Beyond hypomethylating agents failure in patients with myelodysplastic syndromes

Abstract

Purpose of review Although hypomethylating agents (HMAs) significantly improve outcomes in myelodysplastic syndromes (MDS), only half the patients achieve objective responses, and most responders lose response within 1–2 years. Azacitidine prolongs survival by a median of only 9.5 months. Failure of HMA therapy is associated with a very dismal prognosis. Therefore, novel therapeutic approaches are clearly needed. Recent findings The sequential use of the alternative HMA after failure of first line HMA is associated with modest efficacy. The improved understanding of the biologic underpinnings of the disease have opened the door to study investigational agents that target disrupted molecular pathways critical to the pathogenesis of MDS. Combination treatment strategies using an azacitidine backbone are demonstrating promising early results. Expanding the applicability of allogeneic stem cell transplantation (alloSCT), the only curative modality, by reducing toxicity and relapse rates is another area of active research. Summary Sequential switching to the alternative HMA, clinical trials of novel targeted therapies, azacitidine-based combination therapeutic strategies, and improvements in the alloSCT platform are the main directions in improving outcomes of MDS post HMA failure.

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression

“…Intensive myeloablative treatment regimens are possible in only a minority of such patients and are associated with decreased efficacy and increased therapy-related mortality (Zeidan et al, 2014). DNA hypomethylating agents (HMAs) elicit higher overall response rates in MDS and AML patients with TET2 mutations and provide an alternative to aggressive chemotherapy (Bejar et al, 2014).…”

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

“…The topic of HSCT in MDS is complex, with many patientspecific variables to consider, including which patients are suitable transplant candidates, the best timing of transplant in the disease course, the optimal conditioning regimen, and post-HSCT management [73,74]. Nevertheless, HSCT remains the only possible cure for patients with MDS and should be considered in all potentially transplant-eligible patients after failure of HMAs [13,75].…”

The evolving field of prognostication and risk stratification in MDS: Recent developments and future directions

“…Clinical responses to DNMTis are not immediate and may take months to become apparent. Thus, without existing markers able to predict response, many patients may remain on these therapies for months without benefit and with subsequent delay in starting alternative therapies [8,9].…”

“…These agents, in conjunction with supportive care (transfusions, hematopoietic growth factors, iron chelation when indicated), immunosuppressive therapies, allogeneic hematopoietic cell transplantation (alloHCT), and occasionally cytotoxic chemotherapy, comprise therapies commonly used for MDS. Treatment options are utilized in a risk-adapted manner balancing the risk/benefit of the proposed intervention with the patient's predicted survival and probability of leukemic progression in order to avoid undue harm [6][7][8]. Accurate risk stratification is paramount in aiding predictions of survival and for guiding individual treatment decisions.…”