A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity

This trial studied the biodistribution, pharmacology, toxicity, immunogenicity, and biologic characteristics of a trace-labeled, anti- CD33, humanized monoclonal antibody M195 (Hu-M195) in patients with relapsed and refractory myeloid leukemia. Hu-M195 is a computer- modeled, "complementarity-determining region-grafted," IgG1, humanized version of M195. M195 is a murine monoclonal antibody that reacts with CD33, a 67-kD glycoprotein expressed on early myeloid progenitor cells and myeloid leukemia (acute myelogenous leukemia and chronic myelogenous leukemia) cells, but not normal stem cells. 131I-murine- M195 has already shown significant ability to cytoreduce patients with relapsed or refractory myeloid leukemias. Hu-M195 has higher avidity than the original mouse monoclonal antibody and, unlike murine M195, has the capability to mediate antibody-dependent cellular cytotoxicity against leukemia targets. Thirteen patients with relapsed or refractory myelogenous leukemia were treated with Hu-M195 at 4 levels of 0.5, 1.0, 3.0, and 10.0 mg/m2 in a phase I trial. Patients received a total of 6 doses per patient over 18 days. Two patients were retreated for a total of 12 doses. The first dose of Hu-M195 was trace-labeled with 131I to allow detailed pharmacokinetic and biodistribution studies by serial sampling of blood, radioimmunoassays of cells, and whole-body gamma- camera imaging. Cumulative total doses of up to 216 mg of Hu-M195 were administered safely. Reversible fever and rigors were observed after infusion at the highest dose levels. The entire bone marrow was specifically and clearly imaged within hours after infusion, with optimal biodistribution occurring at the 3 mg/m2 level. Adsorption of Hu-M195 onto targets in vivo was demonstrated by flow cytometry; near saturation of available sites occurred at the 3 mg/m2 dose level. Plasma and whole body half lives were 38 and 51 hours, respectively, which may reflect continual replenishment of target sites on new leukemia cells. 131I-Hu-M195 was rapidly internalized into the target cells in vivo within 1 hour. Human antihuman antibody responses were not observed. In conclusion, Hu-M195 can be administered safely in multiple doses, without significant toxicity or any evidence of immunogenicity, and can localize rapidly and efficiently to the bone marrow in patients with myeloid leukemias. Additional phase II trials with this agent alone or in combination with cytokines or isotopes are warranted at the optimal biologic dose.     

Neurologic complications after allogeneic marrow transplantation for sickle cell anemia [see comments]

Seven of 21 patients with sickle cell anemia developed neurologic complications 5 to 243 days (median, 33 days) after allogeneic marrow transplantation. Among these 7 patients, indications for transplantation included either a past history of stroke (4 patients) or recurrent severe vaso-occlusive events (3 patients). All received marrow from an HLA-identical sibling after preparation with busulfan and cyclophosphamide, and in 4 patients with antithymocyte globulin. Five of 6 patients developing seizures received anticonvulsant and supportive treatment with resolution of neurologic abnormalities. Three patients experienced intracranial bleeding, which was fatal in two. Of the 14 patients free of neurologic complications, 4 patients had experienced stroke before transplantation. However, among all patients with prior stroke, the incidence of intracranial hemorrhage was 38% (3/8), whereas none of the 13 patients without prior stroke developed posttransplant intracranial bleeding (P = .026). We conclude that patients with sickle cell anemia are at increased risk for neurologic complications after marrow ablative therapy and that patients with prior stroke are at increased risk for intracranial hemorrhage. Transplantation of patients before the onset of overt stroke may reduce this risk.     

Sp alpha I/78: a mutation of the alpha I spectrin domain in a white kindred with HE and HPP phenotypes

Limited tryptic digestion of spectrin (Sp) from seven related individuals manifesting hereditary elliptocytosis (HE) or hereditary pyropoikilocytosis (HPP) phenotypes revealed the presence of a novel peptide with a molecular weight of 78 Kd and a concomitant decrease in the alpha I domain (80-Kd peptide), which is the domain involved in the dimer self-association process. Sp from the normal members of this white family exhibited a normal peptide pattern, as compared with controls. The abnormal peptide pattern was associated with a decreased ability of Sp dimer to self-associate. In this kindred in which three generations were available for study, the clinical manifestations were quite variable and ranged from the asymptomatic HE carrier state to hemolytic HE or to severe anemia requiring splenectomy. The severity of the disease appeared to be correlated both with the amount of mutant spectrin (31% to 69%) and with the excess of the Sp dimer found in the membrane (26% to 60%, compared with a normal value of 5.6% +/- 2.2%). Partial amino acid sequencing showed that the alpha I/78-Kd peptide resulted from cleavage at lysine residue 10 of the alpha I/80-Kd domain. Knowledge of the exon/intron structure of cloned genomic DNA encoding the alpha I domain allowed us to amplify in vitro a DNA fragment containing the third exon of the alpha-spectrin gene. The amplified fragment was subcloned and sequenced. A G to T transversion was found in the 39th codon (AGT for AGG), which changed the normal arginine to a serine. Hybridization of amplified DNAs with allele- specific oligonucleotides corresponding to the normal and mutant sequences confirmed the presence of the mutation in three other HE members of the family (the propositus mother, brother, and sister).     

Does review of peripheral blood smears help in the initial workup of common anemias?

Sixty-five physicians were tested to determine the effect of their reviews of red blood cell morphology on their subsequent diagnoses of and workup plans for common anemias. The subjects read clinical and laboratory data for six pairs of cases of anemia, reviewing the blood smear for one case in each pair. They correctly identified the presence or absence of morphologic features on the blood smears 82% of the time. In spite of excellent morphologic discrimination, the number of tests ordered was not affected by blood smear review. In fact, the quality of the physicians’ workup plans, measured by numbers of tests appropriately ordered and excluded, was slightly but significantly better when they did not review the smears (p<0.005). In addition, smear review did not significantly improve diagnostic accuracy for any of the common anemias studied. Significantly more correct diagnoses were made without smear review for vitamin B₁₂-folate deficiency anemia (p<0.015) and thalassemia (p<0.0001). Although routine review of blood smears by physicians in the management of common anemias may provide useful information, the authors were unable to demonstrate an improvement in the number or appropriateness of tests ordered or diagnostic accuracy in spite of excellent morphologic discrimination. Received from the Divisions of General Internal Medicine and Hematology, Department of Medicine, Walter Reed Army Medical Center, Washington, DC, and the Uniformed Services University of the Health Sciences, Bethesda, Maryland. Dr. Simmons is now Chief, Division of General Internal Medicine, Brooke Army Medical Center, San Antonio, Texas. Presented in part at the annual meeting of the American Federation of Clinical Research, Washington, DC, May 3, 1986. Supported by a grant from the Department of Clinical Investigation (WU 1013), Walter Reed Army Medical Center, Washington, DC 20307-5001. The opinions and assertions contained herein are the private ones of the authors and are not to be construed as official or as reflecting the views of the Department of Defense, the Department of the Army, or the Uniformed Services University of the Health Sciences.     

Management of alloimmune thrombocytopenia: antenatal diagnosis and in utero transfusion of maternal platelets

Neonatal alloimmune thrombocytopenia (NAIT) can cause severe bleeding in the central nervous system (CNS) and death or severe neurologic sequelae. The expression of the PLA1 antigen is detectable as early as 19 weeks of gestation. Alloimmunization can therefore lead to fetal thrombocytopenia very early in pregnancy. Until recently, we have had no means of detecting and assessing the severity of fetal thrombocytopenia during pregnancy. The level of the maternal antibody is not of a predictable value since 20% of the mothers had no circulating antibodies in our series. An alternative approach is to carry out investigations on fetal blood samplings. This management leads to an exact knowledge of the fetal status and antenatal diagnosis is feasible as early as the 21st week of gestation. Early diagnosis facilitates appropriate management and makes possible such therapeutic options as in utero maternal platelet transfusions. We report our experience in the antenatal diagnosis and management of nine cases with in utero transfusion in the six cases with severe thrombocytopenia. All neonates did well, with no signs of bleeding at birth. No side effects of therapy were noted after a period ranging from 6 months to 3 years.     

Management of a subcutaneous colostomy perforation

Colostomy perforation is an infrequent but often diasastrous and lethal complication. In the majority of patients, the traumatic performation occurs during irrigation through the colostomy stoma. This case report reviews the clinical course of a patient with a subcutaneous colostomy perforation and the subsequent development of an extensive abscess. Aspects of the management included mobilization of the colostomy and thorough surgical debridement and drainage. In addition, the report introduces the use of the new semisynthetic biologic dressing, BioBrane^®. This synthetic, semipermeable skin substitute served as a temporary dessing, provided good stability, and supported the application of a stoma appliance.     

更安全的Curtius重排

1,3，5-苯三甲酰氯和叠氮化钠在水和1,2．二氯乙烷中反应生成的苯三甲酰叠氮不予分离，一锅制备得到1，3，5．三异氰酸基苯，收率97％。操作安全。进而制备三氨基苯等衍生物。