ALBERT

Description: Introduction. Eltrombopag is an oral, non-peptide thrombopoietin receptor agonist that has been shown efficacy and safety in chronic immune thrombocytopenia (ITP) patients not responding to previous therapy , by raising the platelets count in both continued long-term administration and in a repeated short-term administration. However, when eltrombopag is discontinued, platelet counts usually return to baseline within 2 weeks. As reported in different case series only 15 % of patients achieve a durable response after treatment discontinuation. The aims of this study was to evaluate the efficacy and safety of eltrombopag given at a dose of 25 mg every 3 days as maintenance therapy in responding patients after an initial standard dose of 50 mg orally once daily. Methods. A total of 7 consecutive adult patients, female (70 %), median age 47 years (range 28 - 79) were enrolled in the study. Patients had ITP for a median of 3.5 years and had failed a median of four prior therapies. Splenectomy was not taken into account because contraindicated or refused. All patients received eltrombopag 50 mg by mouth once a day as induction treatment .A complete blood count was performed at baseline, on day 5, then weekly for 28 days, every 2 weeks during maintenance. Complete Response ( CR) was defined as platelet count ≥ 100 * 10^9/L measured on two occasions 〉 7 days apart and the absence of bleeding. Relapse Free Survival (RFS) was considered to be from the day of initial response until relapse (Plt

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: Background and aim Administration of azacitidine is planned in-patient daily, there is no experience of its administration to the patient's home. The aim of this work was to evaluate the feasibility of a program of home administration of azacitidine able to reducing the cost-of-illness, to increase adherence to treatment while maintaining the same safety of the therapy given in hospital. Material and methods Between Jan 2008 and Dec 2012, 22 consecutive  patients, (MDSs, n = 15; CMML, n = 4; AML, n = 3), were enrolled in the study. The pharmacoeconomic analysis included assessment of direct costs ( hospital inpatient, physician inpatient, physician outpatient, emergency department nursing home care, specialists’ and other health professionals’ care, diagnostic tests, prescription drugs and drug sundries, and medical supplies),indirect costs incurred by care recipients and unpaid caregivers, including time, productivity and travel cost. Results Azacitidine 75 mg/m2/day was administered as a subcutaneous injection for 7 consecutive days  every 4 weeks,  Median age of the patients was 71 years (range, 65–83). Median number of courses delivered to each patient was 9 (range, 3–31) Hematologic responses (CR/PR/mCR) were induced in 6 patients (27.0%)  Median number of treatment courses to achieve any response was 2 (range, 1–6) Adverse events were evaluated for the first 6 courses for all patients, for a total of 124 courses. Major adverse events were cytopenia and cytopenia-related infection. Grade 3 or higher neutropenia was 64.4%) but incidence of febrile episode requiring intravenous antibiotics was  8,4% slightly lower than reported from the pivotal clinical study. Grade 3 or higher non-hematologic toxicities were infrequent. Injection site reaction 0.4 and site pain 0% Median follow-up duration of surviving patients was 46.9 months (range, 11.8–55.5). Of the 14 patients  who were RBC transfusion dependent at baseline, 48.0% of these patients became RBC transfusion independent during the treatment period. Adherence to treatment was 100%. In our experience, despite the high percentage of elderly patients of whom 36% living in rural area, it was possible to give treatment to all patients with 100% adherence. There has been a reduction in direct medical costs due  to less use of hospitalization, a reduction of indirect costs by 63% due to the lower number of working days lost and a drastic reduction of travel costs, with the same efficacy and safety of administration. Disclosures: Off Label Use: drug administration at patient home instead of hospital.

Description: Introduction. Immune thrombocytopenia (ITP) is characterized by platelet destruction due to the presence of platelet antibodies. This phenomenon is associated with impaired platelet production by bone marrow. Short-course corticosteroids and high-dose intravenous immunoglobulins remain the first-line treatments. Aim of this study was to test if SCIG is equally effective and can be less expensive than hospital-based IVIG in treating chronic-ITP Methods Seven-ITP patients aged between 13-52 years were given liquid intravenously immunoglobulin (IVIg) stabilized with proline in a dose of 400 mg/kg per day for 5 consecutive days.The median time since ITP diagnosis was 18 months (range, 16 – 38) Median (range) baseline platelet count 19 (3 – 32) x 109/L.,median of 2 (1 – 3) prior ITP therapies. Furthermore, none of of the subjects was a good candidate for TPO-receptor agonists (romiplostim and eltrombopag) because of age or other comorbidities.6 / 6 had a good response to the first 5 day course of gammaglobulin therapy, (platelet count ≥50 × 10(9) /l and ≥2× baseline). The peak platelet count occurred within 7 days from the beginning of the therapy. Only in one patient the platelet count peak took place after 12 days. During the first year of treatment, only one of seven initial responder patients achieved CR(defined as platelet count ≥ 100 * 10^9/L measured on two occasions 〉 7 days apart and the absence of bleeding) and was excluded from the study. After a loading dose of 2 g/kg over 2 days of IVIg, home SCIG of 8 gr total weekly dose was started by 87,3% (6/7) to maintain platelet counts in the target range of 50–100x109/L. Results 5/6 patients reached the target. One patient achieved CR during the maintenance therapy.No untoward reactions necessitating cessation of therapy were encountered during this study. The most common side effect observed was headache. Conclusion Application of SCIG was well tolerated, easy to manage, and led to stabilization of the disease course.The therapy facilitates home therapy, as the infusion technique is easy for children, adults and elderly people to learn and there is no need for venous access. SCIG home therapy leads to significantly improved life situations for the patients; the SCIG home therapy regimen in particular reduces the costs of treatment. Overall costs per patient were strongly reduced in SCIG in comparison to IVIg.SCIG may represent an effective new therapeutic option in chronic ITP. Disclosures Abruzzese: novartis, bristol myers squibb, ariad, pfizer, takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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: Chemotherapy-induced-thrombocytopenia (CIT) can prevent the administration of the optimal dose and schedule of anticancer treatment and limit its benefits in the adjuvant or metastatic setting. Therapeutic approaches will include dose delays or reduction ,platelet transfusion and consideration of platelet-stimulating agents. In a review of chemotherapy-induced thrombocytopenia including 〉47 000 patients with solid tumors, CRC was associated with the highest prevalence of thrombocytopenia by cancer type, and most patients had received a platinum-based chemotherapy regimen. Experimental data demonstrated that Platinum is one of the heavy metals which may induce immune manifestations in humans and in experimental animals. However, novel mechanisms of oxaliplatin-related thrombocytopenia have been implicated and include an immune-dependent mechanism, as well as portal hypertension related to sinusoidal injury yielding splenic sequestration of platelets. Eltrombopag is an oral, non-peptide thrombopoietin receptor agonist that has been shown efficacy and safety in chronic immune thrombocytopenia (ITP) patients not responding to previous therapy .Moreover,some clinical studies demonstrate a role for thrombopoietin agonists in improving compliance with cytotoxic regimens in cancer patients whose chemotherapy was delayed due to thrombocytopenia,[and they suggest that prophylactic use of eltrombopag or romiplostim might reduce the degree and duration of chemotherapy-induced thrombocytopenia. Here, we report on a series of 22 patients at high risk of CIT because of platinum chemotherapy schedules who received low doses eltrombopag as prophilaxis .The aim of the study was to prevent CIT in patients who cannot be supported by platelet transfusions and for whom the maintenance of dose intensity is crucial for remission or survival Methods A total of 22 consecutive adult patients, female (60 %), median age 47 years (range 28 - 67) were enrolled in the study. The reason of chemotherapy has been ovary cancer in 5 patients, colon cancer in 8 patients, relapsed DLBC lymhoma in 4 patients,, TNBC in 2 patients, pancreatic cancer in 3 pts. All patients received eltrombopag 25 mg by mouth twice a weekly as soon as the platelet count falls below 80000 mmc, and continued on treatment until completion of cycles of chemotherapy. Results The mean platelet count nadir was 60000 mmc; the number of days with platelet count 〈 80000/µL was 4 days; The maximum value reached was 270,000 mmc. No treatment-related toxicity was observe. 1 out of 22 pts , did not respond to the planned dose and received 50 mg for eight consecutive days before each course of chemotherapy.The principal endpoints of the study : avoid nadir platelet counts 〈 50,000/µL,platelet transfusions, bleeding events, chemotherapy dose reductions , chemotherapy delays. were achieved in all patients. Conclusion In our opinion low dose eltrombopag prophilaxis can be an effective and safe strategy for preventing the CIT. Disclosures No relevant conflicts of interest to declare.

Description: Rituximab, a monoclonal antibody directed against the CD20 antigen expressed on B cells, has been shown to be effective in AIHA, both in idiopathic and secondary including those associated with autoimmune and lymphoproliferative disorders as well as in Evans syndrome. At standard dose of 375 mg/mq weekly for a median of 4 weeks , overall survival (OS), complete response (CR), desease free survival (DFS) were respectively OR 83-87%,CR 54-60% DFS 72% at one and 56% at two years. Moreover rituximab re-treatment is effective and some patients responded to re-treatment more than once. Because is available today a Rituximab solution for subcutaneous injection, we have used this formulation for the treatment of 6 patients (pts) suffering from AIHA. Methods 6 pts (M 2, F 4 ) were enrolled in this study. Median age was 58.3 yr (range, 52-82) 2 out of 6 pts were idiopathic and the remaining 4 were associated with chronic lymphoproliferative syndromes. 2 out of 6 pts had relapsed after a first-line treatment with intravenous rituximab and steroids.For 2 pts mean Hb value and Ht at presentation were 6.2 g/dL ± 1.2, and 26 mL/dL, Median reticulocyte percentage was 10%, and median reticulocyte production index was 2.9 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. 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.6/6 pts had serial reticulocyte measurements, Rituximab subcutaneous formulation was administered at a fixed dose of 1400 mg weekly for 4 weeks; Before starting MabThera subcutaneous injections, all patients received beforehand, a full dose of Rituximab by intravenous infusion. Premedication consisting of an anti-pyretic and an antihistaminic was given orally in the evening before and the morning of the subcutaneous administration in order to reduce the time to stay in day hospital . All pts received prednisone 1 mg/Kg/day /for 30 days ; for these reason premedication with glucocorticoids was avoided. Results All pts completed treatment. No major infusion related side effects to subcutaneous Rituximab SC-R) were observed. Response criteria 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.Complete Responses were seen in 6/6 pts .At the end of treatment DAT became negative in 4/6 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. 3 patients required packed red cell transfusions before starting SC-R and all became transfusion-free. A moderate hemolysis still persisted only in one patient. rh-Epo has been administered in three pts initially reticulocytopenic. The reticulocyte production index rapidly increased, indicating a marrow erythropoietic response to rh-Epo Conclusion Our experience demonstrates that SC- Rituximab is an effective and safe alternative to IV formulation both in the first line and in the relapsed pts. SC-Rituximab shortens the treatment time significantly, enabling administration over approximately 5 minutes compared with 3 hours during IV infusion. The ready-to-use SC formulation significantly reduce pharmacy time and the impact on hospital resources as medicine preparation time and hospital staff time per administration are significantly reduced also in our hands. 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.