How I treat chronic myelomonocytic leukemia

Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens. In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m(2) per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French-American-British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799. Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21.1 months (IQR 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group versus 15.0 months (5.6-24.1) for the conventional care group (hazard ratio 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI 42.1-58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7-34.3) in the conventional care group (p<0.0001). Peripheral cytopenias were the most common grade 3-4 adverse events for all treatments. Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.

The myelodysplastic syndromes (MDSs) are heterogeneous with respect to clinical characteristics, pathologic features, and cytogenetic abnormalities. This heterogeneity is a challenge for evaluating response to treatment. Therapeutic trials in MDS have used various criteria to assess results, making cross-study comparisons problematic. In 2000, an International Working Group (IWG) proposed standardized response criteria for evaluating clinically significant responses in MDS. These criteria included measures of alteration in the natural history of disease, hematologic improvement, cytogenetic response, and improvement in health-related quality of life. The relevance of the response criteria has now been validated prospectively in MDS clinical trials, and they have gained acceptance in research studies and in clinical practice. Because limitations of the IWG criteria have surfaced, based on practical and reported experience, some modifications were warranted. In this report, we present recommendations for revisions of some of the initial criteria.

Blockade of immune checkpoints is emerging as new form of anticancer therapy. We studied the expression of PD-L1, PD-L2, PD-1 and CTLA4 mRNA expression in CD34+ cells from MDS, CMML and AML patients (N=124). Aberrant up-regulation (≥2 fold) was observed in 34%, 14%, 15% and 8% of the patients respectively. Increased expression of these 4 genes was also observed in PBMNC (N=61). The relative expression of PD-L1 from PBMNC was significantly higher in MDS (p=0.018) and CMML (p=0.0128) compared to AML. By immunohistochemical (IHC) analysis, PD-L1 protein expression was observed in MDS CD34+ cells, whereas stroma/non-blast cellular compartment was positive for PD-1. In a cohort of patients treated with epigenetic therapy, PD-L1, PD-L2, PD-1 and CTLA4 expression was upregulated. Patients resistant to therapy had relative higher increments in gene expression compared to patients that achieved response. Treatment of leukemia cells with decitabine resulted in a dose dependent up-regulation of above genes. Exposure to decitabine resulted in partial demethylation of PD-1 in leukemia cell lines and human samples. This study suggests PD-1 signaling may be involved in MDS pathogenesis and resistance mechanisms to HMAs. Blockade of this pathway can be a potential therapy in MDS and AML.