ALBERT

Description: Background. Ara-c based chemo-immunotherapy followed by autologous stem cell transplantation (ASCT) is the most effective approach in young mantle cell lymphoma (MCL) patients, though few if any patients are cured. Recent data indicate that subsequent Rituximab maintenance (RM) prolongs PFS and OS (Le Gouill NEJM 2017). Lenalidomide is an oral agent effective in MCL, considered suitable for prolonged maintenance programs, but has never been tested in this setting. The FIL MCL0208 trial (NCT02354313) is a prospective, international randomized, phase III trial, comparing Lenalidomide maintenance (LM) vs observation (OBS) after an intensive Ara-c containing chemo-immunotherapy (R-HDS) program, followed by ASCT in previously untreated MCL patients. Patients and Methods. Adult patients aged 18-65 years, with advanced stage MCL without clinically significant comorbidities were enrolled. Patients received 3 R-CHOP-21, followed by R-HDS i.e. R-high-dose Cyclophosphamide (R-HD-CTX) (4g/m2), 2 cycles of R-high-dose Ara-C (R-HDAC) (2g/m2 q12x3 d). CD34+ cells were collected after the first course of R-HDAC. The conditioning regimen for ASCT was BEAM. After ASCT, responding patients were randomized between LM (15 mg days 1-21 every 28 days) for 24 months or observation. Primary endpoint analysis was scheduled at the occurrence of the 60th PFS event in the randomized population, which occurred on June 20th, 2017 and data were analyzed for the present abstract on March 3rd 2018. Results. Three-hundred three patients were enrolled from May 2008 to August 2015 by 48 Italian and 1 Portuguese Center. Three patients were excluded after central histological review. Median age was 57 years (IQR 51-62), M/F ratio 3.6/1. Ninety-two percent of patients had stage IV, 33% bulky disease (〉5 cm), 33% elevated LDH, and 75% BM infiltration. Ki67 ≥30% was observed in 32%, MIPI was low (L) in 54%, intermediate in 31% and high (H) in 15% of patients. MIPI-c was L in 49%, low-intermediate (LI) in 29%, high-intermediate (HI) in 14%, H in 9%. Nine percent had blastoid variant. Fifty-two (17%) patients interrupted treatment before randomization (8 toxic deaths, 1 death for car accident, 24 progressions and 19 toxicity/refusals). On an ITT basis, the R-HDS + ASCT program induced 78% of CR, 7% of PRs, 10% of PD, 3% of toxic deaths (TRM) and 2% NA. Median follow-up (mFU) from inclusion was 51 months. Three years PFS and OS for the enrolled population were 67% and 84%, respectively. Of 248 patients who received ASCT, 205 were randomized either to LM (n=104) or OBS (n=101) and 43 (17%) were not because of: lack of response (8), refusal/PI decision/delay (8), unresolved infections (3) and inadequate hematopoietic recovery (24). Feasibility and efficacy were assessed on an ITT basis while toxicity was analyzed on subjects receiving at least one Lenalidomide dose. In the LM arm, 53 out of 104 patients did not start or complete the planned maintenance because of death (2), AE (26), PD (7), still ongoing (2), other causes (16). In the OBS arm 32 patients did not complete the observation phase because of death (1), AE (1), PD (20), still ongoing (10), other causes (1). Overall 28% of patients received less than 25% of the planned Lenalidomide dose. Despite suboptimal exposure to study drug, with a mFU from randomization of 35 months, 22 PFS events were recorded in the LM cohort vs 38 in the OBS arm, resulting in a 3y-PFS of 80% (95% CI; 70%-87%) in the LM arm vs. 64% in the OBS arm (95% CI; 53%-73%), stratified HR 0.51; 95% CI 0.30-0.87; p=0.013 (Fig 1A). OS was superimposable in the two arms: 93% vs 86%, stratified HR 0.96, 95% CI 0.44-2.11, p= 0.91 (Fig1B). Two deaths were observed in the LM arm due to pneumonia and thrombotic thrombocytopenic purpura and one in the OBS arm due to pneumonia. Grade 3-4 hematological toxicity was seen in 63% of patients in LM vs 11% in the OBS arm with 59% vs 10% of patients experiencing granulocytopenia. Non-hematological grade 3 toxicity was comparable in the two arms except grade 3-4 infections (11% vs. 4%; Fisher's p=0.10). Second cancers occurred in 7 patients in the LM and 3 in the OBS arm (Fisher's p=0.20). Conclusions. Results from the MCL0208 trial indicate that LM has a clinically meaningful anti-lymphoma activity in MCL. However, the applicability of LM has some limitations in the context of patients undergoing intensified chemoimmunotherapy. Overall these data support the use of a maintenance regimen after ASCT in young MCL patients. Disclosures Ladetto: Roche: Honoraria; Celgene: Honoraria; Acerta: Honoraria; Jannsen: Honoraria; Abbvie: Honoraria; Sandoz: Honoraria. Di Rocco:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Rossi:Novartis: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Amgen: 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: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Mundipharma: Honoraria; Sandoz: Honoraria; Seattle Genetics: Research Funding; Alexion: Other: Travel expenses. Chiappella:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Roche: Other: lecture fees; Teva: Other: lecture fees; Nanostring: Other: lecture fees; Amgen: Other: lecture fees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees. Rusconi:Celgene: Research Funding. Gomes da Silva:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Institution's payment for consultancy, Travelling support; Celgene: Other: Travelling support; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Roche: Other: Institution's payment for consultancy, Travelling support; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Research Funding. Vitolo:Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, 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; Gilead: Speakers Bureau. Martelli:Sandoz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: PTL is a rare extranodal lymphoma characterized by a continuous pattern of systemic relapses in spite of doxorubicin-based therapy. There are also frequent relapses in the contralateral testis and the central nervous system (CNS). Therefore we decided to determine whether prophylaxis of the CNS and the contralateral testis would modify the pattern of relapse of PTL. Patients and methods: From 1993 to February 2002 in IELSG member institutions patients with PTL (presenting with testicular enlargement) were managed with doxorubicin-based therapy according to institutional policy, with the addition of four doses of IT methotrexate (15 mg) during the first 6 weeks. At the end of chemotherapy scrotal RT (30 Gy) was given to all patients and 30–36 Gy nodal RT to those with stage II disease. Rituximab was not used in this cohort because it was not yet generally available for patients with diffuse large B-cell lymphoma. Results: There were twenty seven patients; two refused chemotherapy and/or RT/IT therapy and one RT, leaving 24 eligible for analysis. Median age was 60 years (range 31–80). Ann Arbor stage was I in 17, II in four, and four in three patients. B-symptoms were present in one patient. The right testis was involved in 13 and the left in 11 patients. Serum LDH was elevated in four of 21 with available values. No patient had CNS involvement at diagnosis. Pathology was diffuse large B-cell lymphoma in all patients. Treatment was CHOP in 21, alternating triple therapy in two, and hyper-CVAD in one patient. Three patients died during therapy: one from neutropenic sepsis and two from toxicity of systemic methotrexate. The remaining 21 patients achieved a complete remission. With a median follow-up of 57 months (range 8–123) for survivors, seven patients have relapsed, three in the CNS. There were no testicular relapses. Eight patients have died: three from toxicity during induction, three from relapsed lymphoma, one from gastric carcinoma and one from sudden death, both in complete remission. At 5 years the projected progression-free survival was 78%, and survival 66%, but both without an apparent plateau. Freedom from progression in the CNS was 84%, with a plateau. Conclusions: Patients with PTL treated prospectively with doxorubicin-based therapy before the availability of rituximab exhibit the continuous pattern of relapse previously reported. Scrotal RT seems eliminate testicular relapses, and prophylactic IT methotrexate seems to reduce, but not eliminated CNS relapses. These need to be confirmed by longer follow-up. The ongoing IELSG-10 should determine whether the addition of rituximab alters the continuous pattern of systemic relapses. Future studies should determine the molecular basis of the continuous relapses and minimize both systemic and CNS relapses.

