ALBERT

Description: Background. The prognostic role of cell of origin profile (COO) assessed by immunohistochemistry (IHC) is controversial in Rituximab era. FIL conducted a phase III randomized trial aimed at investigating the benefit of intensification with high dose therapy plus autotransplant compared to R-dose-dense therapy as first line in young DLBCL at poor risk (aa-IPI 2-3). Clinical results were reported (Vitolo, ASH 2012). The aim of BIO-DLCL04 was to correlate the biological markers with PFS. Patients and Methods. From 2005 to 2010, 412 untreated DLBCL at aa-IPI 2-3 were enrolled. Central histology revision was mandatory and 13 patients were excluded due to different histologies. Biological markers were analyzed on DLBCL NAS; COO analysis was performed by IHC and cases were classified in germinal center (GC) and non-GC according to Hans' algorithm; COO determined by gene expression profile using the NanoString® nCounter® Analysis System based on 20-gene assay (Lymph2Cx) using formalin fixed paraffin embedded tissue is ongoing; BCL2, BCL6 and MYC anomalies were tested by IHC; final analysis by fluorescent in situ hybridization (FISH) is ongoing. Cases were deemed positive if at least 30% of lymphoma cells were stained with each antibody (with the exception of at least 40% for MYC). Results. At the time of this analysis, 223 DLBCL NAS were analyzed: 131 non-GC and 92 GC; BCL2, BCL6 and MYC anomalies were tested in 196, 74 and 107 cases respectively. Clinical characteristics for non-GC vs GC were: median age 51 years for both, male 49% vs 45%, aa-IPI 3 15% vs 25%, bone marrow involvement (BM) 16% vs 24%. R-HDC was performed in 45% of non-GC patients and in 49% of GC. Complete response was recorded in 105 (80%) non-GC patients and in 62 (67%) GC. At a median follow-up of 49 months, the 3-year PFS for non-GC vs GC was 75% (95% CI: 67-82) vs 57% (95% CI: 46-67) with crude hazard ratio, HR 0.55 (0.35-0.87), p.01 and adjusted (for age, gender, aa-IPI, BM) aHR 0.56 (0.35-0.88), p.013. No significant differences by treatment were reported. Overexpression of MYC by IHC had a relevant prognostic impact, with aHR 1.84 (0.99-3.44), p.054. By IHC, 3-years PFS for double negative vs single BCL2 or MYC overexpression vs double positive, was 85% vs 68% vs 51% respectively, with an aHR for double expressors compared to double negative of 3.91 (1.13-13.53), p.031. At the time of the present report, FISH analysis was conducted in 88 cases: 43 were triple negative, 37 single hit and 8 double/triple hit. By FISH, 3-years PFS for triple negative vs single hit vs double/triple hit was 74% vs 84% vs 25% respectively, with an aHR for double/triple hit compared to triple negative of 5.73 (2.05 to 16.02), p.001. Conclusions. In conclusion, with the limit of the analysis performed by IHC based on Hans' algorithm, BIO-DLCL04 showed an unexpected better outcome for non-GC compared to GC, irrespective of treatment arm. The ongoing analysis conducted by Nanostring will be more informative. The overexpression of MYC was an unfavourable risk factor, mainly if associated with BCL2 overexpression, irrespective of type of treatment. Moreover, double/triple hit patients represent a subgroup with extremely poor prognosis. High dose therapy plus autotransplant was not able to reverse the inferior outcome of neither double expressors nor double hit patients and new strategies are deemed for these poor prognosis patients. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is an heterogeneous disease: 30-40% of cases have high expression of MYC and BCL2 proteins (Dual Expressor, DE) and 5-10% have chromosomal rearrangements involving MYC, BCL2 and/or BCL6 (Double-/ Triple-Hit, DH/TH). Although the optimal treatment for those high-risk lymphomas remains undefined, DA-EPOCH-R produces durable remission with acceptable toxicity (Dunleauvy K, Lancet 2018). TP53 mutation is an independent marker of poor prognosis in patients (pts) with DLBCL treated with R-CHOP therapy. However, its prognostic value in poor prognosis lymphomas, receiving intensive therapy, has not been investigated yet. Methods: A series of consecutive pts (n=87) with biopsy proven diagnosis of DE DLBCL (MYC expression ≥40% and BCL2 expression ≥ 50% of tumor cells) or DE-Single Hit (DE-SH, i.e., DE-DLBCL with a single rearrangement of either MYC, BCL2 or BCL6 oncogenes) or DE-DH/TH (MYC, BCL2 and/or BCL6 rearrangements obtained by FISH) were treated with 6 cycles of DA-EPOCH-R and central nervous system (CNS) prophylaxis consisting of two courses of high-dose intravenous Methotrexate. Additional eligibility criteria included age ≥18 years and adequate organ functions. Cell of origin (COO) was defined according to Hans algorithm [germinal center B cell like (GCB) and non GCB)]. TP3 mutations were evaluated by next generation sequencing (NGS) based on AmpliseqTM technology or Sanger sequencing and considered positive when a variant allelic frequency ≥10% was detected. Results: Eighty-seven pts were included [n=36 DE only, n=32 DE-SH (n=8 MYC, n=10 BCL2, n=14 BCL6), n=19 DE-DH/TH] with 40 patients (46%) showing a non GCB COO. Pts had a median age of 59 years (range, 24-79 years). Seventy-three pts (84%) had advanced disease and 44 (50%) an high-intermediate/high-risk score as defined by International Prognostic Index (IPI). Only 8 of 87 pts (9%) were consolidated in first clinical remission with autologous stem cell transplantation following DA-EPOCH-R. After a median follow-up of 24 months, 73 are alive (84%) and 14 died [n=12 disease (n=2 CNS disease); n=1 pneumonia; n=1 suicide]. The 2-year PFS and OS were 71% (95%CI, 60-80%) and 76% (95%CI, 61%-85%) for the entire population. For those with IPI 3-5 the PFS and OS were not significant different for DE and DE-SH pts versus DE-DH/TH pts [64% vs 57% p=0.77); 78% vs 57% p=0.12)]. The COO did not influence the outcome for DE only and DE-SH [PFS: 78% vs 71% (p=0.71); 92% vs 86% (p=0.16) for GCB vs non -GCB, respectively]. Fourty-six pts (53%;n=18 DE only, n=18 DE-SH, n=10 DE-DH/TH ) were evaluated for TP53 mutations with 11 pts (24%) carrying a clonal mutation (n=6 in DE, n=3 in DE-SH, n=2 in DE-DH/TH). The 2-year PFS and OS did not significantly change for pts DE and DE-SH TP53 wild type as compared to DE and DE-SH mutated [PFS: 84 % vs 77%, (p=0.45); OS: 87% vs 88%, (p=0.92)]. The two pts DE-DH/TH with TP53 mutation are alive and in complete remission.Conclusions: High risk DLBCL pts treated with DA-EPOCH-R have a favourable outcome independently from high IPI score, DE-SH and DE-DH/TH. Also the presence of TP53 mutations does not negatively affect the outcome of pts treated with this intensive regimen. The efficacy of DA-EPOCH-R in overcoming poor prognostic genetic features in DLBCL should be confirmed in a larger prospective clinical trial. Disclosures Rossi: Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Carlo-Stella:Takeda: Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Genenta Science srl: Consultancy; Janssen: Other: Travel, accommodations; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Corradini:AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Gilead: Honoraria, Other: Travel Costs; Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Travel Costs; Servier: Honoraria; BMS: Other: Travel Costs.

