摘要:

AbstractThis introductory statement to the International Symposium “Ten Years of Blood Stem Cell Transplantation in Heidelberg” provides the opportunity to review the experimental work that was necessary to set the stage for the first successful clinical studies to use blood‐derived stem cells to treat hemopoietic and other malignancies. The Ulm University research group used the preclinical canine model to systematically and extensively explore the possibilities and limitations of the therapeutic use of blood‐derived hemopoietic stem and progenitor cells. It became clear that blood stem cells are physiological elements of the circulating blood, that their concentration can be drastically increased by chemical and biological means, that they do not lose their function during appropriate cryopreservation, and that they can be “purified” and used successfully to restore hemopoiesis after myeloablative conditioning both in the autologous and allogeneic situation. If compared to fetal liver‐derived stem cells, there is excellent experimental evidence that fetal liver‐derived stem cells may have even more potential in their ability to restore hemopoiesis, and it is evident that much more experimental

ISSN:1066-5099    

DOI:10.1002/stem.5530130702

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe adequate production of blood cells is sustained by pluripotent hemopoietic progenitors whose behavior is influenced by a permissive hemopoietic microenvironment. Hemopoietic progenitors have in common the expression of CD34 surface molecules, but are heterogeneous with respect to other properties. It is commonly accepted that primitive progenitors, considered to be candidates for marrow repopulating cells, are HLA‐DR‐, without expressing lineage‐specific determinants. They are usually quiescent with respect to their cell cycle status. In addition to CD34, they may display adhesion molecules on their surface and express receptors for ligands such as c‐kit, FLT2/FLK3 and various other cytokines. Some of these are expressed constitutively, while others emerge as the cells progress through their regular maturation program. This process appears to include a gradual reduction of their proliferative capabilities as demonstrated by a progressive loss of the length of their telomeric str

ISSN:1066-5099    

DOI:10.1002/stem.5530130703

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractSince our initial report of successful peripheral blood stem cell transplantation (PBSCT) in a patient with acute myeloid leukemia (AML), we have performed more than 300 PBSCTs; 49 of them were done for AML patients. PBSC mobilization (and collection) was influenced by the number of previous courses of chemotherapy and significantly increased when G‐CSF was combined with chemotherapy for mobilization. Hematopoietic recovery (HR) was complete in every patient. The HR rate was influenced by the number of cells transplanted. Platelet recovery was significantly quicker for patients given G‐CSF for mobilization. The outcome of patients transplanted in first or second remission was similar to that usually observed after bone marrow transplantat

ISSN:1066-5099    

DOI:10.1002/stem.5530130704

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractAutologous peripheral stem cell transplantation was initiated at the University of Nebraska Medical Center to provide hematopoietic rescue for patients who were candidates for high‐dose therapy but had marrows that were unfit for autografting. From 1984 until 1991, the cells were collected during steady state without mobilization. These cells restored hematopoietic function at a rate similar to that of autologous marrow in patients not treated with total body irradiation. Patients who received total body irradiation experienced slower hematopoietic recovery. When growth factors became generally available in the United States in 1991, mobilization with cytokines became standard at Nebraska.In recent years, the function of cells other than hematopoietic progenitors contained in a peripheral stem cell apheresis product has been studied. Detection of tumor cells using cell culture, immunocytochemical and polymerase chain reaction techniques has revealed that such collections are less likely to contain, or contain fewer, tumor cells than autologous bone marrow harvests. More antitumor cytotoxic activity was found in cells in peripheral stem cell collections than in marrow cell collections. The immunocompetent lymphocyte population is larger in peripheral stem cell collection than in marrow harvests, and immunologic recovery after peripheral stem cell transplant has differed compared to recovery following bone marrow transplantation.The future of peripheral stem cell transplantation is likely to include engineering of the graft products specific for the patient and disease being treated. Determining the function of accessory cells in a peripheral stem cell collection will be important to provide the best engineered product for the patien

ISSN:1066-5099    

DOI:10.1002/stem.5530130705

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractBetween September 1991 and April 1995, high‐dose therapy with peripheral blood progenitor cell (PBPC) support was administered to 105 patients with non‐Hodgkin's lymphoma (NHL). Thirty‐three patients had high‐grade NHL, while 72 patients had different forms of low‐ or intermediate‐grade NHL. Except for three patients who received G‐CSF during steady‐state hematopoiesis, PBPCs were collected following cytokine‐supported cytotoxic chemotherapy. This included G‐CSF or the sequential administration of interleukin 3 (IL‐3) and GM‐CSF. Assessing bone marrow (BM) samples before the start of chemotherapy and leukapheresis (LP) products collected during cytokine‐enhanced marrow recovery, a 2.3‐fold greater mean concentration of CD34+cells was found in peripheral blood (p<0.005). The blood‐derived progenitor cells were enriched with a particular subset of more primitive progenitors, as the mean proportion of CD34+Thy‐1+cells in LP products was three‐fold greater in comparison to premobilization BM samples, respectively (p<0.001). In contrast, the mean proportion of CD34+/CD19+and CD19+cells in LP products was 8.8‐ and 80‐fold smaller compared to BM samples, respectively (p<0.001). Following high‐dose conditioning therapy including TBI in 74 patients, reinfusion of PBPC resulted in rapid and sustained engraftment in the majority of patients, while in seven patients an unsubstituted platelet count of greater than 20 x 109/1 was reached between 31 and 51 days. Five patients died of treatment‐related complications between 13 and 188 days following transplantation. The probability of long‐term disease‐free survival at 30 months in patients autografted while they were in first remission was 70% in high‐grade and 83% in low‐grade NHL, respectively. The data may provide the rationale for the use of PBPC‐supported high‐dose regimens as first‐line t

ISSN:1066-5099    

DOI:10.1002/stem.5530130706

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractIn June 1992, we started a dose‐escalated cytotoxic therapy with peripheral blood progenitor cell (PBPC) transplantation in patients with chemosensitive multiple myeloma (MM). At the time of best response to conventional treatment, 70 patients received high‐dose cyclophosphamide (HD‐CY) or, in case of pre‐existing heart disease, dose‐escalated ifosfamide/mitoxantrone followed by filgrastim (R‐metHuG‐CSF, 300 μg/day). PBPC collection was commenced when CD34+cells were detectable using direct immunofluorescence analysis. Fifty‐four out of 70 patients were successfully harvested ( 2.5 x 106CD34+cells/kg body weight [BW]) after the first cycle of HD chemotherapy. Conditioning therapy consisted of 140 mg/m2melphalan plus TBI (14.4 Gy hyperfractionated) or 200 mg/m2melphalan in patients not eligible for TBI because of previous radiotherapy. To date, 56 patients have been transplanted. Autografts contained a median of 3.4 x 106 CD34+cells/kg BW. Following reinfusion of PBPC, rapid engraftment was achieved in 54 out of 56 patients with a median of 14 days (range 9‐23) to reach 0.5 x 109/l neutrophils and 10 days (range 5‐22) for an unsubstituted platelet count of>20 x 109/l. One patient died of transplantation‐related complications. Sequential HD treatment improved the remission status (European Bone Marrow Transplantation criteria) in 19 out of 46 patients (9 patients too early). Of note, in 11 patients the immunofixation became negative and a polyclonal immunoglobulin reconstitution was achieved. Our protocol provides an effective treatment strategy for patients with advanced MM combined with low trea

ISSN:1066-5099    

DOI:10.1002/stem.5530130707

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractIt was the aim of this study to examine the prognostic value of the detection of minimal residual disease (MRD), with the help of the polymerase chain reaction (PCR), in patients with non‐Hodgkin's lymphoma (NHL) and multiple myeloma (MM) who underwent sequential high‐dose therapy with peripheral blood progenitor cell (PBPC) support, and in patients with acute myeloid leukemia (AML) of the subclass M4Eo who underwent high‐dose consolidation therapy. Basis for the application of a PCR assay in these disease entities are the following specific gene rearrangements: the t(14;18) translocation in a high percentage of NHL, the clonal rearrangement of the Ig heavy chain locus resulting in a unique complementary determining region 3 (CDR3) for MM region and the inversion 16 characteristic for the M4Eo subclass of AML. Before the G‐CSF‐supported cytotoxic chemotherapy was given, 65% of the 52 patients with low‐ and intermediate‐grade NHL enrolled into the study had PCR+bone marrow (BM) and/or peripheral blood (PB) samples. The majority of patients (29 of 52) were autografted with a PCR+transplant. The proportion of harvests containing t(14;18)+cells was two‐fold less in patients mobilized in first remission than in those with a history of previous treatment failure. This was also reflected when examining the B cell contents of the harvests measured as CD19+cells with a 3.3‐fold smaller proportion of CD19+cells in leukapheresis (LP) products of patients mobilized in first remission. Patients who received a PCR‐transplant are in remission and remained PCR‐in BM and PB samples post‐transplantation. Conversion to PCR‐negativity in BM and PB samples post‐transplantation was observed in 11 of 19 patients who were also in remission. In contrast, 6 of 29 patients who were autografted with PCR+products relapsed, while 4 of them presented with PCR‐samples on several occasions post‐transplantation. In patients with MM, the assessment of MRD in PBPC harvests was based on the CDR3 regions of the Ig heavy chain locus as a marker for clonality. The great majority of LP products (17 out of 19) contained tumor cells. To prove positive enrichment procedures for the elimination of tumor cells, CD34+and CD19+cell fractions obtained from LP samples in an experimental setting via preparative flow cytometry were analyzed for MRD resulting in PCR‐negativity for all CD34+fractions. The results of the four patients with AML M4Eo and inversion 16 are preliminary, with a tendency of persistence of PCR‐positivity after finishing the high‐dose consolidation therapy. In one case, recurrence of disease was accompanied by an increase of the signal strength in the PCR assay. Longer follow‐up periods are necessary to determine the prognostic value of these PCR fin

ISSN:1066-5099    

DOI:10.1002/stem.5530130708

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe shortage of HLA‐matched sibling donors for bone marrow transplant patients has stimulated interest in the use of alternative donors. As a result, there has been a dramatic increase in the use of autologous marrow transplantation, which avoids the complications of graft‐versus‐host disease, but may deprive the patient of a potentially beneficial graft‐versus‐disease response and runs the risk of returning occult tumor cells with the graft. There is increasing evidence that these cells may be associated with disease relapse post‐transplant, and many methods have been developed for their removal ex vivo. Combinations of negative and positive selection may achieve elimination of tumor cells to the limits of detection of the most sensitive assays currently available. The marked trend toward the use of autologous grafts derived from blood rather than marrow has raised the question as to whether peripheral blood stem cell (PBSC) preparations should be purged of tumor. Data indicate that these grafts generally contain a lower tumor burden, although the stem cell mobilization procedure may recruit tumor cells into the peripheral circulation. Enrichment of CD34+cells from apheresis products appears, at present, to be less efficient than from marrow and provides at best about a 2‐3 log depletion of tumor. This has prompted proposals to follow positive selection by a small‐scale purging procedure. Technical issues, such as preprocessing and pooling of collections prior to purging, remain to be addressed. Ultimately, the development of successful purging procedures for PBSC grafts will simply reemphasize the necessity of improving the efficacy of hi

ISSN:1066-5099    

DOI:10.1002/stem.5530130709

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractRecombinant G‐CSF has been given to over 150 normal donors for the collection of allogeneic or syngeneic peripheral blood stem cells (PBSCs). G‐CSF was found to be well‐tolerated with mild‐moderate bone pain, edema and mild thrombocytopenia being the observed side effects. To date, approximately 100 unmodified primary PBSC transplants from HLA‐identical related donors have been performed with engraftment that is, in general, considerably more rapid than marrow. Acute graft‐versus‐host‐disease (GVHD) grades II — IV occurred in 44% of patients and grades III — IV in 16%. From a small number of evaluable patients surviving for more than 100 days, it appears the incidence of chronic GVHD is approximately 50%. Despite the infusion of one to two logs more T cells, these results are not remarkably different than would be expected with marrow transplantation. Further studies are needed to define the role of allogeneic PBSCs for transplantation, to refine PBSC mobilization and collection techniques, and to evaluate the long‐term effects of cytok

ISSN:1066-5099    

DOI:10.1002/stem.5530130710

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThalassemia is widely distributed throughout the world and is one of the major public health problems. The use of bone marrow transplantation, the only curative therapy for thalassemia, is limited because less than 30% of the patients have unaffected and HLA‐identical siblings as donors. Cord blood stem cells, an alternative source of stem cells for transplantation, have been successfully transplanted into patients with several diseases after myeloablative therapy. Twenty cord blood samples from unaffected neonates whose siblings had severe thalassemia were collected. The median volume was 80 ml. The median number of cells and colony forming units‐granulocyte‐macrophage in cord blood was 9.2 x 1018and 3.4 x 105, respectively. Four of 20 cord blood samples had HLA‐matched to the affected siblings. One patient underwent cord blood transplantation with success; one patient is waiting for transpla

ISSN:1066-5099    

DOI:10.1002/stem.5530130711

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY