Mojca Jongen-Lavrencic

High-dose daunorubicin in older patients with acute myeloid leukemia

BACKGROUND A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. METHODS Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter every 12 hours [DOSAGE ERROR CORRECTED] for 6 days. The primary end point was event-free survival. RESULTS The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%). CONCLUSIONS In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.)

MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia

Acute myeloid leukemia (AML) is a highly diverse disease characterized by various cytogenetic and molecular abnormalities. MicroRNAs are small noncoding RNAs that show variable expression during myeloid differentiation. MicroRNA expression in marrow blasts in 215 cases of newly diagnosed and (cyto)genetically defined AML was assessed using quantitative reverse-transcription-polymerase chain reaction (RT-PCR) for 260 human microRNAs. In the same series, mRNA gene expression profiles were established, allowing a direct comparison between microRNA and mRNA expression. We show that microRNA expression profiling following unsupervised analysis reveals distinctive microRNA signatures that correlate with cytogenetic and molecular subtypes of AML (ie, AMLs with t(8;21), t(15;17), inv(16), NPM1, and CEBPA mutations). Significantly differentially expressed microRNAs for genetic subtypes of AML were identified. Specific microRNAs with established oncogenic and tumor suppressor functions, such as microRNA-155, microRNA-21, and let-7, appear to be associated with particular subtypes. Combinations of selected sets of microRNAs could predict cytogenetically normal AML with mutations in the genes of NPM1 and CEBPA and FLT3-ITD with similar accuracy as mRNA probe set combinations defined by gene expression profiling. MicroRNA expression apparently bears specific relationships to the heterogeneous pathobiology of AML. Distinctive microRNA signatures appear of potential value in the clinical diagnosis of AML.

The Oncogenic MicroRNA miR-22 Targets the TET2 Tumor Suppressor to Promote Hematopoietic Stem Cell Self-Renewal and Transformation

MicroRNAs are frequently deregulated in cancer. Here we show that miR-22 is upregulated in myelodysplastic syndrome (MDS) and leukemia and its aberrant expression correlates with poor survival. To explore its role in hematopoietic stem cell function and malignancy, we generated transgenic mice conditionally expressing miR-22 in the hematopoietic compartment. These mice displayed reduced levels of global 5-hydroxymethylcytosine (5-hmC) and increased hematopoietic stem cell self-renewal accompanied by defective differentiation. Conversely, miR-22 inhibition blocked proliferation in both mouse and human leukemic cells. Over time, miR-22 transgenic mice developed MDS and hematological malignancies. We also identify TET2 as a key target of miR-22 in this context. Ectopic expression of TET2 suppressed the miR-22-induced phenotypes. Downregulation of TET2 protein also correlated with poor clinical outcomes and miR-22 overexpression in MDS patients. Our results therefore identify miR-22 as a potent proto-oncogene and suggest that aberrations in the miR-22/TET2 regulatory network are common in hematopoietic malignancies.

Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study

In older patients with acute myeloid leukemia (AML), the prevention of relapse has remained one of the major therapeutic challenges, with more than 75% relapses after complete remission. The anti-CD33 immunotoxin conjugate gemtuzumab ozogamicin (GO) has shown antileukemic remission induction activity in patients with relapsed AML. Patients with AML or refractory anemia with excess blasts in first complete remission attained after intensive induction chemotherapy were randomized between 3 cycles of GO (6 mg/m(2) every 4 weeks) or no postremission therapy (control) to assess whether GO would improve outcome. The 2 treatment groups (113 patients receiving GO vs 119 control patients) were comparable with regard to age (60-78 years, median 67 years), performance status, and cytogenetics. A total of 110 of 113 received at least 1 cycle of GO, and 65 of 113 patients completed the 3 cycles. Premature discontinuation was mainly attributable to incomplete hematologic recovery or intercurrent relapse. Median time to recovery of platelets 50 x 10(9)/L and neutrophils 0.5 x 10(9)/L after GO was 14 days and 20 days. Nonhematologic toxicities were mild overall, but there was 1 toxic death caused by liver failure. There were no significant differences between both treatment groups with regard to relapse probabilities, nonrelapse mortality, overall survival, or disease-free survival (17% vs 16% at 5 years). Postremission treatment with GO in older AML patients does not provide benefits regarding any clinical end points. The HOVON-43 study is registered at The Netherlands Trial Registry (number NTR212) and at http://www.controlled-trials.com as ISRCTN77039377.

MiR-17/20/93/106 promote hematopoietic cell expansion by targeting sequestosome 1–regulated pathways in mice

MicroRNAs (miRNAs) are pivotal for regulation of hematopoiesis but their critical targets remain largely unknown. Here, we show that ectopic expression of miR-17, -20,-93 and -106, all AAAGUGC seed-containing miRNAs, increases proliferation, colony outgrowth and replating capacity of myeloid progenitors and results in enhanced P-ERK levels. We found that these miRNAs are endogenously and abundantly expressed in myeloid progenitors and down-regulated in mature neutrophils. Quantitative proteomics identified sequestosome 1 (SQSTM1), an ubiquitin-binding protein and regulator of autophagy-mediated protein degradation, as a major target for these miRNAs in myeloid progenitors. In addition, we found increased expression of Sqstm1 transcripts during CSF3-induced neutrophil differentiation of 32D-CSF3R cells and an inverse correlation of SQSTM1 protein levels and miR-106 expression in AML samples. ShRNA-mediated silencing of Sqstm1 phenocopied the effects of ectopic miR-17/20/93/106 expression in hematopoietic progenitors in vitro and in mice. Further, SQSTM1 binds to the ligand-activated colony-stimulating factor 3 receptor (CSF3R) mainly in the late endosomal compartment, but not in LC3 positive autophagosomes. SQSTM1 regulates CSF3R stability and ligand-induced mitogen-activated protein kinase signaling. We demonstrate that AAAGUGC seed-containing miRNAs promote cell expansion, replating capacity and signaling in hematopoietic cells by interference with SQSTM1-regulated pathways.

Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia

The primary objective of this 2-part phase 1/2 study was to determine the maximum-tolerated dose (MTD) of the potent and selective Aurora B kinase inhibitor barasertib (AZD1152) in patients with newly diagnosed or relapsed acute myeloid leukemia (AML). Part A determined the MTD of barasertib administered as a continuous 7-day infusion every 21 days. In part B, the efficacy of barasertib was evaluated at the MTD. In part A, 32 patients were treated with barasertib 50 mg (n = 3), 100 mg (n = 3), 200 mg (n = 3), 400 mg (n = 4), 800 mg (n = 7), 1200 mg (n = 6), and 1600 mg (n = 6). Dose-limiting toxicities (stomatitis/mucosal inflammation events) were reported in the 800 mg (n = 1), 1200 mg (n = 1), and 1600 mg (n = 2) groups. The MTD was defined as 1200 mg. In part B, 32 patients received barasertib 1200 mg. In each part of the study, 8 of 32 patients had a hematologic response according to Cheson AML criteria. The most commonly reported grade ≥ 3 events were febrile neutropenia (n = 24) and stomatitis/mucosal inflammation (n = 16). We concluded that the MTD of barasertib is 1200 mg in patients with relapsed or newly diagnosed AML. Toxicity was manageable and barasertib treatment resulted in an overall hematologic response rate of 25%. This study is registered at www.ClinicalTrials.gov as NCT00497991.

Comparative therapeutic value of post-remission approaches in patients with acute myeloid leukemia aged 40–60 years

The preferred type of post-remission therapy (PRT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1) is a subject of continued debate, especially in patients at higher risk of nonrelapse mortality (NRM), including patients >40 years of age. We report results of a time-dependent multivariable analysis of allogenic hematopoietic stem cell transplantation (alloHSCT) (n=337) versus chemotherapy (n=271) or autologous HSCT (autoHSCT) (n=152) in 760 patients aged 40–60 years with AML in CR1. Patients receiving alloHSCT showed improved overall survival (OS) as compared with chemotherapy (respectively, 57±3% vs 40±3% at 5 years, P<0.001). Comparable OS was observed following alloHSCT and autoHSCT in patients with intermediate-risk AML (60±4 vs 54±5%). However, alloHSCT was associated with less relapse (hazard ratio (HR) 0.51, P<0.001) and better relapse-free survival (RFS) (HR 0.74, P=0.029) as compared with autoHSCT in intermediate-risk AMLs. AlloHSCT was applied following myeloablative conditioning (n=157) or reduced intensity conditioning (n=180), resulting in less NRM, but comparable outcome with respect to OS, RFS and relapse. Collectively, these results show that alloHSCT is to be preferred over chemotherapy as PRT in patients with intermediate- and poor-risk AML aged 40–60 years, whereas autoHSCT remains a treatment option to be considered in patients with intermediate-risk AML.

Micro-RNA-15a and micro-RNA-16 expression and chromosome 13 deletions in multiple myeloma

We have used copy number variation (CNV) analysis with SNP mapping arrays for miRNA-15a and miRNA-16-1 expression analysis in patients with multiple myeloma (MM) with or without deletion of chromosome 13q14. MiRNA-15a and miRNA-16 display a range of expression patterns in MM patients, independent of the chromosome 13 status. These findings suggest that genes other than miR-15a and miR-16 may explain the prognostic significance of 13q14 deletions.

Recombinant human erythropoietin improves health-related quality of life in patients with rheumatoid arthritis and anaemia of chronic disease; utility measures correlate strongly with disease activity measures.

Abstract Treatment with recombinant human erythropoietin (r-hu-Epo) in patients with rheumatoid arthritis (RA) and anaemia of chronic disease (ACD) resulted in improvement of both anaemia and disease activity. Utilities represent a generic and comprehensive quality of life measure, capable of integrating domain-specific information into one overall value which a patient assigns to his state of health. Therefore, the effect of r-hu-Epo on quality of life was studied by measuring utilities, derived from the rating scale and standard gamble, in a 52-week placebo-controlled randomised double-blind study with r-hu-Epo in 70 patients with active RA and ACD. Furthermore, the relation between anaemia as assessed by haemoglobin levels (Hb), disease activity as assessed with the Disease Activity Score (DAS), and utilities was investigated. Compared to the placebo group, significant improvement of Hb (P<0.001), DAS (P = 0.01) and rating scale utilities (P = 0.002), but not of standard gamble utilities, was observed in the Epo group. Rating scale utilities correlated strongly with DAS (r = –0.47, P<0.01), Hb (r = 0.37, P<0.01) and changes in both DAS (r = –0.74, P<0.01) and Hb (r = 0.44, P<0.01). Both DAS and Hb contributed significantly to the variance in rating scale utilities (21% and 3% respectively) and to changes in rating scale utilities (43% and 3% respectively). Standard gamble utilities correlated less well with clinical disease variables than rating scale utilities did. These results indicate, that r-hu-Epo improves utility-derived health-related quality of life, most probably by improving both disease activity and anaemia. Utilities, particularly rating scale utilities, correlated well with conventional disease activity variables and proved sensitive to change. Utilities may be a useful tool for investigating quality of life in RA-patients.

Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK)

An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m(2) twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P = .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P = .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl).