Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101).

PURPOSE: Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, showed promising efficacy and safety in a phase I study of heavily pretreated patients with KMT2A-rearranged (KMT2Ar) acute leukemia. Here, we evaluated the activity of revumenib in individuals with relapsed/refractory (R/R) KMT2Ar acute leukemia. METHODS: AUGMENT-101 is a phase I/II, open-label, dose-escalation and expansion study of revumenib conducted across 22 clinical sites in five countries (ClinicalTrials.gov identifier: NCT04065399). We report results from the phase II, registration-enabling portion. Individuals age ≥30 days with R/R KMT2Ar acute leukemia or with AML and nucleophosmin 1 (NPM1) mutation were enrolled. Revumenib was administered once every 12 hours, at 163 mg (95 mg/m2 if weight <40 kg) with a strong cytochrome P450 inhibitor, in 28-day cycles. The primary end points were the rate of complete remission (CR) or CR with partial hematologic recovery (CR + CRh) and safety. At a prespecified interim analysis, safety was assessed in all KMT2Ar treated patients; efficacy was assessed in those with centrally confirmed KMT2Ar. The separate NPM1 cohort of the trial is ongoing. RESULTS: From October 1, 2021, to July 24, 2023, N = 94 patients (median [range] age, 37 [1.3-75] years) were treated. Grade ≥3 adverse events included febrile neutropenia (37.2%), differentiation syndrome (16.0%), and QTc prolongation (13.8%). In the efficacy-evaluable patients (n = 57), the CR + CRh rate was 22.8% (95% CI, 12.7 to 35.8), exceeding the null hypothesis of 10% (P = .0036). Overall response rate was 63.2% (95% CI, 49.3 to 75.6), with 15 of 22 patients (68.2%) having no detectable residual disease. CONCLUSION: Revumenib led to high remission rates with a predictable safety profile in R/R KMT2Ar acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.

Outcomes of Haplo-Cord Versus Dual Cord Transplants: A Single-Center Retrospective Analysis.

Despite the concurrent use of haploidentical cord (HCT) and dual cord (DCT) stem cell transplant approaches for over a decade, there have been few comparisons of their outcomes. Our objective in this study is to assess for differences in the outcomes and adverse effects associated with HCTs versus DCTs. Here we report a retrospective analysis of HCTs and DCTs at our institution. From October 2012 to October 2022, 70 HCT and 133 DCT transplants were performed following 50 mg/kg of IV cyclophosphamide, 150 mg/m2 of IV fludarabine, 10 mg/kg of IV thiotepa, and 4 Gy total body irradiation conditioning. With a median follow-up of 3.6 years among survivors, there was no difference in overall survival (OS) (3 years OS 65% DCT versus 63% HCT, P = 1) or relapse-free survival (3 years RFS 62% DCT versus 64% HCT, P = .97) for all patients. Time to neutrophil recovery was faster in HCT recipients (median 17 versus 22 days, P = .021), with no difference in platelet recovery to 20,000/µL (P = .12). Median hospitalization for HCT recipients was 20 days versus 24 days for DCT recipients (P < .0001). Engraftment syndrome treated with steroids occurred in 47/133 (35%) DCT recipients versus 42/70 (60%) HCT recipients (odds ratios 0.37, P value=.001). There was a significant increase in grade 3 to 4 acute graft-versus-host disease (aGVHD) in haplo-cord recipients (P = .007), but no difference in grade 2 to 4 aGVHD (P = .11), all chronic GVHD (cGVHD) (P = .9), or moderate-severe cGVHD (P = .3). Our outcomes demonstrate faster engraftment and shorter hospitalization in HCTs relative to DCTs, but more engraftment syndrome and higher grade 3 to 4 aGVHD. When both are options, these factors should guide the choice between HCTs and DCTs.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Management of hyperleukocytosis and impact of leukapheresis among patients with acute myeloid leukemia (AML) on short- and long-term clinical outcomes: a large, retrospective, multicenter, international study.

Hyperleukocytosis in acute myeloid leukemia (AML) is associated with inferior outcomes. There is limited high quality evidence to support the benefits of leukapheresis. We retrospectively collected data from patients with newly-diagnosed AML who presented with a white cell count (WBC) >50 × 109/L to 12 centers in the United States and Europe from 2006 to 2017 and received intensive chemotherapy. Logistic regression models estimated odds ratios for 30-day mortality and achievement of composite complete remission (CRc). Cox proportional hazard models estimated hazard ratios for overall survival (OS). Among 779 patients, clinical leukostasis was reported in 27%, and leukapheresis was used in 113 patients (15%). Thirty-day mortality was 16.7% (95% CI: 13.9-19.3%). Median OS was 12.6 months (95% CI: 11.5-14.9) among all patients, and 4.5 months (95% CI: 2.7-7.1) among those ≥65 years. Use of leukapheresis did not significantly impact 30-day mortality, achievement of CRc, or OS in multivariate analysis based on available data or in analysis based on multiple imputation. Among patients with investigator-adjudicated clinical leukostasis, there were statistically significant improvements in 30-day mortality and OS with leukapheresis in unadjusted analysis, but not in multivariate analysis. Given the significant resource use, cost, and potential complications of leukapheresis, randomized studies are needed to evaluate its value.