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PubMed1991

In vitro marrow purging in chronic myelogenous leukemia: effect of mafosfamide and recombinant granulocyte--macrophage colony-stimulating factor.

Clinical and experimental evidence revealing Ph1-negative hematopoietic stem cells in the majority of chronic myelogenous leukemia (CML) patients, suggests that autologous bone marrow transplantation (ABMT) may represent a therapeutic approach for these patients. It was the aim of the present study to evaluate the efficacy of the cyclophosphamide derivative mafosfamide as a marrow purging agent in a group (n = 15) of CML patients. Chemical purging was followed by a short-term liquid culture phase supplemented with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). Mafosfamide (100 micrograms/ml) incubation induced a marked inhibition of progenitor cell growth, the percentages of surviving CFU-GEMM, BFU-E, and CFU-GM being 3.4, 5.4, and 4.9, respectively. At the cytogenetic level, the purging procedure failed to show any modulating effect on Ph1-negative clones in 9/15 cases. In contrast, 6/15 cases showed a significant increase in the mean (+/- SD) percentage of Ph1-negative metaphases in response to rGM-CSF (46 +/- 26, p less than or equal to 0.05), mafosfamide incubation (53 +/- 12, p less than or equal to 0.01), and the combination of mafosfamide incubation plus rGM-CSF (63 +/- 29, p less than or equal to 0.025). Immunological analysis revealed that mafosfamide incubation induced a significant enrichment of MY10 (28 +/- 9, 0.05) B73.1-positve cells (25 +/- 9, p less than or equal to 0.05). Four mafosfamide-responsive patients with CML in second chronic phase have been autografted with mafosfamide purged marrow. In all patients a Ph1-negative phase lasting 5-14 months was observed. In conclusion, it appears that (a) in a subgroup of CML patients mafosfamide purging is effective in reducing the size of the malignant clone and might induce through its cytotoxic and immune actions a modification of the balance between leukemic and normal clones, and (b) this experimental approach may be used as a screening test to select patients to undergo marrow harvest and ABMT with mafosfamide purged marrow.

Adult↗
PubMed1995

[Disease-free survival of acute leukemia patients receiving autologous bone marrow transplant following intensive chemotherapy--a report of 11 cases].

Eleven cases of acute leukemia patients were treated with autologous bone marrow transplantation (ABMT) following intensive chemotherapy with TACC protocol. Among them, eight were in first remission, three in second remission. The median age was 38 years (24-45 years). Bone marrow was purged in vitro before transplantation with procaine and hyperthermia in three cases with acute promyelocytic leukemia. In all patients, ABMT was successful. The results of treatment are as follows: as of May, 1994, the median remission and disease-free survival period was 31 months (6-57), seven cases have been in complete remission for 6-57 months (median 42 months) after treatment and are still alive. In four cases, ABMT was complicated by infection but it was controlled by antibiotics.

Adult↗
PubMed1988

Photosensitization of leukemic cells and normal bone marrow cells by 514 nm laser light and effects of laser light on migration inhibition and lymphokine response.

In a model for ex-vivo purging of bone marrow grafts, leukemic cells and normal bone marrow cells were treated with merocyanine 540 and exposed to 514 nm laser light. With this treatment, 99.9999% of leukemic cells were killed while 55% of the normal bone marrow cells survived. The deleterious effects of laser light alone in the absence of photosensitizer were not observed as determined by cell viability, cell migration, and response of target cells to human migration inhibition factor. These results indicate that laser light induced photodynamic therapy can be useful for ex-vivo autologous bone marrow purging without regard to the deleterious effects of laser light alone.

Bone Marrow↗
PubMed1990

Transporting bone marrow for in vitro purging before autologous reinfusion.

We describe the procedures employed for transporting bone marrow to and from a central facility. Marrow has been harvested from 80 patients with neuroblastoma, at 16 centers which are geographically dispersed throughout North America. Marrow from the outside transplant centers was packed on wet ice or cold packs in insulated containers, and transported by commercial carriers or chartered aircraft to the central processing laboratory. Post processed marrows were frozen in liquid nitrogen and returned by commercial carrier to the referring institution. In comparing transported with non-transported but similarly treated marrows, no differences were found in any of the following parameters: (1) CFU-GM recovery, (2) fraction viable cells at thawing, or (3) time to engraftment in patients. We conclude the transportation of harvested marrows to a central purging facility is safe. Based on this experience, we propose a set of standards, which, if adhered to, will insure the continued safe processing, shipping, and storage of bone marrow in all centers so engaged.

Bone Marrow Transplantation↗
PubMed1995

Cost analysis of immunomagnetic marrow purging for neuroblastoma: in-house purging versus submission to purging centers.

High-dose chemoradiotherapy in conjunction with autologous bone marrow transplantation has been used in the treatment of advanced stage neuroblastoma. Because of frequent marrow involvement, marrow purging methods, such as the immunomagnetic technique, have been developed. Current cost constraints force institutions to consider in-house purging versus submission of marrow to purging centers. Our analysis demonstrates that 15 procedures per year are needed to justify an up-front investment in equipment and supplies with a break-even period of 5 years. This number is also required to keep technical proficiency current without frequent retraining of personnel. The analysis includes start-up costs for institutions without a bone marrow processing laboratory, as well as for institutions already processing marrow or peripheral blood stem cells. For institutions performing fewer procedures per year, submission of marrow to purging centers is more cost effective than in-housing purging.

Bone Marrow Purging↗
PubMed1999

Technology evaluation: leukemia therapy, University of Pennsylvania.

The University of Pennsylvania is developing an antisense oligonucleotide (AS ON) as a potential treatmentfor myelogenous leukemia. The 24-mer phosphorothioate (PS) ON targets the c-myb gene (codons 2 to 9), a regulator of transcription. In a pilot study, patient bone marrow was purged with the PS ON before being returned to the patient. In January 1997, it was reported that out of six evaluable patients, four demonstrated marked hematological remission with normalized white blood cell counts. A second phase I trial was initiated, in which myelogenous leukemia patients were treated with systemic infusions of the PS ON at doses of 0.3 to 2.0 mg/kg/dayfor 7 days. By January 1997, 18 patients had been treated, 12 showed stable disease and one patient in blast crisis experienced a transient reversal to the chronic phase of the disease. No dose-related toxicity was noted and c-myb mRNA and protein levels were halved. Preclinical studies in leukemic mice showed that the myb AS PS ON increased survival times 2- to 4-fold and reduced leukemic proliferation in the brain [229790]. The ON was originally developed and patented at Temple University and was being jointly developed by Lynx Therapeutics, however, this collaboration was terminated in 1996 [264351]. New phase I studies are starting in 1999, with INX-3001 (University of Pennsylvania c-myb AS PS) supported by the NIH and Inex Pharmaceuticals Corporation.

Animals↗
PubMed1998

Potential of autologous immunologic effector cells for prediction of progression of disease in patients with chronic myelogenous leukemia.

In autologous bone marrow transplantation, immunologic effector cells such as lymphokine activated killer (LAK) cells may be useful for purging of bone marrow since these cells might have an additional in vivo effect on tumor cells in contrast to other purging protocols. Recently, immunologic effector cells termed cytokine-induced killer (CIK) cells have been shown to be more useful than LAK cells for purging of autologous BM in the context of autologous BMT. Here, we show that the expression of bcr/abl in CIK cells generated from patients with CML correlates with progression of disease in individual patients. In addition, progression of disease from chronic phase to accelerated phase could be predicted in two patients by studying the expression of bcr/abl in CIK cells generated from CML patients. Thus, it might be possible to use CIK cell generation for the prediction of progression of disease in CML patients.

Adult↗
PubMed1995

Autologous bone marrow support and bone disease in metastatic breast cancer.

