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PURPOSE Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches. METHODS We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019. RESULTS In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively. CONCLUSION The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.

7549 Background: MZL is a rare indolent B-cell malignancy considered incurable at recurrent stage. Bruton tyrosine kinase (BTK) inhibitors have produced durable responses in patients (pts) with R/R MZL. Acalabrutinib (acala) is a potent next-generation BTK inhibitor with high selectivity for BTK. We report data for acala monotherapy from the R/R MZL cohort (phase 2) of a phase 1b/2 clinical trial (NCT02180711). Methods: Pts with histologically confirmed MZL, ECOG performance status ≤2, and ≥1 prior therapy (including ≥1 CD20-directed regimen) received oral acala 100 mg twice daily until disease progression or unacceptable toxicity ± R. The primary objective was overall response rate (ORR; Lugano criteria as assessed by the investigator). Secondary objectives were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Data were analyzed descriptively (no formal hypothesis testing). Results: Forty-two pts received acala (median age 69 y [range 42–84]; median 2 prior systemic regimens [range 1–4]). MZL subtypes were extranodal (43%), nodal (31%), and splenic (26%). At data cutoff (Oct 15, 2021), median follow-up duration was 10.7 mo (range 0.4–42.8). Sixteen (38%) pts discontinued acala, most commonly due to disease progression (26%). Among pts evaluable for response (n = 37; 3 pts had not reached the first assessment timepoint and 2 pts exited the study without response assessment), ORR was 54% (95% CI 37%–71%) with 6 complete (16%) and 14 partial (38%) responses; 17 (46%) pts had stable disease. ORRs in extranodal, nodal, and splenic subtypes were 65%, 44%, and 45%, respectively. Median time to initial response was 3.0 mo; median DOR was 19.3 mo (95% CI 8.4–not estimable). Median PFS was 27.4 mo with a 12-mo PFS rate of 66%. Four pts died (disease progression, n = 2; transformation to diffuse large B-cell lymphoma after stopping treatment, n = 1; adverse event [AE], n = 1 [septic shock unrelated to treatment]); median OS was not reached. Treatment was well tolerated with most AEs being grade 1 or 2. Sixteen pts (38%) had grade ≥3 AEs, most commonly (in ≥2 pts) anemia, dyspnea, neutrophil count decrease (n = 3 each), fatigue, thrombocytopenia, and neutropenia (n = 2 each). AEs led to treatment discontinuation in 2 pts (grade 3 hypotension and grade 1 myalgia). Among AEs of clinical interest, hypertension was reported in 2 pts (both grade 2); no cases of atrial fibrillation/flutter or major hemorrhage were reported. Conclusions: These early results indicate that acala is efficacious and well tolerated in pts with R/R MZL. The AE profile is consistent with the known safety profile of acala. Clinical trial information: NCT02180711.

7573 Background: While most patients (pts) with follicular lymphoma (FL) usually have favorable outcomes, those with refractory disease after first-line anti-CD20 based immunochemotherapy (IC), or progression within 24 months of diagnosis (POD24) have higher risk of premature death. There are no standard approaches for treating this vulnerable group and studies testing novel agents are ongoing in this setting. We sought to investigate clinical practice treatment choices and efficacy for pts with POD24 that align with eligibility criteria for the randomized SWOG1608 which compares IC with novel agents in this population. Methods: This was a multicenter observational cohort study from the LEO Consortium. Eligible pts had grade 1-3a FL diagnosed between 1/1/2002 and 2/1/2019, and initiated therapy after POD24 to first-line bendamustine or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) based IC. Observation, radiotherapy, or rituximab monotherapy were permitted prior to IC and pts with transformation prior to the subsequent therapy after IC were excluded as per S1608. Outcomes of interest were overall and complete response rate (ORR/CR), progression-free survival (PFS), and overall survival (OS). Results: We identified 196 eligible pts with early progression to IC (39% antiCD20 Benda; 61% antiCD20 CHOP) who received subsequent therapy. Median age at post IC treatment was 57 years, 78% grade 1-2 FL. Treatments for pts with POD24 included CHOP- or Benda-based in 31%, salvage/hematopoietic stem cell transplant (HSCT) in 27%, novel therapies in 10% (including phosphatidylinositol 3-kinase inhibitors), antiCD20 monotherapy in 9%, and lenalidomide-based treatment in 8% (table); 21% of pts were treated on clinical trials. Across all treatments, ORR (CR) was 63% (37%) (95% CI: 55-70). At a median follow up of 6.2 years, 2 year PFS was 22% (95% CI: 17%-29%) and 5 year OS was 71% (95% CI: 65-79). Outcomes by regimen are shown in the table. Conclusions: Pts with FL experiencing POD24 following first-line IC are treated heterogeneously, with many pts still receiving IC as subsequent therapy. Despite modest CR rates and low 2-year PFS, 5-year OS appear to be improving compared to historical outcomes. This supports the ongoing need to investigate novel treatments in this population. [Table: see text]

