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PubMed1994

[Clinical research on the treatment of acute leukemia with autologous bone marrow transplantation].

38 cases of acute leukemia were treated with autologous bone marrow transplantation (ABMT). The marrow was purged with hyperthermia of 42 degrees C in vitro for one hour in microwave. Twenty-two among them were AML (CR1). Sixteen were ALL (CR1). The mean age was 26 (10-43) years. All the patients were engrafted successfully after ABMT. Mean DFS was 21 (3-69) months. Four cases relapsed at 3 to 8 months after ABMT. Two patients with ALL developed central nervous system leukemia at 12 and 15 months respectively after ABMT. The DFS and probability of relapse at 5 years were 67.8% and 16.8% respectively for all patients.

Adolescent↗
PubMed1988

Differential phthalocyanine photosensitization of acute myeloblastic leukaemia progenitor cells: a potential purging technique for autologous bone marrow transplantation.

The potential value of sulphonated aluminium phthalocyanine (AISPc) as a purging agent for bone marrow autografts in acute myeloblastic leukaemia (AML) has been studied using in vitro clonogenic assays for normal (GM-CFC) and leukaemic (AML-CFC) progenitor cells. In nine out of 13 cases, the leukaemic blasts were found to be highly sensitive to AISPc. In six of the sensitive cases clonogenic assays revealed that only 2 +/- 1% of AML progenitor cells survived AISPc treatment under conditions which permitted a GM-CFC recovery of 60 +/- 11%. AISPc photosensitization was also shown to selectively eliminate the leukaemic cell line K562 from an in vitro model of minimal residual disease. Thus photosensitization using AISPc may be an effective method of purging marrow autografts in some cases of AML. Evaluation of the sensitivity of AML clonogenic cells at diagnosis may identify those patients in whom AISPc photo-purging may be of benefit at the time of an autologous bone marrow transplant.

Bone Marrow Transplantation↗
PubMed2000

Autologous bone marrow transplantation for acute myeloid leukemia in remission or first relapse using monoclonal antibody-purged marrow: results of phase II studies with long-term follow-up.

One hundred and thirty-eight patients with AML underwent ABMT with monoclonal antibody plus complement-purged marrow between August 1984 and March 1997. One hundred and ten patients were in CR (CR1: 23; CR2/3: 87) and 28 were in first relapse (R1) at ABMT. Preparative regimens included busulfan (16 mg/kg) and CY (120 mg/kg) (n = 93), CY (120 mg/kg over 2 days) with TBI (1200 cGy) (n = 35), and busulfan (16 mg/kg) plus etoposide (60 mg/kg) (n = 10). CR1 patients treated with CY/TBI (n = 7) had 3- and 5-year disease-free survival (DFS) rates of 71% and 57%. CR1 patients treated with BU/CY (n = 12), had 3- and 5-year DFS rates of 45%. Three and 5-year DFS for CR2/3 patients treated with CY/TBI (n = 26) was 23%. Three- and 5-year DFS for patients in CR2/3 treated with BU/CY (n = 55) was 31 and 28%. Three- and 5-year DFS for patients in R1 treated with BU/CY (n = 26) was 37%. In multivariate analysis, increased age was associated with greater risk of death and relapse. For CR2/3 patients, the length of CR1 was a significant predictor of DFS. ABMT performed in CR or R1 results in excellent 5-year DFS and OS. The contribution of purging may require a randomized trial comparing purged vs unpurged stem cell infusions.

Acute Disease↗
PubMed1996

In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission.

