Bone marrow transplantation versus chemotherapy in non-Hodgkin's lymphoma.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
A H Goldstone
Publications and source records attributed to A H Goldstone.
Hepatitis B transmission from contaminated cryopreservation tank.
Over a 25-month period, six multiply transfused patients undergoing cytotoxic treatment for haematological or other malignant disorders developed icteric acute hepatitis B virus (HBV) infection. Bone marrow or peripheral-blood stem cells had been harvested from all six patients and stored in the same cryopreservation tank for possible future transplantation. Human DNA, HBsAg, and HBV DNA with sequences identical to those from four patients with related infections were subsequently found in the liquid nitrogen. Leakage of the cryopreservation bags used to store bone marrow harvested from the first patient when acutely infected with HBV led to contamination of the tank and its contents with HBV and subsequent transmission to patients after transplantation. This incident emphasises the continuing need to screen donors of tissue to be cryopreserved for bloodborne virus infections. It also reinforces the requirement for primary containers used to cryopreserve human tissue to be sealed in a way which prevents exchange of material between the specimen and the liquid nitrogen.
Acute Disease↗
Autologous bone marrow transplantation for first remission acute myeloblastic leukemia in patients older than 50 years: a retrospective analysis of the European Bone Marrow Transplant Group.
High-dose chemotherapy, with or without radiotherapy, followed by autologous stem-cell rescue is used increasingly for the intensification of first remission in acute myeloblastic leukemia (AML). However, these treatments have been limited to young patients due to the increased risks of regimen-related toxicities and mortality with age. Several investigators have recently published the upper age limit for autologous bone marrow transplant (ABMT) in AML because of encouraging results. The results of ABMT for AML were studied in 111 patients > or = 50 years of age intensified in first remission. Median age at transplant was 53 years (range, 50 to 63 years). Fifty patients were conditioned with total body irradiation and 61 with polychemotherapy: 23 with busulfancyclophosphamide, 11 with the University College Hospital (UCH; London, UK) regimen, 6 with BAVC, and 21 with various other treatments. Marrow was purged in only 11 cases. Results were compared with 786 ABMTs performed for AML in patients between 16 and 49 years of age (median, 35 years). For AML in first remission, the probability of leukemia-free survival (LFS) at 4 years was 34% +/- 5% for patients aged 50 years or more and 43% +/- 2% for patients less than 50 years of age (P = .004), with a survival probability of 35% +/- 6% and 48% +/- 2%, respectively (P = .004). The probability of relapse was not significantly different between the two groups (52% +/- 7% v 50% +/- 2%), but transplant-related mortality was significantly higher in the older age group (28% +/- 5% v 14% +/- 2%; P < .0001) and mainly due to infectious complications. In a multivariate analysis, age less than 50 years was a favorable risk factor for LFS, treatment-related mortality (TRM), and survival but not for relapse incidence. These data suggest that ABMT should be considered in older AML patients.
Acute Disease↗
Changes in maternal plasma macrophage-colony stimulating factor levels during normal pregnancy.
An enzyme-like immunosorbent assay and a blood autoanalyser were used to determine macrophage-colony stimulating factor (M-CSF) levels and the absolute number and percentage of circulating monocytes in 80 normal women with singleton pregnancies at 12-40 weeks' gestation, and ten healthy non-pregnant volunteers. The mean values of M-CSF and absolute number and percentage of circulating monocytes of the control group were 367 U/ml (SD 43) and 389 x 10(6)/l (SD 180) and 5.3% (SD 1.7) respectively. In pregnancy, M-CSF was significantly higher than non-pregnant controls only after 28 weeks' gestation. The absolute number and the percentage of circulating monocytes increased significantly with gestation after 16 weeks. There was no significant association between the concentration of M-CSF and the number or percentage of circulating monocytes. These data suggest that during pregnancy there is an up-regulation of M-CSF and monocytes.
Adult↗
BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma.
