Citations

The MN1::ETV6 gene fusion resulting from t(12;22)(p13;q12) has been rarely reported in myeloid neoplasms. We describe a 69-year-old male with newly diagnosed acute myeloid leukemia (AML) with erythroid differentiation and t(12;22)(p13;q12) demonstrated by conventional chromosome studies. Subsequent fluorescence in situ hybridization studies demonstrated a balanced ETV6 gene rearrangement (at 12p13). To further characterize this translocation, whole-genome sequencing was performed which confirmed t(12;22) with breakpoints involving the MN1 and ETV6 genes. Herein, we describe our case and review the literature to summarize the clinical and laboratory findings in patients with this rare but recurrent MN1::ETV6 gene fusion observed in myeloid neoplasms. Importantly, this case expands the clinical spectrum associated with the MN1::ETV6 gene fusion to include AML with erythroid differentiation. Lastly, this case demonstrates the importance of moving toward more comprehensive molecular testing to fully characterize the driver events in neoplastic genomes.

Background Hematologic toxicities, including coagulopathy, endothelial activation, and cytopenias, with CD19-targeted chimeric antigen receptor (CAR) T-cell therapies correlate with cytokine release syndrome (CRS) and neurotoxicity severity, but little is known about the extended toxicity profiles of CAR T-cells targeting alternative antigens. This report characterizes hematologic toxicities seen following CD22 CAR T-cells and their relationship to CRS and neurotoxicity. Methods We retrospectively characterized hematologic toxicities associated with CRS seen on a phase 1 study of anti-CD22 CAR T-cells for children and young adults with relapsed/refractory CD22+ hematologic malignancies. Additional analyses included correlation of hematologic toxicities with neurotoxicity and exploring effects of hemophagocytic lymphohistiocytosis-like toxicities (HLH) on bone marrow recovery and cytopenias. Coagulopathy was defined as evidence of bleeding or abnormal coagulation parameters. Hematologic toxicities were graded by Common Terminology Criteria for Adverse Events V.4.0. Results Across 53 patients receiving CD22 CAR T-cells who experienced CRS, 43 (81.1%) patients achieved complete remission. Eighteen (34.0%) patients experienced coagulopathy, of whom 16 had clinical manifestations of mild bleeding (typically mucosal bleeding) which generally subsided following CRS resolution. Three had manifestations of thrombotic microangiopathy. Patients with coagulopathy had higher peak ferritin, D-dimer, prothrombin time, international normalized ratio (INR), lactate dehydrogenase (LDH), tissue factor, prothrombin fragment F1+2 and soluble vascular cell adhesion molecule-1 (s-VCAM-1). Despite a relatively higher incidence of HLH-like toxicities and endothelial activation, overall neurotoxicity was generally less severe than reported with CD19 CAR T-cells, prompting additional analysis to explore CD22 expression in the central nervous system (CNS). Single-cell analysis revealed that in contrast to CD19 expression, CD22 is not on oligodendrocyte precursor cells or on neurovascular cells but is seen on mature oligodendrocytes. Lastly, among those attaining CR, grade 3–4 neutropenia and thrombocytopenia were seen in 65% of patients at D28. Conclusion With rising incidence of CD19 negative relapse, CD22 CAR T-cells are increasingly important for the treatment of B-cell malignancies. In characterizing hematologic toxicities on CD22 CAR T-cells, we demonstrate that despite endothelial activation, coagulopathy, and cytopenias, neurotoxicity was relatively mild and that CD22 and CD19 expression in the CNS differed, providing one potential hypothesis for divergent neurotoxicity profiles. Systematic characterization of on-target off-tumor toxicities of novel CAR T-cell constructs will be vital as new antigens are targeted. Trial registration number NCT02315612 .

AbstractObjectiveTo evaluate recurrence patterns and survival after recurrence among patients with sinonasal mucosal melanoma (SNMM).MethodsThis was a multi‐institutional retrospective review from seven U.S. institutions of patients with SNMM from 1991 to 2022. Recurrence was categorized as local, regional, distant, or multifocal. Kaplan‐Meier tests were used to evaluate disease‐free survival (DFS), overall survival (OS), and post‐recurrence survival (PRS) reported with standard errors (SE) and log‐rank testing used for comparison. Cox‐regression was further used, with hazard ratios (HR) and 95% confidence intervals (CI) reported.ResultsAmong 196 patients with SNMM, there were 146 patients with recurrence (74.5%). Among all patients, 60‐month DFS (SE) was 15.5% (2.9%), 60‐month OS (SE) was 44.7% (3.7%), mean age ± standard deviation at diagnosis was 69.7 ± 12.5 years, and 54.6% were female. In 26 patients who underwent primary treatment of the neck, 60‐month DFS did not differ from no treatment (p > 0.05). Isolated distant recurrence was most common (42.8%), followed by local (28.3%), multifocal (20.7%), and regional recurrence (8.3%). Among patients with regional recurrence in the neck, there was no 60‐month PRS benefit for patients undergoing salvage neck dissection or radiation (p > 0.05). Among patients with distant recurrence, only immunotherapy was associated with improved 12‐month PRS (HR = 0.32, 95% CI = 0.11–0.92, p = 0.034), and no treatment group was associated with improved 24‐ or 60‐month PRS (p > 0.05).ConclusionSNMM is associated with a high recurrence rate and poor survival. Primary treatment of the neck was not associated with reduced recurrence, and immunotherapy for treatment of distant recurrence was associated with increased 12‐month PRS.

