BCR::ABL1 Kinase N-lobe Mutants Confer Moderate to High Degrees of Resistance to Asciminib.

Secondary kinase domain mutations in BCR::ABL1 represent the most common cause of resistance to tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia patients. The first five approved BCR::ABL1 TKIs target the 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 dynamics simulations of the M244V substitution implicate stabilization of an active kinase conformation through impact on the -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.

European Stop Tyrosine Kinase Inhibitor Trial (EURO-SKI) in Chronic Myeloid Leukemia: Final Analysis and Novel Prognostic Factors for Treatment-Free Remission.

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.

Chronic myeloid leukemia diagnosed in pregnancy: management and outcome of 87 patients reported to the European LeukemiaNet international registry.

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.

Tyrosine Kinase Inhibitor Discontinuation in Chronic Myeloid Leukemia: Strategies to Optimize Success and New Directions.

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.

Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials.

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.

[Optimizing the use of bosutinib in patients with chronic-phase chronic myeloid leukemia: Recommendations of a panel of experts from the Fi-LMC (French CML working group)]. / Optimisation du bosutinib dans la leucémie myéloïde chronique : recommandations du Fi-LMC (France Intergroupe des leucémies myéloïdes chroniques).

The treatment of chronic myeloid leukemia relies on orally available tyrosine kinase inhibitors targeting the BCR::ABL1 oncoprotein. Bosutinib is a second generation adenosine triphosphate-competitive inhibitor approved for use in frontline adult chronic phase-chronic myeloid leukemia and all phases-chronic myeloid leukemia in the second line setting or beyond. Its efficacy was demonstrated in several pivotal clinical trials at 400mg once daily in the first line context and at 500mg once daily beyond first line. Bosutinib-related adverse events frequently occur early after treatment initiation and include gastro-intestinal symptoms and cytolytic hepatitis. These drug-related adverse events must be properly managed in order to preserve safety, efficacy and treatment acceptability. The French chronic myeloid leukemia study group gathered a panel of experts in hematology, pharmacology and hepatology in order to elaborate practical recommendations on the management of bosutinib treatment. These recommendations aim at optimizing the short and long-term tolerance and benefit/risk balance of bosutinib, mainly focusing at gastro-intestinal and liver toxicities.

Health care resource utilization in 3L + patients with chronic phase chronic myeloid leukemia receiving asciminib or bosutinib.

OBJECTIVES: To assess and compare health care resource utilization (HCRU) rates of asciminib and bosutinib at the Week 24, Week 48, and Week 96 cutoffs among 3 L + patients with chronic myeloid leukemia in chronic phase (CML-CP) in the randomized ASCEMBL trial. METHODS: Patients in the ASCEMBL trial (Clinicaltrials.gov: NCT03106779) were randomized to receive asciminib 40 mg twice daily (n = 157) or bosutinib 500 mg once daily (n = 76). At each scheduled visit, investigators conducted HCRU assessment on hospitalization, emergency room visit, general practitioner visit, specialist visit and urgent care visit; duration and type of hospitalization for the hospitalized patients; and reasons for HCRU. The number of patients with HCRU, rate of HCRU per patient-year, and length of hospital stay by ward type were compared at Week 24, Week 48, and Week 96 analyses. RESULTS: Lower proportions of patients receiving asciminib versus bosutinib used any resources including hospitalizations, emergency room visits, general practitioner visits, specialist visits, and urgent care visits (23.6% versus 36.8%, 26.1% versus 39.5%, and 28.6% versus 42.6% at Week 24, Week 48, and Week 96 analyses, respectively). After normalizing for treatment exposure, rates of HCRU for any resource per patient-year were significantly lower for asciminib versus bosutinib: 0.25 (95% CI: 0.18-0.34) versus 0.80 (95% CI: 0.55-1.16) at the Week 24 analysis, 0.20 (95% CI: 0.15-0.27) versus 0.47 (95% CI: 0.32-0.66) at the Week 48 analysis, and 0.17 (95% CI: 0.12-0.22) versus 0.40 (95% CI: 0.27-0.55) at the Week 96 analysis. Among the hospitalized patients, mean length of hospital stay was lower for asciminib than bosutinib for most wards at all three timepoints. CONCLUSIONS: In the ASCEMBL trial, asciminib-treated patients with CML-CP in 3 L + maintained lower resource utilization compared to bosutinib over the long-term.

Dose optimisation of ponatinib in chronic phase chronic myeloid leukemia.

INTRODUCTION: Ponatinib exhibits a high inhibition potency on wild-type and most mutated forms of the BCR:ABL1 kinase, but also a significant cardiovascular toxicity. Improving the efficacy/safety ratio should allow patients to safely draw benefit from the drug. AREAS COVERED: Based on pharmacological findings and international guidelines on chronic myeloid leukemia and cardiovascular risk management, as well as on the most recent data collected in real-life studies and in a randomized phase II trial, we propose a decision-tree of dose selection of the drug. EXPERT OPINION: We distinguish (1) highly resistant patients according to poor previous response to second generation tyrosine kinase inhibitors (complete hematologic response or less) or to mutational status (T315I, E255V, alone or within compound mutations), requiring a starting daily dose of 45 mg, reduced to 15 or 30 mg according to the patient's profile, preferentially upon major molecular achievement (3-log reduction or MR3, BCR:ABL1 ≤ 0.1%IS); (2) less-resistant patients justifying an initial dose of 30 mg, reduced to 15 mg upon MR2 (BCR:ABL1 ≤ 1%IS) or preferentially MR3 in patients with a favorable safety profile; (3) intolerant patients to be treated by 15 mg.

Using Measurable Residual Disease to Optimize Management of AML, ALL, and Chronic Myeloid Leukemia.

In this review, we discuss the use of measurable residual disease (MRD) in AML, ALL, and chronic myeloid leukemia (CML). Our aims were to review the different methodologies for MRD assessment; describe the clinical relevance and medical decision making on the basis of MRD; compare and contrast the usage of MRD across AML, ALL, and CML; and discuss what patients need to know about MRD as it relates to their disease status and treatment. Finally, we discuss ongoing challenges and future directions with the goal of optimizing MRD usage in leukemia management.

First-line second generation tyrosine kinase inhibitors in patients with newly diagnosed accelerated phase chronic myeloid leukemia.

Accelerated phase (AP) CML at onset and have poorer prognosis than CP-CML. We hypothesize that off-license use of second generation TKI (TKI2) as front-line therapy might counterbalance this poor prognosis, with limited toxicity. In "real-life" conditions, newly diagnosed patients meeting the ELN cytological criteria for AP-CML or harboring ACA and treated with first-line TKI2 were included in this retrospective multicenter observational study. We enrolled 69 patients [69.5 % male, median age 49.5 years, median follow-up 43.5 months], segregated into hematologic AP [HEM-AP (n = 32)] and cytogenetically defined AP [ACA-AP (n = 37)]. Hematologic parameters were worse in HEM-AP [spleen size (p = 0.014), PB basophils (p < .001), PB blasts (p < .001), PB blasts+promyelocytes (p < .001), low hemoglobin levels (p < .001)]. Dasatinib was initiated in 56 % patients in HEM-AP and in 27 % in ACA-AP, nilotinib in 44 % and 73 % respectively. Response and survival do not differ, regardless of the TKI2: 81 % vs 84.3 % patients achieved CHR, 88 % vs 84 % CCyR, 73 % vs 75 % MMR respectively. The estimated 5-year PFS 91.5 % (95%CI: 84.51-99.06 %) and 5-year OS 96.84 % (95%CI: 92.61-100 %). Only BM blasts (p < 0.001) and BM blasts+promyelocytes (p < 0.001) at diagnosis negatively influenced OS. TKI2 as front-line therapy in newly diagnosed AP-CML induce excellent responses and survival, and counterbalance the negative impact of advanced disease phase.

Treatment-free remission after dasatinib in patients with chronic myeloid leukaemia in chronic phase with deep molecular response: Final 5-year analysis of DASFREE.

Patients with chronic myeloid leukaemia in chronic phase (CML-CP) who have a sustained deep molecular response (DMR) are eligible to discontinue treatment and attempt treatment-free remission (TFR). In the DASFREE study (ClinicalTrials.gov; NCT01850004), the 2-year TFR rate after dasatinib discontinuation was 46%; here we present the 5-year update. Patients with a stable DMR after ≥2 years of dasatinib therapy discontinued treatment and were followed for 5 years. At a minimum follow-up of 60 months, in 84 patients discontinuing dasatinib, the 5-year TFR rate was 44% (n = 37). No relapses occurred after month 39 and all evaluable patients who relapsed and restarted dasatinib (n = 46) regained a major molecular response in a median of 1.9 months. The most common adverse event during the off-treatment period was arthralgia (18%, 15/84); a total of 15 withdrawal events were reported in nine patients (11%). At the 5-year final follow-up, almost half of the patients who discontinued dasatinib after a sustained DMR maintained TFR. All evaluable patients who experienced a relapse quickly regained a DMR after restarting dasatinib, demonstrating that dasatinib discontinuation is a viable and potentially long-term option in patients with CML-CP. The safety profile is consistent with the previous report.

Health-related quality of life of patients with resistant/intolerant chronic phase chronic myeloid leukemia treated with asciminib or bosutinib in the phase 3 ASCEMBL trial.

In ASCEMBL, an open-label, randomized Phase 3 study, asciminib demonstrated superior efficacy and better safety profile compared with bosutinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors. Health-related quality of life (HRQOL) reported by patients is key to understanding the benefit and impact of treatment on patients' lives, and is becoming increasingly important as the life expectancy of CML-CP patients increases and patients require long-term treatment. In ASCEMBL, patients completed questionnaires to assess CML symptoms and interference with daily life (M.D. Anderson Symptom Inventory - CML [MDASI-CML]), general HRQOL (five-level EQ-5D [EQ-5D-5L], Patient Global Impression of Change - CML [PGIC-CML]), and impact of CML on working life and activity (Work Productivity and Activity Impairment questionnaire - CML [WPAI-CML]). Patients' CML symptoms and HRQOL remained stable during 48 weeks of treatment with asciminib, with a general trend for decreased CML symptom severity, particularly for fatigue, and improvement in HRQOL. A clinically meaningful increase in diarrhea severity was observed in patients treated with bosutinib compared to asciminib. These data provide better understanding of the patient perspective and treatment impact on HRQOL in a later-line setting, where little information has been published to date.

Efficacy and safety of nilotinib in chronic myeloid leukaemia patients who failed to achieve a treatment-free remission period after imatinib discontinuation: Results of the French Nilo post-STIM study.

Molecular recurrence (MRec) occurs in about half of all patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitors (TKI) in sustained deep molecular response. A second TKI discontinuation has been attempted in some patients who regain the discontinuation criteria after resuming treatment. Nilotinib treatment affords faster and deeper molecular responses than imatinib as first-line therapy. We prospectively evaluated the efficacy and safety of nilotinib (300 mg twice daily) in chronic-phase CML patients who experienced MRec, after imatinib discontinuation and analysed the probability of TFR after a new attempt in patients treated for 2 years with sustained MR4.5 for at least 1 year. A total of 31 patients were included in the study between 2013 and 2018. Seven (23%) patients experienced serious adverse events after a median of 2 months of nilotinib treatment leading to discontinuation of treatment. One patient was excluded from the study for convenience. Among the 23 patients treated for 2 years with nilotinib, 22 maintained their molecular response for at least 1 year (median: 22 months) and stopped nilotinib. The TFR rates at 24 and 48 months after nilotinib discontinuation were 59.1% (95% confidence interval [CI]: 41.7%-83.7%) and 42.1% (95% CI: 25%-71%) respectively (NCT #01774630).

Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results.

Asciminib is approved for patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10-200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.6% of patients remained on asciminib. The most common grade ≥3 adverse events (AEs) included increased pancreatic enzymes (22.6%), thrombocytopenia (13.9%), hypertension (13.0%), and neutropenia (12.2%); all-grade AEs (mostly grade 1/2) included musculoskeletal pain (59.1%), upper respiratory tract infection (41.7%), and fatigue (40.9%). Clinical pancreatitis and arterial occlusive events (AOEs) occurred in 7.0% and 8.7%, respectively. Most AEs occurred during year 1; the subsequent likelihood of new events, including AOEs, was low. By data cutoff, among patients without the indicated response at baseline, 61.3% achieved BCR::ABL1 ≤ 1%, 61.6% achieved ≤0.1% (major molecular response [MMR]), and 33.7% achieved ≤0.01% on the International Scale. MMR was maintained in 48/53 patients who achieved it and 19/20 who were in MMR at screening, supporting the long-term safety and efficacy of asciminib in this population.

Matching-adjusted indirect comparison of asciminib versus other treatments in chronic-phase chronic myeloid leukemia after failure of two prior tyrosine kinase inhibitors.

PURPOSE: The current standard of care for chronic-phase chronic myeloid leukemia (CP-CML) is tyrosine kinase inhibitors (TKIs). Treatment recommendations are unclear for CP-CML failing ≥ 2 lines of treatment, partly due to the paucity of head-to-head trials evaluating TKIs. Thus, matching-adjusted indirect comparisons (MAICs) were conducted to compare asciminib with competing TKIs in third- or later line (≥ 3L) CP-CML. METHODS: Individual patient-level data for asciminib (ASCEMBL; follow-up: ≥ 48 weeks) and published aggregate data for comparator TKIs (ponatinib, nilotinib, and dasatinib) informed the analyses. Major molecular response (MMR), complete cytogenetic response (CCyR), and time to treatment discontinuation (TTD) were assessed, where feasible. RESULTS: Asciminib was associated with statistically significant improvements in MMR by 6 (relative risk [RR]: 1.55; 95% confidence interval [CI]: 1.02, 2.36) and 12 months (RR: 1.48; 95% CI: 1.03, 2.14) vs ponatinib. For CCyR, the results vs ponatinib were similar by 6 (RR: 1.11; 95% CI: 0.81, 1.52) and 12 months (RR: 0.97; 95% CI: 0.73, 1.28). Asciminib was associated with improvements in MMR by 6 months vs dasatinib but with a CI overlapping one (RR 1.52; 95% CI: 0.66, 3.53). Asciminib was associated with statistically significant improvements in CCyR by 6 (RR: 3.57; 95% CI: 1.42, 8.98) and 12 months (RR: 2.03; 95% CI: 1.12, 3.67) vs nilotinib/dasatinib. Median TTD was unreached for asciminib in ASCEMBL. However, post-adjustment asciminib implied prolonged TTD vs nilotinib and dasatinib, but not vs ponatinib. CONCLUSION: These analyses demonstrate favorable outcomes with asciminib versus competing TKIs, highlighting its therapeutic potential in ≥ 3L CP-CML.

Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL.

Asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), is approved worldwide for the treatment of adults with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs). In ASCEMBL, patients with CML-CP treated with ≥2 prior TKIs were randomized (stratified by baseline major cytogenetic response [MCyR]) 2:1 to asciminib 40 mg twice daily or bosutinib 500 mg once daily. Consistent with previously published primary analysis results, after a median follow-up of 2.3 years, asciminib continued to demonstrate superior efficacy and better safety and tolerability than bosutinib. The major molecular response (MMR) rate at week 96 (key secondary endpoint) was 37.6% with asciminib vs 15.8% with bosutinib; the MMR rate difference between the arms, after adjusting for baseline MCyR, was 21.7% (95% CI, 10.53-32.95; two-sided p = 0.001). Fewer grade ≥3 adverse events (AEs) (56.4% vs 68.4%) and AEs leading to treatment discontinuation (7.7% vs 26.3%) occurred with asciminib than with bosutinib. A higher proportion of patients on asciminib than bosutinib remained on treatment and continued to derive benefit over time, supporting asciminib as a standard of care for patients with CML-CP previously treated with ≥2 TKIs.

Dasatinib plus Peg-Interferon alpha 2b combination in newly diagnosed chronic phase chronic myeloid leukaemia: Results of a multicenter phase 2 study (DASA-PegIFN study).

Superior rates of deep molecular response (DMR) have been reported with the combination of tyrosine kinase inhibitors and pegylated-interferon-alpha (Peg-IFN) in patients with newly diagnosed chronic phase-chronic myeloid leukaemia (CP-CML). In this setting, this study investigated the efficacy and safety of dasatinib combined to Peg-IFN-α2b (Dasa-PegIFN, NCT01872442). A total of 79 patients (age ≤65 years) started dasatinib; 61 were eligible for Peg-IFNα-2b add-on therapy at month 3 for a maximum 21-months duration. Dasatinib was continued thereafter. The primary endpoint was the cumulative rate of molecular response 4.5 log (MR4.5 ) by 12 months. The results are reported for the 5-year duration of the study. Grade 3 neutropenia was frequent with the combination but did not induce severe infection (one of grade 3). Other adverse events were generally low grade (4% of grade 3-4) and expected. Seventy-nine per cent and 61% of patients continued the Peg-IFN until months 12 and 24, respectively. Overall, at these time points, MR4.5 rates were 25% and 38%, respectively. Thereafter, 32% and 46% of patients achieved a sustained (≥2 years) MR4.5 or MR4 , respectively. This work established the feasibility and high rates of achievement of early and sustained DMR (a prerequisite for treatment-free-remission) with dasatinib and Peg-IFNα-2b combination as initial therapy.

[Tyrosine kinase inhibitors for chronic myeloid leukemia]. / Inhibiteurs de tyrosine kinase dans la leucémie myéloïde chronique.

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.

Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia.

Ponatinib, the only third-generation pan-BCR::ABL1 inhibitor with activity against all known BCR::ABL1 mutations including T315I, has demonstrated deep and durable responses in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to prior second-generation (2G) TKI treatment. We present efficacy and safety outcomes from the Ponatinib Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and CML Evaluation (PACE) and Optimizing Ponatinib Treatment in CP-CML (OPTIC) trials for this patient population. PACE (NCT01207440) evaluated ponatinib 45 mg/day in CML patients with resistance to prior TKI or T315I. In OPTIC (NCT02467270), patients with CP-CML and resistance to ≥2 prior TKIs or T315I receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR::ABL1IS or received 15 mg/day continuously. Efficacy and safety outcomes from patients with CP-CML treated with ≥1 2G TKI (PACE, n = 257) and OPTIC (n = 93), 45-mg starting dose cohort, were analyzed for BCR::ABL1IS response rates, overall survival (OS), progression-free survival (PFS), and safety. By 24 months, the percentages of patients with ≤1% BCR::ABL1IS response, PFS, and OS were 46%, 68%, and 85%, respectively, in PACE and 57%, 80%, and 91%, respectively, in OPTIC. Serious treatment-emergent adverse events and serious treatment-emergent arterial occlusive event rates were 63% and 18% in PACE and 34% and 4% in OPTIC. Ponatinib shows high response rates and robust survival outcomes in patients whose disease failed prior to 2G TKIs, including patients with T315I mutation. The response-based dosing in OPTIC led to improved safety and similar efficacy outcomes compared with PACE.