Abstract: Primary cutaneous B-cell lymphomas (PCBCL) are a distinct group of primary cutaneous lymphomas with few and controversial reports on their treatment and prognostic factors. The aim of this retrospective study of a large international series of PCBCL patients was to analyze the patient and lymphoma characteristics as well as treatment-related variables associated with clinical outcome. From 1980 to 2006, 507 patients were referred to 19 cancer centers of 6 countries all over the world. The median age was 55 years (range,16–92 years) and the M/F ratio was 1.4. According to the WHO-EORTC classification indolent lymphomas included 341 FCL and 122 MZL, while aggressive NHL were represented by DLBCL, leg type (n=44). Sixty patients (12%) had stage II. The majority of cases was diagnosed in trunk/arms (52%), while in 29% in head/neck and in 13% in the legs; 7% of patients had a generalized disease ( 〉 1 site). The maximal lesion diameter was 〉 4 cm in 21% of cases and ≥2 lesions were recorded in 39%. The prevailing type of lesions were nodules (74%), while only a minority of patients (6%) were affected by tumors. Few patients had B symptoms (5%), poor ECOG-PS (9%) or elevated LDH (7%). Two hundred eighty-four out of 446 patients (64%) were treated only with surgery (n=86) or chemotherapy (n=95), mostly consisting of a short course of anthracyclin containing regimens, or radiotherapy (30–50 Gy) (n=103). One hundred sixty two cases (36%) received combined therapy, mostly including surgery or chemotherapy, followed by radiotherapy. A small subgroup of 35 patients were given rituximab alone (n=19) or in combination with other treatments. The remaining 26 patients did not receive any therapy. The response rate of 446 patients was the following: 402 achieved CR (86%), 38 PR and 6 were in SD. Neither histology nor treatment significantly influenced CR rate. Among 402 responders, 128 (32%) eventually relapsed, 86% in the skin, 10% in extracutaneous sites and 4% in both. The relapse rate varied according to histology, ranging from 52% in DLBCL leg-type to 29% in MZL and 28% in FL. Moreover, combined treatments significantly reduced relapse rate (24% vs. 37%; p=0.008). The achievement and maintenance of CR significantly influenced the long-term disease specific survival (at 20 year 99 % vs. 45%; p=0.0001). The CR rate of subgroup of 35 patients treated with rituximab, was 74%, while the relapse rate was 35%. These results were not influenced by the addition of other therapies to rituximab. After a median follow-up of 53 months (range, 2–333 months), 5 and 10-year estimate of OS, disease-specific survival, PFS and DFS were 91%, 92%, 61%, 65% and 82%, 88%, 49% and 56%, respectively. Cox multivariate analysis, stratified for age with a stepwise selection of the significant variables, identified DLBCL, leg-type histology, elevated LDH, type of lesion (nodules and tumors), B symptoms and female gender, as significant predictors of a poor OS. In conclusion this retrospective analysis confirms, on a large series of cases, that patients with PCBCL belong to different risk categories requiring a tailored treatment approach. These data can be usefully taken into account for an adequate management strategy of PCBCL patients.

Abstract: Abstract 3965 Introduction. Gene-profiling studies demonstrated a constitutive activation of the NFκB signalling pathway in Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL). Bortezomib, a potent inhibitor of the 26S proteasome, is a good candidate to block this pathway and was tested in relapsed or refractory MCL with encouraging results (objective response up to 45%, with a median PFS of 5–7 months). In vitro, the combination of Bortezomib and Rituximab has been shown synergistic apoptosis and enhanced NFkB depletion in MCL and MZL cells. Aim. On these bases, the IIL conducted a phase II multicenter study to evaluate safety and efficacy of Rituximab and Bortezomib combination in relapsed/refractory indolent non-follicular lymphoma (Linfocytic Lymphoma, LL, or MZL) and MCL not eligible for high-dose chemotherapy. Patients and methods. Inclusion criteria were: age 18–75 years, histological proven relapsed or refractory LL, MZL and MCL after 1–4 lines of therapies. Treatment plan was: one course of four weekly intravenous bolus of 1.6 mg/sqm Bortezomib in combination with four infusion of 375 mg/sqm Rituximab followed by two courses of four weekly bolus of 1.6 mg/sqm Bortezomib. Patients with complete (CR), partial remission (PR) and stable disease at the intermediate evaluation were planned to be given three further courses with the same schedule. Results. From September 2006 to March 2008, 55 patients entered into the study. Central histology revision was performed. Forty-nine patients fulfilled inclusion criteria and were evaluable. Clinical characteristics were: median age 68 (50-74) years; 16 LL, eight MZL, 25 MCL; 42 stage III/IV; 33 bone marrow involvement; 20 at intermediate-high/high International Prognostic Index (IPI) risk. Thirty-eigh patients performed more than two prior lines of chemotherapy; 34 were Rituximab-pretreated; 21 refractory and 28 relapsed disease. Overall Response Rate (ORR) was 53% (CR 26.5%, PR 26.5%); no response 43% and 4% off therapy for other causes. ORR by histology was: 37% in LL, 50% in MZL and 64% in MCL. ORR was not adversely affected by Rituximab pretreatment: Rituximab-pretreated 62% and Rituximab-naïve 33%. ORR was higher in relapsed patients compared with refractory ones: 64% and 38% (p .06). (Table 1). With a median follow-up of 25 months, 2-year Overall Survival (OS) was 80% (95%CI: 66–89) and 2-year PFS was 25% (95%CI: 14–38) (Figure 1A, 1B). Two-year PFS by histology was shown in Figure 1C. A total of 233 courses were delivered with a median of 4.7 courses/patient. Thirty patients completed the treatment plan; 19 did not due to progression disease in 13, adverse events in five (concomitant gastric neoplasia, neurotoxicity grade II, sepsis, pleural effusion and toxic death due to interstitial pneumonia). Grade 3–4 CTC haematological toxicity was rare: neutropenia in 5% of the courses and thrombocytopenia in 〈 2%. Grade 3–4 CTC cumulative non-hematological toxicity was observed in 4.7% of all courses. The most frequent non-hematological toxicities were: neurotoxicity grade III in four patients, with complete recover or return to grade I in all of them. Infections were observed in eight patient with ten events: viral reactivation in four, pneumonia in three, sepsis in one and micosis in two. Conclusions. The combination of Rituximab and Bortezomib in weekly schedule was effective and safe in treatment of relapsed/refractory indolent and MCL. PFS was promising also in Rituximab-pretreated patients and mainly in MZL and MCL. Table 1. ORR (%) MCL/MZL/LL 64/50/37 Rituximab-pretreated/Rituximab-naive 62/33 N of prior therapies 〈 2/≥2 75/46 Relapsed/Refractory 64/38 Disclosures: Off Label Use: The use of Bortezomib is off-label in Relapsed/Refractory Indolent Non-Follicular and Mantle Cell Lymphoma. Vitolo:Roche-Italy: Advisory committee; Celgene-Italy: Advisory committee; Janssen-Cilag: Lecture Fee.

Abstract: Phenotypic and genotypic profiling of MDM2 in DLBCL. MDM2 as a negative regulator of p53 tumor suppressor function.

Abstract: Objective :To evaluate the prognostic significance of RELamplification, expression and c-Rel activation in DLBCL patients and to identify potential mechanisms for impact of c-Rel activation on patient survival. Patients and Design : The study cohort consists 460 de novo DLBCL patients (median follow-up, 46.8 moths) treated with R-CHOP. We assessed the nuclear expression/activation of c-Rel and other NF-κB subunits by immunohistochemistry, REL gene amplification by fluorescence in situ hybridization, and gene expression profiling using Affymetrix GeneChips array. Correlations between expression of nuclear c-Rel, REL mRNA, and expression of TP53, MDM2, MDM4, MYC, BCL2, AKT1, NFKB1, RELA, NFKB2, and RELB, both at the mRNA and protein levels were analyzed using t-tests. The prognostic significance of c-Rel activation, REL mRNA expression, and REL amplification was evaluated in the overall cohort, and different subgroups stratified by COO, status of TP53 mutation (wide type/WT, or mutated/MUT) and expression, Myc, Bcl-2 overexpression, and nuclear expression of other NF-κB subunits. Results :Nuclear c-Rel expression was observed in 29.6% of DLBCL patients and did not correlate with REL mRNA levels (P=0.95) and COO (P=0.77). In contrast, REL mRNA was significantly higher in germinal center B-like (GCB) subtype (P 〈 0.0001). In GCB-DLBCL, nuclear c-Rel expression was associated with significantly lower Myc, p53, MDM4, and pAKT protein levels but not at the transcriptional level. In contrast, in ABC-DLBCL, c-Rel activation was associated with significantly higher MUT-TP53mRNA level and reduced pAKT expression. Correspondingly to the lack of associations with reduced Myc, pAKT, and p53 in ABC-DLBCL, nuclear c-Rel expression showed prognostic impact only in ABC- but not in GCB- DLBCL, especially when it was concurrent with Myc overexpression (P 〈 0.0001 for OS and P=0.0012 for PFS). Importantly, patients with c-Rel activation and p53 mutations had significantly worse survival (for OS, hazard ratio, 3.56; P=0.0011; median survival, 16.2 vs 87.3 months. For PFS, hazard ratio, 3.976; P=0.0004; median survival, 10.4 vs 55.5 months) compared with other MUT-p53 DLBCL patients. The additive impact of c-Rel activation to TP53 mutations was more apparent in the ABC-DLBCL subtype, in which c-Rel activation was associated with significantly upregulated MUT-TP53 transcription (P=0.0087). Conversely, MUT-p53 expression was associated significantly with upregulated REL mRNA expression (P=0.0021), predominantly in the ABC-DLBCL subtype (P=0.0047). Only in ABC-DLBCL patients, TP53 mutations were associated with elevated nuclear c-Rel levels with a borderline P value (P=0.05). In addition to the association of nuclear p65 in GCB-DLBCL (P=0.003), and p50, NFKB1 and RELA mRNA in ABC-DLBCL (P=0.0023), the prognostic significance of c-Rel appears to depend on p50 (P=0.08) and p65 expression (P=0.12). Also, supporting that c-Rel transactivates anti-apoptotic BCL2L1/BCLXL by previous