Somatic mutations in FAS pathway increase hemophagocytic lymphohistiocytosis risk in T- and/or NK-cell lymphoma patients.

While significant progress has been made in understanding the genetic basis of primary hemophagocytic lymphohistiocytosis (HLH), the pathogenesis of secondary HLH, the more prevalent form, remains unclear. Among the various conditions giving rise to secondary HLH, HLH in lymphoma patients (HLH-L) accounts for a substantial proportion. In this study, we investigated the role of somatic mutations in the pathogenesis of HLH-L in a cohort of patients with T- and/or NK-cell lymphoma. We identified a 3-time higher frequency of mutations in FAS pathway in patients with HLH-L. Patients harbouring these mutations had a 5-time increased HLH-L risk. These mutations were independently associated with inferior outcome. Hence, our study demonstrates the association between somatic mutations in FAS pathway and HLH-L. Further studies are warranted on the mechanistic role of these mutations in HLH-L.

Onco-Circuit Addiction and Onco-Nutrient mTORC1 Signaling Vulnerability in a Model of Aggressive T Cell Malignancy.

How genetic lesions drive cell transformation and whether they can be circumvented without compromising function of non-transformed cells are enduring questions in oncology. Here we show that in mature T cells-in which physiologic clonal proliferation is a cardinal feature- constitutive MYC transcription and Tsc1 loss in mice modeled aggressive human malignancy by reinforcing each other's oncogenic programs. This cooperation was supported by MYC-induced large neutral amino acid transporter chaperone SLC3A2 and dietary leucine, which in synergy with Tsc1 deletion overstimulated mTORC1 to promote mitochondrial fitness and MYC protein overexpression in a positive feedback circuit. A low leucine diet was therapeutic even in late-stage disease but did not hinder T cell immunity to infectious challenge, nor impede T cell transformation driven by constitutive nutrient mTORC1 signaling via Depdc5 loss. Thus, mTORC1 signaling hypersensitivity to leucine as an onco-nutrient enables an onco-circuit, decoupling pathologic from physiologic utilization of nutrient acquisition pathways.

Cell-free DNA from nail clippings as source of normal control for genomic studies in hematologic malignancies.

Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patient management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs. In contrast to solid tumors, conventional sources of normal control (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we find nail cfDNA is a robust source of germline control for paired genomic studies. In a subset of patients, nail DNA may have tumor DNA contamination, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1482) compared to lymphoid diseases (5.4%; 61/1128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. For nails collected after allogeneic stem-cell transplantation, donor DNA was identified in 22% (11/50). In this cohort, an association with recent history of graft-vs-host disease was identified. These findings should be considered as a potential limitation for the use of nail as normal control but could also provide important diagnostic information regarding the disease process.

Role of flow cytometric immunophenotyping in the diagnosis of breast implant-associated anaplastic large cell lymphoma: A 6-year, single-institution experience.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon mature T-cell neoplasm occurring in patients with textured breast implants, typically after 7-10 years of exposure. Although cytopathologic or histopathologic assessment is considered the gold standard diagnostic method for BIA-ALCL, flow cytometry (FC)-based immunophenotyping is recommended as an adjunct test. However, the diagnostic efficacy of FC is not well reported. We reviewed 290 FC tests from breast implant pericapsular fluid and capsule tissue from 182 patients, including 16 patients with BIA-ALCL over a 6-year period, calculating diagnostic rates and test efficacy. FC showed an overall sensitivity of 75.9%, specificity of 100%, and negative and positive predictive values of 95.4% and 100%, respectively. Blinded expert review of false-negative cases identified diagnostic pitfalls, improving sensitivity to 96.6%. Fluid samples had better rates of adequate samples for FC testing compared with tissue samples. Paired with FC testing of operating room (OR)-acquired fluid samples, capsulectomy FC specimens added no diagnostic value in patients with concurrent fluid samples; no cases had positive capsule FC with negative fluid FC. Fluid samples are adequate for FC testing more often than tissue. Capsule tissue FC specimens do not improve FC efficacy when paired with OR-acquired fluid FC samples and are often inadequate samples. FC is 100% specific for BIA-ALCL and can serve as a confirmatory test but should not be the sole diagnostic method. Awareness of sample-specific diagnostic pitfalls greatly improves the sensitivity of BIA-ALCL testing by FC.

Current and upcoming treatment approaches to common subtypes of PTCL (PTCL NOS, ALCL, TFHs).

