Inwards, David J.

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 Abstract 3211 Poster Board III-148 Although autologous stem cell transplantation (ASCT) has become standard of care for many patients with hematologic malignancies, many patients fail to collect a minimum number of CD34 + stem cells to support high dose chemotherapy and ASCT. Recently, plerixafor, a CXCR4 antagonist, was FDA approved for use in combination with G-CSF for autologous peripheral blood stem cell mobilization in patients with NHL or Multiple Myeloma. In February 2009, we commenced a risk adapted approach to the utilization of plerixafor. The study was restricted to patients mobilized with GCSF alone and patients undergoing chemotherapy primed PBSC mobilization were excluded. Peripheral blood stem cell mobilization was commenced with G-CSF at 10 mcg/kg/day. On day 4, a peripheral blood (PB) CD34 count was measured. For patients whose PB CD34 was ≥10/μL, apheresis was commenced the following morning. For patients whose PB CD34 was <10/μL, it was measured again on day 5; if ≥10/μL then apheresis was commenced the following morning. If PB CD34 was <10/μL on day 5, plerixafor (0.24 mg/kg sc) was administered on the evening of day 5 and apheresis was commenced the following day (Group A). In addition, during apheresis, for patients whose collection yield was < 0.5 × 106 CD34/kg, in the absence of instrument failure or problems with the collection procedure, plerixafor was added (Group B). Morning administration of G-CSF and evening dosing of plerixafor continued daily until apheresis was complete. From February to July 2009, 174 mobilization attempts occurred; 27 with chemotherapy and 147 with cytokines alone. The 147 pts who underwent mobilization with cytokines alone are presented here. The underlying diagnosis was as follows: Myeloma 61 pts, NHL 54 pts, Amyloid 17 pts, Hodgkin 10 pts, POEMS 4 pts and 1 pt with a solid tumor. For the entire group the median number of CD34 cells collected was 5.5 × 106 CD34/kg (range 0.1-17). The median number of apheresis was 3 (range 1-12). 67 patients (46%) received plerixafor; 37 patients started plerixafor during mobilization (Group A) and 30 patients during collections due to a poor yield (Group B). 12 pts of the 37 received plerixafor on day 4 because of prior mobilization failure or high risk of mobilization failure and are included in Group A. Table 1 outlines the details of mobilization and collection by groups. By disease category, of the 61 patients with MM, 28 (46%) received plerixafor (8 Group A and 20 Group B). Median apheresis in all the MM pts was 2 (range 1-12) with a total of 6.8 × 106 CD34/kg (2.2-16.7). In the 54 NHL pts, 32 (59%) received plerixafor (24 Group A and 8 Group B). Median apheresis for all pts with NHL was 3 (range 1-7) with a total of 4.6 × 106 CD34/kg (range 0-11.4). Overall, only 7 of 147 (5%) mobilization attempts failed to achieve a minimum of 2 × 106 CD34/kg. This compares to a 22% failure rate prior to institution of this risk adapted approach. In conclusion, implementing this risk adapted approach allows poor mobilizers to be identified promptly and for plerixafor to be initiated during mobilization and collection, thereby reducing the number of mobilization failures. In patients who predictably would not have successful collection based on a PB CD34 <10/μL, addition of plerixafor results in a majority of patients achieving an adequate collection. This risk adapted approach may be more cost effective than reattempting mobilization after a prior failure or utilizing combination G-CSF and plerixafor for upfront mobilization. Table 1. Mobilization and Collection data. All patients N=147 Group A1 N=37 Group B2 N=30 No Plerixafor N=80 PB CD34 day 4 Median 11 0 7 19 Range 0-331 0-7 0-32 0-331 PB CD34 day 5 Median 10 4.5 12 15 Range 0-51 2-9 11-23 9-51 Apheresis Yield Median 5.5 4.4 6.0 6.2 Range 0.1-17 3.1-12.7 3.0-12.2 2-17 Number of Apheresis Median 3 3 5 2 Range 1-12 1-7 4-12 1-8 Days of Plerixafor Median n/a 3 2 n/a Rang 1-7 1-8 1 Group A – Plerixafor initiated prior to apheresis 2 Group B – Plerixafor initiated during apheresis Disclosures No relevant conflicts of interest to declare.

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 44 patients with relapsed or refractory CD20+ NHL were enrolled on a phase I trial of dose-escalated 90YZ followed by high-dose BEAM and autotransplant in which the 90YZ dose was patient-specific based on dosimetry. 90YZ doses were calculated to deliver cohort-defined radiation doses (100–1700 cGy) to critical organs (liver, lung or kidney) with 3–6 patients per cohort. On D-22, rituximab (R) 250 mg/m2 was infused followed by 111In Zevalin®. Imaging was performed immediately and at 4, 24, 72 and 144 hours; dosimetry was performed on D-15. On D-14, R was followed immediately by 90YZ at the cohort-prescribed dose. On D-6 through D-1, patients received high-dose BEAM. On D0, a minimum of 2.0 × 106 CD 34+ cells/kg was infused and G-CSF 5 μg/kg SQ daily begun. The median age was 54 (range: 25–73) years. NHL histologic subtypes were as follows: 16% mantle cell, 57% diffuse aggressive, 11% low-grade and 16% transformed. 43% had recieved 3 or more chemotherapy regimens, and 70% had received R either alone or in combination with chemotherapy. The toxicity profile was similar to that associated with high-dose BEAM. The most common grade III/IV toxicities were infection, fever, stomatitis, nausea, vomiting, diarrhea. One patient experienced transient veno-occlusive disease at the 700 cGy dose level. Two dose-limiting toxicities occurred at the 1700 cGy dose level: one patient with grade 4 stomatitis died of pneumonia and sepsis on D+10, and one patient experienced septic emboli to the lung on D+13. Engraftment occurred at a median of 10 days (range: 8–18 ) to granulocytes ≥ 500/μL, and 21 days (range: 11–40 days) to platelets ≥20,000/μL. One heavily pretreated patient developed MDS on D+291 and expired of sepsis on D+483. With a median follow-up of 21 months, the three year overall and progression-free survivals are 52% and 37%, respectively. 90YZ Zevalin ® Dosing for Cohorts 5–9 (median;range) Cohort (cGy) Total Dose (mCi) mCi/kg 900(n=3) 28(27–37) 0.3(0.3–0.4) 1100(n=5) 51(29–65) 0.6(0.5–0.8) 1300(n=5) 61(39–98) 0.6(0.5–1.1) 1500(n=6) 73(51–99) 0.9(0.5–1.4) 1700(n=3) 98(82–104) 1.2(1.1–1.2) For dosimetry-based trials, 1500 cGy to the critical organ (nearly always liver) is the recommended dose. Although patient-specific doses calculated to deliver a cohort-prescribed absorbed radiation dose to the critical organ were highly variable, the two dose-limiting toxicities ocurred at nearly identical doses (1.14, 1.20 mCi/kg) when calculated according to weight. Whereas eight other patients safely received at least twice the conventional 0.4 mCi/kg dose, 0.8 mCi/kg is the recommended dose for phase II studies, if dosing is to be based on weight and not dosimetry. Outcomes are encouraging given the high-risk patient population. A phase III trial will be required to establish whether or not the addition of 90YZ to high-dose BEAM improves outcomes in NHL patients undergoing autotransplant.

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 Background: A previous trial of 2-CDA as a single agent for therapy of mantle cell lymphoma demonstrated this agent to be efficacious with an overall response rate of 81% (31% complete responses) (Blood 1999 Nov 15; 94:660a). A phase II study of the addition of rituximab to 2-CDA was conducted by the North Central Cancer Treatment Group based on improved outcomes achieved by the addition of rituximab to other regimens active in MCL. Methods: This one-stage phase II study was designed to determine the complete response (CR) or complete response/unconfirmed (CRu) rate. Central pathology confirmation of cyclin D1 positive mantle cell lymphoma was required. No previous therapy for lymphoma was allowed, with the exception of splenectomy. The schedule was rituximab 375 mg/m2 IV day 1; 2-CDA 5 mg/m2/d IV days 1–5 of a 4-week cycle. After 2 of the first 6 patients developed grade 4 neutropenia, subsequent patients received either pegfilgrastim or filgrastim support. Patients received 2–6 cycles of therapy, depending on response. Patients were required to achieve at least a PR after 2 cycles of therapy to continue on protocol therapy. Results: Patient characteristics of all 29 eligible pts: median age: 70 (range: 41–86); 21 male, 8 female; PS 0 (55.2%), PS 1 (41.4%), PS 2 (3.5%); stage II (6.9%), stage III (3.5%), stage IV (89.7%); prior splenectomy (20.7%). The only grade 4 adverse events occurring more than once were neutropenia (24.1%) and leucopenia (6.9%). One patient died of cerebral ischemia in the setting of pneumonia without neutropenia. Fifteen (51.7%; 95% CI: 32.5–70.6%) pts achieved a CR; only one has relapsed to date (665 days after starting therapy). Four additional pts achieved a PR. Ten pts have progressed with 4 pts progressing early at 17, 45, 46, and 71 days (two of whom have died). Ten pts (34.0%) went on to receive further therapy off study, 5 in less than a PR after 2 cycles, 2 in PR after study therapy, and 1 who went off study for a rash. Fourteen pts (48.3%) have progressed or gone on to receive additional therapy off study. At last contact, 26 (89.7%) were alive (median follow-up 14.3 months; range: 6–34). One year survival rate is 89.3% (95% CI: 78.5–100). Conclusions: Rituximab and cladribine were well tolerated for the treatment of MCL in a group of elderly patients. The response rate may have been underestimated due to the study design, which required at least a PR after 2 cycles to continue therapy. Despite this, 52% achieved a complete remission. Complete remissions attained with this regimen appear to be durable, with a single relapse to date among 15 patients achieving CR.

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: Follicular lymphoma is a B-cell malignancy in which tumor-immune system interactions have the potential to profoundly influence malignant cell growth. Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a negative regulator of T cell activation that can serve to dampen anti-tumor immune responses. Administration of blocking anti-CTLA-4 monoclonal antibodies has been shown to improve host resistance to immunogenic tumors and amplify the anti-tumor effects of cancer vaccines in a variety of mouse tumor models. Recently, the anti-CTLA-4 antibody ipilimumab (MDX-010) has been shown to have significant clinical activity against melanoma, prostate, and ovarian cancers, with clinical responses associated with autoimmune events. Methods: We have therefore initiated a phase I/II trial of ipilimumab, a blocking fully human monoclonal antibody to CTLA-4, in patients with relapsed or refractory follicular lymphoma (grade 1 or 2). Enrollment is stratified into 2 cohorts, with half of patients required to be previously treated with a lymphoma vaccine (idiotype or other). It is hypothesized that previously vaccinated subjects are more likely to have anti-lymphoma T cells amenable to activation by an anti-CTLA-4 antibody. Study objectives include characterization of drug safety, immunologic activity and potential clinical efficacy. Treatment consists of MDX-010 at 3 mg/kg, then monthly at 1 mg/kg x 3, with plans to escalate to 3 mg/kg monthly x 4 if tolerated. Results: To date, 12 patients have been treated and accrual to the first dose level has been completed. All patients were previously treated and the median number of prior treatment regimens was 2 (range 1–4). Eight patients had previously received rituximab and 6 patients had received prior anti-idiotype vaccines. Nine patients have completed therapy with ipilimumab and 3 patients are still receiving treatment. Ipilimumab was generally well tolerated and the most common adverse events attributed to ipilimumab in the first 9 patients include diarrhea (grade 3–3 patients, grade 1–1 patient), abdominal pain (grade 2–4, grade 1–2), anorexia (grade 2-1, grade 1 – 2), fatigue (grade 2 -2, grade 1–3, and neutropenia (grade 3-1, grade 1– 2). Among 9 patients evaluable for clinical response, 1 previously vaccinated patient had partial regression of multiple abdominal nodes, ongoing at 10+ months. T cell proliferative responses to the recall antigens tetanus toxoid and keyhole limpet hemocycanin (in idiotype-vaccinated cases) were measured pre- and post-ipilimumab. In 3 of 5 cases tested, including the patient with a clinical response, T cell proliferation to KLH and/or tetanus was significantly increased (>2-fold) one month after initiation of ipilimumab, implying expansion and/or activation of the memory T cell pool. Conclusions: Blockade of CTLA-4 signaling using ipilimumab is well tolerated at the dose used thus far in this ongoing study and has anti-tumor activity in patients with follicular B-cell lymphoma. Further evaluation of the efficacy of ipilimumab at this and higher doses is therefore warranted.

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 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.