Objectives:We sought to evaluate the safety and effectiveness of fecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection (CDI) in pediatric immunocompromised (IC) patients.Methods:This is a multicenter retrospective cohort study of pediatric participants who underwent FMT between March 2013 and April 2020 with 12‐week follow‐up. Pediatric patients were included if they met the definition of IC and were treated with FMT for an indication of recurrent CDI. We excluded patients over 18 years of age, those with incomplete records, insufficient follow‐up, or not meeting study definition of IC. We also excluded those treated for Clostridioides difficile recurrence without meeting the study definition and those with inflammatory bowel disease without another immunocompromising condition.Results:Of 59 pediatric patients identified at 9 centers, there were 42 who met inclusion and no exclusion criteria. Included patients had a median age of 6.7 years. Etiology of IC included: solid organ transplantation (18, 43%), malignancy (12, 28%), primary immunodeficiency (10, 24%), or other chronic conditions (2, 5%). Success rate was 79% after first FMT and 86% after 1 or more FMT. There were no statistically significant differences in patient characteristics or procedural components when patients with a failed FMT were compared to those with a successful FMT. There were 15 total serious adverse events (SAEs) in 13 out of 42 (31%) patients that occurred during the follow‐up period; 4 (9.5%) of which were likely treatment‐related. There were no deaths or infections with multidrug resistant organisms during follow‐up and all patients with a SAE fully recovered.Conclusions:The success rate of FMT for recurrent CDI in this pediatric IC cohort is high and mirrors data for IC adults and immunocompetent children. FMT‐related SAEs do occur (9.5%) and highlight the need for careful consideration of risk and benefit.

AbstractObjectiveTo evaluate the effect of a health maintenance reminder (HMR) on human papillomavirus (HPV) vaccine administration and completion across different age, insurance, and race cohorts.Study DesignRetrospective pre‐post analysis.SettingAcademic primary care.MethodsPatients aged 9 to 26 who had initiated the HPV vaccine series from 2016 to 2021 were analyzed, based on current age‐based standards. The cohort was divided based on vaccine uptake before and after the implementation of the HMR program in February 2020. The multivariate analysis estimated the odds of vaccine completion based on sociodemographic factors, and variable interactions were investigated to determine independent associations between sociodemographic factors and HMR implementation.ResultsThere were 7654 individual patients (mean age was 15.8 years; 46.7 were males; and 50.7% were white). HPV vaccine completion rates increased post‐HMR implementation by 59.2% (37% pre‐, and 58.9% post‐HMR; p < .001) in the entire cohort. Overall, black patients (adjusted odds ratio [aOR] = 0.68; 95% confidence interval [CI]: 0.60, 0.70) and patients ≥18 years (aOR = 0.13; 95% CI: 0.11, 0.15) were significantly less likely to complete their vaccine series; however, this improved significantly following HMR in these groups (p < .001). Post‐HMR, race, and insurance status were not independently associated with disparate vaccine completion rates, however, age was, and patients ≤14 or younger had higher odds of vaccine completion (aOR = 3.54; 95% CI: 2.91, 4.32).ConclusionThe implementation of an HMR was associated with increased HPV vaccine uptake across age and race groups in this single‐institution study. Future research should explore barriers to implementing HMRs in different health care settings.

AbstractAcute lymphoblastic leukemia (B‐ALL) with intrachromosomal amplification of chromosome 21 (iAMP21‐ALL) represents a recurrent high‐risk cytogenetic abnormality and accurate identification is critical for appropriate clinical management. Identification of iAMP21‐ALL has historically relied on fluorescence in situ hybridization (FISH) using a RUNX1 probe. Current classification requires ≥ five copies of RUNX1 per cell and ≥ three additional copies of RUNX1 on a single abnormal iAMP21‐chromosome. We sought to evaluate the performance of the RUNX1 probe in the identification of iAMP21‐ALL. This study was a retrospective evaluation of iAMP21‐ALL in the Mayo Clinic and Children's Oncology Group cohorts. Of 207 cases of iAMP21‐ALL, 188 (91%) were classified as “typical” iAMP21‐ALL, while 19 (9%) cases were classified as “unusual” iAMP21‐ALL. The “unusual” iAMP21 cases did not meet the current definition of iAMP21 by FISH but were confirmed to have iAMP21 by chromosomal microarray. Half of the “unusual” iAMP21‐ALL cases had less than five RUNX1 signals, while the remainder had ≥ five RUNX1 signals with some located apart from the abnormal iAMP21‐chromosome. Nine percent of iAMP21‐ALL cases fail to meet the FISH definition of iAMP21‐ALL demonstrating that laboratories are at risk of misidentification of iAMP21‐ALL when relying only on the RUNX1 FISH probe. Incorporation of chromosomal microarray testing circumvents these risks.