Nebraska Lymphoma Study Group Research Articles

Thirty-Five Year Follow-up Analysis of Follicular Lymphoma Patients Treated through the Nebraska Lymphoma Study Group: Prognostic Factor Analysis and Outcomes

Thirty-Five Year Follow-up Analysis of Follicular Lymphoma Patients Treated through the Nebraska Lymphoma Study Group: Prognostic Factor Analysis and Outcomes

Tolerability and Efficacy of Treatments in Elderly Patients with Hodgkin Lymphoma: A Report from the Nebraska Lymphoma Study Group

Introduction: Approximately 20% of classical Hodgkin lymphoma (HL) patients are greater than 60 years old at diagnosis. The survival of this subgroup is inferior to that of younger patients, despite most being treated with curative intent. Possible reasons for this difference include: comorbidities, toxicity of treatment (especially bleomycin, Stamatoullas at al. BJH 2015), poorer baseline performance status, different disease biology, and more frequent chemotherapy dose reductions. Recent advances and refinements in treatment have not improved the outcomes of elderly patients with HL significantly (Johnson and McKenzie. Blood 2014). Selection of a regimen for HL should take comorbidities into account. There is not a clear standard of care treatment regimen for elderly patients with HL.Methods: Patients were treated by physicians of the Nebraska Lymphoma Study Group between 6/1983 and 6/2014. There were 119 patients with biopsy-proven HL who were 60 years of age or older at the time of diagnosis. The Kaplan-Meier method was used to estimate overall survival distributions and the log-rank test was used to compare survival distributions between groups. Comparisons of survival distributions were made using the log-rank test. Chi-square tests and t-tests were used to compare outcomes by treatments received. P-values less than 0.05 were considered to be statistically significant.Results: The mean age was 71 years (range 60.1 to 89.2). Mixed cellularity was the most common histological subtype (28.57%). Therapies given included: non-anthracycline based regimen ChlVPP in 36 patients (30.25%) and radiotherapy alone in 13 patients (10.92%); and anthracycline containing regimens ChlVPP-ABV in 35 patients (29.41%), Stanford V in 9 patients (7.56%) and ABVD in 26 (21.85%). Patients older than 70 did significantly worse OS p<0.001 (Figure 1). OS was not different with regards to stage at diagnosis I/II vs III/IV (p=0.3). Patients receiving an anthracycline containing regimen had a better OS than those receiving ChlVPP alone p<0.001 (Figure 2). In both, early stage (I-II) and late stage (III-IV) HL the best outcomes were seen either ABVD or ChlVPP-ABV. OS was inferior in patients who did not receive bleomycin or in those for whom it was stopped, as opposed to patients receiving full bleomycin planed doses p=0.029. Bleomycin was omitted in 6/70 patients, generally as a result of preexisting pulmonary comorbidities. Bleomycin was stopped/held during treatment in 18 patients (28.1%) because of concerns of toxicity. There were no deaths with a diagnosis of bleomycin lung injury in our series.Conclusions: HL patients performed worse with increasing age and patients above 70 years of age had a median survival of 4.6 years. Anthracyclines seem to be essential for optimal outcome, confirming a previous publication by our group (Weekes at al. JCO 2002). Either ABVD or ChlVPP-ABV appear to be equally effective in patients who can tolerate an anthracycline. Our results appear to compare favorably to other regimens tested in elderly HL patients: VEPEM-B tested in the UK (Proctor et al. Blood 2012) and the PVAG tested by the German group (Boll et al. Blood 2011). Although bleomycin is difficult to give to this population because of increased toxicity, patients who did not receive bleomycin or had it stopped during treatment had a poorer survival. Our results confirms the results of a recent publication from the German Group in which bleomycin omission in early-stage HL patients performed worse (Behringer at al. Lancet 2015). Certainly bleomycin is associated with pulmonary toxicity in this age group, although our incidence was not as high as reported in the North American Intergroup Trial (43%) with bleomycin administration for HL patients (Evens, Br J Haematol 2013). Though limited by the possible occurrence of selection bias conferred by the retrospective design, anthracycline-based regimens appear to be associated with better outcomes in elderly patients with HL. [Display omitted] [Display omitted] DisclosuresLunning:TG Therapeutics: Consultancy; Genentech: Consultancy; Gilead: Consultancy; Juno: Consultancy; BMS: Consultancy; Spectrum: Consultancy.

Clinicopathologic features, management and outcomes of blastoid variant of mantle cell lymphoma: a Nebraska Lymphoma Study Group Experience

The objective of this retrospective study (N = 169) was to compare the overall survival (OS) of different subtypes of mantle cell lymphoma (MCL) treated by the Nebraska Lymphoma Study Group between 1984 and 2012. The overall response rate to various therapies including stem cell transplant (SCT) was similar (p = 0.44) between blastoid, diffuse and nodular subtypes. At 5 years, blastoid and diffuse subtypes had worse OS (overall p = 0.005) compared to nodular subtype. In multivariate analysis, the blastoid and diffuse subtypes had similar risk of death (p = 0.14) whereas the nodular subtype had a lower risk compared to blastoid (HR 0.48, 95% CI 0.27–0.87, p = 0.01). The use of SCT was associated with lower risk of death. In univariate analysis, blastoid subtype had better OS with intensive upfront therapy. In conclusion, the OS of blastoid subtype is worse than nodular MCL but may improve with the use of SCT and probably intensive induction therapy.

Trend Analysis of Clinical Outcomes in Hodgkin Lymphoma over the Last Three Decades: Report from the Nebraska Lymphoma Study Group

BACKGROUND: With improvements in the treatment of Hodgkin lymphoma (HL) over time, we hypothesized a reduction in disease progression, and an increase in progression-free (PFS) and overall survival (OS) over the past 3 decades. METHODS: This is a retrospective study that included previously untreated HL patients reported to the Nebraska Lymphoma Study Group between 1983 and 2012. To analyze trends in outcomes, we divided the cohort into 3 time periods of 10 years each (1983-1992, 1993-2002, 2003-2012) to represent early (E), middle (M) and late (L) time periods. Patient, disease, and treatment-related factors as well as clinical outcomes (cumulative incidence of progression, PFS and OS) were compared according to time period. Multivariate analyses (MVA) were performed using Cox regression to adjust for significant covariates. RESULTS: In this retrospective review, 528 patients were identified during the study period: E (n=120), M (n=208), L (n=200). Patients in the more recent cohort (L) were more likely to be younger (p=0.008), have better performance score (p&lt;0.001), have more sites of nodal involvement (p=0.05) and were more likely to receive ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or Stanford V (mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone) as initial therapy (p&lt;0.0001). In univariate analysis, there was a decrease in the 5-year cumulative incidence rate of disease progression over time (E=27% vs M=22% vs L=21%), and an increase in the 5-year probability of PFS (E=58% vs M=66% vs L=74%, p=0.004) and 5-year OS (E=67% vs M=80% vs L=85%, p=0.001). In MVA, improvement in the cumulative incidence of disease progression, PFS and OS over time was mainly driven by prognostic patient-related (age, sex) and treatment-related factors (type of chemotherapy regimen). Independent predictors of shorter PFS included age ≥45 y and male gender (Hazard Ratio [HR] 2.00 [95% CI 1.52-2.62, p&lt;0.001] and 1.43 [1.09-1.87, p&lt;0.01], respectively), while patients who received ABVD and Stanford V regimens as initial therapy experienced improved PFS (HR 0.39 [0.23-0.65, p&lt;0.001] and 0.42 [0.28-0.64, p&lt;0.001], respectively versus MOPP-like regimens). For OS, patients who were ≥45 y and males were more at risk of death (HR 4.34 [3.08-6.08, p&lt;0.001] and 1.73 [1.26-2.37, p&lt;0.001], respectively) while patients who received ABVD and Stanford V regimens as initial therapy were less likely to die (HR 0.36 [0.19-0.69, p &lt;0.01] and 0.39 [0.23-0.65, p&lt;0.001], respectively compared to MOPP-like regimens). Similarly, in MVA, a decrease in risk of progression was noted for patients who received ABVD and Stanford V regimens (HR 0.36 [0.19-0.69, p&lt;0.01] and 0.39 [0.23-0.65, p&lt;0.001], respectively) compared to MOPP-like regimens, while increased for patients who were ≥45 y and male (HR 4.33 [3.08-6.08, p&lt;0.001] and 1.73 [1.26-3.37, p&lt;0.001], respectively). CONCLUSIONS: Changes in upfront treatment regimens for HL over the last 3 decades have resulted in significant improvement in PFS and OS, and modest improvement in the risk for progression. Disclosures No relevant conflicts of interest to declare.

Clinicopathologic Features, Management and Outcomes of Blastoid Variant (BV) of Mantle Cell Lymphoma (MCL): A Nebraska Lymphoma Study Group (NLSG) Experience

Background: Prior studies have demonstrated unique clinicopathologic features of the BV of MCL including an inferior response to chemotherapy and poor long-term outcomes as compared to other MCL variants in the pre-rituximab era. A paucity of data precludes whether the use of rituximab or intensified therapy can overcome the inferior outcome associated with the BV.Methods MCL patients (n=169) treated by NLSG between 1983 and 2010 were included. Morphologic variants were classified based on published WHO criteria. We compared disease characteristics, therapy and outcomes according to MCL subtypes using the Kruskal Wallis or Chi-square tests. Univariate probabilities of progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. Multivariate analyses were performed using Cox proportional hazards regression to evaluate differences in outcomes of MCL subtypes while adjusting for prognostic covariates.Results The study population included 19% BV, 37% diffuse and 44% nodular subtypes. BV, diffuse and nodular subtypes differed in the median age (61 vs. 68 vs. 59, p=.002) and stage III/IV disease (81% vs. 79% vs. 93%, p=.05) at diagnosis, but did not differ in the distribution of sex, Karnofsky performance status (KPS), MCL international prognostic index (MIPI), lactate dehydrogenase (LDH) level, B-symptoms, or extranodal involvement. Patients received the following therapies: intensified therapy such as Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (Hyper-CVAD) +/- Rituximab (R) (30%), Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-R-like (24%), CHOP-like (35%) or others (11%). Approximately one-third received autologous (25%) or allogeneic (8%) SCT. There was a significant difference in the type of chemotherapy given in each group (p=.002) but not in the use of radiation therapy or proportion in each group receiving autologous/allogeneic stem cell transplant (SCT). Median follow-up across MCL subtypes was similar. Overall response rate was similar for BV, diffuse and nodular subtypes (68% vs. 65% vs. 80%, p=.44). The 5-year progression-free survival for BV vs. diffuse vs. nodular was 16% vs. 22% vs. 31%; p=.06, (Figure 1) and 5-year OS was 24% vs. 32% vs. 56% respectively; p=.005, (Figure 2). In multivariate analysis, compared to BV, diffuse subtype had similar risk of disease progression or death (hazard ratio, HR of 0.78, 95% confidence interval (CI) of 0.48-1.26) whereas nodular subtype had lower risk (HR 0.62, 95% CI 0.39-0.99). Additionally, low or intermediate MIPI, good KPS, absence of B-symptoms and undergoing SCT were associated with lower risk of progression or death. A subset univariate analysis of BV demonstrated no survivors beyond 5 years after conventional chemotherapy, whereas 33% remained alive at 10 years after intensified therapy.Conclusions BV and nodular MCL presented at a somewhat younger median age compared to diffuse MCL, and BV and diffuse MCL was more likely to present as stage I/II disease, compared to nodular MCL. The PFS and OS of BV MCL are similar to diffuse MCL but OS is worse than nodular MCL. The use of SCT may improve survival in MCL including BV variant. [Display omitted] [Display omitted] DisclosuresArmitage:Ziopharm Oncology: Consultancy; GlaxoSmithKline: Consultancy; Spectrum Pharmaceuticals: Consultancy; Roche: Consultancy; Tesaro bio Inc: Membership on an entity’s Board of Directors or advisory committees.

