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Biomedical subjects

R Powles

Publications and source records attributed to R Powles.

At least 91 records · Page 5Linked to original sources
PubMed1996

Platinum agents and secondary myeloid leukaemia: two cases treated only with platinum-based drugs.

With the increasing use of chemotherapy for many different primary malignancies, secondary or therapy-related acute myeloid leukaemias (AML) and myelodysplastic syndromes (MDS) are becoming more common. The risk of developing sAML has been estimated to be between 2% and 10%, depending upon the type, duration and dosage of previous therapy (Michels et al, 1985; Shulman, 1993; Robinson & Mertens, 1993; Ballen & Antin, 1993). It is therefore one of the most serious long-term complications of current cancer treatment and is likely to increase as longer survival rates for the primary tumour are achieved. An increasing range of drugs have been reported to cause sAML, including the alkylating agents, the epipodophyllotoxins and the anthracyclines, both as single agents and in combination (Pedersen-Bjergaard & Philip, 1991; Pedersen-Bjergaard & Rowley, 1994). We report two cases of secondary AML in which platinum compounds were the sole prior chemotherapy.

Acute Disease↗
PubMed1996

The gene for gamma-glutamylcysteine synthetase from Thiobacillus ferrooxidans has low homology to its Escherichia coli equivalent and is linked to the gene for citrate synthase.

The gene for gamma-glutamylcysteine synthetase (gshA) from Thiobacillus ferrooxidans was isolated from a family of cosmids by its ability to complement an Escherichia coli gshA trxA double mutant which was unable to grow on minimal medium lacking glutathione. The predicted sequence of the gamma-glutamylcysteine synthetase was found to have only 18% amino acid sequence identity to the equivalent enzyme from E. coli. In spite of this low sequence homology, concentrations of GSH in a cell extract prepared from the E. coli gshA trxA mutant containing the cloned gene were almost as high as in a cell extract prepared from a wild-type E. coli strain. The gshA gene was found to be physically and transcriptionally linked to the T. ferrooxidans gene for citrate synthase (gltA). The T. ferrooxidans and E. coli citrate synthases shared 37% amino acid sequence identity and the cloned T. ferrooxidans citrate synthase gene was able to complement an E. coli gltA mutant.

Amino Acid Sequence↗
PubMed1996

MRI in the evaluation of late bone marrow changes following bone marrow transplantation.

Measurements of MR spin-lattice (T1), and spin-spin (T2) relaxation times in lumbar vertebrae have been performed in a pilot study on six adult patients, treated for acute myeloid leukaemia (AML). All patients were treated with initial chemotherapy and then proceeded to bone marrow transplantation (BMT), conditioned with Melphalan and total body irradiation (TBI). MR measurements were made between 21 and 89 months after TBI. The relaxation times in the six patients were compared with those in six healthy age-matched volunteers to establish whether there were differences between the two groups. Average T1 values in the vertebrae of the treated patients are significantly shorter (p < 0.01) than in the healthy volunteers. This is consistent with the observation of a relatively hyperintense vertebral bone marrow in the T1 weighted images and is likely to be a consequence of treatment induced fatty replacement of marrow. Shorter T1 values tend to be distributed within the centre of the lumbar vertebrae compatible with observations, made by others, which suggest that the peripheral zone of the vertebral body has been repopulated with bone marrow cells whereas the central zone, around the basivertebral vein, is predominantly fat. Histogram displays of vertebral body relaxation time distributions (T1, T2) for both patients and healthy age-matched volunteers are similar in that both patients and volunteers give histograms that are only slightly skewed. This similarity is probably a reflection of the fact that the patients have been in remission for over a year and have generally healthy bone marrow.

Acute Disease↗
PubMed1996

Renal dysfunction following autologous bone marrow transplantation in adult patients with acute leukemia.

The serum creatinine level was used to determine the incidence of renal dysfunction in 70 adults with acute leukemia who were alive and well one year following autologous bone marrow transplantation (ABMT). Creatinine measurements at the time of ABMT, one year post-ABMT and at the last follow-up (12-128 months, median 35) were recorded, and a level of >120 micromol/l arbitrarily defined as clinically significant renal impairment. The incidence of renal impairment was 2.9% (n = 2) at 1 year, and 4.3% (n = 3) at the last follow-up in continuous remission. Significant renal impairment occurred after relapse in 8 of 12 patients, but was seen in only 3 of 58 patients who remained in remission (p < 0.001, Fisher's exact test), suggesting subclinical renal damage which became obvious with further nephrotoxic therapy. We conclude that clinically significant renal dysfunction is an uncommon long-term complication of ABMT, and should not be a concern in recommending this therapy to eligible patients.

Acute Disease↗
PubMed1996

High-dose hydroxyurea and G-CSF to collect Philadelphia-negative cells in chronic myeloid leukemia: preliminary results.

Five patients with Ph+ chronic myeloid leukemia and no detectable diploid cells in the marrow received 6 g hydroxyurea twice daily for 7 days followed by G-CSF to harvest Ph-cells 1-84 months after diagnosis. Three were in first chronic phase, and two in accelerated phase. One stopped hydroxyurea after 4 doses due to intractable vomiting and was not apheresed, while two stopped hydroxyurea after 9 and 11 doses because of mucositis and skin rash. Two tolerated all doses; one with no significant side effects, and one with mucositis and painful plantar rash. The nadir leukocyte, neutrophil, and platelet counts were 0.4-0.8, 0-0.1, and 2-19 x 10(9)/L respectively. Apheresis was commenced when the leukocytes were 1.2-3.8 x 10(9)/L 9-10 days after starting G-CSF, and 6 aphereses were performed. Four collections were 100% Ph+, and two 22% and 90% Ph-. The total nucleated cell, CD34+/CD34-subset, CD34+/CD33+ subset, and CFU-GM yields per kg per collection were 0.48-2.38 (median 1.18) x 10(8), 0-0.48 (median 0.012) x 10(6), 0.028-10.19 (median 0.92) x 10(6), and 0.29-41.81 (median 21.78) x 10(4) respectively. We conclude that hydroxyurea in the dose we used is poorly tolerated, and is associated with significant adverse effects including severe myelosuppression. It is possible to harvest diploid cells during recovery, but achievement of Ph-negativity appears to be erratic and cell yields are poor.

Adult↗
PubMed1996

Comparison of interferon tolerance after autologous bone marrow or peripheral blood stem cell transplants for myeloma patients who have responded to induction therapy.

Interferon (INF) has been incorporated as part of maintenance therapy after high dose treatment in order to make remissions more durable. In this study we have compared peripheral blood stem cell transplant (PBSCT) versus autologous bone marrow transplant (ABMT) with respect to INF tolerance. Thirty nine PBSCT patients have been compared to 37 ABMT patients for INF tolerance. This is followed by a comparison of 15 PBSCT patients versus 21 ABMT patients for engraftment details, response and survival. INF was started at a median of 61 days in the PBSCT and 58 days in the ABMT patients (P = NS). It was well tolerated in both groups without a significant difference in toxicity in the two arms. Engraftment was more rapid in the PBSCT patients with platelet recovery being significantly faster. Response and survival showed a favourable trend for ABMT patients though statistical significance was not reached and the cost of PBSCT was 12% cheaper. We were thus able to conclude that PBSCT grafts were as durable and could tolerate INF just as well as ABMT. Engraftment was more rapid and the procedure of PBSCT was also cheaper. Further studies with a larger group of patients will be required before comments on the efficacy of treatment can be made.

Adult↗
PubMed1996

Outcome of autologous rescue after failed engraftment of allogeneic marrow.

Ten patients experiencing primary graft failure after allogeneic bone marrow transplantation received autologous marrow or blood cells as hematopoietic rescue 21-40 (median 22.5) days after the original transplant after which immunosuppression with cyclosporine was tapered off rapidly. The leukocyte count at the time of rescue was 0.1-0.3 x 10(9)/l with < 0.1 x 10(9)/l neutrophils. The clinical course was uneventful after rescue with hematologic recovery to 0.5 x 10(9)/l neutrophils occurring 9-61 days (median 20) later in nine patients, and to 50 x 10(9)/l platelets 17-595 days (median 40) later in eight patients. No patient had a life-threatening infection at the time of or after rescue. No patient experienced acute graft-versus-host disease. Four patients with acute leukemia had recurrent disease 46-117 days after autologous rescue, and died of relapse. Five patients with acute leukemia are alive in continuous remission at 270-3382 days, and one patient with chronic myeloid leukemia is alive in hematologic remission at 228 days. We conclude that infusion of back-up autologous cells can prevent the immediate infectious consequences of primary allogeneic graft failure through consistent myeloid recovery, and may result in long-term survival of patients with good-risk disease.

Acute Disease↗
PubMed1996

Myelosuppressive chemotherapy to mobilize normal stem cells in chronic myeloid leukemia.

Ten patients with Ph+ chronic myeloid leukemia (CML) were treated with idarubicin, cytarabine and etoposide followed by G-CSF to harvest Ph-negative progenitor cells. Six were in first chronic phase (CP1), and four beyond CP1. Between two and six aphereses (median 3, total 36) were performed starting 9-26 days (median 14.5) after chemotherapy when the leukocyte count was 0.6-4.7 x 10(9)/l (median 1.2). 1.3-3.6 x 10(8) mononuclear cells/kg (median 2.8), 0-128.4 x 10(4) CFU-GM/kg (median 1.2; seven patients) and 0.3-25.1 x 10(6) CD34+ cells/kg (median 9.8; seven patients) were collected. Seven of 27 harvests showing metaphases were 100% Ph-negative, 11 partially Ph-negative, and nine were 100% Ph+. All three patients with 100% Ph-negative collections were in CP1 and within 4-26 months of diagnosis. Four of six CP1 patients showed significant cytogenetic response compared with none of four beyond CP1 (P = 0.036). The absolute neutrophil count remained < 0.5 x 10(9)/l for 9-44 days (median 15.5) following chemotherapy. Four patients (three Ph-negative) were autografted after 16 mg/kg busulfan (n = 2) or 200 mg/m2 melphalan (n = 2). One of the three patients receiving Ph-negative cells died of graft failure, and two are alive with 15% and 50% Ph-negative cells at 15 and 11 months on interferon-alpha. We conclude that it is possible to harvest Ph-negative cells after myelosuppressive chemotherapy in some CML patients treated early in the course of CP1. However, in view of lack of consistent response, investigation of alternative approaches is necessary.

Adolescent↗
PubMed1996

Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia.

Between 1986 and 1995, 19 patients with Philadelphia chromosome-positive (Ph + ) acute lymphoblastic leukemia underwent 20 autologous (n = 9) or allogeneic (n = 11) blood or marrow transplant procedures in first (n = 12) or second (n = 3) remission, or in relapse (n = 5). Four patients died due to transplant-related causes, 11 relapsed at 3-39 months, one survives with disease which did not remit after transplant, and three are alive in continuous remission at 1, 26 and 65 months. Two of the relapsing patients are alive; one autografted patient after an allograft in second remission and one allografted patient after a donor leukocyte infusion. The projected overall survival is 37.5% at 3 years and 12.5% at 5 years. The 3-year probabilities of relapse and disease-free survival for autografted patients are 65.9% and 25.6% respectively, and for allografted patients, 63.4% and 21.8% respectively. The stage of the disease at the time of transplant or the type of transplant did not affect the outcome significantly, and late relapses beyond 3 years were seen after allogeneic as well as autologous transplantation. In our experience, the outcome of patients with Ph + acute lymphoblastic leukemia continues to be poor despite high-dose therapy due to high relapse rates, and the development of additional measures to enhance the antileukemic efficacy of bone marrow transplantation is necessary.

Acute Disease↗
PubMed1996

Clinical and hematologic response of chronic lymphocytic and prolymphocytic leukemia persisting after allogeneic bone marrow transplantation with the onset of acute graft-versus-host disease: possible role of graft-versus-leukemia.

One patient with refractory B cell chronic lymphocytic leukemia (CLL) and another with refractory B cell prolymphocytic leukemia (PLL) underwent bone marrow transplantation (BMT) from HLA-identical siblings. Circulating malignant cells persisted at high levels in the patient with PLL and there was clinical evidence of disease progression soon after transplant in the patient with CLL. Starting 4-5 weeks post-BMT, cyclosporine was tapered rapidly to stimulate immunologic graft-versus-leukemia (GVL) reactions. There was a fall in the number of malignant cells and reversal of organomegaly with the onset of acute graft-versus-host disease (GVHD). Both patients received conventional doses of corticosteroids for GVHD which also may have contributed to disease response to some extent. Total clearance of the leukemic cells from the peripheral blood was seen in both patients, and clearance of the marrow was seen in the patient with CLL. However, both patients died of complications of severe GVHD. We conclude that GVHD may be associated with a GVL effect after allogeneic BMT for refractory chronic B cell lymphoproliferative diseases. Whether GVL reaction occur in the absence of clinically obvious GVHD after allogeneic BMT for CLL remains to be seen.

Adult↗
PubMed1996

Central nervous system relapse after bone marrow transplantation for acute leukemia in first remission.

Four hundred and eighty-seven patients undergoing allogeneic or autologous BMT for acute leukemia in first remission received no prophylactic intrathecal chemotherapy after BMT. The conditioning regimen included total body irradiation in 433 (89%). Patients with acute lymphoblastic leukemia received cranial irradiation if they had no central nervous system (CNS) disease and all patients with CNS disease received craniospinal irradiation. Eleven of 311 patients examined had CNS disease at presentation, but none had active CNS disease at the time of BMT. Lumbar punctures were performed in 93 patients 1-2229 days (median 98) after BMT because of suspected CNS infection, hemorrhage or relapse (n = 65), or after systemic relapse (n = 28). CNS disease was seen in seven patients at 217-1209 days (median 340), none of whom had CNS disease pre-transplant. Systemic relapse had preceded CNS relapse by 4-207 (median 128) days in all seven and no isolated CNS relapse was seen. The actuarial risk of CNS and systemic relapse at 5 years was 2.9 and 35.9%, respectively. We conclude that CNS relapse is uncommon after BMT for acute leukemia in first remission, and that isolated CNS relapse is likely to be extremely uncommon. Therefore, routine prophylactic intrathecal chemotherapy is not warranted after BMT for acute leukemia in first remission.

Actuarial Analysis↗
PubMed1996

T cell-depleted allogeneic bone marrow transplantation from a partially HLA-mismatched unrelated donor for progressive chronic lymphocytic leukemia and fludarabine-induced bone marrow failure.

A 49-year-old man with a 3-year history of chronic lymphocytic leukemia (CLL, stage B at diagnosis) responded well to four course of fludarabine, but developed marrow failure and prolonged pancytopenia lasting 9 months following the fifth course. Fludarabine therapy could not be continued due to pancytopenia, eventually resulting in disease progression. Bone marrow transplantation from an unrelated donor mismatched at one DRB1 locus and both DQB1 loci was performed as salvage therapy. The marrow was depleted of T cells with Campath-1G. Pre-transplant immunosuppression was enhanced with 600 cGy total lymphoid irradiation and Campath-1G infusions in addition to 120 mg/kg cyclophosphamide and 1200 cGy fractionated total body irradiation. Cyclosporine alone was used as post-transplant immunosuppression. Neutrophils reached 0.5x10(9)/1 on day 14 and platelets 50 x 10(9)/1 on day 40. No acute graft-versus-host disease was seen. Bulk disease detected on CT scanning prior to BMT was found to have disappeared 10 weeks after BMT. The marrow showed residual disease (5% CD5+/CD19+ cells) 9 weeks after transplantation, which had decreased markedly at 13 (0.5%) and 26 (0.4%) weeks. The patient is currently alive and well 10 months after BMT with no clinically detectable disease. We conclude that BMT from an unrelated donor is a feasible treatment option in advanced CLL.

Antineoplastic Agents↗
PubMed1996

Melphalan-total body irradiation and autologous bone marrow transplantation for adult acute leukemia beyond first remission.

Forty-four adults with AML (n = 18) or ALL (n = 26) beyond first remission underwent unpurged (n = 39) or purged (n = 5) autografting after 110-140 mg/m2 melphalan and 1050 cGy TBI. ALL patients were eligible to receive maintenance chemotherapy with 6-mercaptopurine and methotrexate for 2 years after hematologic recovery. The duration of first remission was 1-167 months (median 11). The median time to 50 x 10(9)/I platelets was 76 days, and that to 0.5 x 10(9)/I neutrophils 31 days. Eight patients died of transplant-related toxicity; seven within 1 year. Twenty-two patients relapsed at 1-20 months (median 2.5 months). The 3-year probabilities (95% CI) of relapse and disease-free survival are 58% (43-75%) and 31% (17-45%), respectively. The duration of the first remission (< 1 year vs > or = 1 year) and the stage of transplant (second remission vs other) had no effect on relapse or disease-free survival. There was a trend towards higher relapse rates (76 vs 34%) and poorer disease-free survival (19 vs 49%) among ALL patients compared with AML which did not reach significant levels due to small patient numbers. We conclude that melphalan-TBI is a suitable conditioning regimen for autografting in advanced leukemia. The outcome of AML patients is comparable to standard regimens, but the outcome of ALL patients is poor and measures to enhance the anti-leukemic efficacy are necessary.

Acute Disease↗
PubMed1996

Transfusion requirements after bone marrow transplantation from HLA-identical siblings: effects of donor-recipient ABO incompatibility.

Transfusion requirements of 477 patients with hematologic malignancies undergoing BMT from HLA-identical siblings were studied. The median (range) number of red cells transfused in the first, second and third months were 4 (0-32), 1 (0-39), and 0 (0-22) respectively, and the number of random donor platelet concentrates 32.5 (0-196), 0 (0-220) and 0 (0-135). On multivariate analysis, diagnosis other than acute leukemia, conditioning regimen other than cyclophosphamide-TBI, cyclosporine-methotrexate GVHD prophylaxis, and occurrence of acute GVHD increased platelet requirements significantly in the first month. Diagnosis other than acute leukemia, donor-recipient ABO incompatibility, conditioning regimen other than cyclophosphamide-TBI, and age over 18 years increased red cell requirements significantly in the first month. Platelet requirements in the second month and red cell requirements in the second and third months were increased significantly by the occurrence of acute GVHD, a diagnosis other than acute leukemia, and a conditioning regimen other than cyclophosphamide-TBI. Platelet requirements in the third month were influenced only by acute GVHD. We conclude that ABO incompatibility does not influence platelet requirements after allogeneic BMT. It affects red cell requirements in the first month along with the diagnosis, conditioning regimen, and age. However, other factors outweigh the influence of ABO-incompatibility on red cell requirements beyond the first month.

ABO Blood-Group System↗
PubMed1996

Factors affecting engraftment and hematopoietic recovery after unpurged autografting in acute leukemia.

Factors affecting hematologic recovery to 0.5 x 10(9)/l neutrophils and 50 x 10(9)/l platelets after unpurged autografting (210 marrow, 30 blood) were analyzed in 240 patients with acute myeloid (AML, n = 128) or lymphoblastic (ALL, n = 112) leukemia. Cytokines were not administered routinely after transplant. Age, sex and cryopreservation did not influence hematologic recovery in multivariate analysis. Blood cell grafts (P < 0.0001), ALL (P = 0.003), and a nucleated cell dose of > or = 2 x 10(8)/kg (P = 0.035) were associated with faster neutrophil recovery. First remission (P = 0.001), a higher cell dose (P = 0.011), ALL (P = 0.023), and a short remission-transplant interval (P = 0.023) were associated with faster platelet recovery. There was a strong correlation between blood cell grafts and higher cell doses, and marrow and lower cell doses. Amongst marrow recipients, neutrophil recovery was faster in ALL (P = 0.001) and with higher cell doses (P = 0.032). Platelet recovery was faster in first remission patients (P = 0.005) and ALL (P = 0.043), and with higher cell doses (P = 0.031). We conclude that hematologic recovery after autografting is faster in ALL and first remission patients, probably due to the nature and the amount of prior chemotherapy. Using blood stem cells hastens engraftment, but even if marrow is used due to concern over relapse with blood, higher cell doses are associated with faster recovery.

Adolescent↗
PubMed1996

Long-term follow-up of patients undergoing allogeneic bone marrow transplantation for acute myeloid leukemia in first complete remission after cyclophosphamide-total body irradiation and cyclosporine.

Eighty-five patients (median age 28 years) with acute myeloid leukemia (AML) in first remission underwent allogeneic bone marrow transplantation (BMT) from HLA-identical siblings between 1978 and 1987 after cyclophosphamide and single-fraction total body irradiation with cyclosporine for graft-versus-host disease (GVHD) prophylaxis. The actuarial probabilities of development of acute and chronic GVHD were 57% and 47%, respectively. Twenty-six patients died of transplant-related complications at a median of 3.5 months, and two of unrelated causes. Seventeen patients relapsed at a median of 6.5 months. Forty patients were alive and well at 74-197 months (median 157) after BMT; seven (18%) with limited chronic GVHD requiring therapy. The actuarial 10-year probabilities of transplant-related death, relapse, and disease-free survival were 33%, 25% and 48% respectively. In multivariate analysis, infusion of a lower cell dose, development of GVHD, and age > 35 years were associated with increased transplant-related mortality, donor-recipient ABO incompatibility with a lower relapse rate, and age > 35 years and a lower cell dose with poorer disease-free survival. We conclude that with long-term follow-up, allografting in AML after cyclophosphamide-TBI and cyclosporine has resulted in disease-free survival that is comparable to most currently reported series. Patients who are alive and well 3-4 years after BMT have excellent prospects of long-term survival.

Adolescent↗
PubMed1996

Idarubicin, high-dose cytarabine, and etoposide for induction of remission in acute leukemia.

Between 1990 and 1944, 52 newly diagnosed patients with primary (n = 47) or therapy-related (n = 5) acute myeloid leukemia (AML) under the age of 55 years received an induction chemotherapy protocol (designated BF12) consisting of idarubicin ([IDA] 5 mg/m2), high-dose cytarabine ([HD-Ara-C] 2 mg/m2 per 12 hours, 3-hour infusion), and etoposide ([VP-16] 100 mg/m2, 1-hour infusion) on each of 5 consecutive days. Thirty-seven of 51 assessable patients (72.5%), including all five patients with therapy-related AML, attained remission with one cycle. The overall remission rate was 78.4%. Total therapy of AML, with BF12 followed by two courses of consolidation therapy and allogeneic or unpurged autologous bone marrow transplantation (BMT) in first remission, has resulted in actuarial 3-year survival of 49.9% of consecutive unselected patients with newly diagnosed primary AML (minimum follow-up period, 1 year). Twenty-five patients have received BF12 for relapsed acute leukemia, including 13 relapsing after BMT. Five patients died of toxicity and were not assessable for response. Of the remaining 20 patients, five were refractory, two attained partial remissions, and 13 (65%) achieved complete remission (CR). Four of the 13 patients relapsing after BMT died of toxicity, four were refractory, and five of nine assessable patients (56%) attained CR. We conclude that the combination IDA/HD-Ara-C/VP-16 is highly effective in the treatment of newly diagnosed AML and relapsed acute leukemia.

Acute Disease↗