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PubMed1985

Indication for bone-marrow harvesting and purging in Burkitt's Lymphoma: a three-year experience.

Between 1980 and 1983, 317 bone-marrow (BM) aspirates from 63 cases of Burkitt's lymphoma (BL) were studied with an in-vitro liquid culture monitoring system. BL cell lines were obtained in culture from 14 of 15 patients with cytologically positive marrow. The in-vitro monitoring system was shown to be useful regardless of Epstein-Barr virus (EBV) status, clinical status of patients and cytogenetic anomalies (8 t(8;14) 2 t(8;22) 2 When BM was cytologically normal or suspect, i.e., less than 5% BL cells, the in-vitro monitoring system was shown to be more sensitive than cytological examination in 25 of 56 cases (44%). The sensitivity of the test is 1/100 000, i.e., 3 logs inferior to the level of detection by cytology. When BM was harvested from all patients in complete remission after two months of chemotherapy, marrow purging proved not to be necessary (38/38 negative cultures); 7/10 of those patients will have been harvested to no purpose (no more than 30% with indication for autologous BM transplantation). When BM was harvested at relapse or in partial remission, the purging procedure was shown to be necessary in 9 of 16 cases (56%).

Bone Marrow↗
PubMed1985

Optimal elimination of leukemic T cells from human bone marrow with T101-ricin A-chain immunotoxin.

In view of bone marrow purging before autologous transplantation in T cell malignancies, an anti-human T cell immunotoxin (IT) has been prepared by coupling ricin A-chain to the monoclonal antibody T101 that binds the T1 differentiation antigen expressed by T lymphocytes as well as by T cell-derived hematologic malignancies. Using a sensitive and reliable clonogenic assay, optimal conditions were defined for the elimination of clonogenic human T leukemic cells among bone marrow cells. Maximal cytoreduction was obtained with IT at a dose of 2 micrograms/mL in the presence of 10 mmol/L NH4Cl. This treatment led to the reduction of more than six orders of magnitude of T101-positive clonogenic leukemic cells, with no harm to T101-negative cells. Moreover, we observed no toxicity of IT to human hematopoietic stem cells (CFU-GEMMT) derived from bone marrow of healthy volunteers. Thus, pretreatment of bone marrow samples with IT plus NH4Cl offers a safe, simple, reliable, and highly efficient means to eliminate undesirable leukemic T cells from the graft.

Ammonium Chloride↗
PubMedDate not supplied

[Transplantation of autologous bone marrow--a new approach in the treatment of neoplastic hematologic diseases. II. Clinical results in acute leukemia, malignant lymphoma and solid tumors].

In this second part of the review the clinical significance of autologous bone marrow transplantation (ABMT) as treatment for acute leukemias (AL) and malignant lymphomas is described. In most adult patients with AL in complete remission treated with conventional maintenance therapy relapse usually occurs within one year. However, the results of ABMT, as an intensive consolidation treatment in patients with AL in remission show long-term disease-free survival in a proportion of 40% of patients. Even better results have been reported in patients with purged bone marrow, although the difference is not statistically significant. A major problem of ABMT is still the high percentage of relapse (50%), while the probability of treatment related mortality is relatively low (up to 10%). ABMT is also showing good results in the treatment of non-Hodgkin's lymphomas of intermediate and high-grade histology and in Hodgkin's disease in cases refractory to the first line therapy and in sensitive relapse. However, in refractory cases the results are poor. It is noteworthy, that in all disorders treated with ABMT, prospective randomised controlled trials are missing and current data are based on heterogenous groups of patients. In the majority of solid tumors, even escalated doses of radiochemotherapy with ABMT are not able to eradicate malignant disease. In contrast, the results are very good in neuroblastoma. Although ABMT is a relatively complex and aggressive method, it is being increasingly applied to the treatment of haematological malignant diseases and the results obtained so far, are encouraging and showing that ABMT, besides allogeneic BMT, represents a promising potentially curative treatment for selected group of patients.

Acute Disease↗
PubMed1996

Efficacy and toxicity of plasma-cell-reactive monoclonal antibodies B-B2 and B-B4 and their immunotoxins.

Immunotherapy based on the delivery of toxic agents to the tumor site using monoclonal antibodies (mAb) may be a promising modality in the treatment of hematological malignancies. In the selection of mAb, both for ex vivo but even more for in vivo therapy, not only their reactivity to the neoplastic cells should be considered, but also reactivity to other body constituents. Here we describe the screening of two human plasma-cell-reactive mAb B-B2 and B-B4, which may be used for immunotherapy of multiple myeloma. Cross-reactivity of B-B2 and B-B4 was determined by immunohistochemistry on a series of tissues. This revealed for both B-B2 and B-B4 a strong staining of epithelial cells in various organs, e.g. lung, liver, skin, kidney and gut, while only a weak and diffuse staining was seen with endothelial cells. In bone marrow reactivity was only found with plasma cells and not with hemopoietic precursors (CD34+ cells). Immunotoxins from B-B2 and B-B4 were constructed by coupling them to the plant-derived ribosome-inactivating protein saporin. Both B-B2 and B-B4 immunotoxins appeared to be efficient in specific inhibition of protein synthesis in plasma cell lines (IC50 respectively 1 nM and 0.1 nm). The immunotoxins were also tested on epithelial cell line A431, on liver cell line HepG2 and on human umbilical vein endothelial cells. The epithelial cell line A431 was reactive with both B-B2 and B-B4, but was only inhibited by B-B4 immunotoxin. Cell line HepG2 was reactive with both mAb, but was not inhibited by either immunotoxin. The endothelial cells showed no reactivity with B-B2 and B-B4 and were not inhibited by either immunotoxin. Bone marrow treated with B-B2 and B-B4 immunotoxin did not show a decrease in colonies of hemopoietic precursor cells. Incubation of multiple-myeloma-derived bone marrow with these immunotoxin resulted in a clear decrease of the number of plasma cells. From these data we conclude that B-B2 and B-B4 immunotoxin can be used for ex vivo bone marrow purging. Discrepancies were found between immunohistochemistry, binding assays and cytotoxicity assays with the mAb and the immunotoxin, which underlines the necessity for these various assays as a preclinical screening.

Antibodies, Monoclonal↗
PubMed1988

[Contribution of bone marrow transplantation to the treatment of children with leukemia].

Bone marrow transplantation (BMT) is an intensive mode of treatment for acute leukemia of childhood. Indication are types and stages of leukemia with a poor prognosis following chemotherapy, such as acute nonlymphocytic leukemia (ANLL) in first complete remission (CR) of the disease, and acute lymphocytic leukemia (ALL) following relapse of the disease, in second CR. On the basis of our own experience and of analysis of published data it can be stated that allogeneic BMT, grafting bone marrow cells from a healthy HLA-identical sibling of the patient, has a long-term therapeutical effect which is superior to that of chemotherapy alone: in cases of ANLL, grafted in first CR, a long-term disease-free survival of 55 to 67% was obtained, and in cases of ALL, grafted in second CR, this was between 38 and 64%. The potential effect of autologous BMT, i.e. with own bone marrow of the patient, sampled during CR of the disease, cannot yet be evaluated properly, because the follow-up period of this mode of treatment is too short. It is worth while to investigate the potential beneficial effect of autologous BMT, e.g. for children with ALL in second CR, who lack a HLA-identical donor. Also the potential contribution of bone marrow purging, e.g. for CALLA-positive lymphocytes, should be investigated in relation to the relapse risk after autologous BMT for common ALL.

Acute Disease↗
PubMed1988

[The detection of residual clonogenic cells using limited dilution analysis].

Limiting dilution analysis, a technique which measures the ability of cells to form colonies in liquid media has been used to quantitative residual cells subsequent to treatment. The reliability of this in vitro test as a tool in the selection of process of bone marrow purging was examined. With conventional methods like release of 51Chrome a 2 log reduction could be evaluated, while a reduction of 4 log was assessed by limiting dilution analysis for a same treatment. However the sensibility of this method depends of several factors which we have been examined in this study.

Bone Marrow Cells↗
PubMed1985

[Autograft of bone marrow treated by immunotoxin T 101 for the treatment of T-cell leukemia and lymphoma. Initial clinical cases].

In order to consolidate a complete or partial remission, 4 patients with T-cell malignancy received cyclophosphamide 120 mg/kg plus total body irradiation, followed by reinfusion of cryopreserved autologous bone marrow purged in vitro by the immunotoxin T 101 (SR 41322) composed of the murine monoclonal T 101 antibody coupled with the A chain of ricin. The immunotoxin was applied in doses of 10(-9) and 10(-8) M for periods of 4 and 20 hours at 37 degrees C. The recovery of CFUc and BFUe progenitors was total following incubation with IT 101, but reduced after cryopreservation (1-15 to 80% for CFUc,-33 to 47% for BFUe), haematopoietic recovery occurred within normal delays, demonstrating that autologous bone marrow pretreated with the immunotoxin can be successfully transplanted. However, the slow increase in lymphocytes and the occurrence of lethal infection in 2 cases indicate that an in-depth study of immunological reconstitution after in vitro treatment of bone marrow with ITT 101 is necessary.

Adolescent↗
PubMed2001

Improved efficiency of remission induction facilitates autologous BMT harvesting and improves overall survival in adults with AML: 108 patients treated at a single institution.

A hundred and eight patients less than 60 years old with de novo acute myeloid leukemia were treated between 1982 and 1994 by protocols including final intensification with a transplant using autologous bone marrow purged by mafosfamide in first remission in the absence of an HLA-matched sibling donor available for allograft. From 1989, we attempted to improve tumor control by using high-dose anthracyclines in induction, by increasing from one to two the number of consolidation courses pre-transplant and by introducing intermediate doses of cytarabine in the first consolidation course. The CR rate was 77% (33/43) before 1989 and 90% (59/65) after 1989 (P = 0.06). Forty-five out of the 59 patients (76%) who achieved CR after 1989 could undergo bone marrow grafting in CR1 vs 16/33 (48%) before 1989 (P = 0.01). In spite of the higher proportion of patients above 50 years after 1989 (32%) toxicity was mild and an adequate graft was obtained more frequently after one collection. The principal factor relating to improvement in graft feasibility was the post-1989 modification of induction and consolidation regimens. This improvement in graft feasibility was associated with a better disease-free survival (DFS) (48 +/- 7% vs 32 +/- 8%, P = 0.04) and overall survival (OS) (53 +/- 6% vs 30 +/- 7%, P = 0.007) at 5 years. By multivariate analysis four factors were associated with overall survival (OS): karyotype, white blood cell count at diagnosis, treatment regimen and bone marrow grafting in CR1. This global approach should be prospectively compared with intensive chemotherapy.

Acute Disease↗
PubMed1992

High dose chemotherapy with autologous marrow transplantation in follicular lymphomas.

Twenty six adult patients with low grade nodular non Hodgkin's lymphoma (NHL) were treated with autologous bone marrow transplantation. Conditioning regimen was BEAM-BEAC in 15 patients and TBI + Cyclophosphamide in 11 patients. Twenty one patients were grafted with haematopoietic stem cells, 12 after bone marrow purging and five with peripheral blood stem cells (PBSC). Two patients were treated in CR1 of leukemic phase, six in PR1 and eighteen in sensitive relapse. With a median follow-up of 30 months, the actuarial survival is 91% and actuarial event free survival 67%. These data confirm some interest of ABMT in the treatment of low grade follicular NHL.

Adult↗
PubMed1994

Combination therapy with nucleoside analogs and alkylating agents.

