Outlook and Management of Patients with Myelodysplastic Syndromes Failed by Hypomethylating Agents

Abstract

The DNA hypomethylating agents (HMAs) azacitidine and decitabine are currently the most frequently administered disease-modifying therapies for patients with higher-risk myelodysplastic syndromes (MDS). However, azacitidine and decitabine are not curative, the median response duration is 11-15 months, and only 10-20 % of patients experience complete hematologic and cytogenetic response. Moreover, once an HMA fails the patient, the prognosis is poor, with a median survival of less than 6 months unless the patient undergoes hematopoietic stem cell transplantation (HSCT). Recent insights into the genetic basis of MDS have enhanced biological understanding and prognostication accuracy, but these developments have not yet led to regulatory approval of new therapies. While there are multiple potential approaches to patients with MDS for whom HMAs have failed, including supportive care alone, cytotoxic therapy, lenalidomide, histone deacetylase inhibitors, and HSCT, favorable responses to these approaches are limited and new therapies are greatly needed. Here, we review clinical and biological data about the population of patients failed by HMAs, evaluate currently available approaches to patients in this clinical situation, and discuss prospects for development of novel active agents.

Hypomethylating agents (HMA) treatment for myelodysplastic syndromes: alternatives in the frontline and relapse settings

“…Eligible patients may attempt transplant; however, many patients are not candidates due to comorbidities and poor performance status. Trials are difficult since HMA refractory patients are a challenging population, and selecting the optimal next line options remains undetermined [13]. …”

“…HMA have been frequently studied in combination with a HDACi, which includes entinostat (SNDX275), vorinostat (SAHA), belinostat (PDX101), panobinostat (LBH589), mocetinostat (MGCD0103), and pracinostat (SB939). Efficacy of these combinations has not shown improvement over HMA monotherapy in initial treatment studies, and studies of this class on patients with HMA failure are limited [13]. Combination therapies with HMA are reviewed by Ball, et al [16].…”

“…Azacitidine, shown to improve overall survival in higher risk patients compared to conventional care [8], is the only approved HMA in Europe, and hence accounts for its more widespread use than decitabine [11, 12]. No direct comparison from clinical trials on azacitidine and decitabine in MDS patients has shown differences in survival although data is lacking; both are accepted as the standard first line treatment [13]. Unfortunately, only 40–50% of patients respond to HMA treatment; complete response is lower at a mere 10–20%.…”

“…Unfortunately, only 40–50% of patients respond to HMA treatment; complete response is lower at a mere 10–20%. Among clinical responders, the majority will experience loss of response and disease progression, with mean duration of response of 11–15 months [13, 14, 15]. A large number of investigational agents are currently combined with HMA and investigated in clinical trials, but to date none has demonstrated improvements in outcome [16].…”

Low clinical trial accrual of patients with myelodysplastic syndromes: Causes and potential solutions

“…28,29 After HMAs fail, patients with higher risk disease have a median survival of <6 months, whereas those with lower risk disease have a median survival of only 15 months. 28,29 After HMAs fail, patients with higher risk disease have a median survival of <6 months, whereas those with lower risk disease have a median survival of only 15 months.…”