Purpose Given the paucity of data on higher-grade transformation (HGT) to aggressive lymphoma in patients with marginal zone lymphoma (MZL), we report on a large cohort of patients, identify risk factors, and determine HGT impact on overall survival (OS). Methods We analyzed 453 patients with biopsy-proven MZL seen at our institution between 1995 and 2016. Kaplan-Meier, Cox proportional hazards regression, and competing risk methods were used in analyses of time-to-event outcomes. Results Thirty-four patients (7.5%) had biopsy-proven HGT to diffuse large B-cell lymphoma, including seven (21%) diagnosed at the time of initial MZL diagnosis. Among 27 incident patients, median time to HGT was 29 months (range, 1.3 to 135 months). Higher risk of HGT was observed in those with nodal/splenic MZL (subdistribution hazard ratio [SHR], 2.60; P = .023). On multivariable competing risk analysis, elevated lactate dehydrogenase (SHR, 2.71), more than four nodal sites (SHR, 2.97), and failure to achieve complete remission (CR) after initial treatment (SHR, 3.76) conveyed significantly higher risk for HGT ( P < .02). International Prognostic Index (IPI), Follicular Lymphoma IPI, and Mucosa-Associated Lymphoid Tissue Lymphoma IPI were only significant predictors of HGT univariably. Patients with HGT had shorter OS (5-year rate, 65% v 86%; P < .001). Patients who presented with HGT within 12 months since MZL diagnosis had shorter OS than those with HGT at MZL diagnosis combined with those with HGT more than 12 months later (4-year rate, 43% v 81%, P < .001). Non-CR and higher scores of IPI, Follicular Lymphoma IPI, and Mucosa-Associated Lymphoid Tissue Lymphoma IPI were the main significant predictors for shorter progression-free survival and OS. Conclusion Failure to achieve CR after initial treatment, elevated lactate dehydrogenase, and more than four nodal sites at the time of MZL diagnosis are the main predictors of increased risk of HGT. Patients with HGT have shorter OS.

