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Biomedical subjects

R L Powles

Publications and source records attributed to R L Powles.

At least 19 recordsLinked to original sources
PubMed2000

Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia.

PURPOSE: Preparative regimens involving total-body irradiation (TBI) produce significant late toxicities in some children who receive bone marrow transplants, including impaired growth and intellectual development. Busulfan is often used as an alternative to TBI, but there are few data regarding its relative efficacy. PATIENTS AND METHODS: We compared outcomes of HLA-identical sibling transplants for acute lymphoblastic leukemia (ALL) in children (< 20 years of age) who received cyclophosphamide plus TBI (CY/TBI) (n = 451) versus those who received busulfan plus cyclophosphamide (Bu/CY) (n = 176) for pretransplant conditioning. Patients received transplants between 1988 and 1995 and their results were reported to the International Bone Marrow Transplant Registry by 144 participating institutions. The CY/TBI and Bu/CY groups did not differ in gender, immune phenotype, leukocyte count at the time of diagnosis, chromosome abnormalities, remission status, or length of initial remission. T-cell depletion was used more frequently in the CY/TBI group; the Bu/CY group included a higher proportion of children who were less than 5 years of age. The median follow-up period was 37 months. RESULTS: The 3-year probabilities of survival were 55% (95% confidence interval [CI], 50% to 60%) with TBI/CY and 40% (95% CI, 32% to 48%) with Bu/CY (univariate P =.003). The 3-year probabilities of leukemia-free survival were 50% (95% CI, 45% to 55%) and 35% (95% CI, 28% to 43%), respectively (univariate P =.005). In a multivariate analysis, the risks of relapse were similar in the two groups (relative risk [RR], 1.30 for Bu/CY v CY/TBI; P =.1). Treatment-related mortality was higher in the Bu/CY group (RR, 1.68; P =.012). Death and treatment failure (relapse or death, inverse of leukemia-free survival) were more frequent in the Bu/CY group (RR, 1. 39; P =.017 for death; RR, 1.42; P =.006 for treatment failure). CONCLUSION: These data indicate superior survival with CY/TBI conditioning, compared with Bu/CY conditioning, for HLA-identical sibling bone marrow transplants in children with ALL.

Adolescent↗
PubMed1999

Systemic candidiasis with candida vasculitis due to Candida kruzei in a patient with acute myeloid leukaemia.

Candida kruzei-related systemic infections are increasing in frequency, particularly in patients receiving prophylaxis with antifungal triazoles. A Caucasian male with newly diagnosed acute myeloid leukaemia (AML M1) developed severe and persistent fever associated with a micropustular eruption scattered over the trunk and limbs during induction chemotherapy. Blood cultures grew Candida kruzei, and biopsies of the skin lesions revealed a candida vasculitis. He responded to high doses of liposomal amphotericin B and was discharged well from hospital.

Acute Disease↗
PubMed1999

Vaginal stenosis following allogeneic bone marrow transplantation for acute myeloid leukaemia.

We report the unusual complication of vaginal stenosis occurring after allogeneic bone marrow transplantation (BMT) for leukaemia. This was in all likelihood a manifestation of chronic graft-versus-host disease (cGVHD), although the patient has no other stigmata of this and suffered little acute graft-versus-host disease (aGVHD) after BMT. Other risk factors for vaginal stenosis were considered and appear to be absent in this patient, although the total body irradiation used as part of her conditioning therapy may play a role. We suggest that vaginal stenosis may be under-reported, since female patients suffer a number of gynaecological complications after BMT, and that regular questioning and examination may aid in making an earlier diagnosis, allowing speedier instigation of therapy and thus improving quality of life.

Acute Disease↗
PubMed1999

Impact of previous high-dose therapy on outcome after allografting for multiple myeloma.

We describe a single centre experience of 33 patients allografted for multiple myeloma, of which 28 received matched sibling marrow, one haploidentical family donor marrow and four matched but unrelated donor marrow. Median follow-up after transplant is 27 months, and 13 patients are currently alive. One out of four patients with an unrelated donor survives and 12 out of 28 (42.8%) with matched sibling donors. Four patients were unevaluable because of early death (<day 21), and one patient experienced graft failure. The probability of overall survival is 35.7 % at 3 years. The probability of disease-free survival is 39% at 3 years, and the probability of treatment-related mortality is 54% at 1 year. Acute GVHD developed in 26 (78.8%) patients and was responsible for six deaths. Twenty-four patients (72.7%) developed renal dysfunction and 22 (66.7%) developed hepatic dysfunction. Seventeen patients (51.5%) died of transplant-related problems in the first 150 days, and one at 6 months. Among the 13 survivors, none has experienced disease progression at a median follow-up of 27 months (range 3-65 months). We conclude that since allogeneic bone marrow transplantation is the only potentially curative option in myeloma, it should be offered to younger patients early in the course of their disease, when procedure-related morbidity and mortality are likely to be at their lowest.

Adult↗
PubMed1999

Recombinant tissue plasminogen activator (rtPA) for the treatment of hepatic veno-occlusive disease (VOD).

Seventeen patients who developed hepatic veno-occlusive disease (VOD) following hematopoietic stem cell transplantation were treated with recombinant tissue plasminogen activator (rtPA) with or without heparin. rtPA was started a median of 13 days post transplant (range 4-35). All patients received rtPA at a dose of 10 mg/day as a starting dose, and 12 patients also received heparin (1500 U bolus; then 100 U/kg/day as a continuous i.v. infusion). The median number of days of rtPA therapy was 2.5 (1-12). The median total serum bilirubin level was 116 mmol/l (range 63-194) at the beginning of treatment. Six patients showed a response to rtPA treatment (29%). It was observed that by day 2 of rtPA therapy, bilirubin levels in responders showed a downwards trend as compared to those in nonresponders. In all except one patient this response was observed after two doses of rtPA. Seven out of the 11 non-responders had a past history of liver dysfunction, compared with none of the responders. There were no differences between the two groups in terms of day of onset of liver dysfunction, manifestations of disease, maximum bilirubin and creatinine levels, and day of commencing treatment. No patient experienced severe hemorrhagic complications during therapy. Four responders survived for more than 100 days compared to none of the non-responders. Probability of survival was 33% at day 100. It is difficult to unequivocally establish the role of rtPA in the treatment of VOD. The importance of bilirubin levels on days 2 or 3 of therapy in predicting outcome should be established, as should the optimum dose of rtPA and optimum duration of therapy.

Adult↗
PubMed1999

Syngeneic transplantation in multiple myeloma - a case-matched comparison with autologous and allogeneic transplantation. European Group for Blood and Marrow Transplantation.

Twenty-five patients with multiple myeloma received bone marrow grafts (n = 24) or peripheral blood stem cells (n = 1) from twin donors. The outcome was compared in a case-matched analysis to 125 patients who underwent autologous transplantation, and 125 who underwent allogeneic transplantation. Seventeen patients (68%) receiving twin transplants entered complete remission, which was not significantly different from that of autologous (48%) or allogeneic (58%) transplants. The median overall and progression-free survival for the twins was 73 and 72 months, respectively. The overall survival tended to be better (73 vs 44 months) and the progression-free survival was significantly better (72 vs 25 months) than with autologous transplantation and both were significantly better than with allogeneic transplantation. Three of 17 patients who entered complete remission following transplantation had relapsed at follow-up. This relapse rate was significantly lower than following autologous transplantation and similar to the relapse rate with allogeneic transplantation. Only two twins died of transplant-related toxicity. Six further patients died of progressive or relapsing disease. Syngeneic transplantation in multiple myeloma appears to be the treatment of choice if a twin donor is available. A lower relapse risk than in autotransplantation may be due to reinfusion of malignant cells in some patients treated with this modality or to the presence of a graft-versus-myeloma effect in some syngeneic transplants.

Adult↗
PubMed1999

Oral idarubicin as a single agent therapy in patients with relapsed or resistant multiple myeloma.

