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Biomedical subjects

A R Zander

Publications and source records attributed to A R Zander.

At least 145 records · Page 8Linked to original sources
PubMed1987

High dose cyclophosphamide, BCNU, and VP-16 (CBV) as a conditioning regimen for allogeneic bone marrow transplantation for patients with acute leukemia.

A high dose combination chemotherapy regimen (CBV) consisting of cyclophosphamide (1.5 gm/m2 day 1 to day 4); BCNU (300 mg/m2 day 1) and etoposide (100 mg/m2 every 12 hours for 6 doses), followed by bone marrow transplant from human leukocyte antigen (HLA) identical sibling donors, was evaluated in 29 patients in whom acute leukemia was in relapse or remission. Engraftment of donor cell type occurred in all but one of 21 patients, in whom marker differences between donor and recipient were established. Two of 11 patients transplanted during relapse of the disease, lived beyond 1 year after bone marrow transplantation. One patient died free of leukemia, 41 months after transplantation of meningitis. Two of seven patients transplanted during the second remission of the disease, are alive and free of leukemia at 42+, and 8+ months. All patients transplanted during the third or fourth remission of the disease have died from either a further relapse, or transplant related causes. The low incidence of organ toxicity with CBV allows for further dose escalation of its drug components.

Acute Disease↗
PubMed1987

Autologous transplantation with circulating hemopoietic stem cells.

Circulating stem cells exist in sufficient numbers in mouse, dog, and man to allow collection and transplantation after ablative treatment. Preclinical studies in the mouse have shown a low concentration, with a transplantation potential ratio of bone marrow to blood of 1:100. The ratio of circulating stem cells to bone marrow stem cells is more favorable in the dog (1:10-20). Recent pilot studies carried out in different centers with 10 patients have shown that this approach is feasible in man, too. It appears that 5 X 10(8) mononuclear cells/kg of body weight collected by seven or eight leukapheresis procedures of about 4 hrs each is sufficient for fast hemopoietic recovery after marrow ablative treatment. Potential advantages of the use of blood stem cells over bone marrow stem cells are the decreased likelihood of contamination with malignant cells, the avoidance of general anesthesia, and the infusion of immunocompetent cells, which might hasten immunorecovery in the autologous setting.

Animals↗
PubMed1987

Regrowth of granulocyte-macrophage progenitor cells (GM-CFC) in suspension cultures of bone marrow depleted of GM-CFC with 4-hydroperoxycyclophosphamide (4-HC).

The hematopoietic capacity of bone marrow treated with 4-hydroperoxycyclophosphamide (4-HC) was studied using long-term suspension cultures. It was shown that, in the presence of a previously established marrow adherent cell layer (ACL), the 4-HC treated bone marrow, deprived of GM-CFC, generates GM-CFC in long-term suspension cultures in vitro. The kinetics of GM-CFC reappearance in in vitro cultures indicate their origin from more primitive progenitors rather than from surviving GM-CFC. In the presented modification, the suspension culture system is useful in evaluating the transplantation potential of bone marrow purged in vitro with chemotherapeutic or biologic agents.

Bone Marrow↗
PubMed1986

High-dose melphalan and total body irradiation with bone marrow transplantation for refractory malignancies.

We investigated if high dose melphalan and total body irradiation could be administered to adult patients with acceptable toxicity. Nineteen adult patients with relapsed disease, 15 of them having hematologic malignancies, were treated with high-dose melphalan (100 mg/m2-140 mg/m2) divided over 2 consecutive days followed by a rest period of 4 days before receiving total body irradiation, 850 rad administered in five fractionated doses over 3 days. Subsequently 11 patients received autologous, seven allogeneic and one syngeneic, bone marrow transplantation. All patients had severe myelosuppression and the major extramedullary toxicity was mucositis. There were three early deaths, two related to septicemia and one to graft-versus-host disease with associated cytomegalovirus pneumonitis. All patients were heavily pretreated, and 16 were demonstrating progressive disease on alternative salvage therapies at the time of bone marrow transplantation. Two of the 16 evaluable patients (12.5%) achieved complete remissions, and 10 (63%) achieved partial remissions for a total response rate of 75%. One patient is a long-term disease-free survivor (over 1 yr). An occasional patient may be cured by this approach. The combination of melphalan, an alternative alkylating agent to cyclophosphamide and total body irradiation are associated with moderate gastrointestinal toxicity in heavily pretreated adult patients. The combination warrants further investigation in a less heavily pretreated population to determine more accurately the complete response rate.

Adult↗
PubMed1986

High-dose cyclophosphamide, BCNU, and etoposide followed by autologous bone marrow rescue as treatment for adult acute leukemia in relapse.

High-dose cyclophosphamide, 1,3-bis-(2 chloroethyl)-1-nitrosourea (BCNU), and VP-16-213 followed by autologous bone marrow rescue was administered to 29 adult patients with acute leukemia in relapse who had failed to respond to prior salvage treatment, with the following results: 14 patients (48%) achieved complete remission (CR), two patients died early of infection and hemorrhage during hypoplasia, and 13 patients had relapsed with leukemia after an initial hypo-plastic phase. Median remission duration was 3 1/2 months (range, 1-8 months). Maintenance treatment with cyclophosphamide and VP-16, which was given to six patients, did not prolong remission duration. Subsequent salvage treatment was well tolerated by both responders and patients who failed to reach CR. This regimen, which is active in both acute lymphocytic leukemia and acute myelogenous leukemia, had a mild toxicity.

Acute Disease↗
PubMed1986

Piperazinedione, total body irradiation, and autologous bone marrow transplantation in chronic myelogenous leukemia.

Eleven patients with Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) in blast crisis (ten patients) or accelerated disease (one patient) were treated with piperazinedione (PIP) and fractionated total body irradiation (TBI) followed by autologous bone marrow transplantation (ABMT). Three patients were transplanted with marrow from which the Ph1 clone had been eradicated by prior intensive chemotherapy. All patients responded with disappearance of blasts in bone marrow and peripheral blood. Six patients achieved a second chronic phase lasting 3 to 14 months (median, 6 months). Two patients had incomplete recovery, and three patients failed to engraft and died from infection. Transplantation with Ph1-negative bone marrow did not improve response duration or survival. Recurrence of blast crisis and incomplete engraftment continue to be the two major problems in this patient group, and more active regimens need to be investigated.

Adult↗
PubMed1986

High-dose cyclophosphamide, carmustine, and etoposide and autologous bone marrow transplantation for relapsed Hodgkin's disease.

Thirty patients with relapsed Hodgkin's disease were treated with high-dose cyclophosphamide, carmustine, and etoposide (CBV) and autologous bone marrow transplantation. The median age of the patients was 28 years, and 18 were male. More than half had extranodal sites of relapse and constitutional symptoms. Most had been heavily pretreated with multiple salvage chemotherapy regimens and radiotherapy. At the time of transplantation, 23 patients were having progressive disease despite salvage chemotherapy. High-dose CBV chemotherapy induced complete responses in 15 patients and partial responses in 10 patients. Eleven patients are still in complete remission, 1 of whom has had an unmaintained remission for more than 44 months. Toxicity was moderate; all patients had severe myelosuppression requiring supportive therapy, and 1 patient failed to reconstitute her bone marrow. High-dose CBV chemotherapy and autologous bone marrow rescue proved to be effective as salvage therapy for a select group of heavily pretreated patients with relapsed Hodgkin's disease.

Adolescent↗
PubMed1986

Regeneration of T lymphocytes from human bone marrow cells after depletion with methylprednisolone.

This study evaluates the propagation of T lymphocytes in bone marrow cells after in vitro methylprednisolone treatment. Previous studies from this laboratory showed that immunocompetent T lymphocytes could be eliminated from the bone marrow cells by incubation with 15 mg/ml (0.04 M) of methylprednisolone for 1 hr. The effectiveness of the chemoseparation was assessed by E-rosette forming cell assay, mitogen-induced lymphoblastogenic responses, and lymphocyte surface markers. In this study, bone marrow cells treated with different concentrations of methylprednisolone were cultured in the presence of PHA and Interleukin-2. The mitogen-induced lymphoblastogenesis was restored in the 15 mg/ml MP-treated bone marrow cells by the 8th day of culture in the presence of Interleukin-2. The cells in the culture were analyzed by E-rosette forming cell assay. It was shown that the predominant cells in the cultures were E-rosette forming cells. This study demonstrates that immunocompetent T lymphocytes can be regenerated in the presence of mitogen and Interleukin-2 from bone marrow cells treated with 15 mg/ml of methylprednisolone.

Bone Marrow↗
PubMed1986

Enhanced recovery of gut-associated lymphoid tissue by infusion of buffy coat cells and gut leukocytes in the murine syngeneic bone marrow transplantation model.

Ways of accelerating recovery of the mucous membrane immune system in lethally irradiated mice following syngeneic bone marrow transplantation were studied over a 35-day period by quantification of jejunal intraepithelial lymphocytes (IELs) and lamina propria plasma cells. Recovery after a low bone marrow dose allowing 100% animal survival (LBM) was compared with a high (five times minimal) dose (HBM), or a minimal dose augmented with equal numbers of buffy coat cells (LBM + BC) or small gut mucosal lymphocytes (LBM + GL). The maximal decline and subsequent peak repopulation of IELs were: LBM, days 7 through 14, peaking suboptimally by day 28; HBM, day 14, peaking suboptimally but higher than LBM by day 35; LBM + BC, days 11 through 14, peaking at control levels by day 35; and LBM + GL, day 7, peaking at control levels by day 28. The IEL decline was most severe with LBM and HBM treatment and least with LBM + GL. All transplant groups experienced maximal plasma cell decline by day 7. LBM had the most severe depletion, and LBM + GL had the least. Recovery to control levels for the LBM, HBM, LBM + BC and LBM + GL groups occurred by days 28, 21, 21, and 14, respectively. In all instances, greater than 95% of the plasma cells were IgA positive.

Animals↗
PubMed1985

Allogeneic bone marrow transplantation for acute leukemia refractory to induction chemotherapy.

This article compares the outcome of 14 patients with primary refractory acute leukemia who underwent bone marrow transplantation from human leukocyte antigen (HLA)-identical donors with that of 18 age-matched control patients who received chemotherapy. Complete clearing of leukemia was seen in all 14 transplanted patients. Five of the transplanted patients are alive 98 to 1790 days posttransplant, and four are free of leukemia. Nine patients have died, eight with severe graft-versus-host disease associated with interstitial pneumonia or systemic infections and one with relapse from chemotherapy-associated infections. Engraftment was seen in all patients. Severe graft-versus-host disease (grades III and IV) was seen in ten patients and resolved in three patients following high-dose corticosteroid treatment. Three of the 18 control patients are alive, none of them in complete remission. It appears that the combination of piperazinedione and total-body irradiation followed by allogeneic transplant is effective induction treatment for primary refractory acute leukemia and will be considered in the future as first salvage treatment for patients failing induction treatment.

Acute Disease↗
PubMed1985

Immune recovery following allogeneic bone marrow transplantation.

A total of 144 evaluations of cell surface markers and cellular immune functions were carried out in 57 patients undergoing allogeneic bone marrow transplantation for acute leukemia in remission and relapse and for aplastic anemia. The periods tested were pretransplant, and 1-3, 4-6, 7-12 and more than 12 months posttransplant. The determination consisted of lymphocyte counts; lymphocyte surface marking using OKT3, OKT4, and OKT8 antibodies; and determination of adherent cells, lysozymes and antibody dependent cellular cytotoxicity (ADCC) against chicken red blood cells, human red blood cells, and CEM cells. Natural killer cells were determined against K562 target cells. Lymphoblastic responses were tested after stimulation with pokeweed mitogen (PWM), concanavalin-A (Con-A), and phytohemagglutinin (PHA). We found that the progression in the leukemic state (first remission, second remission, and relapse), prior to transplantation was paralleled by a decrease in T4 lymphocytes (976/microliter +/- 462; 411/microliter +/- 222; 372/microliter +/- 419; P = .04). There was a lack of helper cells and an inverted T4:T8 ratio beyond one year posttransplant independent of graft-versus-host disease status. Lymphocyte functions persisted to be depressed for more than one year. We found a direct correlation of T4 helper cells and an inverse correlation of T8 suppressor cells with lymphoblastic responses to mitogens. It is hoped that the longitudinal evaluations of immune functions after allogeneic bone marrow transplantation, and the characterization of the immune defects seen may lead to better immunorestorative treatments.

Adolescent↗
PubMed1985

Differential cytotoxic activity of chemotherapy agents on colony-forming cells from human tumors and normal bone marrow in vitro.

We have compared the in vitro differential killing efficacy of doxorubicin, 5-fluorouracil, cis-platinum, etoposide, and bleomycin on human tumor cells in a new adhesive tumor cell culture system (ATCCS), and on normal bone marrow granulocyte-macrophage colony-forming units (GM-CFUC) in culture. All of the above chemotherapy agents were tested with continuous exposure against tumor cells and GM-CFUC. In addition, bleomycin was also tested with a short (60 min) exposure against GM-CFUC. In order to determine chemosensitivity against all five drugs, 48 tumor specimens from patients with heterogeneous tumor types were tested in the ATCCS. Each drug was tested at three different concentrations corresponding to their lethal doses against GM-CFUC. Our results show that all five drugs exhibited a dose-response relationship against tumor cells and GM-CFUC. Bleomycin also showed a pronounced GM-CFUC-sparing quality with 60-min exposure even at very high concentrations (86% survival of GM-CFUC at 10 micrograms/ml and 48% at 50 micrograms/ml). In addition, it has a high tumor response rate with continuous exposure at low concentrations (67% at GM-CFUC LD5 and 91% at LD40). These data suggest that the comparison of differential cytotoxicity of chemotherapy drugs between tumor cells and bone marrow cells may serve as a model to select agents suitable for in vitro chemotherapy of bone marrow for the purpose of autologous bone marrow transplantation. In particular, bleomycin appears very attractive and deserves further investigation.

Antineoplastic Agents↗
PubMed1985

Effect of pretreatment with cyclophosphamide on high-dose toxicity of melphalan in mice.

This study was undertaken to evaluate the effect of pretreatment (or priming) with cyclophosphamide (CY) on lethal toxicity of high-dose melphalan (MELPH) in mice. In C57BL/6 X DBA/2 F1 (hereafter called B6D2F1) mice given an injection of a single dose of CY, 50 mg/kg, 1-5 days before MELPH, 20 mg/kg, improved survival was noted in only one of five experiments. Reducing the challenge dose of MELPH to 17 mg/kg did not improve survival consistently. Priming with CY, 50 mg/kg, 3 days before a dose of MELPH, 20 mg/kg, did not improve survival in CBA/J or C57BL/6 mice. These results indicate that CY is an inconsistent priming agent for abrogating high-dose MELPH toxicity in mice. A slightly earlier recovery of regenerating hemopoietic and of jejunal crypt cells was noted in CY-primed B6D2F1 mice given injections of a low dose of MELPH, 15 mg/kg. The occasional improved animal survival noted in CY-primed B6D2F1 mice might be related to this earlier cell recovery.

Animals↗
PubMed1984

High-dose chemotherapy with autologous bone marrow transplantation.

High-dose chemotherapy using drugs with predominant marrow toxicity and autologous bone marrow support has been investigated in a number of tumor types. High response rates are uniform and complete responses are also high; but long-term disease-free survival is occasional. This review discusses those tumor types where patients treated with this approach have survived disease free for several years. Also discussed is what other tumor types and prognostic subgroups of those tumors might benefit therapeutically from high-dose cytotoxic intensification with autologous bone marrow support or at least have this approach considered as the first alternative for initial relapse.

Antineoplastic Agents↗
PubMed1984

Repeated high-dose cyclophosphamide, BCNU and VP-16-213 and autologous bone marrow transplantation in adult acute lymphocytic leukemia in first remission.

In adult acute lymphocytic leukemia (ALL) cure is rare. The purpose of this study was to try to improve remission duration and survival by administration of two courses of high-dose chemotherapy, each followed by autologous bone marrow rescue, in first remission. Chemotherapy consisted of cyclophosphamide, BCNU and VP-16-213. Rescue bone marrow was fractionated over a discontinuous albumin gradient to minimize contamination with leukemic cells. Fourteen patients entered the study. Median total remission duration was 14 months. Three patients relapsed after one course of treatment. Five patients relapsed after the second course. Four patients died after the second course and two patients remain alive and well in unmaintained remission, with a total remission duration of 42+ and 47+ months. It is concluded that this regimen is toxic but, with careful selection of patients, may lead to long-term unmaintained remissions.

Adolescent↗
PubMed1984

High-dose methylprednisolone treatment for acute graft-versus-host disease after bone marrow transplantation in adults.

High-dose methylprednisolone (HDMP) was used to treat 18 episodes of severe (grades III and IV) acute graft-versus-host disease (GVHD) that developed after allogeneic bone marrow transplantation in 12 patients with acute leukemia and in 2 with aplastic anemia. Most of the patients showed rapid improvement in GVHD, with complete resolution of the skin and gut manifestations. However, the response of liver disease to the treatment was slow and incomplete. Complications seen were interstitial pneumonia and fungal and viral infections. Seven patients survived for more than two months following the treatment of acute GVHD. Five of these became long-term survivors with a median survival of 22+ months (range 11-38 months); all five long-term survivors developed chronic GVHD and are alive at the time of this report. It appears that HDMP is an effective treatment for severe acute GVHD. However, its true efficacy can only be ascertained in a randomized study comparing high-dose and conventional-dose methylprednisolone.

Acute Disease↗