Early platelet elevation after complete remission as a prognostic marker of favourable outcomes in favourable- and intermediate-risk acute myeloid leukaemia: A retrospective study.

OBJECTIVES: Platelet (PLT) recovery after chemotherapy is associated with the prognosis of patients with acute myeloid leukaemia (AML). This study aimed to explore the prognostic significance of early high PLT values in patients with de novo non-M3 AML who achieved first complete remission (CR). METHODS: A total of 206 patients with de novo non-M3 AML were analysed in this retrospective study. A receiver operating characteristic (ROC) curve was used to determine the optimal PLT cut-off. The overall survival (OS) and relapse-free survival (RFS) were assessed using Kaplan-Meier and Cox regression analyses. RESULTS: 312×109 /L was confined as the cut-off of the PLT count. The estimated 3-year OS of patients with high PLT was higher than that of their counterparts (72.3% vs. 34.6%, p = 0.001). In subgroup analysis, patients with high PLT had better OS in the favourable- and intermediate-risk (non-adverse-risk) AML (p = 0.001). The estimated 3-year RFS for the high and low PLT groups was 75.1% and 45.7% respectively (p = 0.078). Multivariate analyses revealed that high PLT count was an independent favourable variable for OS (HR = 0.264, p < 0.001) and RFS (HR = 0.375, p = 0.011) in the non-adverse-risk group. CONCLUSION: Our results showed that early high PLT count recovery at first CR in non-adverse-risk AML patients is a positive prognostic marker for survival outcomes.

Iron deficiency as promoter of heavy metals-induced acute myeloid leukemia.

Iron deficiency (ID) and iron deficiency anemia (IDA) have many adverse effects on human health. Also, iron deficiency anemia and anemia in general are linked with an increased risk of various cancers, particularly blood cancers. It is known that subjects with IDA as well as smokers have elevated blood levels of toxic divalent cations, particularly cadmium (Cd2+) and lead (Pb2+). Cadmium is a proven carcinogen. Most of the circulating cadmium is bound to transferrin and apart from the target organs of cadmium accumulation, kidney and liver, tissues (cells) which highly express transferrin receptor 1 (TfR1) may also accumulate high levels of circulating cadmium. Density of TfR1, glycoprotein that is expressed on cell surface, is not uniform in bone marrow cells. Namely, megakaryocyte/erythrocyte progenitors and pro-erythroblasts express TfR1 incomparably more than other cell lines within the bone marrow and we hypothesize that the mentioned cell lines will uptake most of the circulating cadmium and lead, and will consequently be most suitable for malignant transformation. In this review, we discuss in detail the mechanisms involved in accumulation of cadmium in particular cell lines of the bone marrow and the consequent occurrence of acute myeloid leukemia (AML).

Dysregulation of miRNA in Leukemia: Exploiting miRNA Expression Profiles as Biomarkers.

Micro RNAs (miRNAs) are a class of small non-coding RNAs that have a crucial role in cellular processes such as differentiation, proliferation, migration, and apoptosis. miRNAs may act as oncogenes or tumor suppressors; therefore, they prevent or promote tumorigenesis, and abnormal expression has been reported in many malignancies. The role of miRNA in leukemia pathogenesis is still emerging, but several studies have suggested using miRNA expression profiles as biomarkers for diagnosis, prognosis, and response to therapy in leukemia. In this review, the role of miRNAs most frequently involved in leukemia pathogenesis is discussed, focusing on the class of circulating miRNAs, consisting of cell-free RNA molecules detected in several body fluids. Circulating miRNAs could represent new potential non-invasive diagnostic and prognostic biomarkers of leukemia that are easy to isolate and characterize. The dysregulation of some miRNAs involved in both myeloid and lymphoid leukemia, such as miR-155, miR-29, let-7, and miR-15a/miR-16-1 clusters is discussed, showing their possible employment as therapeutic targets.

Association of elevated vitamin B12 with oncohematological diseases in a cohort of 79,524 patients from Latvia.

AIM: Currently there are some large-scale studies of elevated total vitamin B12 in relation to diseases and their prognosis. Aim of this retrospective study was to determine association of increased B12 as an additional diagnostic marker of oncohematological diseases by a statistical analysis of clinical data of 79,524 patients. MATERIALS AND METHODS: Overall Latvian population representative data on B12  testing in 79,524 patients were obtained from laboratory database. The following exclusion criteria were applied: fluctuating B12 results within a three-month period, elevated (> 100 U/L) alanine transaminase or aspartate transaminase, hepatitis (HAV, HBV, and HCV) infection, reduced glomerular filtration rate (< 45 mL/min/1.73 m2). As a control group, individuals with normal B12 level and any oncologic diagnosis (solid cancer or hematological malignancies) were selected. RESULTS: After application of step-by-step exclusion filters, 1,373 patients were left with significantly increased level of plasma B12 (> 1,700 pg/mL). Odds ratios for oncohematological diseases in total and myeloid leukemia (including acute, chronic and unspecified) in patient group with elevated B12 were found to be 6.0 (95% CI 4.7-7.6; p < 0.0001) and 19.2 (95% CI 13.1-28.0; p <0.0001), respectively, as compared to the control group. CONCLUSION: Elevated total B12 could be considered as a potential marker for oncohematological disorders.

Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes.

BACKGROUND: Patients with haematological malignancies are often vitamin C deficient, and vitamin C is essential for the TET-induced conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), the first step in active DNA demethylation. Here, we investigate whether oral vitamin C supplementation can correct vitamin C deficiency and affect the 5hmC/5mC ratio in patients with myeloid cancers treated with DNA methyltransferase inhibitors (DNMTis). RESULTS: We conducted a randomized, double-blinded, placebo-controlled pilot trial (NCT02877277) in Danish patients with myeloid cancers performed during 3 cycles of DNMTi-treatment (5-azacytidine, 100 mg/m2/d for 5 days in 28-day cycles) supplemented by oral dose of 500 mg vitamin C (n = 10) or placebo (n = 10) daily during the last 2 cycles. Fourteen patients (70%) were deficient in plasma vitamin C (< 23 µM) and four of the remaining six patients were taking vitamin supplements at inclusion. Global DNA methylation was significantly higher in patients with severe vitamin C deficiency (< 11.4 µM; 4.997 vs 4.656% 5mC relative to deoxyguanosine, 95% CI [0.126, 0.556], P = 0.004). Oral supplementation restored plasma vitamin C levels to the normal range in all patients in the vitamin C arm (mean increase 34.85 ± 7.94 µM, P = 0.0004). We show for the first time that global 5hmC/5mC levels were significantly increased in mononuclear myeloid cells from patients receiving oral vitamin C compared to placebo (0.037% vs - 0.029%, 95% CI [- 0.129, - 0.003], P = 0.041). CONCLUSIONS: Normalization of plasma vitamin C by oral supplementation leads to an increase in the 5hmC/5mC ratio compared to placebo-treated patients and may enhance the biological effects of DNMTis. The clinical efficacy of oral vitamin C supplementation to DNMTis should be investigated in a large randomized, placebo-controlled clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02877277 . Registered on 9 August 2016, retrospectively registered.

Myeloid malignancies-related somatic mutations in aging individuals.

We search for the presence of somatic mutations in 12 genes related to MDS, MPN, and AML in a Brazilian cohort composed of 609 elderly individuals from a census-based sample.

Preclinical pharmacokinetics and pharmacodynamics of DCLL9718A: An antibody-drug conjugate for the treatment of acute myeloid leukemia.

Few treatment options are available for acute myeloid leukemia (AML) patients. DCLL9718A is an antibody-drug conjugate that targets C-type lectin-like molecule-1 (CLL-1). This receptor is prevalent on monocytes, neutrophils, and AML blast cells, and unlike CD33, is not expressed on hematopoietic stem cells, thus providing possible hematopoietic recovery. DCLL9718A comprises an anti-CLL-1 IgG1 antibody (MCLL0517A) linked to a pyrrolobenzodiazepine (PBD) dimer payload, via a cleavable disulfide-labile linker. Here, we characterize the in vitro and in vivo stability, the pharmacokinetics (PK) and pharmacodynamics (PD) of DCLL9718A and MCLL0517A in rodents and cynomolgus monkeys. Three key PK analytes were measured in these studies: total antibody, antibody-conjugated PBD dimer and unconjugated PBD dimer. In vitro, DCLL9718A, was stable with most (> 80%) of the PBD dimer payload remaining conjugated to the antibody over 96 hours. This was recapitulated in vivo with antibody-conjugated PBD dimer clearance estimates similar to DCLL9718A total antibody clearance. Both DCLL9718A and MCLL0517A showed linear PK in the non-binding rodent species, and non-linear PK in cynomolgus monkeys, a binding species. The PK data indicated minimal impact of conjugation on the disposition of DCLL9718A total antibody. Finally, in cynomolgus monkey, MCLL0517A showed target engagement at all doses tested (0.5 and 20 mg/kg) as measured by receptor occupancy, and DCLL9718A (at doses of 0.05, 0.1 and 0.2 mg/kg) showed strong PD activity as evidenced by notable reduction in monocytes and neutrophils.