PURPOSE: To evaluate the outcome of patients with relapsed or resistant non-Hodgkin's lymphoma (NHL) undergoing high-dose chemotherapy and autologous bone marrow transplantation (ABMT) and to determine the main prognostic factors. PATIENTS AND METHODS: One hundred seven patients with relapsed or resistant intermediate-/high-grade NHL underwent high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy and ABMT at University College Hospitals between September 1981 and February 1993. The minimum follow-up duration of all patients is 6 months. RESULTS: At 3 months, the overall response rate to BEAM and ABMT was 73% (41% complete response and 32% partial response). The 5-year actuarial overall survival and progression-free survival rates were 41% and 35%, respectively. The early procedure-related mortality rate was 7% (eight of 107 patients). On multivariate analysis, the main prognostic factor was disease status at the time of ABMT. Patients with chemosensitive disease had an actuarial 5-year survival rate of 49% at 5 years compared with 13% for those with chemoresistant disease (P < .001). For patients considered to have chemosensitive disease at the time of transplantation, there is a significant difference in the actuarial progression-free survival rates for those who received high-dose therapy after attaining a partial response to first-line therapy (69% at 5 years) as compared with those with sensitive but relapsed disease (32% at 5 years) (P = .003). CONCLUSION: Patients with chemosensitive disease benefit most from high-dose chemotherapy, and those who receive such therapy early after achieving a partial response to first-line therapy have a high rate of cure.
Adolescent↗
First remission autologous bone marrow transplantation for Hodgkin's disease--preliminary EBMT data.
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Bone Marrow Transplantation↗
Functional hyperactivity of monocytes after bone marrow transplantation: possible relevance for the development of post-transplant complications or relapse.
Bone marrow transplant (BMT) complications such as graft-versus-host disease (GVHD), veno-occlusive disease (VOD) and cytomegalovirus (CMV) infection are associated with high levels of circulating tumour necrosis factor-alpha (TNF), much of which may be monocyte derived. We therefore studied monocyte activation after BMT in 36 patients (18 allografts and 18 autografts); plasma neopterin and in vitro secretion of superoxide, neopterin and TNF by peripheral blood monocytes were assessed. Monocyte respiratory burst was raised at regeneration but returned to near-normal within 7 days. Plasma neopterin, and in vitro secretion of neopterin and TNF, were greater than twice normal at regeneration and remained raised for up to 6 weeks after BMT. Plasma neopterin was higher following allogeneic BMT than autologous BMT and was independent of GVHD or VOD. Low levels were seen in one patient who failed to engraft. There is evidence of increased activation of monocytes at the time of and for several weeks after engraftment post-BMT. Abnormal monocyte activation may predispose to, rather than result from, the development of complications in the early post-transplant period.
Adolescent↗
Delayed neutrophil recovery after BEAM chemotherapy and autologous bone marrow transplantation for lymphoma is not associated with increased mortality from infection.
Administration of high-dose cytotoxic therapy with autologous bone marrow transplantation (BMT) results in prolonged cytopenia and significant morbidity and mortality. Several groups have reported that the administration of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) to patients with delayed haematological recovery following autologous BMT may accelerate neutrophil recovery and decrease mortality. We have determined the prevalence and natural history of delayed neutrophil recovery following BEAM chemotherapy and autologous BMT for malignant lymphoma in 261 patients treated at a single institution without the use of haemopoietic growth factors. Forty of 261 (15%) patients took > 28 days to reach an absolute neutrophil count (ANC) > 0.5 x 10(9)/L; 29 of these 40 (73%) with delayed engraftment reached an ANC > 0.5 x 10(9)/L by day +42. Five patients with delayed engraftment died before day +100, two of progressive lymphoma, one from unirradiated blood product-related GVHD and two of interstitial pneumonitis (IP). The patients with IP had negative culture and bronchoscopic examinations and onset of assisted ventilation was day +15 and +18, respectively. These results show a high rate of relatively rapid spontaneous recovery in individuals with delayed neutrophil recovery after BEAM plus autologous BMT with a low incidence of death from infection.
Adolescent↗
Recombinant interferon-alpha 2 antibodies in chronic lymphocytic leukemia.
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Female↗
Peripheral blood progenitor cells versus bone marrow.
Transplantation of mobilized peripheral blood progenitor cells has generally produced shortening of the period of posttransplant aplasia that is characteristic of bone marrow grafts. However, there has been no large prospective randomized study to compare these two sources of hematopoietic cells or to determine their relative merits. This issue is explored in this review.
Bone Marrow Transplantation↗
Comparison of peripheral blood stem-cell and autologous bone marrow transplantation for lymphoma patients: a case-controlled analysis of the EBMT Registry data. Lymphoma Working Party of the EBMT.
A case-controlled analysis was performed to assess the effect of stem-cell source on autograft in a group of patients with malignant lymphoma reported to the European Bone Marrow Transplant Group (EBMT). The study was performed matching 83 patients autografted with peripheral blood stem cells (PBSC) with 83 autologous bone marrow transplantation (ABMT) patients. The case-matching was carried out following selection of the main prognostic factors for progression-free survival by multivariate analysis. The progression-free survival was similar in both types of transplants (38.5% PBSCT vs. 36.4% ABMT). The overall relapse and progression rate for the PBSCT was 51.2% compared with 50.1% for the ABMT patients. The differences were not significant statistically. The transplant-related mortality was 6% for both groups. The neutrophil and leucocyte recovery occurred faster in the peripheral blood stem-cell transplantation (PBSCT); the platelet recovery was not significant. A higher number of interstitial pneumonitis and fungal infection episodes were observed in the ABMT group. In conclusion, in these closely matched groups, there is no difference in PFS between patients undergoing PBSCT and those undergoing ABMT. However, the patients autografted with PBSC have a more rapid engraftment and a lower toxicity.
Adolescent↗
High-dose therapy and autologous bone marrow transplantation in first complete remission for adult patients with high-grade non-Hodgkin's lymphoma: the EBMT experience. Lymphoma Working Party of the European Group for Bone Marrow Transplantation.
One hundred and eighteen patients presenting with high-grade non-Hodgkin's lymphoma, undergoing autologous bone marrow transplantation (ABMT) in first complete remission (CR), have been reported to the European Group for Bone Marrow Transplantation (EBMT). Of these, 102 were eligible for inclusion in this study following review of registration forms. Patients with lymphoblastic lymphoma were excluded. Remission induction and high-dose regimens varied between contributing centres. A maintained CR was observed in 90% of patients. Early relapse was observed in 6%, and 4% suffered toxic deaths. With a median follow-up of 45 months (3-112 months), the 5-year actuarial overall and progression-free survivals are both 70%. Nineteen (18%) patients relapsed at a median of 3.5 months (0.25-52 months) after ABMT, only 1 achieving a further durable CR. The only factor with prognostic significance was histological subtype, with diffuse small noncleaved-cell lymphoma having a significantly worse outcome. High-dose therapy and ABMT has produced effective consolidation of first remission in this group of patients, even in those with poor prognostic features at presentation.
Adolescent↗
Liposomal amphotericin B in the treatment of fungal infections in neutropenic patients: a single-centre experience of 133 episodes in 116 patients.
Liposomal amphotericin B (AmBisome) was used for suspected or confirmed fungal infection complicating 133 neutropenic episodes in 116 patients not tolerating, or not responding to, conventional amphotericin. Adverse effects were infrequent and no significant renal impairment resulted. Acute reactions occurred in five patients, reversible hepatic dysfunction in 23, and hypernatraemia in 17. The putative mycosis resolved with AmBisome treatment in 81 episodes (61%) and progressed with fatal outcome in 25 (19%), but the diagnosis was equivocal in most, and in 27 episodes (20%) evidence indicating nonfungal pathogenesis emerged. Treatment efficacy is, however, evaluable in those with proven aspergillosis. 13/17 patients with confirmed invasive aspergillosis responded to AmBisome (77%), conventional amphotericin having failed in 11. Treatment was successfully discontinued when the neutrophil count was < 1 x 10(9)/l in eight responders (61%). In four further patients treated for suspected aspergillosis, disseminated infection was documented at post-mortem, but the true incidence is unknown. This analysis confirms that AmBisome is well tolerated and effective against invasive mycoses in neutropenic patients, and may salvage patients when conventional amphotericin proves excessively toxic or ineffective.
Adolescent↗
Interferon-alpha up-regulates bcl-2 expression and protects B-CLL cells from apoptosis in vitro and in vivo.
The bcl-2 oncoprotein, which is involved in the t(14,18) translocation, protects cells against apoptosis. We examined the effects of interferon-alpha (IFN-alpha) on bcl-2 protein expression and apoptosis in B-chronic lymphocytic leukaemia (B-CLL) cells. None of 12 patients with B-CLL examined expressed the t(14,18) translocation; however, all these, and seven other patients, expressed significant levels of bcl-2 protein. In vitro, IFN-alpha (500 U/ml over 18 h) increased bcl-2 expression on CLL cells (to 200 +/- 23% of control MCF, as determined by indirect immunofluorescence and flow cytometry, n = 10, P < 0.001). All of eight patients who received IFN-alpha (3 megaunits subcutaneously three times a week) demonstrated an increase in bcl-2 expression on circulating malignant cells. CLL cells undergo apoptotic cell death when cultured in vitro (35.6 +/- 10.3% DNA fragmentation after 18 h, n = 10). In the presence of IFN-alpha, however, DNA fragmentation was reduced to 6.6 +/- 5.8% (n = 10, P < 0.001). IFN-alpha also protected CLL cells against apoptosis induced by hydrocortisone and gamma irradiation (reducing DNA fragmentation from 63.9 +/- 12.6% to 10.8 +/- 4.5% and from 80 +/- 2.9% to 5.4 +/- 1.6%, respectively, P < 0.001 for both). The protective effect of IFN-alpha was dose dependent, and maintained for up to 24 h. Our data demonstrate that bcl-2 expression and apoptosis of CLL cells can be influenced by cytokines. In addition, it seems unlikely that the observed clinical responses to IFN-alpha in patients with CLL are due to a direct effect on the malignant cells.
Apoptosis↗
Detection and significance of bone marrow infiltration at the time of autologous bone marrow transplantation in Hodgkin's disease.
Bilateral iliac crest biopsies were performed at the time of bone marrow (BM) harvest in patients with poor-risk Hodgkin's disease (HD) undergoing autologous bone marrow transplantation (ABMT). 67 consecutive patients with normal trephine biopsies (58 unilateral; nine bilateral) taken 2 weeks prior to harvest were studied. Nine (13%) of patients had BM infiltration with HD on the harvest biopsies. These patients had all previously had only unilateral biopsies. Three patients did not proceed to ABMT because disease progression became clinically apparent, but the remaining six patients were infused with involved marrow. One patient died 6 weeks post ABMT, with no evidence of disease at post-mortem. One patient showed no response to ABMT and four patients either had a partial or complete response to ABMT. Of the responders, three patients are now in complete remission at 53, 39 and 33 months past ABMT.
Adolescent↗
Myeloperoxidase activity and nuclear segmentation of maternal neutrophils during normal pregnancy.
Myeloperoxidase (MPO) activity and nuclear segmentation of neutrophils were measured in peripheral blood samples from 90 normal pregnant women, arranged in nine groups of ten each, every four weeks at 8-40 weeks gestation and from 25 non-pregnant healthy female controls. A blood autoanalyser (Technicon H*1) was used to determine the mean peroxidase index (MPXI) and the lobularity index (LI) of circulating neutrophils. Mean MPXI levels in pregnancy decreased with gestation to a minimum at 20 weeks' gestation and increased thereafter to reach non-pregnant levels at 36 weeks. Mean LI values did not change significantly with gestation, but were significantly lower throughout pregnancy compared to controls. There was no significant association between MPXI and LI. It could be postulated that the fall in MPXI during mid-gestation is due to degranulation of neutrophils and the subsequent rise at the end of pregnancy could be a consequence of enhanced MPO activity under the influence of oestrogens. Low LI suggests the production of immature neutrophils during pregnancy.
Cell Nucleus↗
Autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma and CNS involvement: those transplanted with active CNS disease have a poor outcome--a report by the European Bone Marrow Transplant Lymphoma Registry.
PURPOSE: CNS involvement of non-Hodgkin's lymphoma (NHL) has always been considered a poor prognostic factor in relation to survival with conventional therapy. However, its effect on the outcome of autologous bone marrow transplantation (ABMT) has not been assessed. We examined this using data from the European Bone Marrow Transplant (EBMT) Lymphoma Registry. PATIENTS AND METHODS: One thousand four hundred sixty-four patients with NHL have been reported to the EBMT registry, of whom 62 had CNS involvement. Patients were divided into those who were clear of CNS disease at the time of ABMT and those who were not. Response, complications, and outcome to ABMT were analyzed, as were details of CNS diagnosis, treatment, and prophylaxis. RESULTS: Status at transplant was the only factor that significantly affected outcome of ABMT on univariate analysis (P = .03). The progression-free survival (PFS) rate of the group that had no CNS involvement at ABMT was 42% at 5 years, compared with 27% in a group of stage IV NHL patients without CNS disease (matched for status at transplant and histology). There were four of 45 (8.9%) toxic deaths. The PFS rate of the group that had CNS involvement at ABMT was 9% at a median follow-up time of 71 months, which was significantly different (P = .001) from that of the other group. There were five of 17 (29.4%) toxic deaths (P = .043). Patients who had CNS involvement at diagnosis, as compared with relapse, and those treated with both intrathecal chemotherapy and irradiation had a better outcome. CONCLUSION: The presence of CNS disease before ABMT but not present at transplant does not adversely affect the outcome of ABMT. In contrast, patients with CNS involvement at the time of ABMT have a poor prognosis, although a small number survive in complete remission (CR).
Adolescent↗
High-dose therapy and autologous bone marrow transplantation for adult patients with lymphoblastic lymphoma: results of the European Group for Bone Marrow Transplantation.
PURPOSE: To investigate the results of treatment and factors that affect prognosis in adult patients undergoing high-dose therapy and autologous bone marrow transplantation (ABMT) for lymphoblastic lymphoma (LBL). PATIENTS AND METHODS: The study was a retrospective analysis of 214 patients reported to the Lymphoma Registry of the European Group for Bone Marrow Transplantation (EBMT) between January 1981 and December 1992, including 105 patients undergoing marrow transplantation in first complete remission (CR). Data on all patients were reviewed, and analysis of prognostic factors conducted. RESULTS: The actuarial overall survival rate at 6 years for the entire group is 42%. Disease status at ABMT was the major determinant of outcome: 6-year actuarial overall survival was 63% for patients transplanted in first CR, compared with 15% for those with resistant disease at the time of transplantation. Transplantation in second CR resulted in a 31% rate of actuarial overall survival at 6 years. For patients transplanted in first CR, univariate analysis failed to identify any factors at presentation that predicted for outcome after transplantation. CONCLUSION: These results suggest that ABMT is effective therapy for adults with LBL, even in patients with disease that is resistant to conventional-dose therapy. Results for patients transplanted in second CR are superior to those reported for conventional-dose salvage regimens. The results in first CR require verification in a prospective randomized clinical study.
Actuarial Analysis↗