Eliana Valentina Liardo

Survival of multiple myeloma patients in the era of novel therapies confirms the improvement in patients younger than 75 years: a population-based analysis.

Novel treatments for multiple myeloma (MM) have shown promising results in clinical trials, but the advantage in unselected patients is still unclear. In order to evaluate whether novel therapies impact survival of MM patients, we performed a population‐based analysis on data collected by the Modena Cancer Registry from 1989 to 2009. The analysis evaluated 1206 newly diagnosed MM patients collected in the years 1988–96 (conventional therapy), 1997–05 (high dose melphalan and autologous transplant), and 2006–09 (novel agents era). Both relative survival (RS) and overall survival (OS) improved over the years, but not equally in the three groups. For patients aged <65 years, RS improved in 1997–05 and 2006–09 compared with previous years and a trend to improvement was observed from 1997–05 to 2006–09. For patients aged 65–74 years, RS improved significantly in 2006–09 compared with 1988–96 and 1997–05. No amelioration was observed for patients 75+ years old. OS confirmed RS. In conclusion, the survival of MM patients aged <65 and, in particular, 65–74 years, has improved over time, especially after 2006. This observation provides circumstantial evidence that novel therapies might impact patient survival. Despite the limits of this study, these data refer to an unselected population, giving a picture of every day clinical practice.

Monocyte count at diagnosis is a prognostic parameter in diffuse large B-cell lymphoma: results from a large multicenter study involving 1191 patients in the pre- and post-rituximab era

In this study we assessed the prognostic significance of absolute monocyte count and selected the best cut-off value at diagnosis in a large cohort of patients with diffuse large B-cell lymphoma. Data were retrieved for therapy-naïve patients with diffuse large B-cell lymphoma followed in Israel and Italy during 1993–2010. A final cohort of 1017 patients was analyzed with a median follow up of 48 months and a 5-year overall survival rate of 68%. The best absolute monocyte count cut-off level was 630/mm3 and the 5-year overall survival for patients with counts below this cut-off was 71%, whereas it was 59% for those with a count >630 mm3 (P=0.0002). Of the 1017 patients, 521 (51%) were treated with chemo-immunotherapy, and in this cohort, using multivariate analysis, elevated monocyte count retained a negative prognostic value even when adjusted for International Prognostic Index (HR1.54, P=0.009). This large study shows that a simple parameter such as absolute monocyte count (>630/mm3) can easily be used routinely in the evaluation of newly diagnosed diffuse large B-cell lymphoma to identify high-risk patients with a worse survival in the rituximab era.

Response-guided ABVD chemotherapy plus involved-field radiation therapy for intermediate-stage Hodgkin lymphoma in the pre-positron emission tomography era: a Gruppo Italiano Studio Linfomi (GISL) prospective trial.

PURPOSE In the pre-positron emission tomography era, the Gruppo Italiano Studio Linfomi (GISL) investigated the feasibility and efficacy of a treatment based on a response-tailored number of doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) courses in 218 intermediate-stage Hodgkin lymphoma patients. PATIENTS AND METHODS Patients with stage I/II showing at least one adverse prognostic factor and stage IIIA without adverse prognostic factors were recruited. Treatment included a first step of 3 ABVD courses, followed by an early-restaging. Patients in CR/CRu received 1 additional ABVD cycle, patients in PR received 3 more ABVD, and nonresponder patients went off study. Involved-field radiation therapy (RT) was recommended on chemotherapy completion. RESULTS The median age was 30 years (range, 15-68 years) and 131 patients (61%) were female. Seven percent of patients were in stage I, 78% in stage II, and 15% in stage III; B-symptoms, bulky tumor and erythrocyte sedimentation rate > 30 were recorded in 20%, 26%, and 43% of cases, respectively. The CR/CRu rate was 62% at early restaging, 72% at the end of chemotherapy, and 95% following RT. With a median follow-up of 74 months (range, 6-193 months), 7-year overall survival, relapse-free survival, and freedom from treatment failure were 91.8% (95% CI, 86%-95.5%), 89.2% (95% CI, 82.8%-93.3%), and 81.8% (95% CI, 75.2%-86.7%), respectively. Patients in CR/CRu on early restaging, receiving 4 ABVD, had an excellent outcome with 7-year RFS and cause-specific survival similar to those of the late responders treated with 6 ABVD (RFS, 87.5% vs. 90.5% and CSS, 96.6% vs. 92.7%, respectively). CONCLUSION The response-guided ABVD program we report, based on standard clinical staging procedures, proved to be feasible and safe in patients with intermediate-stage Hodgkin lymphoma.

