Objective:

Circulating endothelial cells (CECs) in patients with hematological malignancies are assessed as a noninvasive marker of angiogenesis. The aim of this study was to evaluate the numbers of CECs and their subsets during mobilization of hematopoietic stem cells. Patients and methods: Thirty-eight patients were enrolled to the study (19 females and 19 males) at median age of 56.5 years. The group consisted of patients with multiple myeloma (26), lymphoma (10), and acute myeloid leukemia (2). Blood samples were collected before chemotherapy (0), 1 day after chemotherapy (Cht+1), on the day G-CSF commenced (G0), after 1 day of G-CSF (G+1), and on the day of the first apheresis. CECs were evaluated by four-color flow cytometry. Circulating progenitor cells were defined as CD45-/CD34+/CD31+/CD133+. Apoptotic CECs (ApoCECs) were defined as CD146+/AnnexinV+.

Results:

Median (Me) CECs number was 10.5/µl and it decreased after chemotherapy (Me = 8.3/µl, P < 0.001 when compared with baseline). Based on the number of aphereses needed to obtain 2 × 10(6) /kg CD34+ cells, patients were divided into "highly efficient" (one apheresis) and "poorly efficient" mobilizers (two or more aphereses). Median ApoCEC at Day G+1 was lower in highly efficient than in poorly efficient mobilizers (Me = 3.1/µl vs. Me = 5.1/µl, P = 0.02). ApoCEC at Day G+1 correlated with the number of aphereses (r = 0.48, P = 0.03). In multivariate analysis, ApoCEC at Day G+1 was an independent factor for successful mobilization during one apheresis.

Conclusions:

CECs and their subsets change significantly during mobilization of HSCs. ApoCECs measured at the time of G-CSF commencement can predict the efficacy of HSC collection. J. Clin. Apheresis, 2013. © 2013 Wiley Periodicals, Inc.

Either WT1 or leukemia-associated aberrant immune phenotypes (LAIPs) was one of the minimal residual disease (MRD) parameters used to predict leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We first evaluated the clinical value of various positive MRD standards for accurately indicating relapse based on WT1 and FCM data in adult patients with acute leukemia (AL). In total, 824 AL patients treated with allo-HSCT were enrolled in this study. We compared the sensitivity and specificity of diverse, multiple-criteria MRD prognostic standards based on WT1 and FCM assays. Higher sensitivity was achieved without a loss of specificity when MRDco+, which was defined as two consecutive WT10.6+ or FCM+ or both WT10.6+ and FCM+ in the same sample within a year posttransplantation, was used as the positive MRD standard. Similar results were observed, even in 484 patients who had both abnormal WT1 and LAIPs values before transplant. A multivariate analysis showed that MRDco+ was an independent risk factor for leukemia relapse after transplant in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The combined use of FCM and WT1 monitoring could distinguish between patients with low and high risks of relapse. Various positive MRD standards were useful for guiding intervention.

BACKGROUND:

Acute myeloid leukemia (AML) is the most common form of acute leukemia affecting adults, with incidence increasing with patient age. Previous studies have found that older AML patients, constituting the majority of the AML population, generally have poor outcomes, high healthcare expenditures, and median survival of <3 months. Because up-to-date information on treatment patterns, survival trends, and costs of care for elderly AML patients are lacking in the literature, we examined Medicare fee-for-service enrollees with primary AML to update these estimates and report on changes in treatment for this population.

OBJECTIVE:

The primary objective of this study was to examine real-world data on treatment patterns, survival, and costs in elderly patients with primary AML. Factors associated with receipt of chemotherapy and with mortality also were assessed.

METHODS:

This is a retrospective database analysis using the Surveillance, Epidemiology, and End Results cancer registry and linked Medicare claims. Patients aged 65 years and older, who were newly diagnosed with AML between 1 January 1997 and 31 December 2007 were selected if they had no previous neoplasm or hematological disease. Patients were followed until death or to the end of the observation period (31 December 2007). Study measures included chemotherapy and supportive care (SC) received, survival time, and all-cause healthcare utilization and costs accrued from AML diagnosis until death or observation period end. Regression analyses assessed factors associated with receipt of chemotherapy (logistic) and mortality among chemotherapy and SC users (Cox).

RESULTS:

Of the 4,058 patients meeting the inclusion criteria, 43 % received chemotherapy; 57 % received SC only. Among patients receiving chemotherapy, 69.1 % died within 1 year; median survival was 7.0 months. Among patients receiving only SC, 95.0 % died within 1 year; median survival was 1.5 months. The most significant factors associated with receipt of chemotherapy were patient age [odds ratio (OR) = 0.420 among patients 75-84 years and 0.099 among patients 85+ years, compared with patients aged 65-74 years) and Charlson Comorbidity Index (CCI) score (OR = 0.614 for patients with a CCI = 2 or 3 and 0.707 for patients with a CCI >3, compared with patients with a CCI = 0) (all P < 0.001). The most significant factors associated with mortality among patients receiving chemotherapy were patient age [hazard ratio (HR) = 1.321 among patients 75-84 years and 1.832 among patients 85+ years, compared with patients aged 65-74 years] and CCI score (OR = 1.287 for patients with a CCI = 2 or 3 and 1.220 for patients with a CCI >3, compared with patients with a CCI = 0) (all P < 0.01). Mean (standard deviation) all-cause healthcare costs were $96,078 ($109,072); the largest component was inpatient utilization (76.3 %).

CONCLUSIONS:

Younger patients with fewer comorbidities were more likely to receive chemotherapy and had longer survival. AML is associated with a substantial economic burden, and treatment outcomes appear to be suboptimal, with limited therapy options currently available.

Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with a 5-year disease-free survival (DFS) ranging from under 10% to over 70% for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or second remission patients treated with a two-step approach to autologous stem cell transplantation (ASCT). In this study, we tested the hypothesis that polymorphisms in the pharmacokinetic and pharmacodynamic pathway genes of these drugs are associated with DFS in AML patients. A total of 1659 variants in 42 genes were analyzed for their association with DFS using a Cox-proportional hazards model. One hundred and fifty-four genetically European patients were used for the primary analysis. An intronic single nucleotide polymorphism (SNP) in ABCC3 (rs4148405) was associated with a significantly shorter DFS (hazard ratios (HR)=3.2, P=5.6 × 10(-6)) in our primary cohort. In addition, a SNP in the GSTM1-GSTM5 locus, rs3754446, was significantly associated with a shorter DFS in all patients (HR=1.8, P=0.001 for 154 European ancestry; HR=1.7, P=0.028 for 125 non-European patients). Thus, for the first time, genetic variants in drug pathway genes are shown to be associated with DFS in AML patients treated with chemotherapy-based autologous ASCT.Journal of Human Genetics advance online publication, 16 May 2013; doi:10.1038/jhg.2013.38.

A 3-year-old girl with acute myeloid leukemia underwent unrelated cord blood stem cell transplantation (UCBT) due to primary induction failure. Fourteen days after UCBT, she developed central venous catheter (CVC)-related bloodstream infection due to Chryseobacterium indologenes. Despite ciprofloxacin and minocycline being administered according to the results of susceptibility, a high grade fever recurred. Therefore, the CVC was removed 21 days after UCBT and symptoms related to CVC infection improved. Although C. indologenes is widely distributed in nature, it is a rare pathogen in humans. Most cases of C. indologenes bacteremia have been found in immunocompromised patients with malignancies and diabetes mellitus. C. indologenes exhibits specific characteristics, including the progression of resistance to antibiotics and the formation of a biofilm. Therefore, removal of the CVC appears to be the most reasonable treatment for CVC infection due to C. indologenes in patients undergoing hematopoietic stem cell transplantation if clinical symptoms do not improve after appropriate antibiotic therapy.

Rearrangements of the mixed lineage leukemia MLL gene at chromosome 11q23 are common chromosomal abnormalities in human leukemia. MLL fused with numerous partner genes causes different leukemia phenotypes that depend on the function of partner genes. MLLT3-MLL is generated by translocation t(9;11), which primarily induces acute myeloid leukemia in humans, whereas MLLT3-MLL induces ALL or biphenotypic leukemia in mice. The microenvironment that surrounds leukemia cells plays a central role in this process. We report a patient with mixed phenotype acute leukemia with MLLT3-MLL. This patient, a 44-year-old woman, initially exhibited extramedullary leukemia with multiple tumors and subsequently developed bone marrow disease. The leukemia cells exhibited myeloid (CD13 and MPO) and B cell (CD19 and CD79a) phenotypes. Chromosomal analysis and RT-PCR assay revealed tumor cells with the MLLT3-MLL fusion gene. We treated this patient with a drug regimen for AML (Ara-C plus anthracycline), and complete remission was obtained. This report describes the fourth case of mixed phenotypic leukemia with extramedullary disease. The extramedullary circumstance may underlie the biphenotypic features of these patients.

We examined the role of microRNAs (miRNAs) in targeting the stromal-derived factor 1α/CXCR4 (SDF-1α/CXCR4) axis to overcome chemoresistance of AML cells. Microarray analysis of OCI-AML3 cells revealed that the miRNA let-7a was downregulated by SDF-1α-mediated CXCR4 activation and increased by CXCR4 inhibition. Overexpression of let-7a in AML cell lines was associated with decreased c-Myc and BCL-XL protein expression and enhanced chemosensitivity, both in vitro and in vivo. We identified the transcription factor Yin Yang 1 (YY1) as a link between SDF-1α/CXCR4 signaling and let-7a, as YY1 was upregulated by SDF-1α and downregulated by treatment with a CXCR4 antagonist. ChIP assay confirmed the binding of YY1 to unprocessed let-7a DNA fragments, and treatment with YY1 shRNA increased let-7a expression. In primary human AML samples, high CXCR4 expression was associated with low let-7a levels. Xenografts of primary human AML cells engineered to overexpress let-7a exhibited enhanced sensitivity to cytarabine, resulting in greatly extended survival of immunodeficient mice. Based on these data, we propose that CXCR4 induces chemoresistance by downregulating let-7a to promote YY1-mediated transcriptional activation of MYC and BCLXL in AML cells.

Infectious endocarditis is a rarely encountered complication among leukemia patient during induction therapy. We describe a young patient who developed prolonged high fever after aggressive chemotherapy for Acute Myeloid Leukemia. Pseudomonas Aeruginosa endocarditis was found to be the etiology for the febrile state. Our purpose is to emphasize the need for an early diagnosis of this rare, albeit treatable complication.