ALBERT

Description: Introduction: I-131-Tositumomab is a radiolabeled murine monoclonal antibody that binds to the CD20 antigen on the surface of malignant and normal B lymphocytes, targeting radiation to B cells. I-131-Tositumomab has been studied with chemotherapy and in high-doses as part of conditioning regimens for autologous stem cell transplant (ASCT) in relapsed/refractory B cell lymphoma patients (pts). Non-myeloablative I-131-tositumomab was approved in the US and Canada for treatment of CD20 antigen-expressing relapsed or refractory low-grade follicular or transformed non-Hodgkin lymphomas (NHL). Since February 2014, tositumomab and I-131-tositumomab, the Bexxar¨ therapeutic regimen, is no longer commercially available. Methods: We conducted a single-center, phase I trial of I-131-tositumomab in pts with CD20+ B cell NHL with relapsed or progressive lymphoma after ASCT. Eligibility criteria included creatinine grade 3 non-hematologic adverse event. After treatment, pts were monitored weekly for 13 weeks for hematological and other toxicities with response assessments at weeks 7 and 13, and then evaluated at weeks 26, 39, and 52, then every 3 months during year 2, every 4 months during year 3, every 6 months during year 4, and yearly thereafter. Results: 12 pts were enrolled and received both dosimetric and therapeutic doses of I-131-tositumomab; 6 pts (50%) were men. Median age was 58.5 years (range: 49-66). 5 of 12 (41.6%) pts had diffuse large B cell lymphoma (DLCBL), 4/12 (33.3%) follicular lymphoma (FL), and 3/12 (25.0%) FL transformed to DLBCL. Median number of prior therapies was 4 (range: 3 - 8); median time from ASCT was 1.6 years (range: 0.3 - 6.8). 2 pts had progressive disease after ASCT (1 transformed FL; 1 DLBCL); 10 pts had relapsed from complete remission (CR) after ASCT. 7 pts received 25cGy I-131-tositumomab. The cohort receiving 25cGy was expanded to 6 due to grade 4 neutropenia (1 pt), and then expanded to 7 because 1 pt progressed prior to week 7 response assessment. 3 pts received 50cGy and 1 pt each received 65cGy and 75cGy. At all doses, I-131-tositumomab was well-tolerated. Treatment-related toxicities 〉 grade 3 were exclusively hematological and not dose dependent, including thrombocytopenia (2/12: 1 grade 3, 1 grade 4), neutropenia (2/12: 1 grade 3, 1 grade 4) and anemia (2/12: 2 grade 3). Hematologic toxicities were reversible in all cases, with median time to recovery to 〈 grade 3 toxicity 7 days. Non-hematological adverse events were mild and 〈 grade 2. The most commonly reported non-hematological adverse event was fatigue. Overall response rate at week 7 was 41.6% (5/12) with 33.3% (4/12) pts achieving CR (2 pts with FL; 2 pts with DLBCL). Median duration of response was 13.8 months. As of May 2014, 2 pts are still in CR, including 1 pt with FL at 10.3 months and 1 pt with DLBCL at 5.5 years. Median progression free survival is 6.5 months; median time to treatment failure is 4.4 months. At the median follow-up of 21.9 months (range: 10.3 – 66.3), overall survival is 68.7%; no secondary hematologic malignancies have been observed. Conclusion: This is the first study of I-131-tositumomab RIT in pts with relapsed or progressive NHL after ASCT. In pts with CD20+ DLBCL, FL, or transformed FL following ASCT, non-myeloablative I-131-tositumomab is well-tolerated and can achieve sustained complete remissions. Table 1:Dose Escalation SchemaPlatelet count〉100,000, 150,000Dose level 120 cGy25 cGyDose level 240 cGy50 cGyDose level 355 cGy65 cGy Disclosures Schuster: GlaxoSmithKline: Research Funding.

Description: Introduction: Venetoclax (VEN) based therapy has become a standard of care in front line and relapsed-refractory (R/R) CLL based on favorable efficacy and toxicity. Whereas prospective data regarding activity of therapies following ibrutinib (IBR) or idelalisib (IDE) are available in the settings of progression (VEN, non-covalent BTKi) and intolerance (acalabrutinib), how best to manage patients (pts) who discontinue (dc) VEN remains a key unanswered question. With the increased use of VEN in early lines of therapy (LOT; CLL 14, MURANO), the activity of BTK inhibitors (BTKi) and cellular therapies following VEN becomes a critical issue. No prospective study has addressed this question, and currently reported VEN clinical trials have limited information about subsequent treatments. While recent data describe VEN resistance mechanisms (Guieze 2018, Blombery 2019), the impact of VEN resistance on efficacy of post VEN therapies is unknown. To address this gap, we conducted an international study to identify a large cohort of pts who dc VEN and have been subsequently treated. Methods: We conducted an IRB approved multicenter (31 US, EU, South American sites, in partnership with UK CLL Forum and CORE registry), retrospective cohort study of CLL pts who dc VEN for any reason. We examined demographics, dc reasons, responses, survival, adverse events (AEs) and activity of post VEN therapies. Primary endpoints were overall response rate (ORR) and progression free survival (PFS) for the post VEN treatments stratified by treatment type (BTKi, PI3Ki and cellular therapy: CAR-T or alloHSCT). ORR was defined by iwCLL criteria and PFS was defined from VEN dc to disease progression (PD), death, or last follow up for next treatment. Pts were further stratified by BTKi (resistant / intolerant) and PI3Ki exposure prior to VEN. PFS-2 was defined as time from VEN start to tumor progression on IBR or death from any cause. Results: 326 CLL pts who dc VEN in the front line (4%) and R/R settings (96%) were identified. The cohort was 69% male, 87% white, median (med) age 66 (38-91) at VEN start, 27% treated with VEN based combinations (n=88, med 6 cycles anti-CD20 abs). Pre VEN prognostic features: 82% IGHV unmutated (n tested=166), 47% del17p (n=306), 45% TP53 mut (n=217), 39% complex karyotype (n=273), 23% BTK mut (n=79), 18% NOTCH1 mut (n=103), 10% PLCγ2 mut (n=74). Pts received med 3 therapies (0-11) prior to VEN; 40% were BTKi naïve (n=130), 60% were BTKi exposed (196) and 81% were IDE naïve (n=263). Most common reasons for VEN dc were PD (38%), AE (20%), Richter's transformation (RT, 14%), 8% pt preference, and HSCT 5%. Of 326 pts who dc VEN, 188 (58%) were treated with a subsequent LOT, 61 are alive and untreated and 77 died prior to a subsequent LOT. Post VEN sequencing analyses focused on BTKi, PI3Ki and cellular therapy (CAR-T or alloHSCT) activities following VEN dc (Table1). ORR to BTKi was 84% (n=44) vs. 54% (n=30, p

Description: Introduction: Venetoclax (Ven) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (Ven mono) or in combination (Ven paired) with rituximab based on clinical trials with selected patients (pts) and limited ibrutinib exposure. Whether Ven paired is superior to Ven mono, patterns of care, and outcomes following Ven discontinuation are unknown. Further, better delineation of adverse events (AEs) when Ven is used outside of clinical trials is needed. To address these gaps, we conducted a multicenter, international study in partnership with CLL Collaborative Study of Real World Evidence (CORE) and UK CLL Study Forum examining the clinical experience of 348 Ven treated CLL pts, representing the largest series of Ven treated pts reported to date. Methods: We conducted a retrospective cohort analysis of CLL pts treated with Ven across 24 US and 42 UK academic and community centers. We examined demographics, baseline disease characteristics, dosing, AEs, TLS risk and outcomes, response rates, outcomes (overall survival (OS) and progression free survival (PFS)), and tx sequencing. TLS events were defined by Howard criteria. PFS and OS were estimated by the Kaplan Meier method. Comparisons of outcomes used the Log Rank test. Univariate and multivariate analyses were performed with COX regression. All other comparisons were descriptive. Results: Of these 348 CLL pts, 94% were R/R, median age 67 years (range:37-91), 69% male, 85% white, and 73% Rai stage ≥2. 19% received Ven on clinical trial. 79% had Ven mono; Ven was paired most commonly with anti-CD20 (n=51) and ibrutinib (n=10). Pts received a median of 3 tx (range 0-15) before Ven; 78% received ibrutinib, 29% received PI3Ki, 20% had ≥2 prior kinase inhibitors, and 68% had chemoimmunotherapy. Median time from most recent tx to Ven start was 1.1 months (range 0-62). Pre-Ven prognostic markers included 43% del17p, 34% TP53 mutated, 24% del11q, 38% complex karyotype (≥ 3 abnormalities), and 84% IGHV unmutated (Table 1). TLS risk was low in 38%, intermediate in 34% and high in 28%. During ramp up, TLS was observed in 10% (22 lab, 9 clinical TLS events, 3 missing data). Following dose escalation, 70% achieved a stable Ven dose of 400 mg, 33% required ≥ 1 dose interruption and 27% required ≥ 1 dose reduction. AEs included grade 3 neutropenia 39%, grade 3 thrombocytopenia 29%, infections 25%, grade ≥ 2 diarrhea 7.8%, and neutropenic fever 7.7%. AEs were similar whether treated on or off clinical trial. The ORR to Ven mono, Ven paired was 81% (34% CR), 86% (29% CR). With a median follow-up of 14.2 months, median PFS and OS were not reached (12 month PFS 74%, OS 82%). Figure 1 depicts PFS stratified by Ven mono vs. paired, clinical trial vs. clinical practice, del17p status, and complex karyotype. Pts who discontinued Ven due to AEs had better OS compared with those who discontinued due to progression or Richter Transformation (RT) (Median OS 47 vs. 15.1 vs. 8.6 months, respectively). In multivariate analyses, complex karyotype was the only independent predictor of PFS (HR 2.8, p

