Association of CDSS score and 60-day mortality in Chinese patients with non-APL acute myeloid leukemia: a retrospective cohort study.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy, and is one of the triggers of DIC, the latter is an essential factor in the early death of patients with AML. However, the timely identification of DIC remains a challenge. The Chinese DIC Scoring System (CDSS) is a common consensus widely used in China; but, there are few reports on its application in patients with AML. We undertake this retrospective cohort study to investigate the association between CDSS score and 60-day mortality. CDSS scores were evaluated after admission. The outcome was all-cause 60-day mortality. Multivariate Cox regression analyses were performed to calculate the adjusted hazard ratio (HR) and the corresponding 95% confidence interval (CI). Survival curves were plotted by Kaplan-Meier and log-rank analyses. Subgroup analyses were stratified by relevant effect covariates. A total of 570 consecutive patients with primary AML were included. We found an association between a 39% increase in 60-day mortality and a 1 point increase in CDSS score (HR = 1.39, 95% CI 1.25-1.54), which was associated with a 189% increase in 60-day mortality in CDSS scores ≥ 6 compared with that in the CDSS scores < 6 (HR = 2.89, 95% CI 1.91-4.38). After adjusting for all potential con-founders, a 27% and a 198% increase were observed (HR = 1.27, 95% CI 1.01-1.61; HR = 2.98, 95% CI 1.24-7.19), respectively. There is association between 60-day mortality and CDSS score in patients with AML. These findings may help hematologists in making informed treatment decisions.

Prognostic value of combined WT1 and multiparameter flow cytometry assessment for measurable residual disease after induction in non-APL acute myeloid leukemia.

The objective of this study was to investigate the expression pattern of Wilms tumor 1 (WT1) gene at diagnosis, complete remission (CR) and relapse status in non-acute promyelocytic leukemia (non-APL) acute myeloid leukemia (AML) patients, and further explore the prognostic value of measurable residual disease (MRD) assessment by WT1 gene and multiparameter flow cytometry (MFC). Our results showed that the average expression level of WT1 was 4026 ± 616.1 copies/104 ABL at diagnosis, 155.3 ± 36.03 copies/104 ABL at CR, and 1766 ± 238.8 copies/104 ABL at relapse, with statistically significant differences (p = .000). ROC analysis showed that WT1 expression levels were 118.1 copies/104 ABL and MFC-MRD was 0.155%, which had good predictive efficacy for relapse of patients during consolidation therapy. Both WT1-MRD and MFC-MRD had a significant impact on relapse-free survival (RFS) and overall survival (OS). Patients with WT1-MRD positive or MFC-MRD positive were associated with worse RFS (HR 3.840, 95% CI 1.582-9.320, p = .003), (HR 4.464, 95% CI 1.841-10.984, p = .001) and worse OS (HR 2.963, 95% CI 1.058-8.295, p = .039), (HR 3.590, 95% CI 1.254-10.280, p = .017). Besides, compared with patients who were negative for both WT1-MRD and MFC-MRD, patients who were positive both WT1-MRD and MFC-MRD were associated with worse RFS (HR 6.200, 95% CI 2.206-17.430, p = .001) and worse OS (HR 4.886, 95% CI 1.388-17.197, p = .013). This study demonstrates that combined assessment of MRD by WT1 and MFC improves relapse and prognosis prediction in non-APL AML patients, and may help guide interventions for disease relapse.

The Promise of Retinoids in the Treatment of Cancer: Neither Burnt Out Nor Fading Away.

Since the introduction of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL) has become a highly curable malignancy, especially in combination with arsenic trioxide (ATO). ATRA's success has deepened our understanding of the role of the RARα pathway in normal hematopoiesis and leukemogenesis, and it has influenced a generation of cancer drug development. Retinoids have also demonstrated some efficacy in a handful of other disease entities, including as a maintenance therapy for neuroblastoma and in the treatment of cutaneous T-cell lymphomas; nevertheless, the promise of retinoids as a differentiating therapy in acute myeloid leukemia (AML) more broadly, and as a cancer preventative, have largely gone unfulfilled. Recent research into the mechanisms of ATRA resistance and the biomarkers of RARα pathway dysregulation in AML have reinvigorated efforts to successfully deploy retinoid therapy in a broader subset of myeloid malignancies. Recent studies have demonstrated that the bone marrow environment is highly protected from exogenous ATRA via local homeostasis controlled by stromal cells expressing CYP26, a key enzyme responsible for ATRA inactivation. Synthetic CYP26-resistant retinoids such as tamibarotene bypass this stromal protection and have shown superior anti-leukemic effects. Furthermore, recent super-enhancer (SE) analysis has identified a novel AML subgroup characterized by high expression of RARα through strong SE levels in the gene locus and increased sensitivity to tamibarotene. Combined with a hypomethylating agent, synthetic retinoids have shown synergistic anti-leukemic effects in non-APL AML preclinical models and are now being studied in phase II and III clinical trials.

Oral arsenic trioxide for treating acute promyelocytic leukaemia: Implications for its worldwide epidemiology and beyond.

This account describes how orally administered Arsenic-trioxide (ATO) therapy influences the epidemiology of acute promyelocytic leukaemia (APL), and how the experience that ensued may expand the indications for oral ATO as a treatment for diseases/disorders other than APL. Over the last two decades, experience with APL patients in Hong Kong treated with an oral regimen comprising ATO, all-trans retinoic acid (ATRA), and ascorbic acid (also known as "AAA") has confirmed a dramatic improvement in overall survival. Over that period, there has been an estimated 60-fold increase in the prevalence of APL (proportion of surviving APL patients in the population on December 31 including those deemed to be 'cured'). In contrast to regimens entailing intravenous (IV) ATO, the consequential therapeutic benefits of using oral ATO have been achieved with much less patient inconvenience and quality of life disruption, reduced burdens on health care facilities (hospitalisations and staff involvement), and much enhanced affordability (retail drug & other cost reductions). Numerous experimental and a few clinical studies suggest that ATO may also have a therapeutic role in many other diseases/disorders. Several such diseases (e.g. autoimmune disorders & idiopathic pulmonary fibrosis) are far more prevalent than APL, which means that very large numbers of patients may potentially benefit from ATO treatment, even if its efficacy is limited to selected populations with these diseases. The known safety of oral ATO and its advantages over repeated long-term IV delivery suggests that this route be used in future clinical studies of its possible role in treating such patients. If the clinical utility of oral ATO treatment is validated for patients enduring any such non-APL diseases, very large numbers of patients may stand to benefit.

Role for Fgr and Numb in retinoic acid-induced differentiation and G0 arrest of non-APL AML cells.

Retinoic acid (RA) is a fundamental regulator of cell cycle and cell differentiation. Using a leukemic patient-derived in vitro model of a non-APL AML, we previously found that RA evokes activation of a macromolecular signaling complex, a signalosome, built of numerous MAPK-pathway-related signaling molecules; and this signaling enabled Retinoic-Acid-Response-Elements (RAREs) to regulate gene expression that results in cell differentiation/cell cycle arrest. Toward mechanistic insight into the nature of this novel signaling, we now find that the NUMB cell fate determinant protein is an apparent scaffold for the signalosome. Numb exists in the cell bound to an ensemble of signalosome molecules, including Raf, Lyn, Slp-76, and Vav. Addition of RA induces the expression of Fgr. Fgr binds NUMB, which is associated with (p-tyr)phosphorylation of NUMB and enhanced NUMB-binding and (p-tyr)phosphorylation of select signalosome components, thereby betraying signalosome activation. Signalosome activation is associated with cell differentiation along the myeloid lineage and G1/0 cell cycle arrest. If RA-induced Fgr expression is ablated by a CRISPR-KO; then the RA-induced (p-tyr) phosphorylation of NUMB and enhanced NUMB-binding and (p-tyr)phosphorylation of select signalosome components are lost. The cells now fail to undergo RA-induced differentiation or G1/0 arrest. In sum we find that NUMB acts as a scaffold for a signaling machine that functions to propel RA-induced differentiation and G1/0 arrest, and that Fgr binding to NUMB turns the function on. The Numb fate determinant protein thus appears to regulate the retinoic acid embryonic morphogen using the Fgr Src-Family-Kinase. These mechanistic insights suggest therapeutic targets for a hitherto incurable AML.

SPRED1 Is Downregulated and a Prognostic Biomarker in Adult Acute Myeloid Leukemia.

We report herein that Sprouty-Related EVH1 Domain-Containing Protein1 (SPRED1) is downregulated and a prognostic biomarker in adult acute myeloid leukemia (AML). We determined mRNA levels of SPRED1 in the bone marrow mononuclear cells from adult patients, including 113 AMLs and 22 acute lymphoblastic leukemias (ALLs), as well as in 37 healthy control subjects. Significantly decreased SPRED1 mRNA expression was found in AML patients comparing to those in ALL patients and healthy controls, which was confirmed by immunocytochemistry analysis of SPRED1 protein and ELISA measurement of serum SPRED1 level. Further analysis demonstrated that SPRED1 expression was significantly higher for most patients at complete remission after induction treatment than at diagnosis. Moreover, SPRED1 expression was significantly downregulated in M2 and M3 types. Non-acute promyelocytic leukemia (non-APL) patients with decreased SPRED1 had significantly lower 2-year progression-free survival and event-free survival rates. In vitro, ectopic overexpression of SPRED1 leads to a decrease of extracellular signal-regulated kinase (ERK) phosphorylation, induction of apoptosis and reduction of proliferation of THP-1 cells. Our findings suggest SPRED1 is not only a predictor of treatment response, but also an independent prognostic factor for non-APL, and targeting Ras- Mitogen-activated protein kinase (MAPK) signaling may be a promising strategy for the treatment of AML with downregulation of SPRED1.

Epigenetic Therapy Promotes the Ratio of Th1/Th17 Lineage to Reverse Immune Evasion and Treat Leukemia Relapse Post-allogeneic Stem Cell Transplantation in Non-APL AML Patients.

To reverse the early-stage relapse post-hematopoietic stem cell transplantation, we investigated the safety and efficacy of a new epigenetic regimen (chidamide and decitabine plus thymalfasin simultaneously) on acute myeloid leukemia patients (excluding acute promyelocytic leukemia). Twenty-four patients were enrolled in this observational study during April 2015 to May 2018. The most common adverse event was reversible CTCAE grade 2 thrombocytopenia (20/24). Strikingly, all 24 patients had response to this epigenetic regimen accompanied with decreased measurable residual disease. The overall survival rate is 79.2% (19/24), with a relapse-free survival rate of 79.2% (19/24). During this regimen treatment, Th1 cells and CD3+CD4-CD8+T cells increased, and Th17 cells decreased gradually. The status of high Th1 and low Th17 cells was still observed on the 3rd month after discontinuation of this regimen. Interestingly, the significantly elevated ratio of Th1/Th17 seemed to reflect the treatment-related immune effect, which may be a valuable marker to be monitored in the early-relapse stage for evaluating the efficacy and prognosis.