Nicola Vianelli

Liposomal Amphotericin B as Initial Therapy for Invasive Mold Infection: A Randomized Trial Comparing a High–Loading Dose Regimen with Standard Dosing (AmBiLoad Trial)

BACKGROUND Treatment of invasive mold infection in immunocompromised patients remains challenging. Voriconazole has been shown to have efficacy and survival benefits over amphotericin B deoxycholate, but its utility is limited by drug interactions. Liposomal amphotericin B achieves maximum plasma levels at a dosage of 10 mg/kg per day, but clinical efficacy data for higher doses are lacking. METHODS In a double-blind trial, patients with proven or probable invasive mold infection were randomized to receive liposomal amphotericin B at either 3 or 10 mg/kg per day for 14 days, followed by 3 mg/kg per day. The primary end point was favorable (i.e., complete or partial) response at the end of study drug treatment. Survival and safety outcomes were also evaluated. RESULTS Of 201 patients with confirmed invasive mold infection, 107 received the 3-mg/kg daily dose, and 94 received the 10-mg/kg daily dose. Invasive aspergillosis accounted for 97% of cases. Hematological malignancies were present in 93% of patients, and 73% of patients were neutropenic at baseline. A favorable response was achieved in 50% and 46% of patients in the 3- and 10-mg/kg groups, respectively (difference, 4%; 95% confidence interval, -10% to 18%; P>.05); the respective survival rates at 12 weeks were 72% and 59% (difference, 13%; 95% confidence interval, -0.2% to 26%; P>.05). Significantly higher rates of nephrotoxicity and hypokalemia were seen in the high-dose group. CONCLUSIONS In highly immunocompromised patients, the effectiveness of 3 mg/kg of liposomal amphotericin B per day as first-line therapy for invasive aspergillosis is demonstrated, with a response rate of 50% and a 12-week survival rate of 72%. The regimen of 10 mg/kg per day demonstrated no additional benefit and higher rates of nephrotoxicity.

Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments

Polycythemia vera and essential thrombocythemia are typically complicated by thrombosis. According to this multicenter study recurrent thrombosis is observed in about one third of patients. Cytoreduction protects against recurrence of thrombosis. The contemporary use of oral anticoagulants or antiplatelet agents further reduce the incidence of re-thrombosis. Background Prior thrombosis is a well-established risk factor for re-thrombosis in polycythemia vera and essential thrombocythemia but scarce data are available on the rate of re-thrombosis and the optimal strategy for prevention of recurrence. Design and Methods We retrospectively estimated the rate of recurrence in a multicenter cohort of 494 patients (poly-cythemia vera/essential thrombocythemia 235/259) with previous arterial (67.6%) or venous thrombosis (31%) or both (1.4%). First thrombosis was cerebrovascular disease in 191 cases, acute coronary syndrome in 106, peripheral arterial thrombosis in 44, and venous thromboembolism in 160. Microcirculatory events were not computed. Results Thrombosis recurred in 166 patients (33.6%), with an incidence of 7.6% patient-years. Sex, diagnosis (polycythemia vera or essential thrombocythemia), and presence of vascular risk factors did not predict recurrence, whereas age >60 years did (multivariable hazard ratio [HR], 1.67; 95% confidence interval [CI] 1.19–2.32). Increased leukocyte count at the time of the first thrombosis was a risk factor for recurrence in patients <60 years old (HR 3.55; 95% CI 1.02–12.25). Cytoreduction halved the risk in the overall cohort (HR 0.53; 95% CI 0.38–0.73) and the combination with antiplatelet agents or oral anticoagulants was more effective than administration of single drugs. Significant prevention of rethrombosis was independently achieved in patients with venous thromboembolism by both oral anticoagulants (HR 0.32; 95% CI 0.15–0.64) and antiplatelet agents (HR 0.42; 95% CI 0.22–0.77), in those with acute coronary syndrome by cytoreduction (HR 0.30; 95% CI 0.13–0.68), and in those with cerebrovascular disease by antiplatelet agents (HR 0.33; 95% CI 0.16–0.66). The overall incidence of major bleeding was 0.9% patient-years and rose to 2.8% in patients receiving both antiplatelet and anti-vitamin K agents. Conclusions In patients with polycythemia vera and essential thrombocythemia, cytoreduction protects against recurrent thrombosis, particularly after acute coronary syndrome. The contemporary use of oral anticoagulants (after venous thromboembolism) or antiplatelet agents (after cerebrovascular disease or venous thromboembolism) further improves the protective effect. Such findings call for prospective studies aimed at investigating whether strategies tailored according to the type of first thrombosis could improve prevention of recurrences.

Myelofibrosis with myeloid metaplasia: clinical and haematological parameters predicting survival in a series of 133 patients.

The prognostic value of 12 clinical and haematological parameters, recorded at diagnosis, in myelofibrosis with myeloid metaplasia (MMM) was retrospectively analysed in a consecutive series of 133 patients followed for a minimum of 60 months. Multivariate analysis showed that the following features were associated with a significantly shorter survival: (1) short period of time (<13 months) between first symptoms and diagnosis; (2) anaemia (haemoglobin <10 g/dl); (3) leucocyte count >12 × 109/l; (4) peripheral blood granulocyte precursors >10%. Age, splenectomy and percentage of peripheral blood metamyelocytes were found significantly to affect survival only from univariate analysis, whereas sex, size of spleen, thrombocytopenia and thrombocytosis were of no prognostic significance. These data suggest that a more intensive chemotherapy might be useful for younger patients with bad prognostic factors at diagnosis.