Impact of Conditioning Regimen on Outcome of 2-Year Disease-Free Survivors of Autologous Stem Cell Transplantation for Hodgkin Lymphoma

Autologous stem cell transplantation is the standard of care for patients with relapsed HL and the long-term outcomes for survivors 2 years after ASCT have not been well described. No prospective trials have compared the effect of different conditioning regimens on outcomes. We searched the Nebraska Lymphoma Study Group database to identify patients with HL who received ASCT from 1984 to 2007. Patients were conditioned with either CBV (cyclophosphamide, carmustine, and etoposide) or BEAM (carmustine, etoposide, cytarabine, and melphalan). At a median follow-up of 8 (range, 2-26) years, 225 patients were alive and disease-free 2 years after ASCT. Analysis was limited to these patients. At 5 years, the progression-free survival (PFS) was 92% for BEAM and 73% for CBV (P= .002) and the overall survival (OS) was 95% for BEAM and 87% for CBV (P= .07). At 10 years, the PFS was 79% for BEAM and 59% for CBV (P= .01) and the OS was 84% for BEAM and 66% for CBV (P= .02). Patients with HL who are disease-free and alive 2 years after ASCT have favorable outcomes. We observed lower risk of progression and longer survival associated with use of BEAM vs. CBV. Patients in the BEAM group received a transplant in more recent years so we cannot exclude the possibility that the superior outcomes seen in the BEAM group are because of better supportive care, use of peripheral blood stem cell grafts, or improvements in salvage therapies before transplantation.

B‐cell lymphoma, unclassifiable, with features intermediate between diffuse large B‐cell lymphoma and burkitt lymphoma: study of 39 cases

B-cell lymphoma, unclassifiable (B-UCL), with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, is a poorly characterized entity. Therefore, we investigated cases of B-UCL treated by the Nebraska Lymphoma Study Group (NLSG). We searched the NLSG registry for years 1985-2010 for cases of B-UCL. Immunohistochemical stains and fluorescence in situ hybridization studies for MYC, BCL2 and BCL6 gene rearrangements were performed. Among the 39 cases studied, 54% were male and 46% were female, with a median age of 69years. The majority of patients presented with advanced-stage disease (62%) and had high (3-5) International Prognostic Index (IPI) scores (54%). The median overall survival (OS) was only 9months and the 5-year OS was 30%. Patients with low IPI scores (0-2) had a better survival than those with high scores (3-5). The cases were genetically heterogeneous and included 11 'double-hit' lymphomas with rearrangements of both MYC and BCL2 or BCL6. None of the immunohistochemical or genetic features was predictive of survival. This B-cell lymphoma is a morphologically-recognizable entity with a spectrum of genetic abnormalities. New and better treatments are needed for this aggressive lymphoma.

Outcome of Adolescent & Young Adult (AYA) Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

AbstractAbstract 1568 IntroductionNon-Hodgkin lymphoma (NHL) represents 60% of lymphoma diagnoses in children, and NHL subtypes change considerably from childhood to adulthood.[1] Recent studies have implicated age-associated biological differences in certain NHL subtypes.[2] AYAs with cancer fall between pediatric and adult patients clinically and potentially biologically. Although environmental stressors and the psychosocial transition of adolescence likely impacts these outcomes, age-related biological differences need to be better understood.The majority of pediatric NHLs are high-grade tumors, whereas low- and intermediate-grade tumors are more common among adults.[1] Recent studies have found that young adults with NHL have poorer survival compared to children.[2] Although the incidence of AYA lymphoma has increased over the past 20 years, survival has not significantly improved, demanding a better understanding of the epidemiology and biology of lymphoma among this patient population.[3] MethodsCases were identified using the Nebraska Lymphoma Study Group database and chart review. All patients with DLBCL from 1983–2010 were identified (n = 1328), and 36 (2.7%) cases are included in this study of AYA DLBCL (age 13–30 years). The Kaplan-Meier method was used to estimate overall survival (OS) and event-free survival (EFS) distributions, and the log-rank test was used to compare survival distributions between groups. OS is defined as the time from the beginning of therapy to death or last follow-up. EFS is defined as the time from the beginning of therapy to progression, death, or last follow-up. P-values less than 0.05 are considered to be statistically significant. SAS software V 9.2 (SAS Institute Inc., Cary, NC) was used for all data analysis. The study was approved by the Institutional Review Board. ResultsThe median age of the 36 AYA DLBCL patients was 24.2 years (range, 14.5–29.8) with a female to male ratio of 1.8:1, and 53% were primary mediastinal B-cell lymphoma. Patient characteristics are shown in table 1. Of the 36 patients, 18 have died and 18 are alive at last follow-up. Fifteen deaths were due to lymphoma, 1 treatment related, 1 unrelated to disease, and 1 of unknown cause. The 5-year EFS is 52% (95% CI 34–67%, figure 1) and OS is 58% (95% CI 49–72%). The median follow-up of patients alive at last follow-up is 8.8 years (range, 1.8 – 29). OS was not affected by gender (p=0.32), stage (p=0.43), LDH (p=0.11), B symptoms (p=0.98), or size of the largest mass at diagnosis (0.93). Nearly all patients (97%) were treated on adult chemotherapy protocols. DiscussionThis study presents data on 36 AYA patients with DLBCL. The 5-year EFS was 52% and OS was 58%. Pediatric patients report a 5-year EFS of 87–96% [2, 4] compared to adults which have a 5-year EFS of 44–80%.[4] In contrast to other reports, in this study, gender, elevated LDH, and advanced stage (III-IV) did not impact EFS or OS, although the comparisons may be under-powered due to the small sample size. Although pediatric patients have better outcomes compared to adults, AYA patients have worse EFS than both pediatric and adult DLBCL patients, demanding further understanding of the biology of AYA DLBCL and improved treatment strategies.Table 1Patient characteristicsAll patients N=36Age (years)Median (range)24.2 (14.5–29.8)GenderMale23 (64%)Female13 (36%)Karnofsky score> 7032 (89%)<=704 (11%)StageI/II16 (44%)III/IV20 (56%)Lactate dehydrogenaseNormal8 (27%)Elevated22 (73%)Missing6# extranodal sites< 224 (67%)>= 212 (33%)International Prognostic IndexLow (0–2)24 (71%)High (3–5)10 (29%)Missing2B symptomsNo20 (56%)Yes16 (44%)Size of largest mass at diagnosis< 5 cm2 (6%)5–9.9 cm11 (35%)>= 10 cm18 (58%)Missing5ChemotherapyCAPBOP11 (31%)CNOP/CHOP11 (31%)R-CNOPR13 (36%)CCG 59611 (3%)RadiotherapyNo26 (72%)Yes10 (28%) Disclosures:No relevant conflicts of interest to declare.

Guidelines for the investigation and management of mantle cell lymphoma.

The guideline group was selected to be representative of UK-based medical experts and patients representatives. Ovid MEDLINE, EMBASE and NCBI Pubmed were searched systematically for publications in English from 1980 to 2011 using the MeSH subheading 'lymphoma, mantle cell' and 'lymphoma, mantle cell' as a keyword, as well as all subheadings. In addition, all references to mantle cell lymphoma in the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissue (Swerdlow et al, 2008) and the British Committee for Standards in Haematology (BCSH) Guideline: Best Practice in Lymphoma Diagnosis and Reporting (Parker et al, 2010) have been included. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato-oncology Task Force of the BCSH. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found in Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of patients with mantle cell lymphoma. The guidance may not be appropriate to patients with other lymphoma sub-types and in all cases individual patient circumstances may dictate an alternative approach.

The utility of serum lactate dehydrogenase (LDH) in the follow-up of patients with diffuse large B-cell lymphoma (DLBCL).

8047 Background: The prognostic significance of high serum LDH is well established for both indolent and aggressive lymphomas at diagnosis. The performance characteristics of LDH in predicting relapse after treatment in patients (pts) with DLBCL has not been well studied. The determination of utility of LDH monitoring in pts with DLBCL would have widespread practice implications. Methods: We searched the Nebraska Lymphoma Study Group database to identify pts with DLBCL who were treated with a rituximab-based regimen, from 2000 to 2010, and sustained a complete response (CR). For the pts who relapsed (RP), after sustaining a CR, we collected the LDH level at relapse and the LDH level 3 months prior (considered baseline). For pts who never relapsed (NR), we collected the last 2 LDH levels at follow-up; levels had to be at least 3 months apart. The relative increase of LDH was compared, to baseline, among RP vs. NR. Results: We identified 129 pts, 15 pts were excluded from the analysis as their LDH results were not available, 27 relapsed and 87 didn’t. Median age of pts was 57 years. Only 9/27 RP (33%) had increase in LDH above upper limit of normal (ULN) at relapse. The mean increase in LDH at relapse was 1.2 fold above the ULN for RP vs. 0.83 for NR (p=0.59). The mean increase in LDH, from baseline, was 1.1 fold in NR vs. 1.3 in RP (p=0.3). The likelihood ratio (LR) of relapse was 4.65 for pts who had 1.5 fold increase in LDH above baseline (1.5xLDH) vs. those who didn’t (p=0.03). The sensitivity, specificity, positive and negative predictive values of 1.5xLDH for detecting relapse, compared to clinical and imaging findings were 0.18, 0.95, 0.55, and 0.79 respectively. Also, 1.5xLDH at relapse was significantly associated with the presence of fever (LR=5.74; p=0.03) but not with other symptoms including drenching night sweats, anemia, or new/progressive lymphadenopathy. Conclusions: A 1.5 fold increase in LDH, over a period of 3 months, is associated with increased likelihood of relapse from DLBCL. Modest elevations in LDH (&lt;1.5 fold of baseline) doesn’t seem to be associated with relapse. LDH, when elevated at least 1.5 fold of baseline, is a specific (i.e. 56%), but not a sensitive (i.e. 19%) marker, for relapse of DLBCL.

Quantitative Proteomics Reveals that miR-155 Regulates the PI3K-AKT Pathway in Diffuse Large B-Cell Lymphoma

The aberrant expression of microRNA-155 (miR-155), which has emerged as having a significant impact on the biological characteristics of lymphocytes, plays important roles in B-cell malignancies, such as diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common non-Hodgkin's lymphoma in the adult population, accounting for approximately 40% of newly diagnosed non-Hodgkin's lymphoma cases globally. To determine the specific function of miR-155, a quantitative proteomics approach was applied to examine the inhibitory effects of miR-155 on protein synthesis in DLBCL cells. PIK3R1 (p85α), a negative regulator of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, was identified as a direct target of miR-155. A luciferase reporter was repressed through the direct interaction of miR-155 and the p85α 3'-untranslated region, and overexpression of miR-155 down-regulated both the transcription and translation of p85α. The PI3K-AKT signaling pathway was highly activated by the sustained overexpression of miR-155 in DHL16 cells, whereas knockdown of miR-155 in OCI-Ly3 cells diminished AKT activity. Taken together, our results reveal a novel target involved in miR-155 biological characteristics and provide a molecular link between the overexpression of miR-155 and the activation of PI3K-AKT in DLBCL.

Lymphoma with Features Intermediate Between DLBCL and Burkitt Lymphoma: Better Outcome with Intensive Chemotherapy Regimens

Abstract 2710Introduction Recent refinement in B-cell lymphoma classification by the WHO in 2008 has defined an entity that exists in the gray zone between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Varying in morphology, immunohistochemical, or genetic features, B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (Intermediate DLBCL/BL) has been reported to have a poor clinical outcome. We aim to describe the clinical factors affecting outcomes and compare therapy response in a representative population.Methods A retrospective search of the Nebraska Lymphoma Study Group Registry from 1983–2009 meeting the diagnostic criteria for Intermediate DLBCL/BL yielded clinical data at presentation, follow-up, and treatment information. Treatments were grouped as CHOP-like +/− Rituximab (R) vs. intensive regimens (e.g. CODOX-M +/− R, R-EPOCH). Diagnostic slides were re-reviewed to verify the diagnosis. Probabilities of progression-free survival (PFS) and overall survival (OS) were approximated using Kaplan-Meier method. Cox proportional regression analysis was used to evaluate the clinical variables associated with risk of treatment-failure and death.Results Our cohort of 63 patients had a median age of 69 (19–93), male sex in 49%, a Karnofsky performance status of at least 80 at time of diagnosis in 73%, an elevated serum lactate dehydrogenase (LDH) in 62%, and stage IV disease in 46%. International Prognostic Index (IPI) scores were low in 38%, low-intermediate in 27%, high-intermediate in 24% and high in 11%. The probability of PFS at 5 and 10 years was 25% (95% CI 15–37%) and 10% (95% CI 4–21%) respectively, with a median time to treatment-failure of only 5.7 months. The 5 and 10 year probability of OS was 32% (95% CI 21–44%) and 20% (95% CI 10–32%) respectively, with a median survival of 10.4 months. Univariate regression analysis showed the following factors to be associated with an increased risk for treatment-failure: Ann Arbor stage IV disease (HR 2.49, 95% CI 1.33–4.68); elevated LDH (HR 1.85, 95% CI 1.02–3.37) and having at least 2 extra-nodal sites (HR 2.12, 95% CI 1.12–4.04). The following factors were associated with an increased risk of death: elevated LDH (HR 2.03, 95% CI 1.08–3.81), stage IV disease (HR 1.88, 95% CI 1.00–3.45), and having at least 2 extra-nodal sites (HR 2.26, 95% CI 1.15–4.40). The IPI scores of low-intermediate, high-intermediate, and high risk were associated with treatment-failure (HR 2.01, 95% CI 1.00–4.11; 4.62, 95% CI 2.11–10.14; 6.11, 95% CI 2.31–16.17) respectively, and death (HR 2.57, 95% CI 1.23–5.37; 3.13, 95% CI 1.41–6.94; 8.30, 95% CI 3.07–22.43) respectively. The median OS of patients who received CHOP/CHOP-like regimens +/− R was 8.7 months, whereas those who received a more intensive regimen +/− R was 45 months (p=0.38). The median PFS was 5.4 months for CHOP/CHOP-like regimens +/− R and 52.3 months for a more intensive regimen (p=0.08) (Fig.1). [Display omitted] Summary Our analysis confirmed poor clinical outcome with stage IV disease, elevated serum LDH, at least 2 extra-nodal sites at presentation, or worse IPI score. There was a better outcome with intensive chemotherapy regimens. This study underscores the importance of early identification and proper treatment choice. Disclosures:No relevant conflicts of interest to declare.

Impact of conditioning regimen on outcome of 2-year disease-free survivors of autologous stem cell transplantation (ASCT) for Hodgkin lymphoma (HL).

8043 Background: ASCT is the standard of care for patients with relapsed HL. Most relapses occur in the first 2 years (y) after ASCT and the long term outcomes for 2 y post-ASCT survivors have not been well described. No prospective trials have compared the impact of different conditioning regimens on outcomes. Methods: We searched the Nebraska Lymphoma Study Group database to identify patients with HL who received ASCT from 1984 to 2007. Patients were conditioned with CBV (cyclophosphamide 6000 mg/m2, BCNU 300 mg/m2 and etoposide 600-900 mg/m2) or BEAM (BCNU 300 mg/m2, etoposide 800 mg/m2, cytarabine 800 mg/m2 and melphalan 140 mg/m2). Progression, progression-free survival (PFS) and overall survival (OS) were compared between the 2 regimens while adjusting for significant patient, disease and transplant related characteristics. Results: The median duration of follow up was 8 (2-26) y. Among the 461 transplanted patients, during the study period, 330 received CBV and 131 received BEAM. At 2 y post-ASCT, 225 (49%) were alive and disease-free. Median age of patients was 33 (8-64) y. The PFS at 5 y was 92% for the BEAM and 73% for the CBV group (p=0.002). The OS at 5 y was 95% for the BEAM and 87% for the CBV group (p=0.07). The PFS at 10 y was 79% for the BEAM and 59% for the CBV group (p=0.01). The OS at 10 y was 84% for the BEAM and 66% for the CBV group (p=0.02). The cumulative incidence of progression at 5 y was 4% vs 24% (for BEAM and CBV respectively, p<0.01) and at 10 y was 9% vs 33% (for BEAM and CBV respectively, p<0.001). Higher relative risk (RR) of progression (4.54, p<0.001), treatment failure (2.92; p=0.002) and mortality (2.74; p=0.03) was observed with use of CBV compared to BEAM. Higher RR of mortality was also observed with age of 40 y or older at transplant (1.69, p=0.04) and with chemoresistant disease (1.99, p=0.02). Conclusions: Patients with HL, who are disease-free and alive 2 y post-ASCT, have favorable long-term outcomes. In the dose and schedule used, we observed a lower risk of progression and longer survival associated with use of BEAM, as a conditioning regimen, compared to CBV. With this study design, we cannot rule out a selection bias favoring patients transplanted in more recent years.

High-Dose Therapy (HDT) with Hematopoietic Stem Cell Transplantation (HSCT) is effective therapy for patients with Non-Hodgkin Lymphoma (NHL) and Central Nervous System (CNS) involvement

Abstract Abstract 1358 Patients with NHL and CNS involvement have a poor prognosis when treated with conventional therapy. We performed a retrospective review of the Nebraska Lymphoma Study Group database to identify patients with NHL and CNS involvement who underwent HSCT. CNS involvement was defined as the presence of lymphomatous cells in cerebrospinal fluid, clear evidence of leptomeningeal disease by imaging studies, or biopsy proven parenchymal disease. Between January 1991 and December 2006, 24 such patients underwent HDT/HSCT. The median age at transplantation was 43 years (range 20–61). Fifty four percent of patients had diffuse large B-cell lymphoma. Sixty three percent of patients had parenchymal CNS involvement. CNS directed therapy as part of salvage prior to transplantation included intrathecal chemotherapy in 19 patients, high-dose methotrexate in 15 patients, and cranial irradiation in 10 patients. All but one patient achieved CNS remission prior to transplant. Twenty patients underwent autologous HSCT and four underwent allogeneic HSCT. The majority of patients were conditioned with carmustine, etoposide, cytarabine and melphalan (BEAM). At a median follow-up of 67 months for surviving patients (range 35–224 mo) the 1-year progression-free survival (PFS) is 50% (95% confidence interval [CI] 30–67) and the 5-year PFS is 38% (95% CI 20–56). The 1-year overall survival (OS) is 65% (95% CI 44–80) and the 5-year overall survival is 52% (95% CI 31–70). Eleven patients have relapsed and all relapses occurred within 13 months of HSCT. Thirteen patients remain alive and in remission. There have been 9 deaths due to disease recurrence and one death with no evidence of relapse. Among 15 patients who received high-dose methotrexate as part of CNS directed therapy the 5-year probability of PFS was 47% (95% CI 23–68) compared with 22% (95% CI, 3–51) in 9 patients not receiving high-dose methotrexate (p = 0.24). For patients transplanted as consolidation of initial therapy (n = 9) the 3-year probability of PFS was 63% (95% CI 29–96) compared with 36% (95% CI 0–71) for 12 patients transplanted in sensitive relapse (p = 0.36). Those same 9 patients had an 88% probability of survival at three years post transplant (95% CI 65%-100%) compared with 33% (95% CI 0–68) for the 12 patients with sensitive relapse (p = 0.046). In conclusion patients with NHL and CNS involvement who undergo HDT/HSCT appear to have similar outcomes to patients transplanted without CNS involvement. Patients destined to relapse appear to do so relatively soon after transplantation. Patients who received high-dose methotrexate as CNS directed therapy prior to transplant had a trend toward superior PFS compared with those receiving only intrathecal methotrexate, CNS irradiation, or both. Disclosures: No relevant conflicts of interest to declare.

Rituximab Added to Aggressive Chemotherapy Improves the Outcome of Patients with Follicular Lymphoma, Grade 3 and Results In Survival Comparable to Diffuse Large B-Cell Lymphoma.

AbstractAbstract 2810The survival of patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma is improved when rituximab is combined with chemotherapy. However, little is known about the outcome of patients with follicular lymphoma, grade 3 (FL-3), since these patients are generally excluded from DLBCL trials and often from trials evaluating treatment of follicular lymphoma. We therefore performed a retrospective study to evaluate the results of rituximab-based therapy for FL-3. An analysis of the Nebraska Lymphoma Study Group database allowed us to identify patients with FL-3 who were treated with aggressive combination chemotherapy regimens with and without the addition of rituximab. The progression-free survival (PFS) and overall survival of these patients were compared to patients with DLBCL who were treated with similar aggressive chemotherapy regimens combined with rituximab. Patients who were not treated with anthracycline-containing or mitoxantrone-containing regimens were excluded from analyses. We identified 60 FL-3 patients who were treated with aggressive chemotherapy regimens, combined with rituximab, between Feb. 1999 and Jan. 2009. The median age was 56 years (range 37–87 years). There were 27 males and 33 females. The performance status was 0–1 in 80%, the LDH was elevated in 15%, 68% had stage III-IV disease, and 13% had at least 2 sites of extranodal disease. Fifteen patients (25%) had bulky disease (≥5 cm) at diagnosis. The results of treatment for these patients were compared to 144 FL-3 patients treated with aggressive chemotherapy regimens without rituximab between June 1983 and Jan. 1999, and to 341 patients with DLBCL who were treated with aggressive chemotherapy regimens combined with rituximab between Sept. 1996 and Jan. 2009. The treatment outcomes for these three groups of patients are displayed in the table.5-yr Estimate (95% CI)8-yr Estimate (95% CI)Log-Rank p-valueProgression-Free Survival0.04FL-3 with rituximab65% (50–77)45% (23–65)FL-3 without rituximab42% (34–50)33% (26–41)DLBCL with rituximab53% (47–58)47% (40–54)Overall Survival0.06FL-3 with rituximab85% (72–92)71% (54–82)FL-3 without rituximab68% (59–74)54% (46–62)DLBCL with rituximab64% (58–69)56% (48–63)A multivariate analysis (accounting for older patients, and more patients with elevated LDH, extranodal disease, and bulky disease in the DLBCL group) revealed that patients with FL-3 who were not treated with rituximab had a significantly higher risk of disease progression or death (RR 1.75; p=0.02). There were no significant differences in PFS when comparing patients with FL-3 and those with DLBCL who were treated with aggressive chemotherapy regimens and rituximab. Follicular lymphoma, grade 3 patients treated without rituximab had inferior overall survival, when compared to patients treated with rituximab (RR 1.58), although this difference was not significant (p=0.16). The multivariate analysis also revealed no significant differences in survival when patients with FL-3 who received rituximab were compared to similarly treated patients with DLBCL (p=0.50). In conclusion, this analysis demonstrates that the outcome of treatment for patients with FL-3 who are treated with aggressive chemotherapy regimens is improved when rituximab is added to therapy. In the “rituximab era” the outcome of patients with FL-3 is comparable to DLBCL. Disclosures:Vose:Millennium Pharmaceuticals, Inc.: Research Funding.

High-Dose Therapy (HDT) with Hematopoietic Stem Cell Transplantation (HSCT) Is Effective Therapy for Patients with Non-Hodgkin Lymphoma (NHL) and Central Nervous System (CNS) Involvement

AbstractAbstract 1358Patients with NHL and CNS involvement have a poor prognosis when treated with conventional therapy. We performed a retrospective review of the Nebraska Lymphoma Study Group database to identify patients with NHL and CNS involvement who underwent HSCT. CNS involvement was defined as the presence of lymphomatous cells in cerebrospinal fluid, clear evidence of leptomeningeal disease by imaging studies, or biopsy proven parenchymal disease. Between January 1991 and December 2006, 24 such patients underwent HDT/HSCT. The median age at transplantation was 43 years (range 20–61). Fifty four percent of patients had diffuse large B-cell lymphoma. Sixty three percent of patients had parenchymal CNS involvement. CNS directed therapy as part of salvage prior to transplantation included intrathecal chemotherapy in 19 patients, high-dose methotrexate in 15 patients, and cranial irradiation in 10 patients. All but one patient achieved CNS remission prior to transplant. Twenty patients underwent autologous HSCT and four underwent allogeneic HSCT. The majority of patients were conditioned with carmustine, etoposide, cytarabine and melphalan (BEAM). At a median follow-up of 67 months for surviving patients (range 35–224 mo) the 1-year progression-free survival (PFS) is 50% (95% confidence interval [CI] 30–67) and the 5-year PFS is 38% (95% CI 20–56). The 1-year overall survival (OS) is 65% (95% CI 44–80) and the 5-year overall survival is 52% (95% CI 31–70). Eleven patients have relapsed and all relapses occurred within 13 months of HSCT. Thirteen patients remain alive and in remission. There have been 9 deaths due to disease recurrence and one death with no evidence of relapse. Among 15 patients who received high-dose methotrexate as part of CNS directed therapy the 5-year probability of PFS was 47% (95% CI 23–68) compared with 22% (95% CI, 3–51) in 9 patients not receiving high-dose methotrexate (p = 0.24). For patients transplanted as consolidation of initial therapy (n = 9) the 3-year probability of PFS was 63% (95% CI 29–96) compared with 36% (95% CI 0–71) for 12 patients transplanted in sensitive relapse (p = 0.36). Those same 9 patients had an 88% probability of survival at three years post transplant (95% CI 65%-100%) compared with 33% (95% CI 0–68) for the 12 patients with sensitive relapse (p = 0.046). In conclusion patients with NHL and CNS involvement who undergo HDT/HSCT appear to have similar outcomes to patients transplanted without CNS involvement. Patients destined to relapse appear to do so relatively soon after transplantation. Patients who received high-dose methotrexate as CNS directed therapy prior to transplant had a trend toward superior PFS compared with those receiving only intrathecal methotrexate, CNS irradiation, or both. Disclosures:No relevant conflicts of interest to declare.

Chromosomal Alterations in Gene Expression-Defined Pediatric Aggressive B-Cell Non-Hodgkin Lymphoma (B-NHL).

Abstract 2922Poster Board II-898 Introduction:Lymphomas derived from mature lymphocytes in children and adolescents are predominantly aggressive B-cell non-Hodgkin lymphomas (B-NHL), including Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). Differences in the clinical course between pediatric and adult aggressive B-NHL suggest distinct pathogenetic mechanisms. This study sought to identify both shared and unique genetic alterations between gene expression-defined pediatric and adult cases of BL and DLBCL. Patients and Methods:Gene expression profiling (GEP) was done on 45 BL and 18 DLBCL specimens from patients 18 years of age or younger, and 38 BL and 106 DLBCL from adult patients. Pediatric specimens were collected from the Cooperative Human Tissue Network (CHTN) pediatric NHL repository through the Children's Oncology Group (COG) and adult specimens were collected from the Nebraska Lymphoma Study Group Registry and Tissue Bank through the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). Previously-published gene signatures were used to classify lymphomas molecularly into mBL and mDLBCL groups (Dave et al., NEJM, 2006). The mDLBCL tumors were further classified into activated B-cell-like (ABC), germinal center B-cell-like (GCB), and primary mediastinal B-cell lymphoma (PMBL) subtypes (Rosenwald et al., JEM, 2003). High resolution array comparative genomic hybridization (aCGH) was done on a subset of the pediatric cases using the 250K NspI Human Mapping Array (Affymetrix) to detect DNA copy number alterations (CNA). Results:Molecular classification of the pediatric cases resulted in a 20% reclassification rate for cases with a morphologic diagnosis of BL or DLBCL. Among the 63 pediatric cases, there were 38 mBL (3 of which were DLBCL by morphology), 23 mDLBCL (9 of which were BL by morphology) and two cases which were unclassifiable by the molecular gene signatures. Comparison of the GEP profiles for adult and pediatric mBL failed to identify pathways that differed significantly; however high resolution aCGH analysis revealed a number of abnormalities in the pediatric cases not previously reported in BL, including gains of 3q21, 11q13 and 16p11. A predominance of the GCB to ABC subtype (3:1) was found among pediatric mDLBCL patients. Two cases with mediastinal tumors were classified as PMBL molecularly. Both PMBL cases were female and carried copy number gains of the Rel/BCL11A locus. Comparison of adult and pediatric GCB mDLBCL gene expression revealed enrichment in B-cell surface molecules and markers of antigen-dependent B-cell activation in the adult cases. aCGH analysis identified abnormalities that were both shared (+12q15, +19q13, -6q) between adult and pediatric mDLBCL and unique (-4p14, -19q13.32, +16p11.2) to the pediatric cases. Correlation of DNA copy number and gene expression revealed potential candidate genes for these loci. Conclusions:Pediatric BL and DLBCL classified by morphology were reclassified molecularly in a significant fraction of cases. Although pediatric BL and DLBCL are treated similarly, defining homogeneous molecular entities will be relevant for developing new therapies and future clinical trials. In general, pediatric cases have a more favorable outcome relative to adult patients. However, it is unclear whether this is due to the ability of children to tolerate very intensive therapies or whether distinct pathogenetic mechanisms modulate the disease course. Higher B-cell receptor signaling in adult relative to pediatric GCB DLBCL may be relevant to the outcome. The identification of previously undetected chromosomal alterations unique to the pediatric cases also suggests distinct pathogenetic mechanisms. Elucidation of the underlying genes may provide insight into factors which modulate outcome and could provide novel therapeutic targets with reduced toxicity. Disclosures:Gascoyne:Roche Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The Stanford V regimen is effective in patients with good risk Hodgkin lymphoma but radiotherapy is a necessary component

One-hundred and thirteen patients between the ages of 15 and 88 years with biopsy proven, untreated Hodgkin lymphoma were treated by physicians in the Nebraska Lymphoma Study Group using the Stanford V regimen (bleomycin, doxorubicin, etoposide, mechlorethamine, prednisone, vinblastine and vincristine) between January 1997 and January 2006. With a median follow-up of all surviving patients of 63 months, the 5-year overall survival (OS) was 84% and the 5-year progression-free survival (PFS) was 74%. Age >60 years, other than nodular sclerosing histological subtype, Ann Arbor Stage III/IV, and the presence of B-symptoms significantly predicted treatment outcome. Patients with 0-2 of these factors had a 5-year PFS and OS of 80% and 89% vs. 20% and 40% for patients with 3 or 4 factors. Patients who received radiotherapy had a superior 5-year PFS (86% vs. 42%) and OS (96% vs. 53%). Patients with 0-2 adverse risk factors who received radiotherapy had an excellent treatment outcome with 5-year PFS of 88% and a 5-year OS of 97%. The Stanford V chemotherapy regimen has an excellent treatment outcome for good prognosis patients with Hodgkin lymphoma. The results are compromised when radiotherapy is not utilized.

Survival Disparities in Patients with Lymphoma According to Place of Residence and Treatment Provider: A Population-Based Study

Objectives: We evaluated the association of the primary area of residence (urban vs. rural) and treatment (trt) provider (university-based vs. community-based) with overall survival in patients with lymphoma, and determined if there are patient subgroups that could benefit from better coordination of care.Methods: We performed a population-based study in 2,330 patients with centrally confirmed lymphoma from Nebraska and surrounding states reported to the Nebraska Lymphoma Study Group between 1982 and 2006. Patient residential ZIP codes at the time to trt were used to determine rural/urban designation, household income and distance to trt center; while trt providers were categorized into university-based or community based. Multivariate analyses were used to group patients into risk levels based on 8 factors found to be associated with survival at the time of trt (age, performance score, Ann Arbor stage, presence of B symptoms, LDH levels, tumor bulk, nodal and extranodal involvement). The following categories were identified: low-risk (1–3 factors), intermediate risk (4–5 factors), and high-risk (≥6 factors). Cox proportional regression analyses, stratified by type of lymphoma (low-grade NHL, high-grade NHL and Hodgkin) were used to evaluate the association between place of residence and trt provider with overall survival.Results: Among urban residents, 321 (14%) were treated by university-based providers (UUB) and 816 (35%) were treated by community-based providers (UCB). Among rural residents, 332 (14%) were treated by university-based providers (RUB) and 861 (37%) were treated by community-based providers (RCB). Patients from rural areas were more likely to be older and Caucasian, with a lower median household income, greater travel distance to seek trt, and more likely to have high-risk disease when compared to patients from urban areas. In multivariate analysis, using all patients regardless of risk level, the relative risk of death (RR) among UUB, UCB and RUB was not statistically different. However, RCB had a higher risk of death RR 1.37, 95% CI 1.14–1.65, p=0.01; RR 1.18, 95% CI 1.04–1.33, p<0.01; and RR 1.26, 95% CI 1.06–1.49, p=0.01 when compared with UUB, UCB and RUB, respectively. This association remained true in both low- and intermediate-risk patients. Among high-risk patients, both RUB and RCB were at higher risk of death when compared with UUB or UCB, while UCB were not different from UUB. We found no differences in progression-free survival according to place of residence and trt provider. The use of stem cell transplantation was significantly higher in patients coming from urban and rural areas treated by university-based providers (UUB 19%, RUB 16%) compared to urban and rural patients treated by community-based providers (UCB 11%, RCB 10%, p < 0.01). Patients from rural areas (RUB and RCB) were slightly less likely to die from lymphoma-related causes than patients from urban areas (75% versus 80%, p=0.04).Conclusion: Overall survival in patients with lymphoma is inferior in patients coming from rural areas. This relationship varies according to treatment provider and pretreatment risk levels. Further studies in patients from rural areas are needed to understand how coordination of care is carried to design appropriate interventions that may improve the disparity noted.

Nebraska Lymphoma Study Group (NLSG) results of treatment for non-Hodgkin’s lymphoma (NHL) in patients (pts) aged 80 years or greater

8534 Background: Little data has been published describing treatment results in pts with NHL ≥ 80 years of age. Methods: A retrospective study of pts with NHL treated by the NLSG between December 1982 and January 2005. Results: Two hundred forty-nine pts were evaluated/treated. Median age was 83 years (yrs) (range 80–96 yrs). Karnofsky performance status was ≥ 80 in 20% of pts. Ninety percent of pts had aggressive histology. Forty-nine percent of pts had advanced stage disease at diagnosis; 47% had masses ≥ 5 cm; 27% had B symptoms; 34% had elevated LDH values; 63% had extranodal disease. Fifty six percent of pts received ≥ 4 cycles of chemotherapy. Ninety percent of pts received CAPBOP or CNOP/CHOP± rituximab. Twenty four percent of pts received combined modality therapy. Thirty percent were not evaluable for response because of early withdrawal of therapy or lack of follow-up. The response rate for evaluable pts was 86%. With a median follow-up of 54 months (2–161 months) the five year probabilities of progression-free and overall survival are 22% and 28% respectively. Including 206 evaluable pts completing planned therapy the five year probabilities of progression-free and overall survival are 25% and 29% respectively. For pts completing all planned therapy a high age adjusted International Prognostic Index (IPI) score was independently associated with a higher risk of treatment failure (relative risk [RR]=1.84, 95% confidence interval [CI]=1.20–2.80, P=0.005) whereas treatment which included radiation (RR=0.35, 95% CI=0.21–0.56, P<0.001) and reception of ≥ 4 cycles of chemotherapy (RR=0.25, 95% CI=0.13–0.48, P<0.001) were associated with decreased risks of treatment failure. The same factors were independently associated with the risk of death (RR=1.77, 95% CI=1.16–2.71, P=0.009 for high age adjusted IPI, RR=0.36, 95% CI=0.22–0.59, P<0.001 for treatment that included radiation, and RR=0.29, 95% CI=0.15–0.56, P<0.001 for reception of ≥ 4 cycles of chemotherapy. The five year probability of progression was 42%. Conclusions: Anthracycline-based therapy in pts ≥ 80 years is feasible and results in long-term disease-free survival in a good proportion of pts. This intensity of therapy precludes completion of treatment in a sizeable number of pts. No significant financial relationships to disclose.