Rachel M. Pearce

Allogeneic bone marrow transplant is not better than autologous transplant for patients with relapsed Hodgkin's disease. European Group for Blood and Bone Marrow Transplantation.

PURPOSE To compare the results achieved with myeloablative therapy followed by either allogeneic bone marrow transplantation (alloBMT) or autologous bone marrow transplantation (ABMT) for patients with Hodgkins disease (HD). PATIENTS AND METHODS Of more than 1,200 patients with HD reported to the European Bone Marrow Transplantation (EBMT) registry, 49 underwent alloBMT. Of these, 45 with sufficient data were matched to 45 patients who underwent ABMT. The matching criteria were sex, age at time of transplantation, stage of disease at diagnosis, bone marrow involvement at diagnosis and at transplantation, year of transplantation, disease status at time of transplantation, time from diagnosis to transplantation, and conditioning regimen with or without total-body irradiation (TBI). RESULTS The 4-year actuarial probabilities of survival, progression-free survival (PFS), relapse, and non-relapse mortality were 25%, 15%, 61%, and 48% and 37%, 24%, 61%, and 27% after alloBMT and ABMT, respectively. The toxic death rate at 4 years was significantly higher for alloBMT patients (P = .04). For patients with sensitive disease at the time of transplantation, the 4-year actuarial probability of survival was 30% after alloBMT and 64% after ABMT (P = .007). This difference is mainly due to a higher transplant-related mortality rate after alloBMT (65% v 12%, P = .005). Acute graft-versus-host disease (aGVHD) > or = grade II was associated with a significantly lower risk of relapse, but also with a lower overall survival (OS) rate. CONCLUSION Based on this study, alloBMT from a human leukocyte antigen (HLA)-identical sibling donor does not appear to offer any advantage when compared with ABMT. A graft-versus-Hodgkin effect is associated with > or = grade II aGVHD, but its positive effect on relapse is largely offset by its toxicity. In most circumstances, alloBMT cannot be recommended for patients with HD.

Progenitor-cell mobilization after low-dose cyclophosphamide and granulocyte colony-stimulating factor: An analysis of progenitor-cell quantity and quality and factors predicting for these parameters in 101 pretreated patients with malignant lymphoma

PURPOSE To define parameters that predict for rapid engraftment after peripheral-blood stem-cell (PBSC) transplantation, progenitor thresholds, the proportion of patients who achieve these thresholds with a standardized mobilization regimen, and the factors that predict for mobilization efficiency. PATIENTS AND METHODS One hundred and one patients with pretreated lymphoma were mobilized with cyclophosphamide 1.5 g/m2 and granulocyte colony-stimulating factor (G-CSF), with the first apheresis performed when the recovery WBC count was > or = 5.0 x 10(9)/L. The relationship between the number of progenitor cells collected and patient age, sex, diagnosis, prior radiotherapy, and time since last chemotherapy was determined by multivariate analysis. The relationship between these factors, progenitor numbers returned, post-PBSC G-CSF, and hematologic recovery was performed in 81 patients following chemotherapy with carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM protocol). RESULTS No BEAM recipients had delayed neutrophil recovery beyond 28 days. Delayed platelet recovery occurred in 7.4% and minimum and optimum thresholds of 1 x 10(6) and 3.5 x 10(6) CD34+ cells/kg and 1 x 10(5) and 3.5 x 10(5) granulocyte-macrophage colony-forming cells (GM-CFC)/kg were established. Hematologic recovery was adversely affected by prior treatment with mini-BEAM, and neutrophil recovery was accelerated by post-PBSC G-CSF. The minimum GM-CFC threshold was achieved with a single apheresis in 83% of patients and in 90% with two aphereses. The optimal threshold was achieved with two leukaphereses in 69% of patients. Prior radiotherapy adversely affected mobilization. CONCLUSION Hematopoietic recovery following PBSC is dependent on progenitor-cell number infused and affect of previous chemotherapy on progenitor quality. Progenitor-cell mobilization is adversely affected by prior radiotherapy. The minimum threshold of GM-CFC required is achieved in most patients with a single apheresis, but an optimal collection usually requires at least two harvests.