Molecular Remission After Allogeneic or Autologous Transplantation of Hematopoietic Stem Cells for Multiple Myeloma

PURPOSE To assess the clinical relevance of minimal residual disease (MRD) in patients with multiple myeloma (MM), 50 patients were monitored while they were in complete clinical remission (CCR) after autologous or allogeneic stem-cell transplantation. PATIENTS AND METHODS Stringent molecular monitoring using clonal markers based on rearranged immunoglobulin heavy-chain genes was performed in 44 of 50 MM patients in CCR. Molecular clinical remission (MCR) was defined as more than one consecutive negative polymerase chain reaction (PCR) test result. RESULTS Twelve (27%) of 44 molecularly monitored patients achieved MCR; four of the 12 became PCR-positive, and one of these four relapsed. In comparison with patients who did not achieve MCR, patients who achieved MCR had a significantly lower relapse rate (41% v 16%; P <.05) and longer relapse-free survival (35 v 110 months; P <.005). Fourteen of 26 patients in CCR who had received allografts were evaluated on a molecular basis: seven (50%) of the 14 achieved MCR and did not relapse; one of the seven remaining patients relapsed. Thirty of 47 patients in CCR who received autografts were evaluated on a molecular basis: five (16%) of the 30 achieved MCR; two of these five became PCR-negative, and one of these two relapsed. Ten of the 25 remaining patients later relapsed. For these nonrandomized groups, the higher MCR rate after allograft procedures was statistically significant (P <.01; Fishers exact test). CONCLUSION MCR can be obtained in a relatively high proportion of MM patients who have achieved CCR after undergoing allograft procedures and in a smaller fraction of patients after undergoing autograft procedures. In approximately one fourth of MM patients who achieve CCR after transplantation, it may be possible to keep the disease burden constantly below the PCR threshold. Because MCR was associated with prolonged relapse-free survival, these patients could have a relatively favorable clinical outcome.

Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia

Previous observational studies suggest that rituximab may be useful in the treatment of primary immune thrombocytopenia (ITP). This randomized trial investigated rituximab efficacy in previously untreated adult ITP patients with a platelet count of 20 x 10(9)/L or less. One hundred three patients were randomly assigned to receive 40 mg/d dexamethasone for 4 days with or without 375 mg/m(2) rituximab weekly for 4 weeks. Patients who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab. Sustained response (ie, platelet count > or = 50 x 10(9)/L at month 6 after treatment initiation), evaluable in 101 patients, was greater in patients treated with dexamethasone plus rituximab (n = 49) than in those treated with dexamethasone alone (n = 52; 63% vs 36%, P = .004, 95% confidence interval [95% CI], 0.079-0.455). Patients in the experimental arm showed increased incidences of grade 3 to 4 adverse events (10% vs 2%, P = .082, 95% CI, -0.010 to 0.175), but incidences of serious adverse events were similar in both arms (6% vs 2%, P = .284, 95% CI, -0.035 to 0.119). Dexamethasone plus rituximab was an effective salvage therapy in 56% of patients refractory to dexamethasone. The combination of dexamethasone and rituximab improved platelet counts compared with dexamethasone alone. Thus, combination therapy may represent an effective treatment option before splenectomy. This study is registered at http://clinicaltrials.gov as NCT00770562.

Anti-CD20 therapy for chronic lymphocytic leukemia-associated autoimmune diseases.

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) I , axonal degenerating neuropathy (ADN) 1. Rituximab was given at the dose of 375mg/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.

Lower dose rituximab is active in adults patients with idiopathic thrombocytopenic purpura

Rituximab 375 mg/m2 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 > 50×109/L) and complete responses (platelet count > 100×109/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.

ANKRD26 -related thrombocytopenia and myeloid malignancies

To the editor: Since the discovery that mutations in the 5′ untranslated region (UTR) of ANKRD26 are responsible for an autosomal-dominant form of thrombocytopenia ( ANKRD26 -RT),[1][1] 21 affected families were reported.[2][2] A study analyzing this series of patients suggested that ANKRD26 -RT

Rituximab therapy in adult patients with relapsed or refractory immune thrombocytopenic purpura: long-term follow-up results

Objective:  To evaluate the long‐term activity and toxicity profile of rituximab in adult patients with idiopathic immune thrombocytopenic purpura (ITP).

Low‐dose rituximab in adult patients with primary immune thrombocytopenia

Backgrounds: Rituximab 375 mg/m2 weekly for 4 wks has significant activity in adults with primary immune thrombocytopenia (ITP). In this setting, several evidences support the possible use of lower doses of rituximab. Objectives: To investigate the activity of low‐dose rituximab as salvage therapy in previously treated symptomatic ITP. Methods: Forty‐eight adult patients were treated prospectively with rituximab 100 mg weekly for 4 wks. Results: Overall and complete responses (CR) (platelet level ≥ 50 and 100 × 109/L) were 60.5% and 39.5%, respectively. In responders, the median time to response was 35 d (range: 7–112 d). The median time of observation was 18 months (range 3–49 months). Sixteen of 29 responding patients (55%) relapsed and 14 needed further treatments. The 12‐ and 24‐month cumulative relapse‐free survival was 61% and 45%, respectively. In univariate analysis, CR rate was in inverse relation with weight OR = 0.95, CI95% [0.91; 0.99] (P = 0.019) and age OR=0.96, CI95% [0.93; 0.99] (P = 0.047). Cox regression model showed that relapse probability increases as weight (HR = 1.06, CI95% [1.0031; 1.111]) and period between diagnosis and rituximab therapy (HR = 1.01, CI95% [1.002; 1.017]) increase. One patient developed an interstitial pneumonia 1 month after the end of rituximab treatment. No other infectious, hematologic or extra‐hematologic complications were documented during follow‐up. Conclusions: Low‐dose rituximab is active in ITP but has moderate long‐term effect. A comparative study with standard dose is warranted.