Rituximab 375 mg/m 2 weekly for four weeks has significant activity in patients with immune thrombocytopenia. We evaluated the activity of lower dose rituximab (100 mg iv weekly for 4 weeks) in 28 adults with idiopathic thrombocytopenic purpura. Overall (platelet count > 50ϫ10 9 /L) and complete responses (platelet count > 100ϫ10 9 /L) were achieved in 21/28 (75%) and 12/28 (43%) patients respectively. The median time to response and time to complete response were 31 and 44 days respectively. After a median follow-up of 11 months (range 3-18), 7/21 (33%) patients relapsed and 3 needed further treatments. In patients with idiopathic thrombocytopenic purpura, lower dose rituximab seems to show similar activity to standard dose.Key words: immune thrombocytopenia, B-cell depletion, lower dose rituximab.Citation: Zaja F, Battista ML, Pirrotta MT, Palmieri S, Montagna M, Vianelli N, Marin L, Cavallin M, Bocchia M, Defina M, Ippoliti M, Ferrara F, Patriarca F, Avanzini MA, Regazzi M, Baccarani M, Isola M, Soldano F, and Fanin R. Lower dose rituximab is active in adults patients with idiopathic thrombocytopenic purpura. Haematologica 2008; 93:930-933.

Rituximab is active in chronic lymphocytic leukemia (CLL) and may interfere with autoantibodies production in some immune diseases. We report the results of rituximab treatment in 7 patients with CLL-associated symptomatic autoimmune diseases refractory to standard immunosuppressive therapies: warm antibody hemolytic anemia (AHA) 4 patients, cold agglutinin disease (CAD) 1, immune thrombocytopenia (IT) 1, axonal degenerating neuropathy (ADN) 1. Rituximab was given at the dose of 375 mg/m2 per week for 4 weeks. One patient with AHA and one with CAD achieved complete normalization of hemoglobin levels and laboratory signs of haemolysis, with response duration (RD) of 8+ and 38+ months, respectively. In the patient with IT, complete remission was reached after the first week of treatment and RD was 6 months. The patient with ADN achieved a marked neurological improvement after rituximab therapy, with RD of 12 months. Retreatment of both patients with IT and ADN was effective. Rituximab may be an alternative agent for the treatment CLL-associated autoimmune diseases.

Progress in treatment of acute myeloid leukemia (AML) is slow and treatment intensification alone has limited effects, particularly in poor-risk cases. Poor-risk cases, that are identified mainly by prior history, leukemic cell mass and cytogenetic abnormalities, share multiple mechanisms of drug resistance that are responsible for treatment failure. Since Pgp-mediated resistance to anthracycline can be reduced with Idarubicin (IDA) and resistance to arabinosyl cytosine (AC) can be reduced with Fludarabine (FLUDA), we tested a combination of high dose AC (2000 mg/sqm, 5 doses), FLUDA (30 mg/sqm, 5 doses) and IDA (12 mg/sqm, 3 doses) for remission induction and consolidation in 45 consecutive cases of poor-risk AML. The complete remission (CR) rate was 71% after the first course and 82% overall, with a projected 2-year survival and relapse-free survival of 44% and 50% respectively. Non-hematologic toxicity was very mild, that is very important in elderly patients, but hemopoietic toxicity was substantial, with a time to hematologic recovery of 3 to 4 weeks and two cases of death in CR. Peripheral blood stem cells (PBSC) could be mobilized and collected successfully only in 11 cases. This three-drug combination is effective and has a limited non-hematologic toxicity, but FLUDA may increase the difficulty of obtaining PBSC early after remission induction.

Dapsone is an antibacterial sulfonamide with anti-inflammatory property, which showed therapeutic activity in patients with immune thrombocytopenia (ITP) [1][2][3][4][5][6]; the activity in patients who showed refractoriness to rituximab is unknown. We evaluated the effect of dapsone in 20 consecutive adult patients, median age 51 years, with primary ITP previously treated at least with steroids and rituximab. Median baseline platelet count was 19 3 10 9 /L, and the median interval between diagnosis of ITP and dapsone therapy was 46 months. Response (platelet count 30 3 10 9 /L) and complete response (CR; platelet count 100 3 10 9 /L) were 55 and 20%, respectively; median time to response (TTR) was 1 month. All responders were able to interrupt any other specific anti-ITP treatment. The median duration of dapsone therapy in responders and the median response duration were 31 and 42 months, respectively. None of responders lost response during treatment. One patient in CR interrupted dapsone after 9 months and still maintained the response after 48 months. None of the patients interrupted the treatment for toxicity. All the patients were screened for normal glucose-6-phosphate-dehydrogenase (G6PD); two patients showed mild increase of methemoglobin (MHb). These results highlight the therapeutic activity and good safety profile of dapsone in patients with ITP who previously failed rituximab treatment. ITP is an acquired autoimmune disease characterized by increased platelet destruction, impaired megakaryocyte maturation with reduced platelet production, and possible hemorrhagic complications. Treatment is generally indicated for symptomatic patients, that is, those with active bleeding or very low platelet count (usually < 20-30 3 10 9 /L). Glucocorticoids, potentially associated with intravenous high-dose immunoglobulin in those cases with high risk of major bleeding, represent the standard first line of treatment [7]. However, despite the high initial therapeutic efficacy, in most cases, steroids tapering or withdrawal is followed by a drop in platelet count and the need for additional treatment. Treatment of patients with relapsed or refractory symptomatic ITP, particularly of those who are not eligible for, refused or failed splenectomy, still lacks a gold standard therapy. Dapsone is an antibacterial sulfonamide synthesized in 1908 with antimicrobial effect against leprosy, pneumocystic Jiroveci pneumonia in AIDS, toxoplamosis, and malaria. Since 1950s, dapsone also was recognized to have activity in a number of noninfectious inflammatory diseases of the skin as dermatitis herpetiformis and blistering disorders. The anti-inflammatory effect of dapsone is not fully understood, but it appears at least targeted against neutrophils, with interference of myeloperoxidase, inhibition of lysosomal enzymes, chemotaxis, and integrin-mediated adherence function. This agent is contraindicated in patients with G6PD deficiency and has a good safety profile. Hemolytic anemia and an increase of methemoglobin (MHb) are the ma...

