The primary analysis of the phase 2 OPTIC trial (NCT02467270) demonstrated optimal benefit:risk with response-based ponatinib dosing (45 mg once daily (QD) reduced to 15 mg QD) upon achieving ≤1% BCR::ABL1IS in patients with tyrosine kinase inhibitor-resistant or T315I-positive chronic-phase chronic myeloid leukemia (CP-CML). Here, we report 5-year long-term outcomes. Overall, 283 patients were randomized to 45-mg, 30-mg, or 15-mg QD starting doses (n = 94, 95, and 94, respectively), with dose reduction to 15 mg QD upon response in the 45-mg and 30-mg cohorts. At data cutoff, 61 patients remained on trial. Median follow-up time was 75-78 months. By 5 years, 60%, 41%, and 40% of patients in the 45-mg, 30-mg, and 15-mg cohorts, respectively, achieved ≤1% BCR::ABL1IS. Five-year progression-free survival rates were 63%, 57%, and 60%, respectively, by cohort; overall survival rates exceeded 80%. In patients with a T315I mutation, 5-year rates of ≤1% BCR::ABL1IS, PFS, and OS were highest in the 45-mg cohort. Exposure-adjusted rates of adjudicated arterial occlusive events were 4.1, 3.8, and 2.0 patients per 100 patient-years, respectively, by cohort; results were comparable in T315I-positive patients. These findings support long-term clinical benefit of response-based ponatinib dosing in third-line CP-CML, especially in patients with the T315I mutation.

Currently there is no established prognostic scoring system for patients with chronic myeloid leukemia (CML) in blast phase (BP). This study aimed to identify prognostic factors of CML-BP in a large cohort of prospectively and retrospectively collected patients and to develop a readily available prognostic scoring system at the onset of BP to enable future comparison between different trials and series. The analyses were based on 275 patients from thirteen countries, collected within the European LeukemiaNet Blast Phase Registry with a median observation time of 45 months and a median OS of 18.9 months. A Cox proportional hazards model for overall survival (OS) was employed, missing values were imputed. The study identified six independent prognostic factors: blast percentage, platelet count, age (all at onset of CML-BP), immunophenotype of BP, extramedullary disease, and previous history of CML. The low-risk group, encompassing 14% of patients, had a median OS of 97 months, the intermediate-risk group (59% of patients) of 22 months, and the high-risk group (27% of patients) of 9 months. Cross-validation demonstrated a good performance of the score, although external validation is strongly recommended. Despite the inherent limitations of registry data, the findings offer robust insights into prognostic factors for CML-BP.

TPS6608 Background: Chronic myeloid leukemia (CML) is driven by the BCR::ABL1 oncogenic fusion protein. Although tyrosine kinase inhibitors (TKIs) have transformed CML management, normalizing life expectancy for many patients, treatment resistance and intolerance remain significant clinical challenges. Olverembatinib is a novel third-generation BCR::ABL1 TKI with activity against wild-type BCR::ABL1, multiple resistance-conferring mutations including T315I, and challenging compound mutations. The POLARIS-2 study evaluates olverembatinib efficacy and safety in patients with relapsed/refractory chronic phase CML (CP-CML). Methods: This global, multicenter, open-label, randomized phase 3 registrational study includes two patient cohorts based on T315I mutation status (ClinicalTrials.gov identifier: NCT06423911; internal study number: HQP1351CG301). Part A randomly allocates patients with CP-CML previously treated with at least two approved TKIs to receive either olverembatinib or bosutinib (2:1 randomization). The primary endpoint is major molecular response (MMR) rate at 24 weeks. Part B is a single-arm study evaluating olverembatinib in patients with CP-CML with the T315I mutation at screening, and the primary endpoint is MMR rate by 24 weeks. Key inclusion criteria include age ≥18 years, diagnosis of CP-CML, Eastern Cooperative Oncology Group performance status ≤ 2, and adequate organ function. Key exclusion criteria include prior hypersensitivity to study drugs and pregnancy or lactation. Patients in Part A receiving bosutinib who do not achieve MMR by 24 weeks are eligible to cross over to olverembatinib. The study hypothesis posits that olverembatinib will demonstrate superior MMR compared to bosutinib in Part A and provide clinical benefit in T315I-positive patients in Part B. Clinical trial information: NCT06423911 .

Introduction: Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) that potently inhibits native and mutant forms of BCR::ABL1, including T315I. The phase 2 OPTIC (NCT02467270) study evaluated a response-based ponatinib dosing strategy to optimize efficacy and improve safety of ponatinib in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) whose disease was resistant to ≥2 TKIs or who had the T315I mutation. The 45-mg once-daily (QD) starting dose with dose reduction to 15 mg QD upon achievement of BCR::ABL1IS ≤1% (MR2) was associated with optimal benefit:risk outcomes, resulting in FDA approval of this response-based dosing strategy for the treatment of pts with CP-CML with disease resistant to ≥2 TKIs or with T315I. We present results from the 5-year update of efficacy and safety outcomes from OPTIC. Methods: Pts with CP-CML resistant to ≥2 TKIs or with the T315I mutation were randomized to ponatinib starting doses of 45 mg, 30 mg, and 15 mg QD. Upon achievement of ≤1% BCR::ABL1IS, doses were reduced to 15 mg in the 45-mg and 30-mg cohorts. The primary endpoint was ≤1% BCR::ABL1IS at 12 months; secondary endpoints included molecular response rates and safety outcomes, including arterial occlusive events (AOEs) adjudicated prospectively by an independent review committee. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier methods. Exploratory mutational analyses were conducted with baseline and end-of-treatment (EOT) blood samples. Results: A total of 283 pts were randomized (45 mg/30 mg/15 mg: n=94/95/94; median age, 48 years [range: 18‒81 years]; male, 50%; race: White 79%, Asian 15%, Black 2%; ethnicity: 74% not Hispanic or Latino; T315I mutation, 24%). Median dose intensity was 27.7, 23.5, and 14.7 mg/day in the 45-mg, 30-mg, and 15-mg cohorts, respectively. As of the data cutoff (May 2, 2024), when the last pt still on study reached at least 5 years of treatment, 73 pts (26%) remained on ponatinib treatment; the most common reasons for treatment discontinuation were adverse event (45 mg/30 mg/15 mg: n=20/19/17), lack of efficacy (n=16/22/28), and progressive disease (n=8/10/7). By 60 months, 60% (56/93), 41% (38/93), and 40% (36/91) of pts in the 45-mg, 30-mg, and 15-mg cohorts, respectively, achieved ≤1% BCR::ABL1IS. Pts with a T315I mutation at baseline also had a higher MR2 rate by 60 months at the 45-mg starting dose (64%; n=25), which was comparable to those with no mutations at baseline (60%; n=50). Median duration of ≤1% BCR::ABL1IS was not reached in any cohort. By 60 months, the rates of ≤0.01% BCR::ABL1IS were 24% (22/93), 18% (17/93), and 19% (17/91) in the 45-mg, 30-mg, and 15-mg starting dose cohorts, respectively, and rates of ≤0.0032% BCR::ABLIS were 13% (12/93), 14% (13/93), and 15% (14/91), respectively. The estimated PFS rates at 60 months were 63%, 57%, and 60% in the 45-mg, 30-mg, and 15-mg cohorts. Estimated OS rates at 60 months were similar across starting dosing cohorts. Among pts who had dose reduction to 15 mg after achieving ≤1% BCR::ABL1IS, 29% (13/45) in the 45-mg cohort and 23% (6/26) in the 30-mg cohort lost the response after dose reduction. Of the pts in the 45-mg and 30-mg cohorts who had dose re-escalation after loss of ≤1% BCR::ABL1IS response, 69% (9/13) and 80% (4/5), respectively, regained a ≤1% BCR::ABL1IS response. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (27%), neutropenia (18%), and hypertension (10%). Exposure-adjusted AOE rates per 100 pt-years (95% confidence interval) were similar across the 3 cohorts: 45 mg, 4.1 (1.8-6.4); 30 mg, 3.4 (1.0-5.8); 15 mg, 1.2 (0.0-2.5). For the first time, EOT mutation analyses will be shared. Among 74 pts with no baseline mutation and available EOT data, only 6 had BCR::ABL1 mutations detected; 5 received the 15-mg starting dose and 1 had the 45-mg starting dose (E255K). Conclusion: Long-term results from OPTIC highlight the clinical benefits of ponatinib in patients with CP-CML resistant to ≥2 TKIs or harboring a T315I mutation. These results are consistent with previous OPTIC analyses and demonstrate that the approved ponatinib starting dose of 45 mg QD with reduction to 15 mg QD upon attainment of ≤1% BCR::ABL1IS provides the optimal benefit:risk ratio. Mutation data from EOT samples support ponatinib suppression of emerging mutations at the approved 45-mg starting dose.

У больного с иммунофенотипом, характерным для B-клеточного острого лимфобластного лейкоза (B-ОЛЛ), обнаружили хромосомную транслокацию t(9;22)(q34;q11), или филадельфийскую (Ph) хромосому и менее распространенный вариант химерного онкогена BCR::ABL/p210. При этом в дебюте заболевания с повышенным уровнем бластных клеток (77.6%) и лейкоцитов (48×109/л) каких-либо дополнительных мутаций в гене BCR::ABL, включая точечные мутации, вставки или делеции, выявлено не было. После проведения химиотерапии «Ph+ALL-2012m» с добавлением иматиниба (600 мг) и двух фаз консолидации отмечали развитие полной гематологической ремиссии и глубокого молекулярного ответа. Однако спустя 6 месяцев у пациента развился рецидив (бласты: 15%, BCR::ABL/p210: 105%). Через 3 недели после начала терапии дазатинибом (100 мг) количество бластов уменьшилось до 4.8%, а уровень экспрессии BCR::ABL/p210 снизился до 11.8%. Секвенирование по Сэнгеру позволило идентифицировать два варианта мутаций в гене BCR::ABL, а именно, точечную мутацию F317L и новую вставку из 9 нуклеотидов, ранее не обнаруженную. В последнем случае остаток лизина в позиции 294 был замещен на четыре новых аминокислотных остатка: K294SPSQ. После терапии бозутинибом и инотузумабом наблюдалось исчезновение одного лейкозного клона с мутацией F317L, однако сохранялось присутствие другого клона, несущего вставку из 9 нуклеотидов. Смена курса химиотерапии на понатиниб+блинатумомаб оказалась эффективной. Это привело к исчезновению инсерции. После аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) от неродственного HLA-совместимого донора наблюдалось развитие полной клинико-гематологической ремиссии и полного молекулярного ответа. Мониторинг минимальной остаточной болезни спустя 6 месяцев после алло-ТГСК показал сохранение ремиссии.

Vamotinib (PF-114) is a 3rd -generation, ATP-competitive oral tyrosine kinase inhibitor (TKI) active against wild-type and mutated BCR::ABL1 isoforms including BCR::ABL1T315I. We present final results of a phase-1 vamotinib dose-escalation study to identify maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) followed by expansion cohorts. 51 subjects with chronic myeloid leukaemia (CML) failing ≥ 1 2nd generation TKI or with BCR::ABL1T315I were enrolled. Subjects received vamotinib, 50–750 mg/d, continuously. Median exposure was 6 months (range, < 1–52 months). Median CML duration pre-study was 10 years (range, < 1–23 years). 27 subjects received ≥ 3 prior TKIs and 16 had BCR::ABL1T315I. The MTD was 600 mg with the Grade-3 psoriasis-like skin toxicity as the DLT. There were no vascular occlusive events nor deviations of ankle-brachial index. Complete haematologic response (CHR) was achieved in 14 of 30 subjects, major cytogenetic response (MCyR) in 14 of 44 subjects, complete cytogenetic response (CCyR) in 10 of 50 and major molecular response (MMR) in 7 of 51 subjects who did not have a CHR, MCyR, CCyR or MMR at enrollment. The best safety/efficacy dose was 300 mg with MCyR achieved in 6 of 7 subjects, CCyR in 5 of 9 and MMR in 4 of 9 subjects who did not have a MCyR, CCyR or MMR at enrollment. 5 of 16 subjects with BCR::ABL1T315I responded including 3 achieving a CHR, 3, a MCyR, and 1,a CCyR. 2 of 5 subjects failing ponatinib achieved a CHR. Vamotinib dose for further phase-3 study is 300 mg/d.

Background Vamotinib (PF-114), an oral tyrosine kinase-inhibitor (TKI) is active against wild-type and BCR::ABL1 variants. Whether it is safer and more effective compared with high-dose imatinib in people with chronic phase chronic myeloid leukaemia (CML) failing conventional dose imatinib is unknown. Method Multi-centre open-label phase-3 trial with endpoints of safety and 1-year major molecular response (MMR). Other endpoints are rates of BCR::ABL1IS < 1% (MR2), MR4 and MR4.5. Subjects with imatinib-resistant BCR::ABL1 variantswere excluded. Results 180 subject (vamotinib, 300 mg; N = 89; imatinib; 800 mg; N = 91) were enrolled. 117 were men. Median age was 44 years (Range 18-75 years). Median CML duration pre-study was 4 years (Range, < 1-24 years). 65 subjects (73%) in the vamotinib cohort and 65 (71%) in the imatinib cohort had pre-study BCR::ABL1 ≥ 10%. Rate of achieving 1-year MMR with vamotinib was 47% compared with imatinib, 12% ( p < 0.001). Rates of other endpoints were also higher with vamotinib. There were no significant differences frequency of adverse events (AEs). Skin toxicity was the most common AE for vamotinib. Conclusion Vamotinib, 300 mg, is as safe as imatinib, 800 mg, but more effective in achieving 1-year MMR. The study is ongoing.

ABSTRACT:The efficacy of and disease control afforded by tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia in chronic phase (CML-CP) have led to increased longevity and thus the continued pursuit of alternative therapies that are efficacious and maximize tolerability. The 24- and 96-week analyses from ASCEMBL demonstrated superior efficacy, safety, and tolerability of asciminib when compared with bosutinib in later-line therapy, thereby meeting the primary and key secondary objectives. With nearly 4 years of follow-up, data from ASCEMBL continued to demonstrate the superior efficacy, safety, and tolerability of asciminib over bosutinib. At week 156, the major molecular response (MMR) rates remained higher with asciminib (33.8%) than with bosutinib (10.5%); the difference in MMR rates between arms, after adjusting for baseline major cytogenetic response, was 23.2% (95% confidence interval, 13.14-33.18; 2-sided P < .001). Asciminib continued to cause fewer grade ≥3 adverse events (AEs; 59.6% vs 68.4%) and fewer AEs that led to treatment discontinuation (8.3% vs 27.6%) than bosutinib. This updated analysis also includes patients who switched to asciminib because of a lack of efficacy with bosutinib. Two of the 25 patients who switched achieved MMR by the end of study, suggesting that earlier incorporation of asciminib, before other TKIs, may improve responses, albeit modestly. These long-term results further solidify asciminib as the therapy of choice for patients with CML-CP who were previously treated with ≥2 previous TKIs. This trial was registered at clinicaltrials.gov as #NCT03106779.

Importance Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) resistant or intolerant to BCR-ABL1 tyrosine kinase inhibitors (TKIs) have limited treatment options. Olverembatinib, which is approved in China, has only been tested in Chinese patients. Objective To assess the pharmacokinetics, safety, efficacy, and recommended dose of olverembatinib in patients with CML or Philadelphia chromosome-positive ALL resistant or intolerant to at least 2 TKIs. Design, Setting, and Participants This multicenter phase 1b randomized clinical trial was conducted from January 28, 2020, to January 2, 2024, with a median (range) follow-up of 48 (0-166) weeks. Patients with CML or Philadelphia chromosome-positive ALL were enrolled. This bridging study was performed in part to confirm that there are no racial differences in the pharmacokinetic profile of olverembatinib. InterventionsPatients were randomly assigned to 30, 40, or 50 mg of olverembatinib orally every other day in 28-day cycles. Main Outcomes and Measures Pharmacokinetic profile of olverembatinib. Results Of 80 included patients, 46 (58%) were male, and the median (range) age was 54.0 (21-80) years. The pharmacokinetic profile of olverembatinib was compatible with alternate-day dosing and similar to that in Chinese patients. Based on investigators' assessments, 60 patients (75%) experienced at least 1 treatment-related adverse event; 32 (40%) experienced grade 3 or higher treatment-related adverse events; and 12 (15%) experienced treatment-related serious adverse events, none of which were fatal. Frequently reported (10% or more) treatment-emergent adverse events included elevated blood creatine phosphokinase (all grades, 31 [39%]; grade 3 or higher, 10 [13%]) and thrombocytopenia (all grades, 23 [29%]; grade 3 or higher, 14 [18%]). Among evaluable patients with chronic-phase CML, complete cytogenetic response (CCyR) occurred in 31 of 51 patients (61%; 95% CI, 46.1-74.2), and major molecular response (MMR) occurred in 25 of 59 patients (42%; 95% CI, 29.6-55.9). Cytogenetic and molecular responses were similar in patients with or without T315I variants. A total of 15 of 26 patients with prior ponatinib treatment (58%; 95% CI, 36.9-76.6) achieved CCyR, and 11 of 30 (37%; 95% CI, 19.9-56.1) achieved MMR. A total of 4 of 8 patients with asciminib resistance (50%; 95% CI, 15.7-84.3) had CCyR, and 4 of 12 (33%; 95% CI, 9.9-65.1) had MMR. The recommended phase 3 dose of olverembatinib is 30 mg every other day in patients without T315I variants. Conclusions and Relevance In this trial, olverembatinib had a favorable pharmacokinetic profile, was generally well tolerated, and showed strong antileukemic activity in patients with heavily pretreated chronic-phase CML with or without T315I variants, including prior ponatinib and/or asciminib failure. Olverembatinib may provide a viable new treatment option for patients after failure of 2 or more TKIs. Trial RegistrationClinicalTrials.gov Identifier: NCT04260022

Introduction. ABL tyrosine kinase inhibitors (TKIs) have significantly improved the treatment outcomes for patients with chronic myeloid leukemia (CML). Bosutinib is a second-generation TKI that has demonstrated high efficacy and safety in clinical trials in firstand subsequent-line therapy of CML. Aim. To evaluate the long-term efficacy and safety of bosutinib in real-world clinical practice. Mat erials and methods. In our retrospective study all patients in the first chronic phase of CML who had ever received bosutinib therapy as their first, second, or third TKI were included. Only 4 patients (2 men) aged from 30 to 41 years received bosutinib as first TKI. Bosutinib was administered as second or third TKI to 19 patients (12 men) with a median age of 50 (31–71) and 17 patients (8 men) with a median age of 49.8 (21–70), respectively. Most patients had a long history of CML and most of them were resistant to previous TKIs. Results. All four patients who received bosutinib in the first-line achieved a complete hematological response (CHR), and three (75%) of them achieved a complete cytogenetic response (CCR) and a major molecular response (MMR). All 3 patients with MMR continued therapy for more than 16 years without significant adverse events. Among patients with bosutinib treatment after failure of imatinib or 2 TKIs, the CHR was achieved in most cases, and major cytogenetic response (MCR) was achieved in 7/19 (36.8%) and 6/17 (35.3%) cases. During the observation period, the median overall survival was not reached. There were few cases of bosutinib discontinuation due to drug intolerance. Long-term use of the drug did not lead to serious delayed side effects, including cardiovascular complications, associated with bosutinib therapy. Conclusions. Thus, in our group of patients with long-term observation, bosutinib showed not only a high frequency of achieving an optimal response in all lines of therapy in CP CML, but also the absence of severe remote complications, both hematological and non-hematological.

Background . Most patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors achieve durable optimal responses. Loss of the achieved molecular response is observed in 15–30 % of patients. Mutations in the BCR::ABL kinase domain are one of the most common mechanisms for the development of resistance to tyrosine kinase inhibitors. Aim . To conduct a retrospective analysis of the BCR::ABL kinase domain mutational profile in patients with CML observed at the Russian Research Institute of Hematology and Transfusiology from 2012 to 2023. To assess the impact of mutations type and number on the rate of achieving a major molecular response (MMR). To study the risk of MMR loss depending on the therapy line and existing mutational status. Materials and methods . 1831 patients with CML were examined at different times. The mutational status of the BCR::ABL kinase domain was analyzed by direct Sanger sequencing. A standard cytogenetic study was carried out using GTG banding technology with the analysis of at least 20 metaphase plates. Results . Mutations in the BCR::ABL kinase domain were identified in 27.6 % of the total studied patients. The most common mutation, 6.3 % in the overall group or 22.7 % among patients with mutations, was the T315I mutation. Additional chromosomal aberrations (ACAs) were detected in Ph-positive cells in 20.5 % of patients, in Ph-negative clones in 3.9 % of cases (p = 0.0001). The frequency of ACAs detection did not statistically significantly differ (p = 0.25) between patients with BCR::ABL mutations (23.5 %) and with a negative mutation status (17.7 %), and the presence of mutations in the kinase domain did not correlate with ACAs in Ph-positive clones (p = 0.73). However, the frequency of T315I mutation detection in Ph-positive cells had significant differences: 40.9 % in combination with ACAs and 21 % without ACAs (p = 0.032). Patients with the T315I mutation had significantly worse MMR than patients with mutations in other BCR::ABL regions (p = 0.04) and patients without mutations (p = 0.02). The probability of MMR achieving did not differ significantly between patients with different numbers of BCR::ABL mutations (p = 0.14). Loss of MMR occurred more often in patients with mutations (p = 0.04) and not depend on the line of therapy (p = 0.03). Conclusion . For complete monitoring and optimal choice of therapy, CML patients require not only monitoring of BCR::ABL relative expression level, but also standard cytogenetic and analysis of the mutational status.

Context Patients with CML or Ph+ ALL resistant or intolerant to BCR-ABL1 tyrosine kinase inhibitors (TKIs) have limited treatment options. Olverembatinib is a novel, potent, third-generation TKI approved in China for CML. Objective To assess the pharmacokinetics, safety, efficacy, and recommended phase 3 dose (RP3D) of olverembatinib in patients with CML and Ph+ ALL resistant/intolerant to ≥2 TKIs. Design Multicenter, randomized, open-label, phase 1b/2 trial conducted from January 28, 2020, to January 2, 2024. Patients Eighty patients (62 with CP-CML) with a median age of 54.0 (21-80) years were included; 46 of whom (57.5%) had received ponatinib and 25 (31.3%), asciminib. Ponatinib and asciminib had both failed in 11 patients. Interventions Patients were randomly assigned to olverembatinib 30, 40, or 50 mg orally every other day (QOD) in 28-day cycles, with randomization stratified by T315I mutational status. Results The pharmacokinetic profile of olverembatinib was compatible with alternate-day dosing, and olverembatinib was generally well tolerated. A total of 72 patients (90.0%) experienced treatment-emergent adverse events (TEAEs), including elevated blood creatine phosphokinase (38.8%) and thrombocytopenia (28.8%). Sixty-four patients (80.0%) experienced ≥1 grade ≥3 TEAE, and 31 (38.8%) ≥1 serious TEAE. Among evaluable patients with CP-CML, the complete cytogenetic response (CCyR) rate was 60.8% (31/51) and major molecular response (MMR) rate was 42.4% (25/59) (similar rates with or without T315I mutation). Fifteen of 26 patients (57.7%) with prior ponatinib achieved CCyR, and 11 of 30 (36.7%) achieved MMR. Four of 8 patients (50%) with asciminib resistance had CcyR, and 4 of 12 (33.3%) MMR. In patients with prior ponatinib and asciminib treatment, the CCyR rate was 42.9% and MMR rate 27.3%. The RP3D of olverembatinib is 30 and 40 mg QOD in patients with CP-CML without and with the T315I mutation, respectively. Conclusions Olverembatinib was well tolerated and showed strong antileukemic activity in patients with heavily pretreated CP-CML, including those with ponatinib and/or asciminib failure, irrespective of T315I mutation status. Olverembatinib may provide a valuable new treatment option for patients after failure of ≥2 TKIs. Clinicaltrials.gov ID: NCT04260022; internal study number: HQP1351CU101. Funding Ascentage Pharma Group Corp Ltd. (Hong Kong).