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PubMed1989

Peanut agglutinin shows specificity for bone marrow plasma cells.

A panel of lectins was used to study surface carbohydrate expression on myeloma cells with the aim of finding a possible agent for in vitro bone marrow purging. Peanut agglutinin (PNA, galactose beta 1,3 N-acetylgalactosamine-binding) bound to all plasma cells in 33/34 bone marrow samples from myeloma patients and to all plasma cells in 11 bone marrow from patients with monoclonal gammopathy of undetermined significance and 10 normal bone marrow samples. Bone marrow and peripheral blood monocytes reacted weakly with PNA except in one case of acute monoblastic leukaemia and two of chronic myelomonocytic leukaemia in which monocytes were strongly positive. The only case of plasma cell leukaemia studied was PNA negative. All other bone marrow mononuclear cells were negative for PNA but became positive after sialidase treatment. Peanut agglutinin may have potential as an agent to be used in myeloma for in vitro marrow purging prior to autologous transplantation in combination with high dose chemotherapy.

Antigens, Surface↗
PubMed1999

Autologous transplantation. Purging and the impact of minimal residual disease.

Without a randomized trial any benefit of purging on patient survival will remain theoretical. Although molecular techniques may document that the autograft tumor burden is substantial when compared with the patient tumor load following conditioning therapy, a theoretical benefit may not be sufficient to persuade third-party payers to expend additional money for the purging procedure. For insurers, the equation to determine product usefulness does not consider risk as the only negative component, but a combination of risk and cost. When the amount that can be spent is limited, a demonstration that these additional costs will garner a true patient benefit becomes more important. Because it is difficult to assign a dollar amount for a theoretical benefit, third-party payers may be unwilling to accept the potential but unproven benefit from a purging procedure. Nevertheless, if the time to engraftment remains unchanged, the added costs of the purging procedure should be relatively minimal and, in the authors' view, should not be a major impediment to its widespread use. Educated patients and physicians will probably demand that these procedures be performed in cases where autograft purging adds little if any risk and provides at least a significant potential for benefit.

Bone Marrow Purging↗
PubMed1996

Consolidation chemoradiotherapy and autologous bone marrow transplantation versus continued chemotherapy for metastatic neuroblastoma: a report of two concurrent Children's Cancer Group studies.

PURPOSE: To compare event-free survival (EFS) for patients with stage IV neuroblastoma who were treated with induction chemotherapy followed by additional courses of the same chemotherapy or by intensive chemoradiotherapy and autologous bone marrow transplantation (ABMT). METHODS: Two hundred seven children who were diagnosed with stage IV neuroblastoma after 1 year of age were given five to seven courses of induction chemotherapy consisting of cisplatin, etoposide, doxorubicin, and cyclophosphamide (CCC-321-P2). This chemotherapy was continued for 13 total courses for some patients, whereas intensive chemoradiotherapy with ABMT was given to others (CCG-321-P3). The decision to continue chemotherapy versus to consolidate with chemoradiotherapy was not randomized but was made by parents and physicians. Marrow used for ABMT was purged ex vivo and was free of immunocytologically detectable neuroblastoma cells. RESULTS: One hundred fifty-nine of 207 patients (77%) remained event-free during induction therapy. Of these, 67 received chemoradiotherapy/ABMT (CCG-321-P3) and 74 continued chemotherapy (CCG-321-P2). Using Cox regression analysis, the relative risk (RR) of an event after chemoradiotherapy/ABMT was estimated to be 58% of that for patients who continued chemotherapy (P = .01). Similarly, Kaplan-Meier analysis estimated EFS at four years for the chemoradiotherapy/ABMT and chemotherapy groups to be 40% and 19% respectively (P = .019). Subgroups appearing to benefit from chemoradiotherapy/ABMT were those with only a partial tumor response to induction chemotherapy (RR = 0.43; P = .008; EFS, 29% v 6%) and those whose tumors had amplification of the N-myc gene (RR = 0.26; P = .112; EFS, 67% v 0%). CONCLUSION: Consolidation with intensive, myeloablative chemoradiotherapy followed by purged ABMT may be more effective than continuing chemotherapy for patients with stage IV neuroblastoma.

Adolescent↗
PubMed2001

A negative-selection strategy for depleting myeloma cells from patients' BM and/or leukapheresis blood.

