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Summary Background Fit patients with mantle cell lymphoma aged 18–65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population. Methods This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18–59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0–3, or aged 60–65 years with ECOG 0–2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m2 on day 1, oral prednisone 100 mg [total dose] on days 1–5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m2 on day 1; intravenous doxorubicin 50 mg/m2, vincristine 1·4 mg/m2, and cyclophosphamide 750 mg/m2 on day 2; oral prednisone 100 mg/m2 on day 2–6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m2 on day 1, intravenous rituximab 375 mg/m2 on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m2 every 12 h on days 1–3, intravenous rituximab 375 mg/m2 on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 109 cells per L or 10 mg per day for platelets 60–100 × 109 cells per L, days 1–21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009–012807–25) and ClinicalTrials.gov ( NCT02354313 ). Findings Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51–62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24–50), 3-year progression-free survival was 80% (95% CI 70–87) in the lenalidomide group versus 64% (53–73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30–0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3–4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p Interpretation Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma. Funding Fondazione Italiana Linfomi and Celgene.

Background: Patient-related factors, namely comorbidities, impact the clinical outcome of patients with diffuse large B-cell lymphoma (DLBCL). Methods: The prevalence and prognostic impact of comorbidities were examined using the validated scores Charlson Comorbidity Index (CCI) and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) in 181 patients with DLBCL at initial diagnosis before treatment with rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone (R-CHOP). Results: Pronounced comorbidities as defined by CCI and HCT-CI scoring of &ge, 2 were detected in 9.9% and 28.2% of patients, respectively, and occurred more frequently at advanced age (p &lt, 0.001). Higher CCI scoring was associated with lower complete response rate (p = 0.020). Both advanced CCI and HCT-CI were significantly associated with shortened overall survival (3-year OS: CCI &ge, 2 vs. 0&ndash, 1, 38.9% vs. 81.3%, p &lt, 0.001, HCT-CI &ge, 1, 56.9% vs. 84.9%, p &lt, 0.001). Both comorbidity scores remained independent risk factors in the multivariate analysis (HCT-CI &ge, 2 HR: 2.6, p = 0.004, CCI &ge, 2 HR: 3.6, p = 0.001). Conclusion: This study demonstrates the prognostic relevance of comorbidities classified by CCI and HCT-CI in patients with DLBCL undergoing curative treatment with R-CHOP. A structured evaluation of comorbidities might refine prognostication alongside currently used prognostic parameters, namely age, and should be evaluated in prospective trials.

The optimal first-line treatment for advanced-stage Hodgkin's lymphoma (HL) is still a matter of debate. While ABVD is less toxic and as effective as other, more intensive chemotherapy regimens, escalated BEACOPP (BEACOPPesc) is superior to ABVD for initial disease control and prolonged time-to-relapse. However, this advantage is associated with higher rate of early and late toxicities. As most of these data have been accumulated from clinical trials, a retrospective analysis was conducted in a large database of patients treated outside clinical trials to investigate the advantages and disadvantages of these regimes in a real-world setting. From October 2009 to October 2018, 397 advanced-stage HL patients treated with either ABVD or BEACOPPesc were retrospectively assessed in 7 European cancer centers (2 Austrian and 5 Italian centers). Complete metabolic remission (CMR) by PET was achieved in 76% and 85% of patients in the ABVD and BEACOPPesc groups, respectively (p = .01). Severe adverse events occurred more frequently with BEACOPPesc than ABVD. At a median follow-up of 8 years, 9% of the patients who achieved CMR after BEACOPPesc relapsed compared to 16.6% in the ABVD group (p = .043). No statistical difference in progression free survival (PFS) was observed between the two cohorts overall (p = .11), but there was a trend towards a superior PFS in high-risk patients treated with BEACOPPesc (p = .074). Nevertheless, overall survival was similar between the two groups (p = .94). In conclusion, we confirm that ABVD is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control, the long-term outcome remains similar between the two regimens.

// Patrizia Mondello 1,2,3 , Salvatore Cuzzocrea 2 , Michele Navarra 2 and Michael Mian 4,5 1 Department of Human Pathology, University of Messina, Messina, Italy 2 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy 3 Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA 4 Department of Hematology and Center of Bone Marrow Transplantation, Hospital of Bolzano, Bolzano/Bozen, Italy 5 Department of Internal Medicine V, Hematology & Oncology, Medical University Innsbruck, Innsbruck, Austria Correspondence to: Patrizia Mondello, email: // Keywords : multiple myeloma, micro-environment, therapeutic opportunities, osteoclast activation, angiogenesis Received : July 18, 2016 Accepted : January 05, 2017 Published : January 12, 2017 Abstract Despite the advent of many therapeutic agents, such as bortezomib and lenalidomide that have significantly improved the overall survival, multiple myeloma remains an incurable disease. Failure to cure is multifactorial and can be attributed to the underlying genetic heterogeneity of the cancer and to the surrounding micro-environment. Understanding the mutual interaction between myeloma cells and micro-environment may lead to the development of novel treatment strategies able to eradicate this disease. In this review we discuss the principal molecules involved in the micro-environment network in multiple myeloma and the currently available therapies targeting them.

Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with the standard immunochemotherapy R-CHOP, one-third of them relapses with a dismal outcome in most cases. In the recent years, remarkable advances have been achieved based on the discovery of molecular genetics in DLBCL. In addition to the major cell-of-origin designations of germinal center B-cell and activated B-cell subtypes, next-generation sequencing has unveiled the remarkable complexity of DLBCL and identified potential molecular targets for tailored therapies. Despite these findings, the current standard of care for DLBCL patients is still R-CHOP, and optimization of frontline therapy remains an important goal. In this review, we summarize recent updates on the evolution of frontline therapies for DLBCL.

Despite the important progress in the research of myeloproliferative neoplasms (MPN), treatment options are still limited. Currently, a cytoreductive approach is the backbone treatment, with hydroxyurea (HU) being the most important agent. However, this drug is not always well-tolerated and has been questionably linked to a potential leukemogenic effect. A valid alternative is interferon alfa (IFN-α), but it is reserved for selected patients owing to the more frequent side effects and the lack of final results from the studies directly comparing IFN-α with HU, which is why we provided the results of the so far largest real-life analysis.From 2000 to 2016, 63 patients with Philadelphia-negative MPN prospectively received either HU or IFN-α.During a median follow-up period of 121 months (range, 88-168 months), 97% of the patients treated with IFN-α achieved a hematologic response (60% complete, 37% partial) compared with 78% in the HU group (56% complete, 20% partial; P .01). Molecular responses were limited to patients treated with IFN-α. IFN-α was well-tolerated with no secondary malignancy, whereas HU was associated with more toxic events and cases of leukemic transformation. A significantly longer progression-free survival (5.0 vs. 3.1 years; P .001) and overall survival (7.8 vs. 5.8 years; P = .006) were observed in the IFN-α group compared with the HU cohort.Our data support IFN-α as a more valid therapeutic option owing to its more profound hematologic responses, durable molecular remissions, long-term disease control, and reduced risk of leukemic transformation with a favorable toxicity profile.

The optimal first-line treatment for advanced low-grade non-Hodgkin lymphomas (LG-NHL) is still highly debated. Recently, the StiL and the BRIGHT trials showed that the combination of rituximab and bendamustine (R-B) is non-inferior to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with a better toxicity profile. Utilizing a retrospective analysis, we compared the efficacy and safety of both regimens in clinical practice. From November 1995 to January 2014, 263 LG-NHL patients treated with either R-B or R-CHOP were retrospectively assessed in seven European cancer centers. Ninety patients were treated with R-B and 173 with R-CHOP. Overall response rate was 94 and 92 % for the R-B and the R-CHOP group, respectively. The percentage of complete response was similar for both groups (63 vs. 66 % with R-B and R-CHOP, respectively; p = 0.8). R-B was better tolerated and less toxic than R-CHOP. The median follow-up was 6.8 and 5.9 years for the R-CHOP and the R-B group, respectively. Overall, no difference in progression-free survival (PFS) (108 vs. 110 months; p = 0.1) was observed in the R-B group compared to the R-CHOP cohort. Nevertheless, R-B significantly prolonged PFS in FL patients (152 and 132 months in the R-B and R-CHOP group, respectively; p = 0.05). However, this result was not verified in multivariate analysis probably due to the limits of the present study. We confirm that the R-B regimen administered in patients with LG-NHL is an effective and less toxic therapeutic option than R-CHOP in clinical practice. © 2016, Springer-Verlag Berlin Heidelberg.

