Prognostic impact of 'multi-hit' versus 'single hit' TP53 alteration in patients with acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases.

While there is clear evidence to suggest poorer outcome associated with multi-hit (MH) TP53 mutation compared to single-hit (SH) in lower-risk myelodysplastic syndrome (MDS), data are conflicting in both higher-risk MDS and acute myeloid leukemia (AML). We conducted an indepth analysis utilizing data from 10 US academic institutions to study differences in molecular characteristics and outcomes of SH (n= 139) versus MH (n= 243) TP53MTAML. Complex cytogenetics (CG) were more common in MH compared to SH TP53MT AML (p <0.001); whereas ASXL1 (p= <0.001), RAS (p<0.001), splicing factor (p= 0.003), IDH1/2 (p= 0.001), FLT3 ITD (p= <0.001) and NPM1 (p= 0.005) mutations significantly clustered with SH TP53MT AML. Survival after excluding patients who received best supportive care alone was dismal but not significantly different between SH and MH (event free survival [EFS]: 3.0 vs 2.20 months, p= 0.22/ overall survival [OS]: 8.50 vs 7.53 months, respectively, p= 0.13). In multivariable analysis, IDH1 mutation and allogeneic hematopoietic stem cell transplantation (allo-HCT) as a time-dependent covariate were associated with superior EFS (HR; 0.44, 95% CI: 0.19-1.01, p= 0.05/ HR; 0.34, 95% CI: 0.18-0.62, p<0.001) and OS (HR; 0.24, 95% CI: 0.08-0.71, p= 0.01/ HR; 0.28, 95% CI: 0.16-0.47, p<0.001). While complex CG (HR; 1.56, 95% CI: 1.01-2.40, p= 0.04) retained unfavorable significance for OS. Our analysis suggests that unlike in MDS, multihit TP53MT is less relevant in independently predicting outcomes in patients with AML.

Clinical outcomes of hypomethylating agents plus Venetoclax as frontline treatment in patients 75 years and older with acute myeloid leukemia: Real-world data from eight US academic centers.

Venetoclax (VEN) combined with hypomethylating agents (HMAs) is the standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, real-world data published on HMAs plus VEN have been either single-center studies or using community-based electronic databases with limited details on mutational landscape, tolerability, and treatment patterns in elderly patients. Therefore, we conducted a multicenter retrospective study to assess the real-world experience of 204 elderly patients (≥75 years) with newly diagnosed AML treated with HMAs plus VEN from eight academic centers in the United States. Overall, 64 patients achieved complete remission (CR; 38%) and 43 CR with incomplete count recovery (CRi; 26%) for a CR/CRi rate of 64%, with a median duration of response of 14.2 months (95% CI: 9.43, 22.1). Among responders, 63 patients relapsed (59%) with median overall survival (OS) after relapse of 3.4 months (95% CI, 2.4, 6.7). Median OS for the entire population was 9.5 months (95% CI, 7.85-13.5), with OS significantly worse among patients with TP53-mutated AML (2.5 months) and improved in patients harboring NPM1, IDH1, and IDH2 mutations (13.5, 18.3, and 21.1 months, respectively). The 30-day and 60-day mortality rates were 9% and 19%, respectively. In conclusion, HMAs plus VEN yielded high response rates in elderly patients with newly diagnosed AML. The median OS was inferior to that reported in the VIALE-A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.

Disparities in receiving disease-directed therapy, allogeneic stem cell transplantation in non-Hispanic Black patients with TP53-mutated acute myeloid leukemia.

BACKGROUND: Although the clinical outcomes of patients with TP53-mutated acute myeloid leukemia (AML) are dismal, subsets of patients eligible for curative-intent therapies may fare better. Because racial disparities are known to affect outcome in hematologic malignancies, the authors sought to explore disparities among patients with TP53-mutated AML. METHODS: A multicenter, retrospective study was conducted in a cohort of 340 patients who had TP53-mutated AML (275 non-Hispanic White [NHW] and 65 non-Hispanic Black [NHB]) to analyze differences in treatment and outcome among NHW and NHB patients. RESULTS: The median patient age was comparable between NHW and NHB patients (p = .76). A higher proportion of NHB patients had therapy-related AML (31% vs. 20%; p = .08) and had co-mutations (74% vs. 61%; p = .06). A higher proportion of NHW patients received intensive chemotherapy compared with NHB patients (47% vs. 31%; p = .02). Conversely, a higher proportion of NHB patients received low-intensity chemotherapy (9% vs. 5.5%; p = .02) or best supportive care (22% vs. 7%; p < .001). The complete response rate (including complete responses with or without complete count recovery) was 31% versus 24.5% (p = .39) in NHW and NHB patients, respectively. Only 5% of NHB patients received allogeneic stem cell transplantation compared with 15.5% of NHW patients (p = .02). The proportion of patients who were event-free (18.5% vs. 8.5%; p = .49) or who remained alive (24.9% vs. 8.3%; p = .13) at 18 months was numerically higher in NHW versus NHB patients, respectively, but was not statistically significant. CONCLUSIONS: The current study highlights disparities between NHW and NHB patients with TP53-mutated AML. Efforts are warranted to eliminate treatment disparities in minority populations.

Ethno-demographic disparities in humoral responses to the COVID-19 vaccine among healthcare workers.

The COVID-19 pandemic had a profound impact on global health, but rapid vaccine administration resulted in a significant decline in morbidity and mortality rates worldwide. In this study, we sought to explore the temporal changes in the humoral immune response against SARS-CoV-2 healthcare workers (HCWs) in Augusta, GA, USA, and investigate any potential associations with ethno-demographic features. Specifically, we aimed to compare the naturally infected individuals with naïve individuals to understand the immune response dynamics after SARS-CoV-2 vaccination. A total of 290 HCWs were included and assessed prospectively in this study. COVID status was determined using a saliva-based COVID assay. Neutralizing antibody (NAb) levels were quantified using a chemiluminescent immunoassay system, and IgG levels were measured using an enzyme-linked immunosorbent assay method. We examined the changes in antibody levels among participants using different statistical tests including logistic regression and multiple correspondence analysis. Our findings revealed a significant decline in NAb and IgG levels at 8-12 months postvaccination. Furthermore, a multivariable analysis indicated that this decline was more pronounced in White HCWs (odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.07-4.08, p = 0.02) and IgG (OR = 2.07, 95% CI = 1.04-4.11, p = 0.03) among the whole cohort. Booster doses significantly increased IgG and NAb levels, while a decline in antibody levels was observed in participants without booster doses at 12 months postvaccination. Our results highlight the importance of understanding the dynamics of immune response and the potential influence of demographic factors on waning immunity to SARS-CoV-2. In addition, our findings emphasize the value of booster doses to ensure durable immunity.

Survival of TP53-mutated acute myeloid leukemia patients receiving allogeneic stem cell transplantation after first induction or salvage therapy: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND).

We conducted a multi-center study to analyze factors predicting survival among patients with TP53-mutated (m) AML receiving allogeneic hematopoietic stem cell transplant (allo-HSCT) in the recent era. Out of 370 TP53m AML patients, 68 (18%) patients were bridged to allo-HSCT. The median age of the patients was 63 years (range, 33-75), 82% of patients had complex cytogenetics and 66% of patients had multi-hit TP53m. Forty three percent received myeloablative conditioning and 57% received reduced intensity conditioning. The incidence of acute graft versus host disease (GVHD) was 37% and chronic GVHD was 44%. The median event-free survival (EFS) from the time of allo-HSCT was 12.4 months (95% CI: 6.24-18.55) and median overall survival (OS) was 24.5 months (95% CI: 21.80-27.25). In multivariate analysis utilizing variables that showed significance in univariate analysis, complete remission at day 100 post allo-HSCT retained significance for EFS (HR: 0.24, 95% CI: 0.10-0.57, p = 0.001) and OS (HR: 0.22, 95% CI: 0.10-0.50, p ≤ 0.001). Similarly, occurrence of chronic GVHD retained significance for EFS (HR: 0.21, 95% CI: 0.09-0.46, p ≤ 0.001) and OS (HR: 0.34, 95% CI: 0.15-0.75, p = 0.007). Our report suggests that allo-HSCT offers the best opportunity to improve long-term outcome among patients with TP53m AML.

Maternal Knowledge, Attitudes, and Practices Concerning Interpregnancy Interval.

INTRODUCTION: Few studies have examined maternal intentions and practices related to interpregnancy interval (IPI). IPI less than 18 months has been linked to increased preterm birth and infant mortality. This manuscript reports on a cross-sectional survey of mothers conducted to understand maternal knowledge, attitudes, and practice of IPI in Sedgwick County, Kansas. METHODS: New and expectant mothers and mothers of neonatal infant care unit (NICU) graduates (n = 125) were surveyed regarding the issues surrounding IPI. Front desk staff handed out self-administered surveys, which were returned to a nurse upon completion. NICU participants were emailed a link to the survey hosted on SurveyMonkey®. RESULTS: Fewer than 30% of mothers reported previously receiving information about IPI from any source. When asked about risks associated with IPI, women frequently (n = 58, 45%) identified increased risk for birth outcomes with no known association with short IPI. Findings regarding maternal attitudes surrounding optimal IPI were mixed with many mothers defining ideal IPI as less than 18 months (n = 52, 42%), while broadly reporting they believed that a woman's body needs time to heal between pregnancies. Respondents from the NICU sample generally reported shorter optimal IPI values than the other participants. When IPI was estimated from participants' past pregnancies, half of IPIs were less than 18 months. Mothers reported they favored healthcare providers as a source for IPI education. Face-to-face discussions or printed materials were the preferred modes of education. CONCLUSIONS: Women were aware of the need for spacing between pregnancies, however, that knowledge was unassociated with past behavior. These findings should be taken into consideration when formulating future interventions.

Intraobserver reliability of cranial strain patterns as evaluated by osteopathic physicians: a pilot study.

CONTEXT: Few studies of inter- or intraobserver reliability have focused on evaluations of cranial strain patterns. OBJECTIVE: To determine whether substantial intraobserver reliability can be achieved by osteopathic physicians (DOs) using common palpatory tests to diagnose cranial dysfunction. METHODS: Forty-eight subjects were divided into three diagnostic groups, categorized as those with asthma, headaches, or neither asthma nor headaches (ie, healthy control group). Two blinded DO examiners separately evaluated approximately 8 subjects from each group (4 subjects per session), conducting diagnostic tests for cranial rhythmic impulse (CRI) rate, cranial strain patterns, and quadrants of restriction. RESULTS: Overall, among the three diagnostic procedures, cranial strain patterns showed the highest intraobserver reliability (kappa=0.67). The highest intraobserver reliability was achieved in cranial strain patterns for the control group (kappa=0.82), followed by the headache (kappa=0.67) and asthma (kappa=0.52) groups. Diagnoses of the left anterior quadrant of restriction also showed substantial intraobserver reliability for the headache and control groups (kappa=0.60 and 0.61, respectively). Diagnoses of three quadrants of restriction showed moderate overall intraobserver reliability (kappa=0.44-0.52), while the left posterior quadrant had only fair overall intraobserver reliability (kappa=0.33). CONCLUSION: Osteopathic physicians can obtain substantial intraobserver reliability when diagnosing cranial strain patterns in healthy subjects as well as those with asthma or headache. However, results are less promising for diagnoses of CRI and quadrants of restriction.

An accurate VO2max nonexercise regression model for 18-65-year-old adults.

The purpose of this study was to develop a regression equation to predict maximal oxygen uptake (VO2max) based on nonexercise (N-EX) data. All participants (N = 100), ages 18-65 years, successfully completed a maximal graded exercise test (GXT) to assess VO2max (M = 39.96 mL x kg(-1) x min(-1), SD = 9.54). The N-EX data collected just before the maximal GXT included the participant's age; gender; body mass index (BMI); perceived functional ability (PFA) to walk, jog, or run given distances; and current physical activity (PA-R) level. Multiple linear regression generated the following N-EX prediction equation (R = .93, SEE = 3.45 mL x kg(-1) x min(-1), % SEE = 8.62): VO2max (mL x kg(-1) x min(-1)) = 48.0730 + (6.1779 x gender; women = 0, men = 1) - (0. 2463 x age) - (0.6186 x BMI) + (0.7115 x PFA) + (0.6709 x PA-R). Cross validation using PRESS (predicted residual sum of squares) statistics revealed minimal shrinkage (R(p) = .91 and SEE(p) = 3.63 mL x kg(-1) x min(-1)); thus, this model should yield acceptable accuracy when applied to an independent sample of adults (ages 18-65 years) with a similar cardiorespiratory fitness level. Based on standardized beta-weights, the PFA variable (0.41) was the most effective at predicting VO2max followed by age (-0.34), gender (0.33), BMI (-0.27), and PA-R (0.16). This study provides a N-EX regression model that yields relatively accurate results and is a convenient way to predict VO2max in adult men and women.