Risk Of Myeloid Leukemia Research Articles

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.

Chronic myeloid leukemia in an ulcerative colitis patient receiving azathioprine: A case report.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease usually treated by azathioprine. It is a well-established risk factor for colorectal cancers and extraintestinal malignancies. Nevertheless, the risk of myeloid leukemia in patients with UC is less known. We report a case of a 51-year-old patient, with a history of extensive ulcerative colitis, who was treated with azathioprine at a dose of 2.5 mg/kg/day. Seven years later, he presented an increased count of white blood cells at 25,400/μL and of platelets at 1,382,000/μL. Peripheral blood smear showed 1% blasts and 20% myelemia. The karyotype showed the Philadelphia chromosome and the RT-PCR revealed the BCR-ABL transcript. Thus, chronic myeloid leukemia (CML) was confirmed and imatinib was prescribed. This case reported a rare and serious event in a UC patient and illustrates the importance of closely monitoring this population.

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

Alternative polyadenylation quantitative trait loci contribute to acute myeloid leukemia risk genes regulation

Acute myeloid leukemia (AML) is a hematopoietic malignancy with a high relapse rate and progressive drug resistance. Alternative polyadenylation (APA) contributes to post-transcriptional dysregulation, but little is known about the association between APA and AML. The APA quantitative trait locus (apaQTL) is a powerful method to investigate the relationship between APA and single nucleotide polymorphisms (SNPs). We quantified APA usage in 195 Chinese AML patients and identified 4922 cis-apaQTLs related to 1875 genes, most of which were newly reported. Cis-apaQTLs may modulate the APA selection of 115 genes through poly(A) signals. Colocalization analysis revealed that cis-apaQTLs colocalized with cis-eQTLs may regulate gene expression by affecting miRNA binding sites or RNA secondary structures. We discovered 207 cis-apaQTLs related to AML risk by comparing genotype frequency with the East Asian healthy controls from the 1000 Genomes Project. Genes with cis-apaQTLs were associated with hematological phenotypes and tumor incidence according to the PHARMGKB and MGI databases. Collectively, we profiled an atlas of cis-apaQTLs in Asian AML patients and found their association with APA selection, gene expression, AML risk, and complex traits. Cis-apaQTLs may provide insights into the regulatory mechanisms related to APA in AML occurrence, progression, and prognosis.

Abstract LB415: Association between waist circumference, body mass index, high-density lipoprotein cholesterol level, and risk of chronic myeloid leukemia

Abstract LB415: Association between waist circumference, body mass index, high-density lipoprotein cholesterol level, and risk of chronic myeloid leukemia

Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP): a randomised, open-label, phase 3, non-inferiority trial

Whether high-dose cytarabine-based salvage chemotherapy, administered to induce complete remission in patients with poor responsive or relapsed acute myeloid leukaemia scheduled for allogeneic haematopoietic stem-cell transplantation (HSCT) after intensive conditioning confers a survival advantage, is unclear. To test salvage chemotherapy before allogeneic HSCT, patients aged between 18 and 75 years with non-favourable-risk acute myeloid leukaemia not in complete remission after first induction or untreated first relapse were randomly assigned 1:1 to remission induction with high-dose cytarabine (3 g/m2 intravenously, 1 g/m2 intravenously for patients >60 years or with a substantial comorbidity) twice daily on days 1-3 plus mitoxantrone (10 mg/m2 intravenously) on days 3-5 or immediate allogeneic HSCT for the disease control group. Block randomisation with variable block lengths was used and patients were stratified by age, acute myeloid leukaemia risk, and disease status. The study was open label. The primary endpoint was treatment success, defined as complete remission on day 56 after allogeneic HSCT, with the aim to show non-inferiority for disease control compared with remission induction with a non-inferiority-margin of 5% and one-sided type 1 error of 2·5%. The primary endpoint was analysed in both the intention-to-treat (ITT) population and in the per-protocol population. The trial is completed and was registered at ClinicalTrials.gov, NCT02461537. 281 patients were enrolled between Sept 17, 2015, and Jan 12, 2022. Of 140 patients randomly assigned to disease control, 135 (96%) proceeded to allogeneic HSCT, 97 (69%) after watchful waiting only. Of 141 patients randomly assigned to remission induction, 134 (95%) received salvage chemotherapy and 128 (91%) patients subsequently proceeded to allogeneic HSCT. In the ITT population, treatment success was observed in 116 (83%) of 140 patients in the disease control group versus 112 (79%) of 141 patients with remission induction (test for non-inferiority, p=0·036). Among per-protocol treated patients, treatment success was observed in 116 (84%) of 138 patients with disease control versus 109 (81%) of 134 patients in the remission induction group (test for non-inferiority, p=0·047). The difference in treatment success between disease control and remission induction was estimated as 3·4% (95% CI -5·8 to 12·6) for the ITT population and 2·7% (-6·3 to 11·8) for the per-protocol population. Fewer patients with disease control compared with remission induction had non-haematological adverse events grade 3 or worse (30 [21%] of 140 patients vs 86 [61%] of 141 patients, χ2 test p<0·0001). Between randomisation and the start of conditioning, with disease control two patients died from progressive acute myeloid leukaemia and zero from treatment-related complications, and with remission induction two patients died from progressive acute myeloid leukaemia and two from treatment-related complications. Between randomisation and allogeneic HSCT, patients with disease control spent a median of 27 days less in hospital than those with remission induction, ie, the median time in hospital was 15 days (range 7-64) versus 42 days (27-121, U test p<0·0001), respectively. Non-inferiority of disease control could not be shown at the 2·5% significance level. The rate of treatment success was also not statistically better for patients with remission induction. Watchful waiting and immediate transplantation could be an alternative for fit patients with poor response or relapsed acute myeloid leukaemia who have a stem cell donor available. More randomised controlled intention-to-transplant trials are needed to define the optimal treatment before transplantation for patients with active acute myeloid leukaemia. DKMS and the Gert and Susanna Mayer Stiftung Foundation.

Triangulation of epidemiological evidence and risk of bias evaluation: A proposed framework and applied example using formaldehyde exposure and risk of myeloid leukemias

Evidence triangulation may help identify the impact of study design elements on study findings and to tease out biased results when evaluating potential causal relationships; however, methods for triangulating epidemiologic evidence are evolving and have not been standardized. Building upon key principles of epidemiologic evidence triangulation and risk of bias assessment, and responding to the National Academies of Sciences, Engineering, and Medicine (NASEM) call for applied triangulation examples, the objective of this manuscript is to propose a triangulation framework and to apply it as an illustrative example to epidemiologic studies examining the possible relationship between occupational formaldehyde exposure and risk of myeloid leukemias (ML) including acute (AML) and chronic (CML) types.A nine-component triangulation framework for epidemiological evidence was developed incorporating study quality and ROB guidance from various federal health agencies (i.e., US EPA TSCA and NTP OHAT). Several components of the triangulation framework also drew from widely used epidemiological analytic tools such as stratified meta-analysis and sensitivity analysis. Regarding the applied example, fourteen studies were identified and assessed using the following primary study quality domains to explore potential key sources of bias: 1) study design and analysis; 2) study participation; 3) exposure assessment; 4) outcome assessment; and 5) potential confounding. Across studies, methodological limitations possibly contributing to biased results were observed within most domains. Interestingly, results from one study – often providing the largest and least-precise relative risk estimates, likely reflecting study biases, deviated from most primary study findings indicating no such associations. Triangulation of epidemiological evidence appears to be helpful in exploring inconsistent results for the identification of study results possibly reflecting various biases. Nonetheless, triangulation methodologies require additional development and application to real-world examples to enhance objectivity and reproducibility.

Refining the relationship between gut microbiota and common hematologic malignancies: insights from a bidirectional Mendelian randomization study.

The relationship between gut microbiota and hematologic malignancies has attracted considerable attention. As research progresses, it has become increasingly clear that the composition of gut microbiota may influence the onset and progression of hematologic malignancies. However, our understanding of this association remains limited. In our study, we classified gut microbiota into five groups based on information at the phylum, class, order, family, and genus levels. Subsequently, we obtained data related to common hematologic malignancies from the IEU Open GWAS project. We then employed a bidirectional Mendelian Randomization (MR) approach to determine whether there is a causal relationship between gut microbiota and hematologic malignancies. Additionally, we conducted bidirectional MR analyses to ascertain the directionality of this causal relationship. Through forward and reverse MR analyses, we found the risk of lymphoid leukemia was significantly associated with the abundance of phylum Cyanobacteria, order Methanobacteriales, class Methanobacteria, family Peptococcaceae, family Methanobacteriaceae, and genera Lachnospiraceae UCG010, Methanobrevibacter, Eubacterium brachy group, and Butyrivibrio. The risk of myeloid leukemia was significantly associated with the abundance of phylum Actinobacteria, phylum Firmicutes, order Bifidobacteriales, order Clostridiales, class Actinobacteria, class Gammaproteobacteria, class Clostridia, family Bifidobacteriaceae, and genera Fusicatenibacter, Eubacterium hallii group, Blautia, Collinsella, Ruminococcus gauvreauii group, and Bifidobacterium. The risk of Hodgkin lymphoma was significantly associated with the abundance of family Clostridiales vadinBB60 group, genus Peptococcus, and genus Ruminococcaceae UCG010. The risk of malignant plasma cell tumor was significantly associated with the abundance of genera Romboutsia and Eubacterium rectale group. The risk of diffuse large B-cell lymphoma was significantly associated with the abundance of genera Erysipelatoclostridium and Eubacterium coprostanoligenes group. The risk of mature T/NK cell lymphomas was significantly associated with the abundance of phylum Verrucomicrobia, genus Ruminococcaceae UCG013, genus Lachnoclostridium, and genus Eubacterium rectale group. Lastly, the risk of myeloproliferative neoplasms was significantly associated with the abundance of genus Coprococcus 3 and Eubacterium hallii group. Our study provided new evidence for the causal relationship between gut microbiota and hematologic malignancies, offering novel insights and approaches for the prevention and treatment of these tumors.

The Relationship between Telomere Length and Epigenetic Aging with Hematologic Diseases Risk: A Multivariable Mendelian Randomisation Study

Introduction: Aging is a complex phenomenon that involves multifaceted changes, including significant alterations in telomere length and epigenetic aging. When aging affects the hematopoietic system, it leads to a gradual increase in mutations in hematopoietic stem cells, making individuals more susceptible to the development of hematologic diseases. However, due to the limitations of observational studies, such as potential confounding factors and reverse causality, the precise causal direction and magnitude of the relationship between telomere length, epigenetic aging, and the incidence of hematologic diseases remain uncertain. Therefore, we conducted an investigation to determine the causal relevance of telomere length and epigenetic aging in relation to hematologic diseases using Mendelian randomization (MR). Methods: Firstly, we conducted a 2-sample single-variable Mendelian randomization (SVMR) study to examine the genetically predicted effects of telomere length and epigenetic age acceleration, as measured by HannumAge, Horvath Intrinsic Age, PhenoAge, GrimAge, and DNAm PAI-1 (DNA methylation-estimated plasminogen activator inhibitor-1) levels, on multiple hematologic diseases, including anemia, lymphoma, leukemia, myeloproliferative diseases, and hemostasis and coagulation diseases. Additionally, we used lasso regression to exclude multicollinearity in SNPs and subsequently performed multivariable MR using the screened SNPs to adjust for statistically significant risk factors, and MR Bayesian model averaging was performed to rank the significant risk factors based on their genetic evidence (Figure A). Results: Summary data were available for 19 malignant hematological neoplasms and 35 non-malignant hematological disorders, corresponding to 70,813 cases and 12,253,012 controls. Increased telomere length due to germline genetic variation was generally associated with increased risk for hematologic diseases. The strongest associations were observed for lymphoma, lymphoid leukaemia, Hodgkin lymphoma, chronic lymphocytic leukaemia, essential thrombocythaemia, unspecified types of non-Hodgkin lymphoma, multiple myeloma, Non-follicular lymphoma, unspecified iron deficiency, leukaemia, while higher levels of telomere length was associated with a reduced risk of pernicious anaemia (Figure B). Meta-analyzed IVW MR findings suggested that higher PhenoAge acceleration was associated with increased risks of myeloid leukemia, chronic lymphocytic leukemia, and lymphoid leukemia. Conversely, higher PhenoAge acceleration was linked to reduced risks of unspecified disorders of white blood cells and unspecified coagulation defects. Similarly, SVMR showed genetic predisposition for GrimAge acceleration to be associated with increased risks of amyloidosis, unspecified anemias, and myeloid leukemia. Conversely, genetically predicted GrimAge acceleration was associated with reduced risks of hemorrhagic anemia, hemolytic anemias, and idiopathic thrombocytopenic purpura. Furthermore, our findings suggested that elevated HannumAge acceleration increased the risks of lymphoma, leukemia, and lymphoid leukemia.Conversely, higher HannumAge acceleration was associated with a reduced risk of chronic myeloid leukemia. Additionally, higher levels of DNAm PAI-1 were found to be associated with an increased risk of chronic myeloid leukemia. However, there was no evidence of causality between genetically predicted Intrinsic epigenetic age acceleration and the 19 malignant hematological neoplasms and 35 non-malignant hematological disorders mentioned (Figure C). We utilized MVMR-LASSO to estimate the combined effects of telomere length and five epigenetic clocks on hematologic diseases. After adjusting for epigenetic aging, we observed a significant positive association between telomere length and various hematologic diseases, including leukemia, lymphoid leukemia, chronic lymphocytic leukemia, lymphomas, Hodgkin lymphoma, non-follicular lymphoma, unspecified types of non-Hodgkin lymphoma, essential thrombocythemia, and multiple myeloma (Figure D&amp;E). Conclusion: Longer telomeres and epigenetic aging may increase the risk of developing most hematologic malignancies, while simultaneously raising or decreasing the risk of certain non-malignant hematologic diseases.

Ultra-Low-Dose of Decitabine with Venetoclax As Induction and Consolidation Therapy for Elderly or Frail Newly Diagnosed Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome Patients

Background: Venetoclax with hypomethylating agents is a new standard of care for newly diagnosed (ND) patients with acute myeloid leukemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine which has shown promising results in high-risk AML in phase 2 trials. We hypothesized that venetoclax with 10-day decitabine may be effective in ND and secondly AML/MDS, particularly for high-risk subgroups. Methods: We retrospectively analyzed 45 patients with ND AML, secondary AML (sAML), or high-risk MDS who was older than 60 years or unfit for intensive chemotherapy due to frail / due to the COVID-19 pandemic. Patients were required adequate end-organ function. Patients received decitabine (6mg/m2 IV for 10-days) with oral venetoclax (400mg daily for 3 weeks (D10+VEN)) for induction, followed by the same chemo-free regimen for consolidation if patients responsed to induction therapy. The primary efficacy endpoint was overall response rate (ORR). The second endpoint was overall survival (OS) and progress free survival (PFS). Findings: Between January, 2020 and July , 2023, 45 patients were treated with this regimen, 31 (68.9%) had ND AML, 8 patients (17.8%) had untreated sAML, 6 patients (13.3%) had untreated high-risk MDS. The median age was 65 years (IQR, 59-69) and 26(57.8%) patients had ECOG performance status of 3 or higher. The ORR among all patients was 82.2% and in disease subgroups were: ND AML, 87.1% (27/31) (95% CI 79, 94); untreated sAML, 75% (6/8); untreated high-risk MDS, 66.7%(4/6). According 2022 ELN risk classification by genetics, the ORR in favorable risk patients was 87.5%(7/8), intermediate risk patients was 100%(12/12), adverse risk patients was 72%(18/25). The most common treatment-emergent adverse events included infections with grade 3/4 neutropenia (n=36, 80%) and febrile neutropenia (n=7, 15.6%). There were 2 grade 5 adverse events including one infections with Enterobacter cloacae Bacteremias combined with heart failure because of the shortage of Blood product transfusion during the COVID-19 pandemic, and one case of intracranial hemorrhage related to prolonged grade 3/4 thrombocytopenia. The one year OS of all patients was 71.9%(23/32), and in favorable risk patients was 83.3% (5/6), intermediate risk patients was 72.7%(8/11), adverse risk patients was 73.3%(11/15). The two-year OS of all patients was 58.3%(7/12). Conclusion: Ultra-low-dose of ten-day decitabine with venetoclax as induction and consolidation chemo-free therapy in elderly or frail newly diagnosed acute myeloid leukemia and high risk myelodysplastic syndrome result in high overall response rate and high 1-year overall survivial.

Phase 1/2 Multicenter, Open-Label Study of CTX-712 in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

Background and Significance Dysregulation of alternative splicing, caused by abnormal expression or mutation of splicing factors, has been identified as an important contributor to the genesis and progression of cancer, and suggested as a novel target for anticancer treatment. CDC2-like kinases (CLK) represent a family of dual-specificity tyrosine and serine-threonine kinases that are involved in the regulation of splicing by phosphorylation of serine/arginine-rich splicing factors (SRSFs) which play a central role in exon recognition. CTX-712 is an orally available, potent, selective, and a first-in-class pan-CLK inhibitor (CLK 1-4), that inhibits phosphorylation of SRSFs resulting in significant antitumor activity in vitro and multiple xenograft models in vivo. CTX-712 formulated in capsules is currently being evaluated in an ongoing first-in-man study in Japan, evaluating tolerability and early efficacy in patients with solid tumors or hematologic malignancies (JapicCTI-184188). Preliminary data from the Japanese study were presented during ASCO 2022 and ASH 2022, and showed an acceptable safety profile (doses up to 175 mg (MTD 140 mg) twice a week in 28-day cycles, observed DLTs included dehydration, decreased platelets, hypokalemia, and pneumonia) with early signs of clinical antitumor activity (2 partial responses / 26 treated solid tumor patients, 5 complete remissions and complete remission with incomplete hematologic recovery/ 8 treated patients with AML or MDS), warranting further clinical investigations.. (J Clin Oncol (2022) 40(16_suppl):3080. Blood (2022) 140(Supplement 1):6211-2.). This abstract details a second study with CTX-712 that has just been initiated. Study Design and Methods A new film-coated tablet formulation will be evaluated in this phase 1/2 multicenter, open-label study of CTX-712 in patients with (mutated or wild type spliceosomes genes) relapsed/refractory AML, higher risk MDS (IPSS-R intermediate, high, or very high), or high marrow blast (≥5 %) MDS/MPN (including CMML). The phase 1 part of the study will be conducted at 4 US sites, and all sites are currently open for enrolment. The study allows patients with performance status 0, 1, or 2, adequate organ function, and up to four prior lines of therapy. Due to potential risk of interactions (in vitro studies suggest CYP3A4 as main metabolic pathway for CTX-712), concomitant use of strong CYP3A4 inhibitors is prohibited. Use of azole antifungals that are not strong CYP3A4 inhibitors (e.g., isavuconazole) is permitted. The phase 1 part of the study consists of dose-escalation (sequential standard 3 + 3 design), where cohorts of 3 (or 6) patients will receive ascending doses of CTX-712 once weekly in a 28-day cycle with continuous monitoring of emerging clinical PK, PD, safety, and efficacy data, to determine the recommended phase 2 dose (RP2D) based on the suggestion by the Safety Review Committee (SRC). The protocol defines five different dose levels (20-140 mg, once weekly) but also authorizes the SRC to suggest up to two interim dose levels or alternate schedules (e.g., dosing two times a week) if supported by emerging data. The suggested RP2D will be used in a confirmatory phase 1 expansion cohort where an additional 10 patients (total n = 16; 8 patients with AML and 8 patients with MDS) will be treated to gain further confidence in the selected dose level. The phase 2 part of the study will commence after the RP2D has been identified and confirmed and aims at evaluating therapeutic activity in R/R AML (Cohort 2a) or R/R HR-MDS (Cohort 2b), in addition to confirmation of the safety profile. Clinical trial registry number: NCT05732103

A Phase II Study of Single Agent Aspacytarabine (BST-236) in Adults Unfit for Intensive Chemotherapy with Relapsed or Refractory Acute Myeloid Leukemia (R/R AML) or Higher Risk Myelodysplastic Syndromes (R/R HR MDS)

Background-Common treatment approaches for R/R AML and to some extent HR MDS involve intensive chemotherapy regimens, typically combining high dose cytarabine with other drug(s), but these intensive regimens may not be suitable for unfit or elderly patients. To address this issue, a cytarabine prodrug called BST-236 has been developed, which delivers high doses of cytarabine while reducing systemic toxicity, making it a potential option for intensive chemotherapy in older and frail patients. This Phase II study aimed to assess the efficacy and tolerability of BST-236 in unfit patients with R/R AML or HR MDS previously treated with a non-intensive regimen. Methods-This ongoing Phase 2 trial (NCT 04827719) enrolled HR MDS and AML patients (pts) aged ≥ 75 years or with comorbidities incompatible with intensive chemotherapy. MDS pts were refractory or had relapsed to azacytidine (AZA), and AML pts to AZA, low-dose cytarabine (LDAC) or AZA -venetoclax (VEN), given as a first line regimen. Each BST-236 induction and maintenance course consisted of 6 daily 1-hour intravenous infusions at a dose of 4.5 g/m 2/d (containing 3 g/m 2/d of cytarabine). After completing 1 induction cycle, patients with stable disease (SD) or partial response could undergo a second similar cycle, and patients who achieved complete remission (CR) could receive 2 to 4 maintenance cycles at the same schedule. Inclusion of 20 AML and 20 MDS pts was planned. Results-From August 2021 to May 2023, 16 MDS and 20 AML pts from 9 centers were enrolled, with a median follow up of 3 months. MDS: Median age was 74.8 years [IQR, 71.2-76.4] and ECOG was 0- 1 in all but 1 patient . All pts were previously treated with AZA and 4 (29%) had adverse R-IPSS karyotype. 14/16 were evaluable for response after 1 induction: 1 (7%) CR, 2 (14%) marrow CR, 7 (50%) SD. Hematological improvement was observed in 6 (43%) patients. Two serious treatment related adverse events (SAE) - febrile neutropenia and sepsis - occurred in 2 pts. Median duration of hospitalization for the induction cycle was 29.5 days [IQR 25.5-32.5] and 30-day mortality rate was 0%. AML: Median age was 77.6 years [IQR, 73.8-79.4] and all pts had ECOG 0-1. Two pts were previously treated with AZA, 1 with LDAC, 17 with AZA-VEN and 8 (50%) had adverse ELN score. 17/ 20 pts were evaluable for response after 1 induction cycle : 2 (12%) CR including 1 CR with negative MRD, 1 (6%) CRi, 10 (59%) SD. Three SAE- infections and hepatobiliary disorders- occurred in 2 pts. Median duration of hospitalization for the induction cycle was 26 days [IQR 23.2-30.8] and 30-day mortality rate was 10%. Four MDS pts still need to be enrolled, and follow up is ongoing. An update will be presented at the meeting. Conclusion- Response rates with BST-236, in this pretreated older frail R/R AML and MDS population, were modest. Toxicity, including myelosuppression, however appears lower than with conventional intensive chemotherapy, suggesting this treatment could be interesting earlier in the disease course.

TP53 status and impact on AML prognosis within the ELN 2022 risk classification

AbstractThis study reports the following: (1) frequency of TP53 comutation within each component of the European LeukemiaNet 2022 acute myeloid leukemia risk classification, (2) relevance of TP53 mutated variant allelic fraction <10%, (3) prognostic impact of −7, −5/del(5q), −17/abn(17p), complex karyotype/monosomal karyotype, or myelodysplasia-related gene mutations with/without mutated TP53.

Predicted leukocyte telomere length and risk of myeloid neoplasms.

Maintenance of telomere length has long been established to play a role in the biology of cancer and several studies suggest that it may be especially important in myeloid malignancies. To overcome potential bias in confounding and reverse causation of observational studies, we use both a polygenic risk score (PRS) and inverse-variance weighted (IVW) Mendelian randomization (MR) analyses to estimate the relationship between genetically predicted leukocyte telomere length (LTL) and acute myeloid leukemia (AML) risk in 498 cases and 2099 controls and myelodysplastic syndrome (MDS) risk in 610 cases and 1759 controls. Genetic instruments derived from four recent studies explaining 1.23-4.57% of telomere variability were considered. We used multivariable logistic regression to estimate odds ratios (OR, 95% confidence intervals [CI]) as the measure of association between individual single-nucleotide polymorphisms and myeloid malignancies. We observed a significant association between a PRS of longer predicted LTL and AML using three genetic instruments (OR = 4.03 per ~1200 base pair [bp] increase in LTL, 95% CI: 1.65, 9.85 using Codd etal. [Codd, V., Nelson, C.P., Albrecht, E., Mangino, M., Deelen, J., Buxton, J.L., Hottenga, J.J., Fischer, K., Esko, T., Surakka, I. etal. (2013) Identification of seven loci affecting mean telomere length and their association with disease. Nat. Genet., 45, 422-427 427e421-422.], OR = 3.48 per one-standard deviation increase in LTL, 95% CI: 1.74, 6.97 using Li etal. [Li, C., Stoma, S., Lotta, L.A., Warner, S., Albrecht, E., Allione, A., Arp, P.P., Broer, L., Buxton, J.L., Alves, A.D.S.C. etal. (2020) Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length. Am. J. Hum. Genet., 106, 389-404.] and OR = 2.59 per 1000bp increase in LTL, 95% CI: 1.03, 6.52 using Taub etal. [Taub, M.A., Conomos, M.P., Keener, R., Iyer, K.R., Weinstock, J.S., Yanek, L.R., Lane, J., Miller-Fleming, T.W., Brody, J.A., Raffield, L.M. etal. (2022) Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed. Cell Genom., 2.] genetic instruments). MR analyses further indicated an association between LTL and AML risk (PIVW ≤ 0.049) but not MDS (all PIVW ≥ 0.076). Findings suggest variation in genes relevant to telomere function and maintenance may be important in the etiology of AML but not MDS.

The impact of IDH and NAT2 gene polymorphisms in acute myeloid leukemia risk and overall survival in an Arab population: A case-control study.

Acute myeloid leukemia (AML) is a malignancy of the myeloid cells due to the clonal and malignant proliferation of blast cells. The etiology of AML is complex and involves environmental and genetic factors. Such genetic aberrations include FLT3, DNMT3, IDH1, IDH2, NAT2, and WT. In this study, we analyzed the relationship between five, not previously studied in any Arab population, single nucleotide polymorphisms (SNPs) and the risk and overall survival of AML in Jordanian patients. The SNPs are NAT2 (rs1799930 and rs1799931), IDH1 (rs121913500), and IDH2 (rs121913502 and rs1057519736). A total number of 30 AML patients and 225 healthy controls were included in this study. Females comprised 50% (n = 15) and 65.3% (n = 147) of patients and controls, respectively. For AML patients (case group) Genomic DNA was extracted from formalin-fixed paraffin-embedded tissues and from peripheral blood samples for the control subjects group. Genotyping of the genetic polymorphisms was conducted using a sequencing protocol. Our study indicates that NAT2 rs1799930 SNP had a statistically significant difference in genotype frequency between cases and controls (p = 0.023) while IDH mutations did not correlate with the risk and survival of AML in the Jordanian population. These results were also similar in the TCGA-LAML cohorts with the notable exception of the rare NAT2 mutation. A larger cohort study is needed to further investigate our results.

Venetoclax abrogates the prognostic impact of splicing factor gene mutations in newly diagnosed acute myeloid leukemia

AbstractMutations in splicing factor (SF) genes SRSF2, U2AF1, SF3B1, and ZRSR2 are now considered adverse risk in the European LeukemiaNet 2022 acute myeloid leukemia (AML) risk stratification. The prognostic impact of SF mutations in AML has been predominantly derived from younger patients treated with intensive (INT) therapy. We evaluated 994 patients with newly diagnosed AML, including 266 (27%) with a SFmut. Median age was 67 years overall, with patients with SFmut being older at 72 years. SRSF2 (n = 140, 53%) was the most common SFmut. In patients treated with INT, median relapse-free survival (RFS) (9.6 vs 21.4 months, P = .04) and overall survival (OS) (15.9 vs 26.7 months, P = .06) were shorter for patients with SFmut than without SFwt, however this significance abrogated when evaluating patients who received venetoclax with INT therapy (RFS 15.4 vs 20.3 months, P = .36; OS 19.6 vs 30.7 months, P = .98). In patients treated with LI, median RFS (9.3 vs 7.7 months, P = .35) and OS (12.3 vs 8.5 months, P = .14) were similar for patients with and without SFmut , and outcomes improved in all groups with venetoclax. On multivariate analysis, SFmut did not affect hazards of relapse and death for INT arm but reduced both these hazards in LI arm. In a large AML data set with >60% of patients receiving venetoclax with LI/INT therapy, SFmut had no independent negative prognostic impact. Newer prognostic models that consider LI therapy and use of venetoclax among other factors are warranted.

Age and sex associate with outcome in older AML and high risk MDS patients treated with 10-day decitabine

Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery < 9 and 17% ADL index < 6) on overall survival (OS) in 115 older patients (age ≥ 66 years) treated on a clinical trial with a 10-day decitabine schedule. None of the patient-related variables showed a significant association with OS. Multivariable analysis revealed that age > 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival.

A Longitudinal Study of Sleep Habits and Leukemia Incidence Among Postmenopausal Women.

We sought to assess the relationship between sleep duration, sleep disturbance, and leukemia incidence among postmenopausal women. This study included 130,343 postmenopausal women aged 50-79 years who were enrolled in the Women's Health Initiative (WHI) during 1993-1998. Information on self-reported typical sleep duration and sleep disturbance was obtained by questionnaire at baseline, and sleep disturbance level was defined according to the Women's Health Initiative Insomnia Rating Scale (WHIIRS). WHIIRS scores of 0-4, 5-8, and 9-20 comprised 37.0%, 32.6%, and 30.4% of all women, respectively. After an average of 16.4 years (2,135,109 cumulative person-years) of follow-up, 930 of the participants were identified as having incident leukemia. Compared with women with the lowest level of sleep disturbance (WHIIRS score 0-4), women with higher sleep disturbance levels (WHIIRS scores of 5-8 and 9-20) had 22% (95% confidence interval (CI): 1.04, 1.43) and 18% (95% CI: 1.00, 1.40) excess risks of leukemia, respectively, after multivariable adjustment. A significant dose-response trend was found for the association between sleep disturbance and leukemia risk (P for trend = 0.048). In addition, women with the highest level of sleep disturbance had a higher risk of myeloid leukemia (for WHIIRS score 9-20 vs. WHIIRS score 0-4, hazard ratio = 1.39, CI: 1.05, 1.83). Higher sleep disturbance level was associated with increased risk of leukemia, especially for myeloid leukemia among postmenopausal women.

An Updated Overview of the Role of CYP450 during Xenobiotic Metabolization in Regulating the Acute Myeloid Leukemia Microenvironment.

Oxidative stress is associated with several acute and chronic disorders, including hematological malignancies such as acute myeloid leukemia, the most prevalent acute leukemia in adults. Xenobiotics are usually harmless compounds that may be detrimental, such as pharmaceuticals, environmental pollutants, cosmetics, and even food additives. The storage of xenobiotics can serve as a defense mechanism or a means of bioaccumulation, leading to adverse effects. During the absorption, metabolism, and cellular excretion of xenobiotics, three steps may be distinguished: (i) inflow by transporter enzymes, (ii) phases I and II, and (iii) phase III. Phase I enzymes, such as those in the cytochrome P450 superfamily, catalyze the conversion of xenobiotics into more polar compounds, contributing to an elevated acute myeloid leukemia risk. Furthermore, genetic polymorphism influences the variability and susceptibility of related myeloid neoplasms, infant leukemias associated with mixed-lineage leukemia (MLL) gene rearrangements, and a subset of de novo acute myeloid leukemia. Recent research has shown a sustained interest in determining the regulators of cytochrome P450, family 2, subfamily E, member 1 (CYP2E1) expression and activity as an emerging field that requires further investigation in acute myeloid leukemia evolution. Therefore, this review suggests that CYP2E1 and its mutations can be a therapeutic or diagnostic target in acute myeloid leukemia.

The eighth International Forum on Stem Cells: virtual meeting, October 20-21, 2022.

The eighth International Forum on Stem Cells: virtual meeting, October 20-21, 2022.