T-cell Large Granular Lymphocytic Leukemia Manifesting in Patients with HIV-1 Infection: Cases Series and Review of the Literature

We report five patients with human immunodeficiency virus-1/acquired immunodeficiency syndrome (HIV-1/AIDS) who developed T-cell large granular lymphocytic leukemia (T-LGLL). None of the patients fulfilled criteria for diagnosis of diffuse infiltrative lymphocyte syndrome (DILS) or HIV-associated CD8+ lymphocytosis syndrome at the time of diagnosis of LGLL. The immunophenotype of malignant T-cells was identical in three patients with co-expression of CD3, CD8, CD57, and T-cell receptor (TCR) alpha/beta. Three out of five patients were also diagnosed with clonal disorders of B-cell origin including diffuse large B-cell lymphoma, Burkitt’s lymphoma, and monoclonal gammopathy of undetermined significance (MGUS).  Two patients developed cytopenias due to T-LGLL prompting initiation of therapy. Our study suggests that chronic viral infection with HIV can contribute to evolution of T-LGLL. Clinical and laboratory characteristics of T-LGLL associated with HIV-1/AIDS resemble those of immunocompetent  patients

Romidepsin for the treatment of relapsed/refractory peripheral T cell lymphoma: prolonged stable disease provides clinical benefits for patients in the pivotal trial.

BACKGROUND: Achievement of durable responses in patients with relapsed/refractory peripheral T cell lymphoma (PTCL) is challenging with current therapies, and there are few data regarding the potential benefits of continuing treatment in patients with the best response of stable disease (SD). Histone deacetylase inhibitors are a novel class of drugs with activity in T cell malignancies. Romidepsin was approved by the US Food and Drug Administration for the treatment of relapsed/refractory PTCL based on a pivotal trial demonstrating an objective response rate of 25 % (33/130), including 15 % with confirmed/unconfirmed complete response and a median duration of response of 28 months. Our objective was to further study the clinical benefits of romidepsin in patients that had the best response of SD. METHODS: Patients with PTCL relapsed/refractory to ≥1 prior therapy were treated with the approved dose of 14 mg/m(2) romidepsin on days 1, 8, and 15 of six 28-day cycles; patients with SD or response after cycle 6 were allowed to continue on study until progression. By protocol amendment, patients treated for ≥12 cycles could receive maintenance dosing twice per cycle; after cycle 24, dosing could be further reduced to once per cycle in those who had received maintenance dosing for ≥6 months. RESULTS: Of the 32 patients (25 %) with the best response of SD, 22 had SD for ≥90 days (SD90; cycle 4 response assessment). The longest SD was \u3e3 years in a patient who received maintenance dosing of 14 mg/m(2) on days 1 and 15 beginning in cycle 13. Patients with the best response of SD90 or partial response achieved similar overall and progression-free survival. Prolonged dosing of romidepsin was well tolerated. CONCLUSIONS: We concluded that patients who achieve SD may consider continuing treatment because the clinical benefits of romidepsin may extend beyond objective responses. TRIAL REGISTRATION: NCT00426764

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

Erythropoietin Receptor Signaling Is Membrane Raft Dependent

Upon erythropoietin (Epo) engagement, Epo-receptor (R) homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling receptor signal fidelity. Here we show a critical role for membrane raft (MR) microdomains in creation of discrete signaling platforms essential for Epo-R signaling. Treatment of UT7 cells with Epo induced MR assembly and coalescence. Confocal microscopy showed that raft aggregates significantly increased after Epo stimulation (mean, 4.3±1.4(SE) vs. 25.6±3.2 aggregates/cell; p≤0.001), accompanied by a >3-fold increase in cluster size (p≤0.001). Raft fraction immunoblotting showed Epo-R translocation to MR after Epo stimulation and was confirmed by fluorescence microscopy in Epo stimulated UT7 cells and primary erythroid bursts. Receptor recruitment into MR was accompanied by incorporation of JAK2, Lyn, and STAT5 and their activated forms. Raft disruption by cholesterol depletion extinguished Epo induced Jak2, STAT5, Akt and MAPK phosphorylation in UT7 cells and erythroid progenitors. Furthermore, inhibition of the Rho GTPases Rac1 or RhoA blocked receptor recruitment into raft fractions, indicating a role for these GTPases in receptor trafficking. These data establish a critical role for MR in recruitment and assembly of Epo-R and signal intermediates into discrete membrane signaling units

