Shyamala C. Navada

Clinical development of demethylating agents in hematology.

The term epigenetics refers to the heritable changes in gene expression that are not associated with a change in the actual DNA sequence. Epigenetic dysregulation is linked to the pathogenesis of a number of malignancies and has been studied extensively in myelodysplastic syndromes and acute myeloid leukemia. DNA methylation is frequently altered in cancerous cells and likely results in transcriptional silencing of tumor suppressor genes. Re-expression of these genes by inhibition of the DNA methyltransferases has been successful in the treatment of benign and malignant disease. In this Review, we discuss the clinical development of demethylating agents in hematology, with a focus on azacitidine and decitabine.

Therapeutic options for patients with myelofibrosis in blast phase

Myelofibrosis (MF) is a clonal stem cell disorder with the potential to transform to acute leukemia, referred to as myelofibrosis in blast phase (MF-BP). The outcome of patients with MF-BP is grave with a median survival of only 2.7 months. MF-BP is largely refractory to conventional chemotherapy and intensive induction therapy fails to have a significant impact with a median survival of 3.9 months. Eleven consecutive patients were treated at our institution with MF-BP over a 2-year period. Eligible patients with an available donor received an allogeneic stem cell transplant (ASCT) and those that were not eligible or without a donor were treated with Decitabine (DEC). The median time for follow up for the entire group was 9 months (range 5-21 month). At 9 months (range 5-45 months), 67% of the patients treated with DEC were alive and at 20 months (range 9-23 months), 53% of patients treated with ASCT remain alive. Reduced intensity conditioning allogeneic stem cell transplantation (RIC-ASCT) is a viable option that offers the potential for prolonged survival and the possibility of cure for patients with MF-BP. DEC is a tolerable outpatient chemotherapeutic regimen for MF-BP patients ineligible for transplant and deserves further prospective study.

Safety and efficacy of azacitidine in elderly patients with intermediate to high-risk myelodysplastic syndromes

Myelodysplastic syndromes (MDS) represent a clonal hematopoietic stem cell disorder characterized by morphologic features of dyspoiesis, a hyperproliferative bone marrow, and one or more peripheral blood cytopenias. In patients classified according to the Revised International Prognostic Scoring System (R-IPSS) with intermediate or higher-risk disease, there is an increased risk of death due to progressive bone marrow failure or transformation to acute myeloid leukemia (AML). Azacitidine was the first DNA hypomethylating agent approved by the United States (US) Food and Drug Administration (FDA) for the treatment of MDS and the only therapy that has demonstrated a significant survival benefit over conventional care regimens (CCRs) in patients with intermediate or higher-risk disease. Prolonged survival is independent of achieving a complete remission. Azacitidine has been used in older patients with both clinical and hematological improvement as well as an acceptable side effect profile. The most common adverse effect is myelosuppression. These findings support the use of azacitidine as an effective treatment in older patients with higher-risk MDS.

Epigenetic and molecular signatures of cord blood CD34+ cells treated with histone deacetylase inhibitors

Epigenetic modifications tightly regulate the gene expression and cellular function of haematopoietic stem cells. Histone deacetylase inhibitors (HDACIs) alter the gene expression profile of cord blood (CB) CD34+ cells by controlling the genes involved in chromatin modification, thereby influencing the self‐renewal, maintenance and expansion of haematopoietic stem and progenitor cells (HSPCs).

Management of chemotherapy-induced neutropenic fever.

Abstract Fever occurs at high rates in patients with chemotherapy-induced neutropenia and is considered an oncologic emergency. Numerous algorithms have been developed to guide treatment decisions. Prompt care and the initiation of empiric antibiotic therapy are critically important universal aspects of these treatment-decision schemata. Fever may be the only sign of infection, as in patients with cancer who are undergoing chemotherapy, the immune response is attenuated. In the majority of cases, no etiology for neutropenic fever is uncovered; nonetheless, a thorough workup is essential. The workup allows practitioners to risk stratify patients as being at low or high risk for infectious complications so that appropriate care can be administered. Although it is important to note that there are management algorithms to follow, every patient may present and respond differently. We generally start with broad-spectrum monotherapy for Gram-negative bacteria and then consider whether Gram-positive or antifungal coverage is necessary based on the clinical picture, including factors such as duration and degree of neutropenia. It is important for all practitioners to understand how to care for patients with neutropenic fever because it is a common and treatable condition.

Therapeutic modalities for patients with lower-risk myelodysplastic syndromes: current options and future directions.

The treatment of myelodysplastic syndromes (MDS) involves a complex algorithm that depends on multiple factors, including symptoms, performance status, and severity of disease. Current therapies are aimed at promoting hematopoiesis, inhibiting apoptosis, and reducing the risk of transformation to acute myeloid leukemia. Although there is no cure for MDS outside of allogeneic stem cell transplantation, goals of treatment include improvement of peripheral blood cytopenias, reduction of transfusions, improvement of the quality of life, and prolongation of survival. Patients with lower-risk MDS are often asymptomatic and can be monitored for long periods without therapeutic intervention. Anemia, the most common symptomatic cytopenia, warrants treatment in an attempt to eliminate transfusion dependence. This article reviews current treatment strategies for lower-risk MDS and examines the data for selected novel agents that are available or are being developed for the treatment of this disease.

A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia

This Phase 1/2, dose-escalating study of rigosertib enrolled 22 patients with higher-risk myelodysplastic syndromes (MDS) (n=9) and acute myeloid leukemia (AML; n=13) who had relapsed or were refractory to standard therapy and for whom no second-line therapies were approved. Patients received 3- to 7-day continuous intravenous infusions of rigosertib, an inhibitor of Ras-effector pathways that interacts with the Ras-binding domains, common to several signaling proteins including Raf and PI3 kinase. Rigosertib was administered at doses of 650-1700mg/m2/day in 14-day cycles. Initial dose escalation followed a Fibonacci scheme, followed by recommended phase 2 dose confirmation in an expanded cohort. Rigosertib was well tolerated for up to 23 cycles, with no treatment-related deaths and 18% of patients with related serious adverse events (AEs). Common AEs were fatigue, diarrhea, pyrexia, dyspnea, insomnia, and anemia. Rigosertib exhibited biologic activity, with reduction or stabilization of bone marrow blasts and improved peripheral blood counts in a subset of patients. Ten of 19 evaluable patients (53%) demonstrated bone marrow/peripheral blood responses (n=4 MDS, n=1 AML) or stable disease (n=3 MDS, n=2 AML). Median survival was 15.7 and 2.0 months for responders and non-responders, respectively. Additional studies of rigosertib are ongoing in higher-risk MDS (NCT00854646).

The safety and efficacy of rigosertib in the treatment of myelodysplastic syndromes.

ABSTRACT Introduction: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk myelodysplastic syndromes (MDS), but patients who relapse or are refractory have a poor prognosis with an estimated survival of 4–6 months. Rigosertib, a Ras mimetic that inhibits the phophoinositide 3-kinase and polo-like kinase pathways, has been tested in patients with higher-risk MDS following treatment with HMAs, where there are no approved second-line therapies. Areas covered: This review will provide an overview of rigosertib, including safety and efficacy demonstrated in clinical trials. Expert commentary: There is an urgent need for new treatment options for patients who have failed or progressed on HMAs. Rigosertib is currently undergoing testing as a single agent in certain subsets of higher-risk MDS patients as well as in combination with azacitidine, where preliminary data show efficacy in patients with de novo MDS as well as HMA failures.

Clinical Significance of Cytogenetic Manifestations in Myelodysplastic Syndromes

Myelodysplastic syndrome (MDS) represents a heterogeneous hematopoietic stem-cell disorder that results in abnormal cellular maturation and peripheral blood cytopenias. MDS is characterized by progressive bone marrow failure, which can lead to bleeding, infections, and complications secondary to anemia. Approximately 35% to 40% of patients diagnosed with MDS progress to acute myeloid leukemia (AML), which confers a poorer prognosis. MDS may develop de novo without underlying risk factors or may be secondary, occurring after exposure to chemotherapeutic agents or ionizing radiation. The earliest attempt to classify MDS into various subgroups was by the French-American-British (FAB) group, which separated MDS by its morphologic and clinical characteristics, such as the percentage of blasts in bone marrow. The progression of disease in patients with MDS is extremely variable, however, reflecting the heterogeneity of this syndrome. Although the FAB classification system has been useful, it has proven to be inaccurate when determining a patient’s prognosis. As studies have evolved, the genetic heterogeneity of MDS has proven to be a clear reason that the FAB classification system is prognostically insufficient. More than 50% of patients with MDS have clonal cytogenetic abnormalities, and the molecular consequences of these abnormalities continue to be elucidated. The chromosomal abnormalities in MDS have helped to stratify the myelodysplastic syndromes into poor-, intermediate-, and good-prognosis groups.

Safety of anticoagulation in patients with atrial fibrillation and MDS/AML complicated by thrombocytopenia: An unresolved challenge: Can they be managed? A report of three cases and literature review

REFERENCES [1] Wang D, Sun J, Solomon SB, et al. Transfusion of older stored blood and risk of death: a meta-analysis. Transfusion. 2012;52(6):1184– 1195. [2] Heddle NM, Cook RJ, Arnold DM, et al. Effect of short-term vs. long-term blood storage on mortality after transfusion. N Engl J Med. 2016;375(20):1937–1945. [3] Cooper DJ, McQuilten ZK, Nichol A, et al. Age of red cells for transfusion and outcomes in critically ill adults. N Engl J Med. 2017;377 (19):1858–1867. [4] Koch CG, Li L, Sessler DI, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med. 2008;358(12):1229–1239. [5] Terra HT, Saad MJ, Carvalho CR, et al. Increased tyrosine phosphorylation of Band 3 in hemoglobinopathies. Am J Hematol. 1998;58(3): 224–230. [6] Ciana A, Minetti G, Balduini C. Phosphotyrosine phosphatases acting on band 3 in human erythrocytes of different age: PTP1B processing during cell ageing. Bioelectrochemistry. 2004;62(2):169–173. [7] Arashiki N, Kimata N, Manno S, et al. Membrane peroxidation and methemoglobin formation are both necessary for band 3 clustering: mechanistic insights into human erythrocyte senescence. Biochemistry. 2013;52(34):5760–5769. [8] Roussel C, Dussiot M, Marin M, et al. Spherocytic shift of red blood cells during storage provides a quantitative whole cell-based marker of the storage lesion. Transfusion. 2017;57(4):1007–1018.