"Real-world" data on the efficacy and safety of lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma who were treated according to the standard clinical practice: a study of the Greek Myeloma Study Group.

Lenalidomide and dexamethasone (RD) is a standard of care for relapsed/refractory multiple myeloma (RRMM), but there is limited published data on its efficacy and safety in the "real world" (RW), according to the International Society of Pharmacoeconomics and Outcomes Research definition. We studied 212 RRMM patients who received RD in RW. Objective response (≥PR (partial response)) rate was 77.4 % (complete response (CR), 20.2 %). Median time to first and best response was 2 and 5 months, respectively. Median time to CR when RD was given as 2nd or >2(nd)-line treatment at 4 and 11 months, respectively. Quality of response was independent of previous lines of therapies or previous exposure to thalidomide or bortezomib. Median duration of response was 34.4 months, and it was higher in patients who received RD until progression (not reached versus 19 months, p < 0.001). Improvement of humoral immunity occurred in 60 % of responders (p < 0.001) and in the majority of patients who achieved stable disease. Adverse events were reported in 68.9 % of patients (myelosuppression in 49.4 %) and 12.7 % of patients needed hospitalization. Peripheral neuropathy was observed only in 2.5 % of patients and deep vein thrombosis in 5.7 %. Dose reductions were needed in 31 % of patients and permanent discontinuation in 38.9 %. Median time to treatment discontinuation was 16.8 months. Performance status (PS) and initial lenalidomide dose predicted for treatment discontinuation. Extra-medullary relapses occurred in 3.8 % of patients. Our study confirms that RD is effective and safe in RRMM in the RW; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease.

Primary treatment with pulsed melphalan, dexamethasone and thalidomide for elderly symptomatic patients with multiple myeloma.

Fifty patients with multiple myeloma >or=75 years of age received primary treatment with melphalan (M) 8 mg/m(2) on days 1-4, dexamethasone (D) 12 mg/m2 on days 1-4 and 17-20 and thalidomide (T) 300 mg at bedtime on days 1-4 and 17-20. This regimen was repeated every 5 weeks for three courses. Patients without evidence of disease progression received nine additional courses of MDT, but without DT on days 17-20, every 5 weeks. Sixty-two percent of patients achieved a partial response and 10% a complete response. The median time to response was 2 months. The median time to progression for all patients was 21.2 months. Deep venous thrombosis and peripheral neuropathy each occurred in 9% of patients.

Recombinant human erythropoietin therapy in critically ill patients: a dose-response study [ISRCTN48523317].

INTRODUCTION: The aim of this study was to assess the efficacy of two dosing schedules of recombinant human erythropoietin (rHuEPO) in increasing haematocrit (Hct) and haemoglobin (Hb) and reducing exposure to allogeneic red blood cell (RBC) transfusion in critically ill patients. METHOD: This was a prospective, randomized, multicentre trial. A total of 13 intensive care units participated, and a total of 148 patients who met eligibility criteria were enrolled. Patients were randomly assigned to receive intravenous iron saccharate alone (control group), intravenous iron saccharate and subcutaneous rHuEPO 40,000 units once per week (group A), or intravenous iron saccharate and subcutaneous rHuEPO 40,000 units three times per week (group B). rHuEPO was given for a minimum of 2 weeks or until discharge from the intensive care unit or death. The maximum duration of therapy was 3 weeks. RESULTS: The cumulative number of RBC units transfused, the average numbers of RBC units transfused per patient and per transfused patient, the average volume of RBCs transfused per day, and the percentage of transfused patients were significantly higher in the control group than in groups A and B. No significant difference was observed between group A and B. The mean increases in Hct and Hb from baseline to final measurement were significantly greater in group B than in the control group. The mean increase in Hct was significantly greater in group B than in group A. The mean increase in Hct in group A was significantly greater than that in control individuals, whereas the mean increase in Hb did not differ significantly between the control group and group A. CONCLUSION: Administration of rHuEPO to critically ill patients significantly reduced the need for RBC transfusion. The magnitude of the reduction did not differ between the two dosing schedules, although there was a dose response for Hct and Hb to rHuEPO in these patients.

Continuous prednisolone versus conventional prednisolone with VMCP-interferon-alpha2b as first-line chemotherapy in elderly patients with multiple myeloma.

We report on a randomised trial that aimed to compare the efficacy of continued daily prednisolone treatment during the entire induction phase, with prednisolone given for 2 weeks of each cycle in combination with VMCP (vincristine, melphalan, cyclophosphamide, prednisolone)-interferon-alpha 2b (IFN-alpha 2b) treatment in 299 previously untreated elderly patients (median age: 67 years) with multiple myeloma. After completion of induction treatment patients were randomised to IFN-alpha 2b with or without prednisolone, thrice weekly. Response rate was 62% in the continuous and 60% in the control arm (intent to treat analysis, P=0.81). Progression-free survival [median: 20 months vs. 19 months; hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.74-1.33, P=0.97] and overall survival (median: 34 months vs. 37 months; HR: 1.16, 95% CI: 0.85-1.59, P=0.35) were similar in both groups. Reduced performance status (Eastern Cooperative Oncology Group, grades 2-4) was the predominant risk factor for poor survival followed by age >65 years, high beta2-microglobulin, and impaired renal function. There was more grades 3-4 dyspnoea and cardiac impairment and grades 1-2 hyperglycaemia, but less nausea, emesis and anaemia in patients on continuous prednisolone therapy. In conclusion, continuing prednisolone treatment during the entire duration of the induction phase with VMCP-IFN-alpha 2b did not improve outcome.

Multiple myeloma in elderly patients: prognostic factors and outcome.

OBJECTIVES: Purpose of this study was to compare prognostic factors and outcome of patients with multiple myeloma (MM) aged >70 yr at diagnosis with those of younger patients. We also applied the recently proposed International Staging System (ISS) for MM in these patients. PATIENTS AND METHODS: Among 1,162 newly diagnosed, symptomatic MM patients included in our database, 357 (31%) were >70 yr of age. Clinical and laboratory variables were evaluated in patients >70 yr and in younger patients and were assessed for possible correlation with survival in patients >70 yr of age. RESULTS: Most clinical and laboratory features were similar in the two groups of patients but older patients presented more frequently with advanced ISS (P = 0.02). Despite similar response rates to primary treatment, younger patients survived longer than patients >70 yr of age (40 vs. 28 months, P = 0.001). There was a longer survival of younger patients than that of older patients diagnosed with ISS stage 1 (median 71 vs. 54 months, P = 0.007) and ISS stage-2 patients (median: 38 vs. 26 months, P = 0.0008) but for patients with ISS stage 3 median survival was similarly poor in the younger and older age group (21 and 20 months, P = 0.283). Other variables associated with impaired prognosis were severe anemia, extensive bone marrow plasmacytosis and elevated serum LDH. CONCLUSIONS: Older patients with MM present more often with advanced ISS and have significantly shorter survival than younger patients. The ISS retained its prognostic significance within the group of elderly patients.

Type 1 and type 2 cytokine-producing CD4+ and CD8+ T cells in primary antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an autoimmune condition characterized by thrombosis and/or recurrent fetal loss as well as the presence of autoantibodies against epitopes present on phospholipid-binding proteins. The role of cellular immunity in the pathogenesis of the syndrome remains unclear. We studied the cellular phenotype and the production of type 1 [interferon (IFN)-gamma, interleukin (IL)-2] and type 2 (IL-4, IL-10) cytokines by CD4+ and CD8+ T-lymphocyte subsets in 13 patients with untreated primary APS (PAPS) and in 32 healthy controls. The production of cytokines was determined in T cells after a 5-h culture with or without mitogenic stimulation using a flow cytometric method of intracellular cytokine staining. In six of the patients these studies were repeated 6 months later. In PAPS patients we found a reduced percentage of circulating CD4+CD45RA+ and an increased percentage and absolute number of CD8+HLA-DR+ cells. A type 1 response was observed in the patients' unstimulated cells, indicated by an increase in IFN-gamma-producing CD8+, IL-2-producing CD4+ T cells, and a decrease in IL-4-producing CD4+ and CD8+ T cells. Similar results were obtained in the patients at follow-up. Taken together, these results suggest a chronic in vivo stimulation of CD4+ and CD8+ T cells in PAPS patients exhibiting a type 1 polarization. Changes of cellular immunity may contribute to the pathogenesis of the clinical manifestations of the syndrome and might be proven to be useful targets for therapeutic interventions in the future.

Markers of endothelial and in vivo platelet activation in patients with essential thrombocythemia and polycythemia vera.

We investigated endothelial and in vivo platelet activation in a cohort of 52 patients with essential thrombocythemia (ET) and polycythemia vera (PV) before and after cytoreductive treatment, 22 healthy controls, and 17 patients with acute cerebrovascular ischemia (ACVI) and normal platelet counts. We measured platelet expression of CD62P and CD63 antigens and levels of soluble vascular cell adhesion molecule 1 (sVCAM-1). We found increased in vivo platelet activation in all patients with ET and PV, both before and after cytoreductive treatment, compared with controls. In patients with arterial thrombosis, platelet expression of CD62P, and in patients with erythromelalgia, expression of both markers was higher compared with expression in patients without thrombotic complications. In patients with ET and PV before and after treatment, sVCAM-1 expression was increased compared with expression in controls but also compared with expression in patients with ACVI and normal platelet counts. In patients with arterial thrombosis and erythromelalgia, in vivo platelet activation correlated with the level of sVCAM-1. Our findings indicated that in vivo platelet activation reflects intrinsic platelet defects in patients with ET and PV, persists after cytoreductive treatment, and results in endothelial damage, probably through release of angiogenic factors and/or activation of white blood cells.

Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response.

Derangement of cellular immunity is central in the pathophysiology of adult autoimmune/idiopathic thrombocytopenic purpura (ITP). Herein we investigated cytokine gene expression in peripheral blood mononuclear cells (PBMCs) of adult chronic ITP patients and attempted to correlate cytokine polarization with the degree of thrombocytopenia. We used semiquantitative reverse-transcriptase-polymerase chain reaction (RT-PCR) to measure the expression of type-1 (interleukin-2 [IL-2], interferon gamma [IFN-gamma]) and type-2 (IL-4, IL-5, IL-10, IL-3, IL-13) cytokines by PBMCs from 21 patients and 11 controls. Plasma transforming growth factor beta1 (TGF-beta1) levels were measured by enzyme-linked immunoassay (ELISA). T helper 1 (Th1)/Th2 ([IL-2 + IFN-gamma]/[IL-4 + IL-5]) cytokine mRNA ratios, thought to reflect the Th deviation of the pathogenic disease-specific T cells, and type-1/type-2 mRNA ratios, thought to reflect the overall immune response polarization, were significantly increased in ITP patients. The Th1/Th2 ratio was inversely correlated with platelet counts. TGF-beta1 levels appeared suppressed in patients with active disease, though not significantly. Our findings show a clear type-1 cytokine polarization of the autoimmune response in adult ITP that persists irrespective of disease status.

Clinical relevance of balance between type 1 and type 2 immune responses of lymphocyte subpopulations in aplastic anaemia patients.

Immune dysfunction, which leads to the suppression of haemopoiesis by cytokines that are secreted by activated T lymphocytes, is considered to play a key role in the pathogenesis of acquired aplastic anaemia (AAA). We investigated the intracytoplasmic expression of type-1 [interferon gamma (IFN-gamma), interleukin (IL)-2] and type-2 (IL-4, IL-10) cytokines in CD4+ and CD8+ T cells before and after in vitro activation in 16 patients with AAA and 17 normal controls. Untreated or refractory patients had a significantly higher proportion of unstimulated CD4+ and CD8+ T cells that produced IFN-gamma and IL-2 whereas the IL-4 and IL-10 producing T cells did not differ from that of controls, resulting in a shift of IFN-gamma/IL-4 ratio towards a type-1 response. Patients in remission had also increased proportion of IFN-gamma-producing unstimulated CD4+ and CD8+ cells, with a parallel rise of IL-4- and IL-10-producing cells and normal IFN-gamma/IL-4 ratio. These data indicate that, in newly diagnosed and refractory patients with AAA, CD4+ cells are polarized towards a type-1 response that in turn leads to activation of cytotoxic CD8+ cells and finally to haemopoietic stem cell destruction. The type-1 response persists in patients in remission although this effect is compensated by the increase of IL-4 and IL-10 production.

Expression patterns of Th1 and Th2 cytokine genes in childhood idiopathic thrombocytopenic purpura (ITP) at presentation and their modulation by intravenous immunoglobulin G (IVIg) treatment: their role in prognosis.

Childhood idiopathic thrombocytopenic purpura (ITP) resolves usually after the first episode, although it may recur, and in 10% to 20% of patients develops into a chronic disorder. Evidence of the immunoregulatory role of Th1/Th2 responses in autoimmune diseases prompted us to perform a prospective study of Th1/Th2 gene expression profiles and transforming growth factor beta (TGF-beta) plasma levels in 18 children (median age, 6.4 years) with acute ITP, before and after intravenous immunoglobulin G (IVIg) infusion, and during a follow-up period (0.5-5 years). Initially, 12 of 18 patients had either low Th0/Th1 plus interleukin 10 (IL-10) or no in vivo cytokine gene expression (0). At 24 hours after IVIg infusion this pattern became 0 or Th2 (9 of 12) or remained low Th0/Th1 (3 of 12). During follow-up these patients did not relapse and maintained 0 or Th2 pattern without IL-10. Of the remaining 6 patients, 4 presented with a Th1 or Th0/Th1 pattern plus IL-10 that persisted after IVIg treatment (although interferon gamma [IFN-gamma] expression diminished) and stabilized to Th1 plus IL-10 at follow-up, which was marked by infrequent episodes of ITP. Two patients presenting with a strict Th1 pattern characterized by high expression of IFN-gamma, which remained unchanged after IVIg and at follow-up, can be characterized as chronic ITP. TGF-beta plasma levels were low in patients with active disease and increased in remission. Overall, acute ITP presents with Th1, Th0/Th1, or 0 in vivo cytokine gene expression. Stable remission is associated with a 0 or Th2 pattern. A 0 or Th2 pattern after IVIg gave the best prognosis, whereas sustained high expression of IFN-gamma and refractoriness to IVIg were the main indicators of poor prognosis.