studies, there was no significant difference in survival of ABC-DLBCL patients with isolated BCL2 overexpression and with nuclear c-Rel expression. Comprehensive gene-expression profiling analysis and cell line study are undergoing in order to identify pathways to activate c-Rel and oncogenic mechanisms for c-Rel–mediated chemoresistance. REL amplification was predominantly observed in GCB-DLBCL (frequency, 7%) and correlated with significantly higher mRNA level (P 〈 0.0001). However, REL amplification did not correlation with nuclear c-Rel expression or patient survival, illustrating the importance of posttranslational regulations in c-Rel activation and function. Consistent with the adverse impact of c-Rel activation at the protein level, a strong trend toward poor survival was observed for elevated RELmRNA in ABC- but not in GCB-DLBCL. Conclusions : Nuclear c-Rel activation was associated with reduced level of proteins whose degradation involves with ubiquitin-proteasome in GCB-DLBCL, and upregulated TP53 transcription in ABC-DLBCL. Reciprocal regulation of c-Rel and MUT-p53 at the transcriptional level may underlie the synergetic adverse effect of c-Rel activation and TP53 mutations. c-Rel cooperated with Myc and conferred significantly worse survival in ABC-DLBCL patients. These subsets of c-Rel+ DLBCL patients likely will benefit from c-Rel targeted therapies. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction: Phosphoinositide-3-kinases (PI3Ks) are pivotal in various cellular functions including cell proliferation and survival, cell differentiation, intracellular trafficking and immunity. The delta (δ) and gamma (γ) isoforms of PI3K are highly expressed in cells of hematopoietic origin, and often dysregulated in various hematologic malignancies. Because these isoforms contribute to the development, maintenance, transformation, and proliferation of immune cells, dual targeting of PI3K δ and γ represents a promising approach in the treatment of lymphomas. RP6530 is a novel, highly specific dual PI3K δ/γ inhibitor with nanomolar inhibitory potency at the enzyme and cellular level. Besides, RP6530 was effective in inhibiting Akt phosphorylation and inducing apoptosis in various lymphoma and leukemic cell lines. Herein we present preliminary results of a Phase I, first in human, open label study of an oral PI3K δ/ γ inhibitor, RP6530. (NCT02017613). Methods: The dose escalation will determine the maximum tolerated dose (MTD) of RP6530 using a standard 3+3 design. Patients (pts) with a confirmed diagnosis of B-cell non-Hodgkin lymphoma, peripheral T-cell lymphoma, chronic lymphocytic leukemia, Acute lymphoblastic leukemia (CLL), Primary central nervous system lymphomas or Multiple myeloma who have at least one prior therapy are eligible. Additional eligibility criteria include ECOG performance status ≤ 2, and measurable/evaluable disease with a life expectancy of at least 12 weeks. Primary endpoints are safety and pharmacokinetic (PK) parameters; secondary endpoints include pharmacodynamic and drug activity (overall and complete response rates). Correlative biomarker samples including quantitative/qualitative measurements of cytokines, chemokines and aberrations indicative of PI3K function and RP6530 efficacy will be analyzed. RP6530 is given orally twice daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal from treatment. The study is designed to enroll up to 30 pts in the dose-escalation phase with up to an additional 42 pts in the cohort expansion phase. Efficacy evaluations are planned every 8 weeks. Adverse events (AE) are assessed using the CTCAE v4.0/ IWCLL guidelines as applicable. Results: Nine pts were enrolled to date across 3 dose levels: BID 25mg, 50mg and 100mg. Five pts were males; ECOG score was 0/1/2 in 5/1/3 pts, respectively, with mean age of 74 yrs (range: 54-82). Pts had median 5 (range: 1-11) prior treatment regimens, and 6 were refractory to prior treatments. Lymphoma categories included DLBCL (2 pts), Mantle Cell Lymphoma (2 pts), follicular lymphoma (1 pt), Marginal Zone Lymphoma (1 pt); and CLL/SLL (2 pts); one pt had multiple myeloma. All nine pts are evaluable for DLT assessment. Of the 9 evaluable pts, 6 are currently on study; 1 patient discontinued treatment due to disease progression. Pts tolerated the treatment well. To date, there have been no DLTs. One pt experienced G4 neutropenia that was unrelated to RP6530. No other G3/4 related hematologic or non-hematologic toxicities were observed. Of the six pts who completed 2 cycles of treatment (8 wks) at 50 mg daily dosing or less, 5 showed stable disease while 1 had disease progression. Three pts did not reach the first response assessment. Mean PK parameters determined on Day 1 of Cycle 1(C1D1) are: median Tmax of 1 hrs (range 0.5-2.0hrs), harmonic mean t1/2 of 2 (± 0.47) hr, and CL/F of 39.55 (± 19.3) L/hr. A linear relationship exists between dose and both AUC (r2 = 0.97) and Cmax (r2 = 0.97). The average accumulation index represented by Cmin on Cycle 2 day 1 is 1.12 (± 0.1). PK data from the first 3 cohorts on C1D1 is summarized below. Table 1.Dose25 mg (n=3)50 mg (n=3)100 mg (n=3)Cmax (µg/mL)0.356 (± 0.08)0.563 (± 0.12)1.329 (± 0.55)AUC (µg*hr/mL)0.775 (± 0.32)1.619 (± 0.67)2.482 (± 1.18) Conclusions: To date, RP6530 has been well tolerated in pts with heavily pre-treated relapsed/refractory hematologic malignancies. There were no DLTs and toxicities were minimal. Enrollment continues at higher dose cohorts. Updated safety, efficacy, PK, and PD data will be presented. Disclosures Scarfò: Rhizen Pharmaceuticals SA: Research Funding. Barde:Rhizen Pharmaceutical SA: Employment. Fazi:Rhizen Pharmaceuticals SA: Research Funding. Kumar:Rhizen Pharmaceuticals SA: Employment. Viswanadha:Incozen: Employment. Vakkalanka:Rhizen Pharmaceuticals SA: Employment, Equity Ownership. Ghia:Rhizen Pharmaceuticals SA: Research Funding. Ferreri:Rhizen Pharmaceuticals SA: Research Funding.

Abstract: Background: Previous trials from the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) showed that therapy with single-agent rituximab can produce long-term remissions in a sizeable subset of follicular lymphoma (FL) patients, with overall survival not inferior to chemo-immunotherapy, providing the rationale for the development of chemotherapy-free treatment strategies. Promising results have also been reported with the combination of rituximab and lenalidomide. The SAKK 35/10 phase-2 study was developed and conducted by the SAKK in cooperation with the NLG to compare the activity of rituximab plus lenalidomide versus single-agent rituximab in the first-line FL therapy. Methods: Patients with histologically confirmed untreated FL, grade 1, 2, 3a and in need of systemic therapy, were randomized either to rituximab monotherapy (R) (8 infusions of 375mg/m2 at day 1 of weeks 1, 2, 3, 4, and repeated at day 1 of weeks 12, 13, 14 and 15) or to rituximab (given at the same schedule) in combination with lenalidomide (RL) (lenalidomide given orally, 15 mg daily, starting 14 days before the first rituximab administration and continuously until 14 days after the last). The primary endpoint was the complete response (CR/CRu) assessed at week 23, defined according to the NCI standardized criteria (Cheson et al 1999). The study sample size was calculated to allow the detection of a 20% increase of the CR/CRu rate with RL over R, with 90% power and a type I error of 0.10. The 2 arms were compared using a one-sided Z-test with unpooled variance for proportions. Trial treatment was discontinued in patients who at week 10 did not achieve at least a minimal response, defined as reduction of more than 25% in the sum of product of tumor diameters (SPD), and rescue chemotherapy was given at the discretion of the treating physician. Results: In total, 154 patients were randomized; 77 (40 women and 37 men; median age 63yrs, range 29-85; 52% with stage IV and 47% with poor-risk FLIPI score) were allocated to arm R and 77 (42 women and 35 men; median age 61yrs, range 26-80; 48% with stage IV and 47% with poor-risk FLIPI score) to arm RL. Treatment was discontinued by 21 (28%) patients in arm R, in 16 due to lack of response at week 10 and in 1 due to toxicity, and by 19 (25%) patients in arm RL, in 3 due to lack of response at week 10 and in 13 due to toxicity. Adverse events of any grade were reported in 91% of patients in arm R and 100% in arm RL and adverse events of grade ≥3 were more common in arm RL than in arm R (51% vs 18% of patients). Grade 3-4 neutropenia was observed in 5% of patients in arm R and 19% in arm RL. The primary endpoint analysis (using the response assessment from the local investigators, reviewed by the study chairs) showed a significantly higher CR/CRu rate in patients treated with RL in comparison with those receiving R. This difference was observed both in the intent-to-treat (CR/CRu rate, 36% vs. 25%, respectively; p=0.056) and the per-protocol population (CR/CRu rate, 42% vs. 28%, respectively; p=0.049). Conclusions: The addition of lenalidomide to rituximab results in a significantly better CR/CRu at the cost of an expected increased toxicity. Further follow-up is needed to ascertain whether the response improvement will translate into prolonged time to next treatment and superior progression-free and overall survival rates. TableInvestigators’ assessment of the response at week 23 in the intent-to-treat (ITT) population Rituximab (N=77) Rituximab+Lenalidomide (N=77)Response category n (%)[95% C.I.]n (%)[95% C.I.] CR/CRu19 (25) [16-36%]28 (36)[26-48%] PR28 (36) [26-48%]35 (45)[34-57%] SD6 (8) [3-16%]4 (5)[1.4-13%] PD/relapse2 (3) [0.3-9%] 3 (4)[0.8-11%]Not evaluable*22 (29) [19-40%] 7 (9)[4-18%]*Patients with no assessment at week 23, including patients not achieving at least a minimal response at week 10. Disclosures Kimby: Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide, not approved for follicular lymphoma. Mey:Celgene: Membership on an entity's Board of Directors or advisory committees. Ferreri:Celgene: Research Funding. Bargetzi:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Krasniqi:Roche, Takeda: Membership on an entity's Board of Directors or advisory committees. Zucca:Roche, Mundivarma, Novartis: Consultancy, Honoraria, Research Funding.

Abstract: Abstract 1566 Background. Response-tailored management of PMLBCL is a major challenge in everyday practice, mostly due to the persistence of post-treatment residual masses of uncertain nature. PET/CT is now widely used in the definition of response and as a prognostic indicator, in Hodgkin lymphoma (HL) and diffuse large B cell lymphoma (DLBCL), while its role in patients with PMLBCL remains to be defined. Aim of the study. The IELSG-26 study was designed to prospectively evaluate the clinical role of PET/CT after rituximab and anthracycline-containing immunochemotherapy (R-CHT) in patients with PMLBCL. Methods. Between January 2007 and July 2010, 125 patients (pts) with PMLBCL were enrolled in 21 institutions and treated with R-CHOP-like (20 pts), R-VACOP-B (34 pts) or R-MACOP-B (71 pts) regimens according to the local policy; consolidation with mediastinal involved field radiotherapy (IFRT) as indicated by local guidelines was allowed. PET/CT scans were planned at baseline, at 3–4 weeks after R-CHT and at 12 weeks after radiotherapy. Central PET/CT review was performed at the end of treatment using the Deauville score (Meignan et al. Leuk Lymphoma 2009) and complete response (CR) was defined as a negative PET scan or one having minimal residual uptake lower than mediastinal blood pool (MBP) activity in regions which were FDG-PET positive at baseline according to the criteria of the International Harmonization Project in Lymphoma (Juweid et al. JCO 2007). Results. Treatment was administered as initially planned in 119 pts (including IFRT in 106); there were 6 early withdrawals (4 with early progression and 2 with stable disease receiving second-line chemotherapy). PET imaging was not done (n=2) or not evaluable due to technical problems (n=2) in 4 pts, therefore, central review of PET/CT was possible in 115/119 patients. PET/CT visual assessment at 3–4 weeks post-R-CHT showed metabolic CR in 54/115 patients (47%; 95% CI, 36%–56%): in 12 cases (10%; 95% CI, 6%–18%) PET/CT scan was completely negative (score 1 according to the Deauville criteria), while in 42 (37%; 95% CI, 28%–46%) there were small residual masses with an uptake less than MBP (score 2). PET/CT scans showed a positive residual mass after R-CHT in 61/115 pts (53%; 95% CI, 44%–62%). The residual uptake was higher than MBP but below the liver uptake (score 3) in 27 pts (23%; 95% CI, 16%–32%), slightly higher than the liver uptake (score 4) in 24 pts (21%; 95% CI, 14%–29%) and markedly higher than the liver uptake (score 5) in 10 pts (9%; 95% CI, 4%–15%). Despite only 47% of patients attaining a CR -defined by the uptake below MBP activity- after R-CHT, at a median follow-up of 2.8 years, the estimated 5-year overall survival (OS) and progression-free survival (PFS) rates were 96% (95% CI, 89%–98%) and 91% (95% CI, 84%–95%), respectively. The achievement of a CR at 3–4 weeks after R-CHT predicted a longer PFS (p=0.015) with high sensitivity but poor specificity (negative predictive value of 0.98 but positive predictive value of only 0.15) and showed a borderline impact (p=0.052) on OS. Patients with Deauville score 3 had a clinical outcome identical to that of ‘PET negative’ (score 1–2) pts and ROC analysis suggested that moving the cut-point for the definition of CR from the MBP to the liver uptake, will increase specificity while maintaining sensitivity. Indeed, defining the response using the liver uptake as a cutpoint is a better predictor for both PFS (p 〈 0.001) and OS (p=0.001); of 10 pts with disease progression, 9 had score 4–5 and one score 2. The latter was one of the five pts with score 1–3 who were not irradiated. All the 4 recorded deaths occurred in the group of patients with score 4–5. Conclusions. Using the MBP cut-point, the PET-positive rate (Deauville score 〉 2) after R-CHT in PMLBCL was higher (53%) than in DLBCL. However, more than 90% of pts are projected to be alive and progression-free at 5 years post treatment and a negative PET/CT after R-CHT is significantly associated with a longer PFS. Pts with score 4 and 5 had a significantly worse PFS and OS. Hence, the liver uptake may represent a more appropriate cut-point than MBP to identify poor-risk pts who may need early intensification of therapy. The frequent use of IFRT in this study precludes any clear conclusion about its role, but the new IELSG-37 randomized trial will assess whether mediastinal irradiation can be safely omitted in PMLBCL pts achieving a CR after R-CHT. Disclosures: No relevant conflicts of interest to declare.

