Search

Background: CD19-specific chimeric antigen receptor (CAR) T-cell therapy has shown promising disease responses in patients with high-risk B-cell malignancies. However, its use may be related to complications such as immune-mediated complications, infections, and end-organ dysfunction. The incidence of post-CAR T-cell therapy acute kidney injury (AKI) in the children, adolescent, and young adult (CAYA) patient population is largely unreported. Methods: The objectives of this study were to determine the incidence of AKI in CAYA patients with high-risk B-cell malignancies treated with CD19-CAR T-cell therapy, evaluate potential risk factors for developing AKI, and determine patterns of kidney function recovery. We conducted a retrospective analysis of 34 CAYA patients treated with CD19-CAR T-cell at a single institution. Results: There was a cumulative incidence of any grade AKI by day 30 post-infusion of 20% (n = 7), with four cases being severe AKI (stages 2–3) and one patient requiring kidney replacement therapy. All episodes of AKI developed within the first 14 days after receiving CAR T-cell therapy and 50% of patients with AKI recovered kidney function to baseline within 30 days post-infusion. No evaluated pre-treatment risk factors were associated with the development of subsequent AKI; there was an association between AKI and cytokine release syndrome and neurotoxicity. We conclude that the risk of developing AKI following CD19-CAR T-cell therapy is highest early post-infusion, with most cases of AKI being severe. Conclusions: Frequent monitoring to facilitate early recognition and subsequent management of kidney complications after CD19-CAR T-cell therapy may reduce the severity of AKI in the CAYA patient population. [ABSTRACT FROM AUTHOR]

Background: Relapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen. Methods: In this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy. Results: The 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72–98) and 88% (95% CI: 67–96); ≥ CR2 were 81% (95% CI: 61–92) and 68% (95% CI: 47–82) and refractory disease were 32% (95% CI: 11–54) and 20% (95% CI: 6–40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64–87) with no difference amongst recipients with or without minimal residual disease (P = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/μL and 140/μL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors (P = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors (P = 0.035). Conclusion: The combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population. The trial is registered at ClinicalTrials.gov (NCT01807611). [ABSTRACT FROM AUTHOR]

The need to model a cure fraction, the proportion of a cohort not susceptible to the event of interest, arises in a variety of contexts including tumor relapse in oncology. Existing methodology assumes that follow‐up is long enough for all uncured subjects to have experienced the event of interest at the time of analysis, and researchers have demonstrated that fitting cure models without sufficient follow‐up leads to bias. Few statistical methods exist to evaluate sufficient follow‐up, and they can exhibit poor performance and lead users to falsely conclude sufficient follow‐up, leading to bias, or to falsely claim insufficient follow‐up, possibly leading to additional, costly data collection. We propose a new quantitative statistic (RECeUS) to evaluate whether cure models may be appropriate to apply to censored data. Specifically, we propose that the estimated proportion of censored uncured subjects in a study can be used to evaluate cure model appropriateness. We evaluated the performance of RECeUS against existing methods via simulation and with two data examples, and we observe that RECeUS displays superior performance. In simulated and real‐world settings, RECeUS correctly identifies both situations in which data appear appropriate for cure modeling and when data seem inappropriate for fitting cure models. [ABSTRACT FROM AUTHOR]

Background: Platform trials facilitate efficient use of resources by comparing multiple experimental agents to a common standard of care arm. They can accommodate a changing scientific paradigm within a single trial protocol by adding or dropping experimental arms—critical features for trials in rapidly developing disease areas such as COVID-19 or cancer therapeutics. However, in these trials, efficacy and safety issues may render certain participant subgroups ineligible to some experimental arms, and methods for stratified randomization do not readily apply to this setting. Methods: We propose extensions for conventional methods of stratified randomization for platform trials whose experimental arms may differ in eligibility criteria. These methods balance on a prespecified set of stratification variables observable prior to arm assignment that remains the same across experimental arms. To do so, we suggest modifying block randomization by including experimental arm eligibility as a stratifying variable, and we suggest modifying the imbalance score calculation in dynamic balancing by performing pairwise comparisons between each eligible experimental arm and standard of care arm participants eligible to that experimental arm. Results: We provide worked examples to illustrate the proposed extensions. In addition, we also provide a formula to quantify the relative efficiency loss of platform trials with varying eligibility compared with trials with non-varying eligibility as measured by the size of the common standard of care arm. Conclusions: This article presents important extensions to conventional methods for stratified randomization in order to facilitate the implementation of platform trials with differing experimental arm eligibility. [ABSTRACT FROM AUTHOR]

Background: After colorectal cancer (CRC) surgery, surveillance with colonoscopy is an important step for the early detection of local recurrence. Unfortunately, surveillance colonoscopy is underused, especially among racial/ethnic minorities. This study assesses the association between patient and neighborhood factors and receipt of surveillance colonoscopy. Methods: This retrospective, population‐based cohort study used Surveillance, Epidemiology, and End Results–Medicare linked data (2009‐2014). Beneficiaries with surgically resected stage II or III CRC between the ages of 66 and 85 years were identified, and multivariable logistic regression was used to assess the effect of factors on receipt of colonoscopy. Results: Overall, 57.5% of the patients received initial surveillance colonoscopy. After adjustments for all factors, Blacks and Hispanics had lower odds of receiving colonoscopy than non‐Hispanic Whites (NHWs; 29.6% for Blacks; P =.002; 12.9% for Hispanics; P >.05). NHWs with Medicaid coverage had 35% lower odds of surveillance colonoscopy than NHWs without Medicaid coverage. Minority patients with Medicaid were more likely to receive colonoscopy than their racial/ethnic counterparts without Medicaid coverage (P >.05). Hispanics residing in neighborhoods with incomes of ≥$90,000 had significantly lower odds of surveillance colonoscopy than Hispanics residing in neighborhoods with incomes of $0 to $30,000. Conclusions: Receipt of initial surveillance colonoscopy remains low, and there are acute disparities between Black and NHW patients. The association between factors that assess a patient's ability to access colonoscopy and actual receipt of colonoscopy suggests inequitable access to surveillance colonoscopy within and across racial/ethnic groups. There are disparities in the receipt of initial surveillance colonoscopy between Black and non‐Hispanic White patients. The association between factors that assess a patient's ability to access colonoscopy and actual receipt of colonoscopy suggests inequitable access to surveillance colonoscopy within and across racial/ethnic groups. [ABSTRACT FROM AUTHOR]

Background: Given the increase in antimicrobial drug resistance of several pathogens that affect the ear, there is a need for alternative therapy for canine otitis externa (OE). We hypothesised that the efficacy of modified Burow's solution would be non‐inferior to that of standard treatment with Surolan. Methods: The treatment success rate of a topical aluminum acetate 2% and betamethasone 0.1% (modified Burow's) otic solution was compared with that of a standard topical otic treatment of polymyxin B sulfate, prednisolone acetate and miconazole (Surolan) suspension in a prospective, open‐label clinical trial. For 10 days, 142 dogs (232 ears) with OE were treated with modified Burow's solution or Surolan. The primary study endpoint was the cure rate at 10 days. Clinical efficacy was analysed as a secondary endpoint but without assessment for non‐inferiority. Results: The 10‐day OE cure rate was 65% and 59% in the Burow's and Surolan groups, respectively. The modified Burow's solution was non‐inferior to Surolan at a non‐inferiority margin of –11.5% and was more clinically effective than Surolan in dogs with OE caused by yeast or bacteria. Conclusion: The results of this study demonstrate that modified Burow's solution is an effective treatment for OE in dogs. [ABSTRACT FROM AUTHOR]