Genetic variants of platelet glycoprotein receptors and risk of stroke in young women

BACKGROUND AND PURPOSE A number of studies have examined the relationship between genetic platelet glycoprotein variants and early-onset atherothrombotic disease, particularly acute myocardial infarction. Data on the association of these genetic susceptibility markers with ischemic stroke are more limited, and their role in hemorrhagic stroke has not been previously examined. METHODS We performed genotype analysis for 5 common diallelic platelet glycoprotein polymorphisms in a population-based study of 78 white women aged <45 years with arterial stroke (36 ischemic cases and 42 hemorrhagic cases) and 346 demographically similar control subjects. RESULTS The 807T variant of glycoprotein Ia was associated with a 2-fold increased risk of ischemic stroke (age-adjusted odds ratio [OR]=2.24; 95% CI=0.99 to 5.06). The Met(145) allele of glycoprotein Ibalpha was associated with a trend toward an increased risk of ischemic stroke that was more pronounced in the homozygous state (OR=10.36), but the CI is extremely wide because of the small numbers of subjects (95% CI=1.43 to 79.34). Homozygosity for the Ser(843) allele of the glycoprotein IIb was associated with an approximately 5-fold increased risk of ischemic stroke among subgroups of women who carried a diagnosis of hypertension or diabetes (OR=4.51; 95% CI=1.01 to 20.13) or had elevated plasma homocysteine levels (OR=5.94; 95% CI=1.53 to 23.05). The genotype distributions for all 5 platelet glycoprotein polymorphisms were similar among hemorrhagic stroke cases and controls. CONCLUSIONS Several inherited platelet glycoprotein variants may be associated with an increased risk of ischemic stroke in young women. These associations seemed to be confined to women with other cardiovascular risk factors. Additional studies involving larger numbers of subjects are needed to confirm these preliminary findings.

Adult Burkitt's and Burkitt-like non-Hodgkin's lymphoma--outcome for patients treated with high-dose therapy and autologous stem-cell transplantation in first remission or at relapse: results from the European Group for Blood and Marrow Transplantation.

PURPOSE To investigate the results of treatment for adult patients with Burkitts and Burkitt-like non-Hodgkins lymphoma (NHL) undergoing high-dose therapy and autologous stem-cell transplantation (ASCT), and to determine prognostic factors for this group. PATIENTS AND METHODS A retrospective analysis of 117 adult patients reported to the lymphoma registry of the European Group for Blood and Marrow Transplantation (EBMT) between June 1984 and November 1994. Seventy of these patients received high-dose therapy and stem-cell transplantation in first complete remission (CR). Data on all patients were reviewed, and prognostic factors were determined by univariate and multivariate analysis. RESULTS The actuarial overall survival (OS) rate for the entire group was 53% at 3 years. The major factor predicting for outcome after transplantation was disease status: the 3-year actuarial OS rate was 72% for patients transplanted in first CR, compared with 37% for patients in chemosensitive relapse, and 7% for chemoresistant patients. For patients transplanted in first CR, disease bulk at the time of ASCT was the only factor predictive of progression-free survival (PFS) and OS. CONCLUSION The results of high-dose therapy and ASCT for patients with relapsed disease, particularly chemosensitive relapse, are superior to those reported for conventional-dose salvage regimens. The results for patients transplanted in first CR require comparison with modern dose-intensive regimens.

Purging of bone marrow in autologous bone marrow transplantation for non-Hodgkin's lymphoma: a case-matched comparison with unpurged cases by the European Blood and Marrow Transplant Lymphoma Registry.

PURPOSE The use of in vitro purging of bone marrow in autologous bone marrow transplantation (ABMT) for non-Hodgkins lymphoma (NHL) has been a controversial issue; its benefit is as yet unproven. Its effect on the clinical outcome of ABMT in these patients is still unclear. We look at this issue using data from the European Blood and Marrow Transplant (EBMT) Lymphoma Registry. PATIENTS AND METHODS Seventeen hundred twenty-six patients with NHL have been reported to the EBMT registry, of whom 270 had bone marrow purged at transplant. Two hundred twenty-four of these patients were compared with a case-matched group of 224 unpurged patients who had undergone the same procedure. The case matching was made following selection of the main prognostic factors for progression-free survival (PFS) by multivariate analysis. Response, complications, and outcome in ABMT were analyzed. RESULTS Time to hematologic engraftment, response to ABMT, and number of procedure-related deaths were similar in purged and unpurged patients. The overall survival (OS) rate was 54% at 5 years in purged patients and 48.3% in unpurged patients (P = .1813). The PFS rate was 44.3% and 44.6%, respectively (P = .1961). Patterns of relapse, including bone marrow relapse, were similar in both groups. Patients with low-grade lymphoma did not have a significantly improved PFS if the bone marrow was purged (P = .1757); however, they did have a significantly improved OS (P = .00184). This increased OS was found to be associated with non-totalbody irradiation (TBI) conditioning and also with the purged patients undergoing transplantation at large transplant centers (P = .0016). CONCLUSION Purging of bone marrow in ABMT for NHL does not affect the rate of hematologic engraftment or risk of procedure-related death (PRD). There is no significant difference in PFS for patients whose bone marrow is purged as compared with unpurged.

Peripheral-blood stem-cell transplantation versus autologous bone marrow transplantation in Hodgkin's and non-Hodgkin's lymphomas: a new matched-pair analysis of the European Group for Blood and Marrow Transplantation Registry Data. Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.

PURPOSE To address the question of short-term and long-term advantages of peripheral-blood stem-cell transplantation (PBSCT) over autologous bone marrow transplantation (ABMT), we have reviewed the data of 3,214 patients with lymphoma, 2,859 undergoing ABMT, and 355 undergoing PBSCT. PATIENTS AND METHODS Analysis of prognostic factors for progression-free survival (PFS) was conducted separately for non-Hodgkins lymphoma (NHL) (N = 1,915) and Hodgkins disease (HD) (N = 1,299). In multivariate analysis, the relevant factors were status at transplant for NHL and sex, size of largest mass at transplant, status at transplant, and conditioning regimen for HD. The pair analysis was carried out by matching NHL and HD patients separately by their prognostic factors. Additionally, NHL patients were matched for histology, whereas both HD and NHL patients were matched for date of transplant. With this method, 454 patients were matched in the NHL group and 256 were matched in the HD group. RESULTS The overall survival (OS) and PFS unexpectedy were better for ABMT versus PBSCT patients in the HD group (OS, 65.3% at 4 years for ABMT v 52.7% for PBSCT; P = .0198). There was no difference in OS or PFS in the NHL group (OS, 56.6% at 4 years for ABMT v 52.7% for PBSCT; P = .4148). The overall relapse or progression rate at 4 years for NHL was 42% after ABMT and 49.2% after PBSCT (P = .1220); for HD, it was 40% and 58.6%, respectively (P = .0164). Transplant-related mortality was lower, but not significantly, with PBSCT: 7.0% for ABMT versus 3.5% for PBSCT in NHL (P = .1356) and 7% for ABMT versus 4.7% for PBSCT in HD (P = .6056). Hematologic recovery occurred faster significantly with PBSCT irrespective of disease. CONCLUSION This study confirms the advantage of PBSCT in terms of hematopoietic reconstitution, but it fails to show any superiority in the long term. Poorer results for both progression free and overall survival observed in HD patients who are receiving PBSCT are unexplained and should be confirmed with randomized studies.

Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant

Disease relapse following an allogeneic transplant remains a major cause of treatment failure, often with a poor outcome. Second allogeneic transplant procedures have been associated with high TRM, especially with myeloablative conditioning. We hypothesized that the use of reduced-intensity conditioning (RIC) would decrease the TRM. We performed a retrospective national multicentre analysis of 71 patients receiving a second allogeneic transplant using RIC after disease relapse following an initial allogeneic transplant. The majority of patients had leukaemia/myelodysplasia (MDS) (N=57), nine had lymphoproliferative disorders, two had myeloma and three had myeloproliferative diseases. A total of 25% of patients had unrelated donors. The median follow-up was 906 days from the second allograft. The predicted overall survival (OS) and TRM at 2 years were 28 and 27%, respectively. TRM was significantly lower in those who relapsed late (>11 months) following the first transplant (2 years: 17 vs 38% in early relapses; P=0.03). Two factors were significantly associated with a better survival: late relapse (P=0.014) and chronic GVHD following the second transplant (P=0.014). These data support our hypothesis that the second RIC allograft results in a lower TRM than using MA. A proportion of patients achieved a sustained remission even when relapsing after a previous MA transplant.

Outcome following Reduced-Intensity Allogeneic Stem Cell Transplantation (RIC AlloSCT) for relapsed and refractory mantle cell lymphoma (MCL): a study of the British Society for Blood and Marrow Transplantation.

Reduced-intensity allogeneic stem cell transplantation (RIC-AlloSCT) is being increasingly considered for patients with aggressive lymphoma, but limited evidence exists in mantle cell lymphoma (MCL). We report a retrospective study of transplant outcomes of RIC-AlloSCT for MCL in 70 patients (median age, 48 years, range: 30-67 years), with 57 patients receiving an Alemtuzumab-containing regimen. Thirty-four percent of patients had received a prior autologous stem cell transplant. The 1- and 5-year nonrelapse mortality (NRM) was 18% (95% confidence interval [CI] 10-27) and 21% (95% CI 12-31), respectively. The incidence of severe (grade III and IV) acute graft-versus-host disease (aGVHD) was 10%, and the 5-year incidence of chronic GVHD (cGVHD) was 61%. The cumulative relapse risk was 65% (95% CI 48-77) at 5 years, significantly affected by disease status at transplant (P = .0495), specifically the presence of chemosensitive disease (P = .0364). Fifteen of 18 relapsed patients received donor lymphocyte infustion (DLI) (n = 14) or a second RIC-AlloSCT (n = 1), with 11 of 15 currently in CR. The 5-year overall survival (OS) and progression-free survival (PFS) were 37% (95% CI 25%-56%) and 14% (95% CI 6%-34%), respectively. Age at transplantation and having <2 prior lines of therapy influenced the OS, whereas having <2 prior lines of therapy was the only factor to influence PFS. The use of Alemtuzumab in the conditioning was associated with an improved OS at 3 years (P = .0271). RIC-AlloSCT is a potential treatment modality for aggressive MCL. For patients relapsing post-AlloSCT, the disease is salvageable with DLI. The timing of RIC-AlloSCT should be explored in prospective studies to establish the optimal role in the management of this aggressive lymphoma.

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.

The role of allogeneic SCT in primary myelofibrosis: a British Society for Blood and Marrow Transplantation study

Fifty-one patients with primary myelofibrosis (PMF) received allogeneic haematopoietic stem cell transplants from related (n=33) or unrelated (n=18) donors. Twenty-seven patients, 19–54 years old, were prepared with myeloablative regimens including CY plus BU (n=4) or TBI (n=23). Twenty-four patients, 40–64 years old, received reduced-intensity conditioning (RIC) regimens. All RIC regimens contained fludarabine, combined with melphalan (n=19) or BU (n=5), and alemtuzumab or anti-thymocyte globulin (ATG) in the majority (n=19). Four patients (17%) in the RIC group had primary graft failure. Previous splenectomy reduced time to engraftment in the RIC group (13 versus 20 days; P=0.008). For MA and RIC groups, respectively, at 3 years, overall survival rates were 44 and 31% (P=0.67), progression-free survival 44 and 24% (P=0.87), and actuarial relapse rates 15 and 46% (P=0.06). Non-relapse mortality at 3 years was 41% for the myeloablative and 32% for the RIC group. Acute GVHD occurred in 29 and 38% of patients in the myeloablative and RIC groups, respectively. Extensive chronic GVHD developed in 30 and 35% of evaluable patients, respectively.