PURPOSE: To evaluate in a prospective study the efficacy of autologous bone marrow transplantation (BMT) in adult patients with acute myelogenous leukemia (AML) in first remission, using a single course of high-dose Cytarabine (HD Ara-C) consolidation therapy as in vivo purging. PATIENTS AND METHODS: Sixty consecutive adult patients with AML in first complete remission (CR) were treated with HD Ara-C consolidation therapy as a method of in vivo purging before marrow collection. High-dose therapy consisted of fractionated total-body irradiation (FTBI) 12 Gy, intravenous etoposide 60 mg/kg, and cyclophosphamide 75 mg/kg, followed by reinfusion of cryopreserved marrow. RESULTS: Sixty patients underwent consolidation treatment with HD Ara-C with the intent to treat with autologous BMT. Sixteen patients were unable to proceed to autologous BMT (10 patients relapsed, one died of sepsis, one developed cerebellar toxicity, two had inadequate blood counts, and two refused). Forty-four patients underwent autologous BMT and have a median follow-up time of 37 months (range, 14.7 to 68.7) for patients who are alive with no relapse. The cumulative probability of disease-free survival (DFS) at 24 months in the intent-to-treat group is 49% (95% confidence interval [CI], 37% to 62%) and in those who actually underwent autologous BMT is 61% (95% CI, 46% to 74%). The probability of relapse was 44% (95% CI, 31% to 58%) and 33% (95% CI, 20% to 49%) for the intent-to-treat and autologous BMT patients, respectively. CONCLUSION: This approach offers a relatively high DFS rate to adult patients with AML in first CR. The results of this study are similar to those achieved with allogeneic BMT.

Adolescent↗
PubMed1987

Variability in 4-hydroperoxycyclophosphamide activity during clinical purging for autologous bone marrow transplantation.

We examined the effects of varying incubation conditions on the in vitro activity of 4-hydroperoxycyclophosphamide (4HC). 4HC activity against CFU-GM and against the K562 tumor cell line decreased with increasing the RBC concentration of the incubation mixture. Increasing the concentration of nucleated bone marrow cells in the incubation mixture also decreased the 4HC activity. Evaluation of 53 consecutive patients undergoing autologous bone marrow transplantation (BMT) revealed that the incubation RBC concentration during clinical purging showed a similar effect on CFU-GM recovery. Aldehyde dehydrogenase content of RBCs and nucleated marrow cells appears to be the cause of the inhibition of 4HC activity. Although there was no difference in individual CFU-GM sensitivity to 4HC among normals, previously treated patients undergoing autologous BMT showed significant variability in CFU-GM sensitivity to 4HC. The combined effects of incubation RBC concentration and individual patient 4HC sensitivity appear to account for most of the variability in CFU-GM recovery and speed of hematologic recovery after clinical purging with 4HC.

Bone Marrow↗
PubMed1989

In vitro pharmacological purging of human bone marrow is enhanced by the use of lonidamine.

Lonidamine (LND), previously reported as a useful antitumor substance in combination with physical or chemical agents, has been studied for its capacity in increasing pharmacological elimination in vitro of residual tumor cells from human bone marrow. Different drugs were tested in association with LND against mixtures of human bone marrow and a tumor cell line, clonogenic human leukemic blast progenitors, and normal human bone marrow precursors. The results demonstrated that LND increased the efficacy of anthracycline derivatives (Adriamycin, Mitoxantrone) both on the tumor cell line and on the leukemic blast progenitors, while VP-16 or ASTA-Z 7654 was not affected by the same substance. The toxicity on normal stem cells reflected that of each drug and was not modified by the addition of LND. While a consistent dose-dependent CFU-GM reduction was observed immediately after treatment with the different drugs, a complete recovery was reached after 7 and 14 days of long-term marrow cultures. Because of the low toxicity and the efficacy demonstrated in association with certain agents in increasing tumor cell elimination in vitro, LND could play an important role in in vitro purging prior to autologous bone marrow transplantation.

Antibiotics, Antineoplastic↗
PubMed1993

Progenitor cells purging: negative selection.

Disease relapse after autologous bone marrow transplantation (ABMT) may arise from residual tumor in the recipient and/or from cancer cells that are reinfused. The aim of purging by negative selection is to remove tumor cells from the marrow without adversely affecting the engraftment potential of the normal cell. We report the results of a study on fifty-six patients (pts) with non Hodgkin's lymphoma or acute leukemia submitted to ABMT after immunomagnetobead (IMB) purging (11 pts), Maphosphamide purging (31 pts) and no purging (14 pts). The IBM procedure involved one incubation of 3 monoclonal antibodies (CD10, CD19 and CD22) and two incubations with magnetic beads (Dynabeads M-450). The median recovery of mononuclear cells and CFU-GM was 40% and 45% after IMB purging and 84% and 5% after Maphosphamide purging respectively. The rate of leukocyte, neutrophils and platelets recovery following ABMT was similar in the three groups of pts, although platelet recovery was slow in patients received graft purged with Maphosphamide. Our study confirms the clinical feasibility of the IMB procedure, but only randomized studies will be able to definitely address the question of the clinical utility of purging.

Adolescent↗
PubMed1998

Ex vivo expansion of bone marrow from breast cancer patients: reduction in tumor cell content through passive purging.

High-dose chemotherapy (HDC) with hematopoietic support appears promising in the treatment of breast cancer, although reinfusion of contaminating tumor cells may contribute to disease relapse. Ex vivo expansion may reduce tumor cell content through use of a small inoculum volume and by passive purging during culture. We assessed the ex vivo expansion potential of tumor cell positive bone marrow (BM) from breast cancer patients and the effect of ex vivo expansion on tumor cell content. Cryopreserved/thawed mononuclear cell (C/T MNC) BM harvests with known tumor cell contamination (n = 7) were assessed for tumor cells pre- and post-expansion using immunocytochemical (ICC) staining. Pre-expansion inoculum samples contained a range of 6-2128 tumor cells per 5.0 x 10(6) nucleated cells. Ex vivo expansion resulted in fold expansions of 6.67 and 11.37 for total cells and CFU-GM, respectively. Tumor cells were undetectable in four of the seven post-expansion samples and were reduced in the remaining three samples. The data demonstrate passive purging of breast cancer cells during ex vivo expansion, with hematopoietic progenitor cell expansion comparable to that of normal BM. Reduction in tumor cell number contained in the small volume culture inoculum combined with passive purging during the ex vivo expansion process suggest a potential 2-4+ log reduction in tumor cell content in the reinfused cell product.

Adult↗
PubMed1992

Differential sensitivity of adherent CFU-blast, CFU-mix, BFU-E, and CFU-GM to mafosfamide: implications for adjusted dose purging in autologous bone marrow transplantation.

The availability of an in vitro assay able to detect hematopoietic progenitor cells closely related to those responsible for marrow engraftment following autologous bone marrow transplantation (ABMT) prompted us to establish a procedure aimed at maximally increasing the concentration of the cyclophosphamide derivative mafosfamide used for marrow purging. It, therefore, was the aim of the present study to investigate in a group of patients with acute nonlymphoblastic leukemia (ANLL; n = 19) and acute lymphoblastic leukemia (ALL; n = 19) in complete remission the effect of mafosfamide at the level of adherent blast colony-forming units (blast colony-forming units, CFU-Blast), as well as multipotential (granulocyte erythrocyte macrophage megakaryocyte colony-forming units, CFU-GEMM), erythroid (erythroid burst-forming units, BFU-E), and granulocyte-macrophage (granulocyte-macrophage colony-forming units, CFU-GM) progenitor cells. When nonadherent marrow mononuclear cells (MNCs) were incubated (30 min, 37 degrees C) with increasing doses of mafosfamide (30-120 micrograms/ml), a statistically significant (p less than or equal to 0.0005) dose-dependent suppression of CFU-Blast growth was observed. The mean (+/- 1 standard error of the mean [SEM]) values of 50% inhibition (ID50) of the CFU-Blast growth were not significantly different for ANLL (106 +/- 5) and ALL (107 +/- 5) patients. Analysis of CFU-Blast ID50 distribution demonstrated that ID50 ranged from 100 to 120 micrograms/ml in 17 cases (45%), whereas it ranged from 60 to 100 micrograms/ml in 12 cases and from 120 to 160 micrograms/ml in 9 cases. A statistically significant (p less than or equal to 0.05), dose-dependent suppression of colony growth from multi-potential and lineage-restricted progenitor cells was also observed. However, the value of CFU-Blast ID50 was significantly higher (p less than or equal to 0.05) than CFU-GEMM, BFU-E, and CFU-GM ID50 and ID95 values. In conclusion, our data demonstrate that: 1) the CFU-Blast assay allows to detect on an individual basis the doses of mafosfamide used for marrow purging, and 2) the concentrations of mafosfamide extrapolated by using the CFU-Blast assay are significantly higher than those obtained with the CFU-GM assay. The absence of any detrimental effect on marrow engraftment in vivo supports the safety of the CFU-Blast assay to evaluate the dose of mafosfamide used for marrow purging before ABMT.

Antineoplastic Agents↗
PubMed1990

Density-gradient separation for 4-hydroperoxycyclophosphamide purging of autologous bone marrow grafts.

We studied density-gradient separation of autologous bone marrow grafts in preparation for ex vivo 4-hydroperoxy-cyclophosphamide (4-HC) purging. A two-step procedure of buffy coat isolation followed by Ficoll-diatrizoate separation was used. Buffy-coat cells were isolated primarily either using the COBE 2991 Blood Cell Processor or Haemonetics 30 Cell Separator. All density-gradient separations were performed using the COBE 2991. The nucleated cell recoveries after buffy-coat isolation were 44.3 +/- 10.4% and 85.1 +/- 10.5% (+/- standard deviation, P less than 0.001) for the Haemonetics 30 and COBE 2991 isolated grafts, respectively. The final nucleated cell recoveries after density-gradient separation for these two buffy-coat techniques were 24.2 +/- 10.1% and 29.5 +/- 14.7% (p = 0.30). Compared to manual density-gradient separation, the techniques using the COBE 2991 recovered slightly higher numbers of nucleated cells and CFU-GM. The red blood cell concentration of the 4-HC incubation mixture was 1.0 +/- 0.6% and the CFU-GM survival after treatment was 2.4 +/- 2.6%. The variability in CFU-GM survival after 4-HC incubation of the density-gradient separated grafts appears less than previous experience treating buffy-coat cells. Density-gradient separation of autologous bone marrow appears to provide a more uniform treatment with 4-HC and may improve the clinical transplant course of the autograft recipient.

Bone Marrow↗
PubMed2000

New approaches to treating malignances with stem cell transplantation.

Stem cell transplantation has been successfully used to treat a wide variety of hematologic malignancies. New and exciting strategies being developed for use in conjunction with transplant will be useful in overcoming tumor resistance. It is now clear that a significant part of the antitumor effect of allogeneic stem cell transplantation is derived from the graft itself and is independent of the preparative regimen. Immune therapy derived from the donor's graft is uniquely suited for killing chemoresistant tumor cells and may prove to be an invaluable tool for decreasing the risk of relapse in patients with advanced disease. Among patients who have relapsed after allogeneic bone marrow transplantation (BMT), an immunologically based antitumor effect may be obtained simply by transfusing T cells obtained by leukopheresis of the original bone marrow donor. Referred to as donor leukocyte infusion (DLI), this technique has been used to obtain complete remissions in relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), multiple myeloma, non-Hodgkin's lymphoma, myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML). Another approach that uses the donor's graft to obtain a potent antitumor effect is the combination of nonmyeloablative BMT followed by immunotherapy with DLI. Numerous investigators are exploring ways of combining autologous BMT with immune therapy. Animal studies using tumor vaccines in conjunction with autologous transplantation offer a promising method for eliminating tumor. Patients undergoing autologous transplantation may have marrow that has been contaminated with tumor, which places them at a higher risk of relapse. Attempts have been made to eliminate contaminating tumor from the marrow by purging.

Bone Marrow Purging↗
PubMed1988

Heterogeneity among the non-Hodgkin's lymphomas. Implications for autologous bone marrow transplantation with in vitro purging using monoclonal antibodies.

To investigate the possible implications of heterogeneity among the non-Hodgkin's lymphomas for bone marrow purging using complement-fixing monoclonal antibodies to lymphoma-associated antigens, a panel of large cell lymphoma cell lines of diverse phenotypes was treated with monoclonal antibodies DLC-48 and LN-1. An association was demonstrated between the percentage of suppression of colony formation by the cell line and both the percentage of cells staining with the antibody and the intensity of its binding. Flow cytometric analysis of cells surviving treatment with antibody and complement demonstrated that the population that escaped lysis showed weak immunofluorescent staining. Similarly, 40% of the clones derived from cells surviving treatment with antibody and complement stained weakly compared with the parent cell line. For a given fluorescence intensity, cells differed in their susceptibility to treatment. Some cells with moderate to strong staining survived incubation with antibody and complement. In five cases, treatment of bone marrow contaminated with malignant lymphoma cells resulted in complete eradication of even cells with weak staining. In two cases, a population of cells that stained dimly survived treatment with either antibody. DNA-content analysis showed that the cell cycle distribution of cells surviving treatment with DLC-48 or LN-1 and complement was similar to that of cells treated with control antibody 46-1G7 and complement. Phenotypic heterogeneity may hinder efforts to purge malignant lymphoma cells from human bone marrow with complement-fixing monoclonal antibody reagents. Relative resistance to complement-mediated lysis may underlie differences in the susceptibility of cells to treatment and also limit the effectiveness of this technique.

Antibodies, Monoclonal↗
PubMed1995

Randomized comparison of cyclophosphamide-total body irradiation versus busulfan-cyclophosphamide conditioning in autologous bone marrow transplantation for acute myeloid leukemia.

PURPOSE: This prospective trial of autologous bone marrow transplantation for acute myeloid leukemia was undertaken to compare the outcome using two different preparative regimens. METHODS AND MATERIALS: Between October 1987 and April 1993, 35 patients with acute myeloid leukemia in first (n = 12) or greater (n = 23) remission were stratified by remission status and randomized to undergo 4-hydroperoxycyclophosphamide purged autologous bone marrow transplantation after either cyclophosphamide (120 mg/kg) and total body irradiation (1320 Gy in eight fractions over 4 days) (CY/TBI), or busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg) (BU/CY) conditioning. RESULTS: At 2 years, overall survival and disease-free survival were 39% (95% confidence intervals (CI) 22-57%) and 36% (95% CI 19-52%), respectively. Patients in first complete remission had a significantly better outcome with a 2-year disease free survival of 57% (95% CI 28-86%) compared to others at 24% (95% CI 6-43%, log rank p = 0.048). For patients conditioned with CY/TBI, the estimated 2-year disease-free survival was 50% compared to 24% for patients conditioned with BU/CY (log rank p = 0.12). Estimated 2-year relapse rates were 43% vs. 70% (log rank p = 0.17), respectively. For patients in first complete remission no differences in disease-free survival (2-year estimates 67% vs. 50%, log rank p = 0.69), between the two regimens were observed. For patients in greater than first complete remission there was a trend towards improved disease-free survival in the CY/TBI arm (2-year estimates 42% vs. 9%, log rank p = 0.06). There were no differences in time to white blood cell count (WBC) engraftment, absolute neutrophil count of > 500, incidence of bacteremias, or median time to hospital discharge between the two regimens. Acute toxicities were similar. Interstitial pneumonitis developed in two patients (one on each arm), while veno occlusive disease developed in three BU/CY patients, but none of the CY/TBI patients (log rank p = 0.07). CONCLUSIONS: Cyclophosphamide-total body irradiation provided an equivalent or better outcome to BU/CY, particularly in advanced patients, and should remain the standard by which new regimens are judged. The high relapse rate with both regimens, especially patients who were in greater than in first complete remission, emphasizes the need for early transplant and for new strategies to improve outcome.

Adolescent↗
PubMed1995

The synthesis of a peanut agglutinin-ricin A chain conjugate: potential as an in vitro purging agent for autologous bone marrow in multiple myeloma.

The lectin peanut agglutinin (PNA) and CD19 monoclonal antibody have been covalently linked to magnetic beads and utilized in an in vitro purging system for autologous bone marrow in multiple myeloma (MM). An alternative to mechanical purging involves the use of immunotoxins to provide specifically targeted cellular toxicity; however, no studies to date have examined the utility of a lectin-ricin A chain (RCA) combination as a purging agent in MM. Initially, we studied the internalization of PNA by target cells (Raji) using flow cytometry. The surface fluorescence intensity of PNA-treated Raji cells was reduced upon incubation at 37 degrees C, and subsequent studies with fixed cells detected the endocytosed PNA. Complete internalization occurred within 120 minutes, indicating the potential of PNA as a purging agent. We manufactured a novel PNA-RCA conjugate and demonstrated its strong and specific binding to PNA reactive cell targets. Subsequent experiments assessed the toxicity of the conjugate to Raji cells and normal bone marrow progenitor cells. 3H-leucine uptake assays showed that PNA-RCA was capable of reducing protein synthesis in Raji cells and that the toxic effects were specific. In addition, at concentrations of conjugate achieving greater than 99% selective cytotoxicity for Raji cells, adequate CFU-GM were preserved in normal marrow. These studies suggest that PNA-RCA may be of value as an in vitro purging agent for MM.

Bone Marrow Purging↗
PubMed1993

Prolonged disease-free survival after ablative chemoradiotherapy and autologous bone marrow transplantation in adult malignant lymphoma.

From June 1983 to December 1991, 21 adult patients with intermediate or high-grade malignant lymphoma (ML) were treated by ablative chemoradiotherapy, including vincristine, cytosine arabinoside, BCNU and cyclophosphamide plus total lymphoid or body irradiation with boost irradiation over bulky and original tumor areas (Hd-VCCA+TL(B) I) together with autologous bone marrow transplantation (ABMT). Five patients were in advanced stage, 2 in drug-resistant relapse, 6 in drug sensitive relapse, 6 in first complete remission (CR1) and 2 in CR2. One with marrow involvement at ABMT. The 8-year disease-free survival after ABMT in patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) in 89% and 63%, respectively, with a median follow-up up to 34 months. This study demonstrated that our Hd-VCCA+TL(B) I regimen and ABMT performed early in CR or drug-sensitive relapse of adult poor prognosis lymphoma, may potentially cure more than 70% of them. The toxicity of the present treatment is tolerable. The results confirm the value of ABMT in the treatment of adult ML, and suggest that it is necessary to purge the residual tumor cells in the bone marrow at ABMT in patients with marrow infiltration, or lymphoblastic lymphoma.

Adolescent↗
PubMed1985

Autologous bone-marrow transplantation for Burkitt's lymphoma: marrow purging with anti-Y 29/55 monoclonal antibody and complement.

Reinfusion of undetected tumour cells is a possible cause of relapse after autologous bone-marrow transplantation. In this paper, a system for in-vitro purging of bone marrow is presented which involves the B-cell neoplasia-associated monoclonal antibody anti-Y 29/55 and complement. Five patients with Burkitt's lymphoma were transplanted with purged marrow, demonstrating the clinical feasibility of the method. The pretransplant regimen included vincristine 2 mg/m2, adriamycin 60 mg/m2, four doses of cyclophosphamide 45 mg/kg and total body irradiation with 6 Gy. Tumour control appears to be better in patients with purged bone marrow as compared to an earlier patient group with unpurged marrow.

Adolescent↗