BackgroundCD19-directed chimeric antigen receptor T-cell therapy (CAR-T) represents a promising treatment modality for an increasing number of B-cell malignancies. However, prolonged cytopenias and infections substantially contribute to the toxicity burden of CAR-T. The recently developed CAR-HEMATOTOX (HT) score—composed of five pre-lymphodepletion variables (eg, absolute neutrophil count, platelet count, hemoglobin, C-reactive protein, ferritin)—enables risk stratification of hematological toxicity.MethodsIn this multicenter retrospective analysis, we characterized early infection events (days 0–90) and clinical outcomes in 248 patients receiving standard-of-care CD19 CAR-T for relapsed/refractory large B-cell lymphoma. This included a derivation cohort (cohort A, 179 patients) and a second independent validation cohort (cohort B, 69 patients). Cumulative incidence curves were calculated for all-grade, grade ≥3, and specific infection subtypes. Clinical outcomes were studied via Kaplan-Meier estimates.ResultsIn a multivariate analysis adjusted for other baseline features, the HT score identified patients at high risk for severe infections (adjusted HR 6.4, 95% CI 3.1 to 13.1). HThigh patients more frequently developed severe infections (40% vs 8%, p<0.0001)—particularly severe bacterial infections (27% vs 0.9%, p<0.0001). Additionally, multivariate analysis of post-CAR-T factors revealed that infection risk was increased by prolonged neutropenia (≥14 days) and corticosteroid use (≥9 days), and decreased with fluoroquinolone prophylaxis. Antibacterial prophylaxis significantly reduced the likelihood of severe bacterial infections in HThigh (16% vs 46%, p<0.001), but not HTlow patients (0% vs 2%, p=n.s.). Collectively, HThigh patients experienced worse median progression-free (3.4 vs 12.6 months) and overall survival (9.1 months vs not-reached), and were hospitalized longer (median 20 vs 16 days). Severe infections represented the most common cause of non-relapse mortality after CAR-T and were associated with poor survival outcomes. A trend toward increased non-relapse mortality in HThigh patients was observed (8.0% vs 3.7%, p=0.09).ConclusionsThese data demonstrate the utility of the HT score to risk-stratify patients for infectious complications and poor survival outcomes prior to CD19 CAR-T. High-risk patients likely benefit from anti-infective prophylaxis and should be closely monitored for potential infections and relapse.
Precision cancer medicine is based on the ability to predict the dependencies of a given tumor from its molecular makeup. Despite successes in multiple common cancers, such prediction remains challenging for the majority of rare and understudied tumors given the absence of laboratory model systems in which to discover and/or validate therapeutic hypotheses. Here, we describe our efforts to address this challenge systematically with the ultimate goal of making it possible to learn how to predict ex vivo growth requirements for cancer samples based on technical, clinical and genomic properties of the starting tumor material. Over the last 5 years, we have processed nearly 2,000 tumor biospecimens and created over 375 genomically-confirmed patient-derived cell lines, organoids and neurosphere cultures, with >10% of these representing rare cancers. To make this possible, we have implemented three key workflows including (1) direct-to-patient sample sourcing, (2) a tissue cryopreservation and genomic credentialing system to ensure quality prior to model creation, and (3) a systematic empirical approach to screening rich medias and variations on organoid technologies ex vivo (HYBRID). We have begun performing genome-wide CRISPR viability screens in these cultures as part of our larger activities to generate a systematic laboratory-based functional map of cancer dependencies (a ‘Cancer Dependency Map'). The novel organoid, spheroid and cell line models created as part of this effort are being made publically available to the scientific community. Looking ahead, as the barriers to culturing rare tumors are overcome, we expect that preclinical functional genomics data will be useful for difficult-to-treat tumors without existing molecularly guided standard-of-care regimens. Citation Format: Yuen-Yi Tseng, Mushriq AI-Jazrawe, Rebecca Deasy, Paula Keskula, Grace Johnson, Andrew Hong, Priya Chatterji, Francisca Vasquez, Adam Bass, Barbara Van Hare, David Sandak, Keith Ligon, Jesse Boehm. Cancer Cell Line Factory: A systematic approach to create next-generation cancer model at scale [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3453.
Real-world evidence suggests a trend toward inferior survival of patients receiving CD19 chimeric antigen receptor (CAR) T-cell therapy in Europe (EU) and with tisagenlecleucel. The underlying logistic, patient- and disease-related reasons for these discrepancies remain poorly understood. In this multicenter retrospective observational study, we studied the patient-individual journey from CAR-T indication to infusion, baseline features, and survival outcomes in 374 patients treated with tisagenlecleucel (tisa-cel) or axicabtagene-ciloleucel (axi-cel) in EU and the United States (US). Compared with US patients, EU patients had prolonged indication-to-infusion intervals (66 versus 50 d; P < 0.001) and more commonly received intermediary therapies (holding and/or bridging therapy, 94% in EU versus 74% in US; P < 0.001). Baseline lactate dehydrogenase (LDH) (median 321 versus 271 U/L; P = 0.02) and ferritin levels (675 versus 425 ng/mL; P = 0.004) were significantly elevated in the EU cohort. Overall, we observed inferior survival in EU patients (median progression-free survival [PFS] 3.1 versus 9.2 months in US; P < 0.001) and with tisa-cel (3.2 versus 9.2 months with axi-cel; P < 0.001). On multivariate Lasso modeling, nonresponse to bridging, elevated ferritin, and increased C-reactive protein represented independent risks for treatment failure. Weighing these variables into a patient-individual risk balancer (high risk [HR] balancer), we found higher levels in EU versus US and tisa-cel versus axi-cel cohorts. Notably, superior PFS with axi-cel was exclusively evident in patients at low risk for progression (according to the HR balancer), but not in high-risk patients. These data demonstrate that inferior survival outcomes in EU patients are associated with longer time-to-infusion intervals, higher tumor burden/LDH levels, increased systemic inflammatory markers, and CAR-T product use.
Introduction Ibrutinib is a tyrosine kinase inhibitor approved for multiple B-cell malignancies, including Waldenstrom's macroglobulinemia in 2014. Although the drug portends favorable outcomes, it also bears a profile of side effects. Current literature describes only two cases of nonhemorrhagic pericardial effusion associated with ibrutinib use, and here we present the third. This case recounts an episode of serositis causing pericardial and pleural effusions and diffuse edema after eight years of maintenance ibrutinib for Waldenstrom's macroglobulinemia (WM). Case report A 90-year-old male with WM and atrial fibrillation presented to the emergency department for a week of progressive periorbital and upper and lower extremity edema, dyspnea, and gross hematuria, despite increasing at-home diuretic dose. The patient was on 140 mg ibrutinib twice daily. Labs showed stable creatinine, serum IgMs of 97, and negative serum and urine protein electrophoresis. Imaging revealed bilateral pleural effusions and pericardial effusion with impending tamponade. All other workup was unrevealing, diuretics were ceased, pericardial effusion was monitored with serial echocardiograms, and ibrutinib was exchanged for low-dose prednisone. Management and outcome After five days, the effusions and edema dissipated, hematuria resolved, and patient was discharged. Resumption of lower dose ibrutinib one month later led to a subsequent return of edema, which again subsided with cessation. Reevaluation of maintenance therapy continues outpatient. Conclusion Patients on ibrutinib presenting with dyspnea and edema should be monitored for pericardial effusion; the drug should be held in exchange for anti-inflammatory therapy, and future management should involve cautious, low-dose resumption, or exchange for alternative therapy.
spirit of the Food and Drugs Act. Towns pleaded guilty and was lined $25.-| Notice of Judgment, No. 1170.] DIXIE FEVER ANI) VAIN POWDER These "headache powders" were prepared and sold by the Morris-Morton Drug Co., Fort Smith, Ark. The following claims were made for them : "Useful In nil cases of revetto lower Ihe temperature and relieve pain.1' "A positive and immediate relief tor headache, neuralgia, catarrh, in grippe, cold in the heads rheumatism, sleeplessness, and ail nervous conditions.""il relieves all pains in the Head, B"ace and Body, which are caused by ('old, La Grippe, Neuralgia, Exposure or Dissipation.""if suffering from periodical attacks of the above troubles (Headache, Neuralgia, La Grippe, Cold in Head, Earache, Toothache, Pains over Byes, Rheumatism), they will grow less frequent and less severe by using these powders." "For Insomnia or Sleeplessness, one powder taken on going to bed win produce a natural and healthy sleep." As these claims were severally and individually false and misleading the nostrum was declared misbranded. The company pleaded guilty and was fined $10.-[Notice of Judgment, No.' 1178.] STELLO'S ASTHMA Ol 111:Slello's Asthma Cure was a product of one W. II. Müller, New York City, and was sold under the following preposterous claims:"II is entirely vegetable." "Everyone Is promised n cure.""A permanent cure Is assured in nil.""A preven radical and permanent cure."This "entirely vegetable" product was found to contain, according to the government chemists, the following drugs: Potassium lodld Cannabis indica Glycerin Alcohol It was declared niishrnnilcd because the quantities and proportions of cannabis indica and of alcohol were not stated on the label. Müller pleaded guilty and was fined $50.-[A'ofice of Judgment, No.
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