Chronic Lymphocytic Leukemia/small Lymphocytic Lymphoma Research Articles

Recurrent Chromosomal Abnormalities in Tumoral Lesions of Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia: A Large-Scale Fluorescent in-Situ Hybridization Study on Tissue Biopsy Sections

Background: Small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) is a lymphoproliferative disorder of small mature B-cells, most commonly presenting with peripheral blood and bone marrow involvement. Tumoral lesions are variably encountered, resulting from either lymph node involvement or, less commonly, infiltration into virtually any extramedullary site. The prognostic assessment of patients with SLL/CLL relies strongly on the identification of recurrent chromosomal abnormalities, which are routinely tested by fluorescence in situ hybridization (FISH) on peripheral blood or bone marrow specimens. However, the incidence of such recurrent chromosomal abnormalities on tumoral lesions has only been studied on small series, and its concordance with peripheral blood and/or bone marrow testing remains unknown. We hereby report a large series of chromosomal abnormalities detected on tumoral SLL/CLL lesions, based on a validated FISH panel for formalin-fixed/paraffin-embedded (FFPE) biopsy sections. Methods: FISH was performed at Mayo Clinic on FFPE tissue sections from biopsies obtained from May 2014 to November 2018, as clinically indicated. Pathology reports and H&E-stained sections were reviewed and were consistent with a diagnosis of SLL/CLL in all cases. Probes were validated to detect previously described chromosomal abnormalities in SLL/CLL, including trisomy 12 (+12) and deletions of 6q23 (6q-), 11q22.3 (11q-), 13q14.3 (13q-) and 17p13.1 (17p-). Available FISH results performed on peripheral blood or bone marrow samples from these patients were also reviewed for comparison. Results: Tissue biopsies involved by SLL/CLL from 346 patients were evaluated by FISH. The majority of specimens were either lymph nodes (65%) or soft tissue masses (29%). The median age was 66.9 years (range: 36 to 91), and the male to female ratio was 2.1:1. FISH abnormalities were identified in 60% of evaluated tissue sections. The most frequently detected aberration was +12 (35%), followed by 13q- (24%), 11q- (15%), 17p- (6%) and 6q- (2%) (Figure A). In particular, the incidence of +12 was significantly higher, and the incidence of 13q- significantly lower compared to frequencies previously reported on peripheral blood or bone marrow specimens (p<0.01 for both abnormalities, in comparison to a recently published cohort of 1585 patients: Br J Haematol 2016;173:105). Most cases had 1 abnormality (55%), with fewer patients having 2 abnormalities (13%), and only 1 case showing 3 abnormalities. Of 47 patients with 2 or more chromosomal aberrations, most (72%) had 13q- in combination with either 11q- (7 cases), +12 (10 cases) or 17p- (7 cases) (Figure 1B). Of 29 patients with positive blood or bone marrow FISH results within 12 months of tissue biopsy, 7 patients (24%) had discrepant results, all of which were limited to discordant +12 and/or 13q- detection. In 14 additional patients with positive blood or bone marrow FISH results more than 12 months before or after tissue biopsy, discordant results were found in 3 cases (21%), all of which indicated gains of 17p- (2 cases) or 11q- (1 case) on the follow-up analysis. Conclusions: We hereby report the largest documented series (to the best of our knowledge) of FISH results performed on tumoral lesions of SLL/CLL. Trisomy 12 was overrepresented in tumoral lesions, as compared to the reported predominance of 13q- in leukemic involvement. Discrepant results between concurrent tumoral and leukemic FISH testing were limited to differences in +12 and 13q- in our series. We also document the acquisition of aberrancies of unfavorable prognosis (17p- and 11q-) on follow up FISH analysis in a small subset of patients, which should be taken into account when considering repeat FISH studies. Figure Disclosures Horna: MorphoSys AG: Research Funding.

Treatment with the Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) Demonstrates High Overall Response Rate and Durable Responses in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Updated Results from a Phase 1/2 Trial

Treatment with the Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) Demonstrates High Overall Response Rate and Durable Responses in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Updated Results from a Phase 1/2 Trial

Risk of Serious Adverse Events, Infection and Sepsis in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Treated with Idelalisib

Introduction: Idelalisib is a first-in-class potent, oral, selective small-molecule inhibitor of δ isoform of phosphatidylinositol 3-kinase (PI3Kδ), which involves in the signaling of B-cell receptor pathways via activation of downstream serine threonine kinases AKT and mammalian target of rapamycin (mTOR), and has been implicated in the pathogenesis of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL). Yet, there are considerable safety concerns. We undertook a systematic review and combined analysis of phase 3 randomized controlled trials to determine the risk of serious adverse events, infection and sepsis in patients with relapsed/ refractory CLL/SLL treated with idelalisib. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing idelalisib in patients with relapsed and refractory CLL/SLL that mention serious adverse events, infection and sepsis as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Three phase 3 RCTs with a total of 892 patients with relapsed and refractory CLL/SLL were eligible for analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 83, suggesting moderate heterogeneity among RCTs. The incidence of serious adverse events was 341 (69.59%) in study group vs 177 (44.03%) in control group with RR of 1.50 (95% CI: 1.28-1.75; p < 0.0001). Pneumonitis was noted in 14 (2.86%) vs 1 (0.25%) in control group (RR, 5.42; 95% CI: 1.22-24.13; p = 0.03). The incidence of any-grade pneumonia was 78 (15.92%) in study group vs 45 (11.19%) in control group (RR, 1.38; 95% CI: 0.98 - 1.96; P = 0.07). High-grade pneumonia was reported in 59 (12.04%) in idelalisib arm versus 33 (8.21%) in control group with RR of 1.36 (95% CI: 0.82 - 2.27; P = 0.23). Pneumocystis jiroveci (PJP) pneumonia rate was 2.56% higher in study group compared to control arm (RR, 4.25; 95% CI: 1.10 - 16.34; P = 0.04). Febrile neutropenia was noted in 13.47% in study group versus 4.73% in control arm (RR, 2.39; 95% CI: 0.90-6.34; p = 0.08). Sepsis rate was 3.36% higher in idelalisib group compared to control arm and the pooled RR was statistically significant at 2.64 (95% CI 1.10-6.30; p = 0.03). Treatment-related deaths were 45 (6.92%) in idelalisib arm vs 21 (3.74%) in control arm according to analysis of 2 trials. The pooled RR was not statistically significant at 1.64 (95% CI: 0.99 -2.71; P = 0.06). Conclusion: Patients on idelalisib experienced higher risk of serious adverse events, pneumonitis, PJP pneumonia, and sepsis, with RR of 1.50 for serious adverse events, RR of 5.42 for pneumonitis, RR of 4.25 for PJP pneumonia and RR of 2.64 for sepsis respectively. Nevertheless, there was no significant increase in treatment-related deaths due to TRAE in the idelalisib group, compared to control arm. Preemptive measures with proper supportive care are required to reduce those toxicities which can ultimately improve patients' quality of life and may probably affect patients' compliance. Disclosures No relevant conflicts of interest to declare.

Rapid Undetectable MRD (uMRD) Responses in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated with Lisocabtagene Maraleucel (liso-cel), a CD19-Directed CAR T Cell Product: Updated Results from Transcend CLL 004, a Phase 1/2 Study Including Patients with High-Risk Disease Previously Treated with Ibrutinib

Rapid Undetectable MRD (uMRD) Responses in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated with Lisocabtagene Maraleucel (liso-cel), a CD19-Directed CAR T Cell Product: Updated Results from Transcend CLL 004, a Phase 1/2 Study Including Patients with High-Risk Disease Previously Treated with Ibrutinib

Incidence of High-Grade Hematologic Toxicities and Hypertension in Patients with Hematological Malignancies Treated with Ibrutinib

Introduction: Ibrutinib, a Bruton's tyrosine kinase inhibitor, has been approved for the treatment of many hematological malignancies including but not limited to, chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma, and marginal zone lymphoma. Despite the efficacy of this drug in the treatment of hematologic diseases, multiple adverse effects have been well reported. This study seeks to present a combined analysis of currently available randomized controlled trials (RCTs) on the incidence of high-grade hematological toxicities and hypertension, in patients being treated with ibrutinib for hematological malignancies. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing ibrutinib in patients with hematologic malignancies that mention high-grade hematological toxicities and hypertension were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: A total of 3,920 patients with CLL/SLL, mantle-cell lymphoma, Waldenstrom's macroglobulinemia and diffuse large b-cell lymphoma, from 10 phase III RCTs were eligible. Studies compared ibrutinib+ obinutuzumab vs chlorambucil+ obinutuzumab, ibrutinib vs chlorambucil, bendamustine+ rituximab vs ibrutinib vs ibrutinib+ rituximab, ibrutinib+ rituximab vs fludarabine+ cyclophosphamide+ rituximab, ibrutinib vs rituximab, ibrutinib vs ofatumumab, ibrutinib+ bendamustine+ rituximab vs bendamustine+ rituximab, ibrutinib vs temsirolimus, ibrutinib+ rituximab+ cyclophosphamide+ doxorubicin+ vincristine+ prednisone vs rituximab+ cyclophosphamide+ doxorubicin+ vincristine+ prednisone were included in the analysis. The randomization ratio was 2:1 in E1912 study and Huang et al study and 1:1 in other studies. The I2 statistic for heterogeneity was 32, suggesting some heterogeneity among RCT. The RR of high-grade hematologic side effects were as follows: anemia, 0.60 (95% CI: 0.36 - 1.02; p = 0.06); neutropenia, 0.76 (95% CI: 0.55 - 1.05; p = 0.10); thrombocytopenia, 0.69 (95% CI: 0.35 - 1.37; p = 0.29); and febrile neutropenia, 0.65 (95% CI: 0.30 - 1.42; p = 0.29). The incidence of high-grade hypertension (HTN) was 187 (8.59%) in study group vs 40 (2.29%) in control group with RR of 2.51 (95% CI: 1.64 -3.85; P < 0.0001). In a subset of patients with CLL/SLL treated with ibrutinib (n= 2658), the RR of high-grade hematologic side effects were as follows: anemia, 0.51 (95% CI: 0.35 - 0.74; p = 0.0005); neutropenia, 0.73 (95% CI: 0.52 - 1.01; p = 0.06); thrombocytopenia, 0.72 (95% CI: 0.38 - 1.39; p = 0.33); and febrile neutropenia, 0.54 (95% CI: 0.22 - 1.37; p = 0.20). High-grade HTN rate was 8.11% higher in ibrutinib group compared to control arm (RR, 2.49; 95% CI: 1.47 - 4.22; P = 0.0007). Conclusions: This literature review determined that ibrutinib's efficacy must be carefully balanced against the mentioned side effects on a case by case basis. Of special consideration is the rate of HTN in the Ibrutinib group compared to the control. These findings need to be further explored to determine the efficacy of Ibrutinib in specific patient populations with varying underlying diseases. Disclosures No relevant conflicts of interest to declare.

Preliminary Results from a Phase I Study of SHC014748M in Patients with Relapsed or Refractory Indolent B-Cell Lymphomas

Introduction: The phosphatidylinositol-3-kinase (PI3K) pathway plays an important role in multiple cellular functions, including proliferation, differentiation, and trafficking, and deregulation of PI3K is a hallmark of many malignancies. The preferential expression of the PI3Kδ isoform on leukocytes provides an attractive target for hematologic malignancies. SHC014748M is a novel, potent, and highly selective PI3Kδ inhibitor. This study is a phase I, first-in-human study to assess the safety, tolerability and pharmacokinetics of SHC014748M in patients with relapsed or refractory indolent B-cell lymphomas (NCT03588598). Methods: Dose escalation was performed in a 3+3 design in sequential cohorts at doses of 50-250 mg QD, and then dose expansion was conducted at the selected cohorts to find recommended Phase II dose (RP2D). Eligible patients were those with relapsed or refractory indolent B-cell lymphomas, having at least 1 measurable lesion, and with ECOG performance status 0-2. Patients received a single dose on day 1, and then after 3 days washout multiple dosing once daily was initiated until disease progression or unacceptable toxicity. Primary endpoints included safety, tolerability and pharmacokinetics. Secondary endpoints included overall response rate (ORR), lymph node response (LNR), time to response (TTR), progression-free survival (PFS) and duration of response (DOR). Results: As of Jul 16, 2019, 38 patients with relapsed or refractory indolent B-cell lymphomas were enrolled in the study, including 23 with follicular lymphoma (FL), 11 with chronic lymphocytic leukemia/Small lymphocytic lymphoma (CLL/SLL), 1 with marginal zone lymphoma (MZL) and 3 with Waldenstrom's macroglobulinemia (WM). 15 patients were treated in the dose escalation phase and 23 were treated in the dose expansion phase (12 in 150 mg cohort, 11 in 200 mg cohort). The average number of prior therapies was 2.2 (range 1-8), and 84 percent of patients had received rituximab before. No dose-limiting toxicities occurred. The most common adverse reactions were neutropenia (39.5%), fatigue (21.1%), thrombocytopenia (18.4%), diarrhea (13.2%), pneumonia (13.2%), cough (13.2%), lymphopenia (13.2%), anemia (13.2%) and rash (13.2%). Grade ≥ 3 adverse reactions were neutropenia (23.7%), pneumonia (13.2%), rash (7.9%) and diarrhea (5.3%). Among 14 FL patients who were available for efficacy evaluation, ORR was 57.1% (8 PR, 5 SD, 1 PD). Of 9 CLL/SLL evaluable patients, 5 (55.6%) had partial response, 3 (33.3%) had partial response with lymphocytosis, and 1 had stable disease. Of 3 WM patients, 1 had partial response and 2 had minor response. Conclusion: SHC014748M was well tolerated and demonstrated promising clinical activity in patients with relapsed or refractory indolent B-cell lymphomas. Disclosures Wang: Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment.

BTK Inhibitors Induce ABC-DLBCL Cell Apoptosis By Inhibiting CYLD Phosphorylation

BTK inhibitors induce ABC-DLBCL cell apoptosis by inhibiting CYLD phosphorylation Xin Xu1, Zhigang Zhu1, Feng Liu1 , Weijie Zhong1,Huabao Xiong2, Tiefeng Feng3, and Qingshan Li3 1Geriatrics Department, GuangZhou First People's Hospital, GuangDong, 510180, People's Republic of China. 2Precision Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029, U.S.A. 3Hemotology Department, GuangZhou First People's Hospital, GuangDong, 510180, People's Republic of China. Activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL) is a common aggressive diffuse large B cell lymphoma (DLBCL). Even though CD20 antibody (Rituximab) combination therapy improved the total prognosis of DLBCL, there are still many relapsed and refractory ABC-DLBCL cases. The new treatment options are urgently needed. Pathogenesis of ABC-DLBCL is different from germinal center B cell-like diffuse large B cell lymphoma (GCB-DLBCL), which is related to activation of B cell antigen receptor(BCR) signaling. The Bruton tyrosine kinase(BTK) plays a central role in BCR signaling. Inhibition of BTK function will affect BCR signaling activity, which is involved in maintaining the malignant phenotype in B-cell lymphoma. Now in clinic, BTK inhibitors like Ibrutinib or Acalabrutinib are used extensively in chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma(MCL) as first line therapy or second line therapy. But in DLBCL its role is unclear now.Some DLBCL clinic trials got the better PFS and OS in BTK inhibitor combination therapy group(combined with Rituximab or RCHOP) but some got the negative results. Whether BTK inhibitors can definitely improve ABC-DLBCL survival and the mechanism how BTK inhibitors inducing cell death are needed further investigations. CYLD (cylindromatosis) is a tumor suppressor, its activity is inhibited by phosphorylation, which is related to apoptosis regulation pathway NF-kB in many kinds of tumors.In this study, we found that CYLD to be constitutively phosphorylated in ABC-DLBCL cell line models (HBL-1 and OCI-Ly10) as well as primary samples from patients with non-GCB DLBCL. We subsequently examined the effect of BTK inhibitors Ibrutinib (PCI-32765) and Acalabrutinib (ACP-196) on CYLD phosphorylation. We found that BTK inhibitors Ibrutinib and Acalabrutinib both induced ABC-DLBCL apoptosis by down-regulating CYLD phosphorylation in vivo and in vitro, even in the Rituximab resistant ABC-DLBCL cell line.Combination of BTK inhibitors and Rituximab would enhance this effect. Knockdown of CYLD in ABC-DLBCL cells reduced the level of cell death induced by BTK inhibitors, which showed that this cell death induced by BTK inhibitors was CYLD dependent. Through this study, we conclude that BTK inhibitors induce CYLD inactivation by regulating CYLD phosphorylation is clinical beneficial in ABC-DLBCL therapy, especially the relapsed or refractory ABC-DLBCL cases after Rituximab therapy. Disclosures No relevant conflicts of interest to declare.

Isolation and Characterization of a CD34+ Sub-Clone in B-Cell Lymphoma

Non-Hodgkin's lymphoma (NHL) is the most common hematological malignancy in the US. Many types remain incurable despite response to initial therapy and achievement of complete remission (CR). Advanced laboratory techniques like multicolor flow cytometry (MCF) and polymerase chain reaction (PCR) have demonstrated persistence of rare malignant cell population post therapy referred to as minimal residual disease (MRD). However, the functional and biological characteristics of this population have not been fully elucidated. Established B-lymphoma cell lines (B-NHL) and patient-derived samples (PDS) were analyzed using 8-color FCM of leukemia and lymphoma antibody panels (28 antibodies). The CD34+ sub-population was enriched using in vitro exposure to 2-chlorodeoxyadenosine (2-CdA), and a CD34-coated magnetic beads isolation procedure (Miltenyi Biotech). Genetic analysis of CD34+ and CD34-/parent cell fractions was done by karyotyping, and by chromosomal microarray (CMA) using the oligonucleotide-single nucleotide polymorphism (Oligo-SNP), whole genome Agilent 180K GGXChip+SNP (Agilent Technologies, Inc). Sensitivity to chemotherapy was assayed by short-term in vitro exposure to drugs. Clonogenicity was determined by soft agar colony formation assay, and proliferation was determined using DNA staining with propidium iodide and flow cytometry. The side population was determined using the fluorescent vital dye Hoechst 33342 and flow cytometry. Analysis of three B-NHL cell lines revealed the presence of a minute sub-clone (<1%) of monotypic B-cells that expresses CD34. This sub-population enriched several folds in response to exposure of the cells to 2-CdA. Enrichment was highest in the follicular lymphoma cell line, WSU-FSCCL reaching more than 50 folds compared with control (13.2% vs 0.26%), followed by WSU-WM, 10-fold (2.36% vs 0.23%), and least in WSU-DLCL2 (1.25% vs 0.71%). Using a CD34 microbead positive selection technique, we were able to enrich the CD34+ population up to 80% purity. Western blots confirmed higher expression of CD34 protein in the enriched population compared with parent cells. Using StemPro media (Gibco by Life Technologies), CD34+ cell fraction of WSU-WM showed more sustained growth and viability in culture over 9-day period compared with parent cells. This technique allowed the generation of large number of CD34+ cells for further characterization. Except for CD34 expression, this cell fraction expressed identical phenotype, karyotype, SNP and MCA profile to parent cells. However, the CD34+ fraction was more proliferative with an increase in S-phase cells (~60% vs 20% in control cells) and Hoechst 33342-positive cells (~40%). These cells were clonogenic even in presence of the cytotoxic agents Doxorubicin and 2-CdA that completely inhibited colony formation in parent cells. Resistance to chemotherapy was also noticed in liquid culture. A CD34+ population within clonal B-cells was also detected in 8 of 8 PDS. The lowest number of CD34+ cells was detected in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and the highest (5.35%) was seen in Richter's transformation of CLL. The isolated CD34+ cells in this study show many features of what is known as Lymphoma Stem Cells implicated in resistance to therapy and disease recurrence. Its relatedness to MRD cells is uncertain, however, since CD34 is not routinely included in MRD antibody panel. The observation that CD34+ cells are genetically identical to parent cells suggests an epigenetic modification. This conclusion is supported by our finding that Ehd3 expression is dramatically reduced in the CD34+ cell population of WSU-DLCL2 compared with parent cells. Ehd3 was recently identified as an epigenetically-silenced gene in solid tumors and in hematological malignancies including leukemia and lymphoma. The Ehd3-encoded protein belongs to the family of C-terminal Eps15 homology domain-containing (EHD) proteins, implicated in intracellular trafficking of tubular recycling endosomes (TRE), apoptosis, and cell cycle arrest. Further studies are underway to determine the contribution of Ehd3 to the biological and functional characteristics of the CD34+ cells in B-NHL. Utilizing the CD34+ monotypic B-cells in B-NHL as a model for screening new therapeutic agents and to identify potential new therapeutic strategies may lead to a more effective treatment of B-NHL. Disclosures No relevant conflicts of interest to declare.

Decreased Thrombin Generation Potential in Lymphoma Patients Is Associated with Increased D-Dimer, CRP, Vwf and TNF-α. Interrelationship between Thrombogenesis and Inflammation

Introduction: The prevalence of thrombosis in lymphoma patients is reportedly high and ranges from 3 - 10%, and further increased at advanced stages of the disease especially in hgNHL. Inflammation and other vascular factors contribute to the pathogenesis of these thrombotic complications. Biomarkers of hemostatic activation, vascular dysfunction and inflammation are elevated in lymphoma. We have previously reported that thrombin generation biomarkers such as D-Dimer, thrombin anti-thrombin complex (TAT) and prothrombin fragment (F1.2) along with inflammatory biomarkers are increased in cancer patients. Interestingly, despite an increase in thrombin generation markers, thrombin generation potential in these patients is decreased. This study was designed to compare the thrombin generation potential and its relevance to the generation of various biomarkers of hemostatic activation process and inflammatory responses. Methods: Citrated blood samples from 90 patients with confirmed diagnosis of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) and Chronic lymphocytic leukemia/Small lymphocytic lymphoma (CLL/SLL) were collected from the Clinic of Hematology Unit, University of Belgrade, Belgrade, Serbia. 50 samples of normal human plasma (NHP) was obtained from George King Biomedical (Overland park, KS). NHP was prepared for referencing purposes. Thrombin generation studies were carried out using a commercially available a kinetic fluorogenic substrate method (calibrated automated thrombogram; CAT). Thrombin generation parameters such as peak thrombin (PT), lag time (LT) and area under the curve (AUC) were compiled. Plasma levels of D-Dimer, CRP, vWF and TNF- α were measured by using commercially available Sandwich ELISA assays. Results were compiled in terms of mean ± SD. Correlation analysis carried out by using Prism, Graphpad. Results: On a cumulative basis, lymphoma patients showed an increase in lag time (2.9 1.17) in comparison to the NHP (2.7). The peak thrombin levels was decreased (119.0 46.2) in the lymphoma patients in comparison to NHP (159.7 31.1). The AUC was decreased (670.2 290.01) in the lymphoma patients in comparison to NHP (700.9 ). When the lymphoma patients were sub grouped, peak thrombin levels were similar in HL (129.9), NHL (114.7) and CLL (127.4) and were decreased compared to NHP (159.7). However the AUC was increased in the HL (769), decreased in NHL (642.4) and was comparable for CLL (715.4) compared to NHP (700.9). Variations in lag time were noted in the three groups. The lymphoma patients also exhibited elevated levels of D-Dimer (878 1205 ng/ml) in comparison to NHP (280 ng/ml), CRP (15.2 26.6 ug/ml) in comparison to NHP (0.9 ug/ml), vWF (271.8 189.7 %) in comparison to NHP (122%) and TNF-α (16.4 20.64 pg/ml) in comparison to NHP (4.2 pg/ml). Interestingly, when the lymphoma group were subdivided into various groups, the D-Dimer level was highest in HL following the order HL>NHL>CLL. CRP and vWF levels were highest in HL and comparable in both NHL and CLL. Wide scatter in TNF-α data was noted with CLL exhibiting highest levels with the ranked order CLL>NHL>HL. The composite data on thrombin generation parameters and biomarkers is shown on the table 1A. In the HL group D-Dimer and CRP correlated well with AUC and PT, in this group vWF also showed a good correlation with PT. In the NHL group, CRP correlated well with LT. In the CLL group none of the biomarkers correlated well with the thrombin generation parameters. On a cumulative basis, D-Dimer, CRP, vWF and TNF-α had no significant relevance to thrombin generation parameters. The composite regression coefficience data is shown on table 1B. Conclusion: Lymphoma patients represent a heterogenous group in which both the hypercoagulable state and inflammatory responses simultaneously occur as evident by increase in D-Dimer and inflammatory biomarkers. While the overall thrombin generation potential in the plasma of these patients is decreased, thrombin is constantly generated in some of these patient leading to the formation of fibrin. The observed decrease in thrombin generation potential in these patients may be due to the consumption of prothrombin and other coagulation factors. Wide variations among these lymphoma groups are noted. Profiling of thrombin generation and inflammatory biomarkers may be helpful in thrombotic risk stratification of lymphoma patients and their anti-thrombotic management. Disclosures No relevant conflicts of interest to declare.

Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: A Retrospective, Single-Institution Analysis Based on Risk Features and Debulking Strategy with Anti-CD20 Monoclonal Antibody

Background: The treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) has continued to evolve in recent years, offering the patients different therapeutic options. Venetoclax (ven) is a selective, small molecule inhibitor of B-cell receptor-2 (BCL-2) approved by the FDA for patients with newly diagnosed and relapsed/refractory CLL. Stratification based on tumor lysis syndrome (TLS) risk is recommended and may guide debulking strategies. Methods: We retrospectively analyzed 36 patients with relapsed/refractory (RR) CLL who received treatment with ven at the Moffitt Cancer Center between January 2016 and July 2019. Objective response to therapy was determined based on iwCLL. Progression free survival (PFS) and overall survival (OS) were evaluated via Kaplan-Meier method; overall response rate (ORR) and complete response (CR) via Fisher's exact test. Adverse events (AEs) were graded by CTCAEv5. Results: The median age was 58.5 years (28-82). Median follow up was 12.97 months. The vast majority of patients had high risk disease; Chromosomal analysis by Fluorescence In Situ Hybridization (FISH) reported Del17p and Del11q (+/- others, except Del17p) in 18 (50%) patients and 6 (16.7%) patients respectively. Twenty one (58.3%) patients had a TP53 mutation by next generation sequencing. Twenty five (80.6%) patients had unmutated IGHV status, and 24 (79.9%) patients had high or very high CLL-International prognostic Index (CLL-IPI) score. Twenty-four patients (66.7%) had been previously treated with Ibrutinib, 11 of those progressing on it. Further characteristics are described in table 1. Median OS was not reached. Median PFS was 23.93 months, figure 1a. Median duration of response was 25.97 months. The ORR (PR+CR) at the time of analysis was 63.9%, with CR rate of 33.3%, and PR rate of 30.6%. Nine patients (25%) had stable disease (SD), while four patients (11.1%) progressed on treatment. Minimal residual disease (MRD) was evaluated as part of the response assessment in 7 patients (19.4%) by flow cytometry (1 patient) and by clonoSEQ (6 patients), and 4 (11.1%) had achieved undetectable disease. Response rates were also based on risk stratification; OS and PFS were not affected by the presence of TP53 mutation (p=0.1145) as described in figure 1b, IGHV unmutated status, or NOTCH1 mutation. PFS was inferior in patients with high-very high CLL-IPI score (p=0.0414), figure 1c. The presence of bulky lymphadenopathy (≥5 cm) did not affect outcomes (p=0.5772), figure 1d. Reasons for treatment discontinuation were: progressive disease (PD) in 6 (16.7%), MD/patient preference in 5 (13.9%), Richter's transformation in 2 (5.6%), AEs in 1 (2.8%), allogeneic transplant in 1 (2.8%), and death while on treatment in 1 (2.8%) case. Twenty patients (55.6%) were considered to be at intermediate/high risk of developing TLS, of whom 15 (75%) received debulking therapy with rituximab (1), ofatumumab (11), or obinutuzumab (3) prior to ven. Based on the absolute lymphocyte count (ALC), the risk of TLS became low in 12 patients. The use of a debulking monoclonal antibody (MoAb) improved lymphocytosis, but did not impact PFS. Treatment was well tolerated, and was not dependent on the use of debulking MoAb; however, out of the 18 patients (50%) who underwent debulking therapy, 9 (25%) had grade 3/4 toxicities. Neutropenia was the most common grade 3/4 toxicity in all patients, which was seen in 7 (19.4%) patients, and diarrhea was the most common grade 3/4 non-hematologic toxicity, seen in 4 (11.1%) patients; grade 3/4 neutropenia was seen in 4 (57.1%) of those patients who received debulking therapy, while diarrhea was only seen in 1 (25%). No cases of TLS were observed. Ten patients (27.8%) were admitted for ramp up of ven as per physician preference, independent of TLS risk and comorbidities. Conclusion: Venetoclax is a very active agent for R/R CLL with an acceptable toxicity profile. Debulking strategy is a tolerable option for patients with high burden disease and may reduce the incidence of TLS and/or hospitalization. Nonetheless, based on this retrospective study, it does not seem to have a significant impact in outcomes, and it carries a higher risk for potential cumulative toxicity. Disclosures Chavez: Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc.: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Sandoval-Sus:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Shah:Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria. Bello:Celgene: Speakers Bureau. Sokol:EUSA: Consultancy. Nodzon:Pfizer: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy, Other: Speaker Fees; Abbvie: Other: Speaker Fees. Pinilla Ibarz:Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Sanofi: Speakers Bureau.

Fruit and Vegetable Consumption and Risk of Non-Hodgkin Lymphoma

Background: The few established risk factors for non-Hodgkin lymphoma (NHL) exhibit considerable heterogeneity by NHL subtype and suggest an etiologic role for factors with immune- or inflammation-modulating properties, or which otherwise influence lymphocyte proliferation and survival. Epidemiologic evidence supports a potential inverse association for fruit and vegetable intake and NHL risk, but with limited subtype-specific evidence. Glucosinates and indole-3-carbinol, both found in cruciferous vegetables, may mediate tumor suppressive effects, including anti-inflammatory and anti-proliferation effects or restoration of phosphatase and tensin homolog (PTEN), a known tumor suppressor frequently down-regulated in cancer cells. We conducted a prospective study to further elucidate the etiologic role of fruit and vegetable consumption for NHL and its most common histologic subtypes. Methods: We followed 47,971 men in the Health Professionals Follow-Up Study (HPFS; 1986-2012) and 77,115 women in the Nurses' Health Study (NHS; 1984-2012) with baseline information on diet and no baseline history of cancer. We queried diet every four years using validated food-frequency questionnaires. We calculated fruit and vegetable consumption, in broad categories and for specific food groups, by summing the intake of individual foods excluding fruit juices, potatoes and legumes. Incident NHL diagnoses were first self-reported in study questionnaires then confirmed by review of medical records. We classified histologic subtypes according to the World Health Organization (WHO) and International Lymphoma Epidemiology (InterLymph) Consortium guidelines. We analyzed all NHL (in aggregate) and separate endpoints of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, other B-cell NHL and T-cell NHL. We used multivariate Cox proportional hazards regression adjusting for potential confounding variables to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of various fruit and vegetable intake variables with risk of each NHL endpoint. Those intake variables were based on the pre-diagnosis questionnaire returned most recent to NHL diagnosis and modeled as continuous variables in increments of one serving/day. Results: During 2,747,939 person-years of follow-up, we confirmed 1,732 incident NHL cases (986 women, 746 men). In preliminary multivariable-adjusted analyses, no fruit and vegetable intake variable was significantly associated with risk of all NHL (Table 1). Each additional serving/day of all, green leafy, beta carotene rich and lycopene rich vegetables was significantly associated with a 15%-45% lower risk of DLBCL per serving/day but not with other NHL subtypes; cruciferous and lutein rich vegetable intakes had a suggestive but statistically non-significant inverse association with several B-cell NHL subtypes (Table 1). Other associations were only weakly suggestive or null. Conclusions: In this prospective investigation, preliminary findings suggest a modest reduction of risk of several individual B-cell NHL subtypes, including statistically significantly lower risks of DLBCL, with increasing intake of green and antioxidant rich vegetables. These findings warrant further exploration and confirmation in other study populations. We note that this abstract reports preliminary findings; ongoing analyses will extend the follow-up period, add a third large cohort (NHS II) and assess potential reverse causation, explore sex- and subtype-related heterogeneity and test for non-linearity of observed associations. If confirmed, these results will contribute to evidence-based prevention strategies for NHL and further support general health recommendations concerning benefits of fruit and vegetable intake. Disclosures No relevant conflicts of interest to declare.

Using Ibrutinib in Earlier Lines of Treatment Results in Better Outcomes for Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Using Ibrutinib in Earlier Lines of Treatment Results in Better Outcomes for Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Prediagnostic serum sCD27 and sCD30 in serial samples and risks of non-Hodgkin lymphoma subtypes.

Elevated prediagnostic serum levels of the immune activation markers sCD27 and sCD30 have been associated with non-Hodgkin lymphoma (NHL). However, the use of a single sample per participant in these studies has limited etiologic inferences. We report findings, overall and by NHL subtype, from a case-control analysis (422 cases, 434 controls) within the Janus Serum Bank with two samples per subject collected on average 5 years apart. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was associated with elevated sCD27 in the later, but not earlier, prediagnostic sample (odds ratio [OR] 4.2, 95% confidence interval [CI] 1.5-11.6 and 1.7, 0.7-4.7 per log increase, respectively) in analyses adjusting for both analytes, while follicular lymphoma (FL) was associated with elevated sCD30 in both the later and earlier samples (OR 2.9, 95% CI 1.4-4.4 and 2.3, 1.2-4.4, respectively). CLL/SLL cases were significantly more likely than controls to have higher sCD27 in the later vs. earlier sample (OR 1.4, 95% CI 1.1-1.9 per standard deviation increase); no such difference in sCD30 was apparent for FL. In a joint analysis, NHL cases were more likely than controls to have below-median sCD27 in the earlier sample and above-median sCD27 in the later sample (OR 1.5, 95% CI 1.0-2.3). For sCD30, the association between sCD30 and FL was confined to subjects with above-median analyte levels in both samples (OR 2.5, 95% CI 1.1-5.9). Our findings are compatible with elevated sCD27 representing a disease-induced effect and sCD30 representing a marker of increased FL susceptibility.

Ibrutinib in CLL/SLL: From bench to bedside (Review).

B-cell receptor (BCR) signaling is important for the development and maturation of normal B-cells and plays a key role in B-cell malignancies. Bruton's tyrosine kinase (BTK), a crucial terminal kinase enzyme in BCR signaling, has emerged as an attractive target and has been successfully applied in the treatment of hematological malignancies. Ibrutinib, a BTK inhibitor, has demonstrated marked efficacy and tolerability in treatment-naïve, relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). Ibrutinib has been approved by the Food and Drug Administration (FDA) for the treatment of CLL/SLL, MCL, marginal zone lymphoma and Waldenström macroglobulinemia and by the China FDA for the treatment of CLL/SLL and MCL. Clinical trials of ibrutinib, as a single agent or combined with chemoimmunotherapy and other promising novel agents in the treatment of B-cell malignancy therapy, such as diffuse large B-cell lymphoma, follicular lymphoma, multiple myeloma, primary and secondary CNS lymphoma and acute lymphoblastic leukemia, T-cell lymphoma and myelodysplastic syndrome, are ongoing (https://clinicaltrials.gov/). The aim of the present review was mainly to cover the clinical developments regarding the use of ibrutinib in the treatment of CLL/SLL, as well as its safety and toxicity profile.

The impacts of zanubrutinib on immune cells in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.

Ibrutinib, a first-generation Bruton's tyrosine kinase (BTK) inhibitor, could improve immunity of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Whether zanubrutinib, a second-generation selective BTK inhibitor, has similar effects as ibrutinib remains to be determined. Dynamics of number and immunophenotype of immune cells during zanubrutinib treatment in 25 R/R CLL/SLL patients were examined by flow cytometry and blood routine tests. The expression intensity of programmed death-1 (PD-1) on total CD4+ (P < .01), total CD8+ (P < .01), and T helper cells (P < .05) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on total CD4+ (P = .010) and regulatory T cells (P < .05) reduced after treatment. There were significant differences in expression intensity of CD19 (P < .01), C-X-C chemokine receptor type 5 (CXCR5) (P < .01), and CD49d (P < .05) on B cells before and after treatment. Downregulation of PD-1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. Programmed death-ligand 1 expression downregulated, especially in the female, CLL, normal spleen, normal β2-macroglobulin (β2-MG) and abnormal lactate dehydrogenase (LDH) subgroups, and CTLA-4 expression on CD4+ T cells tended to decrease in the male, old, CLL, splenomegaly, abnormal β2-MG, normal LDH, IGHV-mutated and wild-type tumor protein 53 subgroups after zanubrutinib treatment. These findings suggest that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through downregulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors.

Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL

Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Posttransplant Classic Hodgkin Lymphoma: Richter Transformation or Posttransplant Lymphoproliferative Disorder?

Abstract Richter transformation (RT) is defined as the transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) into high-grade lymphoma. An average of 5% of patients with CLL/SLL will have disease that undergoes RT during their clinical course. While most (75%) of these transformed cases manifest as diffuse large B-cell lymphoma, other variants occur, including a small minority (0.4%–0.7%) that progress to a classic Hodgkin lymphoma variant. Richter transformation portends a poor outcome in comparison to nontransformed CLL/SLL. Allogeneic stem cell transplantation (allo-SCT) can be offered, with a 5-year survival rate of 50% to 70%. In addition to disease relapse, transplantation carries significant risk of nonrelapse morbidity, including posttransplant lymphoproliferative disorder (PTLD). The distinction between disease progression or recurrence and PTLD can be challenging and has critical prognostic and therapeutic implications. In this report, we describe a patient whose initial CLL/SLL transformed to diffuse large B-cell lymphoma, who then received allo-SCT. Subsequent development of classic Hodgkin lymphoma proved to be a diagnostic conundrum, for which PTLD and disease progression/recurrence were both reasonable considerations. This case illustrates the diagnostic dilemma and semantic confusion faced by both pathologists and clinicians when lymphoproliferative disorders emerge within the immunologically complex interface of CLL/SLL, RT, and allo-SCT. As molecular technologies are becoming more commonplace in routine diagnostics, subpopulation clonal analysis may be useful in such cases. It may also be worth reevaluating the classification and criteria for PTLD and different subtypes of RT, especially in light of implications for prognosis and optimal therapies.

The Impacts of Zanubrutinib on Immune Cells in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Ibrutinib, a first-generation Bruton's tyrosine kinase (BTK) inhibitor, could improve immunity of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Whether zanubrutinib, a second-generation BTK inhibitor, has similar effects as ibrutinib remains to be determined. Dynamics of number and immunophenotype of immune cells during zanubrutinib treatment in 25 R/R CLL/SLL patients were examined by flow cytometry and blood routine tests. The expression intensity of programmed cell death protein 1 (PD-1) on total CD4+, total CD8+ and T helper cells, and cytotoxic T lymphocyte-associated antigen-4 on total CD4+ (P=0.010) and regulatory T cells (P<0.05) reduced after treatment (P<0.05). There were significant differences in expression intensity of CD19 (P<0.01), C-X-C chemokine receptor type 5 (CXCR5) (P<0.01) and CD49d (P<0.05) on B cells before and after treatment. Down-regulation of PD-1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. The number of B cells and programmed death-ligand 1 expression down-regulated, especially in the young, CLL, normal spleen, normal I²2-macroglobulin (I²2-MG), abnormal lactate dehydrogenase (LDH) and normal tumor protein 53 subgroups, while CD49d expression tended to decrease in the male, old, CLL, splenomegaly, abnormal I²2-MG and abnormal LDH subgroups after zanubrutinib treatment. These findings suggest that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through down-regulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors. Funding: This study was supported by National Natural Science Foundation of China (81370657, 81470328, 81470329, 81600130, 81770166, 81720108002), Jiangsu Province’s Medical Elite Programme (ZDRCA2016022), Project of National Key Clinical Specialty, National Science & Technology Pillar Program (2014BAI09B12), Jiangsu Provincial Special Program of Medical Science (BL2014086 and BE2017751) and National Science and Technology Major Project (2018ZX09734-007). Declaration of Interest: No potential conflicts of interest were disclosed. Ethical Approval: This study was approved by the hospital ethics committee and all patients were provided informed consent according to the Helsinki Declaration of 1975.

Abstract 5037: Erythrocyte levels of cadmium and lead and risk of B-cell non-Hodgkin lymphoma and multiple myeloma

Abstract Heavy metals such as cadmium and lead are ubiquitous in the environment and have been classified as carcinogens by the International Agency for Research on Cancer. While research is limited, associations of heavy metals with risk of lymphoid malignancies is plausible given that other environmental factors have been associated with these cancers. To further explore associations of cadmium and lead exposure with risk of lymphoid malignancies, we conducted a nested case-control study within the Cancer Prevention Study-II (CPS-II) Nutrition cohort, a U.S. prospective cohort of men and women. Incident B-cell non-Hodgkin lymphomas (B-NHL) and multiple myelomas (MM) were identified from 32,704 CPS-II participants who were cancer-free at time of blood collection between 1998-2001. Cases included the following histologic subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), multiple myeloma (MM), and other B-cell lymphoma. Each case was matched to two eligible controls that were selected among those who were cancer-free at the time of the case’s diagnosis. The matching factors included race, age, gender, and blood draw date. Cadmium and lead levels were measured in stored erythrocytes from the blood draw. Conditional logistic regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI) for lymphoid malignancy overall and stratified by NHL subtype. The final analytic cohort consisted of 375 B-NHL or MM cases (95 DBLCL, 90 CLL/SLL, 62 FL, 76 MM, and 52 other B-cell lymphoma), and 750 matched controls. The cohort was 56% male, and an average of 69.9 years of age at the time of blood draw. There was a significant, positive association between erythrocyte levels of lead and risk of lymphoid malignancy overall (RR: 1.17, 95% CI: 1.03 - 1.33 per 1 standard deviation (SD; 17.6 µg/L) increase in lead level). This association appeared to be driven by FL (per SD of lead RR: 1.76, 95% CI: 1.21 - 2.57). No associations between lead and DLBCL, CLL/SLL, MM, or other B-cell lymphoma were observed. Results appeared similar when additionally controlling for alcohol use and smoking status. There was no association between cadmium and lymphoid malignancies overall; however, cadmium was inversely associated with risk of multiple myeloma (Q4 vs Q1 RR: 0.30, 95% CI: 0.12 - 0.75). Preliminary results from this nested case-control analysis suggests that a positive association between erythrocyte lead levels and risk of lymphoid malignancies (particularly follicular lymphoma) may exist. Reasons for an inverse association between cadmium and risk of multiple myeloma are unclear but might be due to chance. Further research is needed to fully explore and confirm these findings. Citation Format: Emily L. Deubler, Susan M. Gapstur, W. Ryan Diver, Mia M. Gaudet, James M. Hodge, Victoria L. Stevens, Marjorie L. McCullough, Laura G. Haines, Keith E. Levine, Lauren R. Teras. Erythrocyte levels of cadmium and lead and risk of B-cell non-Hodgkin lymphoma and multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5037.

An Interesting Case of Lineage Switch to Histiocytic Sarcoma in a Case of Diffuse Large B Cell Lymphoma

Lineage switch involves change in the phenotypic characteristics from one type to another. It is a rare phenomenon described in mature lymphoid neoplasms which transform to histiocytic/dendritic cell tumor, more commonly described in low-grade lymphoma like follicular, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), wherein the neoplasm loses the phenotypic characteristics of non-Hodgkin lymphoma and acquires the markers of histiocytic differentiation. Here, we present a case of diffuse large B cell lymphoma transforming to histiocytic sarcoma post 6 months of start of therapy. Histiocytic sarcoma being a very aggressive tumor, the patient had a very rapid deteriorating course and succumbed to disease.