Failure to reach hematopoietic allogenic stem cell transplantation in patients with myelodysplastic syndromes planned for transplantation: a population-based study.

The only potential cure for patients with myelodysplastic syndrome (MDS) is allogeneic hematopoietic stem cell transplantation (HCT). However, a proportion of patients who are HCT candidates do not finally get transplanted. This population-based study aimed to characterize HCT candidates were attempting to reach HCT fail and to identify causes and risk factors for failure. Data were collected from (1) the national Swedish registry, enrolling 291 transplant candidates between 2009-2018, and (2) Karolinska University Hospital, enrolling 131 transplantation candidates between 2000 and 2018. Twenty-five % (nation-wide) and 22% (Karolinska) failed to reach HCT. Reasons for failure to reach HCT were progressive and refractory disease (47%), no donor identified (22%), identification of comorbidity (18%), and infectious complications (14%). Factors associated with failure to reach HCT were IPSS-R cytogenetic risk-group very poor, mixed MDS/MPN disease, low blast count (0-4.9%), and low hemoglobin levels (≤7.9 g/dL). Transplanted patients had a longer overall survival (OS) compared to patients who failed to reach transplantation (83 months versus 14 months; p < 0.001). The survival advantage was seen for the IPSS-R risk groups intermediate, high, and very high. This study demonstrated that a high proportion of HCT-candidates fail to reach HCT and underlines the difficulties associated with bridging MDS patients to HCT.

Treatment of myelodysplastic syndrome in the era of next-generation sequencing.

Next-generation sequencing (NGS) is rapidly changing the clinical care of patients with myelodysplastic syndrome (MDS). NGS can be used for various applications: (i) in the diagnostic process to discriminate between MDS and other diseases such as aplastic anaemia, myeloproliferative disorders and idiopathic cytopenias; (ii) for classification, for example, where the presence of SF3B1 mutation is one criterion for the ring sideroblast anaemia subgroups in the World Health Organization 2016 classification; (iii) for identification of patients suitable for targeted therapy (e.g. IDH1/2 inhibitors); (iv) for prognostication, for example, where specific mutations (e.g. TP53 and RUNX1) are associated with inferior prognosis, whereas others (e.g. SF3B1) are associated with superior prognosis; and (v) to monitor patients for progression or treatment failure. Most commonly, targeted sequencing for genes (normally 50-100 genes) reported to be recurrently mutated in myeloid disease is used. At present, NGS is rarely incorporated into clinical guidelines although an increasing number of studies have demonstrated the benefit of using NGS in the clinical management of MDS patients.

Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS: Results from the nordic NMDSG08A phase II trial.

This prospective phase II study evaluated the efficacy of azacitidine (Aza)+erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo+granulocyte colony stimulation factors for >8 weeks and a transfusion need of 4 units over 8 weeks were included. Aza 75 mg m(-2) d(-1), 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received one cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza+Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n=3) and DNMT3A (n=4) were only observed in non-responders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations.

Early detection of relapse in patients with myelodysplastic syndrome after allo-SCT.

Allo-SCT is the only potentially curative regimen for myelodysplastic syndromes (MDSs), but it is associated with a high relapse risk. The role of chimerism analysis for prediction of relapse is yet to be determined. To assess the clinical usefulness of mixed chimerism (MC) for predicting hematological relapse, 75 consecutively transplanted patients with MDS were analyzed with regard to lineage-specific chimerism, encompassing CD33(+) cells in peripheral blood (PB, n=49) and CD34(+) cells in BM (n= 35). A cutoff of 5% recipient cells was used to discriminate complete donor chimerism from MC. A total of 19 patients (25%) experienced hematological relapse after a median of 5 (1-31) months. Sensitivity for detection of relapse was 59% for CD33(+) PB cells and 92% for CD34(+) BM cells with corresponding specificities of 91% and 65%. CD34(+) BM cells were analyzed before relapse in seven patients, five of whom showed MC at a median of 2.5 (0.5-7) months before relapse. In contrast, 8 of 18 patients showed MC involving CD33 PB with a median of one month (0.5-2) before relapse. Here, we provide a model for early detection of relapse after SCT in MDS, in which serial characterization of both CD33(+) PB cells and CD34(+) BM cells gives an opportunity for early treatment before overt relapse.