While resistance to imatinib is
While resistance to imatinib is rare in patients treated in CML-CP, resistance does eventually develop in the majority of patients treated in the advanced phases. In a high proportion of patients who develop secondary resistance after initial responses, point mutations in the BCR-ABL kinase domain have been identified, often associated with reactivation of the dys-regulated enzymatic activity of the Bcr-Abl protein. The first such mutation identified was a C→T nucleotide change that results in a threonine to isoleucine substitution at position 315 in the Abl component of Bcr-Abl (Thr315→Ile; T315I). Thr315 forms a critical hydrogen bond with imatinib. The absence of the oxygen atom normally provided by the side chain of Thr315 precludes formation of a hydrogen bond with the secondary amino group of imatinib, but does not interfere with mitoxantrone binding. Although a large number of such mutations have now been identified, the most important one still remains T315I, referred to as the “gatekeeper” mutation, because it uniformly confers resistance to all first and second generation Bcr-Abl TKIs. Allogeneic hematopoietic stem cell transplantation (HSCT), effective in a proportion of cases by virtue of a strong graft-versus-leukemia (GVL) effect has, therefore, been the only recourse for these patients.
Ponatinib Ponatinib (AP24534, Iclusig™) is a multi-targeted TKI optimized using structure-based drug design to bind to the inactive conformation of Abl and AblT315I. It does not form a hydrogen bond with the side chain of Thr315 in native Abl. The key structural feature of the molecule is a carbon-carbon triple bond linkage that makes productive hydrophobic contact with the side chain of Ile315, allowing inhibition of the T315I mutant. In the ongoing pivotal phase II PACE trial in patients with refractory CML (all phases) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who were resistant or intolerant to dasatinib or nilotinib, or carried the T315I mutation, it showed substantial activity in all patients, although activity appeared particularly pronounced in CP patients with T315I. In this group, at a median follow-up of 12 months, rates of CCyR and major molecular response (MMR) were 67% and 56%, respectively. In patients with accelerated and blastic phase CML and Ph+ ALL bearing the T315I mutation, respectively, CCyR rates were 22%, 16% and 50%. Response rates continued to improve with longer follow-up. Based on the findings of this trial, the US FDA granted accelerated approval to ponatinib for the treatment of adults with CML (all phases) or Ph+ ALL who are resistant or intolerant to prior TKI therapy on December 14, 2012. Although unquestionably a major breakthrough in Bcr-Abl TKI therapy, there have been concerns regarding the ability of ponatinib, except at high concentrations, to inhibit compound mutants involving T315I, such as Y253H/T315I or E255V/T315I that sometimes pose a challenge, particularly in later lines of therapy, and that it might actually be relatively less potent against native Bcr-Abl. To answer the latter question, a phase III trial comparing ponatinib with imatinib as initial therapy for newly diagnosed patients with CML-CP (NCT01650805) is currently enrolling patients.
Homoharringtonine/omacetaxine Homoharringtonine is a natural alkaloid obtained from various Cephalotaxus species that exerts antitumor activity through inhibition of protein synthesis and promotion of apoptosis. Among other actions, homoharringtonine down-regulates short-lived anti-apoptotic proteins such as myeloid cell leukemia-1 (Mcl-1) through translational inhibition. Because of its unique mechanism of action, the activity of this agent against CML cells is independent of their BCR-ABL mutational status. Omacetaxine mepesuccinate (Synribo®) is a semisynthetic form of homoharringtonine that has excellent bioavailability upon subcutaneous administration. Although known for over three decades, the clinical development of these compounds has been impeded by the success of the Bcr-Abl TKIs. In a very recently reported large phase II trial of omacetaxine in CML patients with T315I and TKI failure, 48 of 62 (77%) patients in CP achieved complete hematologic response (CHR), and 10 (16%) achieved CCyR. Myelosuppression, typically manageable by dose reduction, was the major toxicity. On October 26, 2012, omacetaxine mepesuccinate received accelerated approval from the FDA for the treatment of adults with chronic and accelerated phase CML with resistance and/or intolerance to two or more TKIs.