Nelli Bejanyan

TP53 Mutations in Myeloid Malignancies are either Homozygous or Hemizygous due to Copy Number-Neutral Loss of Heterozygosity or Deletion of 17p

Our previous studies demonstrated that single nucleotide polymorphism arrays (SNP-A), applied as a karyotyping platform, complement traditional metaphase cytogenetics (MC) and improve the diagnostic yield of cytogenetic studies because SNP-A can more precisely resolve smaller genetic defects and allow for detection of copy number-neutral loss of heterozygosity (CN-LOH), a defect frequently found in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Like balanced translocations, CN-LOH represents a chromosomal abnormality that occurs without a concurrent change in gene copy number (CN). CN-LOH is an increasingly recognized chromosomal mechanism by which homozygous somatic mutations may be acquired during evolution of hematologic malignancies and can pinpoint the location of such gene(s); examples include CEBPA, FLT3, WT1, RUNX1, JAK2, and NF11.

Clonal drift demonstrates unexpected dynamics of the T-cell repertoire in T-large granular lymphocyte leukemia

T-cell large granular lymphocyte leukemia (T-LGLL) is characterized by chronic lymphoproliferation of cytotoxic T lymphocytes (CTLs) and is associated with lineage-restricted cytopenias. Introduction of T-cell receptor (TCR) variable β-chain (Vβ) monoclonal antibodies has facilitated identification and enumeration of clonal CTLs by flow cytometry. A highly skewed TCR Vβ repertoire identified by flow cytometry is strongly associated with monoclonal CDR3 regions by quantitative sequencing and positive TCRγ rearrangement assays. Therefore, Vβ expansions can serve as surrogate markers of CTL clonality to assess clonal kinetics in T-LGLL. We analyzed the TCR repertoire in 143 patients, 71 of which were available for serial measurements over 6 to 96 months. Although the majority (38/71, 54%) maintained a consistent monoclonal expansion, many (26/71, 37%) unexpectedly displayed a change in the dominant clone, whereby the original CTL clone contracted and another emerged as demonstrated by Vβ typing. Our results demonstrate that the T-cell repertoire is more dynamic in T-LGLL than recognized previously, illustrating the heterogeneity of disorders under this categorization.

Spectrum of mutations in RARS-T patients includes TET2 and ASXL1 mutations

While a majority of patients with refractory anemia with ring sideroblasts and thrombocytosis harbor JAK2V617F and rarely MPLW515L, JAK2/MPL-negative cases constitute a diagnostic problem. 23 RARS-T cases were investigated applying immunohistochemical phospho-STAT5, sequencing and SNP-A-based karyotyping. Based on the association of TET2/ASXL1 mutations with MDS/MPN we studied molecular pattern of these genes. Two patients harbored ASXL1 and another 2 TET2 mutations. Phospho-STAT5 activation was present in one mutated TET2 and ASXL1 case. JAK2V617F/MPLW515L mutations were absent in TET2/ASXL1 mutants, indicating that similar clinical phenotype can be produced by various MPN-associated mutations and that additional unifying lesions may be present in RARS-T.

T/NK Large Granular Lymphocyte Leukemia and Coexisting Monoclonal B-Cell Lymphocytosis-like Proliferations An Unrecognized and Frequent Association

T-cell large granular lymphocyte leukemia (T-LGLL) is a T-cell lymphoproliferative disorder that has recently been associated with B-cell dyscrasias on a spectrum ranging from dysgammaglobulinemia to lymphoma. To investigate the relationship between clonal B-cell and LGLL lymphoproliferations, we systematically studied lymphocytes in 57 patients with T-LGLL or NK lymphocytosis using flow cytometric methods sensitive to low-level B-cell populations. We identified 16 patients (28%) with abnormal B-cell populations; 9 (16%) of the patients had no known history of a B-cell lymphoproliferative disorder. We characterized these abnormal B-cell populations as monoclonal B-cell lymphocytosis and report a high frequency of monoclonal B-cell lymphocytosis in T/NK LGLL. Our findings suggest that certain pathologic factors may operate in patients with T/NK LGLL to drive low-level clonal B-cell proliferations.

A phase 2 trial of combination therapy with thalidomide, arsenic trioxide, dexamethasone, and ascorbic acid (TADA) in patients with overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) or primary myelofibrosis (PMF)†

Primary myelofibrosis (PMF) and overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal hematopoietic disorders that share similar clinical features and molecular abnormalities, such as the Janus kinase 2 (JAK2) valine to phenylalanine mutation at codon 617 (V617F) and the tet methylcytosine dioxygenase 2 (TET2) mutation. There are limited therapeutic options available for these diseases, and single agents have only modest efficacy. In this phase 2 study, the authors combined multiple active agents (thalidomide, arsenic trioxide, dexamethasone, and ascorbic acid [TADA]) to treat patients with these disorders.

Risk Factors for 30-Day Hospital Readmission following Myeloablative Allogeneic Hematopoietic Cell Transplantation (allo-HCT)

Patient readmission within 30 days from discharge has been perceived by the Centers for Medicare and Medical Services as an indicator of poor healthcare quality for specific high-cost medical conditions. Patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) are often being readmitted. Our study identified the risk factors for 30-day readmission among 618 adult recipients of myeloablative allo-HCT from 1990 to 2009. Two hundred forty-two (39%) of 618 patients (median age = 42 years [range: 18-66]) were readmitted a median of 10 days (range: 1-30) from their hospital discharge. Median duration of readmission was 8 days (range: 0-103). Infections (n = 68), fever with or without identified source of infection (nxa0= 63), gastrointestinal complications (n = 44), graft-versus-host disease (GVHD) (n = 38), and other reasons (n = 29) accounted for 28%, 26%, 18%, 16%, and 12% of readmissions, respectively. During their index admission, patients who were subsequently readmitted had more documented infections (P < .001), higher hematopoietic cell transplantation comorbidity index (HCT-CI) (P < .01), total body irridiation (TBI)-based conditioning (P < .001), unrelated donor (P < .001), and peripheral stem cell (P = .014) transplantation. In multivariable analysis, HCT-CI (odds ratio [OR] = 1.78; 95% confidence interval [CI], 1.25-2.52), TBI-based preparative regimen (OR = 2.63; 95% CI, 1.67-4.13), and infection during admission for allo-HSCT (OR = 2.00; 95% CI, 1.37-2.92) predicted 30-day readmission. Thirty-day readmission itself was an independent predictor of all-cause mortality (hazard ratio [HR](Adj) = 1.66; 95% CI, 1.36-2.10). Our data emphasize the importance of a risk-standardized approach to 30-day hospital readmission if it is used as a quality-of-care metric for bone marrow transplantation.

Impact of weekend admissions on quality of care and outcomes in patients with acute myeloid leukemia

Hospital services are expectantly reduced over the weekend, which may result in a delay in treatment or in obtainment of medical procedures. The authors investigated quality of care and clinical outcomes of newly diagnosed acute myeloid leukemia (AML) patients who were hospitalized on weekends versus weekdays and treated with induction chemotherapy.

The Revolution of Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are clonal disorders of the hematopoietic system with resultant cytopenias and shortened survival. Better recognition of MDS and an aging population, some of whom have been treated with chemotherapy and radiation therapy for other cancers, is largely responsible for the growing incidence of this malignancy, which is divided into lower- and higher-risk subtypes. Erythropoiesis-stimulating agents are the first-line treatment options for patients with lower-risk MDS and symptomatic anemia or for those requiring transfusion support. Lenalidomide has been successfully used for patients with the del(5q) chromosomal abnormality who are also transfusion dependent. Hypomethylating agents, such as azacitidine and decitabine, are indicated for patients with higher-risk disease, with azacitidine demonstrating a survival advantage. Hematopoietic stem cell transplantation (HSCT) is a curative therapeutic approach available to less than 5% of patients with MDS. Combination therapies and newer single agents targeting the important cellular pathways are being explored for treatment of MDS with promising results.