Clinical importance of eflornithine (α-difluoromethylornithine) for the treatment of malignant gliomas

Abstract

This review covers the literature between 1989 and 2007 on studies relevant to the neuro-oncology usage of eflornithine (α-difluoromethylornithine), an oral agent that irreversibly inhibits the enzyme ornithine decarboxylase. It covers the use of eflornithine, alone or in combination, to treat high-grade gliomas. In addition, we provide an update on overall survival from The University of Texas MD Anderson Cancer Center Community Clinical Oncology Program and Clinical Trials Data Office that demonstrates a meaningful benefit in overall survival for eflornithine as a single agent and in combination with nitrosourea-based therapies for anaplastic gliomas. We also provide a framework for understanding the basis and study design of the ongoing pivotal, registrational Phase III multicenter trial for recurrent/progressive anaplastic astrocytoma.

Keywords: anaplastic oligoastrocytoma; anaplastic oligodendroglioma; astrocytoma; glioblastoma; polyamine inhibition.

Figure 1.. Kaplan–Meier representations of progression-free survival and overall survival of eflornithine patients treated on US FDA Orphan Drug Grant Study T88–0236 and study DM88–130 with diagnosis of AA and GBM.

PFS and OS for (A) AA and overall survival for (B) GBM were updated in 2001. There were 34 evaluable AA from the original study and 38 GBM [9]. AA: Anaplastic astrocytoma; GBM: glioblastoma; PFS: Progression-free survival; OS: Overall survival.

Figure 2.. Study DM88–130 subgroup of patients failing RT compared with those who failed RT and adjuvant chemotherapy prior to eflornithine.

The median values were the same whether we used 34 AA or 38 AA/anaplastic oligoastrocytoma as only 7 AA received RT only prior to eflornithine. AA: Anaplastic astrocytoma.

Figure 3.. The year 2012 analysis for DM92–035 study for overall survival of patients with the diagnosis of anaplastic astrocytoma or anaplastic oligoastrocytoma.

It was assumed, based on current molecular-based pathology definitions [15], that most anaplastic oligoastrocytoma would be considered anaplastic oligoastrocytoma today. The log rank comparison found hazard ratio = 0.75 (95% CI: 0.52–1.07) with p = 0.12, the Gehan–Breslow–Wilcoxon test found p = 0.07.

Figure 4.. Hazard rate and hazard ratio plots for the reanalyzed 2009 anaplastic glioma dataset.

(A) Overall survival hazard rate for 114 patients receiving eflornithine–PCV (solid line) and 114 patients receiving procarbazine, lomustine, vincristine (dashed line). (B) Shows the log hazard ratio (solid line) and 95% CI (dashed line). The Cox model fit between 0 and 2.5 years had a hazard ratio = 0.49 and p = 0.004 (see Table 2).