BACKGROUND: Autologous transplantation improves survival in multiple myeloma patients, however, most eventually relapse. As an attempt towards improving relapse-free survival, we designed a negative-selection purging strategy, to remove myeloma cells from leukapheresis harvests using MAbs specific for Ags on myeloma cells. METHODS: CD38 is highly expressed on myeloma plasma cells, but expressed at lower levels on normal progenitors and absent on in vivo repopulating cells. We evaluated depletion of CD38-expressing cells, with or without depletion of B-cell Ag-expressing cells. Using myeloma BM or blood cells diluted into allogeneic G-CSF primed leukapheresis cells, bispecific tetrameric Ab complexes that bind dextran iron particles were used to label and retain cells in a magnetic column, StemSep. Depletion efficacy was measured by semi-quantitative allele-specific oligonucleotide (ASO)-PCR amplification of patients' clonotypic IgH gene. RESULTS: Low (0.2 microg/mL) concentrations of anti-CD38 with CD19 and CD20 complexes depleted approximately 3-5 logs of clonotypic cells, with recovery of approximately 19% of colony-forming cells, approximately 50% primitive progenitors measured by LTCIC and retention of non-obese diabetic /SCID engrafting ability. Scale-up experiments using leukapheresis harvests and 0.5-1 x 10(10) cell capacity columns demonstrated no loss of log depletion of highly positive cells, or recovery of unlabelled cells. DISCUSSION: These results compare favorably with other purging techniques and allow the retention of most normal BM cells, including T cells, which may be important for immunity. These results support the development of a clinical trial using this strategy for purging myeloma cells.

Animals↗
PubMed1996

A combination of CD34 selection and complement-mediated immunopurging (anti-CD15 monoclonal antibody) eliminates tumor cells while sparing normal progenitor cells.

Autologous bone marrow transplantation (ABMT) for acute myeloid leukemia (AML) in first complete remission (CR) results in a prolonged disease-free survival (DFS) of 34%-57%. Relapse of the underlying disease is the major cause for failure of ABMT. Relapse can result fom tumor cells either surviving in the patient or reinfused in the autograft. Genetic marking of autografted cells has demonstrated that transplanted cells contribute to relapse. This finding supports the use of purged autografts. Several purging techniques have been used. Immunologic purging using the monoclonal antibody (mAb) PM-81 (anti-CD15) has been used by our center with a long-term DFS in 50% of AML patients. PM-81 reacts with 90% of AML patients, and we have used it for over 10 years. We have investigated a two-stage purging technique involving initial selection for CD34+ cells followed by mAb purging in bone marrow (BM) and peripheral blood stem cell (PBSC) harvests. This method achieved up to a 7 log diminution in leukemic cells and 1-4 log reduction in CD15+ cells, without a significant loss of hematopoietic progenitor cells. This double-purging technique has the advantages of cytoreduction, elimination of CD34- leukemic cells, and possible improvement in the clinical efficacy of purging by concentrating for CD34+ cells. Cytoreduction by CD34 enrichment followed by purging may facilitate the use of PBSC transplants in AML.

Antibodies, Monoclonal↗
PubMed1987

Comparison of the sensitivity of normal and leukaemic myeloid progenitors to in-vitro incubation with cytotoxic drugs: a study of pharmacological purging.

The sensitivity of myeloid leukaemic colony forming cells (AML-CFC), to five cytotoxic drugs has been compared in two culture systems with the sensitivity of normal myeloid progenitor cells (GM-CFC). No increased sensitivity was found for AML-CFC to any of the chemotherapeutic agents studied. AML-CFC were significantly less sensitive than normal GM-CFC to mafosfamide at the doses commonly used to purge bone marrow autografts. It is suggested that AML cells probably display similar sensitivity to cytotoxic agents as normal myelopoietic cells at a similar stage of differentiation. Hence complete elimination of the leukemic clone by pharmacological purging may be incompatible with bone marrow re-engraftment. We conclude that purging AML autografts with any of the agents examined has little scientific basis.

Antineoplastic Agents↗
PubMed1998

CD34+ subset and tumor cell quantitation by flow cytometry--step toward quality assessment of autografts in B cell malignancies.

To day it is possible to predict the probability of fast engraftment based on a very simple flow cytometry standard analysis of CD34+ cells as documented by the 28 laboratories within the NSCL-G. However, the risk for delayed platelet engraftment still needs to be predicted in clinical practice for patients receiving less than 10 x 10(6) CD34+ cells/kg. Here we present data from our center supporting that identification by double staining of uncommitted (CD34+/CD38-) and lineage specific (CD34+/CD61+) progenitors may allow us to predict patients at high risk for prolonged platelet recovery. Following high dose therapy more than 30% of patients with haematological malignancies do suffer from disease recurrence within the first 3-6 months following high dose therapy. Today there are strong indications that such patients may have been transplanted with an autograft contaminated with a high number of potentially malignant B cells. Here we present a novel methodology for quantitation of blood circulating tumor cells by combining flow cytometry, cell sorting, limiting dilution and single cell RT-PCR. Such methodology has documented mobilization of clonal B cells following priming of the peripheral blood stem cell harvest and it can be used to identify minor populations and predict the efficacy of patient specific purging strategy. Consequently, quality assessment of autografts may include techniques which can predict fast three lineage engraftment as well as the risk for prolonged platelet recovery and can identify the group of patients/autografts with a strong contamination of potential tumor cells with a risk of early relapse. The future supportive cell therapy may depend upon improvements of such technologies and strategies including the selective administration of lineage specific growth factors e.g., trombopoietin as well as patient specific controlled purging strategies.

Antigens, CD19↗
PubMed1991

Model experiments for immunomagnetic elimination of leukemic cells from human bone marrow. Presentation of a novel magnetic separation system.

Optimal conditions for removing leukemic cells from human bone marrow with monoclonal antibodies (mAb) and magnetic immunobeads were investigated. Monodisperse 3 microns polystyrene microspheres containing magnetite were coated with affinity-purified rabbit antimouse IgG at 4 degrees C, pH 9.6 for 18 h. SKW-3 cells (T-CLL cell line) were marked with the supravital DNA stain Hoechst 33342, seeded into normal human bone marrow, and then incubated with the mAb CD1, CD6, and CD8 at 4 degrees C for 30 min. In preliminary experiments REH cells (cALL cells) and mouse anti-REH cell antibodies were used to find the most favorable conditions for the binding of magnetic beads to tumor cells. Optimal formation of cell-bead rosettes was achieved by rotating beads and tumor cells together at room temperature at a concentration of 1 x 10(7) cells/ml, a bead: tumor cell ratio of 100:1 and an incubation time of one hour. The novel magnetic separation apparatus consists of three polystyrene chambers connected by silicone rubber tubing. The chambers contain four steel inserts each equipped with 32 nickel wires, which are magnetized by permanent magnets in such a way that the inhomogeneous high gradient magnetic field could be established within the cell suspension containing the cells to be depleted. The fluid flow was established by a peristaltic pump. At a flow rate of 1.5 ml/min and a field strength of 160 kA/m, no beads could be detected in the purged marrow. A cocktail of the three mAb was more effective than any single antibody in forming bead-cell rosettes. Two sequential purging cycles were superior to one. The marrow recovered was highly viable as assessed by trypan blue dye exclusion and by growth of CFU-GM.

Antibodies, Monoclonal↗
PubMed1999

Adenovirus p53 purging for human breast cancer stem cell products.

Tumor cell (TC) contamination of stem cell products can contribute to relapse after high dose chemotherapy and stem cell rescue. A new purging technology using replication-deficient recombinant adenovirus (Adv) containing the p53 tumor suppressor gene (Adv-p53) has been suggested to reduce tumor contamination of autologous stem cell product. We demonstrate herein a safe and effective Adv-p53 purging procedure using four human breast cancer TC lines. Multiple parameters need to be achieved to successfully purge stem cell products, including a high cell:virus ratio, a small incubation volume, a long incubation time and 37 degrees C rather than room temperature. These parameters are all interrelated and equally important for the inhibition of TC clonogenic growth. In our studies, we also observed that Adv could nonspecifically inhibit TC clonogenic growth, although Adv-p53 treatment led to a significantly greater inhibition of clonogenic growth by cells expressing mutated p53. The presence of peripheral stem cell (PSC) products was found to decrease the effect of Adv-p53 on TC clonogenic growth, suggesting that PSC products could compete with TC for infection by recombinant Adv. However, X-Gal staining after incubation with Adv containing-galactosidase demonstrated that PSC products were 2, 000-fold more resistant to Adv infection than TC. We conclude that a 4-hour incubation of stem cell products (2 x 10(8)/ml) with 4 x 10(11) Adv-p53 particles is sufficient to completely purge TC with no effect on hematopoietic cell function.

