Citations

Introduction: Endometrial carcinoma (EC) is the most prevalent gynecological cancer. It is characterized by a clinical, pathological, and prognostic trajectory that has become inextricably linked to the disease’s molecular profile. Therefore, it is imperative to examine its relevance across all facets associated with the disease. Methods: This is a single-center retrospective study to assess tumor molecular profile concordance between EC diagnosis and recurrence. All patients who underwent hysterectomy for EC between 2016 and 2020 were included. Results: In total, 221 cases of EC were collected. In total, 18 recurrences were found. In two cases, there was a molecular classification (MC) change: an MMR-deficient endometrioid EC shifted to a “multiple classifier” subtype. The second, an NSMP subtype, at second recurrence revealed a switched MC to an aberrant mutated p53 profile. This discordance rate was non-significant in our cohort. However, considering the lack of evidence, it opens new insights to be revealed. Conclusions: This is the first study focusing on the discordance rate of MCs in EC relapses compared to the initial diagnosis. Future large-scale retrospective and prospective multicenter studies are essential for exploring this aspect.

Abstract Purpose: Combined mTOR and MEK inhibition, critical components of the RAS effector pathway underlying the pathogenesis of neurofibromatosis type 1 (NF1)–related tumors, caused regression in a malignant peripheral nerve sheath tumor (MPNST) transgenic mouse model. The primary objective was to determine the clinical benefit rate in patients with unresectable/metastatic MPNST. Patients and Methods: The study design was a multi-institutional, open-label, Simon two-stage, phase II study of the MEK inhibitor selumetinib and mTOR inhibitor sirolimus. Patients ≥12 years with histologically confirmed MPNST received selumetinib 50 mg twice daily and sirolimus 4 mg once daily, in continuous 28-day cycles. Correlative studies evaluated patient-reported pain, immune signature in peripheral blood, and cell-free DNA (cfDNA). Results: A total of 21 heavily pretreated patients [seven females; median age, 41 years (range, 16–72); and 14 with NF1] with advanced disease enrolled at five participating sites. Clinical benefit was observed in only one of seven in stage 1 and one of 14 patients in stage 2. The median number of cycles was two (range, 1–6). Most common adverse events (AE) were grade ≤2 gastrointestinal toxicity, acneiform rash, hypertriglyceridemia, mucositis, and transaminase elevation. Unlike the preclinical model, early 18F-fluorodeoxyglucose PET scan performed during cycle 1 demonstrated partial metabolic responses in five patients (24%), but these did not correlate with objective responses after cycle 2. cfDNA was able to detect MPNST with the potential to be a biomarker of response. Conclusions: The combination was safe, with manageable and expected AEs, but did not meet study parameters for further evaluation in MPNST. Correlative studies were informative and may guide future therapeutic trials of MPNST.

Abstract Background Bedaquiline, pretomanid, and linezolid with or without moxifloxacin (BPaL/M) are recommended oral 6-month treatment regimens for multidrug- or rifampin-resistant (MDR/RR) tuberculosis (TB). Since the US rollout of these regimens in 2019, the US Centers for Disease Control and Prevention (CDC) and partners have identified patients who failed or relapsed on these regimens. Methods Here, we report a case series of US patients with TB treated with BPaL/M-containing regimens, who experienced adverse outcomes during the period 2022‒2024, including drug resistance, relapse, and treatment failure. Results Clinical and public health outcomes were significant for US patients reported. There were 8 patients identified (n = 8). 5 (62.5%) were male, with a median age 57 years, 2 (25%) were previously treated for TB, and 8 (100%) presented with cavitary disease. This included a patient who died from infectious TB with acquired resistance after exposing over 100 healthcare workers, a waitress who was found to have highly infectious TB at the time of her relapse, and a son who contracted Mycobacterium tuberculosis (Mtb) with reduced activity to bedaquiline from his mother in a household transmission event. Conclusions These patients highlight consequences, both for the individual and public health, of relapse and treatment failure in real-life operational settings that may not be readily evident in well-controlled and well-resourced clinical trials. Despite the advent of shorter and better tolerated bedaquiline-based regimens, US clinicians continue to face challenges in managing drug-resistant TB. These data support the need for expert management of these patients beyond routine TB care, as well as the need for close monitoring and follow-up months after treatment completion.

Objectives: To evaluate evolving management, ICU admission, and outcomes for critically ill chimeric antigen receptor (CAR) T-cell patients over a 6-year period. Design: Multicenter retrospective cohort study from January 2018 to September 2023. Setting: Eight U.S. centers. Patients: Adult CAR T-cell patients requiring ICU admission. Interventions: None. Methods: Summary statistics included mean, sd , median, and interquartile range (IQR). Fisher exact test or chi-square test were used to evaluate association between year treated and other categorical variables. Cochran-Armitage test was performed to assess significance of trends across years. Multivariable logistic regression was performed to assess covariates associated with mortality. Measurements and Main Results: Demographics, toxicity management, ICU admission, support modalities, toxicity severity, and survival (ICU, hospital, and 3-mo) were compared year-to-year. From 2018 to 2023, 2238 patients received CAR T cells, with increasing number of patients treated yearly; 398 (17.8%) required ICU care. Of those admitted to the ICU, 66.1% were male, 89.2% had lymphoma, and median age was 64 years (53–71 yr). ICU admission rates declined from 38.5% (95% CI, 31.6–45.8%) in 2018 to 16.4% in 2023 (95% CI, 13.5–19.7%; p < 0.0001). Cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome was the reason for ICU admission in 87.9%. In 2023 vs. 2018, ICU patients were older (median, 65 yr [IQR, 55–73 yr] vs. 58 yr [48–67 yr]; p = 0.003) with higher comorbidity indices (4 [4–6] vs. 3 [2–4]; p = 0.005) and more severe toxicities (≥ grade 3: 90.1% vs. 69.9%; p = 0.004). Corticosteroid use for less severe toxicities (≤ grade 2 toxicity: 73.8% vs. 40.6%; p = 0.0001) and anakinra use (56% vs. 5.5%; p < 0.0001) increased throughout the years. Mortality from cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome remained low (5.5%). Age, Sequential Organ Failure Assessment greater than or equal to 10 at ICU admission, and ICU admission for noncytokine release/neurotoxicity syndrome reasons were associated with hospital mortality (odds ratios, 1.02 [95% CI, 1–1.04; p = 0.046], 4.69 [2.44–9.01; p < 0.0001], and 3.74 [1.91–7.3; p = 0.0001], respectively). Conclusions: ICU admission rates after CAR T-cell treatment are declining. Although ICU patients are older with higher severity of illness and toxicity grades, ICU mortality after CAR T-cell therapy remains low.

Importance The choice of induction agent during rapid sequence intubation (RSI) of critically ill adults may affect clinical outcomes. Although ketamine and etomidate are frequently used for RSI, their comparative effectiveness remains controversial. Objective To compare the safety of etomidate vs ketamine for emergency RSI in critically ill adults. Design, Setting, and Participants This cohort study used a target trial emulation with observational data collected between March 1, 2022, and April 30, 2024, from 18 emergency departments across Brazil, with data from the Brazilian Airway Registry Cooperation. Adults who underwent RSI and received either etomidate or ketamine as a sole hypnotic agent were included; those with preintubation cardiac arrest or immediate postintubation transfer were excluded. Exposure Administration of etomidate or ketamine as the induction agent for RSI. Main Outcomes and Measures The primary outcome was 28-day in-hospital mortality. Secondary outcomes included 7-day in-hospital mortality, first-attempt intubation success, and major adverse events (new hemodynamic instability, severe hypoxemia, and cardiac arrest) within 30 minutes after intubation. Inverse probability of treatment weighting was used to adjust for confounding. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were used to compare outcomes between groups. Results Among 1810 patients (median age, 64 years [IQR, 50-74 years]; 1048 men [57.9%]), 514 received ketamine and 1296 received etomidate. The median shock index was higher in the ketamine group than the etomidate group (0.81 [IQR, 0.65-1.01] vs 0.76 [IQR, 0.59-0.99]), and preintubation vasopressor use was more common in the ketamine group than the etomidate group (191 of 514 [37.2%] vs 391 of 1296 [30.2%]). Weighted 28-day mortality was higher with etomidate than ketamine (60.5% [95% CI, 57.2%-63.8%] vs 54.4% [95% CI, 45.0%-63.9%]; RR, 1.14 [95% CI, 1.03-1.27]; RD, 7.6% [95% CI, 2.0%-13.3%]). Seven-day mortality was also higher with etomidate than ketamine (35.2% [95% CI, 32.0%-38.3%] vs 30.1% [95% CI, 23.5%-36.7%]; RR, 1.19 [95% CI, 1.04-1.35]). New hemodynamic instability within 30 minutes after intubation was more frequent with ketamine (24.2% [95% CI, 20.4%-28.0%] vs 18.9% [95% CI, 16.7%-21.0%]; RR, 0.78 [0.64-0.95]). There were no statistically significant differences in the other secondary outcomes. Conclusions and Relevance In this cohort study of critically ill adults undergoing RSI, etomidate use was associated with higher in-hospital mortality at 7 and 28 days compared with ketamine. These findings highlight the need for definitive randomized clinical trials to compare both agents.

Abstract Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to affect overall survival (OS). However, the influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium from 1990 to 2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and 79.7%, respectively. Age ≥5 years, donor type, and a pre-HCT history of severe infection had a negative impact on OS and EFS, whereas pre-HCT autoimmunity had no impact. Reduced-intensity regimens were associated with lower T-cell and myeloid donor chimerism, particularly when non–busulfan-based regimens were used. Low myeloid donor chimerism was associated with lower platelet counts. Mixed chimerism was not consistently associated with post-HCT autoimmunity. Patients with class I (exon 1-2 missense and intron 5 hot spot variants) and class II variants (all others) had similar pre-HCT clinical symptom severity and no difference in OS, EFS, or platelet recovery post-HCT. In conclusion, our study showed excellent long-term OS and EFS after HCT for WAS, highlighting the importance of early HCT, before the development of severe infections. We confirmed that HCT using busulfan-based conditioning was associated with improved donor chimerism and platelet recovery. This trial was registered at www.clinicaltrials.gov as NCT02064933.

Abstract Introduction The International Prognostic Index (IPI) is widely used to stratify risk in large B-cell lymphoma (LBCL) across all ages, with age-adjusted (aa)IPI applied to younger patients. While there have been efforts to develop prognostic indices (PIs) tailored to older patients, few are adopted in clinical practice due to their complexity and reliance on functional assessments, which are not routinely collected in real-world registry datasets. Recently proposed SENIOR-IPI (Dubois, ASH 2024) was developed for older patients with LBCL receiving anthracycline (A)-based therapy. We assessed the performance of standard and novel PIs in patients aged 80+ years and externally validated the SENIOR-IPI. Methods We harmonized and pooled data of patients aged 80+ years with newly diagnosed LBCL from a national registry and two prospective cohorts: NiHiL (Czech Republic, enrolled 2010–2023), LEO (USA; n=222, 2015–2020), and MER (USA; n=77, 2010–2015), forming a cohort of 819 individuals. We included 536 individuals with complete data on IPI components and albumin, including 485 treated with chemotherapy and 397 with A-based regimens (primary cohort). Following PIs were evaluated: IPI, NCCN-IPI, (aa)IPI, and SENIOR-IPI (age per year, aaIPI components, LDH &gt;3x ULN as extra point, and albumin, all weighted six-fold; extranodal involvement excluded due to lack of prognostic significance). Multivariable hazard ratios (HR) were estimated using Cox proportional hazards models; discriminative ability was assessed using C-index and calibration plots. The primary endpoint was overall survival (OS); event-free survival results were consistent (230/357 events were deaths) and are not reported here. Results Among the 397 A-treated patients (median age 82 years, range 80–99), ECOG performance status (PS) 2–4 was observed in 35% of patients, clinical stage III–IV in 67%, elevated LDH in 65% (8% with &gt;3x ULN), &gt;1 extranodal (EN) site in 32%, and albumin levels &lt; 3.5 g/dL in 27%. In multivariable modeling, only age per year (HR=1.07, P&lt;0.01), and clinical stage (HR=1.36, P=0.048) were independent predictors of OS, whereas ECOG PS (HR=1.27, P=0.12), trichotomized LDH by ULN (HR=1.23, P=0.08) and albumin (HR=1.17, P=0.35) were not significant. SENIOR-IPI had the highest discrimination (C-index 0.631) in A-treated patients, outperforming IPI (0.617), NCCN-IPI (0.591), and aaIPI (0.620), with consistent results across cohorts: NiHiL (0.633), LEO (0.619), and MER (0.621). SENIOR-IPI stratified patients into low- (L-Risk, 0–9 points, 28%), low-intermediate (L-Int, 10–19 points, 42%), high-intermediate (H-Int, 20–29 points, 23%), and high-risk (H-Risk, 30–40 points, 7%) categories, with OS medians of 6.3, 3.8, 2.4, and 1.4 years, respectively (P&lt;0.01), and significant separation between L-Int and H-Int (HR=1.47, P=0.02). By comparison, IPI categorized patients as L-Risk (12%), L-Int (24%), H-Int (27%), and H-Risk (37%), with median OS of 8.7, 4.6, 4.8, and 1.9 years, resp. (P&lt;0.01). aaIPI yielded following distributions: 13%, 29%, 37%, and 21%; and median OS: 8.7, 5.3, 3.4, and 1.5 years; P&lt;0.01. NCCN-IPI stratified patients into three groups: L-Int (13%), H-Int (49%), and H-Risk (39%), with respective OS medians of 8.7, 4.1, and 2.5 years (P&lt;0.01). All PIs showed modest overestimation of mortality (calibration slopes: SENIOR-IPI 1.36; IPI 1.24; aaIPI 1.30; NCCN-IPI 1.26; intercept: -0.97, -0.87, -0.92, -0.87, resp.). In the entire cohort (n=536), SENIOR-IPI showed highest C-index (0.651 vs IPI 0.622, aaIPI 0.631, NCCN-IPI 0.606), and stratified patients into L-Risk (26%, 2-year OS: 6.4 years), L-Int (40%, 3.2 years), H-Int (24%, 1.5 years), and H-Risk (10%, 0.6 years). Calibration slope was 1.18 (intercept -0.33). Among patients not receiving chemotherapy, SENIOR-IPI also performed best (C-index 0.759 vs IPI 0.738, aaIPI 0.757, NCCN-IPI 0.728). Conclusion SENIOR-IPI enables effective risk stratification of patients aged 80+ years with LBCL into four prognostically distinct groups, outperforming traditional indices (IPI, NCCN-IPI, aaIPI) in patients receiving A-based therapy, as well as in the entire cohort and in patients not receiving chemotherapy. While its discrimination is superior, modest miscalibration suggests that future recalibration may improve precision. These findings support SENIOR-IPI as a clinically relevant prognostic tool for the elderly LBCL patient population. Funding: NU21-03-00411, P50 CA97274, U01 CA195568.

Abstract Background: Older adults with newly diagnosed ALL treated with conventional chemotherapy have poor survival due to high rates of toxic death and disease relapse. The Alliance A041703 trial (NCT0373981) tested chemotherapy-free treatment with the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin (InO) followed by the anti-CD19-CD3 bifunctional T-cell engager blinatumomab (blina) without maintenance in older adults to reduce toxicity and increase efficacy of therapy for this patient (pt) population. We previously reported with 22-month (mo) median follow-up that the study met its primary endpoint with a 1-year (yr) event-free survival (EFS) of 75% (90% confidence interval [CI] 63-89% lower bound exceeding null rate of 10%; JCO 2023 41, 7006). Here we report secondary outcomes with 45-mo median follow-up: 3-yr EFS, 3-yr overall survival (OS), response, and relapse characteristics. Methods: Eligible pts were ≥60 yrs old with newly diagnosed, Ph-negative, CD22-positive (≥20% of blasts) B-cell ALL without planned allogeneic HCT (alloHCT), liver disease, or CNS involvement at enrollment. Induction IA was InO 0.8 mg/m2 day (d) 1, 0.5 mg/m2 d8, d15 IV on a 21d cycle. Pts with adequate cytoreduction (marrow blasts reduced ≥50% or marrow cellularity ≤20%) after IA went to IB if in CR/CRi (InO 0.5 mg/m2 d1, d8, d15 IV; 28d cycle) or IC if no CR/CRi (InO 0.8 mg/m2 on d1 and 0.5 mg/m2 on d8 and d15 IV; 28d cycle). Those without cytoreduction to IA started course II blina. Pts without events in IA/B/C received course II blina continuous IV (9 mcg/d x 7d then 28 mcg/d x 21d; 14d break; 28 mcg/d x28d). Pts with CR/CRi to InO received 2 more 28d cycles of blina; others received 3 more. CNS prophylaxis was methotrexate 15 mg intrathecal x 8 doses. EFS was time from therapy start to failure to achieve CR/CRh/CRi by the end of course II, progression, relapse, or death, whichever occurred first, censored at last follow up. OS was time from registration to death from any cause censored at the last known alive date. Results: The median age of the 33 treated pts was 71 yrs (range 60-84). Eight pts had prior therapy for alternate malignancy in CR for &gt;2 yrs prior to enrollment (6 multiple myeloma, 1 non-Hodgkin lymphoma, 1 breast cancer). Median CD22 expression was 92% (range 21-100%) and 49% had NCCN poor-risk genetics. Five pts underwent alloHCT in first CR/CRi and 2 pts received POMP maintenance after early discontinuation of blina (1 toxicity, 1 physician choice). The CR/CRi rate after InO was 85% (1 early death/refractory, 2 refractory, 2 undetermined due to low marrow cellularity on remission assessment marrow) with CR/CRi rate of 97% by completion of course II blina. With 45 mo median follow-up, the estimated 3-yr EFS was 48% (95% CI 33-70%) with a median EFS of 31 mo (95% CI 17.4-not reached [NR]) and no events after 31 mo. Sixteen events occurred: 12 relapses, 1early death, and 3 deaths in remission (1 encephalopathy, 1 relapse of multiple myeloma, 1 pulmonary complications after alloHCT). No isolated CNS relapse has been reported. Among relapses, 10 had immunophenotyping. Four (40%) were CD19-negative, one of which was also CD22-negative. Among CD19-negative relapses, genetics were hypodiploid (2), Pax5alt (1), and ZNF384-like (1, also CD22-negative). TP53 mutation or loss was observed in 5/12 (42%) relapses. Thirteen pts died. The estimated 3-yr OS was 59% (95% CI 44-79%) with median OS NR (95% CI 32-NR) with no deaths after 36 mo. In univariate analysis, EFS and OS were not impacted by age, gender, genetic risk (NCCN), prior therapy for alternate malignancy, or alloHCT in first remission. EFS was better with higher CD22 expression at diagnosis (≥90% vs &lt;90%, 3-yr EFS 60% vs 25%, P=0.044). EFS and OS were worse for detectable minimal residual disease (MRD) at any timepoint by ASO-PCR. Undetectable MRD after course IA (1 cycle InO induction) was associated with EFS with a 3-yr EFS of 52% vs 0% for detectable MRD (median NR vs 8 mo, hazard ratio [HR] 0.07, P=0.004) and a 3-yr OS of 100% vs 0% for detectable MRD (median NR vs 20 mo, HR 0.00, P=0.0014). Conclusions: Longer follow-up of chemotherapy-free treatment with InO and blina for older pts with newly diagnosed, Ph-negative, CD22-positive, B-cell ALL reveals durable remissions and survival. The A041703 regimen is a compelling option for first-line treatment of this pt population. Support: U10CA180821, U10CA18088; https://acknowledgments.alliancefound.org.

Abstract Introduction: Clinical outcomes for patients (pts) with Philadelphia chromosome positive (Ph+) B-cell precursor Acute Lymphoblastic Leukemia (B-ALL) have significantly improved with the incorporation of tyrosine kinase inhibitors (TKI) and immunotherapy. Although the incidence of central nervous system (CNS) relapse in Ph+ B-ALL is rare, it has become an emerging challenge with chemotherapy-free approaches. While IKZF1, CDKN2A/B and emergence of T315I kinase domain mutations in ABL1 have been associated with worse outcomes (Foà R, JCO, 2024),further characterization of patients with CNS relapse could prove useful in risk stratification and optimizing treatment intensification. Currently, high white blood cell count (WBC) is being assessed as a marker to identify pts who may benefit from addition of CNS penetrant chemotherapy (ex. cytarabine or high-dose methotrexate (HD-MTX)) to TKI and immunotherapy protocols (Short NJ, J Hematol Oncol, 2025). Methods This is a multicenter retrospective study of relapsed/refractory Ph+ B-ALL pts under the COMMAND consortium. Age, gender, induction regimen and TKI of choice during induction were descriptively reported for the entire cohort. Categorical variables were compared, using Fisher's exact test, between pts with CNS relapse and pts with systemic relapse. Variables of interest were the presence of IKZF1 or CDKN2A/B alterations, emergence of T3151 mutation, CNS disease at diagnosis (dx), WBC &gt;70K/microliter at dx, use of high-dose methotrexate (HD-MTX) during induction or consolidation, and use of TKI as part of the induction regimen. Odds ratio (OR) and 95% confidence intervals (CI) were reported for each variable. Results A total of 654 Ph+ B-ALL pts were initially identified across multiple centers in the United States, of whom 20 (3%) experienced a CNS relapse and 157 (24%) experienced a systemic relapse on median follow up of 29 months (range, 0-207). A total of 15 pts with CNS relapse and 114 pts with systemic relapse were used for this analysis after exclusion of pts without molecular data. The median age for the 129 pt cohort was 55 years (range 22-85), of whom 65 pts (50%) were male. Induction regimens used were intensive chemotherapy (IC)+TKI for 79 pts (61%), low-intensity chemotherapy or steroids (LDC-S)+TKI for 40 pts (31%), IC without TKI during induction for 5 pts (4%) and blinatumomab+TKI for 1 pt (1%). TKI of choice during induction included second-generation TKIs (dasatinib, nilotinib) for 77 pts (60%), imatinib for 30 pts (23%), ponatinib for 15 pts (12%) and none during induction for 5 pts (4%). CNS disease at dx was found in 6/15 pts (40%) with CNS relapse and 9/114 pts (8%) with systemic relapse, which was a statistically significant difference (p=0.002, OR= 7.57, 95% CI= 1.81 - 31.08). The systemic treatment regimens for the 15 pts with CNS disease at x were IC+TKI for 10 pts (66%) and LDC-S+TKI for 5 pts (33%), 9 of the pts (60%) received HD-MTX during induction. Intrathecal (IT) chemotherapy administration data at dx was available for 8 pts (53%) with CNS disease at dx, of whom 2 pts received &lt;9 doses, 4 pts received 9-12 doses and 2 pts received &gt;12 doses of IT chemotherapy. Although not statistically significant, pts with CNS relapse were more likely to have IKZF1 or CDKN2A/B alterations (p = 0.648, OR= 1.44, 95% CI= 0.14-7.78), WBC &gt;70K/mcl (p = 0.472, OR= 1.73, 95% CI= 0.34-7.41), emergence of T3151 mutations (p = 0.123, OR= 2.54, 95% CI= 0.72-8.84) and use of HD-MTX during induction or consolidation (p = 0.262, OR= 2.15, 95% CI= 0.61-8.61); while they were less likely to have received a TKI during induction (p = 0.106, OR= 0.18, 95% CI= 0.02-2.34). Conclusion This data confirms that the presence of CNS disease at dx is associated with CNS relapse. Despite recent incorporation into clinical trials, WBC≥70K/mcl and omission of HD-MTX were not seen more frequently in pts with CNS relapse in this cohort. However, this analysis is limited by the small number of pts who experienced CNS relapse. With the rising use of chemotherapy-free regimens, prospectively trialing treatment intensification, such as with additional IT chemotherapy or HD-MTX, could be prospectively trialed in pts with CNS disease at dx to potentially improve outcomes for this subset of pts. The impact of increasing IT chemotherapy doses or additional cycles of systemic chemotherapy in this pt population is yet to be elucidated.