Complete and Durable Response to Nivolumab in Recurrent Poorly Differentiated Pancreatic Neuroendocrine Carcinoma with High Tumor Mutational Burden

Poorly differentiated pancreatic neuroendocrine carcinomas (NECs) are rare and aggressive malignancies with rapid disease progression and early widespread metastasis. Given histology similarity, they are commonly treated with platinum-based chemotherapy as small cell lung cancer (SCLC). However, no standard treatment has been established for recurrent or progressive disease. We present an Asian patient with recurrent poorly differentiated pancreatic NEC after curative surgery and adjuvant chemotherapy with cisplatin and etoposide. The tumor mutational burden (TMB) was high. The patient received chemotherapy combined with maintenance immunotherapy with nivolumab and achieved promising and durable response, suggesting TMB could be a biomarker to identify NEC patients for immune checkpoint inhibitor (ICI) treatment.

CAR T Therapy Referral for Diffuse Large B Cell Lymphoma (DLBCL) By U.S. Community Hematology/Oncology (cH/O) Practices: Perceptions and Patterns

Introduction Chimeric antigen receptor T-cell (CAR T) therapy has resulted in a treatment paradigm shift for certain hematologic malignancies, with United States Food and Drug Administration approval of several products for patients with relapsed/refractory (RR) aggressive B cell lymphomas (BCL). Although most BCL patients are initially treated by cH/O physicians, current delivery of CAR T is limited to major academic centers. Consequently, there is a dearth of reporting on the complex aspects of cH/O involvement before and after CAR T therapy administration, which complicates determination of the magnitude of potential benefits. To appropriately incorporate this therapeutic option, and optimize patient care, communication and cooperation between cH/O and the CAR T center is critical; at a minimum, the referring cH/O's access to all aspects of the CAR T therapy continuum is paramount. To that end, this study surveyed cH/O physicians to determine: 1) whether adequate data were recorded and available to the cH/O; 2) timing of referral, leukapheresis, and CAR T infusion; 3) treatment prior to CAR T referral, and 4) physician perceptions on patient eligibility, barriers to access, and noncompliance. Methods This retrospective, observational, multicenter chart review assessed adult patients with RR DLBCL who received CAR T therapy in 2019. Patients with ≥6 months of post-CAR T therapy administration follow-up were identified by cH/O physicians participating in the Cardinal Health Oncology Provider Extended Network (OPEN). cH/O physicians provided their perceptions and experience with CAR T therapy via survey and abstracted patient data using electronic case report forms. Patient demographic/clinical/treatment characteristics and physician perceptions were summarized descriptively. Results Surveyed Perceptions: Top barriers to CAR T referral: patient choice (39%), location of CAR T center (31%), and preference for other therapy (31%); 39% reported no specific barriers. Rapid disease progression (69%) was the main reason patients would not undergo CAR T therapy after referral, followed by patient ineligibility (62%), patient choice (62%), and insurance coverage/patient cost (46%). Chart Abstraction: Data on 65 RR DLBCL patients were collected from 13 cH/O practices in all 4 U.S. regions (Table). Median duration of follow-up from CAR T therapy referral was 15 months. Median age at RR DLBCL diagnosis was 60 years, and most patients were male (63%) and White (79%). Most patients (92%) received anti-CD20 monoclonal antibody (mAb) + CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) as 1L therapy. At referral, 80% of patients (48/60) had lactate dehydrogenase levels above the upper limit of normal. Prior to CAR T infusion, all patients were reported to receive lymphodepletion treatment with fludarabine + cyclophosphamide. Median intervals among patients with and without disease progression, respectively, were: 9 weeks (8 vs 10) from CAR T referral to CAR T infusion, which comprised 5 weeks (4 vs 6) from CAR T referral to leukapheresis and 4 weeks (both groups) from leukapheresis to CAR T infusion. Conclusions The cH/O physicians' perceived barriers to CAR T therapy for their patients appear to conflict with the patient data; 69% thought that rapid disease progression precluded CAR T therapy but the reported 9-week interval from referral to CAR T infusion suggests reasonably timely intervention. This highlights the critical need for early referral with a commitment to prompt patient evaluation by the treatment center. The cH/O physician is vital for CAR T referrals and treatment decisions, and the recent increasing access to patients via telemedicine may help better integrate the cH/O, the patient, and the treatment center to promote access of patients to CAR T cell therapies, particularly when limited other options are available. Figure 1 Figure 1. Disclosures Porter: DeCart: Membership on an entity's Board of Directors or advisory committees; American Society for Transplantation and Cellular Therapy: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. Klink: Cardinal Health: Current Employment, Current holder of stock options in a privately-held company. Balanean: Cardinal Health: Current Employment; Georgia State University: Other: former student and employee. McAllister: Cardinal Health: Current Employment. Feinberg: Cardinal Health: Current Employment.

Evaluation of Functional and Cytogenetic High-Risk Multiple Myeloma Using Real-World Data

Introduction: Multiple myeloma (MM) is a heterogeneous disease with wide variability in outcomes. The presence of cytogenetic abnormalities in MM is of critical importance for prognosis and risk stratification. However, patients who may or may not have sufficient cytogenetic abnormalities to classify as high-risk can still experience rapid disease progression despite therapy, or functional high risk (FHR) disease. These two high risk cohorts comprise vulnerable subpopulations who have a significant burden of disease, and it is critical that we understand the underlying patient characteristics and optimal treatment sequence. We sought to investigate these two high risk patient populations treated in the contemporary real-world practice setting. Methods: A total of 1719 patients were identified in the COTA real-world database as having been diagnosed with active MM on or after January 1, 2015 and classified as either FHR, cytogenetic high risk (CHR), or both. The COTA real-world database is a USA-based real-world evidence database comprised of longitudinal, Health Insurance Portability and Accountability Act (HIPAA)-compliant, data on the diagnosis, clinical management, and outcomes of patients with cancer. Of the 1719 patients, 1260 were identified to be FHR, defined as relapse <18 months from initial active MM diagnosis. A total of 459 patients were identified as CHR, among which 347 were both FHR and CHR. CHR was defined as a patient having at least one of the following abnormalities: t(4;14), t(14;16), t(14;20), del(17p), 1q gain, or hypoploid. Line of therapy was applied programmatically using an algorithm based on International Myeloma Working Group criteria and clinical guidance. The primary outcome was time to next treatment (TTNT) calculated using the Kaplain Meier method. Univariate and multivariate analyses were conducted to understand predictors of rapid disease progression among high-risk patients. Results: In our real-world population, FHR patients tended to be slightly younger, African American, and treated predominantly in the academic setting (Table 1). First-line (1L) and second-line (2L) treatment patterns by category are shown in Table 2. A lower proportion of FHR patients received 1L immunomodulators as compared to the other high-risk groups, while almost half of the CHR patients received 1L stem cell transplant (SCT). In 2L, among patients not receiving 2L SCT, a higher proportion of CHR patients received a daratumamab-based treatment as compared to FHR (23.2% vs. 12.0%, respectively). We observed a longer median (95% CI) TTNT for high-risk patients receiving 2L daratumamab-based treatment as compared to patients who did not: 8.5 months (6.4-13.0) vs. 6.0 months (5.3-6.9), p=0.07 (Figure 1). Univariate and multivariate analyses showed age at diagnosis (HR: 0.98, CI: 0.97, 0.99), normal cytogenetics (HR: 0.78, CI: 0.63, 0.97), 1L immunomodulator (HR: 0.39, CI: 0.22, 0.69), 1L proteasome inhibitor (HR: 1.4, CI: 1.1, 1.8), and 1L SCT (HR: 0.22, CI: 0.15, 0.32) as significant predictors of rapid disease progression. Conclusions: Our study provides important insights comparing high risk populations with MM treated in the real-world setting. A higher proportion of CHR patients received 1L SCT and this provided the longest 1L TTNT as compared to other treatments. In 2L, among patients not receiving 2L SCT, we observed a trend towards significantly longer TTNT provided by dara-based treatment as compared to non-dara based treatment; however, our TTNT is lower than progression-free survival results observed in pivotal trials. We identified potential underlying differences in our patient populations that may be driving the predictors of rapid disease progression, including 1L SCT eligibility and renal disease, and these will be further investigated in propensity score matched populations. Future research will continue to explore optimal treatment sequences in high-risk populations with multiple myeloma to improve patient outcomes. These data highlight an urgent need to better predict FHR patients at diagnosis and develop clinical trials incorporating novel compounds in high risk patients. Figure 1 Figure 1. Disclosures Hansen: COTA, Inc.: Current Employment. Belli: COTA, Inc.: Current Employment, Other: Equity ownership. Goran: COTA, Inc.: Current Employment. Wang: COTA, Inc.: Current Employment, Other: Equity ownership.

High Effectiveness and Safety of Anti-CD7 CAR T-Cell Therapy in Treating Relapsed or Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Background Compared with the substantial efficacy of chimeric antigen receptor T-cell (CAR-T) therapy that has achieved in B-ALL, whether CAR-T therapy is effective and safe for patients with T-ALL is still being explored in early stage clinical trials. Here, we present outcomes from our phase 1 clinical trial of CD7-targeting CAR-T (CD7CAR) cells therapy for R/R T-ALL (NCT04572308). Methods Peripheral blood (PB) mononuclear cells were obtained by leukapheresis. T cells were separated and transduced with lentivirus. The second-generation CD7CAR is composed of an anti-CD7 single-chain antibody, a IgG4 hinge region, a CD28TM transmembrane domain, an intracellular co-stimulatory domain of 4-1BB and CD3ζ, and the truncated EGFR protein linked by T2A. All patients received intravenous fludarabine (30 mg/m 2/d) and cyclophosphamide (300 mg/m 2/d) for 3 days prior to CD7CAR infusion. Results Seventeen R/R T-ALL patients were enrolled between December 2020 and June 2021. Characteristics of patients are shown in Table 1. Data from 14 patients with a median age of 17 years (range: 3-42 years) were available for evaluation. The rest 3 patients were withdrawn from study within 14 days due to rapid disease progression. High-risk subtype patients enrolled including 1 with Ph-positive T-ALL and 3 with early T-cell precursor (ETP)-ALL. Seven of the 14 patients also had high-risk genotypes, namely SIL-TAL1, EZH2, TP53, RUNX1, BCR-ABL, JAK1 and JAK3. At enrollment, the median percentage of bone marrow (BM) blasts was 11.53% (range: 0.18%-65.03%), and 5 of 14 patients had extramedullary involvements, including optic nerve involvement (N=2), central nervous system leukemia (N=3), diffuse extramedullary involvements (N=2), and bulky lymph nodes in the neck (N=1). Patients were heavily pretreated with a median of 5 prior lines of therapies (range: 3-8 lines) and three relapsed from prior allogeneic hematopoietic stem cell transplantation (allo-HSCT). CD7CAR-T cells were 100% successfully manufactured with a transfection efficiency of 93.8% (range: 59.6%-99.9%). Twelve of 14 participants received bridging chemotherapy. A single dose of CD7CAR-T cells was infused to patients, with 2 receiving a low-dose (0.5x10 5 cells/kg), 11 receiving a medium dose (1-1.5x10 6 cells/kg) and 1 receiving a high-dose (2x10 6 cells/kg). By the data cutoff date (July 12, 2021), the median follow-up time was 105 days (range: 32-206 days, Fig.1A). By day 28 post infusion, 92.9% (13/14) of patients achieved complete remission (CR, N=4) or CR with incomplete hematological recovery (CRi, N=9) in their BM, with all 13 patients achieving minimal residual disease (MRD) negative CR/CRi. Additionally, 4/5 patients with extramedullary involvement also achieved extramedullary remission at a median of day 32 (range: 28-90 days) post infusion. Consolidation allo-HSCT was permitted at the treatment physician's discretion and the patient's preference. A total of 11/14 patients were bridged to consolidation allo-HSCT at a median of 57 days post CD7CAR infusion, of which 9 patients have remained MRD-negative CR/CRi. One patient who had allo-HSCT prior to CD7CAR infusion died following a second haplo-HSCT due to acute graft-versus-host disease. Of the other 3 patients who were not bridged to allo-HSCT, 1 patient relapsed on day 28 due to rapid disease progression after initial CRi on day 14. Thirteen of 14 patients experienced mild CRS (Grade ≤2). One patient had Grade 3 CRS. The median time to onset of CRS was 1 day (range: 0-11 days), with a median duration of 14 days (range: 3-25 days). Neurotoxicity (Grade 1) occurred in only 1 patient. After infusion, the median peak of CAR-T copy number was 2.38 ×10 5copies/µg DNA (range: 0.2-6.67 ×10 5 copies/µg DNA), which occurred on day 20 (range: 10-42 days, Fig.1B). Importantly, CD7CAR persisted well in PB at a median of 52.5 days (range:20-120 days) at last evaluation regardless of transplantation status. Maximum proportion of CD7CAR-T cells proliferation reached 84.95% by flow cytometry (Fig.1C). Conclusions Our results demonstrate that CD7CAR therapy is safe and highly effective in treating patients with heavily pretreated R/R T-ALL, including those with extramedullary involvements, a history of prior allo-HSCT or with high-risk subtypes. More patients and a longer observation time are needed to further evaluate the potential beneficial advantages and side effects of CD7CAR therapy for T-ALL patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Atypical Parkinsonian Syndromes

The cardinal characteristics of parkinsonism are represented in the mnemonic TRAP: tremor at rest, rigidity, akinesia and bradykinesia, and postural instability. The parkinsonian phenotype encompasses a broad range of clinical and pathologic disorders; the most common (about 55% of cases) is idiopathic (sporadic) Parkinson disease. Rapid disease progression, poor initial response to dopaminergic therapy, or the early presence of certain other signs may suggest an atypical parkinsonian syndrome, sometimes called parkinsonism-plus syndrome.

6-Phosphogluconolactonase Promotes Hepatocellular Carcinogenesis by Activating Pentose Phosphate Pathway

Hepatocellular carcinoma (HCC) has a poor prognosis due to the rapid disease progression and early metastasis. The metabolism program determines the proliferation and metastasis of HCC; however, the metabolic approach to treat HCC remains uncovered. Here, by analyzing the liver cell single-cell sequencing data from HCC patients and healthy individuals, we found that 6-phosphogluconolactonase (PGLS), a cytosolic enzyme in the oxidative phase of the pentose phosphate pathway (PPP), expressing cells are associated with undifferentiated HCC subtypes. The Cancer Genome Atlas database showed that high PGLS expression was correlated with the poor prognosis in HCC patients. Knockdown or pharmaceutical inhibition of PGLS impaired the proliferation, migration, and invasion capacities of HCC cell lines, Hep3b and Huh7. Mechanistically, PGLS inhibition repressed the PPP, resulting in increased reactive oxygen species level that decreased proliferation and metastasis and increased apoptosis in HCC cells. Overall, our study showed that PGLS is a potential therapeutic target for HCC treatment through impacting the metabolic program in HCC cells.

Circulating Tumor Cell Clusters Are Cloaked with Platelets and Correlate with Poor Prognosis in Unresectable Pancreatic Cancer

Circulating tumor cells (CTCs) are known to be heterogeneous and clustered with tumor-associated cells, such as macrophages, neutrophils, fibroblasts, and platelets. However, their molecular profile and clinical significance remain largely unknown. Thus, we aimed to perform a comprehensive gene expression analysis of single CTCs and CTC clusters in patients with pancreatic cancer and to identify their potential clinical relevance to provide personalized medicine. Epitope-independent, rapid (>3 mL of whole blood/min) isolation of single CTCs and CTC clusters was achieved from a prospective cohort of 16 patients with unresectable pancreatic cancer using a centrifugal microfluidic device. Forty-eight mRNA expressions of individual CTCs and CTC clusters were analyzed to identify pancreatic CTC phenotype. CTC clusters had a larger proportion of mesenchymal expression than single CTCs (p = 0.0004). The presence of CTC clusters positively correlated with poor prognosis (progression-free survival, p = 0.0159; overall survival, p = 0.0186). Furthermore, we found that most CTCs in these patients (90.7%) were cloaked with platelets and found the presence of a positive correlation between the increase in CTC clusters and rapid disease progression during follow-ups. Efficient CTC cluster isolation and analysis techniques will enhance the understanding of complex tumor metastasis processes and can facilitate personalized disease management.

SOD1 D91A variant in the southernmost tip of Europe: a heterozygous ALS patient resident on the island of Gozo

Amyotrophic lateral sclerosis (ALS) is frequently caused by mutations in the SOD1 gene. Here, we report the first SOD1 variant in Malta, an archipelago of three inhabited islands in southern Europe. We describe a patient with a sporadic form of ALS living on the island of Gozo in which the heterozygous SOD1 c.272A>C; p.(Asp91Ala) variant was detected. The patient had a late onset (79 years), sensory impairments and rapid disease progression culminating in respiratory failure. ALS has not yet developed in any of the three additional family members in which the D91A variant was identified. None of the healthy controls from the Maltese population were found to carry this variant. This report underscores the high prevalence of the D91A variant in Europe, despite the presence of a North-South gradient in its frequency, and confirms that this variant can be associated with dominant cases in Mediterranean countries.

Illness Cognitions in ALS: New Insights Into Clinical Management of Behavioural Symptoms

Timely management of frontotemporal dysfunction associated with amyotrophic lateral sclerosis (ALS) has important prognostic and therapeutic implications. However, there remains a paucity of research on best practise recommendations to guide the development of interventions for cognitive and behavioural symptoms as part of ALS care. Accordingly, a focus on illness perceptions may provide a preliminary framework for managing cognitive and behavioural symptoms. The aim of the present study was to explore the nature of illness perceptions among ALS patients with cognitive and behavioural symptoms. A total of 39 patients were recruited from a specialised ALS clinic. Factor analysis showed three independent and clinically interpretable factors corresponding to “cognitive and emotion related ALS perceptions,” “cognitive- specific ALS perceptions” and “ALS coherence”. Of these factors, greater perceived cognitive and emotional impacts of ALS were associated with an approximate 4-fold increased risk of behavioural changes (p < 0.05). Greater perceived cognitive and emotional impacts of ALS was also associated with more rapid disease progression (p < 0.001). As such, timely provision of intervention addressing perceptions about the impact of ALS on functioning as well as associated emotional distress may optimise clinical management of cognitive and behavioural symptoms of ALS.

Rapid Progression of Endogenous Endophthalmitis in Immunocompromised Patients

Endophthalmitis is a severe inflammatory disease classified as either endogenous or exogenous, depending on the route of infection. The disease may be caused by trauma, intraocular surgery, infectious keratitis or other endogenous causes.1,2 Endogenous endophthalmitis develops when the infectious agent travels via the bloodstream, crosses the blood ocular barrier and proliferates within the eye.3 Endogenous endophthalmitis accounts for approximately 5 – 8 % of all endophthalmitis cases.1 Specific predisposing factors may cause patients more at risk for rapid disease progression.3,4 Besides, source of the infection varies widely from the respiratory tract to urinary tract or liver abscess.5 We report a case series of endogenous endophthalmitis among immunocompromised patients. These cases highlighted the importance of early diagnosis with appropriate timely intervention to prevent further spread of infection and reduce the complications.