Background Mantle cell lymphoma (MCL) is an aggressive lymphoma with a dismal prognosis because of numerous relapses. Because the most promising results have been obtained with immunochemotherapy followed by autologous cell stem transplantation (ASCT), we evaluated the efficacy of yttrium-90 ibritumomab ( 90 Y-IT) consolidation after such an intensive treatment. Patients and Methods We retrospectively assessed 57 patients affected by intermediate or high-risk MCL in complete remission (CR) or partial remission (PR) after 3 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisolone) plus 3 cycles of R-DHAP (dexamethasone, cytarabine [Ara-C], cisplatin [platinum]) followed by ASCT and additional consolidation treatment with 90 Y-IT in 28 cases. All patients underwent 2 years of rituximab maintenance. Results After ASCT, 94% achieved CR and 4% achieved PR. The median follow-up was 6.2 years (range, 1.8-9.7 years). Treatment intensification was well tolerated and led to a significantly longer response duration in comparison to standard treatment. In contrast to the historical cohort, the addition of 90 Y-IT seems to overcome important risk factors such as Mantle Cell Lymphoma International Prognostic Index (MIPI) score and bone marrow infiltration. Conclusion In the present retrospective analysis, immunochemotherapy followed by ASCT resulted in a very high response rate, and subsequent 90 Y-IT consolidation significantly reduced the number of relapses and increased survival, suggesting that 90 Y-IT consolidation might be a valid option in first-line treatment. However, a prospective confirmatory trial is warranted.

Y-ibritumomab tiuxetan (90Y-IT) combines the benefits of a monoclonal antibody with the efficacy of radiation in the treatment of B-cell non-Hodgkin lymphoma (NHL), a remarkably radiosensitive hematologic malignancy. 90Y-IT activity has been well established in the indolent setting, being approved in front-line treatment of follicular lymphoma (FL) patients as well as salvage therapy. However, no advantage in OS was observed with respect to standard treatment. Promising data are available also for aggressive B-cell lymphoma. In particular, the addition of RIT to short-course first line chemotherapy enables reduction of chemotherapy while maintaining cure rates in elderly, untreated diffuse large B-cell lymphoma (DLBCL) patients. Furthermore, 90Y-IT improves response rate and outcomes of relapsed/refractory DLBCL patients, eligible and ineligible for autologous stem cell transplantation (ASCT). Clinical results have shown a role of 90Y-IT even in mantle cell lymphoma (MCL). RIT might improve responses and treat minimal residual disease when used as consolidation after first-line chemotherapy in MCL. Moreover, 90Y-IT has demonstrated its efficacy in combination with high-dose chemotherapies as conditioning regimen for ASCT, with evidence suggesting the ability to overcome chemotherapy resistance. Herein, we review the available evidence for this approved drug and examine the recently published and ongoing trials for potential novel indication in aggressive B-cell NHL.

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with >90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background Rituximab plus bendamustine (R-B) has been demonstrated to improve outcomes and reduce toxicity compared with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) in follicular lymphoma (FL). Nevertheless, in clinical practice, many centers still prefer R-CHOP to R-B in patients with FL grade 3A (FL3A). Therefore, we retrospectively assessed patients with FL3A treated with either R-CHOP or R-B in five European cancer centers and compared their outcomes. Materials and Methods We retrospectively assessed 132 patients affected by FL grade 3A treated with either R-B or R-CHOP in the first line and evaluated outcome and toxicity according to the type of treatment. This study included 101 patients who were a subgroup of a previously published cohort. Results R-B was less toxic and achieved a similar percentage of complete remissions compared with R-CHOP (97% vs. 96%, p = .3). During follow-up, 10 (16%) patients relapsed after R-B and 29 (41%) after R-CHOP (p = .001), leading to a median progression-free survival (PFS) of 15 versus 11.7 years, respectively (p = .03). Furthermore, R-B overcame the negative prognostic impact of BCL2 expression (15 vs. 4.8 years; p = .001). However, median overall survival was similar between both groups (not reached for both; p = .8). Conclusion R-B as a first-line treatment of FL3A is better tolerated than R-CHOP and seems to induce more profound responses, leading to a significantly lower relapse rate and prolonged PFS. Therefore, R-B is a valid treatment option for FL grade 3A. Implications for Practice Rituximab plus bendamustine (R-B) has shown to be less toxic and more effective than rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) in follicular lymphoma grade 3A. Although both regimens can induce a complete remission in >95% of patients, relapses occur more frequently after R-CHOP than R-B, leading to a significantly longer progression-free survival in the latter. R-B is also able to overcome the impact of negative prognosticators, such as BCL2 expression. However, because of the indolent course of this disease and efficient salvage treatments, overall survival was similar in both treatment groups. Therefore, R-B is a valid treatment option in this patient setting.

Introduction Patients with non–small-cell lung cancer (NSCLC) and cardiovascular (CV) disease often share a comparable demographic profile. The aim of this analysis was to assess the significance and prevalence of preexisting CV comorbidity and events in NSCLC. Patients and Methods A total of 715 consecutive NSCLC patients diagnosed between 2004 and 2009 at the Medical University of Innsbruck were retrospectively assessed regarding CV comorbidities, risk factors, cancer treatment, CV events occurring after the start of treatment, and outcome. Results At least one CV comorbidity was present in 462 (67.2%) of 687 evaluable patients. CV events were documented in 68 patients (9.5%), with conduction disorders being the most prevalent (n = 19), followed by cardiomyopathy (n = 13), myocardial infarction (n = 13), sudden CV death (n = 12), need of revascularization (n = 6), and pericardial effusion (n = 5). Median time between diagnosis of NSCLC and CV event was 13.9 months. CV comorbidities and events both showed a direct correlation with increasing age, affecting up to 87.3% and 35.2% of all octogenarians in the study, respectively. The following CV comorbidities were significantly associated with CV events: atrial fibrillation, myocardial infarction, and cardiomyopathy. Overall survival was not reduced in patients experiencing a CV event compared to patients without an event. Conclusion CV disease and events are frequently observed in NSCLC patients. To provide definitive recommendations on impact, prevention, and screening of CV disease in NSCLC, prospective trials are desirable.

Primary lymphoma of the lung or pleural is a very rare condition. Due to the outdated literature data, the approximate occurrence of primary and secondary lung and/or pleural involvement according to the most common B cell lymphoma entities is unknown. To answer this open question in Austria, we screened the Tyrolean registry for B cell non-Hodgkin's lymphomas regarding primary and secondary lung involvement. Of 854 patients affected by B cell lymphoma, 7.5% had lung/pleural disease. This organ was the primary site in only 0.7%, while a secondary involvement was registered in 6.8%. Most of them were affected by diffuse large B cell lymphoma (DLBCL; 29/368, 8%) followed by follicular lymphoma (7/188, 4%), mantle cell lymphoma (7/57, 12%), mucosa-associated tissue lymphoma (10/37, 27%), posttransplant lymphoproliferative disease (6/24, 25%), Burkitt lymphoma (3/19, 16%), other lymphomas (1/32, 3%) and Richter transformation (1/11, 9%). Moreover, primary lung/pleural lymphoma is one of the rarest neoplasias affecting the lung, accounting for only 0.4% of cases. Lung/pleural involvement is a very rare condition among B cell lymphomas since it mainly occurs in the setting of a generalized disease. A large majority of patients with secondary organ involvement are affected by DLBCL and have similar clinical features at diagnosis to others with advanced-stage disease. © 2014 S. Karger AG, Basel

