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Results for “Bone Marrow Purging”

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PubMed1993

Fractionated total body irradiation and high-dose VP-16 with purged autologous bone marrow rescue for children with high risk relapsed acute lymphoblastic leukemia.

Twenty-two children with ALL in high risk second (n = 13), third or subsequent complete remission (n = 9) were treated with high-dose VP-16 60 mg/kg and fractionated total body irradiation (fTBI) 12 Gy, 2 x 2 Gy daily followed by autologous BM rescue. Prior to transplantation all patients had been treated according to intensive German BFM front-line or BFM relapse protocols. In all cases the marrow was purged using monoclonal antibodies attached to magnetic microspheres. All patients engrafted. There was no severe toxicity related to the pre-transplant high-dose chemoradiotherapy. Two patients died in the early course of transplantation from infections (Legionella and Aspergillus). Sixteen patients relapsed within 259 days (median 109 days); 13 died from leukemia. Four patients are alive in CR at a median of 1328 days with a Karnofsky score of 100%. The Kaplan-Meier estimation shows a probability of event-free survival (EFS) of 18% and a probability of relapse of 80%. Considering the otherwise poor prognosis of these children the results are acceptable although the high relapse rate is still disappointing. We conclude that high-dose VP-16 and fTBI combined with ABMT is a curative treatment for some children and should therefore be considered for those who lack an HLA-identical sibling donor. In future better therapy concepts are needed either in pre-transplant conditioning regimens or in post-transplant treatment schedules.

Adolescent↗
PubMed1996

4-Hydroperoxycyclophosphamide purged autologous bone marrow transplantation in non-Hodgkin's lymphoma patients at high risk of bone marrow involvement.

Between June 1990 and January 1994, 19 patients with non-Hodgkin's lymphoma (NHL) at high risk for bone marrow involvement underwent 4-hydroperoxycyclophosphamide (4-HC) purged bone marrow transplantation. Eleven patients had low grade, seven intermediate grade and one high grade NHL and 7/19 patients had received three or more previous chemotherapeutic regimens. Four patients were transplanted in first partial remission (PR) and the remainder in responsive relapse. Fourteen patients had bone marrow (BM) involvement at diagnosis and/or at relapse. The median times to granulocyte and platelet recovery were 26 and 29 days, respectively. There were two toxic deaths and one complete responder developed secondary AML at 31 months post-BMT. Seventeen of 18 evaluable patients achieved a complete remission (CR) and one patient a PR. Fourteen patients (74%) are progression-free at a median follow-up of survivors of 34 months (range 29-55). The 3 year event-free (EFS) and overall survival (OS) probabilities are both 67%. No statistically significant difference was seen between EFS or OS and BM involvement or histologic grade at diagnosis. At 29 months, 4/7 patients with a morphologically involved BM harvest had relapsed or died compared to 1/12 patients with negative BM (P = 0.03). These results are encouraging and warrant further investigation of 4-HC purging in NHL.

Adult↗
PubMed1994

Cryopreservation of human bone marrow after purging T-cells or tumor cells.

Bone marrow transplantation (BMT) is a valuable measure for treatment of leukemia. In order to reduce, even to eliminate, the graft versus host disease after allogenic BMT and prevent the reinfusion of tumor cells during autologous BMT, the cryopreservation of human BM after purging T-cells with immunotoxin or purging tumor cells with monoclonal antibody 55 (McAb55) was studied. Results demonstrated that: (1) treatment with McAb55 and rabbit complement (RC) did not affect the GM-CFU of BM, but treatment with immunotoxin slightly decreased the GM-CFU of BM; (2) a freeze-thawing procedure obviously decreased the GM-CFU number of BM, the GM-CFU numbers of frozen BM samples were lower than those of the nonfrozen samples; (3) there were no differences in GM-CFU numbers between normal BM and BM treated with McAb55 and RC when the cooling rate used was the same; (4) there was a negative linear correlation between cooling rates and GM-CFU numbers of BM in the cooling rate range used and the optimal cooling rate for the cryopreservation of normal BM and BM treated with McAb55 and RC or immunotoxin was the same, namely, 0.5 degrees C/min.

Antibodies, Monoclonal↗
PubMed1989

Monoclonal antibody purging and autologous bone marrow transplantation in acute myelogenous leukemia in complete remission.

A mouse monoclonal antibody (S4-7) reacting with human myelomonocytic cells has been previously shown to be suitable for bone marrow purging in selected acute myelogenous leukemia (AML) patients with S4-7 positive leukemic clonogenic cells at diagnosis. The results obtained in seven AML patients who underwent such a treatment, followed by autologous bone marrow transplantation (ABMT), are now reported. Six patients underwent ABMT in first complete remission (CR), one in second CR, after BAVC conditioning regimen. One patient died of infection 1 month after ABMT; in the other six a complete recovery of hemopoiesis was observed. In spite of S4-7 reactivity with normal myelomonocytic cells, a prompt recovery of granulopoiesis was however observed both in in vitro liquid culture and in vivo with a median time of 20 days to reach granulocyte values of 500 x 10(6)/l. The patient transplanted in 2nd CR relapsed 3 months after ABMT. Of the five evaluable patients transplanted in 1st CR, two relapsed 8 and 9 months post-ABMT while three remain in continuous CR at 35, 47, 57 months. Leukemic cells of two of the three patients with recurrent disease were studied at relapse and in both could be detected a significant percentage of S4-7 negative cells, detectable neither at diagnosis nor (one patient) at the time of first relapse after standard chemotherapy.

Antibodies, Monoclonal↗
PubMed1998

BCR-ABL antisense oligodeoxynucleotide in vitro purging and autologous bone marrow transplantation for patients with chronic myelogenous leukemia in advanced phase.

BCR-ABL antisense oligodeoxynucleotides (ODN) have provided evidence of antileukemia effect when tested in vitro against Philadelphia-positive (Ph-pos) cells and in vivo when injected into leukemic mice. On the basis of the results obtained in vitro at diagnosis, eight patients with chronic myelogenous leukemia (CML) were selected and submitted to autologous bone marrow transplantation (ABMT) with bone marrow (BM) cells purged in vitro with junction-specific (J-sp) BCR-ABL antisense ODN at the time of transformation in accelerated phase or during second chronic phase. Mononuclear BM cells were treated in vitro for 24 or 72 hours with 150 micro/mL of antisense ODN yielding a median recovery of 47.6% mononuclear cells, 48.8% CD34(+) cells, and 20.3% clonogenic cells. After a conditioning regimen including busulphan and etoposide, the reinfused treated cells allowed engraftment and hematologic reconstitution in all patients. Evaluation of the antileukemic effect by standard cytogenetic analysis and fluorescence in situ hybridization showed a complete karyotypic response in two cases and a minimal or no response in the other six. The patient autografted in second chronic phase died in blast crisis 7 months after ABMT; of the seven patients autografted in transformation, three developed blast crisis 21 to 39 months after reinfusion, one died from unrelated BMT complications 30 months after ABMT, and three are in persistent second chronic phase 14 to 26 months after autograft. The low toxicity of the protocol and the hemopoietic reconstitution observed in all patients make this approach feasible; the marked karyotypic response observed in some patients and the duration of the second chronic phase show that ODN-mediated BM purging and autograft is a promising treatment for this high-risk group of CML.

Adult↗
PubMed1988

Immunotoxins for ex vivo marrow purging in autologous bone marrow transplantation for acute nonlymphocytic leukemia.

Two potent antimyeloid immunotoxins (IT) were generated by conjugating AML-2-23 (anti-CD14) and MCS-2 (anti-CD13) monoclonal antibodies (mAb) to the ribosome-inactivating phytotoxin, ricin. Both IT selectively bound to target cells, inhibited protein synthesis, and prevented the clonogenic growth of fresh marrow blasts from acute nonlymphocytic leukemia patients as well as KG-1 (ANLL) cells. Cryopreservation did not inhibit IT activity. We conclude that AML-2-23-ricin and MCS-2-ricin show potential for effective ex vivo marrow purging in autologous bone marrow transplantation (ABMT) for ANLL. To our knowledge, this study represents the first evidence of the clinical potential of IT in high-risk ANLL.

Acute Disease↗
PubMed1994

Clinical status of the new cytoprotective agent, amifostine.

In summary, the data presented and reviewed at this symposium provide a strong rationale for the use of amifostine as a cytoprotective agent. Amifostine has been shown to reduce morbidity in cancer patients receiving radiation and chemotherapy without compromising the antineoplastic activity of the cancer therapies employed. Amifostine has been investigated extensively and appears particularly effective with cisplatin and cyclophosphamide, which operate via direct binding to the active species of these alkylating agents. It may also have a role in the protection of normal hematopoietic stem cells during bone marrow purging prior to bone marrow transplantation. Finally, amifostine may act synergistically with hematopoietic growth factors (ie, G-CSF) to protect and accelerate the recovery of hematopoietic stem cells exposed to high doses of radiation.

Agranulocytosis↗
PubMed1993

Guanine arabinoside as a bone marrow-purging agent.

Arabinosylguanine (araG) is a nucleoside analogue that is rapidly converted by cells of the T lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate (araGTP), 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 (ALL). We have previously demonstrated 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 hours, up to 6 logs of clonogenic T cells are eliminated without appreciable toxicity to the normal myeloid, erythroid, and megakaryocytoid clonal progenitor cells. We subsequently described studies in a murine model of T cell acute lymphoblastic leukemia (ALL) in which we tested whether bone marrow contaminated with malignant T cells and purged ex vivo with araG, could reconstitute both the lymphoid and myeloerythroid lineages in the absence of leukemic relapse. The model utilized 6C3HED tumor cells, derived from a Thy 1.2+ malignant murine T cell line, which were shown to cause lethal leukemia in C3H/HeN mice. Intravenous injection of 10(6) 6C3HED cells resulted in 100 percent mortality within 18 days, with autopsy revealing tumor infiltration of multiple organs. Evidence of araG's ability to purge bone marrow of malignant tumor cells without causing significant toxicity to normal marrow-derived hematopoietic progenitor cells was documented in experiments in which 75 percent of lethally irradiated mice receiving transplants of syngeneic bone marrow contaminated with 6C3HED tumor cells and treated ex vivo with 100 mM araG for 18 hours survived for 250 to > 400 days. Reconstitution of the lymphoid, myeloid, and erythroid lineages with donor cells in surviving mice was documented. The data presented indicate that araG may effectively purge bone marrow of malignant T cells without irreversible toxicity to hematopoietic stem cells. This purging regimen is recommended for consideration for clinical trials in patients with T cell malignancies undergoing autologous bone marrow transplantation and may also be a viable option for T cell depletion as a strategy to prevent graft versus host disease.

Animals↗
PubMed1995

Cost-effectiveness of autologous bone marrow transplantation.

The impact of filgrastim on the use of health care resources during recovery from autologous bone marrow transplantation (ABMT) was studied. The charts for patients with metastatic breast cancer treated with ABMT at a general hospital between November 1989 and July 1993 were reviewed by Blue Cross of Western Pennsylvania. The 58 patients were divided into five groups: group 1-bone marrow purged, no filgrastim therapy; group 2-bone marrow not purged, no filgrastim therapy; group 3-bone marrow purged, filgrastim therapy after ABMT; group 4-bone marrow not purged, filgrastim therapy after ABMT; and group 5-peripheral blood stem cells (PBSCs) given, followed by filgrastim therapy. The groups were compared for total length of stay (LOS), number of days the absolute neutrophil count (ANC) was < 500/cu mm, total number of days of filgrastim therapy, and total number of cumulative unit days of antimicrobial use. Total LOS was shorter for patients who received filgrastim (groups 3-5) than for patients who did not. Filgrastim was associated with fewer days of ANC < 500/cu mm in groups 4 and 5. The total number of cumulative unit days of antimicrobial use was lower in filgrastim recipients. Patients who received PBSCs needed fewer days of filgrastim therapy than the other filgrastim recipients. The health insurance company determined that, as a result of filgrastim therapy and PBSC transplantation, ABMT costs to the company have dropped by more than 50% since 1990. Patients now have available an alternative to conventional therapy for metastatic breast cancer without prejudice or penalty from their payer.

Bone Marrow Purging↗
PubMed1985

Eradication of neuroblastoma cells in vitro by monoclonal antibody and human complement: method for purging autologous bone marrow.

We describe an in vitro method which is useful for purging autologous bone marrow of neuroblastoma cells. The method utilizes a single murine monoclonal antibody 3G6 (an immunoglobulin MK) which we have previously developed against the ganglioside GD2; undiluted human complement; and unfractionated whole bone marrow at 1 X 10(7) nucleated cells/ml. Tumor cell clonogenic assays, Hoechst 33342 fluorescent nuclear stain, and trypan blue viability stain methods were used to assay cytotoxicity. This complement-mediated cytotoxicity technique killed 99.9-100% of neuroblastoma cell lines NMB-7, LAN-1, LAN-5, and IMR-6, while normal marrow precursor cells were not detectably damaged. The presence of normal bone marrow did not inhibit the human complement-mediated cytotoxicity. Applying the cytotoxicity method to whole unseparated bone marrow demonstrated killing of seeded neuroblastoma cells, with no gross hemolysis or cell clumping. The method did not require expensive special equipment, use of animal complement sera, or prior fractionation of the bone marrow. The average marrow nucleated cell recovery was 95%. These studies indicate that in vitro purging of autologous marrow infiltrated with neuroblastoma with monoclonal antibody 3G6 and human complement is both technically feasible and effective in eradicating residual tumor while preserving bone marrow stem cells.

Animals↗
PubMed1988

Purging tumor cells from bone marrow by use of antibody and complement: a critical appraisal.

This review highlighted several problems associated with the use of antibody and complement in the elimination of tumor cells from bone marrow that was to be used for transplantation, and it discussed some of the difficulties encountered in developing this approach in model systems. These problems should be seriously considered by any clinician contemplating this method for bone marrow purging.

Antibodies↗