Evens, Andrew M.

Abstract Introduction For patients with Stage III/IV Hodgkin lymphoma (HL), lack of response as assessed by PET scan following cycle 2 (PET2) of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is predictive of poor clinical outcomes. SWOG Study S0816 utilized response-adapted therapy, where patients achieving a complete remission (CR) on PET2 (Deauville Score ≤ 3) continued 4 additional cycles of ABVD and those patients unable to achieve a complete remission (CR) on PET2 (Deauville Score > 3) were switched to therapy with escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. This study demonstrated a 2-year PFS of 64% in the PET2+ patients after switching to eBEACOPP, which was much higher than expected (Press 2016). Herein, we report the 5-year follow-up of survival and toxicities of the patients treated on S0816. Methods Patients with Stage III/IV HL were enrolled to S0816 from 7/1/09-12/2/12 (n=358). Eligible patients were age 18-60 years, had measurable disease, no prior lymphoma therapy, a Zubrod performance status of 0-2, and no serious medical comorbidities. Patients were treated with response-adapted therapy as above. A subset of 336 eligible and HIV-negative patients were analyzed. Of 336, 331 had central review of PET2. PFS and OS estimates were calculated using the Kaplan-Meier method. The two-sided Fisher's exact test was used to compare the rate of second cancer between patients switched to treatment eBEACOPP and those treated with continued ABVD after 2 initial cycles of ABVD. Results The median age of patients was 32 years (range, 18-60). All were Stage III/IV and 51% had an International Prognostic Score of ≥ 3. PET2 was negative in 271 patients (82%) and positive in 60 patients (18%). Of PET2+ patients, 49 (82%) switched to eBEACOPP as planned and 11 (18%) declined. Median follow-up is now 5.9 years (range, 0.2-8.3 years). Eighty-five (25%) patients have either progressed or died, for an estimated 5-year PFS of 74% (95% CI: 69%-79%; Figure 1). There were 64 (24%) events in those patients who were PET2- for a 5-year PFS of 76% (95% CI: 71-81%; Figure 2). There were 20 (33%) events in those patients who were PET2+ for a 5-year PFS of 65% (95% CI: 51-76%; Figure 2). One event occurred in a patient without central review of PET2. Nineteen patients have died for an estimated 5-year overall survival of 94% (95% CI: 91%-96%; Figure 1). Eleven (3%) patients died of HL including 6 (2%) that had PET2- and 5 (8%) that had PET2+. Other causes of death included: treatment-related toxicity [sepsis (eBEACOPP n=1), bleomycin lung injury (eBEACOPP n=1; ABVD n=1), and graft versus host disease (ABVD n=1)]; second primary cancers [(eBEACOPP n=2; cervical cancer and non-Hodgkin lymphoma (NHL)]; and unknown causes (ABVD n=2). Post-therapy grade 3 adverse events were uncommon but included 1 case each of heart failure, peripheral neuropathy, prolonged neutropenia, diarrhea, DVT (catheter-related) in patients who received continued ABVD and osteonecrosis of hips/shoulders in patients who received eBEACOPP. There were 13 (4%) cases of reported second cancers, including 7 (14%) in patients treated with eBEACOPP [1 each of myelodysplastic syndrome, kidney, melanoma, NHL, cervical, medullary thyroid, and basal cell carcinoma] and 6 (2%) in patients treated with ABVD (1 each of kidney, melanoma, NHL, bladder, prostate, and squamous cell carcinoma; 2-sided Fisher's exact P value = 0.001). Conclusions The long-term overall survival of the patients treated on S0816 remains high (94%) at 5 years. Despite historical data suggesting favorable clinical outcomes in patients with a negative PET2, nearly 25% of these patients experienced relapse events, demonstrating limitations of a PET-adapted approach and of standard frontline therapy with ABVD. In patients who were PET2+, PFS was favorable relative to historical series, but was associated with a high rate of secondary malignancies. Our results emphasize the importance of long-term follow-up in this disease, and the need for better biomarkers at diagnosis of HL and less toxic approaches for patients with a positive PET2. Acknowledgment In memory of Oliver W. Press, principal investigator of this trial, who died in 2017. Disclosures Straus: DAVA Oncology: Consultancy, Honoraria; Medical Crossfire: Speakers Bureau; Millenium (Takeda): Consultancy, Research Funding; JUNO: Consultancy; Bayer: Consultancy; Onco Tracker: Consultancy; Seattle Genetics: Consultancy; Roch China: Speakers Bureau; InPractice Elselvier: Consultancy; Memorial Sloan Kettering Cancer Center: Employment. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Bartlett:ImaginAB: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Evens:Janssen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Acerta: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria. Barr:AbbVie, Gilead: Consultancy. Leonard:Gilead: Consultancy; Sutro: Consultancy; BMS: Consultancy; Juno: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Biotest: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Genentech/Roche: Consultancy; ADC Therapeutics: Consultancy; United Therapeutics: Consultancy. Kahl:Genentech: Consultancy; Celgene: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Juno: Consultancy; CTI: Consultancy; ADC Therapeutics: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.

Abstract Background: Bortezomib has efficacy in follicular lymphoma (FL). Though generally well tolerated, it is associated with a few known toxicities, including neurotoxicity. As a chronically administered agent, it is important to investigate the tolerability of bortezomib over time as a single agent and in combination with chemotherapy. The current method of summarizing adverse events (AEs) -focusing on the maximum grade and reporting only grade 3 or higher incidences- fails to capture toxicity that evolves over time or chronic low grade AEs that may occur at significant expense to patients' quality of life. In this study, we applied the Toxicity over Time (ToxT) analytic approach (Thanarajasingam et al, Lancet Oncol 2016), which graphically and analytically depicts AEs longitudinally, to a randomized Phase 2 ECOG-ACRIN sponsored study, E2408, to characterize chronic toxicity of bortezomib (V) when added to standard bendamustine-rituximab (BR) induction in previously untreated high risk FL. Methods: In E2408, patients (pts) were randomized to one of 3 arms at a 1:2:2 ratio: A) BR x 6 followed by maintenance rituximab (MR) x 2 years (yrs) vs B) BVR x 6 (bortezomib 1.3 mg/m2 IV/SQ days 1, 4, 8, 11) then MR x 2 yrs vs C) BR x 6 then MR x 2 yrs + lenalidomide 20mg/day x 1 yr. Pts enrolled 1/2011-5/2015. This analysis focuses on the 6 cycles of induction only, with arms A and C combined. Six AEs of interests were selected, 4 symptomatic (subjective) AEs (peripheral sensory neuropathy (PSN), diarrhea, febrile neutropenia, fatigue); and 2 non-symptomatic (objective) AEs (neutropenia and thrombocytopenia). Treatment-related post baseline AEs of any grade were investigated by conventional maximum grade toxicity analysis (ToxC) and ToxT methods. The mean AE grades over cycles were analyzed by repeated measures models, time to grade 2 or higher (gr2+)AE were analyzed with time-to-event analysis; and AE profile over the entire course of the study was summarized by area under the curve (AUC) analyses. Comparisons were performed between treatment arms (BVR vs. BR). Results: All 280 randomized treated pts (187 on BR, 93 on BVR) were included in the analysis regardless of eligibility status; 87% (163/187 BR, 81/93 BVR) completed all 6 cycles. Analyzing the symptomatic AEs,ToxC indicates that the overall incidence of grade 3+ PSN was significantly higher in BVR (12%) than BR (1%) (p<.0001). Additional, ToxT captures the trajectory, demonstrating a rapid, rising incidence and worsening grade of PSN on BVR vs BR over 6 cycles in a steam plot of mean gr. by cycle (Fig 1a) and bar chart of incidence and grade per cycle (c1: 13% gr1 3% gr2, c6: 36% gr1 12% gr2 6% gr3 on BVR; c1: 3% gr1, c6: 10% gr1 1% gr2 on BR, Fig. 1b). Risk of developing gr2+ PSN was significantly higher in BVR than BR with 28% vs 0.5% by day 100 (HR=0.01, p<.0001, Fig. 1c). ToxC captures a higher incidence of grade 3+ diarrhea on BVR (7% vs. 1% , p=.01) while AUC from ToxT includes chronic lower grade diarrhea, that is substantial over time on BVR vs. BR (p<.0001), but is not cumulative. Furthermore, the risk of developing gr2+ diarrhea affecting drug tolerability is significantly higher on BVR than BR(13% vs 5% by day 100) (HR=0.3, p=.05). Febrile neutropenia appeared to be similar, and fatigue was marginally more severe under BVR (p=.06 by AUC). For objective AEs, ToxC reveals no significant difference in neutropenia or thrombocytopenia BVR vs BR (neutropenia gr 3+: 36% vs 31%, p=.4; thrombocytopenia gr3+: 10% vs. 5%, p=.12). However, ToxT illustrates that neutropenia is cumulative, worsening over repeated exposure to drug (c1: 2% gr1 5% gr2 5% gr 3+ , c6: 7% gr1 10% gr2 12% gr3+ both arms combined; p<.0001) on mean grade over time (Fig. 2a). In contrast, thrombocytopenia does not worsen with continued treatment (Fig 2b, p=.73). Conclusions: Compared with conventional toxicity analysis (ToxC), ToxT delineated important additional and clinically relevant depictions of both symptomatic and laboratory AEs over time for bortezomib added to BR in FL pts. In patients receiving BVR, close monitoring is suggested for PSN, diarrhea and neutropenia for reassessment of risks and benefits, symptom interventions and dose modification. Longitudinal toxicity analyses such as ToxT can guide AE interventions as well as patient and clinician education, and provide a more patient-centered toxicity assessment of chronically administered therapies for lymphoma. Disclosures Hong: Merck: Consultancy. Evens:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Affimed: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees. Advani:Kura: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Infinity: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Janssen: Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Forty Seven Inc.: Research Funding; Merck: Research Funding; Millenium: Research Funding; Agensys: Research Funding; Celgene: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dueck:Bayer: Employment; Pfizer: Honoraria; Phytogine: Employment. Kahl:Genentech: Consultancy; Acerta: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; Abbvie: Consultancy; Juno: Consultancy; Gilead: Consultancy; Celgene: Consultancy; CTI: Consultancy; AstraZeneca: Consultancy.