Background: Despite the important progress in the research of myeloproliferative neoplasms (MPN) in the last years, treatment options are still limited. Currently, a cytoreductive approach is the backbone treatment, with hydroxyurea (HU) being the most important agent. However, this drug is not always well tolerated and seems to be associated with a potential leukemogenic effect. A valid alternative treatment is interferon alfa (IFN-α), but is reserved for selected patients due to the unfavorable toxicity profile. Furthermore, studies directly comparing IFN-α to HU are lacking, which is why we performed the so far largest Philadelphia negative (Ph-) MPN real-life analysis. Methods: From 2000 to January 2016 we prospectively assessed 63 Ph- MPN patients who received either HU at induction dosage of 25 mg/kg daily until achievement of hematologic remission, followed by maintenance therapy at 10 to 15 mg/kg daily, or IFN-α 3 MU subcutaneously three times a week. The treatment was selected based on physician's choice. All patients were screened for molecular genetic and cytogenetic analysis at diagnosis and during treatment. Results: Between January 2000 and January 2016, 63 consecutive patients were diagnosed with Ph- MPN: 28 were affected by polycythemia vera (PV) and 35 by essential thrombocytosis (ET). Fifteen patients with PV (54%) and 20 with ET (57%) were treated with IFN-α, while 13 with PV (46%) and 15 with ET (43%) received HU, respectively. Clinical characteristics were similar between both treatment groups and no significant differences were observed. During a median follow-up period of 81 months (range, 48-168 months) 97% of the patients treated with IFN-α achieved a hematologic response [60% complete (CHR), 37% partial (PHR)] compared to 78% in HU group (56% CHR, 20% PHR; p< 0.01). Molecular responses were limited to patients treated with IFN-α. Among these, the overall molecular response rate was 60% in both PV and ET. Complete molecular response (CMR) was achieved in 20% patients with PV and in 10% with ET, whereas partial molecular response (PMR) in 33% and 20% of patients with PV and ET, respectively. (Fig.1) Importantly, no patient who achieved CMR was observed to experience hematologic or molecular relapse after a median follow up of 92 months (range 53-132 months), suggesting that this drug is able to modify the natural course of Ph- MPN. In contrast, HU did not influence molecular response. In addition to molecular genetic analysis, we performed conventional cytogenetics on all patients at diagnosis and during treatment. Six patients were found to have abnormalities on metaphase cytogenetics pretreatment with IFN-α. Of these 6 patients, 1 had a resolution of cytogenetic abnormalities during the study. We did not observe the acquisition of new cytogenetic abnormalities in these 6 patients or in the others with normal baseline cytogenetics during therapy. Four patients were found having cytogenetic abnormalities before HU and two more developed new abnormalities over the course of the treatment, suggesting that this drug is not able to prevent leukemogenesis. IFN-α was well tolerated with no secondary malignancy, while HU was associated with more toxic events and seemed to increase risk of leukemia. Conclusion: We provide evidence that IFN-α might be a more valid therapeutic option due to its more profound hematologic responses, the ability to induce molecular responses and the potential ability to reduce the risk of leukemic transformation. Disclosures No relevant conflicts of interest to declare.

Despite the advent of new treatment strategies, many patients with diffuse large B-cell lymphoma (DLBCL) relapse or die of the disease. Prospective clinical trials have demonstrated that lenalidomide is an effective and safe treatment option, especially for non-germinal center B-cell (non-GCB) DLBCL. However, routine clinical data are lacking, which is why we provide the results of the so-far largest relapsed/refractory (R/R) DLBCL real-life analysis.We retrospectively assessed 123 R/R DLBCL patients who received either 15 or 25 mg/day of lenalidomide from January 2006 to January 2015.During a median follow-up period of 4.5 years, complete remission was achieved in 32% and a partial remission in 33% non-GCB patients compared with 0% and 3% in the GCB group (p.001 and .001, respectively), with median response durations of 15 and 5 months, respectively (p.001). Lenalidomide at 25 mg was superior to 15 mg in terms of response (complete remission 21% and partial remission 23% vs. 0% and 8%; p = .007 and .05) and median response duration (10 vs. 4 months; p = .03). Toxicity was limited and reversible. Median progression-free survival differed between non-GCB and GCB patients (37 vs. 30 months; p.001) and between the two dosages (24 vs. 34 months; p = .002). However, overall survival was similar between the subgroups (38-42 months).We provide evidence that lenalidomide is a valid treatment option for R/R DLBCL, with limited and reversible toxicity, and is more efficient in non-GCB DLBCL and at higher doses.Despite the advent of new treatment strategies, many patients with diffuse large B-cell lymphoma (DLBCL) relapse or die of the disease; hence, novel therapeutic approaches are urgently needed. This study confirms that lenalidomide is a valid and well-tolerated treatment option for relapsed/refractory (R/R) DLBCL. Superior outcomes were observed in non-germinal center B-cell (GCB) DLBCL, probably because of inhibition of the nuclear factor-κB pathway. Similarly, high drug doses resulted in greater clinical benefits. Overall, lenalidomide is a suitable therapeutic option for R/R DLBCL, especially in non-GCB DLBCL, and 25 mg/day dosing should be preferred.

Unlike cytotoxic agents, novel antineoplastic drugs can variably affect thyroid function and so impair patient outcomes. However, the widely used standard thyroid tests have demonstrated low sensitivity for detecting early thyroid damage that leads to dysfunction of the gland. To find a more reliable thyroid marker, we assessed the presence of antibodies binding thyroid hormones (thAbs) in a cancer population undergoing potentially thyrotoxic treatment. From April 2010 to September 2013, 82 patients with hematologic malignancies treated with tyrosine kinase inhibitors or immunoregulatory drugs were recruited. Healthy volunteers (n = 104) served as control subjects. Thyroid function, autoimmunity tests, thAbs, and thyroid sonography were assessed once during treatment. Overall, thAb positivity was recorded in 13% of the entire cohort. In most cases, the thAbs were of a single type, with a predominance of T3 immunoglobulin G. More specifically, thAbs were detected in 11 cancer patients, and abnormal levels of thyroid-stimulating hormone, thyroglobulin antibody, and thyroperoxidase antibody were detected in 6 (p = 0.05), 0 (p = 0.0006), and 2 cancer patients (p = 0.001) respectively. Ultrasonographic alterations of the thyroid were observed in 12 cancer patients. In contrast, of the 104 healthy control subjects, only 1 was positive for thAbs (1%). We have demonstrated for the first time that thAbs are a reliable marker of early thyroid dysfunction when compared with the widely used standard thyroid tests. A confirmatory prospective trial aiming at evaluating thAbs at various time points during treatment could clarify the incidence and timing of antibody appearance.

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Background Although the clinical outcome of patients with diffuse large B cell lymphoma (DLBCL) has been improved by the addition of rituximab to standard chemotherapy, almost one-third fails or relapses after first line treatment. The presence of monoclonal gammopathy (MG) is a known adverse prognostic factor for DLBCL. Because this subset of patients does not benefit from R-CHOP, new therapeutic options are required. Herein, we report the first case of extranodal DBCL of the lung with a concomitant MG who achieved a long lasting complete remission with lenalidomide. Case presentation The 73-year-old male patient presented with lateral cervical lymphadenopathy, B symptoms, lactate dehydrogenase and beta2-microglobulin elevation. Computed tomography (CT) showed mediastinal lymphadenopathy and bilateral lung involvement. Biopsy of both disease locations revealed the presence of DLBCL. Successive bone marrow trephine biopsy proved the presence of concordant DLBCL involvement. At the time of diagnosis, a MG was present as well. The patient did not respond to the standard treatments, and subsequently underwent lenalidomide 25 mg/m2 days 1–21 q28 plus dexamethasone 40 mg days 1–4, 9–12 e 17–20. This therapeutic regimen was efficacious and safe as salvage therapy in extranodal DBCL with a MG. Furthermore, we observed a close association between DLBCL response to therapy and MG levels, suggesting that the amount of M-protein might be a surrogate marker of disease response. Conclusion Although DLBCL associated with MG does not respond properly to the standard treatments, it is highly sensitive to lenalidomide, which is why we endorse its role as treatment of choice in this subset of patients. In addition, MG levels appear to correlate with tumor burden, suggesting that it might be a useful marker of disease response. Prospective trials to validate these observations are warranted.

Splenic marginal zone lymphomas (MZL) express mutated (M)) or unmutated (U)) immunoglobulin heavy chain (IGHV) genes. To investigate the IGHV mutational status impact on genetic lesions, this study combined single nucleotide polymorphism-arrays and IGHV sequencing in 83 cases. Clinical features and outcome were similar between U- and M-IGHV cases. Recurrent lesions frequency was higher in U-IGHV cases, including poor prognosticators. Frequencies differed among cases bearing individual IGHV genes or lambda light chains. In conclusion, SMZL comprises subgroups based on genetic abnormalities and immunogenetic status. Genomic lesion frequency differed and was higher in U-IGHV cases, possibly affecting the outcome.

Despite recent therapeutic improvements, the clinical course of diffuse large B-cell lymphoma (DLBCL) still differs considerably among patients. We conducted this retrospective multi-centre study to evaluate the impact of genomic aberrations detected using a high-density genome wide-single nucleotide polymorphism-based array on clinical outcome in a population of DLBCL patients treated with R-CHOP-21 (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 d). 166 DNA samples were analysed using the GeneChip Human Mapping 250K NspI. Genomic anomalies were analysed regarding their impact on the clinical course of 124 patients treated with R-CHOP-21. Unsupervised clustering was performed to identify genetically related subgroups of patients with different clinical outcomes. Twenty recurrent genetic lesions showed an impact on the clinical course. Loss of genomic material at 8p23.1 showed the strongest statistical significance and was associated with additional aberrations, such as 17p- and 15q-. Unsupervised clustering identified five DLBCL clusters with distinct genetic profiles, clinical characteristics and outcomes. Genetic features and clusters, associated with a different outcome in patients treated with R-CHOP, have been identified by arrayCGH.

Purpose Treatment of secondary CNS dissemination in patients with aggressive lymphomas remains an important, unmet clinical need. Herein, we report the final results of a multicenter phase II trial addressing a new treatment for secondary CNS lymphoma based on encouraging experiences with high doses of antimetabolites in primary CNS lymphoma and with rituximab plus high-dose sequential chemoimmunotherapy (R-HDS) in relapsed aggressive lymphoma. Patients and Methods HIV-negative patients with aggressive B-cell lymphoma and secondary CNS involvement at diagnosis or relapse, age 18 to 70 years, and Eastern Cooperative Oncology Group performance status ≤ 3 were enrolled and treated with high-doses of methotrexate and cytarabine, followed by R-HDS (cyclophosphamide, cytarabine, and etoposide) supported by autologous stem-cell transplantation (ASCT). Treatment included eight doses of rituximab and four doses of intrathecal liposomal cytarabine. The primary end point was 2-year event-free survival; the planned accrual was 38 patients. Results Thirty-eight patients were enrolled; CNS disease was detected at presentation in 16 patients. Toxicity was usually hematologic and manageable, with grade 4 febrile neutropenia in 3% of delivered courses and grade 4 nonhematologic toxicity in 2% of delivered courses. Four patients died because of toxicity. Autologous stem cells were successfully collected in 24 (89%) of 27 patients (median, 10 × 106/kg); 20 patients underwent ASCT. Complete response was achieved in 24 patients (complete response rate, 63%; 95% CI, 48% to 78%). At a median follow-up of 48 months, 17 patients remained relapse free, with a 2-year event-free survival rate of 50% ± 8%. At 5 years, 16 patients were alive, with a 5-year overall survival rate of 41% ± 8% for the whole series and 68% ± 11% for patients who received transplantation. Systemic (extra-CNS) and/or meningeal disease did not affect outcome. Conclusion The combination of high doses of antimetabolites, R-HDS, and ASCT is feasible and effective in patients age 18 to 70 years old with secondary CNS lymphoma, and we propose it as a new standard therapeutic option.

BACKGROUND On the basis of a multicolor-FISH test we aimed at verifying whether there is any molecular biological background for the different behavior of Gleason Score 7 prostate cancer (PCa). PATIENTS AND METHODS Biopsies of 44 patients with histological verified PCa, 20 with Gleason score 3 + 4 (group A) and 24 with 4 + 3 (group B), were analyzed using FISH. RESULTS In group A, FISH detected a unique gain of 8q24 in 2 patients (10.0%) and a unique loss of 8p22 in 9 patients (45.0%). No concurrent loss and gain of both sites were found in this group. Of group B (4 + 3) a unique loss of 8p22 was observed in 14 patients (58.3%) and a concurrent loss of 8p22 and gain of 8q24 in 6 patients (25.0%). CONCLUSION Different molecular genetic patterns could explain the different biological behavior of the 2 groups. The analysis of chromosomal aberrations could therefore influence the clinical decision process in the future. Prostate 66: 966–970, 2006. © 2006 Wiley-Liss, Inc.

The anthracycline doxorubicin plays a major role in the treatment of lymphoproliferative disorders. However, its use is often limited due to cardiac toxicity, which seems to be much less in the liposomal non-pegylated formulation (Myocet®). The aim of this study was the evaluation of efficacy and toxicity of Myocet®-containing treatment regimens, with a focus on cardiotoxicity during treatment in lymphoma patients. A total of 326 consecutive patients, treated between March 2008 and December 2013 in 11 Austrian and 1 Italian cancer centers, were retrospectively assessed. Patients’ baseline and treatment-related parameters were obtained by reviewing hospital records. Median age was 74 years (range 26–93). The most common histology was DLBCL (60 %), followed by FL (13 %) and MCL (8 %). At least one cardiovascular comorbidity was present in 72 % of patients. Most common grade 3/4 toxicities were hematologic, namely, leukopenia, neutropenia, thrombocytopenia, and febrile neutropenia in 44, 40, 17, and 16 %. Overall, 43 patients suffered a cardiac event (any grade) with most patients developing congestive heart failure. Parameters significantly associated with severe cardiac events (grades 3–5) were the presence of cardiovascular comorbidities, chronic obstructive pulmonary disease, and elevated baseline NT-proBNP. Treatment response after first line Myocet®-containing therapy was ≥58 % among all entities (range 58–86 %) and therefore comparable to those of conventional therapeutic regimens. Herein, we provide a detailed toxicity profile of Myocet®-containing chemotherapy regimens. Despite the high rate of patients with preexisting comorbidities, the number of adverse events was encouraging. However, these results need to be confirmed in a prospective randomized trial.

The first-line standard treatment for diffuse large B-cell lymphoma (DLBCL) is the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). It is associated with cardiotoxicity, which is why new treatment strategies are needed. Liposomial doxorubicin has been proven to reduce these side-effects, but until now a direct comparison regarding efficacy has not yet been published. We retrospectively assessed 364 consecutive DLBCL patients who underwent either R-CHOP (218; 60%) or R-COMP (doxorubicin replaced by non-pegylated liposomal doxorubicin; 146; 40%) in first line and compared outcome and survival. We provide evidence that both regimens induce a high and comparable number of complete remissions and that both are able to cure patients with DLBCL. Confirmatory data are needed.

Background: In the rituximab era, the conventional International Prognostic index (IPI) lost at least in part its predictive power, while the National Comprehensive Cancer Network-IPI (NCCN-IPI) seems to be a new and valid prognosticator. However, it has not yet been evaluated in patients with localized disease and it has not been compared with the modified IPI (mIPI) of the pre-rituximab era. In order to evaluate the different prognosticators and to assess the importance of rituximab and radiotherapy (RT), we carried out the so far largest retrospective analysis of patients with localized diffuse large B-cell lymphoma (DLBCL). Patients and methods: We retrospectively assessed clinical and therapeutical data of 1405 patients treated in from 1987 to 2012 in 10 cancer centers in Italy and 1 in Austria. Results: All patients underwent an anthracycline containing polychemotherapy and 254 additional rituximab. The median follow-up was 5.7 years (range 0.1-23 years). The 5-year overall survival (OS) was 75%, being significantly superior in those who underwent additional rituximab, while RT consolidation did not improve the outcome of those who received immunochemotherapy. Patients with extranodal disease benefited from the addition of rituximab, while RT did not improve OS of the immunochemotherapy subgroup. In the pre-rituximab era, the mIPI showed a better performance than the others. In rituximab-treated patients, the NCCN-IPI had the highest discriminant value and the 5-years OS varied significantly (P < 0.001) between the three risk groups and was 98% in low-risk patients, 82% in those with a low-intermediate risk and 57% among high-intermediate and high-risk cases. Conclusions: The NCCN-IPI is so far the best prognosticator for patients with localized DLBCL who underwent R-CHOP(-like). The addition of rituximab is indispensable regardless of the risk category and site of involvement, while the addition of RT should be reserved to those cases who are ineligible to rituximab.

The proviral insertion in murine (PIM) lymphoma proteins are a serine/threonine kinase family composed of three isoformes: Pim-1, Pim-2 and Pim-3. They play a critical role in the control of cell proliferation, survival, homing and migration. Recently, overexpression of Pim kinases has been reported in human tumors, mainly in hematologic malignancies. In vitro and in vivo studies have confirmed their oncogenic potential. Indeed, PIM kinases have shown to be involved in tumorgenesis, to enhance tumor growth and to induce chemo-resistance, which is why they have become an attractive therapeutic target for cancer therapy. Novel molecules inhibiting Pim kinases have been evaluated in preclinical studies, demonstrating to be effective and with a favorable toxicity profile. Given the promising results, some of these compounds are currently under investigation in clinical trials. Herein, we provide an overview of the biological activity of PIM-kinases, their role in hematologic malignancies and future therapeutic opportunities. Electronic supplementary material The online version of this article (doi:10.1186/s13045-014-0095-z) contains supplementary material, which is available to authorized users.

Background. Mantle Cell Lymphoma (MCL)represents an aggressive lymphoma for which an effective treatment has still to be determined. The FIL-MCL0208 phase III trial (EudraCTNumber: 2009-012807-25) is exploring R-CHOP followed byi) high-dose cytarabine, autologous stem cell transplantation, and ii) randomization between lenalidomide maintenance vs observation (Cortelazzo et al, EHA 2015). We performed genome-wide DNA profiling to identify unbalanced copy number variations (CNVs) with a clinical significance in patients enrolled in the FIL-MCL0208 phase III trial. Patients and Methods. The study included untreated, advanced stage MCL patients ( Results. 161 patients were currently evaluable for CNVs and clinical outcome. Patients had an intermediate/high-risk MIPI and a Ki67 ³ 30% in 43% and 42% of the cases, respectively. Twenty-five recurrent unbalanced CNVs were defined (Table 1). By multiple test corrected univariate analysis, seven CNVs had a negative impact on PFS: +3, 7p gain, 9p loss (CDKN2A), 17p loss (TP53), 8p loss, and 2 losses at 22q (Table 1). MIPI (intermediate/high vs low risk), Ki67+ and the TP53/KMT2D model (Rossi et al, ASH 2015) were also statistically significant. Combining CNVs and mutations, TP53 was inactivated in 27/147 cases (18%): mutated/deleted in 7/147 (5%), deleted but not mutated in 14/147 (10%), and mutated but not deleted in 6/147 (4%). The negative prognostic impact was equal for all the 3 inactivation modalities, which were then considered as a single group for further analyses. ATM was inactive in 69/147 (47%): mutated/deleted in 24/147 (16.3%), deleted in 12/147 (8%), and mutated in 33/147 (22.4%). KMT2D (MLL2) was inactive in 18/147 (12%): mutated/deleted in 1/147 ( The lesions with a significant impact at univariate were included in a multivariate analysis alongside MIPI, KMT2D inactivation and Ki67+ as continuous variable. Only TP53 inactivation by deletion and/or mutation, 7p22.2-p12.1 gain and KMT2D inactivation maintained their independent prognostic significance. Conclusions. Genome wide DNA profiling in the FIL-MCL0208 phase III trial identified lesions, namely TP53 and KMT2D inactivation and gains at 7p, which maintain a poor outcome significance in young MCL patients even following high-dose cytarabine and autologous stem cell transplantation. Disclosures Rossi: Gilead: Honoraria, Research Funding; Abbvie: Honoraria; Janseen: Honoraria. Stelitano:Azienda Ospedaliera: Employment. Gaidano:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria.

It is known that extranodal head and neck diffuse large B cell lymphomas (eHN-DLBCL) can affect various anatomical structures what is not well-known, however, is whether they differ in terms of clinical presentation and outcome. Clinical data of the multi-institutional series, the largest of its kind as yet, has been analysed with the aim of answering these open questions and providing long-term follow-up information. Data from 488 patients affected by stage I/II eHN-DLBCL was collected: 300 of the Waldeyer’s Ring (WR), 38 of the parotid and salivary glands (PSG), 48 of the thyroid gland (TG), 53 of the nasal cavity and paranasal sinuses (NPS), 24 of the palate and oral cavity (POC) and 25 with more than one involved site. Different eHN-DLBCL arising have distinct characteristics at presentation. The intermediate high risk-modified IPI was 67 % in TG, 44 % in WR, 38 % in PSG and POC and 20 % in MS. The worst 5-year survival rate had TG-DLBCL (61 %) due to the 61 % of patients with a mIPI >1. The addition of radiotherapy (cRT) to remitters did not translate into a survival advantage (5-year disease-free survival of 67 % in the cRT group vs. 70 % in the other). Three of four central nervous system recurrences occurred in NPS-DLBCL. Survival of HN-DLBCL was inferior to nodal DLBCL. This study showed that eHN-DLBCL remitters have an inferior survival when compared to nodal DLBCL, and that the addition of cRT does not provide a survival advantage. Since the standard of care nowadays is chemo-immunotherapy, survival of these patients might have been improved.

Idiopathic Bence-Jones proteinuria (BJP) is a rare plasma cell dyscrasia, of which the clinical and biological characteristics are yet unclear. Historical data suggested that they are at higher risk of progression to multiple myeloma or other related neoplasms, while recent findings are contradictory. To address these open questions, we evaluated a series of both BJP and monoclonal gammopathy of undetermined significance (MGUS) with production of an intact immunoglobulin plus Bence-Jones proteinuria (MGUS+BJP) with long-term follow-up, regarding their clinical characteristics and progression to multiple myeloma, amyloidosis or other related B cell lymphoproliferative disorders. Two hundred and twenty-nine persons fulfilling the 2004 criteria of MGUS were included in the final analyses: 31 had BJP and 198 had MGUS+BJP. At the time of diagnosis, significantly more persons in the BJP group had renal impairment, anaemia and polyneuropathy. A more detailed analysis revealed discrepancies between the serum and urine light chain type in nine cases, reflecting clonal heterogeneity. The number of disease progressions was higher in MGUS+BJP (n = 30) when compared to BJP (n = 1), with a rate of 1.6 and 0.4 progressions per 100 person-years, respectively. In conclusion, BJP has distinct clinical characteristics and a lower risk of progression when compared to MGUS+BJP. Our data suggest that MGUS+BJP being closer to malignant transformation may be due to the higher portion of genetically heterogeneous, pre-malignant plasma cell subclones.

Bendamustine proved to be effective for the treatment of chronic lymphocytic leukemia (CLL). However, the relationship between its activity with clinico-biological prognosticators has been addressed only in few studies. We retrospectively evaluated the efficacy of bendamustine, in a real-life contest, on 142 patients, median age 70 years, median number of previous regimens 2 (0–8, 13% previously untreated). Bendamustine was administered for a median number of 4 cycles, in 84% of cases with rituximab. Overall (ORR) and complete response (CRR) rates were 68 and 16.5%, respectively. Multivariate analysis demonstrated a relationship between ORR and number of prior treatments (OR 0.25, 95% CI 0.08–0.71; P = 0.009), del(17p) (OR 0.10, 95% CI 0.03–0.32; P

Background: Genomic complexity can predict the clinical course of patients affected by chronic lymphocytic leukemia (CLL) with a normal FISH. However, large studies are still lacking. Here, we analyzed a large series of CLL patients and also carried out the so far largest comparison of FISH versus single-nucleotide polymorphism (SNP) array in this disease. Patients and methods: SNP-array data were derived from a previously reported dataset. Results: Seventy-seven of 329 CLL patients (23%) presented with a normal FISH. At least one large (>5 Mb) genomic aberration was detected by SNP array in 17 of 77 patients (22%); this finding significantly affected TTT. There was no correlation with the presence of TP53 mutations. In multivariate analysis, including age, Binet stage, IGHV genes mutational status and large genomic lesion, the latter three factors emerged as independent prognosticators. The concordance between FISH and SNP array varied between 84 and 97%, depending on the specific genomic locus investigated. Conclusions: SNP array detected additional large genomic aberrations not covered by the standard FISH panel predicting the outcome of CLL patients.

This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced B-cell chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (B-PLL) to definitely describe the impact of this antibody in clinical routine use. Data were collected from 208 consecutive, mainly pretreated, patients with CLL (n = 202), and B-PLL (n = 6) who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) in various settings were assessed, and toxicities were documented. In these routine patients, a comparably low cumulative dose of alemtuzumab (median, 403 mg) was applied. In CLL, overall response rate was 32 %, and various pre-therapeutic parameters were predictive for inferior response, among them, the prior administration of ≥3 therapy lines (P < 0.001), refractoriness to fludarabine (P = 0.002), and bulky lymphadenopathy (P = 0.003). PFS and OS after start of alemtuzumab were 6.2 and 21.0 months, respectively. Bulky lymphadenopathy was the prominent risk factor for both inferior PFS (P < 0.001) and OS (P = 0.002). In B-PLL, four patients experienced a fatal outcome, whereas two patients had some benefit with alemtuzumab. The main adverse effects were CMV reactivation (20 %) and a broad spectrum of infections, which together were the main reasons for treatment interruption and/or premature termination. In conclusion, alemtuzumab administered even at low dose levels was effective but overall considerably toxic in routine CLL patients. We emphasize that alemtuzumab remains an important therapeutic option in subsets of CLL patients.

Consolidation radiotherapy (cRT) in patients with stage I/II diffuse large B-cell lymphoma of the Waldeyer's ring (WR-DLBCL) in complete remission (CR) after induction chemotherapy (CHT) is often associated with relevant acute and chronic toxicity, and its impact on survival remains to be defined. A total of 184 patients in CR after anthracycline-based chemotherapy were retrospectively analyzed: 62 underwent CHT alone (CHT group), while 122 (66%) patients were referred to cRT (CHT + RT group). After a median follow-up of 54 months, 36 patients (20%) experienced relapse: 19% in the CHT group and 20% in the CHT + RT group. At the time of analysis 47 (76%) CHT patients and 97 (80%) CHT + RT patients were alive. Five-year overall survival (OS), disease-free survival (DFS) and lymphoma-specific survival (LSS) were 80%, 74% and 86%, respectively. Five-year OS was significantly prolonged in the CHT + RT group, while DFS and LSS were similar between groups. This discrepancy was attributed to a high percentage of deaths due to unrelated causes in CHT patients. cRT does not prolong LSS in patients with early-stage WR-DLBCL in CR after anthracycline-containing chemotherapy. An international confirmatory trial is warranted.

To analyze time in relation to biochemical recurrence (BCR) and antiandrogen therapy (ADT) in patients with node metastasis at retropubic prostatectomy (RRP) and to identify prognostic factors of BCR- and ADT-free survival. Positive node patients at RRP and extended pelvic lymph node dissection (ePLND) were recruited retrospectively. Neoadjuvant and adjuvant therapy were exclusion criteria. BR was defined as PSA ≥ 0.3 ng/ml or the beginning of salvage radiotherapy or, ADT. Between 1995 and 2008, 70 node-positive patients after RRP were followed without ADT. Overall, BCR-free survival was 77.9% at 2 years and 29.7% at 8 years. The median time to BCR was 59.2 months for patients with only one node compared to 27.7 months for those with ≥2 nodes. The number of positive nodes was the only independent predictor of BCR in Cox regression multivariable analysis. ADT-free survival was 78% at 2 years and 39% at 8 years. The median time to ADT for patients with only one positive node was 115 months, and the 5 years ADT-free survival was 68.8%. Gleason score and the number of positive nodes were the only independent prognostic factors of time to ADT in the Cox regression multivariable analysis. The prognosis of patients with positive nodes after RRP and ePNLD is good in terms of BCR- and ADT-free survival. After 8 years, 29.7% were still free from BCR, and 39% did not receive ADT. The number of positive nodes was the most important predictor of BCR- and ADT-free survival.

The impact of different treatment modalities and prognostic factors on the clinical course of primary thyroid diffuse large B-cell lymphoma (PTDLBCL) is still the subject of research. This study was conducted to clarify these clinical aspects of this disorder. The clinical parameters of 48 patients with PTDLBCL at time of diagnosis were comparable to those of previous studies. Patients underwent either radiotherapy (RT) ±° surgery (SX), chemotherapy (CHT) alone or in combination with local treatments (RT or SX), or SX followed by CHT and RT. A 90% complete remission (CR) rate was observed among patients who underwent combined treatment modalities (CTM), compared to 76% among the others. The 5-year progression-free survival differed significantly between both groups (p = 0.028). Poor performance status and advanced age correlated with decreased survival. PTDLBCL is a curable disease prevalent in elderly patients. Combined treatment modalities were able to induce an elevated rate of CR, improving long-term survival in younger patients. However, the outcome in elderly patients still remains unsatisfactory. © 2011 Informa UK, Ltd.

International audience; Indolent primary cutaneous B cell lymphomas (PCBCL) generally have a good prognosis, but they often relapse leading in some cases to extracutaneous disease and therefore, to poor survival. We developed a prognostic model to improve the therapeutic approach to these lymphomas. Two hundred and seventeen patients with diagnosis of indolent PCBCL stage IE or IIE were assessed retrospectively. The prognostic model was built to fit a Cox proportional hazard model using all the covariates affecting progression-free survival (PFS) at 2 lesions were independent predictors for PFS. To each prognostic factor was assigned a value of 1. Patients were then stratified to three risk groups: score 0 (28%), low risk; score 1 (55%), intermediate risk; score 2 and 3 (17%), high risk with a 5-year PFS of 91%, 64%, and 48%, respectively (

P>To characterize diffuse large B-cell lymphoma (DLBCL) with chromosome 7 gains, we combined clinical data with genomic, RNA and miRNA profiling. Gains were associated with age > 60 years, female gender, a trend for higher complete response rate, lower death rate, and better overall survival in patients treated with R-CHOP. Lesions were inversely associated with bone marrow involvement and number of extra-nodal sites. Differentially expressed transcripts were enriched of genes belonging to specific pathways and miRNAs targets. MIR96, MIR182, MIR589, MIR25 were shown significantly up-regulated in 7q+ DLBCL by real-time PCR.

