Newly-diagnosed Acute Myeloid Leukemia Patients Research Articles

Myelomonocytic and monocytic acute myeloid leukemia demonstrate comparable poor outcomes with venetoclax-based treatment: a monocentric real-world study.

Venetoclax (VEN), a BCL-2 inhibitor, has transformed treatment strategies for elderly and unfit acute myeloid leukemia (AML) patients by significantly improving response rates and survival. However, the predictive factors for VEN efficacy differ from traditional chemotherapy. The clinical relevance of the FAB (French-American-British) monocytic subtype, including M4 and M5, has been debated as a marker for VEN resistance. This real-world study examined 162 newly diagnosed (ND) and 85 relapsed/refractory (R/R) AML patients who received VEN-based therapy at West China Hospital, Sichuan University, from January 2019 to January 2023. We retrospectively collected clinical and treatment data from electronic medical records. The median age of the cohort was 55.5years (range: 16.5-83.5). The composite complete remission (cCR) rate in the entire cohort was 60.7%. Specifically, among newly diagnosed (ND) patients, FAB monocytic subtypes exhibited lower cCR compared to non-monocytic subtypes (55.1% vs. 76.3%, P = 0.007). Additionally, there were no significant differences observed between M4 and M5 subtypes, both in the ND group (61.7% vs. 40.9%, p = 0.17) and the R/R group (38.2% vs. 40%, p > 0.9). Furthermore, the median follow-up was 238 (range: 7-1120) days. ND patients with monocytic subtypes had shorter overall survival compared to non-monocytic subtypes (295days vs. not reached, p = 0.0017). Conversely, R/R patients showed no such difference (204 vs. 266days, p = 0.72). In summary, our study suggests that the FAB monocytic subtype can predict VEN resistance and shorter survival in ND AML patients. Moreover, there is no significant distinction between M4 and M5 subtypes.

Prognostic Significance of NCAM1 (CD56) Expression in AML Patients Treated with HMA+Venetoclax

Introduction : NCAM1 (CD56) is a cellular adhesion molecule highly expressed on natural killer (NK) cells and other immune cells. NCAM1 is aberrantly expressed in 20% of patients with acute myeloid leukemia (AML) and is associated with resistance to chemotherapy, upregulation of the MAPK pathway, and poor prognosis. The significance of NCAM1 in the setting of venetoclax (VEN) therapy has not been explored. We set out to determine the functional and prognostic role of CD56 in vitro and in newly diagnosed (ND) patients receiving VEN-based therapy. Methods : OCI-AML2, KG-1, and MOLM-14 cell lines were purchased from ATCC and maintained in RPMI, 10% or 20% FBS, L-Glutamine, and penicillin/streptomycin. Ex vivo drug testing on cell viability was performed using an MTS assay. Briefly, AML cells were plated for 72 hours in replicates of six at 1,250 cells/well in R20 and titrated using a log scale over 7 doses (0-1000 nM) of VEN. After 3 days of culture at 37 °C in 5% CO2, MTS reagent was added, optical density was measured at 490 nm, and raw absorbance values were adjusted to a positive control and (normalized to untreated wells to produce cell viability estimates). VEN-resistant (VR) OCI-AML2 cells were generated by continuous incubation with escalating doses of VEN. Viability was monitored by Guava EasyCyte. Cells maintained resistant by co-culture with 1 µM of VEN twice weekly. Flow for NCAM1 was performed with commercially available antibodies on parental and VR cells. NCAM1 expression on parental vs. VR OCI-AML2 cells was compared with student's T test. Inactivation of NCAM1 in OCI-AML2 cells was carried out by CRISPR/Cas9 using sgRNAs cloned into plentiCRISPRv2 (Addgene, #52961). AUC was derived from 4-parameter logistic regression curves fit to normalized cell viability values for the 7 tested drug doses. Clinical outcomes including overall survival (OS) were assessed in a retrospective cohort of ND AML patients treated with a hypomethylating agent (HMA)+VEN at Oregon Health & Science University (OHSU). CD56 positivity on AML blasts was based on surface immunophenotype determined by multiparameter flow cytometry. OS was measured from AML diagnosis (with time from diagnosis to VEN start as left-truncation), estimated by Kaplan-Meier, compared with the log-rank test, and modeled with Cox regression to estimate unadjusted and adjusted hazard ratios (HRs) for CD56. Results : Across the 3 AML cell lines evaluated, higher baseline NCAM1 expression levels correlated with increased ex vivo resistance to VEN. The MOLM14 cell line was most resistant with highest median NCAM1 expression (90%), followed by OCI-AML2 with median NCAM1 expression (55%) and then KG-1 with lowest NCAM1 expression (3%). VR OCI-AML2 cells had higher expression of NCAM1 compared to parental OCI-AML2 cells (80% expression vs 55%; p=0.0003). CRISPR knockout of NCAM1 sensitized parental OCI-AML2 cells to VENcompared to cells containing a non-targeting control guide (Fig 1). To support our pre-clinical findings, we retrospectively identified N=98 ND AML patients treated with HMA+VEN at OHSU from 12/2018 to 12/2022. Median follow-up was 16 months and 60% of patients died. Median age at diagnosis was 73 (range=19-87), with 39% at least 75 years old. While 65% of patients were male, 63% had de novo AML and 23% had an antecedent hematologic disorder (AHD). By European LeukemiaNet (ELN) 2022 prognostic risk classification, 58% had adverse risk (14% unknown). The most common somatic mutations were IDH1/2 (27% of patients), NRAS/KRAS (26%), FLT3 ITD or TKD (19%), NPM1 (13%), and TP53 (13%). According to diagnostic flow, 30% of patients were CD56+, 22% CD11b+, 15% CD64+, and 85% HLA-DR+. Median (range) days between diagnosis and VEN start was 13 (1-285). NCAM1 positivity significantly correlated with shorter OS in the univariable (HR=1.80 [95% CI: 1.04-3.09], p=0.032; Fig 2) and multivariable settings (HR=2.10 [95% CI: 1.17-3.75], p=0.012, N=97), with the latter model controlling for age ≥75, AHD, and CD11b. Conclusion : NCAM1 expression is a marker of poor prognosis in ND AML patients treated with HMA+VEN. Knockout of NCAM1 in the OCI-AML2 cell line sensitized cells to VEN. Our data suggest that NCAM1 expression on AML blasts plays a biological role in promoting cellular resistance to VEN. Given emerging knowledge of VEN targeted downstream pathway associations, experiments are underway to explore the role of MAPK pathway and BCL2 family member dependence.

Real-World Treatment Patterns and Overall Survival Among Newly Diagnosed and Relapsed/Refractory Acute Myeloid Leukemia (AML) Patients: A Retrospective Cohort Study Using Claims Data

Introduction: Acute myeloid leukemia (AML) is a malignant disorder of the bone marrow, characterized by abnormal clonal proliferation and differentiation arrest of myeloid progenitor cells. Prognosis is generally poor and worsens with age. While curative therapies are available, they are often unavailable to older patients and those with significant comorbidities due to high morbidity and mortality associated with intensive therapy. Since 2017, seven new systemic therapies have been approved for various AML patient populations, including those unfit for intensive therapy. This study aims to characterize first-line (1L) and second-line (2L) treatment patterns and outcomes in newly diagnosed (ND) and relapsed/refractory (R/R) AML patients, in the context of these newly available therapies. Methods: A large US administrative claims database (Optum) was used to identify ND AML patients between January 1, 2016, and August 31, 2022. The “ND index date” was defined as the first date a non-R/R AML diagnosis code was observed. To confirm that the initial AML diagnosis represented a true case of AML, ≥2 subsequent AML diagnoses within 60 days post-index were required. A washout period of 12 months was used to confirm no previous AML diagnosis. ND patients were required to have continuous enrollment from 1 year prior to the index until ≥30 days after the index date or death, whichever was earlier. A subgroup of R/R patients was then identified: all ND cohort members who 1) had an R/R AML diagnosis code, 2) had continuous enrollment between ND index date and ≥30 days after the RR index date, and 3) did not receive 1L hematopoietic stem cell transplant (HSCT) after the ND index date were eligible for inclusion. In this subgroup, the “RR index date” was defined as the first date an R/R AML diagnosis code was observed. Demographic characteristics, clinical characteristics, and treatment patterns over time were reported descriptively. Treatment regimens over time were described using the following classification: HSCT, intensive chemotherapy without targeted agents, intensive chemotherapy with targeted agents, hypomethylating agent (HMA) therapy only, other targeted therapy, Venetoclax-based therapy, unspecified/other treatment, no treatment/supportive care only. Overall survival (OS) was described using the Kaplan-Meier estimator. All analyses were stratified by line of therapy and transplant status. Results: We identified 5,135 ND AML patients and 934 R/R AML patients (ND cohort: mean age at initial AML diagnosis 73.5 years, mean follow-up time 6.1 months). ND patients receiving transplant in 1L tended to be younger and had fewer comorbidities than those not receiving transplant ( Table 1). Over the entire study period, 61% of ND patients and 69% of R/R patients received some treatment for AML; older patients were more likely to receive supportive care only. In 1L, Venetoclax-based and intensive chemotherapy without targeted agents were the most common treatment regimens (21% and 17% of all ND patients). In 2L, Venetoclax-based and HMA-only therapies were most common (17% and 16% of all R/R patients). Increases in the use of novel therapies (Venetoclax, intensive chemotherapy with targeted agents, or other targeted therapies) were observed in both 1L and 2L over the study period ( Figure 1). 1-year OS among ND patients was 32% in non-transplant recipients, and 84% in transplant recipients; among R/R patients, 1-year OS from RR index date was 21% in non-transplant recipients and 81% in transplant recipients. Conclusions: The findings from the present study indicate substantial disease burden and ongoing unmet need among ND and R/R AML patients in the USA. While treatment patterns for AML have changed significantly following the advent of novel therapies (with 41% of 1L patients and 31% of 2L patients being treated with novel therapies in 2022), OS remained low. Notably, around 1/3 of patients with RR AML did not receive active treatment; these patients tended to be older and were more frail. Increasing off-label use of Venetoclax in 2L further underscores high unmet need for patients who require more effective treatment options.

Venetoclax Combined with Hypomethylating Agents in Acute Myeloid Leukemia Patients Serious Complications Admitted to a Special Hematological Intensive Care Unit

Objective: The objective of this study was to investigate the efficacy and safety of venetoclax (VEN) in combination with demethylating agents (HMAs) among newly-diagnosed acute myeloid leukemia (AML) who have fatal comorbidities. Methods: The study conducted a retrospective analysis of 16 patients with severe complications of primary acute myeloid leukemia (AML) who were admitted to the Hematology Intensive Care Unit (H-ICU) of the First Affiliated Hospital of Soochow University between January 1, 2021 and January 31, 2023. These patients were treated with the VEN+HMAs regimen. The study analyzed the remission rate, overall survival (OS) rate, and the incidence of adverse events. Results. The study included sixteen patients diagnosed with primary unfit-AML who were admitted to H-ICU. The median age was 51 years (range: 20-83), and 9 of them were male (56.2%). The mean APACHE II score was 18.9, the mean SOFA score was 6.2. The average number of days spent in the ICU was 27.3 days. Among them, 15 patients had coexisting pulmonary infections, 5 were on noninvasive ventilators, 2 were on invasive ventilators, and 5 were receiving vasoactive drugs. Additionally, 2 patients had pulmonary hemorrhage, 2 had cerebral hemorrhage, and 4 had severe tumor lysis syndrome and received CRRT treatment. Among the patients, 13 (81.25%) had primary AML, 3 (18.75%) had MDS-transformation, 4 were classified as low-risk, 2 as intermediate-risk, and 10 as high-risk. Decitabine was used in 3 patients, azacitidine in 13 patients, VEN at a maximal dose of 100 mg in 3 patients, 200 mg in 9 patients, and 400 mg in 4 patients. The median duration of venetoclax administration was 16 days. After first course of VEN+HMAs, 12 cases (75%) achieved CR/CRi, and 3 cases (18.75%) achieved partial remission (PR), resulting in an overall response rate (ORR) of 93.75%. Among the patients with TP53 mutation (5 cases), 2 achieved CR and 2 achieved PR, with an ORR of 90%. Additionally, there were 8 cases of AML-M5, of which 6 achieved CR/CRi and 2 achieved PR, with an ORR of 100%. The ORR rate was 50% in patients with invasive ventilators and 100% in patients with CRRT. The average duration of granulopathy was 23 days. All patients experienced grade 3-4 hematological adverse events (AE), with an infection incidence of 44.4% during the period of granulopathy. Among these infections, 3 cases were caused by Acinetobacter baumannii, and 1 case was caused by Klebsiella pneumoniae. There were two cases of early mortality due to cerebral hemorrhage and septic shock respectively. With a median follow-up of 9.5 months (range: 0.5-23), the overall survival (OS) rate was 43.75%, with OS rates of 83.3% and 20% in the low- and high-risk groups, respectively. Discussion: The combination of VEN+HMAs resulted in a high therapeutic response rate among newly-diagnosed AML patients with severe complications. It was found to be safe, well-tolerated, and associated with a high remission rate using reduced dosage and dosing regimen.

Healthcare Resource Utilization and Costs Among Newly Diagnosed and Relapsed/Refractory Acute Myeloid Leukemia (AML) Patients: A Retrospective Cohort Study Using Contemporary US Claims

Introduction: Prognosis for acute myeloid leukemia (AML) patients is generally poor, with rapid progression and high probability of relapse. AML has previously been associated with high healthcare resource utilization (HRU). Changes in the AML treatment landscape may have impacts on the economic burden of AML: since 2017, seven new systemic therapies have been approved for various AML patient populations, including those unfit for intensive therapy. The frequency of hematopoietic stem cell transplantation (HSCT) has also increased over this period. This retrospective cohort study aims to characterize first-line (1L) and second-line (2L) healthcare resource utilization (HRU) and costs in newly diagnosed (ND) and relapsed/refractory (R/R) AML patients, in the context of newly available AML treatments from 2017-2022. Methods: A large US administrative claims database (Optum) was used to identify ND AML patients between January 1, 2016, and August 31, 2022. The “ND index date” was defined as the first date a non-R/R AML diagnosis code was observed. To confirm that the initial AML diagnosis represented a true case of AML, ≥2 subsequent AML diagnoses within 60 days post-index were required. A washout period of 12 months was used to confirm no previous AML diagnosis. ND patients were required to have continuous enrollment from 1 year prior to the index until at least 30 days after the index date or death, whichever was earlier. A subgroup of R/R patients was then identified: all ND cohort members who 1) had an R/R AML diagnosis code, 2) had continuous enrollment between ND and at least 30 days after the R/R index date, and 3) did not receive 1L HSCT after the ND index date were eligible for inclusion. In this subgroup, the “R/R index date” was defined as the first date an R/R AML diagnosis code was observed. Patient per-patient-per-month (PPPM) HRU and costs were followed through the earliest of HSCT, clinical trial enrollment, death, loss of enrollment, end of data availability (September 30, 2022),or R/R diagnosis (for ND patients only). All results were reported descriptively by line of therapy and treatment received (HSCT vs. non-HSCT). Subgroup analyses were performed by age category. Results: We identified 3,145 ND and 644 R/R AML patients who received treatment over the study period. 3.4% of all treated ND patients received HSCT in 1L (n=107), while 19% of all treated R/R patients received HSCT in 2L (n=122). HSCT patients were younger and healthier than non-HSCT patients, reflecting selection into HSCT treatment by underlying patient characteristics (for ND patients, mean age at diagnosis 71.4 vs. 61.1; Mean Charlson Comorbidity Index (CCI) score 2.8 vs. 2.0; unfit for intensive chemotherapy 69% vs. 36%, Table 1). Patients receiving HSCT in 1L and 2L appeared to have more outpatient encounters (ND: mean 7.4 vs. 5.6; RR: mean 7.5 vs. 6.1, PPPM) than those not receiving HSCT. Number of inpatient days appeared somewhat higher among transplant recipients in 1L, but were similar to non-transplant recipients in 2L ( Table 2). While baseline pre-AML costs increased with age in 1L ($4,478 among patients 75 or older, $3,508 among patients younger than 65, PPPM), 1L follow-up costs were highest in the youngest cohort and lowest in the oldest cohort ($74,083 vs. $40,547, PPPM). Treatment-associated PPPM costs (medical + pharmacy) appeared higher in 1L vs. 2L ($54,457 vs. $48,595). When stratified by transplant status, total PPPM costs for patients receiving HSCT in 1L were higher than for those not receiving HSCT ($74,538 vs. $53,751), driven primarily by higher medical costs ($70,757 vs. $50,283). The same pattern was observed in 2L transplant vs. non-transplant patients ($56,380 vs. $46,979 total costs, $51,712 vs. $41,986 medical costs). Conclusions: The economic burden of AML for both ND and R/R patients in the context of newly available therapies remains substantial. Total costs were comparable but slightly higher for 1L therapy as compared to 2L, and significantly higher among patients receiving HSCT compared to those not receiving HSCT in both 1L and 2L. Decreasing economic burden with age was driven by lower medical costs associated with higher rates of supportive/palliative care, suggesting a lack of available active treatment options among older AML patients.

