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E. Hellström-Lindberg et al.
Decitabine
Decitabine has been evaluated in two phase II studies assessing higher-risk MDS patients.153,154 Both studies showed similar efficacy, with overall response rates of 32- 39% and median survivals of ~20 months. The safety and efficacy data were similar to those for azacytidine, although phase III data, available for azacitidine, are lacking for decitabine. Both HMA are recommended by the NCCN for treating higher-risk patients, with a special focus also as a bridge to allogeneic SCT for eligible patients. High response rates have been reported for TP53-mutated AML patients treated with a 10-day decitabine regimen, although the durations of the responses were short.155
Intensive chemotherapy
Since the advent of HMA and other disease-modifying drugs, the use of intensive chemotherapy has decreased substantially but it may be considered after failure to bene- fit from HMA in younger fit patients, particularly as bridg- ing-therapy to SCT. The rate of complete responses achieved with intensive chemotherapy is around 50%, which is lower than that for de novo AML patients, and time to relapse is often short.156-158 The clinical benefit of this approach for non-SCT candidates in whom azacitidine therapy has failed has not been established.
Allogeneic stem cell transplantation
SCT is the only potentially curative treatment for patients with MDS. Due to potential severe complications, SCT is generally offered only to fit patients up to around 70-75 years of age. Historical data document long-term survival rates of between 25% and 45% with non-relapse mortality and relapse occurring in approximately a third of the patients.159-161 A more recent prospective study found a high- er 2-year relapse-free survival of 60%.162 Since the median age (50 years) in that study was relatively low, the outcome does not represent a real-world population.
Optimal timing of SCT is essential, considering that patients with high-risk MDS have a high risk of both relapse and mortality after SCT.163 A general recommenda- tion is to transplant higher-risk patients as part of an upfront process, while lower-risk MDS patients should be moni- tored and transplanted upon disease progression. Defining which patients should be considered low- and high-risk is therefore crucial for a correct transplantation plan. All three prognostic scoring systems (IPSS, IPSS-R and WPSS) are predictive of survival after allogeneic SCT.160,161,164,165 Genetic aberrations have a large impact on relapse risk. Relapse-free survival at 5 years in the five IPSS-R cytogenetic risk groups ranges between 10% and 42%.160,166 In addition, mutations in TP53 and the RAS-pathway genes have been reported to be risk factors for relapse.167-169
Disease status is also important for SCT outcome.161,168,170 Disease-modifying treatment is usually given to patients with a more proliferative disease, aiming for the best possi- ble remission before SCT. The usefulness of such treatment has, however, not been tested in prospective clinical trials. Retrospective studies have demonstrated similar outcomes for treated and untreated patients although selection bias is an obvious potential pitfall in these studies.171-173 Similarly, retrospective studies have not shown any advantage for either HMA or intensive chemotherapy as disease-modify- ing treatment before SCT.174
Retrospective studies have shown higher relapse rates but lower non-relapse mortality for reduced intensity con-
ditioning, generating similar overall survival rates.159,161,162 Good results have been reported for the fludarabine plus treosulfan regimen which is often used in younger patients.175-177
The prognosis after a post-SCT relapse is dismal although donor lymphocyte infusions and HMA may reverse the relapse in some cases.178 No validated minimal residual dis- ease markers are yet available for MDS. The Nordic MDS group is presently conducting a clinical trial (NCT02872662) in which patient-specific mutations are tracked in serial post-SCT samples using digital droplet PCR. Preliminary data indicate that these markers may pre- dict relapse and can be used for initiation of pre-emptive treatment.
Investigational therapies for myelodysplastic syndromes
There are limited therapeutic options available to exploit our increasing understanding of the molecular pathophysi- ology of MDS. As indicated above, only one therapy, lenalidomide, targets a specific clinical subset [patients with del(5q) cytogenetics], and two epigenetic modulators (aza- cytidine and decitabine) have been approved for the treat- ment of patients with presumed hypermethylation. Recurrently mutated intracellular functional pathways are frequently implicated in MDS and a number of novel ther- apies targeting these molecular defects have recently shown potential utility for treating MDS patients. In addition, drugs capable of modifying the toxic marrow microenvi- ronmental influences for erythropoiesis have been devel- oped.
IDH1 and IDH2 mutation inhibitors
Understanding of the pathophysiology of IDH1/2 muta-
tions in MDS and AML has led to development of clinical IDH1 and IDH2 mutation inhibitors. IDH1 and IDH2 muta- tions occur in approximately 5-12% of MDS patients (P51). Recent data have shown encouraging results from the use of ivosidenib or enasidenib for patients with IDH1 or IDH2 mutations, respectively.179,180
BCL2 inhibitor
The anti-apoptotic protein B-cell leukemia/lymphoma-2 (BCL2) is overexpressed in hematologic malignancies including some cases of MDS, in which it has been impli- cated in the maintenance and survival of myeloid cells, resistance to therapy, and poor clinical outcomes.181 In recent studies in higher-risk MDS patients either previously untreated or resistant to HMA, initial data suggest potential clinical efficacy of the BCL2 inhibitor, venetoclax, when combined with azacytidine.182,183
Drugs acting on p53
In hematologic malignancies, including MDS, TP53 mutations confer a poor prognosis. These mutations are particularly common in therapy-related MDS and a portion of patients with del(5q) cytogenetics.184 The drug APR-246 restores wildtype conformation to the mutant p53 and has recently shown beneficial clinical activity in MDS.185,186 Another approach to reactivate p53-mediated tumor sup- pression is to inhibit the frequently overexpressed p53 sup- pressor proteins MDMX and MDM2 in tumors. ALRN- 6924, a cell-penetrating stapled α-helical peptide disrupts
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haematologica | 2020; 105(7)