Follicular lymphoma (FL) is considered an indolent but incurable disease. It remains to be clarified whether the outcome has changed after the recent introduction of novel treatment modalities. We retrospectively analyzed the outcome of 281 patients with FL treated at the Oncology Institute of Southern Switzerland from 1979 to 2007. Three diagnostic eras were considered, according to the major therapeutic changes: before 1989 ('alkylating agents era', n = 73), 1990 to 1999 ('aggressive regimens and G-CSF era', n = 119), and 2000 to 2007 ('rituximab era', n = 89). The distribution of prognostic factors was similar in the three eras. A significant improvement in cause-specific survival (CSS) was observed over time (p = 0.0088), but not in overall survival. Median CSS was 12.5 years for patients with FL diagnosed before 1989, but was not reached in the more recent groups. The estimated CSS rate at 5 years in the three eras was 80%, 86%, and 91%, respectively. The CSS of patients with FL treated at our institution has improved over the last 25 years. This improvement, already evident before the wide introduction of rituximab in clinical practice, may be a result of the sequential application of effective therapies and improved supportive care.

Abstract 3957 Poster Board III-893 BACKGROUND Despite recent therapeutic improvements, the clinical course of DLBCL still differs considerably among patients. Here, we present the final results of a study to identify distinct DLBCL subgroups in patients treated with R-CHOP. METHODS DNA from 166 frozen DLBCL samples (PMBL,HIV-related DLBCL, post-transplant DLBCL and Richter's Syndromes were excluded) was analyzed with Affymetrix Human Mapping 250K arrays. Affymetrix U133 PLUS 2.0 gene expression profiles (GEP) were available for 54 cases. An optimized non-negative matrix factorization (NMF) was used for unsupervised clustering. The impact of the recurrent lesions on OS, PFS and DFS was evaluated with the log-rank test followed by multiple test correction (MTC). RESULTS 20 lesions showed a statistical significant impact on OS. Only 8p23.1 loss maintained its significance after MTC and was associated with additional aberrations, such as 17p- and 15q-. Unsupervised clustering identified 5 clusters with distinct genetic profiles, clinical characteristics and outcome: 1 (61/166, 37%), 2 (22/166, 13%), 3 (5/166, 4%), 4 (29/166, 17%), 5 (7/166, 6%). Cluster 1 was characterized by a heterogeneous genomic profile, lacking the most recurrent lesions. When compared to cluster 2 and 4, there were more HCV infections (9/38, 24% vs 1/12, 8% and 0/20; p=0.014) and bone marrow involvement (16/57, 28% vs 1/19, 5% and 2/24, 8%; p=0.008). GEP and morphology data suggested that cluster 1 could represent DLBCL with a high content of infiltrating T-cells, partially explaining the low rate of aberrations. This cluster has characteristics similar to the “host response” cluster previously identified by Monti et al., 2005. The outcome was poor with a high relapse rate (13/49, 26%) and a 5-yr OS of 76%. Cluster 2 (1q+/3q+/6q-/17p-) had also a relatively poor OS 80%. Cluster 4 (7+/12+) had a good outcome with a 5-yr OS of 92%. Clusters 2 and 4 showed differences in the number of pts with a high IPI-score (9/16, 56% vs. 7/26, 27%; p=0.057) and in single IPI factors, CR-rate (17/22, 77% vs. 25/29, 86%) and relapse rate (5/17, 29% vs. 2/25, 8%; p= 0.068). Cluster 3 (6q-/9-/11q+) had a trend for a good outcome. Instead, cluster 5 (3q+/11q+/18q+/6q-/8p-/15q-/17p-) showed a poor outcome. Clusters 2 and 4 were similar to ABC and GCB, respectively. CONCLUSIONS ArrayCGH provides the capability to identify genetic features and clusters, associated with a different outcome in patients treated with R-CHOP. The 8p23.1 locus should be investigated further for a gene that may be important in the pathogenesis of DLBCL. Disclosures: No relevant conflicts of interest to declare.

We compared clinical characteristics, prognostic factors and treatment outcome of primary thyroid DLBCL (PTL) with those of other locations of primary extranodal head and neck lymphomas (PEHNL) and we further analyzed somatic hypermutation in pts with PTL. From December 1990 to June 2004, 48 PTL out of 478 PEHNL patients (pts) (10%) were enrolled in this study, including 10 males and 38 females, with a median age of 73 years (range, 34–90 years). In comparison with other locations PTL cases had more frequently advanced age (>60 yrs), female sex, bulky disease, poor ECOG-PS, elevated LDH and >1 adverse factors according to stage-modified IPI (MIPI). The commonest treatment was a short course of anthracycline-based chemotherapy (CHT) ± involved field radiotherapy (IFRT). Forty-two percent of PTL pts also underwent surgery. Clonal IGHVDJ rearrangements were analyzed in 17/48 cases. The CR rate of PTL pts (85%) was comparable to those of other locations. After a median follow-up of 41 months (range 1–154.months), 5-yr OS, EFS and DFS were 51%, 46% and 86%, respectively. The OS compared unfavourably with other locations (75%), while the disease-specific survival rate was similar in both groups (80%). Moreover, MIPI was not predictive of survival, probably due to a high mortality unrelated to disease (19% Vs 7%). Regarding treatment PTL pts seem to benefit more from surgery in combination with chemotherapy and/or IFRT than from other treatments not including partial or complete thyroid resection (p=0.04). Somatic hypermutation of IGHV genes was observed in the majority of PTL cases, suggesting that they derive from germinal center experienced B-cell, while the unmutated status in a fraction of pts indicates a different histogenetic and pathogenetic pathway. The significant clustering of S and R mutations in CDRs and FRs in a fraction of cases with high homologous CDR3 suggests that antigen stimulation may have an important role in the pathogenesis of these lymphomas. In conclusion, in spite of more adverse features at presentation PTL pts showed a favorable disease-specific survival, comparable to that of other PEHN. Biological study in PTL pts suggests different histogenetic and pathogenetic pathway. The comparison of thyroid biological profile with that of other PEHNL could help to clarify the different clinical behaviour of this uncommon malignancy.

INTRODUCTION: Secondary central nervous system (CNS) dissemination is a lethal event in patients (pts) with aggressive lymphomas. A few studies focused on the treatment of this condition are available, confirming the dismal prognosis and the high rate of severe neurotoxicity in pts managed with radiotherapy-based induction. Thus, the most effective treatment for secondary CNS lymphoma remains an important, unmet clinical need. Herein, we report the final results of a multicenter phase II trial addressing a new treatment in pts with aggressive B-cell lymphoma and CNS involvement (NCT00801216). Experimental treatment is based on the encouraging experiences with high doses of antimetabolites in pts with primary CNS lymphoma (Ferreri et al. Lancet 2009), and with high-dose sequential chemotherapy combined with rituximab (R-HDS) and supported by autologous stem cell transplant (ASCT) in pts with relapsed aggressive B-cell lymphoma (Tarella et al. JCO 2008). METHODS: Selection criteria were: 1) histological diagnosis of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma blastoid variant (MCLb) or grade-3 follicular lymphoma (FL); 2) secondary CNS involvement at diagnosis or relapse; 3) age 18-70 years; 4) ECOG PS ≤3; 5) absence of HIV infection; 6) adequate organ functions. Pts with primary CNS lymphoma (exclusive CNS disease at diagnosis) were excluded. Experimental treatment consisted of an induction phase with 2 courses of methotrexate 3.5 g/m2 d1 + cytarabine 2 g/m2 x2/d d2-3, followed by an intensification phase with R-HDS (cyclophosphamide 7 g/m2 d1; cytarabine 2 g/m2 x2/d d22-25; pts with residual extra-CNS disease received also etoposide 2 g/m2 d43) and a consolidation phase with BCNU-thiotepa conditioning + ASCT (figure). Treatment included 8 doses of rituximab and 4 of intrathecal liposomal cytarabine. The primary endpoint was 2-year PFS; the planned accrual was 38 pts. RESULTS: 39 pts were registered (age 32-70 ys, median 59; M/F ratio 1.5): 33 had DLBCL, 3 MCLb, 3 FL. CNS disease (brain 21, meninges 5, spinal cord 2, multiple 11) was detected at diagnosis in 16 pts (all with extra-CNS disease) and at relapse in 23 (8 with extra-CNS disease). The median TTP from the previous treatment line was 3 months (range 0-77 months). Thirty-four pts completed the induction phase; 73 (93%) of 78 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 77%, 63% and 5% of courses, G3-4 febrile neutropenia in 16%, CMV reactivation in 3 pts. Transient G4 transaminases increase (3% of courses) was the only G4 non-hematological toxicity. Drugs dose reduction was indicated in 3 pts. Response after induction phase was complete in 11 pts and partial in 19 (ORR= 77%; 95%CI=64-90%). Thirty pts were referred to intensification phase (figure); 58 (97%) of 60 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 67%, 60% and 7% of courses, G3-4 febrile neutropenia in 22%, G4 sepsis in 8%. CMV reactivation was diagnosed in 4 pts, pulmonary aspergillosis in 1. No cases of G4 extra-hematological toxicity were recorded. Response after intensification phase (before conditioning) was complete in 22 pts and partial in 2 (ORR= 62%; 95%CI=47-77%). ASCs were collected in 21/22 (95%) pts (median 9.5 x 106/kg; range 6-19); 20 pts underwent ASCT. Response at the end of the whole program was complete in 23 pts and partial in 1 (ORR= 62%, 95%CI= 47-77%), 1 pt had SD, 10 experienced PD (all in the CNS), and 4 died of toxicity (sepsis 2, stroke, acute tracheal obstruction). Importantly, no pt was irradiated to the brain to achieve lymphoma remission, and no evidence of neurotoxicity was recorded in pts with a survival longer than 3 years. One pt was referred to sibling-donor transplant due to sMDS, and is alive and NED at 91 months of follow-up. At a median follow-up of 42 months, 16 pts remain relapse-free, with a 2-yr PFS of 42±8%. Sixteen pts are alive, with a 2-yr OS of 42±8%; 2-yr OS of transplanted pts was 72±11%. Extra-CNS and/or meningeal disease did not affect outcome, and survival was similar in both pts treated at presentation or at relapse. CONCLUSION: This radiotherapy-free combination of high doses of antimetabolites, R-HDS and ASCT is feasible and effective in pts ≤70 ys with secondary CNS lymphoma. Toxicity is usually haematological and manageable. Survival benefit is attainable also in pts with meningeal and/or concomitant extra-CNS disease. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: The salivary gland is one of the most common sites of involvement by non-gastric extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). This multicenter, international trial sought to characterize the clinical course, treatment and outcome of patients with salivary gland MALT lymphoma. Methods: Patients were identified from multiple international sites including the Mayo Clinic Lymphoma Database (n=89), three International Extranodal Lymphoma Study Group (IELSG) cohorts (n=138), and the University of Athens (n=21). All patients had biopsy-confirmed MALT lymphoma of the salivary gland by WHO criteria. Clinical characteristics, treatment, and outcomes were obtained from the respective patient databases. Survival probability was estimated using the Kaplan-Meier method and compared between groups with the Wilcoxon or log-rank. The impact of variables on survival was assessed by the Cox proportional hazards model. Results: Patients and clinical features: From 1983 to 2012, 247 patients with MALT lymphoma were included. Clinical characteristics are shown in Table 1. The median age at diagnosis was 59, and the male-to-female ratio was 1:3. The majority of patients (76%) presented with limited stage disease, and the parotid gland was the most common site of involvement (78%). There was a history of antecedent autoimmune disease in 41% of patients, and Sjögren’s disease was the most common (83%). Treatment: Information on initial treatment was available on 242 patients. 137/242 patients (57%) initially received local therapy with either surgery (n=81), radiation (n=26), or both (n=30). Of these, 25 received adjuvant systemic therapy. 90/242 patients (37%) were treated initially with systemic therapy, of whom 54% had localized and 46% had stage IV disease. Rituximab was used alone (n=16) or in combination with chemotherapy (n=26) in 42 of the 90. 15/242 patients (6%) were initially observed. Survival: The median OS for all patients was 18.3 years. PFS following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first line for all patients, or for those with stage I or II disease. On univariate analysis age Relapse/progression: The site of progression was known in 51 of 76 patients who progressed. 15 (29%) patients progressed in the same salivary gland or regional nodes; in 16 (21%) recurrence involved the contralateral salivary gland; 20 (31%) had distant progression. Relapse histology was identified in 30. The most common pathology at relapse was MALT (n=28), with one patient progressing to diffuse large B-cell lymphoma. A second patient developed a mantle cell lymphoma. Conclusions: Salivary gland MALT lymphoma commonly presents at an early stage, and has a favorable prognosis with a median OS of 18 years. Surgical or radiation therapy does not appear to have benefit over systemic therapy. Patients with Sjögren’s disease appear to have a better survival. The role of rituximab and optimal first-line therapy should be evaluated further in prospective trials. Table 1: Characteristics of 247 patients with salivary MALT Characteristic N (%) Age, median; range 59; 18-93 Sex, Male: Female 62: 185 (25: 75) Primary site of involvement Parotid 193 (78) Submandibular 12 (5) Other/not specified 42 (17) Extent (unilateral: bilateral) 89:21 Missing data 137 Autoimmune disorder* 101(41) Sjögren’s 84 (33) Rheumatoid arthritis 9 (4) Raynaud’s phenomenon 8 (3) Scleroderma 5 (2) Other 19 (8) Stage IE 147 (59) IIE 42 (17) IV 56 (23) Missing data 2 (1) IPI Score Low (0-1) 126 (51) Low-Intermediate (2) 20 (8) High-intermediate (3) 21 (8) High (4-5) 5 (2) Missing data 75 (31) Elevated LDH 17 (7) ECOG PS 0-1 246 2 1 Extranodal sites 1 58 (23) 2 187 (76) Missing data 2 (1) B symptoms 9 (4) * Percents may not equal 100 as some patients had more than one disorder. Figure One: Overall survival of patients with and without Sjögren’s disease Figure One:. Overall survival of patients with and without Sjögren’s disease Disclosures Nowakowski: Celgene, Morphosis: Consultancy. Zucca:Roche, Mundipharma, Novartis, Jannsen, Celgene: Consultancy, Honoraria, Research Funding.

Aim: Almost 30% of FL presents with stage I-II disease. The standard of care consists of involved-field radiation therapy (IFRT). Nevertheless, relapses occur in almost half of patients and usually outside the primary irradiation field, leading to death in a substantial number of cases. Systemic immunotherapy with rituximab (R) with or without IFRT could reduce distant recurrences leading to a better outcome. Therefore, we compared the efficacy of IFRT alone or in association with R (R + IFRT) versus R alone in stage I/II FL (grade 1-3A). Methods: From 1995 to September 2012, 108 consecutive patients affected by FL were retrospectively assessed at the Medical University of Innsbruck and at the University Hospital “G. Martino” in Messina. Treatment response was evaluated 6-12 weeks after the end of treatment and consisted of a physical examination, blood testing and CT scan. Results: 36 patients underwent IFRT (24–40Gy), 38 R alone (4-8 doses at 375mg/m2) and 34 R + IFRT (24–30Gy). Overall, median age at time of diagnosis was 60 years (range 31 - 88 years). In patients who underwent R or R + IFRT the percentage of adverse prognostic factors (B-symptoms, LDH, B2-Microglobulin, FLIPI score) was significantly higher. Among all three treatment groups no grade 3/4 toxicities were registered. Complete response rate was 84% in the IFRT-group, 87% in the R group and 97% in the R + IFRT-group (p = 0.1). Overall, median follow-up was 8 years (range, 1-20). Progression free survival (PFS) and time to next treatment (TTNT) were significantly higher in both rituximab arms compared to IFRT alone: median PFS was 5 and 6 years in the R and R + IFRT groups vs. 2.3 years in the IFRT one (p Conclusions: In conclusion, patients who underwent R or R + IFRT had a clearly better long-term control of the disease despite a significantly poorer prognostic profile at time of diagnosis. In the R + IFRT group results were even better than in the R group. Longer follow-up is needed to evaluate the impact on OS. Disclosure: All authors have declared no conflicts of interest.