Higher-dose venetoclax with measurable residual disease-guided azacitidine discontinuation in newly diagnosed acute myeloid leukemia.

Venetoclax+azacitidine is the standard of care for newly-diagnosed patients with acute myeloid leukemia (AML) for whom intensive chemotherapy is inappropriate. Efforts to optimize this regimen are necessary. We designed a clinical trial to investigate two hypotheses: i) higher doses of venetoclax are tolerable and more effective, and ii) azacitidine can be discontinued after deep remissions. Forty-two newly diagnosed AML patients were enrolled in the investigator-initiated High Dose Discontinuation Azacitidine+Venetoclax (HiDDAV) Study (clinicaltrials gov. Identifier: NCT03466294). Patients received one to three "induction" cycles of venetoclax 600 mg daily with azacitidine. Responders received MRD-positive or MRDnegative "maintenance" arms: azacitidine with 400 mg venetoclax or 400 mg venetoclax alone, respectively. The toxicity profile of HiDDAV was similar to 400 mg venetoclax. The overall response rate was 66.7%; the duration of response (DOR), event-free survival (EFS) and overall survival were 12.9, 7.8 and 9.8 months, respectively. The MRD negativity rate was 64.3% by flow cytometry and 25.0% when also measured by droplet digital polymerase chain recation. MRD-negative patients by flow cytometry had improved DOR and EFS; more stringent measures of MRD negativity were not associated with improved OS, DOR or EFS. Using MRD to guide azacitidine discontinuation did not lead to improved DOR, EFS or OS compared to patients who discontinued azacitidine without MRD guidance. Within the context of this study design, venetoclax doses >400 mg with azacitidine were well tolerated but not associated with discernible clinical improvement, and MRD may not assist in recommendations to discontinue azacitidine. Other strategies to optimize, and for some patients, de-intensify, venetoclax+azacitidine regimens are needed.

NCCN Guidelines® Insights: Myelodysplastic Syndromes, Version 3.2022.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.

Sweet syndrome in patients with and without malignancy: A retrospective analysis of 83 patients from a tertiary academic referral center.

BACKGROUND: Sweet syndrome is a neutrophilic dermatosis that may be categorized into classic, malignancy-associated, and drug-induced subtypes. Few studies have systematically analyzed this rare disorder. OBJECTIVE: To describe the clinicopathologic characteristics and treatment of Sweet syndrome and identify characteristics associated with concurrent malignancy. METHODS: We retrospectively reviewed patients with Sweet syndrome at the University of Pennsylvania from 2005 to 2015. RESULTS: We identified 83 patients (mean age, 57 years; 51% male) with Sweet syndrome: 30% with the classic form, 44% with the malignancy-associated form, 24% with the drug-induced form in the setting of malignancy, and 2% with the drug-induced form. Acute myeloid leukemia was the most common malignancy (in 24 of 83 patients [29%]). Filgrastim was the most common medication (used in 8 of 83 patients [10%]). Leukopenia (P < .001), anemia (P = .002), thrombocytopenia (P < .001), absence of arthralgia (P < .001), and histiocytoid or subcutaneous histopathology (P = .024) were associated with malignancy (χ2 test). LIMITATIONS: This was a retrospective study that represents patients from a single tertiary academic referral center, which may limit its generalizability to other settings. CONCLUSION: When caring for patients with Sweet syndrome, dermatologists should be aware of the potential association of leukopenia, anemia, thrombocytopenia, absence of arthralgia, and histiocytoid or subcutaneous histopathology with malignancy.

Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations.

Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage(-)/CD34(+)/CD38(-)/CD90(+)) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS is characterized by expansion of phenotypic common myeloid progenitors, whereas higher-risk cases revealed expansion of granulocyte-monocyte progenitors. Genome-wide analysis of sorted MDS HSCs revealed widespread methylomic and transcriptomic alterations. STAT3 was an aberrantly hypomethylated and overexpressed target that was validated in an independent cohort and found to be functionally relevant in MDS HSCs. FISH analysis demonstrated that a very high percentage of MDS HSC (92% ± 4%) carry cytogenetic abnormalities. Longitudinal analysis in a patient treated with 5-azacytidine revealed that karyotypically abnormal HSCs persist even during complete morphologic remission and that expansion of clonotypic HSCs precedes clinical relapse. This study demonstrates that stem and progenitor cells in MDS are characterized by stage-specific expansions and contain epigenetic and genetic alterations.

Advancements and Challenges in the Treatment of AML.

The therapeutic arsenal for the management of AML has expanded significantly in recent years. Before 2017, newly diagnosed AML was treated with either standard cytarabine- and anthracycline-based induction chemotherapy (for all fit patients) or a single-agent hypomethylating agent (in unfit patients or those 75 years and older). While assessing patient fitness remains important, characterizing the disease biology has become critical to select the optimal initial therapy for each patient with more options available. FLT3 inhibitors, gemtuzumab ozogamicin, and CPX-351 have been shown to improve outcomes for specific subsets of patients. Venetoclax (VEN) with a hypomethylating agent (HMA) is the standard-of-care frontline regimen for most older patients, except perhaps for those with an IDH1 mutation where ivosidenib with azacitidine may also be considered. On the basis of the success seen with HMA/VEN in older patients, there is now increasing interest in incorporating VEN into frontline regimens in younger patients, with promising data from multiple early phase studies. This article focuses on recent updates and ongoing challenges in the management of AML, with a particular focus on the ongoing challenge of secondary AML and considerations regarding the selection of initial therapy in younger patients. An overview of common side effects and toxicities associated with targeted therapies is also presented here, along with recommended strategies to mitigate these risks.

White blood cell count nadir to zero following intensive chemotherapy as a predictive factor for patients with acute myeloid leukemia.

Predictors for response to intensive therapy in AML have focused on baseline factors: percent leukemic blasts in marrow, cytogenetic/molecular genetic abnormalities, and presence of secondary AML. Non-baseline dynamic factors, occurring after induction but before response, may be useful for decisions related to salvage chemotherapy. We hypothesized white blood cell (WBC) count nadir after induction may be a real time indicator of treatment efficacy. We also examined whether time to stem cell transplant (SCT) or baseline molecular genetic abnormalities are associated with a low nadir. Data showed WBC nadir = 0 was a negative predictor for response to intensive induction and was correlated with reduced overall survival and progression free survival. Patients with WBC nadir = 0 did not have a significantly longer time to SCT, and none of the mutations increased the likelihood of reaching WBC nadir = 0. WBC nadir may be a useful real-time monitor in AML patients receiving intensive induction chemotherapy.

Venetoclax is safe and tolerable as post-transplant maintenance therapy for AML patients at high risk for relapse.

Relapse is the most common cause of mortality in acute myeloid leukemia (AML) patients after allogeneic stem cell transplant (SCT). Post-SCT maintenance strategies that prevent relapse are desirable but must be well tolerated and convenient to administer. We hypothesized single agent venetoclax (ven) may be an effective maintenance therapy among high relapse risk patients. Between February 2019 and December 2021, we administered post-SCT ven maintenance to 49 AML patients at high-risk for relapse as a prospectively defined off-label practice at our institution. Ven was planned to be administered until 1-year post-SCT. While temporary interruptions were common (67.3% of all patients), of those with >1 year follow up, 22/25 (88%) completed the full year of planned therapy. Cytopenias (40.8%) and gastrointestinal adverse events (34.7%) were the most common toxicities. At 1-year post-SCT, overall survival (OS) and relapse-free survival (RFS) were 70% and 67% respectively. Our experience demonstrates single agent ven is a safe, tolerable, and feasible maintenance therapy that may improve RFS and OS in high relapse risk post-SCT patients.

Myelodysplastic neoplasm-associated U2AF1 mutations induce host defense defects by compromising neutrophil chemotaxis.

Myelodysplastic neoplasm (MDS) is a hematopoietic stem cell disorder that may evolve into acute myeloid leukemia. Fatal infection is among the most common cause of death in MDS patients, likely due to myeloid cell cytopenia and dysfunction in these patients. Mutations in genes that encode components of the spliceosome represent the most common class of somatically acquired mutations in MDS patients. To determine the molecular underpinnings of the host defense defects in MDS patients, we investigated the MDS-associated spliceosome mutation U2AF1-S34F using a transgenic mouse model that expresses this mutant gene. We found that U2AF1-S34F causes a profound host defense defect in these mice, likely by inducing a significant neutrophil chemotaxis defect. Studies in human neutrophils suggest that this effect of U2AF1-S34F likely extends to MDS patients as well. RNA-seq analysis suggests that the expression of multiple genes that mediate cell migration are affected by this spliceosome mutation and therefore are likely drivers of this neutrophil dysfunction.

A Novel Type of Monocytic Leukemia Stem Cell Revealed by the Clinical Use of Venetoclax-Based Therapy.

The BCL2 inhibitor venetoclax has recently emerged as an important component of acute myeloid leukemia (AML) therapy. Notably, use of this agent has revealed a previously unrecognized form of pathogenesis characterized by monocytic disease progression. We demonstrate that this form of disease arises from a fundamentally different type of leukemia stem cell (LSC), which we designate as monocytic LSC (m-LSC), that is developmentally and clinically distinct from the more well-described primitive LSC (p-LSC). The m-LSC is distinguished by a unique immunophenotype (CD34-, CD4+, CD11b-, CD14-, CD36-), unique transcriptional state, reliance on purine metabolism, and selective sensitivity to cladribine. Critically, in some instances, m-LSC and p-LSC subtypes can co-reside in the same patient with AML and simultaneously contribute to overall tumor biology. Thus, our findings demonstrate that LSC heterogeneity has direct clinical significance and highlight the need to distinguish and target m-LSCs as a means to improve clinical outcomes with venetoclax-based regimens. SIGNIFICANCE: These studies identify and characterize a new type of human acute myeloid LSC that is responsible for monocytic disease progression in patients with AML treated with venetoclax-based regimens. Our studies describe the phenotype, molecular properties, and drug sensitivities of this unique LSC subclass. This article is featured in Selected Articles from This Issue, p. 1949.

Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q.

Myelodysplastic syndromes (MDS) are characterized by abnormal and dysplastic maturation of all blood lineages. Even though epigenetic alterations have been seen in MDS marrow progenitors, very little is known about the molecular alterations in dysplastic peripheral blood cells. We analyzed the methylome of MDS leukocytes by the HELP assay and determined that it was globally distinct from age-matched controls and was characterized by numerous novel, aberrant hypermethylated marks that were located mainly outside of CpG islands and preferentially affected GTPase regulators and other cancer-related pathways. Additionally, array comparative genomic hybridization revealed that novel as well as previously characterized deletions and amplifications could also be visualized in peripheral blood leukocytes, thus potentially reducing the need for bone marrow samples for future studies. Using integrative analysis, potentially pathogenic genes silenced by genetic deletions and aberrant hypermethylation in different patients were identified. DOCK4, a GTPase regulator located in the commonly deleted 7q31 region, was identified by this unbiased approach. Significant hypermethylation and reduced expression of DOCK4 in MDS bone marrow stem cells was observed in two large independent datasets, providing further validation of our findings. Finally, DOCK4 knockdown in primary marrow CD34(+) stem cells led to decreased erythroid colony formation and increased apoptosis, thus recapitulating the bone marrow failure seen in MDS. These findings reveal widespread novel epigenetic alterations in myelodysplastic leukocytes and implicate DOCK4 as a pathogenic gene located on the 7q chromosomal region.

Diurnal variation in mortality in older nocturnal fallers.

BACKGROUND: The prevalence of older trauma patients is rising in Westernised populations. Age has an independent adverse affect on survival from injury. Factors contributing to this increased mortality are incompletely understood. OBJECTIVE: To examine the independent effects of age, time and mechanism of injury on survival from trauma at 30 days. METHODS: We analysed prospectively collected data from the Trauma Audit and Research Network database. Isolated femoral neck and pubic rami fractures are not included in this data set. Univariate and multivariate regression analyses were undertaken. Independent effects of age, time of injury and mechanism of injury on survival following trauma were evaluated. RESULTS: A total of 137,521 trauma patients were included in the study. Trauma victims aged over 65 years had increased odds of death of 9.58 (95% CI: 8.78-10.45), adjusting for known confounders of outcome. Analysis of two-way interactions of age and time of arrival to hospital, revealed patients ≥65 years had a higher odds of death if they presented between midnight and 8 a.m., compared with 08:00-16:00 h; OR = 1.5, (95% CI: 1.29-1.73). Further analysis of this older group, examining the interaction of time and mechanism of injury, revealed a doubling of the odds of death in patients injured following a fall <2 m, when they presented between midnight and 8 a.m.; OR = 2.1, (95% CI: 1.32-3.30). This diurnal variation in mortality was exclusive to older fallers. CONCLUSIONS: Age over 65 years has an independent detrimental affect on survival from trauma. A distinct diurnal variation in mortality from injury occurs in older patients injured as a result of a low velocity fall.

Venetoclax and azacitidine followed by allogeneic transplant results in excellent outcomes and may improve outcomes versus maintenance therapy among newly diagnosed AML patients older than 60.

The combination of venetoclax (ven) and azacitidine (aza) has resulted in high response rates in the upfront treatment of AML in patients age > 75 and patients unfit for intensive chemotherapy. Given the poor historical outcomes in patients age ≥ 60 treated with induction chemotherapy, ven/aza has become our institutional preference for the initial treatment of non-core binding factor (CBF) AML patients age ≥ 60. The benefit of allogeneic stem cell transplant (SCT) in patients who achieve response to ven/aza is uncertain. We report outcomes of SCT-eligible patients treated at our center. Between 1/2015 and 1/2020, 119 newly diagnosed non-CBF AML patients age ≥ 60 received ven/aza as initial therapy. 21 patients underwent SCT; 31 additional patients were potentially SCT eligible but deferred SCT. Overall survival (OS) was significantly greater among SCT patients (median survival not reached) versus potentially SCT eligible patients not undergoing SCT (median 518 days) (p = 0.01). Our data suggest that ven/aza followed by SCT in newly diagnosed AML patients older than ≥ 60 results in excellent outcomes and likely improves outcomes over maintenance therapy. Ongoing investigation will further refine the optimal timing of and selection of patients for SCT based on prognostic disease features and response assessments.

Exposure to biologic therapy and associated maternal and neonatal outcomes in pregnancies complicated by inflammatory bowel disease.

BACKGROUND: There is growing evidence that biologic therapy is safe in pregnancies complicated by inflammatory bowel disease and that its use outweighs the risk of worsening disease activity, which is associated with adverse pregnancy outcomes. To our knowledge, there are limited data regarding the use of biologic therapy and the associated maternal adverse effects such as the risk of hypertensive outcomes, postoperative complications, and infectious risk. OBJECTIVE: Our objective was to evaluate a variety of obstetrical complications including maternal infectious outcomes, hypertensive outcomes, other adverse maternal outcomes including postoperative complications, venous thromboembolism, and postpartum hemorrhage; we also evaluated the neonatal outcomes associated with biologic use in pregnancies affected by inflammatory bowel disease. STUDY DESIGN: This was a retrospective cohort study including patients with inflammatory bowel disease who were pregnant and delivered at our institution. The maternal demographics and the incidence of maternal and neonatal outcomes were compared among groups on the basis of biologic exposure using the chi-square or Fisher exact test for categorical variables and the t test or Mann-Whitney test for continuous variables. Multivariable logistic regression analysis was performed on composite outcomes adjusting for age, disease activity, maternal obesity, history of cesarean delivery, and history of corticosteroid use in pregnancy. The statistical significance was defined as P<.05. RESULTS: A total of 322 patients who were pregnant, had inflammatory bowel disease, and delivered at our institution from 2012 to 2019, were included for analysis. Of these, 112 (34%) were on biologics during pregnancy. The patients in the biologic group had significantly lower body mass indices than the patients in the nonbiologic group (median body mass index, 22.4 vs 24.0, respectively; P=.04), and they were less likely to be multiparous (41% vs 59%, respectively; P=.003). In addition, more patients in the biologic group were likely to have Crohn disease with previous inflammatory bowel disease surgery (33% vs 20%, respectively; P=.01); otherwise, the 2 groups had similar baseline characteristics. Maternal infectious and hypertensive outcomes occurred significantly more frequently in the biologic group than the nonexposed group (22% vs 7%; P=.0003 and 19% vs 8%; P=.003, respectively). This remained statistically significant in multivariable logistic regression models. Specifically, maternal infectious and hypertensive outcomes occurred significantly more frequently in the patients on a single-agent antitumor necrosis factor treatment than the patients on no inflammatory bowel disease medication (24% vs 6%; P=.002; 22% vs 6%; P=.004), which remained statistically significant in multivariable logistic regression models. There was no difference in the neonatal adverse outcomes between the 2 groups. CONCLUSION: Our data suggest an association between antepartum biologic use- specifically antitumor necrosis factor alpha therapy-and an increased risk of maternal infectious and hypertensive outcomes. This increased risk may be related to underlying disease activity and the same should be incorporated into a discussion with the patient. However, the discussion must be balanced with the important benefit of optimal disease control associated with biologic use in patients being treated for IBD.

