Intermediate Cytogenetic Risk Research Articles

Effectiveness and safety of granulocyte colony-stimulating factor priming regimen for acute myeloid leukemia: A systematic review and meta-analysis of the Clinical Practice Guideline for the use of G-CSF 2022 from the Japan Society of Clinical Oncology.

The outcomes of relapsed or refractory acute myeloid leukemia (AML) remain poor. Although the concomitant use of granulocyte colony-stimulating factor (G-CSF) and anti-chemotherapeutic agents has been investigated to improve the antileukemic effect on AML, its usefulness remains controversial. This study aimed to investigate the effects of G-CSF priming as a remission induction therapy or salvage chemotherapy. We performed a thorough literature search for studies related to the priming effect of G-CSF using PubMed, Ichushi-Web, and the Cochrane Library. A qualitative analysis of the pooled data was performed, and risk ratios (RRs) with confidence intervals (CIs) were calculated and summarized. Two reviewers independently extracted and accessed the 278 records identified during the initial screening, and 62 full-text articles were assessed for eligibility in second screening. Eleven studies were included in the qualitative analysis and 10 in the meta-analysis. A systematic review revealed that priming with G-CSF did not correlate with an improvement in response rate and overall survival (OS). The result of the meta-analysis revealed the tendency for lower relapse rate in the G-CSF priming groups without inter-study heterogeneity [RR, 0.91 (95% CI 0.82-1.01), p=0.08; I2=4%, p=0.35]. In specific populations, including patients with intermediate cytogenetic risk and those receiving high-dose cytarabine, the G-CSF priming regimen prolonged OS. G-CSF priming in combination with intensive remission induction treatment is not universally effective in patients with AML. Further studies are required to identify the patient cohort for which G-CSF priming is recommended.

Flow cytometric minimal residual disease measurement accounting for cytogenetics in children with non-high-risk acute lymphoblastic leukemia treated according to the ALL-MB 2008 protocol.

Quantitative measurement of minimal residual disease (MRD) is the "gold standard" for estimating the response to therapy in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Nevertheless, the speed of the MRD response differs for different cytogenetic subgroups. Here we present results of MRD measurement in children with BCP-ALL, in terms of genetic subgroups with relation to clinically defined risk groups. A total of 485 children with non-high-risk BCP-ALL with available cytogenetic data and MRD studied at the end-of-induction (EOI) by multicolor flow cytometry (MFC) were included. All patients were treated with standard-risk (SR) of intermediate-risk (ImR) regimens of "ALL-MB 2008" reduced-intensity protocol. Among all study group patients, 203 were found to have low-risk cytogenetics (ETV6::RUNX1 or high hyperdiploidy), while remaining 282 children were classified in intermediate cytogenetic risk group. For the patients with favorable and intermediate risk cytogenetics, the most significant thresholds for MFC-MRD values were different: 0.03% and 0.04% respectively. Nevertheless, the most meaningful thresholds were different for clinically defined SR and ImR groups. For the SR group, irrespective to presence/absence of favorable genetic lesions, MFC-MRD threshold of 0.1% was the most clinically valuable, although for ImR group the most informative thresholds were different in patients from low-(0.03%) and intermediate (0.01%) cytogenetic risk groups. Our data show that combining clinical risk factors with MFC-MRD measurement is the most useful tool for risk group stratification of children with BCP-ALL in the reduced-intensity protocols. However, this algorithm can be supplemented with cytogenetic data for part of the ImR group.

Organomegalies as a predictive indicator of leukemia cutis in patients with acute myeloid leukemia.

Leukemia cutis (LC) is an extramedullary acute myeloid leukemia (AML) infiltrate. No previous study has described the clinical characteristics and outcomes of Thai patients diagnosed with AML with LC. We conducted a 7-year retrospective case-control study on Thai AML patients at Siriraj Hospital from November 2013 to July 2020. Patients were divided into LC and non-LC groups. Initial clinical presentations and laboratory findings were examined to identify LC-associated factors. Overall survival (OS) and relapse-free survival (RFS) were assessed. Pathological tissues underwent re-evaluation to validate the LC diagnoses. The study included 159 patients in a 2:1 ratio (106 non-LC and 53 LC). The LC group had a mean ± SD age of 54.3 ± 15.5 years; females were predominant. Three-fifths of the LC patients had intermediate-risk cytogenetics; 20.4% had an adverse risk, and 10.2% had a favorable risk. Most were classified as AML-M4 and AML-M5. Leukemic nodules were the primary finding in 58.5% of the cases, mainly on the legs. In the multivariate analysis of predictive factors associated with LC, organomegalies, specifically hepatomegaly, and lymphadenopathy, remained significant factors associated with LC [OR 4.45 (95%CI 1.20, 16.50); p = 0.026 and OR 5.48 (95%CI 1.65, 18.20); p = 0.005], respectively. The LC group demonstrated a significantly reduced OS (log-rank test p = 0.002) (median OS of 8.6 months vs. 32.4 months). RFS was considerably lower in the LC group (log-rank test p = 0.001) (median duration of 10.3 months vs. 24.4 months in the non-LC). AML patients who developed LC tended to experience notably poorer prognoses. Therefore, it is imperative to consider aggressive treatment options for such individuals. The presence of organomegalies in AML patients serves as a strong predictor of the possible occurrence of LC when accompanied by skin lesions.

Class III Obesity Is Associated with Worse Overall Survival in Previously Untreated Younger Patients with Acute Myeloid Leukemia Enrolled on SWOG 1203

Mohamed Sorror and Mary-Elizabeth Percival contributed equally to this project. Introduction: There has been inconsistent evidence supporting the association between obesity and outcomes in patients with newly diagnosed acute myeloid leukemia (AML). Prior studies have studied obesity as defined by body mass index (BMI) ≥ 30. However, this general definition of obesity can be further subdivided into class I obesity (BMI 30 to <35), class II obesity (BMI 35 to <40) and class 3 obesity (BMI ≥40). Given the high prevalence of obesity in the United States (41.9%; with class III obesity 9.2%), distinctions in degree of obesity may be associated with outcomes for patients with AML (Stierman et al, 2021). We were interested in studying outcomes in patients with AML stratified by class I, class II and class III obesity after induction chemotherapy and allogeneic hematopoietic cell transplant (HCT). Identification of at-risk patient populations could aid in design of future interventions. Methods: We retrospectively reviewed a group of 738 previously untreated subjects with AML randomized to daunorubicin and cytarabine (DA), idarubicin and cytarabine (IA), and IA with vorinostat as part of clinical trial SWOG 1203, conducted by the SWOG Cancer Research Network between 2012 and 2015. Subjects with adverse risk cytogenetics were recommended to receive HCT in their first complete remission (CR1); subjects with intermediate risk cytogenetics were selected for HCT in CR1 per local institutional standards. Nine patients who did not receive protocol therapy or had missing BMI were excluded (final cohort 729 patients). Early death was defined as death within 56 days of induction chemotherapy. Multivariable time-dependent Cox regression model and Fisher's exact test were used for analysis of overall survival (OS). HCT in first complete remission (CR1) was included as a time-dependent covariate. Results: The median age was 49 years (range, 18 to 60), 51% were male, 90% had de novo disease, and 88% had a performance status (PS) of 0-1 (Table 1). Among these patients, 1% (n=9) were underweight, 25% (n=182) were normal weight, 31% (n=225) were overweight, 20% (n=145) had class I obesity, 11% (n= 82) had class II obesity and 12% (n= 86) had class III obesity. There was no difference in the rate of achieving composite CR (CR with or without count recovery) between different weight categories (p=0.17). There was no clear trend in early death rate by weight (underweight: 11%; normal weight: 4%; overweight: 6%;class I obesity: 7%; class II obesity: 4%; class III obesity: 17%), though class III obesity had a significantly higher early death rate as compared to all the other groups combined (p=0.004). In multivariable Cox regression analyses, class III obesity was significantly associated with worse OS when compared to normal weight (hazard ratio (HR) 2.56, 95% confidence interval (CI) 1.68-3.90; p<0.001); though not statistically significant, we identified a trend towards worse OS for patients with class I (HR 1.40, 95% CI 0.95-2.06; p=0.09) and class II obesity (HR 1.48, 95% CI 0.95-2.31; p=0.09) (Figure 1). Other co-variates with a significant association with OS included age (HR 1.03, 95% CI 1.01-1.04; p<0.001), intermediate cytogenetic risk (HR 2.45, 95% CI 1.33-4.51; p=0.004), and adverse cytogenetic risk (HR 5.86, CI 3.10-11.06; p<0.001). HCT during CR1 was not found to be significantly associated with OS (HR 0.88, CI 0.67-1.15; p=0.3). No significant difference was identified in time to HCT based on BMI category. In patients who underwent HCT during CR1, class III obesity (HR 2.32, 95% CI 1.22-4.43; p=0.01) and older age (HR 1.02, 95% CI 1.00-1.04; p=0.01) were significantly associated with worse OS; in contrast no significant association was identified between OS and class I obesity (HR 1.30, 95% CI 0.77-2.20;p=0.32), while a higher HR and a trend existed for class II obesity (HR 1.76, 95% CI 0.97-3.17; p=0.06). Conclusions: Our retrospective analysis suggests that among newly diagnosed younger patients with AML, those with class III obesity are at increased risk of early death and shorter overall survival. Future directions include assessing lean body mass in addition to BMI in patients with newly diagnosed AML, as sarcopenic obesity is known to portend poor outcomes. Identifying this at-risk patient population may help guide future investigation of early weight management interventions in patients with newly diagnosed AML.

Correlation between Number of Molecular Mutations and Outcomes in De Novo Acute Myeloid Leukemia

Introduction 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 Kentucky Cancer Registry (KCR) 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. The list of clinically significant mutations was obtained from My Cancer Genome and was compared to the mutations present in our patients. Statistical analysis was done using the Mann-Whitney U test for continuous variables and proportions were compared using Chi-square test. Overall survival (OS) was calculated by the Kaplan-Meier method and compared using a log-rank test. P value was considered significant if < 0.05. 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 CS mutations, 43% (n=97) had 3-5 mutations, and 6 % (n=13) had > 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 >5 mutations when compared to those with 5 or less mutations (23 vs 7 months, p= 0.012, Figure 1). When analyzing the number of CS mutations per cytogenetic group, those 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 < 0.001). In patients with > 5 CS mutations, 11/13 had a mutation associated with an adverse prognosis. 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 > 5 CS mutations had a significantly shorter OS compared to patients with ≤ 5 CS mutations (43 vs 9 months, p= 0.001, Figure 2). Conclusion In summary, we found that patients with intermediate-risk cytogenetics have a high number of CS mutations. When patients were stratified by number of mutations, we found that a higher number of mutations (>5) led to statistically significant difference in survival compared to those with ≤5 mutations. 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 compared to ≤ 5 mutations. It appears that 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. This finding will need to be validated in a large prospective clinical trial.

Differences within the Immune Microenvironment May Account for Poorer Outcomes in African American AML Patients Compared to European American Patients with AML

Background: Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from an immature myeloid progenitor with notoriously poor outcomes. A critical factor responsible for the difficulty in treating this disease evasion of the host immune system by AML. Both the innate and adaptive immune systems have been shown to be dysfunctional in AML with poor type I interferon responses, decreased STING signaling and increased populations of granulocytic and monocytic myeloid derived suppressor cells ultimately leading to poor adaptive response. Studies in solid tumors have demonstrated that variation in immunity contributes to racial disparities in cancer and outcomes. This is felt to be due to variation in geographic ancestry leading to differences in the innate immune genome required due to the need for protection against environmental pathogens. However, no data exists comparing innate and adaptive immunity by race in patients (pts) with AML. Here we sought to characterize the immune microenvironment with treatment outcomes in racially diverse AML pts. Methods: Adults with newly diagnosed AML were identified who had corresponding cryopreserved bone marrow mononuclear cells available within Roswell Park Hematologic Procurement bank. Pts were matched as closely as possible for age, gender, cytogenetic risk per ELN 2017 and molecular profile. Transcriptional differences between African American (AA, n=26) and European American (EA, n=26) AML pts and healthy controls (n=10) were analyzed using transcriptomics data from NanoString Pan Cancer Immune Profile panels. AA and EA AML samples were compared to each other, as well as their race-matched healthy controls. The ‘Limma’ package in R was utilized for differential gene expression analysis. Research was conducted according to the Declaration of Helsinki in accordance with the Institutional Review Board regulated protocol. Results: The median age of the entire cohort (n=52) was 65 years (range: 28-92), with 28 female patients (53.8%) ( Table 1). Within the AA cohort, the majority of pts had intermediate risk cytogenetics per ELN 2017 (n=19; 73.1%, and 6 pts had FLT3 mut (26.1%). Three pts (11.5%) underwent allogeneic stem cell transplant, with a median overall survival (OS) censoring for transplant of 5 months (range; 0.5-68 months) ( Figure 1). Within the EA cohort, most pts had poor risk cytogenetics (n=15; 57.7%). Six pts had FLT3 mut (26.1%), and three pts had TP53 mut (12%). Five pts underwent allogeneic stem cell transplant (19.2%), with a median OS of 16.4 months (range; 0.8-67 months). Sixty-nine significantly (p<0.05, |logFC|>1.5) differentially expressed genes in AA vs. EA pts were identified. Gene set enrichment analysis (GSEA) revealed alterations to Interferon, Jun kinase and STAT signaling pathways in AA pts. In contrast, EA pt samples were enriched for pathways related to amyloid metabolism and other T and B cell immune pathways. Master regulator analysis using LISA highlighted transcriptional dysregulation attributed to PDGB5, CTCF, AR, and NOTCH in AA pts and to GLIS2, SMAD1 and NFE2 in EA pts. Conclusions: As previously reported, we found that a clinically matched cohort of AA AML patients experienced significantly worse OS as compared to EA counterparts. We have identified several significant alterations within the immune microenvironment between cohorts, which may potentially explain this discrepancy in survival in AA patients. These differences could potentially serve as targetable alterations for therapeutic purposes. This work represents the first of its kind evaluating the immune microenvironment by race in AML patients and are awaiting confirmation in a larger cohort.

Outcomes for Children with High Risk Acute Myeloid Leukemia on the Myechild 01 International Phase III Clinical Trial

Background: Outcomes for pediatric acute myeloid leukemia (AML) remain disappointing, particularly for patients with poor risk cytogenetic/molecular genetic abnormalities and those who fail to achieve complete remission following course 1 of induction chemotherapy. Despite upfront allogeneic hematopoietic stem cell transplantation (HSCT) for these patients, high rates of relapse persist. The optimal approach to chemotherapy intensification and timing of HSCT for high risk (HR) patients remains unknown, with variable approaches employed by cooperative trial groups. Methods: The MyeChild 01 international phase III trial (NCT02724163) in children with de novo AML allocated patients up to 3 doses of gemtuzumab ozogamicin (GO 3mg/m 2/dose) during the first course of induction chemotherapy (mitoxantrone 12 mg/m2/dose x4; cytarabine 100 mg/m2/dose x20). Patients classified as HR after course 1 received FLA-Ida for course 2 followed by allogeneic HSCT. If required, a third course of bridging therapy (FLA) was given prior to HSCT. HR patients in MyeChild 01 included those with NUP98 fusions, selected KMT2A fusions ( KMT2A::MLLT10, KMT2A::MLLT4, KMT2A::AFF1, KMT2A::ABI1), CBFA2T3::GLIS2, DEK::NUP214, MECOM ( EVI1) rearrangements and all 12p abnormalities including MNX1::ETV6, in addition to the traditional HR abnormalities -7, -5/del(5q) and FLT3-ITD (without concurrent good risk abnormalities, including NPM1 mutations). Patients with induction failure after course 1 (≥ 5% blasts confirmed by flow) and those with non-HR cytogenetics/molecular genetics who remained MRD positive after course 2 (intermediate risk cytogenetics) or 3 (good risk cytogenetics) were also classified as HR. Here, we report the estimated 2-year outcomes for patients assigned HR post course 1 who received mitoxantrone and cytarabine and at least 1 dose of GO during course 1 (MA-GO). Outcomes of trial randomisations (1 vs 2 or 3 GO doses; consolidation for standard risk patients; HSCT conditioning) will be reported separately. Results: Of 749 patients enrolled at initial diagnosis, 183 received MA-GO during course 1 and were assigned HR post course 1. Of these, 172 (94%) patients had poor risk cytogenetic/molecular genetics, of which 32 also failed to achieve CR. Additionally, 11 (6%) patients did not have poor risk cytogenetic/molecular genetics but failed to achieve CR with MA-GO and thus were assigned to the HR group. Post course 1, 140 (77%) of these HR patients achieved CR/CRi, with 102/155 (66%) patients with evaluable samples achieving MRD negativity post course 1. Following course 1, 174 (95%) remained on trial and received FLA-Ida as course 2 and 163 patients (89%) proceeded to HSCT, 55 on trial and 108 following discontinuation from the trial. Estimated event-free survival (EFS) and overall survival (OS) at 2 years was 62% (95% CI: 56-70%) and 71% (64-78%) respectively (Figure 1 & 2). Estimated cumulative incidence of relapse (CIR) and death in remission at 2 years was 26% (19-33%) and 7% (3-11%) respectively. For HR patients who received MA-GO in course 1, on trial FLA-Ida as course 2 and on or off trial HSCT (n = 156), 2 year estimated outcomes were EFS 69% (62-77%), OS 77% (70-85%) and CIR 24% (17-32%). The most common cytogenetic/molecular genetic abnormalities were rearrangements of KMT2A (50/183, 27%), with KMT2A::MLLT10 predominating (70%). FLT3-ITD (19%), NUP98 fusions (14%), -7 (13%), abn(12p) (11%), del(5q) (8%) and CBFA2T3::GLIS2 (6%) accounted for the majority of other abnormalities with outcomes varying by subtype. Collectively, KMT2A-rearranged patients had EFS and OS of 68% (55-83%) and 71% (59-86%) respectively and CIR of 26% (12-40%). For FLT3-ITD, the EFS and OS was 75% (62-92%) and 83% (69-99%) respectively with a CIR of 14% (1-26%). Of the 25 patients with a NUP98 fusion, 17 (68%) were NUP98::NSD1. The EFS and OS for patients with NUP98 fusions was 71% (55-92%) and 96% (88-100%) respectively with CIR 25% (1-48%). Conclusions: Two intensive courses of induction chemotherapy, including GO and mitoxantrone in course 1 and FLA-Ida in course 2, consolidated with allogeneic HSCT, appears to be an effective approach for most HR patients. 2 year estimated outcomes for HR patients compare favourably to recent trials of GO in pediatric AML, with particularly encouraging data for patients with KMT2A-r and FLT3-ITD.

Venetoclax in Combination with Pediatric-Inspired Chemotherapy in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia: Results of a Phase I Trial

Introduction: Young adults with acute lymphoblastic leukemia (ALL) have favorable outcomes compared with historical standards when treated with an asparaginase-containing pediatric regimen (Stock et al., Blood 2019). We have demonstrated the safety and efficacy of pediatric inspired chemotherapy (PIC) for adults up to age 60 (MSK protocol 12-266, Geyer et al., Haematologica 2021). However, cure rates for adults with ALL remain below 60%, prompting the need for novel agents. Venetoclax (ven) is a BCL2 inhibitor being tested in several clinical trials for ALL. Here, we present the first report of ven used in combination with a multiagent, asparaginase-containing chemotherapy regimen for the upfront treatment of ALL. Methods: We conducted a Phase I, single-center, single-arm clinical trial (NCT05386576) to evaluate the safety and efficacy of ven in combination with PIC in adults with newly diagnosed ALL. Adults aged ≤60 years diagnosed with Philadelphia chromosome negative ALL were eligible for the study. The primary objective was to evaluate the safety of ven in combination with asparaginase-based PIC and identify the maximum tolerated dose and recommended phase II dose. The secondary objectives were to assess the rate of complete remission (CR) and measurable residual disease (MRD) negative CR at day 15 and 28 of Induction I, and end of Induction II. The regimen consisted of 6 treatment phases as previously published (12-266). Ven was administered at a final dose of 400mg (with a rapid dose escalation from 100mg over 3 days) during Induction I (days 5-7 dose escalation, days 7-28 full dose), Induction II (days 1-14 and 29-42), Intensification I & II (days 1-22), and Re-Induction I & II (days 1-14 and 29-42). Measurable residual disease (MRD) was assessed by multiparameter flow cytometry with 10 -4 sensitivity. We used historical data from 22 patients (pts) treated on our previous study, who received the same chemotherapy backbone without ven, as a comparator. Median follow up was calculated using the reverse Kaplan Meier indicator. Duration of treatment was compared using the Wilcoxon rank-sum test. Proportions of pts who achieved MRD-CR were compared with the chi squared test. Results: At the time of analysis, 8 pts had enrolled in the study; all 8 pts completed induction I and 6 (75%) pts had completed induction II (Table 1). Median follow up was 171 days. The median age was 38.5 years (min 25, max 60). 50% of pts had B-cell ALL, and 50% T-cell (including 1 patient with early T-cell progenitor). One patient (12.5%) had CNS disease (CNS 3) at diagnosis. Four (50%) pts had intermediate risk cytogenetics by CALGB 19802 classification (Stock et al., Cancer 2013), 2 (25%) had unfavorable, and 1 (12.5%) favorable. Two (40% of B-ALL) had a Philadelphia-like phenotype. During Induction I & II, 4 (50%) pts experienced febrile neutropenia, 6 (75%) grade 4 thrombocytopenia, and all 8 (100%) grade 4 neutropenia. No dose limiting toxicities, as defined per protocol, were observed. The average duration of Induction I on study was 46.6 days compared to 43.6 on 12-266 (p = 0.11). The average duration of Induction II on study for pts who had completed it at the time of analysis was 102 days compared to 74 days on 12-266 (p = 0.02), primarily due to cytopenias. Three (37.5%) of pts achieved an MRD negative CR by the end of Induction I. Of the 6 pts who had completed Induction II by time of analysis, 5 (83%) had achieved an MRD- CR, compared to 81% on 12-266 (p = 0.90) and 1 patient had refractory extramedullary disease. We assessed kinetics and depth of response by plotting the average blast percentage in the bone marrow by flow cytometry across three different timepoints. Pts on the study had numerically lower blast percentages at day 15, end of Induction I and end of Induction II compared to 12-266 (Figure 1). At the time of this analysis, no patient who entered CR had experienced disease relapse. Conclusions: Ven addition to a PIC backbone was overall safe with high MRD negative remission rates in this preliminary report. Compared to historical controls, pts treated with ven had a longer duration of Induction II primarily due to cytopenias, and we are amending the study to shorten ven duration during induction II. Pts treated with ven had a numerically faster reduction in bone marrow blasts compared to historical controls. Longer follow up in a larger patient population in this ongoing study will be required to assess long term toxicity and efficacy of this regimen.

Association between Cytogenetic Risk and Obesity in Patients with Acute Myeloid Leukemia (AML): A Meta-Analysis

Background: The global obesity epidemic has been well characterized over decades of research, linking increased body mass index (BMI) ≥ 25 to multiple medical conditions including increased cancer risk, morbidity, and mortality. The International Agency for Research on Cancer (IARC) group found a positive correlation between obesity to 13 cancers and multiple studies suggest leukemia should be added to this list. The causation behind this risk in leukemia however is not well understood and the prognostic factors have not been well characterized. Acute Myeloid Leukemia (AML) specifically defines risk based on cytogenetics between favorable, intermediate and unfavorable which significantly affects treatment decisions. The link between obesity and cytogenic risk factors in AML have not previously been thoroughly evaluated. To address this knowledge gap, we conducted a comprehensive meta-analysis aiming to evaluate the cytogenetic risk with obesity and prognostic significance in patients with AML. Methods: A systematic search was conducted across major databases until June 2023, using tailored search structures, subject headings, and keywords developed in collaboration with a medical research librarian. Two investigators independently screened the studies for inclusion. The inclusion criteria encompassed retrospective and prospective clinical studies that reported on the association between established cytogenetic classifications and standardized measures of excessive weight (BMI 25-30) and obesity (BMI ≥ 30). Meta-analysis was conducted using restricted maximum likelihood random-effects model. Results: From an initial pool of 1673 identified studies, eleven studies met the inclusion criteria, encompassing a total of 5887 patients. Among these patients, 1363 met the criteria for obesity (BMI ≥ 30) and 2176 met the criteria for excessive weight (BMI 25-30). The median patient's age was 54 (ranging from 15 to 89). The included studies originated from diverse geographic regions, including the USA, Japan, and France. Baseline patient characteristics are summarized in Table 1. Compared to overweight patients, our meta-analysis revealed a significant association between obesity and higher odds of unfavorable/intermediate cytogenetic risk (odds ratio [OR] 1.27, 95% CI [1.04; 1.54]), as seen in Figure 1. However, no meaningful statistical inference could be made regarding the association between obesity and specific gene mutations (such as FLT3, NPM1, CEBPa, TET2, IDH1, IDH2, RUNX1, and KRAS) due to the limited number of studies and small number of patients involved. Conclusion: Our meta-analysis demonstrates a significant association between obesity and unfavorable/ intermediate cytogenetic risk in patients with AML. Although the precise biological mechanisms remain elusive, several potential explanations have been proposed. These include the impact of obesity leading to chronic low-grade inflammation, altered adipokine secretion and insulin resistance, and metabolic changes on leukemic cell growth and survival. Despite the limitations of unknown cytogenetic risk in 590 patients and limited mutation data in some studies, our findings suggest that obesity may impact the prognosis of AML. Future research should address these limitations and provide a more comprehensive understanding of the intricate interplay between obesity, cytogenetics, and AML prognosis.

Pre-Transplant Somatic Co-Occurring Mutations (by next generation sequencing) in Acute Myeloid Leukemia: Frequency and Impact on Clinical Outcomes after Allogeneic Hematopoietic Cell Transplantation - a Large Study on Behalf of the EBMT Acute Leukemia Working Party

Background: Acute myeloid leukemia (AML) is a very heterogeneous hematological malignancy, which includes numerous genetically defined subsets. The genomic classification of AML with the identification of mutations in transcription factors, epigenetic modifiers, spliceosome, cohesin complex, and signaling pathways has led to a more accurate risk stratification model. The main genetic aberrations included in the European LeukemiaNet (ELN) 2022 classification are NPM1 (risk group according to karyotype and FLT3-ITD status), FLT3-ITD (intermediate risk), bZIP in-frame mutated CEBPA (favorable risk), and RUNX1, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2 and TP53 mutations (all belonging to the adverse risk group). In the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), the frequency and prognostic value of different gene-gene interactions has not been studied and may differ from that of patients treated with chemotherapy alone. We aimed at evaluating, through the European Society for Blood and Marrow Transplantation (EBMT) database, the frequency and impact of different recurrent somatic mutations, either alone or in association, on prediction of relapse and survival in patients receiving allo-HSCT. Methods: This is a retrospective, registry-based, multicenter analysis from the EBMT with the approval of the EBMT Acute Leukemia Working Party. Adult patients aged more than 18 years with a diagnosis ofAML who received an allo-HSCT between 2013-2022, with an available genetic profile determined at diagnosis by next generation sequencing (NGS) were included. Results: We identified 836 allografted AML patients who had NGS performed at diagnosis. Most of these patients had de novo AML (88%), with a median age of 53 years (range: 18-78 years). Karyotype was favorable in 7%, intermediate in 69% and adverse in 24% of patients. At transplant, 74% of patients were in first remission (CR1) and 13% in CR2. The most frequent detectable mutations by frequency were DNMT3A (33%), FLT3 (29%), NPM1 (29%), TET2 (28%), NRAS (23%), RUNX1 (22%), WT1 (22%), BCOR (19%), ASXL1 (17%), IDH2 (17%), IDH1 (15%), SRSF2 (13%), STAG2 (12%), CEBPA (11%), TP53 (10%), KRAS (10%), and PTPN11 (10%) . By multiple correspondence analysis, two independent groups of co-occurring mutations were identified, the first group included DNMT3A, NPM1 and FLT3, the second group included ASXL1, SRSF2 and RUNX1. Outcome analysis was performed on the subset of 298 patients allografted in CR1 with available data for the aforementioned six genes ( DNMT3A, NPM1, FLT3, ASXL1, SRSF2 and RUNX1). Most of these patients had de novo AML (90%), with a median age of 53 years (range: 19-75 years). Patients received primarily reduced intensity conditioning (58%) and peripheral blood stem cells (93%) from matched sibling donors (35%), matched unrelated (28%), and haploidentical donors (21%). Seventy percent of these patients had intermediate-risk cytogenetics, while 27% were classified as adverse-risk. Median follow up calculated by the reverse Kaplan-Meier method was 2.5 years. Overall, the 2-year relapse incidence (RI), leukemia-free survival (LFS) and overall survival (OS) were 24%, 62% and 69%, respectively. When outcome analysis was performed according to the presence or absence of single mutations, none of the six mutations significantly affected RI or LFS. The 2-year OS was positively affected by the presence of NPM1 mutation (78% vs 66%; p=0.02) and FLT3 (79% vs 65%, p=0.01) but not significantly affected by the other 4 mutations. When mutations were investigated in groups, the 2-year RI, LFS and OS were 24%, 70% and 78%, respectively, for patients with NPM1 mutation regardless of other co-mutations, 35%, 56% and 69% for patients with FLT3-ITDand/or DNMT3A mutation, wild type NPM1, regardless of other co-mutations, 17%, 70% and 74% for patients with RUNX1 and/or ASXL1 and/or SRSF2 mutation without FLT3-ITD and with wild type NPM1 and wild type DNMT3A and 20%, 56% and 61% for patients with all six genes unmutated. Conclusion: NGS at diagnosis can be extremely useful in risk stratification of AML patients undergoing allo-HSCT, potentially allowing adequate post-transplant interventions. Notably, the 2-year LFS of 70% for patients harboring RUNX1 and/or ASXL1 and/or SRSF2 mutation indicates that allo-HSCT can overcome the adverse risk associated with these somatic mutations at diagnosis.

Real-World Study in Acute Leukemia: Epidemiology, Treatment Patterns and Outcomes for Newly Diagnosed AML in Adult Patients from Latin America - Loyal Study

Introduction. Acute myeloid leukemia (AML) is the most frequent leukemia among adults and representing 90% of all cases of acute leukemia in adults. Differences in incidence and burden of AML among regions of the world have been reported. When compared with registries from the US, UK and Sweden, Latin-America (LA) AML has a younger age at diagnosis (median age of 40-47 versus 64 -67 years old). Furthermore, single center studies have suggested poor treatment outcomes in LA. For example, Silveira et al reported a median age at diagnosis of 46 y, frequency of favorable cytogenetics of 26% and median overall survival (mOS) of 12 months in the Brazilian cohort of patients with newly diagnosed AML (nAML) whereas the respective values at Oxford University were 51.5y, 11% and 48 months in British patients. However, wider studies across the region are scarce and there is a need to further explore AML patient characteristics and treatment outcomes in LA. Methods. This is a non-interventional, retrospective multicenter study that aims to describe the epidemiology, clinical and demographic characteristics, treatment patterns, survival outcomes and healthcare resource use of adult patients with nAML in Argentina, Brazil, Chile, and Colombia. Data from medical records of eligible patients that met the inclusion criteria (≥ 18 years old at diagnosis, confirmed diagnosis of nAML between 01 January 2015 and 31 December 2019, and receiving at least one line of treatment) in these LA countries were considered for the analysis, which was descriptive in nature as no hypothesis has been tested. Results: A total of 518 nAML patients were included in the study, 166 from Argentina, 205 from Brazil, 63 from Chile, and 84 from Colombia. Table 1 shows the demographics and clinical characteristics. At treatment initiation, an evaluation of fitness (eligibility) for intensive chemotherapy was available for 94% of the patients (n=489). The majority were considered fit (75.5%; n=391) and received standard 7+3 therapy. About 11% of patients (n=9) were refractory to induction therapy. Median OS for fit patients was 11.9 months, whereas for unfit patients was 5.8 months. Mutational status of genes listed by the European LeukemiaNet (ELN) Classification of 2017 was not available for the majority of cases; risk categories were assigned based on cytogenetics. Patients in the favorable-risk category had a mOS of 30.5 months, whereas those in the intermediate- and unfavorable-risk had 11.1 and 9.1 months, respectively (Figure 1). The probability of 5year OS rates for favorable, intermediate- and unfavorable-risk groups were of 38.8%, 16.6% and 20.9%, respectively. Eighty-six patients (17%) discontinued treatment with reasons being adverse event/toxicity (33%; n=28), death (32%; n=27), and disease progression (17%; n=14). Only 24% of patients (n=125) underwent a subsequent stem cell transplantation (SCT), mainly allogenic (98%; n=121). For SCTs, identical (matched) related (50%; n= 59) and haploidentical donor (35%; n=41) were the most common. Patients not eligible to intensive chemotherapy were treated with HMA (9%; n=47) and LDAC (5%; n=25), with 10% of the patients receiving palliative/supportive care. The most common treatment protocols used in relapsed or refractory (R/R) patients were high-dose cytarabine (HDAC) (31%; n=85), followed by FLAG-IDA (24%; n=66). Conclusions: This study of newly diagnosed acute leukemia characterizes real-world treatment patterns and outcomes in LA clinical practices. Prior to this study, there has been limited published data on the epidemiology and treatment patterns across LA. This study highlights that for nAML patients, the most common treatment in LA is 7+3 and most patients are classified as fit. The vast majority of patients had their risk accessed by cytogenetics analysis only, reflecting the limited access to molecular tests. Fewer patients underwent stem cell transplantation as part of the treatment compared to that reported in US and Europe, probably due to restricted availability of hospital beds dedicated to bone marrow transplantation. When evaluating the overall survival, the study shows higher mOS for favorable risk. In addition, mOS for intermediate and poor cytogenetic risk were similar. A broader access in the region to molecular tests, transplant and new therapies are needed in order to reduce the gap in outcome, especially for patients with intermediate-risk.

Efficacy and Safety of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Treatment-Naive, Higher-Risk Myelodysplastic Syndromes

Introduction: Azacitidine (Aza) has been shown to prolong survival in patients with treatment-naive, higher-risk myelodysplastic syndrome (HR MDS) compared to lower-intensity, conventional treatment regimens; however, improvement in clinical outcomes are needed. Clinical data on the synergy of Aza with venetoclax (Ven)-a selective, potent BCL-2 inhibitor-in the treatment of myeloid malignancies and the unmet need in HR MDS provide a rationale to evaluate Ven in combination with Aza in treatment-naive HR MDS. Here, we report efficacy and safety data in patients with treatment-naive HR MDS treated with Ven+Aza at the recommended Phase 2 dose (RP2D) in the safety expansion part of the Phase 1b study (NCT02942290). Methods: Adult patients were enrolled with de novo treatment-naive HR MDS defined by the Revised International Prognostic Scoring System (IPSS-R) score of >3 with an Eastern Cooperative Oncology Group performance status of ≤2, and bone marrow (BM) blasts <20% at baseline. Patients received Ven 400 mg orally daily on Days 1-14 and Aza 75 mg/m 2 intravenously or subcutaneously on Days 1-7 or on Days 1-5, 8, and 9 of each 28-day cycle (RP2D). The primary objective was to assess the complete remission (CR) rate. Key secondary objectives included determining marrow CR (mCR), overall response rate (ORR), hematologic improvement (HI), postbaseline red blood cell (RBC) and platelet transfusion independence (TI), overall survival (OS), duration of CR, time to next treatment (TTNT), transformation to acute myeloid leukemia (AML), and time to AML transformation. Responses were assessed by International Working Group 2006 criteria. Prophylactic antibiotics were mandated in Cycle 1 and recommended for Grade ≥3 neutropenia thereafter. Safety was analyzed in patients who received ≥1 dose of study treatment. Results: At thedata cutoff of May 31, 2023, 107 patients had received Ven+Aza at the RP2D. Key baseline characteristics for all treated patients are shown in Table 1A. Median age was 68 years (range, 26-87), 64% of patients had intermediate or poor cytogenetic risk, and >89% had ≥5% BM blasts. Median number of treatment cycles before transplantation was 3.0 (range, 1.0-11.0). At the median follow-up of 31.9 months (95% CI, 30.4-42.5), CR rate was 29.9% (95% CI, 21.4-39.5), with a median CR duration of 16.6 months (95% CI, 10.0-not reached [NR], Table 1B). Median OS was 26 months (95% CI, 18.1-51.5), with an estimated 12-month OS of 71.2% (95% CI, 61.4-78.9)and 24-month OS of 51.3% (95% CI, 41.2-60.5). Median OS for CR was NR. Median TTNT including transplantation was 6.8 months (95% CI, 5.6-8.3). Sixty-two (57.9%) patients received subsequent treatment, including transplantation in 42 (39.3%) patients; the median time to transplantation was 4.8 months (range, 1.4-16.8). Among patients who received transplantation post-study, 17 were transplant ineligible at study entry. Postbaseline TI rate was 61.7% for RBC and 72.0% for platelets. Median maximal duration of TI achieved was 5.4 months (range, 1.8-50.8) and 5.4 months (range, 1.9-56.0) for RBC and platelets, respectively. Postbaseline overall hematologic improvement (HI) was achieved in 51 (49.0%) of 104 evaluable patients, and specific responses included erythroid (40/93; 43.0%), platelet (32/74; 43.2%) and neutrophil (10/57; 17.5%) indices. All patients experienced ≥1 treatment-emergent adverse event (TEAE), with 94.4% of patients reporting grade ≥3 TEAEs. Serious adverse events (SAEs) occurred in 68.2% of patients. Common TEAEs of any grade were constipation (53.3%), nausea (49.5%), neutropenia (48.6%), thrombocytopenia (44.9%), febrile neutropenia (42.1%), diarrhea (41.1%), anemia (39.3%), vomiting (36.4%), and hypokalemia (26.2%). Grade ≥3 TEAEs reported in ≥20% of patients were neutropenia (48.6%), thrombocytopenia (43.0%), febrile neutropenia (42.1%), and anemia (34.6%). Infections were reported in 57% of patients, including SAEs in 40.2% of patients. Of the 59 deaths (55.1%) reported, 23 (21.5%) were due to disease progression and 7 (6.5%) to adverse events. Within 60 days after study start, 7 deaths (6.5%) were reported. Conclusion: Ven 400 mg for 14 days plus Aza combination was well tolerated with favorable responses of CR+PR+mCR in >80% and HI in nearly 50% of patients with treatment-naïve HR MDS. A separate Phase 3 study of this combination is ongoing to confirm survival benefit.

Oral Decitabine/Cedazuridine with Venetoclax in High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia: Analysis By Different Response Criteria

Introduction: Patients with higher-risk myelodysplastic syndromes (HR-MDS) have poor survival. The standard of care for HR-MDS are hypomethylating agents (HMA). The addition of venetoclax (Ven) to HMA has been shown to improve outcomes in acute myeloid leukemia (AML) and potentially in HR-MDS. The combination of oral decitabine/cedazurridine (DEC-C) with Ven has been shown to induce high response rates in patients with HR-MDS. Herein we analyze the responses of patients treated with DEC-C with Ven according to different response criteria. Additionally, we analyze the cytogenetic responses and mutation dynamics. Methods: We analyzed patients included in a phase I/II single center clinical trial (NCT04655755). diagnosed with treatment-naïve MDS (IPSS intermediate-2 or high) or CMML with excess blasts. Responses were analyzed by the International Working Group (IWG) criteria for MDS of 2006 and 2023, as well as the European LeukemiaNet (ELN) criteria for AML (2022). Cytogenetic responses and mutations were analyzed by conventional cytogenetics/FISH and NGS, respectively. Results: Between January 2021 and January 2023, 39 patients were enrolled. The median age of the entire cohort was 71 years old (range, 27-94), with 26 (70%) male patients. The WHO 2016 diagnosis was MDS with excess-blasts 1 (n=6, 16%), MDS with excess-blasts 2 (n=24, 65%), CMML-2 (n=6, 16%) and atypical chronic myeloid leukemia (n=1, 3%). The cytogenetic risk according to IPSS was good (n=11, 30%), intermediate (n=12, 32%) and adverse (n=14, 38%). The most common mutations found were ASXL1 (n=18, 49%), RUNX1 (n=14, 38%), SRSF2 (n=11, 30%), TET2 (n=8, 22) and TP53 (n=7, 19%). According to the IWG-2006 classification, the overall response rate was 95%, with 17 (43%) patients achieving complete remission (CR) and 20 (52%) patients achieving marrow CR (mCR). When using the IWG-2023 criteria, the overall response rate was 82%, with 23 (59%) patients achieving CR and 9 (23%) achieving CR with limited count recovery/CR with partial hematologic recovery. Of note, 5 patients achieved mCR according to the IWG-2006 but did not achieved CR by the IWG-2023 due to the peripheral blood count. Moreover, we did not find differences in overall survival (OS) between CR and mCR (OS of 60% for both groups, p=0.5). When using the ELN 2022 criteria for acute myeloid leukemia, the ORR was 80% with 2 patients not responding and 2 patients in a morphologic leukemia-free status (MLFS) (Figure 1). Both IWG-2006 and 2023 define cytogenetic response as complete disappearance of chromosomal abnormalities present at diagnosis. 14 patients out of 29 (48%) with cytogenetic abnormalities achieved cytogenetic response after a median of 2 courses of treatment (1-9). The IPSS cytogenetic risk of patients responding was good in 1 (7%) patient, intermediate in 8 (57%) patients and poor in 5 (36%) patients, including 3 patients with complex karyotype. Among patients not achieving cytogenetic response, 5 (33%) and 10 (67%) patients had an intermediate and adverse IPSS cytogenetic risk, respectively. Although molecular responses are not defined in the IWG-2023, we studied the molecular dynamics between diagnosis and best response. 23 patients of the study had molecular data in paired samples at diagnosis and at CR while on treatment. When analyzing the dynamics of each individual mutation, STAG2 (11/11, 100%), NRAS (3/3, 100%), BCOR (4/5, 80%) and IDH1 (2/3, 67%) showed the higher rate of clearance from diagnosis to CR. On the contrary, ZRSR2 (3/4, 75%), U2AF1 (3/4, 75%), TP53 (3/4, 75%), SRSF2 (5/7, 71%) and ASXL1 (10/14, 71%) showed the higher rate of persistence from diagnosis to CR (Figure 2). Among all patients in the study, 19 (49%) proceeded to hematopoietic stem cell transplantation (HSCT). Eleven patients had molecular data after HSCT, all achieving complete mutation clearance after HSCT. Conclusion: DEC-C with Ven achieves a high rate of responses, although with the IWG-2023 criteria responses are lower due to the disappearance of mCR and more strict criteria in terms of peripheral blood count recovery. Almost half of patients with cytogenetic abnormalities can acquire cytogenetic responses, including poor risk cytogenetics. Subclonal mutations (like STAG2 or NRAS) can be cleared with this combination while founding mutations (like ASXL1 or TP53) tend to persist, although HSCT has a potential to eliminate them.

Stratification Using ECOG, ADL and HCT-CI Scales, but Not CGA Enables Identifying Elderly AML Patients Fit for Intensive Chemotherapy - a Multicenter Study from Polish Adult Leukemia Group

Introduction: A key part of decision-making in older AML patients is an insightful clinical assessment before qualification for treatment with intensive chemotherapy (IC). It was demonstrated that among the patients initially deemed “fit” for IC, there are vulnerable patients who experience greater treatment toxicity and have poorer outcomes. Comprehensive geriatric assessment (CGA) is a well-recognized tool for identifying such patients. However, due to its time-consuming nature, it is not commonly used. A number of other prognostic models exist, but none of them enable fast and optimal identification of patients eligible for IC. Aim: In this prospective observational study our group aimed to I) assess clinical outcomes of elderly AML patients who were stratified by Eastern Cooperative Oncology Group Performance Status (ECOG PS), Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), Activity of Daily Living (ADL) scales and received IC and II) evaluate the predictive and prognostic value of CGA components. Material and methods: AML patients aged between 60 and 75 were considered fit for IC if they met all 3 stratification criteria: ECOG PS<2 and HCT-CI<3 and ADL=6. IC regimens included daunorubicin and cytarabine (DA) or daunorubicin, cytarabine and cladribine (DAC) followed by 2 consolidation cycles according to local references. CGA was performed by a qualified medical professional before treatment initiation. CGA included Instrumental Activities of Daily Living Score (iADL), timed up and go test (TUG), geriatric depression scale (GDS), Mini-mental scale Examination (MMSE) and Mini Nutritional Assessment (MNA). The correlations between CGA and complete response (CR) rate were determined by Chi-square test or Fisher's exact test. The Kaplan-Meier analysis and log-rank test were used to compare relapse-free survival (RFS) and overall survival (OS) Results: In total, 85 patients with a median age of 65 years [IQR:63.5-69.0] and slight male predominance (53%) were included in the study. Most patients had HCT-CI score <2 (71.8%). Secondary AML was diagnosed in 23.5% of patients, and most patients had intermediate (32.9%) or adverse (37.6%) ELN cytogenetic risk. Fifty-five (58.8%) patients achieved CR after induction. Median OS reached 16.0 months [95% CI: 11.0-21.00] with median RFS 15.3 months [95% CI: 12.1-18.4]. No significant difference in CR rate (p=0.451), OS (p=0.484) or RFS (p=0.529) was demonstrated between DA or DAC groups. Regardless of induction regimen, patients with CR presented significantly improved OS (p=0.015 for DA, p=0.029 for DAC) compared with non-CR patients. None of the CGA components was shown to influence the CR rate, OS or RFS. Conclusions: In patients aged 60-70 years with AML, stratification by ECOG, ADL, and HCT-CI is an effective tool for qualifying patients for intensive chemotherapy. Comprehensive geriatric assessment does not improve identification of vulnerable patients in this group.

Real World Clinical Characteristics, Treatment Patterns and Outcomes of R/R B-Cell ALL Adult Patients in Latin America

Introduction. Acute lymphoblastic leukemia (ALL) frequently affects mainly children and young adults. ALL has seen important progresses in diagnosis techniques and treatment approaches in the last decade. However, in some developing countries, there are inequalities in ALL management, such as heterogeneous access to diagnosis technologies (e.g., cytogenetic and molecular profiling) and access to target therapies treatments. To date, there is scarce data on those impacts in treatment patterns and real-world outcomes of adult relapsed/refractory (R/R) B-cell ALL (R/R ALL) patients in Latin America (LA). Therefore, this study aims to describe treatment patterns, clinical characteristics, and outcomes of R/R ALL adult patients treated in LA. Methods. This was a retrospective multicenter non-interventional study to evaluate treatment patterns, clinical characteristics and outcomes conducted in Argentina, Brazil, and Colombia. The study included patients ≥ 18 years old at diagnosis with confirmed R/R ALL between January 1, 2015, to December 31, 2019 that received at least one line of treatment for R/R ALL. Data collected from medical records was considered for the analysis, which was descriptive in nature, as no hypothesis has been tested. Results: A total of 71 patients diagnosed with R/R ALL were included in the study (23 from Argentina, 27 from Brazil, and 21 from Colombia). Table 1 shows the demographics and clinical characteristics. The median age at diagnosis was 31 years (Q1-Q3: 24.0-46.0), 56.3% were male, and 50% were White/Caucasian patients. At diagnosis, the most common comorbidities were diabetes, hypertension, gastrointestinal disease, and thyroid disease, with 11% each. At diagnosis, most patients presented with poor or intermediate cytogenetic risk prognosis, in 55.1% and 31.6%, respectively. Most of the patients presented with good performance status, 50.9% ECOG 0 and 36.8% ECOG 1. As for treatment patterns, patients received up to six treatment lines (LOT-1 to LOT-6), with a median of 2.0 LOTs (Q1-Q3: 1.5-3.0) within the R/R setting. Fifty-three (74.6%) out of the 71 patients enrolled in the study received two lines of R/R treatment (up to LOT-2), and 27 patients (38%) received 3 lines (up to LOT-3). The median treatment duration of LOTs were 3.4 months (Q1-Q3: 1.14 - 5.7), 1.4 months (Q1-Q3: 0.62 - 2.6) and 0.9 months (Q1-Q3: 0.4 - 2.1) for LOT-1, -2 and -3, respectively. The most frequently used treatment regimens at LOT-1 were the Hyper-CVAD (22.9%), BFM (20.0%) and GRAAL (15.7%). The most reported reasons for patients discontinuing their regimen in LOT-1 were progression of disease (37.5%), followed by adverse events (25%). For LOT-2 discontinuation, adverse events and/or toxicity (33.3%) were most frequently reported, followed by progression of the disease (25%). Of the total number of R/R ALL patients, 26 (36.6%) underwent stem cell transplantation (SCT), with a median time from diagnosis to transplantation of 9.6 months. All those patients (n=26) received allogeneic hematological SCT (100%), and haploidentical donors were most common (42.3%), followed by identical (matched) related (34.6%), mismatched unrelated donor (15.4%), and identical (matched) unrelated donors (7.7%). For R/R ALL patients, the median overall survival (mOS) was 18.96 months, with a probability of survival of 66.6% at 1 year, 32.3% at 3 years, and 16.2% at 5 years. Philadelphia Chromosome (Ph) molecular results were reported in 53 patients: 38 (71.7%) were Ph- and 15 (28.3%) were Ph+. The mOS in Ph+ patients was 31.5 months, numerically longer than the 17.7 months seen in Ph- patients (p = 0.500); however, the Kaplan-Meiers crossed over and separation was not clearly evident within the follow-up period (Figure 1). Conclusions: This study enabled a better understanding of R/R ALL in LA in the real-world. Data from this study demonstrate the high heterogenicity within first salvage (LOT-1) treatment patterns in R/R ALL, likely due to no established single standard of care in the region and highlights that only a fraction of the patients undergo SCT, which should be the treatment goal following induction therapy. In addition, our study reinforces already published data that overall survival on R/R ALL adult patients remain poor. Consistent guidelines and access to new treatments and are needed to remove inequalities in the management of ALL in LA.

Cluster of Differentiation 38 Protein Significantly Adds to the Prognostic Value of Cytogenetic Risk in Patients with Acute Myeloid Leukemia.

There is some controversy regarding the clinical significance of cluster of differentiation 38 (CD38) protein in acute myeloid leukemia (AML). We aimed to study the prognostic value of CD38 expression in relation to the standard cytogenetic risk stratification in AML patients. In this prospective study, adult patients with AML were diagnosed based on the finding of ≥ 20% blasts in the bone marrow and the flow cytometry. The control group was selected from normal bone marrow samples examined at the same period in the lab. The CD38 expression levels were assessed by immunophenotyping the bone marrow samples of the patients prior to therapy, as well as those from the controls. The subjects were N = 52 newly diagnosed adult AML patients, while n = 25 sex-and-age matched normal volunteers served as the control. The CD38 expression among AML patients ranged from 3.6% to 79.9%, significantly higher levels than in the control population (p =0.001). Positive CD38 expression was higher in AML patients with favorable cytogenetics when compared to those with intermediate and poor cytogenetics (75.0%, 57.1%, and 68.2%, respectively) (p =0.007). Median CD38 expression in AML patients was higher in the favorable cytogenetic group and lower in intermediate and poor cytogenetic groups, though lacking in significance (p =0.578). Patients with poor cytogenetic risk were associated with significantly shorter median overall survival when compared to favorable and intermediate cytogenetic risk (p =0.010). The expression of CD38 significantly adds to the prognostic value of cytogenetic risk stratification at diagnosis of AML patients.

Genetic landscape of acute myeloid leukemias with leukocytosis

Background. Tumor cell proliferation in acute myeloid leukemia (AML) may manifest with high leukocyte counts. In our work, we evaluate the association of high leukocyte counts with individual mutations, as well as their total contribution to the development of leukocytosis in AML. The results obtained should improve our understanding of pathogenic mechanisms leading to the leukocytosis in AML.Aim. To study the genetic landscape of AML with leukocytosis.Materials and methods. The laboratory data of 214 AML patients admitted to the National Medical Research Center for Hematology (Moscow) from 2010 to 2022 were retrospectively examined. Real-time PCR, capillary electrophoresis and NGS (next generation sequencing) methods were used to detect mutations of FLT3, NPM1, CEBPA, IDH1/2, DNMT3A, TET2 genes, and CBFB::MYH11, RUNX1::RUNX1T1 chimeric gene transcripts.Results. Mutations of the FLT3 gene (odds ratio 5.45; p < 0.0001), inv(16)/CBFB::MYH11 (odds ratio 10.03; p = 0.0009) are most associated with leukocyte counts higher than 30 × 109 / L in the debut of AML. Translocation t(8;21)/RUNX1::RUNX1T1 and adverse cytogenetic aberrations, such as -5/del(5q); -7 / del(7q); -17 / abn(17p), complex and monosomic karyotype were significantly associated with leukocyte counts lower than 30 × 109 / L at the time of disease manifestation (p < 0.0001). In the group of patients with intermediate cytogenetic risk bearing only IDH1/2, DNMT3A, and TET2 gene mutations, leukocyte counts at AML debut were significantly lower, whereas the most pronounced leukocytosis was observed in patients with a combination of driver mutations with IDH1/2, DNMT3A, and TET2 gene mutations or FLT3, NPM1, and CEBPA gene mutations.Conclusion. In addition to the individual effect of certain genetic lesions and cytogenetic aberrations on the proliferative potential of tumor cells, there is a total contribution of various types of genetic events to the development of leukocytosis in AML. High leukocyte counts at the time of AML manifestation in patients with intermediate cytogenetic risk can serve as an indirect marker of the presence of a large number of genetic aberrations with a combination of IDH1/2, DNMT3A, and TET2 gene mutations or FLT3, NPM1, and CEBPA gene mutations.

Mutational Profile Enables the Identification of a High-Risk Subgroup in Myelodysplastic Syndromes with Isolated Trisomy 8.

Trisomy 8 (+8) is the most frequent trisomy in myelodysplastic syndromes (MDS) and is associated with clinical heterogeneity and intermediate cytogenetic risk when found in isolation. The presence of gene mutations in this group of patients and the prognostic significance has not been extensively analyzed. Targeted deep sequencing was performed in a cohort of 79 MDS patients showing isolated +8. The most frequently mutated genes were: TET2 (38%), STAG2 (34.2%), SRSF2 (29.1%) and RUNX1 (26.6%). The mutational profile identified a high-risk subgroup with mutations in STAG2, SRSF2 and/or RUNX1, resulting in shorter time to acute myeloid leukemia progression (14 months while not reached in patients without these mutations, p < 0.0001) and shorter overall survival (23.7 vs. 46.3 months, p = 0.001). Multivariate analyses revealed the presence of mutations in these genes as an independent prognostic factor in MDS showing +8 isolated (HR: 3.1; p < 0.01). Moreover, 39.5% and 15.4% of patients classified as low/intermediate risk by the IPSS-R and IPSS-M, respectively, were re-stratified as a high-risk subgroup based on the mutational status of STAG2, SRSF2 and RUNX1. Results were validated in an external cohort (n = 2494). In summary, this study validates the prognosis significance of somatic mutations shown in IPSS-M and adds STAG2 as an important mutated gene to consider in this specific subgroup of patients. The mutational profile in isolated +8 MDS patients could, therefore, offer new insights for the correct management of patients with a higher risk of leukemic transformation.

Clinical and molecular characteristics of patients with AML with an exceptional response to ivosidenib.

7036 Background: Ivosidenib (IVO) twas approved based on a CR/CRh rate of 31.8% in IDH1 mutant (IDH1m) R/R AML; median duration of CR/CRh (DOR) was 8.2 months (mo). The purpose of this study is to elucidate the clinical and molecular characteristics of exceptional responders to single agent IVO. Methods: We analyzed all patients (pts) with IDH1m R/R AML who received IVO 500mg QD on the phase 1 dose escalation/expansion study and had a DOR of &gt;12 mo. Results: Of 179 pts who received IVO 500 mg QD, 57 (31.8%) achieved a CR/CRh. Of these, 20 (35.1%) had a DOR &gt;12 mo. After excluding 7 pts who went to HSCT, 13 (22.8% of responders, 7.3% of cohort) had DOR &gt;12 mo (exceptional response) and 8 (14% of responders, 4.5% of cohort) had DOR &gt;24 mo. The 13 exceptional responders all achieved CR as best response, and median DOR was 42.6 mo. Median OS was not reached; estimated OS at 48 mo was 67.1%. Median EFS was 44.4 mo. Reasons for discontinuing treatment included relapse (n=4), adverse event unrelated to IVO (n=3), and patient (pt) decision (n=3). Three pts remain on treatment. All pts who relapsed had DOR between 1-2 years; none of the 8 pts with DOR &gt;2 years relapsed. Baseline characteristics are in the table. The most common co-mutations were DNMT3A, ASXL1, SRSF2, and JAK2 (3 each, 23%). Five pts (39%) had a splicing factor mutation. No pts had FLT3 or RTK pathway mutations other than JAK2. Only 1 pt with NPM1 had an exceptional response, and 1 pt had TP53 (VAF 3.6%). Six pts (46%) had an abnormal karyotype, 6 normal (46%), and 1 missing (8%). Most pts had intermediate-risk cytogenetics (10 pts, 77%), 2 poor-risk, and 1 missing. The median IDH1 VAF was 25% (range 10-50%). The median number of co-mutations was 1 (range 0-6). Having 0-1 co-mutations was associated with a longer response. Eleven pts (85%) had an IDH1 R132C mutation; 1 each (7.7%) had R132H and R132L mutations. Mutation clearance of IDH1 was noted in 8 pts (61.5%). Conclusions: A subset of pts with IDH1m R/R AML have prolonged CR on single agent IVO without HSCT (22.8% of CR/CRh responders) and no pts in CR for &gt;2 years (14% of CR/CRh responders) relapsed. A low mutational burden, lack of RTK pathway mutations and canonical AML drivers, and co-occurrence of mutations associated with clonal hematopoiesis appear to be associated with exceptional response. Clinical trial information: NCT02074839 . [Table: see text]

Intensive chemotherapy with or without gemtuzumab ozogamicin in patients with NPM1-mutated acute myeloid leukaemia (AMLSG 09–09): a randomised, open-label, multicentre, phase 3 trial

Acute myeloid leukaemia with mutated NPM1 is associated with high CD33 expression and intermediate-risk cytogenetics. The aim of this study was to evaluate intensive chemotherapy with or without the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin in participants with newly diagnosed, NPM1-mutated acute myeloid leukaemia. This open-label, phase 3 trial was conducted at 56 hospitals in Germany and Austria. Eligible participants were 18 years or older and had newly diagnosed NPM1-mutated acute myeloid leukaemia and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned, using age as a stratification factor (18-60 years vs >60 years), 1:1 to the two treatment groups using allocation concealment; there was no masking of participants and investigators to treatment groups. Participants received two cycles of induction therapy (idarubicin, cytarabine, and etoposide) plus all-trans retinoic acid (ATRA) followed by three consolidation cycles of high-dose cytarabine (or an intermediate dose for those older than 60 years) and ATRA, without or with gemtuzumab ozogamicin (3 mg/m2 administered intravenously on day 1 of induction cycles 1 and 2, and consolidation cycle 1). The primary endpoints were short-term event-free survival and overall survival in the intention-to-treat population (overall survival was added as a co-primary endpoint after amendment four of the protocol on Oct 13, 2013). The secondary endpoints were event-free survival with long-term follow-up, rates of complete remission, complete remission with partial haematological recovery (CRh), and complete remission with incomplete haematological recovery (CRi), cumulative incidences of relapse and death, and number of days in hospital. This trial is registered with ClinicalTrials.gov (NCT00893399) and has been completed. Between May 12, 2010, and Sept 1, 2017, 600 participants were enrolled, of which 588 (315 women and 273 men) were randomly assigned (296 to the standard group and 292 to the gemtuzumab ozogamicin group). No difference was found in short-term event-free survival (short-term event-free survival at 6-month follow-up, 53% [95% CI 47-59] in the standard group and 58% [53-64] in the gemtuzumab ozogamicin group; hazard ratio [HR] 0·83; 95% CI 0·65-1·04; p=0·10) and overall survival between treatment groups (2-year overall survival, 69% [63-74] in the standard group and 73% [68-78] in the gemtuzumab ozogamicin group; 0·90; 0·70-1·16; p=0·43). There was no difference in complete remission or CRi rates (n=267 [90%] in the standard group vs n=251 [86%] in the gemtuzumab ozogamicin group; odds ratio [OR] 0·67; 95% CI 0·40-1·11; p=0·15) and complete remission or CRh rates (n=214 [72%] vs n=195 [67%]; OR 0·77; 0·54-1·10; p=0·18), whereas the complete remission rate was lower with gemtuzumab ozogamicin (n=172 [58%] vs n=136 [47%]; OR 0·63; 0·45-0·80; p=0·0068). Cumulative incidence of relapse was significantly reduced by gemtuzumab ozogamicin (2-year cumulative incidence of relapse, 37% [95% CI 31-43] in the standard group and 25% [20-30] in the gemtuzumab ozogamicin group; cause-specific HR 0·65; 0·49-0·86; p=0·0028), and there was no difference in the cumulative incidence of death (2-year cumulative incidence of death 6% [4-10] in the standard group and 7% [5-11] in the gemtuzumab ozogamicin group; HR 1·03; 0·59-1·81; p=0·91). There were no differences in the number of days in hospital across all cycles between treatment groups. The most common treatment-related grade 3-4 adverse events were febrile neutropenia (n=135 [47%] in the gemtuzumab ozogamicin group vs n=122 [41%] in the standard group), thrombocytopenia (n=261 [90%] vs n=265 [90%]), pneumonia (n=71 [25%] vs n=64 [22%]), sepsis (n=85 [29%] vs n=73 [25%]). Treatment-related deaths were documented in 25 participants (4%; n=8 [3%] in the standard group and n=17 [6%] in the gemtuzumab ozogamicin group), mostly due to sepsis and infections. The primary endpoints of the trial of event-free survival and overall survival were not met. However, an anti-leukaemic efficacy of gemtuzumab ozogamicin in participants with NPM1-mutated acute myeloid leukaemia is shown by a significantly lower cumulative incidence of relapse rate, suggesting that the addition of gemtuzumab ozogamicin might reduce the need for salvage therapy in these participants. The results from this study provide further evidence that gemtuzumab ozogamicin should be added in the standard of care treatment in adults with NPM1-mutated acute myeloid leukaemia. Pfizer and Amgen.