Reversible cardiomyopathy in a patient with chronic myelomonocytic leukemia treated with decitabine/cedazuridine: a case report.

Background: Hypomethylating agents (HMAs) have shown efficacy in the treatment of hematological malignancies and are indicated for the treatment of chronic myelomonocytic leukemia (CMML). While the HMA decitabine, in its intravenous formulation, has been used since 2006 for the treatment of CMML, use of its oral formulation has been limited by poor bioavailability due to first-pass metabolism by the enzyme cytidine deaminase. The dose of intravenous decitabine is limited by toxicities such as cardiomyopathy and heart failure.

Dabrafenib Versus Dabrafenib + Trametinib in -Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial.

Oncogenic BRAF mutations are commonly found in advanced differentiated thyroid cancer (DTC), and reports have shown efficacy of BRAF inhibitors in these tumors. We investigated the difference in response between dabrafenib monotherapy and dabrafenib + trametinib therapy in patients with BRAF-mutated radioactive iodine refractory DTC. In this open-label randomized phase 2 multicenter trial, patients aged ≥18 years with BRAF-mutated radioactive iodine refractory DTC with progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.

Evaluating Blinatumomab for the Treatment of Relapsed/Refractory ALL: Design, Development, and Place in Therapy.

Although adults with B-cell acute lymphoblastic leukemia (B-ALL) achieve high complete remission (CR) rates following treatment with intensive multi-agent chemotherapy regimens, up to two-thirds of these patients eventually relapse. Unfortunately, adults with relapsed or refractory (R/R) B-ALL have a poor prognosis, with variable responses to salvage chemotherapy regimens and allogeneic stem cell transplant. As such, the need to develop effective and well-tolerated treatments for this patient population has been of paramount importance over the past decade.

AML with Myelodysplasia-Related Changes: Development, Challenges, and Treatment Advances.

Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is a distinct biologic subtype of AML that represents 25-34% of all AML diagnoses and associates with especially inferior outcomes compared to non-MRC AML. Typically, patients with AML-MRC experience low remission rates following intensive chemotherapy and a median overall survival of merely 9-12 months. In light of these discouraging outcomes, it has become evident that more effective therapies are needed for patients with AML-MRC.

Multi-Domain Photopatterned 3D Tumor Constructs in a Micro-Physiological System for Analysis, Quantification, and Isolation of Infiltrating Cells.

Cancer cell motility plays a central role in metastasis and tumor invasion but can be difficult to study accurately in vitro. A simple approach to address this challenge through the production of monolithic, photopatterned 3D tumor constructs in situ in a microfluidic device is described here. Through step-wise fabrication of adjoining hydrogel regions with and without incorporated cells, multidomain structures with defined boundaries are produced.

The Changing Landscape of Treatment in Acute Myeloid Leukemia.

The treatment of acute myeloid leukemia is evolving, with increased understanding of molecular pathogenesis allowing better risk stratification and development of new therapies. Tests to identify and drugs to target specific molecular abnormalities are improving remission rates and prolonging survival in patients with high-risk disease. Allogeneic hematopoietic stem cell transplantation remains an important curative therapy, with advances in donor availability and approaches to reduce transplant-related mortality making it applicable in many more patients.

Relapsed or primary refractory AML: moving past MEC and FLAG-ida.

Purpose Of Review: Treatment of relapsed and refractory acute myeloid leukemia (AML) is still very challenging, with poor response rates and low chance for cure. This is especially true when treating patients who are elderly, have multiple comorbidities, or who are too unfit for traditional salvage chemotherapy regimens.

Recent Findings: Recently, advances in the treatment of relapsed/refractory AML utilizing novel chemotherapy combinations, hypomethylating, and targeted therapies have shown promising results.

A novel regimen for relapsed/refractory adult acute myeloid leukemia using a partial tandem duplication targeted therapy: results of phase 1 study NCI 8485.

partial tandem duplication occurs in approximately 5-10% of patients with acute myeloid leukemia and is associated with adverse prognosis. wild type is epigenetically silenced in partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors , sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of wildtype contributes to partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemoresponse.

Granulocyte Colony-Stimulating Factor-Mobilized Allografts Contain Activated Immune Cell Subsets Associated with Risk of Acute and Chronic Graft-versus-Host Disease.

We defined associations among immune cell subsets in granulocyte colony-stimulating factor (G-CSF)-mobilized allografts and clinical outcomes after allogeneic hematopoietic cell transplantation (alloHCT). Fresh peripheral blood stem cell (PBSC) aliquots from 238 G-CSF-mobilized allografts were extensively characterized by immunophenotype. Subset-specific transplanted cells were correlated with acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), malignant disease relapse, nonrelapse mortality, and overall survival.

The dual epigenetic role of PRMT5 in acute myeloid leukemia: gene activation and repression via histone arginine methylation.

Changes in the enzymatic activity of protein arginine methyltransferase (PRMT) 5 have been associated with cancer; however, the protein's role in acute myeloid leukemia (AML) has not been fully evaluated. Here, we show that increased PRMT5 activity enhanced AML growth in vitro and in vivo while PRMT5 downregulation reduced it. In AML cells, PRMT5 interacted with Sp1 in a transcription repressor complex and silenced miR-29b preferentially via dimethylation of histone 4 arginine residue H4R3.

Pharmacological targeting of miR-155 via the NEDD8-activating enzyme inhibitor MLN4924 (Pevonedistat) in FLT3-ITD acute myeloid leukemia.

High levels of microRNA-155 (miR-155) are associated with poor outcome in acute myeloid leukemia (AML). In AML, miR-155 is regulated by NF-κB, the activity of which is, in part, controlled by the NEDD8-dependent ubiquitin ligases. We demonstrate that MLN4924, an inhibitor of NEDD8-activating enzyme presently being evaluated in clinical trials, decreases binding of NF-κB to the miR-155 promoter and downregulates miR-155 in AML cells.

Pharmacokinetics and dose escalation of the heat shock protein inhibitor 17-allyamino-17-demethoxygeldanamycin in combination with bortezomib in relapsed or refractory acute myeloid leukemia.

Abstract This phase I study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of the heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) in combination with bortezomib, and to provide pharmacokinetic data in relapsed or refractory acute myeloid leukemia (AML). Eleven patients were enrolled. The MTD was 17-AAG 150 mg/m(2) and bortezomib 0.

Increased anti-leukemic activity of decitabine via AR-42-induced upregulation of miR-29b: a novel epigenetic-targeting approach in acute myeloid leukemia.

Histone deacetylase (HDAC) inhibitors either alone or in combination with hypomethylating agents have limited clinical effect in acute myeloid leukemia (AML). Previously, we demonstrated that AML patients with higher miR (microRNA)-29b expression had better response to the hypomethylating agent decitabine. Therefore, an increase in miR-29b expression preceding decitabine treatment may provide a therapeutic advantage.

Dose escalation of lenalidomide in relapsed or refractory acute leukemias.

Purpose: Lenalidomide is effective in myeloma and low-risk myelodysplastic syndromes with deletion 5q. We report results of a phase I dose-escalation trial of lenalidomide in relapsed or refractory acute leukemia.

Patients And Methods: Thirty-one adults with acute myeloid leukemia (AML) and four adults with acute lymphoblastic leukemia (ALL) were enrolled.