Is there a role for omacetaxine in the management of chronic myelogenous leukemia in the era of the tyrosine kinase inhibitors?

Chronic myelogenous leukemia (CML) is defined by the fusion of the Bcr and Abl genes, producing a constitutively active tyrosine kinase, which gives cells a proliferative advantage leading to expansion of the myeloid lineage. Tyrosine kinase inhibitors (TKIs) have changed the landscape of the disease and have dramatically improved patient outcomes, including affording a normal life expectancy for many patients [1]. Progression of the disease to the more advanced stages, accelerated phase (AP) and blast crisis (BC), however, still occurs. It is associated with the acquisition of additional cytogenetic abnormalities, tyrosine kinase mutations and ultimately TKI resistance [2]. These phases of disease remain a challenging therapeutic area. Allogeneic stem cell transplant can be a curative option for eligible patients, but long-term outcome is largely determined by the stage of disease of the time of transplant. Disease-free survival at 35–40% is seen in patients in whom a second chronic phase disease is restored (CP2), 26–27% for AP and 8–11% in BC [3]. Thus it is ideal to achieve a CP2 prior to transplant if feasible.

Omacetaxine mepesuccinate, “omacetaxine,” has a unique mechanism of action affecting Bcr–Abl levels without directly binding the enzyme, in contrast to the TKIS. It binds to the ribosomal subunit, inhibiting the translation of many oncoproteins, including Mcl-1, Myc and Bcr–Abl [4]. Cells dependent on such oncoproteins for survival ultimately undergo apoptosis. This distinct property of omacetaxine makes it less susceptible to tyrosine kinase mutations which confer resistance to TKI therapy, such as the gatekeeping mutation T315I. Clinical activity was demonstrated in patients with CML and was the basis for accelerated approval by the US Food and Drug Administration in October 2012 for patients with CP and AP CML failing two prior TKI agents [5]. The drug is administered as a subcutaneous injection twice daily with induction followed by a maintenance schedule. The reported adverse events are mostly hematologic and are generally well managed. Non-hematologic toxicities are primarily low grade and mostly related to fatigue, infection, nausea and diarrhea [6,7].

In this issue of Leukemia and Lymphoma, Khoury and colleagues report their pooled analysis from the international CML-202 and -203 study groups on the efficacy of omacetaxine for the treatment of AP- and BC-CML in heavily pretreated patients [8]. The results of the CP-CML cohort from the same phase II prospective trials were presented earlier and showed promising clinical activity [6]. All patients failed at least two prior TKI therapies due to resistance or intolerance, and almost two-thirds of patients had confirmed T315I mutation status. Fifty-one and 44 patients were in AP- and BC-CML, respectively. The primary endpoint was maintaining or achieving a major hematologic response (MHR). Other endpoints investigated included cytogenetic response, duration of response, progression-free survival and overall survival. Amongst the study cohort, 37% of patients with AP and 9% with BC achieved or maintained MHR, with a median response duration of 5.6 and 1.7 months, respectively. A third of responding patients with AP had MHR at baseline. Additionally, at the end of the study, the majority of patients had discontinued therapy, mostly due to progression. Omacetaxine thus showed limited activity in advanced phase CML, and is unlikely to produce clinically meaningful responses as a sole agent at this stage of disease.

TKI therapy in advanced disease has shown higher hematologic and cytogenetic activity: between 64 and 47% of patients achieved a MHR with dasatinib and nilotinib [9–11]. Responses are dependent on the mutation status of the enzyme, and no inhibition is seen with T315I using first- or second-generation TKIs. Ponatinib inhibits mutated and native Bcr–Abl, and over half of patients achieved MHR in AP [12]. Emerging concerns over arterial thrombosis are likely to limit the use of ponatinib in the future in patients with the T315I mutation or those who failed other therapies [13]. Direct comparison of efficacy between omacetaxine and TKIs is not possible, as TKIs were tested in a first- or second-line setting; however, generally all available therapy options have limited efficacy in advanced disease. Interestingly, among patients with AP with the T315I mutation, omacetaxine response rates are almost double. This difference is also observed in patients treated with ponatinib, where patients with T315I have higher response rates. This indicates again that patients with a T315I mutation are a less resistant population overall. So where does omacetaxine fit in the treatment of CML in the TKI era, and particularly in its advanced phase? Which cohorts would benefit the most? The available literature highlights three potential groups of patients who may benefit. The first group includes allograft eligible patients in advanced stages of disease. The current study showed limited cytogenetic improvement and duration of response, and omacetaxine will not likely alter the course of the disease in a significant manner. Attempting to achieve a CP2 using omacetaxine is of relevance for patients eligible for an allogeneic graft, and is certainly an attractive option as bridge therapy. In the current cohort, a very limited number of patients were offered allografting, and in fact this was an exclusion criterion in the CML-202 cohort [14]. In patients with BP this rate is much lower, but one in four patients with a hematologic response was able to receive an allogeneic stem cell transplant. Second, for non-transplant eligible patients who cannot tolerate or are resistant to all available TKIs regardless of stage, omacetaxine should be available, but this represents a small proportion of patients. Lastly, there will be a growing number of patients, with or without T315I mutations, who will have had to stop ponatinib due to serious arterial complications and who are not transplant candidates [13]. For this group, omacetaxine is required at least until more effective agents become available. The therapeutic options and overall prognosis for patients with CML has never been better. Omacetaxine is a recent addition to the therapeutic armamentarium in CML with potential activity in other malignancies. It has a unique mechanism of action and mode of administration different from the TKIs, and is currently approved in patients resistant or intolerant to TKI therapy. The majority of patients with CML will fare well on first- or second-generation TKIs, but a small proportion will progress for various reasons. Omacetaxine is an appealing choice in this subset of patients with limited treatment options.

Potential conflict of interest

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