Citations

Abstract High-dose methotrexate (MTX) results in high rates of acute kidney injury (AKI), neutropenia, and hepatotoxicity. Glucarpidase is a recombinant enzyme that cleaves MTX, but clinical data supporting its use are scarce. We examined the association between glucarpidase administration and outcomes in adults with MTX-AKI from 28 cancer centers across the United States using a sequential target trial emulation framework. The primary end point was kidney recovery at hospital discharge, defined as survival to discharge with serum creatinine <1.5-fold baseline and without dialysis dependence. Key secondary end points were time to kidney recovery, neutropenia, and transaminitis on day 7, and time to death. Using multivariable logistic and Cox regression models, we compared outcomes in patients who received glucarpidase within 4 days following MTX initiation with those in patients who did not. Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase. Overall, 183 (25.8%) had a primary end point event. Glucarpidase receipt was associated with a 2.70-fold higher adjusted odds of kidney recovery (95% confidence interval [CI], 1.69–4.31) compared with no glucarpidase receipt. Patients treated with glucarpidase also had faster time to kidney recovery (adjusted hazard ratio [aHR], 1.88; 95% CI, 1.18–3.33) and lower risks of grade ≥2 neutropenia (adjusted odds ratio [aOR], 0.50; 95% CI, 0.28–0.91) and grade ≥2 transaminitis (aOR, 0.50; 95% CI, 0.28–0.91) on day 7. There was no difference in time to death (aHR, 0.76; 95% CI, 0.49–1.18). These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI.

Trends in diagnostic biopsy sample collection approaches for primary bone sarcomas have shifted in the past 2 decades. Although open/incisional biopsies used to be the predominant approach to obtain diagnostic material for Ewing sarcoma and osteosarcoma, image-guided core needle biopsies have increased in frequency and are safe for patients. These procedures are less invasive and reduce recovery times but have potential limitations. The quantity and quality of tissue obtained through these procedures vary between institutions. Acquired viable tissue volumes can be low, limiting the conduct of downstream expanded clinical workup, molecular analyses, and research. Patients with advanced Ewing sarcoma and osteosarcoma continue to have overall poor outcomes despite dose-intensive cytotoxic chemotherapy. The biology of treatment resistance is not currently well understood, partly due to limited availability of relevant tissue to study. There is a need for access to quality tumor specimens for molecular and other analyses to identify high-risk tumor subsets and drive discovery to improve patient outcomes. Given broad variability in bone tumor tissue procurement and processing across member institutions, the Children’s Oncology Group Bone Tumor Committee convened a multidisciplinary group of experts to outline the current and near-future tissue needs for optimal clinical care and access to research platforms. The goal of this working group was to provide high-level guidance on biopsy practices that safely meet these evolving needs. Harmonizing tissue collection practices is paramount to improving the care of children, adolescents, and young adults diagnosed with Ewing sarcoma and osteosarcoma.

Juxtaglomerular cell tumor (JxGCT) is a rare type of renal neoplasm demonstrating morphologic overlap with some mesenchymal tumors such as glomus tumor (GT) and solitary fibrous tumor (SFT). Its oncogenic drivers remain elusive, and only a few cases have been analyzed with modern molecular techniques. In prior studies, loss of chromosomes 9 and 11 appeared to be recurrent. Recently, whole-genome analysis identified alterations involving genes of MAPK-RAS pathway in a subset, but no major pathogenic alterations have been discovered in prior whole transcriptome analyses. Considering the limited understanding of the molecular features of JxGCTs, we sought to assess a collaborative series with a multiomic approach to further define the molecular characteristics of this entity. Fifteen tumors morphologically compatible with JxGCTs were evaluated using immunohistochemistry for renin, single-nucleotide polymorphism array (SNP), low-pass whole-genome sequencing, and RNA sequencing (fusion assay). In addition, methylation analysis comparing JxGCT, GT, and SFT was performed. All cases tested with renin (n=11) showed positive staining. Multiple chromosomal abnormalities were identified in all cases analyzed (n=8), with gains of chromosomes 1p, 10, 17, and 19 and losses of chromosomes 9, 11, and 21 being recurrent. A pathogenic HRAS mutation was identified in one case as part of the SNP array analysis. Thirteen tumors were analyzed by RNA sequencing, with 2 revealing in-frame gene fusions: TFG::GPR128 (interpreted as stochastic) and NAB2::STAT6. The latter, originally diagnosed as JxGCT, was reclassified as SFT and excluded from the series. No fusions were detected in the remaining 11 cases; of note, no case harbored NOTCH fusions previously described in GT. Genomic methylation analysis showed that JxGCT, GT, and SFT form separate clusters, confirming that JxGCT represents a distinct entity (ie, different from GT). The results of our study show that JxGCTs are a distinct tumor type with a recurrent pattern of chromosomal imbalances that may play a role in oncogenesis, with MAPK-RAS pathway activation being likely a driver in a relatively small subset.

Abstract Introduction COVID-19 infection is associated with an increased risk of complications, prolonged hospitalization, and mortality despite vaccination in patients with cancer. Evusheld (tixagevimab-cilgavimab) was granted emergency use approval in December 2021 for pre-exposure prophylaxis based on preliminary results from the PROVENT trial. However, studies evaluating the impact of Evusheld in cancer patients in the real-world are limited. In this study, we assessed the impact of Evusheld on the incidence and severity of COVID-19 infection in cancer patients at our institution. Methods and Materials We conducted a retrospective descriptive study at our institution on patients with current and prior history of cancer diagnosis regardless of treatment history who received Evusheld between December 2021 and March 2022. The primary outcome was incidence of COVID-19 during a 6 month follow up period. Secondary outcomes included rate of hospitalization related to COVID-19 and associated mortality. Results A total of 228 patients were included, 43% of which received 2 doses of Evusheld during the study period. Twenty-nine patients (12.7%, 95% CI 9.4% – 18.7%) developed COVID-19, with an average time to diagnosis of 2.5 months (SD 1.6) from receiving Evusheld. Most had hematologic malignancies (68.4%) and were receiving active chemotherapy (71.5%) at the time of diagnosis. Five (17.2%) patients were hospitalized for COVID-19, of whom 4 had hematological malignancy. One patient with hematological malignancy required mechanical ventilation and died. Conclusion Overall, the incidence of COVID-19 following Evusheld was higher than in the PROVENT trial. Infections appeared to be more common and severe in patients with hematologic malignancies.

Purpose: To identify areas of consensus among experts on the performance of endothelial keratoplasty by using a modified Delphi approach, to help create a framework for novice surgeons to adopt these procedures. Methods: Thirty-one international experts in endothelial keratoplasty participated. Two rounds of electronic survey were followed by a hybrid, virtual meeting. Consensus was set at 75%, and results with agreement between 70% and 75% were deemed as achieving near consensus. Results: A consensus was reached for 98 statements covering the preoperative, intraoperative, and postoperative aspects of Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping endothelial keratoplasty/Descemet stripping automated endothelial keratoplasty. Four statements achieved near consensus, and consensus could not be achieved for 11 statements. For DMEK, the panel supported a peel technique to prepare tissue for endothelium out DMEK, implanted via an injector and supported by a near full air/gas fill as a baseline procedure onto which more advanced techniques can be built. DMEK tissue should be marked to ensure correct orientation. An inferior peripheral iridotomy should be used to prevent pupil block when a near full air/gas fill in used in endothelial keratoplasty (EK). Descemet stripping automated endothelial keratoplasty was considered preferable to Descemet stripping endothelial keratoplasty where access to microkeratome preparation was available. Conclusions: The Delphi process allowed areas of consensus on the performance of EK to be established by a group of international experts. The statements generated are a helpful framework for novice surgeons learning EK. Further research is needed to help determine what specific tomographic features indicate EK, when guttae are considered visually significant and how to approach combined aphakia and endothelial dysfunction.

Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC). Hereditary syndromes associated with EC include Lynch syndrome, PTEN hamartoma tumor syndrome, and Peutz-Jeghers syndrome. This manuscript provides the latest recommendations from the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric on the screening and management of EC in patients at high risk for these syndromes, as well as the advantages and limitations of multigene panel testing. This manuscript also describes recent updates to these guidelines regarding de-implementation of colon cancer screening in individuals with CHEK2 pathogenic/likely pathogenic variants, based on the most up-to-date evidence regarding the association between CHEK2 pathogenic/likely pathogenic variants and colon cancer risk.

This Viewpoint summarizes recent progress in gene therapy for hemoglobinopathies.

Background: PV is a myeloproliferative neoplasm that leads to excessive production of erythrocytes and increased platelet and leukocyte counts. The current standard of care is to use therapeutic phlebotomy (TP) with or without cytoreductive therapy (CRT) to treat PV. Over time, the CRT dose often needs to be increased to treat PV progression. Preliminary results from the phase 2 REVIVE study (NCT04057040) demonstrated that rusfertide was superior to placebo in achieving hematocrit (Hct) levels <45% and reducing or eliminating the need for TP in patients who were phlebotomy-dependent prior to study entry (Kremyanskaya et al. EHA2023. [Abstract LB2710]; Kremyanskaya et al. New Engl J Med 2024;390:723-35).Final data from REVIVE will be presented. Methods: In Part 1 (Weeks 1-29), subcutaneous rusfertide (starting dose: 20 mg q1w) was initiated and titrated to control Hct to <45%. In Part 2 (Weeks 29-41; blinded randomized withdrawal phase), patients were randomized to receive rusfertide or placebo. Randomized patients were eligible to participate in the open-label extension (OLE) portion of the study (Part 3), in which all patients could receive rusfertide and investigators could make CRT dose adjustments. Results: In Part 1, 70 patients were enrolled; 59 were randomized in Part 2. Fifty-eight patients continued to Part 3. As of 9 July 2024, 50 (71.4%), 37 (52.9%), and 17 (24.3%) patients received rusfertide for ≥2, ≥2.5, or ≥3 years, respectively.Overall, median (range) patient age was 57.5 years (27-77); the majority were male (70%) and had high-risk disease (55.7%). Overall, 52.9% and 47.1% of patients were treated with TP alone or TP plus CRT, respectively. Prior to enrollment, the estimated average (mean) phlebotomy rate (EAPR) in patients who enrolled on study was 8.5/year, which was reduced to <1.0/year in Part 1. In Part 2, the EAPR was <1.0/year and 6.6/year in the rusfertide and placebo groups, respectively. For patients who continued onto Part 3 and received rusfertide, the EAPR remained at <1.0/year. In Parts 1, 2, and 3, the mean (SD) weekly average rusfertide dose was 30.7 mg (12.2), 38.5 mg (21.3), and 44.9 mg (20.3), respectively. Rusfertide consistently maintained Hct <45%, including in patients receiving therapy for ≥3 years. Platelets increased following initiation of rusfertide therapy and stabilized over time; mean leukocyte counts remained stable. Prior to enrollment, iron-related parameters were consistent with systemic iron deficiency. Throughout the study, rusfertide resulted in the normalization of mean serum ferritin levels, increased mean transferrin saturation, and increased mean serum iron levels. Overall, mean corpuscular volume increased slightly over the duration of the study. Throughout the study, there was no evidence of increased markers of inflammation (eg, C-reactive protein or interleukin 6). The most common (≥20%) treatment-emergent adverse events (TEAEs) were injection site reactions (85.7%), fatigue (38.6%), COVID-19 (32.9%), pruritus (34.3%), arthralgia (30.0%), dizziness (30.0%), nausea (24.3%), headache (24.3%), and anemia (21.4%). Grade 3 TEAEs occurred in 25.7% of patients.There were no Grade 4 or 5 TEAEs. One patient developed acute myeloid leukemia after treatment discontinuation. After more than 150 patient-years of rusfertide exposure, malignancies (most of which were skin cancers) were reported in 11 patients (all had risk factors that may have contributed to the development of these malignancies). There was no obvious correlation between increasing exposure to rusfertide and malignancies reported. Six thrombotic events (5 arterial and 1 venous) occurred in 5 patients with high-risk PV. Conclusions: In REVIVE, rusfertide added to TP with or without CRT provided long-term durable control of Hct and decreased the need for TP. Patients are eligible to roll over to the phase 2 THRIVE OLE study (NCT06033586), which will continue to assess the long-term safety and efficacy of rusfertide for a total period of up to 5.8 years. The randomized phase 3 VERIFY study (NCT05210790) is ongoing and will evaluate rusfertide vs placebo in PV patients.

Introduction: Patients with chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) have a higher risk of developing other malignancies compared to the general population (Greene et al, J NCI 1978). Chemoimmunotherapy has previously been the mainstay of treatment and was associated with increased rates of other cancers (OC) (Thompson et al, Blood 2023). Targeted therapies such as Bruton tyrosine kinase inhibitors (BTKi) and BCL2 inhibitors were approved in the frontline setting in 2016 and 2019, respectively, and are now the standard of care for initial therapy (Shanafelt et al, NEJM 2019; Fischer et al, NEJM 2019). This study aims to compare the incidence of OC in patients with CLL/SLL treated with frontline therapies or managed with active surveillance. Methods: This is a retrospective case-control analysis of patients diagnosed with CLL/SLL during or after 2016 using the Department of US Veteran Affairs Central Cancer Registry (VACCR). Cases were patients with CLL/SLL diagnosed with incident OC, excluding nonmelanoma skin cancers. Frontline treatment with chemoimmunotherapy, monoclonal antibodies alone, or targeted therapies, such as BTKi or BCL2 inhibitor, was the exposure of interest compared to patients on active surveillance. Patients were followed until date of OC, death, or last follow up. Descriptive statistics were used to summarize continuous and categorical variables. Logistic regression was used to analyze the risk of developing OC while adjusting for potential confounders. Results: We identified 5244 patients with CLL/SLL who met inclusion criteria. Median follow up was 3.19 years (interquartile range [IQR] 1.61-5.14). The median age at diagnosis of CLL/SLL was 71.7 years (IQR 66.1-77.3) and most patients were white (78%) and male (97%). 3,460 (66%) patients were managed with active surveillance and 1,784 (34%) patients required frontline treatment: 1,318 (25%) targeted therapy, 329 (6%) chemoimmunotherapy, and 137 (3%) monoclonal antibodies alone. In patients treated with targeted therapies, patients were treated with ibrutinib (776, 59%), acalabrutinib (246, 19%), zanubrutinib (129, 10%), venetoclax (164, 12%), or combination of ibrutinib and venetoclax on a clinical trial (3, <1%). 505 (10%) patients were diagnosed with OC and 4739(90%) patients did not develop OC during the follow up period after diagnosis of CLL/SLL. Types of OC observed included neoplasms of the lung (120, 24%), prostate (105, 21%), gastrointestinal tract (72, 14%), hematologic malignancies (68, 13%), melanoma (45, 9%), kidney and bladder (43, 9%), head and neck (16, 3%), and other/unknown (36, 7%). More patients with OC had a history of tobacco use compared to those diagnosed with CLL/SLL without OC (70% vs 54%, p<0.0001). Fewer patients with OC had a history of alcohol use (60% vs 67%, p<0.0001). In a logistic regression analysis adjusted for age at diagnosis of CLL, race, and tobacco and alcohol use patients treated with chemoimmunotherapy had a higher risk of OC compared to those on observation (OR 2.4, 95% CI: 1.7-3.3, p<0.0001) whereas patients treated with targeted therapies or monoclonal antibodies alone did not have a higher risk of OC (OR 1.1, 95% CI 0.9-1.4 and OR 1.4, 95% CI 0.8-2.6, respectively) compared to the patients on active surveillance. A higher proportion of patients with OC were deceased compared to those without OC, 219/505 (43%) vs 1261/4739 (27%), respectively (p<0.0001) at cutoff date. Similar analyses of occurrence of OC in patients followed at tertiary centers including MD Anderson in Houston, Texas and Mayo Clinic in Rochester, Minnesota are ongoing and will be presented at the meeting. Conclusion: Initial treatment with targeted therapies or monoclonal antibodies alone was not associated with an increased risk of OC in US veterans diagnosed with CLL/SLL during and after 2016. However, initial treatment with chemoimmunotherapy was associated with a significant increase of OC compared to patients with CLL/SLL managed with active surveillance.