Abstract: Abstract 1220 Poster Board I-242 Background The outcome of B-cell diffuse large B-cell lymphoma (DLB-CL) patients has definitely improved since the introduction of therapeutic programs combining chemotherapy and the anti CD20 rituximab. However, the outcome of patients with adverse prognostic factors still needs a substantial improvement and intensive therapy with autologous stem cell transplantation (ASCT) may represent a feasible option. In a previous Phase II study the combination of rituximab and high-dose (HD) sequential chemotherapy, delivered with multiple autologous peripheral blood progenitor cell (PBPC) support (R-HDS regimen), proved effective and well tolerated in previously untreated patients with DLB-CL and age-adjusted International Prognostic Score (aaIPI) score 2-3 (Tarella et al.: Leukemia 2007). Based on this study, a multicenter Phase III study was planned to compare the R-HDS regimen to a standard dose dense, rituximab supplemented R-CHOP-14 chemotherapy program. Patients and Methods The multicenter phase III trial R-HDS 0305 (Clinical Trials.gov.number NCT00355199) was planned to include 240 patients with DLBCL without CNS with stage '2 II B, bulk, age 18-60 years, with ECOG-PS=0-3 and aaIPI 2-3 or age 61-65 years with ECOG-PS=0-2 and IPI 3-5. The control group received 8 courses of R-CHOP-14, supported by GCSF ± involved field radiotherapy (IFRT), if they achieved at least a PR after 4 cycles. Cases refractory to R-CHOP-14 were rescued with R-HDS. Experimental arm (RHDS) included: 3 courses of doxorubicin-containing chemotherapy (APO), followed by sequential administration of cyclophosphamide (CTX) 7 g/sqm, Cytarabine (Ara-C) 2g/sqm every 12 hours for 6 days, etoposide 2 g/sqm plus cisplatin 100 mg/sqm; the program was completed by mitoxantrone plus melphalan (60 and 180 mg/sqm) or BEAM conditioning regimen with ASCT± IFRT. Rituximab (375 mg/sqm) was given for a total of 6 doses, twice after CTX and Ara-C, as in vivo purging before CD 34+ cells harvest, and twice after ASCT. The primary outcomes of the study were CR, DFS, OS, EFS and toxicity. From June 2005 to February 2009, 165 patients were enrolled in the study (R-CHOP-14=83; RHDS=82). The planned interim analysis has been carried out on 119 patients who have been randomized up to March 2008. Results The median age was 49 years (range, 18-65), 11 patients (9.2%) were 〉 60 years and the M/F was 1.38. Patients in two arms presented with comparable adverse features such as advanced stage (87%), BM infiltration (24%), bulky disease (67%), elevated LDH (81%) and beta 2-microglobulin (mean 3.9 mg/dl, SD = 4.5), poor ECOG-PS (60%), B-symptoms (62%), and ≥1 extranodal site (63%). Until now 10 patients (8%) did not complete the planned program because of toxicity or PD, 6 and 4 cases, respectively. One patient resistant to R-CHOP-14 was shifted to R-HDS. Overall, 24 patients (20%) deceased during the course of the study, 20 (17%) died from lymphoma, 2 (2%) due to therapy complications and 2 (2%) from hepatitis B reactivation. Moreover, 6 patients (5%) recovered from severe adverse events: 1 interstitial pneumonia, 1 graft failure, 1 sepsis, 1 colon diverticulitis, 1 shock, 1 prolonged aplasia. The main G 〉 2 hematological toxicity were: anemia, granulocytopenia and thrombocytopenia, in 42%, 60 % and 45 % of patients, respectively. Grade 〉 2 gastrointestinal, hepatic and infectious toxicity were recorded in 32 %, 11 % and 20% of patients, respectively. One-hundred and eight of 119 patients (91%) were alive and assessable for the response rate and clinical outcome at final restaging. Eighty-nine patients (82%) achieved CR, 8 PR and 7 had SD or PD. With a median follow up of 18.1 months (SD= 9.3, range 0.3–40.6 months) the 2year OS, DFS and EFS of the 119 evaluable patients are 80%, 84% and 74%, respectively. Conclusion This interim analysis shows that in high-risk DLBCL patients aged =/ 〈 65 years, R-CHOP 14 and R-HDS with ASCT: i. are feasible therapeutic strategies with an acceptable risk profile; ii. induces an overall high response rate, markedly superior to historical results reported for high-risk aggressive lymphoma. The favorable survival projections allow to continue the study protocol until its planned conclusion in order to verify any possible difference between R-CHOP14 and R-HDS in terms of therapeutic efficacy. Disclosures No relevant conflicts of interest to declare.