Background. A sustained deep molecular response (MR4 or better) is a validated criterion for discontinuation of Tyrosine Kinase Inhibitors (TKI) in patients with Chronic Myeloid Leukemia (CML), but only a minority of patients attain this response. Predictive factors of stable MR4 have been reported in patients treated with different dosages of imatinib (i.e from 400 to 800 mg daily) but data about long-term treatment with standard dose imatinib are lacking. Moreover, various definitions of sustained MR4 have been used in these studies. Aims and methods. To assess the probability and the predictors of a stable MR4 we restrospectively analyzed our cohort of chronic phase CML patients treated with imatinib 400 mg daily, as first-line therapy or after interferon (IFN) failure. IFN-treated patients already in complete cytogenetic response at the time of imatinib start were excluded from the analysis. Major molecular response (MMR) was defined as BCR-ABLIS ratio <0.1%. Deep molecular response (MR4) was defined as BCR-ABLIS ratio ≤0.01% or undetectable disease with ≥10,000 ABL copies. Patients with MR4 lasting ≥ 2 years and at least a Q-PCR test every 6 months were defined as stable MR4. Patients with any sample >0.01% BCR-ABLIS after the achievement of MR4 were defined as unstable MR4. Baseline factors (age, sex, Sokal, Hasford and EUTOS risk score, type of BCR-ABL transcript, pre-treatment with IFN) and response to imatinib at 3, 6, and 12 months according to the European LeukemiaNet (ELN) 2013 recommendations have been examined for the association with stable MR4. Frequencies were compared by Fisher's exact test. Univariate and multivariate regression analysis were performed using the competing risk model of Fine and Gray, where the achievement of the response was the event of interest, and cessation of imatinib 400 mg daily for any reason (including dose increase for resistance, and death) were the competing risks. The significance of individual parameters comprising more than 2 variables was determined by the Wald test. Results. A total of 320 patients (260 treated with imatinib front-line and 60 after IFN) was evaluated. Median age at diagnosis was 57 years (range 20-88). Sokal distribution was 42%, 40% and 15% for low, intermediate and high risk, respectively (3% were not evaluable). After a median follow-up from imatinib start of 74 months, 146 patients (46%) never reached MR4, 84 patients (26%) obtained an unstable MR4 and 90 patients (28%) achieved a stable MR4. The cumulative incidence of stable MR4 was 26.8% (95% CI: 20.8-32.3%) at 5 years and 39.3% (95% CI: 32.1-45.7%) at 10 years. Median time to first MR4 for patients subsequently obtaining a stable MR4 was 25.3 months and all but 5 stable responders achieved the MR4 within 5.5 years of imatinib. As compared to patients with unstable MR4, those with stable MR4 tended to have a higher frequency of e14a2 transcript (63% vs 53%; p=0.07) and had a marginally significant lower frequency of IFN pre-treament (16.7% vs 29.8%; p=0.048) while no differences were observed concerning the other baseline factors, including sex. Predictors of stable MR4 were: type of transcript (e14a2 vs e13a2 HR 2.07; p=0.003), pre-treatment with IFN (no IFN vs IFN HR 2.45; p=0.002), BCR-ABL level at 3- (≤10%IS vs >10%IS HR 3.48; p=0.004), 6- (<1%IS vs 1-10%IS HR 9.95; p=0.001) and 12-months (MMR vs no MMR HR 12.5; p<0.001). Considering only patients with optimal response to imatinib, rates of stable MR4 were significantly higher for e14a2 than e13a2 or e13a2/e14a2 patients both at 3 (47.8% vs 23.2% and 21%; p=0.003), 6 (48.6% vs 28.8% and 33.3%; p=0.027) and 12 months (53.7% vs 25.9% and 40%; p=0.037). Conclusions. Biological variables such as the type of BCR-ABL transcript could influence the achievement and the stability of MR4, also in patients with optimal kinetics of response to imatinib. Moreover, our results suggest that a rapid attainment of MR4 during the first years of imatinib treatment is a predictor of a subsequent sustained response, a prerequisite for TKI discontinuation. Disclosures Bonifacio: Amgen: Consultancy; Novartis Farma: Research Funding; Ariad Pharmaceuticals: Consultancy; Pfizer: Consultancy. Fanin:Novartis Farma: Speakers Bureau. Tiribelli:Bristol Myers Squibb: Consultancy, Speakers Bureau; Novartis Farma: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau.