ABSTRACT
Asciminib targets the BCR::ABL1 myristoyl pocket, maintaining activity against BCR::ABL1T315I, which is resistant to most approved adenosine triphosphate-competitive tyrosine kinase inhibitors. We report updated phase I results (NCT02081378) assessing safety/tolerability and antileukemic activity of asciminib monotherapy 200 mg twice daily in 48 heavily pretreated patients with T315I-mutated chronic-phase chronic myeloid leukemia (CML-CP; data cutoff: January 6, 2021). With 2 years' median exposure, 56.3% of patients continued receiving asciminib. Overall, 62.2% of evaluable patients achieved BCR::ABL1 ≤1% on the International Scale (IS); 47.6% and 81.3% of ponatinib-pretreated and -naive patients, respectively, achieved BCR::ABL1IS ≤1%. Of 45 evaluable patients, 48.9% achieved a major molecular response (MMR, BCR::ABL1IS ≤0.1%), including 34.6% and 68.4% of ponatinib-pretreated and -naive patients, respectively. MMR was maintained until data cutoff in 19 of 22 patients who achieved it. The most common grade ≥3 adverse events (AEs) included increased lipase level (18.8%) and thrombocytopenia (14.6%). Five (10.4%) patients experienced AEs leading to discontinuation, including 2 who discontinued asciminib and died due to COVID-19; these were the only deaths reported. These results show asciminib's effectiveness, including in almost 50% of ponatinib pretreated patients, and confirm its risk-benefit profile, supporting its use as a treatment option for T315I-mutated CML-CP.
Subject(s)
Fusion Proteins, bcr-abl , Leukemia, Myeloid, Chronic-Phase , Mutation , Protein Kinase Inhibitors , Humans , Male , Middle Aged , Female , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Aged , Adult , Follow-Up Studies , Leukemia, Myeloid, Chronic-Phase/drug therapy , Leukemia, Myeloid, Chronic-Phase/genetics , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/antagonists & inhibitors , Aged, 80 and over , Young Adult , Drug Resistance, Neoplasm , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Niacinamide/analogs & derivatives , PyrazolesABSTRACT
ABSTRACT: Secondary kinase domain mutations in BCR::ABL1 represent the most common cause of resistance to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia. The first 5 approved BCR::ABL1 TKIs target the adenosine triphosphate (ATP)-binding pocket. Mutations confer resistance to these ATP-competitive TKIs and those approved for other malignancies by decreasing TKI affinity and/or increasing ATP affinity. Asciminib, the first highly active allosteric TKI approved for any malignancy, targets an allosteric regulatory pocket in the BCR::ABL1 kinase C-lobe. As a non-ATP-competitive inhibitor, the activity of asciminib is predicted to be impervious to increases in ATP affinity. Here, we report several known mutations that confer resistance to ATP-competitive TKIs in the BCR::ABL1 kinase N-lobe that are distant from the asciminib binding pocket yet unexpectedly confer in vitro resistance to asciminib. Among these is BCR::ABL1 M244V, which confers clinical resistance even to escalated asciminib doses. We demonstrate that BCR::ABL1 M244V does not impair asciminib binding, thereby invoking a novel mechanism of resistance. Molecular dynamic simulations of the M244V substitution implicate stabilization of an active kinase conformation through impact on the α-C helix as a mechanism of resistance. These N-lobe mutations may compromise the clinical activity of ongoing combination studies of asciminib with ATP-competitive TKIs.
Subject(s)
Drug Resistance, Neoplasm , Fusion Proteins, bcr-abl , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors , Humans , Drug Resistance, Neoplasm/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/chemistry , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Mutation , Adenosine Triphosphate/metabolism , Proto-Oncogene Proteins c-abl/genetics , Proto-Oncogene Proteins c-abl/metabolism , Proto-Oncogene Proteins c-abl/chemistry , Niacinamide/analogs & derivatives , PyrazolesABSTRACT
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The European Stop Kinase Inhibitors (EURO-SKI) study is the largest clinical trial for investigating the cessation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia in stable deep molecular remission (DMR). Among 728 patients, 434 patients (61%; 95% CI, 57 to 64) remained in major molecular response (MMR) at 6 months and 309 patients of 678 (46%; 95% CI, 42 to 49) at 36 months. Duration of TKI treatment and DMR before TKI stop were confirmed as significant factors for the prediction of MMR loss at 6 months. In addition, the type of BCR::ABL1 transcript was identified as a prognostic factor. For late MMR losses after 6 months, TKI treatment duration, percentage of blasts in peripheral blood, and platelet count at diagnosis were significant factors in multivariate analysis. For the entire study period of 36 months, multiple logistic regression models confirmed duration of treatment, blasts, and transcript type as independent factors for MMR maintenance. In addition to the duration of treatment, transcript type as well as blasts in peripheral blood at diagnosis should be considered as important factors to predict treatment-free remission.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors , Remission Induction , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Protein Kinase Inhibitors/therapeutic use , Female , Middle Aged , Male , Adult , Aged , Prognosis , Imatinib Mesylate/therapeutic use , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/antagonists & inhibitors , Pyrimidines/therapeutic use , Europe , Young Adult , Aged, 80 and over , Treatment OutcomeABSTRACT
PURPOSE OF REVIEW: The discovery that patients suffering from chronic myeloid leukemia who obtain deep and long-lasting molecular responses upon treatment with tyrosine kinase inhibitors may maintain their disease silent for many years after therapy discontinuation launched the era of treatment-free remission as a key management goal in clinical practice. The purpose of this review on treatment-free remission is to discuss clinical advances, highlight knowledge gaps, and describe areas of research. RECENT FINDINGS: Patients in treatment-free remission are a minority, and it is believed that some may still retain a reservoir of leukemic stem cells; thus, whether they can be considered as truly cured is uncertain. Strengthening BCR::ABL1 inhibition increases deep molecular responses but is not sufficient to improve treatment-free remission, and we lack biomarkers to identify and specifically target residual cells with aggressive potential. Another level of complexity resides in the intra- and inter-patient clonal heterogeneity of minimal residual disease and characteristics of the bone marrow environment. Finding determinants of deep molecular responses achievement and elucidating varying biological mechanisms enabling either post-tyrosine kinase inhibitor chronic myeloid leukemia control or relapse may help develop innovative and safe therapies. In the light of the increasing prevalence of CML, targeting the residual leukemic stem cell pool is thought to be the key.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Remission Induction , Neoplasm, Residual , Treatment OutcomeABSTRACT
The management of chronic myeloid leukemia (CML) diagnosed during pregnancy is a rare and challenging situation. We report the treatment and outcome of 87 cases diagnosed in chronic phase from 2001-2022 derived from the largest international observational registry, supported by the European LeukemiaNet (ELN), of 400 pregnancies in 299 CML women. Normal childbirth occurred in 76% without an increased rate of birth abnormalities or life-threatening events, including in patients untreated or treated with interferon-α and/or imatinib in 2nd-3rd trimester. The low birth weight rate of 12% was comparable to that seen in the normal population. Elective and spontaneous abortions occurred in 21% and 3%, respectively. The complete hematologic response rate before labor was 95% with imatinib and 47% with interferon only. No disease progression during pregnancy was observed, 28% of the patients switched their therapy at varying times after delivery. Treatment options balance the efficacy and safety for mother and infant: interferon-α can commence in the 1st trimester and continued throughout in cases of good disease control and tolerability. Because of limited placental crossing, selected tyrosine kinase inhibitors (imatinib and nilotinib) seem to be safe and effective options in 2nd and 3rd trimester while hydroxycarbamide offers few benefits.