Inwards, David J.

Abstract Abstract 4136 Background: The serum free light chain (FLC) assay quantitates free kappa and free lambda immunoglobulin light chains. This assay has prognostic value in MGUS, multiple myeloma (MM), solitary plasmacytoma, and amyloid light chain (AL) amyloidosis, and has been incorporated in response criteria for both MM and AL amyloidosis. We previously showed elevated FLC was associated with poor outcome in diffuse large B-cell lymphoma (DLBCL) patients from a phase II cooperative group clinical trial (Blood (ASH Annual Meeting Abstracts) 2009 November 20, 2009; 114(22): 136). Here we replicate those findings in a large clinic based epidemiology cohort, as well as examine FLC abnormalities in other lymphoma subtypes. Methods: Newly diagnosed lymphoma patients were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER). Serum FLC was quantitated from enrollment research serum draws within 9 months of diagnosis using the Freelite FLC assay (The Binding Site, Ltd., Birmingham, UK). Elevated FLC was defined as either kappa or lambda above the published reference range. Monoclonal elevated FLC was defined as elevated FLC with an abnormal FLC ratio; polyclonal elevated FLC was defined as elevated FLC with an FLC ratio in the normal reference range. Clinical data was abstracted using a standard protocol for the MER and patients were followed systematically for event-free (progression, retreatment, or death due to any cause) and overall survival (EFS and OS, respectively). Cox proportional hazards models were used to evaluate the unadjusted association between FLC and outcome. Results: 1118 lymphoma patients diagnosed between September 2002 and February 2008 with available serum were assayed. At a medium follow-up of 49 months (range 1–94), 484 patients (43%) had an event and 249 patients died (22%). Elevated FLC was present in 27% of lymphomas, with prevalence ranging from 13% in follicular lymphoma (FL) to 64% for mantle cell lymphoma (MCL) and 77% for lymphoplasmacytic lymphoma. Elevated FLC was present in 27% of DLBCL and associated with poor EFS (monoclonal hazard ratio (HR)=2.56, polyclonal HR=1.99, all p<0.001) and OS (monoclonal HR=3.22, polyclonal HR=2.91, all p<0.0001), replicating our previous findings. Elevated FLC was generally polyclonal (FLC ratio normal) across lymphoma subtypes, though monoclonal elevated FLC (FLC ratio abnormal) was common in MCL and the post-follicular lymphomas. Elevated FLC was associated with inferior EFS in all lymphomas combined (monoclonal HR=1.92, 95% CI:1.44-5.55, polyclonal HR=1.38, 95% CI:1.09-1.74); this association remained consistent in most subtypes (see table). In addition, elevated FLC was associated with poor EFS in MCL (monoclonal) and Hodgkin lymphoma (HL; polyclonal). Elevated FLC was also significantly associated with OS in HL (polyclonal HR=6.24, 95% CI 2.44–15.9), FL (polyclonal HR=5.85, 95% CI 2.62–13.0), post follicular lymphomas (polyclonal HR=4.16, 95% CI 1.17–14.8), as well as for all lymphomas combined (monoclonal HR=2.24, 95% CI 1.52–3.29, polyclonal HR=2.33, 95% CI 1.74–3.11). Conclusions: A significant percentage of lymphoma patients have elevated FLC. Our previous discovery of elevated FLC predicting poor outcome in DLBCL was confirmed in a large, independent dataset. Prevalence and type of elevated FLC (monoclonal vs. polyclonal) varies by lymphoma subtype. Elevated monoclonal and polyclonal FLC is associated with poor outcome broadly in lymphoma, as well as specifically for a number of lymphoma subtypes, supporting FLC as a potentially useful prognostic biomarker in many lymphoma subtypes. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is curable for the majority of patients treated with anthracycline based immunochemotherapy (IC). However, up to 40% of patients will relapse or require retreatment of DLBCL and outcomes are poor in this setting. Here we examine the incidence, treatment patterns and outcomes of relapsed DLBCL in the R-CHOP era. Methods: Patients were prospectively enrolled in the University of Iowa / Mayo Clinic SPORE Molecular Epidemiology Resource (MER) within 9 months of diagnosis and followed for relapse, retreatment, and death. Clinical management at diagnosis and subsequent therapies were per treating physician. This analysis includes patients with DLBCL or primary mediastinal B-cell lymphoma (PMBCL) who underwent front-line anthracycline based IC; patients with primary CNS lymphoma or PTLD were excluded. All relapse and re-treatments were verified by medical record review. Response to front-line therapy was retrospectively classified per 2007 Revised Response Criteria for Malignant Lymphoma from available clinical and radiology records. Unplanned consolidative radiation (RT) without biopsy proven disease after achieving PR from IC (N=21) was not classified as a relapse. Results: 1039 patients with newly diagnosed DLBCL or PMBCL and treated with IC were enrolled in the MER from 2002-2012. Median age at diagnosis was 62 years (range 18-92) and 577 patients (56%) were male. 647 patients (63%) had stage III/IV disease and IPI at diagnosis was 0-1 in 350 patients (34%), 2 in 305 patients (29%), 3 in 250 patients (24%) and 4-5 in 134 patients (13%). At a median follow-up of 59 months (range 1-148), 258 patients had relapse or retreatment of DLBCL of which 184 (71%) died. Incidence of relapse was 21.7% (95% CI: 19.3%-24.4%) at 2 years and 25.5% (95% CI: 22.9%-28.5%) at 5 years. In addition, the incidence of lymphoma related death without documented relapse or retreatment was 4.7% (95% CI: 3.6%-6.2%) at 2 years. At first relapse, 174 patients (67% of relapsed) received platinum based salvage therapy with 90 (52%) subsequently proceeding to autologous stem cell transplant (ASCT). 22 patients received CNS directed systemic therapy at relapse with 9 (41%) proceeding to transplant, and 43 received non-platinum-based salvage systemic therapy with 7 proceeding to transplant (17%), 15 patients received RT only as 2nd line therapy, and 4 were untreated. At a median follow-up of 56 months (range 6-121) post-transplant, 39 of 107 patients who underwent transplant remain in remission with a 2-year post-transplant progression-free survival of 45% (95% CI 37%-56%). Response to front-line IC was predictive of post-relapse outcome. Survival post-relapse was superior in the 162 patients with responsive disease (CR or PR) at the end of front-line IC (median OS 21.0 months) compared to the 88 patients who had stable or progressive disease (median OS 6.8 months, HR = 2.33, 95% CI: 1.73-3.14 p<0.0001). Transient response in midst of front-line IC was similar to no response. Patients achieving a CR or PR to front-line IC were more likely to proceed to ASCT at relapse (55%) compared to patients with either SD or PD at the end of front-line IC (25% and 17% respectively, p<0.0001). Other factors associated with poor survival at first relapse were relapse within 12 months of diagnosis (HR = 2.24, 95% CI: 1.57-3.18, p<0.0001), IPI at diagnosis of 3-5 (HR=1.51, 95% CI: 1.13-2.03, p=0.0058), and age > 60 (HR =1.51, 95% CI: 1.12-2.03, p=0.0064). There was no difference in survival at first relapse by cell of origin (HR = 1.13, 95% CI: 0.74-1.72, p=0.59). Conclusions: Most patients undergo therapy after relapsed/refractory DLBCL but only one-third receive ASCT. Outcomes following all treatments for relapsed/refractory DLBCL remain poor. Factors associated with adverse outcomes include refractory to front-line therapy, early relapse, baseline IPI and advanced age. These outcomes provide relevant historical control for the many novel agents being tested in this unmet need. Figure 1. Figure 1. Disclosures Farooq: Kite Pharma: Research Funding. Maurer:Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding.

Abstract Abstract 1926 Background: Follicular lymphoma (FL) is the second most common non Hodgkin lymphoma in the United States, comprising up to 30% of all non Hodgkin lymphomas. Typically an indolent disease, relapses are common. High dose therapy followed by autologous stem cell transplant is an option that has shown to produce prolonged progression-free and relapse-free survival in patients who relapse. Adequate bone marrow reserve for peripheral stem cell mobilization has been shown to be adversely effected by prior regimens such as fludarabine and radioimmunotherapy. Concerns regarding stem cell mobilization at the point of relapse have led some to collect stem cells early in the course of disease to allow for potential subsequent transplant after relapse. Recent advances in stem cell mobilization have resulted in a 3% collection failure rate for lymphoma patients at the point of planned transplant at our institution versus a historical rate of up to 30%. We studied the utilization of stem cells collected for potential future use in FL patients in remission or prior to therapy at the point of relapse or progression in order to determine the utility of this approach. Methods: Record review of patients diagnosed with FL through the Mayo Clinic Tumor Registry and the Mayo Clinic Lymphoma Data Base who had cryopreserved stem cells for potential future transplant at relapse. Cost of stem cell storage at our institution was reviewed as was the subsequent use of the collected cells. Results: 73 patients with FL had stem cells collected and stored. 37 (51%) were collected prior to a double dose yttrium-90 (90Y) ibritumomab tiuxetan trial for relapsed lymphoma as required by the study. The median age at collection of this group was 56 years (range 28–70). Stem cells remain in storage for a median of 44 months (range 8–119). The median cost of cryopreservation and storage is $4,094 based on the median storage time of 44 months (range $3,628 to 5,065) with a collection cost of $3,524.20 and an annual storage fee of $155.39. This does not include the cost of filgrastim for mobilization, nor line placement. At 5 years, 60% of the cells were not utilized, and at 10 years, 56% of the cells were not utilized. 36 (49%) of the total number of patients were not part of the double dose 90Y ibritumomab tiuxetan trial, but were collected in remission for possible future use or in the setting of relapsed, progressed or transformed disease for potential future transplant. Five of these patients required the use of plerixafor for adequate mobilization. The median age at collection of this group was 47 years (range 24–76). Stem cells remain in storage for a median of 39 months (range 2–128). The median cost of cryopreservation and storage is $4,029 based on the median storage time of 39 months (range $3,550 to 5,182) with a collection cost of $3,524.20 and an annual storage fee of $155.39. This does not include the cost of filgrastim or plerixafor for mobilization, nor line placement. At 5 years, 89% of these cells were not used, and at 10 years, 71% of cells were not used. Conclusion: The utilization of stem cells collected early in the course of FL patients is low, with the majority of cells not being utilized at 10 years. Given improved mobilization techniques resulting in 97% efficacy of stem cell collection at relapse, routine collection and storage of stem cells early in the course FL is not recommended. Disclosures: Micallef: Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Abstract 4168 Background: Primary Pulmonary MALT lymphoma represents 15–20% of Extranodal Marginal Zone Lymphomas of Mucosa Associated Lymphoid Tissue (MALT). In contrast to the more common gastric MALT lymphoma, natural history, prognosis and treatment outcomes for primary pulmonary MALT lymphoma are not well defined. Herein, we report a single institution experience. Methods: Consecutive patients with primary pulmonary MALT lymphoma registered in the Mayo Clinic Lymphoma Database, which includes all consenting patients with lymphoma seen at Mayo Clinic Rochester, were reviewed for clinical features, treatment outcome progression free survival (PFS) and overall survival (OS). The pathology for all patients was centrally reviewed by hematopathologist and the diagnoses were based on WHO lymphoma classification criteria. PFS and OS were assessed using the Kaplan–Meier method and the Cox proportional hazard model was used to assess the impact of variables on PFS and OS. Results: Between December 1986 and June of 2009, ninety-seven patients with primary pulmonary MALT lymphoma were enrolled. The median age at diagnosis was 63 years (range 31–87). There were 43 (44%) males. The initial presentation was a unilateral pulmonary lesion (n=47, 48%), bilateral pulmonary lesions (n=41, 42%), and pulmonary lesion with intrathoracic lymphadenopathy (n= 4, 4%). Bone marrow involvement and presence of B symptoms were 4, 4% and 5, 5%, respectively. International Prognostic Index (IPI) was 0–1, 2–3 and 4–5 in 69, 25 and 1 patient(s) respectively. The median follow-up was 10.4 years. The estimated median OS was 13. 6 years and the median PFS was 5.5 years (Figure). In a multivariate analysis, age >60 (p=0.02) and ECOG PS>2 (p=0.01) were associated with shortened survival. The IPI and age adjusted IPI were not predictive of overall survival. The treatment outcomes for the most common treatment modalities are summarized in the Table below. The median PFS of the 38% of patients who had a complete surgical resection was excellent at 11.2 years; whereas for observed patients with residual disease after biopsy was 3.2 years. Only 8 patients received single agent rituximan with relatively low response rate. Summary: The prognosis of primary pulmonary MALT lymphoma is favorable, with a median survival of over 13 years. In patients with resectable disease, surgery alone is associated with excellent disease control. Further prospective studies are needed to define the optimal treatment of primary pulmonary MALT lymphoma. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4127 Introduction: Mantle cell lymphoma (MCL) is an aggressive lymphoma. NF-κB has been shown to be constitutively activated in MCL cell lines and patient biopsy samples and may play a key role in the growth and survival of MCL cells. We previously reported in a pilot study of 39 MCL patients from the NCI-SEER Survival Study that host genetic variation in candidate TNF and NF-κB genes was associated with overall survival after accounting for clinical variables (Blood 2007;110(11):472a). Here, we attempt to replicate the top 8 genes (NFKB1, IRF4, TNFSF13B, TNFRSF25, NFKBIA, LTA/TNF, TRAF5, RELB) and associated single nucleotide polymorphisms (SNPs) in an independent sample of MCL patients. Methods: We genotyped 71 SNPs from 8 genes in a prospective cohort of newly diagnosed MCL patients with germline DNA enrolled at the Mayo Clinic and University of Iowa from 2002–2008 as part of the Molecular Epidemiology Resource of the Iowa/Mayo Lymphoma SPORE. All patients were systematically followed through 2009 for overall survival (OS) and event-free survival (EFS, defined as disease progression, retreatment or death due to any cause). Genotyping was performed on an Illumina Golden-Gate platform. Cox regression was used to estimate Hazard Ratios (HRs) and 95% confidence intervals (CI) for individual SNPs with OS and EFS. Each SNP was modeled with the most prevalent homozygous genotype used as the reference group. An ordinal test was used to assess the trend across genotype. A principal components methodology was used for gene-level analyses. All Cox models were adjusted for MIPI and treatment. We compared our results to the previously reported NCI-SEER study that included MCL patients diagnosed from 1998–2000. The NCI-SEER study had a median age at diagnosis of 64 years (range 38–74), 27 deaths (69%), and a median follow-up for living patients of 47 months (23-85 months). Replication was declared based on a p-trend<0.10 in the gene-level test or p-trend<0.10 in the SNP-level ordinal trend test and a HR of similar direction and magnitude to the NCI-SEER study result. Results: The median age at diagnosis of the 101 patients in the SPORE was 64 years (range 42–88), and by simplified MIPI score there were 38% low risk, 37% intermediate risk, and 26% high risk patients. The most common initial therapy was anthracycline-based chemotherapy ± rituximab (59%) with or without stem cell transplantation. Through 2009, there were 61 events (60%) and 31 (31%) deaths, with a median follow-up for living patients of 59 months (range 29–90). At the gene-level, none of the 8 genes replicated at p<0.10. However, at the SNP level, the genes with SNPs that replicated for OS included TRAF5 (rs3738199, rs6684874, rs12569232), TNFRSF25 (rs3138156), and RELB (rs10424046, rs1560725). The strongest TRAF5 SNP was rs3738199 which had a minor allele frequency (MAF) of 0.35. Compared to patients with the AA genotype, those with the AG (HR=2.14, 95% CI 0.91–5.01) or GG (HR=3.72, 95% CI 1.34–10.3) genotypes had inferior survival (p-trend=0.0092). The TNFRSF25 SNP rs3138156 had a MAF of 0.054; compared to patients with the AA genotype, those with the AG or GG genotype (HR=2.46, 95% CI 0.88–6.89) had inferior survival (p=0.087). Finally, the strongest RELB SNP was rs10424046, and had a MAF of 0.54. Compared to patients with the GG genotype, those with the GC (HR=0.57, 95% CI 0.25–1.28) or CC (HR=0.39, 95% CI 0.14–1.12) genotypes had superior survival (p-trend=0.065). Similar results for EFS were observed for the TRAF5 and RELB SNPs. Discussion: Germline genetic variation in the TNF and NF-κB pathway genes TRAF5, RELB, and TNFRSF25 were associated with prognosis in MCL after adjustment for clinical and treatment factors, and this result replicates findings from an independent dataset. TRAF5 is one of the components of a multiple protein complex which binds to TNF receptor cytoplasmic domains and mediates TNF-induced activation; RELB is part of the NF-κB complex; and TNF super family receptor member 25 stimulates NF-κB activity and regulates apoptosis through signal transduction that is mediated by various death domain containing adaptor proteins. In summary, genetic variation in TNF and NF-κB pathway genes may play a role in disease progression and overall survival in MCL, supporting further targeting of this pathway for therapy. Support: Lymphoma Research Foundation, P50 CA97274, R01 CA129539. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3088 Background: Despite the use of modern immunochemotherapy (R-CHOP) regimens, almost 50% of patients with diffuse large-B-cell lymphoma (DLBCL) will relapse. Current prognostic models, most notably the International Prognostic Index, are comprised of patient and tumor characteristics and are unable to identify patients with less than a 50% chance of long-term survival. However, recent observations demonstrate that factors related to host adaptive immunity and the tumor microenvironment are powerful prognostic variables in non-Hodgkin lymphoma Methods: We retrospectively examined the absolute neutrophil count (ANC), monocyte count (AMC) and lymphocyte count (ALC), obtained from an automated complete blood count with differential, as prognostic variables in a cohort of 255 consecutive DLBCL patients that were uniformly treated with R-CHOP between 2000 and 2007 at a single institution. The primary study objective was to assess if ANC, AMC, and ALC at diagnosis were predictors of overall survival (OS) in DLBCL. Results: At diagnosis, the median ANC was 4720/uL (range 1190–17690), the median AMC was 610/uL (range 30–4040), and the median ALC was 1220/uL (range 140–5410). The median follow-up for these patients was 48 months. In the univariate analysis, each of these variables predicted OS as continuous variables. As dichotomized variables, an elevated ANC (≥5500/μL; hazard ratio 1.75, 95% confidence interval 1.14–2.60, p=0.01) and AMC (≥610/μL; hazard ratio 3.36, 95% confidence interval 2.10–5.59, p<0.0001) were each associated with inferior OS. In contrast, the presence of lymphopenia, defined as an ALC ≤1000/uL, was associated with inferior OS (hazard ratio 2.21, 95% confidence interval 1.43–3.39, p=0.0004). When components of the IPI were included on multivariate analysis only the AMC and ALC were independently significant prognostic factors for OS, with hazard ratios of 3.37 (95% confidence interval 2.05–5.74, p<0.0001) and 2.19 (95% confidence interval 1.38–3.44, p=0.0009), respectively. The dichotomized AMC and ALC generated the AMC/ALC prognostic index (PI) and stratified patients into 3 risk groups: very good (AMC <610/uL and ALC >1000/uL), good (AMC ≥610/uL or ALC ≤1000/uL), and poor-risk (AMC ≥610/uL and ALC ≤1000/uL) populations. For both the very good (n=79) and good-risk (n=134) groups median OS has not been reached with estimated 5-year overall survival of 88% and 69%, respectively. Median OS for poor-risk (n=42) patients was 1.7 years (95% confidence interval 1.1–2.7 years) with an estimated 5-year overall survival of 28% (p<0.0001). By comparison, the R-IPI was unable to identify a group of patients with a median survival less than 8 years. The estimated 5-year OS was 93%, 71% and 53% for very good, good and poor-risk patients, respectively. We sought to determine whether the AMC/ALC PI may provide additional prognostic information when combined with the R-IPI. To test this possibility, the 171 very good/good risk and 84 poor risk patients identified by the R-IPI were subsequently risk stratified using the AMC/ALC PI. Among R-IPI very good/good risk patients a subset of poor risk patients (n=21) with a median OS of 2.2 years (95% confidence interval 1.1–6.6 years) and 35% 5-year OS could be identified with the AMC/ALC PI. In contrast, 5-year OS ranged from 75%-88% among very good and good risk patients. Similarly, stratification of R-IPI poor risk patients by the AMC/ALC PI identified subsets of very good (n=19) and good risk (n=44) patients with median OS that had not been reached and 86% and 55% 5-year OS, respectively. High risk (n=21) patients had a median OS of 1.4 years (95% confidence interval 0.9–2.2 years) and an estimated 5-year OS of less than 25%. Conclusions: Measurement of AMC and ALC at diagnosis is widely applicable, cost effective, predicts OS, and identifies high-risk patients with DLBCL. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2802 Background: Redundancy of pro-survival signaling pathways promotes survival and drug resistance in lymphoid and plasma cell malignancies. In particular, the PI3K-Akt and the MEK-ERK pathways have been shown to play an important role in the proliferation and survival of these malignant cells induced by various cytokines in the tumor microenvironment. Sorafenib, a Raf kinase and VEGF receptor inhibitor, and everolimus, an mTOR inhibitor, have synergistic cytotoxicity in myeloma and lymphoma cells due to inhibition of multiple signaling pathways. Methods: We designed a Phase 1/2 clinical trial to identify the maximum tolerated doses of the two drugs used in combination and the efficacy of the combination. Patients (Pts) with relapsed myeloma or lymphoma were eligible for enrollment. Pts were required to have an absolute neutrophil count ≥1500 × 10(6)/L, a platelet count ≥75,000, and a serum creatinine 21.5 mg/dL. The study utilized the classic 3+3 design. Extensive pharmacokinetic studies were performed to better delineate potential drug interactions. Results: Twenty-six pts were accrued from August 2007 to February 2009. Four pts discontinued sorafenib during cycle 1 for various reasons (2 patient refusal, 1 unrelated medical condition and 1 physician discretion) and were excluded from MTD determination. An additional pt did not have measurable disease and was ineligible, leaving 19 pts with lymphoma (including 6 with Hodgkin lymphoma) and 2 with myeloma for phase I analysis. The pts had a median age of 56 years (range, 22, 69) and were heavily pretreated with a median of 4 prior therapies (range, 1–10). Eighteen (86%) had received a prior stem cell transplant. Four dose limiting toxicities were seen across all dose levels (Table). These included grade 3 vomiting (level 1), grade 4 thrombocytopenia (level 2 and 3, one each) and grade 2 hand and foot rash leading to treatment delay (level 3). Overall, 13 pts experienced a grade 3 or 4 hematologic toxicity. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 19%, 43%, and 38% of pts, respectively. Four pts have experienced a grade 3 non-hematologic toxicity; no grade 4 non-hematologic toxicities were seen. Grade 3 non-hematologic toxicities included hypokalemia, weight loss, vomiting, hand-foot skin reaction, fatigue, and elevated alkaline phosphatase. Dose level 1 (sorafenib 200 mg and everolimus 5 mg daily) was best tolerated and was selected for phase 2 evaluation. The ORR was 33% (7/21;95% CI: 15–57%, Table) with 3 pts at dose level 0 (2 PR, 1 CR), one at level 2 (1 PR) and three at level 3 (2 PR, 1 CR) responding. The responders included 5 pts with Hodgkin's disease and one each with an NK cell and T-cell lymphoma. Pts have received a median of 6 cycles (range: 1–19) of treatment. 16 pts have discontinued treatment due to disease progression (13 pts), non-resolution of cytopenias (1 pt), physician discretion (1 pt), and death on study due to lymphoma (1 pt). Disease progression has been seen in 16 pts; 9 pts have died. Median follow-up for pts still alive is 18.7 months (range: 11.5–29.4). 6 pts died from disease progression, one each due to sepsis unlikely related to treatment, cholecystitis, and unknown causes. Sorafenib is metabolized by the cytochrome P450 CYP3A enzyme and RAD-001 mainly by the CYP3A4 system in the liver, hence there is a potential for interactions. The detailed PK analyses performed as part of this trial showed a decrease in the RAD001 levels following initiation of sorafenib on day 8 of cycle 1 (Figure). Conclusion: The combination of sorafenib and everolimus is safe at a recommended phase 2 dose of sorafenib 200 mg and everolimus 5 mg daily. There is no significant drug interaction seen. Activity has been observed, especially in the setting of Hodgkins Disease. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Witzig:Novartis and Celgene: Patents & Royalties, Research Funding, Served on advisory boards with Novartis and Celgene – both uncompensated with compensation to Mayo Clinic.

Abstract Abstract 3557 Introduction: Autologous stem cell transplantation for patients with amyloidosis results in high reported hematologic and organ response rates compared with conventional chemotherapy. Patients: Four-hundred and thirty-four patients have undergone transplantation between March 8, 1996, and April 13, 2010 Table 1. Clinical parameters seen in patients with amyloid are given in Table 2. The overall day-100 mortality seen in this group of patients is 44 of 434 patients (10%). Results: The most important determinant of outcome is stage defined by BNP and troponin levels. Figure 1 demonstrates the survival for patients for all 3 cardiac stages. Troponin <.035; NT-proBNP <332. Stage 1 both low, Stage 3 both elevated. The survival of all patients based on whether they achieved a complete response, a partial response (>50%), or no response was analyzed. Median survival has not been reached for the complete response group, is 107 months for the partial response group, and is 32 months for the no response group (p<0.0001). Figure 2, divides the patients at the median dFLC level of 13.5 mg/dL demonstrating that for patients with a higher level of free light chain, the median survival is 87.6 months and has not been reached for those with a lower level of free light chain. A proportional hazards model for variables that impact on survival was done in all patients, and the only relevant predictor of outcome was stage (p<0.0001). When the same analysis was performed using a landmark of 6 months, the only predictor of outcome was stage (p=0.0005). When best response was incorporated into the landmark model, it was the strongest predictor of survival. The amyloid stage predicted survival (p= 0.0005), and the best response to therapy (p <0.0001). When the same analysis was performed in the entire group of 434, stage and best response each remained significant (p<0.0001). Discussion: There is a high response rate associated with high-dose therapy that was not observed in the melphalan and prednisone era. For eligible patients who can be transplanted safely, high-dose melphalan is an effective therapy for many patients with amyloidosis. Best response and stage at diagnosis are the best predictors of overall survival. Disclosures: Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Abstract Abstract 2634 The peripheral blood absolute lymphocyte/monocyte ratio (ALC/AMC) at diagnosis has been recently reported [Porrata et al, Hematologica 2012; 97(2):262-9] and confirmed [Koh et al, Oncologist 2012; 17(6):871-80] to be a predictor of clinical outcomes in classical Hodgkin lymphoma (HL). In addition, an inversed correlation has been reported between the ALC/AMC ratio and tumor associated macrophages in classical HL suggesting an association between the host biological response in the macro-environment and micro-environment. However, a limitation of the ALC/AMC ratio at diagnosis, the International Prognostic Score at diagnosis, the Positron-Emission Tomography (PET-scan) at diagnosis, or interim PET-scan during treatment is their inability to sequentially assess the host/tumor interaction during treatment. Therefore, we studied the ALC/AMC ratio recovery, as a surrogate marker of host immunity (i.e., ALC) and tumor micro-environment (i.e., AMC), at each treatment cycle phase to assess its predictive ability for clinical outcomes in classical HL. To participate in the study, patients were required to be diagnosed, treated, and followed at Mayo Clinic, Rochester, Minnesota and treated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) with or without radiation therapy. An ALC/AMC ratio ≥ 1.1 cut-off was used in the study based on our previous publication [Porrata et al, Hematologica 2012; 97(2):262-9]. From 1990 until 2008, 190 classical HL patients qualified for the study. The cohort was evenly split with 50% males and 50% females. Fifty-eight percent of the patients had an interim PET-scan performed. The median age at diagnosis was 36 years (range: 18–83 years). Seventeen patients received 2 cycles; 5 patients 3 cycles; 51 patients 4 cycles; 5 patients 5 cycles and 112 patients 6 cycles. The median follow-up was 3.7 years (range: 0.2–20 years). The ALC/AMC ratio ≥ 1.1 at each treatment cycle phase of ABVD was a predictor for overall survival (OS), lymphoma-specific survival (LSS), progression-free survival (PFS) and time to progression (TTP). Patients were stratified based on how many cycles the ALC/AMC ratio did not reach the cut-off of 1.1. The more cycles with an ALC/AMC < 1.1 the worse survival was observed. The 23 patients who did not achieve an ALC/AMC ≥ 1.1 during the treatment cycles phase experienced the worst survival rates: 5 year OS of 33%; 5 year LSS of 43%; 5 year PFS of 16%; and 5 year TTP of 27%. Patients were then dichotomized into patients that did not achieve an ALC/AMC ratio ≥ 1.1 for all the cycles versus patients with an ALC/AMC ratio ≥ 1.1 in any cycle during treatment. Patients with an ALC/AMC ratio ≥ 1.1 in any cycle (N=167) experienced better survival compared with patients that in all cycles the ALC/AMC ratio was < 1.1 [ OS, the hazard ratio(HR) was 0.09, 95% CI (0.04–0.19), p < 0.0001; for LSS, HR =0.07, 95% CI (0.02–0.17), p <0.0001; for PFS, HR = 0.08, 95%CI (0.04–0.14), p < 0.0001; and for TTP, HR = 0.05, 95% CI (0.02–0.11), p < 0.0001]. In the multivariate analysis, an ALC/AMC ratio ≥ 1.1 in any cycle versus none was an independent predictor for clinical outcome when compared to ALC/AMC ratio at diagnsosis, PET-scan, International Prognostic Score, limited verus advanced stage, and radiation therapy [OS, HR = 0.14, 95% CI (0.04–0.40), p< 0.0002; for LSS, HR = 0.09, 95% CI (0.01–0.37), p <0.0006); for PFS, HR = 0.19, 95% CI (0.05–0.82), p < 0.03); and for TTP, HR = 0.15, 95% CI (0.02–0.89), p < 0.02]. In conclusion, the ALC/AMC ratio during ABVD treatment cycles in classical HL is a predictor for survival and provides an opportunity to develop therapeutic modalities to manipulate the ALC/AMC ratio during ABVD chemotherapy to improve clinical outcomes in classical HL. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 287 Purpose: Farnesyltransferases are key cellular enzymes involved in the prenylation of proteins. Prenylated proteins are important for malignant cell growth. The purpose of this phase II study (NCT00082888) was to assess tumor response and toxicity associated with the oral farnesyltransferase inhibitor tipifarnib (R115777, Johnson and Johnson) in patients with relapsed aggressive, indolent, or uncommon lymphoma. The uncommon group included low incidence lymphoma types such as Hodgkin lymphoma (HL) and T-cell non-Hodgkin lymphoma- cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). Patients and Methods: Patients with relapsed or refractory non-Hodgkin (NHL) or Hodgkin (HL) were eligible if they had measurable disease, performance status ≤2, platelet count ≥75,000 × 10(6)/L, an absolute neutrophil count ≥1000 × 10(6)/L and a creatinine ≤2 × upper limit of normal. Patients initially received tipifarnib 300 mg twice daily, days 1–21 every 28 days. The trial was conducted by the University of Iowa/Mayo Clinic Lymphoma SPORE. Results: Ninety-three patients with lymphoma (42 aggressive, 15 indolent, and 36 uncommon) enrolled in the trial between March 2004 and November 2008. The median age was 62 years (range, 18–91). The median number of prior therapies was 5 (range, 1–17). The overall response rate (ORR) was 20% (19/93) with 6% (6/93) complete responses (CR) and 14% (13/93) partial responses (PR). The ORR was 17%, 7%, and 31% for the aggressive, indolent, and uncommon groups, respectively (Table). Among the 19 responders were 7 diffuse large B-cell lymphoma (DLBCL), 7 T-cell NHL, 1 follicular grade II, and 4 HL. The overall median response duration for the 19 responders was 7.5 months (mean, 12.8; range, 1.8 – 48.1 months). The median response duration was 11.3 months (mean, 10.1; range, 1.8 – 18.5 months), 2 months, and 7.5 months (mean, 15.5; range, 1.9 – 48.1 months) for the aggressive (7), indolent (1), and uncommon (11) groups, respectively. Five patients in the uncommon group are still receiving treatment with a range of treatment duration between 25 – 60+ months. Among the 5 still receiving treatment 4 responded and 1 is stable. The range of response duration is 15.4, 17.7, 43.1, and 48.1 months. These five patients (2 with HL, 1 anaplastic large cell cutaneous, and 2 PTCL) are currently receiving doses of 400 (1), 200 (2), and 100 (2) mg twice daily. The median time to progression for all patients was 3.6 months (95% CI: 2.1 – 4.5 months). The grade 3,4 toxicities observed were primarily fatigue (10%) and reversible myelosuppression with 11% anemia, 37% neutropenia, and 32% thrombocytopenia. Correlative studies demonstrated tipifarnib-induced upregulation of Bim, a marker of tipifarnib action in lymphoma cell lines, in 7 of 9 paired lymphoma biopsies. Conclusions: Tipifarnib has activity in lymphoma, with responses in patients with heavily pretreated DLBCL, HL and T-cell types, but little activity in follicular NHL. This agent has an excellent toxicity profile and targets a novel pathway. Further studies in combination with other agents are warranted for patients with DLBCL, HL or T-cell NHL. Disclosures: No relevant conflicts of interest to declare.