Treatment of the common nodal peripheral T-cell lymphomas (PTCLs), which include PTCL, not otherwise specified (PTCL, NOS), anaplastic large cell lymphomas, and T-follicular helper lymphomas, is evolving. These entities are currently treated similarly with CHOP or CHOEP for CD30-negative diseases or brentuximab vedotin plus CHP for CD30-positive diseases, followed by consolidation with autologous stem cell transplant in first remission. Ongoing improvements in PTCL classification, identification of predictive biomarkers, and development of new targeted agents will lead to more specific therapies that address the unique biologic and clinical properties of each entity. For example, widespread efforts focused on molecular profiling of PTCL, NOS is likely to identify distinct subtypes that warrant different treatment approaches. New agents, such as EZH1/2 and JAK/STAT pathway inhibitors, are broadening treatment options for relapsed or refractory disease. Furthermore, promising strategies optimizing immune therapy for PTCL are currently under investigation and have potential to significantly alter the therapeutic landscape. Ongoing front-line study designs incorporate understanding of disease biology and drug sensitivities and are poised to evaluate whether newer targeted agents should be incorporated into the front-line settings for the various disease entities. Although current treatment strategies lump most disease entities together, future treatment will include distinct strategies for each disease subtype that optimizes therapy for individuals. This movement towards individualized therapy will ultimately lead to dramatic improvements in prognosis for patients with PTCL.

Breast Implant Associated Anaplastic Large Cell Lymphoma: Evidence-Based Consensus Conference Statement From The American Association of Plastic Surgeons.

BACKGROUND: In the absence of high-quality evidence, there is a need to provide guidelines and multidisciplinary consensus recommendations on Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL). The purpose of this expert consensus conference was to evaluate the existing evidence regarding the diagnosis, and management of BIA-ALCL caused by textured implants. The aim is to provide evidence-based recommendations regarding the management and prevention of BIA-ALCL. METHODS: A comprehensive search was conducted in the MEDLINE, Cochrane Library, and Embase databases, supplemented by manual searches of relevant English language articles and "related articles" sections. Studies focusing on breast surgery and lymphoma associated with breast implants were included for analysis. Meta-analyses were performed and reviewed by experts selected by the American Association of Plastic Surgeons by a Delphi consensus method. RESULTS: 840 articles between January 2011 and January 2023 were initially identified and screened. Full-text of 188 articles were assessed. An additional 43 articles were excluded for focus, and 145 articles were included in the synthesis of results, with 105 of them being case reports or case series. The analysis encompassed a comprehensive examination of the selected articles to determine the incidence, risk factors, clinical presentation, diagnostic approaches, and treatment modalities related to BIA-ALCL. CONCLUSIONS: Plastic surgeons should be aware of the elevated risks by surface type, implement appropriate patient surveillance, and follow the recommendations outlined in this statement to ensure patient safety and optimize outcomes. Ongoing research on pathogenesis, genetic drivers, and preventative and prophylactic measures is crucial for improving patient care.

Matched control analysis suggests R-CHOP followed by (R)-ICE may improve outcome in non-GCB DLBCL compared to R-CHOP.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard-of-care for patients with advanced-stage diffuse large B-cell lymphoma (DLBCL), despite findings that non-germinal center B-cell-like (non-GCB) patients have significantly worse outcome with this regimen. We evaluated the prognostic significance of baseline risk factors, including cell of origin (COO) classified by the Hans algorithm, within an alternative chemoimmunotherapy program. At Memorial Sloan Kettering Cancer Center (MSK), 151 patients with DLBCL received sequential R-CHOP induction and (R)-ICE (rituximab, ifosfamide, carboplatin, and etoposide) consolidation. Outcome analysis based on COO was validated with a propensity score matched cohort treated with R-CHOP from the Mayo Clinic component of the Molecular Epidemiology Resource (MER). Among the GCB (n=69) and non-GCB (n=69) patients at MSK, event-free survival (EFS) of non-GCB was superior to that of GCB (HR 0.53, 95% CI 0.29-0.98). Overall survival (OS) demonstrated an association in the same direction but was not statistically significant (HR 0.68, 95% CI 0.33-1.42). Propensity score matched patients from MSK (n=108) demonstrated a small attenuation in the HRs for EFS (HR 0.57, 95% CI 0.27-1.18) and OS (HR 0.76, 95% CI 0.33-1.79) and were no longer statistically significant. In contrast, the matched MER cohort (n=108) demonstrated an EFS association (HR 1.17, 95% CI 0.70-1.95) and OS association (HR 1.13, 95% CI 0.64-2.00) in the opposite direction, but were also not statistically significant. R-CHOP induction and (R)-ICE consolidation may overcome the negative prognostic impact of the non-GCB phenotype, per the Hans algorithm, and can be preferentially selected for this population.

Diffuse large B-cell lymphoma involving osseous sites: utility of response assessment by PET/CT and good longterm outcomes.

Osseous involvement by diffuse large B-cell lymphoma (DLBCL-bone) is a heterogeneous disease. There is limited data regarding response assessment by positron emission tomography with fluorodeoxyglucose, which may demonstrate residual avidity despite a complete response. We analyzed clinical data of patients with newly diagnosed DLBCL and identified all cases with DLBCL-bone. End of treatment scans were reviewed by two independent experts classifying osseous lesions into Deauville (DV) ≤3; DV ≥4, or reactive uptake in the bone marrow (M), site of fracture (F) or surgery (S). We compared outcomes of DLBCL-bone to other extranodal sites (EN) matched on International Prognotic Index features and regimen. Of 1,860 patients with DLBCL (bone 16%; EN 45%; nodal 39%), 41% had localized disease and 59% advanced. Only 9% (n=27) of patients with initial bone involvement had residual fluorodeoxyglucose avidity at the osseous site. In half of these cases, the uptake was attributed to F/S/M, and of the remaining 13, only two were truly refractory (both with persistent disease at other sites). Overall survival and progression-free survival (PFS) were found to be similar for early- stage nodal DLBCL and DLBCL-bone, but inferior in EN-DLBCL. Advanced-stage disease involving the bone had a similar 5-year PFS to nodal disease and EN-DLBCL. After matching for International Prognotic Index and treatment regiments, PFS between bone and other EN sites was similar. Osseous involvement in DLBCL does not portend a worse prognosis. End of treatment DV ≥4 can be expected in 5-10% of cases, but in the absence of other signs of refractory disease, may be followed expectantly.

Surgical Management and Long-Term Outcomes of BIA-ALCL: A Multidisciplinary Approach.

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a subtype of ALCL that arises as a seroma or a mass in the capsule surrounding textured breast implants. However, collections of cases usually come from large groups of institutions or countries, with different approaches regarding surgery and treatment. Here we describe a cohort of 18 cases undergoing implant removal and capsulectomy followed at Memorial Sloan Kettering Cancer Center (MSKCC). PATIENTS AND METHODS: We retrospectively analyzed all the cases of women with breast implants undergoing implant removal and capsulectomy for BIA-ALCL at MSKCC from January 2011 to June 2020. RESULTS: Median age at diagnosis was 57 (range 35-77) years following a median implant exposure of 11 (range 7-33) years. All known implants were macrotextured with the proprietary Biocell macrotexturing pattern from salt-loss technique. A total of 16 patients (89%) had implants placed for breast cancer reconstruction. Patients presented with clinically evident effusion in 78% of cases and a mass in 17% of cases, and 83% of patients presented with stage 1 BIA-ALCL. Patients were followed for a median of 43.4 months (SD 45 months) after diagnosis. There were no cases of recurrent ALCL. All patients remain disease free and no patients died of ALCL. CONCLUSIONS: In this cohort of patients with BIA-ALCL surgically treated and followed at a single institution, we confirm the importance of adequate surgery (bilateral implant removal and complete capsulectomy) in patients presenting with seroma-confined disease. This dataset reinforces high rates of progression-free and overall survival when diagnosis is identified and treatment performed in those with limited-stage disease.

Few and far between: clinical management of rare extranodal subtypes of mature T-cell and NK-cell lymphomas.

While all peripheral T-cell lymphomas are uncommon, certain subtypes are truly rare, with less than a few hundred cases per year in the USA. There are often no dedicated clinical trials in these rare subtypes, and data are generally limited to case reports and retrospective case series. Therefore, clinical management is often based on this limited literature and extrapolation of data from the more common, nodal T-cell lymphomas in conjunction with personal experience. Nevertheless, thanks to tremendous pre-clinical efforts to understand these rare diseases, an increasing appreciation of the biological changes that underlie these entities is forming. In this review, we attempt to summarize the relevant literature regarding the initial management of certain rare subtypes, specifically subcutaneous panniculitis-like T-cell lymphoma, hepatosplenic T-cell lymphoma, intestinal T-cell lymphomas, and extranodal NK/T-cell lymphoma. While unequivocally established approaches in these diseases do not exist, we make cautious efforts to provide our approaches to clinical management when possible.

TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence.

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)-histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63-rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.

Retrospective characterization of nodal marginal zone lymphoma.

Nodal marginal zone lymphoma (NMZL) is a rare non-Hodgkin B-cell lymphoma that has historically been difficult to define, though is now formally recognized by the World Health Organization Classification. To better characterize the clinical outcomes of patients with NMZL, we reviewed a sequential cohort of 187 patients with NMZL to describe baseline characteristics, survival outcomes, and time-to-event data. Initial management strategies were classified into five categories: observation, radiation, anti-CD20 monoclonal antibody therapy, chemoimmunotherapy, or other. Baseline Follicular Lymphoma International Prognostic Index scores were calculated to evaluate prognosis. A total of 187 patients were analyzed. The five-year overall survival was 91% (95% confidence interval [CI], 87-95), with a median follow-up time of 71 months (range, 8-253) among survivors. A total of 139 patients received active treatment at any point, with a median follow-up time of 56 months (range, 13-253) among survivors who were never treated. The probability of remaining untreated at five years was 25% (95% CI, 19-33). For those initially observed, the median time to active treatment was 72 months (95% CI, 49-not reached). For those who received at least one active treatment, the cumulative incidence of receiving a second active treatment at 60 months was 37%. Transformation to large B-cell lymphoma was rare, with a cumulative incidence of 15% at 10 years. In summary, our series is a large cohort of uniformly diagnosed NMZL with detailed analyses of survival and time to event analyses. We showed that NMZL commonly presents as an indolent lymphoma for which initial observation is often a reasonable strategy.

Treatment of Adult T-Cell Leukemia/Lymphoma: Established Paradigms and Emerging Directions.

OPINION STATEMENT: Adult T-cell leukemia/lymphoma (ATL) is a rare, aggressive subtype of peripheral T-cell lymphoma developing after many years of chronic, asymptomatic infection with the retrovirus human T-cell lymphotropic virus type 1 (HTLV-1). HTLV-1 is endemic to certain geographic areas of the world, and primary infection generally occurs in infancy through mother-to-child transmission via breastfeeding. In less than 5% of infected individuals, a decades-long pathogenic process culminates in the development of ATL. Aggressive subtypes of ATL are life-threatening and challenging to treat, with median overall survival typically less than 1 year in the absence of allogeneic hematopoietic cell transplantation (alloHCT). Owing to the rarity of this illness, prospective large-scale clinical trials have been challenging to perform, and treatment recommendations are largely founded upon limited evidence. Herein, we review the current therapeutic options for ATL, providing a broad literature overview of the foremost clinical trials and reports of this disease. We emphasize our own treatment paradigm, which is broadly based upon disease subtype, patient fitness, and intent to perform alloHCT. Finally, we highlight recent advances in understanding ATL disease biology and important ongoing clinical trials that we foresee as informative and potentially practice-changing.

The SALENTO prognostic model for limited-stage peripheral T-cell lymphoma from the International T-Cell Project Network.

The natural history of limited-stage peripheral T-cell lymphomas (PTCLs) remains poorly defined. We investigated outcomes and prognostic variables in patients registered in the T-Cell Project (TCP) (#NCT01142674) to develop a model to predict overall survival (OS) for the common nodal PTCL subtypes (PTCL-NOS, AITL, ALCL). The model was validated in an independent data set from Australian and Brazilian registries. 211 patients registered in the TCP between 2006-2018 were studied. The median age was 59 years (range 18-88) and median follow-up was 49 months. One hundred twenty-seven patients (78%) received anthracycline-based regimens, 5 patients (3%) radiotherapy alone (RT), 24 patients (15%) chemotherapy+RT. 5-year OS and PFS were 47% and 37%, respectively. Age >60 years, elevated LDH and low serum albumin were independent prognostic factors. The model identified 3 groups with low- (26%, score 0), intermediate- (41%, score 1), and high-risk (33%, score 2-3) with 5-year OS of 78% (95% confidence interval [95% CI], 29-127), 46% (95% CI, 24-68), and 25% (95% CI, 20-30), respectively (P < 0.001) and 5-year PFS of 66% (95% CI, 33-99), 37% (95% CI, 9-65), and 17% (95% CI, 9-25), respectively (P < 0.001). The model demonstrated greater discriminatory power than established prognostic indices and an analogous distribution and outcomes in the 3 groups in the validation cohort of 103 patients. The SALENTO Model (Limited Stage Peripheral T-Cell Lymphoma Prognostic Model) is an objective, simple and robust prognostic tool. The high-risk group has poor outcomes, comparable to advanced stage disease, and should be considered for innovative first-line approaches.

Final results of a phase II study of CHOEP plus lenalidomide as initial therapy for patients with stage II-IV peripheral T-cell lymphoma.

