ALBERT

Description: Abstract 4872 Clinical history of Kaposi sarcoma-associated herpesvirus (KSHV),-related Multicentric Castleman Disease is characterized by a rapidly progressive and often fatal course. We report a case successfully treated sequentially with a course of 4 infusions of rituximab 375mg/m2 at weekly intervals, Endoxan, 750 mg/m2 as an intravenous infusion once weekly for 2 weeks, intravenous ganciclovir, 5 mg/kg twice daily for 2 weeks and then once daily, dexamethasone 20 mg on days 1–4, 9–12, 17–20 and anti-interleukin-6 receptor antibody (tocilizumab) administered intravenously at a dose of 8 mg/kg every 2 weeks, starting at day 32. On December 12, 2009, a 54-year-old man came to the medicine department because of a 2-week history of progressive fatigue, wasting, high-grade fever (39°C), profuse sweating, and severe autoimmune hemolytic anemia (4.2 mg/dL). He had been diagnosed with asymptomatic MCD 6 months before admission. Generalized lymphadenopathy and hepato-splenomegaly were evident on physical examination and enlarged lymph nodes in retroperitoneal regions (CT scan). Blood biochemistry showed very high CRP, IL-6, beta 2 microglobulin serum levels, low LDH and albumin, increase polyclonal immunoglobulin, grade 3 thrombocytopenia and neutropenia. Serologic tests (Epstein-Barr virus, hepatitis B and C viruses, cytomegalovirus and human immunodeficiency virus) were negative. On hospital day 10, 250.000 copies of HHV-8 DNA were detected in 1 mL plasma by RT-PCR. The patient achieved CR two months after admission, still maintained at 8 month follow-up. HHV-8 DNA became undetectable over the course of 8 weeks, at which time ganciclovir was discontinued. Conclusions: In our case the onset of the disease was serious and life-threatening. Sequential therapy has proven to be able to save the life of the patient acting on different biological targets. To date is the first case treated with this schedule. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4665 Introduction The thrombopoietic growth factors (TGFs) are a novel class of compounds for the treatment of chronic immune thrombocytopenia (ITP). The first of these agents to receive regulatory approval, romiplostim and eltrombopag, have demonstrated impressive efficacy and tolerability in randomized controlled trials and open-label extension studies of several years duration and stand poised to revolutionize the management of ITP. Nonetheless, critical questions regarding the safety of these agents, remain partially unanswered. The aim of this report is to focus on the incidence of thrombocytosis and rebound thrombocytopenia mimicking cyclic thrombocytopenia in a series of 15 patients treated with romiplostim in a single institution. Methods 15 patients (8 M and 7 F, median age 45 years range 21–76) with chronic ITP (median onset 6 years, range 1–11), 1/15 splenectomized, plts median 2 ×109/L, (range 18–24) were treated with Romiplostim initial dose of 1 mg/kg, weekly checks, with only weekly increase of 1 mg/kg to reach a platelet count ≥ 50 × 109/L. The target platelet count range was 50 to 250 × 109/L. Twenty-two percent of patients (3/15) were receiving concurrent treatment for ITP (corticosteroids, danazol) at the time of first romiplostim dose. These medications were discontinued after platelet counts reached 50 × 109/L. Results A platelet response had been achieved by 30% of patients after the first dose and by 51% of patients after the third dose. Treatment response was observed in 100% of pts treated after 6 weeks. In three patients after the eighth week, with average values plts 120×109/l, the subsequent administration of the drug led to an increase in platelet count 〉 1000×109/l, with rapid fall to

Description: Abstract 1099 Background (TPO)-receptor agonists (romiplostim and eltrombopag) are new therapeutic modalities in the treatment of ITP. Romiplostim treatment was associated with a number of benefits compared with the standard of care in non splenectomized ITP patients: higher platelet response rate, lower rates of treatment failure and splenectomy, fewer bleeding events, and fewer blood transfusions. Nevertheless there are not enough data on the long-term side effects and economic consequences of prolonged treatment. Furthermore, there are no criteria to identify patients potentially cured and that could stop therapy. For all these reasons we have carried out a study of platelet kinetics in all patients treated with TPO- receptor agonists and we have identified a subset who achieved a normal platelet kinetics and that is no longer relapsed two years after discontinuation of the drug Patients and Methods A total of 18 adult patients, female (63%),median (range) age 55 (31 – 78) years, median (range) baseline platelet count 19 (3 – 32) × 109/L.,median of 4 (1 – 7) prior ITP therapies, received romiplostim administered once weekly sc, with dose adjustments to maintain platelet counts in the target range of 50–150×109/L. The median time since ITP diagnosis was 6,8 years (range, 0.6–12.8 years) and 10% had undergone a splenectomy. Patients received romiplostim for a median of 98 weeks (range, 18–104); taking the average weekly dose of all patients, the median was 4 mcg/kg. Home administration was started by 16% of patients (3/18) but 2/3 patients discontinued home administration and resumed weekly outpatient injection. All patients achieved a platelet count ≥50×109/L. Results 3 out of 18 experienced thrombocytosis and rebound thrombocytopenia. A PKS with (111)In oxine-labeled autologous platelets was performed in all patients failing steroid treatment, before romiplostim was started. A gamma function was used for the calculation of platelet mean life span (MLS) that was greatly reduced in 100% of patients.3 patients, who had achieved early a stable platelet count ≥150×109/L. despite the discontinuation of romiplostim maintain normal platelet count after 24 months of follow-up. Stricking a second PKS six months after starting the treatment showed in these subset, a normal platelet half-life with normal uptake on the spleen and liver. Conclusions In our opinion PKS, in romiplostim responding patients who discontinued treatment for the stability of response, may easily detect patients probably cured Disclosures: No relevant conflicts of interest to declare.

Description: Background Recently published data suggest that high doses of imatinib mesylate (IHD) (800 mg/daily) may be more effective than standard dose (400 mg/daily) in newly diagnosed Philadelphia chromosome-positive chronic phase CML. Furthermore escalating the dose of imatinib to 800 mg per day can overcome some cases of resistance to imatinib but tolerability of high-dose imatinib continues to be an issue. Aims To evaluate the efficacy and safety of pregabalin dosed twice daily (BID) for relief of musculoskletal and neuropathic pain associated with IHD. Methods 13 patients in chronic phase (CP) were enrolled because complained of severe, persistent pain, requiring nonoppioid analgesics. Patients were asked to quantify their pain using a visual analogue scale (VAS) (numeric range 0–10). QoL assessment was based on Therapy Impact Questionnaire. At baseline, the median pain-rate was 5 (range 3–8). Pts received pregabalin in doses ranging from 75 to 300 mg twice daily for 12 weeks. Results Despite a short study duration, a significant reduction was seen in weekly pain score (p 〈 0.0001), as well as VAS score (p 〈 0.0001) allowed pts to receive the scheduled dose of imatinib. Pregabalin was well tolerated, and the most common adverse event was only somnolence. The short study duration precluded the assessment of longer term safety issues such as weight gain. Conclusions Pregabalin was safe and effective in decreasing pain associated with high dose of imatinib, and also improved mood, sleep disturbance, and quality of life.

Description: Abstract 4401 Background Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder characterized by lymphoplasmacytic bone marrow infiltration along with an immunoglobulin M (IgM) monoclonal gammopathy. Asymptomatic patients with monoclonal IgM and without morphologic evidence of bone marrow infiltration 〈 10% clonal marrow cells) are classified as having IgM-MGUS.Therapy is postponed for asymptomatic patients, and progressive anemia is the most common indication for initiation of treatment. Resveratrol (3,4',5-tri-hydroxy-trans-stilbene) is an antioxidant constituent of a wide variety of plant species including grapes. It has gained considerable attention because of its anticancer properties, as shown in solid and hematologic malignancies. Published data show that resveratrol has significant antitumor activity in WM cells line. Moreover, simvastatin, a 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor, induced inhibition of proliferation, cytotoxic effect and apoptosis in IgM secreting cell lines as well as in primary CD19(+) WM cells. With this background we have treated 4 patients with asymptomatic WM with an association of simvastatin and resveratrol to test the efficacy of such of drugs in asymptomatic Waldenstrom macroglobulinemia Methods 4 pts (3 males and 1 female), median age 42,3 yrs (range, 42–73) and asymptomatic WM were treated with a schedule containing resveratrol 40 mg/die and simvastatin 20 mg/die for at least 90 days. At enrollment patients characteristic were hemoglobin level median, 12.1 g/dL,serum beta(2)-microglobulin level median, 2.4 mg/L, and IgM peaks median, 1.8 g/dL. All patients have taken regularly the drugs and there have been no adverse events.CK and LDH serum levels were kept in the normal range. Results In all IgM-MGUS patients a reduction of more than 50% of the IgM peak was observed after 3 months of therapy and it was still maintained at 12 months of follow-up. In SWM patient the reduction was about 25% and it was manteined over time. Striking, another patient with Waldentrom disease resistant to the previous therapy with EDX and anti-CD20 MoAb achieved a CR only after adding resveratrol and simvastatin. Conclusions Our data demonstrate clearly that the association between resveratrol with simvastatin decreases IgM secretion in Waldenstrom macroglobulinaemia and can be useful in asymptomatic or low risk patients not having any adverse effects. Disclosures: Off Label Use: Simvastatin showed in vitro activity on waldentrom cell lines Resveratrol showed in vitro activity on waldenstro cell lines.