Description: Introduction Patients (pts) with autoimmune diseases (AD) are at increased risk of developing non-Hodgkin lymphoma (NHL) (Smedby et al. J Natl Cancer Inst, 2006). The presence of chronic inflammation and use of immunosuppressive medications may contribute to the higher incidence lymphoma in AD pts over the general age-matched population. While previous studies have described outcomes of AD pts with marginal zone lymphoma (MZL), there is no available data on the outcomes of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in this patient population. We investigated characteristics of NHL pts with a concurrent diagnosis of AD with a specific focus on outcomes in DLBCL and FL. Methods This was a retrospective cohort study of pts with AD and concomitant NHL diagnosis. NHL pts with AD [including rheumatoid arthritis (RA), systemic lupus erythematous (SLE), Sjogren syndrome (SS) and psoriatic arthritis (PsA)] were identified by searching our institutional database of lymphoma pts. They must have previously received systemic treatment for their AD to be included in the study. We collected data on the AD and treatment, NHL subtype and therapy, stage, and prognostic index. Lymphoma response to therapy was based on the consensus criteria from the International Harmonization Project (Cheson et al. J Clin Oncol, 2007). Descriptive and survival analysis were performed using Fisher’s exact test and Kaplan-Meier methodology for a cohort of patients with DLBCL and FL. Results We identified 58 NHL pts who had previously received systemic treatment for an AD. The majority (71%) of affected pts were female and the median age at diagnosis was 60 years (range 22-85 years). The most common NHL subtypes represented were MZL (29%, N=17), DLBCL (26%, N=15), and FL (21%, N=12). RA was the most commonly identified AD (47%, N=27), followed by SLE (31%, N=18), PsA (12%, N=7) and SS (10%, N=6). Therapies received for AD prior to developing lymphoma were heterogeneous: oral methotrexate (40%, N=23), hydroxychloroquine (34%, N=20), anti-TNF agents (14%, N=8), and rituximab (7%, N=4). Twenty-three pts (40%) received multiple therapies for their AD. There was no relationship between the use of anti-TNF agents and the type of lymphoma diagnosed (p=0.81). In the DLBCL cohort (N=15), stage at diagnosis was I in 13% (N=2), II in 27% (N=4), III in 13% (N=2) and IV in 47% (N=7) pts. IPI was 0-1 in 47% (N=7), 2-3 in 40% (N=6) and 4-5 in 13% (N=2) at diagnosis. Nine pts were treated with R-CHOP, 3 received CHOP, 2 were treated with DA-R-EPOCH and 1 received R-CEOP. Fourteen pts (93%) had a complete response (CR) to therapy and one had a partial response (PR). Only 2 out of the 15 pts had disease progression and neither pt died due to DLBCL. One pt died of unrelated causes. The median OS for pts with DLBCL was not reached with a range of follow-up of 5 to 309 months. Median PFS was 207 months. In the FL cohort (N=12), stage at diagnosis was I in 42% (N=5), II in 8% (N=1), III in 8% (N=1) and IV in 42% (N=5). FLIPI score was 0-1 in 42% (N=5), 2 in 17% (N=2) and 3-5 in 42% (N=5). All pts were treated with withdrawal of their immunosuppression used to treat their AD. Two pts received no additional therapy, 5 received rituximab monotherapy, and the remaining 4 received other regimens such as FCR, R-bendamustine and R-CHOP. Eight pts (67%) had a CR to therapy, 3 (25%) had a PR and 1 (8%) had stable disease (SD). Of the 2 who were only treated with withdrawal of immunosuppression, 1 had a CR and 1 had SD. Five pts (42%) had disease progression and all 5 were alive at the conclusion of the study. Only 2 pts (17%) with FL died, both of causes unrelated to their lymphoma. For pts with FL, the median OS was not reached with a range of follow-up of 19 to 223 months and the median PFS was 153 months. Conclusions To our knowledge, this is the first work describing outcomes of DLBCL and FL pts with concurrent AD. Pts in this cohort had better outcomes when compared with identical NHL subtypes reported in pts without AD. This may reflect different biology of these lymphomas driven by the autoimmune process and/or immunosuppression. The unique clinical characteristics of lymphomas in AD pts should be studied further in order to guide our appropriate lymphoma-directed therapies in this population. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) comprise approximately 7% and 2%, respectively, of non-Hodgkin's lymphomas (NHL) (Teras 2016). MZL is further subclassified as splenic MZL (sMZL), nodal MZL (nMZL), or extranodal MZL (eMZL). Standard first-line therapies for LPL/WM include rituximab plus an alkylating agent and/or proteasome inhibitor or ibrutinib (Castillo 2017), while standard first-line treatment for MZL varies by subtype (Rosand 2017). There are limited treatment options for patients who have relapsed after first-line therapy. Idelalisib, a selective oral inhibitor of PI3Kδ, demonstrated efficacy in indolent NHL (iNHL), including MZL and LPL/WM, at a median follow-up of 9.7 months (mos) in a phase 2 study (NCT01282424; 101-09; Gopal 2014). Here, we present the final, long-term results for patients with double-refractory MZL and LPL/WM from the 101-09 study. Methods: Eligible iNHL patients had measurable disease and were refractory to both rituximab and an alkylating agent. Refractory status was defined as lack of response to or progression of lymphoma within 6 mos of completion of preceding therapy, documented by imaging. Oral idelalisib 150 mg twice daily was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee using standard criteria (Cheson 2007; Owen 2013). Endpoints included overall response rate (ORR), time to response, duration of response (DOR), lymph node response, progression-free survival (PFS), overall survival, and safety. The final data cutoff date was 22 Oct 2018. Results: Of 125 patients enrolled, 15 (12%) had MZL (sMZL, n = 1; nMZL, n = 5; eMZL, n = 9) and 10 (8.0%) had LPL/WM. Median age was 65 years and most were non-Hispanic (n = 24; 96%) and White (n = 23; 92%). At diagnosis, 80% of MZL and 100% of LPL/WM patients had stage IV disease. The largest lesion at baseline was ≥5 cm for 5 (33%) MZL and 3 (30%) LPL/WM patients. Baseline median IgM level was elevated for 80% of LPL/WM patients (median 1.9, IQR 1.0-2.7 g/dL). Baseline beta2-microglobulin level was 〉3 µg/mL for 1 of 9 LPL/WM patients with values recorded (median 2.5 [range 1.7-3.1] µg/mL). For MZL and LPL/WM patients, 7 (47%) and 7 (70%) had ≥3 prior therapies, respectively. Common regimens for all 25 patients included rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (44%), rituximab-cyclophosphamide-vincristine-prednisone (40%), rituximab only (28%), bendamustine only (24%), and bendamustine-rituximab (20%). For MZL, the ORR (95% confidence interval [CI]) was 47% (21%, 73%), with median duration of therapy of 6.4 (range 1.8-37) mos. Of 7 responders, 1 had a complete response and 6 had partial responses (PR). Seven had stable disease (SD) and 1 had progressive disease (PD). Fourteen (93%) patients had reduction in lymph nodes, with 8 (53%) having ≥50% reduction in the sum of the products of the greatest perpendicular diameters (SPD). Median PFS was 6.6 (95% CI 3.5, 22) mos and median DOR was 18 (range 0-18) mos (Table). For LPL/WM, the ORR (95% CI) was 80% (44%, 98%), with a median duration of therapy of 29 (range 6.4-51) mos. Of 8 responders, 7 had PR and 1 had a minor response. There was 1 SD and 1 PD. Nine (90%) patients had lymph node reduction, with 5 (50%) having ≥50% reduction in SPD. Median PFS was 22 (95% CI 1.4, 56) mos and median DOR was 20 (range 1.7-50) mos (Table). All 25 patients had ≥1 treatment-emergent adverse event (TEAE), 16 (64%) had a serious AE, and 11 (44%) had dose reduced due to a TEAE. Grade ≥3 TEAEs occurred for 22 (88%) patients; neutropenia (n = 7, 28%), diarrhea (7, 28%), alanine aminotransferase increased (4, 16%), asthenia (3, 12%), and pneumonia (3, 12%) were the most frequent. All patients eventually discontinued treatment due to disease progression (14, 56%), AE (6, 24%), death (3, 12%), investigator request (1, 4%), or other (1, 4%). Ten patients have died, 3 during the study and 7 during the long-term follow-up. Conclusions: Monotherapy with idelalisib showed high rates of antitumor activity in this small subset of patients with MZL and LPL/WM refractory to prior therapy with rituximab and an alkylating agent; prolonged disease control was achieved for LPL/WM patients. No new safety signals were identified despite longer follow-up. Disclosures Wagner-Johnston: Bayer: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Schuster:Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; AstraZeneca: Honoraria; Pharmacyclics: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Loxo Oncology: Honoraria; Nordic Nanovector: Honoraria; Pfizer: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. de Vos:Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Salles:Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jurczak:Bayer: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Celtrion: Research Funding; MorphoSys: Research Funding; Gilead: Research Funding; Roche: Research Funding; Servier: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria. OffLabel Disclosure: Idelalisib is a selective oral inhibitor of PI3K-delta that has shown antitumor activity in previously treated indolent non-Hodgkins lymphomas in phase 1 and 2 studies. It is approved for treatment of relapsed follicular lymphoma that has progressed on 2 prior systemic therapies, relapsed chronic lymphocytic leukemia in combination with rituximab when rituximab alone would be considered appropriate due to other comorbidities, and relapsed small lymphocytic lymphoma that has progressed on 2 prior systemic therapies. In this presentation, we provide results of 2 less common subgroups of indolent non-Hodgkins lymphoma, Âmarginal zone lymphoma and lymphoplasmacytic lymphoma/Waldenstrom's Macroglobulinemia, Âfrom the completed phase 2 trial with long-term follow-up.

Description: Background: Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor that was recently approved by the FDA for treatment of patients (pts) with relapsed/refractory marginal zone lymphoma (MZL) who have already received one or more anti-CD20 containing treatment regimens and require systemic therapy. Approval was based on a clinical trial in 60 pts that showed durable responses and a median progression-free survival (PFS) of 14.2 months (mos) (Noy et al., Blood 2017). Since pts outside clinical trials may have different disease and demographic characteristics, our study investigates the safety and efficacy of ibrutinib when implemented in a non-trial setting. Materials and Methods: This is a retrospective analysis of MZL pts who received ibrutinib monotherapy as part of their treatment at the University of Pennsylvania. Subjects were identified by a database search for any MZL pts prescribed ibrutinib. Primary endpoints were PFS and overall survival (OS) since initiation of ibrutinib. Secondary endpoints were overall response rate (OR) and complete response rate (CR), adverse events, and reasons for discontinuation. The first patient was treated on April 10, 2014, and the data cutoff was July 1, 2019. Analyses were performed using STATA 15.0 software. Results: There were 28 pts included in this study with a median age of 69 years (range 36-90) and median ECOG performance status at diagnosis of 0 (range 0-2). All pts had advanced disease (all stage III/IV & 68% with bone marrow involvement). The distribution of MZL subtypes was 43% extranodal, 25% nodal, and 32% splenic. Most pts (89%) had received one or more treatments prior to ibrutinib (32% received first-line rituximab only). The median number of previous therapies was 2 (range 0-5), and 43% of pts were refractory to the previous line of therapy. A minority of pts (11%) received rituximab or another anti-CD20 antibody concurrently with ibrutinib. Pts started ibrutinib a median of 56 mos after their initial diagnosis (range 0.5-221 mos) with a median duration of therapy of 7 mos (range 0.7-62 mos). The median starting dose was 420 mg daily (range 70-560 mg daily). In 26 pts with response data available, the OR was 73% with CR 15%. The 12-mo PFS and OS were 77% and 87% respectively (see Figures 1 & 2, median PFS and OS not yet reached). PFS and OS at median follow-up were 55% and 69% respectively. There was no significant difference in response or survival rates among MZL subtypes. Pts who received rituximab only prior to ibrutinib had an OR of 86% compared to 69% in those with more than one previous therapy (Χ2 = 0.73, p = 0.39). Ibrutinib was discontinued in 43% of pts after a median of 2.9 mos (range 0.7-13.7 mos) due to disease progression (50%), intolerance (42%), or other reasons (8%). Most (67%) pts subsequently received other therapies. All pts who stopped due to toxicity were responding at the time of discontinuation. Ibrutinib was also temporarily held or dose-reduced in 46% of pts due to toxicity (77%), preparation for surgery (15%), or drug interactions (8%). One patient experienced acute rebound of symptoms until ibrutinib was restarted. Most commonly reported toxicities are summarized in Table 1. Grade 3 toxicities included pneumonia (7%), sepsis (4%), hemorrhage (4%), arthralgia (4%), fatigue (4%), URI (4%), and hepatitis (4%). Toxicities responsible for cessation of treatment were arthralgia, hepatitis, thyroiditis, and hemorrhage. There were no reported treatment-related deaths. Conclusion: To our knowledge, this is the first study to report the efficacy and safety of ibrutinib in a large cohort of MZL pts treated outside of a clinical trial. We found that the therapy was well-tolerated and observed response rates that compared favorably to those shown in the prospective clinical trial. Disclosures Hughes: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Acerta Pharna/HOPA: Research Funding. Dwivedy Nasta:47 (Forty Seven): Research Funding; Rafael: Research Funding; Millenium/Takeda: Research Funding; Debiopharm: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Roche: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding. Barta:Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria. Chong:Novartis: Consultancy; Merck: Research Funding; Tessa: Consultancy. Schuster:Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. OffLabel Disclosure: This paper looked at the effectiveness of ibrutinib, a Bruton's tyrosine kinase inhibitor, in treating patients with marginal zone lymphoma (MZL). Ibrutinib is FDA approved for MZL patients who have received at least one anti-CD20 containing therapy and now require systemic treatment. Some patients in the study had not previously received an anti-CD20-based therapy and received ibrutinib off-label.

Description: In vitro studies have suggested that AML cells are sensitive to treatment with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. In particular, mTOR inhibition is known to enhance the sensitivity of primary AML cells and AML stem cells to etoposide based chemotherapy leading to inhibition of leukemic SRC activity in NOD/SCID mice. To determine the feasibility of applying this approach in vivo, we performed a Phase I dose escalation study of the mTOR inhibitor sirolimus (rapamycin) with a combination chemotherapy induction regimen in adults with relapsed or refractory non-M3 AML. The purpose of this trial was to determine the safety and dose limiting toxicities of sirolimus and chemotherapy in this patient population. Patients received a loading dose of oral sirolimus on day 1 followed 24 hours later by daily doses of oral sirolimus on days 2–7 plus MEC (mitoxantrone 8 mg/m2/day IV, etoposide 100 mg/m2/day IV, and cytarabine 1000 mg/m2/day IV) on days 1–5. Five sirolimus dose levels were explored by a standard 3+3 design. Sirolimus was studied at loading doses from 3–15 mg and daily doses from 1–5 mg/d. Clinical response was assessed by bone marrow biopsy upon hematologic recovery or day 42, whichever occurred first. 23 adults (14 women, 9 men) of median age 58 (range 22 to 65) with relapsed, refractory, or secondary AML were treated with sirolimus and MEC. Five subjects had antecedent hematologic disorders or prior leukemogenic chemotherapy, 18 had relapsed or refractory disease. Sirolimus was well tolerated and did not increase non-hematologic toxicity of MEC chemotherapy. Asymptomatic, reversible liver transaminase or bilirubin elevations occurred in 4 patients, two of which were 〉 grade 2. One patient with a history of prior cytarabine cerebellar toxicity (unknown at the time of study entry) developed reversible cerebellar ataxia. Three patients died of complications related to bacterial infections during chemotherapy-induced aplasia. Dose limiting toxicity was prolonged myelosuppression at the highest planned dose level and was responsible for one treatment-related death due to infectious complications from unresolved aplasia on study day 119. For the first four dose levels the median time to ANC recovery 〉500/uL among evaluable patients was 27 days (range16–38). Pharmacokinetic data showed that doses of 3 mg and higher consistently achieved rapamycin levels considered therapeutic in solid organ transplantation (4–9.2 ug/L). Bone marrow studies in 2/2 evaluable patients on dose level 4 (12 mg loading dose and 4 mg per day sirolimus) showed inhibition of p70S6 kinase phosphorylation consistent with effective inhibition of mTOR at this dose level. Complete remissions occurred in four patients, all treated for first relapse. Two patients subsequently proceeded to allogeneic transplantation. These results indicate that the combination of mTOR inhibition and chemotherapy is feasible in human AML and establish an appropriate dose for phase II studies to be 12mg loading dose followed by 4 mg daily. Patient recruitment at this dose is ongoing. Confirmation of the efficacy of this regimen, which targets signal transduction in leukemic 〈 stem cells, is planned in a randomized phase II trial at the cooperative group level.

Description: Introduction: FL is generally responsive to conventional-dose chemotherapy but long term disease-free survival (DFS) is uncommon. High-dose chemo-radiotherapy followed by ASCT has the potential to induce remission in this disease but the long-term benefit of this modality remains to be determined. Methods: Between 1990 and 2003, we transplanted 52 pts originally diagnosed with low-grade FL (31 grade 1, 21 grade 2). Twenty-five (48%) had biopsy-proven large cell transformation (FL grade 3 or diffuse large cell lymphoma) before ASCT. The median number of prior therapies was 2 (range: 1 to 7). Prior to ASCT, 45 pts (87%) were responsive to salvage therapy with 20 pts (38%) in CR. Five pts (10%) had chemo-resistant disease at the time of ASCT. High-dose regimens included BCNU-cyclophosphamide-etoposide (31%), melphalan/TBI (27%), and cyclophosphamide/TBI (25%). Thirty-eight pts (73%) received peripheral stem cells (PSCT) and 14 pts (27%) received autologous bone marrow (BM) with 4-hydroxyperoxycyclophosphamide (4-hc) purging in 9 cases (17%). The median age was 49 yrs (range: 29–65). Results: There was 1 treatment-related death during the first 100 days. After ASCT, 36 pts (69%) achieved a CR, 2 (4%) had a PR, and 7 (13%) had stable disease. Among those in CR, 20 (56%) had a CR pre-ASCT, 14 (41%) had a lesser response, and 1 (3%) was chemo-resistant. Median follow-up (f/u) of survivors was 5.3 yrs (range: 1.7 months to 12.4 yrs). The median overall survival (OS) has not yet been reached. The median event-free survival (EFS) is 3.4 yrs (range: 1.7 months to 12.4 yrs). Among complete responders, more than 50% are disease free at last follow-up (range 1.7 months to 12.1 yrs). Variables favorably affecting EFS and OS are age 〈 60 yrs (p = 0.007, 0.015 respectively), achievement of a CR after ASCT (p = 0.002, 0.001), absence of transformation (p = 0.038, 0.017), BM vs. PSCT (p = 0.042, 0.086), and 4-hc BM purging (p = 0.044, 0.059). Number of prior regimens, response prior to ASCT, type of preparative regimen, and addition of TBI, were not significantly associated with EFS, DFS, or OS. In multivariable analysis, achievement of CR after ASCT and age 〈 60 yrs are the only significant predictors of EFS and OS. Adjusted for age, 53% of pts with a CR after ASCT are alive and event-free at last f/u (range: 2.4 months to 12.4 yrs) (Figure 1). In contrast, the median EFS among pts without a CR is 0.5 yrs (range: 1.7 months to 5.3 yrs). Conclusion: ASCT is a reasonable therapeutic approach to FL, resulting in long term EFS for some pts, even with relapsed, refractory and/or transformed disease. In our experience, significant predictors of EFS and OS after ASCT are complete response and age

Description: Background: PMBCL is a unique subtype of aggressive B-cell lymphoma representing about 5% of lymphoma cases. The diagnosis is generally based on a combination of clinical features (e.g., mediastinal mass) and pathological findings on tissue biopsy (e.g., large neoplastic B-cells with variable CD30 positivity by immunohistochemistry). However, the histopathologic diagnostic criteria are not well defined and the distinction between PMBCL and diffuse large B-cell lymphoma (DLBCL) or gray zone lymphoma (GZL) involving the mediastinum can be challenging. Most PMBCL trials use the traditional diagnostic criteria for study entry. Specific treatment approaches based on results of these trials are designed for patients with PMBCL. In this study, we hypothesized that a gene expression based assay that characterizes the molecular signature of PMBCL using formalin-fixed, paraffin-embedded (FFPE) tissue may improve the diagnostic criteria and allow more accurate interpretation of results for lymphoma patients enrolled in clinical trials. Methods: This exploratory study compared the PMBCL diagnosis established by clinicopathologic criteria alone to the diagnosis assigned by a combination of clinicopathologic features and gene expression-based assay on FFPE tissue specimens of patients enrolled in a multisite phase I/II prospective trial using brentuximab vedotin (BV) in combination with rituximab - cyclophosphamide-hydroxydoxorubicin-prednisone (R-CHP) for CD30+ B-cell lymphomas (Svoboda, Blood 2017). The original diagnostic categories of PMBCL vs. DLBCL vs. GZL were assigned by investigators based on traditional clinicopathologic features. For exploratory Nanostring based diagnostic categorization, we used previously described and validated Lymph3Cx assay which consists of 64 probes with cut‐points defined at the 0.1 and 0.9 probability scores to distinguish between DLBCL and PMBCL (Mottok, Hematol Oncol 2017). The tissue was examined by a hematopathologist for adequate tumor content and nucleic acids were extracted from 10 mm FFPE scrolls or unstained slides. Survival curves were generated for PMBCL patients as categorized by investigator assessment alone and by investigator assessment plus molecular classification using STATA. Results: We enrolled 31 treatment-naïve patients with CD30+ B-cell lymphomas between January 2014 and April 2017 (NCT01994850). Based on investigator assessment, patients were categorized as PMBCL (N=23), DLBCL (N=6), and GZL (N=2). As of June 15, 2018, we obtained and analyzed diagnostic FFPE tissue using the Lymph3Cx assay on 14 pts with all 3 subtypes of CD30+ B-cell lymphomas: PMBCL (N=11), DLBCL (N=2), and GZL (N=1). Of 11 pts with PMBCL by investigator assessment alone, 8 pts (73%) had Lymph3Cx probability scores 〉 0.9 which was consistent with a diagnosis of PMBCL by gene expression; 2 pts (18%) scored in the indeterminate category (0.1 to 0.9); 1 pt (9%) scored as DLBCL (〈 0.1). All 8 pts with a concordant diagnosis of PMBCL by investigator assessment and gene expression assay achieved complete remission (CR) and remain progression free after completing BV+R-CHP with median follow-up of 18 months. However, 1 pt re-classified as DLBCL by Lymph3Cx and 1 of 2 pts with an indeterminate score by Lymph3Cx achieved only partial responses and ultimately progressed; 1 pt with an indeterminate score remains in CR. None of the non-PMBCL pts in our exploratory analysis (2 DLBCL; 1 GZL) as assessed by investigators were categorized as PMBCL by Lymph3Cx. The CR rate for patients categorized as PMBCL by investigator assessment alone was 82% compared to 100% in those categorized as PMBCL by both investigator and gene expression assay (Table 1). The reportable progression free survival would also be different for these two cohorts (Figure 1). We will complete Lymph3Cx testing of diagnostic tissue for all 31 enrolled patients with CD30+ B-cell lymphomas enrolled on our clinical trial by the meeting. Conclusion: Preliminary results of this ongoing study suggest that a diagnosis of PMBCL by clinicopathologic assessment alone that is not supported by molecular classification may include non-PMBCL pts and affect treatment outcomes. We recommend that future clinical trials for PMBCL include gene expression based diagnostic assays to improve diagnostic accuracy and interpretation of results. Disclosures Svoboda: TG Therapeutics: Research Funding; Kyowa: Consultancy; KITE: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Regeneron: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Steidl:Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Roche: Consultancy; Tioma: Research Funding; Nanostring: Patents & Royalties: patent holding; Bristol-Myers Squibb: Research Funding. Ruella:University of Pennsylvania: Patents & Royalties. Landsburg:Curis: Consultancy, Research Funding; Takeda: Consultancy. Dwivedy Nasta:Takeda/Millenium: Research Funding; Incyte: Research Funding; Debiopharm: Research Funding; Pharmacyclics: Research Funding; Rafael/WF: Research Funding; Aileron: Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Other: DSMC. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Chong:Novartis: Consultancy. Schuster:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: Venetoclax (VEN) is a highly effective agent for chronic lymphocytic leukemia (CLL) that targets BCL-2. Thus, it has been hypothesized to have efficacy in NHL and tested in phase-1/2 studies (Gerecitano JF, Blood 2015; de Vos S, Blood 2015; Davids MS, J Clin Oncol 2017). Overall response rates (ORR) observed in r/r NHL were 44% for all subtypes combined, 38% for follicular lymphoma (FL), 75% for mantle cell lymphoma (MCL), and 18% for diffuse large B-cell lymphoma (DLBCL). The adverse effect profile was consistent with the labeling despite dose escalation to doses higher than used in CLL. Additionally, VEN is a potential option in the r/r NHL setting, potentially providing less T cell toxicity compared to other agents used as bridging to T-cell therapies (Cummins NW, mBio, 2016; Dzhagalov I, J Immunol, 2008). We performed an analysis of all NHL patients (pts) treated with VEN at our institution to assess efficacy and safety of VEN in r/r NHL. Patients and Methods: We conducted a retrospective cohort study of all adult pts who received VEN for r/r NHL at the University of Pennsylvania between 4/2016 and 6/2018. Demographics, tumor lysis syndrome (TLS; events, prophylaxis and management), duration of therapy, reason for discontinuation, overall response, survival, and toxicities were examined. The primary endpoints were progression-free survival (PFS; defined as time from VEN start to disease progression or regimen change, death due to NHL or last-follow-up in remission), and overall survival using the Kaplan-Meier method. All other analyses were descriptive. Results: We identified 23 NHL pts for this analysis. NHL subtypes included DLBCL (35%; n=8), MCL (30%; n=7), Richter transformation (RT) (9%; n=2), transformed FL (tFL) (12%; n=4), post-transplant lymphoproliferative disease (PTLD) (4%; n=1), and marginal zone lymphoma (MZL; n=1) (4%). Median age at VEN start was 65 years; most pts were Ann Arbor stage IV (87%) and ECOG performance 2-4 (57%). NHL characteristics were MYC rearrangement (35%), BCL2 rearrangement (22%), double-hit lymphoma (26%), BCL2 IHC+ (22%), non-germinal center phenotype (13%). Median number of prior therapies was 4 (range: 2-13) with 17% having a prior autologous stem cell transplant. Median time to VEN initiation from prior therapy was 1 month (range, 0.5-9). Median VEN dose achieved was 400 mg (Range, 100-1200). Data for TLS are in Table 1. Median time on VEN was 2 months. While on VEN, 17% received radiation and 43% were on other anti-neoplastic therapy. Overall response rate (ORR) for the entire cohort was 26% (100% Partial Response [PR]). Subtypes with PR included MCL (13%), DLBCL (9%), and RT (4%). No PRs were observed with tFL, PTLD, nor MZL. Pts most commonly discontinued VEN for disease progression (74%); 2 pts (9%) remain on VEN therapy (range: 2-11 months). Median PFS and OS for the entire cohort were 2 months and 3 months, respectively, (Figure 1). Analyzed as histologic cohorts, large B-cell lymphomas (DLBCL, RT, PTLD, tFL) had similar median PFS and OS. However, small B-cell lymphomas (MCL, MZL) had median PFS and OS of 2.5 and 4 months, respectively. Two pts subsequently received CAR T-cell therapy post-VEN; one collected T-cells during VEN therapy and one collected T-cells prior to VEN start. Adverse events (AEs) occurred in approximately 65% while on VEN. AEs included: neutropenia (48%), thrombocytopenia (43%), TLS (30%), infection (26%), neutropenic fever (26%), and diarrhea (22%). One pt had an opportunistic infection (Pneumocystis jiroveci pneumonia) while on VEN and concurrent high-dose steroids. Conclusion: VEN monotherapy appears effective for NHL in phase I clinical trials. We describe our experience outside the setting of a clinical trial, including VEN used as part of multi-agent salvage therapy. Median PFS for our entire cohort is 2 months; AEs, while expected, were observed frequently, reflecting comorbidities. Clinical TLS events are attributed to pre-existing renal dysfunction (61% below 80 mL/min) during VEN escalation. The wide heterogeneity of VEN dose escalation, multi-agent combinations, and timing of initiation of VEN therapy are factors that require further investigation best designed as prospective clinical trials using other agents in combination with VEN. Disclosures Landsburg: Takeda: Consultancy; Curis: Consultancy, Research Funding. Schuster:Genentech: Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Research Funding; OncLive: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Consultancy, Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Physician's Education Source, LLC: Honoraria. Svoboda:Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; TG Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Regeneron: Research Funding; KITE: Consultancy; Kyowa: Consultancy; Merck: Research Funding. Gill:Novartis: Research Funding; Extellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Carisma Therapeutics: Equity Ownership. Mato:TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy; Portola: Research Funding; Johnson & Johnson: Consultancy; Regeneron: Research Funding; Acerta: Research Funding; Celgene: Consultancy; Prime Oncology: Honoraria; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Medscape: Honoraria. Altman:Epizyme: Other: payment to the institution to conduct clinical trial work; Incyte: Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Pfizer: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Other; GSK: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Bayer: Other: payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work; Cyclacel: Other: payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genetech: Other: Payment to the institution to conduct clinical trial work; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Dwivedy Nasta:Pharmacyclics: Research Funding; Incyte: Research Funding; Roche: Research Funding; Aileron: Research Funding; Rafael/WF: Research Funding; Debiopharm: Research Funding; Merck: Other: DSMC; Takeda/Millenium: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees.