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During the last decades, the prognosis of Hodgkin lymphoma (HL) has been improved significantly with the introduction of effective chemotherapy and the implementation of risk-adapted treatment approaches. Identification of reliable risk factors is crucial to guide treatment over the course of disease. Both clinical and biological factors have been implicated in the prognosis of HL and are often used in prognostic scores to discriminate risk groups. To prevent under- or overtreatment, patients are usually assigned to one of the three widely established risk groups for first-line treatment, based solely on clinical risk factors. To further individualize therapeutic approaches, functional imaging with positron emission tomography (PET) is becoming more widely implemented and precisely investigated within clinical trials. Biological prognostic factors have been widely evaluated but are still not a part of standard prognostication. This review will discuss the currently established factors and risk models at first diagnosis and in the setting of relapsed/refractory disease and also focus on biological factors and PET, summarizing current standards and future perspectives.

There are reports about the presence of paroxysmal nocturnal hemoglobinuria (PNH) clones in multiple myeloma (MM), but these have been demonstrated only in red blood cells (RBCs) and the previous reports utilized an obsolete diagnostic method. We carried out a study to identify the clones by flow cytometry (FC) and to understand their clinical significance.

The biological and clinical significance of a clonal B-cell lymphocytosis with an immunophenotype consistent with marginal-zone origin (CBL-MZ) is poorly understood. We retrospectively evaluated 102 such cases with no clinical evidence to suggest a concurrent MZ lymphoma. Immunophenotyping revealed a clonal B-cell population with Matutes score ≤2 in all cases; 19/102 were weakly CD5 positive and all 35 cases tested expressed CD49d. Bone marrow biopsy exhibited mostly mixed patterns of small B-lymphocytic infiltration. A total of 48/66 (72.7%) cases had an abnormal karyotype. Immunogenetics revealed overusage of the IGHV4-34 gene and somatic hypermutation in 71/79 (89.8%) IGHV-IGHD-IGHJ gene rearrangements. With a median follow-up of 5 years, 85 cases remain stable (group A), whereas 17 cases (group B) progressed, of whom 15 developed splenomegaly. The clonal B-cell count, degree of marrow infiltration, immunophenotypic, or immunogenetic findings at diagnosis did not distinguish between the 2 groups. However, deletions of chromosome 7q were confined to group A and complex karyotypes were more frequent in group B. Although CBL-MZ may antedate SMZL/SLLU, most cases remain stable over time. These cases, not readily classifiable within the World Heath Organization classification, raise the possibility that CBL-MZ should be considered as a new provisional entity within the spectrum of clonal MZ disorders.

During the last 50 years there has been great progress in understanding the biology of Hodgkin disease, which is now called Hodgkin lymphoma (HL), since it has been definitely shown to be a lymphoid neoplasm and its B-cell origin has been documented in the vast majority of cases. Progress in biology has also resulted in the identification of numerous biological prognostic factors, which may facilitate the definition of high-risk groups of patients and provide guidance for individualized therapy. Unfortunately, biological prognostic factors have not been incorporated in prognostic models applicable in everyday practice and need prospective validation. More importantly, during the last 50 years, advanced stage HL has been transformed from a rather incurable into a highly curable disease. Chemotherapy has gradually improved in terms of efficacy. MOPP was replaced by the more efficacious and less toxic ABVD regimen, but higher cure rates with BEACOPP-escalated have come at the expense of increased toxicity. Better risk stratification, probably based on early, interim positron emission tomography (PET) evaluation, may in the near future better identify those patients who really need intensified chemotherapy. Furthermore, the intensification of chemotherapy and the optimal use of PET at the end of chemotherapy have already minimized the use of radiotherapy in advanced disease, thus reducing the risk of long-term complications. Relapsed and refractory disease has also been rendered curable in almost half of the patients with the advent of effective salvage regimens, and, mainly, autologous stem cell transplantation. Furthermore, better understanding of the biology of HL has permitted the development of targeted therapy. Anti-CD30 targeting with brentuximab vedotin (BV) was the first targeted therapy to be approved for relapsed/refractory HL, either after autologous stem cell transplantation (auto-SCF) failure or after failure of two regimens in patients who were not candidates for transplant. Hopefully, the determination of the optimal role and timing of BV treatment and the development and approval of other targeted compounds will further improve the outcome of advanced stage as well as relapsed/refractory HL.

A better understanding of the biology and pathogenesis of hematological malignancies has led to the development of immunotherapeutic and immunoregulatory drugs. Many of these agents have revolutionized the current treatment modalities, while others are under investigation. Rituximab (anti-CD20 antibody) has been established as the gold standard of treatment for aggressive B-cell lymphomas in combination with CHOP and has shown significant activity as monotherapy in the treatment of indolent B-cell lymphomas. In follicular lymphomas the combination of Rituximab with chemotherapy improves the outcome compared to chemotherapy alone. CD 20-based radioimmunotherapy, with the advantage of the bystander effect, represents an additional therapeutic alternative in B-cell lymphomas and may produce tumor regression in Rituximab resistant patients. The anti-CD52 monoclonal antibody, alemtuzumab, further expands the armamentarium against lymphoid malignancies producing high response rates in these entities. Antibody-targeted chemotherapy such as gemtuzumab ozogamicin, consisting of an anti-CD33 antibody combined to calicheamicin, has shown efficacy in the treatment of refractory acute myeloid leukemia; exact indications, timing and dosing schedule for optimized efficacy remain to be determined. Interferons have proven significant activity in cutaneous lymphomas, hairy cell leukemia and chronic myelogenous leukemia by mechanisms that are not fully elucidated. Thalidomide, by acting as an immunomodulatory and antiangiogenic agent can modulate neoplastic cells microenvironment and lead to disease control in multiple myeloma as well as in numerous other hematological malignancies. Bortezomib, a proteasome inhibitor, displays significant anti-tumor activity, especially in multiple myeloma and lymphoproliferative disorders. The addition of these agents in therapeutic regimens has improved considerably the treatment of hematological malignancies.

We developed a clinical prediction rule for bone marrow involvement (BMI) in Hodgkin lymphoma based on 826 patients and validated it in 654 additional patients. Independent prognostic factors for BMI were x1, B symptoms; x2, stage III/IV prior to bone marrow biopsy; x3, anemia; x4, leukocytes fewer than 6 × 109/L; x5, age 35 years or older; and x6, iliac/inguinal involvement. Each factor was graded as xi= 1, if present, or xi= 0, if absent. A simplified score Zs= 8x1+ 6x2+ 5x3+ 5x4+ 3x5+ 3x6– 8 was assigned to each patient. The sensitivity, specificity, and positive and negative predictive value of this prediction rule was 97.8%, 51.5%, 10.6%, and 99.8%, respectively. In the validation group, they were 98.1%, 40.3%, 12.7%, and 99.6%. According to Zsvalue, 3 risk groups for BMI were defined: low risk (Zs< 0, 44% of patients, 0.3% risk), standard risk (Zs, 0-9; 37% of patients; 4.2% risk), and high risk (Zs≥ 10, 20% of patients, 25.5% risk). Patients with low risk (stage IA/IIA without anemia and leukopenia; stage IA/IIA, younger than 35 years, with either anemia or leukopenia but no inguinal/iliac involvement; and stage IIIA/IVA without any of these 4 risk factors) do not need bone marrow (BM) biopsy. Patients with standard risk should be staged with unilateral biopsy, but patients with high risk may benefit from bilateral biopsy.

