CD19-targeted chimeric antigen receptor-modified T cell (CAR-T cell) therapy has shown excellent antitumor activity in patients with relapsed/refractory B cell malignancies, with very encouraging response rates and outcomes. However, the late effects following this therapy remain unknown. Here we report late adverse eventsdefined as starting or persisting beyond 90 days after CART cell infusion-in patients who survived at least 1 year after therapy. The median duration of follow-up was 28.1 months (range, 12.5 to 62.6 months). At last follow-up, 73% of patients were still alive and 24% were in ongoing complete remission (CR). The most common late adverse event was hypogammaglobulinemia (IgG <400 mg/dL or i.v immunoglobulinm (IVIG) replacement, observed in 67% of the patients with available data. Infection density was .55 infection/100 days at risk (2.08 per patient-year). The majority (80%) of the infections were treated in the outpatient setting, and 5% necessitated admission to the intensive care unit (ICU). Subsequent malignancies occurred in 15% of patients, including 5% with myelodysplastic syndrome (MDS). Among patients with ongoing CR and with no MDS, 16% experienced prolonged cytopenia requiring transfusions or growth factor support. Graft-versus-host disease occurred in 3 of 15 patients (20%) who had undergone previous allogeneic hematopoietic cell transplantation. Most of the late events observed in this cohort were not severe, and many could be related to previous or subsequent therapies, suggesting a safe longterm profile of CD19-targeted CART cell immunotherapy.

CD19-targeted chimeric antigen receptor (CAR) modified T cell immunotherapy is a novel treatment with promising results in patients with relapsed/refractory lymphoid malignancies. CAR T cell therapy has known early toxicities of cytokine release syndrome and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We have used patient-reported outcomes, including Patient-Reported Outcomes Measurement Information System (PROMIS) measures, to assess neuropsychiatric and other patient-reported outcomes of 40 patients with relapse/ refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, and acute lymphoblastic leukemia 1 to 5 years after treatment with CD19-targeted CAR T cells. Mean T scores of PROMIS domains of global mental health, global physical health, social function, anxiety, depression, fatigue, pain, and sleep disturbance were not clinically meaningfully different from the mean in the general US population. However, 19 patients (47.5%) reported at least 1 cognitive difficulty and/or clinically meaningful depression and/or anxiety, and 7 patients (17.5%) scored 40 in global mental health, indicating at least 1 standard deviation worse than the general population mean. Younger age was associated with worse long-term global mental health (P = .02), anxiety (P = .001), and depression (P= .01). Anxiety before CAR T cell therapy was associated with increased likelihood of anxiety after CAR T cell therapy (P = .001). Fifteen patients (37.5%) reported cognitive difficulties after CAR T cell therapy. Depression before CAR T cell therapy was statistically significantly associated with higher likelihood of self-reported post-CAR T cognitive difficulties (P = .02), and there was a trend for an association between acute neurotoxicity and self-reported post-CAR T cognitive difficulties (P = .08). Having more post-CAR T cognitive difficulties was associated with worse global mental health and global physical health. Our study demonstrates overall good neuropsychiatric outcomes in 40 long-term survivors after CAR T cell therapy. However, nearly 50% of patients in the cohort reported at least 1 clinically meaningful negative neuropsychiatric outcome (anxiety, depression, or cognitive difficulty), indicating that a significant number of patients would likely benefit from mental health services following CAR T cell therapy. Younger age, pre-CAR T anxiety or depression, and acute neurotoxicity may be risk factors for long-term neuropsychiatric problems in this patient population. Larger studies are needed to confirm these findings.

Objectives ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- and older-onset patients are still incompletely understood. Methods We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: &lt;65 years or ≥65 years. We adjusted associations for the type of AAV and the type of ANCA (anti-MPO, anti-PR3 or negative). Results A total of 1338 patients with AAV were included: 66% had disease onset at &lt;65 years of age [female 50%; mean age 48.4 years (s.d. 12.6)] and 34% had disease onset at ≥65 years [female 54%; mean age 73.6 years (s.d. 6)]. ANCA (MPO) positivity was more frequent in the older group (48% vs 27%; P = 0.001). Younger patients had higher rates of musculoskeletal, cutaneous and ENT manifestations compared with older patients. Systemic, neurologic,cardiovascular involvement and worsening renal function were more frequent in the older-onset group. Damage accrual, measured with the Vasculitis Damage Index (VDI), was significantly higher in older patients, 12% of whom had a 6 month VDI ≥5, compared with 7% of younger patients (P = 0.01). Older age was an independent risk factor for early death within 6 months from diagnosis [hazard ratio 2.06 (95% CI 1.07, 3.97); P = 0.03]. Conclusion Within 6 months of diagnosis of AAV, patients &gt;65 years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients.

Background: The vasculitides are a group of rare diseases with different manifestations and outcomes. New therapeutic options have led to the need for long-term registries. The Rheumatic Diseases Portuguese Register, Reuma.pt, is a web-based electronic clinical record, created in 2008, which currently includes specific modules for 12 diseases and > 20,000 patients registered from 79 rheumatology centres. On October 2014, a dedicated module for vasculitis was created as part of the European Vasculitis Society collaborative network, enabling prospective collection and central storage of encrypted data from patients with this condition. All Portuguese rheumatology centres were invited to participate. Data regarding demographics, diagnosis, classification criteria, assessment tools, and treatment were collected. We aim to describe the structure of Reuma.pt/vasculitis and characterize the patients registered since its development. Results: A total of 687 patients, with 1945 visits, from 13 centres were registered; mean age was 53.4 ± 19.3 years at last visit and 68.7% were females. The most common diagnoses were Behçet's disease (BD) (42.5%) and giant cell arteritis (GCA) (17.8%). Patients with BD met the International Study Group criteria and the International Criteria for BD in 85.3 and 97.2% of cases, respectively. Within the most common small-and medium-vessel vasculitides registered, median [interquartile range] Birmingham Vasculitis Activity Score (BVAS) at first visit was highest in patients with ANCA-associated vasculitis (AAV) (17.0 [12.0]); there were no differences in the proportion of patients with AAV or polyarteritis nodosa who relapsed (BVAS≥1) or had a major relapse (≥1 major BVAS item) during prospective assessment (p = 1.00, p = 0.479). Biologic treatment was prescribed in 0.8% of patients with GCA, 26.7% of patients with AAV, and 7.6% of patients with BD. There were 34 (4.9%) deaths reported.

Recently two CD19-targeted CAR-T cell products were approved by the FDA for treatment of relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Excellent anti-tumor activity has been observed in patients with B cell malignancies. However, data regarding long-term effects of this therapy are very limited. Here we report long-term effects in 59 patients (pts) with R/R NHL and chronic lymphocytic leukemia (CLL) who received a total of 85 CD19-targeted CAR-T cell infusions on a clinical trial in our institution (NCT01865617), survived more than a year, and had at least one year follow-up data after their first CAR-T cell infusion. One patient who survived more than a year was excluded from this report due to incomplete data. Median follow-up was 23 months (range, 13-57) after the first CAR-T cell infusion. We report adverse events that occurred or persisted beyond 90 days after the last CAR-T cell infusion, excluding events related to disease progression. Median age at CAR-T cell infusion was 60 years (range, 34-73). There were 42 (71%) pts with NHL and 17 (29%) with CLL. The median number of prior lines of treatment was 4 (range, 1-8). 23 (39%) pts had received prior autologous (auto) hematopoietic cell transplantation (HCT), and 9 (15%) pts had received prior allogeneic (allo) HCT. 35 (59%) pts received one CAR-T cell infusion, 22 (37%) pts received 2 infusions, and 2 (3%) pts received 3 infusions. 3 (5%) pts received a maximum cell dose of 2x10(5)/kg, 40 (68%) pts received a maximum cell dose of 2x10(6)/kg, and 16 (27%) pts received a maximum cell dose of 2x10(7)/kg. 65 (76%) infusions were preceded by cyclophosphamide and fludarabine. CRS grade I/II occurred in 38 (64%) pts, and grade III in 4 (7%) pts (graded per Lee et al. Blood, 2014). No grade IV CRS was reported in this cohort. Acute neurotoxicity occurred in 20 (34%) pts. At 2 months after CAR-T cell infusion complete response (CR) was documented in 34 (58%) pts, partial response (PR) in 12 (20%) pts, and disease progression (PD) in 13 (22%) pts. During the follow-up period, another 15 (25%) pts developed PD. 29 (49%) pts received salvage therapy after CAR-T cell infusion, 8 (14%) of them received allo HCT. 5 (8%) pts received allo HCT as consolidation after CAR-T cell. 5 of 25 (20%) pts who did not receive additional therapy after last CAR-T cell infusion experienced ongoing cytopenias requiring G-CSF support, or RBC or platelet transfusions, beyond 90 days after last CAR-T cells infusion. 8 (14%) pts were diagnosed with subsequent malignancies, including 3 (5%) myelodysplasia, 4 (7%) non-melanoma skin cancer, and 1 non-invasive bladder cancer. All, but 1 patient with skin cancer, had auto or allo HCT before CAR-T cell therapy. Neuropsychiatric disorders were documented in 5 (8%) pts; including major depression, suicidal attempt, myoclonic seizures, and TIA. 5 (8%) pts experienced cardiovascular events. 4 (7%) pts developed renal dysfunction. 3 (5%) pts developed respiratory disorders. One pt had gastrointestinal bleeding. Of the 9 pts who had undergone allo HCT before CAR-T cell therapy, 1 pt (11%) developed GVHD flare. Severe hypogammaglobulinemia (IgG &lt; 400 mg/dL) or IgG replacement beyond day 90 after last CAR-T cell infusion (and before HCT if was done) were documented in 24 (41%) pts. 54 pts were included in the infection analysis. 178 suspected infection events beyond day 90 after last CAR-T cell infusion were documented in 40 (74%) pts. Antimicrobial treatments were documented for 124 infection events. 44 (25%) of the events were microbiologically proven. The most common infections were upper (92) and lower (29) respiratory tract infections. 25 (46%) pts required hospital admission due to infections, of them 8 (15%) were admitted to the ICU. When excluding infections that occurred after salvage therapy following CAR-T cell, we identified 117 infections in 28 (52%) pts. 3 pts died of non-relapse causes (2 due to infection after allo HCT, and 1 due to duodenal ulcer and gut perforation). In conclusion, our data suggest that long-term effects of CD19-targeted CAR-T cell therapy are acceptable. Most effects identified in our cohort were not severe, and many may have been related to prior or subsequent therapies (e.g. HCT before or after CAR-T cell therapy, or subsequent salvage treatments). Our data is consistent with recent published data demonstrating excellent long-term disease outcome for this heavily pre-treated population. Disclosures Turtle: Juno/Celgene: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribu Biosciences: Membership on an entity's Board of Directors or advisory committees. Maloney:Juno Therapeutics: Research Funding; GlaxoSmithKline: Research Funding; Janssen Scientific Affairs: Honoraria; Roche/Genentech: Honoraria; Seattle Genetics: Honoraria.

We present a case of reactive amyloidosis that developed secondary to common variable immunodeficiency and rheumatoid arthritis. A 66-year-old woman, with prior history of common variable immunodeficiency and rheumatoid arthritis, was referred to our clinic for chronic diarrhea investigation. The patient was submitted to colonoscopy with ileoscopy, which did not show relevant endoscopic alterations. However, undertaken biopsies revealed amyloid deposition. Since amyloidosis with GI involvement is a rare cause of chronic diarrhea, this pathology should be considered in etiologic investigation, especially when associated with chronic inflammatory diseases.

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