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Leukemia, Myeloid, Chronic-Phase , Humans , Female , Pregnancy , Imatinib Mesylate , Protein Kinase Inhibitors/adverse effects , Placenta , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Interferon-alpha/therapeutic use , Treatment OutcomeABSTRACT
Ponatinib, the only approved all known-BCR::ABL1 inhibitor, is a third-generation tyrosine-kinase inhibitor (TKI) designed to inhibit BCR::ABL1 with or without any single resistance mutation, including T315I, and induced robust and durable responses at 45 mg/day in patients with CP-CML resistant to second-generation TKIs in the PACE trial. However, cardiovascular toxicities, including arterial occlusive events (AOEs), have emerged as treatment-related AEs within this class of TKIs. The OPTIC trial evaluated the efficacy and safety of ponatinib using a novel, response-based, dose-reduction strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I. To assess the dose-response relationship and the effect on the safety of ponatinib, we examined the outcomes of patients with CP-CML enrolled in PACE and OPTIC who received 45 mg/day of ponatinib. A propensity score analysis was used to evaluate AOEs across both trials. Survival rates and median time to achieve ≤1% BCR::ABL1IS in OPTIC were similar or better than in PACE. The outcomes of patients with T315I mutations were robust in both trials. Patients in OPTIC had a lower exposure-adjusted incidence of AOEs compared with those in PACE. This analysis demonstrates that response-based dosing for ponatinib improves treatment tolerance and mitigates cardiovascular risk.
Subject(s)
Antineoplastic Agents , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Leukemia, Myeloid, Chronic-Phase , Pyridazines , Humans , Drug Resistance, Neoplasm , Leukemia, Myeloid, Chronic-Phase/drug therapy , Leukemia, Myeloid, Chronic-Phase/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Imidazoles/therapeutic use , Imidazoles/pharmacology , Pyridazines/therapeutic use , Pyridazines/pharmacology , Fusion Proteins, bcr-abl/genetics , Protein Kinase Inhibitors/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacologyABSTRACT
TYROSINE KINASE INHIBITORS FOR CHRONIC MYELOID LEUKEMIA. About 20 years ago, the discovery of imatinib, the first ATP-competitive inhibitor of BCR::ABL1 the driving oncoprotein of chronic myeloid leukemia (CML), revolutionized patients' outcome by transforming a fatal condition into a chronic one. Today, five more tyrosin kinase inhobitors (TKIs) have been approved, allowing to some extent individualization of drug therapy. The main therapeutic objective is to protect patients from progression towards a fatal blast crisis and to restore of a near-to-normal life expectancy on lifelong TKI treatment. Only a minority of patients manage to achieve a state called treatment-free remission. Research efforts must go on as some challenges remain such as improving scoring systems, increasing TKI safety profile, fighting against resistance and finding how to cure CML.
INHIBITEURS DE TYROSINE KINASE DANS LA LEUCÉMIE MYÉLOÏDE CHRONIQUE. Il y a un peu plus de vingt ans, l'imatinib, premier inhibiteur compétitif de l'adénosine triphosphate (ATP) ciblant l'oncotyrosine kinase BCR::ABL1, a révolutionné le pronostic de la leucémie myéloïde chronique. Aujourd'hui, cinq autres inhibiteurs ont rejoint la pharmacopée et permettent, dans une certaine mesure, une personnalisation des stratégies thérapeutiques. L'objectif premier de la prise en charge est la protection contre la progression de l'hémopathie vers une forme aiguë fatale et la restauration d'une espérance de vie normale sous traitement à vie une minorité de patients parviennent tout de même à arrêter le traitement. Malgré la richesse de l'arsenal thérapeutique, la recherche doit continuer : des progrès restent nécessaires pour améliorer les systèmes pronostiques existants, augmenter la sécurité d'emploi des inhibiteurs de tyrosine kinase, combattre la multirésistance et la transformation aiguë et parvenir à la rémission sans traitement pour tous les patients.