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Emerging evidence indicates that chemoresistance is closely related to altered metabolism in cancer. Here, we hypothesized that distinct metabolic gene expression profiling (GEP) signatures might be correlated with outcome and with specific fluorodeoxyglucose positron emission tomography (FDG-PET) radiomic profiles in diffuse large B-cell lymphoma (DLBCL). We retrospectively analyzed a discovery cohort of 48 consecutive patients with DLBCL treated at our center with standard first-line chemoimmunotherapy by performing targeted GEP (T-GEP)– and FDG-PET radiomic analyses on the same target lesions at baseline. T-GEP–based metabolic profiling identified a 6-gene signature independently associated with outcomes in univariate and multivariate analyses. This signature included genes regulating mitochondrial oxidative metabolism (SCL25A1, PDK4, PDPR) that were upregulated and was inversely associated with genes involved in hypoxia and glycolysis (MAP2K1, HIF1A, GBE1) that were downregulated. These data were validated in 2 large publicly available cohorts. By integrating FDG-PET radiomics and T-GEP, we identified a radiometabolic signature (RadSig) including 4 radiomic features (histo kurtosis, histo energy, shape sphericity, and neighboring gray level dependence matrix contrast), significantly associated with the metabolic GEP–based signature (r = 0.43, P = .0027) and with progression-free survival (P = .028). These results were confirmed using different target lesions, an alternative segmentation method, and were validated in an independent cohort of 64 patients. RadSig retained independent prognostic value in relation to the International Prognostic Index score and metabolic tumor volume (MTV). Integration of RadSig and MTV further refined prognostic stratification. This study provides the proof of principle for the use of FDG-PET radiomics as a tool for noninvasive assessment of cancer metabolism and prognostic stratification in DLBCL.

•A gene expression signature related to mitochondrial metabolism is associated with specific FDG-PET radiomics profiles and outcome in DLBCL.•Integration of FDG-PET radiomics with metabolic tumor volume refines PET–based prognostication in DLBCL.

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare and aggressive variant of diffuse large B-cell lymphoma (DLBCL) that usually affects young to middle-aged patients, with disseminated disease at presentation. The tumor microenvironment (TME) plays a key role in THRLBCL due to its peculiar cellular composition (<10% neoplastic B cells interspersed in a cytotoxic T-cell/histiocyte-rich background). A significant percentage of THRLBCL is refractory to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-based regimens and to chimeric antigen receptor T-cell therapy; thus, the development of a specific therapeutic approach for these patients represents an unmet clinical need. To better understand the interaction of immune cells in THRLBCL TME and identify more promising therapeutic strategies, we compared the immune gene expression profiles of 12 THRLBCL and 10 DLBCL samples, and further corroborated our findings in an extended in silico set. Gene coexpression network analysis identified the predominant role of the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis in the modulation of the immune response. Furthermore, the PD-1/PD-L1 activation was flanked by the overexpression of 48 genes related to the functional exhaustion of T cells. Globally, THRLBCL TME was highly interferon-inflamed and severely exhausted. The immune gene profiling findings strongly suggest that THRLBCL may be responsive to anti–PD-1 therapy but also allowed us to take a step forward in understanding THRLBCL TME. Of therapeutic relevance, we validated our results by immunohistochemistry, identifying a subset of TCF1+ (T cell–specific transcription factor 1, encoded by the TCF7 gene) progenitor exhausted T cells enriched in patients with THRLBCL. This subset of TCF1+ exhausted T cells correlates with good clinical response to immune checkpoint therapy and may improve prediction of anti–PD-1 response in patients with THRLBCL.

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare and aggressive variant of diffuse large B-cell lymphoma (DLBCL) that usually affects young to middle-aged patients, with disseminated disease at presentation. The tumor microenvironment (TME) plays a key role in THRLBCL due to its peculiar cellular composition (<10% neoplastic B cells interspersed in a cytotoxic T-cell/histiocyte-rich background). A significant percentage of THRLBCL is refractory to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-based regimens and to chimeric antigen receptor T-cell therapy; thus, the development of a specific therapeutic approach for these patients represents an unmet clinical need. To better understand the interaction of immune cells in THRLBCL TME and identify more promising therapeutic strategies, we compared the immune gene expression profiles of 12 THRLBCL and 10 DLBCL samples, and further corroborated our findings in an extended in silico set. Gene coexpression network analysis identified the predominant role of the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis in the modulation of the immune response. Furthermore, the PD-1/PD-L1 activation was flanked by the overexpression of 48 genes related to the functional exhaustion of T cells. Globally, THRLBCL TME was highly interferon-inflamed and severely exhausted. The immune gene profiling findings strongly suggest that THRLBCL may be responsive to anti–PD-1 therapy but also allowed us to take a step forward in understanding THRLBCL TME. Of therapeutic relevance, we validated our results by immunohistochemistry, identifying a subset of TCF1+(T cell–specific transcription factor 1, encoded by the TCF7gene) progenitor exhausted T cells enriched in patients with THRLBCL. This subset of TCF1+exhausted T cells correlates with good clinical response to immune checkpoint therapy and may improve prediction of anti–PD-1 response in patients with THRLBCL.

The Swiss Group for Clinical Cancer Research (SAKK) conducted the SAKK 35/03 randomized trial (NCT00227695) to investigate different rituximab monotherapy schedules in patients with follicular lymphoma (FL). Here, we report their long-term treatment outcome. Two-hundred and seventy FL patients were treated with 4 weekly doses of rituximab monotherapy (375 mg/m2); 165 of them, achieving at least a partial response, were randomly assigned to maintenance rituximab (375 mg/m2 every 2 months) on a short-term (4 administrations; n = 82) or a long-term (up to a maximum of 5 years; n = 83) schedule. The primary end point was event-free survival (EFS). At a median follow-up period of 10 years, median EFS was 3.4 years (95% confidence interval [CI], 2.1-5.5) in the short-term arm and 5.3 years (95% CI, 3.5-7.5) in the long-term arm. Using the prespecified log-rank test, this difference is not statistically significant (P = .39). There also was not a statistically significant difference in progression-free survival or overall survival (OS). Median OS was 11.0 years (95% CI, 11.0-NA) in the short-term arm and was not reached in the long-term arm (P = .80). The incidence of second cancers was similar in the 2 arms (9 patients after short-term maintenance and 10 patients after long-term maintenance). No major late toxicities emerged. No significant benefit of prolonged maintenance became evident with longer follow-up. Notably, in symptomatic patients in need of immediate treatment, the 10-year OS rate was 83% (95% CI, 73-89%). These findings indicate that single-agent rituximab may be a valid first-line option for symptomatic patients with advanced FL.

The Swiss Group for Clinical Cancer Research (SAKK) conducted the SAKK 35/03 randomized trial (NCT00227695) to investigate different rituximab monotherapy schedules in patients with follicular lymphoma (FL). Here, we report their long-term treatment outcome. Two-hundred and seventy FL patients were treated with 4 weekly doses of rituximab monotherapy (375 mg/m2); 165 of them, achieving at least a partial response, were randomly assigned to maintenance rituximab (375 mg/m2every 2 months) on a short-term (4 administrations; n = 82) or a long-term (up to a maximum of 5 years; n = 83) schedule. The primary end point was event-free survival (EFS). At a median follow-up period of 10 years, median EFS was 3.4 years (95% confidence interval [CI], 2.1-5.5) in the short-term arm and 5.3 years (95% CI, 3.5-7.5) in the long-term arm. Using the prespecified log-rank test, this difference is not statistically significant (P= .39). There also was not a statistically significant difference in progression-free survival or overall survival (OS). Median OS was 11.0 years (95% CI, 11.0-NA) in the short-term arm and was not reached in the long-term arm (P= .80). The incidence of second cancers was similar in the 2 arms (9 patients after short-term maintenance and 10 patients after long-term maintenance). No major late toxicities emerged. No significant benefit of prolonged maintenance became evident with longer follow-up. Notably, in symptomatic patients in need of immediate treatment, the 10-year OS rate was 83% (95% CI, 73-89%). These findings indicate that single-agent rituximab may be a valid first-line option for symptomatic patients with advanced FL.

•Primary testicular lymphoma is characterized by high risk of contralateral testis and central nervous system relapse in historical series.•Combined intravenous and intrathecal prophylaxis is feasible and effective in preventing central nervous system relapses, improving outcome.

The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (=90%). Toxicity grade =3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. This trial was registered at www.clinicaltrials.gov as #NCT01307605.

The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m2IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (≥90%). Toxicity grade ≥3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. This trial was registered at www.clinicaltrials.govas #NCT01307605.

Fixed duration venetoclax-obinutuzumab (VO) is approved in treatment naïve (TN) chronic lymphocytic leukemia (CLL), based on CLL14 study addressed to patients (pts) with coexisting conditions. The combinations showed also to be effective and well tolerated in the younger population enrolled in the randomized CLL13 trial. The aim of this retrospective, multicenter Italian study is to evaluate the feasibility and tolerability of this combination in TN CLL in common clinical practice as well as reasons for choosing fixed-duration VO instead of continuous BTKi.

Background:The Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) conducted the SAKK 35/10 randomized phase-2 trial (NCT0137605) to compare the effectiveness of rituximab (R) alone versus R combined with lenalidomide (L) as the initial treatment for symptomatic follicular lymphoma (FL). The primary endpoint analysis, which demonstrated higher complete remission (CR) rates with the combination therapy, was previously reported (Zucca et al. Blood 2019). This report provides a long-term analysis of time-to-event endpoints with a median follow-up of approximately 10 years.

Background:In classical Hodgkin lymphoma (cHL), 20%-30% of patients experience relapse or progressive disease after standard chemotherapy, requiring salvage treatment strategies including targeted immunotherapy with brentuximab vedotin (BV). Molecular mechanisms underlying treatment resistance to BV in cHL are still poorly understood. The unique characteristics of cHL microenvironment, which represents >90% of the cellular infiltrate, make targeted gene expression profiling (T-GEP) a suitable technique to investigate immune-related determinants of BV sensitivity.

Background: Interim PET (PET-2), performed after two cycles of chemotherapy (CT), is widely adopted to select patients (pt) with classical Hodgkin lymphoma (cHL), who might benefit from omitting radiotherapy (RT) or reducing the number of CT cycles in early stages, as well as intensifying or de-escalating first-line therapy in advanced stages. Furthermore, PET-2 has prognostic value in the front-line and in the salvage treatment. In a retrospective multicenter Italian study on patients experiencing failure of first-line treatment, we recently observed that PET-2 seems to be an early unfavorable predictor for subsequent salvage high-dose (HD) CT and autologous stem cell transplant (ASCT).

Metabolic rewiring is a hallmark of cancer and a predominant feature of aggressive lymphoproliferative disorders such as diffuse large B-cell lymphomas (DLBCL), which need a reshaped metabolism in order to meet the increased demands related to rapid cell proliferation.

The role of first-line single agent Rituximab immunotherapy in follicular lymphoma (FL) is still a matter of debate. Although a subset of patients (pts) may obtain long term benefit with upfront immunotherapy, first-line therapy with standard chemoimmunotherapy offers better results in terms of progression free survival (PFS) compared to single agent Rituximab. On the other hand, there is no clear demonstration of sizeable long term benefit with first-line Rituximab compared to an initial wait and see approach, as most FL pts will ultimately be exposed to chemotherapy at some point in their disease course.

Derenzini: TG-THERAPEUTICS: Research Funding; ASTRA-ZENECA: Consultancy, Other: ADVISORY-BOARD; ADC-THERAPEUTICS: Research Funding; TAKEDA: Research Funding; BEIGENE: Other: ADVISORY BOARD. Pileri: CELGENE: Other: ADVISORY BOARD; NANOSTRING: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY-BOARD. Tarella: ADC-THERAPEUTICS: Other: ADVISORY BOARD; Abbvie: Other: ADVISORY BOARD.First line single agent Rituximab in Follicular Lymphoma

Tarella: ADC-THERAPEUTICS: Other: ADVISORY BOARD; Abbvie: Other: ADVISORY BOARD. Pileri: CELGENE: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY-BOARD; NANOSTRING: Other: ADVISORY BOARD. Derenzini: TAKEDA: Research Funding; BEIGENE: Other: ADVISORY BOARD; ASTRA-ZENECA: Consultancy, Other: ADVISORY-BOARD; TG-THERAPEUTICS: Research Funding; ADC-THERAPEUTICS: Research Funding.

Derenzini: TG-THERAPEUTICS: Research Funding.

No relevant conflicts of interest to declare.

INTRODUCTION AND BACKGROUND: Lymphoma during pregnancy is a rare and highly challenging condition. Recent evidences show that chemotherapy can be safely administered during pregnancy, however the effects on obstetric and neonatal outcomes are still largely unknown. Aim of this study is to illustrate the oncologic management and to investigate the obstetric, neonatal and maternal outcomes in a series of cases diagnosed with lymphomas during pregnancy.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare form of T-cell non-Hodgkin lymphoma, recently recognized by the World Health Organization classification of lymphoid neoplasms. Clinical and histologic findings suggest a distinct entity from systemic ALCL. Except in advanced cases, BIA-ALCL usually has an indolent course. The prognosis is often favorable and complete surgical excision for localized disease is generally the only treatment. The disease often presents with a delayed seroma around the breast implant - almost exclusively with a textured surface - breast pain, swelling and asymmetry, capsular contracture, but it can also present with a breast mass and lymph node involvement. Tumor nodules, axillary node involvement, bilateral breast involvement and infiltrative pattern on capsule histology are associated with more aggressive behavior. Systemic involvement has also been less commonly reported. In accordance with the FDA recommendation, all cases of histologically confirmed BIA-ALCL should be reported to the BIA-ALCL PROFILE Registry. In Italy, the Ministry of Health sensitizes to notify each BIA-ALCL diagnosis through the compilation of a specific online form. Since 2015 all the notified cases were collected in the Italian Ministry of Health's database, named Dispovigilance. So far, 47 cases have been reported, as of the last updated survey.

Diffuse large B-cell lymphoma (DLBCL) overexpressing MYC and BCL-2 have a poor outcome with standard therapies irrespective of the cell of origin (COO), representing an unmet medical need. Furthermore, precision therapy approaches specifically designed for MYC/BCL-2 positive DLBCL are lacking. Recently we reported that MYC positive DLBCL harbor high levels of inherent DNA damage and display constitutive activation of the DNA damage response (DDR) pathways, these alterations being correlated with poor outcome (Derenzini et al. Oncotarget 2015). In an effort to design specific therapies for MYC/BCL-2 positive DLBCL, we integrated nanostring-based gene expression profiling and functional characterization of replicative and oxidative stress biomarkers in 2 independent DLBCL cohorts treated with chemoimmunotherapy: 69 patients from the DLC04 study (Chiappella et al. Lancet Oncol 2017), and 66 patients treated in real life clinical practice (total 135 patients). We used a digital multiplex gene expression profiling (Nanostring technology) panel containing 28 genes: 20 genes used to assign COO subtype according to LST algorithm (Scott et al. Blood 2014), and 8 additional genes employed to assess the MYCand BCL-2status and to detect potential therapeutic targets (STAT3, TP53, NFKBIA, PTEN, PIK3CA, CD68). Immunohistochemistry (IHC) profiling for MYC, BCL-2, the phosphorylated form of H2AX at S139 (γH2AX: a biomarker of DNA damage and DDR activation) and for 8-hydroxy-2'-deoxyguanosine (8-OHdG) (an oxidative DNA damage marker) was available in all patients.

Zucca: Celltrion: Consultancy; AstraZeneca: Consultancy. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Chiappella: Nanostring: Other: lecture fees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Roche: Other: lecture fees; Teva: Other: lecture fees; Amgen: Other: lecture fees. Zinzani:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vitolo:Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background: Follicular lymphoma is usually a disase with a prolonged course and a chemotherapy-free regimen might be a favourable treatment strategy. SAKK 35/03 investigated two different durations of rituximab maintenance (5 years vs. 6 months) in patients with follicular lymphoma after induction with 4 weekly doses of rituximab monotherapy. With a median follow-up of 6.4 years we were not able to show a benefit with long-term rituximab maintenance up to five years in event-free survival (EFS) or overall survival (OS ). Here we report the final results with a median follow-up of 10 years.

Introduction: Nivolumab is the first checkpoint inhibitor approved for the treatment of patients (pts) with relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL). In previous studies, agents who target the PD-1 pathway have demonstrated to show substantial and durable response rates, with encouraging survival data and acceptable safety profile in this pts population. The Expanded Access Programme (EAP) provided the opportunity to treat pts before market availability of the drug. The aim of this analysis is to provide information about nivolumab use in a real world setting as well as in pts subgroups usually excluded from clinical trials.

Rusconi: Janssen: Consultancy, Other: Congress attendance; Teva: Consultancy, Other: Congress attendance; Takeda: Consultancy. Spina:Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.

Rusconi: Takeda: Consultancy; Teva: Consultancy, Other: Congress attendance; Janssen: Consultancy, Other: Congress attendance. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.

No relevant conflicts of interest to declare.

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.

From November 2012 to July 2014, brentuximab vedotin (BV) was available in Italy for patients with relapsed Hodgkin’s lymphoma (HL) outside a clinical trial context based on a local disposition of the Italian Drug Agency (AIFA) issued according to a national law (Law 648/96: "medicinal products that are provided free of charge on the national health service"). A large Italian observational retrospective study was conducted on the use of BV in the everyday clinical practice to check if clinical trial results are confirmed even in a real life context. Primary endpoint was the best response; secondary endpoints were the overall response rate at the end of the treatment, duration of response, survival and the safety profile. BV was infused intravenously at the dose of 1.8 mg/kg every 3 weeks. A total of 234 HL patients were treated in 40. All patients had histologically documented CD30+ HL; 49% had relapsed and 51% had refractory disease. Patients were heavily pretreated with a median of 3 previous therapies (including autologous stem cell transplant [SCT] in the 69% of cases). Best response was observed after a median of 4 cycles in 140 patients (59.8%): 74 (31.6%) patients obtained a complete response (CR) and 66 (28.2%) achieved a partial response (PR); overall response rate at the end of the treatment was 48.3% (62 CR and 51 PR). The best response rate was higher in the elderly subset (>60 years): 14 (50%) CR and 5 (17.8%) PR. Disease free survival was 26.3% at 29 months and progression free survival 31.9% at 55 months. We identified 30 long term responders (patients with a response ≥ 12 months) of whom 18 are still in CR, 7 with a consolidative SCT and 11 without any consolidative procedure. Duration of response did not differ who achieved at least PR and then either did or did not undergo consolidative SCT. All patients were included in the safety profile for the analysis; in general, the treatment was well tolerated in everyday clinical practice and the toxicity profile was closely similar to the previously published data; no death has been linked to BV-induced toxicity. This preliminary analysis could indicate that BV displays a number of features favoring its use as a bridge to transplant in patients with active disease who achieve a suboptimal response to salvage treatment. Even in a real life context, BV induces clinical responses quite rapidly, i.e. within the first 4 cycles in most responders, thus permitting the timely application of the transplantation phase. BV displays a favorable toxicity profile, without overlapping toxicities with most of the agents employed in high-dose conditioning regimens. Furthermore, for HL patients ineligible for transplant or for who transplant failed, may represent a feasible effective therapeutic option.

From November 2012 to July 2014, brentuximab vedotin (BV) was available in Italy for patients with relapsed systemic anaplastic large cell lymphoma (ALCL) outside a clinical trial context based on a local disposition of the Italian Drug Agency (AIFA) issued according to a national law (Law 648/96: "medicinal products that are provided free of charge on the national health service"). A large Italian observational retrospective study was conducted on the use of BV in the everyday clinical practice to check if clinical trial results are confirmed even in a real life context. Primary endpoint was the best response; secondary endpoints were the overall response rate at the end of the treatment, duration of response, survival and the safety profile. BV was infused intravenously at the dose of 1.8 mg/kg every 3 weeks for a maximum of 16 cycles. A total of 40 ALCL (18 anaplastic lymphoma kinase [ALK] negative and 22 ALK-positive status) patients were treated with BV in 40 Hematology Centers. All patients had histologically documented CD30+ ALCL; 16 (40%) had relapsed and 24 (60%) had refractory disease. Patients were heavily pretreated with a median of 2 previous therapies (including autologous transplant in the 32.5% of cases). Best response was observed after a median of 4 cycles in 31 patients (77.5%): 19 (47.5%) patients obtained a complete response (CR) and 12 (30%) achieved a partial response (PR); overall response rate at the end of the treatment was 62.5% (18 CR and 7 PR). The best response rate was higher in the elderly subset (>60 years): 9 (64.2%) CR and 3 (21.4%) PR, achieving a total of 85.6%. At the latest follow up 15/18 patients are still in CR (3 with consolidative procedure). Global progression free survival was 39.1% at 29 months and disease free survival 54% at 23.9 months (median not reached). Median duration of response was 12 months (range 9-24 months). We identified 5 long term responders (patients with a response ≥ 12 months), all were still in CR at the latest follow up (1 underwent allogeneic transplant). Particularly, all the long term responders were aged <30 years at first BV infusion.

T-cell lymphomas represent a rare and heterogeneous group of non-Hodgkin lymphomas (NHLs) characterized by dismal prognosis. Current first line chemotherapeutic approaches have not significantly changed during the last 20 years, and several efforts have been made for early risk stratification of T-cell NHL patients with unsatisfactory results. Functional imaging with 2-deoxy-2-[fluorine-18]fluoro- D-glucose positron emission tomography scan (FGD-PET) has demonstrated improved outcome stratification and response evaluation in Hodgkin lymphoma and B-cell NHL, in comparison with computed tomography (CT) scan. Most T-cell lymphomas are FDG avid and FDG-PET is routinely used in clinical practice, however limited and conflicting data are available on the value of FDG-PET in response assessment at the end of treatment (FDG-PETend). With the aim of evaluating the prognostic value of FDG-PETend in T-cell lymphomas we performed a retrospective study evaluating all T-cell NHL patients treated at the European Institute of Oncology (IEO, Milan) over the past 20 years. Clinical data of all T-cell NHL patients treated at IEO from 1995 to 2015 were retrospectively collected. The back bone of first line therapy did not significantly change over time, being based on the administration of CHOP/CHOP-like chemotherapy eventually followed by treatment intensification with autologous stem cell transplantation (ASCT). Post first-line therapy FDG-PET scans were visually evaluated according to the criteria of the international Harmonization Project (positive vs negative). Ninety-eight consecutive patients (58 males, 40 females) with complete clinical data were considered in this analysis. FDG-PET was used for response evaluation starting from 2002, but only 18 patients considered in the present analysis were treated before 2002. Median age at diagnosis was 54 years (range 14-82). Fifty-two patients (53.1%) had Peripheral T-cell lymphomas not otherwise specified (PTCL-NOS), 23 (23.5%) had anaplastic large T-cell lymphoma (ALCL), 15 (15.3%) had acute lymphoblastic T-cell lymphoma (LAL-T), 8 (8.1%) had NK/T-cell lymphoma. Ten patients were diagnosed in stage I, 21 in stage II, 17 in stage III, 50 patients in stage IV. Thirty-two patients underwent ASCT during the study period. Median follow-up was 16 months (range 1-182). 42 patients were evaluated with FDG-PET at the end of first line therapy: 25 had negative (60%), and 17 (40%) positive PET scans. In 56 patients response was evaluated with CT scan only, and complete responses or complete responses unconfirmed (CR/CRu) were detected in 29 cases (51%). The 10-year progression free survival (PFS) and overall survival (OS) of the whole patient cohort were 22% and 32% respectively. To determine the prognostic value of FDG-PETend we first assessed the PFS of PET positive vs PET negative patients. Those patients who were PET positive at the end of treatment had a statistically inferior PFS compared to PET negative ones (5-year PFS: 29% vs 47% respectively; p<0.01). These data indicate that although a negative PET after initial therapy is a good prognostic predictor, about half of all patients still relapse after achievement of a negative PET. To better define the prognostic value of FDG-PETend scan in T-cell lymphomas, we restricted our analysis to those patients who obtained a CR after first line therapy, comparing the outcome of PET negative patients (n=25) with the outcome of patients who did not have a PET scan but were deemed in CR after a negative CT scan (n=17). Interestingly we did not observe significant differences between the 2 groups (5-year PFS was 47% in both groups). These data were also confirmed when the analysis was restricted to the PTCL-NOS and ALCL subgroups, suggesting unsatisfactory improvements in the quality of CR assessment with a limited negative predictive value of negative PET scans after first line therapy. In conclusion, although our data confirm the prognostic value of end of treatment FDG-PET scan in T-cell lymphoma, they also highlight the limits of current prognostic stratification tools suggesting that different timing of response evaluation or alternative methods to detect minimal residual disease in those patients in CR after first line therapy are warranted.

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).

Rituximab maintenance has been shown to be effective in patients with follicular lymphoma. The optimal duration of maintenance treatment remains unknown.270 patients (median age 57 years: range 25-82) with either untreated, relapsed, stable or chemotherapy resistant follicular lymphoma of all grades were treated with 4 weekly doses of rituximab monotherapy (375 mg/m²). Patients responding to the induction treatment (partial or complete response) received rituximab (375 mg/ m²) maintenance and were randomized either to a short maintenance consisting of four administrations every two months (arm A), or a prolonged maintenance for a maximum of five years or until disease progression or unacceptable toxicity (arm B). The primary endpoint was event-free survival (EFS) from randomization. Sample size calculation allowed detecting a median EFS increase with prolonged maintenance from 2.5 to 4.5 years with 80% power. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and objective response. Comparisons between the two treatment arms were performed using the log-rank test for survival endpoints.From October 2004 to November 2007 165 patients were randomized, 82 in arm A and 83 in arm B. 124 patients were chemotherapy-naïve. The median EFS is 3.4 years (95% CI 2.1-5.3) in arm A and 5.3 years (95% CI 3.5-NA) in arm B. Using the prespecified log-rank test this difference is statistically not significant (p=0.14). We observed an unexplained difference in disease progression and relapse during the first 8 months after randomization (3 in arm A vs. 10 in arm B) when treatment in both arms was the same which led to an early crossing of the EFS curves at 18 months. Considering only patients at risk after 8 months from randomization EFS in arm B is significantly prolonged compared to arm A (median EFS 7.1 (95% CI 4.4-NA) vs. 2.9 years (95% CI 1.8-4.8); log-rank test p=0.004). Median PFS is significantly longer in arm B (7.4 (95% CI 5.1-NA) vs. 3.5 years (95% CI 2.1-5.9); log-rank test p=0.04). There is no significant difference in OS and in the observed best response. Maintenance treatment was stopped due to unacceptable toxicity in no patient in arm A vs. 3 in arm B. Six subsequent cancers developed in arm A and 8 in arm B. One infection grade ≥3 was reported in arm A whereas seven infections grade ≥3 occurred in 5 patients in arm B.EFS, the primary endpoint was not met which is mainly due to the early separation of the survival curves favouring arm A, at a time when the treatment in both arms was the same. However, a retrospectively defined analysis considering only EFS events from the time when treatment was different in the two arms, shows a statistically significant increase in EFS with long-term maintenance compared to the 8 months maintenance regimen. Long-term rituximab maintenance also doubles the median PFS without leading to increased undue toxicity.Off Label Use: Rituximab for 5 years. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Rituximab maintenance has been shown to be effective in patients with follicular lymphoma. The optimal duration of maintenance treatment remains unknown.

No relevant conflicts of interest to declare.

Abstract 4876

To evaluate clinical activity of 90Y-Ibritumomab Tiuxetan in Extranodal Marginal-Zone Lymphoma.PATIENTS AND METHODS: From May 2004 to April 2011 thirty patients affected by relapsed/refractory Marginal-Zone Lymphoma - arisen at any extranodal site - were enrolled to receive 90Y-Ibritumomab Tiuxetan at the activity of 0,4 mCi/kg. Median age was 57 years (range 36–83 ys); 16 female and 14 male. Thirtheen patients had Helicobacter Pylori-negative gastric Mucosa-Associated Lymphoid tissue Non Hodgkin Lymphoma, while 17 patients had extra-gastric Marginal-Zone Lymphoma. At time of treatment 13 out of 30 patients had disseminated disease (stage III/IV; Ann-Arbor Staging System); 4 patients bone marrow involvement. All patients had received a previous treatment with a maximum of 7. The median number of previous treatments administered - including antibiotics, CT, RT or surgery - was 1 with a maximum of 7; 14/30 had received at least 2 previous treatments, 5 of them more than 3.Toxicities were primarily hematological, as expected, and reversible; infection or febrile neutropenia was observed in 3 patients. Up to now no myelodisplastic syndrome occurred. Overall Response Rate was 90%: twenty-three patients achieved a complete response (77%); partial response occurred in 4 patients (13%), stable disease in 2 patients (7%) and 1 progression (3%). With a median follow-up of 47 months, 2 patients relapsed after complete response; 8 out of 20 complete responses are still responder after > 3 years and 5 patients after > 5 years.90Y-Ibritumomab Tiuxetan seems to be active in patients with Extranodal Marginal-Zone Lymphoma resistant or refractory to conventional systemic treatment. These results suggest as a single shot of radioimmunotherapy could represent a possible option for the treatment of relapsed Marginal Zone Lymphoma.No relevant conflicts of interest to declare.

Abstract 3713

Recently in large randomized studies, the addition of Rituximab to standard chemotherapy in the first-line treatment of follicular lymphoma (FL) demonstrated improvements in long-term outcome in FL.We compared the outcome of 111 naive FL patients (pts) treated at our institution from 1995 to 2009 with a single alkylating agent in combination or not with Rituximab: 58 pts received Chlorambucil plus Rituximab (R-Chl) and 53 pts Chlorambucil and prednisone (Chl+PDN). The 2 schedules included an induction phase, where Chlorambucil was given at 6mg/mq for 6 consecutive weeks in both groups and the Rituximab in 4 weekly administrations. The maintenance phase was longer in the Chl+PDN group: Chlorambucil was administered 6mg/mq daily 14 days each month for a total of 12-months of treatment versus 14 days with monthly-Rituximab for 4 consecutive months in the R-Chl group.The demographic and prognostic factors are reported in Table 1.At the end of treatment the ORR was 98% in the R-Chl pts and 77% in the Chl+PDN group, with a percentage of complete response of 79% and 55% respectively. No significant incidence of adverse events were reported and only one HBsAg positive patient in R-Chl group discontinued the therapy. One case of myelodysplastic syndrome was described in a Chl+PDN relapsed patient. With a median follow up of 34 months, the OS and the EFS in R-Chl pts is 95% and 76% respectively. Otherwise, with a median observation time of 82 months in the Chl+PDN group 73% are alive and only 28% of pts maintained the response. The median time to subsequent therapy (TTST) is 21 and 15 months respectively in the 2 groups.The addition of Rituximab to alkylating in first-line treatment in previously untreated FL pts improves significantly the EFS and prolongs the time to next antilymphoma therapy compared with alkylating alone. Because of its low toxicity profile, our combination with Rituximab and Chlorambucil could be considered a first-line therapy, especially in FL patients not eligible for aggressive chemotherapy regimens.No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Abstract 3956

Abstract 5030

High-dose chemotherapy followed by autologous Peripheral Blood Stem Cell (PBSC) transplantation represents an effective option in relapsing/refractory malignant lymphoma as well as in selected solid tumors. Collection of a sufficient amount of stem cells (CD34+ ≥ 2.0×106/kg) by apheresis is mandatory for the procedure. However many factors could influence the mobilization of PBSC and about 30% of patients eligible for this therapeutic option fail stem cell mobilization. Peripheral CD34+ counts of 20/μL is conventionally considered the cut-off for a successful collection.With the aim to identify those factors affecting PBSC mobilization, we retrospectively reviewed data about our experience at European Institute of Oncology from 01/2005 to 05/2009. By evaluating the number of CD34+cells after mobilization, patients were considered as good mobilizers (peripheral CD34+ ≥ 20/μL, group A), relative poor mobilizers (peripheral CD34+ counts <20 and ≥8/ μL, group B) and absolute poor mobilizers (peripheral CD34+ counts <8/μL, group C). A total of 248 patients were enrolled into a mobilizing PBSC program; apheresis was performed when the CD34+ cell count was >5/μL. Patients characteristics were: 140 male, 108 female; median age was 51 yrs; diagnosis included: 124 Non Hodgkin Lymphoma (NHL), 50 Hodgkin Lymphoma (HL), 35 Multiple Myeloma (MM), 5 Acute Leukemia (AL) and 33 solid tumors, 1 Chronic Lymphocitic Leukemia (CLL); mean number of previous chemotherapy lines was 1 (0-9). The main mobilization regimens in hematological patients were cyclophosphamide 4g/mq (n=118) and ESHAP either followed by G-CSF (n=27) or pegylated G-CSF (n=48); the majority of patients affected by solid tumors received ICE regimen plus G-CSF (n=26).By evaluating the number of CD34+cells after mobilization, 163 (65.7%) patients resulted good mobilizers, 43 (17.3%) patients relative poor mobilizers and 42 (17%) patients absolute poor mobilizers. All patients in group A, 31 patients in group B (72%) and 8 patients in group C (19%) collected >2.0×106 CD34+cells/kg. According the Two-sided Fisher's exact test, more than 3 previous chemotherapy lines before mobilization (p<0.001), pretreatment with purine analogues (p=0.007) or 90Y-Ibritumomab Tiuxetan (p=0.002) were found to be independent factors able to affect PBSC mobilization. In a multivariate analysis, these factors were confirmed as detrimental (purine analogs p=0.019, 90Y-Ibritumomab Tiuxetan p=0.003).These results could help to identify those factors affecting PBSC mobilization. To reduce poor mobilizers we suggest to anticipate mobilization program and to evaluate the opportunity to reserve purine analogs or radioimmunotherapy after collection. About 20% of patients defined as absolute poor mobilizers might successfully mobilize PBSC by lowering the CD34+ cut-off before apheresis.No relevant conflicts of interest to declare.

Follicular lymphoma (FL), one of the most common B-cell non-Hodgkin's lymphoma (NHL), is an indolent disease characterized by a continuous relapse pattern. In the last years the treatment have changed with the introduction of Rituximab, that in combination with chemotherapy prolongs the progression-free survival (PFS) and the overall survival (OS) of FL pts. We report here the results of a regimen containing Rituximab and Chlorambucil (Chl) in untreaed FL pts.Since December 2001 48 pts (22 male and 26 female) with naive FL were treated in first-line with R-Chl. The schedule consisted of an induction phase with four weekly infusion of Rituximab at standard dose and 6 consecutive weeks of Chl at 6mg/mq/daily. Pts were restaged and in absence of disease progression received four cycles of consolidation with a monthly Rituximab infusion and 14 days of Chl each month.Median age at diagnosis was 56 years (range 29-79). Ann Arbor stage was I-II in 13 pts and III-IV in 35 pts (73%); 15 pts had bulky disease and 14 pts presented an extranodal localization. B symptoms were present in 8 pts. Histological grading was available in 42 cases, and was 1 in 10 pts, 2 in 26 pts and 3 in 6 pts. FLIPI was evaluable in 46 pts, and was 0-1 in 25 pts (52%), 2 in 12 pts (25%), and >2 in 9 pts (18%). After the induction phase overall response rate (ORR) was 98% with 14 pts in complete remission (CR). After the consolidation phase 39 pts (81%) obtained a CR and eight (17%) a partial response (PR); the remaining patient had a stable disease and underwent high-dose chemotherapy and autologous transplantation. All pts but one concluded the planned treatment. The mean daily dose of Chl administered during the induction phase was 10 mg, while 8 mg in the prolonged treatment. Twenty-eight pts (58%) experienced a neutropenia during treatment, and Chl dose was reduced in 22 pts (46%); however, only 11 pts (23%) had a G3-4 neutropenia. The Chl was stopped only in a patient because of a persistent G3 neutropenia after the first consolidation cycle. After a median observation time of 42.5 months (range 7-94) nine pts relapsed (19%), with a median time to relapse of 20 months (range 7-66). Two pts died, one of disease progression and one of a pre-existing ovarian cancer.Our results described a safe and feasible combination of immuno-chemotherapy in untreated FL pts. With respect to traditional treatments, our regimen shows a similar efficacy and a lower toxicity, that leads to an easier handling. The schedule including four monthly additional Rituximab administrations confirms the superiority of a prolonged exposure to Rituximab over the standard 4-weekly administrations. In conclusion, our data suggest that this combination may be considered as a valid first-line treatment of FL patients, especially in those not eligible for more aggressive chemotherapy regimens.No relevant conflicts of interest to declare.