Infusion of Cryopreserved Autologous Marrow in the Treatment of Acute Leukemia: A Preliminary Report

Autologous marrow was collected from patients with acute leukemiaduring their first remission, and cryopreserved. In relapse,four of the patients were treated with remission-induction chemotherapymore intensive than the previous treatment, followed by infusionof the cryopreserved autologous marrow. Autologous marrow infusioncaused relatively rapid hematological recovery from the bonemarrow depression induced by high-dose chemotherapy. All fourpatients achieved a second complete remission, but with no maintenancetherapy leukemic relapses were observed in three of them. Onepatient survived without leukemic relapse for 19 months, 13months longer than the previous remission period. Another effectof autoinfusion was reduction in blood products required duringthe bone marrow depression. These observations suggest thatcryopreserved autologous marrow may retain its hemopoietic activityand autologous marrow infusion may be effective in providingearly recovery or rescue from bone marrow failure.     

A Preliminary Report on Autologous Bone Marrow Transplantation for the Treatment of Advanced Non-Hodgkin's Lymphoma

Four patients with advanced non-Hodgkin's lymphoma of unfavorablehistology were treated with marrow-lethal doses of cyclophosphamide(CY) and total body irradiation (TB1) followed by the infusionof cryopreserved autologous marrow. All four patients showedengraftment after autologous bone marrow transplantation andachieved complete remission (CR). Three of them, however, developedrelapse in 1.7, 12.9 and 14.5 mo respectively after the transplantation.The other patient has survived in drug-free CR for more than16.6 mo. There was no treatment-related death although therewere some tolerable complications. These data suggest that theCY-TBI regimen may be effective in inducing CR in patients withadvanced non-Hodgkin's disease but it does not contribute topreventing relapse.     

Successful bone marrow transplantation for idiopathic hypereosinophilic syndrome

A 21-year-old man who had an increased number of eosinophils with morphological abnormalities, bone marrow fibrosis and multiple organ dysfunction failed to respond to methylprednisolone and hydroxyurea. He was diagnosed with hypereosinophilic syndrome (HES) probably due to myeloproliferative disorder, and underwent allogeneic bone marrow transplantation (allo-BMT) from an HLA-identical sibling. The engraftment was confirmed on day 21 after BMT, but the patient developed acute graft-versus-host disease (GVHD) with grade I veno-occlusive disease, and transient increase of eosinophils of the donor type followed by chronic GVHD of the extensive type. These complications were eventually controlled with cyclosporin A. The patient survived free of disease for more than a year after BMT. Allo-BMT seems to be a possible treatment of HES/MPD.     

Controlled Study of Therapeutic Granulocyte Transfusions in Granulocytopenic Patients with Severe Infections

The effectiveness of therapeutic granulocyte transfusions wasstudied in a controlled trial involving 75 granulocytopenicpatients with severe infections. Patients who had granulocytecounts of less than 200/mm³ and no response to antibiotic therapywere assigned to receive antibiotic therapy alone or granulocytetransfusions plus antibiotic therapy. Granulocytes were collectedby filtration leukapheresis (FL), intermittent flow centrifugeleukapheresis (IFCL) or continuous flow centrifuge leukapheresis(CFCL). Therapeutic effects of granulocyte transfusions wereevaluated on the basis of 20-day survival after entry into thestudy. The patients were divided into three groups: 1) 22 patientsreceived antibiotic therapy alone for 29 infectious episodes(control group); 2) 27 patients received 131 transfusions ofgranulocytes collected by FL for 31 infectious episodes (FLgroup); 3) 26 patients received 139 transfusions of granulocytescollected by IFCL and CFCL for 27 infectious episodes (IFCL& CFCL group). The overall survival of the transfused patientswas not significantly different from that of the untransfusedpatients. Similarly, there was no significant difference insurvival between the transfused and untransfused patients whenthe data concerning septicemia were analyzed. When patientsshowed bone-marrow recovery, which was indicated by recoveryof granulocytes to 500/mm³ or more during the study, 20-daysurvival was observed in 13 of 14 untransfused patients andin all of 26 transfused patients. In contrast, the survivalrate for the patients without bone-marrow recovery was 13% (2/15)in the control group, 39% (7/18) in the FL group and 57% (8/14)in the IFCL & CFCL group respectively. Thus, the survivalrate was significantly higher for the transfused than for theuntransfused patients. These observations suggest that therapeutic granulocyte transfusionsmay be of limited value in improving the outcome of severe infectionsin persistently granulocytopenic patients. Since bone-marrowrecovery is a critical factor for the prognosis of severe infections,therapeutic granulocyte transfusions do not provide any beneficialeffects in granulocytopenic patients whose bone-marrow functionwill recover.     

Dose-related protective efficacy of immunoglobulins in experimentally induced group B streptococcal infection

This study investigates the dose-dependent effect of administration of commercially available intravenous immunoglobulins (IVIG) on the survival of newborn rats experimentally infected with group B streptococci (GBS). The opsonic activity of various concentrations of IVIG in vitro was determined by examination of opsonophagocytosis of GBS by peritoneal macrophages and bacterial killing by blood neutrophils. The best survival was observed in newborn rats who received immunoglobulins at doses of 250, 500 and 1000 mg/kg of bodyweight. The survival of animals that received either 125 mg/kg or 2.5 g/kg of immunoglobulins was no better than that of animals who received no immunoglobulins. The maximal phagocytosis and bacterial killing were observed at in vitro immunoglobulin concentrations ranging from 32 to 250 mg/dL (these in vitro concentrations may correspond roughly to in vivo administration doses ranging from 150 to 1200 mg/kg). These doses are comparable to the doses of IVIG currently administered to neonates. However use of very high doses may be harmful to babies since the high concentration of non-specific immunoglobulins inhibited in vitro phagocytosis and bacterial killing by phagocytes.     

Hepatitis GB virus C genome in the serum of aplastic anaemia patients receiving frequent blood transfusions

GB virus C (GBV-C) RNA was detected in five of 18 patients with aplastic anaemia who had received blood transfusions, whereas it was not detected in eight patients who had not received any transfusions. Antibody against hepatitis C virus (anti-HCV) was detected in nine patients in the transfusion group, compared with one of eight who had not received any transfusions. Therefore, the route of transmission of both GBV-C and HCV in these patients appeared to have been multiple blood transfusion. Since all of the GBV-C RNA-positive patients harboured anti-HCV, GBV-C seems to frequently superinfect with HCV. Neither GBV-C nor HCV is likely to have been a causative agent of the anaemia in the cases examined.     

Mutations in type I collagen genes in Japanese osteogenesis imperfecta patients

BACKGROUND: Osteogenesis imperfecta (OI) is an autosomal dominant disorder of connective tissue characterized by bone fragility and low bone mass. COL1A1 and COL1A2 genes are very large and have been rarely analyzed systematically in Japan. The aim of this project was to develop an effective and convenient method of finding mutations in the COL1A1 and COL1A2 gene by using denaturing high-performance liquid chromatography (DHPLC). METHODS: Polymerase chain reaction (PCR) amplicons of genomic DNA from the COL1A1 or COL1A2 gene were followed by heteroduplex analysis by DHPLC. Products containing heteroduplexes were then sequenced. RESULTS: Twenty-two OI families were analyzed, and 193 of the 1122 PCR products in the COL1A1 gene, all containing heteroduplexes, were sequenced. Sixty-two samples had single-base substitutions or single-base deletions or insertions within introns. Eight had single-base substitutions in exons. Six were pathogenic mutations, and two were silent mutations. In 16 families not identified with pathogenic mutation in COL1A1, COL1A2 was similarly analyzed. A total of 138 of the 848 PCR products were sequenced, and 46 samples had single-base substitutions, or single-base deletions or insertions within introns. Twenty-four samples had single-base substitutions in exons. Three were pathogenic mutations and the others silent. CONCLUSIONS: Mutations were identified in nine COL1A1/COL1A2 associated with OI type I-IV genes by scanning with DHPLC. Software was used to detect point mutation and large deletions/insertions in COL1A1 and COL1A2 genes.     

Allogeneic Bone Marrow Transplantation for the Treatment of Acute Leukemia: The Kanazawa Experience

Twelve patients with acute leukemia (7 with nonlymphoblasticleukemia and 5 with lymphoblastic leukemia) were treated withhigh-dose cyclophosphamide and 1,000 rad total body irradiationfollowed by allogeneic bone marrow transplantation from theirHLA-identical sibling donors. Of eight patients given transplantsat relapse, only one patient has become a long-term survivor;he is alive in disease-free complete remission (CR) 4 yr afterthe transplantation. A cure is probable in this patient. Offour patients given transplants during remission, two have survivedin unmaintained CR for almost 1 yr or more. Recurrent leukemiawas observed in two patients whose disease was resistant toconventional therapy at the time of transplantation. Major causesof treatment failure were interstitial pneumonia, hepatic failuredue to veno-occlusive disease, severe infection and relapse.Transplantation-related complications were more frequent andserious in patients who received transplants at relapse thanin those receiving them during remission. The incidence of graft-versus-hostdisease was relatively high but the disease was neither primarynor leading cause of death. These preliminary but relativelyencouraging data suggest that transplantation during remissionmay reduce posttransplant morbidity and mortality. This approachwill contribute to producing long-term survival or cure in patientswith adult acute leukemia if a suitable donor is available.