Molecular biology of primary familial and congenital polycythemias

The overall objective of this dissertation was to identify defects of the erythropoietin receptor gene (EPOR), a newly distinguished protooncogene, in patients with primary familial and congenital polycythemia (PFCP) and to study the role of EPOR defects in pathogenesis of this disease. PFCP has only recently been recognized as a new disease entity. Various designations have been used in the past to describe PFCP, a rare clinical syndrome, including benign familial erythrocytosis, polycythemia vera of childhood, pure erythrocytosis etc. Some of these terms stressed a relatively benign, non progressive course of the disease with normal lifespan of affected subjects. However, an apparent benignity of some these disorders has been questioned. These disorders are familial and/or congenital that in its best defined variant is inherited in an autosomal dominant fashion. When no family history is present, recessive inheritance or a new germinal mutation should be suspected. Only about two dozen familial and sporadic cases with PFCP have been reported. The missense mutations can not explain disease phenotype alone as determined by functional in vitro tests. Mutations of other genes involved in post EPOR signaling pathway such as JAK-2, HCP, STAT 5 may also play a causative role in pathogenesis of some of PFCP families where mutations of the EPOR were not found. In contrast to our original report, we have found that some of PFCP patients suffered from severe cardiovascular and cerebrovascular disorders, such as stroke or myocardial infarction, although their hematocrit was controlled. We hypothesize that mitogenic effect of EPO on nonerythroid tissues expressing truncated EPOR, such as endothelial cells, may account for pathogenic mechanism of these complications in PFCP patientsAvailable from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Progressive Multifocal Leukoencephalopathy and Monoclonal Antibodies: A Review

Progressive multifocal leukoencephalopathy (PML) is a viral infection predominantly seen in patients with HIV infection. However, with the increased use of monoclonal antibodies (MAB) for various lymphoproliferative disorders, we are now seeing this infection in non-HIV patients on drugs such as natalizumab, rituximab, and so on. The aim of this article is to review the relationship between the occurrence of PML and MAB used in the treatment of hematological malignancies and autoimmune diseases. Review of articles from PubMed-indexed journals which study PML in relation to the use of MAB. Relevant literature demonstrated an increased risk of reactivation of latent John Cunningham polyomavirus (JCV) resulting in development of PML in patients on long-term therapy with MAB. The highest incidence of 1 PML case per 1000 treated patients and 1 case per 32 000 was observed in patients treated with natalizumab and rituximab, respectively. Serological and polymerase chain reaction tests for the detection of JCV can be helpful in risk stratification of patients for the development of PML before and during therapy with MAB. Treatment with MAB can result in development of PML. Clinicians should include PML in differential diagnosis in patients treated with these agents if they manifest central nervous system symptoms

Progressive Multifocal Leukoencephalopathy and Monoclonal Antibodies: A Review

Progressive multifocal leukoencephalopathy (PML) is a viral infection predominantly seen in patients with HIV infection. However, with the increased use of monoclonal antibodies (MAB) for various lymphoproliferative disorders, we are now seeing this infection in non-HIV patients on drugs such as natalizumab, rituximab, and so on. The aim of this article is to review the relationship between the occurrence of PML and MAB used in the treatment of hematological malignancies and autoimmune diseases. Review of articles from PubMed-indexed journals which study PML in relation to the use of MAB. Relevant literature demonstrated an increased risk of reactivation of latent John Cunningham polyomavirus (JCV) resulting in development of PML in patients on long-term therapy with MAB. The highest incidence of 1 PML case per 1000 treated patients and 1 case per 32 000 was observed in patients treated with natalizumab and rituximab, respectively. Serological and polymerase chain reaction tests for the detection of JCV can be helpful in risk stratification of patients for the development of PML before and during therapy with MAB. Treatment with MAB can result in development of PML. Clinicians should include PML in differential diagnosis in patients treated with these agents if they manifest central nervous system symptoms