Asciminib for chronic myeloid leukaemia: Next questions

Abstract

The therapeutic landscape of chronic myeloid leukaemia (CML) has dramatically shifted in the past two decades, 1 transforming the disease from a primary indication for an allogeneic stem cell transplant to essentially a chronic illness. The altered paradigm is solely due to the development of tyrosine kinase inhibitors (TKIs) that target the diseasedefining BCR-ABL1 fusion 2 with the first foray into targeted therapy being imatinib, the first-generation TKI. 3 With the introduction of imatinib, and the subsequent development of more potent TKIs including the second-generation agents (nilotinib, 4 dasatinib 5 and bosutinib 6 ) and the third-generation TKI (ponatinib), 7 the 10-overall survival for patients diagnosed with chronic phase (CP) CML exceeds 80%, 8 almost matching age-matched healthy population comparators. 9 However, following the initial survival benefits observed with imatinib, the more potent TKIs did not demonstrate substantive gains in overall survival when used frontline, 10,11 the benefits probably tempered by the toxicity associated with the second-generation TKIs. Furthermore, while many CP CML patients will achieve deep molecular responses, there remains a small proportion of patients who progress to the more advanced stages of accelerated phase (AP) or blast phase (BP) CML 3 which remain therapeutic challenges. The critical determinants of resistance and progression while on TKI therapy are poorly understood but development of point mutations in the kinase domain of BCR-ABL1 remains the best recognised mechanism of resistance, influencing sensitivity to TKI therapy. 12 Therefore,

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

“…Based on the current evidence, we do not recommend switching from imatinib to nilotinib for a second attempt. The recommendation may differ for news inhibitors, such as asciminib, particularly if their safety profile and efficacy are confirmed in the future 27 …”

Asciminib a new player in treatment of TKI-resistant/intolerant chronic phase chronic myelogenous leukemia

“…Asciminib was introduced after approval by the US Food and Drug Administration (FDA) into clinical practice in 2021 in CML patients after resistance and/or intolerance to two previous lines of treatment [47]. The detailed characteristics of asciminib are set out in Table I.…”

“…On fusion of ABL1 to BCR, myristoylated N-terminal is lost and ABL1 kinase is activated. By allosterical binding of myristoyl site, asciminib mimics myristate and restores inhibition of BCR-ABL1 kinase activity [46,47] After binding to myristoyl pocket of ABL1 kinase domain, asciminib induces an inactive conformational change and inhibits kinase activity [45] Half-life time (T CCyR were obtained and maintained in 74% and 53% of patients, respectively. MR 4.5 was confirmed in 16% of the studied patients (10.5% in PPT vs. 19.4% in the non-PPT group).…”

Italian Physicians’ Perceptions about the Role of Asciminib in Later Lines Chronic Myeloid Leukemia in Clinical Practice: A GIMEMA Survey

“…These unmet needs motivate the search for additional drugs to manage this subset of patients. Asciminib, the first example of an allosteric inhibitor, has been recently approved by the FDA and EMA as third-line treatment in chronic-phase CML (CP-CML) patients after resistance and/or intolerance to two previous lines of treatment [ 6 ]. Recently, a median 4-year follow-up of a phase 1a trial has been reported for 115 non-T315I mutated patients.…”