Machine Learning-Based Exploratory Clinical Decision Support for Newly Diagnosed Patients With Acute Myeloid Leukemia Treated With 7 + 3 Type Chemotherapy or Venetoclax/Azacitidine.

PURPOSE: There are currently limited objective criteria to help assist physicians in determining whether an individual patient with acute myeloid leukemia (AML) is likely to do better with induction with either standard 7 + 3 chemotherapy or targeted therapy with venetoclax plus azacitidine. The study goal was to address this need by developing exploratory clinical decision support methods. PATIENTS AND METHODS: Univariable and multivariable analysis as well as comparison of a range of machine learning (ML) predictors were performed using cohorts of 120 newly diagnosed 7 + 3-treated AML patients compared with 101 venetoclax plus azacitidine-treated patients. RESULTS: A variety of features in the two patient cohorts were identified that may potentially correlate with short- and long-term outcomes, toxicities, and other considerations. A subset of these diagnostic features was then used to develop ML-based predictors with relatively high areas under the curve of short- and long-term outcomes, hospital stays, transfusion requirements, and toxicities for individual patients treated with either venetoclax/azacitidine or 7 + 3. CONCLUSION: Potential ML-based approaches to clinical decision support to help guide individual patients with newly diagnosed AML to either 7 + 3 or venetoclax plus azacitidine induction therapy were identified. Larger cohorts with separate test and validation studies are necessary to confirm these initial findings.

Systemic mastocytosis in a child with t(8;21) acute myeloid leukemia.

Mastocytosis is primarily limited to the cutaneous variant in pediatric patients. Systemic mastocytosis (SM) has been associated with t(8;21) acute myeloid leukemia (AML) in adults. We provide the first report of a child with t(8;21) AML, diagnosed with asymptomatic SM following four cycles of chemotherapy. Unlike most adults with SM/AML, she was not found to have a c-KIT (D816V) mutation. SM persisted in the bone marrow after completion of chemotherapy, and her AML relapsed 9 months off-treatment. Although she achieved a second remission, mastocytosis persists in the marrow. Pediatric patients with t(8;21) AML/SM may represent a high-risk group despite favorable cytogenetics.

The propriety of upgrading responses to venetoclax + azacitidine in newly diagnosed patients with acute myeloid leukemia.

Widely-used response criteria, conditional upon count recovery, were developed for acute myeloid leukemia (AML) in the context of intensive chemotherapy (IC). Extending these definitions to continuously-administered venetoclax-based therapies might underestimate responses. Best practices for venetoclax-based therapies mandate interruption after an end-of-cycle 1 bone marrow biopsy shows morphologic remission with cytopenias. We analyzed 435 patients with newly-diagnosed AML and follow-up response assessments. Of the 101 who responded to venetoclax + azacitidine, overall survival for patients whose response was upgraded due to count recovery during a 14-day post-disease assessment period, from complete remission (CR) with incomplete recovery of blood counts to CR, was not different compared to patients who did not need the 14-day period for count recovery. These results were distinct from 138 IC patients. Although sample sizes for the comparison groups were small, and conclusions are exploratory and must be verified, these findings support consideration of new response criteria for venetoclax-based regimens.

Accuracy of third trimester ultrasound in predicting neonatal birthweight in patients with inflammatory bowel disease.

OBJECTIVE: To evaluate the accuracy of third trimester ultrasound in predicting birthweight in patients with inflammatory bowel disease (IBD) using the gestation-adjusted projection (GAP) method. STUDY DESIGN: Retrospective cohort study including pregnant patients with IBD who had third trimester ultrasounds and delivered at a single institution from 2012 to 2017. Controls included pregnant patients without IBD seen during the study period with third trimester ultrasounds. Correlation plots of GAP birthweight and actual birthweight (AB) were created for IBD-positive cases, IBD-negative controls, and IBD-positive cases with and without prior abdominal surgery. GAP predicted birthweight error was calculated for cases and controls. Univariable linear regression models estimated the association between predicted birthweight and AB. Multivariable linear regression models estimated the association between GAP birthweight and AB adjusting for age, BMI, race, and IBD status. RESULTS: 320 patients were included (172 cases and 148 controls). Cases were more likely to be older (p < 0.001), white (p < 0.001), and have a lower BMI (p = 0.001). Correlation plots of GAP birthweight and AB showed linear correlations in cases (Spearman ρ = 0.81), controls (ρ = 0.74), cases with (p = 0.78) and without prior surgery (ρ = 0.83). GAP birthweight was significantly associated with AB in controls and cases in univariable linear regression models (ß = 0.85, standard error = 0.04, p < 0.001; ß = 0.90, standard error = 0.06, p < 0.001, respectively). No significant difference was found between the parameter estimates of the two models (p = 0.47). GAP birthweight remained significantly associated with AB in a multivariable linear regression model (ß = 0.86, standard error = 0.03, p < 0.001). There were no significant differences between GAP predicted birthweight error between controls and cases (APE 11% vs 10% respectively, p = 0.56) and between cases without and with prior surgery (APE 10% vs 11%, p = 0.7). CONCLUSION: The accuracy of fetal biometry in the third trimester for predicting actual birthweight was equivalent between patients with and without IBD and those with prior abdominal surgery.

Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia.

Venetoclax (ven) plus azacitidine (aza) is the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (IC). Some patients who are IC candidates instead receive ven/aza. We retrospectively analyzed patients with newly diagnosed AML who received ven/aza (n = 143) or IC (n = 149) to compare outcomes, seek variables that could predict response to 1 therapy or the other, and ascertain whether treatment recommendations could be refined. The response rates were 76.9% for ven/aza and 70.5% for IC. The median overall survival (OS) was 884 days for IC compared with 483 days for ven/aza (P = .0020). A propensity-matched cohort was used to compare outcomes in the setting of equivalent baseline variables, and when matched for age, biological risk, and transplantation, the median OS was 705 days for IC compared with not reached for ven/aza (P = .0667). Variables that favored response to ven/aza over IC included older age, secondary AML, and RUNX1 mutations. AML M5 favored response to IC over ven/aza. In the propensity-matched cohort analyzing OS, older age, adverse risk, and RUNX1 mutations favored ven/aza over IC, whereas intermediate risk favored IC over ven/aza. In conclusion, patients receiving IC have improved OS compared with those receiving ven/aza. However, in a propensity-matched cohort of patients with equivalent baseline factors, there was a trend toward favorable OS for ven/aza. Specific variables, such as RUNX1 mutations, reported here for the first time, can be identified that favor ven/aza or IC, helping to guide treatment decisions for patients who may be eligible candidates for either therapy.

Histology-specific FGFR2 alterations and FGFR2-TACC2 fusion in mixed adenoid cystic and neuroendocrine small cell carcinoma of the uterine cervix.

Neuroendocrine small cell carcinoma of the uterine cervix portends a dismal prognosis with limited treatment options. Rarely, tumors of mixed-lineage appear in gynecologic malignancies. Here, we report a 77-year-old woman who presented with complete uterine prolapse and 4-month history of vaginal bleeding. Histopathologic evaluation revealed a mixed adenoid cystic carcinoma and neuroendocrine small cell carcinoma of the uterine cervix. The tumor was PD-L1 and HPV 35 positive. The patient was treated with up-front surgery and adjuvant radiation. Independent, histology-specific alterations in FGFR2 and a FGFR2-TACC2 fusion were identified. Progression of disease occurred within 6 months for which she received chemotherapy and immunotherapy. However, the patient expired within a year. We comprehensively review how screening for and targeting of FGFR alterations in recurrent and metastatic cervical cancer might serve as a touchstone for future treatment regimens.