 54 vs 27 months in CP-e (with vs without RUX; p=0.001, HR 0.50, 95% CI 0.29-0.85, Graph 1B, C). Furthermore, OS of patients in CP-e who were exposed to RUX has reached OS of patients in CP group, both with and without RUX, with respective OS of 54, 61, and 52 months (p>0.05, Graph 2B, C). RUX had no impact on OS among AP patients (with and without RUX, 23 vs 23.4 months, p>0.05, graph not shown). Progression to AML occurred in total of 139 (9%) patients, with overall incidence of 3.96 cases per 100 persons-years. Nine percent (n=93), 20% (n=25), and 39% (n=22) of patients have progressed to AML among CP, CP-e, and AP groups, respectively, (p Conclusions: RUX, the only FDA approved JAK2 inhibitor for patients with MF, has a potential to significantly improve an outcome of patients with 5-9% blast percentage whose clinical characteristics and outcome appear to be worse than patients with CP MF and Download : Download high-res image (181KB) Download : Download full-size image Table 1 . Disclosures Pemmaraju: abbvie: Research Funding; cellectis: Research Funding; novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; roche diagnostics: Consultancy, Honoraria; affymetrix: Research Funding; Incyte Corporation: Consultancy, Honoraria. Daver: Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Immunogen: Research Funding; Pfizer Inc.: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Otsuka America Pharmaceutical, Inc.: Consultancy; Kiromic: Research Funding; Jazz: Consultancy. Cortes: Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding. Kantarjian: Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding. Verstovsek: Gilead: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Lilly Oncology: Research Funding; Bristol Myers Squibb: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Astrazeneca: Research Funding; Celgene: Research Funding; Blueprint Medicines Corp: Research Funding; Bristol Myers Squibb: Research Funding; Genentech: Research Funding; Promedior: Research Funding; Astrazeneca: Research Funding; Pfizer: Research Funding; Galena BioPharma: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Galena BioPharma: Research Funding; CTI BioPharma Corp: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; CTI BioPharma Corp: Research Funding; Seattle Genetics: Research Funding; Roche: Research Funding; Lilly Oncology: Research Funding; Blueprint Medicines Corp: Research Funding.

Comparison of the Outcome between Newly Diagnosed Patients in the Accelerated Phase and Chronic Phase with Chronic Myeloid Leukemia Treated with Frontline Tyrosine Kinase Inhibitors

Background: Accelerated phase (AP) chronic myeloid leukemia (CML) has an aggressive clinical course. Some patients with CML present as AP at the time of diagnosis. Although many studies have confirmed that tyrosine kinase inhibitors (TKIs) significantly improved survival in patients with CML in the chronic phase (CP), there is limited data on the outcome of newly diagnosed CML-AP patients in the era of TKIs.Aims: To compare progression-free survival and overall survival in CML-AP patients with those in CML-CP patients treated with frontline TKIs and identify factors associated with the outcome.Methods: According to the definition of European LeukemiaNet 2013, data of newly diagnosed CML-AP and CML-CP patients receiving TKIs at least 3 months from 2002 to 2016 were retrospectively analyzed. Kaplan-Meier curves were used to compare the probabilities of PFS and OS. Uni- and multivariate Cox regression models were built to identify independent variables (demographics; co-morbidity; disease phase and risk, CBC, and additional cytogenetic aberrations in Ph-positive cells at diagnosis; interval from diagnosis to start TKI-therapy; initial TKI used and early treatment-response) associated with the outcome.Results: In total, 101 CML-AP patients [with excess blasts (blasts ≥15%), n=13; with excess basophils (basophils ≥20%), n=88] and 656 CML-CP patients (Sokal low-risk, n=291; intermediate-risk, n=194; high-risk, n=111; unknown, n=60) were included. 463 (61%) were male. Median age was 39 (14-87) years. Patients received initial therapy with imatinib (n=660), nilotinib (n=85), or dasatinib (n=11) within 6 months from diagnosis. At 3 months, CML-AP patients with excess blasts (62%, 15% and 23%) and excess basophils (65%, 27% and 8%) achieved similar response (optimal, warning and failure) rates to CML-CP patients in Sokal intermediate-risk (66%, 20% and 14%) and high-risk (58%, 26% and 16%) (p=0.338), but significantly lower than those in Sokal low-risk (83%, 13% and 4%) and unknown (77%, 17% and 7%) (p<0.001). With a median follow-up of 39 months (range, 3-184 months), probabilities of PFS (p=0.014) and OS (p=0.152) at 5 years were the lowest in the CML-AP patients with excess blasts (78% and 92%), followed by CML-CP patients in Sokal high-risk (87% and 91%), intermediate-risk (92% and 95%), low-risk (95% and 97%), CML-AP patients with excess basophils (95% and 97%), and those with unknown-risk (96% and 98%). In multivariate analyses, while analyzing baseline and initial therapy variables, interval from diagnosis to starting TKI-therapy >2 months [HR 2.4 (1.1-4.9), p=0.020 and HR 2.6 (1.1-6.5), p=0.037) was associated with inferior PFS and OS; in addition, CML-CP patients in Sokal high-risk [HR 3.6 (1.1-6.5), p=0.038] was associated with inferior PFS, >60 years [HR 3.9 (1.2-13.3), p=0.027], inferior OS. While involving early therapy response, interval from diagnosis to starting TKI-therapy >2 months [HR 3.1 (1.4-6.6), p=0.009 and HR 3.2 (1.2-8.4), p=0.016] and achieving a response of “failure” at 3 months [HR 7.6 (3.7-15.6), p<0.001 and HR 8.1 (3.1-21.3), p<0.001] were variables associated with inferior PFS and OS; in addition, >60 years [HR 4.8 (1.4-16.1), p=0.010], inferior OS. There was no impact of initial TKI used (imatinib or 2nd generation TKI) on the outcome.Conclusions: Newly diagnosed CML-AP patients have comparable outcome to CML-CP patients treated with frontline TKIs, especially CML-AP patients with excess basophils. However, delayed therapy and poor early response to TKIs are significantly associated with unfavorable prognosis in either AP or CP patients with CML. Our data indicates timely and proper TKI-therapy and close monitoring will be a reasonable option for the treatment strategy in CML-AP patients in the era of TKIs. DisclosuresNo relevant conflicts of interest to declare.

Optimal Timing of Allogeneic Stem Cell Transplantation (Allo-SCT) for Chronic Myeloid Leukemia (CML) Patients in the Tyrosine Kinase Inhibitor (TKI) Era

Optimal Timing of Allogeneic Stem Cell Transplantation (Allo-SCT) for Chronic Myeloid Leukemia (CML) Patients in the Tyrosine Kinase Inhibitor (TKI) Era

A Multicenter Prospective Study on Efficacy and Safety of Ponatinib in Patients with Chronic Myeloid Leukemia Resistant or Intolerant to Previous Therapy: A 3-Year Report

Introduction Tyrosine kinase inhibitors (TKIs) have transformed outcomes in chronic myeloid leukemia (CML). Patients who respond to imatinib, have a life expectancy comparable with that of the global population, however, up to 40% of patients discontinue imatinib due to resistance or intolerance. Ponatinib is a third-generation highly-potent-pan-inhibitor of tyrosine kinases, active in all single resistance ABL kinase mutations, including the T315l mutation. This report presents the results of a prospective analysis of 3-year ponatinib therapy available in Poland by Angelini's donation program for patients in all phases of CML resistant or intolerant to previous TKI therapy. Methods 43 CML patients (20 women, 24 men, aged 19 to 76 years, mean age 49 ± 15 years) were treated in 20 Polish Hematology Centers with ponatinib initiated between March 2016 and December 2019. 23 pts (53%) were in the chronic phase (CP), 3 pts (7%) in accelerated phase (AP), and 17 pts (40%) in blastic phase (BP) (9 myeloblastic and 8 lymphoblastic). The majority of patients received three lines of TKI therapy. The T315I mutation was detected in 30% of patients (the initial characteristics of the 43 analyzed patients are shown in Table 1). The indication for ponatinib and its dose schedule was made according to the discretion of the attending physician. The initial dose of ponatinib was 45 mg/d in 60% of all patients (without statistically significant differences in the initial dose between patients starting treatment in CP, AP, and BP). Molecular biology tests were performed according to ELN guidelines and BCR-ABL/ABL ratios were expressed as % [IS] in all patients. Treatment responses were calculated at each specific time points recommended by ELN. Statistica 12 software (StatSoft, Tulsa, OK, USA) was used for calculations. Results The follow-up ranged from one week to 35.4 months (median 11.4 months) (one male patient died on infection one week after ponatinib introduction and was excluded from further analysis, he did not achieve CHR and he transformed to blast phase-BP). The responses to ponatinib are shown in Table 2. Among 23 CP patients, 18 achieved CHR (78%), 6 (26%) MCyR, 5 (22%) CCyR, and 1 (4%) MMR at 1 month of treatment. There were only 2 patients in this group (9%) who did not achieve CHR. Eleven CP patients (48%) achieved stable MMR. In all 3 AP patients, the best responses (CHR, CCyR, and MMR) were maintained until the end of observation (Table 2). Among 17 BP patients, 8 (47%) achieved CHR. The overall survival was significantly better in those patients who achieved CHR at 1 month of therapy (Figure 1). 19 patients (44%) experienced toxicity of ponatinib including: increase in blood pressure overall 9 patients (21%), hematological toxicity grade 3-4- 12 patients (28%).A total of 19 patients (44%) remained on ponatinib at the end of the observation. Ponatinib dose was reduced during the study in 18 patients (42%): in 11 (61% of those requiring dose reduction) because of toxicity, in 6 (33%) because of good response to treatment, and in 1 patient (6%) because of both reasons. The need for dose reduction was not significantly associated with comorbidities (p=0.4). Eight patients (19%) underwent allo-SCT during the observation. Ponatinib was discontinued in eight patients (19%), in six CP and two BP-patients. In five patients (12%), ponatinib was discontinued because of toxicity (hematological in one, non-hematological in two, and both in one patient); all were CP patients. In two patients (one CP, one BP patient), ponatinib was discontinued as they underwent allo-SCT. Overall, 16 patients (37%) died during the study: 12 of them (28%) due to CML progression. In all 43 patients, median survival was not reached. The estimated 2-year survival was 60% (95% confidence interval 44-76%) (Figure 2A) 84% in CP patients, 100% in AP patients (Figure 2B), and 20% in BP patients. None of the CP patients progressed to AP or BP during the study, i.e. progression-free survival was 100% at the end of observation (35.4 months). The presence of T315I mutation (p=0.2) or the initial dose of ponatinib (p=0.4) was not significantly associated with the overall survival. Conclusion Our study confirmes that ponatinib could induce durable responses with acceptable toxicity profiles in highly pretreated patients with CML resistant or intolerant to previous TKIs treated in standard clinical practice. Disclosures Sacha: Adamed:Consultancy, Honoraria;Bristol-Myers Squibb Company:Consultancy, Honoraria, Speakers Bureau;Pfizer:Consultancy, Honoraria, Speakers Bureau;Novartis:Consultancy, Honoraria, Speakers Bureau;Incyte:Consultancy, Honoraria, Speakers Bureau.Niesiobedzka-Krezel:Angelini Pharma:Other: lecture fee and meeting partcipation.Ciepluch:Copernicus Wojewodzkie centrum Onkologii:Current Employment.

An Updated Safety and Efficacy Results of Phase 1 Study of HQP1351, a Novel 3rd Generation of BCR-ABL Tyrosine Kinase Inhibitor (TKI), in Patients with TKI Resistant Chronic Myeloid Leukemia

Background: HQP1351, a novel, orally active potent 3rd generation TKI, was designed for treatment of patients with chronic myeloid leukemia (CML) resistant to current TKI-therapies including those with T315I mutation. This is an updated report of the safety and efficacy of HQP1351. Methods: It is an open-label, dose escalation and expansion phase 1 trial of HQP1351 which was designed to determine maximum tolerated dose (MTD) and to identify dose-limiting toxicities (DLTs) in patients with CML in the chronic phase (CP) or accelerated phase (AP) resistant or intolerant to ≥ 2 prior TKIs or those with T315I mutation after ≥1 prior TKI. HQP1351 was orally administered once every other day (QOD) in 28-day cycles at 11 dose cohorts ranging from 1mg to 60 mg. The eligible patients received continuous treatments until disease progression to AP or BP, developing intolerant toxicity, consent withdrawal, or death. Blood samples were collected at certain time points on Day 1-2 and Day 27-28 during cycle 1 for PK analyses. Results: From 26 October, 2016 to 27 May, 2019, 101 patients including 87 CP patients and 14 AP patient were enrolled in this study. Seventy-one (70.3%) patients were male. Median duration of follow-up was 12.8 (range, 1.2-31.5) months. Median age was 40 (range, 20-64) years. Median interval from CML diagnosis to starting HQP1351 treatment was 5.8 (range, 0.3-15.2) years. Eighty-three (83.8%) patients received ≥2 prior lines of TKI-therapy. Sixty-two (61.4%) patients harbored T315I mutation. Seventeen patients who initially assigned to the dose escalation cohorts ranging from 1mg to 20 mg moved to 30 mg or higher dose cohorts via intra-patient dose escalation. Fifty-six patients enrolled in the dose expansion part of the trial, including 30mg,40mg and 50mg dose cohorts. Two out of 3 patients at 60mg dose cohort experienced DLT and 50mg QOD was considered as the MTD. During the follow-up period, HQP1351 was well-tolerated in each dose cohort with an exception of 60 mg cohort. All patients experienced ≥1 treatment related adverse events (TRAEs), most of the non-hematologic TRAEs were reported as grade 1 or grade 2. The most common hematologic TRAE of grade 3/4 was thrombocytopenia (49.5%). The incidences of TRAEs tended to be dose-dependent. No death and grade 5 AEs occurred. The incidence of common TRAEs (≥ 10% any grade) are summarized in Table1. HQP1351 showed potent anti-leukemic activities in CML patients. In the 68 evaluable patients with non-CHR at baseline, 63 (92.6%) achieved CHR including 52 out of 55 (94.5%) CP patients and 11 out of 13 (84.6%) AP patients, respectively. In the 95 evaluable patients with non-CCyR at baseline, 56 out of 81 (69.1%) CP patients achieved MCyR including 49 (60.5%) CCyR; and 6 out of 14 (42.9%) AP patients, achieved MCyR including 5 (35.7%) CCyR, respectively. In the 100 evaluable patients, 32 out of 86 (37.2%) CP patients and 5 out of 14 (35.7%) AP patients achieved MMR, respectively. HQP1351 showed highly efficacious in the patients with T315I mutation (Figure A, B). The probability and the depth of response increased with prolonged treatment period (Figure C). As the cut-off date of May 27 2019, 9 patients (5 CP and 4 AP) withdrawn from the study, including progression to AP or BP (n=5), intolerant AEs (n=2), consent withdrawal (n=1), and newly diagnosis of breast cancer (n=1). The progression free survival (PFS) rate at 18-month was 94% in the CP patients and 61% in the AP patients (Figure D). PK analyses indicated an approximately dose proportional increase in exposure (AUC and Cmax) following oral administration of HQP1351 at doses from 1mg to 60 mg. The peak concentration of HQP1351 was reached at 4-8h. The elimination appeared to be linear with a mean terminal T1/2 of 17.5 to 42.5 h. Slight to moderate accumulation was observed on Day 27 following multiple dosing. Reduction of CRkL phosphorylation in PBMCs, a biomarker of BCR-ABL inhibition, has shown to be dose and time dependent in 53 evaluable patients treated with HQP1351. Conclusions: HQP1351 was well tolerated and exhibited significant and durable antitumor activity in the patients with TKI-resistant CML, including those with T315I mutation. Two pivotal studies of HQP1351 in CML-CP and CML-AP patients with T315I mutation are ongoing in China. Disclosures Chen: HealthQuest Pharma Inc.: Employment. Niu:HealthQuest Pharma Inc.: Employment. Men:HealthQuest Pharma Inc.: Employment. Wang:HealthQuest Pharma Inc.: Employment. JI:HealthQuest Pharma Inc.: Employment. Huang:HealthQuest Pharma Inc.: Employment. Yang:Ascentage Pharma Group: Employment. Zhai:Ascentage Pharma Group Inc.: Employment; HealthQuest Pharma Inc.: Employment.

Safety and Efficacy of HQP1351, a 3rd Generation Oral BCR-ABL Inhibitor in Patients with Tyrosine Kinase Inhibitor—Resistant Chronic Myelogenous Leukemia: Preliminary Results of Phase I Study

Background: HQP1351, a novel, potent 3rd generation TKI, was designed to treat patients with chronic myeloid leukemia (CML) resistant to current TKI-therapies including those with T315I mutation.Aims: A single-agent, open-label dose escalation and dose expansion Phase I study to assess the safety, preliminary efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) properties of orally administered HQP1351 in the TKI-resistant patients with chronic phase (CP) or accelerated phase (AP) CML.Methods: HQP1351 was administered once every other day (QOD) in 28-days cycles at 11 dose cohorts ranging from 1mg to 60 mg. The eligible patients received treatments until disease progression or intolerable toxicities. The primary efficacy endpoint in the CML AP and CP patients, was complete hematological response (CHR) and major cytogenetic response (MCyR) respectively, MCyR includes partial cytogenetic response (PCyR) and complete cytogenetic response (CCyR).Blood samples were collected at various time points on Day 1-2 and Day 27-28 during cycle 1 for PK analyses. BCR-ABL inhibition was evaluated using tyrosine phosphorylation of CRKL and STAT5 in peripheral blood mononuclear cell (PBMCs) collected from the patients before and 4, 8, 24 and 48 hours post HQP1351 treatments on Day 1, 15 and 27 during cycle 1.Results:From November 2016 to July 2018, 70 patients (CP n=58 and AP n=12) enrolled received ≥1 cycle of HQP1351-treatment, only 1 patient withdrew from the study due to disease progression. Median age was 39 (range: 23-59) years. Median interval from CML diagnosis to starting HQP1351-treatment was 6.1 (1.1-14.7) years. Sixty-one (87%) patients received ≥2 prior lines of TKI-therapy. Fifty-three (76%) patients had BCR-ABL mutations and 45 (64%) had T315I mutation at baseline.With a median follow-up of 4.1 (1.0-21.2) cycles, HQP1351 was well-tolerated in all dose cohorts other than the 60mg cohort. In all patients, 67 (96%) patients experienced ≥1 treatment related adverse events (TRAEs) and 44 (63%) experienced TRAE(s) of grade 3-4 (Table 1). There was no patient withdrawal from the study because of TRAEs. Two out of 3 patients in the 60mg cohort experienced dose-limiting toxicity(DLT) and HQP1351 at 50mg QOD was considered as MTD.The anti-leukemic activities of HQP1351 were observed in this study. Sixty-five (93%) patients including 58 (100%) CP and 7 (58%) AP patients achieved CHR at the dose of 2mg to 60mg within 3 cycles. In 47 evaluable patients receiving HQP1351-treatment ≥3 cycles, 24 (51%) achieved MCyR including 21 (54%) CP and 3 (38%) AP patients at the dose of 12mg to 50mg, and 14 (30%) patients achieved CCyR including 12 (31%) CP and 2 (25%) AP patients. Total 6 (15%) CP patients achieved MMR. More than 65% of the patients achieved MCyR or MMR at the end of cycle 3. HQP1351 was highly active in patients with or without T315I mutation at baseline (Table 2).Following oral administration of HQP1351 at doses ranging from 1mg to 60 mg, the peak concentration was reached at 2-8 hrs. The elimination appeared to be linear with a mean terminal T1/2 of 15.3-36.5 hrs on Day 1, 18.8-42.5 hrs on Day 27, respectively. The ratios for AUC0-t and Cmax of HQP1351 on Day 27 versus Day 1 ranged from 1.03 to 2.12 and from 0.78 to 1.93, respectively. Thus, HQP1351 exhibited an approximately dose proportional increase in Cmax and AUC0-t following single or multiple oral administration dose ranging from 1 to 60 mg. PD study results demonstrated that reduction of CRKL phosphorylation was schedule and dose-dependent, ≥50% reduction was observed at doses ranging 12mg-60mg.Conclusions: The preliminary results of the phase 1 study showed that HQP1351, a novel 3rd-generation TKI, is safe and highly active in treatment of the TKI-resistant patients with CP-CML and AP-CML,with or without T315I mutation. DisclosuresChen:HealthQuest Pharma Inc.: Employment. Men:HealthQuest Pharma Inc.: Employment. Liu:HealthQuest Pharma Inc.: Employment. Sun:HealthQuest Pharma Inc.: Employment. JI:HealthQuest Pharma Inc.: Employment. Wang:HealthQuest Pharma Inc.: Employment. Hu:HealthQuest Pharma Inc.: Employment. Zou:HealthQuest Pharma Inc.: Employment. Yan:HealthQuest Pharma Inc.: Employment. Huang:Ascentage Pharma Group Inc.: Employment; HealthQuest Pharma Inc.: Employment. Yang:Ascentage Pharma Group Inc.: Employment. Zhai:Ascentage Pharma Group Inc.: Employment.

Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR-ABL kinase domain mutations.

Kinase domain (KD) mutations of ABL1 represent the most common resistance mechanism to tyrosine kinase inhibitors (TKI) in CML. Besides T315I, mutations in codon 255 are highly resistant mutations in vitro to all TKI. We aimed to study the incidence, prognosis, and response to treatment in patients with E255K/V. We evaluated 976 patients by sequencing of BCR-ABL1 fusion transcript for ABL1 KD mutations. We identified KD mutations in 381 (39%) patients, including E255K/V in 48 (13% of all mutations). At mutation detection, 14 patients (29%) were in chronic phase (CP), 12 (25%) in accelerated phase (AP), and 22 (46%) in blast phase (BP). 9/14 CP patients responded to treatment (best response complete hematologic response-CHR-4; complete cytogenetic response-CCyR-1; major molecular response-MMR-4); only 4/12 AP patients (CHR 3; MMR 1) and 7/22 BP patients responded (CCyR 2; MMR 2; partial cytogenetic response-PCyR-3). After a median follow-up of 65months from mutation detection, 36 patients (75%) died: 9/14 (64%) in CP, 9/12 (75%) in AP, and 18/22 (82%) in BP (p=0.003); median overall survival was 12months. Patients with E255K/V mutation have a poor prognosis, regardless of the stage of the disease at detection.

Brief Research Report: Novel Compound BCR-ABL Mutations in Late Chronic Phase Imatinib Sensitive CML Patients Are Associated with Progression to Advance Disease Phase

Introduction: BCR-ABL kinase domain (KD) mutations have well established role in tyrosine kinase inhibitors (TKIs) resistance and disease progression in chronic myeloid leukemia (CML)1. In recent years, compound BCR-ABL mutations have emerged as a new threat to CML patients by causing higher degrees of resistance involving multiple TKIs, including ponatinib2. However, there are limited reports about association of compound BCR-ABL mutations with disease progression in imatinib sensitive CML patients3. Furthermore, BCR-ABL mutation detection is currently recommended only in case of drug resistance and disease progression and clinical significance of BCR-ABL mutation detection in TKI responder chronic phase CML is not well documented4. Therefore, we investigated presence of ABL-KD mutations in chronic phase (CP) and advanced phase imatinib sensitive CML to find out association of BCR-ABL mutations with progression to advanced disease phases in CML patients. .Patients and Methods: Imatinib sensitive CML patients in CP and advanced phases of the disease were included in the study.All CP patients were incomplete hematological, complete cytogenetic and major molecular responses. Due to specific study objectives, patients manifesting drug resistance during follow-up studies were excluded from the study. A total of 90 imatinib sensitive CML patients (CP=41, late CP=33, and accelerated phase=16) were finally available for analysis. All patients as well as 10 healthy controls were investigated for BCR-ABL mutations using Sanger sequencing. All response criteria were per European LeukemiaNet guidelines4. Data was analyzed using SPSS software (version 19).Results: Mean age of the patients was 33 years (Table 1). Eleven out of 33 (33.3%) patients in late-CP CML harbored 24 types of point mutations, out of which eight (72.72%) harbored compound mutated sites (Figure 1, Table 2). E355G (3.33%) was the most prevalent mutant. Five patients (45.45%), all of which had compound mutations, progressed to advanced phases of disease during follow up studies. No BCR-ABL mutation was detected in healthy subjects and in early CP CML patients. Therefore, early CP CML patients served as additional control in this study. BCR-ABL mutations were found in 3 accelerated phase patients as well. Late-CP mutations were associated with elevated platelet count (p= 0.037) and male gender (p= 0.049). The median overall survival and event free survival of CML patients (n=90) was 6.98 and 5.8 years respectively. Seven year survival was found to be 94.2%.Discussion and conclusions: Compound BCR-ABL mutations were associated with progression to advanced disease in imatinib sensitive late-CP CML patients. Although single BCR-ABL mutations have previously been found to cause CML progression5, this is first report of association of compound BCR-ABL mutations with disease progression in stable imatinib responders at late CP. Detection of new mutations can help in defining mechanism of CML progression6. Moreover, BCR-ABL mutation detection in late CP CML patients sensitive to TKI treatment can help in early assessment of risk for disease progression and/or drug resistance and subsequent clinical intervention to delay disease progression which is a major challenge of CML therapy in TKI era7.

Dasatinib treatment based on BCR- ABL mutation detection in imatinib- resistant patients with chronic myeloid leukemia

目的探讨在BCR-ABL突变检测指导下选用达沙替尼治疗伊马替尼耐药慢性髓性白血病（CML）患者的有效性。方法83例伊马替尼耐药和39例伊马替尼与尼洛替尼均耐药的CML患者，持续口服达沙替尼，其中慢性期（CP) 55例，加速期（AP) 21例，急变期（BP) 46例。达沙替尼治疗前，经BCR-ABL突变筛查，除外具有对达沙替尼高度耐药突变类型（T315I/A、F317L/V/C和V299L）的患者。定期监测血液学、细胞遗传学和分子学反应，评估疾病进展和生存情况。当发生达沙替尼治疗失败时检测BCR-ABL突变。结果CP患者中，完全血液学反应（CHR）率为92.7%，完全细胞遗传学反应（CCyR）率为53.7%，主要分子学反应（MMR）率为29.6%，MR4.5率为14.8%，4年疾病无进展生存（PFS）率和总生存（OS）率分别为84.4％和89.5%。AP患者中，血液学反应（HR）率和CCyR率分别为81.0％和35.0%，3年PFS率和OS率分别为56.1％和59.3%。BP患者中，HR率和CCyR率分别为63.0%和21.4%，1年PFS率和OS率分别为43.6％和61.8%。达沙替尼作为二线和三线酪氨酸激酶抑制剂时，治疗反应相似。当发生达沙替尼治疗失败时，75例患者中37例（48.7%）检出新突变，T315I最为多见（59.5%）。达沙替尼治疗前存在突变的患者与无突变患者相比，治疗反应、PFS和OS差异均无统计学意义，但当出现达沙替尼耐药时，发生新突变的可能性显著增高（65.7％对34.1%，P=0.006）。结论达沙替尼可以有效治疗伊马替尼耐药或伊马替尼与尼洛替尼均耐药的CML各期患者，CP和AP患者疗效持久。达沙替尼治疗前BCR-ABL突变筛查及治疗中突变监测非常重要。

Management of advanced-phase chronic myeloid leukemia.

The introduction of tyrosine kinase inhibitors (TKIs) has dramatically changed the management of patients with chronic myeloid leukemia (CML). Despite improved outcomes for most CML patients, disease progression from chronic phase (CP) to accelerated phase (AP) or blast phase (BP) occurs in 1-1.5% of cases per year with current TKI therapy. In addition, about 10-15% of newly diagnosed patients present in AP or BP. Even in the TKI era, the prognosis of patients with advanced-phase CML is not satisfactory. Although de novo AP patients who respond optimally to TKI have excellent outcomes, the prognosis of the remaining advanced-phase CML patients treated with TKI remains poor. For advanced-phase CML patients, allogeneic stem cell transplantation (allo-HSCT) is the only curative therapy. Patients eligible for allo-HSCT should first be treated with TKI with or without chemotherapy, in order to obtain reversion to CP, followed promptly by allo-HSCT. At present, the survival rates of patients undergoing allo-HSCT for advanced-phase CML are still disappointing. Prophylactic or preemptive administration of TKIs after allo-HSCT may improve long-term survival. Further investigation to improve the treatment outcomes of patients with advanced-phase CML is warranted.

Treatment with dasatinib or nilotinib in chronic myeloid leukemia patients who failed to respond to two previously administered tyrosine kinase inhibitors – a single center experience

OBJECTIVE:To evaluate hematological, cytogenetic and molecular responses as well as the overall, progression-free and event-free survivals of chronic myeloid leukemia patients treated with a third tyrosine kinase inhibitor after failing to respond to imatinib and nilotinib/dasatinib.METHODS:Bone marrow karyotyping and real-time quantitative polymerase chain reaction were performed at baseline and at 3, 6, 12 and 18 months after the initiation of treatment with a third tyrosine kinase inhibitor. Hematologic, cytogenetic and molecular responses were defined according to the European LeukemiaNet recommendations. BCR-ABL1 mutations were analyzed by Sanger sequencing.RESULTS:We evaluated 25 chronic myeloid leukemia patients who had been previously treated with imatinib and a second tyrosine kinase inhibitor. Nine patients were switched to dasatinib, and 16 patients were switched to nilotinib as a third-line therapy. Of the chronic phase patients (n=18), 89% achieved a complete hematologic response, 13% achieved a complete cytogenetic response and 24% achieved a major molecular response. The following BCR-ABL1 mutations were detected in 6/14 (43%) chronic phase patients: E255V, Y253H, M244V, F317L (2) and F359V. M351T mutation was found in one patient in the accelerated phase of the disease. The five-year overall, progression-free and event-free survivals were 86, 54 and 22% (p<0.0001), respectively, for chronic phase patients and 66%, 66% and 0% (p<0.0001), respectively, for accelerated phase patients. All blast crisis patients died within 6 months of treatment. Fifty-six percent of the chronic phase patients lost their hematologic response within a median of 23 months.CONCLUSIONS:Although the responses achieved by the third tyrosine kinase inhibitor were not sustainable, a third tyrosine kinase inhibitor may be an option for improving patient status until a donor becomes available for transplant. Because the long-term outcome for these patients is poor, the development of new therapies for resistant chronic myeloid leukemia patients is necessary.

Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up.

Omacetaxine, a protein synthesis inhibitor, is indicated in the United States for the treatment of patients with chronic-phase (CP) or accelerated-phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors. The final analysis, with 24 months of follow-up, included additional efficacy and safety analyses to assess the benefit of long-term omacetaxine administration (1.25 mg/m(2) twice daily for 14 days every 28 days followed by 7 days every 28 days) in CP-CML and AP-CML patients receiving >3 cycles. Eighteen percent of CP-CML patients achieved a major cytogenetic response (MCyR) with a median duration of 12.5 months (95% confidence interval [CI], 3.5 months to not reached [NR]); responses were maintained for ≥12 months in 3 of 14 responders, and the median overall survival (OS) was 40.3 months (95% CI, 23.8 months to NR). Among patients with AP-CML, 14% achieved or maintained a major hematologic response for a median of 4.7 months (95% CI, 3.6 months to NR); MCyR was not achieved, and the median OS was 14.3 months (95% CI, 6.7-18.7 months). In patients with CP-CML and patients with AP-CML who received >3 cycles of treatment (n = 50 and n = 14, respectively), the median OS was 49.3 months (95% CI, 23.8 months to NR) and 24.6 months (95% CI, 12-37.2 months), respectively. Grade 3 or higher hematologic toxicities were the major side effects (79% and 73% for CP-CML and AP-CML, respectively), with discontinuation due to toxicity in 10% of CP patients and in 5% of AP patients. These results suggest that the long-term administration of omacetaxine is feasible with dose adjustments to manage toxicities and that omacetaxine provides a durable benefit for some patients.

Clinical Outcome Following Change of Tyrosine Kinase Inhibitor (TKI) According to the Detection of an ABL Kinase Mutation

IntroductionPoint mutations in the kinase domain of BCR-ABL are the most frequent mechanism of acquired imatinib resistance in patients with chronic myeloid leukemia (CML). Mutation analysis is recommended to guide the selection of appropriate second line therapy in patients with imatinib failure, since some frequently occurring mutations confer clinical resistance to nilotinib and/or dasatinib. To date, more than 80 point mutations have been described following imatinib exposure, but mutations at 7 sites (G250, Y253, E255, T315, M351, F359, and H396) comprise approximately 60% of mutations reported in large series. We retrospectively analysed the impact of 83 ABL kinase mutations (P-loop mutations = 28, T315I mutation = 12 and other mutations = 43) arising in 65 chronic phase (CP) CML patients with imatinib failure. The aim of this study was to define the clinical characteristics of these patients, and to assess their outcome following introduction of second line agents.MethodsBetween July 2002 and August 2013, 123 CML patients were found to have ABL kinase mutations in our centre. Patients presenting in blast crisis (BC) or accelerated phase (AP), and those who did not require change in therapy (including patients who required imatinib dose escalation) following detection of an ABL kinase mutation were excluded from the analysis. Sixty-five patients in CP who had imatinib failure and detectable ABL kinase mutation, and who required change in therapy were evaluated. Definitions of CML phases, treatment responses and failures were as per definitions of the European LeukaemiaNet. Direct sequencing method was used to detect a range of mutations within the tyrosine kinase domain at the level of ~20% sensitivity and pyrosequencing to detect specific mutations with a sensitivity of ~5%.ResultsEighty-three ABL kinase mutations were detected in 65 CP patients at the time of imatinib failure with 35% of patients (23 of 65) harbouring P-loop mutations (including M244V), 18% (12 of 65) with T315I mutation and 46% (30 of 65) with other mutations (catalytic domain, imatinib binding site, activation loop and C-terminal). Composite mutations were present in 10 patients (15%), with 2 patients harbouring both P-loop and T315I mutations. Median time on imatinib therapy was 29.5 months (range, 2-144 months). At the time of mutation detection, 20% of patients (13 of 65) were in CCyR, 54% (35 of 65) in CP, 17% (11 of 65) in AP and 9% (6 of 65) had progressed to BC. Median time from CML diagnosis to mutation detection was 21 months for patients with T315I mutation, 45.5 months for P-loop mutations and 48 months for other mutations. Following mutation detection, patients in CP and AP were treated on second-line agents with dasatinib, nilotinib, bosutinib or ponatinib (based on sensitivity of ABL kinase mutants to ABL kinase inhibitors), and those in BC were treated with chemotherapy +/- TKI. Thirteen patients (20%) underwent allogeneic stem cell transplantation (SCT) for disease control (P-loop = 7, T315I = 5, other = 1).Following the change in TKI therapy, the best response was CMR or MMR in 54% of patients (35 of 65), CCyR in 12% (8 of 65), MCyR in 3% (2 of 65) and CHR in 26% (17 of 65). 5% (3 of 65) progressed to BC. In those who only achieved CHR, MCyR or developed progressive disease despite change in TKI, 6 out of 22 patients were found to have additional mutations during their treatment course, including 5 patients with re-emergence of their original mutation. After a median follow-up of 60 months (range, 3-137 months) from detection of mutation, 12 of the 65 patients (18%) have died, including 6 of 23 (26%) with P-loop mutations, 3 of 12 (25%) with T315I mutation, and 3 of 30 (10%) with other mutations. One patient who died had composite P-loop and T315I mutations. Median overall survival was 250 months for patients harbouring P-loop mutations (P=0.37) and not reached for T315I and other mutations.ConclusionWith longer follow-up and the availability of second and third generation TKIs, we have demonstrated that most clinically relevant ABL kinase mutations respond to change in TKI therapy following imatinib failure, with the majority of patients achieving durable cytogenetic and molecular response. This study emphasizes the importance of early detection and characterization of ABL kinase mutations in imatinib resistant patients in order to identify those patients who may benefit from alternative TKI therapy or stem cell transplantation. DisclosuresNo relevant conflicts of interest to declare.

Status of Leptin in MBCR-ABL p210 Positive Chronic Myeloid Leukemia Patients Before and After Imatinib Therapy: A Conflicting Scenario

Chronic myelogenous leukemia (CML), a myeoloproliferative disorder, is characterized by the presence of the fusion gene BCR-ABL in hematopoietic cells. Leptin, considered a link between cancer and obesity, has been reported to be actively involved in hemopoiesis and pathophysiology of CML. There are few and conflicting reports about the status of serum leptin levels and recently alteration in leptin has been reported due to imatinib mesylate. Leptin and CRP were estimated in 30 (male: 20; female: 10) newly diagnosed and confirmed MBCR- ABL p210 positive CML patients before and after 3 months of therapy by commercial enzyme linked immunosorbent assays. Leptin levels were compared with 30 (male: 20; female: 10) age matched healthy controls accounting for the differences due BMI and gender. Leptin/BMI ratio was significantly raised in both male and female chronic phase patients as compared to controls (p < 0.001, p = 0.048) and accelerated phase patients as compared to controls (males, p < 0.001; females, p < 0.001). The normal gender difference and dependence on BMI was lost in patients. In patients, who failed to achieve hematological baseline, leptin/BMI was higher only in male patients (p = 0.012). Leptin/BMI also correlat- ed with TLC and blast percentage (TLC, R2 = 0.412, p = 0.001; Blast %, R2 = 0.408, p < 0.001). There was no correlation between leptin and CRP levels. Levels decreased significantly after complete hematological remission in both males and females (p = 0.001, p = 0.028). Levels after 3 months of imatinib therapy were significantly higher than controls in all patients not in remission (males, p < 0.001; females, p = 0.018) but only in male patients in re- mission (p = 0.002). Leptin levels were increased in CML patients. The findings suggest a possible role of leptin in patho- genesis of CML or disease progression independent of inflammatory state or reactionary rise. Imatinib itself may increase leptin levels, and, as leptin plays an active role in the pathophysiology of CML, this conflicting scenario needs further investigation. Alterations in leptin need to be investigated cautiously accounting for confounding and differences due to BMI and gender.

Final Analysis Of The Efficacy and Tolerability Of Subcutaneous Omacetaxine Mepesuccinate, ≥24 Months After First Dose, In Patients With Chronic Phase (CP) Or Accelerated Phase (AP) Chronic Myeloid Leukemia (CML)

Final Analysis Of The Efficacy and Tolerability Of Subcutaneous Omacetaxine Mepesuccinate, ≥24 Months After First Dose, In Patients With Chronic Phase (CP) Or Accelerated Phase (AP) Chronic Myeloid Leukemia (CML)

BCR-ABL Splice Variants In Three Phases Of CML: Association With Disease Biology and Response To Imatinib

BackgroundPhiladelphia chromosome, a characteristic chromosomal translocation (breakpoint cluster region-Abelson [BCR–ABL]; t [9; 22] [q34; q11]) in chronic myeloid leukemia (CML) encodes a product, which is the target of tyrosine kinase inhibitors (TKIs). In most CML patients, during translocation, the break takes place within a 5.8-kb region on both sides of BCR exons12-16 (originally referred to as exons b1-b5), described as themajor breakpoint cluster region (M-bcr)1. It can be either between exons b2 and b3, or between exons b3 and b4. The ABL exon which is mostly inserted in break points of BCR is a2. As a result of alternativesplicing, fusion transcripts with either b2a2 or b3a2 splicing variantcan be produced. Occasionally, breakpoints occur in unusual places, resulting in generation of rare BCR-ABL transcripts (b2a3, b3a3, e1a2, e8a2, e19a2). Association of BCR-ABL splice variants with clinical outcome in different phases of CML has rarely been studied2. We studied BCR/ABL splice variants and their association with disease biology and response to imatinib in 3 phases of CML in 70 patients. MethodsTotal RNA was extracted and reverse transcribed. PCR primers and nested PCR protocol for the detection of BCR-ABL splice variants in CML patients were adopted from van Dongen et al., 1999 3. Data was analyzed using SPSS Software version 17. ResultsMedian age of the patients was 34 years; 10 patients were 18 or younger and there were 40 females. 26 patients were in chronic phase (CP), 26 in accelerated phase (AP) and 18 in blast phase (BP). Overall, the frequencies of BCR/ABL splice variants b3a2, b2a2 and b3a2+b2a2 were found in 49 (70%), 15 (21.4%) and 6 (8.6%) patients, respectively. No rare BCR-ABL transcripts were identified. Percentage of BCR-ABL splice variant b2a2 was similar in patients with CP (31) and BP (28) of CML and low in AP (7.75). While the percentage of BCR-ABL splice variant b3a2 was more common in AP (84.5) and BP (72) as compared to CP (54). The combined expression of both transcripts (b3a2 and b2a2) was found in 4 patients with CP and 2 in AP of CML but none in BP of CML (Table 1). The co-existence of b2a2 and b3a2 transcripts was observed only in male patients. The BCR-ABL transcripts had no correlation with the age. Patients with the splice variant b2a2 had a better response to imatinib treatment and better survival as compared to patients with b3a2. The patients expressing both transcripts (b3a2 and b2a2) also showed better survival as compared to patients with only b3a2 transcript (figure 1). [Display omitted] Discussion and ConclusionsWe found a higher percentage of BCR-ABL splice variant b3a2 in AP & BP as compared to CP. Patients with the BCR-ABL splice variant b2a2 had a better response to imatinib and better survival, which is in contrast to previous reports 4. Co-existence of two transcripts b3a2 and b2a2 was observed mostly in CP, and in some patients in AP; it was also associated with a better response to imatinib. Larger studies are needed to further define the role of BCR-ABL splice variants in different phases of CML and their association with response to TKIs and prognosis. Studies of BCR-ABL splice variants can provide further insights into CML biology and new targets for BCR-ABL positive leukemia treatment 1, 5.

Do SLCO1B3 (T334G) and CYP3A5*3 polymorphisms affect response in Egyptian chronic myeloid leukemia patients receiving imatinib therapy?

BackgroundImatinib has so far been the first-choice treatment in chronic myeloid leukemia (CML) with excellent results. However, only a proportion of patients achieve major molecular response. Hence, the need to find whether there are some factors that affect the response to treatment is essential. This study aimed to investigate the allele and genotype frequencies of single nucleotide polymorphisms (SNPs) of SLCO1B3 (T334G) and CYP3A5*3 in CML patients undergoing imatinib treatment and to determine whether SNPs of these two genes could predict the response of imatinib therapy in CML patients.Subjects and methodsWe investigated SLCO1B3 (T334G) and CYP3A5*3 polymorphisms by Polymerase Chain Reaction-restriction fragment length polymorphism in 86 Philadelphia positive newly diagnosed Egyptian CML patients (78 patients in chronic phase and 8 patients in accelerated phase). All patients received imatinib therapy and were followed for at least one and half years. The response to imatinib therapy was evaluated by recording the hematological response, cytogenetic response, and molecular response according to the European Leukemia Net criteria.ResultsThis study included 86 Philadelphia positive newly diagnosed CML patients, 78 in the early chronic phase and 8 in the accelerated phase. In the chronic phase patients, no association between SLCO1B3 (T334G) exon 3 polymorphism and response to imatinib therapy was detected (P = 0.938) while CYP3A5*3 gene polymorphism was associated with inferior outcome (P < 0.001). In the group of accelerated phase patients, the SLCO1B3 polymorphic variants (TG) and (GG) were detected equally with none of the patients in this group having the homozygous wild form (TT). The homozygous state for the CYP3A5*3 allele was the most frequent (50%) and the homozygous state for the CYP3A5*1 allele was the least frequent (12.5%) in this group.ConclusionCYP3A5*3 polymorphism was associated with imatinib efficacy while the SNP SLCO1B3 (T334G) was not associated with the response to imatinib treatment in Egyptian patients with CML in chronic phase. These results prompt us to explore the effect of CYP3A5*3 in CML patients taking imatinib in a larger scale study.

Post hoc analysis of sustained efficacy/tolerability of ≥12 cycles of omacetaxine mepesuccinate in chronic myeloid leukemia (CML).

7066 Background: Subcutaneous omacetaxine mepesuccinate (OMA), a first-in-class cephalotaxine, inhibits protein synthesis independent of Bcr-Abl signaling. It showed clinical activity in 2 phase II, open-label CML trials, 1 in patients with a T315I Bcr-Abl mutation failing imatinib, and 1 in patients failing ≥2 tyrosine kinase inhibitors (TKIs). Methods: This post hoc analysis pooled patients with chronic phase (CP) or accelerated phase (AP) from the 2 trials. 28-day cycles of OMA 1.25 mg/m2BID were given ≤14 days for induction, ≤7 days as maintenance with dose delay/change as needed. Primary endpoints were major cytogenetic response (MCyR) for CP and complete hematologic response (CHR) for AP. Adverse events (AEs) were assessed. Results: Of 108 CP and 51 AP patients from the 2 trials, 31 (29%) CP and 7 (14%) AP patients received ≥12 cycles (Table). At baseline in the ≥12-cycle groups, most CP (median age 59 y) and AP patients (median age 67 y) had received hydroxyurea (17/31, 4/7) and ≥2 TKIs (22/31, 5/7), were not in CHR (22/31, 5/7), and were T315I positive (23/31, 3/7). As of March 31, 2012, 9 CP and 2 AP patients continued OMA treatment. Overall, mean days dosed per cycle were 6.1 for CP, 9.7 for AP; 5.3 and 8.9 at cycle 12. Grade 3/4 AEs occurred in 35/38 patients in this post hoc analysis, most in early cycles; 15/31 CP, 2/7 AP had grade ≥3 AEs first occurring at ≥12 cycles. Across all cycles, most common grade ≥3 AEs were thrombocytopenia (24/31 CP, 5/7 AP), anemia (16/31, 7/7), and neutropenia (17/31, 3/7).Nine patients receiving ≥12 cycles (5/31, 4/7) discontinued, most commonly due to disease progression (n=2). Conclusions: In this post hoc analysis of heavily pretreated CML-CP and CML-AP patients who had failed prior TKI therapy, efficacy was often durable for those who received OMA for ≥12 cycles. Most grade 3/4 AEs were hematologic and declined with time. Support: Teva BPP R and D, Inc. Clinical trial information: NCT00375219, NCT00462943.