The established treatment for multiple myeloma (MM) comprises induction with infusional chemotherapy, high dose chemotherapy (HDC) and autologous transplantation followed by maintenance interferon. On relapse, patients (pts) are reconsidered for this however some are unsuitable and in this situation the therapeutic options are limited. Between June 1995 and May 1997, 14 pts with previously treated relapsed or refractory MM were recruited. Using a prospective database, the tolerability and efficacy of chronic low dose oral idarubicin was evaluated. The median age of pts was 63 years. All had received previous anthracycline in the form of infusional cVAMP chemotherapy. 11/14 had received previous HDC. Median time from diagnosis to commencing idarubicin was 77 months. 10 mg idarubicin was administered 3 times/week for 3 weeks of a 5 week cycle. The maximum number of courses was 6. Three pts completed 6 courses, 5 pts 3 courses, 2 pts 2 courses and 4 pts 1 course. The reasons for stopping treatment were death due to progressive disease (PD) in 7 pts, persistent thrombocytopenia in 2 pts, PD in 1 pt and 1 pt suffered a cerebral infarction not considered to be related to the idarubicin therapy. Two pts showed evidence of response, neither amounting to a partial response. One had stabilisation of paraprotein with a reduction in bone marrow infiltration (47% to 7% plasma cells), the other had a reduction in bone marrow infiltration after 3 course but an increase after 6 courses. In total forty-one courses of treatment were administered. Grade 3/4 haematological toxicities were noted in a minor fraction of cases and were as follows: anaemia 6/41, neutropenia 10/41 and thrombocytopenia 11/41. Our data therefore shows a minor response in 2/14 (14%) of heavily pretreated patients with MM, without evidence of severe toxicity. It provides the rationale for using oral idarubicin as either single agent or in combination therapy for patients earlier on in their disease course especially if they are unsuitable for standard therapy.

Adult↗
PubMed1999

Acute erythroid leukemia (M6): outcome of bone marrow transplantation.

Erythroid leukemia is an uncommon form of acute myeloid leukemia (AML) which has previously been associated with a poor prognosis. We present the outcome of 27 patients with AML-M6 (19 de novo and 8 secondary) treated with intensive regimens including bone marrow transplantation (BMT). In the de novo group, median age was 30 years (2-72); 5 cases were under 15 years. Remission rate after induction chemotherapy was 95%. Consolidation in those achieving remission with BMT was 82%. Transplant related mortality was 36%. Median survival for de novo M6 was 2.9 years which was not significantly different to matched controls with AML (non M6). Overall relapse rate was 35%. In contrast, patients with secondary disease had a poor prognosis with lower remission rates (57%) and higher relapse rates (75% of those achieving remission after induction chemotherapy). In our series, the prognosis of patients with AML-M6 was most closely related to age and disease status at presentation (de novo or secondary). The disease is sensitive to AML induction regimens and long-term survival can be achieved with BMT in first complete remission.

Adolescent↗
PubMed1999

Outcome of biphenotypic acute leukemia.

BACKGROUND AND OBJECTIVE: Although biphenotypic leukemia is now a defined entity, outcome of this rare form of acute leukemia has not been well documented. We present the first comprehensive study analyzing induction and consolidation therapy of biphenotypic leukemia and correlate outcome to prognostic factors. DESIGN AND METHODS: In this retrospective study, the incidence of biphenotypic leukemia was found to be 3.6% from 693 adult and pediatric acute leukemias referred to our center for treatment over the last 8 years. Of these, 15 were B-lymphoid/myeloid, 8 were T-lymphoid/myeloid, one was T/B lymphoid and one had trilineage differentiation. RESULTS: Induction of remission in de novo cases was achieved in 70% of patients and relapse of disease occurred in 15%. The use of combined lymphoid and myeloid drugs for induction resulted in a high incidence of early deaths (25%). The overall probability of survival at 2 years was 39.4%. Patients with secondary disease had a uniformly poor outcome with low remission rates and high relapse rates. INTERPRETATION AND CONCLUSIONS: Prognosis was most strongly related to the presence of the Philadelphia chromosome (p=0.03) and age under 15 years (p=0.01). We conclude that patients with biphenotypic leukemia should have risk stratification with treatment tailored to their prognostic factors.

Acute Disease↗
PubMed1998

Secondary leukaemia characterised by monosomy 7 occurring post-autologous stem cell transplantation for AML.

Secondary leukaemia has rarely been reported as a complication of autologous stem cell transplantation for AML. We report two cases of AML who presented with well-characterised cytogenetic abnormalities at presentation: t(8;21) and t(15;17) respectively, and who, after achieving complete morphological and cytogenetic remissions post-autograft, developed MDS/AML associated with monosomy 7. This secondary change is most frequently seen following alkylating agent therapy for solid tumours. The secondary leukaemia seen in our patients may thus be due to exposure of the residual stem cells to the alkylating agents used in the transplant conditioning.

Adult↗
PubMed1998

The importance of CD34+/CD33- cells in platelet engraftment after intensive therapy for cancer patients given peripheral blood stem cell rescue.

The study was designed to determine whether the number of CD34+/CD33- cells given at autologous peripheral blood stem cell (PBSC) rescue after intensive therapy for cancer was a better predictor of platelet engraftment than the total number of CD34+ cells infused. Comparison between the total number of CD34+ cells/kg infused with the number of CD34+/CD33- cells/kg infused showed that, generally, 2 x 10(6) total CD34+ cells contained 1.38 x 10(6) CD34+/CD33- cells. There was poor correlation between the number of CD34+/CD33- and CD34+/CD33+ cells in the graft (r = 0.332). Engraftment times for platelets and neutrophils were evaluated in 68 patients. There was no significant difference between the times for platelets to reach >25 x 10(9)/l or neutrophils to reach >0.5 x 10(9)/l among patients who received > or <2 x 10(6) total CD34+ cells or > or <1.38 x 10(6) CD34+/CD33- cells although the latter was consistently the better predictor. Platelet recovery to >50 x 10(9)/l and >100 x 10(9)/l was delayed significantly in patients who received <1.38 x 10(6) CD34+/CD33-/kg infused (P < 0.02 and P < 0.05, respectively). The number of CD34+/CD33- cells/kg infused was a stronger predictor of platelet recovery than the total number of CD34+ cells infused (P < 0.05 for platelets >50 or >100 x 10(9)/l). Although platelet recovery was delayed significantly in patients who had <4 x 10(4) granulocyte-macrophage colony-forming units (CFU-GM)/kg infused, the time delay between receipt of PBSCs and availability of the colony counts limits the use of this assay to patients who do not require stem cells to be given immediately. Our data suggest that the number of CD34+/CD33- cells given at PBSC rescue provide information about the quality of the graft necessary for long-term platelet engraftment. However, since the percentage of CD34+/CD33- cells shows considerable inter-patient variation, measurement of this cell population may be important in patients who experience poor stem cell mobilization or when a target dose of 2 x 10(6) total CD34+ cells/kg is not achieved.

Adolescent↗
PubMed1998

Detection of minimal residual disease in B-lineage acute lymphoblastic leukaemia by quantitative flow cytometry.

The clinical significance of detecting minimal residual disease (MRD) in B-lineage acute lymphoblastic leukaemia (ALL) was evaluated by quantitative flow cytometry using a combination of TdT with CD10 and CD19. 53 patients with B-cell precursor ALL were followed during and after completion of treatment (median follow-up 23 months). Nine patients relapsed and MRD had been detected in six of them, 5-15 weeks before relapse despite morphological complete remission. 43 patients remain in clinical remission and in none of these was MRD detected. Disease-free survival based on the detection of MRD by flow cytometry showed a statistically significant difference between both groups (P<0.0001). The absence of MRD correlates with a low relapse rate, whereas the presence of MRD predicted early relapse. This study has shown that flow cytometry can improve the morphologic assessment of bone marrow (BM) remission status in B-lineage ALL. The finding of < 5% blasts in BM aspirates did not correlate with 'true' remission in a proportion of cases as residual leukaemic blasts were detected by flow cytometry in nine samples from six patients. On the other hand, the presence of > 5% blasts assessed by morphology was not necessarily a feature of relapse in five patients as these cells were shown to have a phenotype identical to normal TdT-negative B-cell precursors. Quantitative flow cytometry was more informative than conventional morphology to assess remission status and showed a strong correlation with clinical outcome. This methodology is useful to define MRD in the majority of patients with B-lineage ALL and should be tested in prospective clinical trials.

Adult↗
PubMed1998

Inhibitory effect of simvastatin on the proliferation of human myeloid leukaemia cells in severe combined immunodeficient (SCID) mice.

SCID mice were inoculated intravenously with cells from the human HL60 myeloblastic leukaemia cell line and then treated with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, simvastatin, by subcutaneous continuous infusion. The effect of the drug was measured by subsequent colony formation of surviving HL60 cells in vitro and flow cytometry. The number of clonogenic HL60 cells was reduced in the bone marrow of mice that received simvastatin compared with control mice by 65% and 68% in two separate experiments. The number of clonogenic, normal, murine, bone marrow progenitor cells concomitantly exposed to simvastatin in vivo, was not affected in either experiment. Flow cytometric analysis of bone marrow and spleen cells confirmed these results by showing that simvastatin had reduced the percentage of human leukaemia cells in these tissues by 70% and 88% respectively. The data show that the reported selective effect of simvastatin against acute myeloid leukaemia cells in vitro, can be extended to this in vivo model. HL60 bears an N-ras mutation. In further in vitro studies, ketoconazole, an inhibitor of cholesterol biosynthesis post farnesyl pyrophosphate synthesis, had a similar effect to simvastatin on HL60 colony development. Furthermore, the clonogenicity of a population of N-ras mutated, primary acute myeloid leukaemia (AML) cells was no more sensitive to simvastatin than a population without the mutation. The data suggest that the inhibition of AML cell proliferation by simvastatin may be independent of the RAS signalling pathway.

Acute Disease↗
PubMed1998

Liposomal vincristine for the treatment of human acute lymphoblastic leukaemia in severe combined immunodeficient (SCID) mice.

Non-obese diabetic NOD/SCID mice have been used to grow human leukaemia as a systemic disease. The animals were inoculated with leukaemic cells obtained from a 36-year-old male with early B-cell precursor acute lymphoblastic leukaemia and on day 15 were given the first of three weekly injections of 1 mg/kg vincristine or equimolar liposomal vincristine. The development of leukaemia in the mice was monitored by taking weekly blood samples and measuring the cell content by flow cytometry. The median time to 50% human cells in the peripheral blood of mice treated with free vincristine was 41 d from the start of treatment compared with 49 d for mice treated with liposomal vincristine (P < 0.01). The median day of death for mice treated with free vincristine was 47 d from the start of treatment and 57 d for mice receiving liposomal vincristine (P<0.01), thus providing a 21% increase in lifespan for animals treated with the liposomal preparation. There was slightly greater weight loss in mice treated with free vincristine than those given liposomal vincristine. Measurement of in vitro colony forming bone marrow progenitor cells in similarly treated, tumour-free mice, showed no difference in progenitor cell survival between mice that received either type of vincristine. We conclude that encapsulating vincristine in liposomes improves the therapeutic index of this drug measured in mice bearing human leukaemia. This may lead to use of the drug in conventional combination chemotherapy with greater safety or, in this setting, at higher dosage.

Adult↗
PubMed1997

Growth of human T-cell lineage acute leukemia in severe combined immunodeficiency (SCID) mice and non-obese diabetic SCID mice.

Primary leukemic cells from patients with acute lymphoblastic leukemia (ALL) can be injected intravenously into mice with severe combined immunodeficiency (SCID) to create a model of human leukemia. Leukemic cells disseminate to murine tissues in a clinicopathologic pattern similar to that seen in humans. Thus far, reports of engraftment of lymphoid leukemia in SCID mice have mainly been from patients with B-cell lineage ALL, for which engraftment occurs more frequently with cells from high-risk patients. There are few data on the engraftment of T-cell lineage ALL in SCID mice. Leukemic cells from 19 patients (16 adult and three pediatric) with T-cell lineage ALL were injected into SCID mice, with overt engraftment of 12 cases (63%). Engraftment of leukemia in SCID mice was associated with earlier death due to leukemia of the patient donors (P < .01, log-rank test). The recently developed non-obese diabetic (NOD)/SCID mouse may expand the uses of the SCID model. Cells from the seven patients with T-cell lineage ALL that failed to cause leukemia in SCID mice were injected into NOD/SCID mice. Overt leukemia engraftment was observed in all seven cases. Thus, growth of human T-cell lineage ALL cells in SCID mice was associated with a high-risk patient group. However, this association was not observed when NOD/SCID mice were used, suggesting that this model would no longer predict patients likely to die early of leukemia, but may provide a more realistic system for studying the biology and treatment of the disease.

Acute Disease↗