Acute Myeloid Leukemia Patients Who Stopped Venetoclax or/and Azacytidine for Other Reasons Than Progression Have a Prolonged Treatment Free Remission and Overall Survival. a Filo Study

Background Recent update of the VIALE-A study showed a long-term survival for approximately 30% of acute myeloid leukemia (AML) patients treated with venetoclax and azacitidine (VEN-AZA) for a newly-diagnosed AML (ND-AML) (Pratz K.W et al., ASH 2022). A recent report of a small cohort of responding patients who interrupted VEN-AZA displayed a sustained treatment-free remission (TFR) period suggesting that treatment interruptions might be considered (Chua CC. et al., Blood Adv. 2022). To evaluate the impact of VEN-AZA discontinuation on survival and time without treatment, we retrospectively analyzed the characteristics and outcomes of patients who stopped VEN and/or AZA for reasons other than progression (e.g. hematological or other toxicities). We presented the first 51 patients from our cohort last year at ASH meeting (Garciaz S. et al, ASH 2022). In this abstract, we analyzed separately ND-AML and relapsed/refractory (R/R) AML. Methods Eligible patients 1) have been treated with VEN-AZA for a ND or R/R AML, 2) have stopped AZA and/or VEN for more than 3 months, 3) are in remission (CR, CRi or Morphologic leukemia-free state, [MLFS]) at the time of treatment interruption, 4) are ≥ 18-year-old. Main endpoints were overall survival (OS) and treatment-free remission (TFR) calculated from the time between the last day of VEN to relapse, retreatment, or death. We measured the impact of prognostic factors on OS by a Cox regression taking disease status (ND vs R/R), the discontinued treatment (VEN vs VEN-AZA), the cytogenetics and NPM1 or IDH mutations. Results We included 83 patients from French Innovative Leukemia Organization (FILO) centers and Moffit Cancer Center (US) treated with VEN-AZA for a ND-AML or a R/R AML between 11/18 and 07/23. Regarding the ND-AML patients (n=60; 32 males and 28 females), the median age was 76 (range, 26-86.5), median platelet count, WBC, ANC and bone marrow blast involvement was 52 G/L (range, 9-296), 2.8 G/L (range, 0.6-200), 0.6 G/L (range, 0.02-31.6) and 40% (range, 10-99), respectively. Cytogenetics was intermediate (int.) in 48 cases (80%) and unfavorable (unfav.) in 12 patients (20%). Eleven AML (18.3%) had NPM1 mutations, and 19 (31.6%), IDH alterations including 7 IDH1, 8 IDH2R140 and 4 IDH2R172. Six (10%) and 5 (8.3%) patients had FLT3 or TP53 mutations, respectively. The median number of VEN-AZA cycle was 4 (1-17). The best response was CR (n=44, 73.3%), CRi (n=13, 18.3%) and MLFS (n=3, 5%). Twenty-one patients out of 25 (78%) reached MRD negativity assessed by molecular (n=11) or flow cytometry (n=10) techniques. Twenty-six patients (43.3%) stopped VEN-AZA and 34 (56.7%) stopped VEN and continued AZA monotherapy for a median number of 7 AZA cycles (1-41). Reasons for treatment discontinuation were prolonged cytopenia, non-hematological toxicities, patient choice or unknown in 35 (58%), 6 (10%), 8 (13.3%), and 11 (18.3%) patients, respectively. We registered 27 relapses and 24 deaths. Fourteen patients were retreated including 11 patients who were rechallenged with VEN-AZA. Second CR/CRi rate with VEN-AZA was 3/11 (27.7%). With a median follow of 23 months, median TFR was 15 months (ranges, 3-47) and median OS was 44 months (ranges, 7-50). We also analyzed a smaller cohort of 23 R/R responding patients who stopped AZA and/or VEN. The median age was 73, median number of previous lines was 1 (1-3). Twenty-one patients (91.3%) received prior intensive chemotherapy and 4 (17.4%) prior allogeneic hematopoietic transplantation. Cytogenetic risk was int. in 17 (73.9%) and unfav. in 5 patients (21.7%) and missing in one patient. NPM1 and IDH genes were mutated in 6 (26%) and 10 (43.4%) cases, respectively. Sixteen patients (69.6%) stopped VEN-AZA and 7 (30.4%) interrupted VEN only. Nine patients resumed a treatment including 6 patients rechallenged with VEN-AZA. Among them, 3/6 (50%) obtained a second CR/CRi. Median TFR and OS were 10 (ranges, 3-23) and 19 (ranges, 7-32), respectively. Factor impacting OS in multivariate analysis were R/R AML disease status (Hazard Ratio [HR] =0.47, ranges, 0.23-0.87), and IDH mutations (HR= 2.1, ranges, 1.05-4.34), but not unfav. cytogenetics, NPM1 mutations, or the discontinued treatment (VEN vs VEN-AZA). Conclusion: Discontinuation of VEN and/or AZA in responding patients was associated with sustained responses and long-term survival rates. Resuming treatment may induce a second remission in some patients.

Survival and Prognosis Among 301 Patients with Newly-Diagnosed Acute Myeloid Leukemia Following Venetoclax Plus Hypomethylating Agent Therapy

Background: Venetoclax (Ven) in combination with hypomethylating agent (HMA) is the preferred treatment for elderly/unfit patients with newly-diagnosed acute myeloid leukemia (AML). Current prognostication for AML is based on European LeukemiaNet (ELN) genetic risk stratification which has limited applicability in patients treated with Ven-HMA ( Blood, 2022). Accordingly, our primary objective was to determine predictors of treatment response and survival outcomes in treatment-naïve AML patients receiving Ven-HMA. Methods: Our study population was recruited from Mayo Clinic (MN, FL, AZ), after institutional review board approval and based on documentation of newly-diagnosed AML treated with Ven-HMA outside of clinical trials between November 2018 and April 2023. Cytogenetic and molecular studies were performed by conventional karyotype, and next-generation sequencing, respectively. Response was assessed according to the 2022 ELN criteria Results: Patient characteristics A total of 301 newly-diagnosed AML patients (median age 73 years, 66% male, 62% de novo) received a median of 3 cycles (range 1-48) of azacitidine 75 mg/m2 days 1-7 ( n=100) or decitabine 20 mg/m2 days 1-5 ( n=201) with Ven. ELN 2022 cytogenetic risk included favorable (1%, n=4), intermediate (61%, n=184) or adverse (38%, n=113). Mutations involved TP53 in 77/301 (25%), ASXL1 in 54/279 (19%), RUNX1 in 54/296 (18%), NPM1 in 44/299 (15%), DNMT3A in 40/296 (13%), K/NRAS in 41/296 (14%), IDH1 in 20/301 (6%), IDH2 in 30/301 (10%), FLT3-ITD in 25/301 (8%) and DDX41 in 9/247 (4%) of informative cases. Predictors of response Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients, including CR in 36% and measurable residual disease (MRD) negative by flow cytometry in 77% of 105 informative cases that achieved CR/CRi. Median time to CR/CRi was 1.4 months. In univariate analysis, CR/CRi was more likely to occur in the presence of NPM1 mutation, (86% vs. 56%; p < .01), IDH2 mutation, (80% vs. 58%; p = .02), DNMT3A mutation, (78% vs. 57%; p = .01), or DDX41 mutation, (100% vs. 58%; p <.01), and in the absence of adverse karyotype, (71% vs. 42%; p < .01), TP53 mutation, (67% vs. 40%; p <.01), FLT3-ITD mutation, (63% vs. 36%; p = .01), or RUNX1 mutation, (64% vs. 44%; p = .01); in multivariable analysis, adverse karyotype, ( p < .01), FLT3-ITD ( p < .01), RUNX1 ( p < .01), NPM1 ( p = .03), IDH2 ( p = .04), and DDX41, ( p = .01) mutations remained significant. Predictors of survival After a median follow-up of 8.5 months (range 0.5-56), 13.2 months for living patients, 174 (58%) deaths, 73 relapses (40% of those achieving CR/CRi), and 41 (14%; including 35 in CR/CRi) allogeneic hematopoietic stem cell tranplants (AHSCT) were documented. In univariate analysis of pre-treatment variables, thrombocytopenia < 100 x 10 9/l, (HR 1.5, 95% CI 1.03-2.2; p = .03), adverse karyotype, (HR 2.8, 95% CI 2.1-3.8; p < .01) TP53 mutation, (HR 2.5, 95% CI 1.8-3.5; p < .01), or absence of IDH2 mutation, (HR 3.5, 95% CI 1.7-7.6; p < .01) predicted inferior survival. Failure to achieve CR/CRi (HR 4.5, 95% CI 3.3-6.1; p < .01) was also associated with inferior survival and in multivariable analysis, failure to achieve CR/CRi, (HR 3.4, 95% CI 2.5-4.8; p< .01), presence of adverse karyotype, (HR 1.6, 95% CI 1.1-2.6; p = .02), TP53 mutation, (HR 1.6, 95% CI 1.002-2.4; p = .04), and absence of IDH2 mutation (HR 2.2, 95% CI 1.004-4.7; p = .04) were identified as risk factors for survival. Subsequent HR-weighted scoring resulted in three-tiered risk stratification: low (0-1 point; n= 130), intermediate (2-3 points; n= 105), and high (4-5 points; n= 66), with respective median survival (3-year rate) of 28.9 (48%), 9.6 (6%), and 3.1 (0%) months ( p < .01) (Figure). AHSCT had an independent favorable impact on survival (HR 0.3, 95% CI 0.1-0.6; p < .01), most apparent in low ( p =0.04), and intermediate ( p <.01), as opposed to high ( p = .06) risk. Conclusions: In the current single institutional series of Ven-HMA treated newly-diagnosed AML, response to Ven-HMA was the foremost predictor of survival. Additional risk factors for survival included adverse karyotype, presence of TP53 and absence of IDH2 mutations. These observations allowed for a three-tiered genetics-enhanced survival model with CR/CRi as a backbone, and also confirmed survival advantage from AHSCT, regardless of risk category.

ELN 2022 Favorable Genetic Risk Acute Myeloid Leukemia Treated with Venetoclax Plus Hypomethylating Agent: Predictors of Response and Survival

Background: The 2022 European LeukemiaNet (ELN) genetic-risk stratification for acute myeloid leukemia (AML), assigns favorable prognosis to t(8;21)(q22;q22.1)/ RUNX1:: RUNX1T1, inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/ CBFB:: MYH1, NPM1 mutations without FLT3-ITD or adverse karyotype, and bZIP in-frame CEBPA mutations (Döhner , Blood, 2022 ). This risk stratification was derived from intensively treated patients; accordingly, prognostication in ELN favorable genetic risk AML, following venetoclax and hypomethylating agent (VEN-HMA) therapy, remains unclear and was the subject of the current study. Methods: Under an institutional review board approved minimum risk protocol, the Mayo Clinic database was searched to identify AML patients with favorable genetic risk, who received treatment with VEN-HMA in the frontline setting. All patients received at least one cycle of either azacitidine 75 mg/m 2 days 1-7 or decitabine 20 mg/m 2 days 1-5 with VEN dose adjusted based on azole antifungal prophylaxis. Genetic risk stratification and treatment response were assessed according to the 2022 ELN criteria. Survival was estimated from the time of VEN-HMA treatment start to last follow-up or death. Results: Patient characteristics A total of 46 newly-diagnosed AML patients with ELN 2022 favorable genetic risk [ NPM1 mutation, n=36 (78%), CEPBA bZIP mutation, n=7 (15%) and t(8;21)(q22;q22.1)/ inv(16)(p13.1q22), n=4 (9%)] received a median of 4 cycles (range 1-32) of VEN-HMA. Median age was 71 years, with 63% males, and 87% de novo AML. Additional mutations frequently involved TET2 in 17/43 (40%), DNMT3A in 14/45 (31%), SRSF2 in 10/43 (23%), K/NRAS in 10/45 (22%), IDH1 in 8/46 (17%), FLT3-TKD in 7/46 (15%), ASXL1 in 6/43 (14%) and IDH2 in 6/46 (13%),of informative cases.Myelodysplasia (MDS)-related gene mutations ( ASXL1, RUNX1, BCOR, EZH2, SRSF2, U2AF1, SF3B1, STAG2, and/or ZRSR2) were present in 15 of 40 (38%) of patients (93% males). Predictors of response Of the 39 (85%) patients that achieved complete remission, with (CR) ( n=24; 52%), or without count recovery (CRi) ( n=15; 33%); CR/CRi rates were not significantly higher in patients with NPM1 mutations (89%), t(8;21)(q22;q22.1)/ inv(16)(p13.1q22) (75%), or CEPBA bZIP mutations (67%) ( p=0.37). Among patients achieving CR/CRi, measurable residual disease by multiparametric flow cytometry was negative in 15 of 16 (94%) of evaluable cases after cycles 1 or 2. In addition, NPM1 qPCR was negative in 15 of 24 (63%) informative patients. Median time to response was 1.2 months with median response duration of 9.4 months. CR/CRi rates were significantly higher in females vs males (100% vs 76%, p=0.01), and in the absence vs presence of MDS-related gene mutations (96% vs 60%, p=0.004). Multivariable analysis confirmed superior response in the absence of MDS-related gene mutations ( p=0.04). Predictors of survival At a median follow-up of 10.6 months (range; 1.1-51 months), 21 patients (46%) have died, 9 relapsed (23% of those achieving CR/CRi), and 6 (13%) underwent allogeneic hematopoietic stem cell transplant. Median overall survival was 21 months with 1/2/3-year survival rates of 65%/41%/41% (Figure 1a); median relapse-free survival (RFS) was not reached; 1/2/3-year RFS rates were 81%/66%/57% (Figure 1b). Overall survival was superior in patients achieving CR/CRi (23 months vs 5.6 months; p<0.01), in females vs males (not reached vs 9.7 months; p<0.01), and in the absence of MDS-related gene mutations (not reached vs 5.6 months; p=0.01) (Figure 1c). Subsequent multivariable analysis identified female gender ( p=0.01), and absence of MDS-related mutations ( p=0.17) as independent predictors of superior survival. Similar results were obtained when analysis was restricted to NPM1 mutated patients. Conclusions: In the current retrospective study, VEN-HMA therapy in elderly/unfit AML patients with ELN 2022 favorable genetic risk, resulted in response rates that were comparable to those previously appreciated from published reports of patients receiving intensive induction therapy; however, follow-up in the current study was too short to accurately assess long-term overall and relapse-free survival impact. Our study also highlights the adverse prognosis retained by MDS-related gene mutations.

PGK1 Represents a Therapeutic Target for Pediatric Acute Myeloid Leukemia Via Regulating c-Myc/SLC7A5/mTOR Pathway

Acute myeloid leukemia (AML) is a clonal disorder of hematopoietic stem and progenitor cells characterized by abnormal growth, differentiation blockade, and accumulation of immature myeloblasts, which accounts for 15-20% of pediatric leukemia. Emerging literature has shown that metabolism disorder and their related pathways, play pivotal roles in leukemogenesis and disease progression. Phosphoglycerate kinase 1 (PGK1), an essential enzyme in glycolysis pathway, has been demonstrated to be up-regulated in several malignancies, and was related with tumor stage and poor prognosis. This study aimed to investigate the correlation between PGK1 expression and tumorigenesis of AML, explore the possible underlying mechanism as well as provide a potential therapeutic target for pediatric AML. The research included 64 AML patients and 10 healthy donors recruited from July, 2012 to June, 2020 in Children's Hospital of Soochow University. Expression of PGK1 mRNA in bone marrow of newly-diagnosed AML patients was higher than normal group (p<0.001). Based on median expression of PGK1, 64 patients were divided into PGK1high group (n=32) and PGK1low group (n=32). Patients in PGK1high group had lower complete remission (CR) rate after first course of chemotherapy (65.6% vs 75.0%, p=0.027), overall survival (OS) (53.1%±8.8% vs 84.4%±6.4%, p=0.004) and relapse-free survival (RFS)(63.5%±10.4% vs 90.1%±5.4%, p=0.018). PGK1-knockdown cell lines were constructed to figure out the correlation between PGK1 expression and AML development in vitro. Knockdown of PGK1 inhibited the proliferation, suppressed colony formation and promoted apoptosis of AML cells. In addition, PGK1KD AML cells became more sensitive to Cytarabine (Ara-C) and daunorubicin (DNR). AML model was established by injecting PGK1KD P388-D1 cells of BALB/c mice via tail veins. The results indicated that growth of PGK1KD cells in vivo was significantly suppressed compared to negative control group. Moreover, the median survival time of PGK1 KD group was shorter (10 days vs 13 days, p=0.035). NG52, a newly reported small molecule kinase inhibitor of PGK1, could block glycolysis pathway by suppressing the kinase activity of PGK1. NG52 promoted MV4-11 and Kasumi-1 apoptosis in a dose-dependant manner, and showed synergism with Ara-C and DNR in MV4-11 and Kasumi-1. To identify downstream targets of PGK1, RNA-sequencing analysis was performed in PGK1 KD cell lines. SLC7A5 was found to be the most significant down-regulated gene of differentially expressed genes (DEGs). Meanwhile, c-Myc, p-S6 and p-4EBP1 expression were reduced in PGK1 KD cell lines, indicating that c-Myc/SLC7A5/mTOR pathway was suppressed in PGK1 KD AML cells. We subsequently established SLC7A5 KD cells. Inhibition of proliferation and increased apoptosis was found in SLC7A5 KD cells, which was consistent with the results in PGK1 KD cells. Expression of c-Myc and activation of mTOR pathway were observably decreased in SLC7A5 KD cells, which supported the hypothesis above. We found that SLC7A5 expression level was also higher in AML patients than in healthy donors. In conclusion, our study indicated that PGK1 is a molecular biomarker of poor prognosis and a potential therapeutic target of pediatric AML. Inhibition of PGK1 suppressed progression of AML by regulating c-Myc/SLC7A5/mTOR pathway, providing a promising intervention for AML precision medicine.

Poor Prognosis of SRSF2 Gene Mutations in Patients Treated with Venetoclax-Azacitidine (VEN-AZA) for Newly Diagnosed Acute Myeloid Leukemia. a Multicentric Real-Life Study of 117 Patients

Introduction Spliceosomes are complexes composed of small nuclear RNA that remove introns in protein-encoding genes. Spliceosome mutations ( SRSF2, SF3B1, U2AF1, ZRSR2), are encountered in ∼50% of secondary AML cases. Splicing mutations (splice-mut), in particular SRSF2, correlate with inferior outcomes to standard induction therapy. A recent report in a cohort of 119 patients, of whom 33 had splice mutations and 24 were SRSF2 mutated, reported the lack of impact of splice-mut on prognosis of AML patients treated upfront with Hypomethylating agents (HMA) + VEN in clinical trials (Lachowiez, C. A. et al Blood Adv. 2021). Aims We aimed to assess the impact of splice-mut in a population of patients with newly diagnosed acute myeloid leukemia (ND-AML), treated with VEN-AZA. Methods We performed a retrospective multicentric study including patients treated in three French centers in Marseille (Institut Paoli-Calmettes, CHU La Conception) and Nice (Hôpital L'Archet). Inclusion criterias were ND AML adult patients treated with VEN (7 to 28 days per cycle) and AZA at conventional doses. Next Generation Sequencing (NGS) was performed at diagnosis and was available for all patients. Data were collected from patients' electronic medical records. Statistical analyses were performed using GraphPad Prism v9.5.1 Results We included 117 ND-AML patients (median age = 75 yo; range, 32-89) treated with VEN-AZA between October 2019 and March 2023. The five most frequently mutated genes in the whole cohort were TET2, ASXL1, TP53 and RUNX1in thirty-seven (32%), 36 (31%), 32 (27%) and 31 (26%) patients, respectively. Thirty-four patients (29%) had a mutation in at least one of the spliceosome genes (=Splice-mut), including 20 (17%), 11 (9%), 4 (3%) and 1 (1%) mutations in SRSF2, U2AF1, SF3B1 and ZRSR2, respectively (Fig.1). Median variant allele frequency (VAF) was 42%, 43% and 26% for SRFS2, U2AF1 and SF3B1 respectively. Secondary AML was found in 18 (53%) of the splice-mut AML and 21 (25.3%) of the splice-wt AML groups of patients. Prior HMA was given in seven (20.6%) patients in the splice-mut versus 6 (7.2%) in the splice-wt cohort. Complex cytogenetics was identified in 7 (20.6%) patients in the splice-mut cohort and 28 (33.7%) in the splice-wt cohort. We found a TP53 mutation in 17.6% and 31.3% of splice-mut and wt cohorts, respectively. Best overall response rate (= CR, CRi and MLFS) was 72.6%; with CR, CRi and MLFS observed in 63 (54%), 16 (14%) and 6 (5%) patients, respectively. We did not find any difference in response rate between the splice-mut (=73.5%) and splice-wt (72.3%) AML. Prior treatment with hypomethylating agents and TET2 mutation were the only factors significantly associated with lower response rates (42% vs 82%, p=0.004, and 64% vs 85%, p=0.025, respectively), while IDH2 mutation was predictive of a better response (100%vs 75%, p=0.037, OR: 9.9 [CI 95% 0.57-173]). Median overall survival (OS) and leukemia-free survival (LFS) for the whole cohort was 10.8 and 7.1 months, respectively. In multivariate analysis taking into account TP53 and/or del17p, NRASmut and/or FLT3-ITD, IDH2mut, complex karyotype, and SRSF2, the only factors predicting OS and LFS were mutations in TP53 and SRSF2 genes. Patients mutated for SRSF2 had a 4.8 months OS and a 5 months LFS compared to 11.3 and 8 months, respectively (p=0.034 and p=0.037), comparable with TP53mut AML patients ( Fig.2). Conclusions SRSF2mut seems to be predictive of a worse survival in ND AML treated with VEN-AZA. This finding warrants further exploration in larger cohorts.

PB0922 Predictive Scores of Thrombosis and Bleeding Complications in Newly-Diagnosed Acute Myeloid Leukemia Patients

PB0922 Predictive Scores of Thrombosis and Bleeding Complications in Newly-Diagnosed Acute Myeloid Leukemia Patients

Real-world genomic testing and treatment patterns of newly diagnosed adult acute myeloid leukemia patients within a comprehensive health system.

We evaluated the frequency of genomic testing and treatment patterns by age category in patients with newly diagnosed (ND) acute myeloid leukemia (AML) treated in both academic- and community-based health systems within a single Midwestern State. Retrospective analysis of data from the Indiana University Health System Enterprise Data Warehouse and two local cancer registries, of 629 patients aged ≥18 years with ND AML during 2011-2018. Primary outcome variables were, proportion of patients with genomic analysis and frequency of mutations. Chemotherapy was categorized as "standard induction" or "other chemotherapy"/targeted therapy, and hypomethylating agents. Overall, 13% of ND AML patients between 2011 and 2018 had evidence of a genomic sequencing report with a demonstrated increase to 37% since 2016. Genomic testing was more likely performed in patients: aged ≤60 years than >60 years (45% vs. 30%; p = 0.03), treated in academic versus community hospitals (44% vs. 26%; p = 0.01), and in chemotherapy recipients than non-therapy recipients (46% vs. 19%; p < 0.001). Most common mutations were ASXL1, NPM1, and FLT3. Patients ≥75 years had highest proportion (46%) of multiple (≥3) mutations. Overall, 31.2% of patients with AML did not receive any therapy for their disease. This subgroup was older than chemotherapy recipients (mean age: 71.4 vs. 55.7 years, p < 0.001), and was highest (66.2%) in patients ≥75 years. Our results highlight the unmet medical need to increase access to genomic testing to afford treatment options, particularly to older AML patients in the real-world setting, in this new era of targeted therapies.

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study

Data concerning venetoclax and azacitidine (Ven/Aza) as first-line therapy for newly diagnosed acute myeloid leukemia (ND-AML) in candidates for intensive chemotherapy are limited, and outpatient induction regimens in ND-AML have been poorly explored. The enzyme CYP3A4 metabolizes Venetoclax. Conversely, itraconazole is a strong CYP3A4 inhibitor; thus, it produces a 75 % reduction in the dose and cost of venetoclax. This phase 2 trial assessed the feasibility, safety, and efficacy of outpatient induction with venetoclax 100 mg daily from days 1–21, itraconazole 100 mg twice daily from days 1–21, and azacytidine 100 mg subcutaneously, once daily from days 1–7. Fifteen adults with ND-AML were enrolled. The median age was 53 (range 25–73) and twelve (80 %) were considered candidates for intensive chemotherapy. Nine (60 %) subjects started treatment as outpatients,. The first treatment cycle completion in the outpatient setting was achieved in 77.7 %. Early 14-day, 30-day, and 60-day mortality rates were 6.7 %, 13.3 %, and 13.3 %, respectively. Composite CR/CRi after the first and second treatment cycles were 53.9 % and 85.7 %, respectively. Common adverse events included hematological and gastrointestinal toxicities. Outpatient induction with low-dose venetoclax plus itraconazole is feasible, safe, and has acceptable preliminary efficacy in ND-AML patients. This trial was registered in www.clinicaltrials.gov as #NCT05048615.

Uncovering the expression of circPVT1 in the extracellular vesicles of acute myeloid leukemia patients

Extracellular vesicles (EVs) act as molecular mediators in the tumor microenvironment, by shuttling information contained within malignant cells and functioning as regulators of the immune system. Circular (circ)RNAs are characterized by a closed loop-like structure that makes them more stable in the extracellular milieu and suitable to be packaged inside EVs. circPVT1 (hsa_circ_0001821) showed an oncogenic role in several cancer types and immunosuppressive properties in myeloid and lymphoid cell subsets. In this study, we characterized EVs from acute myeloid leukemia (AML) patients in terms of size, concentrations, surface markers and circPVT1 cargo. We showed that circPVT1 is overexpressed by primary blast cells from newly-diagnosed AML patients compared with hematopoietic stem-progenitor cells and is released as cell-free RNA in the plasma. We isolated EVs from the plasma of AML patients and healthy subjects by size exclusion chromatography and characterized them by nanoparticle tracking analysis. EVs from patients’ plasma are larger compared with those from healthy subjects and their surface profile is characterized by higher levels of the leukemic cell markers CD133, CD105, CD49e and other immune-related epitopes, with differences according to AML molecular profile. Moreover, digital PCR analysis revealed that circPVT1 is more abundant inside EVs from the plasma of AML patients compared with healthy subjects. Our findings provide new insights on the features and content of AML EVs and suggest a role of circPVT1 in the crosstalk between AML cells and the tumor microenvironment.

High Efficacy of Azacitidine Plus Hag in Acute Myeloid Leukemia: A Multi-Center, Phase 2 Clinical Trial

Background Homoharringtonine (HHT) is a plant cytotoxic alkaloid derived from the trees of the genus Cephalotaxus. HAG (HHT, low-dose cytarabine, and G-CSF), as a priming regimen, is utilized to treat acute myeloid leukemia (AML). Azacitidine (Aza), a DNA hypomethylation agent, has been a "backbone" for new combinational therapies. However, so far, it has not been well determined the efficacy and safety of adding Aza to HAG regimen. Methods This is a multi-center, single arm, phase 2 clinical trial done in 17 clinical institutions across China between Aug 2019 and Dec 2021 (ClinicalTrials.gov: NCT04248595). Induction therapy consisted of Aza (75mg/m2/d on days 1-7) was given in combination with the HAG regimen (Fig. 1A). Primary endpoints were complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). Secondary endpoints were overall survival (OS), relapse free survival (RFS), and adverse events (AEs). Mutation screening was conducted through next generation sequencing (NGS) by targeting 58 frequently mutated genes. Results A total of 112 patients, including 72 newly diagnosed (ND) (56 de novo, 16 secondary AML [sAML]), and 40 relapsed/refractory (R/R) AML were enrolled. The CR/CRi was achieved in 79.2% (57/72) in the ND and 40.0% (16/40) in R/R AML, respectively (Fig. 1B). CR/CRi were achieved in 80.4% of de novo AML (45/56) and 75.0% of sAML (12/16), respectively. In addition, the median OS and RFS of ND AML patients were 22.8m (95%CI, 12.6 to not reached) and not reached, respectively (Fig. 1C&1D), which were significantly longer than the R/R group (median OS, 10.8m [95%CI, 9.5 to 12.7], P=0.0056; median RFS 5.21m [95%CI, 4.21 to 9.64], P=0.0051) (Fig. 1C&1D). Furthermore, 94.7% (18/19) of patients with favorable-risk reached CR/CRi (Fig. 1E), with median OS and RFS were both not reached (Fig. 1F&1G). 83.9% (26/31) of patients with intermediate-risk reached CR/CRi (Fig. 1E), and the median OS and median RFS were 22.8m (95%CI, 10.5 to not reached) (Fig. 1F) and 16.9m (95%CI, 4.64 to not reached) (Fig. 1G), respectively. Whereas in those with poor-risk, 59.1% (13/22) reached CR/CRi (Fig. 1E), with the median OS 17.3m (95%CI, 3.79 to not reached) (Fig. 1F) and median RFS not reached (Fig. 1G). In this study, infection was the most common non-hematological adverse event, presenting 58.0% (65/112). Common non-hematological AEs of grade 3 or higher includes: infection (38/112, 33.9%), hemorrhage (11/112, 9.82%), fatigue (6/112, 5.36%), hypokalemia (4/112, 3.57%), cardiac arrhythmia (2/112, 1.79%), and fever (2/112, 1.79%). The median duration of neutropenia and thrombocytopenia were 11 d (IQR, 7-19d) and 16d (IQR, 11-25d) among CR/CRi patients. No patients discontinued the induction therapy due to hematological or non-hematological toxicities. The early deaths within 4 weeks of the induction treatment occurred in 1.79% (2/112). Moreover, we detected 228 mutants involving 33 genes in 103 patients at the enrollment. The most frequently mutated genes were DNMT3A (25/103), TET2 (20/103), and NPM1 (18/103) (Fig. 1H), and mostly involved in DNA methylation (DNMT3A, IDH1/2, TET2; 48/103, 46.6%), followed by signal transducers (FLT3, NRAS, KRAS, KIT, PTPN11; 36/103, 35.0%), and transcription regulation (WT1, RUNX1, CEBPA, SETBP1, GATA2; 32/103, 28.2%). Upon Aza+HAG treatment, we observed the high CR/CRi rate in ND patients with mutated BCOR (100%,7/7), KIT (100%,3/3), IDH1 (100%,7/7), NPM1 (93.3%,14/15), ASXL1 (88.9%,8/9), DNMT3A (80. 0%,16/20), RUNX1 (75.0%,6/8), FLT3 (71.4%,5/7), and TET2 (71.4%,10/14) (Fig. 1I). We further observed the clearance of mutated genes after the induction therapy and found the variant allele fraction (VAF) of mutants was dramatically reduced among the CR/CRi patients. Specifically, VAF change of FLT3 mutant from 3 of 4 available patients reduced to <0.01%, with the other one, decreased by 91.9% (Fig. 1J); 4 out of 6 patients with IDH1 mutant reduced to <0.01%, with the other two, decreased 67.6% and 35.9%, respectively (Fig. 1K); 5 out of 6 patients with ASXL1 mutant reduced to <0.01%, with the other one, decreased by 33.4% (Fig. 1L); and 10 out of 14 patients with NPM1 mutant reduced to <0.01%, respectively (Fig. 1M). Conclusion This study demonstrated that the Aza+HAG regimen is a cost-effective first-line therapy with high efficacy and well tolerance for elderly/unfit AML, especially ND AML patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Utilization of Antifungal Prophylaxis and Treatment for Newly Diagnosed AML Patients Treated with Venetoclax Based Regimens in Routine Clinical Practice - a Prospective Analysis from the Revive Study

