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At least 19 recordsLinked to original sources
PubMed1993

Bone marrow purging for autologous bone marrow transplantation.

High dose therapy with the resulting myeloablation rescued by infusion of autologous bone marrow (ABMT) has become a major treatment option for an increasing number of patients with hematologic and solid tumors. ABMT has several potential advantages over allogeneic transplantation. However, the major obstacle to the use of ABMT is that the infusion of occult tumor cells harbored within the harvested marrow would result in more rapid relapse of disease. To minimize the effects of the infusion of significant numbers of malignant cells, marrow for ABMT is obtained when the patient is either in complete remission or when there is no histologic evidence of bone marrow infiltration of disease. There is increasing evidence that minimal numbers of malignant cells can be detected within the remission marrow of these patients, particularly when assessed by sensitive clonogenic assays or polymerase chain reaction amplification. A variety of methods, pharmacologic and immunologic have been developed to "purge" malignant cells from the marrow. The aim of purging is to eliminate any contaminating malignant cells and leave intact the hematopoietic stem cells that are necessary for engraftment. Although the rationale for removing any contaminating cells from the autologous marrow appears compelling, the issue of purging remains highly controversial. Intense argument persists as to whether attempts to remove residual tumor cells from the harvested bone marrow have contributed to improving disease-free survival in these patients. To date there have been no clinical trials testing the efficacy of purging by comparison of infusion of purged versus unpurged autologous bone marrow. This is due primarily to the large number of patients that would be required for such studies.

Bone Marrow Purging↗
PubMed1989

In vitro synergism of 4-hydroperoxycyclophosphamide and cisplatin: relevance for bone marrow purging.

Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide (4-HC)-purged bone marrow gives long-term remission in almost half of relapsed acute nonlymphocytic leukemia and non-Hodgkin's lymphoma patients, but relapse of disease is the main cause of failure, suggesting ineffective purging in some cases. Cisplatin (CP) has activity against a variety of human tumors and is not commonly used for initial therapy of leukemia and lymphoma. Using established human leukemia cell lines, combinations of 4-HC and CP were investigated as a potential regimen for improving the ex vivo removal of leukemia cells from bone marrow. The cell lines (K-562 and Raji) were incubated for 1 (4-HC) or 4 h (CP), washed, and assayed for inhibition of colony formation in semisolid media. In both cell lines, CP (4h) was more potent than 4-HC (1 h). Combinations of the drugs in various molar ratios were studied after the cells were sequentially incubated with 4-HC and CP. The effects of the drugs were analyzed using the multiple drug-effect analysis of Chou and Talalay. Analysis of data on in vitro inhibition of colony formation suggested that all combinations studied were synergistic in both cell lines, with the greatest synergism being found in the Raji cell line. In addition, for K-562 cells we could detect at least a 4.6 log reduction in cloning with the CP:4-HC combination (1:10 molar ratio). We conclude that CP is a potential candidate in drug combinations for ex vivo bone marrow purging because of its high potency against human leukemia cell lines, its synergistic activity in combination with 4-HC, and its ability to reduce a high tumor burden when combined with 4-HC.

Bone Marrow↗
PubMed1995

Plasma interacts with mafosfamide toxicity to normal haematopoietic progenitor cells: impact on in vitro marrow purging.

Bone marrow purging with cyclophosphamide derivatives in autologous bone marrow transplantation has demonstrated that the killing of leukemic cells and simultaneous preservation of normal progenitor cells depends on a number of parameters, in particular the haematocrit, nucleated cell concentration and nature of the cells. We have previously described a reliable experimental procedure for in vitro bone marrow treatment, based on individual adjustment of the drug dosage. The present study reveals an inhibitory action of plasma on the toxicity of mafosfamide to normal haematopoietic progenitor cells. In an initial series of 42 successive patients, determination of the CFU-GM lethal dose 95% (CFU-GM LD 95) showed this parameter to be inversely correlated to the nucleated cell concentration (NCC) (p < 0.001). Assuming the plasma content of the buffy coat cells (BC) to be higher in the less rich marrow samples, we then investigated the role of plasma in progenitor cell sensitivity to the drug. Results were as follows: (1) in the presence of 60% autologous or allogeneic plasma, CFU-GM LD 95 was increased by a factor of 2.18 +/- 0.35 or 1.98 +/- 0.23 respectively as compared to controls in a solution of 2% bovine serum albumin (p = 0.014), (2) this observation remained valid whatever the origin of the plasma and (3) the same was true whatever the nature of the cells, derived from normal donors or patients with haematological malignancies. These data suggest that plasma contains an inhibitor(s) of mafosfamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Application of serum-free liquid bone marrow cultures to bone marrow purging for autologous bone marrow transplantation in acute lymphoblastic leukemia.

We have previously established a serum-free (SF) culture medium which allows normal haematopoietic progenitor cells to be maintained for at least 4 weeks as in the conventional serum dependent SD) medium. In the present study we investigated the efficiency of the SF liquid system to sustain normal residual haemopoiesis to the detriment of the leukemic population in patients with ALL. Probes for a potential selective effect were brought through leukemic progenitor cell assay (CFU-ALL) and the polymerase chain reaction (PCR) study of the bcr/abl translocation. In 13 experiments done in 12 patients, morphological blast cells and the ALL-CFU were dramatically reduced within 3 weeks of incubation in both SF and SD cultures. In 5/5 experiments in SD conditions and 2/5 experiments in SF conditions, leukemic cells expressing the bcr/abl fusion gene also disappeared within the same period. There was no difference in the CFU-GM production between SF and SD mediums. Erythropoiesis exhibited a slower decline in conditions SF, compared to the conditions SD. These results indicate that the liquid marrow culture may selectively deplete the leukemic lymphoblastic cells and enable repopulation by residual normal hemopoietic cells. It may be useful to purge leukemic cells for clinical autologous bone marrow transplantation in patients with ALL.

Bone Marrow Cells↗
PubMed1994

Differential effect of 4-hydroperoxycyclophosphamide and antimyeloid monoclonal antibodies on T and natural killer cells during bone marrow purging.

Autologous bone marrow (BM) transplantation after high dose therapy is widely used to treat acute leukemia, lymphoma, and selected solid tumors. In studies of BM purging with chemical agents, monoclonal antibodies (MoAbs), or other agents, the emphasis has been on the efficacy of tumor cell removal and sparing of hematopoietic progenitor cells. Two commonly used methods of BM purging for patients with acute myeloid leukemia have been the drug 4-hydroperoxycyclophosphamide (4-HC) and (MoAbs) directed to myeloid antigens such as CD14, CD15, and CD33. Although both methods of BM purging have potent activity against leukemia cells, 4-HC is also quite toxic to normal hematopoietic progenitor cells in the same concentrations that are used to deplete leukemia cells. To further characterize the cellular composition of BM after purging, we examined the effects of MoAbs plus complement and 4-HC on cells of the lymphoid lineage in the BM. 4-HC exerted a concentration-dependent cytotoxicity on clonogenic T lymphocytes, natural killer (NK) cells, and lymphokine (interleukin-2)-activated killer (LAK) cells, whereas the anti-CD14 and anti-CD15 MoAbs had little effect. At a concentration of 4-HC commonly used for BM purging (60 micrograms/mL), there were 4 to 5 logs of T-cell depletion and almost complete elimination of NK- and LAK-cell activity. In contrast, 4-HC at low concentrations (eg, 3 micrograms/mL) spared the majority of lymphoid cells suggesting that low concentration 4-HC combined with MoAb purging may be a desirable alternative to higher concentration 4-HC. These data indicate that purging with antimyeloid MoAbs, but not with 4-HC, spares the function of mature graft lymphocytes. Infusion of viable lymphocytes may be important for the transfer of immune memory against microbial and neoplastic antigens and may hasten immune reconstitution. In addition, mature graft lymphocytes may also be selectively activated and expanded in conjunction with interleukin-2 administration after BM transplantation.

Antibodies, Monoclonal↗
PubMed1987

Low antigen density tumor cells: an obstacle to effective autologous bone marrow purging?

Autologous bone marrow transplantation is a potentially curative approach to the treatment of various tumors that are refractory to conventional therapies. A major problem associated with the procedure is the possibility of tumor cell contamination in the autologous graft used to reconstitute the patient's immune system after supralethal chemoradiotherapy. A variety of different approaches to eliminating tumor cells from bone marrow have been proposed and tested. These include destruction of tumor cells with antibody and complement, use of antibody conjugated to drugs or toxins, and the physical separation of antibody-coated tumor cells by attachment to magnetic microspheres. Each of these approaches has different limitations and technical problems. One problem common to all, however, is that the tumor cells most likely to avoid removal are those demonstrating a low level of surface antigen. In this paper we have offered a practical approach to amplifying the unique surface antigen expression in order to enable this elusive tumor cell population to be eliminated. The approach proposed is adaptable to all the techniques currently being studied, since it is designed to add additional antigens to tumor cells which can then be used as targets at which to direct the various purging strategies.

Antibodies, Monoclonal↗
PubMed1996

Adenovirus-mediated gene transfer to human breast tumor cells: an approach for cancer gene therapy and bone marrow purging.

To examine the potential use of adenovirus vectors in cancer gene therapy as a mechanism for purging bone marrow cells of possible breast cancer contaminants, we compared the infection efficiency of adenovirus and the transfection efficiency of plasmid DNA in the presence of adenovirus in human breast cancer and bone marrow cells. Following infection of breast cancer cells with an adenovirus expressing beta-galactosidase gene, high levels of beta-galactoside activity were observed. No beta-galactosidase activity was observed in low-density human bone marrow cells. A replication-deficient adenovirus mutant dl312 enhanced the transfection efficiency of a plasmid DNA-expressing beta-galactosidase gene into breast cancer cells, and addition of a liposome, lipofectamine, further enhanced the transfection efficiency. In contrast, human bone marrow cells treated under the same conditions expressed very low levels of transfected beta-galactosidase DNA. Transfection of cells with plasmid DNA expressing a truncated but fully active Pseudomonas exotoxin gene in the presence of dl312 and lipofectamine resulted in marked breast cancer cell killing, whereas colony-forming unit granulocyte-macrophage (CFU-GM) were relatively resistant to these treatments. A recombinant adenovirus expressing human wild-type p53 protein (AdWTp53) was also highly cytotoxic to breast tumor cells. Infection of breast cancer cells with AdWTp53 (100 plaque-forming units/cell) resulted in 100% loss of the clonogenicity of breast tumor cells. However, colony formation from CFU-GM was relatively resistant to the cytotoxic effects of AdWTp53 alone or in the presence of pULI100 plasmid and lipofectamine. On the basis of these results, it is proposed that human adenoviruses are potentially useful for cancer gene therapy and bone marrow purging.

ADP Ribose Transferases↗
PubMed1990

CD9 is an unreliable antibody for bone marrow purging.

Various procedures are useful in purging bone marrow of pre-B lineage contamination prior to autologous bone marrow transplantation. Specific monoclonal antibodies are used in combination with complement, magnetic microspheres, chemotoxins, phototherapy or lectins. In this setting, the usual monoclonal antibody cocktail consists of CD9 (DU-ALL-1), CD10 (WCMH 15.14) and CD19 (HD37). Antigens reacting with all three monoclonal antibodies are present on early and mature pre-B lymphocytes. However, CD9 positive antigens have also been shown to be present on megakaryocytes, platelets and mature granulocytes. In our studies, we have found that CD10 and CD19 expression predictably vary according to disease status, with low positivity in remission and higher positivity in relapse. CD9 expression, however, varies independently of disease status and is frequently inconsistent within individual patients. As such, use of CD9 for marrow purging may result in the removal of a broad range of cell populations not related to the underlying disorder.

Antibodies, Monoclonal↗
PubMed1998

Autologous bone marrow transplantation for acute myeloid leukemia using 4-hydroperoxycyclophosphamide-purged bone marrow and the busulfan/etoposide preparative regimen: a follow-up report.

We studied the use of autologous bone marrow transplantation (ABMT) as treatment for acute myeloid leukemia (AML) in adults up to age 60. We used a preparative regimen of busulfan 16 mg/kg plus etoposide 60 mg/kg and bone marrow purged with 100 microg/ml of 4-hydroperoxycyclophosphamide (4HC). We treated 50 first remission patients; there were two treatment-related deaths and 13 relapses. With median follow-up of 6.8 years (minimum 4.5) disease-free survival (DFS) is 70%, relapse rate 27% and overall survival 72%. Patients with favorable cytogenetics had DFS 78% and relapse 18% whereas unfavorable patients had DFS 63% and relapse rate 35%. For 25 patients in second or third remission there were five treatment-related deaths and seven relapses. DFS is 52% and relapse rate 35%. None of six patients with primary refractory AML had long-term disease control. These data support the use of ABMT with an intensive preparative regimen and purged bone marrow as a highly effective treatment for adults with AML.

Acute Disease↗
PubMed1994

Bone marrow purging in acute leukemia with alkyl-lysophospholipids: a new family of anticancer drugs.

The alkyl-lysophospholipids are a new family of anticancer drugs which target the cell membrane as their site of action. Enzymes involved in signal transduction (protein kinase C and phosphatidylinositol phospholipase C), phospholipid biosynthesis (lysophosphatidyl acyltransferase and CTP:cholinephosphate cytidylyltransferase) and maintenance of membrane integrity (Na,K ATPase sodium pump) are inhibited. A unique feature of the alkyl-lysophospholipids is their selective cytotoxicity to neoplastic cells. This suggests that the compound would be an excellent agent for purging residual leukemic cells from marrows of patients in remission prior to autologous bone marrow transplantation. Preclinical studies in a murine leukemia model and in an in vitro human system demonstrated successful elimination of leukemic cells from a mixture of normal and leukemic marrows. Twenty-nine poor risk patients with acute leukemia underwent autologous bone marrow transplantation and were reinfused with marrow treated in vitro with edelfosine. Nine of these patients remain in remission free of leukemia from 368 to 1369 days. These encouraging results warrant further investigation.

Antineoplastic Agents↗
PubMed1990

Bone marrow purging by a xanthine oxidase-antibody conjugate.

The selective cytotoxicity of the xanthine oxidase conjugated to an 8A monoclonal antibody recognizing a human plasma cell-associated antigen has been described. The selectivity and the toxicity of the hypoxanthine/conjugated xanthine oxidase system was increased by removing the excess of conjugate and by adding chelated iron. Under these experimental conditions the cytotoxicity of the conjugate exceeded that of free xanthine oxidase by one order of magnitude. The conjugate effectively purged bone marrow from infiltrating neoplastic plasma cells and added target Raji cells, provided blood was removed and bone marrow peroxidases were exhausted. In conditions of purging effectiveness the conjugate had no toxicity to CFU-GM. No toxicity to mice was observed after i.v. injection of xanthine oxidase-antibody conjugate up to 2.9 U/kg body weight. Thus the hypoxanthine/conjugated xanthine oxidase system could be an effective and nontoxic tool for the ex vivo bone marrow purging in multiple myeloma patients for autologous transplantation.

Antibodies, Monoclonal↗
PubMed1987

CFU-GM content of bone marrow graft correlates with time to hematologic reconstitution following autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide-purged bone marrow.

Autologous bone marrow transplants (BMTs) can repopulate the hematologic system of patients treated with marrow-ablative chemotherapy and/or radiotherapy. However, treatment of the bone marrow graft to eliminate residual tumor cells prior to reinfusion can delay the return of peripheral blood elements, presumably from damage to or loss of hematopoietic stem cells responsible for hematologic recovery. To develop a model predictive of hematologic recovery, we studied the progenitor cell contents of 4-hydroperoxycyclophosphamide (100 micrograms/mL)-purged bone marrow grafts of 40 consecutive patients undergoing autologous BMT at this center. Granulocyte-macrophage colonies (CFU-GM) were grown from all grafts after treatment with this chemotherapeutic agent, but erythroid (BFU-E) and mixed (CFU-GEMM) colonies were grown from only 44% and 33% of the grafts respectively. The recovery of CFU-GM after purging ranged from 0.07% to 23%. The logarithm of CFU-GM content of the treated grafts was linearly correlated with the time to recovery of peripheral blood leukocytes (r = -0.80), neutrophils (r = -0.79), reticulocytes (r = -0.60), and platelets (r = -0.66). The CFU-GM content of purged autologous bone marrow grafts may reflect the hematopoietic stem cell content of the grafts and thus predict the rate of hematologic recovery in patients undergoing autologous BMT.

Adolescent↗
PubMed1993

Monoclonal antibody-purged bone marrow transplantation therapy for multiple myeloma.

Forty patients with plasma cell dyscrasias underwent high-dose chemoradiotherapy and either anti-B-cell monoclonal antibody (MoAb)-treated autologous, anti-T-cell MoAb-treated HLA-matched sibling allogeneic or syngeneic bone marrow transplantation (BMT). The majority of patients had advanced Durie-Salmon stage myeloma at diagnosis, all were pretreated with chemotherapy, and 17 had received prior radiotherapy. At the time of BMT, all patients demonstrated good performance status with Karnofsky score of 80% or greater and had less than 10% marrow tumor cells; 34 patients had residual monoclonal marrow plasma cells and 38 patients had paraprotein. Following high-dose chemoradiotherapy, there were 18 complete responses (CR), 18 partial responses, one non-responder, and three toxic deaths. Granulocytes greater than 500/microL and untransfused platelets greater than 20,000/microL were noted at a median of 23 (range, 12 to 46) and 25 (range, 10 to 175) days posttransplant (PT), respectively, in 24 of the 26 patients who underwent autografting. In the 14 patients who received allogeneic or syngeneic grafts, granulocytes greater than 500/microL and untransfused platelets greater than 20,000/microL were noted at a median of 19 (range, 12 to 24) and 16 (range, 5 to 32) days PT, respectively. With 24 months median follow-up for survival after autologous BMT, 16 of 26 patients are alive free from progression at 2+ to 55+ months PT; of these, 5 patients remain in CR at 6+ to 55+ months PT. With 24 months median follow-up for survival after allogeneic and syngeneic BMT, 8 of 14 patients are alive free from progression at 8+ to 34+ months PT; of these, 5 patients remain in CR at 8+ to 34+ months PT. This therapy has achieved high response rates and prolonged progression-free survival in some patients and proven to have acceptable toxicity. However, relapses post-BMT, coupled with slow engraftment post-BMT in heavily pretreated patients, suggest that such treatment strategies should be used earlier in the disease course. To define the role of BMT in the treatment of myeloma, its efficacy should be compared with that of conventional chemotherapy in a randomized trial.

Adult↗
PubMed1993

Autologous bone marrow purging with LAK cells.

In this study we will demonstrate that LAK cells, in vitro, can lyse hematologic neoplastic cells with a minor toxicity of the staminal autologous marrow cells. In fact, after bone marrow and LAK co-culture at a ratio of 1/1 for 8 hours, the inhibition on the GEMM colonies resulted to be 20% less compared to the untreated marrow. These data made LAK an inviting agent for marrow purging in autologous bone marrow transplantation.

Bone Marrow Purging↗
PubMed1994

Improved outcome for high-risk acute myeloid leukemia patients using autologous bone marrow transplantation and monoclonal antibody-purged bone marrow.

We have conducted a 9-year multicenter trial of autologous bone marrow transplantation (ABMT) for acute myeloid leukemia (AML). Remission BM was purged in vitro using monoclonal antibodies (MoAbs; PM-81, AML-2-23) and complement targeting myeloid differentiation antigens (CD15, CD14). In 1988, the preparative regimen changed from 60 mg/kg/d cyclophosphamide x 2 and fractionated total body irradiation (TBI) total dose, 1,200 cGy (Cy/fTBI), to 4 mg/kg/d busulfan x 4 and 60 mg/kg/d Cy x 2 (Bu/Cy2). Recent analysis (October 1, 1993) shows that the Bu/Cy2 regimen along with the same MoAb purging method yields an improved outcome. Seven first complete-remission (CR) (CR1), 45 second- or third-CR (CR2/3), and 11 first-relapse (R1) patients were treated with chemotherapy and TBI or chemotherapy alone followed by ABMT with MoAb-purged BM. Median age at ABMT for those patients in CR 2/3 and R1 patients was 36 years. Twenty-nine CR 2/3 and R1 patients were conditioned with Cy/fTBI, and 27 CR2/3 and R1 patients were conditioned with Bu/CY. Using the Kaplan-Meier method, the CY/fTBI, CR2/3, and R1 patients have a 3-year disease-free survival (DFS) of 21%. On the other hand, the Bu/Cy2, CR2/3, and R1 patients have a 3-year DFS of 48%. Nineteen CR2/3 and R1 patients relapsed post-ABMT. On analysis by conditioning regimen, those treated with Cy/fTBI have a 3-year relapse rate (RR) of 58%, whereas the patients conditioned with Bu/Cy2 have a 39% 3-year RR. Long-term DFS can be achieved in about 50% of patients with advanced remissions and relapsed AML using Bu/Cy2 with MoAb-purged BM.

Adolescent↗