We developed a clinical prediction rule for bone marrow involvement (BMI) in Hodgkin lymphoma based on 826 patients and validated it in 654 additional patients. Independent prognostic factors for BMI were x1, B symptoms; x2, stage III/IV prior to bone marrow biopsy; x3, anemia; x4, leukocytes fewer than 6 × 109/L; x5, age 35 years or older; and x6, iliac/inguinal involvement. Each factor was graded as xi = 1, if present, or xi = 0, if absent. A simplified score Zs = 8x1 + 6x2 + 5x3 + 5x4 + 3x5 + 3x6 – 8 was assigned to each patient. The sensitivity, specificity, and positive and negative predictive value of this prediction rule was 97.8%, 51.5%, 10.6%, and 99.8%, respectively. In the validation group, they were 98.1%, 40.3%, 12.7%, and 99.6%. According to Zs value, 3 risk groups for BMI were defined: low risk (Zs < 0, 44% of patients, 0.3% risk), standard risk (Zs, 0-9; 37% of patients; 4.2% risk), and high risk (Zs ≥ 10, 20% of patients, 25.5% risk). Patients with low risk (stage IA/IIA without anemia and leukopenia; stage IA/IIA, younger than 35 years, with either anemia or leukopenia but no inguinal/iliac involvement; and stage IIIA/IVA without any of these 4 risk factors) do not need bone marrow (BM) biopsy. Patients with standard risk should be staged with unilateral biopsy, but patients with high risk may benefit from bilateral biopsy.

Waldenström's macroglobulinemia (WM) is characterized by lymphoplasmacytic infiltration of bone marrow and/or other tissues and by the presence of serum monoclonal immunoglobulin M ([IgM], without cutoff limit). Differential diagnosis from other B-cell disorders (BCDs) is usually easy based on clinical, morphologic, histopathologic, immunophenotypic, and genetic features. However, all BCDs potentially produce monoclonal IgM. In this study we reviewed the medical files of 130 patients with IgM-secreting BCDs. Eighty-four patients were diagnosed with WM, 5 with IgM-monoclonal gammopathy of undetermined significance (MGUS), and 41 with other BCDs (9 with B-cell chronic lymphocytic leukemia, 5 with small lymphocytic lymphoma, 14 with marginal zone lymphoma, 5 with mantle-cell lymphoma, 2 with follicular lymphoma, 2 with diffuse large B-cell lymphoma, 2 with cryoglobulinemia, and 2 with low-grade lymphoma not otherwise specified). Median IgM levels were 3215 mg/dL in WM, 840 mg/dL in IgM-MGUS, and 285 mg/dL in other BCDs (5 had IgM levels 1500 mg/dL). In 10% of non-WM BCDs, monoclonal IgM was found only when more sensitive immunofixation methods were used. Forty-four percent of patients with BCDs (splenic marginal zone lymphoma or small lymphocytic lymphoma) had diagnoses that corresponded to that of WM. Careful diagnosis requires the concomitant evaluation of all parameters of BCDs together. Marginal zone lymphoma is the most frequently overlapping entity. Special attention should be given to mantle cell lymphoma in its atypical forms. Research in this field should continue to further clarify the disease entities that overlap with WM. New technology such as gene-expression profile techniques may contribute to this purpose.

Waldenstrom's macroglobulinemia (WM) is a rare lymphoproliferative disorder (LPD) characterized by lymphoplasmacytic infiltration of the bone marrow (BM) and/or occasionally other tissues and by the presence of a serum monoclonal IgM. The disease belongs to the lymphoplasmacytic lymphoma (LPL) subtype. Whether WM is indeed a separate entity or is merely an IgM-secreting subtype of low-grade B-cell lymphoma is still controversial. In our series of 67 patients, WM has a long median overall survival of 110 months, and the male/female ratio is 1.2/1. Clinical features include a wide spectrum of manifestations, many of which may be common to other LPDs. Differential diagnosis is based on: (1) clinical and laboratory features (anemia, organomegaly, lymphadenopathy, IgM paraproteinemia), (2) cell morphology (lymphocytes, lymphoplasmacytes, few plasma cells), (3) histopathology of bone marrow or lymph node, (4) immunophenotype (CD5 expression and the intensity of CD5, CD20, and CD79b antigens may help in discrimination from other LPDs and atypical CLL), and (5) characteristic genetic features (present in other LPDs). Based on the former, diagnosis is usually easy. It may be harder in LPL cases not secreting IgM. We consider that WM should be, for the time being, handled as a separate entity. Further studies are necessary. Semin Oncol 30:201-205. © 2003 Elsevier Inc. All rights reserved.

To determine the clinical significance of BCL-2 expression in Hodgkin-Reed-Sternberg (HRS) cells of classical Hodgkin disease (cHD), we correlated its expression with presenting clinical and laboratory features and failure-free survival (FFS). Eligible patients were untreated and negative for HIV-1; they had biopsy-proven cHD. BCL-2 expression was determined immunohistochemically in available pretreatment tissue biopsy specimens without knowledge of clinical outcome. Tumors were considered positive if any HRS cells expressed BCL-2. We identified 707 patients with cHD, whose median age was 30 years; 54% were men. HRS cells expressed BCL-2 in 359 (65%) of 551 nodular sclerosis, 67 (47%) of 143 mixed cellularity, and all 5 lymphocyte depletion. For all patients, the 5-year FFS was 74% versus 84% for tumors with versus without BCL-2 expression (P= .0016, by log-rank test). For the 412 patients treated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or equivalent regimens, the 5-year FFS for tumors with versus without BCL-2 expression was 74% versus 88% (P= .001, by log-rank test); for the 233 patients with Ann Arbor stage I or II, FFS was 84% versus 92% (P= .04, by log-rank test); and for the 179 patients with Ann Arbor stage III or IV, FFS was 62% versus 81% (P= .006, by log-rank test). Multivariate analysis confirmed that BCL-2 expression is independently associated with inferior FFS along with age 45 or older, Ann Arbor stage IV, low serum albumin and high serum lactate dehydrogenase levels. We conclude that BCL-2 is frequently expressed by HRS cells in cHD and is associated with inferior FFS in patients treated with ABVD or equivalent regimens.

