chiniofon and Leukemia--Myeloid--Acute

Roquinimex, Linomide, a quinoline derivative with pleiotropic immunomodulatory activity, has previously been shown to enhance natural killer (NK) cell number and activity after ABMT in patients with AML. In this study 278 AML patients in remission were randomized to receive Roquinimex 0.2 mg/kg body weight or placebo twice weekly for 2 years following ABMT. Out of 139 patients in each group, 109 Roquinimex patients and 108 placebo patients were in their first CR. Median age at inclusion was 41 years for Roquinimex patients and 39 years for placebo patients. Twelve patients in each group had their marrow purged prior to reinfusion. Relapse and death were study endpoints. Surviving patients were followed for 2.6 to 6. 9 years. The total number of relapses was 60 in the Roquinimex group and 63 in the placebo group (not significant). Leukemia-free and overall survivals were similar in the two groups. Recovery of platelet counts was significantly delayed in the Roquinimex group as compared to placebo. No other significant differences regarding toxicity parameters were recorded. In conclusion, previous findings on NK cells could not be confirmed and the study showed no benefit for Roquinimex over placebo regarding relapse or survival following ABMT for AML in remission.

Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Bone Marrow Purging; Bone Marrow Transplantation; Child; Combined Modality Therapy; Disease-Free Survival; Female; Follow-Up Studies; Humans; Hydroxyquinolines; Killer Cells, Natural; Leukemia, Myeloid, Acute; Male; Middle Aged; Placebos; Recurrence; Survival Rate; Time Factors; Transplantation, Autologous

Immunostimulatory therapy is at present considered after autologous bone marrow transplantation (ABMT) in order to mimic the allogeneic graft-versus-leukemia effect and thereby reduce the relapse rate. In a pilot study, five adults with acute myeloid leukemia were treated with the new immunomodulator Linomide post-ABMT. Linomide (0.3 mg/kg/week orally) was given in cycles of three weeks followed by three weeks of rest for up to six months. During treatment periods cyclic increases of CD56+CD3- and CD16+ NK cells were observed in parallel with enhanced cytotoxic activity of patient cells against both the NK-sensitive K562 and NK-resistant Daudi cell lines. A cyclic increase of CD14+ monocytic cells was also recorded. The proliferative responses of patient cells to PHA and allogeneic cells (MLC) were enhanced during Linomide therapy. The in vitro production of TNF alpha, IFN gamma, and IL-1 followed the same cyclic increase during treatment periods. Side effects were generally mild, and no harmful effects on engraftment were seen. Linomide therapy after ABMT thus induces a broad immunostimulation that offers a potential benefit with regard to leukemia-free survival.

Topics: Adjuvants, Immunologic; Antigens, CD; Bone Marrow Transplantation; Cytokines; Female; Humans; Hydroxyquinolines; Killer Cells, Natural; Leukemia, Myeloid, Acute; Lymphocyte Activation; Male; Middle Aged; Monocytes; Pilot Projects; T-Lymphocytes

Acute myeloid leukemia (AML) is a heterogeneous disease regarding morphology, immunophenotyping, genetic abnormalities, and clinical behavior. The overall survival rate of pediatric AML is 60% to 70%, and has not significantly improved over the past two decades. Children with Down syndrome (DS) are at risk of developing acute megakaryoblastic leukemia (AMKL), which can be preceded by a transient myeloproliferative disorder during the neonatal period. Intensification of current treatment protocols is not feasible due to already high treatment-related morbidity and mortality. Instead, more targeted therapies with less severe side effects are highly needed.. To identify potential novel therapeutic targets for myeloid disorders in children, including DS-AMKL and non-DS-AML, we performed an unbiased compound screen of 80 small molecules targeting epigenetic regulators in three pediatric AML cell lines that are representative for different subtypes of pediatric AML. Three candidate compounds were validated and further evaluated in normal myeloid precursor cells during neutrophil differentiation and in (pre-)leukemic pediatric patient cells.. Candidate drugs LMK235, NSC3852, and bromosporine were effective in all tested pediatric AML cell lines with antiproliferative, proapoptotic, and differentiation effects. Out of these three compounds, the pan-histone deacetylase inhibitor NSC3852 specifically induced growth arrest and apoptosis in pediatric AML cells, without disrupting normal neutrophil differentiation.. NSC3852 is a potential candidate drug for further preclinical testing in pediatric AML and DS-AMKL.

Topics: Apoptosis; Cell Proliferation; Child; Down Syndrome; Drug Screening Assays, Antitumor; Epigenesis, Genetic; High-Throughput Screening Assays; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxyquinolines; Leukemia, Megakaryoblastic, Acute; Leukemia, Myeloid, Acute; Leukemoid Reaction; Nitroso Compounds; Prognosis; Tumor Cells, Cultured

Topics: Adjuvants, Immunologic; Antibodies, Monoclonal; Graft vs Host Disease; Humans; Hydroxyquinolines; Immunotherapy; Interleukin-2; Leukemia, Myeloid, Acute; Leukocyte Transfusion; Neoplasm, Residual

Topics: Humans; Hydroxyquinolines; Indium; Isotope Labeling; Leukemia, Myeloid, Acute; Male; Middle Aged; Organometallic Compounds; Oxyquinoline; Radioisotopes; Radionuclide Imaging; Skin Neoplasms

Topics: Adult; Aged; Bone Marrow; Female; Humans; Hydroxyquinolines; Indium; Isotope Labeling; Kinetics; Leukemia, Myeloid, Acute; Male; Middle Aged; Organometallic Compounds; Oxyquinoline