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Anthony H Goldstone

Publications and source records attributed to Anthony H Goldstone.

29 records · Page 2Linked to original sources
PubMed2002

Role of nonmyeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies.

PURPOSE: Conventional allogeneic stem-cell transplantation (SCT) after a prior failed autograft is associated with a transplant-related mortality rate of 50% to 80%. The aim of the current study was to evaluate the safety and efficacy of sibling, HLA-matched, nonmyeloablative allogeneic SCT with donor lymphocyte infusion (DLI) in patients with lymphoid malignancy after failure of autologous SCT. PATIENTS AND METHODS: A total of 38 patients with refractory, progressive, or relapsed disease after autologous SCT were entered onto this study. The conditioning regimen consisted of the humanized monoclonal antibody CAMPATH-1H, fludarabine, and melphalan. Fifteen of 35 assessable patients received DLI after SCT. RESULTS: Sustained neutrophil engraftment was achieved in 37 recipients, and platelet engraftment was achieved in 35 patients. The estimated transplant-related mortality was 7.9% at day 100 and 20% at 14 months, the median duration of follow-up. Eight patients experienced grade I/II acute graft-versus-host disease (GVHD) after transplantation, but no grade III/IV GVHD was observed in this setting. However, grade III/IV GVHD occurred in seven patients who received DLI. The actuarial overall survival at 14 months was 53%, with a progression-free survival of 50%. DLI produced a further response in three of 15 recipients. CONCLUSION: Nonmyeloablative allogeneic SCT after CAMPATH-1H-containing conditioning is a relatively safe option compared with conventional allogeneic transplantation for patients who have failed previous autologous SCT. The low incidence of early GVHD enabled the subsequent administration of DLI to improve further clinical responses in this poor-risk group of lymphoma and myeloma patients.

Adult↗
PubMed2002

Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation.

We report the outcome of reduced-intensity allogeneic progenitor cell transplantation (alloPCT) for 188 patients with lymphoma from the Working Party Lymphoma of the European Group for Blood and Bone Marrow Transplantation (EBMT). The median age of the patients was 40 years, the median number of prior treatment courses was 3, and 48% of patients had undergone a prior autologous transplantation. Eighty-four percent of the patients received conditioning with fludarabine-based regimens and 10% with the BEAM (BCNU, etoposide, cytosine arabinoside, melphalan) protocol. Full donor chimerism was confirmed in 71% of 100 patients assessed. Acute graft-versus-host disease (GVHD) developed in 37% of patients and chronic GVHD in 17%. A disease response to donor leukocyte infusion (DLI) was seen in 10 of 14 patients. With a median follow-up of 283 days, the overall survival rates at 1 and 2 years were 62% and 50%, respectively. The 100-day and 1-year transplantation-related mortality (TRM) rates were 12.8% and 25.5%, respectively, and were significantly worse for older patients. The probability of disease progression at 1 year for patients with chemoresistant and chemosensitive disease were 75% and 25%, respectively (P =.001). The progression-free survival at 1 year was 46% and was significantly better for those with chemosensitive disease, Hodgkin disease (HD), and low-grade non-Hodgkin lymphoma (NHL). Patients with high-grade NHL, mantle cell lymphoma, or chemoresistant disease had a poor outcome. Reduced-intensity progenitor cell transplantation is associated with a reduced TRM and may control advanced HD and low-grade NHL. A longer period of follow-up is required to determine the benefit of DLI and the graft-versus-lymphoma effect.

Adult↗
PubMed2002

Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial.

BACKGROUND: High-dose chemotherapy followed by transplantation of autologous haemopoietic stem cells (BEAM-HSCT) is frequently used to treat patients with relapsed Hodgkin's disease. We aimed to compare this treatment with conventional aggressive chemotherapy without stem-cell transplantation (Dexa-BEAM). METHODS: 161 patients between 16 and 60 years of age with relapsed Hodgkin's disease were randomly assigned two cycles of Dexa-BEAM (dexamethasone and carmustine, etoposide, cytarabine, and melphalan) and either two further courses of Dexa-BEAM or high-dose BEAM and transplantation of haemopoietic stem cells. Only patients with chemosensitive disease (complete or partial remission after two courses of Dexa-BEAM) proceeded to further treatment. The primary endpoint was freedom from treatment failure for patients with chemosensitive disease. Analysis was per protocol. FINDINGS: 17 patients were excluded from the study after randomisation (ten given Dexa-BEAM and seven given BEAM-HSCT). Median follow-up was 39 months (IQR 3-78). Freedom from treatment failure at 3 years was significantly better for patients given BEAM-HSCT (55%) than for those on Dexa-BEAM (34%; difference -21%, 95% CI -39.87 to -2.13; p=0.019). Overall survival of patients given either treatment did not differ significantly. INTERPRETATION: High-dose BEAM and transplantation of haemopoietic stem cells improves freedom from treatment failure in patients with chemosensitive first relapse of Hodgkin's disease irrespective of length of initial remission.