The Potential of Angiogenin as a Serum Biomarker for Diseases: Systematic Review and Meta-Analysis.

BACKGROUND: Angiogenin (ANG) is a multifunctional angiogenic protein that participates in both normal development and diseases. Abnormal serum ANG levels are commonly reported in various diseases. However, whether ANG can serve as a diagnostic or prognostic marker for different diseases remains a matter of debate. METHODS: Here, we performed a systematic review and meta-analysis of the literature utilizing PubMed, Web of Science, and Scopus search engines to identify all publications comparing plasma or serum ANG levels between patients with different diseases and healthy controls, as were studies evaluating circulating ANG levels in healthy populations, pregnant women, or other demographic populations. RESULTS: This study demonstrated that the serum ANG concentration in healthy populations was 336.14 ± 142.83 ng/ml and remained relatively stable in different populations and regions. We noted no significant differences in serum ANG levels between patients and healthy controls, except in cases in which patients suffered from cancer or cardiovascular diseases. The serum ANG concentrations were significantly higher in patients who developed colorectal cancer, acute myeloid leukemia, multiple myeloma, myelodysplastic syndromes, and heart failure than those in healthy controls. CONCLUSION: ANG has the potential of being a serum biomarker for cancers and cardiovascular diseases.

Correlation of Calcium and Magnesium Levels in the Biological Samples of Different Types of Acute Leukemia Children.

Acute leukemia (AL) is a common childhood malignancy. It is clinically and morphologically heterogeneous. The present work was intended to estimate the concentration of calcium (Ca) and magnesium (Mg) in serum and whole blood samples of children having AL; 1- to 5- and 6- to 10-year-old children age group was chosen of both genders. Healthy children of the same age group were selected as controls for comparative study. For sample pretreatment, a microwave-assisted acid digestion (MAD) was carried out, to assess the concentration of Ca and Mg in biological samples of AL children. The MAD method was validated by analyzing Clinchek® Control certified samples of whole blood and serum. Ca and Mg were analyzed in the digested samples by flame atomic absorption spectrometry (FAAS). The results showed significantly higher concentration of Ca, whereas lower contents of Mg in the serum and whole blood of AL children in both genders, as compared to healthy subjects. The data provide assistance to physician/clinicians and other professional staffs to investigate the imbalance of minerals in biological samples of AL children.

Diagnostic Potential of Imaging Flow Cytometry.

Imaging flow cytometry (IFC) captures multichannel images of hundreds of thousands of single cells within minutes. IFC is seeing a paradigm shift from low- to high-information-content analysis, driven partly by deep learning algorithms. We predict a wealth of applications with potential translation into clinical practice.

Recipient T Cell Exhaustion and Successful Adoptive Transfer of Haploidentical Natural Killer Cells.

Natural killer (NK) cells mediate surveillance for malignancy. In some chemotherapy refractory myeloid leukemia patients, adoptive transfer of NK cells from haploidentical donors can induce remission. We have previously shown that remission induction is linked to NK cell persistence at day +14, but the factors influencing NK cell persistence are unknown. To address this question, patient samples from a phase I trial of National Cancer Institute (NCI) IL-15 in whom either did or did not show NK cell expansion were compared with healthy donor control subjects. Before lymphodepleting chemotherapy, high absolute CD3+ count was predictive of patients who failed to expand their haploidentical NK cell graft. Interestingly, both groups had elevated expression of inhibitory receptors and decreased cytokine production compared with control subjects, suggestive of T cell exhaustion among all patients before haploidentical NK cell infusion. At day +14, however, haploidentical NK cell expanders had persistence of recipient CD8+ T cells with the most exhausted inhibitory phenotype (either PD-1high or dual PD-1+Tim-3+) and elevated expression of T-bet and Eomes compared with NK cell nonexpanders and control subjects. This suggested that maintenance of an exhausted T cell state at day +14 permits haploidentical NK cell expansion and supports further efforts to selectively deplete recipient T cells or modulate their dysfunction.

Cellular and plasma nitrite levels in myeloid leukemia: a pathogenetic decrease.

Nitric oxide (NO) has a contributory role in hemopoietic cell growth and differentiation. The effects of NO on leukemic cell growth have been predominantly studied in in vitro settings. This study was done to assess the alterations in nitrite level in myeloid leukemias. Thirty-six newly diagnosed cases of myeloid leukemia (16 AML and 20 CML) were enrolled in the study. Neutrophil precursors from the marrow aspirate and peripheral blood were separated into cell bands using the Percoll density gradient method of Borregard and Cowland. The blood plasma and marrow fluid was also collected. Nitrite (stable non-volatile end product of NO) was estimated in the cell bands, blood plasma and marrow fluid using Griess reagent. The mean nitrite level in all cell bands from peripheral blood, bone marrow, blood plasma, and marrow fluid of cases was significantly lower as compared to corresponding value in the controls. No significant difference between AML and CML was seen. On follow-up, analysis of 13 CML patients higher nitrite levels were seen (p>0.05). The significant decrease in nitrite levels in myeloid leukemia suggests a decrease in nitric oxide synthase (NOS) activity. Further work may unfold molecular targets for therapeutic role of NO modulators.

Hematologic Response to Vorinostat Treatment in Relapsed Myeloid Leukemia of Down Syndrome.

Children with Down syndrome are at high risk to develop myeloid leukemia (ML-DS). Despite their excellent prognosis, children with ML-DS particularly suffer from severe therapy-related toxicities and for relapsed ML-DS the cure rates are very poor. Here we report the clinical course of one child with ML-DS treated with the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid) after second relapse. The child had previously received conventional chemotherapy and stem cell transplantation, yet showed a remarkable clinical and hematologic response. Thus, HDAC inhibitor may represent an effective class of drugs for the treatment of ML-DS.

High CD3+ and CD34+ peripheral blood stem cell grafts content is associated with increased risk of graft-versus-host disease without beneficial effect on disease control after reduced-intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia - an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Inconsistent results have been reported regarding the influence of graft composition on the incidence of graft versus host disease (GVHD), disease control and survival after reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell transplantation (allo-PBSCT). These discrepancies may be at least in part explained by the differences in disease categories, disease status at transplant, donor type and conditioning. The current retrospective EBMT registry study aimed to analyze the impact of CD3+ and CD34+ cells dose on the outcome of RIC allo-PBSCT in patients with acute myelogenous leukemia (AML) in first complete remission, allografted from HLA-matched unrelated donors (10 of 10 match). We included 203 adults. In univariate analysis, patients transplanted with the highest CD3+ and CD34+ doses (above the third quartile cut-off point values, >347 x 10^6/kg and >8.25 x 10^6 /kg, respectively) had an increased incidence of grade III-IV acute (a) GVHD (20% vs. 6%, P = .003 and 18% vs. 7%, P = .02, respectively). There was no association between cellular composition of grafts and transplant-related mortality, AML relapse, incidence of chronic GVHD and survival. Neither engraftment itself nor the kinetics of engraftment were affected by the cell dose. In multivariate analysis, CD3+ and CD34+ doses were the only adverse predicting factors for grade III-IV aGVHD (HR = 3.6; 95%CI: 1.45-9.96, P = .006 and 2.65 (1.07-6.57), P = .04, respectively). These results suggest that careful assessing the CD3+ and CD34+ graft content and tailoring the cell dose infused may help in reducing severe acute GVHD risk without negative impact on the other transplantation outcomes.

Leukostasis in Children and Adolescents with Chronic Myeloid Leukemia: Japanese Pediatric Leukemia/Lymphoma Study Group.

BACKGROUND: The details of leukostasis in children and adolescents with chronic myeloid leukemia (CML) are unknown. This study determined the characteristics of leukostasis in children and adolescents with CML. PROCEDURE: A total of 256 cases from a retrospective study of patients with CML conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group from 1996 to 2011 were analyzed, and of these, 238 cases were evaluated in this study. RESULTS: Leukostasis was diagnosed in 23 patients (9.7%). The median leukocyte count and spleen size below the left costal margin in cases with leukostasis were significantly higher and larger when compared to those in cases without leukostasis (458.5 × 10(9) /l vs. 151.8 × 10(9) /l (P < 0.01), and 13 vs. 5 cm (P < 0.01), respectively). Leukostasis occurred with ocular symptoms in 14 cases, priapism in four cases, and dyspnea, syncope, headache, knee pain, difficulty hearing, and aseptic necrosis of the femoral head in one case each. One case had two leukostasis symptoms simultaneously. Three cases were diagnosed before imatinib became available. Five cases received special treatment, and in the remaining 15 cases, all of these symptoms resolved after treatment with imatinib. CONCLUSIONS: This retrospective study represents the largest series of children and adolescents in which leukostasis of CML has been reported. Our data provide useful insight into the characteristics of leukostasis in recent cases of children and adolescents with CML.