Defining the best cut-off value for lymphopenia in diffuse large B cell lymphoma treated with immuno-chemotherapy

Arnulf, B., Pylypenko, H., Grosicki, S., Karamanesht, I., Leleu, X., van de Velde, H., Feng, H., Cakana, A., Deraedt, W. & Moreau, P. (2012) Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica, 97, 1925–1928. Bird, J.M., Owen, R.G., D’Sa, S., Snowden, J.A., Pratt, G., Ashcroft, J., Yong, K., Cook, G., Feyler, S., Davies, F., Morgan, G., Cavenagh, J., Low, E. & Behrens, J. (2011) Haemato-oncology Task Force of British Committee for Standards in Haematology (BCSH) and UK Myeloma Forum. Guidelines for the diagnosis and management of multiple myeloma 2011. British Journal of Haematology, 154, 32–75. Boyd, K.D., Ross, F.M., Chiecchio, L., Dagrada, G.P., Konn, Z.J., Tapper, W.J., Walker, B.A., Wardell, C.P., Gregory, W.M., Szubert, A.J., Bell, S.E., Child, J.A., Jackson, G.H., Davies, F.E. & Morgan, G.J. (2012) A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial. Leukemia, 26, 349– 355. Cook, G., Liakopoulou, E., Pearce, R., Cavet, J., Morgan, G.J., Kirkland, K., Lee, J., Davies, F.E., Hall, R., Rahemtulla, A., Russell, N. & Marks, D.I. (2011) British Society of Blood & Marrow Transplantation Clinical Trials Committee. Factors influencing the outcome of a second autologous stem cell transplant (ASCT) in relapsed multiple myeloma: a study from the British Society of Blood and Marrow Transplantation Registry. Biology of Blood and Marrow Transplantation, 17, 1638–1645. Cook, G., Williams, C.D., Cairns, D.A., Fletcher, M., Cavenagh, J.D., Snowden, J.A., Parrish, C., Ashcroft, J., Yong, K.L., Cavet, J., Hunter, H., Bird, J., O’Connor, S.J., Brown, J.M.B. & Morris, C. (2013) A Second Autologous Stem Cell Transplant (ASCT2) induces superior durability of response (DuR) following bortezomib-containing re-induction therapy for relapsed multiple myeloma (MM): final results from the BSBMT/Ukmf Myeloma X (Intensive) Trial. Blood, 122, 765. Kumar, S.K., Mikhael, J.R., Buadi, F.K., Dingli, D., Dispenzieri, A., Fonseca, R., Gertz, M.A., Greipp, P.R., Hayman, S.R., Kyle, R.A., Lacy, M.Q., Lust, J.A., Reeder, C.B., Roy, V., Russell, S.J., Short, K.E., Stewart, A.K., Witzig, T.E., Zeldenrust, S.R., Dalton, R.J., Rajkumar, S.V. & Bergsagel, P.L. (2009) Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clinic Proceedings, 84, 1095– 1110. Mikhael, J.R., Samiee, S., Stewart, A.K., Chen, C., Trudel, S., Franke, N., Winter, A., Chang, H. & Reece, D.E. (2004) Outcome after second autologous stem cell transplantation as salvage therapy in patients with relapsed multiple myeloma. Blood, 104, Abstract 943. Moreau, P., Pylypenko, H., Grosicki, S., Karamanesht, I., Leleu, X., Grishunina, M., Rekhtman, G., Masliak, Z., Robak, T., Shubina, A., Arnulf, B., Kropff, M., Cavet, J., Esseltine, D.L., Feng, H., Girgis, S., van de Velde, H., Deraedt, W. & Harousseau, J.L. (2011) Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. The Lancet Oncology, 12, 431–440. Ross, F.M., Avet-Loiseau, H., Ameye, G., Gutierrez, N.C., Liebisch, P., O’Connor, S., Dalva, K., Fabris, S., Testi, A.M., Jarosova, M., Hodkinson, C., Collin, A., Kerndrup, G., Kuglik, P., Ladon, D., Bernasconi, P., Maes, B., Zemanova, Z., Michalova, K., Michau, L., Neben, K., Hermansen, N.E., Rack, K., Rocci, A., Protheroe, R., Chiecchio, L., Poirel, H.A., Sonneveld, P., Nyegaard, M. & Johnsen, H.E. (2012) Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders. Haematologica, 97, 1272–1277. Sonneveld, P., Schmidt-Wolf, I.G., van der Holt, B., El Jarari, L., Bertsch, U., Salwender, H., Zweegman, S., Vellenga, E., Broyl, A., Blau, I.W., Weisel, K.C., Wittebol, S., Bos, G.M., Stevens-Kroef, M., Scheid, C., Pfreundschuh, M., Hose, D., Jauch, A., van der Velde, H., Raymakers, R., Schaafsma, M.R., Kersten, M.J., van Marwijk-Kooy, M., Duehrsen, U., Lindemann, W., Wijermans, P.W., Lokhorst, H.M. & Goldschmidt, H.M. (2012) Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. Journal of Clinical Oncology, 30, 2946–2955.

A case of skeletal and bone marrow metastases from breast cancer treated with eribulin mesylate

AIM We report our experience with eribulin mesylate in a pancytopenic heavily pretreated patient with multiple bone metastases and bone marrow infiltration from breast cancer. METHODS Eribulin mesylate was given at 1.4 mg/m(2) on day 1 and 8 every 3 weeks for a total of 11 courses. RESULTS After seven cycles, evaluation with a bone marrow biopsy showed a large decrease of neoplastic involvement with substitution of osteolitic lesions for the osteoaddensant type. No unexpected acute toxicity was observed. CONCLUSION To our knowledge, this represents the first report of bone marrow metastases from breast cancer treated with eribulin mesylate that obtained an improvement of hematopoietic values with an acceptable profile of tolerability and good compliance for the subject.

T Cell Large Granular Lymphocytic Leukemia in Association with Sjögren’s Syndrome

T cell large granular lymphocytic (LGL) leukemia is a rare condition accounting for 2–3% of all mature lymphoid leukemias. Here, we present the case of a 73-year-old woman presenting with neutropenia and anemia (hemoglobin 9.9 g/dl). Hematological assessment revealed the presence of a T cell LGL leukemia. At the time of T cell LGL leukemia diagnosis, the patient developed xerophthalmia and xerostomia, and a diagnosis of Sjögren’s syndrome was made following salivary gland biopsy. The finding of large granular lymphocytes in the context of autoimmune disorders is well-known, though it often occurs with rheumatoid arthritis or in association with a positive autoantibody titer in the absence of an overt clinical picture. The concomitant presentation of T cell LGL leukemia with Sjögren’s syndrome is a rare event which is worth reporting. Our patient was managed with immunosuppressive therapy and is still alive.

Non-Hodgkin Lymphoma in Psoriatic Arthritis Treated with Sequential, Multiple Anti-TNF-α Agents: A Case Report

Data obtained by large observational studies and meta-analysis indicate the absence of an increased risk of lymphoma related to therapy with anti-TNF-α, but there is limited information in literature about the safety of sequential, multiple biological agents therapy for a time longer than three years. We hereby present a case of psoriatic arthritis developing non-Hodgkin lymphoma after a six-year history of poorly effective therapy with different anti-TNF-α.

Pentoxifylline-Induced Apoptosis in Chronic Lymphocytic Leukemia: New Insights into Molecular Mechanism

BACKGROUND Chronic lymphocytic leukemia (CLL) is an indolent B-lineage neoplasm, characterized by clonal expansion of CD5 positive B cells with constitutive activation of survival pathways including NF-kB. Pentoxifylline, a xanthine-derivative compound indicated for the treatment of microvascular disturbancies, has been suggested to have anti-proliferative and anti-metastatic activities in various types of cancer. In the present study we extend these data showing one of the potential molecular mechanisms through which Pentoxifylline may promote apoptosis in CLL clonal lymphocytes. METHODS Peripheral blood mononuclear cells were isolated from 15 CLL patients 0 RAI stage and 15 healthy volunteers and treated for 24 and 48 hours with Pentoxifylline. Apoptosis induction was evaluated through Annexin V and TUNEL assays. Mitochondrial membrane potential depolarization analysis, active Caspase-3 assay, reactive oxygen species generation and Western Blot were assessed to further investigate the alterations induced by Pentoxifylline. RESULTS We observed a statistically significant occurrence of apoptosis, DNA fragmentation and active Caspase-3 in lymphocytes from CLL patients compared to healthy volunteers after 48 hours of Pentoxifylline treatment. To clarify the molecular mechanism of the drug, we also evaluated the expression levels of NF-kB/p65 and its related proteins. In treated CLL cells, NF-kB/p65 was significantly decreased in comparison to normal cells, whereas we observed a less marked reduction of Bcl-2 expression. The treatment also induced a decrease of Mcl-1 in CLL cells with a greater down-regulation of the anti-apoptotic alternatively spliced isoform. CONCLUSION These findings showed that Pentoxifylline induced apoptosis in leukemic cells through a molecular mechanism that involves the NF-kB signaling.