Background: Venetoclax (VEN)-based low intensity combinations are approved for the treatment of patients (pts) with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. These combinations can be associated with prolonged cytopenias in particular neutropenia. Invasive fungal infections (IFIs) remain a major cause of morbidity and mortality in pts with AML but their incidence and impact on pts treated with VEN-based low intensity approach are uncertain. In the current study we assess real-world patterns of IFI's and antifungal treatments among newly-diagnosed (ND) AML patients treated with VEN-based low intensity therapies. Methods: The REVIVE study is a prospective, real-life, observational study that assesses patterns of pt. selection, efficacy and toxicity. ND pts with AML were enrolled at the time of VEN-based therapy initiation from 12 medical centers in Israel. Demographic, clinical and pt.-related baseline characteristics were documented. Antifungal medication selection for prophylaxis or therapy use and the incidence of IFIs were documented. The impact of prophylactic antifungal use on the incidence of IFIs and on leukemia related outcomes were assessed. Results: Between August 12, 2019, and April 15, 2022(data cut) ,189 AML pts were enrolled to receive VEN based therapy. Overall, the incidence of possible IFIs was relatively low and was observed in 17 patients (9% of patients). 23 pts (12.1%) were reported to have received prophylactic antifungal treatment, whereas 166 pts (87.8%) did not receive. Baseline characteristics of these two groups are shown in Table 1. Of note, pts. receiving antifungal prophylaxis were more likely to be treated as outpatients. A trend towards treatment in a tertiary center and unfavorable ELN risk was observed in pts. receiving antifungal prophylaxis vs. pts not receiving prophylaxis. All other characteristics seemed equally balanced between both groups. Antifungal prophylaxis included fluconazole (18 pts), voriconazole (6 pts) and posaconzole (1 pt). Of note, 2 patients received two different prophylactic treatments. The incidence of IFIs was not reduced in pts receiving antifungal prophylaxis. Of the 23 patients who received antifungal prophylaxis, 4 were considered to have an IFI (17.4%) compared with 13 in the non-prophylactic group (7.8%). Antifungal treatment in pts with an IFI included fluconazole (10pts) voriconazole (5 pts) posaconazole (1 pt) amphotericin B (1 pt) and anidulafungin (1pt). Of note, 3 patients received two different antifungal treatments. No difference in 30-day mortality was observed between the two groups:1 pt in the prophylaxis group died compared with 8 pts in the no-prophylaxis group (4.3% vs 4.8% respectively, p=0.92). Prophylactic antifungal treatment did not affect the rate of adverse events (AEs) leading to treatment discontinuation: 4 pts in the prophylaxis group and 31 pts in the no prophylaxis group discontinued VEN based treatment due to adverse events (17.4% vs 18.7%, p=0.88). The efficacy of VEN based treatment for AML was similar between pts who received or did not receive antifungal prophylaxis. Composite complete remission (CRc) rates were 60.9% in the antifungal prophylaxis group vs 54.2% in pts with no antifungal prophylaxis (p=0.54). A Kaplan-Meier analysis for overall survival (OS) showed no difference between the prophylaxis and no prophylaxis groups (p=0.505). 1year OS rates were: 50.6% (CI 28-73.3) and 39.4% (CI 30.5-48.3) for prophylaxis and no prophylaxis groups respectively. Median follow up in the prophylaxis group was 237 days (CI 56-878) compared with 173 days (CI 19-850) in the no-prophylaxis group. Conclusion: In this prospective 'real world' observational study, a low rate of IFIs were noted despite low utilization rates of antifungal prophylaxis, mostly with non-mold active azoles. Moreover, administration of antifungal prophylaxis was not associated with a reduced incidence of IFIs. Reassuringly, use of antifungal azoles as prophylactic treatment, which requires VEN dose adjustments, did not affect CRc and OS rates. Similarly, azole based prophylaxis did not affect for the rate of treatment discontinuation due to AEs or early mortality. This study does not support the routine use of antifungal prophylaxis and suggests that such treatment is safe if deemed necessary. Additional insights on antifungal treatment patterns and strategies are pending. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P436: TARGETED DELIVERY OF T22-PE24-H6 TO CXCR4 POSITIVE CELLS FOR ACUTE MYELOID LEUKEMIA TREATMENT

Background: Acute myeloid leukemia (AML) is a malignant heterogeneous group of hematological diseases that originates from a hematopoietic progenitor with altered maturation capacity. Recently, considerable advances have been made in the development of targeted therapies for distinct molecularly defined subtypes. Although many AML patients initially respond to current treatment, the majority of them relapse. Therefore, new targeted therapies are needed to overcome drug resistance and improve treatment effectiveness. CXCR4 is a chemokine receptor that is expressed in over 20 cancer types, both hematologic cancers and solid tumors. CXCR4 receptor and its ligand CXCL12 are key mediators of the interactions between AML cells and the bone marrow (BM) microenvironment. Moreover, CXCR4 is highly expressed in around 50% of AML patients. Thus, we have generated a nanoparticle (T22-PE24-H6) that selectively delivers the exotoxin A from Pseudomonas aeruginosa to CXCR4+ leukemic cells. Aims: To assess the selectivity of T22-PE24-H6 cytotoxicity in CXCR4+ AML cell lines as well as in BM samples from AML patients. In addition, we evaluated the antineoplastic effect of the nanoparticle in a CXCR4+ AML disseminated mouse model. Methods: OCI-AML-3, MONO-MAC-6 and HEL cell lines were characterized for CXCR4 expression using flow cytometry and immunohistochemistry (IHC). The in vitro antineoplastic effect of T22-PE24-H6 was determined by cell viability assays. Competition assays with the CXCR4 antagonist AMD3100 were performed to demonstrate the CXCR4-dependent cytotoxicity of the nanoparticle. In vivo effect was assessed in NSG mice intravenously injected with 1x106 luminescent MONO-MAC-6 cells. Animals were treated with 5 μg T22-PE24-H6 or Buffer (166 mM NaCO3H pH 8) daily for 10 doses. Bioluminescence signal (BLI) was monitored to quantitatively measure and evaluate in vivo disease progression. Animal tissue samples were collected after mice euthanasia and used to analyze AML dissemination and toxicity. CXCR4 expression levels and T22-PE24-H6 effect were also determined in BM samples from 10 newly-diagnosed AML patients. Results: T22-PE24-H6 nanoparticle demonstrated a potent in vitro anticancer effect in MONO-MAC-6 cell line. The specific cytotoxic activity of the nanoparticle was CXCR4 dependent as demonstrated by performing competition assays with AMD3100. Furthermore, T22-PE24-H6 intravenous administrations showed significant BLI reduction in a CXCR4+ AML disseminated mouse model compared to buffer-treated mice. In addition, no differences between groups in mouse body weight, biochemical parameters or histopathological changes in normal tissues were detected. Finally, T22-PE24-H6 causes a significant cell viability reduction in AML patient samples with high CXCR4 expression. In contrast, the nanoparticle has no effect in AML patient samples with low expression of CXCR4. Summary/Conclusion: T22-PE24-H6 selectively kills AML cell lines and BM samples from AML patients with CXCR4 overexpression. The nanoparticle also induces a high antineoplastic effect in a CXCR4+ AML disseminated mouse model without detectable systemic toxicity. These data strongly support that T22-PE24-H6 may obtain therapeutic benefit for AML patients with high CXCR4 expression.

A prediction model for central venous catheter-related thrombosis in patients with newly-diagnosed acute myeloid leukemia: A derivation cohort analysis

BackgroundCatheter-related thrombosis (CRT) is a common complication in cancer patients, that may lead to chemotherapy deferral, elevated risk for systemic infections and pulmonary embolism. This study aimed to assess CRT incidence and risk factors in newly-diagnosed acute myeloid leukemia (AML) patients and create predictive models potentially allowing to decrease CRT occurrence in this population. MethodsThis retrospective single-center analysis included all AML patients treated at the Rambam Health Care Campus between 2006 and 2019. Patient clinical and laboratory data were collected to evaluate thrombosis occurrence and time from AML diagnosis to CRT development. Multivariate classification models were created using logistic regression (LR) and competing risk analyzes. ResultsThe final analysis included 632 newly-diagnosed AML patients (mean age 54 ± 15 years). CRT incidence was 10.1% [confidence interval (CI) 7.7–12.9%], median time from AML diagnosis to CRT was 12.5 days [interquartile range 6–30]. In an LR multivariate model, prior history of venous thromboembolism [adjusted odds ratio (AOR) 12.046, p < 0.0001], acute promyelocytic leukemia (APL) (AOR 2.824, p = 0.015), a high body mass index and initial platelet counts <100 × 10E9/L (AOR 1.059 and 0.546; p = 0.011 and 0.040, respectively) were significantly associated with high CRT risk. Analysis of 587 non-APL patients demonstrated comparable results, with CRT incidence of 9.3% (CI 7.0%-12.1%) and emergence of chronic obstructive pulmonary disease (COPD) as a novel significant co-factor (AOR 34.491, p = 0.004). In both models, the area under curve (AUC) was ≥70%. ConclusionsSignificant CRT risk factors defined using the created model could be used for identification of high-risk newly-diagnosed AML patients requiring CRT prophylaxis.

Azacitidine Plus Venetoclax for the Treatment of Relapsed and Newly Diagnosed Acute Myeloid Leukemia Patients.

Simple SummaryThe combination of venetoclax and azacititine (VEN–AZA) has recently been approved for the treatment of unfit newly diagnosed (ND) acute myeloid leukemia (AML) patients. Few data are available for the relapsed and/or refractory (R/R) AML group. We retrospectively compared the outcome of 39 R/R to 38 concomitant ND AML patients treated in our institution between 01/20 and 12/21. Response rates were lower in R/R AML (37% versus 56%); adverse cytogenetics was associated with treatment failure only in the R/R group (Relative Risk = 0.10, p = 0.005). ASXL1, IDH and SFSR2 mutations were associated with a trend in a higher response rate in the R/R group. Median leukemia-free survival was not different between the two groups (9.4 months and 10.3 months in the ND and R/R groups, respectively). In conclusion, VEN–AZA can be efficient as a salvage treatment for selected R/R AML patients.Venetoclax (VEN) belongs the BH3-mimetic class that selectively targets BCL-2, activating apoptosis. The combination of VEN and azacitidine (AZA) has changed the paradigm of treatment of newly diagnosed (ND) acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy. There is scarce evidence for the use of VEN–AZA for relapsed or refractory (R/R) AML. We compared the outcome of 39 R/R AML and 38 ND AML patients treated between 01/20 and 12/21. The median age was 69 (22–86) and 73 (61–81) in the R/R and ND groups, respectively. Adverse cytogenetics were found in 36% of patients in the R/R group and 59% of patients in the ND group. Overall response rate was 37% in R/R AML, including 13% CR, 8% CRi, 3% PR and 13% MLFS, and 58% in the ND AML, including 32% CR, 13% CRi and 13% MLFS. Adverse cytogenetics was associated with treatment failure in the R/R group (Relative Risk = 0.13, p = 0.005). Median overall survival (OS) was 5.9 months in the R/R group and 9.4 months in the ND group. Median OS was 2.2 months in the adverse cytogenetics group versus 8.7 months in the intermediate cytogenetics group in the R/R group (p = 0.02). Median leukemia-free survival was not different between the two groups (9.4 months and 10.3 months), indicating that VEN–AZA can be an efficient salvage treatment for selected R/R AML patients. In conclusion, VEN–AZA is a promising treatment for ND AML and for selected R/R AML patients.

Anthracycline Choices for Induction Chemotherapy Among 797 Consecutive Adult Patients with Acute Myeloid Leukemia: Daunorubicin-60 Vs Idarubicin-12 Vs Daunorubicin-90

▪Objective : We describe the Mayo Clinic experience in 797 newly-diagnosed patients with acute myeloid leukemia (AML) serially treated with 7+3 induction chemotherapy that included 3 days of daunorubicin at a daily dose of 60 mg/m2 (dauno-60; n=239) or 90 mg/m2 (dauno-90; n=52), or idarubicin 12 mg/m2 (IDA-12; n=506). Our objective was to compare overall (OS) and relapse-free (RFS) survival outcome.Methods : Newly-diagnosed AML patients seen at our institution and received intensive induction chemotherapy were identified from the Mayo Clinic AML database. Treatment period spanned from January 2004 through May 2021. Follow-up information was updated as of June 2021. Conventional criteria were used to diagnose AML, assign cytogenetic risk category, and classify treatment response.Results : The study group included 797 patients (median age 60 years, range 18-88; 58% males): 506 (63%) patients received IDA-12, 239 (30%) dauno-60, and 52 (7%) dauno-90. The respective median (range) ages were 60 (18-88), 61 (19-82), and 53 (22-72) years (p=0.01) (Table). Primary, secondary, and therapy-related AML accounted for 65%, 25% and 10% of patients treated with IDA-12, 69%, 22%, and 9% of those treated with dauno-60, and 75%, 23% and 2% of patients treated with dauno-90, respectively (p=0.1). The corresponding frequencies of adverse karyotype were 34%, 25% and 25% (p=0.05).CR/CRi was documented in 78% (620/793) of all evaluable patients: IDA-12 80% (400/503), dauno-60 75% (175/238), and dauno-90 87% (45/52) (p=0.1). 210 (34%) patients underwent allogenic hematopoietic stem cell transplant (AHSCT), including 125 (25%), 59 (25%) and 26 (50%) patients, in the three treatment groups, respectively (p=0.0004). After a median (range) follow up 19 (0.2-203) months, 348 (54%) relapses and 518 (65%) deaths were documented.Median (range) survivals for IDA-12, dauno-60 and dauno-90 groups were 21 (0.3-243), 14.5 (0.45-198), and 27.7 (0.2-180) months (p=0.07; figure 1). The respective 1-, 3-, and 5-year OS rates were 67%, 42%, and 34% (IDA-12); 66%, 37%, and 30% (dauno-60); and 78%, 51%, and 49% (dauno-90), respectively; the trend favoring dauno-90 was no longer apparent during age-adjusted analysis (p=0.33). Multivariable analysis that accounted for age, cytogenetic risk category, FLT3-ITD/NPM1 status and AML subtype confirmed the lack of additional contribution from IDA-12 vs dauno-60 vs dauno-90 (p=0.2) while affirming the independent prognostic value of the other four variables; AHSCT carried an additional predictive value for superior survival without altering these results. A total of 348 (54%) relapses were documented: 228 (57%) in the IDA-12; 99 (57%) in the dauno-60; and 21 (47%) in the dauno-90 cohorts (p=0.7); RFS was similar in the three treatment groups (p=0.1; figure 2).Conclusion : In the current large single-institution study of consecutive adult patients with AML, neither the choice of anthracycline (idarubicin vs daunorubicin) or the dose of daunorubicin (60 vs 90 mg/m2) appeared to effect outcome in terms of remission rates or overall or relapse-free survival. The study otherwise confirms the independent favorable effect of younger age, non-adverse karyotype, FLT3-ITD-/NPM1+ status, and AHSCT. [Display omitted] DisclosuresPatnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; Biosight: Other: Data monitoring committee; Omeros: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding.