Care For Acute Myeloid Leukemia Research Articles

A chemically adjustable BMP6-IL6 axis in mesenchymal stem cells drives acute myeloid leukemia cell differentiation

Chemotherapy alone or in combination with allogeneic stem cell transplantation has been the standard of care for acute myeloid leukemia (AML) for decades. Leukemia relapse with limited treatment options remains the main cause of treatment failure. Therefore, an effective and safe approach to improve treatment outcomes is urgently needed for most AML patients. Mesenchymal stem cells (MSCs) have been reported to efficiently induce apoptosis and shape the fate of acute myeloid leukemia cells. Here, we identified LG190155 as a potent compound that enhances the antileukemia efficiency of MSCs. Pretreatment of MSCs with LG190155 significantly provoked differentiation in both AML patient-derived primary leukemia cells and AML cell lines and reduced the tumor burden in the AML mouse model. Using the quantitative proteomic technique, we discovered a pivotal mechanism that mediates AML cell differentiation, in which autocrine bone morphogenetic protein 6 (BMP6) in MSCs boosted IL-6 secretion and further acted on leukemic cells to trigger differentiation. Furthermore, the activity of the BMP6-IL6 axis was dramatically enhanced by activating vitamin D receptor (VDR) in MSCs. Our data illustrated an effective preactivated approach to reinforcing the antileukemia effect of MSCs, which could serve as an effective therapeutic strategy for AML.

Abstract 3400: Single-cell proteogenomics analysis of AML samples treated with decitabine and venetoclax reveals divergent treatment escape mechanisms

Abstract The combination therapy of hypomethylating agents and venetoclax (HMA+Ven) has emerged as a standard of care for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. Nonetheless, significant clinical challenges persist including relapse and treatment resistance, to which our understanding remains incomplete. Previous studies have revealed genetic (RAS/RTK pathway mutations and TP53 mutations) and phenotypic (monocytic differentiation) resistance mechanisms. In this context, we hypothesized that integrative assessment of both genetic and phenotypic factors could further unveil the contributors of HMA+Ven resistance. To determine the predictors of treatment response, we first analyzed the baseline characteristics of 208 newly diagnosed, secondary, and relapse/refractory AML patients treated with Decitabine and Venetoclax (Dec+Ven). While complex cytogenetics, KRAS and TP53 mutations were significantly associated with treatment resistance, phenotypic factors such as bone marrow cell compositions or French-American-British (FAB) classifications were not. To identify the factors of resistance at the cellular level, we performed a single-cell targeted DNA-antibody sequencing (DAb-seq) on a subset of 33 patients. In total, 60 multi-timepoint bone marrow samples were analyzed, which included five patients with paired baseline-relapse timepoints. From all five patients, we identified that stem-like cells were largely eradicated and replaced by more differentiated cells such as monocyte-like or erythroid-like cells. At relapse, we identified three patterns of phenotypic shifts: monocytic shift, erythroid shift, and mixed monocytic/erythroid shift. The phenotypic shifts were not always associated with the expansion of new genetic mutations, except for in two cases: one patient had monocytic shift accompanied by the expansion of KRAS mutation, and another patient had erythroid shift accompanied by the expansion of NRAS mutation. To examine the mechanisms behind the phenotypic shifts, we performed a single-cell RNA sequencing on three of the relapsed patients. As a result, we confirmed the upregulation of BCL2L1 in the patient with erythroid shift (N=1), and MCL1 in the patients with monocytic shifts (N=2), but not BCL2 in both. These findings are consistent with known dependency of these cells on non-BCL-2 anti-apoptotic proteins such as MCL-1 and BCL-xL. To summarize, we conclude both genetic and phenotypic factors play a role in Dec+Ven resistance. Most importantly, we report that divergent phenotypic transitions, from stem-like toward more differentiated phenotypes (monocytic or erythroid), were frequently observed in AML relapse following Dec+Ven therapy. Close monitoring of phenotypic alterations during HMA+Ven treatment may facilitate the precise identification of AML patients predisposed to relapse. Citation Format: Yi June Kim, Zongrui Li, Abhishek Maiti, Tomoyuki Tanaka, Hidetaka Uryu, Ken Furudate, Kala Hayes, Naval Daver, Naveen Pemmaraju, Tapan M. Kadia, Farhad Ravandi, Nicholas J. Short, Maro Ohanian, Gautam Borthakur, Nitin Jain, Ghayas C. Issa, Lucia Masarova, Steven M. Kornblau, William G. Wierda, Sanam Loghavi, Sa A. Wang, Guillermo Garcia-Manero, Hagop Kantarjian, Courtney D. DiNardo, Marina Y. Konopleva, Koichi Takahashi. Single-cell proteogenomics analysis of AML samples treated with decitabine and venetoclax reveals divergent treatment escape mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3400.