Adolescent↗
PubMed2002

High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution.

Nonmyeloablative conditioning is increasingly used for transplantation in a wide range of diseases, but little is known about its impact on the incidence of infections and immune reconstitution. We examined the pattern and outcome of cytomegalovirus (CMV) infections monitored by polymerase chain reaction-based assays and treated preemptively in 101 patients following nonmyeloablative conditioning containing in vivo Campath-1H. Fifty-one patients (50%) had a CMV infection at a median of 27 days after transplantation with a probability of 84.8% in patients at risk of CMV infection. The probability of recurrence of CMV infection before and after 100 days was 53.6% and 46.6%, respectively, and was more common in unrelated donor transplant recipients. All 3 patients who developed CMV disease died of this complication. The 2 patients with late CMV disease had grade III to IV graft-versus-host-disease (GVHD), which occurred de novo in only 4% of patients and in another 10% following donor lymphocyte infusions. The median time to CD4(+) T-cell count more than 200/microL was 9 months in the 48 patients studied. The probabilities of overall survival and nonrelapse mortality at 18 months were 65% and 27.8%, respectively, with no significant difference in survival between CMV-infected and -uninfected patients. The use of Campath-1H appeared to be associated with a low incidence of GVHD but a high incidence of CMV infections and prolonged immune paresis.

Adolescent↗
PubMed2002

Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen.

A nonmyeloablative conditioning regimen was investigated in 47 patients with hematological malignancy receiving allogeneic progenitor cells from matched, unrelated donors. The median patient age was 44 years. The majority of patients had high-risk features, including having failed a prior transplantation (29 individuals). Twenty of the transplants were mismatched for HLA class I and/or class II alleles. Recipient conditioning consisted of 20 mg CAMPATH-1H on days -8 to -4, 30 mg/m(2) fludarabine on days -7 to -3, and 140 mg/m(2) melphalan on day -2. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine A alone. Primary graft failure occurred in only 2 of 44 evaluable patients (4.5%). Chimerism studies in 34 patients indicated that the majority (85.3%) attained initial full donor chimerism. Only 3 patients developed grade III to IV acute GVHD, and no patients have yet developed chronic extensive GVHD. The estimated probability of nonrelapse mortality at day 100 was 14.9% (95% confidence interval [CI], 4.7%-25.1%). With a median follow-up of 344 days (range, 79-830), overall and progression-free survivals at 1 year were 75.5% (95% CI, 62.8%-88.2%) and 61.5% (95% CI, 46.1%-76.8%), respectively. In summary, a nonmyeloablative regimen incorporating in vivo CAMPATH-1H is effective in promoting durable engraftment in most patients and in reducing the risk of severe GVHD following matched unrelated donor transplantation.

Adolescent↗
PubMed2002

The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial.

Patients under 55 years in the United Kingdom Medical Research Council Acute Myeloid Leukaemia 10 trial who entered complete remission were tissue typed (n = 1063). Four hundred and nineteen had a matched sibling donor and 644 had no match. When compared on a donor versus no donor basis the relapse risk was reduced in the donor arm (36%vs 52%; P = 0.001) and the disease-free survival (DFS) improved (50%vs 42%; P = 0.01), but overall survival (OS) was not different (55%vs 50%; P = 0.1). Sixty-one per cent of patients with a donor underwent transplantation. When patients were subdivided into risk groups based on cytogenetics alone or with the addition of blast response to course 1, a reduction in relapse risk was seen in all risk groups and in three age cohorts (0-14, 15-34 and 35+ years). Significant benefit in DFS was only seen in the intermediate-risk cytogenetic group (50%vs 39%; P = 0.004). The OS benefit was only seen in intermediate-risk patients (55%vs 44%; P = 0.02). The reduction in relapse risk in good-risk patients was attributable to patients with t(15;17) and not to patients with t(8;21) or inv(16). Allogeneic transplantation given after intensive chemotherapy was able to reduce relapse in all risk and age groups. However, due to the competing effects of procedural mortality and an inferior response to chemotherapy if relapse does occur, there was a survival advantage only in patients of intermediate risk. This trial found no survival advantage in children, patients over 35 years or good-risk disease.

Acute Disease↗
PubMed2002

Respiratory virus infections in transplant recipients after reduced-intensity conditioning with Campath-1H: high incidence but low mortality.

Respiratory virus infections can cause serious morbidity and mortality after conventional allogeneic stem cell transplantation. However, the incidence and outcome of these infections after reduced intensity conditioning has not been reported. Between 1997 and 2001, 35 episodes of respiratory virus infections were noted in 25 of 83 transplant recipients conditioned with fludarabine, melphalan and Campath-1H, and 80% of them received early antiviral therapy. Parainfluenza virus (PIV) 3 was the commonest isolate (45.7%) followed by respiratory syncytial virus (37%). Patients with myeloma were more susceptible to these infections [odds ratio (OR) 4.1, P = 0.01] which were often recurrent in patients with severe acute or chronic graft-versus-host disease (GVHD) (OR 10.6, P = 0.03). Infection within the first 100 d (OR 5.0, P = 0.05) and PIV 3 (OR 9.2, P = 0.01) isolation were risk factors for developing lower respiratory infection. Although more than half of the episodes progressed to lower respiratory infection, the mortality was only 8%. This could have been due to early initiation of antiviral therapy, but the attenuation of pulmonary damage due to the reduced-intensity conditioning, low incidence of GVHD and, paradoxically, the low CD4+ T-cell subset in this setting might also have been contributory factors.

Adolescent↗
PubMed2002

Acute myeloid leukemia.

In this chapter, Drs. Keating and Willman review recent advances in our understanding of the pathophysiology of acute myeloid leukemia (AML) and allied conditions, including the advanced myelodysplastic syndromes (MDS), while Drs. Goldstone, Avivi, Giles, and Kantarjian focus on therapeutic data with an emphasis on current patient care and future research studies. In Section I, Dr. Armand Keating reviews the role of the hematopoietic microenvironment in the initiation and progression of leukemia. He also discusses recent data on the stromal, or nonhematopoietic, marrow mesenchymal cell population and its possible role in AML. In Section II, Drs. Anthony Goldstone and Irit Avivi review the current role of stem cell transplantation as therapy for AML and MDS. They focus on data generated on recent Medical Research Council studies and promising investigation approaches. In Section III, Dr. Cheryl Willman reviews the current role of molecular genetics and gene expression analysis as tools to assist in AML disease classification systems, modeling of gene expression profiles associated with response or resistance to various interventions, and identifying novel therapeutic targets. In Section IV, Drs. Hagop Kantarjian and Francis Giles review some promising agents and strategies under investigation in the therapy of AML and MDS with an emphasis on novel delivery systems for cytotoxic therapy and on targeted biologic agents.

Acute Disease↗
PubMedDate not supplied

Clinical evidence of a graft-versus-Hodgkin's-lymphoma effect after reduced-intensity allogeneic transplantation.

BACKGROUND: In patients with multiply relapsed Hodgkin's lymphoma allogeneic stem-cell transplantation has been limited by prohibitive non-relapse-related mortality rates and by a lack of definitive evidence for a therapeutic graft-versus-tumour effect. Therefore, we aimed to assess the graft-versus-tumour effect of reduced-intensity allogeneic transplantation. METHODS: We undertook reduced-intensity transplantation in 49 patients with multiply relapsed Hodgkin's lymphoma, 44 (90%) of whom had progression of disease after previous autologous transplantation (median age 32 years [range 18-51], number of previous treatment courses was five [range 3-8], and time from diagnosis 4.8 years [range 0.6-4.8]). 31 patients had HLA matched donors who were related and 18 had donors who were unrelated. Median follow-up was 967 days (range 102-2232). The primary endpoints were engraftment, toxic effects, non-relapse-related mortality, incidence of graft-versus-host disease (GVHD), and the toxic effects of adjuvant donor-lymphocyte infusion. FINDINGS: All patients engrafted. Eight of 49 (16%) had grade II-IV acute GVHD and seven (14%) had chronic GVHD before donor-lymphocyte infusion. 16 (33%) patients received donor-lymphocyte infusion from 3 months after transplantation for residual disease or progression. Six (38%) of the 16 developed grade II-IV acute GVHD and five developed chronic GVHD. Nine (56%) showed disease responses after infusion (eight complete, one partial). Non-relapse-related mortality was 16.3% at 730 days (7.2% for patients who had related donors vs 34.1% for those with unrelated donors, p=0.0206). Projected 4 year overall and progression-free survival were 55.7% and 39.0%, respectively (62.0% and 41.5% for related donors). INTERPRETATION: These data show the potential for durable responses in patients who have previously had substantial treatment for Hodgkin's lymphoma. The low non-relapse-related mortality suggests the procedure could be undertaken earlier in the course of the disease.

Adolescent↗