7511 Background: G-len has promising activity and manageable toxicity in R/R FL (Morschhauser et al. 2019). We report the final analysis of an open-label, multicenter, Phase Ib/II trial (NCT02631577) that evaluated the immunomodulatory triplet G-atezo-len in pts with R/R FL. Methods: An initial 3+3 dose‐escalation to identify the Phase II len dose was followed by an expansion phase with G-atezo-len. Enrolled pts (aged ≥18 years) received induction with 6, 28-day cycles of G 1000 mg IV on Day [D] 1, 8, and 15 of Cycle [C] 1 and D1 of C2–6, atezo 840 mg IV on D1 and 15 of C2–6, and len 15/20 mg (dose escalation) or 20 mg (expansion) orally on D1–21 of C1–6. Responders received 24 months (mos) of maintenance with G 1000 mg D1 every 2 mos, atezo 840 mg D1–2 every mo, and len 10 mg D1–21 mos 1–12. The primary endpoint was complete response at end of induction by PET-CT assessed by Independent Review Committee (modified Lugano 2014 criteria; Morschhauser et al. ICML 2019). Exploratory endpoints described herein included progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Adverse events (AEs) were also assessed. Results: At the final analysis (October 7, 2020), 38 pts had completed the trial. Median age was 62 years, 26% had a high-risk FLIPI score, 45% were refractory to their last line of therapy, and 37% had progression of disease within 24 mos of their first-line of therapy (POD24). Median treatment duration was 26 mos (range: 0.4‒30). The 36-mo PFS rate for the overall population (median observation time, 35.9 mos; range: 3‒47) was 64% (95% CI, 45‒79), OS was 85% (95% CI, 70‒93), and median DOR was 38 mos (95% CI, 35‒NE). 36-mo PFS rates for the following subgroups are provided in the table: double refractory (rituximab and an alkylator); with/without POD24; minimal residual disease (MRD) +/-. In total, 32 pts (84%) had a Grade 3/4 AE (majority hematologic), and 18 (47%) had a serious AE. Five pts (13%) during induction and six pts (16%) during maintenance had an AE that led to discontinuation of any drug. Two fatal AEs were reported (1 merkel carcinoma, 1 sarcomatoid carcinoma; both unrelated to any study drug). The most common atezo AEs of special interest were hyperthyroidism (13%), hypothyroidism (11%), increased ALT and AST (both 8%), increased lipase (8%), and hepatocellular injury (5%). Conclusions: G-atezo-len is efficacious in pts with R/R FL, with data from the final analysis suggesting a potential for improved outcomes versus the G-len doublet. AEs were consistent with the safety profile of the individual drugs. Clinical trial information: NCT02631577. [Table: see text]

7553 Background: Dual inhibition of PI3Kδ and BTK pathways may overcome existing or acquired monotherapy resistance. Dual inhibition of these pathways displays synergistic activity in cell lines that is evident even at suboptimal concentrations [Blood 2015;125(14):2306-09]. Zandelisib is a potent, selective, and structurally differentiated oral PI3Kδ inhibitor (i), and zanubrutinib is an oral BTKi. Based on their efficacy as monotherapy, we hypothesized that the combination of zandelisib and zanubrutinib can be well tolerated and may improve the depth and durability of responses. We evaluatedthis combination therapy in pts with R/R B-cell malignancies to determine the optimal dose and schedule for further evaluation in disease-specific expansion cohorts (NCT02914938). Methods: This is a multi-cohort Phase 1b study enrolling pts with FL, CLL, MZL, MCL, DLBCL, or high grade B-cell lymphoma (HGBCL), ≥1 prior therapy, adequate bone marrow and organ function, ECOG performance status ≤2, and no prior PI3Ki or BTKi therapy. For this combination therapy, two dose levels were evaluated in 28-day cycles: Cohort 10A: zandelisib 60 mg once daily for 2 cycles followed by an intermittent schedule (IS) on days 1-7 of subsequent 28-day cycles and zanubrutinib 160 mg twice daily (bid). Cohort 10C: zandelisib 60 mg on days 1-7 starting in Cycle 1 and zanubrutinib at 80 mg bid. Dose limiting toxicity (DLT) observation period was 28 days for cohort 10A and extended to 56 days for cohort 10C. Response was assessed at month 3, 7, 13 and then every 6 months until progression. Results: 20 pts treated, 7 in cohort 10A and 13 in cohort 10C: 8 FL, 5 CLL, 2 DLBCL, 2 HGBCL, 2 MZL, and 1 MCL. Median age 70 years (range, 44-85) and median prior therapies 2 (1-8). Median follow-up of 2.9 months (0.5-17.4+). There were no DLT in cohort 10A, grade (Gr) ≥3 adverse events (AE) occurred after day 28 in 4 pts, including Gr 4 neutropenia (1 pt), Gr 3 neutropenia, fatigue and CMV colitis (1 pt), Gr 3 AST/ALT and rash (1 pt) and Gr 3 AST/ALT (1 pt). In cohort 10C, 2 pts had DLT with Gr 3 AST/ALT in Cycle 2, with 1 pt successfully resuming both drugs and 1 discontinued treatment due to recurrence of Gr 3 AST/ALT upon rechallenge.. Other Gr 3 AE were all laboratory findings: 1 pt (CLL) had laboratory TLS, neutropenia and thrombocytopenia and 2 pts (FL, DLBCL) had neutropenia. Response rate was 100% (2 CR 14 PR) in the following 16 pts with indolent NHL and MCL evaluable for response: FL (2 CR, 6 PR), CLL (5 PR), MCL (1 PR) and MZL (2 PR). No pt with aggressive B-cell lymphomas has responded. Conclusions: The combination of zandelisib 60 mg on IS from Cycle 1 and zanubrutinib 80 mg bid is well tolerated and achieves a high ORR in R/R indolent B-cell malignancies. This schedule is being evaluated in expansion cohorts in R/R FL and MCL. Clinical trial information: NCT02914938.

7520 Background: Mosunetuzumab (M), a full-length, humanized, IgG1 bispecific antibody targeting CD20 and CD3, has shown promising efficacy and safety as monotherapy for R/R B-NHL (NCT02500407; Assouline, et al. ASH 2020). The combination of M with the anti-CD79b antibody-drug conjugate, Pola, showed synergistic anti-lymphoma activity in a mouse xenograft model. These data supported a Phase Ib/II, open-label, multicenter trial of M-Pola for R/R B-NHL (GO40516, NCT03671018). Here we present early clinical data from the Phase Ib cohort. Methods: Pts with R/R follicular lymphoma (FL, grade [Gr] 1–3a) or aggressive NHL (aNHL), including de novo diffuse large B-cell lymphoma (DLBCL), transformed FL (trFL) and FL Gr 3b (FL3b), received Cycle (C) 1 step-up doses of M on Day (D) 1 (1mg) and D8 (2mg), the target dose on C1D15, then continued at the target dose on C2D1 onwards. M was given every 21 days for eight cycles (or 17 cycles if stable disease or a partial response after C8). Pola (1.8mg/kg) was given with M on D1 of each cycle for six cycles. Results: As of November 17, 2020, 22 pts had received M-Pola (M target doses: 9mg, n=7; 20mg, n=3; 40mg, n=6; 60mg [with D1 dose of 30mg from C3 onwards], n=6). Pts had DLBCL (n=12), FL (n=3), FL3b (n=3) and trFL (n=4). Pt characteristics include: median age of 70 (38–81) years; median of 3 (1–10) prior lines of therapy; 7 (32%) pts had prior CAR-T therapy; 17 (77%) and 19 (86%) pts had disease refractory to last prior therapy and prior anti-CD20 therapy, respectively. Median follow-up duration was 9.6 (0.7–23.7) months. The most frequent treatment-related adverse events (AEs) were neutropenia (45.4%), fatigue, nausea and diarrhea (all 36.4%). Cytokine release syndrome (CRS) was observed in 2 pts (9.1%; both Gr 1 by ASTCT 2019 criteria). One dose-limiting toxicity (Gr 3 new onset atrial fibrillation) was observed in the 40mg cohort. The maximum tolerated dose was not exceeded. The most common Gr ≥3 and serious AEs were both neutropenia, observed in 8 (36.4%) and 3 (13.6%) pts, respectively. Two (9.3%) Gr 5 AEs occurred: sudden cardiac death (n=1) and respiratory failure (n=1); neither was deemed treatment related. No immune effector cell-associated neurotoxicity was observed. The Table shows preliminary efficacy data. Preliminary efficacy in the dose-escalation cohort. Conclusions: These data indicate that M-Pola has an acceptable safety profile, with no Gr ≥2 CRS observed, and promising efficacy in pts with R/R NHL with predominantly aggressive disease. The Phase II expansion cohort in R/R DLBCL is ongoing, with no mandatory hospitalization required. Clinical trial information: NCT03671018. [Table: see text]

8043 Background: Prior analyses have suggested better overall survival (OS) of cancer patients (pts) treated in Acad rather than Comm hospitals, but these disparities may reflect different patient characteristics. We examined outcomes of pts with BL in a large RWE cohort from 30 US healthcare systems (Evens, ASH 2019) with a mix of Acad and affiliated Comm sites. Methods: We collected clinical data on adults with BL diagnosed in 2009-2018, individually assigned to Acad or Comm principal setting of care. We compared duration of chemotherapy (CTx, incl. standard CODOX-M/IVAC, hCVAD/MA, DA-EPOCH), rates of complete response (CR), progression-free survival (PFS), and OS adjusting for age, sex, HIV, performance status (PS), stage, LDH > 3x upper limit of normal (ULN), involvement of bone marrow or cerebrospinal fluid (CSF), reporting adjusted risk (RR) or hazard ratio (HR) with 95% CI. Results: Among 641 BL pts, 77 (12%) were managed in Comm setting. Comm pts had lower median age (45 vs 48 in Acad, P= .049), less frequent HIV (13% vs 23%, P= .039), less marrow (21% vs 36%, P= .009) or detected CSF involvement (8% vs 15%, P= .11), and less LDH > 3xULN (21% vs 41%, P= .013), with no significant differences in sex, PS, stage, hemoglobin, or receipt of CTx (97% vs 99%). Acad sites more often applied standard intensive CTx regimens (93% vs 85%, P= .03) and rituximab (92% vs 79%, P= .001), without significant difference in median time to CTx ( P= .69) or treatment-related mortality (TRM, P= .16). Pts managed in Comm (vs Acad) sites were less likely to achieve CR (61% vs 75%, P= .03; RR = 0.79 [0.65-0.95]) and had worse 3-year PFS (46% vs 67%, log-rank P= .003; HR = 2.17 [1.51-3.14]) and OS (53% vs 72%, P= .006; HR = 2.20 [1.48-3.25]). There was no significant interaction with age, sex, HIV, PS, or CSF involvement. Excess mortality concentrated in the 1st year of follow-up. CR, PFS, and OS appeared similar between Acad and Comm settings for pts receiving hCVAD or DA-EPOCH, but outcomes were significantly worse in Comm setting for pts receiving CODOX-M/IVAC. Median number of cycles did not differ between Comm or Acad sites, but median duration of CODOX-M/IVAC delivery was significantly longer in Comm setting (113 vs 101 days, P= .023). Conclusions: In this large RWE analysis, superior outcomes of adults with BL in Acad setting were not explained by baseline patient characteristics or TRM. Differences in the use of standard CTx regimens, rituximab, duration of Ctx, and CR rates suggest need for further research on potential barriers to delivery of intensive CTx for BL in a broader Comm setting.

e14059Background: Primary vitreoretinal lymphoma (PVRL) is a subset of primary central nervous system lymphoma involving the vitreous and retina of the eye and may occur either as an isolated disea...

7559Background: Marginal zone lymphomas (MZLs) are characterized by a long overall survival (OS). High-grade transformation (HGT) to aggressive lymphoma negatively impacts OS. Thus, identifying pat...

10042Background: The VES-13 is a self-reported tool designed to identify people at risk of functional decline and death. We evaluated the prevalence of vulnerable (VUL) status in newly diagnosed NH...

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. Although it represents a curable disease, less than half of the patients are cured with conventional chemotherapy. The highly variable outcome reflects a heterogeneous group of tumors, with different genetic abnormalities and response to therapy. The International Prognostic Index (IPI) is useful in predicting the outcome of DLBCL patients. However, patients with identical IPI still exhibit marked variability in survival, suggesting the presence of significant residual heterogeneity within each IPI category. The discovery of specific genetic alterations and the assessment of protein expression led to the identification of multiple novel single molecular markers capable of predicting the outcome of DLBCL patients independently of clinical variables. The recent application of DNA microarrays and tissue array technologies allowed a better understanding of the biology of lymphoma and the development of novel diagnostic tools capable of improving the current models for outcome prediction. However, much confusion exists in the literature regarding the importance of different prognostic biomarkers and their applicability in routine practice. This review summarizes the recent advances in our understanding of prognostic biomarkers in DLBCL and discusses whether this is the right time for biomarkers-guided risk-adjusted therapy.

8545 Background: There is a deficiency of published data examining non-cytotoxic options for the frontline treatment of HTB iNHL. In addition, few HTB iNHL series have reported outcomes with long-term follow-up (ie, >3-4 years). Methods: All patients (pts) were required to have HTB by GELF criteria. Treatment in this multicenter phase II study consisted of 3 induction cycles of bortezomib (1.6 mg/m2 weekly x 4) and rituximab (4 weeks cycle 1; 1 dose cycles 2 + 3) administered q35 days. This was followed by an abbreviated consolidation (ie, each drug once q 2 months x 4). All outcomes were analyzed by intent-to-treat. Results: 42 pts were enrolled and all were evaluable. Histologies were follicular lymphoma (FL) (n=33, 79%), marginal zone lymphoma (n=6, 12%), small lymphocytic lymphoma (n=2, 7%), and Waldenstroms (n=1, 2%). Pt characteristics included median age 62 years (40-86); 38% bulky disease (>7cm); 19% malignant effusions; 91% advanced-stage; and the median FLIPI was 3. Therapy was well tolerated wi...

TPS3108 Background: CD137 (4-1BB) is a costimulatory molecule that belongs to the TNF superfamily. It is upregulated on activated lymphocytes, NK cells and dendritic cells and plays an important role in the potentiation of antigen-specific immune responses as well as in antibody-dependent cell-mediated cytotoxicity (ADCC). Urelumab is an agonistic antibody targeting the CD137 receptor. Preclinical evidence has shown that there is modulation of CD137 expression on NK cells after exposure to rituximab. Anti-CD137 agonist monoclonal antibody has been shown to have single-agent anti-lymphoma activity and to potentiate the anti-lymphoma activity of rituximab through enhancing ADCC. We hypothesized that upregulation of CD137 on NK cells by rituximab followed by urelumab could afford a mechanism-based approach to achieve enhanced biologic and/or clinical activity compared to either single agent alone. Here we describe a phase Ib study to investigate the clinical and biologic effects of combined treatment with urelumab and rituximab in patients with relapsed/refractory B-cell malignancies. Methods: This phase I study (n=100) will include dose escalation (Part 1) using a 3+3+3 design and cohort expansion (Part 2). In Part 1, successive cohorts of patients with relapsed/refractory B-NHL will be treated as follows: Cohort 1 (0.1 mg/kg q3weeks) and Cohort 2 (0.3 mg/kg q3weeks) with both cohorts in combination with rituximab 375 mg/m2 given weekly for the first 4 weeks of each 12 week cycle. In Part 2, cohorts of CLL (n=30), follicular lymphoma (FL) (n=30), and diffuse large B-cell lymphoma (DLBCL) (n=20) will be treated at the dose level found to be safe for the urelumab/rituximab combination. The primary objective of the study is to evaluate the safety and define a safe and effective dose of the urelumab/rituximab combination. Secondary objectives include assessment of the antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunoregulatory activity of this combination in peripheral blood and paired tumor biopsy specimens and the association of these effects with clinical response/toxicity. Clinical trial information: NCT01775631.

e18562 Background: BDM is approved in the United States for relapsed indolent lymphoma. However, the prospective study establishing the BDM monotherapy indication did not include any MCL pts (Fried...

e12502 Background: Primary central nervous system lymphoma (PCNSL) accounts for approximately 4% of all primary brain tumors and has a poor prognosis in both immunocompetent as well as in immunocom...

8501 Background: Darinaparsin (ZIO-101) is a novel organic arsenical active against diverse cancers in vitro, and in vivo. Darinaparsin i.v. activity in lymphoma is being evaluated in a phase II study. Darinaparsin is orally bioavailable; the oral form is being investigated in two phase I studies in patients with advanced malignancies. Methods: Phase II trial is being conducted in patients diagnosed with advanced lymphomas who had ≥ 1 prior therapy. Patients receive 300 mg/m2/day of darinaparsin i.v. for 5 consecutive days every 28 days. Efficacy and safety are evaluated by standard criteria. Phase I oral dose escalation studies are being conducted in patients with advanced malignancies and explore safety, MTD, DLTs and preliminary efficacy of continuous and intermittent dosing schedules. Starting continuous dose is 100 mg BID for 3 weeks with 1 week rest, starting intermittent dose is 300 mg twice weekly for 3 weeks followed by 1 week rest. Results: The phase II study has accrued 28 lymphoma patients (21 non-Hodgkin's, 7 Hodgkin's); median age at baseline 61 years, ECOG ≤2, median number of prior therapies 3. Seventeen subjects have received at least 2 cycles of darinaparsin and are evaluable for efficacy. Of these, 1 subject (PTCL) has achieved a complete response, 3 - partial responses (2 marginal zone, 1 Hodgkin's), and 4 stable disease (2 PTCL, 1 DLBCL, 1 Hodgkin's). A total of 63 cycles of darinaparsin have been administered to subjects with lymphoma. No Gr. 3 or higher drug-related AEs were reported. Two SAEs were considered possibly drug-related (fall; neutropenic fever). Phase I studies accrued 35 patients; median age at baseline 58 years, ECOG ≤2, median number of prior therapies 3. Predominant tumor types include: colorectal (17), pancreatic (3), NHL (3). Current darinaparsin dose levels: continuous 200 mg BID, 2× weekly 900 mg. Of 18 patients evaluable for efficacy, 10 demonstrate SD ≥ 3 cycles. Oral darinaparsin bioavailability is 58%. Drug-related AEs include nausea/vomiting, fatigue, decreased appetite/anorexia. Conclusions: Darinaparsin is active in heavily pretreated patients with advanced lymphoma and has been very well tolerated. Oral darinaparsin is also well tolerated, and shows early activity. [Table: see text]

8603 Background: Lenalidomide is active in non-Hodgkin s Lymphoma (NHL). The aim of this analysis was to evaluate the safety of lenalidomide monotherapy in patients with relapsed/refractory aggress...

19508 Background: Pulmonary marginal zone lymphoma (BALT lymphoma) is a rare disease. Few small case series suggest an indolent course with favorable outcome; however, there is limited information on clinical presentation, natural history and treatment of this type of lymphoma. Methods: We conducted a retrospective review of patients with biopsy-proven BALT lymphoma diagnosed between 1994 and 2007 and treated at our institution, and patients from the Surveillance Epidemiology and End Results (SEER) database diagnosed between 1988 and 2003. Results: Twenty-one patients, 11 male and 10 female, with a median age of 57, were identified at our institution. Disease stage was IE (n=10) and IV (n=11), including 7 with extrapulmonary involvement. Initial management included observation (n=4), surgery (n=5), combination chemotherapy (n=7), single-agent rituximab (n=3) and radioimmunotherapy (n=2). Following first- line treatment, complete remission was observed in 10, partial remission in 3, stable disease in 7, an...

8052 Background: Lenalidomide (Revlimid), an immunomodulatory drug of the IMiDs class, is approved in the US for treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a deletion 5q[31] cytogenetic abnormality. Lenalidomide also has activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. This study was designed to assess the safety and efficacy of lenalidomide in patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL). Methods: Patients with relapsed/refractory aggressive NHL with measurable disease after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: As of enrollment cut-off, 50 patients were enrolled and 49 received drug. Forty-one patients were evaluable for response. The median age was 65 (46–84) and 18 were female. Histology was diffuse large B-cell lymphoma [DLBCL] (n=21), follicular center lymphoma grade 3 [FL] (n=3), mantle cell lymphoma [MCL] (n=14) and transformed [TSF] (n=3). Median time from diagnosis to lenalidomide was 3.2 (0.4–32) years and median number of prior treatment regimens was 3 (1–7). Fourteen patients (34%) exhibited an objective response (5 complete responses unconfirmed (CRu) and 9 partial responses (PR)), 12 had stable disease (SD) for a tumor control rate (TCR) of 63% and 15 progressive disease (PD). Responses were seen in each of the aggressive histologic subtypes studied: DLBCL (5/21), MCL (6/14), FL (2/3), and TSF (1/3). Five of 11 patients (45%) with a prior stem cell transplant responded. Progression free survival although ongoing is currently > 239 (>191 - >373) days in patients experiencing CRu and > 160 (>54 - >251) days in patients with PR. Most common Grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%) while most common Grade 3 adverse events were neutropenia (22%), leukopenia (14%) and thrombocytopenia (12%). Conclusion: Lenalidomide oral monotherapy is active with manageable side effects in relapsed/refractory aggressive NHL. No significant financial relationships to disclose.

8072 Background: Primary intraocular lymphoma (PIOL) is a very rare high grade malignant non-Hodgkin lymphoma, usually of the diffuse large B cell lymphoma (DLBCL) type, which presents in the vitreous, retina and/or the optic nerve. Sixty to 80% of patients with PIOL eventually disseminate to the brain, whereas up to 15% of primary central nervous system lymphoma (PCNSL) patients exhibit ocular involvement. For these reasons, PIOL is regarded as a subtype of PCNSL. Analysis of the immunoglobulin heavy chain (VH) sequences in PCNSL tumors demonstrated biased overrepresentation of the VH4–34 gene and indicated derivation of these tumors from highly mutated germinal center (GC) B cells with ongoing mutational activity. Whether PIOL tumors are of similar or different origin is presently unknown. Methods: Immunoglobulin VH genes were examined in vitrectomy specimens of 4 PIOL patients, 1 patient with concomitant PCNSL and 1 patient with systemic DLBCL involving the eye. The extracted DNA was amplified by PCR using VH family specific primers, cloned and sequenced. Results: Seven clonal VH rearrangements belonging to the VH4, VH3 and VH1 families were cloned from the analyzed cases. In concordance with previous reports, the lymphomatous eye infiltrate from the PCNSL patient revealed a mutated clonal VH4–34 gene with intraclonal heterogeneity -a manifestation of active ongoing mutational activity. All the PIOL clonal VH rearrangements also exhibited mutated sequences with homology to the germline sequences ranging between 76 to 95%. However, in contrast to PCNSL, 3 out of 4 PIOL cases exhibited no intraclonal heterogeneity while the remaining case demonstrated ongoing somatic mutations in one of the 2 clonal VH rearrangements detected in this tumor. Interestingly, the clinical course of this patient was highly unusual, since he exhibited systemic dissemination during follow-up. Conclusions: Analysis of VH gene sequences from PIOL tumors indicate a post- GC derivation and suggest that they belong to the activated B cell (ABC)-like subtype of DLBCL. This is in contrast to the GC-origin of closely related PCNSL. No significant financial relationships to disclose.

17569 Background: Lenalidomide is an immunomodulatory drug of the IMiD class that has activity in multiple myeloma, myelodysplastic syndromes and chronic lymphocytic leukemia. We report preliminary results of two Phase II studies assessing the safety and efficacy of lenalidomide monotherapy in subjects with relapsed/refractory indolent or aggressive non-Hodgkin’s lymphoma (NHL). Methods: Subjects with indolent (study NHL-001) or aggressive (study NHL-002) relapsed/refractory NHL following ≥ 1 prior treatment regimen with measurable disease are eligible. Subjects receive 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continue therapy for 52 weeks as tolerated until disease progression. Response and progression are evaluated using cross sectional imaging by the NCI criteria. Results: 10 subjects (2 indolent (I), 8 aggressive (A)) of a planned 80 (40 in each study) have enrolled thus far. Median age is 66 (45–80) and 7 subjects are female. Indolent histology is follicular center lymphoma grade 1, 2 (n = 2) and aggressive histology diffuse large cell lymphoma (n = 7) and follicular center lymphoma grade 3 (n = 1). Median time from diagnosis to lenalidomide monotherapy is 2.9 years (1.1–10) and median number of prior treatment regimens per subject is 3 (1–6). Median duration of follow-up is 2 months. Of eight subjects (2 I, 6 A) evaluable for response at two months, three demonstrated a decrease in their tumor burden by 72% (I), 68% (A) and 52% (A), two subjects (2 A) exhibited stable disease and three subjects (1 I, 2 A) had disease progression. Six of the ten subjects (2 I, 4 A) demonstrated no Grade 3 or 4 adverse events. Grade 3 or 4 hematological adverse events (neutropenia, thrombocytopenia) occurred in four subjects including one febrile neutropenia and one of these four subjects also exhibited Grade 3 cellulitis. No tumor flare or tumor lysis has been observed to date. Conclusions: Preliminary data of lenalidomide monotherapy in relapsed and refractory NHL are encouraging. [Table: see text]