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PubMed1988

Autologous bone marrow transplantation in children.

Autologous bone marrow transplantation is a procedure that allows for the delivery of high doses of chemotherapy and radiation to treat pediatric malignancies. There have been many studies showing a dose-response curve for many of the drugs that have been used for cytoreductive therapy in autologous bone marrow transplantation. These dosage ranges are achievable in many of the preparative regimens used in autologous bone marrow transplantation. The results in neuroblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, Ewing's sarcoma, rhabdomyosarcoma, osseous sarcoma, other soft tissue sarcomas, and acute leukemias (acute lymphoblastic leukemia and acute non-lymphoblastic leukemia) are reviewed. The question of purging of bone marrow during autologous bone marrow transplantation is addressed. The different techniques of purging are reviewed and the advantages and disadvantages of each are discussed. Finally, new areas of treatment and future directions of autologous bone marrow transplantation are addressed.

Bone Marrow Transplantation↗
PubMed1997

Bone marrow transplantation for non-Hodgkin's lymphoma: a review.

High dose chemotherapy and stem-cell rescue (bone marrow transplantation) is used increasingly in the treatment of malignant disorder. Numerous trials have demonstrated the effectiveness of bone marrow transplantation in the treatment of non-Hodgkin's lymphoma. However, there are many unanswered questions as to the role of high-dose therapy in certain subtypes of lymphoma, the timing of transplant, and even the type of transplant to perform. An attempt will be made to clarify many of these unanswered questions. The utilization of high-dose therapy for non-Hodgkin's lymphoma is recommended for most patients who have relapsed after initial therapy. Transplantation in first remission is not recommended routinely. Allogeneic bone marrow transplantation should by reserved for individuals with poorly responding disease or in individuals with bone marrow involvement. The precise roles of purging and transplantation of individuals with low grade lymphoma are being investigated.

Bone Marrow Purging↗
PubMed1988

Immunomagnetic removal of B-lymphoma cells from human bone marrow: a procedure for clinical use.

B-lymphoma cells were purged from human bone marrow by incubating the cell suspension with a cocktail of three different pan-B cell mouse IgG1 monoclonal antibodies, and then with immunobeads charged with sheep anti-mouse antibody, followed by magnetic separation. The primary antibodies used, HD37 (CD19), HD6 (CD22), and HH1 (CD37), bind to a very high percentage of the cells in non-Hodgkin's lymphomas of poor prognosis. The secondary antibody is directed against the Fc portion of the IgG antibodies. In model experiments Burkitt's lymphoma cells (Rael) were admixed to mononuclear bone marrow cells in the ratio 1/9. With a ratio of immunobeads/total antibody-binding B cells of 50/1 in a first treatment cycle and repeating the procedure with the same number of beads in a second cycle, a tumor cell depletion of more than 5 logs was achieved, as judged by a clonogenic assay. The concomitant reduction of CFU-GM and CFU-GEMM was about 20%. The purging procedure has been scaled up to clinical use. Equipment suitable for purging patients' marrow specimens, employing standard transfusion facilities, is described. With this equipment the efficacy of tumor cell removal was the same as in the model experiments, and the whole magnetic separation could be completed in 2 hours.

Animals↗
PubMed1992

Strategies in the treatment of acute myelogenous leukemia.

The current treatment of acute myelogenous leukemia is far from satisfactory despite some recent advances. This review focuses on current strategies designed to improve treatment outcome. With advances in molecular biology, the definition of a complete remission should be redefined as a molecular remission where any abnormal gene rearrangement has disappeared or a clonal remission with morphologic characteristics of a complete remission, but with detectable genetics or molecular abnormalities. Abnormal gene rearrangements permit the detection of minimal residual disease, the significance of which remains to be determined. New drug development remains an important area of research and several new drugs are active in acute myelogenous leukemia. These include etoposide, idarubicin, mitoxantrone and carboplatin. Various combinations are undergoing clinical trials. Prognostic factors which predict for outcome include phenotyping, cytogenetics, cytokinetics, drug resistance and age. Proto-oncogene expression as a predictor of response is under investigation. Post-induction therapy remains controversial and approaches have included allogeneic bone marrow transplantation, autologous bone marrow transplantation with or without purging, intensive consolidation and maintenance programs. The superiority of one approach over the other has not been firmly established. Differentiating agents such as all-trans retinoic acid, and growth factors, the latter for supportive care, or recruitment of leukemic cells into the cycle are being investigated. Understanding the mechanisms of drug resistance should lead to the development of new approaches. Thus, with knowledge generated in many areas, the future should bring increasing success in treating AML.

Antineoplastic Agents↗
PubMed1995

In vitro effects of etoposide purging on natural killer cells.

Autologous bone marrow transplantation (ABMT) is widely used to treat hematologic and non-hematologic malignancies. In an attempt to reduce potential neoplastic contamination of the graft, pharmacologic purging with cyclophosphamide derivatives and etoposide (VP16) is often used. Trilineage hemopoietic engraftment is seen following ABMT with VP16-purged bone marrow (BM), but little is known about immune reconstitution in this setting. We studied the in vitro development of natural killer (NK) cells from VP16-purged BM. These cells, defined by phenotypic and functional criteria, undergo rapid regeneration, expansion, and maturation in the presence of interleukin 2 (IL-2). VP16 seems to spare subsets of NK cells, and this cell lineage develops rapidly in VP16-treated BM cultures from patients with acute myelogenous leukemia (AML) and healthy donors. Since relapse rates remain high, immunotherapy following ABMT with purged BM may be useful and should be considered in these patients.

Adolescent↗
PubMed1990

Mafosfamide induces less sister chromatid exchange in Ph-positive cells than in normal bone marrow.

The frequency of induced sister chromatid exchange (SCE) is a sensitive tool for the monitoring of DNA damage and has been shown to indicate chemotherapy resistance. Mafosfamide is presently used for the purging of bone marrow in autologous bone marrow transplantation in the treatment of acute leukemia. We studied the SCE-inducing effect of mafosfamide on leukemic cells of Philadelphia (Ph)-positive chronic myeloid leukemia (CML) as a model for leukemic cells. Corresponding data from normal bone marrow were analyzed for comparison. A positive linear correlation (r = 0.99, P = 0.0005) was found between the dose of mafosfamide and induced SCE in Ph-positive CML and normal bone marrow. The concentration of mafosfamide used was 0.1, 0.2, 0.4, and 0.8 micrograms/ml. Additionally, we analyzed five cases of CML and six cases of normal bone marrow. A significant difference in the frequency of induced SCE/metaphase was found between CML and normal bone marrow even after addition of 0.8 micrograms/ml mafosfamide. Also, spontaneous SCE was significantly lower in CML. Our data indicate a lower sensitivity of the leukemic cells to mafosfamide as shown by the induction of a lower frequency of SCE events.

Bone Marrow↗
PubMed2006

A novel HSV-1 virus, JS1/34.5-/47-, purges contaminating breast cancer cells from bone marrow.

PURPOSE: Oncolytic herpes simplex virus type 1 (HSV-1) vectors show considerable promise as agents for cancer therapy. We have developed a novel recombinant HSV-1 virus (JS1/34.5-/47-) for purging of occult breast cancer cells from bone marrow of patients. Here, we evaluate the therapeutic efficacy of this oncolytic virus. EXPERIMENTAL DESIGN: Electron microscopy was used to determine whether human breast cancer and bone marrow cells are permissive for JS1/34.5-/47- infection. Subsequently, the biological effects of JS1/34.5-/47- infection on human breast cancer cells and bone marrow were established using cell proliferation and colony formation assays, and the efficiency of cell kill was evaluated. Finally, the efficiency of JS1/34.5-/47- purging of breast cancer cells was examined in cocultures of breast cancer cells with bone marrow as well as bone marrow samples from high-risk breast cancer patients. RESULTS: We show effective killing of human breast cancer cell lines with the JS1/34.5-/47- virus. Furthermore, we show that treatment with JS1/34.5-/47- can significantly inhibit the growth of breast cancer cell lines without affecting cocultured mononuclear hematopoietic cells. Finally, we have found that the virus is effective in destroying disseminated tumors cells in bone marrow taken from breast cancer patients, without affecting the hematopoietic contents in these samples. CONCLUSION: Collectively, our data show that the JS1/34.5-/47- virus can selectively target breast cancer cells while sparing hematopoietic cells, suggesting that JS1/34.5-/47- can be used to purge contaminating breast cancer cells from human bone marrow in the setting of autologous hematopoietic cell transplantation.

Adenocarcinoma↗
PubMed1991

Pediatric bone marrow transplantation.

Bone marrow transplantation is a high-visibility, high-technology discipline with a growing list of potentially curative applications in neoplastic, hematologic, immunologic, and genetic diseases of children. The clinical problems experienced by children who have received bone marrow grafts involve pediatricians in both general and subspecialty practice and require a working knowledge of the applied immunobiology of bone marrow transplantation. As the transplantation procedure has evolved from a research tool to an established therapeutic modality, collaboration between basic scientists and clinicians has led to a greater understanding of the pathophysiology of the immunobiologic events that occur after allogeneic bone marrow transplantation and, thus, to improvements in the clinical care of transplant recipients. As its applications in pediatric medicine grow, bone marrow transplantation presents additional challenges for the future: expansion of the allogeneic donor pool, use of more effective or aggressive preparative regimens and autologous bone marrow-purging strategies, more effective prevention and treatment of graft-versus-host disease, and development of gene-replacement therapy by infusion of modified autologous bone marrow cells.

Bone Marrow Transplantation↗
PubMed1993

Effect of recombinant human stem cell factor on mafosfamide-treated bone marrow clonogenic cells.

The availability of early-acting cytokines could allow the establishment of new approaches to chemical marrow purging. It was the aim of the present study to investigate the capability of recombinant human stem cell factor (SCF) in combination with other growth factors to support the in vitro growth of mafosfamide-treated progenitor cells such as mixed colony forming units (CFU-GEMM), erythroid burst forming units (BFU-E) and granulocyte-macrophage CFU (CFU-GM). When marrow cells were incubated (30 min, 37 degrees C) with increasing doses of mafosfamide (30-120 micrograms/ml) a statistically significant (p < or = .05), dose-dependent suppression of colony growth was observed. Addition of SCF (50 ng/ml) to marrow cultures stimulated with the standard mixture of growth factors (interleukin 3 or IL-3, granulocyte-macrophage colony stimulating factor or GM-CSF, and erythropoietin or Epo) significantly increased the mean (+/- SD) concentration of mafosfamide inducing 95% inhibition of CFU-GM (106 +/- 17 versus 130 +/- 29, p < or = .0005), but not granulocyte/erythroid/macrophage/megakaryocyte CFU (CFU-GEMM) (85 +/- 4 versus 90 +/- 1, p < or = .1) and BFU-E (90 +/- 5 versus 92 +/- 5, p < or = .1). SCF induces a dose-dependent, statistically significant enhancement of colony formation by CD34+, mafosfamide-treated cells. As shown by single colony transfer experiments, mafosfamide-resistant clones promoted by SCF have a significantly higher replating capacity as compared with mafosfamide-resistant clones grown without SCF.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗
PubMed2006

Purging of murine erythroblastic leukemia by ZnPcS2P2-based-photodynamic therapy.

A key point for successful transplantation of autologous hematopoietic stem cells in the treatment of leukemia is the purging technique, of which photodynamic therapy (PDT) proved effective and promising. The aim of this study was to evaluate the purging effect of a novel amphipathic photosensitizer, di-sulfo-di-phthalimidomethyl phthalolcyanine zinc (ZnPcS2P2)-based PDT (ZnPcS2P2-PDT) on murine erythroblastic leukemic EL9611 cells. Bone marrow cells (BMC), harvested from normal BALB/c mice, were contaminated with variable EL9611 cells. Cell suspensions were incubated with 4 microg/ml ZnPcS2P2 for 5 h and then exposed to 2.1 J/cm2 irradiation by a semiconductor laser 670 nm. Lethally irradiated recipient BALB/c mice (7 Gy) received syngeneic bone marrow transplantation with purged or nonpurged cell mixtures of 10(7) BMC contaminated with variable numbers (10(2)-10(5)) of EL9611 cells. All of the irradiated controls died due to sepsis. All of the mice injected with nonpurged cell mixtures developed leukemia and died, whereas the mice transplanted with ZnPcS2P2-PDT-treated mixtures had a longer survival time, and the fewer leukemic cells there were in the cell mixtures, the higher the leukemia-free survival rate. We conclude that ZnPcS2P2-PDT could purge leukemic cells from bone marrow autografts but could retain sufficient progenitor cells for the hematopoietic activity.

Animals↗
PubMed1993

Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia.

Twenty patients with poor prognosis B-cell chronic lymphocytic leukemia (B-CLL) underwent uniform high-dose chemoradiotherapy followed by rescue with multiple monoclonal antibody-purged autologous bone marrow (BM) (12 patients) or T-cell-depleted allogeneic BM from HLA-identical siblings (8 patients) in a pilot study to assess the feasibility of BM transplantation (BMT) in this disease. All had poor prognosis disease by either staging, BM pattern, tumor doubling time criteria, or cytogenetics. All patients achieved remission criteria (defined as < or = 2 adenopathy, absence of splenomegaly, < or = 20% of the intertrabecular space involved on BM biopsy) before BMT. Despite the use of fludarabine, a median of three treatment regimens were required to achieve BMT eligibility. After BMT, all patients achieved complete hematologic engraftment. Toxicities were not significantly different between autologous versus allogeneic BMT. Two toxic deaths were observed. Of 19 evaluable patients, 17 clinical complete clinical remissions (89%) were observed, with 2 patients (1 allogeneic and 1 autologous) exhibiting persistent BM disease. Complete clinical remissions were documented at the phenotypic and molecular level for the majority of patients in whom dual fluorescence for CD5 and CD20 (15 of 15; 100%) and Ig gene rearrangements (11 of 14; 79%) were performed. Although long-term follow-up is needed to assess any potential impact on the disease-free and overall survival of these patients, this study shows the feasibility of using high-dose chemoradiotherapy and BMT in patients with poor prognosis B-CLL.

Adult↗
PubMed1993

Automated processing of human bone marrow grafts for transplantation.

Prior to purging or cryopreservation, we concentrated 21 bone marrow (BM) harvests using a modification of the 'grancollect-protocol' of the Fresenius AS 104 cell separator with the P1-Y set. Within 40-70 min, the initial marrow volume of 1,265 ml (+/- 537 ml) was processed two to three times. A mean of 47% (+/- 21%) of the initial mononuclear cells was recovered in a mean volume of 128 ml (+36 ml). The recovery of clonogenic cells, measured by CFU-GM assays, was 68% (+/- 47%). Red blood cells in the BM concentrates were reduced to 7% (+/- 4%) of the initial number. The procedure was efficient and yielded a BM cell fraction suitable for purging, cryopreservation and transplantation. At this time, 10 of the 21 patients whose BM was processed using this technique have been transplanted. Seven of these 10 patients have been grafted using the BM alone. Three of the 10 patients showed reduced cell viability and colony growth in the thawed BM samples, and therefore obtained BM and peripheral blood-derived stem cells. All transplanted patients showed an evaluable engraftment, achieving 1,000 granulocytes per microliter of peripheral blood in a mean of 18 days.

Automation↗
PubMed1990

Suitability of a new stable acetal analogue of aldoifosphamide for purging leukemic cells from human bone marrow.

The in vitro cytotoxic properties of acetaldoifosphamide, a new chemically stable bis-acetate analogue of aldoifosphamide that requires enzymatic activation by cellular carboxylate esterases, has been compared with that of 4-hydroperoxycyclophosphamide (4-HC). On a molar basis, acetaldoifosphamide was 8-10 times more potent than 4-HC against two different human leukemic myeloid cell lines, but only twice as potent as 4-HC against normal bone marrow granulocyte-macrophage colony-forming cells (GM-CFC). Acetaldoifosphamide retained its activity against leukemic cell lines that were highly resistant to the antileukemic drugs doxorubicin and m-AMSA. GM-CFC doubling times after exposure of bone marrow to high concentrations of acetaldoifosphamide in suspension cultures were 6-12 hours. Similar doubling times were obtained after incubation of marrow with 4-HC. Acetaldoifosphamide has a sparing effect on hematopoietic stem cells that is similar to that found for 4-HC; however, it is considerably more potent than 4-HC. Acetaldoifosphamide is different from 4-HC in its chemical stability and its unique requirement for carboxylate esterase activation. We conclude that acetaldoifosphamide may have advantages over 4-HC for in vitro purging of leukemic cells from human bone marrow.

Antineoplastic Agents↗
PubMed1987

High-dose melphalan, vincristine, and total-body irradiation with autologous bone marrow transplantation in children with relapsed neuroblastoma: a phase II study.

Seven children with neuroblastoma who had relapsed on or after conventional therapy (3 originally stage IV, 3 stage III, 1 stage II) were entered on a study of "massive therapy" with purged autologous bone marrow rescue. In 5 patients attempts were made to reinduce remission with alternative chemotherapy, and a partial or complete response was achieved in 3. The massive therapy regimen comprised melphalan, vincristine, and total-body irradiation. Of 6 patients with measurable disease, all showed objective response to high-dose therapy (5 partial, 1 complete remission), but the median duration of remission was only 5 months (range 1/2 to 10). One patient remains disease-free at 18 months post graft. This patient was the only one treated in second complete remission. These data confirm the high response rate achieved by high-dose melphalan, total-body irradiation regimens, but it appears unlikely that a single high-dose chemoradiotherapy procedure will cure patients after relapse, particularly if they are unresponsive to conventional salvage regimens. Such protocols may, however, have a role as consolidation in first remission. The use of double-autograft procedures is an alternative that warrants further investigation in patients with relapsed neuroblastoma.

Adolescent↗