To determine the clinical significance of BCL-2 expression in Hodgkin-Reed-Sternberg (HRS) cells of classical Hodgkin disease (cHD), we correlated its expression with presenting clinical and laboratory features and failure-free survival (FFS). Eligible patients were untreated and negative for HIV-1; they had biopsy-proven cHD. BCL-2 expression was determined immunohistochemically in available pretreatment tissue biopsy specimens without knowledge of clinical outcome. Tumors were considered positive if any HRS cells expressed BCL-2. We identified 707 patients with cHD, whose median age was 30 years; 54% were men. HRS cells expressed BCL-2 in 359 (65%) of 551 nodular sclerosis, 67 (47%) of 143 mixed cellularity, and all 5 lymphocyte depletion. For all patients, the 5-year FFS was 74% versus 84% for tumors with versus without BCL-2 expression (P = .0016, by log-rank test). For the 412 patients treated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or equivalent regimens, the 5-year FFS for tumors with versus without BCL-2 expression was 74% versus 88% (P = .001, by log-rank test); for the 233 patients with Ann Arbor stage I or II, FFS was 84% versus 92% (P = .04, by log-rank test); and for the 179 patients with Ann Arbor stage III or IV, FFS was 62% versus 81% (P = .006, by log-rank test). Multivariate analysis confirmed that BCL-2 expression is independently associated with inferior FFS along with age 45 or older, Ann Arbor stage IV, low serum albumin and high serum lactate dehydrogenase levels. We conclude that BCL-2 is frequently expressed by HRS cells in cHD and is associated with inferior FFS in patients treated with ABVD or equivalent regimens.

B‐CLL is the most common adult leukemia in the Western world. It is a neoplasia of mature looking B‐monoclonal lymphocytes co‐expressing the CD5 antigen (involving the blood, the bone marrow, the lymph nodes and related organs). Much new information about the nature of the neoplastic cells, including chromosomal and molecular changes as well as mechanisms participating in the survival of the leukemic clone have been published recently, in an attempt to elucidate the biology of the disease and identify prognostic subgroups. For the time being, clinical stage based on Rai and Binet staging systems remains the strongest predictor of prognosis and patients' survival, and therefore it affects treatment decisions. In the early stages treatment may be delayed until progression. When treatment is necessary according to well‐established criteria, there are nowadays many different options. Chlorambucil has been the standard regimen for many years. During the last decade novel modalities have been tried with the emphasis on fludarabine and 2‐chlorodeoxyadenosine and their combinations with other drugs. Such an approach offers greater probability of a durable complete remission but no effect on overall survival has been clearly proven so far. Other modalities, included in the therapeutic armamentarium, are monoclonal antibodies, stem cell transplantation (autologous or allogeneic) and new experimental drugs. Supportive care is an important part of patient management and it involves restoring hypogammaglobulinemia and disease‐related anemia by polyvalent immunoglobulin administration and erythropoietin respectively. Copyright © 2002 John Wiley & Sons, Ltd.

The use of novel small molecule inhibitors alone or in combination with anti-CD20 monoclonal antibodies for chronic lymphocytic leukemia (CLL) has raised a number of questions on efficacy, tolerability, long-term treatment adherence in patients with heterogeneous clinical features. To fill this gap, we designed a study focusing on treatment sequencing in patients with CLL in order to (i) compare the outcome of patients treated with chemoimmunotherapy (CIT) combinations in first-line versus those receiving Bruton's tyrosine kinase inhibitors (BTKi); (ii) characterize the efficacy and tolerability of venetoclax-based regimens; (ii) understand the impact of treatment sequencing when it comes to chemo-free options including venetoclax after BTKi and vice versa. Data from consecutive sets of patients diagnosed with CLL between 2000-2020 attended at 77 institutions affiliated with ERIC were collected and analyzed. Collected variables included: demographics, clinical stage at diagnosis, IGHV gene somatic hypermutation status; cytogenetic status for chromosomes 11q, 13q 17p and 12 determined by fluorescence in situhybridization; TP53gene mutation status; treatment; treatment response; discontinuation; reason for discontinuation; death. We included 9173 patients with a diagnosis of CLL who received at least one line of treatment. The median age at diagnosis was 67 years with a male:female ratio of 1.9. The median follow-up was 78 months (IQR, 48-120 months). Regarding novel targeted agents, 1860/9173 (20.2%) patients had received at least one line of treatment with BTKi (ibrutinib, n=1788; acalabrutinib, n=72) over the disease course; 631/9173 (6.9%) with venetoclax; and, 447/9173 (4.9%) with the PI3K inhibitor idelalisib. Seventy-nine patients were treated with both BTKi and venetoclax (59 BTKi followed by BCL2i, 20 vice versa). At last follow-up, 5870/9173 patients (64.0%) were alive, 3229/9173 (35.2%) died and 74/9173 (0.8%) were lost to follow-up. Patients treated with BTKi in first-line were enriched for TP53aberrations [del(17p) 27.6%, TP53mutation 26.3%] and unmutated IGHV genes (69%) and obtained an ORR of 87.7%. Of these, 136 (26.3%) discontinued treatment after a median of 1.2 years (0.07-5.98); main reasons of discontinuation were toxicity (40.5%) and failure (26.2%). Among 631 patients treated with venetoclax at any line, 100 (15.8%) received BCL2 +/- anti-CD20 as first-line; 170 (26.9%) as second line (125 previously treated with CIT, 27 with BTKi); and, 361 as third or subsequent line. ORR ranged between 71.5% (≥3 lines) with 30.5% CR/CRi to 90.3% (first-line) with 68.1% CR/CRi. Treatment discontinuation was due to toxicity in 28.6% of patients treated in the first-line, and 17.6% and 21.8% of patients treated in second and third-or-higher-line, respectively. Disease progression led to treatment discontinuation in 14.3%, 20.6% and 33.6% in first, second and third-or-higher line, respectively. CIT was used as front-line treatment in 5465 patients (59.6%). Of these, 2070 (37.9%) and 1018 (18.6%) patients received a second and third line of treatment, respectively. The great majority (865/1086 cases, 79.7%) of patients who received a second line before 2014 were retreated with CIT, most commonly Bendamustine-Rituximab (284/1086, 26.1%) and Fludarabine-Cyclophosphamide-Rituximab (252/1086, 23.2%); alemtuzumab monotherapy was used in 55/1086 (5%) of patients. After 2014, 415/984 patients (42.1%) were retreated with BTKi; 93 (9.5%) with venetoclax; 70 (7.2%) with idelalisib; 50 (5%) with Alemtuzumab monotherapy, and 315 (32%) with CIT. Similarly, in the third-or-higher line of treatment, most patients (86.3%) were retreated with CIT before 2014, while BTKi, BCL2i, and PI3Ki were mainly used after 2014 (in 43.1%, 15.7% and 14.7% of cases, respectively). Finally, our cohort included 1075 patients with TP53aberrations. The ORR of patients receiving BTKis (n=171) as first-line of treatment was 86.5% (22.2 CR+64.3 PR), while the ORR with venetoclax +/- anti-CD20 (n=15) was 91% (45.5% CR+45.5 PR). Patients treated with CIT (n=694) had an ORR of 68.7% (28.3% CR+40.4% PR). In conclusion, in a large international study we provide real world data regarding the selection and sequencing of treatment in CLL, charting a major shift in treatment patterns before and after the introduction of novel trargeted agents and confirming their efficacy even in high-risk CLL.

Introduction: Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies, especially under therapy with monoclonal antibodies targeting B-cells. Herein, we evaluated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with chronic lymphocytic leukemia (CLL), Non-Hodgkin Lymphoma (NHL) and Hodgkin's Lymphoma (HL) after vaccination with the mRNA BNT162b2 vaccine, up to 50 days post their first vaccine dose.

Terpos: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Janssen: Honoraria; GSK: Honoraria; Genesis: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria. Baltadakis: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Alexion: Honoraria; Astellas: Honoraria; Pfizer: Honoraria, Other: Travel Grants; Gilead: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Genesis Pharma: Other: Travel Grants; Gilead: Other: Travel Grants; WinMedica: Other: Travel Grants; Baxalta Hellas: Other: Travel Grants. Dimopoulos: BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Beigene: Honoraria.

Scarfo: Janssen: Honoraria, Other: Travel grants; Astra Zeneca: Honoraria; Abbvie: Honoraria. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Collado: Abbvie,: Other: pharmaceutical Company, Research Funding; Janssen: Other: Pharmaceutical Company, Research Funding. Galimberti: AbbVie, Janssen: Honoraria, Other: Travel grants; Incyte: Speakers Bureau. García-Serra: AbbVie: Other: Educational grands; Janssen: Other: Educational grants; Novartis: Other: Educational grants. Gozzetti: Janssen: Honoraria; AbbVie: Honoraria. Hatzimichael: Amgen, Roche, Genesis, Novartis, Bristol Mayer Squibb, Celgene, Pfizer: Consultancy; Abbvie, Amgen, Bristol Mayer Squibb, MSD, Gilead, Janssen Cilag, Genesis Pharma, Roche, Takeda: Honoraria. Herishanu: AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Medison: Honoraria. Jaksic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Kater: Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee. Kotsianidis: Astellas: Other: NONE, Research Funding, Speakers Bureau; Genesis: Consultancy, Other: NONE; Janssen Hellas: Consultancy, Other: NONE, Speakers Bureau; Bristol Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Novartis Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Abbvie: Consultancy, Other: NONE, Research Funding, Speakers Bureau. Kreitman: NIH: Patents & Royalties: Moxetumomab Pasudotox; Genentech: Research Funding; Teva: Research Funding; AstraZeneca/MedImmune: Research Funding; Innate: Research Funding; GSK/Novartis: Research Funding; Array BioPharma/Pfizer: Research Funding. Laribi: BeiGene: Other: Personal Fees; Jansen: Research Funding; Novartis: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Le Mans Hospital: Research Funding; Takeda: Other: Personal Fees, Research Funding; AbbVie: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees. Lopez-Garcia: Roche: Other: Speaker Honoraria, Travel and accommodation grants; Novonordisk: Other: Speaker Honoraria; Fresenius: Other: Speaker Honoraria; Celgene: Other: Speaker Honoraria; Abbvie: Other: Speaker Honoraria, Advisor, Travel and accommodation grants; Janssen: Other: Speaker Honoraria, Advisor, Travel and accommodation grants, Research Funding. Milosevic: Roche: Honoraria; Abbvie,: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Reda: Beigene: Consultancy; Astra Zeneca: Consultancy; Abbvie: Consultancy; Janssen: Consultancy. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Šimkovič: Janssen, Gilead, Roche, AstraZeneca, and AbbVie: Other: consultancy fees, advisory board participation fees, travel grants, and honoraria; University Hospital Hradec Kralove: Current Employment; AbbVie: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Merck: Current equity holder in publicly-traded company; Eli Lilly: Current equity holder in publicly-traded company; J&J: Current equity holder in publicly-traded company; Gilead: Other: Travel, Accommodations, Expenses. Špaček: AbbVie, AstraZeneca, Gilead, Janssen, and Roche: Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Visentin: Italfarmaco and Gilead: Speakers Bureau. Vassilakopoulos: AstraZeneca: Honoraria; Amgen: Honoraria, Research Funding; Pfizer: Research Funding; Dr. Reddy's: Research Funding; Novartis: Consultancy, Honoraria; GlaxoSmithKline: Honoraria, Other: Travel; Merck: Honoraria, Research Funding; Integris: Honoraria; Roche: Consultancy, Honoraria, Other: Travel; Genesis Pharma: Consultancy, Honoraria, Other: Travel; Takeda: Consultancy, Honoraria, Other: Travel, Research Funding; AbbVie: Consultancy, Honoraria; Karyopharm: Research Funding. Vitale: Janssen: Honoraria. Yáñez: Gilead-Kite, Janssen, AbbVie, AstraZeneca, Beigene, Roche, Pfizer, Jazz, BMS, and Merck: Other: Advisory board participation fees ; Janssen, AbbVie, AstraZeneca, Gilead-Kite, Roche, Pfizer, and Merck: Speakers Bureau. Antic: AbbVie, Janssen, and Roche: Honoraria. Coscia: Janssen: Honoraria, Other, Research Funding; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Other. Cuneo: AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Gaidano: Beigene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Guièze: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Astrazeneca: Consultancy, Honoraria. Laurenti: AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Consultancy, Honoraria; BeiGene: Honoraria. Murru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation; Janssen: Consultancy, Honoraria. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Tam: Beigene: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Loxo: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Trněný: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: 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, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Bosch Albareda: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Abbvie: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Kite: Honoraria; Sanofi: Honoraria; Lilly: Honoraria. Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Chatzidimitriou: Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Ghia: AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding. Stamatopoulos: AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

The outcome of patients with relapsed/refractory classical Hodgkin lymphoma (rr-cHL) has improved considerably in recent years owing to the approval of highly active novel agents such as brentuximab vedotin and Programmed Death-1 (PD-1) inhibitors. Although no randomized trials have been conducted to provide formal proof, it is almost undisputable that the survival of these patients has been prolonged. As autologous stem-cell transplantation (SCT) remains the standard of care for second-line therapy of most patients with rr-cHL, optimization of second-line regimens with the use of brentuximab vedotin, or, in the future, checkpoint inhibitors, is promising to increase both the eligibility rate for transplant and the final outcome. The need for subsequent therapy, and especially allogeneic SCT, can be reduced with brentuximab vedotin consolidation for 1 year, while pembrolizumab is also being tested in this setting. Several other drug categories appear to be active in rr-cHL, but their development has been delayed by the appearance of brentuximab vedotin, nivolumab and pembrolizumab, which have dominated the field of rr-cHL treatment in the last 5 years. Combinations of active drugs in chemo-free approaches may further increase efficacy and hopefully reduce toxicity in rr-cHL, but are still under development.

Symeonidis: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Pappa:Gilead: Honoraria, Research Funding; Amgen: Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Angelopoulou:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesiaPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hatzimichael:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zikos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria. Pangalis:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vassilakopoulos:WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction:Chemotherapy associated osteoporosis is a severe problem in patients with malignant diseases as it increases the risk for fractures and deteriorates quality of life. There are very limited data in the literature for the effect of chemotherapy on bone metabolism of adult patients with Non-Hodgkin Lymphoma (NHL). Thus, there is lack of formal recommendation regarding bone investigations at baseline or prophylactic bone management during treatment administration. The aim of this study was to perform a thorough assessment of bone remodeling in newly diagnosed patients with NHL, prior and post chemotherapy administration, to provide insight on the mechanisms of bone loss in these patients.

Terpos: Amgen: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Genesis: Honoraria, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria. Vassilakopoulos:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees. Makras:Amgen: Honoraria, Research Funding; Glaxo: Honoraria; Eli-Lilly: Honoraria; Pfizer: Honoraria; Leo: Honoraria; Genesis: Honoraria; UCB: Honoraria. Angelopoulou:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesiaPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Panayiotidis:Bayer: Other: Support of clinical trial. Dimopoulos:Sanofi Oncology: Research Funding.

Background - Objectives: Primary Bone non-Hodgkin's Lymphoma (PB-NHL) is a rare disease and constitutes about 3% of the total NHL patient population. We estimated the prevalence of this type of lymphoma in the local lymphoma registry of Western Greece and retrospectively analyzed 102 cases, in an effort to describe the clinical, histological and prognostic features of this tumor.

Background: Lenalidomide (Len) has been approved for anemic patients with Del(5)q syndrome and induces high response rates. However, patients exhibiting Del(5)q abnormality, but not classified as Del(5)q syndrome or presenting additional abnormalities over Del(5)q are not usually treated with lenalidomide and the experience on these patient groups is limited.

Stamatopoulos: Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria, Other: Travel expenses; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding.

Deregulated NF-κB signaling is a hallmark of most, if not all, lymphoid malignancies, and recurrent gene mutations in both the canonical and non-canonical NF-κB pathway are known to lead to NF-κB activation. However, the full compendium of NF-κB gene mutations in lymphoid malignancies remains to be elucidated. Recently, we reported a 4-bp truncating mutation in the NFKBIEgene, which encodes IκBε, a negative regulator of NF-κB, in patients with chronic lymphocytic leukemia (CLL). The NFKBIEdeletion was enriched in clinically aggressive CLL patients (7-8%) and associated with a worse clinical outcome. At the functional level, NFKBIE-deleted CLL showed reduced IκBε levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65, compared to wildtype patients. Preliminary data has indicated an increased frequency of NFKBIEaberrations in other lymphoid malignancies as well. To explore this further, we screened for NFKBIEdeletions in a large cohort of patients diagnosed with a range of different lymphoid neoplasms. Overall, NFKBIEdeletions were identified in 76 of 1414 patients (5.4%). While NFKBIEdeletions were relatively infrequent in patients diagnosed with follicular lymphoma (3/225, 1.3%), splenic marginal zone lymphoma (3/175, 1.7%), and T-cell acute lymphoblastic leukemia (1/94, 1.1%), moderate frequencies were observed among diffuse large B-cell lymphoma (18/521, 3.5%), mantle cell lymphoma (8/189, 4.2%), and primary CNS lymphoma (1/34, 2.9%) patients. In contrast, a remarkably high frequency of NFKBIEdeletions (41/176 cases, 23%) was observed among primary mediastinal B-cell lymphoma (PMBL) patients. Noteworthy, the prevalence of NFKBIE-deleted PMBL cases was similar in the different contributing centers. All PMBL patients in the present series received a CHOP based treatment regime; in ~75% of cases rituximab was added and ~25% were treated with dose intensified schemes. For the latter, the vast majority of patients received CHOEP, while individual cases were treated with MegaCHOEP, DA-EPOCH or ACVBP. Regarding clinicobiological associations, there were no significant differences between NFKBIE-deleted and wildtype PMBL patients with respect to age, sex, Ann Arbor stage, IPI risk-groups, extranodal or bone marrow involvement, bulky disease, and LDH elevation. However, NFKBIE-deleted patients were more likely to be refractory to primary chemotherapy (31% vs. 3%, P=.001) and had a shorter overall survival compared to wildtype patients (5-year overall survival: 63% vs 84%, P=.013). In multivariate analysis (including age, gender, Ann Arbor stage, IPI, and NFKBIEmutation status), NFKBIEmutation status (95% CI: 1.23-10.61; HR: 3.61; P=0.020) remained an independent factor for poor prognosis. In summary, we document NFKBIEdeletions as a common genetic event across B-cell malignancies, albeit at varying frequencies. The high frequency of NFKBIEdeletions in PMBL alludes to the critical role of this aberration in the pathophysiology of the disease. NFKBIEdeletions were associated witha worse clinical outcome, hence potentially representing a novel poor-prognostic marker in PMBL.

Granulopoiesis abnormalities have been described in association with thyroid disorders (TD). However, data regarding systematic evaluation of adult neutropenia and concurrent or prior TD are scarce.

The negative prognostic consequences of extramedullary plasmacytomas in the context of symptomatic MM is well known. On the contrary, the clinical impact of bone plasmacytomas (BP) has not been extensively studied, although their presence is one of Duries' major MM diagnostic criteria.

Two hundred and twelve symptomatic MM patients were studied from diagnosis to last follow-up. Their median age was 66 years and 60% were men. Twenty-three percent, 27% and 50% of patients were in ISS stage 1, 2 and 3 respectively; MM type was IgG in 59% , IgA in 26%, light chain only in 12%, IgD in 1,5% and non- or oligo-secretory in 1,5%. All patients required treatment and BP ones were additionally given radiotherapy. The median follow-up time of the whole cohort was 46,4 months.Forty patients (19%) had a BP at the time of their diagnosis. BP was located in the spine (BP-S) in 19 out of 40 and in other sites (BP-O: skull, pelvis, long bones, and ribs) in 21 patients. BP patients had equivalent demographics, stage and MM type as the others. Non-BP patients tended to have a better survival than BP ones but the difference was not statistically significant (p=0.1). However, BP-S patients had a significantly worse outcome than BP-O patients (24±6 versus 48±11 months, p<0.00001), and indeed worse than non-BP patients. It is worthwhile to outline that 17 out of 19 BP-S patients had received new drugs (thalidomide, lenalidomide, Bortezomib) during their course while 8 of them underwent high dose treatment with autologous stem-cell transplantation. In addition, the ISS staging has absolutely no prognostic impact in these patients (p=0.5), on the contrary to the whole cohort (p=0.03).In conclusion, MM patients presenting spine plasmacytoma at diagnosis constitute a distinct subgroup with adverse outcome that is difficultly predictable, given that the current staging system does not separate them. Further confirmation of this finding in larger cohorts is needed, as well as exploration of the biologic background.No relevant conflicts of interest to declare.

Changes in the production of monoclonal intact immunoglobulin (M-Ig) or of serum free light chains (sFLC) during symptomatic MM patients' relapse eventually reflect molecular myeloma cells changes and / or reveal clonal cell competition.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder characterized by the somatic mutation of X-linked gene PIG-A, required for glycosylphosphatidylinositol (GPI)-anchor biosynthesis. This results in absent or decreased expression of all membrane proteins normally anchored by GPI - including CD55 and CD59 - in all circulating cells, leading to an unusual sensitivity of red blood cells (RBCs) to complement lysis and subsequently intravascular hemolysis and hemoglobinuria. According to the “dual pathogenesis” model, there is an immunoregulatory selection in favor of PNH clones to proliferate preferentially over normal hemopoiesis on a microenvironment of bone marrow failure. The incidence of “PNH-like” defect has been also demonstrated in many hematological diseases and on peripheral blood cells (PBC) of normal individuals.

No relevant conflicts of interest to declare.

232 symptomatic MM patients with available follow-up sFLC measurements, were retrospectively studied. Light chain escape (LCE) was defined as sFLC increase with stable or falling M-Ig concentrations, M-Ig escape (MCE) as decreasing sFLC with increasing M-Ig, de-differentiation (DD) as clinical relapse with normal or decreased M-Ig and sFLC and Clonal Domination (CD) as normalization of formerly increased IgG, IgA or FLC in relapsing patients presenting increase of another component. Survival was calculated from diagnosis or from CIg date to last follow-up or death, survival curves were plotted by Kaplan-Meyer Method and assessed by the log-rank test.There were 94 women and 128 men, median aged 66 years; 29%, 42%, 29% and 22%, 30%, 48% were in Durie-Salmon and ISS stages I, II, III and 1, 2, 3 respectively. MM type was IgG MM in 59%, IgA in 21%, light chain only in 17%, IgD in 2% and non-secretory in1%. Median survival of the whole cohort was 46,4 months. CIg was observed in 39 patients (17%), consisting in LCE in 15 patients (6%), MCE in 7 (3%), DD in 5 (2%) and CD in 10 (4%); two additional patients (1 IgD and 1 LC) transiently produced another monoclonal component that was IgG in both cases, while in stringent complete remission. In CD patients, the dominated clone was IgG in 9 out of 10 patients, while the dominating one was LC in 8 and IgA in 2. LCE and MCE were more frequent in IgG patients. The median number of treatment lines received prior CIg was 5 for LCE, 4 for MCE, 2 for DD and 1 for CD. LCE and MCE patients had all received novel agents and/or ASCT. The median time from CIg to last follow-up or death was 2,6 months (2,2-3) for LCE, 3,3 months (2,2-4,4) for MCE, 6,3 months (1,1-11,6) for DD and 31,1 months (23,6-38,6) for CD. Patients presenting LCE, MCE and DD had a considerably shorter survival after CIg compared to patients presenting CD (p=0,0002). However because CIg was usually a late event in the course of the disease the overall survival of CIg patients was 60,6 months.In conclusion, LCE, MCE and DD are late events in the course of MM, mainly observed in patients whose previous treatments included with novel drugs. They reflect a very aggressive disease behavior with shortened survival thereafter, probably due to the emergence of a new resistant clone. CD was mainly observed in patients secreting low IgG levels and FLCs, and possibly reflect IgG clone remission in biclonal patients, given that thereafter, the disease behaves as a usual multiple myeloma, secreting however the other clone.No relevant conflicts of interest to declare.

Given the recent identification of the mTOR pathway as a possible target for cancer therapy, the expression pattern of phosphorylated mTOR (p-mTOR) pathway components has attracted vivid scientific interest in several neoplasms, including primary cutaneous T cell lymphomas. However, published information examining crosstalk between AKT/mTOR cascade and interconnected signaling pathways in mycosis fungoides (MF) is limited.We analysed immunohistochemically 54 skin biopsies (21 tumour and 33 plaque stage) from 50 patients with MF, for whom clinical information was available. Paraffin embedded tissue was stained for p-mTOR, its upstream p-AKT, its downstream effectors p-p70S6K and p-4E-BP1, as well as for p-ERK1/2 (extracellular signal-related kinase 1/2), the transcription factor Notch-1 and a member of the mammalian family of signal transducer activator of transcription, namely p-STAT-3. For statistical analysis only the predominant pattern i.e. cytoplasmic for p-mTOR, p-AKT, and NOTCH1 and nuclear for p-STAT3, p-p70S6K, p-4E-BP1 and p-ERK1/2 was taken into account. A Histo-score (H-score) based on the percentage of stained neoplastic cells (labelling index-LI) multiplied by staining intensity for each protein was calculated and was correlated with clinicopathological features and cancer-free (CSS), disease-free (DFS) and progression-free (PFS) survival.p-p70S6K expression was recorded in all cases, whereas the rate of positivity for the remaining molecules ranged from 52.8% to 67.3%. p-mTOR was coexpressed with p-p70S6K in 67.3% of cases, but coexpression with other molecules was less common (27.4–38.5%). Notch-1 displayed higher H-scores in tumours than in plaques (p=0.0475), as previously demonstrated. The same applied to p-p70S6K, but this correlation was of borderline significance. Significant correlations were recorded between p-4E-BP1 and p-p70S6K (p=0.0019), p-ERK and p4E-BP1 (p=0.0588), as well as between Notch-1 and p-p70S6K (p=0.0001) and p-4E-BP1 (p=0.0003). The latter two correlations remained when plaques and tumours were analysed separately. Interestingly, p-STAT3 showed a weak positive correlation with p-AKT in the entire cohort, but when analysis was restricted to plaques this relationship became statistically significant (p=0.0419). Notch1, p-4E-BP1 and p-p70S6K expression were associated with advanced stage. In univariate survival analysis increased p-p70S6K (p=0.0174) and p-AKT (p=0.0198) H-scores as well as p-4E-BP-1 immunopositivity adversely affected CSS but not DFS in plaques, along with CD30 expression (p=0.0004). In particular, blood clonality affected both DFS and CSS, as well as time to disease progression (p=0.0009, p=0.0031 and p=0.0216 respectively). The CSS time was also substantially shortened for subjects with simultaneous overexpression of p-AKT and p-p70S6K along with p-4E-BP1 immunopositivity (p= 0.0001). On the contrary in the subgroup of tumours decreased p-STAT3 H-score was only parameter that adversely affected CSS in tumour stage (p=0.0394), with the presence of blood clonality attaining marginal significance in this regard.Activation of AKT-mTOR components appears to have an intimate liaison with NOTCH1, p-ERK and p-STAT-3 and seems to be implicated in disease progression and in the acquisition of a more aggressive phenotype. Phosphorylation of several key components of this pathway, namely AKT, p70S6K and 4E-BP1 in MF, single or in combinations emerge as potential markers of prognostic value in plaque stage, whereas in tumours p-STAT-3 is brought forward as a favourable prognostic marker.No relevant conflicts of interest to declare.

Epstein-Barr virus (EBV) is a ubiquitous pathogen that chronically infects B lymphocytes and is implicated in the pathogenesis of lymphoproliferative diseases. Latent membrane protein 1 (LMP1), the major oncoprotein of the virus, has been shown to inhibit apoptosis and trigger survivin expression in malignant cell lines. Although EBV has not been implicated in the pathogenesis of low grade B-cell lymphomas, LMP1-mRNA has been detected in a significant proportion of patients with chronic lymphocytic leukemia (CLL). LMP1 is known for its antiapoptotic properties, but recent data show that LMP1 can simultaneously induce and inhibit apoptosis in B-cells. These opposite functions of LMP1 have not been studied in patients with low grade B-cell lymphomas.Our objectives were to detect LMP1-mRNA in patients with leukemic low grade B-cell lymphomas ant to investigate the postulated apoptotic properties of the protein, by correlating its expression to survivin levels.Peripheral whole blood from 64 patients with leukemic low grade B-cell lymphomas was tested by qRT-PCR for the presence of BXLF-1 gene of EBV. The patients' characteristics are shown in table 1. All positive samples were tested by conventional PCR for LMP1-mRNA. Subsequently, survivin m-RNA levels were measured by qRT-PCR in all samples and compared between LMP1 positive and negative patients (Mann-Whitney U Test).The BXLF-1 gene was detected in 27/64 (42.1%) patients. LMP1-mRNA was detected in 23/64 (35.9%) patients and in 23/27 (85.2%) EBV-positive patients. Among CLL patients, LMP1-mRNA was detected in 19/44 (43.2%). Finally, surviving-mRNA levels were found to be 8.37 times higher in EBV-negative vs EBV-positive patients, (p=0.002) and 7.19 times higher in LMP1-negative vs LMP1-positive patients (p=0.009). The results are reported in detail in Table 1.Data from this year's studies suggest that LMP1 may exert both antiapoptotic and apoptotic functions. While the carboxy-terminal domain of LMP1 drives the proliferation and survival of EBV-infected B cells in vitro and in vivo, LMP1 may activate, through its amino-terminal six-transmembrane domains (6TM), the transmembrane receptor proteins PERK, ATF6 and IRE-1, leading to unfolded protein response (UPR) induction. UPR is a cellular stress response that promotes apoptosis. In different environments, LMP1 signaling may show differences regarding its apoptotic effects on B lymphocytes.In our study, we detected LMP1-mRNA in 43.2% of CLL patients, a proportion significantly higher than previously reported (14%). Moreover, for the first time, LMP1-mRNA was detected in patients with other than CLL low grade B-cell lymphomas (Table 1).In patients with leukemic low grade B-cell lymphomas, in the pathogenesis of which EBV is not causally implicated, LMP1 may have apoptotic instead of anti-apoptotic properties, as evidenced by the lower survivin m-RNA levels in LMP1-positive patients. This finding deserves further investigation, in order to reveal the clinical significance of the different functions of LMP1 in non-EBV related lymphomas.No relevant conflicts of interest to declare.

Multiple Myeloma (MM) is characterized by bone marrow (BM) plasma cell infiltration and the presence of serum/urine monoclonal immunoglobulin (Ig). The depth of response has been associated with longer PFS in MM causing subsequent prolonged survival.Recently novel M-based biomarker immunoassays have been developed (Freelite™, Hevylite™) and their significance in MM diagnosis and prognosis has been demonstrated.1,2 Furthermore serum Free Light Chains (sFLC) are used for better assessment of treatment response, thus patients are considered to achieve stringed Complete Response (sCR) by having CR criteria plus normal serum Free Light Chains Ratio (sFLCR) and absent clonal cells on BM.3 The significance of Hevylite™ on response has not been assessed so far. Patients in nCR or better do not automatically restore their ratio of intact monoclonal Ig/intact polyclonal Ig of the same class (Hevylite™ or HLCR). We therefore investigated the importance of sFLCR and HLCR normalisation at plateau on PFS, in a series of patients with intact Ig MM.50 intact immunoglobulin MM patients were studied from diagnosis to last follow up. Immunofixation was IgG (26 -kappa and 12 –lamdba) and IgA (6 –kappa and 6 -lambda). All patients were symptomatic at diagnosis. Sera samples (n=312) were analyzed for sFLC-kappa and sFLC-lambda with Freelite™ and sFLCR were calculated, and for IgGkappa, IgGlambda IgAkappa, IgAlambda with Hevylite™ and ratios IgGkappa/IgGlambda, IgGlambda/IgGkappa, IgAkappa,/IgAlambda and IgAlambda/IgAkappa (HLCRs) were calculated. sFLCRs and HLCRs values above the 95%-ile of normal individuals were considered abnormal. Statistical analysis was performed using SPSS ver 15.0. File data were reviewed.At diagnosis sFLCR was abnormal in 86% of patients while HLCR was abnormal in all. All treatment lines were initiated according to standard criteria and median lines of therapy were 2 (range 1–11). Median follow up was 33 months (7–145). During patients' cumulative follow-up, 145 lines of therapy were studied and the subsequent responses were estimated. Thirty eight percent of responses were sCR, CR and nCR, 20% PR, 18% MR and 24% refractory and progressive disease. HLCR normalized in 44% of patients with sCR, CR and nCR. The depth of response correlated to PFS and patients in sCR, CR and nCR had longer PFS than the others (p<0.001). Serum FLCR and HLCR normal values at response were both strong parameters of increased PFS after treatment at any line (p=0.035 and p=0.046 respectively).Serum HLCR normalization at plateau reflects prolonged responses in intact Ig MM.Harding: Binding Site: Employment. Bradwell:The Binding Site: shareholder Other.

TGF-beta1 normally down-regulates B-cell proliferation. Resistance to its effects is reported in malignant cells of B-lineage such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) cells. There are however very few studies on serum TGF-beta1 levels in patients with B-cell lymphoproliferative diseases and their eventual correlations with parameters of disease activity and survival. The purpose of our study was to assess any eventual relationship between serum TGF-beta1 levels and disease parameters, as well as time to first treatment (TFT) and overall survival (OS) in a series of MM, Waldenstrom's macroglobulinemia (WM) and CLL patients at diagnosis.92 MM, 64 WM and 110 CLL patients were studied. In the MM group, paraprotein was IgG in 64, IgA in 18, LC in 8 and IgD in 2 patients while 32, 25 and 43% of patients were in ISS stage 1, 2 and 3 respectively. MM patients' median follow-up was 51 months. All patients required treatment a some point, 55% immediately. In the WM group, 44, 27 and 29% of patients were in WM – IPSS stage 1, 2 and 3 respectively. WM patients' median follow-up was 49 months; 75% of them required treatment during follow – up. In the CLL group, 54% and 74%, 25% and 20%, 14% και 6%, were in stage 0 and A, 1 and β, 2 and C according to Rai and Binet respectively. Median follow up was 43 months; 14 patients needed immediate treatment, 30 more required treatment during follow up while the others are still just followed. Patients' frozen sera, drawn at diagnosis, were retrospectively analyzed while sera from 20 healthy individuals (HI) were tested as controls. Serum TGF-beta1 measurements were done by ELISA according to the manufacturer's instructions. Statistical analysis was performed by SPSS software, version 15. 0.Median serum TGF-beta1 levels were 36330 pg/ml (range 4. 6 – 77976) in MM patients, 33965 pg/ml (range 1665–615000 pg/ml) in WM, 12207 pg/ml in CLL (range 0 – 42970) and 32902 pg/ml in HI (range 1941 – 58123). CLL patients presented significantly lower TGF-beta1 levels than those with MM and WM (p<0. 00001). Patients with TGF-beta1 levels above median presented a longer TFT than the others in MM and CLL (p=0. 0003, and p=0. 002 respectively) while in addition a longer OS was observed in MM and WM patients with increased serum TGF-beta1 median (p=0. 001, and 0. 02 respectively). Furthermore, serum TGF-beta1 levels stongly correlated with clinical and laboratory parameters of adverse prognosis such as staging, anemia, beta-2 microglobulin levels, serum LDH and serum free light chain concentrations.Our results of longer TFT in MM and CLL and improved OS in MM and WM patients with increased serum TGF-beta1 levels, suggest that a degree of sensitivity to the suppressive effect of TGF-beta1 may remain in neoplastic B-cells in the majority of B-cell lymphoproliferative disorders.No relevant conflicts of interest to declare.

Symptomatic CLL patients need treatment immediately. For these patients, molecular-genetic factors (mutated-unmutated, ZAP 70, ATM, p53) are important prognostic factors of response and survival. Nevertheless, 2/3 of newly diagnosed patients are asymptomatic and require only of follow up that can last for months or years. For these patients overall survival (OS) depends on the time to first treatment (TFT). The most frequent paraprotein produced in CLL is serum free light chain in 50% of the patients. It has recently been shown that serum free light chains (sFLC) and their sum above 60 (κ+λ above 60) are useful prognostic factors for TFT. We therefore studied the eventual prognostic implication of sFLC and the summated FLC-kappa plus FLC-lambda in a CLL patients' series.143 CLL patients were studied of which 18 needed immediate treatment while 37 more needed treatment during their follow up. 64% and 72%, 28% and 18%, 7.5% and 10%, were in stage 0 and A, 1 and β, 2 and C according to Rai and Binet respectively. Median patients' follow up was 32 months (range 4–228). Light chain restriction was established by flow cytometry or bone marrow biopsy immunohistochemistry. Serum free light chain values were retrospectively determined by nephelometry (Freelite™, the Binding Site Birmingham, UK) in frozen sera drawn at diagnosis. Elevated sFLC values were defined using as cut-off values the 95th percentile range of healthy individuals. Statistical analysis was performed using SPSS v15.0. Hazard ratios and prognostic significance of abnormal sFLC, HLC and ratios were determined by univariate Cox regression analysis. Kaplan Meier method was used for pictorial representation of survival and time to treatment.Increased sFLC were found in 45% of the patients while the summated FLC-kappa plus FLC-lambda was higher than 60 mg/dl in 14%. Increased sFLC values as well as values of FLC κ+λ>60 were related to shorter TFT (p=0,0005 and p=0,000003 respectively). In addition, high levels of sFLC and FLC κ+λ >60 correlated with β2-microglobulin (r=0.2, p=0.009 και r=0.2, p=0.03 respectively), serum albumin (r=0.2, p=0.009 only for FLC κ+λ > 60), negatively with hemoglobin (r=-0.3, p=0.000003 και r=-0.2, p=0.0002 respectively), increased LDH (p=0.037 και 0.001 respectively), Rai stage (p=0.03 και 0.003 respectively) and Binet stage (p=0.02 only for FLC κ+λ > 60) and with the presence of beta-symptoms (p=0.004 only for FLC κ+λ > 60). Finally, increased sFLC and FLC κ+λ>60 values correlated with shorter OS (p=0.05 and p=0.003 respectively).The results of our study confirmed the significance of sFLC in CLL with regard to TFT and their relationship with adverse prognostic clinical and laboratory parameters but also demonstrated for the first time their impact on OS.No relevant conflicts of interest to declare.

Reduced serum IgM levels were proposed as an unfavorable prognostic factor in multiple myeloma1. We therefore investigated the possible impact of decreased serum IgM concentrations on the outcome of Chronic Lymphocytic Leukemia (CLL) patients, a disease that is frequently characterized by severe hypogammaglobulinemia. Serum IgM levels were measured by 2 methods.188 patients with CLL were studied. Of them 54%, 27%,10%, 7% και 2% where in RAI stage 0, 1, 2, 3, 4 respectively while 65%, 22% and 13% in Binet stages A, B and C. IgM was determined at diagnosis by both classical nephelometry and the new Hevylite™ methods; the first measures total IgM levels while the second one measures the immunoglobulin fractions bound to either kappa or lambda light chains therefore enabling us to determine the ratio of IgM-kappa/lambda (HLCR). Hevylite™ measurements were retrospectively performed in 69/188 patients with available frozen sera aliquots from drawn at the time of diagnosis. Of them the Ig subclasses IgMkappa and IgMlambda, IgGkappa and IgGlambda, IgAkappa and IgAlambda (HLC) were measured by Hevylite™ antibodies nephelometrically. Light chain restriction (kappa or lambda) was determined by flow cytometry or bone marrow/lymph node biopsy immunohistochemistry. The ratios (HLCRs) were calculate with the monoclonal immunoglobulin as numerator, i.e IgMkappa/IgMlambda, IgGkappa/IgGlambda and IgAkappa,/IgAlambda in kappa-restricted patients and IgMlambda/IgMkappa, IgGlambda/IgGkappa, IgAlambda/IgAkappa in lambda-ones. Serum IgM concentration by both methods were related to time to first treatment (TFT) and overall survival (OS). Statistical analysis was performed conventionally; survival curves were drawn by Kaplan-Meyer method and compared by the log-rank test.Total IgM ranged from 12 to 246 mg/dl (median 47.6). The sum of IgMkappa plus IgMlambda from 12 to 369 (median 60). IgMkappa from 7.9 to 349 mg/dL (median 41) in kappa-restricted patients and IgMlambda from 7.6 ωζ 98 mg/dL (median 22) in lambda restricted ones. Low total IgM level (<50 mg/dL) was present in 52% of patients but it did not correlate to TFT or OS. Summated IgMkappa plus IgMlambda lower than 50 mg/dL was present in 41% and correlated with worse OS (p=0.016). Furthermore non-clonal IgM subclass suppression correlated with TFT (p=0.019) and OS (p=0.021). The same was not confirmed for non-clonal IgG and IgA subclasses suppression.Finally IgM-HLCR was abnormal in 35% of patients. Of them, 25% had also abnormal IgG-HLCR and/or IgA-HLCRs leading to the hypothesis of multiple clones coexistence within the neoplastic B-cell lymphocytic population.Low IgM levels determined by novel immunoassays (Hevylite™) correlate to shorter TFT and OS in patients with CLL. Their use may reveal new disease characteristic and are suggestive of a multi-oligoclonal disorder.No relevant conflicts of interest to declare.

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