Predicting Survival for Chimeric Antigen Receptor T-Cell Therapy: A Validation of Survival Models Using Follow-Up Data From ZUMA-1

ObjectivesSurvival extrapolation for chimeric antigen receptor T-cell therapies is challenging, owing to their unique mechanistic properties that translate to complex hazard functions. Axicabtagene ciloleucel is indicated for the treatment of relapse or refractory diffuse large B-cell lymphoma after 2 or more lines of therapy based on the ZUMA-1 trial. Four data snapshots are available, with minimum follow-up of 12, 24, 36, and 48 months. This analysis explores how survival extrapolations for axicabtagene ciloleucel using ZUMA-1 data can be validated and compared.MethodsThree different parametric modeling approaches were applied: standard parametric, spline-based, and cure-based models. Models were compared using a range of metrics, across the 4 data snapshot, including visual fit, plausibility of long-term estimates, statistical goodness of fit, inspection of hazard plots, point-estimate accuracy, and conditional survival estimates.ResultsStandard and spline-based parametric extrapolations were generally incapable of fitting the ZUMA-1 data well. Cure-based models provided the best fit based on the earliest data snapshot, with extrapolations remaining consistent as data matured. At 48 months, the maximum survival overestimate was 8.3% (Gompertz mixture-cure model) versus the maximum underestimate of 33.5% (Weibull standard parametric model).ConclusionsWhere a plateau in the survival curve is clinically plausible, cure-based models may be helpful in making accurate predictions based on immature data. The ability to reliably extrapolate from maturing data may reduce delays in patient access to potentially lifesaving treatments. Additional research is required to understand how models compare in broader contexts, including different treatments and therapeutic areas.     

Disparity in Utilization of Multiagent Therapy for Acute Promyelocytic Leukemia in the United States

BackgroundDespite high rate of cure in acute promyelocytic leukemia (APL) in clinical trials, outcomes in real-world practice are dismal. We utilized National Cancer Database (NCDB) to explore utilization of multiagent therapy in APL and identify any disparities in treatment in real-world practices.Patients and MethodsNCDB categorizes use of systemic chemotherapy into single agent versus multiagent therapy. Some patients received hormonal therapy, immunotherapy, and unknown therapy; details of these treatments could not be ascertained. We therefore used multiple logistic regression analysis to evaluate effects of covariates on the probability of multiagent therapy use in 6678 patients.ResultsCompared to patients >60 years, patients aged 0 to 18 years (hazard ratio[HR] 3.2, 95% confidence interval [CI] 1.8-5.5, P< .0001), 19 to 40 years (HR 1.6, 95% CI 1.03-2.54, P= .03), and 41 to 60 years (HR 1.6, 95% CI 1.3-1.9, P< .0001) were more likely to receive multiagent therapy. Patients with Charlson comorbidity index (CCI) of 0 (HR 1.6, 95% CI 1.2-2.3, P= .001) and CCI of 1 (HR 1.4, 95% CI 1.0-1.9, P= .04) had a higher likelihood of receiving multiagent therapy than patients with CCI ≥ 3. Patients treated at academic cancer centers, compared to those treated at community cancer center (HR 0.5, 95% CI 0.3-0.7, P= .001), comprehensive community cancer center (HR 0.7, 95% CI 0.6-0.8, P< .0001), and integrated network cancer center (HR 0.8, 95% CI 0.6-0.9, P= .02) were more likely to be treated with multiagent therapy. Compared to the patients with private insurance, those with Medicaid had increased likelihood (HR 1.2, 95% CI 1.0-1.4, P= .04) whereas uninsured patients had a lower likelihood of receiving multiagent therapy (HR 0.6, 95% CI 0.5-0.8, P= .0005).ConclusionTo our knowledge, this study is the first and the largest scale analysis of treatment practices in APL in real-world practices. Our findings highlight significant disparities in treatment of APL based on age, insurance, and health-system factors.     

Características y resultados oncológicos del carcinoma epidermoide de ano: análisis comparativo entre los pacientes inmunocompetentes y los inmunodeprimidos

ObjectiveMost evidence, including recent randomized controlled trials, analysing anal squamous cell carcinoma (SCC) do not consider immunocompromise patient population. The aim of this study was to compare clinical and oncological outcomes among immunocompetent and immunocompromised patients with anal squamous cell carcinoma.MethodMulticentric retrospective comparative study including 2 cohorts of consecutive patients, immunocompetent and immunocompromised, diagnosed with anal SCC. This study evaluated clinical characteristics, clinical response to radical chemoradiotherapy (CRT) and long-term oncological results including both local and distant recurrence, overall survival (OS) and disease-free survival (DFS).ResultsA total of 84 patients, 47 (55.6%) female, diagnosed with anal SCC from January 2012 to December 2017 were included, 22 (26%) and 62 (74%) patients in immunocompromised and immunocompetent groups respectively. Patients in immunocompromised group were significantly younger (53 vs. 61 years; P=0.001), with smaller tumoral size (P=0.044) and reported higher rates of substance abuse.including tobacco use (P=0.034) and parenteral drug consumption (P=0.001). No differences were found in administered therapies (P=301) neither in clinical response to chemoradiotherapy (83 vs. 100%). Moreover, similar 5-year OS (60 vs. 64%; P=0.756) and DFS (65 vs. 68%; P=0.338) were observed.ConclusionThe present study shows no significant differences in long-term oncological results among immunocompetent and immunocompromised patients diagnosed with anal SCC, with a similar oncologic treatment. This evidence might be explained due to the close monitoring and adequate therapeutic control of HIV positive patients.     

Survival after reoperation for recurrent glioblastoma multiforme: A prospective study

PurposeGlioblastoma multiforme (GBM) is the most common malignant brain tumor. Moreover, GBM recurs in nearly all patients. Although a standard STUPP protocol has been widely used for newly diagnosed GBM, no standard regimen has been established for recurrent patients. Here we evaluated the clinical value of recurrent GBM reoperation by comparing overall survival and quality of life (QoL) in patients with recurrent GBM undergoing repeat surgery or conservative treatment.MethodsThis was a prospective study of 165 patients with GBM receiving first operations for their disease between 2011 and 2013 at two tertiary neurosurgery centers in Poland. Thirty-five eligible patients were re-operated for recurrence (the study group), and 35 patients were selected as the control group using propensity score matching. A model was created to determine advantageous prognostic factors for longer survival of patients qualifying for reoperation using stepwise linear regression.ResultsThe mean overall survival of patients undergoing repeat surgery was 528 days compared to 297 days in patients who did not undergo repeat surgery. Reoperation did not result in a significant deterioration in performance status as measured by the Karnofsky Performance Scale. Older age, the presence of symptoms of increased intracranial pressure, and a shorter period between initial operation and reoperation were independent predictors of a worse outcome.ConclusionIn selected patients, reoperation for recurrent GBM prolongs survival with no significant deteriorations in performance status.     

Association between pancreatic intraductal papillary mucinous neoplasms and extrapancreatic malignancies: A systematic review with meta-analysis

BackgroundIt is unclear whether patients with intraductal papillary mucinous neoplasia harbor a higher risk of developing extrapancreatic malignancies.AimsWe performed a pooled estimate of the incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasia, with a particular focus on the comparison to the general population.MethodsComputerized bibliographic search of main databases was performed through February 2021. The primary endpoint was the pooled incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasms. Additional outcome was the comparison between intraductal papillary mucinous neoplasia patients and the general population, expressed in terms of standardized incidence ratio along with 95% confidence intervals.ResultsEighteen studies with 8709 patients were included. The pooled rate of metachronous extrapancreatic malignancies was 10 (6–13)/1000 persons-year. No difference was observed according to intraductal papillary mucinous neoplasia histology and sex, whereas a significantly superior incidence of extrapancreatic malignancies was observed in patients with main-duct (36.7%, 25.4%–48%) as compared to branch-duct intraductal papillary mucinous neoplasia (26.2%, 17.6%–34.8%; p = 0.03). Pooled standardized incidence ratio comparing expected rates in the general population was 1.01 (0.79–1.29); no difference was observed concerning rates of metachronous gastric cancer (standardized incidence ratio 1.60, 0.72–3.54) and colorectal cancer (1.29, 0.92–1.18), whereas biliary cancer was observed more frequently in intraductal papillary mucinous neoplasia patients (2.29, 1.07–4.93).ConclusionPatients with intraductal papillary mucinous neoplasia harbor an overall rate of extrapancreatic malignancies as high as 27.3%. The rate of metachronous extrapancreatic malignancies is not superior to the general population.     

Microwave Ablation as Bridging to Liver Transplant for Patients with Hepatocellular Carcinoma: A Single-Center Retrospective Analysis

PurposeTo evaluate the efficacy and safety of microwave (MW) ablation as first-line locoregional therapy (LRT) for bridging patients with hepatocellular carcinoma (HCC) to liver transplant.Materials and MethodsThis retrospective study evaluated 88 patients who received percutaneous MW ablation for 141 tumors as first-line LRT for HCC and who were listed for liver transplantation at a single medical center between 2011 and 2019. The overall survival (OS) rate statuses after liver transplant, waitlist retention, and disease progression were evaluated using the Kaplan-Meier techniques.ResultsAmong the 88 patients (72 men and 16 women; mean age, 60 years; Model for End-Stage Liver Disease score, 11.2) who were listed for transplant, the median waitlist time was 9.4 months (interquartile range, 5.5–18.9). Seventy-one (80.7%) patients received transplant after a median waitlist time of 8.5 months. Seventeen (19.3%) patients were removed from the waitlist; of these, 4 (4.5%) were removed because of tumors outside of the Milan criteria (HCC-specific dropout). No difference in tumor size or alpha-fetoprotein was observed in the transplanted versus nontransplanted patients at the time of ablation (2.1 vs 2.1 cm and 34.4 vs 34.7 ng/mL for transplanted vs nontransplanted, respectively; P > .05). Five (5.1%) of the 88 patients experienced adverse events after ablation; however, they all recovered. There were no cases of tract seeding. The local tumor progression (LTP) rate was 7.2%. The OS status after liver transplant at 5 years was 76.7%, and the disease-specific survival after LTP was 89.6%, with a median follow-up of 61 months for all patients.ConclusionsMW ablation appears to be safe and effective for bridging patients with HCC to liver transplant without waitlist removal from seeding, adverse events, or LTP.     

Drug-Eluting Embolics Chemoembolization for the Management of Recurrent or Advanced Head and Neck Cancer

PurposeTo characterize the safety, tolerability, and efficacy of chemoembolization using drug-eluting embolic (DEE) microspheres in patients with recurrent and advanced head and neck cancer.Materials and MethodsIn this retrospective study, 32 patients (mean age, 57.2 years ± 2.8; 17 women) with recurrent (n = 16) and advanced (n = 16) head and neck cancer were treated with chemoembolization using DEE microspheres loaded with doxorubicin. Treatment response, overall survival, local progression-free survival, and adverse events were evaluated.ResultsAt 6 months after the procedure, the objective response and disease control rates were 25% and 69%, respectively. The median overall survival and local progression-free survival were 14.5 and 13.6 months, respectively. Seven (22%) patients experienced adverse events after the chemoembolization procedure. All the adverse events were related to postembolization syndrome, including vomiting and nausea (n = 1), pyrexia (n = 2), and localized pain (n = 7). No severe adverse events or procedure-related deaths were observed.ConclusionsChemoembolization using DEE microspheres was safe and tolerable in patients with recurrent and advanced head and neck cancer.     

The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes

Two Janus-associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate-risk and high-risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. At the same time, however, clinical trial experiences with JAKi agents in MF have demonstrated a high frequency of discontinuations because of adverse events or progressive disease. In addition, overall survival benefits and clinical and molecular predictors of response have not been established in this population, for which the disease burden is high and treatment options are limited. Consistently poor outcomes have been documented after JAKi discontinuation, with survival durations after ruxolitinib ranging from 11 to 16 months across several studies. To address such a high unmet therapeutic need, various non-JAKi agents are being actively explored (in combination with ruxolitinib in first-line or salvage settings and/or as monotherapy in JAKi-pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B-cell lymphoma 2/B-cell lymphoma 2-xL inhibitor), parsaclisib (a phosphoinositide 3-kinase inhibitor), navtemadlin (formerly KRT-232; a murine double-minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non-JAKi treatments to modify the natural history of MF.