Allogeneic transplantation in multiple myeloma: long-term follow-up and cytogenetic subgroup analysis.

This phase 3 trial compared tandem autologous stem cell transplantation (autoSCT) versus autoSCT followed by reduced-intensity conditioning allogeneic stem cell transplantation (auto/alloSCT) in patients with newly diagnosed multiple myeloma (MM) with deletion of (del) chromosome 13q (del13q). The availability/absence of a human leukocyte antigen-matched-related or matched-unrelated donor (MUD) determined the nature of the second SCT. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population (n = 199). Auto/alloSCT was performed in 126 patients; 74 received MUD allografts. After 91 months median follow-up, median PFS with auto/allo versus tandem autoSCT was 34.5 versus 21.8 months (P = 0.003; adjusted hazard ratio 0.55, 95% confidence interval 0.36-0.84). Median overall survival (OS) was 70.2 versus 71.8 months (P = 0.856). Two-year non-relapse mortality with auto/allo versus tandem autoSCT was 14.3% versus 4.1% (P = 0.008). In patients harboring both del13q and del17p, median PFS and OS were 37.5 and 61.5 months with auto/allo (n = 19) versus 6.1 and 23.4 months with tandem autoSCT (n = 6) (P = 0.0002 and 0.032). Our findings suggest that auto/alloSCT significantly extends PFS versus tandem autoSCT in del13q MM, and indicate some survival benefit for first-line alloSCT in high-risk MM.

Association of the LILRA3 deletion with B-NHL and functional characterization of the immunostimulatory molecule.

LILRA3 is the sole soluble member of the LILR family. Previous studies from our group had shown that a 6.7 kb genetic deletion of LILRA3 is associated with MS and Sjögren's syndrome. An impairment of the immune response leads to a predisposition for B-NHL, so we wanted to study whether the deletion of LILRA3 is also a risk factor for B-NHL, as well as the function of LILRA3. We discovered that the frequency of the homozygous LILRA3 deletion was significantly higher in B-NHL (6%) than in blood donors (3%) (P = 0.03). We detected binding of fluorochrome-conjugated recombinant LILRA3 to monocytes and B-cells. Incubation of PBMCs with recombinant LILRA3 induced proliferation of CD8(+) T-cells and NK cells, as determined by CFSE staining. Using a transwell system, we demonstrated that LILRA3-stimulated lymphocyte proliferation was mediated by monocytes and required both cell contact and soluble factors. Secretion of IL-6, IL-8, IL-1ß and IL-10 in the cell supernatant was stimulated by LILRA3. We conclude that LILRA3 is an immunostimulatory molecule, whose deficiency is associated with higher frequency of B-NHL.

B-cell lymphoma infiltration of cerebrospinal fluid with minimal symptoms and benign course.

We report a patient diagnosed with a B-cell lymphoma after detecting monoclonal B-cells in the cerebrospinal fluid (CSF) and who had only minimal symptoms and a benign course. A 46-year-old man experienced three transitory episodes with neurological symptoms. On examination papilledema in both eyes was found. Flow cytometry (FACS)-analysis detected monoclonal B-cells in the CSF as well as in the peripheral blood and the bone marrow. Results were consistent with a low-risk lymphoma, most probably a marginal zone B-cell lymphoma. Interestingly, our patient had no progressive clinical symptoms and remained without specific therapy during 36 months of follow-up. Nevertheless, CSF-analysis led to the diagnosis of the B-cell lymphoma.

Legionnaires' disease in immunocompromised patients: a case report of Legionella longbeachae pneumonia and review of the literature.

In addition to Legionella pneumophila, about 20 Legionella species have been documented as human pathogens. The majority of infections by non-pneumophila Legionella species occur in immunocompromised and splenectomized patients. Here, we report a case of 'classical' lobar pneumonia caused by Legionella longbeachae in a splenectomized patient receiving corticosteroids for chronic immune thrombocytopenia. Tests for Legionella antigen were negative. L. longbeachae was immediately detected in bronchoalveolar fluid by PCR and subsequently confirmed by culture on legionella-selective media. The features of Legionnaires' disease in immunocompromised patients with special emphasis on significance and detection of non-pneumophila species are reviewed.

Adult onset of T-cell deficiency with impaired CD2 expression complicated by Rhodococcus infection: a case report.

BACKGROUND: The functional importance of CD2 in vivo is currently the subject of discussion. OBJECTIVE: To describe a 47-year-old white man with systemic Rhodococcus infection, a rarely observed opportunistic disease, secondary to severe lymphopenia. METHODS: We extensively characterized lymphocyte phenotype and function. RESULTS: Both CD4+ and CD8+ T cells were severely diminished, with a particular reduction in alpha:beta T cells. Human immunodeficiency virus infection was excluded. CD2 expression was decreased not only on T cells but also on nonaffected natural killer cells. Production of interferon-gamma interleukin 2, and tumor necrosis factor a was normal. Neither B-cell numbers nor humoral immune responses were affected. In addition, adhesion molecules CD11a, CD54, and CD154 were normally expressed, as were the costimulatory molecules CD28, CD80, and CD86. CONCLUSIONS: We hypothesize that prolonged disturbance of CD2 expression led to an acquired severe cellular immunodeficiency. This underlines the importance of CD2 in vivo, where it may play a role in the fine regulation of T-cell proliferation.

Combining prenylation inhibitors causes synergistic cytotoxicity, apoptosis and disruption of RAS-to-MAP kinase signalling in multiple myeloma cells.

The high incidence of activating RAS mutations, coupled with accumulating evidence linking RAS to multiple myeloma (MM) pathogenesis, indicate that novel therapies utilising inhibitors of RAS prenylation and signalling may be successful in the management of this disease. While preclinical studies investigating prenylation inhibitors, such as lovastatin, farnesyltransferase inhibitors (FTI) and geranylgeranyltransferase inhibitors (GGTI), have been promising, recent phase I/II clinical trials with FTI R115777 were disappointing, suggesting resistance to FTI monotherapy. To address this issue, the effects of FTI, GGTI and lovastatin alone and in combination were analysed in MM cell lines and primary cells. FTI treatment blocked H-RAS processing, but was ineffective at inhibiting K- and N-RAS prenylation because of alternative geranylgeranylation of these isoforms. However, combinations of FTI and GGTI or lovastatin were found to synergistically inhibit MM cell proliferation, migration, K- and N-RAS processing, RAS-to-mitogen-activated protein kinase signalling and to induce apoptosis. In contrast to FTI, lovastatin and some GGTI were found to cause intracellular accumulation of Rho proteins. Our results suggest that clinical efficacy of prenylation inhibitors in MM are limited by alternative prenylation of several small G-proteins, such as RhoB, K- and N-RAS. Furthermore, strategies combining FTI with GGTI or statins may provide greater efficacy in MM treatment.