Abstract Background: There remains a critical need to identify untreated HR FL patients (pts) who are at increased risk of early progression and death with conventional treatment. Data examining baseline PET has been reported to be prognostic in FL, however, there remains a paucity of data analyzing this in the context of bendamustine/rituximab (BR) induction followed by maintenance rituximab (MR). We examined the prognostic impact of baseline PET metabolic imaging from the randomized BIONIC study for pts with untreated HR FL. Methods: The BIONIC study conducted by the ECOG-ACRIN Cancer Research Group enrolled untreated grade I/II or IIIa FL pts with HR disease defined as GELF high tumor burden and/or FLIPI score of 3-5. Pts were randomized to: a) standard BR induction x 6 followed by maintenance rituximab (MR) q 2 months x 2 years vs b) bortezomib + BR x 6 followed by MR q 2 months x 2 years vs c) BR x 6 followed by q 2 months MR x 2 years + lenalidomide given concurrently with the first year of MR. Survival analyses showed no significant differences in 4-year progression-free survival (PFS) or overall survival (OS) for any study arm (Evens AM et al, ASH 2017). All pts were thus pooled for the purpose of analyzing baseline PET imaging and other characteristics and for correlation with clinical outcomes. Kruskal-Wallis & Wilcoxon Rank Sum test were used to assess differences in distribution of: metabolic measurements (SUVmax and SUVmean of the dominant mass (i.e., the mass/lesion with the highest SUV uptake); metabolic tumor volume (MTV); and total lesion glycolysis (TLG) by categorical variables); induction treatment response; and end-of-induction (EOI) PET response vis-à-vis Deauville scoring (1-3 = negative). Cox proportional hazards regression was used to correlate these metabolic measurements with PFS & OS and multivariable analyses were conducted. An optimal cutoff threshold (grouping into 'High' or 'Low' categories) was used for the metabolic measurements that were significantly associated with PFS & OS. Results: Metabolic data were received and measurements were analyzed centrally on 182 (71%) of 257 eligible pts. The EOI overall response rate (ORR) for all pts on study was 92% with a complete remission (CR) rate of 73%. Additionally, 12% of pts experienced early progression of disease (POD) within 2 years. SUVmax was borderline for association with PFS (P=0.06) and MTV and TLG were not associated with PFS or OS. We demonstrated a statistically significant linear relationship between continuous SUVmean score with PFS and OS, and thereafter, used the minimum p-vlaue approach to determine the optimal cutoff threshold of 7.03 to group pts into 'High' and 'Low' risk groups; with this threshold, baseline SUVmean of the dominant mass was categorized as high risk in 27% pts. The 4-year PFS rates for SUVmean low vs high groups were 80% (95% CI 72, 90%) vs 55% (40, 74%), respectively, P<0.001; and the corresponding 4-year OS rates were 93% (89, 98)% vs 80% (95% CI 69, 93%), respectively, P=0.01 (see Fig. 1). Sensitivity analyses showed no differences in baseline SUVmean by study arm, GELF or FLIPI. The only clinical characteristic that varied among patients with low vs high baseline SUVmean was Black race (0.8 vs 8.0%, respectively, Chi-square P=0.08); there were no other differences based on age, sex, stage, FLIPI, GELF status, ECOG PS, LDH, or # of extranodal sites. In addition, baseline SUVmean correlated with EOI PET (negative EOI PET with baseline SUVmean Low vs High: 81% vs 62%, respectively, P=0.03). In multivariable analyses, both baseline SUVmean and EOI PET remained significant (SUVmean: PFS HR 2.62 (95% CI 1.40-4.92), P=0.001, OS HR 2.37 (95% CI 1.01-5.56), P=0.02; EOI PET PFS HR 4.70 (95% CI 2.74-9.54), P<0.001, OS HR 2.78 (95% CI 1.18-6.56), P=0.01). Finally, baseline SUVmean was also strongly predictive of FL pts who experienced early 2-year POD (Chi-square P<0.001). Conclusions: High baseline SUVmean of the dominant mass was a strong independent prognostic factor for survival for untreated HR FL pts treated with BR-based induction with rituximab maintenance and significance was independent of FLIP or GELF criteria. Collectively, this represents a novel and simple method to identify FL pts at increased risk of early POD and poor survival with standard therapy. Continued investigation of combined PET imaging analyses and other correlative studies to enrich prognostication are warranted. Disclosures Hong: Merck: Consultancy. Advani:Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Kyowa: Other: Consulting/Advisory Role; Infinity: Other: Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Millenium: Other: Institutional Research Support; Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Autolus: Other: Consultancy/Advisory Role; Takeda: Other: Consultancy/Advisory Role; Celgene: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; AstraZeneca: Other: Consultancy/Advisory Role; Cell Medica: Other: Consultancy/Advisory Role; Gilead/Kite: Other: Consultancy/Advisory Role; Agensys: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Janssen Pharmaceutical: Other: Institutional Research Support. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kahl:Acerta: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Juno: Consultancy; CTI: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy. Evens:Affimed: Consultancy; Novartis: Consultancy; Acerta: Consultancy; Bayer: Consultancy; Tesaro: Research Funding; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy.

Abstract Background Survival rates for older pts with advanced HL (aged ≥60 yrs) were historically poor with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). Reasons may include decreased tolerance of therapy, increased toxicity (particularly with bleomycin), comorbidities, and disease biology. The pivotal phase 3 ECHELON-1 study demonstrated superior 2-yr modified progression-free survival (mPFS) with frontline brentuximab vedotin + doxorubicin, vinblastine and dacarbazine (A+AVD) vs ABVD in pts with stage III/IV cHL (Connors JM et al, NEJM 2018). The study allowed entry of older pts, with no upper age limit. Alternative dosing schedules of the A+AVD regimen have been studied (e.g., sequential brentuximab vedotin before and after AVD; NCT01476410, Evens AM et al, J Clin Oncol 2018). We report efficacy and safety results from ECHELON-1 for older pts with cHL and compare these with those for pts aged <60 yrs. Methods mPFS per independent review facility (IRF) for pts ≥60 years was a prespecified subgroup analysis of ECHELON-1. Additional exploratory safety and efficacy analyses were also assessed and compared with younger pts (<60 yrs). The study was not powered for age-based subgroup analyses; p-values are descriptive without multiplicity adjustment. Results 14% (186/1334) of pts in the intent-to-treat (ITT) population were aged ≥60 yrs (A+AVD, n=84; ABVD, n=102) and included in the sub analyses. Median age (range) of older pts was: A+AVD, 68.0 yrs (60-82); ABVD, 66.0 yrs (60-83). Baseline pt and disease characteristics in older pts were similar in both arms. ECOG PS scores were 0 (36% vs 36%), 1 (52% vs 54%), and 2 (12% vs 10%) in A+AVD and ABVD arms, respectively. Pts received a median of 6 cycles with mean relative dose intensities for each drug (%) in older pts of: A+AVD, 92.3, 96.6, 93.3, and 97.9; ABVD, 97.3, 88.7, 93.3, and 95.9. With median follow-up of ~25 months, 2-yr mPFS per IRF was similar in both arms for older ITT pts (A+AVD 70.3% [95% CI: 58.4, 79.4] vs ABVD 71.4% [95% CI: 60.5, 79.8]; HR=1.00 [95% CI: 0.58, 1.72]; p=0.993). An exploratory analysis of standard PFS per investigator (INV) showed HR=0.85 ([95% CI: 0.49, 1.48]; p=0.576) (Table 1). For older pts with stage IV cHL (A+AVD n=51; ABVD n=67), there was an increase in 2-yr PFS per INV with A+AVD vs ABVD (74.0% [95% CI: 59.5, 84.0] vs 59.9% [95% CI: 45.6, 71.5]; HR, 0.66 [95% CI: 0.34, 1.26]; p=0.20); mPFS per IRF improvement with A+AVD in older stage IV pts was lower (HR=0.80; [95% CI: 0.42, 1.53]). In younger stage III/IV pts (<60 yrs) 2-yr mPFS per IRF and PFS per INV were also higher compared with older pts in both arms (Table 1). 66 of 83 older A+AVD pts required ≥1 dose modification of brentuximab vedotin, reasons were: dose reduction (n=27), dose held (n=4), dose delayed (n=51), brentuximab vedotin discontinued (n=17). In older pts, grade (G) 3/4 AEs occurred in 88% of A+AVD pts vs 80% ABVD pts; for younger pts, rates were 82% (A+AVD) vs 63% (ABVD) (Table 2). In older pts there were 3 (4%) on-study deaths in the A+AVD arm (1 each: hemophagocytosis, neutropenic sepsis, and myocardial infarction) and 5 (5%) with ABVD (all pulmonary-related). In pts <60 yrs, there were 6 on-study deaths (1%) with A+AVD vs 8 (1%) with ABVD. G3 neutropenia in older pts was (70%) A+AVD pts vs (59%) ABVD pts, and febrile neutropenia (FN) in 31 (37%) vs 17 (17%) pts. In older pts who had G-CSF primary prophylaxis (PP) neutropenia was seen in 4/10 (40%) A+AVD pts vs 1/9 (11%) ABVD pts (on-study FN in 3 [30%] vs 2 [22%] pts). In older pts, treatment-emergent peripheral neuropathy (PN) was reported in 54 (65%) of A+AVD pts vs 42 (43%) of ABVD pts (G≥3 in 15 [18%] vs 3 [3%] pts), respectively. In pts <60 yrs PN was reported in 388 (67%) A+AVD pts vs 244 (43%) ABVD pts (G≥3 in 55 [9%] vs 8 [1%] pts), respectively. In older pts at last follow-up, 65% (35/54) of A+AVD pts and 60% (25/42) of ABVD pts had complete resolution (A+AVD, 39%; ABVD, 38%) or improvement (A+AVD, 26%; ABVD, 21%) of PN events. 2% older A+AVD pts had pulmonary AEs (both G1/2 pulmonary infiltration) vs 13% older ABVD pts. Conclusions For older ECHELON-1 pts, mPFS and PFS were similar in both arms. In the larger subgroup of younger pts, mPFS and PFS were improved vs older pts. As expected, incidence of treatment-emergent AEs was higher in older pts, with regimen-specific AEs seen, including fatal pulmonary events in ABVD pts. The high incidence of FN in older A+AVD pts points to the need for G-CSF PP. Disclosures Evens: Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Tesaro: Research Funding; Novartis: Consultancy. Connors:Merck: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Roche Canada: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Seattle Genetics: Honoraria, Research Funding; Janssen: Research Funding; F Hoffmann-La Roche: Research Funding; Bayer Healthcare: Research Funding; Cephalon: Research Funding; Bristol Myers-Squibb: Research Funding; Lilly: Research Funding; Genentech: Research Funding. Younes:Sanofi: Honoraria; Merck: Honoraria; Astra Zeneca: Research Funding; Celgene: Honoraria; Incyte: Honoraria; Seattle Genetics: Honoraria; Bayer: Honoraria; Novartis: Research Funding; Curis: Research Funding; J&J: Research Funding; Genentech: Research Funding; Takeda: Honoraria; Roche: Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; BMS: Honoraria, Research Funding. Ansell:Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding. Radford:Takeda: Consultancy, Research Funding, Speakers Bureau; GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Seattle Genetics: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Pfizer: Research Funding; Celgene: Research Funding; BMS: Consultancy, Speakers Bureau. Feldman:Seattle Genetics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Celgene: Speakers Bureau; Portola: Research Funding; KITE: Speakers Bureau. Tuscano:Takeda: Research Funding; Genentech: Consultancy, Research Funding; Amgen: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. Oki:Seattle Genetics: Research Funding; Takeda Millenium: Honoraria, Research Funding; Jazz Pharmaceuticals: Employment. Grigg:Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pocock:Kent & Canterbury Hospital: Employment. Dlugosz-Danecka:Roche: Consultancy; Servier: Consultancy. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Engley:Seattle Genetics: Employment. Liu:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Miao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jolin:Takeda Pharmaceuticals International Co.: Employment. Gautam:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gallamini:Takeda: Consultancy, Speakers Bureau.

