bluuebunny/crossref_metadata_2025_split huggingface dataset:
Racial disparities in patients with TP53 mutated acute myeloid leukemia.
Authors: Badar Talha , Litzow Mark Robert , Shallis Rory , Stahl Maximilian , Bewersdorf Jan Philipp , Saliba Antoine N , Sacchi de Camargo Correia Guilherme , Patel Anand Ashwin , Abaza Yasmin , Guru Murthy Guru Subramanian , Duvall Adam , Burkart Madelyn , Al-Kali Aref , Palmisiano Neil , Dinner Shira , Goldberg Aaron David , Atallah Ehab L. 
Published: June 2022

e19007 Background: While clinical outcomes of patients (pts) with TP53 mutated (m) acute myeloid leukemia (AML) are dismal, subsets of pts with eligibility to curative intent therapies can do better. As racial disparities are known to impact outcome in hematological malignancies, we sought to explore disparities in TP53m AML. Methods: We conducted a multicenter study of 304 TP53m AML pts, divided into 2 groups, White (n= 240) and Black/Hispanic (n=64), to compare difference in disease characteristics and clinical outcome. We grouped Black and Hispanic together as the number of pts were small in each group and our aim was to evaluate outcome in under-represented races/ethnicities. Results: Baseline characteristics are summarized in Table. The median age of the pts was comparable between White and Black/Hispanic (p= 0.97). A significantly higher proportion of Black/Hispanic pts (23%) had diabetes mellitus when compared with White (14%) pts (p= 0.02). A higher proportion of Black/Hispanic pts had therapy-related AML (33% vs. 20%, p= 0.03), complex cytogenetics (98% vs. 87%, p= 0.003) and co-mutations (70% vs. 57%, p= 0.02). The proportion of pts who received hypomethylating agent + venetoclax (29% vs 20%, p= 0.20) or CPX-351 (22% vs 20%, p= 0.13) were comparable between White and Black/Hispanic, respectively. A higher proportion of Black/Hispanic pts received supportive care (17% vs. 4%, p= 0.002). White pts had higher rates of complete remission with or without count recovery (25% vs. 19%, p= 0.07). Only 6% of Black/Hispanic pts received allogeneic stem cell transplantation (alloHCT) compared to 16% for White pts (p= 0.01). The median event free survival was 2 months (mo) (95% CI;1.52-2.41) and 2.5 mo (95% CI:1.62-3.31) in White and Black/Hispanic pts, respectively (p= 0.71). The median overall OS was shorter for Black/Hispanic (6.37 mo [95% CI:2.88-9.85]) than for White (6.90 mo [95% CI:5.55-8.24] [p= 0.009]). Conclusions: Our study demonstrates poorer OS in Black/Hispanic pts with TP53m AML. Potential drivers of this disparity include lower alloHCT rates, higher rates of pts receiving supportive care, and higher-risk disease in Black/Hispanic pts.[Table: see text]
Tracking C-type lectin-like receptor positive leukemic stem cells to determine therapeutic efficacy in acute myeloid leukemia.
Authors: Liu Suhu , Lin Hong , Lan Fengshou 
Published: June 2022

e19011 Background: Although the importance of leukemia stem cells (LSC) in disease course of acute myeloid leukemia (AML) is well established in basic research, detecting and tracking LSC is seldom adopted in routine clinical practice. This is partly due to difficulty in tracking LSC in routine clinical practice and the paucity of evidence to support the benefit of detecting LSC in guiding clinical practice. Recently, a functional LSC population has been methodically characterized immunophenotypically, and the C-type lectin-like receptor (CLL1; aka CD371) has been shown to be widely expressed on LSC but not on normal hematopoietic stem cells (HSC). We postulate that CLL1 can be used to track LSC in a clinical setting and by analyzing changes in the LSC Compartment, we may be better able to assess response to therapy. Methods: Bone marrow samples from non-M3 CD34+ AML patients that were positive for CLL1 expression were included. Flow cytometry data were retrospectively analyzed for CLL1 percent positivity in the HSC compartment, which was defined as the CD34+CD38low/- fraction. A chart review was conducted to determine correlation between CLL1 positive LSC compartment change and clinical outcome. Statistical analysis was performed using GraphPad Prism version 9. Results: From 12/2018 to 12/2021, 49 AML cases with both pre- and post-treatment data from a single institution, were identified for the study. Among them, fourteen patients with CLL1 positivity higher than 50% were analyzed for CLL1+/HSC fractional change between pre- and post-treatment. We found that 6 of these 14 patients with significant reduction in CLL1+/HSC achieved longer remission, while the other 8 patients with no significant decrease in the CLL1+/HSC fraction demonstrated no or only a temporary remission. Importantly, several cases of patients with significant reduction in CLL1 positive cells will be presented to highlight the fact that LSC fractional change was more accurate in evaluating therapeutic effects and more predictive of clinical outcome than traditional morphology and flow cytometric analysis. This may even alter interpretation of specific treatment outcomes by predicting, for example, the brief nature that can be expected from certain remissions. Lastly, the CLL1+/HSC compartment in the peripheral blood is highly correlated with that of the bone marrow, indicating future feasibility of tracking LSC fractional change non-invasively to guide therapeutic decisions. Conclusions: CLL1 as a LSC marker is readily applicable to the clinical setting. Tracking LSC before and after AML treatment provides critical information regarding therapeutic effects that can sometimes be missed by traditional morphological and flow cytometric analysis. Thus, measuring changes in the LSC compartment using CLL1 analysis should be incorporated routinely in clinical practice to guide therapy decisions.
Predicting early mortality and overall survival (OS) in acute promyelocytic leukemia (APL) based on Charlson comorbidity index (CCI).
Authors: Dhakal Prajwal , Lyden Elizabeth , Pyakuryal Avantika , Bhatt Vijaya Raj 
Published: June 2022

e19017 Background: CCI is an established tool used to measure the comorbidity burden in patients, with higher CCI signifying a greater comorbidity burden. We performed a large database analysis to evaluate CCI as a predictor of one-month mortality and OS in patients < 60 years with APL. Methods: Using the National Cancer Database, we identified a total of 4969 patients < 60 years diagnosed with APL between 2004 and 2015. We divided patients into 3 groups with CCI of 0, 1, and ≥2. Multiple regression analysis was used to evaluate the effects of CCI on one-month mortality. Cox regression model determined the impact of CCI on OS. Results: Seventy-eight percent of patients had CCI of 0; 16% had CCI 1, and 6% had CCI ≥2. Median age was 42 years (range 0-59), and patients 41-59 years comprised 53% of the total cohort. Fifty-one percent were female, 32% were treated at academic centers, and 67% had private insurance. One-month mortality was 5%, 14%, and 25% for patients with CCI 0, 1 and ≥2, respectively. After adjusting for other co-variates, one-month mortality was worse for patients with CCI 1 (Odds ratio 2.6, 95% confidence interval [CI] 2.0-3.4, p < 0.001) and CCI ≥2 (Odds ratio 5.3, 95% CI 3.9-7.4, p < 0.001) compared to patients with CCI 0. Median 5-year OS was 85%, 71%, and 60% for patients with CCI 0, 1, and ≥2, respectively. After adjusting for other co-variates, OS was worse for patients with CCI 1 (Hazard ratio [HR] 1.8, 95% CI 1.5-2.1, p < 0.001), and CCI ≥2 (HR 2.7, 95% CI 2.2-3.3, p < 0.001) compared to patients with CCI 0. Patients 41-59 years had worse OS than 0-18 years (HR 2.4, 95% CI 1.3-4.5, p = 0.003). Private insurance was associated with better OS than Medicare (HR 2.1, 95% CI 1.7-2.6, p < 0.001) and Medicaid/other government insurance (HR 1.3, 95% CI 1.1-1.6, p < 0.001). Conclusions: This is one of the first and the largest database analyses examining the prognostic association of comorbidity burden in younger patients with APL. CCI independently predicted both one-month mortality and OS. Compared to CCI of 0, one-month mortality increased by 2.5-fold with CCI 1 and more than five-fold with CCI ≥2. The higher chances of one-month mortality in patients with greater comorbidity burden may reflect the risks associated with initial APL diagnosis and treatment such as coagulopathy, infection, and differentiation syndrome. One-month mortality was the key driver for OS. OS was also worse among patients with higher CCI. Our results indicate CCI as an important predictor of one-month mortality and OS in APL. CCI should be taken into consideration while interpreting clinical trial results.
Induction mortality (IM) of acute myeloid leukemia (AML) patients treated with purine analogues-cytarabine-anthracycline at a general hospital.
Authors: Rios Adan , Yohannan Binoy , Cervoni-Curet Frances Natalia 
Published: June 2022

e19019 Background: Cytarabine-anthracyclines (7+3) induction chemotherapy (IC)) has been the mainstay therapy for over four decades and it remains the standard AML IC regimen internationally. Triplet IC using purine analogues (fludarabine/cladribine) in combination with cytarabine and idarubicin (FIA/CLIA) is superior to the standard 7+3 regimen, but challenging to administer in general hospital settings due to myelosuppression. We reviewed AML IM rate in patients induced with (fludarabine/cladribine) combined with cytarabine and idarubicin (FIA/CLIA) at Memorial Hermann Hospital, Texas Medical Center (MHH at TMC). Patients and Methods: Of 44 AML reviewed records from January 2013 to January 2022, 40 received 5 days FIA/CLIA IC, and four 3-4 days due to age and comorbidities. For clinical characteristics see Table. Results: Median age was 51.5 years (range: 18-68). Three died before assessment. After 1 cycle the composite CR (CR+ CR i) was 82.9% (34/41) and 87.8% (36/41) after 2 cycles. MRD negative composite CR was 92%. Four patients had adverse risk cytogenetics and primary induction failure (modified FIA). 37% had febrile neutropenia. 25% had bacteremia with 15% requiring ICU admission and 4% mechanical ventilation. The 30-day induction mortality was 9%. Conclusions: FIA/CLIA has a higher CR rate than ‘3+7’ (which historically is 60%). The 30-day induction mortality in non-academic centers is about 30%. Given the fact that in AML achieving a CR is the most important factor to improve survival, with adequate treatment expertise, triplet IC regimen can be safely administered with a low induction mortality. [Table: see text]
Re-induction with venetoclax in combination with hypomethylating agents (HMAs) versus FLAG-IDA in relapsed or refractory AML.
Authors: Bouligny Ian Michael , Maher Keri Renee 
Published: June 2022

e19030 Background: The optimal selection and sequence of salvage regimens during treatment of acute myeloid leukemia (AML) remains unclear. While venetoclax augmentation of a hypomethylating agent backbone is now routinely used as salvage following impressive performance in the front-line setting, little is known about outcomes in relapsed or refractory AML, especially when compared to re-inductions with anthracycline-based regimens. Thus, the aim of this study was to compare outcomes of venetoclax-based regimens versus FLAG-IDA in patients under 70 years. Methods: We retrospectively analyzed 47 patients with AML that were younger than 70 years in the relapsed and refractory setting treated with either FLAG-IDA (fludarabine, cytarabine, G-CSF, and idarubicin) or venetoclax in combination with decitabine or azacitidine from July 2017 to December 2020. Two cohorts were created: a FLAG-IDA cohort and a matched venetoclax cohort for age, ECOG score, and comorbidities. Cytogenetic risk and molecular profiling (through next-generation sequencing [NGS]) at diagnosis and throughout treatment, dates and doses of induction, toxicity, responses, and measurable residual disease (MRD) analysis were recorded and analyzed. Results: In the venetoclax cohort of 32 patients, the median age was 60 years, the median ECOG score was 1, and the median Charlson Comorbidity Index (CCI) score was 4. Six out of 22 evaluable patients achieved either a CR or CRi for a composite response rate (CRR) of 27.3%. Out of three evaluable patients that responded, none were MRD-negative by NGS. The overall survival (OS) of the venetoclax cohort was 8.2 months. In the FLAG-IDA cohort of 15 patients, there were no statistical differences between age (p = .114), ECOG score (p = .249), or CCI score (p = .137) compared to the venetoclax cohort. The CRR of the FLAG-IDA cohort was 85.7%, a significant difference from the venetoclax cohort (p = .011), and 50% were negative for MRD by either NGS or PCR. The overall survival was not reached at a median follow-up time of 15.5 months, significantly different compared to the venetoclax cohort by the log-rank test (p = .001). A Cox proportional hazards model was used to investigate the effects of commonly mutated genes ( NPM1, ASXL1, FLT3, IDH1/2, RAS, TP53, TET2) on OS in venetoclax-based re-induction, and identified IDH1/2 mutations as having a favorable impact in the relapsed/refractory setting (HR 0.01, 95% CI 0.0001-0.7214). Conclusions: Our results highlight the efficacy of FLAG-IDA compared to venetoclax-based regimens with respect to CRR and survival, significantly favoring FLAG-IDA at the time of relapsed or refractory disease. Although limited by sample size, IDH1/2 mutations may convey a better prognosis in the relapsed/refractory setting when treated with venetoclax + HMAs. Larger studies are needed to confirm these findings.
Molecular stratification of response and survival of venetoclax in combination with hypomethylating agents in AML.
Authors: Maher Keri Renee , Bouligny Ian Michael 
Published: June 2022

e19033 Background: The use of venetoclax, a BCL-2 antagonist, in combination with decitabine or azacitidine has become routine for the upfront treatment of patients with acute myeloid leukemia (AML) not eligible for intensive induction. The impact of the addition of venetoclax to hypomethylating agents (HMAs) on outcomes with respect to various gene mutations is currently unclear. The aim of this study was to investigate response and survival of patients with AML receiving venetoclax-based induction with respect to specific molecular aberrations. Methods: We retrospectively analyzed 41 patients with AML treated with upfront venetoclax + HMAs from July 2017 to December 2020 at VCU Massey Cancer Center. Baseline patient demographics were obtained, including molecular profiling either through PCR or NGS at the time of induction, alongside cytogenetic risk, doses of induction regimens, response including MRD analysis, and survival. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. Results: Nine patients were identified with NPM1mut and 66.6% were ELN adverse risk. The composite response rate (CRR = CR + CRi) was 44.4% and the OS was 8.2 months. Seven patients had either DNMT3Amut or DNMT3Bmut and 57.1% were classified as adverse risk. The CRR was 28.6% and the mOS was not reached after a median follow-up time of 15.1 months. Eleven patients had FLT3-ITDmut or FLT3-TKDmut and 81.8% were classified as adverse risk. The CRR was 45.6% and the OS was 6.3 months. Six patients had either NRASmut or KRASmut. The CRR was 16.7% and the OS was 8.9 months. Seven patients had ASXL1mut, the CRR was 28.5% with the OS not reached at a median follow-up time of 8.9 months. Six patients with RUNX1mut demonstrated a CRR of 50.0% and the OS was not reached at a follow-up time of 12.8 months. Nine patients had TP53mut with a CRR of 33.3% and OS 12.6 months. Conclusions: Survival with venetoclax + HMA appears to numerically favor TP53mut AML when compared to more intensive strategies, consistent with prior literature reporting favorable responses to HMA monotherapy in this subset of disease. FLT3mut appeared to have a relatively lower OS, though not significantly different from either NPM1mut or TP53mut at the time of this analysis. DNMT3mut AML may preferentially respond to venetoclax + HMAs given the 15.1 month duration of follow-up, though longer follow-up with larger cohorts are needed to further identify subsets of molecularly stratified preferential responders to venetoclax-based strategies.[Table: see text]
Trends of leukemia mortality in the United States, 1999-2018.
Authors: Bakhati Bibek , Chamarti Karthik , Sibi Victoria , Dang Thao , Bajaj Kelash 
Published: June 2022

e19034 Background: Malignant neoplasms are the second leading cause of mortality in the United States. Among the cancer sites, leukemia is the seventh most common cause of deaths. It accounts for 3.2% of all new cases of cancer and 3.9% of all cancer deaths. The Mortality-to-Incidence Ratio (MIR) has previously been applied as a measure to examine health disparities and outcomes of cancer therapy. In this study, we aim to analyze leukemia incidence, mortality, and trends of MIR for gender and race over the previous two decades. Methods: We conducted a retrospective population-based study using Cancer Statistics from the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research system (CDC WONDER). Subjects with leukemia as the cancer site were selected. Age-adjusted mortality and age-adjusted incidence rates for race and gender were obtained and reported over 100,000 people. Negative binomial regression analysis using age-adjusted rates was subsequently used to analyze mortality, incidence, and trends of MIR. Results: 448,893 deaths were reported to be associated with leukemia between 1999 and 2018, of which males accounted for 56.85%. A total of 894,726 incident cases of leukemia were recorded during the same period. Males had a higher age-adjusted mortality rate than females (9.3 vs 5.2, OR: 1.70 [1.48-1.95]). Compared to Native Americans, African Americans and White cohorts had substantially higher age-adjusted mortality rates (3.5, 6.0, 7.2, OR: reference, 1.74, 2.05), whereas Asians had a non-significantly higher rate (3.8, OR: 1.09 [0.87-1.36]). In males, incidence rates were significantly higher (17.9, OR: 1.61 [1.58-1.64]). Against White population, Asian and African American race had a significantly lower age-adjusted incidence rate (14.4, 7.9, 10.6, OR: reference, 0.60, 0.79), while Native American race had a significantly higher rate (8.2, OR: 1.15 [1.06-1.24]. The mortality-to-incidence ratio has decreased significantly over time in both male and female populations (22.82% and 27.62%, respectively), as well as in African American and White cohorts (24.36% and 23.24%, respectively). Conclusions: Over the last 20 years, the mortality-to-incidence rate ratio significantly declined, possibly suggesting the effectiveness of cancer treatment outcomes in the United States. Yet, the reduction in mortality was not observed in all races. More efforts and further research are needed to guide the policy change.
Outcomes stratified by molecular aberration following induction with daunorubicin 60 mg/m2 versus daunorubicin 90 mg/m2 in AML.
Authors: Maher Keri Renee , Bouligny Ian Michael 
Published: June 2022

e19035 Background: Prior work investigating the optimal dose of daunorubicin in combination with cytarabine for upfront treatment of AML has resulted in several studies suggesting differential responses following daunorubicin dose optimization when analyzed by molecular cohort (such as NPM1, FLT3-ITD, or DNMT3A). While some studies advocated for a dose of 90 mg/m2 in younger patients with NPM1mut (following induction with either daunorubicin 45 mg/m2 versus 90 mg/m2), little is known regarding outcomes stratified by molecular lesion between daunorubicin 60 mg/m2 and daunorubicin 90 mg/m2. Methods: We retrospectively analyzed 92 patients with AML treated with upfront daunorubicin 60 mg/m2 or 90 mg/m2 from July 2017 to December 2020 at VCU Massey Cancer Center. Baseline patient demographics were obtained, including cytogenetic risk, molecular profiling either through PCR or NGS at the time of induction, doses of induction regimens, response including MRD analysis (when available), and survival. Results: In the 60 mg/m2 cohort, 10 patients had NPM1mut, the CRR (CR+CRi) was 60.0% and the OS was 1.7 y. Four patients with DNMT3mut had a CRR of 25.0% and a 4.1 m. OS. Nine patients with FLT3-ITD or FLT3-TKD all treated with FLT3 inhibitors achieved a CRR of 22.2% with a 4.9 m. OS. Ten patients with NRASmut or KRASmut had a CRR of 50.0% and a 20.7 m. OS. In the adverse category, five with ASXL1mut had a 20.0% CRR and a 6.4 m. OS; 7 with RUNX1mut had a CRR of 42.9% and a 14.5 m. OS; and 6 with TP53mut demonstrated a CRR of 0% and an 13.1 m. OS. In the 90 mg/m2 cohort, 8 patients had NPM1mut with a CRR of 75.0% and an 18.8 m. OS. Two patients with DNMT3mut both achieved CR and the OS was not reached. Three of 5 patients with FLT3mut treated with midostaurin achieved CR or CRi and a 16.2 m. OS. Four of 5 patients with RASmut achieved CR and the OS was not reached at a 15.8 m. follow-up time. In the adverse category, there were no patients treated with a dose of 90 mg/m2 with ASXL1mut and one with RUNX1mut with non-evaluable response. Two out of 4 patients achieved CR or CRi with TP53mut and the OS was not reached. Conclusions: Response rates appear numerically higher across molecular subtypes favoring daunorubicin 90 mg/m2, although no significant differences in survival were appreciated, likely due to limited sample size. This may argue for intensification of anthracycline doses in carefully selected patients regardless of molecular profiling. Toxicity with high-dose daunorubicin must be weighed against any potential response or survival benefit, particularly for TP53mut and ASXL1mut – especially in the setting of alternative induction strategies such as CPX-351 and venetoclax with a hypomethylating agent. Larger prospective studies analyzing outcomes with regards to molecular profiling and treatment strategies are warranted.