Impact of Lenalidomide Treatment on Overall Survival in Patients With Lower-Risk, Transfusion-Dependent Myelodysplastic Syndromes.

BACKGROUND: For patients with lower-risk (LR) myelodysplastic syndromes (MDS), overall survival (OS) is rarely a primary clinical trial endpoint. Treatments such as lenalidomide can reduce red blood cell (RBC) transfusion burden (TB) and serum ferritin, but the long-term impact on OS remains undetermined. PATIENTS AND METHODS: Data from 3 trials evaluating lenalidomide in patients with LR-MDS (the phase 2 MDS-003 and phase 3 MDS-004 trials in del[5q]; the phase 3 trial MDS-005 in non-del[5q] patients) were pooled. Predictors of OS were assessed by multivariate analysis using time-dependent models for TB and RBC transfusion independence (RBC-TI), and a landmark analysis of RBC-TI at 17 weeks. Separate analyses using MDS-004 and MDS-005 data determined the relationship between OS and serum ferritin. RESULTS: Median follow-up for MDS-003, MDS-004, and MDS-005 was 3.2, 3.0, and 1.7 years, respectively. In multivariate analyses, transfusion of ≥6 RBC units over 8 weeks was a significant predictor of shorter OS vs. 0 units in the time-dependent TB model (hazard ratio [HR] 4.65; 95% confidence interval [CI] 3.32-6.52; P < .0001). RBC-TI achievement was associated with prolonged OS in the time-dependent (HR 0.48; 95% CI 0.37-0.62; P < .0001) and landmark model (HR 0.57; 95% CI 0.44-0.75; P < .0001). Increased serum ferritin was associated with shorter OS (P < .0001). CONCLUSION: This analysis of prospective trial data in patients with LR-MDS confirms lenalidomide may improve OS by reducing TB and serum ferritin. OS should be considered as an endpoint in future lower risk MDS clinical trials.

Optimal Dose, Timing and Ratio of Blood Products in Massive Transfusion: Results from a Systematic Review.

Optimal dose, timing and ratio to red blood cells (RBC) of blood component therapy (fresh frozen plasma [FFP], platelets, cryoprecipitate or fibrinogen concentrate) to reduce morbidity and mortality in critically bleeding patients requiring massive transfusion is unknown. We performed a systematic review for randomized controlled trials (RCT) in MEDLINE, The Cochrane Library, Embase, CINAHL, PubMed the Transfusion Evidence Library and using multiple clinical trials registries to 21 February 2017. Sixteen RCTs were identified: six completed (five in adult trauma patients, one pediatric burn patients) and ten ongoing trials. Of the completed trials: three were feasibility trials, comparing a FFP, platelets and RBC ratio of 1:1:1 to laboratory-guided transfusion practice [n=69], early cryoprecipitate compared to standard practice [n=41], and early fibrinogen concentrate compared to placebo [n=45]; one trial compared the effect of FFP, platelets and RBC ratio of 1:1:1 with 1:1:2 on 24-hour and 30-day mortality [n=680]; one compared whole blood to blood component therapy on 24-hour blood use [n=107]; one compared a FFP to RBC ratio of 1:1 with 1:4 [n=16]. Data from two trials were pooled in a meta-analysis for 28-day mortality because the transfusion ratios achieved were similar. Results from these two trials suggest higher transfusion ratios were associated with transfusion of more FFP and platelets without evidence of significant difference with respect to mortality or morbidity. On the limited evidence available, there is insufficient basis to recommend a 1:1:1 over a 1:1:2 ratio or standard care for adult patients with critical bleeding requiring massive transfusion.

BET inhibitor resistance emerges from leukaemia stem cells.

Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/ß-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.

Insights into cell ontogeny, age, and acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogenous disease of hematopoietic stem cells (HSCs) and progenitor cells (HSPCs). The pathogenesis of AML involves cytogenetic abnormalities, genetic mutations, and epigenetic anomalies. Although it is widely accepted that the cellular biology, gene expression, and epigenetic landscape of normal HSCs change with age, little is known about the interplay between the age at which the cell becomes leukemic and the resultant leukemia. Despite its rarity, childhood AML is a leading cause of childhood cancer mortality. Treatment is in general extrapolated from adult AML on the assumption that adult AML and pediatric AML are similar biological entities. However, distinct biological processes and epigenetic modifications in pediatric and adult AML may mean that response to novel therapies in children may differ from that in adults with AML. A better understanding of the key pathways involved in transformation and how these differ between childhood and adult AML is an important step in identifying effective treatment. This review highlights both the commonalities and differences between pediatric and adult AML disease biology with respect to age.

Epigenetics in the hematologic malignancies.

A wealth of genomic and epigenomic data has identified abnormal regulation of epigenetic processes as a prominent theme in hematologic malignancies. Recurrent somatic alterations in myeloid malignancies of key proteins involved in DNA methylation, post-translational histone modification and chromatin remodeling have highlighted the importance of epigenetic regulation of gene expression in the initiation and maintenance of various malignancies. The rational use of targeted epigenetic therapies requires a thorough understanding of the underlying mechanisms of malignant transformation driven by aberrant epigenetic regulators. In this review we provide an overview of the major protagonists in epigenetic regulation, their aberrant role in myeloid malignancies, prognostic significance and potential for therapeutic targeting.