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Editorials
their cytogenetic and molecular characteristics, failing HMA therapy is still associated with a dismal prognosis reflected by a median survival of six months.6 Until now, almost nothing has been known about the mechanisms underlying HMA-resistance. Thus, as frequently as possi- ble, patients experiencing HMA failure should be evaluat- ed for clinical trial options, given the current absence of any available standard treatment in that setting. In clini- cally fit patients with HR-MDS or secondary AML (sAML) and normal karyotype, intensive chemotherapy with a subsequent allogeneic stem cell transplantation may also be considered.
In this issue of the Journal, Sébert et al. report results of a phase II study of the Groupe Francophone des Myélodysplasies (GFM) investigating the novel HMA guadecitabine (SGI-110) as a salvage treatment in HR- MDS and low blast count AML (<30% bone marrow blasts) patients after azacitidine failure.7 Guadecitabine is a dinucleotide of decitabine and deoxyguanosine with similar potency but longer half life due to resistance to cytidine deaminase degradation. This results in an extended exposure of blasts to its active metabolite decitabine. The study included fifty-six patients (median age 75 years) who failed or relapsed after at least six pre- vious azacitidine cycles. Patients' characteristics indicated a study population with advanced disease, including 87.5% of patients carrying high-risk somatic mutations such as ASXL1 (25%), RUNX1 (21%), TP53 (20%) and U2AF1 (20%).7 Patients achieving hematologic response after 3, 6 or 9 cycles of guadecitabine (60 mg/m2/day sub- cutaneously days 1-5 of 28-day treatment cycles) were considered to be responders and were allowed to contin- ue treatment until loss of response. Sébert et al. identified eight (14.3%) responding patients, including two CR, one partial response (PR), three hematologic improvements
(HI), and two marrow CR (mCR). Median response dura- tion was 11.5 months and median OS 7.1 months; responders had a prolonged median OS of 17.9 months.7
Therefore, even after failure to an HMA, HMA-based treatment with guadecitabine can be an effective alterna- tive treatment option prolonging survival in a small pro- portion of HR-MDS and AML patients, with a toxicity profile similar to that of standard HMA. The authors present an analysis of prognostic factors for response and prolonged OS after guadecitabine treatment. Especially patients with primary azacitidine failure, absence or lim- ited number of somatic mutations and lower methylation level in blood during the first cycle of treatment benefited from guadecitibaine treatment.7 A phase III trial compar- ing guadecitabine with treatment of choice in MDS patients after HMA failure is currently ongoing (clinicaltri- als.gov identifier: 02907359).
One other promising approach to improving efficacy of hypomethylation in HR-MDS and AML patients is the addition of the orally selective B-cell lymphoma 2 (BCL-2) inhibitor venetoclax to HMA. BCL-2 protein, a key regu- lator of leukemic blast survival, has been reported to play an important role in regulating apoptosis via the intrinsic mitochondrial cell death. Overexpression of the BCL-2 protein has been shown to be associated with poor out- comes, conferring chemotherapeutic resistance in AML.8 Recent data suggest that 400 mg of venetoclax has an opti- mal benefit-risk profile when used in combination with azacitidine.8 This combination has already demonstrated impressive rates of CR both in the frontline and relapse settings: AML patients treated with first-line venetoclax and HMA showed favorable overall response rates (ORR) (CR: 71% and CRi: 74%).9,10 Median duration of response after achieving CR was 21.2 months and median overall survival was 16.9 months.9 Comparing these results with
Figure 1. New options after hypomethylating agent failure.
haematologica | 2019; 104(8)