Adenoviridae↗
PubMed1988

The role of high-dose therapy and autologous bone marrow reinfusion in the treatment of malignant lymphomas.

In a significant fraction of patients with NHL or HD, disease develops that is resistant to conventional chemotherapy. Experience using high-dose chemotherapy, with or without TBI, and ABMR is expanding. In HD, remissions can be achieved in approximately half of the patients with relapsed advanced disease. This may also be true in patients with NHL who do not respond to conventional regimens. High-dose chemoradiotherapy regimens are toxic and require extensive supportive care. Relapse frequently occurs in areas of previous disease, suggesting failure of the conditioning regimen rather that an infusion of occult tumor cells in the autologous bone marrow had occurred. Thus, the role of marrow purging in this therapy needs to be further evaluated and compared with findings involving nonpurged marrow reinfusion. It is also important to evaluate the effects of more vigorous attempts at cytoreduction of bulky disease prior to high-dose therapy and ABMR. We recommend that high-dose therapy and ABMR in an investigational setting be used (1) in patients with HD who experience relapse after MOPP/ABVD or equivalent regimens and (2) in patients with intermediate or high-grade NHL whose disease recurs or is resistant to conventional regimens. Potential areas for development include the use of this modality as intensification therapy following conventional therapy in patients with intermediate or high-grade NHL with poor prognostic features. Toxicity can be decreased and efficacy increased only if therapy is administered to patients who have not been heavily pretreated and who have lower tumor burden and a good performance status. The role of high-dose chemotherapy of ABMR in the nodular lymphomas is not known at this point. Finally, high-dose ABMR therapy has a definite role in salvaging patients with malignant lymphomas. Many issues need to be resolved, including (i) the optimal timing of this approach, (ii) the optimal conditioning regimen, and (iii) the need for purging bone marrow prior to reinfusion. The past 10 years have led to significant gains. During the next 10 years, it may be possible to refine this therapy and find solutions to the above issues.

Antineoplastic Agents↗
PubMed1999

Ex vivo photodynamic purging in chronic myelogenous leukaemia and other neoplasias with rhodamine derivatives.

Photodynamic therapy (PDT), a cancer treatment already used early in this century, has distinctive advantages over conventional chemotherapy, namely its often observed preferential accumulation in cancer cells and its low intrinsic toxicity. Aggressive therapeutic modalities using high doses of chemotherapy and/or radiation therapy are now commonplace treatments for leukaemia, lymphoma and various non-haematologic malignancies. These intensive approaches have often been used in association with haematopoietic-progenitor-cell support and have induced major responses and remissions in patients with relapsed and refractory diseases, ultimately contributing to improve the disease-free survival of patients with high risk. This has encouraged Theratechnologies, a Montreal-based pharmaceutical company, to develop photodynamic ex vivo purging procedures, including the development of new photosensitizers and irradiation devices for the safe eradication of neoplastic cells from autologous grafts. Our first specific objective, therefore, was to design, synthesize, purify and test photoactive rhodamine derivatives. We have also selected a gas and phosphorus coating characteristic of an efficient scanning fluorescent source for extra-corporeal PDT using rhodamine derivatives. 4,5-Dibromorhodamine 123 (TH9402) was selected because of its photophysical properties, low toxicity and stability. TH9402 photodynamic-cell-therapy process conditions recognized as safe for normal human haematopoietic stem cells and progenitors demonstrated the efficacy of the purging procedure on various leukaemias (including chronic-myelogenous-leukaemia as well as non-Hodgkin-leukaemias and metastatic-breast-cancer cell lines.

Animals↗
PubMed1994

Autologous transplant for chronic myelogenous leukemia using marrow treated ex vivo with mafosfamide.

Ten adult patients with Ph-positive chronic myelogenous leukemia (CML) received autologous transplantation using marrow treated ex vivo with mafosfamide. At transplant, 7 patients were in chronic phase (5 in first, 2 in second) and 3 in accelerated phase. The median time to achieve 500 x 10(6)/l neutrophils was 32 days (range 17-72 days). A platelet count of 20 x 10(9)/l was achieved at a median of 40 days (range 24-151 days). After transplant, cytogenetic analysis revealed 100% Ph-negative marrow metaphases in 6 of 9 analyzable patients with a median duration of Ph-negative hematopoiesis of 6.5 months. After a median follow-up of 16 months (range 3-31 months), five patients evolved into blast crisis, two died of non-hematological causes, one is Ph-negative in chronic phase at +4 and one is in chronic phase, but Ph-positive, at +22. In conclusion, this pilot study demonstrates that: (1) engraftment can occur from Ph-negative stem cells selected by mafosfamide, (2) mafosfamide purging may induce a transient period of Ph-negative hematopoiesis, and (3) modifications of the purging procedure and post-transplant manipulations of the immune-hematopoietic system are required to prolong cytogenetic remission.

Adult↗
PubMed2001

The effect of graft purging with 4-hydroperoxycyclophosphamide in autologous bone marrow transplantation for acute myelogenous leukemia.

BACKGROUND: Autologous bone marrow transplantation is an important therapy for patients with acute myelogenous leukemia (AML). However, leukemia in the graft may contribute to posttransplant relapse. Treatment of the graft with 4-hydroperoxycyclophosphamide (4HC) is sometimes used to decrease numbers of infused leukemia cells (4HC purging). No large controlled trials evaluating efficacy and toxicity of 4HC purging are reported. METHODS: We studied 294 patients reported to the Autologous Blood and Marrow Registry receiving either a 4HC-purged (n = 211) or unpurged (n = 83) autograft for AML in first (n = 209) or second (n = 85) remission. Analyses were restricted to patients transplanted less than 6 months after achieving remission. Using Cox proportional hazards regression, we compared time to treatment failure (death or relapse, inverse of leukemia-free survival) after 4HC-purged vs unpurged transplants while controlling for important prognostic factors. RESULTS: Median duration of posttransplant neutropenia was 40 (range, 10-200) days after 4HC-purged transplants and 29 (9-97) days after unpurged transplants (p < 0.01). Transplant-related mortality was similar in the two groups. In multivariate analysis, patients receiving 4HC-purged transplants had lower risks of treatment failure than those receiving unpurged transplants (relative risk, 0.69, p = 0.12 in the first posttransplant year; relative risk, 0.28, p < 0.0001 thereafter). Adjusted three-year probabilities of leukemia-free survival (95% confidence interval) were 56% (47-64%) and 31% (18-45%) after 4HC-purged and unpurged transplants in first remission, respectively. Corresponding probabilities in second remission were 39% (25-53%) and 10% (1-29%). CONCLUSION: Grafts purged with 4HC are associated with higher leukemia-free survival after autologous bone marrow transplants for AML.

Acute Disease↗
PubMed1993

Is our current strategy in manipulating hemopoiesis in autologous transplantation correct?

Autologous hemopoietic stem cell rescue following high-dose chemoradiotherapy is increasingly used in the treatment of lymphohemopoietic malignancy and selected solid tumors. While encouraging disease control has been reported in acute leukemia, lymphoma, multiple myeloma and breast carcinoma, such an approach suffers from a number of limitations. This review addresses a number of issues that may lead to better stem cells for transplant: which stem cell rescue provides the most rapid hemopoietic reconstitution, how can we get sufficient high quality stem cells for transplant to ensure complete and sustained reconstitution, what are the predictors of rapid and sustained hemopoietic reconstitution, what impact on hemopoietic reconstitution purging and positive selection technology may have, and how can we abrogate the obligatory delay to blood count recovery.

Animals↗
PubMed1997

High-dose therapy and transplantation for low-grade lymphoma.

Because of the indolent natural history of low-grade lymphomas, long follow-up is needed to assess the overall success of high-dose therapy and autografting. Results to date suggest that patients with brief first or second remission with chemotherapy or those who attain only a partial remission with second-line or subsequent chemotherapy, but remain drug sensitive, may enjoy prolonged remissions relative to conventional treatment. The role of autografting in first remission is uncertain because the data from clinical trials are not mature. Furthermore, the risk of myelodysplasia after transplantation, the broad range of therapeutic alternatives available, and the option to give high-dose therapy upon relapse argue against autografting as primary treatment. Although purging the autograft of residual lymphoma as assessed by molecular methods has been associated with longer remission duration in one major center, the data from published series are remarkably similar, whether the graft was purged or not. Promising anecdotal data suggest that allogeneic transplantation for low-grade lymphoma deserves further study in prospective clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