Bruno Fattizzo

Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical efficacy and biologic studies

This prospective study investigated the efficacy, safety, and response duration of low-dose rituximab (100 mg fixed dose for 4 weekly infusions) together with a short course of steroids as first- or second-line therapy in 23 patients with primary autoimmune hemolytic anemia (AIHA). The overall response was 82.6% at month +2, and subsequently stabilized to ∼ 90% at months +6 and +12; the response was better in warm autoimmune hemolytic anemia (WAIHA; overall response, 100% at all time points) than in cold hemagglutinin disease (CHD; average, 60%); the relapse-free survival was 100% for WAIHA at +6 and +12 months versus 89% and 59% in CHD, respectively, and the estimated relapse-free survival at 2 years was 81% and 40% for the warm and cold forms, respectively. The risk of relapse was higher in CHD and in patients with a longer interval between diagnosis and enrollment. Steroid administration was reduced both as cumulative dose (∼ 50%) and duration compared with the patients past history. Treatment was well tolerated and no adverse events or infections were recorded; retreatment was also effective. The clinical response was correlated with amelioration biologic markers such as cytokine production (IFN-γ, IL-12, TNF-α, and IL-17), suggesting that low-dose rituximab exerts an immunomodulating activity. This study is registered at www.clinicaltrials.gov as NCT01345708.

Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients

The clinical outcome, response to treatment, and occurrence of acute complications were retrospectively investigated in 308 primary autoimmune hemolytic anemia (AIHA) cases and correlated with serological characteristics and severity of anemia at onset. Patients had been followed up for a median of 33 months (range 12-372); 60% were warm AIHA, 27% cold hemagglutinin disease, 8% mixed, and 5% atypical (mostly direct antiglobulin test negative). The latter 2 categories more frequently showed a severe onset (hemoglobin [Hb] levels ≤6 g/dL) along with reticulocytopenia. The majority of warm AIHA patients received first-line steroid therapy only, whereas patients with mixed and atypical forms were more frequently treated with 2 or more therapy lines, including splenectomy, immunosuppressants, and rituximab. The cumulative incidence of relapse was increased in more severe cases (hazard ratio 3.08; 95% confidence interval, 1.44-6.57 for Hb ≤6 g/dL; P < .001). Thrombotic events were associated with Hb levels ≤6 g/dL at onset, intravascular hemolysis, and previous splenectomy. Predictors of a fatal outcome were severe infections, particularly in splenectomized cases, acute renal failure, Evans syndrome, and multitreatment (4 or more lines). The identification of severe and potentially fatal AIHA in a largely heterogeneous disease requires particular experienced attention by clinicians.

Sustained response to low‐dose rituximab in idiopathic autoimmune hemolytic anemia

To evaluate the sustained response to low‐dose (LD) rituximab in autoimmune hemolytic anemia (AIHA), the ex vivo effect on anti‐RBC antibody production by mitogen‐stimulated direct antiglobulin test (MS‐DAT), and the in vitro dose effect of the drug on the production of anti‐RBC antibodies.

Increased prevalence of autoimmune phenomena in myelofibrosis: Relationship with clinical and morphological characteristics, and with immunoregulatory cytokine patterns

Autoimmune phenomena and cytokines were investigated in 100 patients with myelofibrosis (MF) and related to marrow fibrosis and clinical risk. Anti-erythrocyte antibodies by mitogen-stimulated direct antiglobulin test (MS-DAT) were positive in 45%, anti-platelets in 15% and organ/non organ-specific in 57% of cases, without clinically overt disease, and mostly in low-risk/intermediate-risk-1 and MF-0/MF-1. TGF-β and IL-8 were increased in MS-DAT positive cases, and IFN-γ in patients with serological autoantibodies. TGF-β and IL-17 were elevated in early clinical and morphological stages, while IL-8 increased in advanced stages. These data suggest that autoimmune phenomena and cytokine disregulation are particularly relevant in early MF.

Toll-like receptor 4 and 9 expression in B-chronic lymphocytic leukemia: relationship with infections, autoimmunity and disease progression

Abstract Toll-like receptors (TLRs) represent major agents of innate immunity and initiators of adaptive immunity. TLR4 and TLR9 gene expression was related to the occurrence of infections, autoimmunity and disease progression in 95 patients with B-chronic lymphocytic leukemia (B-CLL), grouped according to stage, therapy and known prognostic markers, and followed prospectively (median 33.6 months, range 25–50). A retrospective analysis (median 6.8 years, range 6–26) was also performed. TLR4 gene expression was decreased and TLR9 increased in patients versus controls, the former being more pronounced in advanced and multi-treated disease, and in patients with unmutated immunoglobulin heavy chain variable (IgVH) region and unfavorable cytogenetics. Patients with reduced TLR4 had an increased risk of disease progression and development of autoimmune complications. No relationship was found between reduced TLR4 expression and infectious episodes, which were observed in advanced stages and treated patients. These findings suggest that impaired innate immunity identifies patients with B-CLL with a poor prognosis and reduced ability to silence autoreactive phenomena.

Lessons from very severe, refractory, and fatal primary autoimmune hemolytic anemias

persists with hemoglobin level always above 90 g/L and platelet level stabilized below 600 3 10/L (Fig. 1). Neither hematological toxicity nor other adverse events have been recorded until now. A bone marrow aspirate performed after 3 years of treatment showed the persistence of dyserythropoiesis and of ring sideroblasts. This case confirms that the low-dose, single-agent lenalidomide could be effective in patients with a diagnosis of RARS-T and JAK2 V617F mutation, after failure of EPO and cytoreduction, leading to transfusion independence and good platelet count control, with a favorable safety profile.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) role in hematopoiesis and in hematologic diseases: A critical review.

Dioxin exposure and its effect on hematopoiesis and cancer have been largely investigated in both human and non-human settings. Here we systematically reviewed literature to address the question of what we know about TCDD biology and exposure. Most effects are due to TCDD interaction with a receptor of xenobiotics called AHR, which is ubiquitously represented and also works on hematopoietic myeloid and lymphoid stem cells, inducing proliferation and stem cell release from bone marrow to peripheral circulation. Epidemiologic studies on TCDD exposure demonstrated an association with onco-hematologic diseases, particularly with non Hodgkin lymphomas and multiple myeloma, and non hematologic cancers, such as sarcomas, although these relationships are affected by multiple confounding factors.

Is chronic neutropenia always a benign disease? Evidences from a 5-year prospective study.

AIM To evaluate infections and oncohematologic evolution in adult patients with chronic idiopathic and autoimmune neutropenia in a prospective study. PATIENTS AND METHODS 76 consecutive patients were enrolled from September 2008 to April 2012. Complete blood counts and clinical evaluation were performed at enrolment, at month 3, 6, and then every 6 months. Anti-neutrophil antibodies were tested by GIFT method. RESULTS Patients (49 chronic idiopathic- and 27 autoimmune neutropenia) were followed for a median of 5 years (range 24-84 months). At enrolment, neutropenia was mild in 44 patients (median neutrophils 1.27×10(3)/μL), moderate in 23 (median 0.8×10(3)/μL), and severe in 9 (median 0.4×10(3)/μL). Neutrophil counts showed a great inter-subject but no intra-subject variability, with lower values in autoimmune neutropenia, in males, and in MGUS cases. Over time, no grade >3 infections occurred; 13/49 chronic idiopathic and 6/27 autoimmune neutropenia patients experienced a grade 2 event, irrespective of mean and nadir neutrophil values. Bone marrow evaluation at enrolment showed reduced cellularity in 23% of cases, and dyserythropoietic features in 55%, with no definite hematologic diagnosis. During the follow-up, 5 cases were diagnosed with NK expansion, 4 with hairy cell leukemia, and 3 with myelodysplasia (1 myelomonocytic leukemia, 1 refractory cytopenia with unilineage dysplasia, and 1 multilineage dysplasia), with a median time to evolution of 30 months. CONCLUSION Chronic idiopathic and autoimmune neutropenia, although usually benign, deserve hematological follow-up with a bone marrow evaluation at diagnosis and a re-evaluation in the presence of worsening neutropenia, appearance of additional cytopenias, and lymphocytosis.

Rituximab in immune thrombocytopenia: gender, age, and response as predictors of long-term response

To evaluate the efficacy of a salvage treatment with rituximab (RTX) in adults with primary immune thrombocytopenia (ITP), in terms of short‐term response and long‐term response (LTR, i.e., probability to achieve and maintain response) and to identify biological and clinical predictors of response.

Short course of bortezomib in anemic patients with relapsed cold agglutinin disease. A phase II prospective GIMEMA study

TO THE EDITOR: Cold agglutinin disease (CAD) is a chronic hemolytic disorder caused by anti–red blood cell immunoglobulin M (IgM) autoantibodies most often monoclonal with k light-chain restriction.[1][1],[2][2] The autoantibody reacts at temperatures lower than the body temperature, causing