High-dose chemotherapy (HDCT) and autotransplantation of hematopoietic cells is being investigated as a therapy for either metastatic or localized high-risk breast cancer. Breast cancer has a tendency to metastasize to the bones and the bone marrow (BM) and therefore the probability of harvesting malignant cells when collecting stem cells for autotransplantation appears high. Thus, the elimination or decrease of this contamination in the transplanted product appears mandatory. Autologous peripheral blood stem cell transplantation (PBSCT) has shown significant advantages over autologous bone marrow transplantation (ABMT) in improving the feasibility of HDCT, while possible limiting the BM contamination. The transplantation of only CD34+ products may even be a further advance. The role of ex vivo purging of cancer cells has not been established in ABMT or PBSCT. The question remains if the positive selection of CD34+ products is sufficient for controlling cancer cell contamination or if this product should be purged as well. The review of the literature suggests that contamination of the bone marrow could have an impact in terms of risk or relapse and could thus play a role as a pejorative prognostic factor. These data, although not totally adequate for the autotransplantation setting, are raising concerns over the probability of reinfusing malignant cells at time of autotransplantation following HDCT. There is a tremendous need to address these concerns in the laboratory along with prospective clinical trials. Until further data is available, this risk must be taken into consideration when patients with breast cancer are treated with curative intent.

Antigens, CD34↗
PubMed1995

Autologous bone marrow support and bone disease in metastatic breast cancer.

High-dose chemotherapy (HDCT) and autotransplantation of hematopoietic cell is being investigated as a therapy for either metastatic or localized high-risk breast cancer. Breast cancer has a tendency to metastasize to the bones and the bone marrow (BM) and therefore the probability of harvesting malignant cells when collecting stem cells for autotransplantation appears high. Thus, the elimination or decrease of this contamination in the transplanted product appears mandatory. Autologous peripheral blood stem cell transplantation (PBSCT) has shown significant advantages over autologous bone marrow transplantation (ABMT) in improving the feasibility of HDCT, while possibly limiting the BM contamination. The transplantation of only CD34+ products may even be a further advance. The role of ex vivo purging of cancer cells has not been established in ABMT or PBSCT. The question remains if the positive selection of CD34+ products is sufficient for controlling cancer cell contamination or if this product should be purged as well. The review of the literature suggests that contamination of the bone marrow could have an impact in terms or risk of relapse and could thus play a role as a pejorative prognostic factor. These data, although not totally adequate for the autotransplantation setting, are raising concerns over the probability of reinfusing malignant cells at time of autotransplantation following HDCT. There is a tremendous need to address these concerns in the laboratory along with prospective clinical trials. Until further data is available, this risk must be taken into consideration when patients with breast cancer are treated with curative intent.

Antigens, CD34↗
PubMed1991

Reactivity of anti-CD15 monoclonal antibody PM-81 with breast cancer and elimination of breast cancer cells from human bone marrow by PM-81 and immunomagnetic beads.

The CD15 carbohydrate antigen, lacto-N-fucopentaose III is expressed on a variety of human cancer cells including acute myeloid leukemia, small cell carcinoma of the lung, and colorectal carcinomas. We have found that cells from breast cancer cell lines and patient-derived tissue are strongly CD15 positive, as seen by binding to the PM-81 monoclonal antibody. In this report we show that monoclonal antibody PM-81 and immunomagnetic beads can remove breast cancer cells from bone marrow and thus be used as "purging" agents for autologous bone marrow transplantation. PM-81 and immunomagnetic beads removed up to 3 log of SK-BR-3 and MCF7 breast carcinoma cell line cells while minimally affecting normal hematopoietic progenitor cells. This technique may be useful for purging marrow for autologous bone marrow transplantation in breast cancer.

Antibodies, Monoclonal↗
PubMed1993

Normal hematopoietic reconstitution following ASTA-Z 7557-purged grafts in the absence of in vitro CFU-GM colony growth.

Hematopoietic reconstitution was assessed in 26 consecutive patients who underwent autologous bone marrow transplantation (ABMT) with ASTA-Z 7557 purged bone marrows. Of the 26, 17 had acute non-lymphoblastic leukemia (ANLL), 7 had acute lymphoblastic leukemia (ALL), 1 had non-Hodgkin's lymphoma (NHL) and 1 had multiple myeloma (MM). Twelve patients had practically no CFU-GM growth after ASTA-Z treatment. No statistical difference was observed in hematopoietic reconstitution between patients with or without in vitro CFU-GM colony growth. No significant linear correlation was observed between CFU-GM content in the treated graft and day of engraftment. In vitro CFU-GM growth has no predictive value in assessing hematopoietic recovery in vivo. Patients with no CFU-GM growth demonstrated normal engraftment.

Adolescent↗
PubMed1991

Pharmacologic purging of malignant T cells from human bone marrow using 9-beta-D-arabinofuranosylguanine.

Arabinosylguanine (araG) is a nucleoside analog that is rapidly converted by cells of the T lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate, resulting in inhibition of DNA synthesis and selective in vitro toxicity to T lymphoblastoid cell lines as well as to freshly isolated leukemia cells from patients with T cell acute lymphoblastic leukemia. In this report, we demonstrate that araG is an effective agent to use for chemoseparation of malignant T lymphoblasts from human bone marrow. When freshly isolated human T leukemia cells or T lymphoblastoid cells were treated with 100 microM araG for 18 hr, up to 6 logs of clonogenic T cells could be eliminated without appreciable toxicity to the normal myeloid, erythroid, and megakaryocytoid clonal progenitor cells. We discuss the use of this agent in ex vivo elimination of residual malignant T cells from marrow of patients requiring myeloablative chemotherapy with autologous bone marrow rescue.

Antineoplastic Agents↗
PubMed1992

Spermine dialdehyde, a novel ex vivo purging agent for both allogenic and autologous bone marrow transplantations.

The use of ex vivo purging agents has shown to be beneficial for both allogeneic and autologous bone marrow transplantations. We have shown previously that spermine dialdehyde (SDA), an oxidized product of spermine, when used in phosphate-buffered saline (PBS) preferentially inhibits T-cell proliferation while sparing myeloid cells. Lethally irradiated mice were rescued by reconstitution with SDA-treated allogeneic marrow and showed no sign of graft-vs-host disease (GVHD). In this paper, we show by HPLC analysis that SDA degraded rapidly in PBS but remained intact in saline. Administered in saline, SDA was more inhibitory on leukemic cell lines than normal myeloid or T-cells. Lethally irradiated mice receiving a syngeneic bone marrow leukemic cell mixture treated ex vivo with SDA in saline did not manifest leukemia. Thus, the preferential inhibitory effect of SDA and its degraded products in different buffers suggest that SDA could act as a novel purging agent for both allogeneic and autologous bone marrow transplantations.

Acrolein↗
PubMed1994

Bone marrow protection.

During the Third International Conference on Negative Control of Hematopoiesis (Paris, April 1993), a special session was devoted to bone marrow protection. Myelotoxicity is often a limiting factor in the use of efficient doses of chemo- or radiotherapy. It appeared therefore of great importance to protect hematopoietic stem cells in order to allow the restoration of hematopoiesis and to prevent the occurrence of lethal aplasia. Several approaches to decrease the myelotoxicity of chemo- and/or radiotherapy were discussed: MDR gene therapy, use of chemical compounds (AS101, WR 2721), cytokines such as TNF alpha and IL-1 and small peptides, pEEDCK and AcSKDP. Interestingly, several of these molecules appear of interest to protect normal stem cells during marrow purging for autograft.

Amino Acid Sequence↗
PubMed1991

Bone marrow processing for transplantation.

As indications for BMT increase, so do variations in bone marrow processing and manipulation techniques. Many centers have their own unique methods of mononuclear cell purification, concentration and storage. This is particularly evident in the processing of bone marrow for autologous BMT to allow dose intensification as salvage therapy for malignant disease. Unique procedures have been developed to maximize yields, concentrate mononuclear cells necessary for engraftment, and reduce the likelihood of GVH disease. Graft rejection and disease relapse still remain a problem in some of these "manipulated" marrows. Newer procedures may allow titration of the optimum numbers of immune reconstituting cells; however, at this time, these techniques are not precise and the balance between preventing GVH disease at the expense of graft failure or relapse may still jeopardize disease-free survival. Innovative purging techniques that include pharmacologic and immunologic methods, continue to evolve, necessitating standards for bone marrow processing that are flexible yet practical. Quality control and viability assays are essential to verify the biologic proliferative potential of progenitor cells capable of marrow reconstitution. Although no standards are yet established, all centers should have criteria to monitor the quality of the processed marrow. Blood banks and transfusion services are well versed in regulations governing processing, labeling, storage, and quality control of blood components. Bone marrow is the ultimate blood component, and it stands to reason that methods outlined in this article be integrated into transfusion medicine.

Blood Component Transfusion↗