TP53 and MDM2 single nucleotide polymorphisms influence survival in non-del(5q) myelodysplastic syndromes

Abstract:P53 is a key regulator of many cellular processes and is negatively regulated by the human homolog of murine double minute-2 (MDM2) E3 ubiquitin ligase. Single nucleotide polymorphisms (SNPs) of either gene alone, and in combination, are linked to cancer susceptibility, disease progression, and therapy response. We analyzed the interaction of TP53 R72P and MDM2 SNP309 SNPs in relationship to outcome in patients with myelodysplastic syndromes (MDS). Sanger sequencing was performed on DNA isolated from 208 MDS cases. Utilizing a novel functional SNP scoring system ranging from +2 to -2 based on predicted p53 activity, we found statistically significant differences in overall survival (OS) (p = 0.02) and progression-free survival (PFS) (p = 0.02) in non-del(5q) MDS patients with low functional scores. In univariate analysis, only IPSS and the functional SNP score predicted OS and PFS in non-del(5q) patients. In multivariate analysis, the functional SNP score was independent of IPSS for OS and PFS. These data underscore the importance of TP53 R72P and MDM2 SNP309 SNPs in MDS, and provide a novel scoring system independent of IPSS that is predictive for disease outcome

Molecular Action of Lenalidomide in Lymphocytes and Hematologic Malignancies

The immunomodulatory agent, lenalidomide, is a structural analogue of thalidomide approved by the US Food and Drug Administration for the treatment of myelodysplastic syndrome (MDS) and multiple myeloma (MM). This agent is also currently under active investigation for the treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL), as well as in drug combinations for some solid tumors and mantle cell lymphoma (MCL). Although treatment with lenalidomide has translated into a significant extension in overall survival in MM and MDS and has superior safety and efficacy relative to thalidomide, the mechanism of action as it relates to immune modulation remains elusive. Based on preclinical models and clinical trials, lenalidomide, as well as other structural thalidomide derivatives, enhances the proliferative and functional capacity of T-lymphocytes and amplifies costimulatory signaling pathways that activate effector responses and suppress inflammation. This paper summarizes our current understanding of T- and natural killer (NK) cell pathways that are modified by lenalidomide in hematopoietic neoplasms to inform future decisions about potential combination therapies

Abstract 5417: Expansion of effector regulatory T-cells represents a novel and independent prognostic factor marking escape from immune surveillance in Myleodysplastic Syndrome

Abstract Myelodysplastic syndromes (MDS) refer to a group of pathophysiologically diverse hematopoietic neoplasms associated with cytopenias, myeloid dysplasia, and variable acute myeloid leukemia risk. Response to immunosuppressive therapies (IST) in a subset of younger patients classified as lower-risk by the International Prognostic Scoring System (IPSS) suggests that inflammation and immune reactivity in the bone marrow likely plays a role in early MDS pathogenesis. Conversely, higher-risk patients with more established disease do not respond to IST. Previous reports of increased regulatory T-cells (Tregs) in these patients suggest that immune escape may be required for progression to higher-risk disease. The distinct changes in the role of the immune system between lower and higher-risk disease suggests that MDS may progress according to established principles of cancer immuno-editing involving elimination, equilibrium and escape phases. Because Treg suppressive activity is dependant upon auto-antigen presentation, we hypothesized that analyzing the activation state of Tregs may better reflect the onset of tumor-induced immune suppression in MDS and have better prognostic utility than measuring total Treg numbers alone. Here, we use a panel of surface markers on Tregs that are normally employed to distinguish effector and memory populations among conventional T-cells and analyzed the resulting subpopulations for associations with clinical features including overall survival (OS) among patients predominantly classified as lower-risk. Abnormal numbers of Treg subtypes were seen in 18 (34.6%) of 52 patients compared to age-matched controls. The most prominent and unique change in MDS patients was an expansion of effector Tregs (TregEff) which was significantly associated with anemia (p=0.046) and reduced hemoglobin (p=0.038). This group of patients had increased blast percentage (p=0.006) and displayed worse OS by Cox-regression (HR 4.3, 95% CI 1.6-11.6, p=0.004) independent of IPSS (p=0.002) and the MD Anderson Scoring System (MDAS) (p=0.047). Increased TregEff numbers were not dependant on total Treg numbers. Rather, they came at the expense of central memory Tregs suggesting that Treg “class switching” may reflect active presentation of auto-antigens. When isolated, TregEff cells displayed increased suppressive capacity compared to other Treg subpopulations and heightened TregEff numbers were limited to patients with elevated blasts (tumor burden), suggesting a mechanistic link between immune-evasion and MDS progression. The MDAS significantly refined OS estimates (p<0.001) compared to IPSS. Using the MDAS, OS in higher-risk patients could be further stratified using TregEff numbers (p=0.018), suggesting that enumeration of TregEff cells may improve prognostication and impact therapeutic selection in MDS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5417. doi:1538-7445.AM2012-541

Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling

Large granular lymphocyte (LGL) leukemia is commonly associated with poor hematopoiesis. The first case of pulmonary artery hypertension (PAH) was observed in a 57-year-old woman with natural killer (NK)–LGL leukemia and transfusion-dependent anemia. Using a genetic approach, we demonstrated that killing of pulmonary endothelial cells by patient NK cells was mediated by dysregulated balance in activating and inhibitory NK-receptor signaling. Elevated pulmonary artery pressure and erythroid differentiation improved after disrupting the NK-receptor signaling pathway with 4 courses of a farnesyltransferase inhibitor, tipifarnib. Coincidental association between PAH and LGL leukemia suggest a causal relationship between the expanded lymphocyte population and these clinical manifestations. This trial is registered at www.ClinicalTrials.gov as NCI 6823