Abstract: Background: Cereblon (CRBN), a subunit of cullin 4-based E3 ubiquitine ligase complex, has been characterized as the main immunomodulatory drugs (IMiDs), thalidomide, lenalidomide and pomalidomide, binding protein that is crucial for their antiproliferative and immunomodulatory properties. Several recent reports have suggested that CRBN gene and protein expression or alternative splicing affect sensitivity to IMiDs in multiple myeloma (MM). It can be speculated that CRBN expression level, alternative splicing or CRBN-E3 ubiquitine ligase substrate specificity in MM and microenvironment cells may be partially determined by inherited genetic background including functional single nucleotide polymorphisms (SNPs). Aim: The objective of this study was to verify whether naturally occurring SNPs in CRBN encoding CRBNgene (locus chromosome 3p26.2) may influence outcome of lenalidomide-based therapy in patients with MM. Methods: We genotyped 14 tagging SNPs in CRBN gene in 169 Polish Caucasian patients with refractory/relapsed MM treated with lenalidomide-based therapy. Among these patients 151 (89%) received lenalidomide/dexamethasone (Len-Dex) regimen while the remaining patients were treated with lenalidomide-based three drug combinations. Genomic DNA samples were collected and genotyped in the context of the IMMEnSE consortium. The influence of CRBNallelic variants on probability to achieve clinical response (at least partial response, PR) to lenalidomide-based therapy, achievement of complete response (CR), duration of progression-free survival (PFS) and overall survival (OS) were tested in regard to established clinical and laboratory predictive factors using logistic regression and proportional-hazards regression models. For all genotyped SNPs co-dominant, dominant and recessive inheritance modes were tested. Results: We found that carriers of minor alleles of two studied SNPs, namely CRBN rs1714327G 〉 C and CRBN rs1705814T 〉 C significantly associated with lower probability of achievement of clinical response (≥PR) to lenalidomide-based therapy using dominant inheritance model (OR=0.25, 95%CI 0.10-0.63; p=0.0033, Bonferroni corrected p=0.019 and OR=0.21, 95%CI 0.07-0.61; p=0.0041, Bonferroni corrected p=0.024, respectively). Moreover, in concordance with these findings one of these two SNPs, namely CRBN rs1705814T 〉 C, was also significantly associated with shorter PFS in the analyzed group of lenalidomide treated MM patients (OR=2.49; 95%CI 1.31-4.74; P=0.0054, Bonferroni corrected p=0.032). In contrast, none of the tested allelic variants of CRBN showed significant influence on OS. Conclusions: Taken together, our observations suggest that selected germline CRBN SNPs (rs1714327G 〉 C and rs1705814T 〉 C) affect lenalidomide efficacy in relapsed/refractory MM. Further studies are needed to explain functional mechanisms underlying these associations as well as to establish whether CRBN genetic variants may be useful as potential biomarkers for IMiDs-based therapy. Acknowledgments: This work was supported by the grants of Polish Young Heamatologists Club and Polish Myeloma Consortium. The work of Pawe³ Gaj was supported by a grant from the European Commission 7th Framework Programme: FP7-REGPOT-2012-CT2012-316254-BASTION Disclosures No relevant conflicts of interest to declare.

