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PubMed1990

Tumour cell purging for autologous bone marrow transplantation.

Interest in autologous bone marrow transplantation as treatment for haematological disease has increased considerably in the past 10 years. Remission bone marrow can be collected, stored until the patient has received myeloablative therapy, then re-infused. A disadvantage of this form of treatment is the possibility of re-infusion of residual malignant cells. The methods currently available for removal of neoplastic cells from autologous marrow prior to transplantation are reviewed.

Bone Marrow Transplantation↗
PubMed1993

Allograft and autograft purging using immunotoxins in clinical bone marrow transplantation for hematologic malignancies.

Bone marrow manipulation is an essential procedure when bone marrow transplantation (BMT) is used to improve the chances of survival among high risk patients with hematologic malignancies. Ex vivo purging of donor T cells effectively prevents a fatal reaction known as graft-versus-host disease in allogeneic BMT. Ex vivo purging of residual leukemia cells from autologous marrow can virtually eliminate the risk of autograft contamination. Immunotoxins are powerful and selective reagents for these tasks. However, ex vivo purging may be insufficient by itself to overcome the high risk of relapse that confronts many patients undergoing autologous BMT. Bone marrow manipulation may even present problems of its own, such as loss of the graft-versus-leukemia effect when allogeneic marrow is T cell depleted. We are currently evaluating immunotoxins containing pokeweed antiviral protein in clinical trials as in vivo purging reagents that may reduce the risk of relapse for BMT patients.

Bone Marrow Purging↗
PubMed1992

Purging in autologous and allogeneic bone marrow transplantation.

The success of hematoablative dosages of cytotoxic therapy followed by stem cell transplantation depends on the disease response to the intensive drug dose and the ability of the transplant to provide durable hematopoietic reconstitution. In autologous stem cell transplantation, patients' own bone marrow or peripheral blood is used for hematopoietic engraftment. In several diseases the bone marrow is involved, and in such situations, the success of autologous stem cell transplantation may improve if the hematopoietic elements are enriched (positive selection) or if the contaminating cancer cells are purged by negative selection. In patients undergoing allogeneic bone marrow transplantation, the T lymphocytes of the donor cells contribute to the development of graft-versus-host disease with significant morbidity and mortality. Selective purging of T lymphocytes has dramatically decreased the incidence of graft-versus-host disease. In this paper, various methods for purging hematopoietic stem cells are detailed with emphasis on treatment planning. Exciting new possibilities include growing stem cells from a small amount of bone marrow, enhancing immune surveillance, and decreasing drug resistance by genetic engineering.

Animals↗
PubMed1988

Lymphokine-activated killer cell purging of leukemia cells from bone marrow prior to syngeneic transplantation.

We have studied the effect of using lymphokine-activated killer (LAK) cells as an in vitro means for eliminating leukemic cells from normal bone marrow prior to transplantation of experimental animals. Rat LAK cells exhibit broad cytolytic activity against a variety of hematopoietic neoplasms, but do not kill normal bone marrow cells or lectin-stimulated blasts. Bone marrow was harvested from normal Fischer 344 rats, combined with increasing numbers of CRNK-16 tumor cells, and then incubated with LAK cells. The BM/tumor/LAK mixture was then administered to untreated Fischer rats, and the ability of the LAK cells to purge the bone marrow of neoplastic cells and prevent the transmission of the leukemia to recipient animals monitored. Our results demonstrate that LAK cells are capable of efficiently purging the bone marrow of neoplastic cells. Treatment of the BM/tumor mixtures with LAK cells is associated with significant prolongation of survival in the higher tumor doses (10(5) tumor cells/recipient) and complete elimination of the tumor in a high percentage of recipients at lower tumor levels (10(3)-10(4) tumor cells/recipient). At levels of BM transfer comparable to that used in humans, there was no evidence of a failure of LAK-treated bone marrow to reconstitute lethally conditioned recipient animals. However, with lower numbers of BM cells, there was an increased mortality in animals receiving LAK-treated BM, suggesting a minimal inhibition of pluripotent hematopoietic stem cell function when suboptimal numbers of BM cells are used for reconstitution. These experiments demonstrate that LAk cells are capable of eliminating neoplastic cells in bone marrow without significant destruction of immature syngeneic stem cells. LAK cells display a broad range of cytolytic activity against hematopoietic and solid tissue tumors, and are therefore capable of eliminating small numbers of tumor cells from a wide variety of neoplastic diseases of the marrow. The ability to detect and eliminate malignant cells, without interfering with reconstitution with donor marrow, suggests that immune therapy with LAK cells can be a relatively simple and efficient method to purge bone marrow prior to autologous transplantation in patients following high-dose chemotherapy for neoplastic diseases.

Animals↗
PubMed1995

Influence of serum levels on leukemic cell destruction by the ether lipid ET-18-OCH3.

The effect of serum on the antineoplastic action of the alkyl-lysophospholipid 1-octadecyl-2-O-methyl-sn-glycerol-3-phosphocholine (ET-18-OCH3) was studied in two human leukemia cell lines, HL60 and K562, and in leukemic cells of patients. Decreasing amounts of serum in the culture medium enhanced the cytotoxic action of ET-18-OCH3 dramatically in both cell lines and in the leukemic cells, as measured by cell survival and proliferation. Uptake of ET-18-OCH3 was likewise increased at reduced serum levels. Similar effects were obtained when fetal calf serum (FCS) in the culture medium was substituted by bovine serum albumin (BSA, fatty acid free). Selectivity of the alkyl-lysophospholipid at reduced serum or BSA level was demonstrated by clonogenic assays of normal marrow progenitor cells. Our study provides an optimalization of the purging conditions in autologous bone marrow transplantation, by using a low concentration of BSA during ET-18-OCH3 treatment (20 micrograms/ml for 4 h) in serum-free culture medium.

Antineoplastic Agents↗
PubMed1994

[Technical aspects of autologous bone marrow transplantation].

Autologous bone marrow transplantation has become an established procedure in the treatment of malignancies. Especially in patients with hematological malignant diseases, who have no compatible allogeneic bone marrow donor or in patients with solid tumors, in whom the threshold of irreversible bone marrow toxicity is reached by the intensified chemotherapy, this procedure allows the use of a myeloablative therapy. As stem cell sources, bone marrow (BM), peripheral blood-derived stem cells (PBSC), and umbilical cord blood can be used. The risk of contaminating malignant cells in BM or PBSC can be reduced by an in vitro purging of the stem cells. In principle, two different methods exist: one is the negative depletion of contaminating tumor cells and the other is the positive selection of non-malignant hematopoietic pluripotent stem cells. Which of the purging principles will be most effective can only be answered through clinical studies.

Bone Marrow Purging↗
PubMed2003

NK-cell purging of leukemia: superior antitumor effects of NK cells H2 allogeneic to the tumor and augmentation with inhibitory receptor blockade.

Natural killer (NK) cells are composed of subsets characterized by the expression of inhibitory or activating receptors, or both, specific for different major histocompatibility complex (MHC) class I determinants. We have previously shown that inhibitory receptor blockade of syngeneic NK cells was an effective means of ex vivo purging of leukemia-contaminated bone marrow and that the transplantation of mice with the purged bone marrow cells (BMCs) resulted in long-term, relapse-free survival. We have extended the investigation to assess the antitumor effects mediated by NK cells H2-allogeneic to tumor cells. We demonstrate that various tumor cell lines are more susceptible to lysis by H2-allogeneic NK cells than by syngeneic NK cells in vitro even though comparable percentages of Ly49 NK cells were present. Using allogeneic NK cells to purge leukemia-contaminating BMCs before transplantation resulted in a higher proportion of mice with long-term survival than using syngeneic NK cells. Allogeneic NK cells did not suppress hematopoietic reconstitution as measured by granulocyte/monocyte-colony-forming unit (CFU-GM), complete blood count (CBC), and donor chimerism at various days after transplantation. Inhibitory receptor blockade of allogeneic NK cells also significantly increased these antitumor effects at lower NK/tumor ratios compared with those of syngeneic NK cells. These results demonstrate that H2-allogeneic NK cells mediate more potent antitumor effects than syngeneic NK cells without adverse hematologic effects and thus may be useful in cancer therapy.

Animals↗
PubMed1993

[A clinical study of autologous hematopoietic stem cells transplantation in 41 patients with leukemia and other malignant diseases].