Abstract: Background: The antibiotic clarithromycin displays immunomodulatory properties, partially mediated by the suppression of IL-6 and other inflammatory cytokines. This macrolide can directly induce TNF-mediated apoptosis in mouse lymphoma cells, with a DNA fragmentation degree similar to that seen in cells treated with chemotherapeutic agents. In recent trials on multiple myeloma and Waldenstrom’s macroglobulinemia, the combination of clarithromycin with other immunomodulatory agents exhibited high tumour regression rates, and some case reports suggested an antineoplastic effect of clarithromycin in marginal zone B-cell lymphoma of MALT-type (EMZL) of the colon and the lung. Method: This is a phase II trial aimed to assess tolerability and activity of a 6-month regimen of oral clarithromycin in patients (pts) with relapsed/refractory EMZL. Clarithromycin (500 mg) was given orally twice daily for 6 months to 14 HIV-negative pts (age 318 ys; ECOG-PS ≤3) with relapsed/refractory EMZL and at least one measurable/parametrable lesion. Pre-registration assessments included physical examination, hemogram and biochemical profile, HIV, HBV and HCV serology, gastroscopy, gastric Helicobacter pylori (Hp) infection assessment (3 methods: histology, breath test, serology, and/or cagA in faeces), Chlamydia psittaci (Cp) infection assessment (PCR on tissue and PBMC, only in pts with ocular adnexal MALT lymphoma), total body CT scan, and bone marrow biopsy. Tolerability (physical examination and blood exams) was assessed every 8 weeks and objective response was assessed every 3 months. Results: Median age of eligible pts was 59 ys. (range 36–81; 7 females). Clarithromycin was the salvage therapy at first relapse in 8 pts, and the 3rd–6th line of treatment in the others. All pts had local disease at the time of treatment, two pts had also systemic dissemination. Extranodal sites were stomach (n=2), conjunctiva (n=4), orbit (n=7), and breast (n=1). No pt had increased LDH serum levels; only one pt had B symptoms. Chronic infections were caused by HCV in 2 pts, Hp in 2 and Cp in 5. Hp and Cp infections were successfully eradicated with specific antibiotics as part of upfront treatment, that is with a median time from bacterial eradication to clarithomycin treatment of 14 (7–40) months. This excludes that a potential clarithomycin antitumor activity could be due to antimicrobial effect. The treatment was completed in 13 pts and is ongoing in the remaining one. Two pts achieved a complete remission (22+, 24+) and 2 pts achieved a partial response (11+, 14), with an ORR of 31%; 1 pt had a minimal response (11+), 5 pts had stable disease (15+, 15+, 16+, 22, 24), 3 pts experienced disease progression (10, 10, 16). The median time to the best response was 10 months. Three of the major responses were observed among the 4 pts with conjunctival lymphoma, treatment is ongoing in the remaining one. The number of previous lines of treatment did not influence response. Tolerability was excellent-good in all pts but two (episodic nausea). No biochemical abnormalities were detected after 6 months of treatment. After a median follow-up of 15 months, 6 pts experienced disease progression, with a median time to progression of 11+ months. The pt with B symptoms experienced a high-grade transformation and was not responsive to clarithromycin. All pts but one (HCV-related cirrhosis) are alive with a median OS of 42 months. Conclusions: This 6-month regimen of oral clarithromycin seems to be safe and active in EMZL, mostly in pts with conjunctival MALT lymphoma. Response to clarithromycin does not seem to be mediated by eradication of common MALT-related bacterial infections. Clarithromycin deserves to be further investigated in EMZL.

Abstract: BACKGROUND Outcomes for patients (pts) with primary CNS diffuse large B cell lymphoma (PCNSL) have improved over recent years, largely through optimisation of first-line methotrexate (MTX)-containing protocols and dose-intensive chemotherapy consolidation. However, 30-50% of pts experience refractory or relapsed (r/r) disease, which confers very poor outcomes and short survival. By contrast to systemic DLCBL, there is no accepted standard approach for r/r PCNSL. Thiotepa is an alkylating agent highly efficient at crossing the BBB and widely incorporated within high-dose therapy and autologous stem cell transplantation (HDT-ASCT) protocols for PCNSL, but has not undergone dose-finding studies nor been incorporated within salvage regimens for PCNSL. The TIER study investigates the safety and efficacy of adding thiotepa, in a dose-escalation design, to the Rituximab, Ifosphamide and Etoposide (R-IE) salvage regimen1. METHODS TIER is an open label, phase I/II UK NCRI TAP study for pts with r/r PCNSL, previously treated with a high-dose MTX-based regimen. In phase I, the RP2D of thiotepa within the TIER combination was established using a 3+3 design, with dose escalations of 30, 40 and 50mg/m2 (dose level 2 (n=4), 3 (n=5) and 4 (n=27) respectively), given on day 5 of R-IE cycle1. The Phase II primary endpoint was overall response rate (ORR) after cycle 2 of TIER (C2) by centrally reviewed contrast-enhanced MRI2, on an intention-to-treat (ITT) basis. Further treatment and consolidation after the primary endpoint MRI was at the discretion of investigators. Key secondary end-points were 2-year PFS, EFS and OS. RESULTS Thirty-six pts were recruited from Jun 2015-Apr 2019 at 13 centres (characteristics: Table 1). The median number of prior lines was 2 (range 1-4) with 44% of patients deemed refractory to their previous line of therapy. During phase I (n=10) no dose limiting toxicities (DLTs) were observed up to and including 50mg/m2 thiotepa, constituting the RP2D (n=27). 56 cycles of TIER were administered across both phases; 5 pts had 〉 1 dose reductions. Median time between C1D1 and C2D1 was 24.7 days (range 22-38). Relative mean dose intensity of thiotepa, ifosphamide and etoposide was 71.8 (SD 44.9), 76.4 (SD 41.6), and 76.8 (SD 41.8) respectively. Further therapy after 2 cycles of TIER was delivered to 41.7% of pts (16.7% ASCT, 22.2% TIE, and 2.8% WBRT). The most common grade 3 / 4 adverse events were thrombocytopenia and neutropenia (47.2 and 55.6% occurring in 15 and 18 pts respectively). 17 serious adverse events (SAEs) were reported in 12 pts, of which 4 were haematological. Of these, 13 were considered related to TIER. Commonly occurring non-haematological SAEs were respiratory tract infections (23.5%) and seizures (11.8%). At data lock, 10/27 pts had responded to treatment as assessed by local investigators (ORR 37%, CR rate 15%). 13 pts were non-evaluable (7 progressed prior to C2 scan, 2 withdrew consent, and 4 awaiting scans) and classed as non-responders. Following data lock, responses were reported for 3 further pts (2 by local investigators and 1 by central review), resulting in a provisional ORR of 13/27 (48%). For the ITT population, median OS time was 3.52 months (95% CI 2.50, 14.17), and median PFS 2.86 months (95%CI 2.34, 6.05) (Figure 1). 6 pts underwent ASCT consolidation after TIER, of whom 2 have relapsed. CONCLUSIONS This is an early analysis of data from the phase I/II TIER study for a heavily pre-treated group of r/r PCNSL; the first such dose-escalation study for this patient group. Phase I determined a RP2D of 50mg/m2 of thiotepa incorporated in the R-IE regimen. There were no DLTs and toxicities, consistent with an intensive ifosphamide-based regimen. ORR was 10 pts (37%) with 3 further responses reported after data lock. If confirmed by central review, the primary endpoint of activity (ORR 40%) will have been reached. However, notwithstanding the response endpoint, most pts experienced very poor survival outcomes. These data describe the feasibility of TIER as a salvage regimen for r/r PCNSL but question the utility of this approach as a standard option, given the short PFS and OS times, except for the minority of pts who received ASCT. Biological and imaging sub studies are underway to identify predictors of outcome. In the modern era of effective first line immunochemotherapy approaches, pts with r/r PCNSL remain a major area of unmet need for whom novel experimental approaches are urgently required. Disclosures Fox: Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support. Martinez-Calle:ABBVIE: Other: Travel support. Collins:Gilead: Consultancy, Honoraria. Ferreri:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Roche: Research Funding; Kite: Consultancy. Davies:BioInvent: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Bayer: Research Funding; ADCT Therapeutics: Honoraria, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees. Johnson:Roche: Consultancy, Honoraria, Speakers Bureau; Takeda: Other: Travel, accomodations, expenses. Cwynarski:Adienne: Consultancy; Takeda: Consultancy, Other: conference and travel support , Speakers Bureau; Roche,: Consultancy, Other: conference and travel support, Speakers Bureau; Autolus: Consultancy; KITE: Consultancy; Gilead: Consultancy, Other: conference and travel support, Speakers Bureau; Celgene: Consultancy; Atara: Consultancy; Janssen: Other: conference and travel support, Speakers Bureau.