Abstract: Background: The LYM-3002 study compared the efficacy and safety of frontline VR-CAP (n=243) vs R-CHOP (n=244) in newly diagnosed MCL pts who were ineligible or not considered for autologous stem cell transplantation. VR-CAP substitutes bortezomib for vincristine in the standard R-CHOP regimen. LYM-3002 met its primary endpoint, demonstrating a 59% improvement in progression-free survival (PFS) per independent radiology review committee (IRC) with VR-CAP vs R-CHOP (median 24.7 vs 14.4 mos; HR 0.63 [0.50, 0.79] ; p 〈 0.001) and a 96% improvement in PFS per investigator (INV) (HR 0.51; p 〈 0.001). Significant and clinically relevant improvements in secondary efficacy endpoints were also demonstrated with VR-CAP, including a more-than-doubling of median duration of complete response (CR), and a doubling of median treatment-free interval. In addition, 4-yr overall survival (OS) rates were 10% higher with VR-CAP (64.4% vs 53.9%). These findings were accompanied by additional but expected and manageable toxicities (Cavalli F, et al. ASCO 2014, Abs 8500; Robak T, et al. EHA 2014, Abs S1345). Reflecting the real-life situation, the protocol allowed for inclusion of pts not considered for transplantation for non-medical reasons (e.g. pt refusal, financial affordability). This post-hoc analysis of the LYM-3002 study evaluated the efficacy and safety of VR-CAP vs R-CHOP in a subgroup of 80 pts who were aged 〈 60 yrs and without medical reasons for transplant ineligibility per the sponsor’s medical monitor assessment. Methods: Adults with measurable stage II–IV MCL and ECOG PS 0–2 were randomized 1:1 (stratified by IPI score and disease stage) to 6–8 x 21-d cycles of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, all IV d 1, and prednisone 100 mg/m2 PO d 1–5, plus bortezomib 1.3 mg/m2 IV d 1, 4, 8, 11 (VR-CAP) or vincristine 1.4 mg/m2 (max 2 mg) IV d 1 (R-CHOP). Endpoints of this analysis were PFS, rates of CR/unconfirmed CR (CR/CRu), duration of CR/CRu, OS, and safety (adverse events [AEs]; NCI-CTCAE v3.0). PFS and response were assessed by IRC and by INV per International Lymphoma Workshop Response Criteria. PFS and OS were estimated by Kaplan-Meier methodology. The Cochran-Mantel-Haenszel Chi-squared test was used for response rate comparisons. Results: The 80 pts (38 VR-CAP; 42 R-CHOP) included in this analysis were enrolled in countries in the EU (11%), North America region (1%), and Rest of World (88%; mainly China [36%] and Russia [23%] ). Median age was 54 yrs (34–59). 78% of pts were male, 53%/48% were Asian/White, 58%/38%/5% had ECOG PS 0/1/2, 8%/33%/60% had stage II/III/IV MCL at diagnosis, and 56%/31%/11%/1% had IPI score 0–1/2/3/4–5. 76%/16%/8% had MIPI low-/int-/high-risk status (54%/28%/18% MIPIb low-/int-/high-risk) and 38%/62% had Ki-67-high/-low MCL. Baseline characteristics and stratification factors were generally similar between arms. Pts completed a median of 6 cycles. With VR-CAP vs R-CHOP, median PFS by IRC was 32.6 vs 12.0 mos (HR 0.59; p=0.108; Figure) and by INV was 42.6 vs 20.6 mos (43 [54%] events; HR 0.54 [0.28, 1.03] ; p=0.057). In response-evaluable pts (36 VR-CAP; 41 R-CHOP), rates of CR/CRu by IRC (bone marrow and LDH verified) were 67% vs 39% (OR 3.7 [1.3, 10.4]; p=0.012) and by INV were 50% vs 29% (OR 2.2 [0.8, 5.9] ; p=0.126). Median duration of CR/CRu by IRC (24 vs 16 pts evaluable) was 45.9 vs 28.6 mos, and by INV (18 vs 12 pts evaluable) was 48.0 mos vs not reached (NR). Median OS with VR-CAP vs R-CHOP was NR vs 47.3 mos (24 [30%] events; HR 0.81 [0.33, 1.96] ; p=0.634). 4-yr OS rates were 74.1% (54.0%, 86.5%) vs 48.7% (28.5%, 66.2%), respectively. 95% vs 81% (VR-CAP vs R-CHOP) of pts had grade ≥3 AEs which were mainly hematologic and included neutropenia (89% vs 67%), leukopenia (57% vs 31%), thrombocytopenia (59% vs 0), lymphopenia (22% vs 12%), anemia (16% vs 14%), and febrile neutropenia (8% vs 12%). Rates of serious AEs (19% vs 19%), discontinuations due to AEs (2 vs 1 pt), and grade 5 AEs (2 vs 2 pts) were similar between arms. Conclusions: In younger pts not considered for transplantation, VR-CAP appears to provide a benefit vs R-CHOP in terms of PFS, CR/CRu rate, duration of CR/CRu, and OS, consistent with findings in the overall LYM-3002 pt population. Notably, a 67% CR/CRu rate by IRC with a median CR/CRu duration of 45.9 mos was achieved with VR-CAP. Further research is needed to determine how these results might be improved by consolidation with transplantation and maintenance therapy. Figure 1 Figure 1. Disclosures Drach: Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Off Label Use: The proteasome inhibitor bortezomib is approved in the US for the treatment of multiple myeloma and for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy. In the present study, bortezomib is being investigated in combination with immunochemotherapy for previously untreated patients with mantle cell lymphoma, an indication for which it is currently not approved.. Belch: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, Speakers Bureau. Farber:Alexion: Equity Ownership, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau; Janssen/Pharmacyclics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Leukemia Lymphoma Society NJ Chapter: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bosly:Amgen: Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zaucha:Roche: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Robak:Janssen Research & Development: Consultancy, Research Funding. Pei:Janssen: Employment. Rooney:Janssen: Employment; Johnson & Johnson: Equity Ownership. van de Velde:Janssen: Employment; Johnson & Johnson: Equity Ownership. Cavalli:Mundipharma: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Takeda: Consultancy; Novartis: Consultancy.

Abstract: Negative [ 18 F]fluorodeoxyglucose (FDG) –positron emission tomography (PET)/computed tomography (CT) after two cycles of chemotherapy indicates a favorable prognosis in Hodgkin lymphoma (HL). We hypothesized that the negative predictive value would be even higher in patients responding rapidly enough to be PET negative after one cycle. This prospective study aimed to assess the prognostic value of PET after one cycle of chemotherapy in HL and to assess the dynamics of FDG uptake after one cycle (PET1) and after two cycles (PET2). Patients and Methods All PET scans were read by two blinded, independent reviewers in different countries, according to the Deauville five-point scale. The main end point was progression-free survival (PFS) after 2 years. Results A total of 126 patients were included, and all had PET1; 89 patients had both PET1 and PET2. The prognostic value of PET1 was statistically significant with respect to both PFS and overall survival. Two-year PFS for PET1-negative and PET1-positive patients was 94.1% and 40.8%, respectively. Among those with both PET1 and PET2, 2-year PFS was 98.3% and 38.5% for PET1-negative and PET1-positive patients and 90.2% and 23.1% for PET2-negative and PET2-positive patients, respectively. No PET1-negative patient was PET2 positive. Conclusion PET after one cycle of chemotherapy is highly prognostic in HL. No other prognostic tool identifies a group of patients with HL with a more favorable outcome than those patients with a negative PET1. In the absence of precise pretherapeutic predictive markers, PET1 is the best method for response-adapted strategies designed to select patients for less intensive treatment.

Abstract: Abstract 4844 Introduction CHOP-based chemotherapy is a standard I line regimen for most non-Hodgkin's lymphomas (NHL). All prognostic indices, like international prognostic index (IPI) for DLBCL, follicular lymphoma IPI (FLIPI), mantle cell lymphoma IPI (MIPI) assess the risk associated both with lymphoma and the patient's performance status/age. No co-morbidity scale is used on a large scale in evaluation of younger patients. The effect of diabetes mellitus (DM) was assessed in a large, multicenter, retrospective analysis. Materials and methods 610 young NHL patients (median age 55 years, range 18–86) treated with (R)-CHOP chemotherapy, from 7 PLRG centers were assessed (427 DLBCL, 70 MCL, 45 FL, 22 MZL, 8 CLL/SLL and 38 PTCL). Medical records of all non-Hodgkin's lymphoma patients treated with first line CHOP-based therapy have been reviewed in order to collect data concerning the type of lymphoma, coexistence of DM, type and treatment of DM, modification of treatment during (immuno)-chemotherapy and finally overall survival and cause of death. Patients with impaired glucose tolerance and post-steroid hyperglycemia/ diabetes which developed only after initiation of treatment were classified as non-diabetic patients. Results There were 43/610 (7%) diabetic patients. Type 2 DM was diagnosed in 40 patients (6.5%), one patient (0.16%) had LADA (Latent Autoimmune Diabetes of Adulthood) and two patients had prior post-steroid diabetes. The median duration of diabetes prior to lymphoma diagnosis was 5 years (range 1–25 years). Body Mass Index (BMI) at the moment of diagnosis was calculated for 31 patients (median 28.1, range 20.3–42.8). Six patients (19.4%) had normal weight while 25 (80.6%) patients were either overweighed (16, 51.6%) or obese (9, 29%). Age and other risk factor distribution was similar between diabetic and non-diabetic patients. Diabetic patients had significantly shorter survival compared to those without DM, with median OS of 3.3 years versus not reached at average observation of 5 years (p=0.001, Figure 1). Diabetes treatment modification undertaken during chemotherapy did not influence survival (p=0.64). Lymphoma progression was the most common cause of death in both DM and non-DM patients (41% and 45.5% respectively), followed by cardiovascular diseases (29.5% and 31% respectively). In DM patients we observed doubling of fatalities due to complications (predominantly infectious): 23.5% compared to 12.5 % in non diabetic patients. Conclusions Diabetic patients had shorter survival than non-diabetic patients in the analyzed group (p=0.001). While diabetic and non-diabetic patients had similar mortality rate due to lymphoma or cardiovascular complications, deaths secondary to infection complications were twice as frequent in DM cases. It probably correlates with sustained immunosuppression, aggravated by (immuno)-chemotherapy. Disclosures: Jurczak: Pharmacyclics: Research Funding.

Abstract: Abstract 2632 Background. Disease stage remains the most powerful prognostic factor in HL and guides optimal therapy. Despite high (18)F-FDG avidity in HL, PET-CT is not mandatory in the initial staging of HL. To establish if PET-CT should substitute classical CT in the initial staging of HL we evaluate the influence (18)F-FDG PET-CT on HL stage migration and its impact on treatment selection. Materials and methods. 96 HL patients (pts) underwent conventional CT and PET-CT staging with a median time 19 days between two tests; the stage of HL was defined separately based on CT or PET-CT results that were read afresh independently by the radiologist and the nuclear medicine specialist. The number of nodal areas and extranodal sites involved, detected by each imaging modality were scored and compared. In CT assessment, classical radiologic criteria were used. Lymph nodes 〉 15mm in longest dimension were considered pathological. In PET-CT assessment sites of nonphysiological uptake above background were reported as pathologically involved. Focal uptake in the spleen, liver and bones/bone marrow (BM) was treated as indicative of HL involvement. Diffuse uptake in the spleen was also assumed to be indicative of HL involvement if the uptake was greater than the liver uptake. In contrast diffuse uptake in the BM even if higher than the liver was conservatively not treated as HL infiltration. Results. The number of patients in stage I, II, III, IV was 5, 49, 28, 14 using CT and 7, 37, 22, 30 using PET-CT. In 33 (34%) patients PET-CT changed HL stage, specifically 27 (28%) pts were upstaged whereas 6 (6,3%) pts were downstaged compared to CT results. As a consequence 20 (21%) patients required treatment modification: reduction in 4 pts and intensification in 16 pts. All 4 patients with treatment reduction had CT stage III, most (3 pts) were without B symptom. The stage was reduced due to lack of (18)F-FDG uptake in increased ( 〉 15mm) single nodes on the other site of diaphragm. All 16 pts with treatment intensification had CT stage II and two third suffered from B symptoms. The stage was upgraded mainly to the extranodal involvements (47 sites in 26 pts) detected by PET-CT that were not seen on conventional CT. Among them the most often was bone marrow (10 pts), following by spleen (5pts) and lung (2pts) involvement. In 9 pts two or more coexisting locations were detected. Extended nodal involvement seen in PET-CT compared to CT resulted in upstage only in one patient despite detection of more nodal areas compared to CT; Depending on location, 36–56% of these nodes were smaller than 15mm in greatest dimension. Moreover, PET-CT helped to define atypically located small nodes in 25 patients; in 7 of them radiotherapy was a part of radical treatment and the omission of PET-CT could have resulted in a geographical miss. BM biopsy was positive in 3 of 96 pts; in all cases PET-CT revealed diffuse BM uptake higher than the liver uptake. Conclusions. The addition of PET-CT in the initial staging of HL modifies the disease stage in a significant proportion of patients, leading to treatment modification in majority of them. The impact of PET-CT on staging is of special significance in patients with CT stage II especially with B symptoms. Disclosures: No relevant conflicts of interest to declare.

Abstract: Antiviral therapy (interferon alpha with ribavirin) for chronic hepatitis C virus infection (c-HCVI) frequently causes decrease of cell blood counts (CBC) which may affect undertaken treatment. The aim of the study was to evaluate the frequency of CBC changes during antiviral therapy and to assess if pre-treatment CBC declines affect the incidence and severity of CBC alterations. This retrospective analysis included 618 patients, diagnosed with c-HCVI in the years 1998-2010 at the Pomeranian Region, Poland treated with interferon alpha +/- ribavarin. The data were collected at the following time points: start of treatment (week 0) and at the end of 12-th, 24-th and 48-th week of treatment. Hemoglobin (HGB), leukocyte count (WBC) absolute neutrophil count (ANC) and platelet count (PLT) declines were graded as mild//moderate if HGB was not lower than 10//8 g/dl, WBC than 3//2 G/l, ANC than 1//0.75 G/l and PLT than 100//50 G/l. To determine the clinical significance of the observed CBC changes, values:​​ HGB 〈 10 g/dl, ANC 〈 0.75 G/l, PLT 〈 50G/l listed in the Summary of Product Characteristics Pegasys (peginterferon alpha-2a) as the dose reduction and stop-treatment values were used as cut-off values. Data were analyzed using Wilcoxon test. During the first 12-th weeks of antiviral therapy a statistically significant decrease (p 〈 0.05) in HGB, WBC, ANC, lymphocyte count (ALC) and PLT was observed leading to the statistically significant increase in the frequency of anemia (HGB≤11.5 g/dl), leucopenia (WBC 〈 4 G/l), neutropenia (ANC 〈 1.5 G/l), lymphopenia (ALC 〈 1 G/l) and thrombocytopenia (PLT 〈 150 G/l) at week 12. The most common abnormality was leucopenia that occurred in 78.4% of women and 67.8% of men. In the majority of patients (about 94%) CBC declines were mild or moderate. Taking into account the dose reduction and stop-treatment values CBC declines exceeded at least one of them in 17.5% of patients. The most frequent decline was observed in ANC: 8% of patients had clinically significant ANC decrease. During the therapy the frequency and severity of CBC changes didn't change with the exception of lymphopenia that progressively increased from 29.1% to 50.4% in women and from 21.2% to 39.6% in men at 48-th week (Figure 1) . Figure 1. The incidence of CBC abnormalities during antiviral treatment in patients with c-HCVI. Figure 1. The incidence of CBC abnormalities during antiviral treatment in patients with c-HCVI. To determine, if pre-treatment CBC abnormalities affected the CBC results during therapy, we compared the patients with and without CBC pre-treatment declines. Patients with normal CBC before treatment had statistically significant decrease in the HGB concentration, WBC, ANC, ALC and PLT at the 24-th and 48-th week of the treatment. Among patients with pre-treatment CBC declines only patients with leucopenia and thrombocytopenia had a statistically significant decrease in WBC and PLT numbers at the 24-th and 48-th week of treatment. Clinically significant decrease in CBC during antiviral therapy was more frequent in patients who had reduced CBC before the therapy. The most frequent clinically significant decrease was observed in ANC at the 12-th and 24-th week of the treatment in respectively 43% and 41% of patients with neutropenia before the treatment. The clinically significant decrease in the HGB and PLT at the 12-th and 24-th week of the treatment was observed in respectively 33%, 29% and 8.6%, 7.5% of patients with anemia and thrombocytopenia before the treatment. We conclude that CBC declines in patients treated for c-HCVI occur frequently, but remain mild and moderate. The number of patients with clinically significant declines in CBC (mainly ANC) was very small. CBC falls occurred more often in patients with pre-treatment reduced CBC, however in most of the patients the CBC declines did not reach clinical significant CBC values. To conclude, reduced CBC before the treatment should not preclude antiviral treatment with interferon alpha +/- ribavirin though clinically significant declines occur more often in these patients. Disclosures No relevant conflicts of interest to declare.