41 patients (35 with leukemia, 4 lymphoma, 1 myeloma and 1 neuroblastoma) were treated with autologous hematopoietic stem cells transplantation. 8 patients were treated with autologous bone marrow transplant without purging (ABMT) 15 with autologous bone marrow transplant and purging (pABMT) and 18 with autologous blood hematopoietic stem cells transplant (ABHSCT). The mean hematopoietic reconstitution time was 60, 53, and 29.5 days respectively and the mean GM-CFU recovery time was 37, 44, and 30.5 days respectively in these three groups. The infection complication rates were 37.5%, 26.6% and 16.6% and the relapse rates were 37.5%, 30% and 18.7% respectively in the three groups. The results indicated that the ABHSCT had an earlier hematopoietic reconstitution time, a lesser infection complication rate and a lower relapse rate. Comparing with conventional chemotherapy, all the three transplant groups had an obviously longer disease-free survival time and a better curative effect.

Adolescent↗
PubMed1997

The mechanisms involved in the impairment of hematopoiesis after autologous bone marrow transplantation.

Hematopoiesis after autologous bone marrow transplantation (BMT) is characterized by a prolonged and severe deficiency of marrow progenitors for several years, especially of erythroid and megakaryocyte progenitors, while the peripheral blood cells and marrow cellularity have reached relatively normal values within a few weeks. These anomalies are comparable to those reported for allogeneic BMT, despite the absence of any allo-immune reaction or post-graft immunosuppressive therapy. Post-graft hematopoietic impairment is the consequence of quantitative and qualitative changes involving both stem cell and stromal compartments which are expressed by an impaired capacity of stem cell self-renewal and commitment towards erythroid and megakaryocytic lineages. Besides the toxicity of conditioning regimens, hematopoietic reconstitution using autologous grafts is particularly dependent on a combination of factors related to the patient, such as underlying disease and pre-graft chemotherapy regimens, and to the graft processing itself, such as in vitro purging with chemotherapeutic agents.

Antineoplastic Agents↗
PubMed1994

Autologous bone marrow transplantation in acute lymphoblastic leukaemia.

There has been a great deal of interest in the use of high dose chemotherapy and/or radiotherapy, with autologous bone marrow/peripheral blood stem cell rescue, in the treatment of haematological malignancies including acute lymphoblastic leukaemia (ALL). In this review we assess the role of autologous bone marrow transplantation (ABMT) in ALL. The heterogeneity of this disease makes the analysis of treatment results in ALL difficult to interpret. There is some evidence that ABMT may be useful in second complete remission (CR) and increasing interest in ABMT as a therapeutic option in first CR in adults. At the moment there is little evidence that such an approach will have an impact in childhood ALL. ABMT is considerably less toxic than allogeneic bone marrow transplantation and the major cause of 'treatment failure' is disease relapse. There has been considerable effort put into purging autologous bone marrow of malignant stem cells but whether purging is effective remains controversial and not proven. Newer studies involving cytokines post-ABMT to stimulate an artificial 'graft versus leukaemia' effect may prove of value.

Adult↗
PubMed1993

Role of autologous bone marrow transplantation for patients with acute and chronic leukemias.

Autologous bone marrow transplantation has been increasingly used as effective curative therapy for patients with acute myelocytic leukemia or acute lymphoblastic leukemia who are not candidates for allografting. Its potential role for patients with chronic myelocytic leukemia is considered investigational; however, recent advancements in stem cell separation may make autologous transplantation an attractive alternative for this disease as well. The timing of the autologous transplant and the role of marrow purging are discussed in depth. In addition, post-transplant immune modulation and the use of growth factors and other cytokines following autologous reinfusion are currently being investigated.

Acute Disease↗
PubMed2000

Autologous blood cell vs marrow transplantation for acute myeloid leukemia in complete remission: an EBMT retrospective analysis.

In order to compare autologous bone marrow (BMT) and blood cell transplantation (BCT) in patients with acute myeloid leukemia (AML) in first remission (CR1), we retrospectively reviewed the data of 1393 patients registered to EBMT and undergoing either BCT (n = 100), purged (n = 252) or unpurged (n = 1041) BMT. Hematopoietic recovery was significantly quicker after BCT than after either purged or unpurged BMT. The 2-year leukemia-free survival (LFS), relapse incidence (RI) and overall survival for the entire population of patients were 52 +/- 1%, 43 +/- 1% and 58 +/- 1% and were significantly influenced by FAB subtype (M3 vs other) and the intervals between diagnosis and CR1 or CR1 and transplant. After BCT, LFS and RI were 44 +/- 6% and 50 +/- 6% and did not differ significantly from that found for unpurged BMT (49 +/- 2% and 45 +/- 2%; P = NS). However, LFS (57 +/- 3%) and RI (37 +/- 3%) of patients undergoing purged BMT were significantly different from that found for BCT patients (P = 0.01 and P = 0.006). As some characteristics of patients undergoing BCT or purged BMT differed significantly (age, intervals between diagnosis and CR1 or CR1 and transplant), the better outcome observed for purged BMT over BCT patients needs to be prospectively investigated.

Acute Disease↗
PubMed2003

[Comparison of curative effect of autologous peripheral blood stem cell transplantation versus bone marrow transplantation for acute leukemia].

To compare the clinical outcome of autologous peripheral blood stem cell transplantation (APBSCT) and autologous bone marrow transplantation (ABMT) in treatment of patients with acute leukemia in first remission, 41 patients received APBSCT, 17 patients received unpurged ABMT and 30 patients received purged ABMT. The results showed that hematopoietic recovery was significantly earlier after APBSCT than that after purged or unpurged ABMT. The 3-year disease-free survival (DFS), relapse rate (RR) and transplant-related mortality (TRM) for all patients of 3 groups were 51.7%, 41.7% and 6.8%, respectively. DFS and RR were significantly influenced by disease types (ALL or AML) and intervals between diagnosis and CR(1) or CR(1) and transplant. The main causes of transplant-related death were infection and hemorrhage. After APBSCT, DFS, RR and TRM were 48.4%, 43.9% and 4.9%, respectively, and did not differ significantly from those found in unpurged ABMT (47.1%, 45.6% and 11.8%) or purged ABMT (66.5%, 29.6% and 6.7%). It is concluded that the clinical outcome of APBSCT is similar to unpurged or purged ABMT but APBSCT allows faster recovery of hematopoiesis and needs less transfusion support.

Acute Disease↗
PubMed1991

Phenotyping of peripheral blood hemopoietic progenitor cells--in vitro cultures using CD34-/CD33-immunomagnetic purging.

In contrast to many detailed studies on the antigenic profile of hemopoietic progenitor cells from human bone marrow, sparse information, so far, has been gathered with regard to the antigen expression of hemopoietic progenitors present in peripheral blood. Previous studies by multiparameter flow-cytometry have revealed substantial differences of the coexpression of the CD33-, CD19-, and CD74- antigens, respectively, on CD34-positive cells from blood versus those from bone marrow, respectively. Immunomagnetic purging with monoclonal antibodies detecting the CD34-, and the CD33- antigen, respectively, has been used to further characterize the expression of these antigens on day 8 and d-14 granulocyte/macrophage and erythroid colonies as grown from circulating progenitor cells. Purging with CD34 monoclonal antibody abrogated all colony formation, whereas purging with CD33 antibody led to differential inhibition of the various progenitors. Purging bone marrow cells with CD34 antibody, an inhibition of only about 25% was observed with regard to erythroid colonies, whereas an inhibition of about 85% was observed for CFU-GM. These findings reinforce the view that circulating progenitor cells represent relatively immature stages of differentiation, when compared to bone marrow progenitors. Particularly, d-8 erythroid colonies from blood do not represent the equivalent of the genuine CFU-E as described from bone marrow, but they seem to be early stages of BFU-E development.

Adult↗
PubMed2000

Prolonged survival after intensive therapy and purged ABMT in patients with multiple myeloma.

Despite numerous strategies, the cure of multiple myeloma remains a difficult challenge. Recent approaches have involved dose-intensive therapy followed by stem cell transplantation, most often with autologous stem cells (ASCT). Although ASCT is of benefit, it is not considered curative. Between 1988 and 1995, we utilized an aggressive three-drug conditioning regimen followed by ABMT using marrow purged with either 4-hydroperoxycyclophosphamide (4-HC) or mafosphamide (MAF). Twenty-nine of 42 patients who had first received VAD (14 patients) or VAD followed by cyclophosphamide (7 g/m2 i.v.) + dexamethasone (40 mg/day p.o. x4) + GM-CSF (15 patients) met the eligibility criteria needed to undergo bone marrow harvest and ABMT, ie < or =10% marrow plasma cells and > or =50% decrease in paraprotein level. Alpha-interferon maintenance therapy was given post ABMT. Median follow-up is 7.5 years (range 5.0-11.25). Six early and two late non-relapse deaths occurred; 15 patients have relapsed. Seven patients remain in continuous CR (five) or PR (two), including three with stage IIIB disease at diagnosis. One patient developed a soft tissue sarcoma 8 years post ASCT. Although this protocol produced excessive toxicity compared with current approaches, the results demonstrate that dose-intensive therapy and ASCT can produce durable remission in this disease. Further development of dose-intensive strategies is warranted.

Adult↗
PubMed1992

Interleukin-6 fused to a mutant form of Pseudomonas exotoxin kills malignant cells from patients with multiple myeloma.

IL-6-PE4E is a recombinant protein consisting of interleukin-6 (IL-6) fused to a mutant form of Pseudomonas exotoxin in which four basic amino acids are changed to glutamate (PE4E). The chimeric toxin has been previously shown to specifically kill malignant hepatic, prostatic, epidermoid, and myeloma cell lines in vitro. To explore the possible clinical utility of IL-6-PE4E, particularly as an agent for ex vivo purging of marrow for autologous bone marrow transplantation (ABMT), we tested malignant cells from patients with multiple myeloma for sensitivity to this chimeric toxin. Ficoll-purified bone marrow cells were incubated with and without IL-6-toxin for 2 to 3 days. Eight of the 15 myeloma patients had cells that were sensitive to IL-6-toxin as measured by a decrease in the level of protein synthesis. Cells from five patients were very sensitive to IL-6-PE4E, with 50% inhibition of protein synthesis (ID50) achieved at or below 6 ng/mL (7 x 10(-11) mol/L). Cells from three additional patients showed moderate sensitivity, with ID50s between 30 and 140 ng/mL. The remaining seven samples showed little or no sensitivity, with ID50s greater than or equal to 400 ng/mL. Normal bone marrow cells or normal BFU-E and CFU-GM were resistant to the IL-6-toxin even at 1,000 ng/mL. Neither IL-6, IL-2-PE4E, nor an enzymatically deficient mutant of IL-6-PE4E was cytotoxic toward the myeloma cells, indicating that the cytotoxic effect of IL-6-PE4E required the adenosine diphosphate-ribosylation function as well as the specific ligand. Our data suggest that IL-6-toxin could be effective in ex vivo marrow purging in selected multiple myeloma patients who are candidates for ABMT, and that this toxin should also be investigated further for in vivo therapy.

ADP Ribose Transferases↗
PubMed1996

High-dose fractionated total-body irradiation, etoposide and cyclophosphamide for treatment of malignant lymphoma: comparison of autologous bone marrow and peripheral blood stem cells.

Consecutive patients with non-Hodgkin's lymphoma (NHL, n = 133) or Hodgkin's disease (HD, n = 20) were treated with 12.0 Gy of fractionated total body irradiation, etoposide 60 mg/kg, and CY 100 mg/kg followed by infusion of autologous hematopoietic stem cells. Seventy-nine patients received purged (n = 62) or unpurged BM (n = 17), and 74 received unpurged PBSCs alone (n = 56) or with BM (n = 18). The median day for achieving a sustained granulocyte count of 0.5 x 10(9)/I was 14 range (7-66) for BM recipients and 10 (7-30) for PBSC +/- BM recipients (P = 0.03). A platelet count of 20 x 10(9)/I was achieved at a median of day 24 (6-145) in BM recipients and day 11 (range, 7-56) in PBSC +/- BM recipients (P = 0.007). The median number of platelet units transfused was 86 (0-1432) for BM recipients and 30 (6-786) for PBSC +/- BM recipients (P = 0.001). The median number of hospital days was 36 (10-88) for BM recipients and 27 (14-76) for PBSC +/- BM recipients (P = 0.0001). The unadjusted Kaplan-Meier (KM) estimates of survival, event-free survival (EFS) and relapse at 2 years were 0.57, 0.45 and 0.43 for patients receiving BM and 0.55, 0.36 and 0.59 for patients receiving PBSC +/- BM. After adjusting for confounding variables, the estimated relative risk (RR) of death from any cause was 0.92 (P = 0.75), of relapse was 1.25 (P = 0.39), of non-relapse mortality was 0.71 (P = 0.42) and of mortality and/or relapse was 1.17 (P = 0.48) for patients receiving PBSC +/- BM as compared to BM. For 46 patients with NHL receiving unpurged PBSC alone, the unadjusted KM estimate of relapse was 0.61 compared with 0.48 for 52 comparable patients receiving purged BM, while the RR for relapse for patients receiving unpurged PBSCs was 1.37 (P = 0.33) after adjusting for other significant covariates. These data confirm previous observations that patients who receive PBSC +/- BM have faster engraftment, fewer transfusions and shorter hospital stays than patients who receive only BM. There were no statistically significant differences between the two groups in survival, relapse, death from causes other than relapse and event-free survival.

Adolescent↗