Description: Abstract 2720 Introduction: Bendamustine is a promising agent that has been showed high efficacy in combination with Rituximab in indolent lymphomas; however experiences on its use in combination with other cytotoxic agents are scant, particularly in FL. A previous FIL trial showed that a brief R-FND induction chemoimmunotherapy with only 4 courses of R-chemotherapy followed by 4 rituximab doses as consolidation can achieve high CR and PFS rates in FL patients, supporting the feasibility of this regimen in the elderly (Vitolo et al, ASH 2011). These promising results prompted FIL to investigate safety and efficacy of a similar combined brief regimen substituting Bendamustine for Fludarabine aimed at reducing toxicity and maintaining efficacy. Patients and methods: From September 2009 to November 2011, 76 elderly patients (age 65–80) with advanced stage FL at diagnosis were enrolled. Inclusion criteria were: untreated grade I, II and IIIa FL; advanced disease requiring treatment (stage III/IV) or stage II including at least one of the following conditions: bulky disease (〉7 cm), active disease with rapid lymph node progression, lactate dehydrogenase or β2 microglobulin above normal, systemic symptoms and extranodal involvement. A comprehensive geriatric assessment (ADL, I-ADL, CIRS) was also performed at diagnosis and only “FIT” patients were enrolled into the study. Treatment plan was: 4 monthly courses of R-BM (375 mg/m2 Rituximab day 1, 90 mg/m2 Bendamustine days 1–2, 8 mg/m2 Mitoxantrone day 1), followed by consolidation with 4 weekly Rituximab infusions. Polymerase chain reaction (PCR) for BCL2/IgH rearrangement was performed on bone marrow samples at diagnosis, after R-BM and after consolidation. Results: At the time of analysis, 69/76 patients are evaluable for clinical characteristics, response to treatment and toxicity. Median age was 71 years (range 65–80); 26 males, 43 females; WHO grading was as follow: I 16%, II 55% and IIIa 29%; 19% had advanced stage II disease, 27% stage III and 54% stage IV; 49% had BM involvement, 19% B symptoms and 7% leukemic dissemination; 58% patients had no comorbidity, 20% one and 22% two or more comorbidities. According to FLIPI patients were: 12% at low, 30% at intermediate and 58% at high risk. PCR analysis was carried out in 64 patients at diagnosis: 58% were Bcl-2 positive. Sixty three patients completed the planned treatment and the whole program was completed according to the planned time in 60/63 patients. Six patients did not complete the treatment: 1 for progressive disease, 4 for adverse events (2 haematological toxicity with prolonged neutropenia; 1 CMV colitis and 1 for infection and concomitant worsening of pre-existing oral pemfigo) and 1 patient for worsening of performance status. Overall response after R-BM + Rituximab was observed in 64 (96%) patients with 52 (75%) patients in complete remission and 12 (18%) in partial remission (PR). Response to 4 cycles of R-BM was as follow: 27 (39%) in CR, 37 (54%) in PR and 5 (7%) patients in stable (SD) or progressive disease. Of the 40 patients in PR or SD after 4 R-BM, 26 (65%) converted to CR following further Rituximab consolidation. At the time of this analysis, of the 37 patients Bcl-2 rearranged at diagnosis, 19 (51%) were evaluable for molecular response during and after treatment. PCR negativity was achieved in 16/19 (84%) patients after R-BM and in 18/19 (95%) patients at the end of treatment. A total of 521 courses of R-BM and Rituximab were given. The most frequent severe toxicity (CTC grade 3–4) was neutropenia reported in 18% of the courses; nevertheless only four serious infections were recorded (all due to bacterial agents). Pulmonary and cardiac toxicities were 〈 1%. Two deaths were recorded: one due to lymphoma after second line treatment and one due to hepatic carcinoma occurred 3 months after completion of therapy. Conclusions: A brief course of chemo-immunotherapy R-BM followed by Rituximab consolidation is safe and effective with a high CR rate in elderly patients with untreated advanced stage FL. Planned future analysis of the entire study will give further information on late toxicity and outcome. Disclosures: Off Label Use: In Europe use of Bendamustine in first-line treatment of follicular lymphoma is off-label. Drug was provided free by Mundipharma. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 3707 Poster Board III-643 Introduction response to salvage chemotherapy prior to high–dose therapy (HDT) is of major prognostic concern in relapsed/refractory HL. FDG-PET is able to distinguish between persistent disease and fibrosis/necrosis and has thus become the mainstay to define clinical response in this setting (Cheson et al, JCO 2007). The value of FDG-PET in this subset of patient is less well established. IGEV chemotherapy has shown very encouraging results as induction therapy in refractory/relapsed HL (Santoro et al, Haematologica 2007). Aims to retrospectively evaluate the predictive value of PET in pts with relapsed/refractory HL receiving IGEV and HDT. Methods seventy-two multicentric cases with refractory/relapsed HL who had completed IGEV x 4 courses and HDT between 01/98 and 05/07 were reviewed. FDG-PET evaluation was performed before HDT and, according to revised Cheson criteria, complete remission (CR) was defined as negative FDG-PET, independently from the presence of residual masses at CT scan. Univariate analysis was performed considering FDG-PET as well as other usually evaluated prognostic factors. Results patient characteristics: M/F 30/42, median age 33 (range 16-71), Nodular sclerosis 61 (85%), refractory 28 (39%), relapsed 44 (61%), one previous regimen 60 (83%), B symptoms 18 (25%), bulky disease 7 (10%), extranodal disease 32 (44%), previous radiotherapy 39 (54%). After induction, 36 pts (50%) received single (with BEAM as conditioning regimen ), and 36 (50%) tandem HDT (with melphalan as first and BEAM as second conditioning). After IGEV, on the basis of PET 47 pts (65%) were classified as complete remission (CR), 21 (29%) as partial remission (PR) and 4 (6%) did not respond. Ten of the 47 PET negative pts, and 18 of the 25 PET positive pts relapsed. With a median follow up 48 months, the 3-year PFS was 80% vs 25% for patient with negative vs positive PET respectively (HR 5.7 no CR vs CR - CI 95%: 2.6-12.4). The 3-year overall survival (OS) was 91% vs 56 % for patient with negative vs positive PET respectively (HR 7.8 no CR vs CR CI 95%: 2.6-23.7). In univariate analysis, factors influencing the probability of achieving CR to IGEV were disease status (refractory vs relapse) (p.096) and bulky disease at IGEV (p .088). Factor significantly associated with PFS and OS are reported in table. In multivariate analysis only response to therapy, as defined by pre-transplant PET result, maintained significance as prognostic indicator for both PFS (HR 5.7) and OS (HR 7.8). Conclusions these data in homogeneously treated pts with refractory/relapsed HL underline the crucial prognostic relevance of pre-transplant FDG-PET, even overwhelming the impact of disease status at progression. FDG-PET driven trials are highly recommended in this subset of patients. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Diffuse large B-cell lymphoma (DLBCL) of the testis (PTL) is a rare presentation of extranodal lymphoma at poor prognosis with a 5-yr overall survival of 40-55%. Contralateral testis, CNS and extranodal sites relapses are the main cause of failures. IELSG 10 study is a prospective phase II international trial for patients with stage I or II PTL and was designed to define a standard treatment for PTL. It aims to evaluate efficacy and toxicity of a combined treatment of R-CHOP, intrathecal methotrexate and prophylactic scrotal radiotherapy (RT) with the addition, in stage II, of loco-regional RT. The trial was conducted by IELSG and Intergruppo Italiano Linfomi. Patients and methods: From June 2001 to June 2006, 50 pts with stage I-II PTL were enrolled from 26 centres. Treatment plan was: R-CHOP21 (R 375mg/m2, Ctx750 mg/m2, Doxo50 mg/m2, Vcr1.4 mg/m2 day 1 and Pdn40 mg/m2 days 1–5) for 6 courses and 2 additional ones in stage II patients with slow response; intrathecal methotrexate (IT MTX) 15mg for 4 doses during courses 1 and 2; at the end of chemotherapy 30 Gy scrotal RT to contralateral testis was planned to all pts and 30–36 Gy nodal loco-regional RT for those with stage II disease. Results: To date 45 pts who completed the treatment are evaluable. Median age was 64 (range 22–80); 36 stage I and 9 stage II disease; 3 had bilateral testicular involvement; 4 LDH〉normal and 2 B symptoms. All received R-chemotherapy as planned. Forty-two (93%) pts received adequate CNS prophylaxis (at least 4 IT MTX); 3 less than 4 IT MTX because of poor tolerance or toxicity. Scrotal RT was given to 40 pts (89%) as planned; 5 did not performe it (3 refusal, 1 progressive disease and 1 bilateral orchiectomy). Forty-four patients (98%) achieved a CR and one progressed after 4 R-CHOP courses. With a median follow-up of 28 months, 3-yr OS, 3-yr PFS and 3-yr EFS were: 88% (95% CI 69–96%), 82% (95% CI 63–92%) and 78% (95% CI 58–89%). Seven patients relapsed or progressed: 2 in nodal sites, 3 in extranodal ± nodal sites and 2 in CNS (1 isolated meningeal and 1 eningeal + nodal relapse). The actuarial risk of CNS relapse at 3 years is 2.5% (95% CI 0–7%). No contralateral testis relapses were observed. Five patients died: three because of DLBCL; one of peripheral T-cell lymphoma and one of ANLL 21 months off therapy while in CR. No toxic death occurred during treatment. Main grade 3–4 toxicities were: hematological 27% and neurological 15%. Conclusions: Although the follow-up is short, these results compare favorably with those previously reported in IELSG retrospective study in PTL (Zucca et al J Clin Oncol 2003). Contralateral testis relapses has not been observed and the incidence of CNS relapse seems to be reduced. If these results are confirmed with a longer follow-up, a combined treatment of R-CHOP, IT MTX and prophylactic scrotal RT ± nodal RT in stage II patients would improve the prognosis of these pts and should be regarded as the standard treatment in localized stage PTL. However, if further relapses are observed there will be a need for innovative strategies to address the issues of systemic and CNS relapse.

Description: Abstract 3890 Introduction: Early stage classical Hodgkin lymphoma (cHL) is highly curable with a combination of chemotherapy and radiotherapy. Nevertheless a small proportion of patients with localized stage do not respond to therapy and progressed. We want to explore the predictive value on therapy outcome of an early evaluation of treatment response by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan performed after two corses of ABVD in pts with localized Hodgkin's disease. Patients and methods: From 2002, 246 new localized stage cHL pts were consecutively admitted to twelve Italian hematological centers on behalf of Intergruppo Italiano Linfomi. Pts with stage I-IIA according to Ann Arbor stage, independent of presence of bulky disease, were considered for the study. FDG-PET was mandatory at baseline, after two cycles and at the end of therapy. International Harmonization Project (IHP) interpretation criteria were recommended to define PET positivity. We evaluated the progression free survival of pts starting from the time of diagnosis to relapse or progression of disease or last follow-up. No treatment variation based only on PET-2 results was allowed. All bulky-disease pts reports were centrally reviewed. Results: The median age was 33 years (13-78), 133 pts were female, 225 pts were stage II, bulky was reported in 76 pts, 231pts were treated with combined modality and 15 pts were treated with chemotherapy alone. The FDG-PET performed after two cycles (PET2) was positive in 32 pts (13%). Seventeen non-bulky pts were PET2 positive: 10 (59%) progressed or relapsed and 7 remained in CR. By contrast 152/153 (99%) non-bulky pts with a negative PET2 remained in CR. Thus the PPV value of a PET2 in non-bulky pts was 59% and the NPV was 99%, moreover the sensitivity and specificity of PET2 were 91% and 96%, respectively. In bulky disease pts we performed a revision of all reports according to Deauville criteria and 3 cases were converted from PET2 positive to PET2 negative. In revised bulky disease pts 15 were PET2 positive: 6 (40%) progressed or relapsed and 9 remained in CR. In this group of pts the PPV was 40%, the NPV 93% and sensitivity and specificity were 60% and 90% respectively. In univariate analysis negative FDG-PET performed after two cycles (p .0000), absence of bulky disease at diagnosis (.005) were statistically correlated with a better progression free survival. In multivariate analysis only PET2 was independently predictive of relapse/progression probability (p .000). With a median follow-up of 35 months (range 4–87), the 2-yr FFS probability for PET2 negative and for PET2 positive non-bulky patients were 98% and 29% respectively (p: .000) for patients with bulky-disease were 99% and 45% respectively (p: .002). Conclusion: This multicentric study confirms that FDG-PET scan performed after two courses of conventional standard dose chemotherapy was able to predict treatment outcome in early stage non-bulky cHL. In bulky disease we suggest new interpretation criteria to define interim PET results. Disclosures: Vitolo: Roche: Membership on an entity's Board of Directors or advisory committees.

Description: INTRODUCTION: high-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) is a curative option for relapsed diffuse large B-cell lymphoma (DLBCL). However, relapse within 1 year after diagnosis, previous therapy with rituximab and secondary IPI = 2 or 3 have been associated with unsatisfactory outcome even after ASCT, thus the better treatment of these patients is matter of debate and efforts are ongoing in order to improve survival. METHODS: on a total of 146 DLBCL patients receiving ASCT, we identified 78 adult patients who had responsive but still measurable disease after first-line therapy or relapsed/progressive disease with one or more adverse features as specified above. All patients were 〉18 years old and received ASCT at our institution. Patients were grouped according to the administered treatment: 1) n= 21 patients were in response but not in complete remission (CR) after first-line and received HDC and ASCT; 2) n= 48 patients had refractory or relapsed disease and received salvage chemotherapy followed by HDC and ASCT (n=46 single ASCT, n=2 double ASCT); 3) n=9 patients received salvage therapy then tandem autologous-allogeneic SCT due to the presence of any of the above mentioned adverse features. For all patients, salvage chemotherapy was mostly VIHA or DHAP with the addition of rituximab. Most used regimens of HDC were Melphalan 200 mg/mq or BEAM. Among the nine patients undergoing tandem auto-allo, eight received Melphalan 200 mg/mq and one BEAM; allogeneic donors were either HLA-identical siblings (n=3), unrelated (n=1) or haploidentical ones (n=5). All conditioning regimens before allogeneic SCT were reduced-intensity or nonmyeloablative. RESULTS: at last follow-up, survival rate is 57% for group 1 (12 alive out of 21 patients), 27% for group 2 (13/48) and 67% for group 3 (6/9). Cause of death in this last group was disease relapse/progression for all 3 cases (2 patients were in partial remission (PR) before allo, 1 in CR). Disease status before allogeneic SCT for the 6 alive patients was CR (n=3) and PR (n=3). Their follow-up is +8, +24, +26, +40, +45 and +70 months since ASCT. Of note, survival rate was 74% for the 47 patients receiving HDC and ASCT in first CR (candidated upfront to ASCT due to high-risk IPI at diagnosis) and 62% for the 21 relapsed patients who did not present any of the above mentioned adverse features at relapse. Those two groups were taken from the same initial sample of 146 patients. CONCLUSION: for patients affected by relapsed DLBCL with one or more adverse prognostic features, administration of allogeneic SCT after ASCT as a tandem strategy provides promising results compared with patients receiving ASCT alone and deserves further investigation, especially taking into account the rapid expansion of platforms using T-cell replete haploidentical grafts. Upfront HDC followed by ASCT appears to be a valid option for those patients in PR after first-line therapy, with a 57% survival rate in our series. Disclosures No relevant conflicts of interest to declare.

Description: Rituximab plus CHOP (R-CHOP) is the standard chemotherapy (CT) regimen for elderly patients (pts) with CD20 positive DLBCL. However, many pts aged 70 years (yrs) or more are often unable to received R-CHOP and the majority of them are excluded from clinical trials. Moreover, comprehensive geriatric assessment (CGA) has been demonstrated a useful instrument to predict the clinical outcome of elderly pts with cancer even if it has never been tested in a prospective way. Within the GOL (Gruppo Oncoematologico Linfomi) from June 2000 to March 2006 we started a phase II prospective study with the aim to evaluate the feasibility and activity of a CGA-driven CT for elderly pts with DLBCL. Rituximab was used in all pts after its introduction in the marketing in Italy (February 2002). Pts with no comorbidity received CHOP or R-CHOP; in pts with mild cardiopathy epirubicin was used instead of doxorubicin (CEOP or R-CEOP); in pts with moderate or severe cardiopathy the use of antracyclines was omitted (CVP or R-CVP); pts with diabetes didn’t receive prednisone (CHO,CEO or R-CHO,R-CEO); pts with neuropathy received CHP or R-CHP or CEP or R-CEP (vincristine was omitted). Moreover, the dosage of CT was decided according to the CGA: pts with a good score of CGA (i.e. ADL=6 and IADL〉6) received full doses of CT; pts with an intermediate score (ADL=5 and IADL〉4) received 75% of the planned dose; pts with a poor score (ADL

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 The role of bone marrow (BM) involvement as prognostic factor in untreated young patients with diffuse large B-cell lymphoma at poor prognosis is still a matter of debate. Recent data showed an adverse prognostic role of BM involvement in DLBCL including patients both at low and high IPI score (Sehn L et al, J Clin Oncol 2011). On this basis, FIL analyzed the impact of BM involvement in the prospective randomized phase III trial DLCL04 (Vitolo U et al, Blood, ASH annual Meeting 2012) that included only young patients at high-risk age-adjusted IPI (aa-IPI) score 2 or 3. Patients and Methods Inclusion criteria were: age 18-65; untreated DLBCL or follicular grade IIIb; aa-IPI score 2 or 3. Patients were stratified according to aa-IPI and randomized at diagnosis to receive: R-CHOP14 x 8 cycles; R-MegaCHOP14 (1200 mg/sqm Cyclophosphamide, 70 mg/sqm Doxorubicin, standard dose Vincristine and Prednisone) x 6; R-CHOP14 x 4 + R-HDC (Rituximab + High Dose Cytarabine + Mitoxantrone + Dexamethasone) followed by BEAM and ASCT; R-MegaCHOP14 x 4 + R-HDC + BEAM and ASCT. BM biopsy and aspirate were mandatory at diagnosis; at the end of treatment, BM assessment was mandatory only in case of positivity at baseline. BM involvement was defined as concordant if marrow was involved by large B-cell and discordant if involved by small B-cells. Flow cytometry, immunohistochemistry, and/or molecular studies were utilized to confirm a clonal B-cell population. Results From June 2005 to September 2010, 399 patients were randomized to receive: 199 R-HDC+ASCT and 200 R-dose-dense chemotherapy without ASCT. All patients were evaluable for analysis. BM involvement was reported in 84 patients (21%): 39 (20%) in the R-HDC+ASCT group and 45 (22%) in the R-dose-dense chemotherapy group. Pattern of involvement was: concordant in 63 patients, discordant in 14 and not specified in 7 patients. Patients with BM involvement (BM positive: 84) compared to those without BM involvement (BM negative: 315) were significantly older (median age 53 years vs 47 years, p1 43% vs 45%, bulky 25% vs 33%, extranodal sites 〉 1 26% vs 33%, LDH higher than normal value 93% vs 89%). With a median follow-up of 49 months, 3-year PFS for the whole series of 399 patients enrolled in the trial was: 67% (95% CI: 62-72). Three-year PFS was significantly worse in BM positive vs. BM negative: 46% (95% CI:35-56%) vs. 73% (95% CI:67-77%) p