ALBERT

Description: Background While kidney disease (KD) is a well described complication of multiple myeloma (MM), occurring in up to 40% of patients, the incidence, pathological manifestations, and clinical correlations associated with KD in patients with Waldenström's Macroglobulinemia (WM) or IgM MGUS remain to be clarified. Methods Out of 1,738 patients with consensus criteria defined WM (N=1,655) or IgM MGUS (N=83) diagnosis who were evaluated in the WM clinic at our institution from 2001-2015, we selected those individuals with at least one of the following abnormalities: serum creatinine ≥1.3; estimated GFR (eGFR)

Description: BACKGROUND: CD19-specific chimeric antigen receptor (CAR) T-cell therapy has proven to be highly effective in patients with relapsed or refractory large B-cell lymphomas, yielding early complete response (CR) rates of ~40%, which are typically sustained. Unfortunately, most patients will not experience prolonged disease control. Despite this fact, little data exist defining the outcomes and impact of subsequent therapies for such individuals. Limited data also exist on the ability for such patients to pursue further clinical trials or allogeneic hematopoietic stem-cell transplant (HSCT). This project details the specific interventions and outcomes of this population to better inform the management of patients who suffer progressive disease (PD) after CD19-specific CAR T-cell therapy. METHODS: Adults with diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), primary mediastinal B-cell lymphoma (PMBCL), and high-grade B-cell lymphomas (HGBCL) who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance were included in this analysis. Patients who received CAR T-cell therapy in conjunction with additional protocol-specified therapy were excluded. Those who exhibited PD or persistent lymphoma after CAR T-cell therapy were the focus of this study. We defined initial PD as patients who had evidence of disease progression on the initial response assessment. Delayed PD was defined as achieving a CR, partial response (PR), or stable disease (SD) on the initial response assessment, but eventually progressed or received subsequent anti-lymphoma therapy. Baseline characteristics and all data were retrieved from the electronic medical record up until date of death or date of last contact in our system, including subsequent interventions and outcomes. Primary endpoint of this analysis was overall survival (OS). RESULTS: Between October 2013 and May 2018, we identified 51 patients with PD following CD19-specific CAR T-cell therapy. Baseline characteristics are listed in the Table 1. Histologies included DLBCL (29), HGBCL (11), tFL (8) and PMBCL (3). Median age was 60 years (range 26-75), 65% were male, median prior regimens was 3 (range 1-8). Median time from CAR T infusion to PD was 42 days (range 11-609), with 27 (53%) patients exhibiting initial PD. Median follow up after time of progression was 4.2 months. Initial PD was associated with a higher risk of death (HR 2.376, 95% CI 1.19-4.75, p=0.0143, Figure 1). The median OS for those with initial PD and delayed PD was 5.1 months (95% CI 2.0-9.3) and 13.6 months (4.1-not reached) respectively. 39 (76%) patients received ≥ 1 subsequent therapies after PD. Initial therapies included: 2nd CAR T infusion (14), targeted therapy (10), chemotherapy +/- rituximab (7), other immunotherapy (3), radiotherapy (3), intrathecal chemotherapy (1) and allogeneic HSCT (1). 12 (24%) patients received no further therapy despite PD. Those who received ≥ 1 subsequent therapies after PD had a lower risk of death (HR 0.344, 95% CI 0.149-0.793, P=0.0122) compared to those who did not. There was no difference in survival if 2nd CAR T infusion was the next line therapy compared to others (p=0.449), targeted therapy compared to others (p=0.417), or chemotherapy compared to others (p=0.565). 5 (10%) patients enrolled onto a clinical trial as next line therapy. 