Maintenance DFMO Increases Survival in High Risk Neuroblastoma

Abstract

High risk neuroblastoma (HRNB) accounts for 15% of all pediatric cancer deaths. Despite aggressive therapy approximately half of patients will relapse, typically with only transient responses to second-line therapy. This study evaluated the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) as maintenance therapy to prevent relapse following completion of standard therapy (Stratum 1) or after salvage therapy for relapsed/refractory disease (Stratum 2). This Phase II single agent, single arm multicenter study enrolled from June 2012 to February 2016. Subjects received 2 years of oral DFMO (750 ± 250 mg/m2 twice daily). Event free survival (EFS) and overall survival (OS) were determined on an intention-to-treat (ITT) basis. 101 subjects enrolled on Stratum 1 and 100 were eligible for ITT analysis; two-year EFS was 84% (±4%) and OS 97% (±2%). 39 subjects enrolled on Stratum 2, with a two-year EFS of 54% (±8%) and OS 84% (±6%). DFMO was well tolerated. The median survival time is not yet defined for either stratum. DFMO maintenance therapy for HRNB in remission is safe and associated with high EFS and OS. Targeting ODC represents a novel therapeutic mechanism that may provide a new strategy for preventing relapse in children with HRNB.

Polyamine synthesis as a target of MYC oncogenes

“…DFMO was well tolerated, and the therapy resulted in longer progression-free survival (8). Currently, several DFMO clinical trials are in progress (see Table 2) and include a recently completed DFMO phase II maintenance trial with neuroblastoma patients that are in remission but at high risk for relapse (9). Table 2 also shows that DFMO is being tested in addition to standard chemotherapy in newly diagnosed patients with high-risk disease.…”

“…DFMO reached FDA approval for the treatment of West African sleeping sickness (trypanosomiasis; intravenous formulation) (6) and for the treatment of excessive facial hair growth (hirsutism; topical formulation). More recently, DFMO, in an oral formulation (powder or tablets), has been under investigation in multiple clinical trials, for example, the chemoprevention of colorectal cancer and pediatric neuroblastoma (7)(8)(9).…”

“…These preclinical efforts ultimately led to the first phase I neuroblastoma clinical trial with DFMO in 2010 (8). Today, multiple independent phase I and II DFMO neuroblastoma clinical trials are ongoing across the United States of America and in Australia (9).…”

Arginase Pathway in Acute Retina and Brain Injury: Therapeutic Opportunities and Unexplored Avenues

“…However, there is no clinically tested drug that can specifically target A2 or PAO. DFMO, which inhibits ODC and therefore can reduce polyamine levels, has been tested in neuroblastoma patients and found to be protective (Sholler et al, 2018). As was noted above, DFMO lacks specificity and can also inhibit arginase activity.…”

Regulation of the hypothalamic GnRH–GnIH system by putrescine in adult female rats and GT1‐7 neuronal cell line

“…Studies have also shown that DFMO treatment has decreased luteinizing hormone (LH), progesterone, and prolactin levels and number of ovulated oocytes in female adult rodents (Nicholson & Wynne‐Jones, 1989; Nicholson, Aslam, Chuang, Gillham, & Jones, 1988). A study showed that the metabolism and requirement of polyamines in cancer is altered (Nowotarski, Woster, & Casero, 2013), and recently, DFMO maintenance therapy for neuroblastoma in remission has been shown to be safe (Sholler et al, 2018). However, it is also known that anabolism of polyamines is linked to the synthesis of a molecule, known as 5′‐methylthioadenosine (MTA).…”