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Biomedical subjects

R L Powles

Publications and source records attributed to R L Powles.

At least 73 records · Page 4Linked to original sources
PubMed1991

High dose melphalan and total body irradiation with autologous marrow rescue in childhood acute lymphoblastic leukaemia after relapse.

High dose melphalan (HDM 110-140 mg/m2) and total body irradiation (TBI, 10.5 Gy, single fraction) followed by infusion of autologous bone marrow (ABMT) was evaluated for toxicity and efficacy in 24 children with acute lymphoblastic leukaemia (ALL) in second (CR2) or third remission (CR3). Marrow was purged with Campath 1 in six children (four were children in CR3). All children had engraftment with a median of 30 days (range 18-70 days) to neutrophil count greater than 0.5 x 10(9)/l. Four children (16%) died from toxicity 1-4 months after autograft, two from pneumonitis, one from an intracerebral haemorrhage and one from sepsis. Apart from fever and mucositis the procedure was well tolerated. Nine of 17 children treated in CR2 remain in complete remission 6-72 months after ABMT (median 25 months). Seven of these have a follow-up of greater than 12 months. Three of the seven children treated in CR3 are alive 17, 22 and 29 months post ABMT. Seven children relapsed within 10 months (median 4 months) of the autograft. Only one relapse has occurred beyond 10 months. HDM and TBI followed by ABMT is a relatively well tolerated regimen and may contribute to survival in children with relapsed ALL.

Adolescent↗
PubMed1990

Bone-marrow transplant from father to son and subsequent graft from son to father.

An 11-year-old boy with acute myeloblastic leukaemia in first remission received an allogeneic mismatched bone-marrow transplant (BMT) from his father in 1979; subsequent HLA typing showed that his haemopoietic system had been repopulated by the donor cells. In 1986 hypereosinophilic syndrome, secondary to a T-cell lymphocytic lymphoma, developed in the father, then aged 45 years. A full haematological remission was obtained by means of standard acute lymphoblastic leukaemia treatment. He then received melphalan, total body irradiation, and a BMT from his son. Graft-versus-host disease was transient in both patients, and father and son remain well and disease-free 20 months and 10 years, respectively, after BMT.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Thrombocytopenia after bone marrow transplantation for leukaemia: changes in megakaryocyte growth and growth-promoting activity.

Megakaryocyte growth-promoting activity (MK-GPA) was scored on a scale of 0-3 in the serum of 23 patients up to 120 d following bone marrow transplantation (BMT) for leukaemia. Nine of 19 allografts and two of four autografts had thrombocytopenia requiring platelet transfusion more than 30 d after BMT. There was a close correlation between MK-GPA and platelet count. MK-GPA reached a maximum before day 30 after BMT but remained elevated in patients with persisting thrombocytopenia secondary to poor engraftment, graft-versus-host disease (GVHD) or relapse. Recent platelet transfusion did not suppress serum MK-GPA. Two of four patients undergoing autologous BMT for acute myeloid leukaemia (AML) showed delayed platelet recovery and persistence of MK-GPA in the serum. Seven further AML remission marrows were tested for megakaryocyte production before or after autologous BMT, using pooled sera with known MK-GPA activity. Megakaryocyte generation was reduced before BMT and absent in post transplant samples. This failure of MK production was not corrected by T-cell depletion or by the presence of adherent cells from normal marrow. We conclude that thrombocytopenia after BMT is associated with an appropriate increase in MK-GPA levels in response to a reduction in the megakaryocyte pool rather than the platelet pool, and that persisting thrombocytopenia after autologous BMT is due to decreased numbers of available megakaryocyte precursors.

Adolescent↗
PubMed1990

Cyclosporine-induced graft-versus-host disease following autologous bone marrow transplantation in acute myeloid leukaemia.

Cyclosporine was used to induce graft-versus-host disease (GVHD) in patients with acute myeloid leukaemia (AML) receiving autologous bone marrow transplantation (ABMT). Nine consecutive patients with AML in remission were conditioned with either busulphan and cyclophosphamide or melphalan and total body irradiation (TBI) followed by ABMT. Cyclosporine, 1 mg/kg daily from days 1-28 was administered intravenously in four patients and orally in five. Acute GVHD of the skin, confirmed by histological and immunological criteria occurred in three patients, 4-28 days after ABMT and lasted 8-18 days. Incidence and severity of GVHD were independent of cyclosporine levels. Three patients subsequently relapsed, of whom two had had evidence of GVHD. All of these patients were in second remission at time of graft, and therefore poor risk. The potential of cyclosporine to induce GVHD in the AML autograft setting is demonstrated, although the significance of this observation in terms of an antileukaemia effect needs clarification.

Adult↗
PubMed1989

The prophylactic role of intravenous and long-term oral acyclovir after allogeneic bone marrow transplantation.

Eighty-two patients were randomly allocated to receive intravenous acyclovir 5 mg kg-1 t.d.s. for 23 days followed by oral acyclovir 800 mg 6-hourly for 6 months or matching placebos after allogeneic bone marrow transplantation. Herpes simplex and varicella zoster virus infections were significantly reduced during the period of administration of acyclovir. No reduction in cytomegalovirus infection was demonstrated. The drug was not toxic.

Acyclovir↗
PubMed1989

Growth of xenografted human bone marrow: comparison with hemopoietic reconstitution in patients after allogeneic bone marrow transplant and response to granulocyte macrophage colony stimulating factor.

Normal human bone marrow was grown as xenografts in mice immune-suppressed by thymectomy and total body irradiation. Mononuclear cell fractions isolated from marrow harvests from 17 donors all gave rise to subcutaneous nodules which grew to a variable maximum size and then regressed. Human granulocyte/macrophage progenitors (CFU-GM) were recovered from xenografts up to 20 days postimplantation. Xenograft growth, measured by maximum nodule volume, area under the growth curve, and rate of regression, did not correlate with the speed of neutrophil or platelet recovery in bone marrow transplant patients infused with the same marrow. Assay of numbers of stromal fibroblastoid colony forming cells (CFU-F) in donor marrow was also not predictive of subsequent hemopoietic recovery in recipients. Treatment of host animals with daily intraperitoneal injections of 100 micrograms/kg human recombinant granulocyte/macrophage colony stimulating factor produced a more rapid growth of subcutaneous nodules. This technique may therefore be of use in determining the in vivo efficacy of human hemopoietic regulatory factors.

Animals↗
PubMed1989

Recovery of circulating haemopoietic progenitor cells in the early phase of haemopoietic reconstitution after autologous and allogeneic bone marrow transplantation.

The recovery of circulating haemopoietic progenitor cells was evaluated serially in seven patients for 3-4 weeks after bone marrow transplantation (two autologous and five allogeneic) as treatment for leukaemia. Eight normal healthy volunteers were used as controls. CFU-G (colony forming unit-granulocyte) was found to be the earliest progenitor cell to recover at a mean interval of 16 +/- 1 (SE) days post-transplantation. A lag of 7 days was found before circulating CFU-GM (colony forming unit-granulocyte, monocyte) reappeared, while BFU-E (burst forming unit-erythroid) were detectable in only two patients in the first 4 weeks. The peak level of circulating progenitors was very low, 28 +/- 8/ml, compared with a mean level of 619 +/- 235/ml in eight normal individuals. This pattern of circulating progenitor cell recovery post-transplantation was consistently seen in all patients. CFU-G reappeared significantly earlier than CFU-GM suggesting that early granulocytic recovery after bone marrow transplantation is mediated by proliferation of mature progenitors committed to the granulocytic lineage, whereas later reconstitution is accompanied by the emergence of CFU-GM.

Adult↗
PubMed1988

Prevention of herpes zoster in patients by long-term oral acyclovir after allogeneic bone marrow transplantation.

Following allogeneic bone marrow transplantation for leukemia, herpes zoster infections that are potentially severe with a high risk of dissemination develop in 30 to 50 percent of patients. Intravenous acyclovir is an effective treatment for established zoster in immunocompromised persons. Oral acyclovir has relatively low bioavailability, which has made the value of this route of administration for the treatment or prophylaxis of herpes zoster infections uncertain. In this trial, 82 patients undergoing allogeneic bone marrow transplantation for leukemia were randomly assigned to receive either intravenous acyclovir for 23 days followed by oral acyclovir for six months, or matched placebos; the random groups were well-matched in all clinical characteristics. During the six-month period of acyclovir/placebo administration, no patient receiving acyclovir developed herpes zoster, whereas six patients receiving placebo did so (p = 0.006). During the six-month follow-up, there were six cases of zoster in the treatment arm of the study and two cases in the placebo arm. Herpes zoster was not restricted to those patients who had positive evidence of antibody before transplant. This study shows that oral acyclovir is capable of preventing zoster infection during its period of administration; once the drug treatment is stopped, infections occur. In selected patients, the use of long-term oral acyclovir may be of value in preventing zoster infections during the time of greatest immunosuppression.

Acyclovir↗
PubMed1988

Inhibition of human leukaemic thymidylate kinase and L1210 ribonucleotide reductase by dinucleotides of adenosine and thymidine and their phosphonate analogues.

Dinucleotides of adenosine and thymidine in the ApnT series (n = 3,4,5 and 6) and their corresponding phosphonate analogues, where a methylene group replaces the oxygen between the alpha and beta phosphorus atoms adjacent to thymidine, have been evaluated as inhibitors of human leukaemic thymidylate kinase (dTMP kinase, EC 2.7.4.9) and ribonucleotide reductase (EC 1.17.4.1) from L1210 cells. Ap3T, Ap4T, Ap2cpT and Ap3cpT were poor inhibitors of both enzymes. Ap5T, Ap6T and their phosphonate analogues were potent inhibitors of dTMP kinase, possibly acting as bisubstrate analogues (IC50 values: Ap5T, 7.9 microM; Ap4cpT, 5.8 microM; Ap6T, 5.4 microM; Ap4cpT, 4.0 microM). For CDP reductase, where these compounds may bridge activity/effector sites on the M1 subunit of the enzyme, Ap5T and Ap6T were inhibitors with IC50 values of 14.4 microM and 20.3 microM respectively. The phosphonate series of compounds was far less active. The thymidine moiety of the compounds was essential for inhibition since Ap5A was inactive against both enzymes. dTTP, although a poor inhibitor of thymidylate kinase was a potent negative effector of CDP reductase (IC50, 19.3 microM). Significantly, Ap5T was not hydrolysed to release dTTP under the conditions of the assay. These studies show that the activities of both enzymes may be modulated by nucleotide analogues.

Adenosine↗
PubMed1988

Melphalan and total body irradiation (TBI) versus cyclophosphamide and TBI as conditioning for allogeneic matched sibling bone marrow transplants for acute myeloblastic leukaemia in first remission.

Between June 1981 and April 1986 63 patients with acute myeloid leukaemia (AML) in first remission and HLA-identical sibling donors were entered into a prospective study comparing cyclophosphamide (CY) + total body irradiation (TBI) with melphalan + TBI as conditioning therapy prior to transplantation. Thirty-six patients received CY/TBI and 27 received melphalan/TBI. The actuarial probability of remaining in remission for patients receiving melphalan/TBI was 94% compared with 66% following CY/TBI (p greater than 0.01). By including a comparable group of 41 patients with AML in first remission, conditioned with CY/TBI prior to the onset of the study, the greater anti-leukaemic effect of melphalan/TBI compared to CY/TBI was unchanged and statistically the chance of this being wrong is 1 in 10 (p less than 0.1). The overall survival in remission of both arms of the study was the same with 15/27 patients (55%) surviving in remission following melphalan/TBI compared with 19/36 patients (53%) following CY/TBI. The benefit obtained in reduced relapse was offset by the combined nephrotoxic effect of melphalan and cyclosporin which was not identified until the programme had been underway for a period of time. This shows that misinterpretation of 'no survival advantage' for the new treatment may occur due to unforeseen and preventable toxicities.

Actuarial Analysis↗
PubMed1988

One haplotype matched bone marrow grafts: an investigation using the HLA system as a marker of cellular origin.

HLA antigens were used as markers to study the lymphocyte population in 31 patients with leukaemia, treated with a one-haplotype matched bone marrow transplant (BMT). In 24 patients substained engraftment was achieved and the recipient was repopulated with B and T lymphocytes of donor HLA type. Repopulation occurred at the same rate for lymphocytes of the B and T cell classes, usually within 2 weeks of grafting. In two additional cases bone marrow engraftment was successful but the lymphocyte population was chimeric and cells of both donor and host HLA type were present in the recipient for many weeks. Three patients relapsed after engraftment and peripheral blood lymphocytes were exclusively of host or donor HLA type, or a chimeric population was present. In one chimeric case, peripheral blood T lymphocytes were of donor origin, and B lymphocytes were of host origin. Mononuclear cells in the bone marrow were of host HLA type. The use of the HLA system as a marker is a useful additional approach to determine engraftment or chimerism following an allogeneic one haplotype matched bone marrow transplant.

Adolescent↗
PubMed1987

Cytogenetic studies using Q-band polymorphisms in patients with AML receiving marrow from like-sex donors.

After bone marrow transplantation (BMT), it is important to monitor the bone marrow and lymphoid cell populations of the recipient to document engraftment. When donor and recipient are of unlike sex, the sex chromosomes serve as a useful marker to determine cellular origin. When donor and recipient are of like sex, autosomal heteromorphisms can be used to identify the origin of cells in metaphase. Using Q-banding, we found that 17 of 20 patient/donor pairs (85%) examined showed at least one chromosome heteromorphism that distinguished between recipient and donor cells with certainty. Five of the patients were followed up after BMT in order to document engraftment. Donor metaphases could be detected in the marrow within two weeks of BMT when the graft was successful. Chimaerism was detected in the lymphocyte population even when the graft persisted. In a case of graft failure, donor cells did not persist in the marrow, and the lymphocyte population did not convert to donor type. These studies demonstrate that autosomal heteromorphisms are useful in the study of myeloid and lymphoid chimaeric states after BMT.

Adolescent↗
PubMed1987

Cytogenetic follow-up studies of recipients of T-cell depleted allogeneic bone marrow.

Serial cytogenetic studies of bone marrow and blood cells were made in leukaemic patients who had received an allogeneic bone marrow graft from a donor of unlike sex. The donor marrow was treated with the monoclonal antibody Campath-1 before infusion. The persistence of a significant proportion of dividing recipient cells in marrow and blood was observed after grafting. These recipient cells showed evidence of radiation damage of both the stable and unstable types. More than one transient clone of chromosomally abnormal recipient cells was observed in three cases. The differences between the cytogenetic findings in patients receiving donor marrow from which T cells have been removed and those cases previously studied in our Leukaemia Unit who had received untreated donor marrow are discussed.

Adolescent↗
PubMed1987

Multiple myeloma treated with high dose intravenous melphalan.

High dose melphalan (HDM, 140 mg/m2 i.v.) has been evaluated in 58 patients under 63 years with multiple myeloma. Among previously untreated patients 11/41 (27%) entered a complete remission (CR: no measurable myeloma protein and a normal bone marrow) and 21 (51%) entered a partial remission (more than 50% reduction in myeloma protein and improvement in all other features). Median duration of remission is 19 months. Two patients who had responded to previous conventional treatment entered CR after HDM. Among 15 patients who had failed on previous chemotherapy the response rate was 66% including two CRs. However, in this group all patients have relapsed within 1 year. Profound myelosuppression, moderate nausea, vomiting, mucositis and diarrhoea with reversible alopecia occurred in all patients. There were 10 deaths within 2 months of treatment mainly due to sepsis and haemorrhage. In a subsequent study, high dose methyl prednisolone (1 g/m2 daily for 5 d) has been added to HDM. Response rates are similar with 6/22 (27%) CR, 13/22 (59%) PR and 2/22 NR but there was only one early death, reflecting improvements in medical management. The high CR rate is an encouraging feature of this approach which is now to be the basis of a prospective trial sponsored by the Medical Research Council in which HDM, with and without steroids, is compared to the best available conventional therapy (the MRC VI Myelomatosis trial).

Adult↗