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Current treatment of patient with mantle cell lymphoma (MCL) is insufficient and does not result in cure. To assess the efficacy and safety of maintenance therapy for patients with MCL, we performed a systematic review and meta-analysis of randomized controlled trials. Six trials randomizing 858 patients were included in the meta-analysis. In 5 trials, maintenance therapy consisted of rituximab. The pooled hazard ratio (HR) of death with rituximab maintenance compared to observation was 0.79, 95% CI 0.58 to 1.06 (4 trials, 737 patients). Progression free survival was longer with rituximab maintenance in each of the trials and in the pooled analysis (HR 0.58, 95% CI 0.45-0.73). The risk of neutropenia was higher with maintenance compared to observation risk ratio (RR) 1.31, 95% CI 1.03 to 1.66. None of the trials reported on quality of life outcomes. The grade 3 to 4 infection rate was 7% in each of the treatment groups. The risk of grade 3 to 4 infection was not affected by allocation to maintenance. Rituximab maintenance is recommended after R-CHOP or R-cytarabine-containing induction in the frontline setting for transplant eligible and ineligible patients, and after R-CHOP in the relapse setting. It is unclear if maintenance is of benefit after different induction chemotherapy such as bendamustine or fludarabine. It is too early to conclude on other type of maintenance for MCL patients.

e18065Background: Previous studies suggested that cisplatin and cetuximab administered concurrently to radiotherapy (RT) improve only marginally the outcome of patients older than 65 years. Methods...

Mantle cell lymphoma (MCL) has a poor prognosis with often short and incomplete remissions. We aimed to test the efficacy and tolerability of gemcitabine in treating MCL. Gemcitabine was given in doses of 1000 mg/m(2) as a 30 min infusion on days 1 and 8 of each 3 week cycle for a maximum of nine cycles. Eighteen patients with a median age of 70 years were recruited. MCL was newly diagnosed in half of patients and relapsed in the remainder. Fifteen patients had Ann Arbor stage IV. The best-recorded responses were 1 CR (complete remission), 4 PRs (partial responses), 8 SDs (stable diseases) and 4 PDs (diseases progression). The response rate (RR) (CR + PR) was 5 (28%; 95% confidence interval: 7.1, 48.5). The patient achieving a CR had stage IV disease. Most haematological adverse events occurred during the first chemotherapy cycle. Three patients developed non-haematological serious adverse events: dyspnea, glomerular microangiopathy with haemolytic uremic syndrome (HUS) and hyperglycaemia. The median time-to-progression and treatment response duration (TRD) was 8.0 (95% confidence interval: 5.5, 9.3) and 10.6 (95% confidence interval: 5.5, 10.9) months, respectively. We conclude that Gemcitabine is well tolerated, moderately active and can induce disease stabilization in patients with MCL.

Esophageal localization of adenoid cystic carcinoma of minor salivary glands is rare; it may occur in the early to mid-sixties' age group and is more frequently encountered in men than women. In the majority of cases, it arises from subepithelial glands of the middle to lower third of the esophagus, a similar distribution as squamous cell carcinoma. Prognosis depends mostly on tumor staging and resectability, which represents the only chance of cure. Due to the extreme rarity of this condition, there is limited experience with systemic therapy for advanced disease. We report a case of a patient with metastatic primary esophageal adenoid cystic carcinoma progressing on platinum- and irinotecan-based regimens, who achieved an objective response with oxaliplatin-based chemotherapy in combination with cetuximab.

Aims and background To evaluate the outcome of adult patients with de novo acute myeloid leukemia in the Italian-speaking part of Switzerland and to identify prognostic factors, time to progression and overall survival. Methods and study design Data of all adult patients diagnosed with acute myeloid leukemia from January 1984 to December 2003 were collected retrospectively. Univariate and multivariate analysis for time to progression and overall survival were performed. Results The incidence of acute myeloid leukemia in the adult population in southern Switzerland is 2.6/100,000 per year. Complete clinical and pathological data and follow-up information were available for 128 patients. The median age was 67 years (range, 18 to 94). The median follow-up was 97 months. Median overall survival was 6 months, with a 2-year overall survival of 16%. Median time to progression was 3 months. Thirty-five patients (median age, 80 years) were given best supportive care and/or palliative chemotherapy. The median survival in this subset was 2 months. Of the 93 patients treated with a curative intent, 48 were older than 60 years. The complete remission rate after induction chemotherapy was 80% for patients younger than 60 years and 31% for those older than 60 years (P 1 (P = 0.001) and treatment given before/after 1993 (P = 0.044) were found to be independent prognostic factors for both overall survival and time to progression. Conclusions Most patients with acute myeloid leukemia are older than 60 years, and their outcome is still disappointing. For younger patients, the prognosis is better if they receive high-dose cytarabine as post-remission therapy and if they are treated in the setting of a clinical trial.

Purpose: This phase I infusion rate escalation trial was undertaken to evaluate the maximum applicable infusion rate for rituximab without steroid premedication in patients having received one previous rituximab infusion. Experimental Design: Cohorts of at least three patients were assigned to rituximab with or without concomitant chemotherapy. The initial infusion rate was 200 mg/h in the first cohort, and was increased by 100 mg/h in each subsequent cohort to a maximum of 700 mg/h. In each patient the infusion rate was increased by 100 mg/h every 30 minutes to the total dose (375 mg/m2). In the first six cohorts (21 patients), two well-tolerated rituximab administrations were required; in the 7th cohort (11 patients) one previously well-tolerated rituximab infusion was required. Patients did not receive steroid premedication and were monitored with electrocardiograms (ECG), echocardiograms, Holter ECGs, troponin, and brain natriuretic peptide (BNP). Results: Thirty-two patients were included and 128 cycles were done, 85 at a rate of 700 mg/h. Patients tolerated infusion rates without major side effects. There were no new clinically relevant ECG alterations. Troponin (< 0.1 ng/L) and mean cardiac ejection fraction (65%) remained in the reference range; BNP baseline level increased significantly 24 hours after rituximab administration (from 30.4 to 64.1 ng/L; P < 0.0001). Conclusions: Rituximab can be administered safely at 700 mg/h without steroid premedication in patients having received at least one rituximab dose in the previous 3 months.

Background Addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy improves response rates and survival in patients with B-cell non-Hodgkin lymphoma (NHL). However, rituximab induces a transient B-cell depletion and a dose-dependent T-cell inactivation that could impair T-cell immunosurveillance. The impact of rituximab on second primary malignancy (SPM) risk remains unclear so far. We thus carried out a systematic review to compare SPM risk among patients treated or not with rituximab. Patients and methods We retrieved trials from MEDLINE and EMBASE and updated data presented at American Society of Hematology and American Society of Clinical Oncology meetings from 1998 to 2013. We selected randomized, controlled trials addressing newly or relapsed/progressive B-cell NHL in which randomization arms differed only from rituximab administration. Two authors extracted data and assessed the study quality. Results We analyzed nine trials involving 4621 patients. At a median follow-up of 73 months, a total of 169 SPMs were observed in patients randomized to rituximab compared with 165 SPMs in patients not randomized to rituximab (OR = 0.88; 95% CI 0.66–1.19). The proportion of females, histology subtypes, use of rituximab in first line or in maintenance did not influence SPM risk (P = 0.94, P = 0.80, P = 0.87, P = 0.87, respectively). Cumulative exposure through prolonged administration in trials with rituximab maintenance did not contribute to an increased risk of SPM (P = 0.86). Conclusion Our meta-analysis suggests no SPM predisposition among NHL survivors exposed to rituximab at a median follow-up of 6 years.

The outcome of patients with follicular lymphoma has substantially improved in recent years, mainly due to the widespread use of the monoclonal antibody rituximab and partially due to autologous and allogeneic transplantation, and the introduction of new drugs and to the improvement in diagnostic accuracy. The choice of therapy is still based on patient characteristics, extension of disease and clinical prognostic factors. The majority of patients in need of treatment are still treated with cytotoxic agents in combination with rituximab; nevertheless a number of new agents, which are active in this disease, have recently been developed. It has yet to be determined, whether they will partly or completely replace chemotherapy in the near future. This review focuses on the role and the choice of chemotherapy in different clinical situations of follicular lymphoma, in a time when chemotherapy-free treatment becomes more and more of a topic of discussion.

Background: This study was aimed at investigating the clinical features and outcomes of follicular lymphoma ( FL) patients younger than 40 years, which have not been extensively investigated yet. Patients and methods: One hundred and fifty- five patients younger than 40 years were retrospectively studied from a series of 1002 FL patients diagnosed in four different European Oncology Centres ( Barcelona, Spain; Bellinzona, Switzerland; London, UK; Novara, Italy) from 1985 to 2010. Results: Patients younger than 40 had a lower incidence of elevated LDH, high beta2- microglobulin, and a high- risk Follicular Lymphoma International Prognostic Index ( FLIPI) score, whereas bone marrow involvement and bulky and disseminated lymphadenopathy were more frequent. At a median follow- up of 10 years, younger patients, in comparison with those older than 40, had significantly better overall ( OS), cause- specific survival ( CSS), and progression- free survival ( PFS), with 10- year OS rate of 81% versus 51% ( P < 0.0001), 10- year CSS rate of 82% versus 60% ( P < 0.0001), and 10- year PFS of 39% versus 24% ( P = 0.0098). However, there were no significant CSS and PFS differences in comparison with the patients aged 40- 60. In multivariate analysis, having the lymphoma diagnosed in the last two decades and a favourable FLIPI score were associated with a significantly longer PFS and CSS in younger patients, whereas only FLIPI retained statistical significance for OS. Conclusions: In our series, FL patients younger than 40 have a median OS of 24 years and their outcome seems to be improving over time. However, they still have a significantly shorter life expectancy than that of an age- matched general healthy population.

Purpose To evaluate the effect of single-agent rituximab given at the standard or a prolonged schedule in patients with newly diagnosed, or refractory or relapsed mantle cell lymphoma (MCL). Patients and Methods After induction treatment with the standard schedule (375 mg/m2 weekly × 4), patients who were responding or who had stable disease at week 12 from the start of treatment were randomly assigned to no further treatment (arm A) or prolonged rituximab administration (375 mg/m2) every 8 weeks for four times (arm B). Results The trial enrolled 104 patients. After induction, clinical response was 27% with 2% complete responses. Among patients with detectable t(11;14)-positive cells in blood and bone marrow at baseline, four of 20, and one of 14, respectively, became polymerase chain-reaction–negative after induction. Anemia was the only adverse predictor of response in the multivariate analysis. After a median follow-up of 29 months, response rate and duration of response were not significantly different between the two schedules in 61 randomly assigned patients. Median event-free survival (EFS) was 6 months in arm A versus 12 months in arm B; the difference was not significant (P = .1). Prolonged treatment seemed to improve EFS in the subgroup of pretreated patients (5 months in arm A v 11 months in arm B; P = .04). Thirteen percent of patients in arm A and 9% in arm B presented with grade 3 to 4 hematologic toxicity. Conclusion Single-agent rituximab is active in MCL, but the addition of four single doses at 8-week intervals does not seem to significantly improve response rate, duration of response, or EFS after treatment with the standard schedule.

We retrospectively analysed toxicities and clinical results of 61 Hodgkin's lymphoma patients treated with chlorambucil, vinblastine, procarbazine, doxorubicin, bleomycin, vincristine and etoposide (ChlVPP/ABVVP), delivered in a weekly alternate schedule. Of 61 patients, 33 were in stages III-IV, 21 in stage IIB and seven in stage IIA with bulky disease or extranodal presentation. ChlVPP/ABVVP was administered for 6-8 cycles. Involved field radiotherapy (IFRT) (30-35 Gy) was delivered to 31 patients with residual disease after chemotherapy or bulky disease at diagnosis. Of 61 patients, 58 (95%) achieved complete clinical or radiological remission after chemotherapy and IFRT. With a median follow-up of 60 months, 5-year overall survival, relapse- and event-free survival were 78.8% (95% CI 68.2-91.1%), 81% (95% CI 70.6-92.2%) and 71.9% (95% CI 68.2-82.2%) respectively. Grades 3-4 neutropenia was the most relevant haematological toxicity and occurred in 82% of patients. Non-haematological toxicities were mild and reversible. No toxic deaths were recorded. One patient developed secondary acute myeloid leukaemia 1 year after ChlVPP/ABVVP. Due to the retrospective nature of this study, no definitive conclusions could be drawn about the clinical activity of ChlVPP/ABVVP. Nonetheless, clinical results seem better than those reported with standard regimens [ABVD (doxorubicin, bleomycin, vincristine, dacarbazine), MOPP (methotrexate, vincristine, procarbazine, prednisone), MOPP/ABVD] and as good as those reported using standard or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone), with a lower degree of haematological and non-haematological toxicity. Long-term results of the ongoing randomized trial, comparing ABVD versus high-dose intensity weekly regimens will be useful to confirm our results.

Mantle cell lymphoma (MCL) shares immunophenotypic and karyotypic features with chronic lymphocytic leukaemia. The latter comprises two distinct entities with prognosis dependent upon immunoglobulin heavy chain (IgH) gene mutational status and the presence of 11q deletion. We evaluated the relevance of IgH gene mutational status, IgV gene family usage and presence of 11q deletion in a series of 42 histologically reviewed classical MCL cases to determine the prognostic impact. VH3 was the most common VH family, with VH3-21 being the most frequent individual VH gene. Approximately 30% of the cases had a IgH somatic mutation rate higher than 2%, but was only higher than 4% in ter), with two minimal deleted regions, at 11q22.2 and 11q23.2. There was no association between 11q loss and IgH gene somatic mutation rate; the use of VH3-21 gene could be associated with a better prognosis.

A haematotoxicity model was proposed by Parchment in 1998 to predict the maximum-tolerated dose (MTD) in humans of myelosuppressive antitumour agents by combining data from in vitro clonogenic assays on haematopoietic progenitors and in vivo systemic exposure data in animals. A prospective validation of this model in humans was performed with PNU-159548, a novel agent showing selective dose-limiting myelosuppression in animals. PNU-159548 and its main metabolite, PNU-169884, were tested in vitro on murine, canine and human colony forming units-granulocyte macrophages (CFU-GM) and in vivo on mice and dogs. The IC(90x) ratios (IC(x)=concentration inhibiting x% of colony growth) for CFU-GM and drug plasma protein binding were used to adjust the target plasma concentrations versus time curve (AUC) and predict the human MTD. The predicted MTD was compared with values achieved in phase I studies. Canine CFU-GM were 6-fold more sensitive (P0.01) and murine CFU-GM 1.7-fold less sensitive (P0.05) to PNU-159548 treatment than the human progenitors. PNU-169884 behaved similarly to PNU-159548. The predicted MTDs in humans calculated from data in mice and dogs were 15 and 38 mg/m(2), respectively. Overall, 61 patients were treated in two phase I studies, at doses ranging from 1.0 to 16 mg/m(2). Thrombocytopenia was dose-limiting with a MTD of 14 and 16 mg/m(2) in heavily and minimally pretreated/non-pretreated patients, respectively. Adjusting animal MTD data by means of the CFU-GM ratio between species can predict the human MTD with a good quantitative accuracy. Inhibition of common haemopoietic progenitors by PNU-159548 induced neutropenia/thrombocytopenia in animals and thrombocytopenia in patients, probably due to the higher sensitivity to the compound observed in human colony forming units-megakaryocyte (CFU-MK).

Indolent non-Hodgkin's lymphomas (NHLs) are essentially incurable with current treatments. Rituximab is a specific anti-CD20 chimeric monoclonal antibody against the CD20 antigen, which is stably expressed on most B-cells (from the pre-B-cell stage). Compared with chemotherapy, rituximab has an excellent tolerability profile, making it a good therapeutic option for patients with indolent NHL. In the pivotal study for rituximab, patients with relapsed or refractory indolent or follicular lymphoma (FL) had an overall response rate of 50%. There is evidence that first-line rituximab therapy may be associated with better response rates; in previously untreated FL with a low tumor burden, rituximab monotherapy has produced an overall response rate of 73%. Attempts to improve response rates to rituximab by increasing the dose or frequency of dosing showed that the addition of four extra infusions of rituximab (in addition to the standard treatment schedule) resulted in an overall response rate of 76% in patients with FL. Augmenting rituximab with cytokines is also an option for increasing response rates in patients with indolent NHL. In a trial by the Nordic Lymphoma Study Group in patients with previously untreated or first-relapse indolent NHL, who had stable disease or a partial response after four doses of rituximab, 48% of the patients treated with rituximab plus interferon-alpha2a achieved a complete response. A further option is to combine rituximab with chemotherapy. Interim analyses from the East German Study Group have shown that rituximab plus mitoxantrone, chlorambucil and prednisolone (MCP) resulted in overall response rates of 89% in patients with untreated indolent lymphoma. Rituximab is therefore an excellent treatment option both as first-line and as salvage therapy for patients with indolent NHL.

INTRODUCTION. In classical Hodgkin lymphoma (cHL), the low representation (~5%) of Hodgkin-Reed-Sternberg cells (HRS) challenged tumor genotyping on the tissue biopsy. Cell free DNA (cfDNA) is shed into the blood by tumor cells and can be used as source of tumor DNA for the identification of somatic mutations, track clonal evolution of tumors and detect minimal residual disease during therapy. AIMS. The study aimed at: i) showing that cfDNA mirrors the genetics of HRS cells in cHL patients; ii) characterizing the mutational profile of a large cohort of newly diagnosed and chemorefractory cHL; iii) identifying molecular prognostic subtypes; iv) early detecting residual disease during therapy; and v) longitudinally tracking tumor clonal evolution under different treatment modalities. METHODS. The study included 80 newly diagnosed cHL and 32 chemorefractory cHL. The following biological material was analyzed: i) cfDNA from plasma collected at diagnosis, during ABVD courses, at refractory progression, before and during therapy with brentuximab or nivolumab; and ii) normal germline genomic DNA (gDNA) from granulocytes. For comparative purposes, paired tumor gDNA from microdissected HRS cells of 13 cases was also analyzed. A targeted resequencing panel optimized to include the coding exons and splice sites of 77 genes recurrently mutated in B-cell lymphomas was used for genotyping. Ultra-deep next-generation sequencing (NGS) of the gene panel was performed on NexSeq 500 (Illumina) using the CAPP-seq library preparation strategy (NimbleGen). RESULTS. In cHL patients, cfDNA surrogated gDNA from HRS cells, since it harbored 87.5% of the tumor confirmed mutations. Genes recurrently affected by non-synonymous somatic mutations in >20% of cHL included STAT6 (37.5%), TNFAIP3 (35%), and ITPKB (27.5%) (Fig. 1A). Mutations clustered in major pathways, including NF-κB, PI3K-AKT, cytokine and NOTCH signaling, and immune evasion. ITPKB mutations: i) were quite specific for cHL, being rare or absent in other lymphomas; ii) caused the subcellular delocalization of the protein in primary HRS cells of mutated patients; iii) correlated with clues of PI3K-AKT signaling activation both at gene expression and protein levels; and iv) consistent with the positioning of ITPKB downstream PI3K in the pathway, associate with resistance to PI3K inhibitors. Mutations of CD58, encoding a co-stimulatory molecule for T-cells, associated with short PFS independent of interim PET/CT results, pointing to immune escape genetic lesions as biomarkers of aggressive disease (Fig. 1B). Newly diagnosed and chemorefractory cHL shared a largely overlapping mutational landscape. TP53 mutations were not enriched in refractory cHL as instead commonly found in other types of refractory B-cell tumors. Conversely, more TET2 mutations were documented in refractory cHL, including newly acquired mutation, thus signaling towards aberrant DNA methylation programming as a mechanism of resistance in cHL with potential therapeutic implications. By longitudinal analysis, in patients relapsing under/after chemotherapy or brentuximab vedotin, pre-treatment/relapse tumor pairs branched through the acquisition of phase specific mutations from an ancestral clone, that always persisted (Fig. 1C). Conversely, in patients maintained under nivolumab, clones were cyclically suppressed and replaced by completely novel clones. We utilized the change in circulating tumor cfDNA load from baseline to interim timepoint to predict the best response to ABVD and to complement interim PET/CT in anticipating cure. A drop of 100-fold or 2-log drop in tumor cfDNA after 2 ABVD courses associated with an eventual complete response and cure. All cured patients that were inconsistently judged as interim PET/CT positive turned out to have a >2 log drop in tumor cfDNA. A drop of less than 2-log in tumor cfDNA after 2 ABVD courses associated with an eventual progression. All relapsed patients that were inconsistently judged as interim PET/CT negative turned out to have a Download : Download high-res image (196KB) Download : Download full-size image Figure 1 . Disclosures Stathis: Celgene: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Roche: Consultancy, Other: Advisory board; Amgen: Honoraria. Bertoni: Acerta Pharma: Research Funding; Bayer: Research Funding; Cellestia: Research Funding; Menarini: Research Funding; Piqur: Research Funding; Immunogen: Research Funding. Santoro: Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Zucca: Bayer: Consultancy, Other: Advisory Role; Jannsen: Consultancy, Honoraria, Other: Advisory role; Takeda: Consultancy, Other: Advisory role; Celltrion Healthcare: Consultancy, Other: Advisory Role; Celltrion Healthcare: Consultancy, Other: Advisory Role; Celgene: Honoraria, Research Funding; Sandoz: Consultancy, Other: Advisory role; Bayer: Consultancy, Other: Advisory Role; Gilead Science: Consultancy, Other: Advisory role; Roche: Honoraria, Research Funding; Jannsen: Consultancy, Honoraria, Other: Advisory role; Roche: Advisory role, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Research Funding; Mundipharma: Research Funding; Gilead Science: Consultancy, Other: Advisory role; Takeda: Consultancy, Other: Advisory role; Sandoz: Consultancy, Other: Advisory role. Gaidano: Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Carlo-Stella: ADC Therapeutics: Research Funding.

Lessons Learned Panitumumab shows activity in terms of disease control rate and preventing disease progression but not for tumor shrinkage in head and neck squamous cell cancer for second-line treatment. Epidermal growth factor receptor (EGFR) copy number gain, a property of tumor cells that theoretically could identify patients more likely to experience disease response, was common among patients having disease control. Our trial, given the lower toxicity with an every-2-week schedule, provides guidance for future trials, for example, in combinations of immune therapies and anti-EGFR-antibodies. Background The objective of this study was to investigate the efficacy and safety of panitumumab (anti-epidermal growth factor receptor [EGFR] antibody) given as a single agent in platinum-pretreated head and neck squamous cell cancer (HNSCC). Methods Patients with advanced HNSCC previously treated with platinum-containing therapy were included. Panitumumab was administered intravenously every 2 weeks at a dose of 6 mg/kg. Primary endpoint was overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1; secondary endpoints were progression-free survival (PFS) and safety. A Simon's two-step design was chosen; 4 partial remissions (PR) in the first 32 patients were required for continuing to step two. An exploratory biomarker analysis was performed. Results Thirty-three patients were enrolled. Two patients obtained a PR for an ORR of 6%, and 15 (45%) showed stable disease (SD) for at least 2 months, resulting in a 51% disease control rate. Median PFS was 2.6 months (95% confidence interval [CI]: 1.7–3.7), while median OS was 9.7 months (95% CI: 6.3–17.2). The most frequent adverse drug reactions were cutaneous rash (64%) and hypomagnesemia (55%). Overall, 30% of patients experienced grade 3/4 adverse events. No infusion-related reactions occurred. EGFR copy number gain (CNG) was more frequent in patients who benefitted from panitumumab. Two uncommon KRAS mutations (G48E, T50I) and 3 canonical PIK3CA mutations (all E545K) were detected. High-risk HPV16 was found in 10 patients and EGFR CNG in 13 treated patients. EGFR CNG seems to be more frequent in individuals with at least SD compared with patients with progressive disease (59% vs. 30%). PFS for patients with EGFR CNG was 4.6 months (95% CI: 1.0–9.2 months) and 1.9 months (95% CI: 1.0–3.2 months) for patients without CNG (p = .02). Conclusion Panitumumab monotherapy in pretreated HNSCC patients was well tolerated but moderately active. We observed a considerable disease control rate. Future strategies with this agent comprise right patient selection through the identification of reliable biomarkers and gene signatures predicting response and, considering good tolerability and convenience, combination strategies with novel agents and immune therapeutic agents.

The aim of the present study was to retrospectively evaluate whether a high-dose sequential chemotherapy programme (HDS: cyclophosphamide, methotrexate, etoposide) administered prior to autologous transplantation could optimize the salvage of patients with refractory or relapsed aggressive non-Hodgkin's lymphoma. Between 1985 and 1999, 103 patients (median age 43 years, range 16-65) from eight Italian centres and one Swiss centre, with refractory (n = 38) or relapsed (n = 65) diffuse large B-cell and T-cell lymphoma, were treated using HDS followed by high-dose regimens with autologous haematopoietic stem cell transplantation. Eighty-three patients responded to the HDS regimen (81%, 95% C.I., 73- 88%) and 79 eventually achieved a complete response (CR) after autotransplantation (90%, 95% C.I., 81- 96%). None of 20 cases resistant to HDS attained CR. Treatment-related mortality was 4%. After a median follow-up of 24 months (range 6-174 months), 3-year estimates of overall survival, event-free survival and disease-free survival were 47% (95% C.I., 36-59%), 44% (95% C.I., 34-54%) and 64% (95% C.I., 50-74%) respectively. Multivariate analysis showed that chemosensitivity to HDS represented the strongest predictor of both CR and survival. This retrospective study shows that salvage treatment using HDS had relatively low toxicity and was associated with remarkable response rates, allowing further effective therapy with high-dose autograft programmes.

Purpose: To evaluate the feasibility and clinical effects of increasing doses of amifostine administered four times in 1 day with high-dose (HD) cyclophosphamide (CTX). Methods: A group of 16 patients with a diagnosis of lymphoma were treated with HD-CTX given at a total dose of 7 g/m2 subdivided into four doses, each preceded by increasing doses of amifostine. A group of 12 lymphoma patients previously treated with the same HD-CTX regimen was used as historical controls. Results: The dose of amifostine was escalated in cohorts of three patients each from 4×570 mg/m2 to 4×910 mg/m2 without severe toxic effects. Further patients were treated at the highest dose level. Side effects included a fall in blood pressure (always less than 20% of baseline value), asymptomatic hypocalcemia (from a median value of 2.4 to 1.7 mmol/l) and a decrease in creatinine clearance (from a median value of 102 to 85 ml/min). The parameters of hematotoxicity for patients treated in the study were not significantly different from those of the historical control patients. Conclusions: Amifostine can be given safely at a dose of 910 mg/m2 four times in 1 day in combination with HD-CTX. With this schedule amifostine did not show a myeloprotective effect.

Rituximab 375 mg/m(2) weekly x 4 has been reported to induce a 60% response rate in patients with relapsed follicular lymphomas (FL). Our aim was to examine the effect of this rituximab schedule on circulating FL cells in an ongoing multicenter study. One hundred fifty-four patients with FL were examined by nested polymerase chain reaction (PCR) at baseline for the presence of t(14;18) translocation-carrying lymphoma cells in bone marrow and/or blood. Sixty-four patients (42%) had PCR-detectable t(14;18)(+) FL cells. Pretreatment characteristics of these 64 patients were as follows: one had stage I, nine had stage II, 14 had stage III, and 40 had stage IV disease. Thirty-five patients had bulky disease (or = 5 cm) and 25 patients had an elevated serum lactate dehydrogenase (LDH) level. Bone marrow was morphologically assessed in 64 patients, and 39 of these patients had an infiltration with FL cells. Blood samples from 51 patients were available for PCR analysis between weeks 8-12 after induction therapy, and 28 of these patients (55%) were PCR negative. Paired blood and bone marrow samples were available for PCR analysis from 39 patients between weeks 8-12 after induction therapy with rituximab. Thirteen of these patients (33%) did not have PCR-detectable cells in blood and bone marrow, while 26 patients (67%) still had circulating t(14;18)(+) cells in either bone marrow (eight patients), blood (one patient), or both (17 patients). PCR negativity in blood and bone marrow in 13 patients was statistically significantly associated with partial or complete response after induction therapy with rituximab (P = 0.006). However, clearance of PCR-detectable t(14;18)(+) cells in bone marrow and/or blood could not be associated with any low tumor burden pretreatment characteristics such as stages I/II, absence of morphological bone marrow infiltration or tumor bulk ofor = 5 cm, and normal serum LDH.

Background: The randomized phase-2 trial SAKK 35/10 was conducted by the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) to compare the activity of single-agent rituximab versus rituximab plus lenalidomide in the first-line treatment of symptomatic follicular lymphoma (FL). The results of primary endpoint (complete remission [CR/CRu] at week 23) assessment were previously reported, showing that addition of lenalidomide to rituximab results in a significantly higher CR/CRu rate at the expected cost of increased but manageable toxicity (Kimby et al. Blood 2014.124 (21):799; Zucca et al. Hematol Oncol 2015. 33(s1): 105). Here we report the first analysis of secondary endpoints, progression-free survival (PFS), time to next anti-lymphoma treatment (TTNT), CR duration, as well as CR/CRu rate at 30 months (CR30). Methods: 154 patients (pts) with grade 1 to 3a FL, untreated and in need of systemic therapy, were randomized to receive either rituximab (375mg/m2 at week 1, 2, 3, 4, 12, 13, 14 and 15) or rituximab (same schedule) plus lenalidomide (15 mg daily, from 14 days before the first until 14 days after the last rituximab administration). The sample size was calculated to allow the detection of a 20% increase of the CR/Cru rate with 90% power and type I error 0.10; a one-sided Z-test for proportions was used to compare the two arms. Treatment was discontinued in pts who did not achieve at least a 25% reduction in the sum of products of tumor diameters at week 10. Primary and secondary endpoints were defined according to the NCI international standardized criteria (Cheson et al 1999). Results: 77 pts (median age 63 years, 52% with stage IV and 47% with poor-risk FLIPI score) were allocated in the single-agent rituximab arm and 77 (median age 61 years, 48% with stage IV and 47% with poor-risk FLIPI score) in the combination arm. A higher CR/CRu rate in the combination arm was documented both by the investigator assessment (36% vs 25%) and by the independent response reviewers of CT scans (61% vs. 36%). Adverse events of grade ≥3 were more common (56% vs 22% of pts) in the combination arm, including neutropenia (23% vs 7%). At a median follow up of 3.1 years, a longer CR duration was seen for the pts in the combination arm (median not reached vs 2.3 years) as well as a longer PFS (median not reached vs. 2.3 years), these differences were not statistically significant. The CR30, recently identified as a reliable surrogate of PFS (Sargent et al. Hematol Oncol 2015. 33(s1): 166), was significantly improved by the addition of lenalidomide to rituximab (42% vs 19%, p=0.001). Moreover, TTNT was significantly longer with the combination (median not reached vs 2.1 years, p=0.02) [Figure1]. Overall survival rates at 3 years were 93% and 92%, respectively. Conclusions: The SAKK 35/10 randomized trial confirmed that lenalidomide plus rituximab is an active and feasible initial treatment for FL pts in need of therapy. Addition of lenalidomide significantly increased the CR/CRu rate at week 23 (primary endpoint) and was maintained throughout 30 months. Although the trial was not powered to detect survival differences (secondary endpoints), a significantly better TTNT and a trend towards prolonged PFS and CR duration was seen in the combination arm. The excellent overall survival in both arms suggests that chemotherapy-free strategies should be further explored. Figure 1. Time to next anti-lymphoma therapy by treatment arm Figure 1. Time to next anti-lymphoma therapy by treatment arm Disclosures Kimby: Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lecture at educational session; Celgene: Other: Honoraria for lecture. educational meeting; Pfizer: Other: Research grant; Roche: Other: Honoraria for lecture in educational meetings; Gilead: Honoraria, Other: honoraria for educational lecture in meeting sponsored by Gilead. Mey:roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Wahlin:Roche: Consultancy. Hernberg:Roche: Consultancy, Honoraria. de Nully Brown:Roche: Research Funding. Ferreri:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zander:Bristol Myers, Celgene, Amgen, Mundipharma, Janssen-Cilag, Takeda Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background: MCL is characterized by a dismal long term prognosis with a median overall survival of 3-5 years. Rituximab maintenance treatment (MR) improves survival of patients with follicular lymphoma, and its effect was assessed for MCL patients in several trials with inconsistent results. Other agents as bortezomib were also evaluated as maintenance therapy for MCL. Aims: We performed a systematic review and meta-analysis of RCTs in order to assess the effect of maintenance therapy on clinical outcomes of patients with MCL. Methods: We included RCTs that compared any type of maintenance to no maintenance or a different maintenance for patients with MCL, either in first line or relapsed disease. In July 2016 we searched The CochraneLibrary, MEDLINE, conference proceedings, and databases of ongoing trials. Two reviewers independently assessed the qualityof the trials and extracted data. The primary outcome wasall cause mortality. Secondary outcomes included progression free survival (PFS) and infectious adverse events. Relative risk (RR) for dichotomous data and hazard ratio (HR) for time to event datawere estimated and pooled using random-effects model. Results We identified 6 trials that reported relevant outcomes, conducted between the years 1998 to 2012 and randomizing 857 patients with MCL. Most patients were males, with a median age ranging from 57 to 70 years, and predominantly good performance status. Ninety-six percent of the patients received their first line of treatment. MIPI score was reported in three trials: 20 to 42 percent of patients had a high MIPI score. Induction therapy included rituximab in all trials. In five trials chemotherapy induction was applied and consisted of fludarabine, cyclophosphamide (FC) and mitoxantrone (Forstpointner, Blood 2006), cyclophosphamide, vincristine, adriamycin, prednisone (CHOP) or FC in one trial (Kluin-Nelemans et al.), bendamustine (Rummel et al.), DHAP followed by autologous stem cell transplantation (ASCT) (Le Gouill et al.), and CHOP/cytarabine followed by ASCT (Doorduijn et al.); in one trial rituximab was given alone (Ghielmini et al.). Maintenance consisted of rituximab in five trials and bortezomib in one trial (Doorduijn et al.). The control group received no maintenance in two trials and interferon alfa in one trial. All included trials were judged at low risk of selection bias, none were blinded. No statistically significant effect on mortality rate was shown with rituximab maintenance therapy compared to no maintenance or interferon alfa RR 0.72, 95% CI 0.50 to 1.04, I2 of heterogeneity 57%, 751 patients. The RR of mortality with bortezomib maintenance was 0.67, 95% CI 0.12 to 3.71, but that is based on only 60 patients. PFS improved with rituximab maintenance compared to no maintenance or interferon alfa: HR 0.59, 95% CI 0.46 to 0.75. With bortezomib maintenance vs. no maintenance the HR of event free survival was 0.84, 95% CI 0.32 to 2.20. There was no statistically significant difference in infection rate with or without maintenance (RR 0.80, 95% CI 0.37 to 1.69, 419 patients). Conclusions Maintenance therapy improved PFS of patients with MCL, but no survival benefit could be shown. The pooled analysis is based mainly on the results of rituximab maintenance as data of the effect of bortezomib maintenance is scarce. The absence of significant increase of infection rate as opposed to maintenance rituximab in follicular lymphoma might be attributed to the small sample size. Based on these results patients treated for both first line and relapsed/refractory MCL should receive rituximab maintenance after achieving response to induction. Table disease control (*progression free survival, **event free survival) of patients with MCL who responded to induction and treated with rituximab maintenance compared to observation or interferon alfa. Table. disease control (*progression free survival, **event free survival) of patients with MCL who responded to induction and treated with rituximab maintenance compared to observation or interferon alfa. Disclosures Dreyling: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The proportion of CD34+ cells in the bone marrow (BM) is predictive of the size of progenitor cell mobilisation into the blood (PB). To investigate which other PB and BM parameters may be related to mobilisation, we analysed at steady state PB and BM of 23 patients with relapsed or resistant lymphoma before administering high-dose cyclophosphamide and G-CSF Cell morphology, number of CD34+ cells, and growth in clonogenic assay and in long-term cultures (LTC) were determined and then correlated with mobilisation extent (CD34+ and GM-CFC) and quality (growth of harvested cells in LTC). We found that the good mobilising patients (CD34 > 50 x 10(3)/ml, n=10) had several baseline BM characteristics (number of CD34+ MNC, GM-CFC, BFU-E, production of CFCs in LTC) similar to a group of 12 healthy controls, while patients with reduced mobilisation (CD34 < 50 x 10(3)/ml, n=13) had clearly reduced BM progenitors and LTC growth (p< 0.05). In a multivariate analysis including baseline clinical, blood and bone marrow characteristics, the most significant PB and BM factors independently associated with a higher number and/or quality of mobilised cells were a higher number of CD34+ and GM-CFC in the BM and a higher baseline haemoglobin, platelet, and CD34+ blood count. The capacity to release progenitor cells into the circulation is therefore not predicted by the distribution of morphologically distinguishable cells, marginally predicted by the BM content of highly undifferentiated cells (growth in long term culture), while it is proportional to the number of BM progenitors (CD34+, GM-CFC and BFU-E).

Background: Clinical activity of the anti CD-20 monoclonal antibody Rituximab has been reported in patients with follicular lymphoma (FL) and mantle-cell lymphoma (MCL). Patients and methods: 120 patients with bi-dimensionally measurable FL or MCL (R.E.A.L. Classification) were treated with Rituximab 375 mg/m 2 /week for 4 weeks. A central pathology review confirmed the diagnosis of FL in 76 of 78 and of MCL in 39 of 42 cases. The response was evaluated after 8 weeks and confirmed after 12 weeks from the start of treatment. Results: The toxicity of the treatment was, as expected, grade 1-2 fever and rigors during the first infusion and mild asthenia during the treatment period. Serious adverse events, probably or possibly related to the study treatment, included four deaths (3 of cardiac origin, 1 caused by P. carinii pneumonia) and 10 further nonfatal cases, including a permanent agranulocytosis and one case of heart failure. Response rate at week 12 was 52% for FL and 22% for MCL. After treatment, the BCL-2 rearrangement disappeared in 15 of 29 blood but only in 5 of 23 bone marrow samples; BCL-1 disappeared in 5 of 12 blood and 0 of 7 bone marrow specimens, as determined by PCR. Conclusions: Rituximab is an active agent for the treatment of FL, while its efficacy is modest in MCL. The effect in reducing minimal residual disease is more pronounced on the blood than it is on the bone marrow.

Background: The high-dose sequential (HDS) regimen developed in Milan for high-grade lymphomas is very active, but its toxicities are still partly unknown. We evaluated prospectively by doppler-echocardiograpy the cardiotoxicity of this treatment. Patients and methods: Over seven weeks, 20 patients received a sequence of cyclophosphamide, methotrexate, etoposide, mitoxantrone and melphalan, each at its maximum tolerable dose, and the latter in conjunction with autologous peripheral stem-cell transplantation. Echocardiography was performed at baseline, before administration of mitoxantrone and 2, 6 and 12 months after transplantation. The following parameters of the left ventricular systolic and diastolic functions were determined: end diastolic (LVD) and end systolic (LVS) dimensions, the ejection fraction (EF), and the Doppler derived diastolic parameters: peak velocity of the early (E) and late (A) transmitral flow, the E: A ratio, deceleration time of the E wave (DT) and isovolumetric relaxation time (IVRT). A group of 20 normal volunteers served as control. Results: At baseline, in comparison to controls, the patients had altered diastolic function (diminished E: A ratio) and, although still within the normal range, a slightly reduced systolic function (EF). During treatment or in the course of follow-up none of the patients showed clinical signs or symptoms of cardiac failure, nor significant changes of systolic or diastolic parameters, apart from a transient increase in the E:A ratio after the first three chemotherapy cycles (from 1.14 to 1.37, P < 0.05). The EF remained constant during, and up to six months after, transplantation, decreasing only slightly after one year (from 62% to 59%, P < 0.05). Using analysis of covariance we showed that the major determinants of baseline cardiac function and of its evolution over time were patient age and gender, with previous treatment with anthracyclines having a minor role. Conclusions: The HDS chemotherapy regimen produced no significant sign of cardiotoxicity up to one year after transplantation in patients with normal baseline cardiac function and no history of cardiac disease, pretreated with up to 550 mg/m 2 of doxorubicin.

Background and Objectives: Continuous-flow and intermittent-flow blood cell separators (CFCS and IFCS) are both used to collect stem cells from the blood to rescue patients undergoing myeloablative treatment for cancer. Materials and Methods: We designed a study to compare the collection efficiency of the two systems. The continous-flow Cobe Spectra and the intermittent-flow Haemonetics MCS-3P were used to collect cells on consecutive days from 9 patients mobilised with G-CSF with or without chemotherapy. Blood obtained before leukapheresis and the leukapheresis product were analysed for their content of red and white cells, platelets, CD34-positive cells, GM-CFC, CFC-E, and BFU-E. An extraction ratio was calculated. Results: We found that the CFCS extracted about 4 times more mononuclear cells per unit time, 3 times more CD34-positive, and 4 times more clonogenic cells than the IFCS. The subject acceptability of the two systems was similar. Conclusion: The CFCS is a more efficient system for stem cell collection. IFCS requires a longer harvesting time for the same result.

Purpose: MMDX {3′-deamino-3′-[2(S)-methoxy-4-morpholinyl] doxorubicin}, an anthracycline derivative active in vitro and in vivo against multdrug-resistant tumors, is currently under investigation in phase I clinical trials. In vivo it is metabolically activated, resulting in more cytotoxic compounds. We determined in vitro the toxic concentration of a 1-h period of exposure to doxorubicin (DX), MMDX, and bioactivated MMDX on hematopoietic progenitors and tumor cell lines. Methods: DX and MMDX were tested on both bone marrow- (BM) and cord blood (hCB)-derived clonogenic cells, whereas the metabolites were tested on hCB only. All substances were tested on seven tumor cell lines. Results: BM cells proved to be twice as sensitive as hCB cells to cytotoxics, and MMDX was twice as toxic as DX against hCB cells; MMDX activated with normal rat-liver microsomes and with dexamethasone-induced rat microsomes were, respectively, 70 and 230 times more toxic than MMDX. A comparison of the cytotoxic concentrations on hematopoietic progenitors and tumor cells, revealed that DX and MMDX had 5-fold stronger activity on tumor cell lines than on granulocyte/macrophage colony-forming cells (GM-CFCs), whereas bioactivated MMDX showed comparable cytotoxicity against tumor cells and hematopoietic progenitors. Conclusions: MMDX metabolites are very potent but display a lower degree of tumor selectivity than MMDX. Strategies to reduce MMDX metabolization should be developed to optimize the therapeutic index of this new anthracycline.

Hematopoietic progenitor and stem cells for transplantation can be mobilized into the circulation and collected by leukapheresis. In this procedure, the leukocytes are distributed in the buffy coat along a density gradient, and the composition of the final product depends on which layer was collected. For the Haemonetics MCS3p Cell Separator, the manufacturer recommended starting the progenitor cell collection at a light transmission of 30%-40% (compared with plasma) and continue it for 40-50 ml. To optimize the use of this machine, the buffy coat it produces was studied in 12 patients by collecting it in fractions of increasing specific weight. Each fraction was analyzed by morphology, immunocytometry, and cell culture. We found that the buffy coat uniformly contains 8 times more leukocytes than blood, but the proportion of each white cell type varies along a gradient. The lymphocyte-predominant lighter layers are richer in CD34+ cells when compared with the granulocyte-predominant denser layers (6-14 times versus 2-4 times more than blood). The majority of CD34+ cells are found at a light transmission of 10%-70% (hematocrit 6-9). We conclude that cells for transplantation should be collected in a lighter fraction of the buffy coat than originally suggested by the manufacturer.

We evaluated the myelotoxicity and the anti-tumor potential of tallimustine, three of its analogues and carzelesin, with melphalan as reference substance. Tallimustine was tested by clonogenic assays on both human bone marrow (BM) and cord blood (hCB) cells, the other compounds on hCB only. The degree of inhibition of the haemopoietic progenitors GM-CFC, CFC-E and BFU-E was evaluated after exposure to different concentrations. The same schedules were tested on five tumour cell lines. We found that the dose-response curves for tallimustine on BM and hCB cells were similar. Carzelesin was shown to be the most potent of the substances tested and to be the one with the best in vitro therapeutic index; of the distamycin analogues, the one bearing an alpha-bromoacrylic group (FCE 25450) had the best index. For melphalan, tallimustine and carzelesin, the concentration inhibiting the growth of 70% of progenitor cells in vitro (ID70) was similar to the concentrations found in the serum of patients treated at the maximum tolerated dose (MTD). We conclude that hCB cells may be used instead of BM cells for in vitro myelotoxicity tests. Therapeutic indexes can be extrapolated from this model and could help in selecting the most promising analogue for further clinical development. The in vitro-active concentrations are similar to myelotoxic concentrations in patients, suggesting a predictive value for the assay.

We conducted a systematic review of grade 3/4 adverse events (AEs) reported in prospective trials enrolling patients with follicular lymphoma (FL) and mantle cell lymphoma (MCL) receiving maintenance rituximab (MR). Random-effects models were used to calculate summary estimates and 95% confidence intervals for the proportion of AEs occurring during MR. Differences by induction program, histology, setting and MR schedule were examined by stratified analyses and univariate random-effects meta-regression. Eleven trials met the search criteria, with nine sufficiently reporting AEs during the MR phase. Of 1009 patients receiving MR, the proportion experiencing cumulative grade 3/4 toxicity was 24% (95% confidence interval [CI]: 14-36%). Patients receiving MR every 6 months as four weekly infusions for 2 years had significantly less toxicity compared with those receiving MR every 2 months (10% vs. 28%; p = 0.035). Patients treated with rituximab alone during induction had fewer toxicities compared to those treated with rituximab plus chemotherapy induction (12% vs. 35%; p = 0.031). Myelosuppression and infections were the most common toxicities. Our literature analysis suggests that MR given every 6 months and rituximab alone as induction may be associated with fewer grade 3/4 AEs for patients with FL and MCL; however, assessing the true independent impact of induction regimens and schedule on toxicity will require prospective trials.

Follicular lymphoma (FL) accounts for approximately 20% of all lymphomas and represents the prototype of 'indolent' lymphoma. Many patients enjoy a long period of asymptomatic and generalized lymphadenopathy, with slow clinical progression. For stage I FL and selected cases of stage II, the administration of definitive involved field radiation usually results in long-lasting remission and is still considered the treatment of choice. For advanced disease (stages III-IV), the treating physician is called to select therapy from several options. Because many patients are asymptomatic and have limited disease, clinical observation has been considered appropriate for selected patients. For patients in need of treatment, the systemic treatment has historically been based on chemotherapy; however, rituximab monotherapy or radioimmunotherapy have recently been shown to be effective enough to merit consideration. Moreover, there is considerable evidence to suggest that the first-line treatment should contain rituximab. Maintenance therapy with rituximab extends remission after chemotherapy in untreated patients and in patients who have relapsed. Newer promising treatments include anti-CD20 antibodies (or other surface antigens) engineered for greater efficacy, biological agents or vaccination therapy. This article presents an overview of the current therapeutic options for the management of newly diagnosed FL.

Summary An increased number of circulating monocytes at presentation has recently been associated with shorter survival in Hodgkin lymphoma, follicular lymphoma and diffuse large B cell lymphoma. This study aimed to assess the prognostic impact of the absolute monocyte count (AMC) at diagnosis in mantle cell lymphoma (MCL). AMC at diagnosis was available in 97 MCL cases recorded in the databases of the Oncology Institute of Southern Switzerland in Bellinzona (Switzerland) and the Division of Haematology of the Amedeo Avogadro University of Eastern Piedmont in Novara (Italy). With a median follow up of 7 years, the 5-year overall survival was 29% for patients with AMC >0·50 × 109/l and 62% for patients with AMC ≤0·50 × 109/l (P = 0·008). Elevated AMC and beta-2 microglobulin at diagnosis remained independent outcome predictors at multivariate analysis, controlling for the MCL International Prognostic Index (MIPI), and have been used to build a simple prognostic scoring system. In this relatively small and heterogeneous series an increased AMC identified poor-risk patients. Our results suggest that AMC together with the beta-2 microglobulin level might provide an inexpensive way to stratify MCL patient risk as a complement to the MIPI, which was confirmed to be a very powerful prognostic tool.

The natural history of follicular lymphoma is usually characterized by an indolent course with a high response rate to the first line therapy followed by recurrent relapses, with a time to next treatment becoming shorter after each subsequent treatment line. More than 80% of patients have advanced stage disease at diagnosis. The time of initiation and the nature of the treatment is mainly conditioned by symptoms, tumor burden, lymphoma grading, co-morbidities and patients preference. A number of clinical and biological factors have been determined to be prognostic in this disease, but the majority of them could not show to be predictive of response to treatment, and therefore can’t be used to guide the treatment choice. CD20 expression is the only predictive factor recognized in the treatment of FL and justifies the use of “naked” or “conjugated” anti-CD20 monoclonal antibodies as single agent or in combination with chemo- or targeted therapy. Nevertheless, as this marker is almost universally found in FL, it has little role for the choice of treatment. The outcome of patients with FL improved significantly in the last years, mainly due to the widespread use of rituximab, autologous and allogeneic transplantation in young and fit relapsed patients, the introduction of new drugs and the improvement in diagnostic accuracy and management of side effects. Agents as new monoclonal antibodies, immuno-modulating drugs and target therapy have recently been developed and approved for the relapsed setting, while studies to evaluate their role in first line treatment are still ongoing. Here we report our considerations on first line treatment approach and on the potential factors which could help in the choice of therapy.

Background Mantle cell lymphoma accounts for 6% of all B-cell lymphomas and is generally incurable. It is characterized by the translocation t(11;14) leading to cyclin D1 over-expression. Cyclin D1 is downstream of the mammalian target of rapamycin threonine kinase and can be effectively blocked by mammalian target of rapamycin inhibitors. We set out to examine the single agent activity of the orally available mammalian target of rapamycin inhibitor everolimus in a prospective, multicenter trial in patients with relapsed or refractory mantle cell lymphoma ([NCT00516412][1]). Design and Methods Eligible patients who had received a maximum of three prior lines of chemotherapy were given everolimus 10 mg for 28 days (one cycle) for a total of six cycles or until disease progression. The primary endpoint was the best objective response. Adverse reactions, progression-free survival and molecular response were secondary endpoints. Results Thirty-six patients (35 evaluable) were enrolled and treatment was generally well tolerated with Common Terminology Criteria grade ≥3 adverse events (>5%) including anemia (11%), thrombocytopenia (11%) and neutropenia (8%). The overall response rate was 20% (95% CI: 8–37%) with two complete remissions and five partial responses; 49% of the patients had stable disease. At a median follow-up of 6 months, the median progression-free survival was 5.5 months (95% CI: 2.8–8.2) overall and 17.0 (6.4–23.3) months for 18 patients who received six or more cycles of treatment. Three patients achieved a lasting complete molecular response, as assessed by polymerase chain reaction analysis of peripheral blood. Conclusions Everolimus as a single agent is well tolerated and has anti-lymphoma activity in relapsed or refractory mantle cell lymphoma. Further studies of everolimus in combination with chemotherapy or as a single agent for maintenance treatment are warranted. ([Clinicaltrials.gov][2] identifier: [NCT00516412][1]) [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00516412&atom=%2Fhaematol%2F97%2F7%2F1085.atom [2]: http://Clinicaltrials.gov

In loco-regionally advanced head and neck squamous cell cancer (HNSCC), concurrent 3-weekly cisplatin improves overall survival (OS) compared to radiotherapy alone, but is often associated with renal toxicity. The use of radiotherapy with accelerated fractionation schedules has been reported to improve survival but its optimal combination with chemotherapy is unclear. Retrospective analysis of treatment outcome and nephrotoxicity of radiotherapy given with an intensity-modulated approach (IMRT) concurrent with either 3-weekly or weekly cisplatin in 94 patients with stage III/IV HNSCC. Patients treated with weekly cisplatin were significantly older (p=0.0014) and received a significantly lower total cisplatin dose (p=0.0002). With a median follow-up of 2.8 years, at univariate analysis, 3-weekly cisplatin shows a longer OS (p=0.041) but progression-free survival (PFS) is similar for both schedules (p=0.47). Cisplatin doses >240 mg/m(2) were associated with better OS but not PFS. Chronic renal failure rate was significantly higher with 3-weekly cisplatin (p=0.04). Multivariate analysis (Cox regression controlling for age) confirmed the significant and independent impact of alcohol and smoking habits on both PFS (HR, 2.2) and OS (HR, 2.3), while the treatment schedule affected only OS (HR, 2.2). Weekly cisplatin is less nephrotoxic. Both schedules can be combined to curative IMRT. PFS was not significantly different even if patients treated with the weekly schedule were significantly older and received reduced cisplatin doses. The study suggests that the different cisplatin dose doesn't affect the PFS results if concomitant to IMRT. Controlled prospective studies are needed.

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.

Purpose We report the long-term results of a randomized clinical trial comparing induction therapy with once per week for 4 weeks single-agent rituximab alone versus induction followed by 4 cycles of maintenance therapy every 2 months in patients with follicular lymphoma. Patients and Methods Patients (prior chemotherapy 138; chemotherapy-naive 64) received single-agent rituximab and if nonprogressive, were randomly assigned to no further treatment (observation) or four additional doses of rituximab given at 2-month intervals (prolonged exposure). Results At a median follow-up of 9.5 years and with all living patients having been observed for at least 5 years, the median event-free survival (EFS) was 13 months for the observation and 24 months for the prolonged exposure arm (P < .001). In the observation arm, patients without events at 8 years were 5%, while in the prolonged exposure arm they were 27%. Of previously untreated patients receiving prolonged treatment after responding to rituximab induction, at 8 years 45% were still without event. The only favorable prognostic factor for EFS in a multivariate Cox regression was the prolonged rituximab schedule (hazard ratio, 0.59; 95% CI, 0.39 to 0.88; P = .009), whereas being chemotherapy naive, presenting with stage lower than IV, and showing a VV phenotype at position 158 of the Fc-gamma RIIIA receptor were not of independent prognostic value. No long-term toxicity potentially due to rituximab was observed. Conclusion An important proportion of patients experienced long-term remission after prolonged exposure to rituximab, particularly if they had no prior treatment and responded to rituximab induction.

Mantle cell lymphoma is included in the World Health Organization classification as distinct lymphoma subtype characterized by the t(11;14)(q13;q32) translocation, which results in overexpression of Cyclin D1. The clinical presentation often includes extranodal involvement, particularly of the bone marrow and gut. The prognosis of patients with mantle cell lymphoma (median overall survival, 3-5 years) is poorest among B-cell lymphoma patients, even though a prospectively difficult to identify subgroup can survive for years with little or no treatment. Conventional chemotherapy is not curative but obtains frequent remissions (60%-90%) which are usually shorter (1-2 years) compared with other lymphoma entities. Very intensive regimens, including autologous and allogeneic stem cell transplantation, seem required to improve the outcome, but with the median age of diagnosis being 60 years or more, such approaches are feasible only in a limited proportion of patients. The possibility of treating patients based on prognostic factors needs to be investigated prospectively.

The availability of active monoclonal antibodies, either as single agents or in combination with cytotoxic agents, has improved treatment results in non-Hodgkin's lymphoma (NHL). Despite this and the increasing number of available active monoclonal antibodies, alone or conjugated with radioisotopes, not all types of lymphoma are sensitive to these biological agents and often they become resistant because of different molecular mechanisms. New molecular targets in neoplastic cells are emerging and provide the rationale for novel discovery initiatives. In fact, a greater knowledge of the biology of lymphoma and the identification of compounds selectively active against a potential therapeutic pathway have already improved the time to progression and survival time of patients with some subtypes of NHL. The growing list of new drugs provides the exciting prospect of developing disease-specific and even patient-specific therapies. The aim of this review is to identify and discuss non-monoclonal antibody new therapeutic agents in terms of mechanism of action and clinical results. The preclinical and clinical features of proteasome inhibitors, histone deacetylase inhibitors, thalidomide and lenalidomide, mammalian target of rapamycin inhibitors, antisense oligonucleotides, heat shock protein inhibitors, protein kinase C inhibitors, antiangiogenic agents, and new cytotoxics are reviewed.

Background: Peliosis hepatis (PH) is a benign condition characterized by sinusoidal ectasia and blood-filled lacunar spaces within the liver parenchyma. The disease has been associated with a number of drugs and illnesses such as immunodeficiency states, infections, malignancy and other miscellaneous diseases. Patients and Methods: We describe the association of PH and cancer in two consecutive patients. In case 1, the peliotic lesions mimicked metastatic dissemination of a neuroendocrine tumor in a patient with normal octreoscan and tumor markers, parameters that were abnormal at the initial tumor diagnosis. In case 2, PH mimicked systemic candidiasis complicating the treatment of an acute myeloid leukemia, although in a clinical setting in which an infection was unlikely. Results: Computed tomography (CT) imaging and a high level of clinical suspicion had a major role in the correct identification of this uncommon disorder, avoiding unnecessary antitumor-or anti-infection-oriented diagnostic procedures or therapies. Conclusions: PH should be considered in the differential diagnosis of new liver lesions in patients in whom the clinical settings do not clearly favor metastasization or infection. The detailed analysis of multiphase CT scan imaging is essential for a correct diagnosis. A liver biopsy should be performed to confirm this entity.

In the last decade rituximab, alemtuzumab, and gemtuzumab ozogamicin (GO) have been used to treat patients with hematologic malignancies. Their efficacy and safety are now well established. Since their preclinical development, many studies have been performed to optimize dose and schedule. Rituximab is usually given at 375 mg/m 2 , a dose that shows activity and little toxicity. It is normally administered as single agent or in combination with chemotherapy to induce remission in B-cell neoplasias. Moreover, given its low toxicity and long half-life, rituximab also can be used as maintenance therapy. Alemtuzumab is administered with a schedule of 30 mg, three times per week, after an initial dose escalation in the first week, showing activity against chronic lymphocytic leukemia (B-CLL) and some T-cell neoplasias. GO is administered at a dose of 9 mg/m 2 at 2-week intervals for two doses; it is the first monoclonal antibody approved for the treatment of relapsed or refractory CD33 + acute myeloid leukemia (AML).

ECF is an active regimen in advanced gastric adenocarcinoma (GAC). We used ECF as an adjuvant therapy in a cohort of patients with GAC who underwent curative surgery and describe their results in terms of feasibility and outcome.Forty-seven patients with locally advanced GAC underwent curative surgery followed by 4 to 6 courses of adjuvant ECF. Their median age was 59 years (range 32-74) and UICC stage was III-IV in 28 patients (59%). Partial or total gastrectomy was performed in 49% and 47% of cases, respectively.Chemotherapy was well tolerated, the main grade 3/4 toxicities being neutropenia (47%) without severe infections, and anorexia (11%). Port adverse events were recorded in 17%. There where no treatment-related deaths. With a median follow-up of 65 months, the median overall- and relapse-free survivals were 50.1 months and 42.6 months, respectively.The adjuvant ECF regimen is safe and feasible in resected patients with locally advanced GAC. The survival in our series compares favorably with cohorts described by others, supporting our confidence on using adjuvant ECF for patients who decide to undertake such type of treatment. ECF might be a reasonable treatment arm to be used in randomized trials of adjuvant chemotherapy.

Patients with refractory/relapsing lymphoma are rarely cured by chemotherapy. High-dose chemotherapy (HDC) for tumor debulking followed by reduced-intensity conditioning (RIC) hematopoietic stem-cell transplantation (HSCT) has been advocated as a concept. We previously treated 10 patients (group A) with BEAM chemotherapy followed by delayed RIC HSCT at day 28. We now report on the subsequent 11 patients receiving BEAM followed immediately by fludarabine/total body irradiation and allogeneic HSCT (group B), and compare the outcome to group A patients. Non-hematological toxicity before engraftment was comparable, only gut toxicity was higher in group B. Days in aplasia, days on antibiotics and length of hospital stay were significantly longer in group A. Cumulative incidence of acute (GvHD) >or=grade II and incidence of chronic GvHD were lower in group B. At last follow-up, seven patients in group A were alive, with six of them in complete remission. In group B, nine patients were alive, seven of them in complete remission. No significant difference in estimated 3-year overall survival was seen. These data challenge the initial concept of debulking first and delaying allogeneic RIC HSCT. Allogeneic HSCT with standard BEAM conditioning is a valid alternative for patients with resistant/relapsed lymphoma, which might be considered earlier in the disease course.

Rituximab maintenance therapy after effective induction has been shown to prolong progression-free and even overall survival, compared with no further treatment until relapse, in randomized, prospective phase III clinical trials in follicular lymphoma. In addition, the use of rituximab maintenance therapy is likely to have an important psychological and emotional impact for many patients. Currently, all patients are expected to relapse eventually following induction treatment: the knowledge that they are being actively treated to delay relapse for as long as possible may provide significant reassurance and emotional support. Similarly, the experience of relapse itself is also likely to be a traumatic event for patients: reducing the frequency of relapse with rituximab maintenance may thus spare patients some of this trauma. Overall, therefore, rituximab maintenance therapy might be expected to improve quality of life for patients with follicular lymphoma over and above the observed clinical benefits in progression-free and overall survival. At present, however, this can only be speculated from observations and experience. Formal quality-of-life and patient preference assessments will be required to demonstrate this conclusively.

Background MCL is characterized by a dismal long term prognosis with a median overall survival of 3-5 years. The addition of rituximab to induction chemotherapy improved significantly response rates of patients with MCL. MR treatment for these patients has the potential to further improve disease control and overall survival (OS). The few trials that addressed that question showed inconsistent results. Aims We performed a systematic review and meta-analysis of RCTs in order to assess the effect of MR on clinical outcomes of patients with MCL. Methods We included RCTs that compared MR to no treatment or other treatment for patients with MCL, either in first line or relapsed disease. In March 2014 we searched The Cochrane Library, MEDLINE, conference proceedings, and databases of ongoing trials. Two reviewers independently assessed the quality of the trials and extracted data. The primary outcome was all cause mortality. Secondary outcomes included progression free survival (PFS) and infectious adverse events. Relative risk (RR) for dichotomous data and hazard ratio (HR) for time to event datawere estimated and pooled using random-effects model. Results We identified 3 trials, conducted between the years 1998 to 2010 and randomizing 434 adult patients with MCL. Most patients were males, with a median age ranging from 61 to 70 years, and predominantly good performance status. Seventy-nine percent of the patients received their first line of treatment. MIPI score was reported in one trial. Induction therapy included rituximab in all three trials. In two trials additional chemotherapy induction was applied consisting of fludarabine, cyclophosphamide (FC) and mitoxantrone in one trial (Forstpointner, Blood 2006), and cyclophosphamide, vincristine, adriamycin, prednisone (CHOP) or FC in the other (Kluin-Nelemans, NEJM 2012); in the third trial rituximab was given alone (Ghielmini, JCO 2005). The control group received no maintenance in two trials and interferon alfa in one trial. All included trials are judged at low risk of selection bias, none were blinded. Mortality rate decreased with MR compared to no MR or interferon alfa RR 0.67, 95% CI 0.46 to 0.98, I2 of heterogeneity 54%, 392 patients (Figure). PFS improved with MR compared to no MR or interferon alfa: HR 0.60, 95% CI 0.44 to 0.82, I2 of heterogeneity = 0. There was no statistically significant difference in infection rate with or without MR (RR 0.80, 95% CI 0.37 to 1.69, 419 patients). Conclusions The results of this meta-analysis support a survival benefit of MR in patients with first line or relapsed/refractory MCL who responded to induction therapy. Additionally, there is a significant improvement of PFS benefit of MR. The absence of significant increase of infection rate as opposed to MR in follicular lymphoma may be attributed to the small sample size. Based on these results patients treated for both first line and relapsed/refractory MCL should receive MR after achieving response to induction. Figure: Pooled RR of mortality of patients with MCL who responded to induction and treated with MR compared to observation or interferon alfa. Figure:. Pooled RR of mortality of patients with MCL who responded to induction and treated with MR compared to observation or interferon alfa. Disclosures Vidal: Roche: unrestricted grant Other. Ghielmini:Roche: Research Funding, Speakers Bureau. Unterhalt:Roche: Travel Support Other. Shpilberg:Roche: Consultancy, Research Funding.

Background. Rituximab improved outcomes of all CD20+ non-Hodgkin lymphoma (NHL) subtypes. Rituximab induces a transient B-cell depletion and a dose-dependent T-cell inactivation (Stroopinsky et al., Cancer Immunol Immunother 2012) predisposing to T-cell dependent infections and to a potential impaired T-cell immunosurveillance. Secondary neoplasms (SN) is infrequent in trials including rituximab and the SN risk associated to rituximab across multiple trials has not been reported. We performed a systematic review of published trials comparing chemotherapy with or without rituximab to evaluate SN occurrence. Methods. Our primary endpoint was SN risk in patients with NHL treated with rituximab. We searched PubMed and Embase databases for randomised controlled trials on rituximab and lymphoma where rituximab constituted the only difference between treatment arms and where SN incidence or SN related death were reported. Authors were contacted for SN related rituximab exposure if not detailed. Chronic lymphocytic leukemia and HIV-related lymphomas were excluded due to increased risk of SN. Updated follow-up of eligible trials presented at annual meetings of the American Society of Clinical Oncology and American Society of Hematology were retrieved. Data were extracted independently by two authors. A random effects DerSimonian-Laird meta-analysis was performed to estimate the summary effect of rituximab on the hazard of SN. Statistical heterogeneity was tested using Woolf test. Results. We identified nine trials cumulating 4621 patients with 2312 exposed to rituximab and 2309 not exposed. These nine trials are known with the following names: PRIMA (1), GELA LNH98.5 (2), MINT (3), CORAL (4), IELSG-19 (5), EORTC20981 (6), OSHO#39 (7), SAKK 35/98 (8), RICOVER60 (9). Histology were diffuse large B cell (n=4), follicular (n=4) and marginal zone (n=1) lymphomas. Median age was 58.1 years. Sex distribution was available for seven trials with 1650 (47.6%) women and 1814 (52.4%) men. In all these trials but one (SAKK 35/98), rituximab was used associated with chemotherapy: CHOP, CHOEP, FCM, MCP, DHAP, ICE, or chlorambucil. At a median follow-up of 73 months [interquartile range: 72-84], a total of 334 SN was observed, including 169 SN in patients randomised to rituximab as compared to 165 SN in patients not randomised to rituximab (OR= 0.88; 95%CI: 0.66-1.19) (Figure 1). No evidence of significant heterogeneity was noticed across trials (p = 0.93). Notably, the proportion of females, histology subtypes, use of rituximab in first line, and use of rituximab over prolonged periods in maintenance did not influence SN risk (p = 0.94, p = 0.80, p = 0.87, p = 0.87 respectively). The SN risk was not increased in protocols administrating rituximab over periods of 8 months to 12 months (CORAL , OSHO#39) as opposed to periods of 24 months (PRIMA, EORTC20981) (p=0.86). Conclusions. This meta-analysis of nine trials randomising rituximab in NHL patients suggests no SN predisposition at a median follow-up of 6 years. SN risk associated with the combination of rituximab and new targeted therapies warrants prospective monitoring. Figure 1. Standard meta-analysis plot of the odds ratio of SN prevalence in the rituximab arm compared to the control arm Figure 1. Standard meta-analysis plot of the odds ratio of SN prevalence in the rituximab arm compared to the control arm Disclosures Fleury: Lundbeck: Membership on an entity's Board of Directors or advisory committees, Preceptorship Other. Pfreundschuh:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Research Funding. Salles:Roche: Honoraria, Research Funding. van Oers:Roche: Consultancy. Gisselbrecht:Roche: Research Funding. Zucca:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Herold:Roche Pharma AG/Germany: Honoraria, Research Funding. Ghielmini:Roche: Research Funding, Speakers Bureau.