The nucleoside analog, 2'-deoxycoformycin (dCF), and the alkylating agents, chlorambucil (CLB) and cyclophosphamide, are effective agents in the treatment of chronic B cell leukemias and lymphomas. The cyclophosphamide analog, 4-hydroperoxycyclophosphamide (4-HC), generates the same active metabolite as cyclophosphamide in cells and has been used extensively for bone marrow purging in vitro. We have observed that deoxyadenosine (dAdo) plus dCF (dAdo/dCF) inhibit the repair of x-irradiation-induced and bleomycin-induced DNA damage in vitro, and that this results in either synergistic or additive cytotoxicity, respectively. In the present study we examined whether dAdo/dCF, can enhance the antitumor activity of CLB and 4-HC in chronic lymphocytic leukemia (CLL) cells in vitro. CLL cells were treated with CLB for 6 hr and then with dAdo/dCF for 18 hr and cytotoxicity was measured by the MTT assay. Synergy was observed between CLB and dAdo/dCF in CLL cells from 2 patients, with synergy increasing as the CLB dose was raised. In contrast, similar treatment of human bone marrow cells resulted in little or no synergistic cell kill. Treatment of CLL cells from 2 patients with 4-HC for 30 min followed by dAdo/dCF for 18 hr resulted in little synergistic cytotoxicity, although this drug combination did produce an additive cell kill. Thus, combination therapy with nucleoside analogs and alkylating agents may be useful for improving treatment of CLL.

Alkylating Agents↗
PubMed1995

Bone marrow transplantation in low-grade non-Hodgkin's lymphoma.

The low-grade histologic types constitute one quarter of all non-Hodgkin's lymphomas (NHL). Conventional chemotherapy and chemo-radiation therapy have failed to significantly alter the course of this disease, and most patients eventually succumb to lymphoma. Despite the fact that NHLs exhibit a steep dose-response relation to cytotoxic therapy, fewer than 30% of eligible patients undergo bone marrow transplantation. Reasons for fewer patients receiving this course of treatment include: elderly patient population, extensive previous chemotherapy and/or radiation therapy, high incidence of bone marrow involvement, and transformation to higher grade NHLs. In recent years, improvements in several areas have enhanced the therapeutic index for bone marrow transplantation. These advances include the use of more effective preparative regimens, recombinant hematopoietic growth factors, extended-spectrum antibiotics, and an increased expertise in blood transfusion techniques and practices. Other, more effective strategies include sophisticated in vitro bone marrow purging approaches and peripheral blood progenitor cell collection. As a result, more patients have been able to receive dose-intensive therapy followed by hematopoietic cellular rescue. Although follow up is short in most series, encouraging results have stimulated some centers to begin transplanting responding patients earlier in their disease course; in more than 200 patients treated in this fashion, long-term disease-free survival has been achieved in nearly 70% of patients, some patients for a period of greater than 6 years. The new purine analogues fludarabine, pentostatin, and 2-chlorodeoxyadenosine also have shown promise in both initial and salvage treatment of low-grade NHLs. It remains to be determined whether this group of drugs will be complimentary to the bone marrow and/or peripheral blood progenitor cell transplant approach.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Reactivity of rat monoclonal antibody CAMPATH-1 with human leukaemia cells and its possible application for autologous bone marrow transplantation.

The rat monoclonal antibody CAMPATH-1 recognizes a hitherto undefined antigen present on virtually all normal lymphocytes and monocytes. Its reactivity with 105 samples of fresh leukaemic cells and 13 cell lines was measured by indirect fluorescence and peroxidase staining to define in more detail which stages of differentiation it recognizes. It was found to bind to cells from virtually all cases of lymphoid leukaemia (B cell CLL, T cell ALL, cALL and the few examples of HCL, PLL, Sezary syndrome and CGL in lymphoid blast crisis). The single case of cALL in relapse and four of six cases of null ALL were negative. Binding to non-lymphoid leukaemia cells (AML, AMML, AMoL, APL, AEL and CGL in blast crisis) was weaker or undetectable. Binding to established lymphoid cell lines was generally weak compared with fresh cells but some lines (MOLT4, DAUDI and X308) expressed adequate amounts of antigen to be lysed by CAMPATH-1 with human complement. Because CAMPATH-1 is very effective at killing lymphocytes in the presence of human complement, it has been used for removal of T cells in allogeneic transplants. The present results suggest that it might also have a role in purging bone marrow of leukaemia cells prior to autologous transplantation for acute lymphocytic leukaemia.

Animals↗
PubMed1992

Differential effect of the combination methotrexate/(dl)-5-methyltetrahydrofolate on lymphoid malignant and normal bone marrow cells.

It has been reported that high doses of (dl)-5-methyltetrahydrofolate (mTHF) inhibit the growth of leukemic cell lines. We studied the effect of methotrexate (MTX) and mTHF in combination on the lymphoid cell lines BALM 3, CEM, MOLT 4 and P3HR1 by evaluating the clonogenic cell reduction in a limiting dilution assay. Cells were treated with 0.1 mM MTX for 4 h and 1 mM mTHF for 48 h. The growth of the cell lines was inhibited by 1 mM mTHF, with a clonogenic cell reduction of 3.5 log. MTX, following by mTHF after a delay of 8-24 h, caused a substantial killing of lymphoid leukemia cells, greater than the effect of either drug alone. The clonogenic cell reduction caused by the combination MTX-mTHF ranged from about 3.5 to 4.5 log, depending on the cell line studied. Normal hemopoiesis, as evaluated by primitive hematopoietic precursor colonies and granulocyte-macrophage colony-forming units (CFU-GM) was only slightly affected by the MTX-mTHF treatment at a dose and schedule which caused up to 4.5 log reduction of the leukemic cell lines. mTHF-MTX treatment could be useful in vitro for purging bone marrow cells in autologous bone marrow transplantation for acute leukemia.

Bone Marrow↗
PubMed1996

Value of autologous bone marrow transplantation (ABMT) in 42 patients with follicular lymphomas responsive to conventional chemotherapy: a "France Autogreffe" study.

The value of high-dose chemotherapy with hematologic stem cell rescue has not yet been established in the treatment of low-grade non-Hodgkin's lymphoma. We report the results of a retrospective "France Autogreffe" study of 42 patients grafted during first partial remission (N = 13) or chemosensitive relapse (N = 29) for follicular lymphoma before January 1990. The median age was 38 years (range: 26 to 61 years). Preparative therapy was chemotherapy alone in 22 patients and total body irradiation (TBI)-containing regimens in 20 patients. Thirty-seven patients received hematopoietic marrow stem cells. Bone marrow purging was performed in 15 patients. Five patients received peripheral blood stem cells. With a median follow-up of 43 months, relapse-free survival is 66%, event-free survival 58%, and overall survival 83%. To date, no prognostic factors have been shown. Nine of these patients were tested for evaluation of minimal residual disease by polymerase chain reaction analysis of bc12 rearrangement in the blood. Six were positive.

Adult↗
PubMed1999

Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group.

BACKGROUND: Children with high-risk neuroblastoma have a poor outcome. In this study, we assessed whether myeloablative therapy in conjunction with transplantation of autologous bone marrow improved event-free survival as compared with chemotherapy alone, and whether subsequent treatment with 13-cis-retinoic acid (isotretinoin) further improves event-free survival. METHODS: All patients were treated with the same initial regimen of chemotherapy, and those without disease progression were then randomly assigned to receive continued treatment with myeloablative chemotherapy, total-body irradiation, and transplantation of autologous bone marrow purged of neuroblastoma cells or to receive three cycles of intensive chemotherapy alone. All patients who completed cytotoxic therapy without disease progression were then randomly assigned to receive no further therapy or treatment with 13-cis-retinoic acid for six months. RESULTS: The mean (+/-SE) event-free survival rate three years after the first randomization was significantly better among the 189 patients who were assigned to undergo transplantation than among the 190 patients assigned to receive continuation chemotherapy (34+/-4 percent vs. 22+/-4 percent, P=0.034). The event-free survival rate three years after the second randomization was significantly better among the 130 patients who were assigned to receive 13-cis-retinoic acid than among the 128 patients assigned to receive no further therapy (46+/-6 percent vs. 29+/-5 percent, P=0.027). CONCLUSIONS: Treatment with myeloablative therapy and autologous bone marrow transplantation improved event-free survival among children with high-risk neuroblastoma. In addition, treatment with 13-cis-retinoic acid was beneficial for patients without progressive disease when it was administered after chemotherapy or transplantation.

Adolescent↗
PubMed1989

Immunomagnetic removal of B-lymphoma cells using a novel mono-sized magnetizable polymer bead, M-280, in conjunction with primary IgM and IgG antibodies.

The efficacy of a novel monosized and magnetizable polymer bead, denoted M-280, in immunomagnetic removal of Rael B-lymphoma cells was compared with that of M-450 beads, previously used in bone marrow purging. The M-280 beads which are smaller (diameter 2.8 microns) and contain less iron than the M-450 beads were coated with polyclonal IgG sheep antimouse (SAM) antibody. The two types of immunobeads were equally efficacious when used together with the mouse monoclonal IgG antibodies HH1 or FN1, giving tumor cell depletions of about 3 logs in one cycle of operation. However, when used together with the primary IgM monoclonal antibodies (MoAbs) AB1 or HH2, the new immunobeads were significantly more efficacious than the M-450 immunobeads. To elucidate the underlying mechanism flow cytometric studies and measurements of the binding of the labeled primary MoAbs to the cellular antigens as well as to the immunobeads were carried out. Competition experiments showed that in the case of IgG MoAbs, the SAM beads bind predominantly to the Fc portion, whereas in the case of the IgM MoAbs, the Fab part plays a relatively greater role in the binding. The results indicate that if M-280 immunobeads are used, IgM MoAbs may profitably be included in antibody cocktails together with IgG antibodies in immunomagnetic purging of B-lymphoma cells. They suggest that in the case of cell bound MoAbs, the epitopes on IgG are more accessible to SAM beads than those of surface bound IgM molecules.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1999

Intensification of therapy using hematopoietic stem-cell support for high-risk neuroblastoma.

The use of new strategies for dose intensification using peripheral blood stem cell or autologous purged bone marrow rescue has raised expectations for cure in advanced neuroblastoma, although conflicting reports exist regarding the efficacy of these approaches. Using risk groups based on both biological and clinical staging, the Children's Cancer Group and the Pediatric Oncology Group have agreed upon common prognostic criteria for treatment stratification. We summarize below the prognostic classification and treatment approaches that have improved the overall outcome for children with advanced neuroblastoma. Intensive induction therapy, myeloablative therapy, hematopoietic stem cell purging, and post-transplant therapy for minimal residual disease all have an important role in the treatment. Possible future improvements may incorporate more tumor-specific therapy with targeted radiotherapy, monoclonal antibodies, tumor vaccines, and differentiating agents.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

The infusion of human fetal liver cells.

Only transient engraftment of infused fetal liver cells has been demonstrated in a small proportion of patients with hypoplastic bone marrow or patients undergoing treatment for acute leukemia. This presumably reflects the ability of the recipient to reject the infused cells, the infusion of too few viable stem cells or the availability of too few accessory cells; it is clear from the successful engraftment of infused fetal liver cells in a high proportion of infants and fetuses with severe immunodeficiency diseases that, under favorable circumstances, cells derived from human fetal liver are capable of establishing effective grafts and making a substantial contribution to hematopoiesis comparable to that of transplanted cells derived from the liver of the fetal mouse, rat, rabbit or dog. Significant clinical and hematological improvements have been described following infusions of fetal liver cells without evidence of engraftment. These improvements have been attributed to the ability of the infused cells to promote regeneration of autologous hematopoiesis and to inhibit the growth of tumor cells. These possibilities are worthy of evaluation in relation to the production of putative regulators of cellular proliferation in the liver. Meanwhile a suppressor of tumor growth is being used to purge bone marrow prior to autologous transplantation. The generation in vitro of cells which possess the properties of hematopoietic stem cells generated in the liver--from cells which can be maintained as permanent cell lines--would transform hematopoietic cell replacement therapy, and the possibility may not be too unrealistic to contemplate.

Animals↗