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Asciminib, an agent that targets the myristoyl pocket of BCR::ABL, was compared with imatinib and with imatinib plus second-generation tyrosine kinase inhibitors. Outcomes were better with asciminib in both comparisons.

After nearly 11 years of follow-up, long-term administration of imatinib was shown to be associated with prolonged control of chronic myeloid leukemia and no cumulative or late toxic effects have emerged. Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that is characterized by the Philadelphia (Ph) chromosome and driven by its product, the BCR-ABL1 tyrosine kinase. 1 In 2001, imatinib was introduced as a BCR-ABL1 tyrosine kinase inhibitor and was approved for the treatment of CML on the basis of a high level of activity in phase 2 studies. 2 Early results from the phase 3 International Randomized Study of Interferon and STI571 (IRIS) showed that imatinib at a dose of 400 mg once daily was more active and was associated with fewer side effects than interferon alfa plus cytarabine in patients with . . .

This proof-of-principle trial showed that imatinib treatment reduced mast-cell activation and improved airway responsiveness in patients with severe refractory asthma. Many patients with severe asthma do not have adequate disease control despite the use of high-dose inhaled or systemic glucocorticoids. 1 Severe asthma is associated with airway hyperresponsiveness — that is, an exaggerated response to a bronchoconstrictor stimulus — and airway inflammation, both of which persist despite high-dose glucocorticoid therapy. 2 , 3 Increased airway hyperresponsiveness is associated with a progressive loss of lung function, 4 and, among patients with moderate-to-severe asthma, those with airway hyperresponsiveness have a poorer quality of life than those without this trait. 5 In addition, studies have shown that treatment targeting airway hyperresponsiveness leads to more effective control of asthma . . .

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients’ long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR 4.5 ; BCR-ABL ⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.

In the phase 3 PhALLCON trial (NCT03589326), ponatinib demonstrated superior efficacy, patient-reported treatment tolerability, and health-related quality of life (HRQoL) compared to imatinib in adults with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). To explore the association between clinical response and HRQoL and substantiate the superior effect of ponatinib over imatinib on HRQoL, we analyzed the impact of clinical response and treatment tolerability on changes in HRQoL. HRQoL was assessed using the Functional Assessment of Cancer Therapy–Leukemia (FACT-Leu) questionnaire and the EQ-5D-5 L. Treatment tolerability was assessed using the FACT-GP5 item “bothered by treatment side effects.” Linear mixed-effects regression models were used to examine changes in HRQoL over time, with clinical response status and patient-reported overall treatment tolerability as time-varying predictors, while controlling for significant covariates. This analysis included data from 238 patients (159 ponatinib, 79 imatinib). Achieving clinical response (complete remission or incomplete remission) was associated with significantly better changes from baseline across all FACT-Leu domains and the EQ-visual analogue scale than not achieving clinical response ( p  < 0.05). Treatment-related side effects led to significantly and meaningfully worse changes in HRQoL than “not bothered by treatment,” with higher levels of “bother” associated with greater worsening in HRQoL from baseline. Taken together with the better treatment tolerability and longer response duration of ponatinib compared to imatinib, these findings further substantiate the HRQoL benefit of ponatinib over imatinib in patients with Ph + ALL.

The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8–236·6) after the 1-year randomisation, 200·9 months (190·2–208·4) after the 3-year randomisation, and 164·5 months (134·4–176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5–10·1) versus 27·8 months (19·5–37·9; hazard ratio [HR] 0·36 [95% CI 0·20–0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5–11·7) versus 67·0 months (48·8–85·6; 0·15 [0·07–0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0–16·6) versus not reached (NR; NR–NR; 0·13 [0·03–0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1–39·1) versus 90·6 months (25·3–156·1; HR 0·93 [95% CI 0·51–1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0–89·6) versus 127·3 months (15·0–239·7; 0·35 [0·17–0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0–167·4) versus NR (NR–NR; 0·24 [0·05–1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3–82·9) versus 105·0 months (20·6–189·6; HR 0·84 [95% CI 0·46–1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7–118·7) versus 134·0 months (89·7–178·3; 0·40 [0·20–0·82], log-rank p=0·0096), and after 5 years was NR (NR–NR) versus 110·4 months (82·7–154·1; 1·28 [0·41–3·99]; log-rank p=0·67), Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.

Early molecular response is associated with improved probability of deep molecular response and superior survival in patients with CML-CP. However, ~1 in 3 patients on first-line imatinib do not achieve this threshold. The phase 2b DASCERN trial (NCT01593254) assessed the outcome of early switch to dasatinib in patients with suboptimal response to first-line imatinib. Adult patients with CML-CP were randomized (2:1) to receive 100 mg dasatinib (n = 174) or continue imatinib at ≥400 mg (n = 86). The primary endpoint was the rate of major molecular response (MMR) at 12 months, which was 29% (dasatinib) and 13% (imatinib; P = 0.005). After ≥2 years of follow-up, 45 patients (52%) randomized to continue imatinib had crossed over to dasatinib. Considering treatment crossover, the 2-year cumulative MMR rate was 64% with dasatinib and 41% with imatinib (66% and 67%, respectively by intent-to-treat). Adverse events were consistent with the established safety profiles of both drugs. The results of this first prospective study support early monitoring of patients treated with first-line imatinib, and suggest that switching to dasatinib in cases of suboptimal response may offer clinical benefit. Further follow-up is needed to assess the long-term clinical benefit of early switching.

In the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR 4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.