Risk Acute Myeloid Leukemia Research Articles

Measurable residual disease as predictor of post–day +100 relapses after allografting in adult AML

AbstractMeasurable residual disease (MRD) by multiparametric flow cytometry (MFC) before allogeneic hematopoietic cell transplantation (HCT) identifies patients at high risk of acute myeloid leukemia (AML) relapse, often occurring early after allografting. To examine the role of MFC MRD testing to predict later relapses, we examined 935 adults with AML or myelodysplastic neoplasm/AML transplanted in first or second morphologic remission who underwent bone marrow restaging studies between day 70 and 100 after HCT and were alive and without relapse by day +100. Of 935 adults, 136 (15%) had MRD before HCT, whereas only 11 (1%) had MRD at day +70 to +100. In day +100 landmark analyses, pre-HCT and day +70 to +100 MFC MRD were both associated with relapse (both P < .001), relapse-free survival (RFS; both P < .001) overall survival (OS; both P < .001), and, for post-HCT MRD, nonrelapse mortality (P = .001) after multivariable adjustment. Importantly, although 126/136 patients (92%) with MRD before HCT tested negative for MRD at day +70 to +100, their outcomes were inferior to those without MRD before HCT and at day +70 to +100, with 3-year relapse risk of 40% vs 15% (P < .001), 3-year RFS of 50% vs 72% (P < .001), and 3-year OS of 56% vs 76% (P < .001), whereas 3-year nonrelapse mortality estimates were similar (P = .53). Thus, despite high MRD conversion rates, outcomes MRD positive/MRD negative (MRDneg) patients are inferior to those of MRDneg/MRDneg patients, suggesting all patients with pre-HCT MRD should be considered for preemptive therapies after allografting.

Midostaurin added to 10-day decitabine, for patients unfit for intensive chemotherapy with AML and higher risk MDS, irrespective of FLT3 mutational status, does not improve outcome.

The treatment of older patients with acute myeloid leukemia (AML) considered unfit for receiving intensive chemotherapy is challenging. Based on the hypothesis that addition of the broad tyrosine kinase inhibitor (TKI) midostaurin could improve the response to hypomethylating agents, irrespective of FLT3 gene mutational status, we conducted a randomized phase II multicenter study to assess the tolerability and efficacy of the addition of midostaurin to a 10-day schedule of decitabine in unfit (i.e. Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) ≥ 3) AML and higher risk myelodysplasia (MDS) patients (HOVON155 trial). In total, 140 eligible patients were randomly (1:1) assigned to treatment with 10-days of decitabine alone (N = 70) or combined with midostaurin (50mg bid;starting the day following the last dose of decitabine), (N = 70). Addition of midostaurin was well tolerated and the number of AEs was comparable for both treatment arms. Early death rates (< 30 days) were similar as well (10%). In the decitabine plus midostaurin arm 24% reached CR/CRi, the median OS was 4.8 months and 1-yrs OS was 31% which compared with 34% CR/CRi, median OS of 7.4 months and 1-yrs OS of 37% for the decitabine alone group (NS). Thus, while the addition of midostaurin appears safe, it does not enhance therapeutic efficacy of decitabine in unfit AML patients.

Glutamine metabolism-related genes predict the prognostic risk of acute myeloid leukemia and stratify patients by subtype analysis

BackgroundAcute myeloid leukemia (AML) is a genetically heterogeneous disease in which glutamine (Gln) contributes to AML progression. Therefore, this study aimed to identify potential prognostic biomarkers for AML based on Gln metabolism-related genes.MethodsGln-related genes that were differentially expressed between Cancer Genome Atlas-based AML and normal samples were analyzed using the limma package. Univariate, least absolute shrinkage, selection operators, and stepwise Cox regression analyses were used to identify prognostic signatures. Risk score-based prognostic and nomogram models were constructed to predict the prognostic risk of AML. Subsequently, consistent cluster analysis was performed to stratify patients into different subtypes, and subtype-related module genes were screened using weighted gene co-expression network analysis.ResultsThrough a series of regression analyses, HGF, ANGPTL3, MB, F2, CALR, EIF4EBP1, EPHX1, and PDHA1 were identified as potential prognostic biomarkers of AML. Prognostic and nomogram models constructed based on these genes could significantly differentiate between high- and low-risk AML with high predictive accuracy. The eight-signature also stratified patients with AML into two subtypes, among which Cluster 2 was prone to a high risk of AML prognosis. These two clusters exhibited different immune profiles. Of the subtype-related module genes, the HOXA and HOXB family genes may be genetic features of AML subtypes.ConclusionEight Gln metabolism-related genes were identified as potential biomarkers of AML to predict prognostic risk. The molecular subtypes clustered by these genes enabled prognostic risk stratification.

Myelodysplastic syndrome/ Myeloproliferative disorder, Nos.

Background: Population-based research is limited for myelodysplastic syndrome/ myeloproliferative neoplasm, not otherwise specified (MDS/MPN-NOS) which comprises a heterogenous group of patients that do not fit into the other established MDS/MPN subgroups. Methods: We identified patients from the Surveillance, Epidemiology, and End Results (SEER) database with a diagnosis of MDS/MPN-U logged from 2010-2020. Age-standardized incidence rates (ASIR) and incidence rate ratios (IRR) were calculated using eight age subgroups. Subgroup analyses were performed for race and gender. Join point regression analyses were performed to model trends in ASIRs, and annual percent change (APC) was calculated. Results: A total of 2447 patients over age 50 were included in analysis. Incidence of MDS/MPN-U increased gradually between 2010-2016 (APC 12.90) then decreased between 2016-2020 (APC -19.56). ASIR was significantly higher in males compared to females in several age groups (age 65-69, 80-84, 85+). Conclusion: The underlying molecular complexity of these diseases remains a significant challenge. It is critical to identify MDS/MPN- specific therapeutic response criteria and suitable end points correlated with survival and AML risk for transformation to acute myeloid leukemia (AML) uniform assessment of treatment benefit.

Current Insights into CAR T-Cell-Based Therapies for Myelodysplastic Syndrome.

Myelodysplastic syndromes (MDS) are due to defective hematopoiesis in bone marrow characterized by cytopenia and dysplasia of blood cells, with a varying degree of risk of acute myeloid leukemia (AML). Currently, the only potentially curative strategy is hematopoietic stem cell transplantation (HSCT). Many patients are ineligible for HSCT, due to late diagnosis, presence of co-morbidities, old age and complications likely due to graft-versus-host disease (GvHD). As a consequence, patients with MDS are often treated conservatively with blood transfusions, chemotherapy, immunotherapy etc. based on the grade and manifestations of MDS. The development of chimeric antigen receptor (CAR)-T cell therapy has revolutionized immunotherapy for hematological malignancies, as evidenced by a large body of literature. However, resistance and toxicity associated with it are also a challenge. Hence, there is an urgent need to develop new strategies for immunological and hematopoetic management of MDS. Herein, we discuss current limitations of CAR T-cell therapy and summarize novel approaches to mitigate this. Further, we discuss the in vivo activation of tumor-specific T cells, immune check inhibitors (ICI) and other approaches to normalize the bone marrow milieu for the management of MDS.

Trends in allogeneic transplantation for favorable risk acute myeloid leukemia in first remission: a longitudinal study of >15 years from the ALWP of the EBMT.

We assessed outcomes of allogeneic transplantation (HSCT) in favorable risk AML in CR1 over 3 time periods. 1850 patients were included, 2005 to 2009- 222, 2010 to 2014 -392, and 2015 to 2021-1236; 526 with t (8:21), 625 with inv (16), and 699 with NPM1mutFLT3WT. Patients transplanted in 2015-2021 were older (p < 0.0001) with more patients ≥60 years of age (p < 0.0001). The most frequent diagnosis in 2015-2021 was NPM1mutFLT3WT vs. t (8:21) in the 2 earlier periods, (p < 0001). Haploidentical transplants (Haplo) increased from 5.9% to 14.5% (p < 0.0001). Graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) was more frequent in 2015-2021 vs. the other 2 periods (p < 0.0001). On multivariate analysis, incidence of total chronic GVHD was reduced in HSCTs performed ≥2015 vs. those performed in 2005-2009, hazard ratio (HR) = 0.74 (95% CI 0.56-0.99, p = 0.046) and GVHD-free, relapse-free survival (GRFS) improved for patients transplanted from 2010-2014 vs. those transplanted in 2005-2009, HR = 0.74 (95% CI 0.56-0.98, p = 0.037). Other HSCT outcomes did not differ with no improvement ≥2015. LFS, OS, and GRFS were inferior in patients with t (8:21) with HR = 1.32 (95% CI 1.03-1.68, p = 0.026), HR = 1.38 (95% CI 1.04-1.83, p = 0.027) and HR = 01.25 (95% CI 1.02-1.53, p = 0.035), respectively. In conclusion, this retrospective analysis of HSCT in patients with favorable risk AML, transplanted over 16 years showed an increased number of transplants in patients ≥60 years, from Haplo donors with PTCy. Most importantly, 3-year GRFS improved ≥2010 and total chronic GVHD reduced ≥2015, with no significant change in other HSCT outcomes.

Revealing of TLR-9 gene polymorphisms by qPCR HRM technique and their influence on TLR-9 serum level in acute myeloid leukemia patients: Case-control study

Acute myeloid leukemia (AML) is one of the most common and fatal malignancies that affect adults, which can quickly become aggressive if left untreated, and leukemia cells invade the bone marrow. TLR-9 is an innate immune cell receptor sensitive to various PAMPs and encoded by the TLR-9 gene. As is often known, genetic polymorphisms in any gene can help the development of the disease, and these three polymorphisms, rs187084, rs5743836, and rs352140 of TLR-9, have been studied in many different cancer disorders. Therefore, this study aimed to discover the multiple forms of a TLR-9 gene in a sample of Iraqi AML patients. A total of 120 participants in a case-control study were enrolled in the current study. Using CBC, some hematological parameters were evaluated, and the serum level of TLR-9 was assessed using the ELISA technique. DNA was extracted directly from blood, and a high-resolution melting (HRM) analysis was then carried out. The results revealed a significant difference in some blood parameters among patients and healthy control, while WBC and lymphocytes were without an evident difference between the two groups of the current investigation. The serum concentration of TLR-9 showed an elevated level in patients (P value < 0.01). Nonetheless, this increase was not affected by the genotype patterns of polymorphisms. According to the P-value, there was a significant difference in wild genotypes of the three polymorphisms (rs187084, rs5743836, and rs352140). At the same time, the odds ratio revealed the association with the disease as a protective factor. In contrast, there was a significant difference in the heterozygous and mutant genotypes of TLR-9 polymorphisms, though the odds ratio confirmed the association with the AML as a risk factor. The results of rs352140 were compatible with H.W.E since there were no significant differences between the observed and expected values for either patients or healthy controls. In contrast, the result of rs5743836 was not consistent with the HWE. Furthermore, although it corresponds with the healthy one, the finding of rs187084 conflicted with H.W.E. in the patient group. In conclusion, High serum levels of TLR-9 in patients could act as biomarkers for AML. The TLR-9 gene polymorphisms (rs187084, rs5743836, and rs352140) have been linked to an increased risk of AML and may impact the disease progression in the Iraqi population.

Beat-AML 2024 ELN–refined risk stratification for older adults with newly diagnosed AML given lower-intensity therapy

AbstractAlthough the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-, 11% intermediate-, and 78% had adverse-risk AML. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable- from intermediate-risk (P = .71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A “mutation score” was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: −1 to 0 points (“Beat-AML intermediate”) vs 1+ points (“Beat-AML adverse”). In the final refined risk classification, ELN favorable- and intermediate-risk were combined into a newly defined “Beat-AML favorable-risk” group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML risk groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001), providing patients and providers additional information for treatment decision-making.

WT1 gene mutations impact post-transplant relapse in myelodysplastic syndrome with excess blasts 2 patients.

Wilms tumor 1 (WT1) gene mutations are infrequent in myelodysplastic syndrome (MDS), but MDS with WT1 mutations (WT1mut) is considered high risk for acute myeloid leukemia (AML) transformation. The influence of WT1 mutations in patients with MDS after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear. We performed a retrospective analysis of 136 MDS with excess blasts 2 (MDS-EB2) patients with available WT1 status who underwent their first allo-HSCT between 2017 and 2022 in our center. There were 20 (20/136, 15%) cases in the WT1mut group and 116 (116/136, 85%) cases in the WT1 wild-type (WT1wt) group. WT1mut patients had a higher 2-year cumulative incidence of relapse (CIR) than WT1wt cases (26.2% vs. 9.4%, p = 0.037) after allo-HSCT. Multivariate analysis of relapse showed that WT1 mutations (HR, 6.0; p = 0.002), TP53 mutations (HR, 4.2; p = 0.021), and ≥ 5% blasts in bone marrow (BM) at transplantation (HR, 6.6; p = 0.004) were independent risk factors for relapse. Patients were stratified into three groups according to the risk factors. Two-year CIR differed significantly in high-, intermediate-, and low-risk groups (31.8%, 11.6%, and 0%, respectively). Hence, WT1 mutations may be related to post-transplant relapse in patients with MDS-EB2, which warrants further study.

Gemtuzumab Ozogamicin and Stem Cell Mobilization for Autologous Stem Cell Transplantation in Favorable Risk Acute Myeloid Leukemia.

Gemtuzumab ozogamicin (GO), a CD33-targeting antibody drug conjugate, previously showed longer relapse-free survival when combined with induction chemotherapy in patients with favorable-risk acute myeloid leukemia (AML). In this patient population, characterized by lower relapse risk as compared to other ELN risk groups, autologous stem cell transplantation (ASCT) can be used as consolidation strategy. However, there are limited data on the impact of GO on the peripheral blood stem cell (PBSC) mobilization potential. We therefore retrospectively analyzed data from 54 AML patients with favorable-risk AML treated with (n = 17) or without (n = 37) GO during induction treatment. We observed no significant differences in the PBSC mobilization rate between patients treated with vs. without GO. The mobilization success in a first attempt directly following cycle 2 was 65% vs. 70% (p = 0.92); and the mobilization success in a subsequent second attempt after hematologic recovery and repeated stimulation procedure was 24% vs. 19% (p = 0.56). No significant impact on treatment outcome in terms of EFS (p = 0.31) or OS (p = 0.99) was observed. Thus, our results suggest that the addition of GO to induction regimens does not negatively impact PBSC mobilization in favorable-risk AML patients. To our best knowledge, this is the first study comparing the stem cell mobilization potential in favorable-risk AML patients treated with vs. without GO.

Optical genome mapping improves the accuracy of classification, risk stratification, and personalized treatment strategies for patients with acute myeloid leukemia.

Cytogenomic characterization is crucial for the classification and risk stratification of acute myeloid leukemia (AML), thereby facilitating therapeutic decision-making. We examined the clinical utility of optical genome mapping (OGM) in 159 AML patients (103 newly diagnosed and 56 refractory/relapsed), all of whom also underwent chromosomal banding analysis (CBA), fluorescence in situ hybridization, and targeted next-generation sequencing. OGM detected nearly all clinically relevant cytogenetic abnormalities that SCG identified with >99% sensitivity, provided the clonal burden was above 20%. OGM identified additional cytogenomic aberrations and/or provided information on fusion genes in 77 (48%) patients, including eight patients with normal karyotypes and four with failed karyotyping. The most common additional alterations identified by OGM included chromoanagenesis (n = 23), KMT2A partial tandem duplication (n = 11), rearrangements involving MECOM (n = 7), NUP98 (n = 2), KMT2A (n = 2), JAK2 (n = 2), and other gene fusions in 17 patients, with 10 showing novel fusion gene partners. OGM also pinpointed fusion genes in 17 (11%) patients where chromosomal rearrangements were concurrently detected by OGM and CBA. Overall, 24 (15%) aberrations were identified exclusively by OGM and had the potential to alter AML classification, risk stratification, and/or clinical trial eligibility. OGM emerges as a powerful tool for identifying fusion genes and detecting subtle or cryptic cytogenomic aberrations that may otherwise remain undetectable by CBA.

Genetic polymorphism and immunological evaluation of PD-1 in Iraqi patients with acute myeloid leukemia.

PD-1 has a noteworthy function in developing acute myeloid leukemia (AML). The expression of PD-1 on effector T cells is regulated at the protein level depending on the interactions between cells. The objective of the study was to evaluate the PD-1 concentration levels and the polymorphism genetic variants (rs36084323 G/A) in Iraqi Arab patients with AML. Sanger's DNA sequencing was used, and the assessments were done by enzyme-linked immunosorbent assay and PD-1 gene polymorphism SNP rs36084323 G/A. The frequency of rs36084323 was significantly different between AML and control, with a lower risk for AML seen in patients with GA genotype (odds ratio; 95% confidence interval: 0.53; 0.32-0.87). PD-1 elevated AML compared to control (213.1 pg/mL vs. 178.8 pg/mL). in AML patients, there is upregulation in PD-1, which indicates that PD-1 is a possible biomarker for AML. PD-1 rs36084323 G/A may have a role in AML risk.

Interleukin-2 mediated associations between gut microbiota and acute myeloid leukemia: A population-based mediation Mendelian randomization study

The relationship between the gut microbiota and acute myeloid leukemia (AML) has been established, but the exact role of interleukin (IL) in mediating this relationship has remained unclear. This study aimed to utilize whether interleukins mediate the relationships between gut microbiota and AML, thereby identifying potential novel targets for future AML treatment. Mendelian randomization (MR) is a method for finding the causality of exposure and outcome. Final instrumental variables were selected based on MR assumptions, and used to judge validity of the results. Our study identified risk and protective factors for AML, and interleukin-related gut microbiota. Finally, mediation MR analyses resulted in Interleukin-2 (IL-2) mediated associations between Clostridiaceae 1, Clostridium sensu stricto 1 and AML, with IL-2 respectively explaining 13.96 % and 12.11 % of the total effect of the aforementioned gut microbiota on AML. Our results successfully identified causal effects between specific gut microbiota, AML, and interleukins, while also elucidating the mediating role of IL-2 in these associations using MR analysis. These findings provide valuable insights into potential therapeutic targets for AML treatment.

TP53 mutation screening for patients at risk of myeloid malignancy.

6546 Background: Cellular therapy is a promising approach for many diseases but is associated with a risk of subsequent myelodysplastic syndrome and/or acute myeloid leukemia, also known as therapy-related myeloid neoplasms (tMN). This phenomenon has recently been described with allogeneic hematopoietic cell transplantation (HCT) and gene therapy for sickle cell disease (SCD). Mutation(s) in functional domains of TP53 are often associated with the development of tMN but currently no prospective screening or monitoring technology is available. Methods: A next-generation sequencing (NGS) assay with unique molecular identifiers (UMI) and bioinformatic noise-suppression was designed to discover somatic mutations at a variant allele frequency (VAF) 1% throughout the TP53gene. The background error profile at each base position was calculated using blood genomic DNA from healthy donors. The minimal detectable allele fraction with 95% confidence (MDAF) was calculated for all reported known AML/tMN TP53 hotspots. Orthogonal validation was performed using droplet digital PCR (ddPCR). Results: The median error corrected sequencing depth at 62 known TP53 hotspot regions was 14,512 (95% CI: 14,769 – 15,430) with a theoretical median de novo NGS variant discovery limit of 0.058% (range: 0.037% - 0.13%). Experimental evidence of assay performance characteristics was produced using serial dilutions of 4 missense, 2 splicing, and 1 frameshift TP53 variants with 100% discovery specificity observed (lowest detected VAF range: 0.05 – 0.12%). High correlation was observed in quantification using NGS discovery and ddPCR validation ( r = 0.958, p&lt;0.0001). Pre- and post-HCT clinical samples from 19 patients with SCD, 11 of which had graft failure including 4 who developed tMN, were screened for TP53 mutations. In all tMN cases, the AML-associated TP53 variant was detectable at least 6 months and up to 2.5 years prior to clinical diagnosis of myeloid malignancy. In contrast, no pathogenic TP53 variants were detected in 15 SCD patients who underwent HCT but did not develop tMN. Conclusions: This study provides generalizable evidence that ultra-sensitive discovery of TP53 mutations prior to cellular therapy is possible and could be a potentially valuable clinical tool to screen for tMN risk.

Venetoclax combined with hypomethylating agents for favorable risk acute myeloid leukemia: A single center experience.

e18514 Background: Favorable risk acute myeloid leukemia (FR-AML) is typically treated with intensive induction chemotherapy followed by high dose consolidative cytarabine. However, a subgroup of FR-AML are not candidates for high intensity induction because of advanced age, comorbidities, or poor performance status. For these patients, hypomethylating agents (HMA) combined with venetoclax (HMA-Ven) is inferred as the standard of care based upon results of the VIALE-A trial; however, that trial enrolled only intermediate or poor risk AML. The efficacy of HMA-Ven in FR-AML is unclear. Here we present a single center experience of this regimen in FR-AML. Methods: In this retrospective single center case series, we collected data from all patients &gt;18 years old with newly diagnosed FR-AML between January 2018 to December 2022 at AdventHealth Orlando who were treated with HMA-Ven. Patient with relapsed/refractory disease or a diagnosis of acute promyelocytic leukemia were excluded. FR-AML was defined using ELN 2022 guidelines based on the results of genomic testing of the initial bone marrow aspirate. The primary endpoints were the complete remission (CR) rate and 1-year overall survival (OS). Statistical analyses were performed using the R survminer package. Results: Newly diagnosed FR-AML who received HMA-Ven were identified (n=12). The median age was 67.5 years. 3 (25%) cases had inversion of chromosome 16 and 9 (75%) had NPM1 mutations without FLT3-ITD mutations. 11 (92%) patients received decitabine and venetoclax. Patients received a median of 2.5 cycles of HMA-Ven, and all 12 patients achieved CR after one cycle of treatment. 6 (50%) patients were consolidated with intermediate-dose cytarabine (IDAC), 3 (25%) continued HMA-Ven, 2 (17%) underwent allogeneic stem cell transplant, and 1 (8%) received enasidenib. The 1-year OS was 80% (CI 0.59-1), and the median OS was not reached. 1 patient died due to chemotherapy toxicity with IDAC, and 1 patient died due to heart complications. 2 patients relapsed, 1 after IDAC and 1 after intolerance to further treatment after 6 cycles of HMA-Ven. Conclusions: Our findings suggest that HMA-Ven is an effective treatment for newly diagnosed favorable risk AML. All patients achieved CR with one cycle of treatment with most surviving more than one year. Large multicenter studies are needed to further validate these promising results.

Correlation between number of molecular mutations and outcomes in de novo acute myeloid leukemia.

e18513 Background: Genomic sequencing of cancer has led to a deeper genetic understanding of the pathogenesis of acute myeloid leukemia (AML). Studies in myelodysplastic syndrome have shown that as the number of oncogenic mutations increases, patient outcomes progressively worsen. We hypothesized that patients with AML may also have a worse prognosis if they have a higher number of somatic mutations. To test this hypothesis, we examined the somatic mutational profile of 225 patients with previously untreated AML. Methods: A single-center retrospective analysis was done utilizing the cancer registry and evaluated patients with de novo AML diagnosed between January 2015 to January 2021. Patient characteristics, cytogenetics, and molecular data were collected by chart review. Patients with available cytogenetic and somatic mutations profile from next-generation sequencing (NGS) were included. Clinically significant (CS) mutations for AML were detected by NGS performed on the diagnostic bone marrow specimen. Statistical analysis was done using the Mann-Whitney U test for continuous variables and proportions were compared using Chi-square test. Results: A total of 225 De Novo AML patients met inclusion criteria. The median age at diagnosis was 61 (range, 21-86). The population was fairly distributed among males (52%) and females (48%). Approximately 51% (n=115) of patients had 0-2 mutations, 43% (n=97) had 3-5 mutations, and 6 % (n=13) had &gt;5 CS mutations. The median number of CS mutations for the entire cohort was 2 (range: 0-9). Survival was worse in the group with &gt;5 mutations when compared to those with 5 or less mutations (23 vs 7 months, p= 0.012). Patients with intermediate risk cytogenetics had a higher median number of CS mutations compared to the favorable and adverse risk group combined (3 versus 1, p &lt; 0.001). To determine whether overall survival was impacted by the presence of an adverse mutation, a subgroup analysis was done using 43 patients with a normal karyotype and at least 1 adverse mutation. The cohort with &gt;5 CS mutations had a significantly shorter OS compared to patients with ≤5 CS mutations (43 vs 9 months, p= 0.001). Conclusions: We found that patients with intermediate-risk cytogenetics have a high number of CS mutations. We found that a higher number of mutations (&gt;5) led to statistically significant difference in survival. To determine whether this difference in survival was a result of the presence of adverse risk mutations vs. number of mutations alone, we analyzed our patients who had normal karyotype with at least one adverse genetic mutation and stratified them based on number of mutations. The presence of more than 5 CS mutations was associated with a worse OS. The number of clinically significant mutations may be an independent predictor of overall survival in AML. This can serve as another tool in stratifying AML risk with normal karyotype. A large prospective clinical trial is necessary to validate.

Health disparities in acute myeloid leukemia: A decade-long analysis of Afro-Caribbean patients in a safety net New York City hospital.

e18515 Background: Acute Myeloid Leukemia (AML) in the Afro-Caribbean population is associated with poor outcomes due to disparities in health insurance and access to healthcare resources, among other factors, when compared to survival data in the national SEER database. This study reviews clinical characteristics and treatment outcomes of a cohort of 51 Afro-Caribbean patients who were diagnosed with AML and treated in the past 10 years in a urban safety net hospital in Brooklyn, New York. Methods: This is a retrospective review of patients diagnosed and treated for AML at New York City Health and Hospitals/Kings County from 2012 to 2022. Electronic Health Data was reviewed for clinicopathologic data and treatment outcomes. Analysis was performed through descriptive statistics with specific focus on insurance status and survival outcomes. Results: Our AML patient cohort had a mean age of 66, with 84% of patients identifying as Afro-Caribbean, and 51% being female. In this cohort, the AML risk stratification distribution based on 2022 European LeukemiaNet Risk classification includes 21 (41%) patients in the adverse-risk group, 23 (45%) patients in the intermediate-risk group, and 7 (14%) patients in the favorable-risk group. Of the 36 patients with molecular analysis data, 9 (25%) harbored a mutation in FLT3-ITD. Healthcare disparities are evident in insurance coverage, as 58% of patients lacked medical insurance, 19% had Medicare/Medicaid, and 23% had private insurance. At the time of this retrospective chart review, 35% of patients lacked any follow-up information, including appointments or status updates regarding their condition, vital status, or engagement with healthcare, possibly due to missed appointments, transfers, mortality, or other reasons. Of the 27 patients who were deemed transplant eligible, three (11%) successfully completed allogeneic bone marrow transplant. Reasons for non-transplantation include lack of a compatible donor, inadequate social support, insurance-related challenges, or patient refusal. Patients who completed induction and consolidation treatment with documented follow-up had a 23% survival rate at the five-year mark, compared to 31.7% overall survival rate reported in SEER data from 2013 to 2019. Conclusions: Our study highlights persistent healthcare disparities in Afro-Caribbean AML patients leading to poor survival outcomes. Despite treatment advancements, challenges related to insurance coverage, social support, follow-up care, and access to restricted, advanced care remain. Addressing these disparities calls for targeted interventions to enhance access and support systems for this vulnerable population.

RNA expression-based risk stratification of de novo acute myeloid leukemia.

e18503 Background: Prognostication of acute myeloid leukemia (AML) at initial diagnosis relies on the identification of certain underlying genetic abnormalities as proposed by the European LeukemiaNet (ELN) risk classification. However, AML is highly heterogenous at the molecular level and standard guidelines are often not straightforwardly applicable. In this study, we explored gene expression-based risk stratification strategies and found that FLT3 and NPM1 transcript level profiles can predict overall survival in de novo AML. Methods: The Cancer Genome Atlas AML (TCGA-LAML) project’s normalized RNA-Seq transcriptome profile (n=158) published in 2013 was analyzed with MATLAB software. "High” or “low” level of each gene was determined by the median RPKM of the cohort used as cutoff. P-values were obtained from Cox proportional hazards regression model. Results: The low-FLT3 level group was associated with superior median OS (mOS) compared to high-FLT3 group (24 vs. 16 months; p = 0.02), whereas high-NPM1 level group was associated with superior mOS compared to low-NPM1 group (26 vs. 12 months; p = 0.03). The mOS for high-FLT3/low-NPM1 and low-FLT3/high-NPM1 groups were 9 months and 27 months, respectively (p = 0.001). In high-FLT3/low-NPM1 and low-FLT3/high-NPM1 groups, composition of Cancer and Leukemia Group B (CALGB) cytogenetic risk category [favorable, intermediate, adverse] was [9%, 73%, 18%] and [32%, 49%, 19%], respectively; composition of French-American-British (FAB) classification [M0, M1, M2, M3, M4, M5, M6, M7] was [15%, 27%, 3%, 6%, 24%, 24%, 0%, 0%] and [3%, 14%, 41%, 19%, 22%, 0%, 0%, 3%], respectively; composition of FLT3/NPM1c mutations [ wt/wt, mut/wt, wt/mut, mut/mut, NOS] was [45%, 18%, 18%, 18%, 0%] and [61%, 14%, 7%, 14%, 2%], respectively. Conclusions: We demonstrate a de novo AML risk categorization method solely based on FLT3 and NPM1 RNA-Seq transcript levels. The mOS of high-FLT3/low-NPM1 group resembled that of ELN "adverse" risk group, whereas the mOS of low-FLT3/high-NPM1 group resembled that of ELN "favorable" risk group. High-FLT3/low-NPM1 group was composed of fewer "favorable” but more “intermediate” CALGB risk categories compared to low-FLT3/high-NPM1 group. Notably, considerably more FAB M0, M1 and M5 but fewer M2 and M3 classes were enriched in high-FLT3/low-NPM1 group compared to low-FLT3/high-NPM1 group. We also note approximately half of the cases analyzed were FLT3 and NPM1 wild-types and speculate FLT3 and NPM1 transcript profiles may represent a global oncogenic state regardless of the underlying FLT3 or NPM1 mutations. This is also supported by the previously reported FLT3 mutation-like transcriptomic profiles observed in FLT3 wild-type AML cases1). Reference: 1) Mosquera Orgueira A, et al. Gene expression profiling identifies FLT3 mutation-like cases in wild-type FLT3 acute myeloid leukemia. PLoS One. 2021 Feb 16;16(2):e0247093

Occupational exposure to benzene and mortality risk of lymphohaematopoietic cancers in the Swiss National Cohort.

Previous studies established a causal relationship between occupational benzene exposure and acute myeloid leukemia (AML). However, mixed results have been reported for associations between benzene exposure and other myeloid and lymphoid malignancies. Our work examined whether occupational benzene exposure is associated with increased mortality from overall lymphohaematopoietic (LH) cancer and major subtypes. Mortality records were linked to a Swiss census-based cohort from two national censuses in 1990 and 2000. Cases were defined as having any LH cancers registered in death certificates. We assessed occupational exposure by applying a quantitative benzene job-exposure matrix (BEN-JEM) to census-reported occupations. Exposure was calculated as the products of exposure proportions and levels (P × L). Cox proportional hazards models were used to calculate LH cancer death hazard ratios (HR) and 95% confidence intervals (CI) associated with benzene exposure, continuously and in ordinal categories. Our study included approximately 2.97 million persons and 13 415 LH cancer cases, including 3055 cases with benzene exposure. We observed increased mortality risks per unit (P × L) increase in continuous benzene exposure for AML (HR 1.03, 95% CI 1.00-1.06) and diffuse large B-cell lymphoma (HR 1.09, 95% CI 1.04-1.14). When exposure was assessed categorically, increasing trends in risks were observed with increasing benzene exposure for AML (P=0.04), diffuse large B-cell lymphoma (P=0.02), and follicular lymphoma (P=0.05). In a national cohort from Switzerland, we found that occupational exposure to benzene is associated with elevated mortality risks for AML, diffuse large B-cell lymphoma, and possibly follicular lymphoma.

Benzoyl peroxide use in acne therapy: Evaluating the association with acute myeloid leukemia risk

Benzoyl peroxide use in acne therapy: Evaluating the association with acute myeloid leukemia risk