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Clinical Practice Points • Aggressive NK-cell leukemia/lymphoma (ANKL) is a rare natural killer (NK)-cell malignancy, and although it typically presents as rapidly progressive disease, cases may present more indolently, progressing over months rather than weeks. • Unlike the more common extranodal NK-cell leukemia/lymphoma, ANKL may not involve the nasopharynx and can be Epstein-Barr virus (EBV) negative. • Diagnosing ANKL can be challenging. Although not yet standard of care, next-generation sequencing and digital image analysis can be used to clarify this rare diagnosis and confirm EBV negativity. • Treatment of ANKL utilizes asparaginase-based regimens, unlike the anthracycline-based regimens used in peripheral T-cell lymphomas or myeloid disorders. Ensuring the correct diagnosis is crucial in determining the appropriate treatment regimen for this uncommon disease.

Background Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy leads to high overall response rates of ∼80% even in heavily pre-treated diffuse large B-cell lymphoma (DLBCL), though relapse-free survival drops to ∼40% within the first 12 months. There are early data suggesting that inhibiting the programmed cell death protein 1: programmed cell death ligand 1 (PD-1: PD-L1) checkpoint axis may decrease T cell exhaustion and improve CAR T-cell function. However, there is limited data regarding the toxicity of sequencing these two modalities. This case series of three patients with relapsed/refractory DLBCL treated sequentially with CAR T and checkpoint inhibitor explores the immune-related adverse events (irAEs) with this approach. Case Presentation Case 1 is a 47-year-old male with refractory T-cell/Histiocyte-Rich Large B-Cell Lymphoma who was treated initially with pembrolizumab followed by CAR T-cell therapy and developed autoimmune thyroiditis. Case 2 is a 67-year-old male with refractory DLBCL who was treated with CAR T and subsequently pembrolizumab and developed pneumonitis and respiratory failure. Case 3 is a 22-year-old female with primary refractory mediastinal DLBCL who was treated with pembrolizumab following CAR T therapy and subsequently developed a T-cell mediated autoimmune skin reaction. Conclusions T cell exhaustion has been suspected to contribute to poor persistence of CAR T-cells and clinical relapse, which may be overcome by checkpoint inhibition. While the synergy between CAR T-cell therapy and checkpoint inhibition is promising, the interaction may also lead to off-target irAEs. Prospective trials exploring the safety and efficacy of this combination in relapsed/refractory DLBCL are under way.

Context Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who are ineligible for, or relapse after, salvage chemotherapy/stem cell transplant (SCT) have a poor prognosis. Lonca comprises a humanized anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin. Objective To assess updated efficacy and safety findings from a Phase 2 study evaluating Lonca in patients with R/R DLBCL (LOTIS-2; NCT03589469). Design Multicenter, open-label, single-arm Phase 2 study in adult patients (≥18 years) with pathologically defined R/R DLBCL and ≥2 prior systemic treatments. Intervention Lonca (150 µg/kg every 3 weeks [Q3W] for 2 cycles; 75 µg/kg Q3W thereafter). Main Outcomes Measures Primary efficacy endpoint: Overall response rate (ORR), assessed by central review. Secondary efficacy endpoints: Duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Safety analyses: Treatment-emergent adverse events (TEAEs). Follow-up period: Q12W for ≤3 years after end of treatment. Results 145 patients with R/R DLBCL received ≥1 Lonca dose. Median age was 66 years (range 23–94). Patients received a median of 3 prior therapies (range 2–7). At data cut-off (October 26, 2020, ≥12 months since first dose), 2 patients continued treatment. Patients received a mean of 4.6 Lonca cycles (std 4.1; range 1–22). ORR was 48.3% (complete response [CR]: 24.8%; partial response [PR]: 23.4%). Median DoR was 12.6 months for patients with CR or PR (n=70); not reached for patients with CR. Median PFS and OS were 4.9 and 9.5 months, respectively. Post-Lonca treatment, 15 patients received CD19-directed chimeric antigen receptor T-cell therapy with an investigator-assessed ORR of 46.7%, and 11 patients proceeded to SCT as consolidation after Lonca response. Most common (≥25.0%) all-grade TEAEs were increased gamma-glutamyltransferase (41.4%), neutropenia (40.0%), thrombocytopenia (33.1%), fatigue (27.6%), and anemia (26.2%). Grade ≥3 TEAEs occurred in 107 (73.8%) patients. Treatment-related TEAEs leading to treatment discontinuation and dose delays occurred in 26 (17.9%) and 62 (42.8%) patients, respectively. Conclusions After longer follow-up of patients in LOTIS-2, durable responses to Lonca continue to be observed in heavily pre-treated patients with R/R DLBCL. No new safety concerns occurred. Research funding ADC Therapeutics SA.

Pressure ulcers (PUs) are serious skin injuries whereby the wound healing process is frequently stalled in the inflammatory phase. Myeloid-derived suppressor cells (MDSCs) accumulate as a result of inflammation and promote cutaneous wound healing by mechanisms that are not fully understood. Recently, MDSCs have been shown to differentiate into fibrocytes, which serve as emerging effector cells that enhance cell proliferation in wound healing. We postulate that in wound healing MDSCs not only execute their immunosuppressive function to regulate inflammation but also stimulate cell proliferation once they differentiate into fibrocytes. In the current study, by using full-thickness and PU mouse models, we found that Kruppel-like factor 4 (KLF4) deficiency resulted in decreased accumulation of MDSCs and fibrocytes, and wound healing was significantly delayed. Conversely, KLF4 activation by the plant-derived product Mexicanin I increased the number of MDSCs and fibrocytes and accelerated the wound healing. Collectively, our study revealed a previously unreported function of MDSCs in cutaneous wound healing and identified Mexicanin I as a potential agent to accelerate PU wound healing.

Follicular lymphomas are frequently associated with the t(14;18)(q32;q21). This translocation can be detected by karyotype, polymerase chain reaction (PCR), and fluorescence in situ hybridization (FISH). In addition to the breakpoints currently used for diagnosis located in the major breakpoint region (MBR) and the minor cluster region (mcr), recent studies have reported the existence of other breakpoints (3′ BCL2, 5′mcr, and icr). In this study, we examined the frequency of all five breakpoints in 236 cases of follicular lymphomas by real-time PCR analysis. The distribution of breakpoint sites consisted of MBR in 118 cases (50%), mcr in 11 (5%), icr in 32 (13%), 3′ BCL2 in 13 (6%), and 5′ mcr in three cases (1%). These findings illustrate significantly higher frequency of the icr breakpoint as compared with the more frequently studied mcr. Correlation of breakpoints with histology showed that MBR breakpoints occur more frequently in grade 2 lymphomas (P = 0.042). A majority of the PCR-negative cases (75%) contained an IGH/BCL2 translocation with FISH methods, suggesting the presence of other BCL2 breakpoints. Correlation of breakpoints with survival did not reveal significant differences. Diagnostic laboratories should consider expanding their PCR methods to include other BCL2 breakpoints and correlating with FISH methods when appropriate.

Matched Pair Comparison of Busulfan/ Cyclophosphamide/Etoposide (BuCyE) to Carmustine/ Etoposide/Cytarabine/Melphalan (BEAM) Conditioning Regimen Prior to Autologous Hematopoietic Cell Transplantation (autoHCT) for Lymphoma Marcelo C. Pasquini , Jennifer Le Rademacher , Christopher Flowers , Michael Lill , Luciano J. Costa , Tsiporah B. Shore , William Vaughan , Michael Craig , Cesar O. Freytes , Thomas C. Shea , Mitchell E. Horwitz , Joseph W. Fay , Shin Mineishi , Damiano Rondelli , James Mason , Vijay Reddy , Ira Braunschweig , Weiyun Ai , Elizabeth Armstrong , Angela Smith , Cathy Zhao , Agnes Elekes , Jeanette Carreras , Kazunobu Kato , Edmund K. Waller . 1 CIBMTR, CIBMTR/ Medical College of Wisconsin, Milwaukee, WI; 2 Biostatistics, Medical College of Wisconsin, Milwaukee, WI; 3 Department of Hematology and Medical Oncology, Winship Cancer Institute, Division of BMT, Emory University, Atlanta, GA; 4 Cedars Sinai Medical Center, Los Angeles, CA; Medical University of South Carolina, Charleston, SC; 6 Cornell Medical Center Hematology/ Oncology, The New York Hospital, New York, NY; 7 Bone Marrow Transplantation and Cell Therapy Program, University of Alabama in Birmingham, Birmingham, AL; West Virginia University Health Science Center, Morgantown, WV; 9 South Texas Veterans Health Care System and University of Texas Health Science Center San Antonio, San Antonio, TX; 10 Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC; 11 Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC; 12 Baylor University Medical Center, Dallas, TX; 13 Bone Marrow Transplantation Program, University of Alabama at Birmingham, Birmingham, AL; 14 Department of Medicine, Section of Hematology-Oncology, University of Illinois Hospital & Health Sciences System, Chicago, IL; 15 Scripps Clinic, La Jolla, CA; 16 University of Florida, Gainesville, FL; 17 Oncology, Montefiore Medical Center, Bronx, NY; 18 University of California San Francisco, San Francisco, CA; 19 Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ; 20 CIBMTR, Medical College of Wisconsin, Milwaukee, WI; 21 Department of Hematology and Medical Oncology, Winship Cancer Institute, Division of BMT, Emory University, Atlanta, GA

Background/aim: The anterior and posterior vagal trunks supply the each side of the gastric mucosa separately, and the denervation of either side does not impair the functional capacity of the other, leaving gastric acid output and circulating gastrin levels unchanged. In this study, we investigated the importance of the neural innervation and the brain-gut axis in cancer initiation by performing vagotomy in hypergastrinemic transgenic (INS-GAS) mice with a phenotype of spontaneous gastric cancer. Methods: Age/sex matched wild-type (WT) and INS-GAS mice were killed at 1, 2, 4, 6, 8, 10 and 12 months of age (at least 10 mice/ group) for histological examination of gastric cancer. INS-GAS mice at 6 months of age were randomized into 4 groups of surgery: unilateral anterior truncal vagotomy (29 mice), bilateral truncal vagotomy with pyloroplasty (24), pyloroplasty (27), and sham operation (25). Both the anterior and posterior sides of the stomachs were removed at 6 months postoperatively (i.e., 12 months of age) for pathological and immunohistochemical analyses. Results: Gastric cancer was found neither in WT mice regardless of age nor in INS-GAS mice that were