Citations

Abstract Tisagenlecleucel (tisa-cel) is a CD19-directed chimeric antigen receptor T-cell therapy for relapsed/refractory precursor B-cell acute lymphoblastic leukemia (R/R B-ALL). We report infectious complications for 100 days (D100) following tisa-cel therapy in 471 pediatric and young adults (median age 13.8 years) with R/R B-ALL reported from September 2017 to June 2022. By D100, 137 (29%) patients had an infectious event, with an infection density of 0.542 per 100 person-days at risk. D100 cumulative incidences of bacterial, viral, and fungal infections were 14.1%, 11.6%, and 1.3%, corresponding to infection density scores of 0.296, 0.213, and 0.033 per 100 person-days at risk, respectively. In a multivariable analysis, receipt of ≥3 lines of therapy before tisa-cel (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.13-3.08; P = .015), any-grade cytokine release syndrome (HR, 1.78; 95% CI, 1.17-2.71; P = .007), and lack of neutrophil recovery (HR, 2.63; 95% CI, 1.47-4.69; P = .001) were associated with an increased risk for any infection. Similar associations were observed for bacterial infections, with the addition of younger age as an adverse risk (<6 vs 6-15 years; HR, 2.38; 95% CI, 1.23-4.61; P = .01). Risk factors for viral infections included increasing age (1-year increase; HR, 1.05; 95% CI, 1.01-1.09; P = .016), prior history of any infection (HR, 2.76, 95% CI, 1.40-5.46; P = .004), and prior hematopoietic cell transplant (HR, 2.10; 95% CI, 1.18-3.71; P = .011). D100 infection-related mortality (IRM) rate was low at 0.2% (95% CI, 0.0-0.8). In this multicenter real-world study, we observed a high incidence of infectious complications but a low IRM following tisa-cel for R/R B-ALL.

Abstract Checkpoint inhibitors (CPIs) have shown remarkable efficacy in Hodgkin lymphoma (HL), and are now used routinely. While allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for HL, there are concerns prior CPIs may exacerbate post–allo-HCT complications, particularly graft-versus-host disease (GVHD), and lead to worse outcomes. Given the relative paucity of data, we performed a Center for International Blood and Marrow Transplant Research/European Society for Blood and Marrow Transplantation study to examine the impact of prior CPIs in allo-HCT. We included 2186 adult patients aged >18 years who received a first allo-HCT using a matched related, unrelated, or haploidentical donor from 2008 to 2023. Twenty-seven percent of patients received prior CPIs. GVHD prophylaxis was posttransplant cyclophosphamide (PTCy) in 55.8% of patients in the CPI cohort, and 35% in the non-CPI cohort. Median follow-up among survivors was longer for the non-CPI (39 months) than CPI cohort (16.5 months). In multivariate analysis, prior CPI exposure did not affect overall survival (OS) or nonrelapse mortality, but resulted in improved progression-free survival (non-CPI vs CPI hazard ratio [HR], 0.81; 0.67-0.98; P = .03) and lower relapse incidence (HR, 0.58; 0.45-0.76; P < 001). While grade 2 to 4 (HR, 1.26; 1.04-1.53; P = .02) and 3 to 4 (HR, 1.41; 1.04-1.92; P = .03) acute GVHD (aGVHD) were increased, differences in chronic GVHD (cGVHD) were not significant. PTCy–based GVHD prophylaxis resulted in improved OS, lower grade 2 to 4 aGVHD, and cGVHD in patients with prior CPI exposure. In summary, allo-HCT should still be considered a curative option for patients with HL in the era of CPIs.

OBJECTIVE The formation and propagation of intraneural ganglion cysts (INGCs) is being elucidated by the unified articular theory. Its principles include a connection for joint fluid to egress from a synovial joint via an articular branch to a parent nerve and cyst following the path of least resistance, dependent on pressures and pressure fluxes. The occurrence of so-called extreme peroneal or tibial INGCs in the popliteal fossa extending to the sciatic nerve has been reported. One rarely described variant with a circumferential cyst within the subparaneurial compartment outside the epineurium of nerve(s) has been previously illustrated, but its mechanism and morphology have not been clarified. In this study, the authors aimed to investigate this type of cyst to challenge the principles of the unified articular theory. METHODS Four novel cases of patients with peroneal INGCs and "extreme subparaneurial cyst(s)" of the sciatic nerve and its distal branches were investigated: 3 arose from the superior tibiofibular joint (STFJ) and 1 from the knee joint. Three other cases of recognized extreme subparaneurial cyst (2 peroneal and 1 tibial from the STFJ) and 1 case of a peroneal subparaneurial cyst in the literature were reinterpreted. Data on clinical presentation, MR images, and surgical results were analyzed. RESULTS In all 8 cases, subparaneurial extension was observed to different degrees along the sciatic, tibial, common peroneal, sural, and deep and superficial peroneal nerves, as was subparaneurial-to-subparaneurial communication at the sciatic nerve bifurcation (i.e., crossover). Sequential MRI performed in 7 patients showed variable dynamic changes, including extreme ascent and descent. Extraneural rupture of the subparaneurial cyst, with spread into the surrounding tissue, was present at the sciatic nerve bifurcation in 6 cases. CONCLUSIONS The authors provide pathoanatomical and pathophysiological evidence supporting that extreme subparaneurial cysts follow the principles of the articular theory. They propose a distribution pattern that explains the occurrence and evolution of extreme subparaneurial cysts along the sciatic nerve and its distal branches in patients with peroneal or tibial INGCs and subepineurial cysts. Crossover in the subparaneurial compartment allows potentially extensive circumferential distribution within connected nerves. Also, dynamic factors can lead to dramatic changes in cyst size and appearance from reabsorption or extraneural rupture. In Part 2 of this study, the authors provide evidence showing that a fenestration in the epineurium allows cysts to pass from the subepineurial-to-subparaneurial, subparaneurial-to-subparaneurial, and subparaneurial-to-subepimyseal compartments.

OBJECTIVE Extreme subparaneurial ganglion cysts are poorly understood. In Part 1, the authors demonstrated that patterns of distribution in the subparaneurial space are consistent with the principles of the articular theory for intraneural ganglion cysts (INGCs). How a cyst transfers from the subepineurial to the subparaneurial compartment remains to be determined. In this part, the authors provide evidence supporting that cyst transfer occurs at the sciatic nerve bifurcation based on MRI and histological analysis, and introduce the geyser theory as an explanation for the redistribution of cysts. METHODS The authors analyze MR images obtained in patients with extreme subparaneurial cysts as well as newly identified cases of nearly extreme subparaneurial cysts (i.e., cysts visible in the subparaneurial compartment but not to the extreme degree as defined in Part 1) for potential crossover sites. They also analyze histological sections from 10 cadavers around the sciatic nerve bifurcation for the presence of openings in the epineurium and paraneurium. RESULTS MRI studies performed in 8 patients in Part 1 and 8 newly identified examples with nearly extreme subparaneurial INGCs showed evidence to support communication between different compartments at the sciatic nerve bifurcation (subepineurial-to-subparaneurial and subparaneurial-to-neighboring soft tissues). Openings in the epineurium of the common peroneal and tibial nerves at the sciatic nerve bifurcation were consistently found in all 10 cadaver specimens, as were openings in the paraneurium. CONCLUSIONS The authors expand on the evidence to support cyst redistribution at the sciatic nerve bifurcation for INGCs in the knee region. They put forth a logical explanation for the development of a spectrum of extreme INGCs (ranging from a faint amount of cyst around the epineurium [wedding ring sign] to extreme subparaneurial INGCs [owl eyes]) based on principles seen in a geyser. The authors believe that radiological occurrence of crossover can be explained by the presence of fenestrations in both the epineurium and paraneurium at the sciatic nerve bifurcation, allowing cyst crossover in two steps: from the subepineurial to the subparaneurial space ("cross") and between a shared subparaneurial space of different nerves ("over"). Finally, the frequent occurrence of extraneural rupture ("cross-out") is due to cyst transfer into the soft tissue compartment via an opening in the outermost circumneurial layer.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

Abstract Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, viral, and fungal infections were recorded in 527 (15.7%), 374 (11.2%), and 108 patients (3.2%), respectively, with corresponding infection densities of 0.23, 0.15, and 0.04 per 100 patient days. After a 24-month median follow-up, 1482 patients (44%) had died, with infection as the primary cause in 173 cases (12%). The 100-day infection-related mortality (IRM) was 1.6% (95% confidence interval, 1.2-2.0). Patients with a Karnofsky performance score of ≤80, infection history before CAR T-cell therapy, axi-cel therapy, severe cytokine release syndrome (grade ≥3), and severe immune effector cell–associated neurotoxicity syndrome (grade ≥3) had increased infection risk. Infections within 100 days were an independent risk factor for inferior overall survival beyond day 100 after CD19 CAR T-cell therapy. In conclusion, study results show a significant incidence of infection and IRM in patients with R/R LBCL treated with CD19 CAR T-cell therapy. Furthermore, results identify patients at a heightened risk of infection, offering insights to guide potential interventions aimed at mitigating infection and improving patient outcomes after CAR T-cell therapy.

ABSTRACTBackgroundIn this study, we compared outcomes of intensified myeloablative conditioning regimens using large registry data from Japan (Japanese Society for Transplantation and Cellular Therapy) and the United States (Center for International Blood and Marrow Transplant Research).MethodsAdult patients who underwent their first myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for acute leukemia in remission between 2010 and 2018 using conditioning regimens of cyclophosphamide plus total‐body irradiation (CY/TBI), CY/TBI+cytarabine (AraC), or CY/TBI+etoposide (VP16) were included.ResultsThe acute myeloid leukemia (AML) cohort (N = 480, 38.8%) indicated that overall survival (OS) was poorer in CY/TBI+AraC (hazard ratio [HR] 1.46, p < 0.001) and CY/TBI+VP16 (HR 1.39, p = 0.059) compared to CY/TBI. Relapse was not suppressed, while treatment‐related mortality (TRM) was significantly higher (HR 1.78 and 1.74, p < 0.001 and 0.018, respectively). In the acute lymphoblastic leukemia (ALL) cohort (N = 3901, 61.2%), OS was comparable among these regimens. With intensified regimens, relapse was significantly suppressed in CY/TBI+VP16 (HR 0.74, p = 0.005), while TRM was higher (HR 1.21, p = 0.077). No interactions were observed regarding the country.ConclusionIn AML adding AraC and VP16 to CY/TBI had an adverse effect on OS. Conversely, in ALL, adding VP16 or AraC to CY/TBI did not affect survival, but the addition of VP16 reduced the risk of relapse.Clinical Trial RegistrationThe authors have confirmed clinical trial registration is not needed for this submission.