Abstract Background Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin’s lymphomas (NHL) characterized by poor treatment outcomes with conventional chemotherapy, including CHOP [complete remission (CR) ∼40%]. Retrospective studies suggest that the incorporation of etoposide into chemotherapy regimens may improve outcomes compared to CHOP. In contrast, anthracyclines appear to have a limited role in PTCL, largely attributed to p-glycoprotein related resistance. Pralatrexate was the first drug approved for patients (pts) with relapsed PTCL, providing a rationale to evaluate it in the front-line setting. Herein, we evaluated the efficacy of a novel combination for the primary therapy of pts with PTCL whereby the anthracycline in CHOP backbone was replaced with etoposide (CEOP) alternating with pralatrexate (P). Methods Pts > 18 years (yrs) with PTCL stages II-IV with no prior therapy and adequate end organ function were eligible. Eligible histologies included, PTCL-NOS, AILT, ALCL (ALK positive pts only allowed if IPI >3). CEOP (Cycle A) was administered as: cyclophosphamide 750 mg/m2 IV d1, etoposide 100 mg/m2 IV d1-3 (or 100 mg/m2 IV d1 and 200 mg/m2 PO days 2-3), vincristine 2 mg IV day 1 and prednisone 100 mg/day X 5 alternating with P (cycle B) 30 mg/m2 IV d 15, 22 and 29 (with vitamin B12 and folate supplementation). Growth factors were used to support both cycles of therapy. Imaging to assess response was done after cycle 2B, 4B and 6B. Pts achieving a remission were eligible for consolidative autologous stem cell transplant (ASCT) after cycle 4B at physician discretion. The primary statistical aim was to improve the CR rate from 40 to 63% with CEOP-P and optional transplant. Secondary objectives included assessment of event free survival (EFS), overall survival (OS) and toxicity of the regimen. A two-stage Simon design (alpha=0.10, 90% power) tested the null hypothesis that the CR rate would be </= to 40%. For the first stage of 20 evaluable pts, the trial would be terminated if 8 or fewer pts experienced a CR after course 2B of chemotherapy. For the second stage, a total of 34 pts were required with at least 17 achieving a CR at the end of therapy to consider the regimen useful. Results 34 pts were enrolled and one withdrew consent before starting therapy, leaving 33 pts enrolled between 7/2011 and 1/2013. Characteristics are shown in Table 1. 27 pts received at least 2 cycles of therapy. 6 pts received only 1 cycle due to early disease progression in 4 and adverse events in 2. Grade 3-4 toxicities attributed to therapy included, anemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). At the end of stage 1, 10 of 20 pts (50%) achieved a CR; therefore accrual proceeded to stage 2. At the time of this initial analysis, the overall response rate is 70%. To date 15 pts (45%) have achieved a CR with two additional pts pending evaluation. Overall, the 1-yr EFS is 48% (95% CI 28-64), and 1-yr OS 70% (95% CI 47-84) (Figures 1 and 2). 6 pts (18%) to date (n=3 CR, n=2 PR and 1 with stable disease) have received consolidation with ASCT and all are in CR post-transplant. Pts who proceeded to ASCT were younger than the non-transplant cohort (median age 58 versus 64 yrs) with other clinical characteristics being similar. On exploratory bivariate analyses, age <60 yrs, absence of B symptoms, low IPI score (0,1), achieving a CR, and receiving a ASCT were associated with better EFS. Attaining a CR was the only factor associated with better OS and was highest in patients with low IPI (78%) and those with ALCL histology (75%). Conclusions CEOP-P met the pre-defined stage 1 response criteria. Longer follow-up is needed to assess the impact on the final CR rate and secondary objectives of EFS and OS. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need. Disclosures: Advani: Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Research Funding. Off Label Use: Pralatrexate is currently only approved for relapsed/refractory PTCL. Lechowicz:Allos Therapeutics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Carson:Spectrum Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau. Foss:merck: Research Funding; spectrum: Research Funding; eisai: Membership on an entity’s Board of Directors or advisory committees; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees; celgene: Honoraria, Research Funding; seattle genetics: Research Funding. Horwitz:Celgene : Consultancy, Research Funding; Spectrum Pharamaceuticals: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Kyowa Hakko Kirn Pharma: Consultancy; Genzyme : Research Funding; Janssen: Research Funding; Millennium: Consultancy, Research Funding. Pro:Spectrum Pharmaceuticals: Honoraria. Pinter-Brown:Spectrum Pharmaceuticals: Consultancy, Honoraria. Smith:Micromet: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Allos: Consultancy; Genentech: Consultancy; Onyx: Consultancy. Shustov:Spectrum Pharmaceuticals: Consultancy, Honoraria. Savage:Spectrum Pharmaceuticals: Research Funding. Vose:Spectrum Pharmaceuticals: Research Funding.

Abstract Background:The role of radiation therapy (XRT) for advanced stage Hodgkin lymphoma (HL) is controversial. In the HD15 trial, the German Hodgkin Study Group (GHSG) administered XRT for PET-positive residual disease ≥2.5 cm at least 2 weeks after completion of chemotherapy and showed 91.5 % in-field control rate with a median follow-up of 102 months (Engert, A; personal communication). However, there is no comparison arm where patients with PET-positive residual disease ≥2.5 cm did not receive XRT. SWOG S0816 was a US intergroup trial utilizing ABVD-based therapy with response adaptation based on interim PET imaging; XRT was not allowed per protocol, and counted as an event. In this analysis, we identified patients in S0816 who would have met HD15 criteria for XRT, but did not receive XRT per design. We then modeled the potential impact of XRT on disease control. Patients and Methods:Of 336 eligible and evaluable HIV-negative patients enrolled in S0816, 49 had an end-of-treatment PET (termed "PET3," to be done 6-8 weeks after completion of chemotherapy) that was positive (i.e. Deauville 4-5) upon central review. We simulated the progression free survival (PFS) if XRT had been delivered per HD15 criteria (PET positive disease and ≥2.5 cm), evaluating by assumptions of 50, 80 and 90% control of the disease within the XRT fields. Receiver operating characteristics (ROC) analyses were performed with additional size cut-off points of 2.0 and 1.5 cm. Results:The median follow-up for the 49 PET3 positive patients was 71 months (range 9.7-92.6). For these 49 patients, the observed landmark PFS at 2 years after the date of PET3 was 30.6%. Twenty-four (49%), 33(67%), and 40 (82%) of the 49 patients had at least one site of disease that met the HD15 criteria for XRT with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm size cut-offs respectively. Sixteen, 19, and 25 patients had disease progression respectively from each group at median of 1.4-1.5 months. Twelve, 12, and 15 patients had relapses limited to the sites that would have been radiated following HD15 criteria with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm respectively. Estimated landmark PFS at 2 years for the 49 PET3 positive patients assuming 50, 80, and 90 % control of the disease within the radiated sites following HD15 guideline with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm cut-off are summarized in columns A, B, and C of the table respectively. For the entire group of 336 patients, the observed PFS at 2 years was 79%. Estimated 2-year PFS for the entire group of 336 patients assuming 50, 80, and 90 % control of the disease within the radiated sites following HD15 guideline with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm cut-off are in columns D, E, and F of the table respectively. Conclusion: Among the PET3 positive patients, consolidation XRT per HD15 criteria with cut-off points of 2.5, 2.0, and 1.5 cm could have raised the 2-year PFS by 12-28 % assuming 50-90% local control within radiated sites. However, the improvement in PFS is more moderate at 1.6-3.9 % if we consider the entire cohort of 336 patients. Although there may be some gain in PFS as the cut-off point is lowered by our ROC analysis, one needs to consider the trade-off against potentially increasing normal tissue toxicity as more sites are irradiated. Table. Table. Disclosures Brem: Pharamcyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees. Bartlett:Merck & Co: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Immune Design: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImaginAB: Research Funding; Janssen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Millennium: Research Funding; Genentech: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Evens:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Janssen: Consultancy; Tesaro: Research Funding; Bayer: Consultancy; Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Leonard:Novartis: Consultancy; Celgene: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; United Therapeutics: Consultancy; BMS: Consultancy; Biotest: Consultancy; Sutro: Consultancy; Karyopharm: Consultancy; Juno: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Bayer: Consultancy. Kahl:Seattle Genetics: Consultancy; Genentech: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy; Juno: Consultancy; Celgene: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.

Abstract Abstract 94 Background: Lymphoma diagnosed during pregnancy is a rare occurrence. Further, there is heterogeneity in clinical presentation and a range of lymphoma histologies resulting in a continued deficiency of lymphoma-specific data in the literature regarding prognosis, optimal therapy, maternal complications, and fetal outcome. Methods: A comprehensive retrospective analysis was completed for patients (pts) diagnosed (dx) with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) during pregnancy at 9 large U.S. academic centers over a 13-year period (1998–2011). The vast majority of cases were co-managed with high-risk maternal fetal medicine. Data on maternal disease characteristics, treatment details, obstetric complications, and fetal outcomes were analyzed. Results: 88 cases were identified with complete data available in 82. The median age of pts was 31 yrs (18–40). Lymphoma dx occurred at a median of 24 weeks (wks) gestation (5–40). 15% of pts were dx during the 1st trimester, 46% during the 2nd trimester, 35% during the 3rd trimester, while 4% (n=3) of pts had a pre-existing NHL dx (follicular lymphoma (FL)). 52% (n=43) of pts had NHL and 48% (n=39) HL. Of NHL cases, 83% (n=33) were B-cell and 17% (n=10) T-cell. B-cell histologies were DLBCL n=23 (including 2 primary CNS and 1 'double hit' NHL), FL n=5 (including 1 leukemic phase FL), Burkitt's lymphoma n=3, and mixed histology n=1; T-cell histologies were anaplastic large cell n=6, PTCL not otherwise specified n=2, and T-cell/NK NHL n=2. Pts with B-cell NHL and HL were dx at a median age of 29 yrs (range, 18–40), while T-cell NHL pts were dx at a median of 34 years (19–37). MRI without gadolinium was the most common imaging modality utilized for staging. 63% of NHL and 19% of HL pts had stage III/IV disease (25% of HL with stage IIB). Pregnancy was terminated in 6 pts (n=4 aggressive NHL and n=2 HD) to enable immediate chemotherapy (five in the 1st trimester [at 5, 8, 10, 10, and 12 wks] and 1 pt in the early 2nd trimester who required high-dose methotrexate). 48 pts (63%) initiated anti-lymphoma therapy at a median of 25 wks gestation (range, 13–37) with 79% of pts initiating therapy in the 2nd trimester (see Table 1). The median gestation at time of lymphoma dx for pts who received intra-partum treatment was 20 wks vs 34 wks for pts who had therapy deferred to post-delivery (p<0.0001). The overall response rate among pts who received therapy was 87% (74% complete remission). Notably, gestation went to full-term in 54% with delivery occurring at a median of 37 wks (31–40). Therapy was deferred until post-delivery in 28 pts (37%) and the majority of these pregnancies were also carried to term (median delivery at 38 wks). At a median follow-up of 41 months (6–157), the 3-year PFS and OS for all pts were 79% and 89% respectively. Histology-specific 3-year PFS and OS were: B-cell NHL: 73% and 82%, respectively; T-cell NHL: 50% and 90%, respectively; and HL: 90% and 95%, respectively (Figure 1). Detailed obstetrical information was available in 59 pts. There were minimal pre-term complications, the most common being induction of labor in 45%. Perinatal events included spontaneous rupture of membranes in 5% and pre-eclampsia in 8%. Further, there were no differences in these events detected among pts who received intra-partum treatment vs deferred therapy. No episodes of chorioamnionitis or endometritis were noted. There was 1 stillbirth that occurred at 19 wks gestation in a 34-year-old pt with double-hit NHL following 1 cycle of R-CHOP. The median birth weight of infants was 2427 grams (1005–5262) with no difference among pts who received intra-partum chemotherapy vs not (2637 grams vs 2212 grams, respectively; p=NS). Microcephaly was reported in 1 case following 4 intra-partum cycles of CHOP for DLBCL; there were otherwise no malformations detected. Conclusions: To our knowledge, this represents one of the largest experiences reported of lymphoma in pregnancy. Our data show that standard NHL and HL chemotherapeutic regimens (without anti-metabolites) administered during the 2nd and 3rd trimester, including as early as 13 wks gestation in select cases, is associated with minimal maternal complications or fetal detriment. In addition, pts with low risk clinical scenarios (e.g., indolent NHL and/or late gestational dx) had therapy safely deferred to post-partum. In our experience, this approach was associated with overall expected lymphoma-related survival. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 879 Background: Several solid organ transplant (SOT) PTLD series have reported that PCNS disease is a poor prognostic factor (e.g., Leblond et al, JCO 2001; Maeker et al, JCO 2007; Knight et al JCO 2009; Evens et al, JCO 2010). However, these reports contained small PCNS PTLD numbers and most series studied patients (pts) in the pre-rituximab era. Methods: We performed an International retrospective analysis of PCNS SOT-related PTLD diagnosed from 1998 through 2010. Cases with secondary CNS localization were excluded. Detailed pt and disease characteristics, including frontline therapy, were evaluated. Fisher's exact test was used to compare PCNS PTLD vs non-PCNS PTLD cases. Further, univariate associations with survival were determined, while a multivariate Cox regression proportional hazards model was performed. Results: 71 PCNS PTLD cases were identified, of which 65 had complete data. There were 35 men and 30 women; the median age was 53 years (range, 20–77 years). The most common type of SOT was kidney in 72%, followed by lung 18% and 5% each pancreas and heart. The median time from SOT to PCNS PTLD was 46 months (range, 2 to 504 months). Further, only 18% occurred within 12 months of SOT, and 32% of PTLD diagnoses occurred > 10 years after SOT. 85% of pts had received prior mycophenolate, while 30% received tacrolimus prior to PCNS PTLD. According to WHO histology, 83% of PCNS PTLD cases were monomorphic subtype (all B-cell), while tumor was EBV+ in 93% despite EBV being detectable in the peripheral blood (by PCR) in only 38% of these cases. In addition, 49% of pts had poor performance status (i.e., 2–4), 48% had elevated LDH, and 48% were hypoalbuminemic at diagnosis. Interestingly, several of these characteristics were notably different when compared with a non-PCNS PTLD cohort (Table 1A). All pts here presented with CNS-related symptoms and 98% had abnormal findings on MRI showing a parenchymal brain lesion(s); 50% of pts had >1 CNS lesion and 40% had involvement of deep regions of the brain. Further, 12% had concomitant CSF involvement, while no pts had ocular involvement. In terms of therapy, 89% of pts had reduction in immunosuppression (RI). Additional frontline therapy consisted of high dose methotrexate (HD-MTX)-based therapy in 43% (46% of whom also received concurrent rituximab), whole-brain radiation in 20% (61% with rituxmab), high-dose cytarabine (HDAC)-based in 15% (30% with rituximab), while 11% received rituximab alone and 11% had no other therapy (i.e., RI alone). Altogether, 48% of pts received rituximab as part of initial therapy. The overall response rate (ORR) was 55% with 30% complete remission (CR) rate. With a median follow-up of 39 months (1–135), the 3-year progression-free survival (PFS) and overall survival (OS) for all pts were 31% and 32%, respectively (Figure 1). Pts who received rituximab vs not as a component of first line therapy had superior PFS (40% vs 22%, respectively, p=0.02) and borderline improved OS (43% vs 22%, respectively, p=0.06), while pts who did not receive rituximab nor HD-MTX-based therapy as frontline therapy did particularly poor (PFS and OS both 10%). Several pre-treatment and treatment-related factors predicted survival on univariate analysis (Table 1B). When analyzing only pre-treatment related factors in the Cox multivariate regression model, only increasing age remained significant (PFS: HR 1.04 [95%CI 1.00–1.07], p=0.031; and OS: HR 1.04 [95%CI 1.01–1.08], p=0.020). With treatment-related factors included in the model, response to frontline therapy (CR or partial remission) was the dominant predictive factor of survival on multivariate analysis (PFS: HR 0.136 [95%CI 0.047–0.390], p=0.0002; and OS: HR 0.130 [95%CI 0.045–0.381], p=0.0002). Conclusion: These data represent the largest report of PCNS PTLD to date. PCNS PTLD appears to represent a distinct biologic and clinical entity within the PTLD spectrum that retains EBV positivity, occurs late, and presents with additional high-risk features. Furthermore, outcome of PCNS PTLD remains overall modest. However, these data suggest that rituximab and HD-MTX appear to favorably impact survival. Continued study of this subset of pts is critically needed. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 702 Background: Large granular lymphocyte (LGL) leukemia is characterized by clonal expansion of cytotoxic T cells. Prominent clinical features include neutropenia, anemia, and rheumatoid arthritis. The terminal effector memory phenotype (CD3+/CD8+/CD57+/CD45RA+/CD62L-) of leukemic LGL suggest a pivotal chronic antigen driven immune response. LGL survival is then promoted by PDGF and IL-15 (Proc Natl Acad Sci USA 105:16308, 2008), resulting in global dysregulation of apoptosis and resistance to normal pathways of activation-induced death (Blood 112:770, 2008). These pathogenic features explain why treatment of LGL leukemia is based on immunosuppression therapy. However, no standard therapy has been established due to the absence of large prospective trials. Methods: Eligibility criteria included increased number of LGL (CD3+CD57+ cells > 400/ul or CD8+ cells >650/ul) plus evidence of clonal rearrangement of T cell receptor gene. Treatment indications included the following categories: a) severe neutropenia (ANC < 500/ul); b) neutropenia associated with recurrent infections; c) symptomatic anemia; and, d) transfusion-dependent anemia. Initial Treatment: (Step 1) consisted of methotrexate (MTX) at 10 mg/m2 po in divided doses once weekly. Prednisone was given at 1 mg/kg po × 30 days and then tapered off in the subsequent 24 days. Patients not responding to MTX received cyclophosphamide (CY) at 100 mg po daily with the same prednisone schedule (Step 2). Treatment response was assessed after four months of therapy as: complete remission (CR): normal CBC (ANC ≥ 1,500/ul, lymphocyte count <4,000/ul, hemoglobin ≥ 11 g/dl, and platelet count > 100,000/ul. In addition, LGL counts needed to be within normal range. Partial response (PR) was defined as improvement in hematologic parameters in the absence of CR: 1) ANC > 500, as long as this represented 50% increase (category a); 2) improvement in ANC ≥ 50% over baseline (category b); 3) increase in hemoglobin by ≥ 1 g/dl for at least four months duration (category c); and, 4) decrease in monthly transfusion requirement of > 50% for at least four months (category d). Progressive disease (PD) was defined as worsening of hematologic parameters in patients previously achieving PR/CR. No response (NR) was defined as lack of CR/PR. Results: Response data are shown for Step 1 (Table 1) and for Step 2 (Table 2). Overall response rate (CR/PR) for MTX was 37%. In patients failing MTX, the overall response to CY was 64%. There were two infectious deaths during Step 1 therapy. Conclusion: Data documenting efficacy of immunosuppressive therapies commonly utilized in LGL leukemia (MTX, CY, Cyclosporine) are limited to 300 patients published primarily as small retrospective studies. Such data show an overall response rate to MTX of 58% (56/96 patients). Here in the only large prospective trial we observed an overall response rate of 37%. Overall response rate of 64% for CY was not statistically different than MTX. However, given that CY response rate was observed in MTX failures, future studies should consider evaluation of CY as initial therapy. Disclosures: Off Label Use: Immunosuppressive therapies for LGL leukemia including Methotrexate and Cyclophosphamide.

Motexafin gadolinium (MGd, Xcytrin®) is a novel anti-cancer drug that selectively concentrates in cancer cells and disrupts redox dependent pathways by targeting oxidative stress related proteins such as thioredoxin reductase and metallothioneins. MGd has been shown to generate reactive oxygen species and induce apoptosis in tumor cells. We initiated a study to evaluate the safety and efficacy of MGd in two B-cell malignancies, relapsed/refractory LG and relapsed/refractory CLL or CLL/small lymphocytic lymphoma (CLL/SLL). MGd was given intravenously (IV) at 6mg/kg/day for 3 days q 2 weeks for LG and 5mg/kg/day for 10 days q 3 weeks for CLL/SLL. Ten patients (pts) with LG (2 grade 1, 5 grade 2, 1 grade 3 follicular, 2 marginal zone), 2 pts with CLL/SLL and 1 pt with CLL have been enrolled. Median age was 64.5 yrs (range 44–77), median prior treatment regimens was 3.5 (range 1–6) and median time from diagnosis to treatment was 52 mo. Many LG pts had failed prior aggressive treatment regimens including: CHOP (4), ICE (1), HyperCVAD(1), auto-bone marrow transplant (1); all failed rituxamab and 6 failed Zevalin. CLL/SLL and CLL pts had failed rituxamab (3), fludarabine (2), and R-CHOP (1). MGd related adverse events included skin and urine discoloration (6 and 4 pts), diarrhea, nausea, vesiculobullous rash, peripheral neuropathy (3 pts each). MGd related ≥gr 3 adverse events included skin rash (3 pts), fatigue, neuropathy, photosensitivity (1 pt each). Importantly, no MGd-related myelosuppression was observed. In 12 evaluable pts, there have been three PRs of 2+, 5+ and 8 months duration (2 follicular, 1 CLL). Two pts had SD (follicular, SLL) one of these had resolution of lymphoma related autoimmune hemolytic anemia. Responses occurred after ≤2 cycles of therapy and were seen in patients after extensive prior treatment (mean 4.3 prior regimens, range 3–7). MGd is a non-myelosuppressive drug with single agent activity in LG and CLL/SLL.