Johnston, Patrick B.

Abstract Abstract 3231 Poster Board III-168 Background Peripheral blood stem cells (PBSC) are the preferred graft type for autologous stem cell transplantation (ASCT) and mobilization is typically done using growth factor (GF) alone or a combination of chemotherapy (CTX) and GF. The success of mobilization is influenced by several factors such as prior therapy and mobilization strategy. Patients (Pts) failing to mobilize successfully often have GF dose increased and if unsuccessful, mobilization reattempted with chemotherapy + GF or G-CSF (Granulocyte Colony-Stimulating Factor) + GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor). More recently, plerixafor, a CXCR4 inhibitor, has been found to enhance G-CSF based collection allowing potential early intervention in poor mobilizers. However, this approach requires valid cut-points for peripheral CD34 counts (pCD34) for cost efficient use. Methods We studied 910 first time, G-CSF based PBSC mobilizers with MM (565; 62%), or light chain amyloidosis (345; 38%). Salvage attempts were excluded, as were first attempts using CTX+GCSF, plerixafor or GF combinations. Sensitivity-specificity analysis (ROC) was used to define ideal cut-points for predefined outcomes. We used a CD34 yield of 2 million/kg as the minimum required collection and 4 million/kg as the ideal collection for this analysis. Our current practice is to initiate collection at a pCD34 of 10/uL. Results We first determined the best day 1 pCD34 cutoff for being able to collect at least 2 million/kg PBSC to be 9.2/uL. Among those with ≥9.2/uL, only 1.6% failed to collect at least 2 million compared to 27% among the rest (P < 0.001). These numbers were 1.7% and 25% respectively using the traditional cutoff of 10/uL. We then examined how the pCD34 on day 2 predicted collection, among those failing to reach the current threshold of 10/uL. Among this group, a pCD34 on day 2 of 8/uL was the best cutoff to predict a collection of 2 million/kg. Among those with >8/uL, only 9% failed to collect at least 2 million compared to 48% among the rest (P < 0.001). Among those with day 1 pCD34 < 10, 65% achieved a count of 8/uL on day 2. We then examined what pCD34 on day 1 can best predict a pCD34 ≥ 8 on day 2 and found this to be 5/uL. Among those with day 1 pCD34 ≥ 5/uL, 92% reached day 2 pCD34 ≥ 8 compared to 36% among the rest (P < 0.001).We then determined cutoffs based on ideal targets using only those patients achieving pCD34 count > 10/uL by day 2, since these patients would have started collection without any change in the mobilization technique. We used a maximum of 5 collections to achieve the goal as being ideal, taking into account the most commonly used practice of collecting during weekdays. We examined cutoffs both for a target of 4, 8 and 12 million/kg for one, two or three transplants respectively. Among those with a day 1 or day 2 pCD34 > 10/uL 98% collected 4 million/kg in 5 collections. The best day 1 or day 2 pCD34 predicting a 8 million/kg yield in 5 collections was 21.4/uL and a 12 million/kg yield was 27.9/uL. Among those with day 1or 2 pCD34 ≥ 21.4/uL, 90% collected 8 million compared to 54% among those with pCD34 < 21.4/uL. Similarly, among those with day 1 or 2 pCD34 ≥ 27.9/uL, 79% reached 12 million in ≤ 5 days compared to 17% among those with pCD34 < 27.9/uL (P < 0.001).Finally we examined if poor collection on first day, despite a pCD34 > 10 predicts for poor overall yield. A ratio of day 1 collection (million/kg) to pCD34 day 1 or 2 < 5×104 was highly predictive of failure to get eventual yield of 2 million/kg, with 38% below the cutoff failing to reach the goal compared to 2% for those above the cutoff. Conclusions This study provides an estimate of optimal pCD34 count thresholds for early identification of patients at high risk of collection failure. It is reasonable to use the first or second day pCD34 count, since a substantial proportion of patients will achieve the threshold value by day 2 and have similar outcome as those reaching the threshold by day 1. Based on the results here, interventions such as plerixafor can be considered if pCD34 count is < 5/uL on day 1 or < 9/uL by day 2, to achieve the minimum collection of 2 million/kg. However, in order to achieve the ideal targets, a higher threshold should be considered and the recommendation would be 17/uL, and 28/uL for target of 8 or 12 million respectively. Finally, identification of poor mobilizers after start of collection potentially provides another time point for early intervention, and this needs to be prospectively studied. Disclosures Micallef: Genzyme: Research Funding. Gertz:Genzyme: Research Funding. Kumar:Celgene,Genzyme,Millenium,Novartis,Bayer,: Honoraria, Research Funding.

Abstract Background: Peripheral T-cell non-Hodgkin’s lymphomas (PTCL) account for approximately 10% of all non-Hodgkin’s lymphomas in the U.S. and Europe. PTCL, unspecified (PTCL-U), as classified by the WHO, is the most common subtype. The ability of high-dose therapy (HDT) and stem cell transplantation (SCT) to improve patient outcome was evaluated in the current study. Methods: All patients with PTCL-U evaluated at our institution who had tissue specimens available for review from January, 1994 to December, 2005 were identified and both clinical characteristics and treatment course obtained from the medical record. Results: 89 patients with PTCL-U were identified, with a median follow up of 13 months (range 1 month–12 years). The median age at diagnosis was 56 years (range 24–90). The IPI was low, intermediate or high in 34%, 44% and 22% of patients, respectively. On univariate analysis, age >60 (p<.0001), ECOG performance status >1 (p<.0001), LDH greater than normal (p=.004), Ann Arbor Stage III/IV (p=.01) and the presence of B symptoms (p=.0004) were associated with a poorer overall survival, as was an intermediate or high IPI (p<.0001). In contrast, on multivariate analysis only age >60 (p=.0006) and ECOG performance status >1 (p=.007) were independently associated with poorer overall survival. Fifty-seven percent of patients were treated initially with an anthracycline-based regimen, most commonly CHOP (53%). Patients with a low (0–1), intermediate (2–3) or high (4–5) IPI experienced a 61%, 29% and 18% 5-year overall survival, respectively. Fourteen patients (16%) received HDT and autologous (n=12) or allogeneic (n=2) SCT, either at the time of a first partial or complete response (n=11) or at the time of first relapse (n=3). The median survival in those patients treated initially with an anthracycline-based regimen alone was 11 months (95% CI 0.6–1.6 years). Improvement in both 5-year overall (75% vs 24%, HR=5.6, 95% CI 2.0–23.4, p=.0004) and disease-free (60% vs 26%, HR=3.2, 95% CI 1.3–9.3, p=.008) survival was observed in patients who received HDT/SCT, as compared to patients treated with anthracycline-based therapy alone. Furthermore, improvement in both 5-year overall (80% vs 26%, HR=5.8, 95% CI 1.7–35.7, p=.002) and disease free (72% vs 26%, HR=3.8, 95% CI 1.3–15.8, p=.009) survival was observed in patients who received HDT/SCT at the time of a first partial or complete response when compared to patients who received anthracycline-based therapy. When patients who failed to achieve a first partial or complete response were excluded from the analysis, improved 5-year overall (80% vs 57%, HR=0.5, 95% CI 0.1–2.1, p=.4) and disease-free (72% vs 53%, HR=0.7, 95% CI 0.1–2.3, p=.5) survival were observed in patients who received upfront HDT/SCT, although this failed to reach statistical significance. The improved overall and disease free survival observed in patients receiving HDT/SCT, either at the time of a first response or at the time of relapse, remained significant when accounting for differences in the IPI. In conclusion, selected patients with PTCL-U may benefit from treatment with HDT/SCT following a first response to conventional anthracycline-based chemotherapy.

Abstract Background: Patients (pts) with aggressive NHL who relapse after conventional chemotherapy or stem cell transplant have a poor prognosis. Novel agents are needed for this important subset. Tipifarnib is an orally available methylquinolone derivative that is an inhibitor of the farnesyl transferase enzyme that transfers the farnesyl group from farnesyl pyrophosphate to specific polypeptides including small GTPases of the Ras, Rho-B, and Rheb families, as well as nuclear lamins and kinetochore proteins. Tipifarnib has documented activity in acute leukemia and produces stable disease in relapsed multiple myeloma. The goal of this study was to evaluate the activity of single-agent tipifarnib in patients with relapsed aggressive NHL in the context of a phase II trial. Methods: Pts with relapsed diffuse large, follicular grade III, or mantle cell lymphoma were eligible for this study. Pts were treated with oral tipifarnib 300 mg twice daily d1–21 q 28 days until progression. Pts were restaged after 2 cycles, 6 cycles, and every 3 cycles thereafter. Tumor was sampled prior to tipifarnib and at day 8 in selected patients with accessible tumors. These paired samples were assayed for accumulation of unprocessed HDJ-2 and prelamin A, two polypeptides that require farnesylation for processing. Results: Forty-two pts were accrued between March 2004 and June 2006. Thirty-seven pts had diffuse large cell, 1 follicular grade III, and 4 had mantle cell. Of the 38 patients evaluable for response, 7 (18%) had a partial response and 8 (21%) had stable disease. The 7 responders all had diffuse large cell histology. Median progression-free survival (PFS) for all pts was 2 months (range, 0–25+). The PFS of the 7 responders was noteworthy at 4.2, 4.9+, 6.7, 9.6, 14.9+, 21.6+, and 25.1+ months, respectively. The primary toxicity was myelosuppression and 33% of pts required dose reductions. The median dose received in all pts was 300 mg twice daily (mean 275, range, 100–400). The median dose received by the 7 responders was 200 mg twice daily (range, 100–400). The dose of 300 mg twice daily resulted in accumulation of unfarnesylated forms of one or both markers in all pts studied to date. Conclusion: Oral tipifarnib has antitumor activity as a single agent with an excellent toxicity profile in pts with relapsed/refractory aggressive lymphoma. When given in this dose and schedule, tipifarnib is well-tolerated and can be taken for months without cumulative toxicity. This drug warrants further investigation in combination with conventional chemotherapy and other novel agents for the treatment of this important subset of patients.

Abstract Abstract 1222 Poster Board I-244 Background Survival for patients with primary CNS lymphoma (PCNSL), in general, is poor with patients requiring frequent chemotherapy treatments or receiving whole-brain radiation therapy, which can potentially result in significant neurologic decline and dementia. Because of the improved survival of high risk patients with aggressive lymphoma undergoing autologous stem cell transplant (ASCT), we began ASCT for patients with PCNSL in first or later remission with chemotherapy sensitive disease. We now update on outcomes of patients who have had at least 100 day follow up post ASCT. Baseline characteristics Between June, 2000 and January, 2009, 22 patients underwent ASCT for PCNSL. Median age at transplant was 50 years old (range 26-67). Median number of prior treatments 1 (range 1-3). Median time from diagnosis to transplant was 7.2 months (range 2.9 to 75.8). Median International Extranodal Working Study Group Prognostic Score: 2 (range 0-3). Disease status at transplant: First CR 10 patients, later CR or PR 12 patients. Results Twenty-two patients underwent ASCT for PCNSL and have a minimum of 100 days follow-up. All patients received BEAM conditioning. Median follow up post-transplant was 30 months (range 3-107 months). Eight patients have relapsed at a median of 217 days (range 40-1349). Of the patients who relapsed, four have died of disease progression and the remaining four are alive after additional therapy. Median overall survival from diagnosis or transplant has not been reached. Median progression free survival from transplant was 70 months. Conclusions Although limited by patient selection and retrospective biases, this review suggests that ASCT for PCNSL demonstrates improved overall survival when compared to historical controls with similar PCNSL Prognostic Scores (2 year survival for patients from diagnosis with PS 2-3 was 48% in a prior published study). ASCT in first remission in patients with PCNSL appears promising and may limit the need for additional therapy which can be myelosuppressive or result in neurologic decline secondary to radiation therapy in patients who are appropriate candidates. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Absolute lymphocyte count (ALC) recovery is an independent prognostic factor for survival for different hematological malignancies treated with autologous stem cell transplantation. Recently, we reported superior overall survival (OS) in patients with follicular lymphomas that presented with a higher ALC (ALC ≥ 1 x 109/L) at diagnosis. The role of ALC at diagnosis on survival in T cell lymphomas is not known. Methods: All patients evaluated at the Mayo Clinic for T cell lymphomas from October 1984 until April 2005 were analyzed in the study. The primary objective of the study was to assess the role of ALC at diagnosis and survival in T cell lymphomas. ALC at diagnosis was obtained from the standard complete blood cell count (CBC). Results: 223 patients with T cell lymphomas were included in the study. The histology included: peripheral T-cell lymphoma-unspecified (40%), anaplastic large cell (13%), angioimmunoblastic (10%), angiocentric (4%), intestinal T-cell (2%), and other (31%). The median follow-up was 18.6 months (range: 1 month – 229 months [19 years]). The sample population included 60% male and 40% females with a median age of 60 years (15–90 years). The median ALC at diagnosis was 1.2 x 109/L (range: 0.04–6.7 x 109/L). ALC as a continuous variable was identified as predictor for OS in the univariate analysis (HR= 0.690, 95%CI: 0.542–0.862, p < 0.0006). ALC ≥ 1 x 109/L was selected as the dichotomized value because it yielded the maximum difference in survival by c2 analysis looking at different cut-point from 0.6 to 1.7 x 109/L that were included between the 25% and 75% quartiles. Univariately, ALC ≥ 1 x 109/L was also identified as a predictor for OS (HR = 0.682, 95%CL= 0.578–0.804, p < 0.0001). Patients (N = 122) with an ALC ≥ 1 x 109/L experienced superior survival compared to patients (N = 101) with an ALC < 1 x 109/L [median OS: 76.3 vs 10.6 months, respectively; and 5 years OS estimates of 53% vs 23%, respectively, p < 0.0001]. When ALC ≥ 1 x 109/L was compared to the international prognostic index (IPI), ALC ≥ 1 x 109/L remained an independent predictor for survival in the multivariate analysis (HR = 0.779, 95%CL: 0.655–0.925, p < 0.004). Conclusion: This study demonstrates ALC as an independent predictor for OS in T cell lymphomas, suggesting that the host immune system affects survival in this group of patients.

Abstract Abstract 1527 Interim Positron-Emission Tomography (PET-scan), as a functional imaging test for tumor activity, has been shown to be a predictor for progression-free survival (PFS) and time to progression (TTP) in classical Hodgkin lymphoma (HL). The peripheral blood absolute lymphocyte/monocyte ratio (ALC/AMC) at diagnosis, as a surrogate marker of host immunity (i.e., ALC) and tumor microenvironment (i.e., AMC), 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 also a predictor for PFS and TTP in classical HL. Therefore, we evaluated the combination of ALC/AMC ratio at diagnosis and the interim PET-scan to further stratify the clinical outcomes of PFS and TTP in patients with classical HL. To participate in the studies, patients were required to be diagnosed, treated, and followed at Mayo Clinic, Rochester, Minnesota. The treatment consisted of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) with or without radiation therapy. Patients were required to have an interim PET-scan performed. 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 2000 until 2008, 111 classical HL patients qualified for the study. The cohort included 54% males and 46% females. The median age at diagnosis was 37 years (range: 18–83 years). The median follow-up was 2.8 years (range: 0.3–10.4 years). Patients with a negative interim PET-scan (N=98) presented with a higher ALC/AMC ratio at diagnosis (median of 2.32, range: 0.26–37.5) compared with patients with a positive interim PET-scan (N = 13) (median of 0.9, range: 0.29–3.10), p < 0.004. By univariate analysis, the ALC/AMC ratio at diagnosis and the interim PET-scan were predictors for PFS [ ALC/AMC ratio, R =0.13, 95% CI (0.05–0.35), p < 0.0002; and interim PET-scan, HR = 0.13, 95% CI (0.05–0.37), p < 0.0003] and TTP [ALC/AMC ratio, R =0.07, 95% CI (0.02–0.24), p < 0.0001; and interim PET-scan, HR = 0.05, 95% CI (0.01–0.18), p < 0.0003]. By multivariate analysis, ALC/AMC ratio at diagnosis and the interim PET-scan were independent predictors for PFS [ ALC/AMC ratio, R =0.13, 95% CI (0.07–0.63), p < 0.006; and interim PET-scan, HR = 0.11, 95%CI (0.02–0.47), p < 0.003] and TTP [ALC/AMC ratio, R =0.11, 95% CI (0.02–0.71), p < 0.02; and interim PET-scan, HR = 0.10, 95% CI (0.02–0.46), p < 0.003] when compared to the International Prognostic Score, limited versus advanced stage, and radiation. Patients were stratified into four groups: group 1 included patients with a negative interim PET-scan and ALC/AMC ratio at diagnosis ≥1.1 (N = 88); group 2 included positive interim PET-scan and ALC/AMC ratio at diagnosis ≥1.1 (N = 5); group 3 included negative PET-scan and ALC/AMC ratio at diagnosis < 1.1 (N = 10); and group 4 included positive PET-scan and ALC/AMC ratio at diagnosis <1.1 (N = 8). The three year PFS rates for each group were for goup1 95% (Events = 6); group 2 40% (Events = 3); group 3 56% (Events = 4); and group 4 50% (events = 4), p < 0.0001. The three year TTP rates for each group were: for group1 was 100% (Events = 0); for group 2 of 40% (Events = 3); for group 3 of 65% (Events = 3); and group 4 of 50% (events = 4), p < 0.0001. In conclusion, the ALC/AMC ratio at diagnosis is independent of the interim PET-scan to predict PFS and TTP in classical HL. Further studies are warranted to confirm our findings and to assess if the combination of the ALC/AMC ratio at diagnosis and interim PET can be use for planning of risk-adapted treatment. Disclosures: Ansell: Seattle Genetics, Inc.: Research Funding.

Abstract Abstract 2740 Background: Historically, treatment options for the approximately 30% of patients with Hodgkin lymphoma (HL) who have primary refractory disease or relapse after experiencing initial response have been limited to high-dose chemotherapy with autologous hematopoietic stem cell transplant (AHSCT). Development of novel therapeutic options is needed to improve outcomes in patients whose disease is refractory to or relapses after initial chemotherapy or subsequent high-dose chemotherapy with AHSCT. The oral mammalian target of rapamycin inhibitor everolimus showed promising efficacy and acceptable toxicity in 19 patients with heavily pretreated HL enrolled in a phase 2 study of everolimus monotherapy for relapsed, rare lymphomas (Johnston et al. Am J Hematol 2010;85:320-4). To confirm the efficacy and safety of everolimus monotherapy in patients with relapsed/refractory classical HL, we conducted a multicenter, open-label, 2-step, phase 2 study. Methods: Adults with classical HL that progressed after high-dose chemotherapy with AHSCT or a gemcitabine-, vinorelbine-, or vinblastine-containing regimen received everolimus 10 mg/day until disease progression or unacceptable toxicity. Response was assessed every 12 weeks via computed tomography with contrast or integrated positron emission tomography/computed tomography with contrast. The primary study endpoint was the overall response rate (ORR) evaluated according to the modified response criteria for malignant lymphoma (Cheson et al. J Clin Oncol 2007;25:579-86). Secondary endpoints included the disease control rate (DCR), duration of overall response, duration of disease control, progression-free survival (PFS), and safety. Results: A total of 57 patients were enrolled in this study; 57.9% were women, the median age was 32.0 years, 57.9% were pretreated with AHSCT, and 100% were pretreated with gemcitabine, vinorelbine, or vinblastine. Overall, 66.7% of patients experienced disease progression during previous therapies or discontinued previous treatment due to progression. At the time of analysis, 48 patients discontinued study treatment, most commonly due to disease progression (n = 25). The ORR and DCR were 42.1% and 77.2%, respectively (Table). The median time to response was 57 days. Median PFS was 9.0 months. Adverse events experienced by >25% of patients were fatigue (56.1%), thrombocytopenia (47.4%), cough (38.6%), rash (38.6%), pyrexia (31.6%), anemia (29.8%), dyspnea (28.1%), back pain (26.3%), and diarrhea (26.3%). Grade 3/4 adverse events were observed in 33 patients (57.9%); the most common were thrombocytopenia (21.1%) and anemia (12.3%). Stomatitis was experienced by 14 patients (24.6%) and was of grade 3 severity in 2 patients (3.5%). Pneumonitis was observed in 6 patients (10.5%) and was of grade 1 severity in 2 patients (3.5%) and grade 2 severity in 4 patients (7.0%). Conclusions: In this phase 2 study, everolimus monotherapy demonstrated favorable efficacy and a short time to response in patients with heavily pretreated, relapsed/refractory classical HL. The overall safety profile was consistent with that previously observed for everolimus in patients with HL and other cancers. The results of this study confirm previous results and support the further evaluation of everolimus in patients with classical HL. Disclosures: Johnston: Novartis: Consultancy. Off Label Use: Everolimus is an mTOR inhibitor indicated in the US for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with letrozole after failure of letrozole or anastrozole; adults with progressive pancreatic neuroendocrine tumors that are unresectable, locally advanced, or metastatic; adults with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib; adults with renal angiomyolipoma and tuberous sclerosis complex not requiring immediate surgery; and adults and children aged 3 years or greater with subependymal giant cell astrocytoma associated with tuberous sclerosis complex who require therapeutic intervention but are not candidates for curative surgical resection. Pinter-Brown:Millennium: Consultancy. Rogerio:Novartis: Employment; Novartis: Equity Ownership. Warsi:Novartis: Employment; Novartis: Equity Ownership. Chau:Novartis: Employment. Ramchandren:Seattle Genetics: Honoraria.

Abstract Abstract 1546 Background: Follicular lymphoma (FL) is an incurable disease with an undefined optimal management strategy. Global priorities in goals of care are avoidance of death and transformation to aggressive subtypes. Retrospective series, – most including patients diagnosed before ubiquitous rituximab use, - describe diverse rates of transformation with a common consensus of 3% per year, and with a median survival post transformation of less than 2 years. This study sought to characterize transformation events in a prospective observational series begun after diffusion of early rituximab use in FL. Methods: Newly diagnosed FL patients were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) from 2002–2009. Clinical data were abstracted from medical records using a standard protocol. Patients were actively followed for retreatment, transformation, and death. Inclusion criteria for this analysis were initial diagnosis of grade I-IIIa FL. Exclusion criteria for this cohort include composite diffuse large B-cell lymphoma (DLBCL), FL grade IIIb, or evidence of clinical or pathological transformation at the time of FL diagnosis. Transformation was defined as refractory/recurrent disease with either a) biopsy confirmed subtype of FLIIIb, DLBCL or higher grade B-cell lymphoma; or b) clinical indication of transformation (sudden rise in LDH, rapid discordant localized nodal growth, new involvement of unusual extranodal sites, new B symptoms or hypercalcemia). Risk of transformation was analyzed via time to transformation using a death as a competing risk. Time to transformation was defined as the date of initial FL diagnosis to date of transformation. Overall survival was defined as the date of initial diagnosis to date of death or last known follow-up for patients still alive. Results: There were 631 newly diagnosed grade I-IIIa FL patients with a median age at enrollment of 60 years (range 23–93). 54% were male. The most common types of initial therapy were observation (33%), rituximab (R) monotherapy (12%), alkylator based chemotherapy +/− R (22%), and anthracycline based chemotherapy +/− R (20%). At a median follow-up of 60 months (range 11–110), 79 patients had died, 311 patients had an event (death, progression, or retreatment), and 60 patients (9.5%) had transformed. Transformation was biopsy proven in 48 of the 60 patients (80%). The overall transformation rate at 5 years (TX5) was 10.7% (95% CI: 8.3%–13.8%) (Figure 1). Time to transformation was associated with a FLIPI score of 3–5 (HR=2.37, 95% CI 1.28–4.39, p=0.006), but was not significantly associated with other standard clinical characteristics. Risk of transformation was different in the common initial treatment groups with the highest rate in patients who were initially observed (TX5=14.4%) and lowest rate in patients who initially received R monotherapy (TX5=3.2%)(p=0.058). Outcome after transformation was inferior to MER subjects with de-novo diagnosed DLBCL (p<0.0001). The median overall survival from date of transformation was 44 months (95% CI: 22-NA). Survival after transformation was superior in patients who transformed greater than 18 months after FL diagnosis compared to patients who transformed earlier (5 yr OS =70% vs 20%) (p=7 ×10−5), and for those initially observed (median unreached) versus those patients who were initially treated with alkylator or anthracycline based chemotherapy (median survival of 11 months)( p=0.016). Conclusions: Follicular transformation rates in this modern large prospective observational study are similar to risk of death without transformation and slightly lower at 5 years than most previous reports. Post-transformation prognosis is substantially better than described in older series. These observed differences may be a function of the prospective nature of the study design, modern management strategies, or patient selection factors. Initial management strategies may influence the risk of transformation. Marked survival differences following early vs. late transformation suggest that these may be different biologic events. Disclosures: Link: Genentech: Consultancy, Research Funding; Celgene: Consultancy; Millenium: Consultancy. Johnston:Novartis: Consultancy.

Abstract Abstract Our group recently reported a Phase III clinical trial (Porrata et al. Biology of Blood and Marrow Transplantation 2016; 22: 1017-1023) demonstrating that the infusion of the autograft-absolute lymphocyte count (A-ALC) and autograft natural killer cells (A-NKC) are survival prognostic factors in non-Hodgkin lymphoma (NHL) patients treated with autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). A limitation of our Phase III clinical trial was the short-term follow-up of just two years. Therefore, we evaluated longer follow-up and assessed the role of the infused A-ALC, infused A-NKC, and peripheral blood absolute natural killer cell count (ANKC) recovery on survival post-APBHSCT. Of the 122 patients that participated in the Phase III trial, 111 patients were able to complete APBHSCT and included in the current study. With a median follow-up of 57.2 months (range: 2.1-84.6 months), superior overall survival (OS) and progression-free survival (PFS) was observed in patients infused with an A-ALC ≥ 0.5 x 109 lymphocytes/kg [OS: HR = 0.429, 95%CI, 0.128-0.828, p < 0.01; and PFS: HR = 0.456, 95% CI, 0.177-0.863, p < 0.01] and an A-NKC ≥ 0.09 x 109 cells/kg [OS: HR = 1.58e-3, 95% CI, 1.046e-6-0.179, p < 0.003; and PFS: HR= 1.58e-3, 95% CI, 7.81e-7-0.064, p < 0.003]. Furthermore, patients that maintained an ANKC ≥ 250 cells/µl at 3 months, 6 months, 9 months and 12 months post-APBHSCT also experienced superior OS (Figure 1A) and PFS (Figure 1B)[OS and PFS times in months were evaluated from infusion date of stem cells]. In the multivariate analysis a sustained ANKC ≥ 250 cells/µl was an independent predictor for OS (HR = 0.013, 95% CI, 0.001-0.063, p < 0.0001) and PFS (HR = 0.014, 95% CI, 0.001-0.067, p < 0.0001). This study is an extension of our Phase III clinical trial showing that sustained innate immunity by measuring the ANKC correlated with superior clinical outcomes; thus providing a platform to develop innate immunity immunotherapeutic strategists directing to improve clinical outcomes post-APBHSCT in NHL patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 1525 Background: Nodular lymphocyte predominant Hodgkin Lymphoma (NLPHL) is a more indolent form of Hodgkin Lymphoma that is usually associated with favorable outcomes. However, a number of reports have shown a tendency of transformation to more aggressive types of lymphoma, typically diffuse large B-cell lymphoma (DLBCL). Long-term data on the incidence and outcomes of transformed NLPHL is lacking in the literature. The aim of this study was to evaluate incidence, risk factors and outcomes of DLBCL transformation in NLPHL in a cohort of patients followed at a single institution. Methods: The actively maintained Mayo Clinic Lymphoma Database includes all consenting consecutive patients with lymphoma seen at Mayo Clinic Rochester. This was used to retrospectively identify patients with NLPHL. The study was approved by the Institutional Review Board. Pathology was reviewed by a hematopathologist and all transformations were histologically confirmed by WHO criteria. The clinical characteristics, therapy and outcomes of patients with NLPHL and DLBCL transformation were analyzed. The chi-square test was used to compare variables. Risk of progression was calculated using a person-year approach. Survival and freedom from transformation were estimated and compared using the Kaplan Meier method and log rank tests, respectively. Results: Between 1970 and 2010, 222 consecutive adult patients with NLPHL were identified. The median follow-up was 20 years. Of these, 17 (7.7%) developed a transformation to DLBCL during the course of the disease (Figure 1). The median time to transformation was 35 (6–248) months. Of these 17 patients, 13 (76.5%) were male, 11 (64.7%) had stage I/II and 6 (35.3%) had stage III/IV NLPHL. Transformation was the first relapse in most patients (12 patients, 70.6%) while five patients (29.4%) developed one or more relapses of NLPHL before transformation. Prior therapies for NLPHL were as follows: radiation therapy in 5 (29.4%), chemotherapy in 5 (29.4%) and combined chemotherapy and radiation in 6 (35.3%) patients. The median age at transformation was 45 years (30–87). Most patients (10 patients, 58.8%) presented with signs (palpable lymph nodes) or “B” symptoms. Eight patients (47.1%) had stage III/IV disease at the time of transformation. The most commonly used regimens for treatment of DLBCL were R-CHOP or CHOP (9 patients, 52.9%). Platinum based therapy was administered in 4 (23.5%) patients. Five patients (29.4%) required more than one line of therapy, and autologous stem cell transplant was utilized in two (11.7%) patients. Based on the observed 17 transformations during 2304 patient-years of follow-up, the rate of transformation was 0.74 per 100 patient-years. The five-year overall survival (OS) of patients with transformed disease (calculated from time of transformation) was 76.4%. The most common cause of death was lymphoma (75%). Following treatment for transformation, 5 patients (29.4%) relapsed. The OS in transformed patients was independent of prior therapies, and transformation did not adversely affect overall survival in our cohort (median survival of in 129 months in transformed versus 120 in non-transformed patients, P=0.33). In a univariate analysis of prior therapies, use of radiation therapy was associated with a significant delay in time to transformation (P= 0.0035) (Table 1, figure 2). Conclusions: The risk of transformation in NLPHL is 0.74% per year in this large single institution case series of NLPHL, and appears to be lower than that observed in follicular and other types of low grade lymphoma. The outcomes of patients with transformation were significantly better than reported in other types of transformed lymphoma and did not adversely affect OS. Disclosures: No relevant conflicts of interest to declare.