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PubMed1991

Autologous bone marrow transplantation for high-grade lymphoid malignancy using melphalan/irradiation conditioning without marrow purging or cryopreservation. The Northern Regional Bone Marrow Transplant Group.

We report the safety and efficacy of 34 consecutive autologous bone marrow transplant (ABMT) procedures performed in adult patients with high-grade lymphoid malignancy after remission induction therapy. Fifteen patients with acute lymphoblastic leukemia (ALL) and six with high-grade non-Hodgkin's lymphoma (NHL) received pretransplant conditioning with intravenous (IV) melphalan and fractionated total body irradiation (TBI). Thirteen other patients with NHL were conditioned with melphalan alone, having previously received local involved field radiotherapy. Unmanipulated noncryopreserved autologous marrow was reinfused within 48 hours of harvesting. Engraftment occurred in all patients with medians of 10 days of neutropenia (neutrophils less than 0.5 x 10(9)/L), 4-day platelet transfusion requirement, 3 U packed RBC transfusion, and 18 days in hospital posttransplant. There were no procedure-related deaths. Actuarial disease-free survival in the 13 patients with ALL receiving autotransplant early in first remission is 48% with a median follow-up of 3 years. Two other ALL patients who had autotransplants after a period of maintenance therapy also remain in complete remission (CR). These results compare favorably with our 34% disease-free survival (DFS) in 15 allogeneic ALL transplant patients and 21% DFS in 19 patients on standard maintenance after a common induction schedule. No relapses have occurred in the 17 NHL patients transplanted in remission (median follow-up 2 years), but the two NHL patients who developed recurrent disease before ABMT died of progressive disease after temporary responses. We conclude that this method of ABMT results in rapid reengraftment with lack of toxicity and that the conditioning treatment used shows good efficacy against disease. It is applicable in high-grade lymphoid malignancy in first remission, and our results call into question the need for marrow purging in ALL and NHL patients transplanted in first remission.

Adult↗
PubMed1990

Immunomagnetic manipulation of bone marrow and tumour cells: an update.

The immunomagnetic separation procedure for the separation of neuroblasts from bone marrow harvested for autologous transplantation was first described in 1983 (Treleaven et al., 1984). In the intervening period, the technique has been extended to other tumours and modified by several laboratories. In addition, the procedure has been used for the separation of different mammalian cell types (Nilsson et al., 1987), micro-organisms (Lund et al., 1988) and at the subcellular level, organelles (Howell et al., 1988), and DNA (Dudin et al., 1988). Although immunomagnetic separation techniques have been used extensively for bone marrow purging, the recovery of cells from the matrix has remained problematical. This manuscript is intended to offer an update on our experiences in the use of the immunomagnetic purging procedure. In addition, more detailed basic studies have been undertaken to characterize further the antigens recognized by the antibodies for the removal of neuroblasts from bone marrow. The information obtained in these studies may, in part, explain why it is intrinsically more difficult to separate neuroblasts from the magnetic matrix than haematopoietic cells such as either T or acute lymphoblastic leukaemic cells.

Antibodies, Monoclonal↗
PubMed1996

Efficacy of in vitro treatment of chronic myelogenous leukemia cell line, K562 cells, using 4-hydroperoxycyclophosphamide, alpha-interferon and gamma-interferon.

Alpha-interferon (alpha-IFN) and gamma-interferon (gamma-IFN) are highly effective biologic agents in the treatment of chronic myelogenous leukemia (CML). 4-hydroperoxycyclophosphamide (4-HC) is the most commonly used chemotherapeutic drug when purging bone marrow contaminated with malignant cells. To investigate the efficacy of alpha-IFN, gamma-IFN and 4-HC as purging agents in CML patients, K562 cells, a human CML cell line, were treated in vitro with these drugs singly or in combination. The cytotoxic effect was evaluated by MTT assay. Data were analyzed for synergism by the median effect principle of Chou and Talalay. Using Southern blot analysis, the effect of purging on the suppression of bcr gene rearrangement was also evaluated. Alpha-IFN, gamma-IFN and 4-HC all showed good concentration-dependent cytotoxic effect. Median cytotoxic doses of alpha-IFN gamma-IFN and 4-HC were 0.03 microM 0.20 microM and 1.97 microM respectively, and molar ratios of median doses of alpha-IFN to 4-HC, gamma-IFN to 4-HC and alpha-IFN to gamma-IFN were 1:80, 1:10 and 1:8, respectively. The combination treatment of alpha-IFN and 4-HC, and gamma-IFN and 4-HC showed significant synergistic cytotoxic activities, but combination of alpha-IFN and gamma-IFN was antagonistic. Status of bcr gene rearrangements in K562 cells was not changed after the treatments. Our results appear to provide an efficient method for removing CML cells from the bone marrow of CML patients.

Antineoplastic Agents↗
PubMed1989

Targeting of a plasma cell line with a conjugate containing xanthine oxidase and the monoclonal antibody 62B1.

We report on the preparation of an antibody-conjugated enzyme consisting of xanthine oxidase, a free-radical-producing enzyme, linked to the 62B1 monoclonal antibody, which recognizes the last steps of differentiation of B cell lineage (plasma cell and hairy cells). The conjugate specifically kills target cells, retaining both enzymic and immunological properties, without any damage to normal myeloid clonogenic efficiency. The model is suitable for ex vivo bone marrow purging in multiple myeloma patients.

Animals↗
PubMed1985

Autologous bone marrow transplantation. A maximal therapy design for disseminated neuroblastoma.

Patients with disseminated neuroblastoma are considered a poor-risk category, hence, our approach towards their treatment should be reconsidered in terms of the unique clinical and biological characteristics of neuroblastoma tumor growth. To this end, we have devised a treatment program consisting of surgery, and a schedule of sequentially escalating doses of cyclophosphamide combined with other drugs until a minimal disease status is obtained. When this is achieved, the patient is treated with maximal therapy, i.e., total body irradiation, high-dose L-phenylalanine mustard and dianhydrogalactitol followed by reconstitution with an autologous bone marrow graft. Details of this program include problems associated with evaluation of response, i.e., evaluation of risk, determination of minimal tumor burden, avoidance of toxicity, and compensation for supportive measures during maximal therapy. Additional problems of purging bone marrow of tumor cells are considered.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Progressive multifocal leucoencephalopathy with peripheral demyelinating neuropathy after autologous bone marrow transplantation for acute myeloblastic leukemia (FAB5).

Progressive multifocal leucoencephalopathy is an opportunistic JC virus-related pathology occurring in immunocompromised patients. We report a case of severe cellular immunodeficiency in a patient who underwent autologous bone marrow transplantation for acute myeloblastic leukemia, and who subsequently developed progressive multifocal leucoencephalopathy, an unusual pathology in this context. Progressive multifocal leucoencephalopathy was preceded by a peripheral demyelinating neuropathy. We discuss the possible link between these two neuropathies, the possible aggravation or activation from CMV infection, as well as the possible contribution of bone marrow purging in the resultant cellular immunodeficiency.

Adult↗
PubMed1990

Autologous bone marrow transplantation in multiple myeloma: identification of prognostic factors.

Multiple myeloma remains a universally fatal malignancy with a median survival time not exceeding 3 years. A clinical trial was undertaken to determine feasibility and efficacy of marrow-ablative chemoradiotherapy supported by unpurged autologous bone marrow (ABMT) and to define prognostic variables. Total body irradiation and either melphalan or thiotepa were administered to 55 patients (median age 53 years; range 20 to 66 years). The group of 21 patients with resistance to standard melphalan-prednisone and to continuous infusions of vincristine and Adriamycin with high dose dexamethasone (VAD) included 7 with primary unresponsive disease and 14 with resistant relapse; among the 34 patients achieving remission with the VAD regimen, 14 were in first and 20 in a subsequent remission. Marked cytoreduction by greater than or equal to 75% was observed among all 21 patients with refractory myeloma, whereas further cytoreduction of this magnitude was noted in only 56% of the 34 patients already in remission after VAD. Five of the 6 early deaths among all 55 patients occurred in the 14 patients with resistant relapse, none of whom achieved complete remission and who, as a group, had median durations of relapse-free and overall survival of only 8 and 7 months, respectively. Among the 41 remaining patients, there was only one early death, and 27% achieved complete remission including a 36% incidence among the 14 patients treated in first remission; their projected 4-year survival rate was 82% regardless of their disease status (first or later remission or primary resistance). When information about sensitivity to prior therapy is unavailable, the presence before ABMT of both high beta-2-microglobulin levels (greater than 3 mg/L) and non-IgG isotype helped identify 9 among the 55 patients with a very poor prognosis: all 8 responders relapsed within 9 months, and 8 patients died within 15 months. By contrast, a 4-year projected survival rate of over 70% for the other patients (about 80% of this series) justifies further investigation of this novel treatment approach in comparison with standard dose regimens. Our results indicate that marrow-ablative therapy cannot be recommended for myeloma patients with resistant relapse or those with a combination of risk factors (advanced tumor burden, absence of IgG isotype). The apparent lack of an adverse effect of even marked plasmacytosis in autografts (up to 30%) emphasizes the need for better cytoreduction rather than bone marrow purging.

Adult↗
PubMed1993

Treatment of multiple myeloma with intensive chemotherapy followed by autologous BMT using marrow purged with 4-hydroperoxycyclophosphamide.

In August 1988 we began a program in which multiple myeloma patients achieving < or = 10% marrow plasma cells and > or = 50% reduction in paraprotein levels after the VAD (vincristine, doxorubicin, dexamethasone) regimen underwent bone marrow harvest, ex vivo marrow purging with 4-hydroperoxycyclophosphamide (4-HC) and marrow cryopreservation. Conditioning with a regimen of high-dose busulfan (total dose 16 mg/kg), cyclophosphamide (120 mg/kg) and melphalan (90 mg/m2) (BU + CY + MEL) followed by autologous BMT was then carried out. Seventeen of the 24 patients who received VAD (71%, 95% confidence interval [CI] 49 to 87%) were eligible for bone marrow harvest. One patient was not harvested because of non-medical reasons; two patients who underwent marrow harvest had gross plasmacytosis present in biopsies performed intraoperatively and did not undergo BMT. Fourteen patients (58%, 95% CI 37 to 78%) received BU + CY + MEL and 4-HC-purged autologous BMT. The median time to recovery of 0.5 x 10(9)/l neutrophils was 19 days (range 14 to 26) while the last platelet transfusion was given on a median of day 32 (range 10 to 46) post-BMT in the evaluable patients. The major non-hematologic toxicity was hepatic; two patients in complete remission died of hepatic veno-occlusive disease. Another patient succumbed to fungal infection despite neutrophil recovery. The remaining 11 patients achieved responses (complete in six and partial in five) associated with a normal performance status.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Characterization of late and early hematopoietic progenitor/stem cell sensitivity to mafosfamide.

The preservation of the hematopoietic value of the graft is essential in the context of bone marrow purging for autologous transplantation. In the present study we have investigated mafosfamide toxicity to transplantable hematopoietic stem cells using combinations of recombinant growth factors (GF) in semi-solid assays and by measurement of Long-Term Culture Initiating Cells (LTC-IC). Our data show that various subtypes of progenitor/stem cells were inhibited in a dose-dependent manner by mafosfamide. A hierarchy appeared clearly regarding sensitivity to the drug in the following order of increasing resistance: PCM CFU-GM (grown in presence of placenta-conditioned medium), 4R CFU-GM (grown in presence of GM-CSF + IL-3 + G-CSF + EPO), 5R CFU-GM (grown in presence GM-CSF + IL-3 + G-CSF + EPO + SCF) and LTC-IC with respective lethal dose 95 (LD95) levels of 40 micrograms, 55 micrograms, 90 micrograms and 140 micrograms/10(7) MNC (P = 0.05 to P = 0.018). Even the primitive stem cells treated with very high doses of mafosfamide (2 to 4 times the usually recommended dose) responded to a combination of SCF + GM-CSF + G-CSF + IL-3 in liquid marrow culture, suggesting that they were functionally spared by the treatment. We also observed a higher sensitivity of 5R CFU-GM and LTC-IC from patients with hematological malignancies, compared with normal donors, when marrow was treated with the dose chosen for clinical purging.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1992

Effect of combined treatment with interleukin-3 and interleukin-6 on 4-hydroperoxycyclophosphamide-mediated reduction of glutathione levels and cytotoxicity in normal and leukemic bone marrow progenitor cells.

4-Hydroperoxycyclophosphamide (4-HC) is widely used as an ex vivo bone marrow purging agent for acute myeloid leukemia (AML) blasts. We have determined the effect of a combined treatment with interleukin 3 (IL-3) plus IL-6 on 4-HC cytotoxicity against normal (CFU-GEMM) versus AML (L-CFU) bone marrow progenitor cells. Following an 18 h exposure to IL-3 plus IL-6, treatment with 4-HC in conjunction with IL-3 and IL-6 for one hour resulted in a significantly greater inhibition of L-CFU versus CFU-GEMM colony growth. In addition, treatment with IL-3 plus IL-6 reduced the inhibitory effects of higher concentrations of 4-HC on CFU-GEMM but not L-CFU growth. IL-3 and IL-6 did not protect the self-renewing, clonogenic, AML blast progenitor cells from the cytotoxic effects of 4-HC. While the total intracellular glutathione (GSH) levels were not significantly different between untreated normal bone marrow mononuclear cells (NBMMC) and AML blasts, greater intracellular GSH-S transferase activity was observed in the NBMMC. 4-HC produced a marked reduction in GSH levels in NBMMC as well as AML blasts. But treatment with IL-3 plus IL-6 in conjunction with 4-HC resulted in significantly higher GSH levels in NBMMC. These differences in intracellular GSH levels and GST activity may offer an explanation for the differential protective effects of IL-3 plus IL-6 treatment against the cytotoxic effects of 4-HC on CFU-GEMM colony growth.

Acute Disease↗
PubMed1996

Autologous bone marrow transplantation for acute myeloid leukemia.

Despite progress over the past three decades, most patients with acute myeloid leukemia (AML) treated with conventional chemotherapy alone relapse and die of recurrent leukemia. Treatments used to improve outcome include allogeneic (alloBMT) and autologous bone marrow transplantation (ABMT). Indications for transplantation and the relative merits of alloBMT and ABMT remain unclear. In this review, we evaluate evidence supporting a role of ABMT in AML and compare the results with outcomes after alloBMT. In addition, we discuss areas of controversy including the optimal timing for ABMT, the role of bone marrow purging, the place of peripheral blood stem cell collection, the high dose regimen, and post-transplant immunotherapy to reduce relapse.

Acute Disease↗
PubMed2000

Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: a Children's Cancer Group Study.

PURPOSE: This study investigated the prognostic value of quantifying tumor cells in bone marrow and blood by immunocytology in children with high-risk, metastatic neuroblastoma. PATIENTS AND METHODS: Patients with stage IV neuroblastoma (N = 466) registered on Children's Cancer Group study 3891 received five cycles of induction chemotherapy and were randomized either to myeloablative chemoradiotherapy with autologous purged bone marrow rescue or to nonmyeloablative chemotherapy. Subsequently, they were randomized to 13-cis-retinoic acid or no further treatment. Immunocytologic analyses of bone marrow and blood were performed at diagnosis, week 4, week 12, bone marrow collection, and end induction and were correlated with tumor biology, clinical variables, treatment regimen, and event-free survival (EFS). RESULTS: Immunocytology identified neuroblastoma cells in bone marrow of 81% at diagnosis, 55% at 4 weeks, 27% at 12 weeks, 19% at bone marrow collection, and 14% at end induction. Tumor cells were detected in blood of 58% at diagnosis and 5% at collection. There was an adverse effect on EFS of increasing tumor cell concentration in bone marrow at diagnosis (P =.04), at 12 weeks (P =.006), at bone marrow collection (P <.001), and at end induction (P =.07). Positive blood immunocytology at diagnosis was associated with decreased EFS (P: =.003). The prognostic impact of immunocytology was independent of morphologically detected bone marrow disease, MYCN status, and serum ferritin level in bivariate Cox analyses. CONCLUSION: Immunocytologic quantification of neuroblastoma cells in bone marrow and blood at diagnosis and in bone marrow during induction chemotherapy provides prognostic information that can identify patients with very high-risk disease who should be considered for experimental therapy that might improve outcome.

Adolescent↗
PubMed1996

Shiga-like toxin purges human lymphoma from bone marrow of severe combined immunodeficient mice.

Shiga-like toxin-1 (SLT-1) is a bacterial toxin that kills cells by inhibiting protein synthesis. SLT-1 is composed of one cytotoxic A-subunit and five B-subunits that bind to CD77, a cell-surface glycolipid. In the human hematopoietic system, CD77 expression is restricted to a subset of activated B cells and derived cancers. Here we report that SLT-1 treatment of murine bone marrow ex vivo effectively cures severe combined immunodeficient mice of a human B-cell lymphoma xenograft while sparing normal hematopoietic precursor cells. Flow cytometry results using fluorescein isothiocyanate-labeled SLT-1 B-subunit show the high prevalence of expression of SLT-1 receptors (CD77) in human non-Hodgkin's lymphomas, especially follicular lymphomas. These results suggest the use of SLT-1 for the purging of human bone marrow before autologous bone marrow transplant in the case of CD77+ B-cell lymphomas as just one of many possible uses.

Animals↗
PubMed1988

[Processing of clonogenic findings in limited dilution. Application to the quantification of autograft depletion].

Limiting dilution culture is a powerful tool for the quantification of residual clonogenic cells in the evaluation of a depletion procedure in bone marrow purging. The definition of suitable numerical indicators and the choice of the statistical technique for data treatment are of crucial importance. Most common techniques are presented and discussed. A standardization for data treatment is proposed.

Bone Marrow Cells↗
PubMed1985

Comparative in vitro effects of cyclophosphamide derivatives on murine bone marrow-derived stromal and hemopoietic progenitor cell classes.

We investigated the in vitro effects of ASTA-Z-7595, ASTA-Z-7557, ASTA-Z-7654, and 4-hydroperoxycyclophosphamide (4HC) on murine stromal fibroblastoid colony-forming units, committed hemopoietic progenitors (erythroid burst-forming units and granulocyte/macrophage colony-forming units), and pluripotent hemopoietic stem cells assayed by the spleen colony-forming unit (CFU-s) assay. In general, the drugs showed a time-and dose-dependent effect on colony-forming unit survival, and the relative toxicities were in the order in which the drugs are listed above. We found a relative sparing of day 12 CFU-s compared with day 7 CFU-s and committed hemopoietic and stromal progenitors, although colony size of day 12 CFU-s was reduced. Our results support two possible mechanisms for delayed or inadequate hemopoietic reconstitution in clinical studies using bone marrow purged with 4-hydroperoxycyclophosphamide or ASTA-Z-7557, i.e., damage to (a) transplantable stromal cells or (b) the hemopoietic stem cells.

Animals↗
PubMed1991

Phase I study of combination drug purging for autologous bone marrow transplantation.

In a phase I clinical trial of autologous bone marrow transplantation, we determined the feasibility of ex vivo purging with high concentrations of pharmacologics in combination. Light-density cells isolated from the grafts of 26 patients with acute leukemia or lymphoblastic lymphoma were treated with 4-hydroperoxycyclophosphamide (4-HC; 30 to 60 micrograms/mL), vincristine (Vcr; 1.5 to 3.0 micrograms/mL), and methylprednisolone sodium succinate (MP; 5 mg/mL). All patients received marrow-lethal induction therapy followed by infusion of the treated grafts. Three patients died of transplant-related complications before achieving peripheral blood recovery of greater than 0.5 x 10(9) granulocytes per liter. All other patients achieved this parameter of engraftment at a median of 35 days after marrow infusion. The median time to last platelet transfusion was 45 days. These durations of aplasia were similar to those experienced by other patients receiving density-gradient separated grafts treated with 60 micrograms/mL of 4-HC as a single agent. No patient required infusion of untreated reserve marrow because of engraftment failure. The colony-forming unit-granulocyte macrophage (CFU-GM) content of the grafts after purging predicted these parameters of engraftment. Colony-forming unit-leukemia (CFU-L) cultured from the grafts of 12 of the patients treated for acute lymphoblastic leukemia (ALL) were considerably more sensitive to the combination regimen than to 4-HC alone; the sensitivity of CFU-GM from these patients did not differ between the two regimens. The results of this trial indicate the feasibility of treating autologous bone marrow grafts with high concentrations of pharmacologics in combination. The use of combinations may increase the efficacy of ex vivo purging without increasing the toxicity to normal hematopoietic cells.

Adolescent↗
PubMed1987

[Determination of the S-phase fraction of myeloid-determined stem cells (CFU-GM) using the cytosine arabinoside suicide technic in patients with acute myeloid leukemia in complete remission following polychemotherapy].

S-phase fraction of granulocyte-macrophage colony forming cells (CFU-GM) was assessed by cytosine arabinoside suicide technique in five normal volunteers and eight patients with acute myeloblastic leukaemia in complete remission after the cessation of polychemotherapy. An increased proliferation of CFU-GM (S-phase-fraction: 55-80%) was found in bone marrow of patient in complete remission up to the 27th day after polychemotherapy. Reduction of this increased proliferation was seen at day 30 after the cessation of polychemotherapy (S-phase fraction: 22 and 33%). Because of increased proliferation of CFU-GM in the early phase after polychemotherapy cytostatic drugs of the antimetabolite-type seem to be unsuitable for purging bone marrow in remission.

Adolescent↗
PubMed2000

Myeloma progenitors in the blood of patients with aggressive or minimal disease: engraftment and self-renewal of primary human myeloma in the bone marrow of NOD SCID mice.

The myelomagenic capacity of clonotypic myeloma cells in G-CSF mobilized blood was tested by xenotransplant. Intracardiac (IC) injection of NOD SCID mice with peripheral cells from 5 patients who had aggressive myeloma led to lytic bone lesions, human Ig in the serum, human plasma cells, and a high frequency of clonotypic cells in the murine bone marrow (BM). Human B and plasma cells were detected in BM, spleen, and blood. Injection of ex vivo multiple myeloma cells directly into the murine sternal BM (intraosseus injection [IO]) leads to lytic bone lesions, BM plasma cells, and a high frequency of clonotypic cells in the femoral BM. This shows that myeloma has spread from the primary injection site to distant BM locations. By using a cellular limiting dilution PCR assay to quantify clonotypic B lineage cells, we confirmed that peripheral myeloma cells homed to the murine BM after IC and IO injection. The myeloma progenitor undergoes self-renewal in murine BM, as demonstrated by the transfer of human myeloma to a secondary recipient mouse. For 6 of 7 patients, G-CSF mobilized cells from patients who have minimal disease, taken at the time of mobilization or after cryopreservation, included myeloma progenitors as identified by engraftment of clonotypic cells and/or lytic bone disease in mice. This indicates that myeloma progenitors are mobilized into the blood by cyclophosphamide/G-CSF. Their ability to generate myeloma in a xenotransplant model implies that such progenitors are also myelomagenic when reinfused into patients, and suggests the need for an effective strategy to purge them before transplant.

Animals↗