Description: Background. Recent studies have described the landscape of recurrently mutated genes in mantle cell lymphoma (MCL), including genes involved in DNA damage response/cell cycle (ATM, TP53, CCND1), epigenetic regulation (KMT2D also known as MLL2, WHSC1), and cell signaling (BIRC3, TRAF2, NOTCH1). However, with the exception of TP53 abnormalities, little is known about the clinical relevance of recurrent mutations in MCL. Thus, we performed deep sequencing analysis of a MCL gene panel in the prospective series of patients enrolled in the ongoing FIL-MCL0208 phase III trial (EudraCTNumber: 2009-012807-25). Patients and Methods. The study included untreated, advanced stage 70% of cases. The gene panel was analyzed in tumor DNA from baseline bone marrow CD19+ purified MCL cells and, for comparative purposes to filter out polymorphisms, in the paired normal genomic DNA (available in 55% of cases) using a TruSeq Custom Amplicon target enrichment system followed by deep next generation sequencing (Illumina, median depth of coverage 2356x). Variants represented in 〉10% of the alleles were called with VarScan2 with the somatic function when the paired germline DNA was available. For patients lacking germline DNA, a bioinformatic pipeline including a number of stringent filters was applied to protect against the misclassification of polymorphisms as somatic variants. Primary endpoint of the analysis was progression free survival (PFS). Results. Out of the enrolled patients, 151 are currently evaluable for mutations and clinical outcome (median age: 57 years, range 35-66; males 75%). Among prognostic factors, the MIPI was intermediate or high-risk in 49% of patients, the Ki67 ≥30% in 39%, and blastoid histology occurred in 8%. At the first planned interim analysis, median follow-up of alive patients was 26 months. At 2-years, 79% of patients were progression free and 91% alive (Cortelazzo et al EHA 2015). Overall, at least one mutation was detected in 106/151 cases (70%), including mutations of ATM in 42% of cases, CCND1 in 14%, WHSC1 in 13%, KMT2D in 12%, TP53 in 7%, NOTCH1 in 6%, BIRC3 in 5% and TRAF2 in 1% (Figure 1A). By univariate analysis, mutations of TP53 (2-years PFS 48% vs 82%; p

Description: BACKGROUND: Patients (pts) with relapsed DLBCL who cannot be treated with consolidative ASCT or allogeneic transplantation exhibit a poor prognosis, with a 1-year PFS of 30-40%. Despite a high response rate to salvage therapy, these pts invariably experience early relapse and die of lymphoma. Single-drug maintenance may be a good alternative to intensified consolidation to prolong response duration in these high-risk pts. Lenalidomide is an oral immunomodulatory agent, active against DLBCL, which can be taken for years with an excellent safety profile. Accordingly, we designed a multicenter phase II trial addressing safety and efficacy of lenalidomide maintenance in pts with chemosensitive relapse of DLBCL not eligible for consolidative ASCT or experiencing relapse after ASCT (NCT00799513). Herein, we report the primary endpoint analysis. METHODS: Selection criteria were: 1) adult HIV-negative pts; 2) histologically-proven de novo or transformed DLBCL; 3) relapsed disease responsive (partial or complete response) to conventional-dose rituximab-containing salvage therapy; 4) ECOG PS ≤3; 5) time to progression (TTP) from the previous line ≥3 months. After confirmation of objective response to salvage therapy, pts were registered and treated with lenalidomide 25 mg/day once daily for 21 days out of 28, for two years or until lymphoma failure or unacceptable toxicity. Primary endpoint was the 1-yr PFS. Simon's two-stage optimal design was used. The null hypothesis that the true 1-yr PFS is 30% was tested against a one-sided alternative. The trial design yields a type I error rate of 5% and power of 80% when the true 1-year PFS is 50%. To demonstrate this PFS improvement, 47 pts were needed. The null hypothesis would be rejected if 19 or more pts progression-free at one year were observed. RESULTS: 41 pts were enrolled (median age 72, range 34-86; M:F ratio: 1.5). Thirty pts had a de novo DLBCL, 11 had a transformed DLBCL; 29 pts were enrolled after the first relapse, 12 after the 2nd - 4th relapse. All pts were previously treated with anthracycline- and rituximab-based combination, plus ASCT in 6 pts. The median TTP after the previous line was 17 months (range 3-121). Most pts had unfavourable features: IPI ≥2 in 34 (83%) pts, advanced disease in 33 (80%), extranodal disease in 29 (71%), high LDH in 18 (44%). Twelve pts had HCV and/or HBV infection. Salvage combination included high-dose-cytarabine in 23 pts, high-dose-ifosfamide in 6, anthracycline in 6 and bendamustine in 6. Response to salvage therapy was complete in 25 pts and partial in 16. Twenty-three pts received the planned maintenance; lenalidomide was interrupted due to lymphoma relapse in 8 pts, toxicity in 5 (diarrhoea in 2, rash, prolonged neutropenia, intestinal infarction), and patient's refusal in 5 (diarrhoea in 4, rash). Dose reduction to 10 or 15 mg/d, mostly due to rash or neutropenia, was indicated in 17 pts. Toxicity was mild; there were 6 SAEs (febrile neutropenia in 4, diarrhoea, intestinal infarction) in 5 pts. Grade 4 haematological toxicity consisted of neutropenia in 17 pts and thrombocytopenia in 2. Grade 3-4 non-haematological toxicity consisted of diarrhoea in 3 pts and rash in 5. HBV/HCV seropositivity was not associated with higher toxicity. Six of the 16 pts in partial response after salvage therapy achieved a complete remission during lenalidomide maintenance. At a median follow-up of 16 months, 29 pts remained relapse free, with a 1-year PFS of 75±8%. Importantly, 21 pts were progression-free at one year, with the early achievement of the primary endpoint. Thirty-two pts are alive (NED in 25), 8 pts died of lymphoma and one of intestinal infarction, with a 1-yr OS of 84±7%. Age ≤70 years, normal LDH level, and complete response at registration were independently associated with better PFS and OS, whereas gender, DLBCL category, HBV/HCV infection, and TTP after previous line (〈 vs. ≥12 months) were not. Assessment of prognostic effect of ontogenic stratification by NanoString is ongoing. CONCLUSIONS: With the early achievement of the primary endpoint, this is the first prospective trial showing a positive effect of maintenance in pts with relapsed DLBCL. Lenalidomide maintenance is feasible and well tolerated in this elderly population, but diarrhoea and rash remain frequent dose-limiting side effects. The evident improvement in survival figures warrants further investigation of immunomodulators maintenance in these high-risk pts. Disclosures Ferreri: celgene: Consultancy, Research Funding. Rusconi:Roche: Honoraria.

Description: Background: Patients (pts) with rDLBCL not eligible for ASCT or experiencing relapse after ASCT have a low likelihood of cure. Single-drug maintenance after salvage therapy may be an attractive strategy to prolong survival in these pts. Lenalidomide (LEN) is a suitable candidate for long-lasting maintenance as it is an oral drug, active against DLBCL, that can be taken for years with an acceptable toxicity profile. Accordingly, we designed a multicentre phase II trial addressing LEN maintenance in pts with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT (clinicaltrials.gov NCT00799513). Methods: HIV-neg pts (age ≥18 ys) with histologically-proven de novo or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy were registered and treated with LEN 25 mg/day for 21 days out of 28, until lymphoma progression or unacceptable toxicity. Primary endpoint was 1-year progression-free survival (PFS). Simon's two-stage optimal design was used. To demonstrate a 1-yr PFS improvement from 30% (P0) to 50% (P1), 47 pts (one-sided; α 5%; β 80%) were needed. Maintenance would be considered effective if ≥19 pts were progression-free survivors at 1 yr. Cell of origin was assessed by NanoString Technology and Hans algorithm, and cereblon expression was assessed by immunohistochemistry. Results: 46 of 48 enrolled pts were assessable (median age 72 ys; range 34-86); 36 pts had de novo DLBCL, 10 had transformed DLBCL. All pts were previously treated with anthracycline- and rituximab-based combination, plus ASCT in 6 pts; the median TTP after the prior therapy was 16 months (range 3-121). Thirty-three pts were enrolled at 1st relapse, 13 at 2nd relapse; salvage therapy contained high doses of cytarabine or ifosfamide in two-thirds of cases, and response was complete in 26 pts and partial in 20. Most pts had unfavourable features: IPI ≥2 in 38 (83%) pts, advanced stage in 35 (76%), extranodal disease in 29 (63%), high LDH level in 21 (46%); 28 (61%) pts were older than 70 ys. At a median follow-up of 25 (range 6-87) months, 556 LEN courses were delivered, with an average of 12 courses/pt (range 3-41); 19 pts are still in treatment. LEN was well tolerated: with the exception of neutropenia, grade 3-4 toxicities were uncommon, occurring in ≤3% of delivered courses. Infections were rare, and well controlled with oral antibiotics (grade 1-2 in 8 courses; grade 3 in 3). LEN dose reduction was indicated in 23 pts (transient in 19), and was due to neutropenia (12), rash (7), diarrhoea (2), and neurotoxicity (2); LEN was discontinued in 6 of them. One (2%) pt died of acute toxicity (intestinal infarction) and one due to secondary myelodysplastic syndrome at 56 months of follow-up. Pts with HBV/HCV seropositivity (n=12) or prior ASCT (n=6) did not experience unexpected toxicity after 〉1 yr of treatment. At one year from trial registration, 28 pts were still progression free, which was significantly higher than the pre-determined efficacy threshold (n≥19). During the whole observation period, there were 21 events: progressive disease in 19 pts, death of toxicity in one, death while off therapy in one, with a 1-yr PFS (primary endpoint) of 70 ± 7%. The duration of response to LEN was longer than response duration after the prior treatment line in 27 (59%) pts, and was twice as long in 15 of them. The benefit of LEN maintenance was observed both in pts with de novo or transformed DLBCL. According to the Hans' algorithm, the 1-yr PFS was 64 ± 11% for GCB-DLBCL and 67 ± 11% for nonGCB-DLBCL (p= 0.67). Results using the Nanostring technique were consistent with the Hans' algorithm, with a concordance rate of 86%. There was no significant association between cereblon expression and PFS. Multivariate analysis confirmed that treatment at first relapse and a prior TTP ≥12 months were independently associated with better PFS. Overall, 33 (72%) pts are alive, with a 1- and 3-yr OS of 81 ± 6% and 71 ± 8%, respectively. Conclusions: With the limitations of a non-randomized design, this trial soundly promotes the use of LEN maintenance in pts with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. LEN was well tolerated in this elderly population, with survival benefit both in pts with de novo or transformed DLBCL, and both in pts with GCB- or nonGCB-DLBCL. These results warrant further investigation of immunomodulatory drugs as maintenance in these high-risk pts. Disclosures 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. Rusconi:Teva: Consultancy, Other: Congress attendance; Takeda: Consultancy; Janssen: Consultancy, Other: Congress attendance. Couto:Celgene: Employment, Equity Ownership. Ren:Celgene: Employment, Equity Ownership.

Description: Incidence and etiology of lympho node enlargement in adults patients referred to hematologist by primary care doctors for diagnosis are not reported. The aim of this study was to retrospectively evaluate incidence and causes of lymphadenopathy in adults patients evaluated at our Hematology division. Between January 2004 and December 2005 we evaluated 550/7200 (7.6%) consecutively patients referred because of lymphadenopathy. The clinical work up for these patients initially consisted of clinical history and physical examination. According to our previous published criteria, patients showing superficial lymphadenopathy (firmer and rigidly elastic with deep mobility less than normal) underwent to laboratory examinations (blood cell counts, erythrocytes sedimentation rate, serum lactate dehydrogenase, electrophoresis, and serology for main related infective diseases) and instrumental investigations (standard chest X-ray, ultrasonography, and computer axial tomography) (Cancer1999:85, 2488). Patients showing abnormal laboratory values and/or pathological instrumental parameters without a known etiology, underwent to bone marrow needle aspiration/biopsy and/or lympho node biopsy. We evaluated in two years 29% (160/550) of our patient population by lympho node biopsy, while this approach was not utilized in the remaining 71%. Hystopathological lympho node examination allowed identification of the causes of lympho node enlargement in the following patients: 51.9% (83/160) had Non Hodgkin and Hodgkin lymphomas (53 and 30 cases respectively), 16.8% (27/160) had a metastatic solid tumors lympho node involvement, 21.8% (35/160) had inflammatory reactive lympho nodes, and 7.5% (12/160) were classified as infective and granulomatosis diseases; in the remaining 2 (1.2%) patients biopsy revealed neurinoma. Among the 390 patients in which the lympho node biopsy was not performed, 94.2% (367) of them showed spontaneous resolution of lympho node enlargement during clinical follow-up (1–3 months), 2.5% (10/367) were classified according to the bone marrow biopsy as low grade Non Hodgkin Lymphoma, 2.8% (11/367) were represented by a miscellaneous of benign pathologies which emerged by further diagnostic not invasive examinations, 0.5% (2/367) were identified as metastatic solid tumors (lung and neck cancer) by both clinical and instrumental examination. In conclusion, lympho node enlargement is a relatively frequent clinical problem for hematologists, in fact among a large series of adult patients examined in two years at our division the incidence was of 7%. However, among patients presenting lympho node enlargement, the majority of them (two third) did not achieve a defined etiological diagnosis, while one third of the remaining cases were classified as mainly Non Hodgkin and Hodgkin lymphomas, including a discrete percentage of metastatic solid tumors. This retrospective evaluation demonstrates that the clinical, physical and instrumental approach to lympho node enlargement, especially based on ultrasonography criteria, may provide useful information to define patients requiring lympho node biopsy.

Description: Abstract 2919 Poster Board II-895 Background: Flow cytometry (FCM) assessment of cerebrospinal fluid (CSF) has recently been known to increase the rate of positivity of occult leptomeningeal disease (LD) in comparison to conventional cytologic examination (CC). However it's still unknown its prognostic value. Patients and methods: The aim of this study was to compare CC vs FCM in a large cohort of patients with newly diagnosed aggressive NHL at high risk for LD (diffuse large B-cell lymphoma (DLBCL) IPI 2-3 and elevated LDH with at least two extranodal sites or with bone marrow, testis, paranasal sinuses, orbit or paravertebral involvement; Burkitt lymphoma (BL); blastoid variant of mantle cell lymphoma (B-MCL); B-cell precursor lymphoblastic lymphoma (B-LL); HIV+ aggressive lymphoma patients). All patients were required to have no evidence or signs of neurological disease. All patients received intrathecal standard prophylactic therapy with 12 mg of methothrexate except for BL that were given prophylaxis with 50 mg of liposomial aracytin for a total of 4 doses. CFS samples were analysed both with CC and FCM. The incidence of positive test for occult LD with FCM and CC was compared using the McNemar test for paired data. Results: Between August 2004 and June 2008, a total of 159 consecutive patients were enrolled in 11 Italian centres and underwent evaluation of CSF. Out of these, 128 patients (80%) were considered at high risk of occult LD. Clinical characteristics were: median age 53 years (IQR:43-62); DLBCL 96 patients (75%); BL 21 pts (16%); B-MCL 6 pts (5%); B-LL 5 pts (4%); 26 pts (20%) were HIV positive. FCM was able to detect a clonal population in 17 out of 128 patients (13%) whereas CC detected abnormal cells only among 7 pts (5%)(p= 0.0002). Therefore, 10 patients (8%) were discordant: FCM+/CC-. Among the 128 patients, there was no association between the CFS total protein, glucose level and the presence of positive analysis of FCM, whereas the difference between the number of WBC cells in CSF was significantly higher in patients with positive versus negative FCM with a median value of 12 cells/ul (IQR: 3.5;40) versus 1.0 cells/ul (IQR: 0.0;3.0) (p=0.0120). Univariate and multivariate analyses, using logistic models, showed that abnormal LDH (OR 3.98, 95%CI: 1-15.92)(p=0.05) and number of WBC cells in CSF ≥5 (OR 4.57, 95%CI:1.37-15.33)(p=0.014) were the only predictive factors of a positive test performed by FCM. From date of diagnosis, overall median follow up of survivors was 14 months (IQR:8-22). We observed 39 (30%) systemic progressions, 6 (5%) CNS progressions (in 5 cases an isolated CNS progression whereas 1 pts experienced a CNS along with systemic progression). Thirty-two (25%) patients died and causes of deaths were as follows: 27 progressive disease, 1 infection, 1 treatment related toxicity, 1 hepatitis, 2 unknown. PFS at 1 year was 71% (95%CI:62-78) in the whole group of patients. The progression risk was significantly higher in patients both FCM+/CC+ compared with patients both FCM-/CC- (1-yr PFS 43% vs 74%) (HR 3.8 95%CI:1.6-9.0) (p=0.003). An higher but not significant risk of progression was found in pts discordant (FCM+/CC-) with respect to patients both FCM-/CC- (1-yr PFS 65% vs 74%) (HR 1.61, 95%CI:0.63-4.11) (p=0.315). In the univariate and multivariate analyses performed with Cox models, we found that the presence of ECOG PS≥2 (HR 2.14, 95%CI: 1.14-4)(p=0.018) and level of protein in CSF 〉40/ul (HR 1.83 95%CI: 1.01-3.29)(p=0.045) were prognostic factor of PFS. Conclusion: FCM assessment of CSF increase the rate of positivity of occult LD compare with CC but it's clinical relevance is still to be clearly defined. Our preliminary data suggest that patients both FCM+/CC+ have an higher risk of progression compared with those both negative, whereas discordant cases may have an intermediate prognosis. Disclosures: No relevant conflicts of interest to declare.

Description: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare diseases, characterized by an aggressive behavior and a poor clinical outcome. High-dose therapy followed by autologous stem cell transplantation (ASCT) has been used as salvage and upfront treatment with conflicting results. However, no standard therapy has so far been established due to the lack of randomized studies. The records of 54 untreated patients with a confirmed diagnosis of PTCL managed at our Institute between 2001 and 2011 were reviewed. The histologic subtypes were: 37 (68%) peripheral T-cell lymphomas unspecified (PTCL-U), 13 (24%) anaplastic large cell lymphomas (ALCL), of which 4 (30%) ALK-positive, 2 (4%) angio-immunoblastic lymphomas (AITL) and 2 (4%) enteropathy-associated T-cell lymphomas (EATL). The clinical characteristics were: median age 56 years (range 18-79); 40 men and 14 women; 13 (24%) and 41 (76%) patients were, respectively, in Ann Arbor stages I-II and III-IV. An elevated serum LDH was present in 33% of patients, 48% had B symptoms and 24% had a bone marrow involvement. The ECOG performance status was 2-3 in 28% of patients. According to the International Prognostic Index (IPI) and the prognostic index for T-cell lymphomas (PIT), 11% and 22% were classified as low risk, 30% and 33% as low-intermediate risk, 12% and 33% as high-intermediate risk and 29% and 12% as high risk, respectively. CHOP-like regimens were given to 32 (59%) patients, 14 of whom received the CHOEP regimen. The remaining 22 (41%) patients were treated with more intensive third generation regimens (MACOP-B like). ASCT was planned as upfront consolidation therapy for 16/54 (30%) patients. A complete response (CR) was obtained in 30/54 (55.5%) patients, a partial response in 7 (13%), while 17 (31.5%) patients showed a lymphoma progression during induction therapy. No difference in terms of CR rate was observed between the CHOP-like and MACOP-B-like regimens. At a median follow-up of 19 months (range 3-138), the 5-years OS and 5-years PFS were 32% (95% CI 25.3-38.5) and 27% (95% CI 20.2-34.5), respectively. At univariate analysis, bone marrow involvement (p=0.003), PIT high risk group (p

Description: Abstract 966 Backgrounds Previous in vivo and in vitro studies have highlighted the activity of Lenalidomide (Len) in patients with relapsed or refractory mantle cell lymphoma (MCL), achieving a 53% overall response rate (ORR), which included 20% complete responses (CR) (Habermann et al. Br J Haematol. 2009) and the possible synergistic anti-proliferative effect of Dexamethasone (Dex). Purpose: On this basis we performed a prospective, multicenter, phase II study, to evaluate safety and efficacy of Len Dex combination for adult patients with MCL. Patients and Methods Patients had to have ≥1 prior treatment regimen, and were either not eligible for, or had relapsed after, more intensive treatments including stem cell transplantation (SCT). During the induction phase (month 1 to 3), patients received Len 25 mg/day on days 1 to 21 and Dex 40 mg/day on days 1, 8, 15, 22 of a 28-day cycle (Len Dex). Enoxaparin 4000 U/day was administered as anti-thrombotic prophylaxis. Patients who achieved a partial response (PR) or stable disease (SD) at the end of the induction phase continued to the consolidation phase, which consisted of treatment with Len Dex until disease progression or unacceptable toxicity, for a maximum of 12 months. Patients with a CR at the end of the induction phase, or those who achieved a CR during consolidation, received an additional 3 courses of Len Dex. The primary objective was to evaluate the ORR and CRR. Response data were correlated with the modification of angiogenic biomarkers by analyzing immunohistochemistry macrophage infiltration and the bone marrow (BM) microvessel counts, and by measuring plasma levels of VEGF, bFGF and HGF before and after therapy. Results Between July 2008 and July 2009, 33 patients were enrolled on this study. Patients' median age is 68 years (range 51–80); 30 have the classic histology while 3 patients have the blastoid variant; 10 patients previously received two lines of therapy, 10 patients had three lines and 13 patients had 〉3 prior lines (median 3; range 1–7). Twelve patients previously underwent an autologous SCT and 8 received prior therapy with Bortezomib. The number of patients who responded to induction phase was: OR= 22 (67%) including 5 CR (15%), SD= 1 (3%), no response (NR) or progression (PD)= 10 (30%); OR in patients previously treated with Bortezomib or an autologous SCT was 50% each. At present, 13 patients completed the therapeutic program, 15 discontinued therapy prematurely (14 NR or PD, 1 poor compliance) and 5 remain on therapy. The final response status at the end of the therapeutic program is: OR= 18 patients (55%) including 8 CR (24%), NR/PD= 15 (45%). After a median follow-up of 6 months (range 3–13 months) from the end of therapy, none of the CR patients had subsequent progression while 2 PR patients had progression 7 and 10 months after the end of therapy. The macrophage counts increased significantly in the BM after the first three months of therapy (P 〈 0.01; r2=0,8927). This was parallel to a significant increase in the microvessel counts (P 〈 0.05, r2= 0,1547). The within-group comparisons showed that both counts were always significantly correlated (P 〈 0.001). Regarding angiogenic plasma biomarkers, preliminary data of bFGF, VEGF and HGF concentrations showed a trend, albeit not significant, to decrease after the first three cycles of therapy. Most common Grade 3–4 adverse events were hematologic and included neutropenia (48%), thrombocytopenia (18%) and anemia (6%). Other events included 4 patients (12%) with Grade 3–4 neutropenic fever and 3 patients (9%) with Grade 3 bacterial pneumonia. Grade 3–4 hypotension and dyspnea developed in 1 and 3 patients respectively; no patient developed thrombo-embolic or neuropathic complications. Conclusions Results from this study confirm the high therapeutic activity of Len in association with Dex in patients with relapsed and refractory MCL with a favourable safety profile. The significant increase of the macrophage infiltration in the BM seems to be a possible immunomodulatory effect of Len. Perhaps, the increase in microvessel counts may be induced by the activated macrophages and be an example of “indirect angiogenesis”. On the other hand, angiogenic plasma biomarkers tend to be lower, suggesting only a limited effect of Len on the neovascularization. Disclosures: Off Label Use: Lenalidomide in Mantle Cell Lymphoma. Vitolo:Celgene: Membership on an entity's Board of Directors or advisory committees.