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Background/Aim: Primary mediastinal large B-cell lymphoma (PMLBCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL), whose prognosis has greatly improved since the incorporation of the anti-CD20 monoclonal antibody rituximab into current therapeutic regimens. Evidence, however, on the optimal time interval between consecutive chemoimmunotherapy (CIT) cycles is still scarce. This study aimed to evaluate the efficacy outcomes of the more commonly administered 3-weekly regimens to the biweekly ones in a PMLBCL patients’ population, who were mostly treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP-21) or R-CHOP-14. Patients and Methods: We retrospectively studied our cohort of consecutively treated PMLBCL patients, focusing on their treatment density, in order to determine possible differences in treatment outcomes. Results: CIT, in the form of both R-CHOP-21 as well as R-CHOP-14 (or similar regimens), is highly active in PMLBCL, with low rates of early treatment failure. In our cohort of patients, R-CHOP-14 did not result in a meaningful improvement of freedom from progression (FFP) or overall survival (OS). Conclusion: Both R-CHOP-14 and R-CHOP-21 are probably equally effective in PMLBCL, yet further, prospective, randomized studies are warranted to clarify whether dose-dense regimens can be associated with better disease control and long-term results.

The clinical manifestations of Sickle Cell Disease (SCD) include episodes of vascular occlusion, chronic hemolytic anemia and frequent infections. GDF-15, a multifactorial cytokine, is a member of the transforming growth factor- superfamily. Expression of the GDF-15 gene in cardiomyocytes, vascular smooth muscle cells, and endothelial cells is strongly upregulated in response to oxidative stress, inflammation and tissue injury, while high levels of serum GDF-15 associate with ineffective erythropoiesis and may reflect a certain type of bone marrow stress or erythroblast apoptosis. In this context we aimed to evaluate GDF-15 levels in 89 patients with HbS/βthal at steady phase and in 20 apparently healthy individuals, and correlate with clinical features of the disease and markers of hemolysis, iron burden, inflammation, coagulation and endothelial dysfunction. We found that: GDF-15 levels were elevated in patients with HbS/βthal compared to controls (1980.7 ± 159.8 vs 665.4 ± 50.9 pg/mL, p

The “POWERFUL” multicenter, retrospective, and prospective study investigated the effectiveness of pomalidomide plus low-dose dexamethasone (POM/LoDex) therapy in relapsed/refractory multiple myeloma in routine care in Greece. Ninety-nine eligible adult patients treated with POM/LoDex according to the approved label after having received ≥2 prior therapies, including lenalidomide and bortezomib, were consecutively enrolled between 16 November 2017 and 21 February 2019 in 18 hematology departments. Fifty patients (50.5%) started POM/LoDex as third-line treatment. During the treatment period (median: 8.3 months, range: 0.3–47.6 months), the median POM dose was 4 mg/day, and 31.3% of the patients received additional antimyeloma agents. The overall response rate was 32.3%. During a median follow-up period of 13.8 months (Kaplan–Meier estimate), the median progression-free survival (PFS) was 10.5 months (95% CI: 7.4–14.4). The PFS was not significantly different between patients receiving POM/LoDex in the third versus later line of therapy, nor between patients receiving concomitant antimyeloma therapy versus POM/LoDEx doublet. During the prospective safety data collection period (median: 7.6 months) among patients with prospective follow-up (N = 75), POM-related adverse event incidence rate was 42.7% (serious: 18.7%, grade ≥ 3 hematological POM-related adverse events: 8.0%). Only neutropenia (13.3%) was reported at a frequency ≥10%. In conclusion, in this real-world study, POM/LoDex displayed a long PFS with no new safety signals emerging.

Transplant-ineligible relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL) patients represent an unmet medical need. Polatuzumab vedotin (Pola), an anti-CD79b antibody-drug-conjugate (ADG), with bendamustine- rituximab(BR) has recently gained approval for these patients, both in the USA and Europe, based on the GO29365 phase IIb trial. Real-life data with Pola are extremely limited. We report the outcomes of 61 Greek patients, who received Pola-(B)R mainly within a compassionate use program. Treatment was given for up to six 21-day cycles. Bendamustine was omitted in three cases due to previous short-lived responses. Fourty-nine rrDLBCL(efficacy cohort-EC) and 58 rr aggressive B-NHL (safety cohort-SC) patients received at least 1 Pola-BR cycle. Twenty-one (43%) patients of the EC responded with 12/49 (25%) CR and 9/49 (18%) PR as best response. Median progression-free survival, overall survival and duration of response were 4.0, 8.5, and 8.5 months respectively, while 55% of patients experienced a grade ≥3 adverse event, mainly hematologic. Treatment discontinuations and death during treatment were mainly due to disease progression. Twenty-two (41%) patients received further treatment; 11/22 are still alive, including one after CAR-T cells, and two after stem cell transplantation. Our data confirm that Pola-BR is a promising treatment for rrDLBCL patients, inducing an adequate response rate with acceptable toxicity. Pola-BR could be used as bridging therapy before further consolidative treatments.

End-of-treatment (EoT) PET/CT is used as a guide to omit radiotherapy (RT) patients with primary mediastinal large B-cell lymphoma (PMBCL). We present the mature and extended results of a retrospective study evaluating the prognostic significance of EoT-PET/CT after adequate response to R-CHOP. Among 231 consecutive PMLBCL patients, 182 underwent EoT-PET/CT and were evaluated according to the Deauville 5-point scale (D5PS) criteria. Freedom from progression (FFP) was measured from the time of PET/CT examination. Among 182 patients, 72 (40%) had D5PS score 1 (D5PSS-1), 33 (18%) had 2, 28 (15%) had 3, 29 (16%) had 4, and 20 (11%) had 5. The 5-year FFP was 97, 94, 92, 82, and 44% for D5PSS-1, D5PSS-2, D5PSS-3, D5PSS-4, and D5PSS-5, respectively. Among 105 patients with unequivocally negative PET/CT (D5PSS-1/D5PSS-2), 49 (47%) received RT (median dose 3420 cGy) and 56 (53%) did not with relapses in 0/49 vs. 4/56 patients (2 mediastinum and 2 isolated CNS relapses).The 5-year FFP for those who received RT or not was 100% versus 96%, when isolated CNS relapses were censored (p = 0.159). Among D5PSS-3 patients (27/28 irradiated-median dose 3600 cGy), the 5-year FFP was 92%. The 5-year FFP for D5PSS-4 and D5PSS-5 was 82 and 44%; 44/49 patients received RT (median dose 4000 and 4400 cGy for D5PSS-4 and D5PSS-5). Our study supports the omission of RT in a sizeable fraction of PET/CT-negative patients and definitely discourages salvage chemotherapy and ASCT in patients with PMLBCL who conventionally respond to R-CHOP, solely based on PET/CT positivity in the absence of documented progressive or multifocal disease. The persistence of positive PET/CT with D5PSS < 5 after consolidative RT should not trigger the initiation of further salvage chemotherapy in the absence of conventionally defined PD.

End-of-treatment (EoT) PET/CT is used as a guide to omit radiotherapy (RT) patients with primary mediastinal large B-cell lymphoma (PMBCL). We present the mature and extended results of a retrospective study evaluating the prognostic significance of EoT-PET/CT after adequate response to R-CHOP. Among 231 consecutive PMLBCL patients, 182 underwent EoT-PET/CT and were evaluated according to the Deauville 5-point scale (D5PS) criteria. Freedom from progression (FFP) was measured from the time of PET/CT examination. Among 182 patients, 72 (40%) had D5PS score 1 (D5PSS-1), 33 (18%) had 2, 28 (15%) had 3, 29 (16%) had 4, and 20 (11%) had 5. The 5-year FFP was 97, 94, 92, 82, and 44% for D5PSS-1, D5PSS-2, D5PSS-3, D5PSS-4, and D5PSS-5, respectively. Among 105 patients with unequivocally negative PET/CT (D5PSS-1/D5PSS-2), 49 (47%) received RT (median dose 3420 cGy) and 56 (53%) did not with relapses in 0/49 vs. 4/56 patients (2 mediastinum and 2 isolated CNS relapses).The 5-year FFP for those who received RT or not was 100% versus 96%, when isolated CNS relapses were censored (p = 0.159). Among D5PSS-3 patients (27/28 irradiated-median dose 3600 cGy), the 5-year FFP was 92%. The 5-year FFP for D5PSS-4 and D5PSS-5 was 82 and 44%; 44/49 patients received RT (median dose 4000 and 4400 cGy for D5PSS-4 and D5PSS-5). Our study supports the omission of RT in a sizeable fraction of PET/CT-negative patients and definitely discourages salvage chemotherapy and ASCT in patients with PMLBCL who conventionally respond to R-CHOP, solely based on PET/CT positivity in the absence of documented progressive or multifocal disease. The persistence of positive PET/CT with D5PSS5 after consolidative RT should not trigger the initiation of further salvage chemotherapy in the absence of conventionally defined PD.

Background R-CHOP can cure approximately 75% of patients with primary mediastinal large B-cell lymphoma (PMLBCL), but prognostic factors have not been sufficiently evaluated yet. R-da- EPOCH is potentially more effective but also more toxic than R-CHOP. Reliable prognostic classification is needed to guide treatment decisions. Materials and Methods We analyzed the impact of clinical prognostic factors on the outcome of 332 PMLBCL patients ≤65 years treated with R-CHOP ± radiotherapy in a multicenter setting in Greece and Cyprus. Results With a median follow-up of 69 months, 5-year freedom from progression (FFP) was 78% and 5-year lymphoma specific survival (LSS) was 89%. On multivariate analysis, extranodal involvement (E/IV) and lactate dehydrogenase (LDH) ≥2 times upper limit of normal (model A) were significantly associated with FFP; E/IV and bulky disease (model B) were associated with LSS. Both models performed better than the International Prognostic Index (IPI) and the age-adjusted IPI by Harrel's C rank parameter and Akaike information criterion. Both models A and B defined high-risk subgroups (13%–27% of patients [pts]) with approximately 19%–23% lymphoma-related mortality. They also defined subgroups composing approximately one-fourth or one-half of the patients, with 11% risk of failure and only 1% or 4% 5-year lymphoma-related mortality. Conclusion The combination of E/IV with either bulky disease or LDH ≥2 times upper limit of normal defined high-risk but not very-high-risk subgroups. More importantly, their absence defined subgroups comprising approximately one-fourth or one-half of the pts, with 11% risk of failure and minimal lymphoma-related mortality, who may not need more intensive treatment such as R-da-EPOCH. Implications for Practice By analyzing the impact of baseline clinical characteristics on outcomes of a large cohort of patients with primary mediastinal large B-cell lymphoma homogeneously treated with R-CHOP with or without radiotherapy, we developed novel prognostic indices which can aid in deciding which patients can be adequately treated with R-CHOP and do not need more intensive regimens such as R-da-EPOCH. The new indices consist of objectively determined characteristics (extranodal disease or stage IV, bulky disease, and markedly elevated serum lactate dehydrogenase), which are readily available from standard initial staging procedures and offer better discrimination compared with established risk scores (International Prognostic Index [IPI] and age-adjusted IPI).

BACKGROUND Levels of the angiogenic cytokines placental growth factor (PlGF) and soluble Fms-like tyrosine kinase-1 (sFlt-1) and the angiogenic balance, expressed by sFlt-1/PlGF ratio, are perturbed in sickle-cell disease and iron overload, but they have not been evaluated in non-transfusion-dependent thalassemia (NTDT). PATIENTS AND METHODS We measured levels of PlGF, sFlt-1 and vWF:antigen in patients with NTDT of beta-thalassemia genotype, and correlated them with erythrocytic indices and markers of iron overload, inflammation, and tissue hypoxia. Thirty-four NTDT patients with mean hemoglobin level of 8.4 g/dL were included in the study along with 20 apparently healthy individuals who served as controls. RESULTS Ferritin, LDH, and hs-CRP were higher in patients as compared to controls. We found significant differences between patients and controls in regard to levels of PlGF (52.2 vs 17.2 pg/mL, P

The clinical manifestations of Sickle Cell Disease (SCD) include episodes of vascular occlusion, chronic hemolytic anemia and frequent infections. GDF-15, a multifactorial cytokine, is a member of the transforming growth factor- superfamily. Expression of the GDF-15 gene in cardiomyocytes, vascular smooth muscle cells, and endothelial cells is strongly upregulated in response to oxidative stress, inflammation and tissue injury, while high levels of serum GDF-15 associate with ineffective erythropoiesis and may reflect a certain type of bone marrow stress or erythroblast apoptosis. In this context we aimed to evaluate GDF-15 levels in 89 patients with HbS/β

No reliable biomarker exists to predict responsiveness to intravenous (IV) iron (Fe) in iron deficient patients with CKD. We aimed to investigate the clinical value of bioactive Hepcidin-25 and soluble Transferrin Receptor (sTfR) levels in predialysis patients.In this prospective study 78 stable stage III-IV CKD predialysis patients with (responders) (40 patients) and without (non-responders) (38 patients) adequate erythropoiesis after IV administration of ferric-carboxymaltose (FCM). Patients were divided in two groups according to their response to IV administration of ferric-carboxymaltose (FCM). Along with measurements of common hematologic and blood chemistry parameters, determinations of sTfR and bioactive Hepcidin-25 were performed.Hepcidin-25 levels were lower in the responders (p=0.025), while sTfR and sTfR/Hepcidin-25 ratio were higher (p0.01 and p=0.002 respectively). Diagnostic efficacy indicated cut off point of 1.49 for Hepcidin-25 had sensitivity 84% and specificity 48%, while cut off point of 1.21 for sTfR/Hepcidin-25 ratio had sensitivity 82% and specificity 52% to predict correctly response to iron supplementation therapy. Furthermore, log sTfR/Hepcidin-25 correlated negatively with hs-CRP (p=0.005) and IL-6 (p0.04) in non-responders, while such correlations were not found in responders (p0.05).These results suggest that lower Hepcidin-25, as well as higher sTfR and sTfR/Hepcidin-25 ratio were significant predictors of favorable hemoglobin response within a month after IV administration of FCM in patients with CKD. Further experiments and clinical studies in other groups of patients are needed to better elucidate the role of Hepcidin-25 and sTfR/Hepcidin-25 ratio as predictors of response to intravenous iron administration.

Background: Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by pathological polymerization of hemoglobin, increased red cell rigidity and poor microvascular blood flow with consequent tissue ischemia and infarction. Thus, hemolytic anemia, vaso-occlusion and vasculopathy are the hallmarks of its clinical presentation. The transferrin receptor (TfR) mediates the transport of iron into cells and the circulating TfR can be measured as soluble transferrin receptor (sTfR). sTfR levels are frequently used to establish the diagnosis of iron deficiency anemia, especially in the context of inflammation, but they also reflect bone marrow erythropoietic activity (BMA) and mass. Erythropoietic activity has been found to be the most important determinant of sTfR levels. In this context, we aimed to study and evaluate bone marrow activity in patients with compound heterozygous HbS and beta-thalassemia (HbS/βthal) based in sTfR measurements and explore possible correlations with of key features of the disease such as: the hemolytic component, vaso-occlusive crises (VOC), acute chest syndrome, venous thrombosis, arterial thrombosis including stroke, avascular necrosis, pulmonary hypertension, hydroxyurea therapy, inflammation and renal injury. along with other biomarkers of erythropoiesis and iron metabolism such as Placental Growth Factor (PlGF), Growth Differentiation Factor-15 (GDF-15), Ferritin and Hepcidin-25. Patients and Methods: Ninety adult Caucasian patients with HbS/βthal [49 patients under hydroxyurea (HU+) treatment and 41 patients without hydroxyurea (HU-) treatment], were included in this study, while 22 apparently healthy individuals of similar age and gender served as controls. None of the patients has received any transfusions at least 6-monthes before enrollment in the study. Along with hematologic and blood chemistry parameters determination, levels of circulating sTfR, PlGF, GDF-15 and Hepcidin-25 were measured in patients with HbS/βthal and controls using RUO and IVD immunoenzymatic techniques. BMA activity was calculated from the established formula: patient-sTFR/meanControl-sTFR. Results: We found that: sTfR levels were markedly elevated in all patients with HbS/βthal compared to controls (4.8±2.2 vs. 1.0±0.2 mg/L, p0.434). BMA correlated significantly with the markers of the erythropoietic and hemolytic component such as: Hemoglobin (r=-0.434, p0.351 and r=-0.043, p>0.710, respectively), but a negative correlation was found between BMA and Hepcidin-25/Ferritin ratio, (r=-0.330, p=0.005). Conclusions: Our findings demonstrate that all patients with HbS/βthal studied have a significantly increased degree of erythroid BMA as assessed by measurements of sTfR levels. Erythroid BMA correlated significantly with Hepcidin/Ferritin ratio, which is an index of the degree of Hepcidin expression relative to iron overload. The correlation of erythroid BMA with Hb A levels, indicate the important role of βthal genotype in HbS/βthal disease. Furthermore, BMA is not related to hydroxyurea therapy and/or iron metabolism parameters in these patients. This implicates a likely complex action of hydroxyurea, which causes intermittent cytotoxic suppression of erythroid progenitors and cell stress signaling. The latter affects erythropoiesis, leading to recruitment of erythroid progenitors with increased HbF levels, although the number of erythroid progenitors -the main source of sTfR- remains stable. Disclosures Voskaridou: Genesis: Consultancy, Research Funding; Protagonist: Research Funding; Celgene Corporation: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees.

Fc-γ RIIA (CD32), a member of the family of Fc-γ receptors, participates in the phagocytosis of bound to antibody antigens. The effectiveness of this function varies for its several haplotypes, and it participates in the pathogenesis of viral infections, according to recent studies. The genetic locus of Fc-γ RIIA consists of two allelic genes: 131-Arg (R131) and 131-His (H131). Our aim was to correlate Fc-γ RIIA polymorphisms, by studying the prevalence of each allele using PCR-RFLPs (polymerase chain reaction-restriction fragment length polymorphisms), with latent Epstein-Barr virus (EBV) infection and the expression of latent membrane protein 1 (LMP1) in 40 patients with leukemic low grade B-cell lymphomas. R131 was found in 84.2% of EBV-positive patients, but only in 28.5% of EBV-negative patients (p = 0.001). A similar correlation was found for R131 and LMP1 expression (84.6% vs. 28.5%) (p = 0.002). Our results support the hypothesis that Fc-γ RIIA polymorphisms are a genetic risk factor for latent EBV infection and the expression of its oncogenic latency proteins.

Learning Objectives After completing this course, the reader will be able to: Describe the effect of the addition of rituximab to standard CHOP chemotherapy on the outcome of patients with primary mediastinal large B-cell lymphoma.Explain potential changes in the use of radiotherapy and aggressive chemotherapy in the rituximab era. This article is available for continuing medical education credit at CME.TheOncologist.com More aggressive treatment approaches (methotrexate, cytarabine, cyclophosphamide, vincristine, prednisone, and bleomycin [the MACOP-B regimen] or consolidation with high-dose therapy and autologous stem cell transplantation) have been considered to be superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with primary mediastinal large B-cell lymphoma (PMLBCL). Rituximab-CHOP (R-CHOP) is the standard of care for diffuse large B-cell lymphoma, whereas efficacy in PMLBCL has not been adequately confirmed. Patient and Methods. Seventy-six consecutive PMLBCL patients who received R-CHOP with or without radiotherapy (RT) were compared with 45 consecutive historical controls treated with CHOP with or without RT. Baseline characteristics of the two groups were balanced. Results. The rate of early treatment failure was much lower with R-CHOP with or without RT (9% versus 30%; p = .004). The 5-year freedom from progression rate after R-CHOP with or without RT was 81%, versus 48% for CHOP with or without RT (p < .0001). The 5-year event-free survival rates were 80% and 47% (p < .0001) and the 5-year overall and lymphoma-specific survival rates were 89% and 69% (p = .003) and 91% and 69% (p = .001), respectively, with only seven of 76 lymphoma-related deaths. Among R-CHOP responders, 52 of 68 received RT. Conclusions. Based on these results, most patients with PMLBCL appear to be cured by R-CHOP in 21-day cycles with or without RT, which could be the current standard of care. Therefore, the need for more aggressive treatment strategies is questionable unless high-risk patients are adequately defined. Further studies are required to establish the precise role of RT.

Background: The complex pathophysiology of Sickle Cell Disease (SCD) makes unlikely that a single therapeutic agent will prevent or reverse all SCD complications. Metabolomic analysis might help in the characterization of the endogenous and exogenous effects of potential new treatments. Metabolites are small molecules that are chemically transformed during metabolism and provide a functional readout of cellular state. Metabolites serve as direct signatures of biochemical activity and are therefore easier to correlate with phenotype. The metabolome is typically defined as the collection of small molecules produced by cells and offers a window for investigating how mechanistic biochemistry relates to cellular phenotype. There are very few reports associated with SCD providing comprehensive measurements of metabolites present in blood. Low arginine bioavailability has been associated with a clinical phenotype of increased hemolytic rate, pulmonary hypertension risk and early mortality. Recently, the FDA approved the use of L-glutamine for the treatment of adults and children with SCD, on the basis of the results of randomized phase 3 clinical trials1, while L-arginine's involvement is under investigation2,3. In this context we aimed to quantify targeted metabolites' abnormalities in patients with Sickle Cell/beta thalassemia (HbS/βThal), to identify pathways that might be of interest to prevent disease complications. Patients and Methods: Thirty adult Caucasian patients with HbS/βThal aged 45.6±10.9y, (43% male), at steady-state were enrolled in the study, while 20 age-matched healthy individuals (45% male) served as controls. Along with measurements of hematologic and blood chemistry parameters, targeted metabolome analyses for 13 aminoacids and 2 aminoacid's derivatives were performed after extraction from dry blood spots (DBSs) on filter paper using LC/MS/MS, with derivatization (AB SCIEX 5500 triple quadrupole QTRAP® LC/MS/MS Systems, Framingham, MA, USA). Results: Multiple metabolite differences are identified in HbS/βThal vs. Controls (Figure1). From metabolites involved in the biosynthesis of glutathione, only L-glutamine's levels were lower in patients with HbS/βThal compared to controls, while 5-oxyproline levels, a catabolic product of glutathione metabolism, were markedly increased in patients with HbS/βThal compared to controls. Urea cycle amino acids, also involved in the production of nitric oxide, L-arginine and L-ornithine concentrations were significantly lower in patients with HbS/βThal compared to controls, with a trend towards lower L-citrulline in patients with HbS/βThal p=0.06). Finally, amino acids involved in catecholamines (dopamine, nor-epinephrine and epinephrine) biosynthesis, such as L-phenylalanine and L-tyrosine and its metabolite succinylacetone levels were significantly lower in patients with HbS/βThal compared to controls. No significant correlations were found between any metabolites and markers of hemolysis, HbF levels or iron burden. Conclusions: This study confirms prior observations concerning aberrations in multiple blood specific amino acid levels in patients with SCD compared to controls, but this is the first report on Caucasian patients with HbS/βThal and on whole blood from DBS. We also identified for the first time in Caucasian patients with HbS/βThal important metabolic abnormalities of glutathione and nitric oxide biosynthesis pathways associated with altered concentrations of the metabolites serving of substrates in these cycles. Importantly, we also demonstrate low levels of L-phenylanine and L-tyrosine, which are essential sources for multiple neurotransmitters biosynthesis and neurobehavioral health. The latter novel observation should be confirmed in larger studies, while measurements of urinary amino acid clearances are necessary to evaluate for potential etiologies of the deficiencies through urinary losses vs. low substrate availability, increased utilization or abnormal metabolism. Patients with SCD are in a precarious state with respect to many amino acid deficiencies, all of which may have clinical consequences warranting further investigation. 1N Engl J Med. 2018 Jul 19;379(3):226-235. 2Anesth Analg. 2017 Apr;124(4):1369-1370. 3Haematologica. 2013 Sep;98(9):1375-82. Figure 1. Figure 1. Disclosures Morris: Pfizer: Consultancy; Calithera: Consultancy; MAST Therapeutics: Research Funding; UCSF-Benioff Children's Hospital Oakland: Patents & Royalties: For nutritional supplement licensed to Lifetrients; FDA: Research Funding; NIH/NHLBI: Research Funding. Voskaridou:Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding.

This report describes four unrelated Greek patients (one child and three adults) who all had an atypical thalassemia intermedia phenotype, characterized by chronic moderate anemia with mild hemolysis in some cases, and the absence of abnormal hemoglobin (Hb) fractions. DNA analysis identified the inheritance of common alpha(+)-thalassemia (alpha(+)-thal) mutations in trans to an in-frame 3 bp deletion at codons 38/39 (-ACC) on the alpha1-globin gene, previously described as Hb Taybe. Hematological findings in the parents of three of the Hb Taybe carrier cases, together with a fourth unrelated carrier, are also presented. These cases represent the first observation of Hb Taybe in the Greek population, as to date, it has only been observed in Israeli-Arab families. With the exception of one patient and his mother who both originate from Corfu, all our cases come from the Greek island of Crete.

INTRODUCTION Thalidomide is an oral agent with significant activity in one-third of patients with refractory myeloma. However, long-term continuous administration of thalidomide can be associated with significant side effects such as deep-vein thrombosis and peripheral neuropathy. Furthermore, it is not clear whether continuous administration of thalidomide is necessary for its antimyeloma effect. We performed a phase II study with a combination that was based on the intermittent administration of thalidomide. MATERIALS AND METHODS A total of 53 patients with previously treated myeloma received cyclophosphamide 150 mg/m(2) p.o. every 12 h before meals on days 1-5, thalidomide 400 mg p.o. in the evening on days 1-5 and 14-18 and dexamethasone 20 mg/m(2) in the morning after breakfast on days 1-5 and 14-18 (CTD). The CTD combination was repeated every 28 days for three courses. Subsequently, responding patients were scheduled to receive maintenance treatment with monthly courses of CTD administered only for the first five days of each month. RESULTS On an intention-to-treat basis, 32 patients (60%) achieved a partial response with a median time to response of 1.5 months. Among the 43 thalidomide-naive patients, 67% responded. Toxicities were mild or moderate and the cumulative incidence of deep-vein thrombosis and peripheral neuropathy was 4 and 2%, respectively. The median time to progression for responding patients was 12 months and the median overall survival for all patients was 17.5 months. CONCLUSION The oral, outpatient pulsed CTD regimen is associated with significant activity in patients with previously treated multiple myeloma. The incidence of deep-vein thrombosis and peripheral neuropathy appears to be lower than expected when thalidomide is being administered on a continuous basis.

Pomalidomide with low dose dexamethasone (Pd) is a standard treatment for patients who have failed both lenalidomide (Len) & bortezomib (Bor). Phase III studies showed that Pd is active irrespective of the number of prior therapies and whether Len or Bor were the last therapies prior to Pd. However, it remains unclear what is the activity of Pd when administered immediately after refractoriness to Len or when is administered following secondary resistance. Furthermore, the importance of the time elapsed from the administration of Len to Pd has not been explored. We analyzed the outcomes of 116 consecutive patients with MM after failure of both Len & Bor that were treated in the Department of Clinical Therapeutics, National and Kapodistrian University of Athens, and who all received pomalidomide 4 mg with weekly dexamethasone. Median age was 62 years (range 38-86 years); median number of prior treatments was 4 (range 1-9), 58% had received ASCT, 73% were refractory to the last Bor-based regimen and 90% were refractory to the last Len-based regimen. All patients had MM refractory to the last regimen, but 40% had ≥PR to their most recent regimen prior to development of refractoriness. The last regimen prior to Pd included Bor in 62 (53%), Len in 35 (30%) and conventional chemo in 19 (17%). On intent to treat, 34 (29%) patients achieved ≥PR (CR: 3%, VGPR: 7%, PR: 19%). In those which received Len just prior to Pd, ≥PR rate was 26% vs 33% for Bor and 21% for other regimens (p=0.55). Among patients with Median follow up was 29 months and 95 (83%) patients have progressed or died. Median PFS was 5.2 months (95% CI 3.8-6.5). Patients who received Len as their last treatment before Pd had PFS similar to that of patients who received either Bor or other regimens (p=0.8). Patients who had ≥PR when treated with Len immediately before Pd (secondary resistant to Len), had PFS similar to that of those with In conclusion, Pd is active in MM patients refractory to Len, independently of primary or secondary resistance to Len or if Len was used just prior to Pd. However, patients with ≥18 months of Len-free interval may have longer PFS and OS irrespectively of prior lines of therapy. These data indicate the potential role of "clonal tides" and the emergence of IMiD-sensitive clones after "IMiD-free" periods, but further investigation is needed to identify optimal treatment strategy. Disclosures Dimopoulos: Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Delimpasi:Genesis: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Terpos:Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; BMS: Consultancy, Honoraria; Novartis: Honoraria; Celgene: Honoraria. Kastritis:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genesis: Consultancy, Honoraria.

Background: The clinical manifestations of Sickle Cell Disease (SCD) include episodes of vascular occlusion, chronic hemolytic anemia and frequent infections. SCD is also characterized by the presence of chronic inflammation manifested by leukocytosis and monocytosis and increased circulating levels of pro-inflammatory cytokines and chemokines. Growth Differentiation Factor-15 (GDF-15), also known as macrophage inhibitory cytokine 1 (MIC-1) or non-steroidal anti-inflammatory drug-activated gene (NAG-1) is a member of the transforming growth factor- superfamily. Expression of the GDF-15 gene in cardiomyocytes, vascular smooth muscle cells, and endothelial cells is strongly upregulated in response to oxidative stress, inflammation and tissue injury. Recently, GDF-15 and Twisted Gastrulation Protein (TWSG1) have been proposed to be erythroblast-derived factors, although not erythroblast specific, that mediate Hepcidin-25 suppression under conditions of increased erythropoietic activity. High levels of GDF15 associate with ineffective erythropoiesis and may reflect a certain type of bone marrow stress or erythroblast apoptosis. However, the role of GDF15 in Hepcidin-25 regulation under physiologic conditions and in other disorders is unclear and has been debated. Aims: The aim of this study was to evaluate the GDF-15 levels in patients with compound heterozygous HbS and beta-thalassemia (HbS/βthal) and to explore possible associations with disease features, such as Hepcidin-25 production, hemolysis, inflammation, endothelial dysfunction and angiogenesis. Methods: Seventy-five adult Caucasian patients with HbS/βthal were included in the study, while 20 healthy individuals served as controls. Patients with HbS/βthal divided in two groups: group A included 36 patients under hydroxycarbamide (HC+) treatment and group B included 39 patients without hydroxycarbamide (HC-) treatment. Along with hematology and blood chemistry parameters determination, measurements of circulating levels of GDF-15, hepcidin-25, hs-CRP, vWF-antigen, hs-TnT and Placental Growth Factor (PlGF) were performed in both patients with HbS/βthaland controls using immunoenzymatic techniques. Results: The main results of the study included: GDF-15 levels were elevated in patients with HbS/βthal compared to controls ((1,980.7±159.8 vs 665.4±50.9 pg/mL, p Conclusions: These findings demonstrate a multifactorial role of GDF-15 in patients with HbS/βthal as it correlates with erythropoiesis, hemolysis, endothelial dysfunction and angiogenesis. However, we found no direct specific function, despite the negative correlation with Hepcidin-25/Ferritin molar ratio. Interestingly, the higher GDF-15 levels measured in patients treated with hydroxycarbamide may reflect possible drug induced sub-clinical cardiotoxicity, although this has not been described to-date. To this end, our knowledge is restricted only to doxorubicin-induced cardiotoxicity, where GDF-15 up-regulation seems to be more sensitive than that of hs-TnT, LDH and NT-proBNP. Further studies will reveal the role of GDF-15 in the biology of HbS/βthal. Disclosures Ostland: Intrinsic LifeScienc s: Employment, Equity Ownership. Westerman:Intrinsic LifeSciences: Employment, Equity Ownership. Terpos:Genesis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria.

A case of adult osteopetrosis Type I was diagnosed in a 22-year-old female. She presented for investigation of anaemia with 'myelophthisic' characteristics and extramedullary haemopoiesis which was resistant to haematinics, nandrolone and low-dose corticosteroids. She became progressively transfusion-dependent with gradually worsening thrombocytopenia. She was successfully treated with recombinant erythropoietin. Anaemia as well as thrombocytopenia were corrected. There appeared to be a synergistic action of erythropoietin with steroids.

In the present study we report our results on the efficacy of Fludarabine monophosphate in 20 B-chronic lymphocytic leukemia (CLL) patients, refractory to conventional chemotherapy. Of the 20 patients 14 were males and 6 females with a median age of 58 years (44-70). Eight had Binet stage B and 12 stage C. They were previously treated with chlorambucil, prednisone, mini-CHOP or irradiation. Their disease duration prior to fludarabine administration was 49 months (7-180). Fludarabine was given at a dose of 25 mg/m2 daily, for five consecutive days, monthly for six months and if responding for six additional months. Treatment was administered on an outpatient basis. Complete response (CR) was observed in 7 patients (33%) and partial remission (PR) in 5 (25%). Of the complete responders 5 were males and 2 females with a median age of 60 years (range 55-68); three of them had stage B and 4 stage C disease; the median number of fludarabine courses for achieving CR was 3 (range 2-5). In all CR patients a residual monoclonal CD5/CD19 positive lymphocyte population was found in the peripheral blood. All CRs relapsed shortly after discontinuation of therapy within 12 months. The main toxicity observed was upper respiratory tract and/or pulmonary infections in 8 patients, requiring hospitalization. Among the CRs one patient died during the administration of the third course of therapy, due to a severe hypersensitivity reaction with Stevens-Johnson syndrome. The importance of maintenance therapy is also stressed as PR was sustained in some patients using 3 day cycles every 2-4 months. One patient was maintained in this fashion for 60 + months. This study showed that fludarabine is effective in CLL patients refractory to conventional chemotherapy thus it may be given as the treatment of choice if such patients still require treatment.

Background: No reliable biomarker exists to predict responsiveness to intravenous (IV) iron (Fe) in iron deficient patients with chronic kidney disease (CKD). Our aim was to investigate if Hepcidin-25 (Hepc25) and soluble Transferrin Receptor (sTfR) and their Ratio sTfR/Hepc25 ratio prior to treatment can make a distinction between those predialysis patients with and those without adequate erythropoiesis after administration of IV ferric carboxymaltose (FCM). Patients and methods: In this prospective study we enrolled 78 stable stage III-IV CKD patients with iron deficiency (serum ferritin levels lower than 100µg/L) treated with IV FCM 1000mg/100ml NaCl-0.9% and infused over a period of 20min. Patients were divided in two groups according to hemoglobin (Hb) increase within a month after treatment. The responders (Group R, n=40), showed above 1g/dL increase in Hb concentration. The non-responders (Group NR, n=38) had no such a favorable reaction. Patient data, clinical information and blood samples were collected prior to IV iron administration. Hematologic analysis was performed using a hematogy analyzer. Blood chemistry, including measurements of renal, nutrition and inflammation markers along with measurements of Hepc25, IL-6 and sTfR were performed using appropriate techniques. Receiver Operating Curve (ROC) analysis was applied in order to evaluate the diagnostic potential of Hepc25 and sTfR/Hepc25 ratio and conclusions about the specificity and sensitivity were drawn. Results: As shown in Table 1, there were no significant differences at baseline between responders and non-responders in demographic and clinical parameters. No significant differences were revealed for serum creatinine, e-GFR, folic acid (FA), vitamin B12, hs-CRP and IL-6, with the notable exception of ferritin and Hepc25 levels that were lower and sTfR and sTfR/Hepc25 ratio that were higher in the responders as compared to non-responders (Table 1). Diagnostic efficacy was analyzed by ROC analysis. Cut off point of 1.49 for Hepc25 had sensitivity 84% and specificity 48%, and cut off point of 1.21 for sTfR/Hepc25 ratio had sensitivity 82% and specificity 52% to predict correctly response to Fe therapy (Table 2). Conclusions: These results suggest that lower Hepc25 and ferritin levels, as well as higher sTfR and sTfR/Hepc25 ratio were significant predictors of favorable hemoglobin response within a month after IV administration of FCM in CKD patients. Further in vitro and in vivo experiments and clinical studies in a larger population of patients are needed to better elucidate the role of Hepc25 and sTfR/Hepc25 ratio in iron deficiency anemia in CKD. Table 1. Demographic, clinical and biochemical parameters in responders vs non-responders. Group R (n=40 Group NR (n=38) Age (years) 72.7±11.2 74.5±10.3 NS Gender (M /F) 27:13 25:13 NS Medications -RAS inhibitors 21(27%) 19(24%) NS rh EPO 1(27%) 20(26%) NS CCB 10(13%) ) 11(14% NS BMI (Κg/m2) 25.5±3.3 25.1±3.4 NS Comorbidities -Cardiovascular Disease 17(22%) 15(19%) NS -Μechanical valve heart 2(2%) 2(2%) NS -Diabetes Mellitus 20(26%) 17(22%) NS -Polycystic Kidney Disease 2(1%) 1(1%) NS Hemoglobin (g/dL) 10.9±1.6 11.1±1.3 NS Creatinine (mg/dL) 2.4±1.1 2.5±1.1 NS eGFR(mL/min/1.73 m2) 35.2±16.9 30.0±13.4 NS B12 (pg/mL) 512.0±369.0 655.0±414.0 NS hs-CRP (mg/L) 3.9±5.9 3.7± 4.9 NS IL-6 (pg/mL) 6.2±5.3 5.78±4.5 NS sTfR (mg/L) 2.27±0.99 1.76±0.76 0.014 Log (1+Hepc25) 0.552±0.343 0.728±0.348 0.027 sTfR/Hepc25 1.91±1.53 0.80±0.72 0.002 Table 2. Sensitivity and specificity of Hepcidin and sTfR/H as predictors of responsiveness to IV FCM AUC 95%C.I. P-value Cut-off Point Sensitivity Specificity Hepc25 0.648 0.52-0.77 0.025 1.49 84% 48% sTfR/Hepc25 0.680 0.56-0.80 0.006 1.21 82% 52% Disclosures No relevant conflicts of interest to declare.

We present a cohort of 22 patients with type 2 dendritic cell (DC2) acute leukemia (or blastic plasmacytoid dendritic cell neoplasm-BPDCN, as it has been recently named), diagnosed in Greece over the past 12-year period, according to the main clinical and immunophenotypic features of this entity. Four additional cases are discussed, classified as leukemia of ambiguous lineage (LAL), because of the simultaneous detection of a CD56 negative DC2 population and of a second myeloid precursor cell population. The morphological features and cytogenetic findings of the typical BPDCN cases were similar to those previously described. Acute lymphoblastic leukemia-type chemotherapeutic regimens were more efficient in controlling the disease. Immunophenotyping of typical BPDCN cases revealed CD4(+), CD56(+), HLA-DR(+) and CD123(bright) neoplastic cells, in the absence of major B-, T- and myeloid-associated markers, while the phenotype of the four cases characterized as LAL highlights the risk of misdiagnosis. Based on our experience, we propose a flow cytometric algorithmic approach for the distinction of typical BPDCN from certain types of acute myeloid leukemia, but also for the identification of acute myeloid leukemia, admixed with CD56 negative DC2 cells, which could be misdiagnosed as BPDCN.

Background and Aims: Neutrophil gelatinase-associated lipocalin (NGAL) is a protein belonging to the lipocalin superfamily initially found in activated neutrophils, in accordance with its role as an innate antibacterial factor. However, it subsequently was shown that many other types of cells, including in the kidney tubule, may produce NGAL in response to various injuries. The increase in NGAL production and release from tubular cells after harmful stimuli of various kinds may have self-defensive intent based on the activation of specific iron-dependent pathways, which in all probability also represent the mechanism through which NGAL promotes kidney growth and differentiation. NGAL levels clearly correlate with severity of renal impairment, probably expressing the degree of active damage underlying the chronic condition. For all these reasons, NGAL may become one of the most promising next-generation biomarkers in clinical nephrology and beyond. We aimed to investigate the clinical significance of NGAL levels and its correlation with renal function in patients with hemoglobinopathies. Patients and Methods: 117 adult patients with hemoglobinopathies were included in the study divided in 3 groups. Group A: 30 patients with transfusion-dependent thalassemia major (TM); Group B: 29 patients with Non-Transfusion-Dependent Thalassemia (TI) and Group C: 58 patients with HbS/βthal disease, while 20 apparently healthy individuals served as controls (Group D). In patients and controls along with standard blood and urine chemistry. Measurements of serum Cystatin C and NGAL were performed by means of immunonephelometric and immunoenzymatic techniques, (Siemens Healthcare Diagnostics, Liederbach, Germany and R&D Systems, Minneapolis, MN, USA), respectively. Estimated Glomerular Filtration Rate (eGFR) values were calculated with an unadjusted for body surface Cystatin C based equation: eGFR (mL/min)=77.24(Cys C)-1.2623. Results: The main results of the study showed that: a) NGAL levels were significantly higher in all the groups of patients compared to controls: Group A 95.0±45.0µg/L, Group B 139.1±86.1µg/L, Group C 117.8±37.3µg/L vs Group D 50.3±11.3µg/L (p0.300), c) NGAL levels and eGFR values (Group A: 96.9±39.8, Group B: 117.0±26.0, Group C: 86.2±27.8 and group D: 109.6±15.0mL/min, respectively) correlated significantly in patients of Group A and Group C (r=-0.739, p Conclusions: These findings illustrate the tubular-glomerular activation feedback mirrored by NGAL in patients with transfusion-dependent thalassemia major and HbS/βthal disease, who suffer from renal injuries, indicating that tubular damage precedes GFR reduction. Upregulation of NGAL in patients with non-transfusion-dependent thalassemia independently of renal injuries may reflect the compensatory, protective role of NGAL in response to diverse cellular stresses, including inflammation and oxidative stress. However, recent reports have implicated NGAL upregulation as a mechanism that contributes to anemia in the setting of chronic low grade inflammation. In experimental models, systemic and medullary NGAL has been demonstrated to induce inhibition of erythropoiesis through induction of apoptosis and arrest of differentiation of erythroid progenitor cells. Disclosures No relevant conflicts of interest to declare.

Chronic lymphocytic leukaemia and low-grade non-Hodgkin’s lymphomas are diseases for which until recently no treatment leading to long lasting complete remission or cure existed. Fludarabine monophosphate, a purine analogue, was recently introduced into clinical trials for chronic lymphocytic leukaemia and low-grade non-Hodgkin’s lymphomas and found to be very effective. In this report we review the available data relating to fludarabine monophosphate and present our experience with fludarabine administration in refractory B-chronic lymphocytic leukaemia and low-grade lymphocytic lymphoma in Athens and Jerusalem.

Abstract 5212 Background: In all Epstein-Barr (EBV)-associated malignancies, the virus displays a latency program of infection and a restricted pattern of gene expression. Among the products of these genes, latent membrane protein 1 (LMP1) is a potent transforming protein with several different roles. LMP1 has been shown in cell lines to stimulate apoptosis. Survivin, a member of the inhibitor of apoptosis (IAP) family, is an important regulator of the mitochondrial apoptotic pathway, while oxidative stress (OS) is a cellular condition particularly relevant to cell aging. In the present study we enrolled patients with non-EBV-related low grade B-cell lymphoproliferative diseases. The aim was to detect (1) the viral load of EBV-positive patients, (2) the expression of LMP1 oncoprotein, (3) the possible apoptotic properties of LMP1 by correlating the levels of survivin with LMP1 expression, and (4) the levels of oxidative stress in LMP1-positive and negative patients. Patients and Methods: Forty eight Greek patients with EBV-unrelated low grade B-cell leukemic lymphomas, were enrolled in the study (chronic lymphocytic leukemia: 27, marginal zone lymphoma: 12, mantle cell lymphoma: 4, hairy cell leukemia: 2, follicular lymphoma: 2, lymphoplasmacytic lymphoma: 1). The majority of patients (61.2%) were treatment-naïve, while the rest had not received any treatment for at least 6 months. DNA from peripheral blood was tested by quantitative real time (qRT) PCR for the EBV-R gene. RNA from EBV-positive patients was examined by RT-PCR and qRT PCR for LMP-1, while using qRT PCR we measured survivin expression in all patients. Densitometric analysis (DA) was used for semi-quantification of the survivin gene expression. The results were expressed relative to the expression of ABL housekeeping gene. The control group included 30 EBV-negative healthy adults. Oxidative stress was measured in the serum of all patients using the PerOx (TOS/TOC) Kit, by Immunodiagnostik. Non parametric methods (Mann-Whitney test) were used for statistical analysis of the results. Results: Twenty five (25) men and 23 women, with a median age of 74 (51–87 years old) were studied. EBV positivity was detected in 19/48 (39.6%) patients, and LMP1 was expressed in 13/19 (68.4%) EBV-positive patients. Survivin levels were lower in LMP1-positive patients vs LMP1-negative patients (2-tailed p=0.009). The oxidative stress was lower (261.4 μmol/L) in LMP1-positive patients vs LMP1-negative patients (372.3 μmol/L), (2-tailed p=0.014). Discussion: The literature lacks information about the expression of LMP1 in the peripheral blood of patients with non-EBV-related low grade B-cell leukemic lymphomas. Previous studies in LMP1-positive lymphoma cell lines have shown the apoptotic functions of LMP1 during type II latency. In this study LMP1-positive patients express statistically significant lower levels of survivin vs LMP1-negative patients. This finding is in accordance to the hypothesis that LMP1 oncoprotein can induce apoptosis. LMP1-positive patients had lower levels of oxidative stress compared to LMP1-negative patients. According to our findings, in non-EBV-related lymphomas, LMP1 may increase apoptosis and decrease the levels of oxidative stress. Disclosures: No relevant conflicts of interest to declare.

Background: MACOP-B or even chemotherapy (CT) with consolidation high dose therapy with autologous stem cell support (HDT-ASCT) have been considered superior to CHOP in PMLBCL. However, in the absence of randomized trials, there is no established optimal treatment for these patients. The role of R-CHOP in PMLBCL, which usually affects young patients, has not been established. Aims: To evaluate the efficacy of R-CHOP±RT in PMLBCL and to compare this approach with CHOP±RT administered to historical controls. Patients and Methods: Between 1994 and 2006, 74 patients with PMLBCL were treated in 6 participating centers. R-CHOP displaced CHOP in the treatment of PMLBCL at a given timepoint in each center. Thus 31 consecutive patients who received R-CHOP, were compared with 43 consecutive historical controls, who had been treated with CHOP prior to that point. Results: The median age of the patients was 30 years (17–82), only 2 patients (3%) were older than 60 years, and 47/74 (64%) were females. All individual IPI parameters as well as B-symptoms were also balanced between the two groups, with the exception of performance status. The median follow-up of currently alive patients was 28 and 73 months for patients treated with R-CHOP±RT and CHOP±RT respectively, the complete response (CR/CRu) rate was 97% vs 67% (p=0.002), and the overall response rate was 100% vs 79%, respectively (p=0.007). All relapses after CHOP occurred within 22 months from diagnosis. The 3-year failure free survival (FFS) was 93±5% vs 53±8% for patients who received R-CHOP±RT vs CHOP±RT (p=0.0006). Within the subgroup of patients with L/LI risk IPI, the corresponding 3-year FFS rates were 95±5% vs 58±10% (p=0.007), while they were 90±9% vs 45±12% (p=0.03) among patients with HI/H risk IPI. The 3-year event free survival (EFS) for all patients was 90±5% vs 51±8% (p=0.001). The 3-year overall survival (OS) was 97±3% vs 67±7% (p=0.008), while the 3-year lymphoma specific survival (LSS) was 100% vs 67±7% (p=0.002). Conclusions: R-CHOP and RT provided impressive results with no cases of primary refractory disease, no lymphoma-related deaths and only 2 failures recorded so far after a median follow-up of 28 months among 31 patients. Patients treated with R-CHOP had significantly higher CR, FFS, EFS, OS, and LSS rates, when compared with CHOP-treated historical controls. Based on these results we continue to treat PMLBCL patients with R-CHOP and RT, avoiding more intensive strategies. Further studies are warranted to investigate whether RT is needed after R-CHOP, especially in the case of a negative post-chemotherapy PET-scan.

Interactions between myeloma (MM) cells and marrow microenvironment are crucial for myeloma growth and resistance to anti-myeloma therapy. Bortezomib (VELCADE®; V) and thalidomide (T) have proven anti-MM effect and exert their action partly through perturbation of the MM microenvironment. Furthermore, bortezomib enhances the cytotoxic potential of other agents, such as melphalan (M), and dexamethasone (D) in resistant cell lines. We hypothesize that combining VT (to target both MM cells and microenvironment) with M and D may help overcome resistance and increase clinical efficacy of these agents in relapsed/refractory disease. The aim of this phase II study was to determine the efficacy and safety of the VMDT regimen and its effect on angiogenesis and bone remodeling in relapsed/refractory MM. Bortezomib (1.0 mg/m2) was given iv, on days 1, 4, 8, and 11; oral melphalan (0.15 mg/kg) was administered on days 1–4, while thalidomide (100 mg/day) and dexamethasone (12 mg/m2) were given on days 1–4 and 17–20 of a 28-day cycle, for 4 cycles. Responders and patients with SD continued for up to 8 cycles. Effect of VMDT on angiogenesis was evaluated by measuring the serum levels of angiogenic cytokines, such as VEGF, angiogenin, angiopoietin-2, and bFGF at baseline and after cycles 4 and 8. Bone remodeling was studied by the measurement of a series of serum indices: i) osteoclast stimulating factors [sRANKL, osteoprotegerin (OPG), osteopontin, MIP-1α ], ii) bone resorption markers (CTX, TRACP-5b), and iii) bone formation markers [bALP, osteocalcin (OC), and CICP]. Thirty-one pretreated pts (median age: 66 y; range: 45–83 y) have been enrolled in this study, including 20 pts treated during refractory relapse. Median time from 1st treatment to VMDT was 40 months. Many pts had features of advanced disease including ISS stage 3 (32%), high LDH (23%), and creatinine >2mg% (10%). The median number of previous treatments was 2 (range: 1–6), including M (48% of pts), T (65%), D (100%), V (3%) and ASCT (39%). Among 25 pts evaluable for response so far, 14 (56%) achieved an objective response (CR 8% and PR 48%). Furthermore, 2 pts (8%) achieved a MR and 5 (20%) SD. Median time to response was 30 days. Adverse events included fatigue (56%), thrombocytopenia (12% grade 3/4), neutropenia (8% grade 3/4), anemia (8% grade 3), neuropathy (48% grade 1/2, no grade 3/4 observed), infections (36%, including 2 HZ cases), and hyponatremia (12%). No pt experienced DVT, while 2 pts died due to sepsis. At baseline, MM pts had increased serum levels of sRANKL, sRANKL/OPG ratio, MIP-1α , VEGF, angiogenin, angiopoietin-2, and bFGF (p