ALBERT

Description: INTRODUCTION: High-dose salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard of care for refractory/relapsed (R/R) Hodgkin lymphoma (HL). Achieving complete remission (CR) prior to ASCT represents the strongest prognostic factor for R/R HL patients receiving salvage chemotherapy. Therefore, increasing the CR rate prior to ASCT represents a primary goal in these patients. Since Bendamustine monotherapy induces CR in a substantial proportion (25% to 35%) of R/R HL patients, the present phase II study aimed at investigating efficacy and toxicity of a novel salvage regimen combining Bendamustine, Gemcitabine and Vinorelbine (BeGEV) as second-line salvage chemotherapy in patients with relapsed/refractory HL. PATIENTS AND METHODS: HL patients who were refractory to, or have relapsed after one previous chemotherapy line were eligible. The primary endpoint was CR rate after four cycles of therapy. Secondary endpoints were: overall response rate (ORR), stem cell mobilization activity, and toxicity. Progression free survival (PFS) and overall survival (OS) were also evaluated. BeGEV regimen consisted of: Bendamustine (90 mg/sqm, days 2-3), Gemcitabine (800 mg/sqm, day 1 and 4) and Vinorelbine (25 mg/sqm, day 1) every 3 weeks for a total of 4 courses. RESULTS: Between August 2011 and March 2014, 59 consecutive patients with relapsed (46%) or refractory (54%) HL were enrolled. The median age was 33 years (range 18-68). Out of 59 enrolled patients, 43 (73%) achieved a CR and 6 (10%) a partial response (PR) for an ORR of 83%. One case (2%) showed stable disease (SD), while 8 patients (14%) progressed, and 1 (2%) was not evaluable for response. With a median follow-up of 16 months, the 2-year PFS and OS were 51% and 69%, respectively, without significant difference between relapsed and refractory patients. OS was higher for BeGEV-responding (CR+PR) patients compared with those who failed the induction regimen (2-year OS: 86% vs 0%, p

Description: Abstract 3120 Introduction Fluorodeoxyglucose positron emission tomography (FDG-PET) is a functional imaging tool routinely used for staging and response assessment in aggressive lymphomas. Even if mantle cell lymphoma (MCL) is considered FDG avid, current data on the use of PET in this histotype are scant. We retrospectively analysed 43 PET scans in 22 MCL patients (pts) and compared the results to standard contrast-enhanced computerized tomography (CT) in order to define PET sensitivity and specificity in this rare lymphoma. Patients and methods Twenty-two pts with biopsy proven diagnosis of MCL underwent PET in different phases of disease for a total of 43 scans. PET scans were co-registrated with a simultaneous CT and compared to standard contrast-enhanced CT performed within 4 weeks. Nineteen PET (44.2%) were performed for disease staging at diagnosis or relapse, while 24 (55.8%) for response assessment. Negative PET were included in the analysis for response assessment only if a previous positive scan was available. Results PET and standard CT results were concordant in 16/43 cases (37.2%). Discrepancies were found in 27/43 cases (62.8%) and were grouped in four categories: false negative PET (5 cases), PET positive with a disease extension minor or major than CT (7 and 9 cases, respectively) and PET positive with negative CT (6 cases). At staging PET was concordant with CT in 4/19 (21%) cases. In 5/19 cases (26.3%) PET was negative in all disease sites documented by standard CT. In the remaining 10 cases (52.7%) PET was positive but discordant with disease extension evaluation by CT, determining upstaging and downstaging in 5 scans (26.3%) each. Involvement of gastro-intestinal tract was detected only in 4/19 cases (21%). PET performed for response assessment was concordant with CT in 12/24 cases (50%). In 6/12 concordant cases (25%) both CT and PET were negative; in the remaining 6/12 cases (25%) PET was positive and disease extension evaluation was concordant with standard CT. Six out of 12 discordant cases (25%) presented different disease extension evaluation; in the other six cases standard CT was negative while PET documented minimal residual disease (MRD). PET sensitivity and specificity in the entire cohort were 86.5% and 100%, respectively; positive predictive value was 100%, while negative predictive value was 54.5%. No difference in PET sensitivity was found in nodal and extra-nodal sites. No statistical significant correlation was found between PET sensitivity and proliferation index; nevertheless, no pts with Mib-1〉50% presented either false negative PET scan or disease extension underestimated by functional imaging. Conclusion This analysis shows a PET sensitivity (86.5%) lower than expected if compared with other aggressive lymphomas. High specificity registered in this cohort is likely to be ascribed to simultaneous CT co-registration, that allows identification of false positive cases. A false negative PET scan at initial staging was registered in 21% of cases. A gastro-intestinal tract involvement, expected to be near universal in advanced stage MCL, was detected by functional imaging only in 21% of pts at disease onset or relapse. Either downstaging or upstaging of disease burden seldom result in different therapeutic approach since localized MCL is a rare entity. Minimal residual disease, detected by functional imaging in half of standard CT negative pts at response assessment, has uncertain role in MCL, since the disease remains incurable and there is no clear evidence that MRD positivity requires treatment. All these findings advise against utilization of functional imaging for routine management of MCL. Considering heterogeneity of FDG-uptake in MCL, PET is likely to be more reliable in pts presenting high proliferation index. Moreover, current data suggest a prognostic value of baseline FDG-avidity. Further investigations are needed to confirm these preliminary data in larger prospective trial, separating MCL from other aggressive histotypes. Disclosures: No relevant conflicts of interest to declare.

Description: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin Lymphoma. Although a typical presentation as an indolent lymphoma, without systemic symptoms and with a good performance status, the mantle cell lymphoma is an aggressive one, hardly curable with standard chemo-immunotherapy. Although current approaches to mantle cell lymphoma, including newer agents (such as bortezomib, lenalidomide, temsirolimus and ibrutinib) and autologous stem cell transplantation, have greatly improved the outcomes of affected patients, this disease is still characterized by high relapse rates, with most patients eventually dying of lymphoma progression. Before official approval by EMA, patients with relapsed/refractory mantle cell lymphoma with unsatisfied critical medical urgency were granted ibrutinib early access through a Named Patient Program in Italy (NPP, DM 8 May 2003). This observational, non-interventional, retrospective, multicenter study focuses on collecting information about the effectiveness and safety of ibrutinib as single-agent in patients who received at least one dose of ibrutinib under the NPP in the period between 29/Jul/2014 and 25/Jan/2015 in Italy. Data from patients treated with ibrutinib outside a controlled clinical trial within a NPP could give additional information about the clinical use, treatment duration, efficacy and toxicity of ibrutinib given to relapsed or refractory MCL patients in a real life context. Fifty-three heavily pretreated patients were enrolled. They had received a median of previous therapies of 3, comprising lenalidomide, bortezomib, temsirolimus and autologous stem transplant. Ninety-one percent had measurable disease and 83.0% had and ECOG performance status ≤2. At the end of therapy there were 11 complete responses (20.8%), 7 partial responses, 5 stable diseases and 30 progressions with an overall response rate of 33.9%. Twenty-six patients received ≥3 concomitant medications during ibrutinib therapy. At 20 months overall survival (OS) was 26.8% (median reached at 9 months) and disease free survival (DFS) 75% at 15 months: 10/11 patients are in continuous complete response with a median of 10.5 months. Hematological toxicities were manageable, 6 thrombocytopenia occurred, of which only 2 grade 4 (due to disease bone marrow infiltration) and the other 4 related to ibrutinib. Main extra-hematological toxicities were diarrhea (9.4%) and lung infections (7.5%) which all lead to early drug discontinuation. The observed occurrence of diarrhea by severity was 0 for CTCAE Grade 1, 4 for Grade 2, 2 for Grade 3 and 0 for Grade 4. Lung infection had a lower occurrence: 0, 2, 2 and 0 split by CTCAE Grade 1, 2, 3 and 4 respectively. There is a boundary zone in the passage from phase III to phase IV trials, i.e. from experimental to marketing and free use phases: in this zone we can find NPP and compassionate and off-label use. Despite the known potential bias of all the observational retrospective studies, reports on the real life experience make an important contribution to medical knowledge prior to widespread utilization: ibrutinib therapy is effective and tolerable also in a clinical setting mimicking the real world. Our results, in fact, are superimposable to those obtained in clinical trials: for safety, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; for effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL. Disclosures Cascavilla: Janssen-Cilag: Honoraria. 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.

Description: Abstract 1614 Background: Few data are available on the role of fluoro-deoxy-glucose positron emission tomography (FDG-PET) in T-cell non Hodgkin Lymphoma (NHL). We compared standard contrast-enhanced computerized tomography (CECT) and FDG-PET for initial staging and restaging after treatment in T-cell NHL. Methods: We reviewed 58 FDG-PET scans performed in 29 patients (pts) affected by T-cell NHL and we focused on the 42 cases for which a simultaneous standard CECT was available for comparison. The specific T-cell histology was Peripheral T-Cell Lymphoma Not Otherwise Specified in 12 pts, Angioimmunoblastic T-Cell Lymphoma in 4 pts, Anaplastic Large Cell Lymphoma in 10 pts, other T-NHL hystologies in 3 pts. Twelve pts were males and median age at diagnosis was 57 years (range: 25–77). Baseline FDG-PET scans were 20, while FDG-PET performed for disease reassessment were 22. Results: FDG-PET performed at baseline was positive in all cases. In 6 cases (30%) FDG-PET identified fewer disease sites than CECT, while in 14 cases (70%) FDG-PET identified additional disease sites. New sites identified by FDG-PET were: other nodal sites (11 pts), spleen (2 pts), nasopharynx (1 pt) and testicles (1 pt). Different disease extent evaluation according to FDG-PET modified clinical stage in 10 pts (50%): one pt was downstaged and 9 pts were upstaged. FDG-PET-based stage was not considered for therapeutic decision. FDG-PET scans performed at restaging were negative in 16 cases (72%) and positive in the remaining 6 cases (28%). In 13/16 (81%) negative cases CECT was concordant and showed a complete remission, while in the remaining 3 cases CECT showed a residual nodal disease. In the 6 FDG-PET positive cases, CECT was as follows: abnormal in the same site of FDG-PET in 1 case, abnormal in fewer sites than FDG-PET in 3 cases and abnormal in more sites than FDG-PET in 2 cases. With a median follow-up of 32 months, the median overall survival (OS) of the 6 positive FDG-PET cases at restaging was 26 months. With a median follow-up of 23 months, the median OS of the 16 negative FDG-PET cases at restaging was not reached. Conclusion: FDG-PET can be useful in the initial staging of T-cell NHL, since it can allow a more accurate disease extension evaluation: in our experience it could identify additional sites, both nodal and extra-nodal, in 70% of pts. A change in clinical stage according to FDG-PET was observed in 50% of cases, with an upstaging in the majority of pts. We could confirm the high sensitivity of baseline FDG-PET in T-cell NHL. A high level of concordance was observed between PET and CECT at restaging. However, independently on CECT result, the worse OS of FDG-PET positive cases confirms the role of FDG-PET as prognostic factor for survival. Larger prospective trials are needed to confirm the utility of FDG-PET in baseline staging, reassessment after chemotherapy and treatment planning. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 154 Background Follicular lymphoma (FL) has an indolent course during which patients (pts) receive multiple lines of active treatments ranging from single-agent chemotherapy (CHT) or monoclonal antibodies (MoAb), to high-dose therapy with stem cell transplantation (HSCT). In relapsed patients the efficacy of salvage treatments may be affected by the type and the intensity of the previous treatments and it is currently not known whether a definite sequence of treatments throughout the course of the disease could optimize the outcome of patients. Since randomized trials can hardly be designed to answer this important clinical question, the Fondazione Italiana Linfomi (FIL) launched an observational, multicenter, retrospective study (REFOLL) to analyze if combinations of different first-line and salvage treatments could be identified, able to achieve a better long-term outcome. Patients and Methods Of 582 pts with FL at first relapse between 2000 and 2008 registered from 25 Institutions, 548 were included in the study. They had received either alkylating- (AA) (22%), or anthracycline- (AC) (61%) or nucleoside analogues-based (NA)(17%) CHT as first-line treatment, with the addition of rituximab (R) in 284 (52%). AA pts were older (PCHT with R showed a better outcome than CHT -〉CHT without R (HR:0.55, P=0.015; HR 0.61, P=0.047 after adjusting by age and stage at diagnosis). Conclusions Auto-HSCT obtained the best TTNT after relapse compared to any other regimen but its efficacy was maximized when anthracycline-containing CHT was used as first-line treatment, compared to other CHT programs. The addition of R to first-line CHT did not adversely impact on the results of any salvage. This study supports the concept that different sequences of active treatments do not necessarily obtain similar long-term results, which is important in the management of indolent diseases like FL and warrants further studies. The sequence of AC-CHT at diagnosis and auto-HSCT at relapse may be tested as the reference sequence of active treatments in FL patients. Disclosures: No relevant conflicts of interest to declare.

Description: INTRODUCTION Treatment of Diffuse Large B cell lymphoma (DLBCL) in the elderly population is challenging as many patients (pts) are not eligible to receive standard curative therapy, due to comorbid conditions and to a higher susceptibility to the side effects of standard anthracycline containing regimens. Among currently available active drugs, Lenalidomide has been used in the setting of relapsed/refractory DLBCL both as monotherapy and in combination with rituximab, showing a good activity and an acceptable safety profile. We started a prospective, multicenter, single arm, phase II trial to demonstrate activity and safety of a chemofree combination of lenalidomide + rituximab in elderly (≥ 70 years) untreated pts with DLBCL who were prospectively defined as frail according to a simplified comprehensive geriatric assessment (sCGA) (Tucci A. et al., Leuk Lymphoma. 2015 Apr). PATIENTS AND METHODS Pts were eligible if they were previously untreated DLBCL patients, older than 69 years and defined as frail according to sCGA. The treatment consisted of a 28-day cycle (R2) combining oral Lenalidomide (20 mg on days 1 to 21) and i.v. Rituximab (375 mg/m2 on day 1); a maximum number of 6 cycles was planned; response assessment was performed after cycles 4 and 6. At the end of the 6thcycle, patients with partial or complete response continued treatment with Lenalidomide 10mg/d on days 1 to 21 every 28 days, until cycle 12or unacceptable toxicity. Final response was evaluated within 28 days after the last study drug administration. Primary study endpoint was Overall Response Rate (ORR) after 6 R2 cycles, defined according to Lugano 2014 criteria; co-primary endpoint was the rate of extra-hematological toxicity with CTCAE grade 〉2 and of death for any cause during the treatment The study was planned according to a two stage Simon design. A total of 68 pts had to be enrolled to complete the study: 23 pts were required in the first stage. Second stage could be activated withat least 12 patients showing a Partial or Complete Response (PR/CR) in stage I. According to the Ray and Rai method less than 15/23 adverse events were also required for the safety coprimary endpoint. RESULTS From January 2017 to December 2017, 24 newly diagnosed frail DLBCL were enrolled in 8 Italian centers. Median age was 83 years (range 76-89) and 79% had stage III/IV; 42% of pts were male, and 44%, had elevated LDH, 45% had High risk IPI (i.e. 3-5 risk factors). All pts were confirmed eligible and started R2 treatment. The planned 6 courses of R2 were completed in 13 pts (54%). The median number of R2 cycles was 6 (1-6). Treatment was discontinued in 11 pts for the following reasons: lymphoma progression in 4 cases, second malignancy in 2, extra-hematological toxicity in 3 cases, consent withdrawal and investigator choice after 4 cycles in CR in 1 case each. Response assessment after 6 R2 cycles showed12 responding pts (ORR 50%), 4 CR and 8 PR, that was higher than by the inferior limit required by the Simon optimal design. Regarding safety coprimary endpoint 13 events were reported including 9 extra-hematological toxicities 〉 grade 2 CTCAE (3 cardio-vascular and 6 respiratory events, all resolved) and 4 deaths (2 patients due visceral arterial ischemia and 2 due infectious disease). The rate of adverse events was lower than the superior limit of 15 allowed the first stage of the study.Since August 2018 the enrollment in the stage II of the trial has been resumed and it is currently ongoing with 45 patients enrolled. CONCLUSIONS The ReRi is the first study to evaluate activity and safety of a chemo-free therapy in patients with diffuse large B-Cell Lymphoma who are not eligible for conventional cytotoxic therapy. The results of the planned interim analysis of our study confirmed the initial efficacy and safety hypotheses of R2 combination in untreated elderly pts with DLBCL. Treatment of elderly frail DLBCL pts with R2 holds promise in terms of both ORR and safety. Disclosures Bassan: Amgen Inc.: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Shire: Honoraria. Merli:Sandoz: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Janssen: Honoraria; Takeda: Honoraria, Other: Travel Expenses; Gilead: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Mundipharma: Honoraria. Liberati:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Janssen: Honoraria; Novartis: Other: Clinical trial support. Luminari:ROCHE: Other: Role as Advisor ; CELGENE: Other: Role as Advisor & Travel Grant; TAKEDA: Other: Travel Grant; GILEAD: Other: Lecturer .

Description: Introduction Limited stage follicular lymphoma (FL) is usually managed with involved field radiotherapy (IFRT), although different approaches are currently carried out, ranging from watch and wait to combined treatment. RT on involved lymph nodes allows eradication of the disease only in 40-50% of patients. Anti-CD20 monoclonal antibodies (MoAb), widely used in advanced stage FL, are likely to be effective in reducing the relapse risk, although no scientific evidence of their role has been provided. The aim of this multicenter phase II prospective study was to evaluate the role of MRD in identifying patients unlikely to be cured by RT, for whom an immunotherapy-based consolidation could improve outcome. Methods 110 patients with stage I/II FL were enrolled. IFRT was administered to all patients at a dose of 24 Gy. Peripheral blood (PB) and bone marrow (BM) samples were centralized to the Italian FIL (Federazione Italiani Linfomi) MRD Network of EuroMRD-certified laboratories: the presence of a BCL2/IGH rearrangement was investigated at baseline in all patients by nested PCR (NEST) and RQ-PCR (RQ), the latter according to the EuroMRD guidelines. In patients BCL2/IGH+ at baseline by both NEST and RQ in BM and/or PB, MRD was analyzed in both tissues after IFRT and every 6 months over a three-year follow-up period. Patients with positive MRD by both NEST and RQ in BM and/or PB after IFRT or who became positive during the follow-up were treated with 8 weekly doses of the anti-CD20 MoAb ofatumumab. The primary objective of the study was to define the efficacy of immunotherapy in obtaining the disappearance of BCL2/IGH rearranged cells. Results Preliminary data are available for 107 patients, 57 males, 50 females. Median age was 55 years (29-83). 17% had G1 FL, 32% G2, 40% G3A, 11% NOS. The FLIPI score was 0 in 59% of patients, 1 in 35%, 2 in 6%. 69% of patients had inguinal site involvement. Despite a negative BM biopsy, at baseline 30% of patients (n=32) had a BCL2/IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in the BM and/or PB; the concordance between compartments was 90%, with 10% of negative PB showing a positive BM. No significant differences were observed in relapse probability between patients with or without a molecular marker. All patients were submitted to IFRT and all obtained a clinical response, which was complete in 79 of the 101 evaluated patients (78%) and partial in 22 (22%). MRD evaluation after treatment revealed the persistence of BCL2/IGH rearranged cells in the PB and/or BM in 60% of patients. According to the design of the protocol, MRD-positive patients, either after IFRT (n=18) or in case of conversion to a positive signal during the follow-up (n=7), received 8 weekly administration of ofatumumab. A conversion to MRD negativity, evaluated in 23 treated patients, was obtained in 20 (87% - CI 65.1-97.1). This result was significantly superior to the expected 50%. One death occurred after IFRT, due to ischemic stroke. Adverse events likely correlated to ofatumumab occurred in 7/25 treated patients, consisting of infusion reactions in 5, leading to a permanent interruption of immunotherapy in 3. After a median follow-up of 18 months, all patients who achieved a MRD negativity with ofatumumab underwent a regular molecular follow-up and are still MRD-negative. Overall, clinical relapse or progression were observed in 17 patients: 13 (18%) among the 73 "no marker" patients; 2 relapses (16%) were observed among the 12 MRD-negative patients after IFRT and 2 relapses were observed among the 23 patients treated with the anti-CD20 MoAb (8.7%), 1 having achieved a MRD negativity and 1 not. No significant differences in event-free survival have so far been observed between the three groups. Conclusions The MRD data of this phase II trial for early stage FL indicate that RT alone is often insufficient to eradicate the disease, being capable of inducing a negative MRD only in 40% of evaluable cases, with a long-lasting effect only in half of them. The primary objective of this study - MRD negativity after immunotherapy - was achieved, obtaining the disappearance of BCL2/IGH rearranged cells in the majority of patients treated with ofatumumab. The strategy of an immunotherapy consolidation after IFRT in MRD-positive patients allowed to increase molecular responses. A longer follow-up and further studies on larger patient populations will allow to conclusively define the impact of this MRD-driven strategy also on clinical outcome. Disclosures Pulsoni: Roche: Consultancy, Speakers Bureau; Takeda: Consultancy; Pfizer: Consultancy; Sandoz: Consultancy; Gilead: Speakers Bureau; Merk: Consultancy; Bristol Meyer Squibb: Speakers Bureau. Ferrero:Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Luminari:ROCHE: Other: Role as Advisor ; CELGENE: Other: Role as Advisor & Travel Grant; TAKEDA: Other: Travel Grant; GILEAD: Other: Lecturer . Liberati:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Janssen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Novartis: Other: Clinical trial support. Ferreri:Roche: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kite: Consultancy. Nassi:Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Corradini:Roche: Honoraria; Novartis: Honoraria; kite: Honoraria; KiowaKirin: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Servier: Honoraria; Sanofi: Honoraria; Takeda: Honoraria. Mannina:Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arcaini:Celgene: Speakers Bureau; Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses. Galimberti:Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau. Ladetto:AbbVie: Honoraria; Roche: Honoraria; ADC Therapeutics: Honoraria; Acerta: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; J&J: Honoraria; Celgene: Honoraria. Foà:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: The anti-CD20 MoAb Ofatumomab is employed to eradicate Minimal Residual Disease in early stage Follicular Lymphoma(FL). The drug is registered for Chronic Lymphocytic Leukemia, not for FL.

Description: Abstract 4851 Background: Primary Mediastinal B-Cell Lymphoma (PMBL) is an uncommon disease, characterized by aggressive and invasive course but with a good prognosis after anthracycline-based chemotherapy. In the PET era the role of consolidation radiotherapy is under debate and, despite CD20 expression, the efficacy of Rituximab is still unclear. We retrospectively analyzed the outcome of 36 consecutive patients (pts) affected by PMBL treated in the last 10 years at our institution. We focused on anti-CD20 antibody efficacy when added to chemotherapy and on the role of autologous stem cell transplantation (ASCT) in PET positive pts after first-line treatment. Patients and methods: From June 2000 to March 2011 36 pts with biopsy proven PMBL referred to our institution. Median age was 35 years (range: 18–68); 21 pts (58%) were female and a mediastinal bulk at diagnosis was documented in 33 pts (92%). B-symptoms were reported in 16 cases (44%) and an extra-nodal involvement in 19 cases (53%). Age-adjusted IPI score was ≥ 2 in 12 pts (33%). For all patients first line treatment consisted in a third generation anthracycline-based chemotherapy (VACOP-B), with the addiction of 6 Rituximab doses in 15 pts (42%). Pts obtaining complete remission (CR) with negative PET after (R)-VACOP-B were consolidated by radiotherapy (RT), while pts in partial remission (PR) with residual FDG uptake underwent a second-line chemotherapy with 3 DHAP cycles followed by autologous stem cell transplantation (ASCT). Results: In the whole cohort, after first-line therapy overall response rate (ORR) was 97%, with a CR rate of 39%. RT was therefore performed in 14 PET-negative pts. 2/14 pts experienced early relapse and only one of them obtained a second CR after salvage therapy, while the non-responding patient died because of progressive disease. Twenty-one pts (58%) showed a residual FDG uptake after (R)-VACOP-B and underwent second-line therapy. Nineteen pts responding to second-line therapy achieved ASCT, while 2 pts progressed and died after salvage therapy. ORR after ASCT was 86% with a CR rate of 71%. Post-ASCT RT was performed in 10 pts, 7 CR and 3 PR; two PR pts converted to CR after RT. With a median follow-up of 66 months (range: 13–142) 2-year overall survival (OS) and progression free survival (PFS) were respectively 94% and 89%. Among the 15 pts receiving first-line chemotherapy containing Rituximab, ORR after R-VACOP-B was 93% with a CR rate of 40%. RT was therefore performed in 6 PET-negative pts. 1/6 pts experienced early relapse and died of progressive disease. One patient showed progressive disease after R-VACOP-B and underwent second-line therapy with ASCT, obtaining CR. Eight pts (53%) showed a residual FDG-uptake after R-VACOP-B and underwent second-line therapy and ASCT. ORR and CR rate after ASCT were 100% and 75% respectively. Two pts in PR after ASCT converted to CR after RT. Among the 21 pts receiving chemotherapy without Rituximab, ORR after VACOP-B was 100% and CR rate was 38%. RT was therefore performed in 8 PET-negative pts; one of them experienced early relapse and obtained a second CR after salvage therapy. Thirteen pts (62%) showed a residual FDG-uptake after VACOP-B and underwent second-line therapy. Eleven pts responding to second-line therapy achieved ASCT, while 2 pts progressed and died after salvage therapy. ORR and CR rate after ASCT were 77% and 69% respectively. No statistically significant difference in ORR, CR rate, OS and PFS (Figure 1) was found between pts treated with Rituximab plus chemotherapy and pts treated with chemotherapy alone. Conclusions: These data substantially confirm the satisfactory outcome of PMBL, with a 2-year OS and PFS of 94% and 89% for the entire cohort. We registered a residual FDG uptake after first line chemotherapy in a proportion of pts higher than expected (58%). This subgroup of pts clearly take advantage from second line chemotherapy followed by ASCT, obtaining a CR rate of 71%. The addiction of Rituximab to first line chemotherapy instead does not seem to improve PMBL pts outcome in this small and retrospectively analyzed population. The role of immunotherapy in this rare lymphoma subtype and the chance to safely avoid RT consolidation in PET negative pts need to be further investigated in wider prospective trial. Disclosures: No relevant conflicts of interest to declare.

Description: INTRODUCTION: High-dose salvage chemotherapy followed by autologous stem cell transplantation (Auto-SCT) in chemosensitive patients still remains the standard-of-care treatment for relapsed/refractory classic Hodgkin lymphoma (R/R CHL). As previously reported in a multicenter phase 2 study (Santoro et al., J Clin Oncol, 2016), the BEGEVregimen induces an objective response rate (ORR) 〉80% in the second-line salvage setting of R/R cHL, thereby resulting a highly effective treatment. Here, we assess efficacy and safety of the BEGEV regimen after extended follow-up (registered at www.clinicaltrials.gov as #NCT01884441). PATIENTS AND METHODS: cHL patients who were refractory to, or have relapsed after first-line chemotherapy were eligible. The primary endpoint was CR rate after 4 cycles of therapy. Secondary endpoints were: ORR, stem cell mobilization activity, and toxicity. Progression free survival (PFS) and overall survival (OS) were also evaluated. The BEGEV regimen consisted of: Bendamustine (90 mg/sqm, days 2-3), Gemcitabine (800 mg/sqm, day 1 and 4) and Vinorelbine (25 mg/sqm, day 1) every 3 weeks for a total of 4 courses. RESULTS: Between September 2011 and March 2014, 59 consecutive patients with relapsed (46%) or refractory (54%) cHL were enrolled. The median age was 33 years (range 18-68). By intention to treat (ITT), after 4 cycles of therapy, 44 (75%) achieved a CR and 5 (8%) a partial response (PR) for an ORR of 83%. One case (2%) showed stable disease (SD), while 8 patients (14%) progressed, and 1 (2%) was not evaluable for response. In univariate analysis, the only factor which resulted associated with a different probability to reach CR was disease status at study entry, with CR being achieved by 84% of relapsed patients and 59% of refractory patients (P=0.031). With a median follow-up of 56 months (range, 3.4-79), the overall patient population (n=59) has an OS of 78% and a PFS of 61%, respectively, without significant difference between relapsed and refractory patients. Fifty-seven out of 59 patients were evaluable for CD34+ cell mobilization. Two of 57 patients (3.5%) experienced CD34+ cell mobilization failure, whereas the planned target dose of CD34+ cells (3×10^6 CD34+ cells/Kg body weight) was successfully harvested in the remaining 55 patients (96.5%). After AutoSCT, engraftment of neutrophils and platelets was recorded on day 11 (range 9-21) and day 12 (range 9 - 26), respectively. Of the 49 responding patients, 43 (73% by intention to treat) proceeded to Auto-SCT (39/43 in CR, 4/5 in PR); the remaining 6 patients did not proceed to Auto-SCT due to mobilization failure (n=2), physician decision (n=2), early relapse (n=1), patient refusal (n=1).After transplant, 4 patients died [pneumonia (n=1), infection (n=1), multi-organ failure (n=1), PD (n=1)] and 7 patients relapsed. No patient has developed secondary leukemia or myelodysplasia. For transplanted patients, the 5-yr OS and PFS are 91% and 77%, respectively. CONCLUSIONS: These 5-year follow-up data demonstrate that BEGEV is a highly effective and safe salvage regimen. Nearly 80% of BEGEV-treated R/R cHL patients who experience an objective response and are addressed to Auto-SCT achieve long-term disease control and may potentially be cured. These data provide a strong rationale for further development of the BEGEV regimen. Disclosures Luminari: Roche: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Servier: Consultancy; Sandoz: Consultancy. Carlo-Stella:ADC Therapeutics: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau; Boehringher Ingelheim Italia: Consultancy; AstraZeneca: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Sanofi: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Genenta Science: Speakers Bureau; MSD Italia: Speakers Bureau.

Description: Introduction Autologous stem cell transplantation (ASCT) is the standard care for refractory and relapsed Hodgkin and aggressive non Hodgkin lymphoma, but patients (pts) with high tumor burden before transplantation present a very poor outcome. Furthermore, pts with advanced age or co-morbidities could not be eligible to the procedure. We tested efficacy and feasibility of reinforced mini-BEAM followed by hematopoietic stem cell infusion (mini-ASCT) either as extreme debulking attempt in pts with disappointing response to previous salvage therapy or in pts unsuitable for standard transplantation. Patients and methods Ten Hodgkin’s lymphoma (HL), 10 aggressive B-cell non Hodgkin’s lymphoma (B-NHL) and 3 aggressive T-cell non Hodgkin’s lymphoma (T-NHL) pts received mini-BEAM therapy (BCNU 100 mg/m2 on d-6, VP-16 75 mg/m2/d and Ara-C 200 mg/m2/d from d-5 to d-2, Melphalan 100 mg/m2 on -d1) followed by peripheral blood stem cell infusion (PBSC). Median age was 44 years (range 23–67). Fifteen pts (65%) were primary refractory to first line therapy, while 5 pts and 3 pts had early and late relapse, respectively (22% and 13%); all 23 pts had received at least three previous therapies. Disease status before mini-BEAM was partial remission (PR) in 2 pts, stable disease (SD) in 7 pts and progressive disease (PD) in 14 pts. Results Median number of CD34+ cells infused was 5.77×106/kg (range: 1.4–20.0). Median time to neutrophils and platelets engraftment was 9 days (range 7–11) and 10 days (range 8–15), respectively. Nine pts (39%) had fever with a median duration of three days (range 1–5); only in 2/9 cases an infection was documented. Four pts (17%) experienced mucositis, requiring systemic opioid therapy in a single case. Median hospitalization was 25 days (range 21–37). Overall response rate (ORR) was 34.8% (CR 8.7%, PR 26.1%); 8 pts (34.8%) presented SD and 7 pts (30.4%) PD. Standard ASCT was performed in 12 pts; 11 pts were excluded because of co-morbidities (6 pts) or progressive disease (5 pts). Eleven pts are evaluable for response to ASCT: 5 pts reached CR (41.7%) and 6 PR (50%). Considering all the 23 pts, median overall survival (OS) was 28.5 months with a median follow-up of 9.4 months (range 1.1–39.8), while median event-free survival (EFS) was 13 months with a median follow-up of 5.2 months (range 1.0–39.8). Analysing pts undergone mini plus standard ASCT (cohort 1) apart from pts treated with mini ASCT alone (cohort 2), median OS was not reached in cohort 1 and 8.6 months in cohort 2, with a median follow-up of 11.7 months (range: 2.6–31.4) and 5.3 months (range: 1.1–39.8), respectively (Figure 1); median EFS was not reached in cohort 1 and 3.3 months in cohort 2, with a median follow-up of 13.1 months (range: 3.5–31.4) and 2.8 months (range: 1.0–39.8), respectively (Figure 2). Both differences in OS and EFS are statistically significant (logrank test: p = 0.0098 and p = 0.0187). At univariate analysis, a significant association was detected between standard ASCT and OS (p = 0.009), while both histology (p = 0.831) and response to mini-BEAM (p = 0.364) did not exert any valuable impact on OS. Conclusion ASCT with reduced BEAM as conditioning regimen proved to be a feasible and safe strategy for pts with refractory lymphoma which failed multiple salvage therapies. In this unfavourable setting of pts, ORR was better than expected. Survival data show an advantage for pts subsequently treated with standard ASCT, which must be performed whenever possible. Mini-ASCT can play a role for disease reduction in a tandem-fashion before standard ASCT in younger and to some extent chemosensitive pts. Finally, mini-ASCT can be considered as a valid option for pts uneligible to standard transplantation. Figure Figure Figure Figure