Description: Background: The management of AIHA, based mainly on empirical data and uncontrolled studies, relies principally on corticosteroids as a first-line therapy. Patients who are refractory or intolerant to these therapies (approximately 5–10% of the cases) constitute an important therapeutic challenge. The most frequent second-line options are splenectomy or immunosuppressive agents. Rituximab (R), an anti-CD20 chimeric monoclonal antibody being increasingly used in autoimmune disorders. Transfusion in patients with autoimmune hemolytic anemia generally is unwise, because the autoantibody in the serum usually reacts with the RBCs of all potential donors, making a satisfactory cross match impossible. Moreover, the erythroid response, can be inappropriately low, and several reports or senies’ have highlighted cases that have been associated with reticulocytopenia. Aim of this study is to test if the introduction of Rh-Epo in the refractory AIHA treatment may reduce the blood transfusion need and related risks Methods: 14 pts (M 7, F 7) median age 59.2 yr (range, 18–82) and AIHA resistant to standard treatment were treated with a schedule containing Rituximab, rh-EPO and prednisone (R-EP) 6 pts were idiopathic and the remaining 8 were associated with chronic lymphoproliferative syndromes (3), connective tissue diseases (2), primary antiphospholipid syndrome (APS)(1) and ulcerative colitis (2). mean Hb value and Ht at presentation were 6.3 g/dL ± 1.2, and 24 mL/dL, Median reticulocyte percentage was 9%, and median reticulocyte production index was 2.8 times basal. 24 % of cases had an initial reticulocyte count less than 4%, and 40% had an initial reticulocyte production index less than 2.0 times basal. These reticulocytopenic patients were prevalent in secondary cases. Serum erythropoietin level at baseline was (14 +/− 11 mU/mL)) Pts had altered hemolysis markers and direct antiglobulin test (DAT) was positive for both complement and IgG (IgA 1 pts). All cases had a bone marrow examination during hospitalization Erythroid hypoplasia was seen only in CLL pts.14/14 pts had serial reticulocyte measurements, Rituximab was administered intravenously at a dose of 375mg/m2 weekly for 4 weeks; prednisone 1 mg/Kg/day /for 30 days ; rh-EPO 30.000U/weekly for 4 weeks. Results: All pts completed treatment. No major infusion related side effects to R-EP were observed. Response criteria to R-EP were defined as follows: Complete Response (CR): Hb 〉10 g/dl or Hb increase 〉1.5 g/dl, resolution of symptoms of anemia, transfusion independent; Partial Response (PR): Hb 〉 9 g/dl or Hb increase of 1–1.5 g/dl. improvement in symptoms of anemia, transfusion independent; NR (failure to meet CR/PR). 100% were eligible for response. Responses were seen in 14/14 pts. CR in 13/14 and PR in 1/14, median follow up of 25.8 months (range 5–66 months). At the end of treatment DAT became negative in 12/14 pts, concentration of lactic dehydrogenase, total bilirubin and indirect bilirubin began to decrease at 12 days after the first dose of rituximab, and decreased to normal range after 22 days.. Three patients required packed red cell transfusions before starting R-EP and all became transfusion-free. A moderate hemolysis still persisted only in one patient. In the cases that were initially reticulocytopenic, reticulocyte production index rapidly increased, indicating a marrow erythropoietic response to REP Conclusion: Our experience demonstrates that R-EP is an effective and safe alternative for the treatment of refractory autoimmune hemolytic anemia. Awareness of the frequency of an initial reticulocytopenia in cases of autoimmune hemolysis may be important in initial diagnosis and treatment, because low reticulocyte production index may represent a lag in marrow responsiveness to hemolytic stress. Striking, the introduction of rh-Epo clearly avoids blood transfusions and overcame inappropriately low erythroid response in reticulocytopenic patients