There remains no one standard induction for nodal-based peripheral T-cell lymphoma (PTCL). We conducted a phase II study of lenalidomide plus CHOEP as a novel induction strategy. Patients received CHOEP at standard doses in combination with 10 mg of lenalidomide on days 1-10 of a 21-day cycle for six cycles of therapy followed by observation, high-dose therapy with autologous stem cell rescue, or maintenance lenalidomide per provider preference. Among 39 patients evaluable for efficacy, the objective response rate after six cycles was 69%, with complete response in 49%, partial response in 21%, stable disease in 0% and progressive disease in 13%. Thirty-two patients (82%) completed full induction, and seven patients (18%) discontinued for toxicity, primarily hematologic. Any grade hematologic toxicity occurred in over 50% of patients, with grade 3 or 4 febrile neutropenia occurring in 35% of patients despite mandated growth factors. With a median followup of surviving patients of 21.3 months, the estimated 2-year progression-free and overall survival were 55% (95% CI 37%-70%) and 78% (95% CI 59%-89%), respectively. In sum, six cycles of lenalidomide plus CHOEP resulted in a modest response rate primarily due to hematologic toxicity, which prevented all patients from completing planned induction.

TP53 mutations identify high-risk events for peripheral T-cell lymphoma treated with CHOP-based chemotherapy.

Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering Integrated Mutational Profiling of Actionable Cancer Targets next-generation sequencing panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with an increased risk of progression (by multivariate analysis) included advanced-stage disease and bone marrow involvement. The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations and TP53/17p deletions. PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5 months for PTCL with a TP53 mutation (n = 21) vs 10.5 months for PTCL without a TP53 mutation (n = 111). No TP53 aberrancy correlated with inferior overall survival (OS). Although rare (n = 9), CDKN2A-deleted PTCL correlated with inferior OS, with a median of 17.6 months vs 56.7 months for patients without CDKN2A deletions. This retrospective study suggests that patients with PTCL with TP53 mutations experience inferior PFS when treated with curative-intent chemotherapy, warranting prospective confirmation.

Extracorporeal Membrane Oxygenation Characteristics and Outcomes in Children and Adolescents With COVID-19 or Multisystem Inflammatory Syndrome Admitted to U.S. ICUs.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) has been used successfully to support adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related cardiac or respiratory failure refractory to conventional therapies. Comprehensive reports of children and adolescents with SARS-CoV-2-related ECMO support for conditions, including multisystem inflammatory syndrome in children (MIS-C) and acute COVID-19, are needed. DESIGN: Case series of patients from the Overcoming COVID-19 public health surveillance registry. SETTING: Sixty-three hospitals in 32 U.S. states reporting to the registry between March 15, 2020, and December 31, 2021. PATIENTS: Patients less than 21 years admitted to the ICU meeting Centers for Disease Control criteria for MIS-C or acute COVID-19. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The final cohort included 2,733 patients with MIS-C ( n = 1,530; 37 [2.4%] requiring ECMO) or acute COVID-19 ( n = 1,203; 71 [5.9%] requiring ECMO). ECMO patients in both groups were older than those without ECMO support (MIS-C median 15.4 vs 9.9 yr; acute COVID-19 median 15.3 vs 13.6 yr). The body mass index percentile was similar in the MIS-C ECMO versus no ECMO groups (89.9 vs 85.8; p = 0.22) but higher in the COVID-19 ECMO versus no ECMO groups (98.3 vs 96.5; p = 0.03). Patients on ECMO with MIS-C versus COVID-19 were supported more often with venoarterial ECMO (92% vs 41%) for primary cardiac indications (87% vs 23%), had ECMO initiated earlier (median 1 vs 5 d from hospitalization), shorter ECMO courses (median 3.9 vs 14 d), shorter hospital length of stay (median 20 vs 52 d), lower in-hospital mortality (27% vs 37%), and less major morbidity at discharge in survivors (new tracheostomy, oxygen or mechanical ventilation need or neurologic deficit; 0% vs 11%, 0% vs 20%, and 8% vs 15%, respectively). Most patients with MIS-C requiring ECMO support (87%) were admitted during the pre-Delta (variant B.1.617.2) period, while most patients with acute COVID-19 requiring ECMO support (70%) were admitted during the Delta variant period. CONCLUSIONS: ECMO support for SARS-CoV-2-related critical illness was uncommon, but type, initiation, and duration of ECMO use in MIS-C and acute COVID-19 were markedly different. Like pre-pandemic pediatric ECMO cohorts, most patients survived to hospital discharge.