4 (8%) patients eventually received an allogeneic HSCT after PD, 2 of whom are still alive. We identified 8 patients who were alive for ≥ 12 months after progression without evidence of lymphoma. Last line of therapy for these patients included allogeneic HSCT (2), subsequent CD19-specific CAR-T cell infusion (2), ibrutinib (2), lenalidomide/rituximab (1), and radiotherapy (1). CONCLUSIONS: Patients with PD post anti-CD19 CAR T-cell therapy, particularly those exhibiting initial PD, have poor long-term outcomes. Patients receiving at least one anti-lymphoma therapy after PD had improved overall survival, although no single approach appeared to confer a survival benefit. Few enrolled onto a clinical trial or received an allogeneic HSCT. These data reinforce the need to both further improve the durable CR rate after CAR T-cell therapy and to develop effective strategies for those not achieving a CR. Figure 1 Figure 1. Disclosures Gopal: Spectrum: Research Funding; Pfizer: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Brim: Consultancy; Janssen: Consultancy, Research Funding; Asana: Consultancy; Gilead: Consultancy, Research Funding; Aptevo: Consultancy; Incyte: Consultancy; Teva: Research Funding. Maloney:Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; Janssen Scientific Affairs: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding. Turtle:Caribou Biosciences: Consultancy; Adaptive Biotechnologies: Consultancy; Nektar Therapeutics: Consultancy, Research Funding; Bluebird Bio: Consultancy; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptevo: Consultancy; Gilead: Consultancy. Smith:Genentech: Research Funding; Acerta Pharma BV: Research Funding; Incyte Corporation: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding. Shadman:TG Therapeutics: Research Funding; Mustang Biopharma: Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Consultancy; Verastem: Consultancy; Gilead Sciences: Research Funding; AbbVie: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; Beigene: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Celgene: Research Funding. Cassaday:Seattle Genetics: Other: Spouse Employment, Research Funding; Incyte: Research Funding; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy, Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics: Research Funding. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Lynch:Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding.

Description: Background: Whole genome sequencing (WGS) identified activating CXCR4WHIM somatic mutations in nearly 30% of patients with Waldenstrom's Macroglobulinemia (WM) (Blood 123(11):1637-46). Both nonsense and frameshift CXCR4WHIM mutations occur in WM, with over 30 different types of mutations described within the regulatory carboxyl-terminal domain of CXCR4. CXCR4WHIM mutations almost always occur with activating MYD88 mutations, and impact both disease presentation and treatment outcome (Blood 123(18):2791-6; NEJM 372(15):1430-40.). The clonal architecture of CXCR4WHIM mutations relative to MYD88 mutations and their role in disease evolution remains to be clarified. Methods: We used Sanger sequencing and highly sensitive AS-PCR assays that we developed for the most common CXCR4WHIM mutations (S338X C〉A and C〉G) to evaluate for CXCR4WHIM mutations. In conjunction with an AS-PCR MYD88L265P assay that we previously developed (Leukemia 28(8):1698-707), we also profiled tumor samples for MYD88L265P and CXCR4S338X mutations in 164 WM, 12 IgM MGUS, 20 MZL, 32 CLL, 14 MM, 7 non-IGM MGUS patients, and 32 healthy donors. Next generation transcriptome sequencing data was also performed for validation in select cases. Results: AS-PCR detected CXCR4S338X mutations in WM and IgM MGUS patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4WHIM mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%), and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and MZL patients, respectively, but not in CLL, MM, non-IGM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4S338X mutations were primarily subclonal, with highly variable clonal distribution (median 35.1%, range 1.2%-97.5%; Figure 1). Sanger sequencing identified 3 patients with multiple CXCR4 mutations, which were shown to be compound heterozygous by TA cloning and sequencing of at least 40 clones. The addition of AS-PCR to the Sanger sequencing results also revealed multiple CXCR4WHIM mutations in many individual patients that included homozygous and compound heterozygous mutations that were validated by next generation sequencing that offered a median of 5,819 (range 5,217-12,235) reads that overlapped the mutated loci. Conclusions: Taken together, these findings show that CXCR4WHIM mutations are more common in WM patients than previously revealed by WGS or Sanger sequencing. Moreover, CXCR4 mutations are primarily subclonal supporting their acquisition after MYD88L265P in WM oncogenesis. The exclusive finding of frameshift and nonsense but not missense variants within the carboxyl-terminal domain of CXCR4 suggests that significant selection pressures exist for activating mutations within the WM clone. Lastly, multiple CXCR4WHIM mutations are common in WM patients indicative of targeted genomic instability within the carboxyl-terminal domain of CXCR4. Disclosures No relevant conflicts of interest to declare.

Description: Background: Waldenstrom macroglobulinemia (WM) is an indolent malignancy characterized by extended survival, and affects predominantly older individuals, who are at risk for secondary malignancies (SM). The objectives of our study were to characterize incidence and outcomes of SM after WM diagnosis using the Surveillance, Epidemiology and End Results (SEER) database. Methods: Using the SEER-13 data from 1992-2011, we calculated standardized incidence ratios (SIR) with 95% confidence intervals (CI) for rates of solid and hematologic SM in WM patients compared with matched general population, excluding synchronous tumors. We compared SIR in groups defined by attained age, calendar year, sex and race. SIRs from SM with less than 10 cases are not reported. Also, overall survival (OS) after a malignancy diagnosis was compared between patients with or without antecedent WM in Cox proportional-hazard regression models adjusting for attained age, sex, race and tumor stage using SEER-18 data from 2000-2011. The outcome of interest for survival was hazard ratio (HR) with 95% CI. Results: Among the 4,676 WM patients in the SEER-13 database, 681 SM were recorded (Table). The overall SIR was 1.49 (95% CI 1.38-1.61) and the median time to SM was 3.7 years (95% CI 3.2-4.2 years). The cumulative incidence of SM was 9.5% (95% CI 8.6-10.5%) at 5 years, and 16.1% (95% CI 14.8-17.3%) at 10 years. The cumulative incidence at 10 years was 12.2% (95% CI 11.1-13.3%) for solid tumors and 4.2% (95% CI 3.5-4.9%) for hematologic SM. The excess risk of solid tumors peaked between 5-10 years from WM diagnosis (SIR 1.1, 1.4 and 1.1 for latency of 0-5, 5-10 and more than 10 years, respectively), while for hematologic malignancies it grew continuously with time (SIR 3.8, 4.4 and 6.7, respectively). The risk of solid tumors was significantly increased for cancers of the lung, urinary tract, thyroid gland and melanoma, but not for breast, prostate or colorectal cancer. Among lymphomas, diffuse large B-cell (DLBCL) was the most frequent subtype. Patients younger than 65 had a significantly higher SIR for any SM (SIR 2.2, 95% CI 1.9-2.6) than those 65 years or older (SIR 1.4, 95% CI 1.3-1.5). The SIR for SM was similar in the 1990s (SIR 1.3, 95% CI 1.1-1.6) and 2000s (SIR 1.5, 95% CI 1.4-1.7). The SIR for solid tumors was the same (SIR 1.2) among men and women, but for hematologic malignancies the excess risk was significantly higher in women (SIR 5.8, 95% CI 4.6-7.2) than men (SIR 3.4, 95% CI 2.8-4.2). There was no difference for white and non-white patients, either for aggregate SM or for the solid/hematologic categories. Compared with age- and sex-matched population and adjusting for race and stage, OS was worse with antecedent WM for colon cancer (HR, 2.0, 95% CI 1.4-2.7), melanoma (HR, 2.6, 95% CI 1.8-4.0) and DLBCL (HR, 1.9, 95% CI 1.2-3.0). It was not significantly different for acute leukemia (HR 0.9, 95% CI 0.5-1.4), prostate (HR 1.2, 95% CI 0.9-1.6), breast (HR 1.1, 95% CI 0.7-1.9), bladder (HR 1.2, 95% CI 0.8-1.7), thyroid (HR 0.9, 95% CI 0.1-6.0) or lung cancer (HR 1.2, 95% CI 1.0-1.4). Conclusions: Patients with WM have a 49% higher risk of a SM than the general population. Further research is needed to elucidate the increased incidence of leukemia and DLBCL possibly resulting from therapy and transformation, respectively, and melanoma, lung, bladder and thyroid cancers, possibly associated with defective immune surveillance. Comparatively poor survival in WM patients with colon cancer underscores the need for guideline-adherent screening and therapy. Table Incidencea SIR 95% CI Excess casesa All malignancies 681 1.5 1.4-1.6 95 Solid tumors 484 1.2 1.1-1.3 35 Lung 101 1.5 1.2-1.8 14 Prostate 95 1.0 0.8-1.3 1 Urinary tract 62 1.4 1.1-1.8 8 Colorectal 48 0.9 0.7-1.2 -2 Other gastrointestinal 43 1.0 0.7-1.4 0 Breast 43 1.0 0.8-1.4 1 Melanoma 35 1.9 1.3-2.7 7 Other gynecologic 21 1.3 0.8-2.0 2 Head and neck 13 0.9 0.5-1.6 0 Thyroid 10 2.7 1.3-4.9 3 Hematologic malignancies 174 4.2 3.6-4.9 56 All lymphomas 120 4.4 3.6-5.2 39 Diffuse large B-cell 31 4.3 2.9-6.1 10 Extranodal marginal zone 16 14.8 8.5-24.1 6 Other indolent B-cell 19 3.7 2.2-5.8 6 Myeloma 31 4.7 3.2-6.6 10 Acute leukemia 15 3.2 1.8-5.3 4 a per 10,000 person-years Disclosures No relevant conflicts of interest to declare.

Description: Background : Increasing data from single-arm studies suggest da-EPOCH-R may be optimal therapy for subsets of aggressive B-NHL, including primary mediastinal B-cell lymphoma, germinal-center DLBCL, and forms with MYC dysregulation. However, da-EPOCH-R administration is considerably more complex than R-CHOP, requiring twice-weekly laboratory monitoring and critical dose adjustments. Major studies in DLBCL (Wilson Blood 2002, Wilson JCO 2008) employ daily GCSF in particular. When daily GCSF is used, a mean overall dose intensity equivalent to dose level 2 is achieved. In younger patients with mediastinal B-cell lymphoma, more than half of patients attained dose level 4. We hypothesized that the use of da-EPOCH in general would have increased over the last decade. In a key subset of patients receiving first-line da-EPOCH-R for aggressive B-NHL, we sought to identify frequency of peg-filgrastim use, as a fundamental deviation from protocol-specified therapy, and identify maximum dose level achieved with peg-GCSF vs. daily GCSF. Given their similarity, we did not anticipate that choice of growth factor would predict likelihood of reaching dose level 4. Methods: We identified all patients receiving da-EPOCH from 2005 to 2015 at the University of Washington and Seattle Cancer Care Alliance and analyzed cases for baseline features, growth factor employed, and maximum dose level attained. Patients with DLBCL and variants (PMBCL, transformed lymphoma, DLBCL-PTLD) and BCL-unclassifiable (BCLU), who received at least 4 cycles of da-EPOCH with rituximab as first-line standard of care therapy (not in context of a clinical trial) were subject to detailed analysis regarding growth factor and dose level achieved. IRB approval was obtained. Results: 165 patients receiving da-EPOCH were initially identified, demonstrating an over 5-fold increase in use of this regimen over the 10-year period (Figure 1). Of these, 73 patients with DLBCL and BCLU met the above criteria, receiving da-EPOCH-R as first-line therapy. Median age was 60 (range 24-78) and patients received a median of 6 cycles (range 4-8; 75% of pts received 6 cycles) of da-EPOCH-R. Most patients (44/73, or 60%) received peg-GCSF rather than daily GCSF with da-EPOCH-R. Overall, the median, highest dose level during first-line therapy was 2 without a difference in groups receiving peg-GCSF or daily GCSF. 61% of patients attained dose level of 2, 41% achieved level 3, and 15% achieved level 4. The proportion of patients who achieved dose level 4 was comparable in the peg-GCSF group (11%) and daily GCSF (21%, p=.24, chi-2). Conclusions: Infusional da-EPOCH is being increasingly used, despite limited single arm data supporting its benefit. For first-line therapy of aggressive B-NHL, da-EPOCH-R is being broadly applied to older subgroups of patients. In that subgroup, peg-GCSF is used more than half of the time. In our population, only 15% achieved a dose level of 4 or higher, compared to over half of patients with PMBCL and a median age of 30 (Dunleavy NEJM 2013). Age is well known as a predictor of da-EPOCH dose intensity (Wilson 2002). Variations from the published protocol due to clinical judgment, as well as patient factors, are also possible factors influencing our dosing findings. Peg-GCSF vs. GCSF did not appear to impact the ability to attain dose level 4, although our study design cannot answer this definitely. Since peg-GCSF is cost effective compared to daily GCSF in lymphoma treated with CHOP (Lyman Curr Med Res Opin 2009) and more convenient, our data suggests that peg-GCSF may be a reasonable strategy to support the da-EPOCH-R regimen. Disclosures Gopal: Seattle Genetics: Research Funding. Shadman:Gilead: Honoraria, Research Funding; Acerta: Research Funding; Pharmacyclics: Honoraria, Research Funding; Emergent: Research Funding.

Description: Waldenström's macroglobulinemia (WM) is characterized by bone marrow (BM) infiltration with lymphoplasmacytic cells and production of an IgM paraprotein. Lymphocytosis is uncommon in WM, and many patients exhibit peripheral B-cell lymphopenia. Recently, by whole genome sequencing, we identified a highly recurrent somatic mutation (L265P) in MYD88. Using real-time allele-specific polymerase chain reaction (AS-PCR), we demonstrated the presence of MYD88 L265P in 93% and 54% of patients with WM and IgM monoclonal gammopathy of undetermined significance (MGUS), respectively (Xu et al, Blood 2013). To clarify the feasibility of using real-time AS-PCR assay to detect MYD88 L265P in peripheral blood, we first examined unselected mononuclear cells from peripheral blood (PB) samples of 88 patients with untreated WM. 81/88 (92%) of these patients were MYD88 L265P positive by bone marrow (BM) examination of CD19 selected B-cells; Of the 81 BM-MYD88 L265P positive patients, 32 (40%) demonstrated MYD88 L265P by AS-PCR in unselected PB mononuclear cells (PBMC) obtained at the time of BM examination. To enhance the ability to detect MYD88 L265P in PB samples, we next used AS-PCR in CD19 selected PBMC obtained from 198 WM patients which included untreated and previously treated patients. Among untreated patients, 106/118 (89.8%) were positive for MYD88 L265P in CD19 selected PB, whereas among previously treated patients, 55/80 (68.8%) were positive for MYD88 L265P (p=0.0002 vs. untreated). Simultaneously analyzed PB and BM samples from 65 untreated WM patients demonstrated positivity for MYD88 L265P in 58/65 (89.2%) and 55/65 (84.6%) of CD19 selected BM and PB samples, respectively. These findings yielded a sensitivity of 94.8%, specificity of 100%, positive and negative predictive values of 100% and 70%, respectively for AS-PCR testing of PB CD19+ cells for MYD88 L265P in untreated WM patients. In addition, we analyzed 12 untreated IgM MGUS patients with paired sampling of CD19 selected PB and BM cells. 6/12 (50%) IgM MGUS patients were positive for MYD88 L265P in BM CD19+ cells, with 5/6 (83%) of these positive patients demonstrating MYD88 L265P by AS-PCR in CD19 selected PB samples. The overall results demonstrate a high concordance of MYD88 L265P status between PB and BM CD19 selected samples, particularly in untreated WM patients. The detection of MYD88 L265P by CD19 selected PB AS-PCR examination provides a convenient and less invasive method to support the diagnosis of WM and IgM MGUS. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Chemorefractory diffuse large B-cell lymphoma (DLBCL) is associated with poor outcomes. Recent Car-T therapy trials, including Zuma-1 which led to the first FDA approval of Car-T for DLBCL (Neelapu NEJM), have shown sustained complete remission, disease control, and long-term survival in a proportion of patients. As with all trials, results must be interepreted in context of study definitions and eligibility parameters. While selection bias is often discussed, little published data regarding specific eligibility requirements on accrual of DLBCL trials exists. To better understand factors influencing Car-T trial eligibility in DLBCL, and context for observed survival rates in Car-T trials, we examined chemorefractory DLBCL patients seen from 2011-2015 at our center, applying key eligibility criteria from Zuma-1 and describing likely reasons for trial exclusion. Methods: Pts with DLBCL seen at our institution from 2011-2015, who had received at least 2 lines of therapy, were reviewed under IRB approval to determine chemorefractory status based on ZUma-1 definition, and potential eligibility for the Zuma-1 trial. Chemorefractory status per Zuma 1 was defined as stable disease (lasting 6 months or less) or progressive disease as best response to most recent chemotherapy, or disease progression within 12 months of autologous stem cell transplant. "Chemorefractory date" was identified by the chart reviewed, based on biopsy or imaging showing progression, and served as the reference date for reviewing potential Zuma-1 eligibility in detail. Specifically, clinical data (ECOG, labs, organ function) within 8 weeks of chemorefractory date was examined to estimate potential Zuma-1 eligibility. On occasion, more remote studies (e.g., an echocardiogram 〉8 weeks prior) were applied when data appeared relevant. Descriptive statistics and a Kaplan-Meier survival estimate were performed, with a comparison between those potentially Zuma-1 eligible and those not. No attempt was made to compare outcomes among pts receiving specific therapies for chemorefractory DLBCL. The specific eligibility factors examined were: histology (DLBCL, PMBCL and tFL); prior therapy including history of allogeneic SCT; CNS involvement, performance status (ECOG 01- vs 2 or higher), laboratory parameters, cardiac disease, infectious comorbidities; history of second malignancy other than nonmelanoma skin cancer/in situ cance or FL; need for urgent therapy due to tumor mass effect or rapid progression. Results: Of 404 in our DLBCL database from 2011-2015, 163 had received at least 2 therapies and were examined. 36 had inadequate follow up, leaving 127 for detailed analysis. Of these 127, 78 were determined chemorefractory as per Zuma-1. Of these 78 chemorefractory pts, median age was 63 (18-82), 17 had transformed lymphoma, 30 underwent transplant (20 auto, 2 allo, 8 auto-allo), 18 relapsed within 1 year of autologous transplant, and 30 had primary refractory disease. 43 patients (55%) were deemed ineligible for Zuma-1 by retrospective review, for reasons given in Table 1. Figure 1 shows survival. Among "eligible" pts vs not: Median OS was 15 vs 8 months (eligible vs not, p=.04). 1 yr OS was 56% vs 33%, and 2 yrs OS 40% vs 22%. Conclusion: When applied to a historical cohort, about half of chemorefractory DLBCL pts met eligibility criteria for Zuma-1. The survival of "eligible" patients appears significantly better than others. A need for acute therapy (for rapid progression), ECOG performance status 2 or greater, and non-FL transformation (Richter's/CLL history) were the most common reasons for exclusion. Since these three features may not impact safety of Car-T therapy, but are associated with agrgessive disease, broadening eligibility around these criteria could represent a step toward testing Car-T therapies among those with greatest unmet need. Disclosures Lynch: T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Incyte Corporation: Research Funding; Takeda Pharmaceuticals: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Shadman:TG Therapeutics: Research Funding; AstraZeneca: Consultancy; Genentech: Research Funding; Verastem: Consultancy; Mustang Biopharma: Research Funding; Celgene: Research Funding; Gilead Sciences: Research Funding; AbbVie: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Beigene: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:SPECTRUM PHARMACEUTICALS: Consultancy, Research Funding. Gopal:Janssen: Consultancy, Research Funding; Asana: Consultancy; Takeda: Research Funding; Merck: Research Funding; BMS: Research Funding; Spectrum: Research Funding; Teva: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Brim: Consultancy; Aptevo: Consultancy; Incyte: Consultancy. Smith:Pharmacyclics: Research Funding; Genentech: Research Funding; Acerta Pharma BV: Research Funding; Incyte Corporation: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding.

Description: Background: Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) remains standard therapy for previously untreated diffuse large B-cell lymphoma (DLBCL). However, a substantial proportion of patients (pts) will relapse. The anti-PD-1 monoclonal antibody pembrolizumab has shown modest efficacy in previously treated DLBCL. We postulated that the first-line setting, with relatively intact host immunity and coexistence of malignant cells with T-cells in the microenvironment, may represent an opportunity for effective immune checkpoint inhibition. We carried out the first known prospective trial of anti-PD1 therapy with anthracycline chemotherapy in lymphoma, to evaluate the safety of this combination. Methods: Pts age 18 years or older with previously untreated DLBCL, transformed lymphoma and grade 3B follicular lymphoma with a plan for 6-cycle, curative-intent RCHOP were eligible. Steroids within 7 days of treatment, active autoimmune disease, or history of pneumonitis were excluded. This phase I study combined pembrolizumab (200 mg IV q 3 weeks x 6) to RCHOP x 6, with supportive care per standard practice. A 30-pt sample size permitted estimation of the rate of clinically relevant grade 3-5 toxicity, assumed to occur in 40% of pts with RCHOP alone. A stopping rule for more than 3 instances of non-relapse death or inability to complete 6 cycles of RCHOP for any reason was applied. Secondary endpoints included response rates, overall (OS) and progression-free survival (PFS). Baseline PDL1 expression was analyzed centrally (Merck/Qualtek). Peripheral blood flow cytometry for changes in PD1, PDL-1, and PDL-2 subsets were performed. After PET-based response assessment, pts were followed for relapse and survival. Results: Since March 2016, 29 pts were treated on study; 28 have finished all therapy. One is currently on therapy, and 1 remains to be enrolled. Pt characteristics are in Table 1. In 29 pts to date, 18 grade 3-5 clinically significant AE's occurred in 13 unique pts (13/29, 45%). 16 SAE's occurred in 11 pts (11/29, 38%); none qualified as unanticipated events. Two deaths occurred: One in the first accured patient, who had extensive gastric involvement by DLBCL, and died during cycle 1 of bleeding from the responding tumor bed despite maximal inpatient intervention. The other death occurred due to steroid-refractory GVHD after haploidenticial allogeneic transplant for relapsed disease. Four immune-related adverse events (IRAE) occurred: grade 3 rash, resolving with oral steroids and not recurring with further pembrolizumab, grade 1 hyperthyroidism, grade 2 colitis, and 1 episode of grade 3 pneumonitis. This case of pneumonitis was the only immune-related SAE, occurring in a 78 yo with a history of tobacco use and COPD, and resulted in stopping therapy after cycle 3. Among 27 completing treatment (excluding the pt who died during cycle 1), average anthracycline dose was 95% of expected; anthracycline relative dose intensity (RDI: delivered dose intensity/standard dose intensity) was 94%. PET response assessment among 26 evaluable pts showed 18 CR (69%), 7 PR, and 1 primary refractory disease. Among 7 PR, 1 relapsed, 3 had negative biopsies, and 3 remain in remission. Median follow-up of survivors is 13 months and 2 relapses (1 primary progressive disease, 1 after PET PR) occurred. One-year PFS is 87% (Figure 1). Baseline PDL-1 staining available for 19 pts showed a median % tumor cell staining of 30% (moderate 2+ plus strong 3+ staining; range, 0-100%). Tumor PDL1 was ≤5% in 4, 10-29% in 5, 30-49% in 4, and ≥50% in 6 pts. Both EBV+ DLBCL had 60% tumor PDL1 expression. 1 relapsing pt had no detectable tumor PDL1, and the THRLBL failed for technical reasons. Conclusions: RCHOP with pembrolizumab 200 mg q 3 weeks x 6 cycles is safe, with toxicity similar to RCHOP alone and only 4 IRAE's. Anthracycline dose intensity, CR rate, and PFS are favorable. PDL1 tumor cell expression of 10% or more was observed in 15/19 pts. These data support further study of pembrolizumab with chemotherapy in untreated lymphoid malignancies. Final response/progression, correlative studies, and survival data will be presented in December after final accrual. Disclosures Smith: Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Acerta Pharma BV: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Incyte Corporation: Research Funding. Lynch:Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Cowan:Sanofi: Research Funding; Juno Therapeutics: Research Funding; Abbvie: Research Funding; Janssen: Research Funding. Shadman:Acerta Pharma: Research Funding; Genentech: Research Funding; Verastem: Consultancy; Gilead Sciences: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Celgene: Research Funding; Genentech: Consultancy; Beigene: Research Funding; Pharmacyclics: Research Funding; AbbVie: Consultancy; Mustang Biopharma: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Consultancy. Shustov:Seattle Genetics: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Incyte: Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy; Pfizer: Consultancy, Research Funding; Kite Pharma: Research Funding. Gopal:Pfizer: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; Takeda: Research Funding; Incyte: Consultancy; Spectrum: Research Funding; Gilead: Consultancy, Research Funding; Merck: Research Funding; Aptevo: Consultancy; Asana: Consultancy; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Teva: Research Funding.

Description: Background Relapsed or refractory (R/R) transformed indolent B-cell non-Hodgkin lymphoma (iB-NHL) is associated with a poor prognosis. Unfortunately, there is little prospective data using novel agents, including kinase inhibitors, since trials tend to specifically exclude transformed disease. To address this question we evaluated single agent ibrutinib in patients with R/R transformed iB-NHL. Methods This was a single-arm, open-label phase II trial for patients with R/R transformed iB-NHL (NCT02207062). Eligibility included no prior treatment with ibrutinib, ECOG 0-2, measurable biopsy-proven transformed iB-NHL, and prior receipt of at least one line of therapy for the transformed disease. Treatment consisted of oral ibrutinib 560 mg daily until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response rate (ORR, per Lugano criteria), with a predefined threshold of success ≥ 30%. Secondary endpoints included clinical benefit rate (CBR, defined as ORR and/or stable disease of ≥ 6 months), progression-free survival (PFS), and safety. Results As of July 1, 2018, 17 patients were treated. The median age was 68 years (range, 36 to 89) and 53% were women. Median number of treatment regimens prior to enrollment was 4 (range 2-9) and 41% had no response to their last prior treatment. Prior therapies included rituximab (100%), anthracycline (100%), platinum (76%), and a novel agent on protocol (36%). Prior autologous hematopoietic stem cell transplantation (HSCT) had been performed in 47% and prior CAR-T in 12%. The most common histologies of the indolent B-NHL included follicular lymphoma (65%), small lymphocytic lymphoma (12%), and lymphoplasmacytic lymphoma (12%). Histology of the transformed disease was diffuse large B cell lymphoma in all cases, and included germinal center B-cell (GCB) subtype by immunohistochemistry in 71% and MYC rearrangement in 12%. Five patients had bulky disease (at least one tumor mass 〉 5 cm in largest dimension) at the start of treatment. Fifteen patients were evaluable for response at the time of this data cut (Figure 1). The ORR was 40% and CBR was 47% with complete response (CR) seen in 2 patients (13%). Median PFS was 4.1 months and median duration of response was 6.8 months; estimated 12-month PFS was 23%. The 2 patients that achieved CR continue on study in remission at 37 and 15 months, respectively. ORR was associated with disease bulk, with 60% ORR in non-bulky vs 0% ORR in cases of bulky disease (p = 0.04). ORR was not associated with cell of origin (42% in GCB subtype vs 33%) or MYC rearrangement (50% in MYC rearrangement vs 35%). After treatment with ibrutinib, 2 patients proceeded to CAR-T and 1 of these subsequently underwent allogeneic HSCT. No deaths or unexpected toxicities occurred with these therapies. The side effect profile was consistent with other trials with most common adverse events (AEs) for all pts being grade 1-2 and including fatigue (59%), bruising (53%), and diarrhea (24%). Grade ≥ 3 AEs occurred in 8 patients (47%) including neutropenia (6%), lymphopenia (6%), esophagitis (6%), nausea (6%), pneumonia (6%), sepsis (6%), and atrial flutter (6%). Treatment was discontinued due to AE (grade 3 mucositis) in 1 patient after 3 weeks on therapy. One patient died while on treatment due to unknown cause. Conclusions Ibrutinib appears active in patients with R/R transformed iB-NHL that had previously received multiple agents, including rituximab and anthracycline therapy in all cases. Prolonged PFS was observed in some patients, with an estimated 12-month PFS of 23%, with higher efficacy seen in those with lower disease burden. These pilot data indicate that trials in patients with R/R transformed lymphoma can be accomplished and that ibrutinib may be clinically beneficial to a subset of such patients. The final outcome data for full accrual (n = 20) will be reported in December. Figure 1 Waterfall (a) and swimmers (b) plots. In 1a, the best response is noted: CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease. In 1b, the antecedent indolent histology is noted: FL = follicular lymphoma; LPL = lymphoplasmacytic lymphoma; SLL = small lymphocytic lymphoma. Arrowhead = continues on treatment. Disclosures Graf: Beigene: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Kite Pharma: Research Funding; Incyte: Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Adaptive Biotechnologies: Consultancy. Becker:GlycoMimetics: Research Funding. Smith:Incyte Corporation: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding. Gopal:Incyte: Consultancy; Teva: Research Funding; Spectrum: Research Funding; Brim: Consultancy; Pfizer: Research Funding; Merck: Research Funding; Aptevo: Consultancy; Asana: Consultancy; Takeda: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; BMS: Research Funding.

Description: Key Points Carfilzomib, rituximab, and dexamethasone (CaRD) produce overall and CR/VGPR responses in 87% and 36% of frontline WM patients, respectively. CaRD activity was not impacted by MYD88 and CXCR4 mutations and represents a neuropathy-sparing option for treating WM patients.