Influence of Income, Education, and Medicaid Expansion on Palliative Care in Acute Myeloid Leukemia Using the National Cancer Database

Palliative care is integral to symptom management, and we examined its relationship with income, education, and Medicaid expansion in acute myeloid leukemia. This was a retrospective cross-sectional study using the National Cancer Database that included patients with acute myeloid and monocytic leukemias > 18 years of age treated at Commission on Cancer facilities from 2004 to 2016. Univariate and multivariate models were adjusted for demographic variables and facility characteristics. There were 124,988 patients, but only 106,495 had palliative care data, and of this 4111 (3%) received palliative care. The most educated had the highest odds of receiving palliative care (odds ratio, OR 1.23, 95% CI 1.08–1.41; P = 0.002), but the highest income bracket (≥ $63,333) had the lowest odds (OR 0.82, 95% CI 0.72–0.93; P = 0.003). Residence in states with Medicaid expansion (January 2014 onward) had greater palliative care utilization. Palliative care use was associated with higher education but underutilized with higher incomes. Increased access with Medicaid expansion suggests the importance of public insurance.

Future prospects for the development of novel agents for acute myeloid leukemia

For nearly 40 years, combination therapy with cytarabine and anthracycline has been the standard of care for acute myeloid leukemia (AML). The cytogenetics and molecular biology of AML are now understood, and the treatment of AML has undergone dramatic changes in Japan with the launch of drugs such as FLT3 inhibitors, Bcl2 inhibitors, and hypomethylating agents since 2018. However, AML remains very difficult to cure, with a high relapse rate. Here, we review novel agents that have not yet been approved in Japan (CPX-351, IDH inhibitors, menin inhibitors, and oral azacitidine) as potential treatments for AML, as well as therapeutic antibodies (BiTEs, DARTs, immune checkpoint inhibitors) currently under investigation in clinical trials or in development. These novel agents are being investigated not only as monotherapy but also as combination therapy with intensive chemotherapy or azacitidine/venetoclax. The new era of AML treatment is expected to support a variety of goals, including leukemic cell elimination, long-term remission, and improved quality of life.

The Occurrence of Infection and TP53 Mutation Are Risk Factors for Cardiovascular Toxicity of Acute Myeloid Leukemia Induction Therapy

Introduction: For almost 50 years,induction therapy (IT) is the standard of care for acute myeloid leukemia (AML) patients. Nevertheless, little is known about cardiovascular (CV) toxicity during IT. We aimed to describe CV events (CVE)occurring during IT and to identify clinical, hematological and molecular risk factors of such events. Methods: Two hundred and twenty-four patients of 18 years or more (median age 61 (51;67) years, 58% males), treated with ITbetween 2014 and 2021 were enrolled in this study. Two hundred and one (90%) received an anthracycline-based IT, the others received gemtuzumab ozogamicin as part of a clinical protocol research. Survival from the time from initiation of IT until death or until the initiation of the second course of therapy (either salvage regimen in case of primary refractory or relapsed AML, or intensive consolidation therapy in case of response) was considered. The primary endpoint was the time to occurrence of the first CVE after IT initiation, with death as a competing event. Multivariate analysis included significant covariate, identified by univariate models among initial characteristics and occurrence of infection (coded as time dependent covariate). Results: Hematological characteristics were as follows: European LeukemiaNet (ELN) 2022 risk of myelodysplastic neoplasm (MDS)/AML was low, intermediate and adverse in 13%, 29% and 58% of patients respectively. Main mutations encounters were: DNMT3A, FLT3, NPM1, TET2, NRAS, RUNX1, ASXL1, IDH2, PTPN11, BCOR, SRSF2, WT1 and TP53. Main CV risk factors were tobacco (36%), arterial hypertension (35%), obesity (24%), hyperlipidemia (22%), diabetes mellitus (11%). Baseline left ventricular ejection fraction (assessed by transthoracic echocardiography) was >45% in all patients, >55% in 95% of patients. Seventy-five patients (33%) presented a CVE during IT. Eighty-six percent of CVE were severe (grade 3 or more). Patients presenting CVE during IT were significantly older (p=0.02) and presented more often a past history of dilated cardiomyopathy (p=0.04), arterial hypertension (p=0.005) or dyslipidemia (p=0.005). At baseline, CVE patients presented a greater left auricle volume (p=0.005), higher tricuspid regurgitation grade (p=0.01), and more often a right ventricular dilatation or a significative valvopathy (respectively p=0.01 and p=0.03). There was no difference in CVE occurrence between patients treated with and without anthracyclin (p=0.2). Competing risk models identified the following adverse characteristic for the risk of first CVE, namely the occurrence of the first infectious event (Hazard ratio [HR]= 2.43, p=0.005), TP53 mutation (HR=1.79, p=0.04). No other clinical characteristics nor mutation (including TET2 and DNMT3A) were identified. Multivariate analyses demonstrated that TP53 mutation (HR=1.78, p=0.04) and occurrence of infection (HR=2.29, p=0.008) retained independent prognostic value, see Table 1. In a response stratified model, only TP53 mutation was a risk factor of first CVE (HR=2.46, p=0.008). Conclusions: CVE occurred in 33% of patients during IT and were severe. The major adverse role of onset of infection for CVE occurrence after IT could overcome the prognostic value of mutations usually associated with CV risk in the healthy population (i.e. TET2, DNMT3A, ASXL1, ...). TP53 mutation was the only molecular abnormality associated with CVE, in agreement with the increased risk of doxorubicin-induced cardiac toxicity in a mouse model of TP53 clonal hematopoiesis developed by Sano et al. These results suggest that TP53 mutated patients could benefit from careful CV monitoring and optimization of primary prevention treatment.

Single-Cell Proteogenomics Analysis of AML Samples Treated with Decitabine and Venetoclax Reveals Divergent Treatment Escape Mechanisms

Background: The combination therapy of hypomethylating agents and venetoclax (HMA+VEN) has emerged as a standard of care for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. Nonetheless, significant clinical challenges persist, including relapse and treatment resistance. Previous studies have revealed genetic ( RAS/RTK pathway mutations and TP53 mutations) and phenotypic (monocytic differentiation) resistance mechanisms in the context of HMA+VEN therapy. Despite these advancements, our comprehensive understanding of the HMA+VEN resistance mechanisms remains incomplete. To gain further insights into the resistance mechanism in HMA+VEN therapy, we implemented single-cell proteogenomics analysis on longitudinally collected samples from AML patients treated with decitabine+venetoclax (DAC+VEN) trial. Methods: We performed a high-throughput, single-cell targeted DNA-antibody sequencing (DAb-seq) using Tapestri platform from Mission Bio Inc. Sixty-three AML samples sequentially collected from 33 unique patients who participated in DAC+VEN clinical trial (NCT03404193) were analyzed. Our custom DNA panel covered 37 recurrently mutated genes in AML, whereas the custom antibody panel included either 15 cell surface proteins (N = 20 patients) or 48 proteins (N = 13 patients). Cellular phenotypes were inferred based on the patterns of cell surface protein expression. Median 2,767 cells were sequenced per sample, with total 196,719 cells sequenced for this study. Results: The median age of the cohort was 70 years (range 21-84). Twenty-four (73%) patients had primary AML and 9 (27%) had secondary or therapy-related AML. Based on the FAB classification, 13 patients had M0/M1/M2, 6 had M4/M5, one had M7, and the rest had unknown subtypes. The most frequent gene mutation at baseline was DNMT3A (45%), followed by NPM1 (39%), TET2 (30%), and TP53 (24%). Among the 33 patients, 32 had evaluable treatment response; 27 (82%) were defined as responders by achieving CR or CRi, whereas 5 (15%) were non-responders. Six patients experienced relapse after responding to the therapy, and their baseline-relapse pairs were analyzed by the single-cell platform. Using the composition of cellular phenotype data, AML samples were classified into either stem-like (N = 5), progenitor-like (N = 1), predominantly monocytic (N = 4), predominantly erythroid (N = 2) and mixed population AML (mixed population of stem, progenitor, monocyte or erythroid-like population, N = 21). Genotype-phenotype analysis showed a significant correlation between the KRAS mutation and the mixed phenotype (p= 0.0403), as well as between the U2AF1 mutation and the mixed phenotype (p= 0.0471). There was no significant association between treatment response and AML phenotype. Analysis of six baseline-relapse pairs showed that relapse was associated with phenotypic shift of AML cells. Stem-like cells were largely eradicated at relapse and replaced by more differentiated cells. Among the six baseline-relapse pairs, three showed monocytic shift, one showed erythroid shift and two showed mixed monocytic/erythroid shift. Phenotypic shifts at relapse were not always associated with expansion of new genetic mutations, except for in two cases: one had monocytic shift accompanied with expansion of KRAS mutation, and another had erythroid shift accompanied with expansion of NRAS mutation. Conclusions: Phenotypic transition from stem-like cells to more differentiated cells (either monocytic or erythroid) was frequently observed in AML relapse following DAC+VEN therapy. These findings are consistent with the known dependency of these cells on non-BCL-2 anti-apoptotic proteins such as MCL-1 and BCL-xL. Close monitoring of these phenotypic alterations throughout the course of HMA+VEN treatment may potentially facilitate the precise identification of cellular populations predisposed to relapse.

Social determinants of health explored within an electronic patient reported outcomes (ePROs) remote symptom monitoring platform for patients with acute myeloid leukemia (AML).

353 Background: Social determinants of health (SDoH) are non-medical factors, such as income, education, employment, and area of residence that can influence health outcomes. Research shows SDoH impact people’s health, well-being, and quality of life (QoL) and, for patients with cancer, treatment outcomes. Electronic Patient Reported Outcomes (ePROs) integration into routine oncology practice improves patient time on therapy, survival, and resource utilization. This study explores the use of an ePRO platform for routine gathering of SDoH into care for Acute Myeloid Leukemia (AML). Methods: Adult patients with AML undergoing treatment were enrolled in the Carevive remote symptom monitoring (RSM) platform between March 1, 2021 and April 20, 2023. Patients received baseline and weekly surveys to assess symptom burden, physical function, and overall health throughout treatment. Baseline characteristics included age, sex, race, frailty status (modified Geriatric Assessment, CARE survey item, and/or self-reported activity level), comorbidities, and SDoH (living-, caregiver-, marital-, employment-, education-, insurance-status, travel distance to cancer center. Symptoms (derived from the PRO-CTCAE) and QoL (EORTC QLC C30 #29 & #30) were assessed weekly, along with survey compliance. Results were stratified by SDoH status and compared by symptom burden and QoL. Results: 124 patients were included in analysis, with median follow-up time of 12 weeks. Half were male (50%); median age was 66 (range 21-88), majority were White (76%) and had at least one comorbidity (69%). Survey compliance was 69%, measured by total number of surveys completed out of total number of surveys assigned by each patient. Among the 71 (57%) who completed all SDoH responses, 38 (54%) were married, 35 (49%) had at least a bachelor’s degree, 45 (63%) were retired, 45 (63%) reported having a full- or part-time caregiver, 26 (37%) lived with at least one other adult, and 48 (68%) lived more than 20 miles from their nearest cancer center. Patients living with at least one other adult reported symptoms more often than patients living alone (1.65 vs. 1.24 total symptoms per patient-week). Symptom reporting was comparable across all other SDoH responses. Conclusions: This study illustrates feasibility of using RSM for gathering SDoH indicators in routine care. While overall survey compliance was high, 43% did not complete all SDoH items, indicating possible patient reticence to respond to some questions. Symptom reporting differences may indicate a potential need to focus on patients living alone or without a caregiver. Results support the importance and utility of SDoH indicators to identify actionable risk factors for poor health outcomes. Further exploration is needed to understand reporting of symptoms and caregiver/lifestyle arrangements.

Acquired resistance to venetoclax plus azacitidine in acute myeloid leukemia: In vitro models and mechanisms

The combination of venetoclax (VEN) and azacitidine (AZA) has become the standard of care for acute myeloid leukemia (AML) patients who are ≥ 75 years or unfit for intensive chemotherapy. Though initially promising, resistance to the combination therapy is an issue and VEN + AZA-relapsed/refractory patients have dismal outcomes. To better understand the mechanisms of resistance, we developed VEN + AZA-resistant AML cell lines, MV4-11/VEN + AZA-R and ML-2/VEN + AZA-R, which show > 300-fold persistent resistance compared to the parental lines. We demonstrate that these cells have unique metabolic profiles, including significantly increased levels of cytidine triphosphate (CTP) and deoxycytidine triphosphate (dCTP), changes in fatty acid and amino acid metabolism and increased utilization and reliance on glycolysis. Furthermore, fatty acid transporter CD36 is increased in the resistant cells compared to the parental cells. Inhibition of glycolysis with 2-Deoxy-D-glucose re-sensitized the resistant cells to VEN + AZA. In addition, the VEN + AZA-R cells have increased levels of the antiapoptotic protein Mcl-1 and decreased levels of the pro-apoptotic protein Bax. Overexpression of Mcl-1 or knockdown of Bax result in resistance to VEN + AZA. Our results provide insight into the molecular mechanisms contributing to VEN + AZA resistance and assist in the development of novel therapeutics to overcome this resistance in AML patients.

In their own words: a qualitative study of coping mechanisms employed by patients with acute myeloid leukemia.

Positive coping mediates improved outcomes from integrated palliative care in acute myeloid leukemia (AML). We qualitatively explored patients' coping mechanisms to better understand this relationship. We enrolled patients with high-risk AML admitted to Duke Hospital's inpatient hematologic malignancy service for intensive chemotherapy. This study is a secondary analysis of previously collected longitudinal qualitative data, with interviews conducted between February 2014 and August 2015. Interviews were coded in NVivo to identify examples of approach-oriented and avoidant coping. Patients demonstrated approach-oriented coping in many forms including acceptance, positive reframing, active coping, religious coping, and social coping. Acceptance included accepting their prognosis, the uncertainty of AML, and lifestyle changes due to the disease. Patients exhibited positive reframing by speculating about how their situation could be worse, deriving meaning from their experience, and expressing newfound appreciation for activities previously taken for granted. Social coping involved patients receiving support from their community or care team; however, some expressed guilt for being a "burden" on family. Avoidant coping included denial, behavioral disengagement, and self-blame. Some denied their prognosis, but denial was more commonly demonstrated via patients cognitively distancing themselves from their disease. Much of the behavioral disengagement described by patients was attributed to their symptoms (i.e., lethargy) which prevented patients from maintaining relationships or participating in activities previously enjoyed. These results demonstrate the diverse and nuanced applications of coping mechanisms amid a recent AML diagnosis. Future research should examine coping in the context of novel low-intensity AML therapies.

Acute myeloid leukemia (AML) outcomes in the era of novel therapies: A 9-year single-institution experience.

e19053 Background: Recent advances and approval of multiple targeted and non-targeted agents have significantly transformed care for Acute Myeloid Leukemia (AML) over the past 5 years, particularly for older/unfit patients. While this has provided clinicians with several treatment options in both upfront and relapsed/refractory setting, it has also increased the complexity of clinical decision making. Although several trials have shown immense promise of these therapies, the real-world outcomes have not been reported. The primary aim of this study is to compare survival outcomes in newly diagnosed and relapsed AML before and after the introduction of the novel AML treatments that were granted FDA approval over the past 5 years. Methods: We performed a retrospective single-center analysis on adult patients (≥ 18 years) with newly diagnosed and relapsed AML treated at University of Florida Cancer Hospital between January 2012 and December 2020. Patients were stratified according to the time of diagnosis and Overall survival (OS) was estimated using Kaplan Meier method. Survival between groups was compared using log-rank test. Results: A total of 1617 patients were included in this analysis. Median age was 61 years (range 18-83) and 54.4% of patients were men. 71.4% patients were of white race. Median OS was 71.5 months with 1-year OS of 67.4%. Women had significantly better survival than men (1-year OS: 72% vs 63.6%, p=0.0043). 1-year OS for patients diagnosed in 2012-14, 2015-17 and 2018-20 was 73.5%, 67.6% and 58.1% respectively (p < 0.0001). There were no significant differences in survival based on race. 21.4% (n=347) patients had relapse of AML. Median OS for AML relapse was 9.8 months with 1-year survival of 45.1%. There were no significant differences in survival of patients based on race, sex and year of diagnosis. Conclusions: Our study reports decline in 1-year survival of patients with AML in the modern era despite introduction of several novel therapies in recent years. Additionally, relapsed AML continues to have dismal outcomes despite the availability of multiple novel agents for R/R AML. These results are surprising given the reported good efficacy of these agents in clinical trials. Possible explanations include under-representation of real-life patients in clinical trials, poor tolerability of these therapies by the average patient, and/or barriers to access to these novel therapies in healthcare due to prohibitive high cost, inadequate insurance coverage, or limited availability. Larger-scale real-life population-based studies are needed to further investigate the validity of these findings. [Table: see text]

Survival improvement of patients with FLT3 mutated acute myeloid leukemia: results from a prospective 9 years cohort

Midostaurin added to intensive chemotherapy is the standard of care for acute myeloid leukemia (AML) with FLT3 mutations (FLT3mut). We analyzed the impact of midostaurin in 227 FLT3mut-AML patients included in the AML-12 prospective trial for fit patients ≤70 years (#NCT04687098). Patients were divided into an early (2012–2015) and late (2016–2020) cohorts. They were uniformly treated except for the addition of midostaurin in 71% of late group patients. No differences were observed in response rates or the number of allotransplants between groups. Outcome was improved in the late period: 2-year relapse incidence decreased from 42% vs 29% in early vs late group (p = 0.024) and 2-year overall survival (OS) improved from 47% vs 61% (p = 0.042), respectively. The effect of midostaurin was evident in NPM1mut patients (n = 151), with 2-yr OS of 72% (exposed) vs 50% (naive) patients (p = 0.011) and mitigated FLT3-ITD allelic ratio prognostic value: 2-yr OS with midostaurin was 85% and 58% in low and high ratio patients (p = 0.049) vs 67% and 39% in naive patients (p = 0.005). In the wild-type NPM1 subset (n = 75), we did not observe significant differences between both study periods. In conclusion, this study highlights the improved outcome of FLT3mut AML fit patients with the incorporation of midostaurin.

Real-life monocentric experience of venetoclax-based regimens for acute myeloid leukemia.

Combination of venetoclax and hypomethylating agents (HMAs) has become a standard of care in acute myeloid leukemia (AML) aged >75 years or who have comorbidities that preclude intensive induction chemotherapy. We conducted a monocentric retrospective analysis on adult patients affected by treatment-naïve AML not eligible for standard induction therapy or refractory/relapsed (R/R) AML treated with venetoclax combinations outside clinical trials. Venetoclax was administered at the dose of 400 mg/daily after a short ramp-up and reduced in case of concomitant CYP3A4 inhibitors. Sixty consecutive AML were identified. Twenty-three patients (38%) were affected by treatment-naïve AML and 37 (62%) by R/R AML. Median age was 70 years. Among R/R AML 30% had received a prior allogeneic stem cell transplantation (allo-HSCT). In combination with venetoclax, 50 patients (83%) received azacitidine. Antifungal prophylaxis was performed in 33 patients (55%).Overall response rate was 60%, with 53% of complete remission (CR; 78% for treatment-naïve and 49% for R/R, p 0.017). Median overall survival was 130 days for R/R patients and 269 days for treatment-naïve patients; median event free survival was 145 days for R/R cohort and 199 days for treatment-naïve AML.Measurable residual disease was negative in 26% of evaluable patients in CR/CR with incomplete hematologic recovery after 2 cycles and in 50% after 4 cycles, with no significant association with survival.Eleven patients (18%) received an allo-HSCT after venetoclax combinations. Most common grade 3/4 adverse events were infectious (51% of the patients), or hematological without infections (25% of the patients). Use of CYP3A4 inhibitors was associated with a trend to shorter cytopenias and with a lower rate of infections. Invasive fungal infections were less frequent among patients receiving azole prophylaxis (6% vs 26%; p 0.0659). Venetoclax-based regimens are a viable option for AML considered not eligible for standard induction therapy and a valid rescue therapy in the R/R setting.Azole prophylaxis did not significantly affect response and it was associated with a lower rate of invasive fungal infections. Despite a limited number of patients, the association of venetoclax and HMAs proved to be also a feasible bridging therapy to transplantation.

Activation of the PP2A-B56α heterocomplex synergizes with venetoclax therapies in AML through BCL2 and MCL1 modulation

AbstractVenetoclax combination therapies are becoming the standard of care in acute myeloid leukemia (AML). However, the therapeutic benefit of these drugs in older/unfit patients is limited to only a few months, highlighting the need for more effective therapies. Protein phosphatase 2A (PP2A) is a tumor suppressor phosphatase with pleiotropic functions that becomes inactivated in ∼70% of AML cases. PP2A promotes cancer cell death by modulating the phosphorylation state in a variety of proteins along the mitochondrial apoptotic pathway. We therefore hypothesized that pharmacological PP2A reactivation could increase BCL2 dependency in AML cells and, thus, potentiate venetoclax–induced cell death. Here, by using 3 structurally distinct PP2A-activating drugs, we show that PP2A reactivation synergistically enhances venetoclax activity in AML cell lines, primary cells, and xenograft models. Through the use of gene editing tools and pharmacological approaches, we demonstrate that the observed therapeutic synergy relies on PP2A complexes containing the B56α regulatory subunit, of which expression dictates response to the combination therapy. Mechanistically, PP2A reactivation enhances venetoclax-driven apoptosis through simultaneous inhibition of antiapoptotic BCL2 and extracellular signal-regulated kinase signaling, with the latter decreasing MCL1 protein stability. Finally, PP2A targeting increases the efficacy of the clinically approved venetoclax and azacitidine combination in vitro, in primary cells, and in an AML patient-derived xenograft model. These preclinical results provide a scientific rationale for testing PP2A-activating drugs with venetoclax combinations in AML.

Unmodified Dose of Azacitidine Plus Venetoclax Regimen without Drug Interactions during the First Cycle Leads to Similar Outcomes between Viale-a Clinical Trial and Real-Life in Acute Myeloid Leukemia

Introduction: We frequently observe differences between results obtained in clinical trials and real-life. Several reasons may account for these discrepancies: age and coexisting conditions (older patients with additional comorbidities are often excluded from clinical trials), drug interactions and change of schedule (dose-intensity) as compared to the one used in the clinical trials. Azacitidine (AZA) combined with venetoclax (VEN) became the standard of care for acute myeloid leukemia (AML) for patients deemed ineligible for intensive chemotherapy. Composite complete remission (cCR) was 66.4% with median overall survival at 14.7 months (DiNardo et al., NEJM 2020). Recent real-life studies reported less promising results showing cCR between 40-70% and median overall survival (OS) between 7-12 months (Winters et al. Blood 2019; Garciaz et al. EHA 2022; Lam et al. EHA 2022). We report in this study the results of a single center cohort of AML patients receiving an AZA + VEN induction cycle strictly similar to the one reported in the VIALE-A clinical trial without drug interaction. Methods: All patients were treated using VIALE-A guidelines. The first cycle consisted in AZA 75/mg/m² D1-7 + VEN 100mg D1, 200 mg D2, 400 mg D3-28. Treatment was delivered to inpatients, patients were discharged when complete remission was obtained with ANC recovery. All patients received antifungal prophylaxis by liposomal amphotericin B 3mg/kg 3 times a week during the first cycle without VEN dose reduction. For patients who achieved complete remission after cycle 1, the dose of VEN was reduced in case of grade 4 neutropenia and cycle 2 was delayed. For non-responders' patients, cycle 2 started straight after the end of cycle 1. Response was evaluated according to the 2017 European Leukemia Network (ELN) criteria. OS was calculated from the time of diagnosis of AML to the time of death or last known follow-up. Median OS was estimated using the Kaplan−Meier method, and differences between subgroups were assessed using the log-rank test. Results: Twenty-nine (n=29) de novo AML patients were enrolled in this study in University Hospital of Nice. The median age was 79 years [range, 59-90] , Sex ratio M/F was 12/17 and median ECOG was 1 [range,0-3]. ELN 2017 prognostic classification was intermediate in 17 (59%) and adverse in 12 (41%) of patients. The most frequent mutations were NPM1, TP53 and TET2 in 6 (21%), ASXL1 in 5 (17%), DNMT3A in 3 (10%) patients, Median number of AZA + VEN cycles was 2 [range, 1-15]. Each patients of this study (100%) received VEN 400mg/d D1-28 during the first cycle without drug interactions needing VEN dose reduction. Twenty four of the 29 patients (83%) of patients received liposomal amphotericin B prophylaxis during the first cycle. Seven of the 29 patients (24%) patients developed a possible or probable aspergillosis (5 possible, 2 probable). Median duration of neutropenia was 23 days [range,0-116]. Febrile neutropenia occurred in 27/29 (93%) of patients. The overall response rate was 83% including 66% of cCR. Response was obtained after one cycle for 21 patients and after two cycles for 3 patients. Day-30 mortality was 3% and day-60 mortality was 14%. Median OS was 18 months [10.3-25.7, CI 95%]. Conclusions: Our data revealed that a strict introduction of AZA + VEN and a special attention in the monitoring for elderly patients with AML, appears feasible in real-life and was associated to similar outcomes than those observed in the VIALE-A study. Liposomal amphotericin B prophylaxis was also feasible without any need of VEN dose reduction and led to improvements. These outcomes need to be confirmed in a larger cohort. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Early Palliative Care in Acute Myeloid Leukemia.

Simple SummarySeveral new targeted drugs for the treatment of acute myeloid leukemia (AML) have been developed in recent years. However, their potential efficacy should be balanced with the possibility of a poor outcome. For patients with solid tumors, the integration of palliative care (PC) with standard oncologic care, eight weeks after the diagnosis of advanced cancer, has demonstrated many benefits. In patients with hematologic malignancies, this model is underutilized. Here, we review the PC needs and the evidence in the literature supporting the early integration of PC in the disease trajectory of patients with AML. Early PC should be the standard of care for patients with AML. Efforts should also be made to extend the integrated PC model to patients with other hematologic malignancies.Background: Several novel targeted therapies seem to improve the outcome of acute myeloid leukemia (AML) patients. Nonetheless, the 5-year survival rate remains below 40%, and the trajectory of the disease remains physically and emotionally challenging, with little time to make relevant decisions. For patients with advanced solid tumors, the integration of early palliative care (EPC) with standard oncologic care a few weeks after diagnosis has demonstrated several benefits. However, this model is underutilized in patients with hematologic malignancies. Methods: In this article, we analyze the palliative care (PC) needs of AML patients, examine the operational aspects of an integrated model, and review the evidence in favor of EPC integration in the AML course. Results: AML patients have a high burden of physical and psychological symptoms and high use of avoidant coping strategies. Emerging studies, including a phase III randomized controlled trial, have reported that EPC is feasible for inpatients and outpatients, improves quality of life (QoL), promotes adaptive coping, reduces psychological symptoms, and enhances the quality of end-of-life care. Conclusions: EPC should become the new standard of care for AML patients. However, this raises issues about the urgent development of adequate programs of education to increase timely access to PC.

Regionalization of Acute Myeloid Leukemia Treatment in a Community-Based Population: Implementation and Early Results.

Regionalization of care for acute myeloid leukemia (AML) has not been described for community-based settings. In 2015, we shifted AML induction from 21 local centers to 3 regional centers. Using time-specific inception cohorts, we assessed whether regionalization was associated with the frequency of use of induction therapy, receipt of bone marrow transplantation, 60-day mortality (treatment toxicity), and 180-day mortality (treatment effectiveness). Information for all adult patients diagnosed with AML from 2013 to 2017 was obtained from the electronic health record. Multivariable methods were used to estimate the adjusted associations of induction, bone marrow transplantation, and death in relation to year of diagnosis before and after regionalization. Of 661 patients diagnosed during 2013 to 2017, 53% were ≥ 70 years, 22% were ≥ 80 years, and 10% died within the week following diagnosis. Comparing 2017 with 2013, the proportion of patients who received induction therapy increased 2.88 times (95% confidence interval [CI] = 1.55-5.35), and the proportion of non-acute promyelocytic leukemia patients receiving bone marrow transplantation increased 2.00 times (95% CI = 0.89-4.50). Regionalization was associated with lower 180-day mortality (hazard ratio [HR] = 0.64; 95% CI = 0.44-0.92), whereas change in 60-day mortality was not statistically significant (HR = 0.67; 95%CI = 0.43-1.04). In this community-based population, many patients were of advanced age yet benefitted from AML induction therapy delivered at a regionally specialized center. These early results suggest the benefit of regionalizing subspecialty leukemia care.

BET Inhibition Enhances the Antileukemic Activity of Low-dose Venetoclax in Acute Myeloid Leukemia.

The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients. Bromodomain and extraterminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with venetoclax to reduce AML without induction of hematopoietic toxicity. INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines. In vivo efficacy was assessed by tumor reduction in MV-4-11 cell line-derived xenografts. Precision run-on and sequencing (PRO-seq) evaluated effects of INCB054329. Synergy between low-dose BETi and venetoclax was assessed in cell lines and patient samples in vitro and in vivo while efficacy and toxicity was assessed in patient-derived xenograft (PDX) models. INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes, MYC and BCL2, and genes involved in the cell cycle and metabolism. Combinations of BETi and venetoclax led to reduced cell viability in cell lines and patient samples. Low-dose combinations of INCB054329 and venetoclax in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity. Our findings suggest low dose combinations of venetoclax and BETi may be more efficacious for patients with AML than either monotherapy, potentially providing a longer, more tolerable dosing regimen.

A New Standard of Care for Acute Myeloid Leukemia

A New Standard of Care for Acute Myeloid Leukemia

Fentanyl inhibits acute myeloid leukemia differentiated cells and committed progenitors via opioid receptor-independent suppression of Ras and STAT5 pathways.

Fentanyl is a common sedative/analgesic used for intrathecal chemotherapy injection in children with acute leukemia. Given the contradictory findings that fentanyl has both inhibitory and stimulatory activities in cancer cells, we investigated the biological effects of fentanyl alone and its combination with standard of care in acute myeloid leukemia (AML) cells at all stages of development. We showed that fentanyl at clinically relevant concentration inhibited growth and colony formation of AML differentiated cells and committed progenitors without affecting their survival. Compared to AML cells without FLT3 mutation, cells harboring FLT3-ITD mutation are likely to be more sensitive to fentanyl. However, fentanyl did not affect the most primitive AML stem cells. Fentanyl significantly augmented the efficacy of cytarabine but not midostaurin in AML differentiated cells and committed progenitors. We further demonstrated that fentanyl inhibited AML cells via suppressing Ras/Raf/MEK/ERK and STAT5 pathway, and this was not dependent on opioid receptor system. Our findings demonstrate the anti-leukemia activity of fentanyl and synergistic effects between fentanyl and cytarabine in AML, via opioid receptor-independent suppression of Ras and STAT5 pathways. Our work is the first to suggest the beneficial effects of fentanyl in children with leukemia.

Real-world practice patterns and barriers to quality care in acute myeloid leukemia (AML).

e19172 Background: For AML patients who are ineligible for intensive induction, novel therapies have greatly improved treatment options, though practice challenges individualizing care have hindered effective integration. In a quality improvement (QI) program conducted in 3 community oncology systems, we assessed practice patterns and barriers involving the use of novel therapies for AML. Methods: We surveyed 15 hematology team members to assess barriers to quality AML care and audited electronic medical records (EMR) of 100 patients across 3 community oncology centers. EMR demographics, disease characteristics, and treatment selection were reviewed. To address suboptimal guideline-aligned care, teams participated in audit-feedback sessions to develop action plans for resolving identified gaps. Results: The EMR audit demonstrated a lack of documentation for clinically important metrics necessary for individualized treatment selection and monitoring, including performance status and testing for targetable biomarkers (Table). Additionally, there was low documented use of novel therapies, such as venetoclax and gemtuzumab ozogamicin (GO), and no documented use of FLT3 or IDH inhibitors. Further, the audit revealed low adherence to guideline recommendations for frontline regimens – notably, 33.3% patients with FLT3 or IDH mutations (n = 15) were receiving low dose cytarabine alone, and 50% patients with a documented performance status of 3+ (n = 2) received intensive induction therapy. Survey findings indicated very low or low confidence in aligning practice with guidelines (20%), identifying patients who are not candidates for intensive induction (27%), and ordering/interpreting molecular tests (33%). Appropriate treatment selection (47%) and integration of molecular testing (27%) were reported as top challenges for individualized AML care. During audit-feedback sessions, teams identified improved collaboration with hematopathologists, assessment of patient mutational status, and patient engagement in treatment planning as actions they plan to integrate. Conclusions: These findings reveal important performance gaps in individualized AML care in community settings, which may inform future QI initiatives. [Table: see text]