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Tyrosine kinase inhibitors (TKIs) have vastly improved long-term outcomes for patients with chronic myeloid leukemia (CML). After imatinib (a first-generation TKI), second- and third-generation TKIs were developed. With five TKIs (imatinib, dasatinib, bosutinib, nilotinib, and ponatinib) targeting BCR::ABL approved in most countries, and with the recent approval of asciminib in the USA, treatment decisions are complex and require assessment of patient-specific factors. Optimal treatment strategies for CML continue to evolve, with an increased focus on achieving deep molecular responses. Using clinically relevant case studies developed by the authors of this review, we discuss three major scenarios from the perspective of international experts. Firstly, this review explores patient-specific characteristics that affect decision-making between first- and second-generation TKIs upon initial diagnosis of CML, including patient comorbidities. Secondly, a thorough assessment of therapeutic options in the event of first-line treatment failure (as defined by National Comprehensive Cancer Network and European LeukemiaNet guidelines) is discussed along with real-world considerations for monitoring optimal responses to TKI therapy. Thirdly, this review illustrates the considerations and importance of achieving treatment-free remission as a treatment goal. Due to the timing of the writing, this review addresses global challenges commonly faced by hematologists treating patients with CML during the COVID-19 pandemic. Lastly, as new treatment approaches continue to be explored in CML, this review also discusses the advent of newer therapies such as asciminib. This article may be a useful reference for physicians treating patients with CML with second-generation TKIs and, as it is focused on the physicians’ international and personal experiences, may give insight into alternative approaches not previously considered.

Introduction: Patients (pts) with primary and secondary myelofibrosis (MF) have a reduced life expectancy. While several oral Janus Kinase (JAK)-1/2 inhibitors such as ruxolitinib (RUX) have demonstrated improvements in symptom burden and spleen volume reduction compared to physician choice of best available therapy leading to their approval by the US FDA, responses to these agents are generally time-limited. Additionally, these agents are not considered to be disease-modifying and survival in pts after RUX discontinuation is poor with a median survival of 11-14 months. Thus, novel mechanism-based therapies for pts with suboptimal response or progression on RUX are needed. Preclinical Rationale: JAK2 V617F mutations promote transition from G1 to S-phase of the cell cycle via increased expression of CDC25A in preclinical models and CDC25A expression is upregulated in primary MPN patient samples. Additional cell cycle regulators such as CDK6 and Cyclin D also play a role in MF pathogenesis and drive myeloproliferation. Finally, combination of the CDK4/6 inhibitor ribociclib and RUX demonstrated reduction in spleen and liver size when compared to RUX alone in murine models, suggesting synergy (Rampal et al., CCR 2021). Methods: This multicenter, phase I dose-escalation trial evaluates the safety of RUX + the CDK4/6 inhibitor abemaciclib in pts with primary or secondary MF with intermediate-1/2 or high-risk disease by DIPSS who require treatment and had an inadequate response to RUX. An inadequate response will be defined by (I) palpable splenomegaly ≥5 cm below the left costal margin at study entry AND/OR (II) active MPN symptoms [presence of 1 symptom score ≥5 or 2 symptom scores ≥3 using the screening MPN-SAF TSS. This study follows a conventional “3+3” dose-escalation design, in which pts on a stable dose of RUX (10mg or 15mg BID) with sufficient baseline platelet and absolute neutrophil count will be treated with increasing doses of abemaciclib. Abemaciclib was chosen due to less myelosuppression compared with other CDK4/6 inhibitors. The pre-study dose of ruxolitinib will be maintained to determine the maximum tolerated dose of the combination of RUX+ abemaciclib. The primary endpoint is to determine the safety and tolerability, and to identify the recommended phase II dose of abemaciclib in MF pts on a stable dose of RUX. Secondary endpoints include overall response rate, progression-free and overall survival, and duration of response per the modified International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and the European Leukemia Net (ELN) 2013 consensus definitions. Correlative studies are planned to identify biomarkers predictive of response to RUX + abemaciclib, mechanisms of resistance (e.g., MAP kinase pathway activation), and any disease-modifying effects of combination therapy. Citation Format: Jan P. Bewersdorf, Srdan Verstovsek, Andriy Derkach, Lucia Masarova, Naveen Pemmaraju, Eytan M. Stein, Michael Mauro, Raajit Rampal, Prithviraj Bose. A phase I study of ruxolitinib in combination with abemaciclib for patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT242.

Background The phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial of ponatinib showed robust long-term benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred in ≥ 25% of patients based on investigator reporting. However, AOE rates vary depending on the definitions and reporting approach used. Methods To better understand clinically relevant AOEs with ponatinib, an independent cardiovascular adjudication committee reviewed 5-year AOE data from the PACE trial according to a charter-defined process and standardized event definitions. Results A total of 449 patients with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) received ponatinib (median age 59 y; 47% female; 93% ≥ 2 prior tyrosine kinase inhibitors (TKIs); median follow-up, 37.3 months). The adjudicated AOE rate (17%) was lower than the non-adjudicated rate (i.e., rate before adjudication; 25%). The only adjudicated AOE in > 2% of patients was peripheral arterial occlusive disease (4%). Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Patients with multiple baseline cardiovascular risk factors had higher adjudicated AOE rates than those without risk factors. Conclusions This independent adjudication study identified lower AOE rates than previously reported, suggesting earlier overestimation that may inaccurately reflect AOE risk with ponatinib. This trial was registered under ClinicalTrials.gov identifier NCT01207440 on September 23, 2010 (https://clinicaltrials.gov/ct2/show/NCT01207440).

We developed a first-of-kind dasatinib-derivative imaging agent, (18)F-SKI-249380 ((1)(8)F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assessed the feasibility of using (18)F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min after injection of (18)F-SKI (mean, 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney (n = 2) or three 10-min whole-body PET/CT scans (n = 3) immediately after injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of 3 patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of (18)F-SKI. In total, 27 tumor lesions were analyzed, with a median SUV(peak) of 1.4 (range, 0.7–2.3) and tumor-to-blood ratios of 1.6 (range, 0.8–2.5) at 90 min after injection. The intratumoral drug concentrations calculated for 4 reference lesions ranged from 0.03 to 0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30 and 90 min after injection. A blood radioassay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time, 1.31 ± 0.81 min; plasma, 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time, 285 ± 148.49 min; plasma, 240 ± 84.85 min; n = 2) or a small rise to a plateau (n = 2). Like dasatinib, (18)F-SKI underwent extensive metabolism after administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 mSv/MBq (SD, 0.0034 mSv/MBq). Conclusion: (18)F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.