Purpose We investigated the effect on outcome of measurable or minimal residual disease (MRD) status after each induction course to evaluate the extent of its predictive value for acute myeloid ...leukemia (AML) risk groups, including NPM1 wild-type (wt) standard risk, when incorporated with other induction response criteria. Methods As part of the NCRI AML17 trial, 2,450 younger adult patients with AML or high-risk myelodysplastic syndrome had prospective multiparameter flow cytometric MRD (MFC-MRD) assessment. After course 1 (C1), responses were categorized as resistant disease (RD), partial remission (PR), and complete remission (CR) or complete remission with absolute neutrophil count < 1,000/µL or thrombocytopenia < 100,000/μL (CRi) by clinicians, with CR/CRi subdivided by MFC-MRD assay into MRD+ and MRD-. Patients without high-risk factors, including Flt3 internal tandem duplication wt/- NPM1-wt subgroup, received a second daunorubicin/cytosine arabinoside induction; course 2 (C2) was intensified for patients with high-risk factors. Results Survival outcomes from PR and MRD+ responses after C1 were similar, particularly for good- to standard-risk subgroups (5-year overall survival OS, 27% RD v 46% PR v 51% MRD+ v 70% MRD-; P < .001). Adjusted analyses confirmed significant OS differences between C1 RD versus PR/MRD+ but not PR versus MRD+. CRi after C1 reduced OS in MRD+ (19% CRi v 45% CR; P = .001) patients, with a smaller effect after C2. The prognostic effect of C2 MFC-MRD status (relapse: hazard ratio HR, 1.88 95% CI, 1.50 to 2.36, P < .001; survival: HR, 1.77 95% CI, 1.41 to 2.22, P < .001) remained significant when adjusting for C1 response. MRD positivity appeared less discriminatory in poor-risk patients by stratified analyses. For the NPM1-wt standard-risk subgroup, C2 MRD+ was significantly associated with poorer outcomes (OS, 33% v 63% MRD-, P = .003; relapse incidence, 89% when MRD+ ≥ 0.1%); transplant benefit was more apparent in patients with MRD+ (HR, 0.72; 95% CI, 0.31 to 1.69) than those with MRD- (HR, 1.68 95% CI, 0.75 to 3.85; P = .16 for interaction). Conclusion MFC-MRD can improve outcome stratification by extending the definition of partial response after first induction and may help predict NPM1-wt standard-risk patients with poor outcome who benefit from transplant in the first CR.
The introduction of all-trans retinoic acid (ATRA), and more recently of arsenic trioxide (ATO) in the treatment of Acute Promyelocytic Leukaemia (APL), has been instrumental in achieving the high ...cure rates recently reported. For the majority of patients, it is now possible to successfully treat this disease “chemo-free” without the use of cytotoxic chemotherapy as reflected in current clinical guidelines. The Sanz risk score developed by the GIMEMA and PETHEMA groups categorizes patients into three risk groups—low, intermediate, and high and correlates with relapse-free survival (RFS). Low- and intermediate-risk APL are now often considered together as ‘standard-risk’ defined by a white blood cell count (WBC) of less than 10 x 10
9
/L. High-risk APL has a WBC greater than 10 x 10
9
/L. In the UK our approach for patients with standard risk APL is to treat with ATRA and ATO without the use of cytotoxic chemotherapy. This approach is based on results from two large randomized clinical trials. The GIMEMA APL0406 trial showed an overall survival advantage compared to anthracycline-based chemotherapy plus ATRA. The UK NCRI AML17 trial which used an attenuated dose of ATO demonstrated a significant reduction in relapse and improved relapse-free survival. In the UK, the National Institute for Clinical Excellence approved both ATO plus ATRA regimens for re-imbursement for standard risk Acute Promyelocytic Leukaemia (APL). We use the AML17 schedule in standard-risk patients upfront and also in patients with relapsed Acute Promyelocytic Leukaemia (APL) previously treated with chemotherapy or in those with molecular persistence. The treatment of high-risk Acute Promyelocytic Leukaemia (APL) remains an area of contention as ATO is not approved for this indication. These patients have a greater risk of complications during remission induction with ATO including differentiation syndrome. The optimal approach is to incorporate chemotherapy early into the treatment schedule with either Gemtuzumab Ozogamicin (GO) as in the high-risk arm of the NCRI AML17 trial and MD Anderson Cancer Centre studies or Idarubicin as in the Australian APML4 study.
Epigenetic regulators, such as EZH2, are frequently mutated in cancer, and loss-of-function
mutations are common in myeloid malignancies. We have examined the importance of cellular context for Ezh2 ...loss during the evolution of acute myeloid leukemia (AML), where we observed stage-specific and diametrically opposite functions for Ezh2 at the early and late stages of disease. During disease maintenance, WT Ezh2 exerts an oncogenic function that may be therapeutically targeted. In contrast, Ezh2 acts as a tumor suppressor during AML induction. Transcriptional analysis explains this apparent paradox, demonstrating that loss of
derepresses different expression programs during disease induction and maintenance. During disease induction,
loss derepresses a subset of bivalent promoters that resolve toward gene activation, inducing a feto-oncogenic program that includes genes such as
, whose overexpression phenocopies
loss to accelerate AML induction in mouse models. Our data highlight the importance of cellular context and disease phase for the function of Ezh2 and its potential therapeutic implications.
Risk classification and tailoring of treatment are essential for improving outcome for patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. Both patient and leukemia-specific ...characteristics assessed using morphology, cytogenetics, molecular biology, and multicolor flow cytometry are relevant at diagnosis and during induction, consolidation, and maintenance phases of the treatment. In particular, minimal residual disease (MRD) during therapy has potential as a prognostic factor of outcome, determination of response to therapy, and direction of targeted therapy. MRD can be determined by cell surface markers using multicolor flow cytometry, whereas leukemia-specific translocations and mutations are measured using polymerase chain reaction-based techniques and recently using next-generation sequencing. All these methods of MRD detection have their (dis)advantages, and all need to be standardized, prospectively validated, and improved to be used for uniform clinical decision making and a potential surrogate end point for clinical trials testing novel treatment strategies. Important issues to be solved are time point of MRD measurement and threshold for MRD positivity. MRD is used for stem cell transplantation (SCT) selection in the large subgroup of patients with an intermediate risk profile. Patients who are MRD positive will benefit from allo-SCT. However, MRD-negative patients have a better chance of survival after SCT. Therefore, it is debated whether MRD-positive patients should be extensively treated to become MRD negative before SCT. Either way, accurate monitoring of potential residual or upcoming disease is mandatory. Tailoring therapy according to MRD monitoring may be the most successful way to provide appropriate specifically targeted, personalized treatment.
The PML::RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled ...proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML::RARA binding on gene expression and regulation in an inducible PML::RARA cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML::RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a computational machine learning implementation called Regulatory Element Behavior Extraction Learning to deconvolute the complex, local transcription factor binding site environment at PML::RARA bound positions to reveal distinct signatures that modulate how PML::RARA directs the transcriptional response.
Although NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die. Previous studies identified several molecular and clinical features ...associated with poor outcome, however only FLT3-ITD mutation and adverse karyotype are currently used for risk stratification due to inconsistent results and uncertainty around how other factors should influence treatment, particularly given the strong prognostic impact of post-induction measurable residual disease (MRD). Here we analyzed a large group of patients with NPM1mut AML enrolled in prospective trials (NCRI AML17 and AML19, n=1357) to delineate the impact of baseline molecular and clinical features, post induction MRD status and treatment intensity on outcome. FLT3-ITD (HR 1.28, 95%CI 1.01-1.63), DNMT3A (HR 1.65, 95%CI 1.32-2.05), WT1 (HR 1.74, 95%CI 1272-2.38) and non-ABD NPM1 mutations (HR 1.64, 95%CI 1.22-2.21) were independently associated with poorer overall survival (OS). These factors were also strongly associated with MRD positivity. For patients achieving MRD negativity, these mutations (except FLT3-ITD) were associated with an increased cumulative incidence of relapse (CIR) and poorer OS. However, apart from the few patients with adverse cytogenetics, we could not identify any group of MRD negative patients with a CIR >40% or with benefit from allograft in first remission. Intensified chemotherapy with the FLAG-Ida regimen was associated with improved outcomes in all subgroups, with greater benefits observed in the highest risk molecular subgroups.
Dasatinib is a multi-kinase inhibitor with activity against the SRC kinase LCK, which plays a critical role in T-cell receptor signaling. Dasatinib, initially developed as an immunosuppressive agent, ...is by contrast, also noted to result in enhanced tumor immunity in a subset of patients. We studied the impact of dasatinib in chronic myeloid leukemia patients and compared it with patients taking other tyrosine kinase inhibitors (TKI) and healthy controls. We found that patients on dasatinib showed inhibition of both T-cell receptor (TCR) and STAT5 signaling pathways, and reduced expression of Teffector pro-inflammatory cytokines. In addition, dasatinib induced selective depletion of regulatory T cells (Tregs) and effector Tregs, particularly in patients with clonal expansion of effector CD8+ T cells, who demonstrated greater and preferential inhibition of Treg TCR intracellular signaling. In addition, we show that dasatinib selectively reduces Treg STAT5 phosphorylation via reduction of IL-2, in relation with the marked reduction of plasma IL-2 levels in patients taking dasatinib. Finally, patients on other TKI had significantly increased TCR signaling in TIM3+ cells compared to patients taking dasatinib, suggesting that chronic SRC kinase inhibition by dasatinib may play a role in preventing TIM-3-mediated T-cell exhaustion and preserve anti-tumor immunity. These data provide further insight into the selective immunomodulatory effects of dasatinib and its potential use for pharmacologic control of immunotherapies.
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