Mitochondrial RNA helicase DDX28 promotes cell cycle and DNA repair programs and shapes an immunosuppressive microenvironment in acute myeloid leukemia.

AML-205: Health-Related Quality of Life in Patients with Untreated Higher-Risk Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia Receiving Glasdegib + Azacitidine

Leukemia cell-intrinsic somatic mutations and cytogenetic abnormalities have been used to define risk categories in acute myeloid leukemia (AML). In addition, since the immune microenvironment might influence prognosis and somatic mutations have been demonstrated to modulate the immune microenvironment in AML, there is need for developing and evaluating an immune prognostic model (IPM) derived from mutations associated with poor prognosis. Based on AML cases with intermediate and adverse-cytogenetic risk in the Cancer Genome Atlas (TCGA) database, 64 immune-related differentially expressed genes (DEGs) among patients with RUNX1, TP53, or ASXL1 mutations and patients without these mutations were identified. After Cox proportional hazards analysis, an IPM composed of PYCARD and PEAR1 genes was constructed. IPM defined high-risk (IPM-HR) independently predicted lower 2-year overall survival (OS) rates in both patients with intermediate and adverse-cytogenetic risks and non-M3 patients in the TCGA AML cohort. The poor prognostic impact of IPM-HR on OS was further validated by GSE71014, 37642, and 10358 downloaded from the Gene Expression Omnibus (GEO) database. Furthermore, IPM-HR was remarkably associated with higher proportions of CD8+ T cells and regulatory T cells (Tregs), lower proportions of eosinophils, and higher expression of the checkpoint molecules CTLA-4, PD-1, and LAG3 in the TCGA non-M3 AML cohort. In summary, we developed and validated an IPM derived from mutations related with poor prognosis in AML, which would provide new biomarkers for patient stratification and personalized immunotherapy.

FLT3-ITD Induces Immune Escape in AML Via up-Regulating CD47 Expression and Decreased Phagocytic Ability of Macrophages

A Phase I/II Study of Combination of Azacitidine, Venetoclax and Pevonedistat in Patients with Newly-Diagnosed Secondary Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) with Hypomethylating Agent (HMA) Failure

Secondary-type mutations do not impact prognosis in acute myelogenous leukemia AML with mutated NPM1.

Acute myeloid leukemia (AML) is the most prevalent form of acute leukemia. Patients with AML often have poor clinical prognoses. Hypoxia can activate a series of immunosuppressive processes in tumors, resulting in diseases and poor clinical prognoses. However, how to evaluate the severity of hypoxia in tumor immune microenvironment remains unknown. In this study, we downloaded the profiles of RNA sequence and clinicopathological data of pediatric AML patients from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, as well as those of AML patients from Gene Expression Omnibus (GEO). In order to explore the immune microenvironment in AML, we established a risk signature to predict clinical prognosis. Our data showed that patients with high hypoxia risk score had shorter overall survival, indicating that higher hypoxia risk scores was significantly linked to immunosuppressive microenvironment in AML. Further analysis showed that the hypoxia could be used to serve as an independent prognostic indicator for AML patients. Moreover, we found gene sets enriched in high-risk AML group participated in the carcinogenesis. In summary, the established hypoxia-related risk model could act as an independent predictor for the clinical prognosis of AML, and also reflect the response intensity of the immune microenvironment in AML.

Obesity Is An Adverse Prognostic Factor For Overall and Disease-Free Survival In Adult Acute Promyelocytic Leukemia But Not In Acute Myeloid Leukemia: A Pooled Analysis From Four Alliance Prospective Studies

BackgroundKnowledge of immune cell phenotypes, function, and developmental trajectory in acute myeloid leukemia (AML) microenvironment is essential for understanding mechanisms of evading immune surveillance and immunotherapy response of targeting special microenvironment components.MethodsUsing a single-cell RNA sequencing (scRNA-seq) dataset, we analyzed the immune cell phenotypes, function, and developmental trajectory of bone marrow (BM) samples from 16 AML patients and 4 healthy donors, but not AML blasts.ResultsWe observed a significant difference between normal and AML BM immune cells. Here, we defined the diversity of dendritic cells (DC) and macrophages in different AML patients. We also identified several unique immune cell types including T helper cell 17 (TH17)-like intermediate population, cytotoxic CD4+ T subset, T cell: erythrocyte complexes, activated regulatory T cells (Treg), and CD8+ memory-like subset. Emerging AML cells remodels the BM immune microenvironment powerfully, leads to immunosuppression by accumulating exhausted/dysfunctional immune effectors, expending immune-activated types, and promoting the formation of suppressive subsets.ConclusionOur results provide a comprehensive AML BM immune cell census, which can help to select pinpoint targeted drug and predict efficacy of immunotherapy.

The AML HOX-Ome: The Landscape of Developmental Transcription Factors across Pediatric Acute Myeloid Leukemia

A Phase II Study of CPX-351 Plus Venetoclax in Patients with Relapsed/Refractory (R/R) or Newly Diagnosed Acute Myeloid Leukemia (AML)

Simple SummaryDespite remarkable progress in the outcome of childhood acute myeloid leukemia (AML), risk of relapse and refractory diseases remains high. Treatment of the chemo-refractory disease is restricted by dose-limiting therapy-related toxicities which necessitate alternative tolerable efficient therapeutic modalities. By disrupting its immune environment, leukemic blasts are known to gain the ability to evade immune surveillance and promote disease progression; therefore, many efforts have been made to redirect the immune system against malignant blasts. Deeper knowledge about immunologic alterations has paved the way to the discovery and development of novel targeted therapeutic concepts, which specifically override the immune evasion mechanisms to eradicate leukemic blasts. Herein, we review innovative immunotherapeutic strategies and their mechanisms of action in pediatric AML.Acute myeloid leukemia is a life-threatening malignant disorder arising in a complex and dysregulated microenvironment that, in part, promotes the leukemogenesis. Treatment of relapsed and refractory AML, despite the current overall success rates in management of pediatric AML, remains a challenge with limited options considering the heavy but unsuccessful pretreatments in these patients. For relapsed/refractory (R/R) patients, hematopoietic stem cell transplantation (HSCT) following ablative chemotherapy presents the only opportunity to cure AML. Even though in some cases immune-mediated graft-versus-leukemia (GvL) effect has been proven to efficiently eradicate leukemic blasts, the immune- and chemotherapy-related toxicities and adverse effects considerably restrict the feasibility and therapeutic power. Thus, immunotherapy presents a potent tool against acute leukemia but needs to be engineered to function more specifically and with decreased toxicity. To identify innovative immunotherapeutic approaches, sound knowledge concerning immune-evasive strategies of AML blasts and the clinical impact of an immune-privileged microenvironment is indispensable. Based on our knowledge to date, several promising immunotherapies are under clinical evaluation and further innovative approaches are on their way. In this review, we first focus on immunological dysregulations contributing to leukemogenesis and progression in AML. Second, we highlight the most promising therapeutic targets for redirecting the leukemic immunosuppressive microenvironment into a highly immunogenic environment again capable of anti-leukemic immune surveillance.

Introduction: Promotion of self-efficacy can enhance engagement with health care and treatment adherence in patients with cancer. We report the outcomes of a pilot trial of a digital health coach intervention in patients with leukemia with the aim of improving self-efficacy. Methods: Adult patients with newly diagnosed acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) were randomized 1:1 to a digital health coach intervention or standard of care. The primary outcome of self-efficacy was measured by the Cancer Behavior Inventory (CBI) score. Results: A total of 147 patients (37 AML, 110 CLL) were enrolled from July 2020 to December 2022. In the AML cohort, there was a mean increase in CBI score of 7.03 in the digital health coaching arm compared to a mean decrease of −3.57 in the control arm at 30 days (p = 0.219). There were no significant associations between the intervention and other patient-reported outcomes for patients with CLL. Conclusion: There were numerical, but not statistically significant increases in self-efficacy metrics in AML patients who received digital health coaching. Although this trial was underpowered due to enrollment limitations during a pandemic, digital health coaching may provide benefit to patients with hematologic malignancy and warrants further investigation. Introduction: Promotion of self-efficacy can enhance engagement with health care and treatment adherence in patients with cancer. We report the outcomes of a pilot trial of a digital health coach intervention in patients with leukemia with the aim of improving self-efficacy. Methods: Adult patients with newly diagnosed acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) were randomized 1:1 to a digital health coach intervention or standard of care. The primary outcome of self-efficacy was measured by the Cancer Behavior Inventory (CBI) score. Results: A total of 147 patients (37 AML, 110 CLL) were enrolled from July 2020 to December 2022. In the AML cohort, there was a mean increase in CBI score of 7.03 in the digital health coaching arm compared to a mean decrease of −3.57 in the control arm at 30 days (p = 0.219). There were no significant associations between the intervention and other patient-reported outcomes for patients with CLL. Conclusion: There were numerical, but not statistically significant increases in self-efficacy metrics in AML patients who received digital health coaching. Although this trial was underpowered due to enrollment limitations during a pandemic, digital health coaching may provide benefit to patients with hematologic malignancy and warrants further investigation.

Supporting cells in the bone marrow microenvironment are an essential source of growth factors and cytokines that drive both normal hematopoeisis and leukemogenesis. Acute myeloid leukemia (AML) is a heterogeneous and growth factor-dependent disease of the bone marrow. The human macrophage colony stimulating factor (M-CSF, CSF-1) is a cytokine produced by supporting cells in the bone marrow that promotes the differentiation and maturation of monocytes and macrophages from myeloid precursors. Since CSF-1 is an essential factor in myelopoeisis, it has important implications in AML, a disease characterized by the increased proliferation of immature myeloid blast cells. Moreover CSF-1 and CSF-1R are highly expressed in some AML cases, lending further support for their investigation. CSF-1 exists as a full-length secreted (variant 1 or v1) and membrane-bound (variant 3 or v3) isoform. The membrane-bound v3 isoform is the predominant form in the bone marrow. CSF-1 binds to the colony stimulating factor-1 receptor (CSF-1R), a class III receptor tyrosine kinase found on mononuclear phagocytes. CSF-1R activation leads to stimulation of survival, proliferation and differentiation pathways. In this study, the effects of the CSF-1/CSF-1R interaction were investigated in the context of the bone marrow microenvironment in an in-vitro co-culture system. In this model, human leukemic cells (patient samples and cell lines) were grown in co-culture with mouse stromal cells expressing human CSF-1. The cellular and molecular responses arising from the interaction between leukemic cells expressing CSF-1R and stromal cells producing CSF-1 were examined. AML cells cultured with CSF-1-expressing stroma displayed better long-term (2-5 weeks) growth and survival than cells cultured with non-CSF-1-expressing stroma. There was a 2-fold increase in the number of cells on CSF-1 v3 stroma compared to empty vector (ev) control stroma after 5 weeks of co-culture. AML cells were maintained on CSF-1 v3 stroma 1.5-1.75 fold longer than on ev stroma (survival in days). Co-culture of AML cells with CSF-1-expressing stroma led to a decrease in CSF-1R expression on the surface of AML cells, accompanied by an increase in CD34 and decrease in CD38 expression. CSF-1-expressing stroma led to increases in phosphorylation of Akt and p70S6K, effectors of the PI3k/Akt pathway, in AML cells. Analysis of cytokine production in AML-stromal cell co-cultures revealed an increase in the secretion of IL-3 and IL-6 from stromal cells and an increase in IL-8 and vascular endothelial growth factor (VEGF) from AML cells. These findings suggest that CSF-1 presented by stromal cells mediates the growth and survival of AML cells through changes in cell surface markers, molecular signaling effectors and cytokine secretion. This work has helped identify targets of interest that may be exploited for therapeutic purposes in AML-stromal cell interactions. Citation Format: Ayesha Rashid, Mohammed Fateen, Rhe Juan, Rob C. Laister, Mark Minden. Investigation of the role of CSF-1 and its receptor in the bone marrow stroma microenvironment in acute myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3604. doi:10.1158/1538-7445.AM2014-3604

This phase 1b study evaluated glasdegib (100mg once daily) + azacitidine in adults with newly diagnosed acute myeloid leukemia (AML), higher-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) who were ineligible for intensive chemotherapy. Of 72 patients enrolled, 12 were in a lead-in safety cohort (LIC) and 60 were in the AML and MDS (including CMML) expansion cohorts. In the LIC, the safety profile of glasdegib + azacitidine was determined to be consistent with those of glasdegib or azacitidine alone, with no evidence of drug-drug interaction. In the expansion cohort, the most frequently (≥ 10%) reported non-hematologic Grade ≥ 3 treatment-emergent adverse events were decreased appetite, electrocardiogram QT prolongation, and hypertension in the AML cohort and sepsis, diarrhea, hypotension, pneumonia, and hyperglycemia in the MDS cohort. Overall response rates in the AML and MDS cohorts were 30.0% and 33.3%, respectively; 47.4% and 46.7% of patients who were transfusion dependent at baseline achieved independence. Median overall survival (95% confidence interval) was 9.2 (6.2-14.0) months and 15.8 (9.3-21.9) months, respectively, and response was associated with molecular mutation clearance. Glasdegib + azacitidine in patients with newly diagnosed AML or MDS demonstrated an acceptable safety profile and preliminary evidence of clinical benefits.Trial registration: ClinicalTrials.gov NCT02367456.

Introduction: The current treatment of R/R AML and BPDCN is associated with poor outcome. CD123 is overexpressed on AML blasts, leukemic stem cells, and BPDCN cells compared to normal hematopoietic stem cells. This differential expression feature makes CD123 an attractive target for cellular immunotherapy. Here we report results of an ongoing single-center, first-in-human phase 1 dose-escalation study (NCT02159495) evaluating CD123CAR T cells in treating patients with R/R AML (cohort 1) and BPDCN (cohort 2). This study is designed to determine the safety and antileukemic activity of CD123CAR T cells. Methods: Vectors containing the CD123CAR composed of a single-chain variable fragment, an optimized IgG4 linker, a CD28 co-stimulatory domain, and a CD3 zeta domain are used to engineer donor-derived or autologous T cells via lentiviral transduction. Prior to T-cell infusion, all patients undergo lymphodepleting regimen with the majority receiving fludarabine 25-30 mg/m2 and cyclophosphamide 300-500 mg/m2 daily for 3 days. Patients can receive a second infusion if they continue to meet eligibility criteria. To date, 18 patients have been enrolled and 9 treated (7 AML, 2 BPDCN). Results: All 7 patients in the AML cohort had at least one prior allogeneic stem cell transplant and median of 4 (range: 4-10) prior lines of therapy. Of the 2 patients treated at the dose level (DL) 0 (50M CAR+ T), one achieved a morphologic leukemic-free state (MLFS), which lasted 70 days. She received a second infusion 3 months later with blast reduction from 77.9% to 0.9% (flow cytometry) after 35 days. Of the 5 patients on the DL1 (200M CAR+ T), 1 achieved complete remission (CR) with incomplete count recovery at day 28, and 1 MLFS that improved to CR at day 84. The remaining 3 patients had stable disease. All toxicities were reversible and manageable. No patient developed grade 3 or above cytokine release syndrome or neurotoxicity. There were no treatment-related dose-limiting toxicities and no treatment-related cytopenias longer than 12 weeks. One patient with prior cutaneous GVHD developed grade 1 rash 5 weeks after CAR T infusion, which resolved after clinical management. Peak of T-cell expansion occurred within the first 14 days. We did not observe any CD123-loss leukemic variants. In the BPDCN cohort, 2 patients treated at DL0 (100M CAR+ T) tolerated the treatment well with no grade 3 or above treatment-related toxicities. One patient achieved CR with no evidence of disease in the bone marrow and skin at day 28. Conclusions: In this first-in-human clinical trial of CD123CAR T cell therapy, we have demonstrated the feasibility, safety, and promising antileukemic activity of targeting CD123 in patients with AML or BPDCN. Based on the results we have observed and our collaborative work with Mustang Bio at optimizing the manufacturing platform, we will be leading a multicenter phase 1/2 clinical trial to determine the activity of the cells in achieving remission in patients with AML, BPDCN, and myelodysplastic syndrome. This abstract is also being presented as Poster B22. Citation Format: Lihua E. Budde, Joo Song, Marissa Del Real, Young Kim, Candida Toribio, Brent Wood, Jamie Wagner, Emanuela Marcucci, Anthony Stein, Guido Marcucci, Christine E. Brown, Stephen J. Forman. CD123CAR displays clinical activity in relapsed/refractory (r/r) acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN): Safety and efficacy results from a phase 1 study [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR14.