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Background. Aberrant DNA-methylation in the CpG sites of several tumor suppressor genes is considered the dominant pathogenetic mechanism in MDSs and the main cause of progression to AML. The use of hypomethylating agents significantly modified the therapeutic approach to MDS patients, primarily in higher-risk MDS patients. In lower-risk MDSs the use of 5-AZA hypomethylating agent is less understood. Aims. We prospectively evaluated the efficacy and safety of 5-AZA low-dose in Low or Int-1 risk MDS patients who were symptomatic and/or unresponsive to previous treatments. Furthermore, we studied the genetic profile by single nucleotide polymorphism (SNP) arrays and the molecular effects of 5-AZA on PI-PLCbeta1 promoter methylation, in order to identify these biological factors possibly correlated with the response to 5- AZA. Methods. 5-AZA was administered at a dose of 75 mg/mq/daily s.c for 5 consecutive days every 28 days for a total of 8 cycles. Final response was checked at the end of the 8th course. SNP microarray analysis was performed from mononuclear cells isolated from bone marrow aspirate samples before treatment. PIPLC beta1 gene expression was evaluated on peripheral blood samples from patients at baseline, and monthly until the 8th cycle of 5-AZA administration. Results. Between September 2008 and February 2010, 32 MDS patients with IPSS risk Low- or Int-1 were enrolled into the study. Most patients had a normal karyotype (63%) by metaphase cytogenetics, were BRC transfusion-dependent (81%), receiving a median of 4 units/mo, and were previously unresponsive to treatment including ESAs (69%). Twenty-six patients (81%) completed the treatment plan (8 cycles). The Overall Response Rate after the 8th cycle was 58% (15/26 pts) whereas 42% of patients maintained a stable disease; no patient progressed towards a high-risk MDS or AML. Five (19%) patients reached a complete remission whereas 10 (38%) achieved an hematological improvement. Transfusion independent was achieved in 8/26 patients (31%). The median duration of the response was 10 months; five patients maintain their response, that is CR in 2 cases (+24 and +30 months) and HI-E in 3 cases (+14, +25,+26 months) without any treatment or supportive therapy. All but one patients (14/15) who achieved an hematologic response during treatment with 5-AZA showed a statistically significant increase in PI-PLCbeta1 mRNA expression. In all patients the increase of PI-PLCbeta1 levels anticipated the clinical response obtained at the 8th cycle. SNP array karyotyping identified genomic abnormalities in all analyzed patients (100%) compared with only 9/26 (35%) with metaphase cytogenetics; although, SNP array-based assay has been demonstrated to enable the identification of genetic abnormalities in all analyzed patients, the type and the number of copy number abnormalities were not correlated with clinical response to 5-Aza. By contrast, LOH alterations showed to have a trend with stable disease. Conclusions. The current results of our study showed that 5-Aza low-dose schedule may be a safety and effective treatment for low risk MDS pts and may induce durable responsesThe correlation between the hematologic response and the PI-PLC1 expression indicate that PI-PLC1 may be a realiable marker of response to AZA.

We report the case of a young man with a resistant acute myeloid leukemia (AML) who developed a disseminated fungemia due to Fusarium solani involving the skin and lungs, during the neutropenic phase following a chemotherapy course. Despite continuous therapy with liposomal amphotericin B, he developed a bilateral endophthalmitis that rapidly evolved to complete blindness. The patient underwent two procedures of vitrectomy, with detection of F. solani in the vitreous fluid, and continued antifungal therapy, without any recovery of visual acuity. When he eventually died due to recurrence of leukemia and hemorrhagic shock, autopsy revealed a diffuse fusarial involvement of the central nervous sysytem.

We report that early chemosensitivity, defined by a greater than 50% reduction of M-component and plasma-cell marrow infiltration, after 2 cycles of VAD was correlated with a favorable outcome following autologous stem cell transplantation in 46 patients with newly diagnosed multiple myeloma submitted to high-dose therapy.

A population pharmacokinetic analysis of continuous infusion (CI) meropenem was conducted in a prospective cohort of febrile neutropenic (FN) patients with hematologic malignancies. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed for identifying the most appropriate dosages for empirical treatment against common Enterobacterales and P. aeruginosa. The probability of target attainment (PTA) of steady-state meropenem concentration (Css)-to-minimum inhibitory concentration (MIC) ratio (Css/MIC) &ge, 1 and &ge, 4 at the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoint of 2 mg/L were calculated. Cumulative fraction of response (CFR) against Enterobacterales and P. aeruginosa were assessed as well. PTAs and CFRs &ge, 90% were considered optimal. A total of 61 patients with 178 meropenem Css were included. Creatinine clearance (CLCR) was the only covariate associated with meropenem clearance. Monte Carlo simulations showed that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may grant optimal PTAs of Css/MIC &ge, 4 at the EUCAST clinical breakpoint. Optimal CFRs may be granted with these dosages against the Enterobacterales at Css/MIC &ge, 4 and against P. aeruginosa at Css/MIC &ge, 1. When dealing against P. aeruginosa at Css/MIC &ge, 4, only a dosage of 1.5 g q6h by CI may grant quasi-optimal CFR (around 80&ndash, 87%). In conclusion, our findings suggest that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may maximize empirical treatment against Enterobacterales and P. aeruginosa among FN patients with hematologic malignancies having different degree of renal function.

Scleroderma may be one of the most severe forms of chronic graft-versus-host disease (GVHD). We retrospectively evaluated its incidence, predictor variables and outcome in 133 patients who survived at least 4 months after allogeneic hematopoietic stem cell transplantation. The 5-year cumulative incidence was 15.5% in patients with chronic GVHD. The generalized form had a progressive course despite immunosuppressive therapy. Eosinophilia, autoimmune markers, and previous skin involvement by chronic GVHD with disorders of pigmentation were significantly associated with an increased probability of developing scleroderma.

Background Previous reports highlighted the potential short and mid-term therapeutic activity and safety of rituximab in adult patients with autoimmune thrombocytopenias. Objectives Primary objectives of this study were to evaluate the long-term efficacy and toxicity profile. Patients and methods From October 1999 to April 2005, 37 adults patients, median age 54 years, with active and symptomatic autoimmune thrombocytopenias (30 idiopathic thrombocytopenic purpura, 1 idiopathic thrombocytopenia and neutropenia, 4 thrombocytopenia and concomitant undifferentiated connective tissue disease, 2 thrombocytopenia and concomitant B-cell lymphoprolipherative disorders) that had relapsed or were refractory to at least a full course of steroid therapy received weekly infusions of rituximab 375 mg/m2 for 4 weeks. The median interval from diagnosis to rituximab was 34 months (1–264 months) and the platelets median count was 11 x 109/L. The following parameters of efficacy and toxicity were considered: rate of complete and partial response, time to initial and maximum response, relapse rate, relapse free survival, treatment free survival, short and long-term toxicity. The possible prognostic influence of some clinical and laboratory parameters on the patients outcome were also analyzed. Results Complete and partial response (platelets count ≥ 100 x 109/L and ≥ 50 x 109/L) were 20/37 (54%) and 7/37 (19%), respectively. In most of the patients the time to initial and maximum response was prompt, already before the second administration of rituximab. The median period of observation from treatment was 22 months (1–48 months). Nine out 27 responding patients relapsed; 18/37 patients (49%) remained relapse free and 20/37 (54%) did not necessitated further therapy. A shorter interval period from the time of diagnosis and rituximab administration (≤ vs > 36 months) was associated with a lower relapse free survival (p= 0.03). During the period of rituximab administration, 2 patients experienced short term toxicity with one case of serum sickness syndrome; no infectious or other significant long term toxic complications were documented.. Conclusion Rituximab administration may allow to achieve long-lasting remission in nearly 50% of patients suffering from autoimmune thrombocytopenia with good toxic profile. The possibility to achieved long lasting response appeared related with an earlier timing of administration.

Objective Chronic graft-vs-host disease (GVHD) has certain similarities with autoimmune diseases and is associated with the development of various autoantibodies in some patients. In this study, we analyzed the occurrence of autoantibodies in 63 patients surviving longer than 3 months after an allogeneic haematopoietic stem cell transplantation (HSCT), with the aim of detecting a possible association between occurrence of autoantibodies and development of chronic GVHD and immune recovery after HSCT. Patients and Methods The patients were screened every 3 months for the occurrence of the following autoantibodies: anti-nuclear (ANA), anti-mitochondrial (AMA), anti–smooth muscle (ASMA), anti-cardiolipin (ACLA), anti-liver-kidney microsomal (LKM), anti-DNA, anti-neutrophil cytoplasmatic (ANCA), and anti-thyroid antibodies. Peripheral blood immunophenotyping with anti-CD3, CD4, CD8, CD19, CD20, CD16, and CD56 antibodies was evaluated at the same intervals. Results Autoantibodies were not found in 18 patients (29%), at least in one screening in 29 patients (46%), and in all screenings in 16 patients (25%). ANA were found in 41 patients (65%), AMA in 4 (6%), ASMA in 4 (6%), ANCA in 7 (11%), ACLA in 1 (2%), anti-thyroid antibodies in 3 (5%), and anti-DNA in 2 (3%). More than one antibody occurred in 16/63 (25%) positive patients. ANA was significantly more frequent in patients with chronic GVHD and, among these, in those with the extensive form. The nucleolar pattern of immunofluorescence of ANA but not its titer was correlated with the extension of chronic GVHD. Patients who developed autoantibodies had higher CD20 + cell blood counts than negative patients in the third month ( p = 0.006), ninth month ( p = 0.061), and twelfth month ( p = 0.043). Conclusion We conclude that patients with chronic GVHD, particularly those with an extensive involvement, were likely to develop autoantibodies and have a faster B-cell recovery, suggesting a role of B cells in the pathogenesis of chronic GVHD.

We evaluated the incidence, the risk factors, and the outcome of late-onset noninfectious pulmonary complications (LONIPCs) among 50 patients who underwent allogeneic stem cell transplantation from unrelated donors. Of the 39 patients surviving at least 3 months, 10 (26%) fulfilled the diagnostic criteria of LONIPCs and were further subclassified as having bronchiolitis obliterans (four patients), bronchiolitis obliterans with organizing pneumonia (four patients), and interstitial pneumonia (two patients). Two patients had a durable partial remission after treatment with prednisone and cyclosporine; the remaining eight patients did not respond to treatment and five of them died of respiratory failure. Advanced stage of disease at transplant and chronic extensive graft-versus-host disease (GVHD) were significantly associated with the development of LONIPCs. Pulmonary function test (PFT) results before transplantation were similar in all patients, but patients with LONIPCs had a significant decrease in PFT indexes at the third month after BMT compared with controls. Moreover, the rate of cyclosporine taper during the fourth and fifth months after BMT was significantly more rapid in patients with LONIPCs than in controls, suggesting that the risk of LONIPCs may be influenced by a faster reduction of GVHD prophylaxis.