Autologous bone marrow transplantation in acute leukemia.
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Antineoplastic Agents↗
Biomedical subjects
D S Verma
Publications and source records attributed to D S Verma.
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↗
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↗
Identification of T lymphocyte subpopulations that regulate elaboration of granulocyte-macrophage colony stimulating factor.
To determine the role of T lymphocytes (TL) that bear Fc receptors for IgG (T gamma +) and IgM (T mu +) and of those that do not (T gamma- and T mu-) in the elaboration of granulocyte-macrophage colony-stimulating activity (GM-CSA), we coincubated TL or the TL subpopulations in varying proportions with a constant concentration of autologous monocyte-macrophages (M phi) along with methanol extraction residue of BCG (MER). These conditioned media (CM) were assayed for GM-CSA. M phi and TL interacted maximally at 1:3-1:6 ratios, significantly less so at a 1:9 ratio. Coincubation of M phi with T gamma- fraction markedly enhanced GM-CSA elaboration at all M phi:T gamma- ratios, progressively increasing colony-stimulating activity as the proportion of T gamma- cells increased. M phi interacted with the T gamma- fraction significantly better (P = 0.001) at all the ratios tested than it did with the T gamma- mu + or T gamma- mu- subsets, suggesting that the T gamma- mu + and T gamma- mu- subsets must interact. Coincubation of the T gamma + fraction synergistically enhanced GM-CSA elaboration only at M phi:T gamma + ratios of 1:1.5 and 1:3. Further increases in the proportion of T gamma + cells rapidly and progressively decreased the capacity of the CM to stimulate granulocyte-macrophage colony-forming cells (GM-CFC). Also, inclusion of Tgamma+ cells in the coincubation mixtures of M phi and T gamma- fraction significantly suppressed GM-CSA elaboration. Dose-response curves and CM-mixing experiments revealed that the CM from coincubation of M chi and T gamma+ not only contained smaller amounts of stimulating factors but also contained a GM-CFC inhibitor. Experiments also demonstrated that the suppressor subpopulation enriched with the T gamma+ fraction was radiosensitive. These results suggest that the elaboration of GM-CSA is controlled by helper and suppressor subpopulations that are enriched with T gamma- and T gamma+ fractions, respectively. Furthermore, the suppressor effect is radiosensitive.
Antibodies, Monoclonal↗
Mobilization of canine hemopoietic stem cells by pyran copolymer (NSC 46015).
Pyran copolymer (NSC 46015), a divinyl ether maleic anhydride of broad spectrum molecular weight, was infused into six normal mongrel dogs. The effect on canine blood and bone marrow colony forming units in culture (CFU-C) was followed over an 11-day period. Significant elevation of circulating CFU-c was noted 2 days after pyran infusion; normalization occurred by day 7 postinfusion. Bone marrow CFU-C were decreased 2 days and 5 days after pyran administration. A further increase in circulating CFU-C was noted when pyran was administered twice, 5 days apart. The mobilizing effect of pyran copolymer appears promising enough to warrant further exploration of blood as a source of hemopoietic stem cells for transplantation purposes.
Animals↗
High-dose chemotherapy and autologous bone marrow transplantation for the treatment of small cell lung carcinoma.
Fourteen patients with untreated small cell bronchogenic carcinoma were treated initially with 2 chemotherapy courses of cyclophosphamide (1.5 g/m2 days 1-3), 4-dimethyl epipodophylloxtin (200 mg/m2 days 1-3), vincristine (1.5 mg/m2 days 1 and 3), and with Adriamycin (80 mg/m2 day 1) in 8 patients and without Adriamycin in 6 patients. To modify hematopoietic toxicity from these high doses of chemotherapy, autologous marrow collected and frozen before storage was thawed and infused after each of these high-dose therapies. After this therapy patients received prophylactic brain irradiation (3000 rad), 4 courses of usual doses of these same drugs and then 5000 rad chest irradiation if there was still evidence of disease (PR) or randomized to radiation if in complete remission (CR). Response rate was high, with 54% CR and 46% PR, a total of 100%. However, a median response duration of 41 weeks and median survival of 56 weeks, are similar to other chemotherapy programs. Toxicity was mild except for cardiac arrhythmias when Adriamycin was included. The reasons for no therapeutic increment are discussed.
Aged↗
Leukemic cell colony formation in soft agar by bone marrow cells and peripheral blood cells from untreated acute leukemia patients.
An in vitro culture technique for colony formation of marrow cells and peripheral blood cells from untreated acute leukemia patients and from patients in relapse is described. The colonies from bone marrow cells of an untreated acute myelogenous leukemia (AML) patient were demonstrated to be of leukemic origin by cytogenetic analysis. Cells obtained from colonies of leukemic origin contained the human malignancy-associated nucleolar antigen (HMNA) as detected by indirect immunofluorescence. This nucleolar antigen was not present in marrow or peripheral blood cells or cells from colonies of marrow from hematologically normal individuals. Colonies could be grown from over 70% of the marrow and peripheral blood samples from untreated acute leukemia patients. The median number of colonies obtained was 75 per 10(5) marrow cells from patients with AML. In 1/3 of the cases an increased number of colonies could be grown from marrow cell suspensions kept in liquid culture for 5 days. This is indicative of the proliferative capacity of the colony forming cell population. This assay may be useful for detection of residual clonogenic leukemic cells in marrow and peripheral blood cell suspensions.
Adult↗
Evidence for the separate human T-lymphocyte subpopulations that collaborate with autologous monocyte/macrophages in the elaboration of colony-stimulating activity and those that suppress this collaboration.
We investigated the interaction of monocyte/macrophages and autologous T lymphocytes in the methanol extraction residue (MER) of BCG-induced production of granulocyte-macrophage colony-stimulating activity (CSA). Coincubation of monocyte/macrophages and T lymphocytes at a 1:3 ratio produces an optimum collaboration; a change to a 1:9 ratio diminished this collaboration. Coincubation of monocyte/macrophages and T lymphocytes primed with lithium carbonate (2 meq/liter) for 40 hr synergistically increased CSA elaboration and prevented the decline in CSA noted for the 1:9 monocyte/macrophage: T lymphocyte ratio. In contrast, concanavalin-A-primed T lymphocytes did not enhance CSA elaboration at any monocyte/macrophage:T lymphocyte ratio except, occasionally, at 1:9. However, this was overcome if the T lymphocytes were primed with both concanavalin-A and lithium carbonate before their coincubation with monocyte/macrophages. Further cell-mixing experiments revealed that concanavalin-A-primed T lymphocytes contained a subpopulation that suppressed monocyte/macrophage and T-lymphocyte collaboration. Activation of suppressor T lymphocytes could be effectively prevented by lithium carbonate and, in a dose-dependent manner, by irradiation. Also, suppressor T lymphocytes not only diminished the elaboration of colony-stimulating factor(s), but also elaborated an inhibitor of granulocyte-macrophage colony-forming cells. We further demonstrated that the respective hemopoietic helper and suppressor T-lymphocyte activities could be enriched with OKT8- (or OKT4+) and OKT8+ subpopulations.
Antibodies, Monoclonal↗
Human leukocyte interferon-mediated granulopoietic differentiation arrest and its abrogation by lithium carbonate.
Interferon has been shown to inhibit erythropoietic and granulopoietic differentiation. Since lithium carbonate (Li) elevates granulocyte levels in a variety of neutropenic disorders, we investigated the effect of Li on human leukocyte interferon (HLIF)-mediated inhibition of granulopoietic differentiation. Using an agar culture technique for cloning granulocyte-macrophage progenitor cells (GM-CFC), we demonstrated that Li blocks HLIF-induced granulopoietic differentiation arrest in a dose-dependent manner. Results of removal of T lymphocytes from marrow cells suggest that this Li effect is not mediated through marrow T lymphocytes.
Cell Differentiation↗
DR antigen positive monocyte-macrophages control granulocyte-macrophage colony-stimulating activity and burst promoting activity elaboration in man.
To investigate the mechanisms that modulate granulocyte-macrophage colony-stimulating activity (GM-CSA) and burst promoting activity (BPA) elaboration, we studied human peripheral blood-derived monocyte-macrophage (M0) and T-lymphocyte (TL) interaction. Coincubation of live M0 with autologous TL at a 1:3 ratio in the presence of 1% phytohemagglutinin synergistically increased GM-CSA (6 of 6 experiments) and BPA (4 of 6 experiments) (P less than 0.002). Prior treatment of M0 with cycloheximide or actinomycin D significantly (P less than 0.002) diminished this M0's capacity to collaborate with TL. Mitomycin C treatment did not. Live M0 also enhanced TL-derived GM-CSA (P less than 0.002) and BPA (P less than 0.001). This enhancement was again compromised by prior cycloheximide or actinomycin D treatment, but not by mitomycin C treatment. Further experiments in which we blocked DR antigen on M0 membrane with monoclonal anti-DR antibodies suggested that M0 required their membrane DR antigen to collaborate with TL in elaborating GM-CSA and BPA.
Bone Marrow Cells↗
Cyclic neutropenia and T lymphocyte suppression of granulopoiesis: abrogation of the neutropenic cycles by lithium carbonate.
To investigate the mechanisms of cyclic neutropenia, we studied the capacity of a patient's T lymphocytes (TLp) to interact with monocyte-macrophages from her normal HLA-identical sibling (MOb) in the elaboration of colony-stimulating activity (CSA). TLp obtained at the time of decreasing neutrophil counts, increased CSA elaboration (p less than 0.056) when incubated at a 1:1 ratio with MOb. Increasing the TLp to MOb ratios to 3:1 or 5:1 progressively decreased CSA. Also, lithium carbonate, which ordinarily prevents concanavalin A activation of suppressor TL, failed to do so, suggesting that preactivated suppressor TL were present in the patient while neutrophil levels were falling. In similar experiments performed while neutrophil levels were rising these activated suppressor TL were absent. These data suggest that some patients with cyclic neutropenia may have a cyclic increase in suppressor TL activity. As predicted by our in vitro experiments, lithium carbonate administration did not abrogate the first neutropenic cycle, but it did mitigate subsequent cycles.
Adult↗
The mechanism of lithium carbonate-induced augmentation of colony-stimulating activity elaboration in man.
Lithium carbonate (Li) has been reported to elevate granulocyte counts in patients with certain neutropenic disorders and to improve chemotherapy-induced granulocytopenia. To investigate the mechanisms involved in the increase in myelopoiesis, the effect of Li on monocytemacrophage (M phi)- and T-lymphocyte (TL)-derived colony-stimulating activity (CSA) were studied in vitro. Li induced a dose-related increase in both M phi- and TL-derived CSA over that in non-Li-stimulated cell populations. However, the increase was significant (p less than 0.007) only at a higher concentration of Li (2 mEq/l). The results of co-incubating TL with M phi with or without Li indicated that Li significantly enhanced synergistic CSA production by the two cell populations (p less than 0.02). We further demonstrated the presence of a larger proportion of M phi with TL rosettes in the presence of Li (62%) than in its absence (21%). Further experiments with concanavalin A (Con-A)-inducible suppressor TL suggested that Li effectively blocks the suppressor TL-mediated suppression of CSA. These data suggest that Li enhances M phi and TL interaction which results in an augmented CSA elaboration. Further, Li would be more effective in those neutropenic disorders associated with enhanced suppressor TL activity. For an optimal effect, however, Li would require appropriately functioning M phi and non-suppressor subsets of TL and an intact stem cell pool.
Cell Division↗
Monocyte-macrophage modulation of T-lymphocyte-derived colony-stimulating activity elaboration in man.
To investigate the source and the mechanisms of synergistically enhanced colony-stimulating activity elaboration by the coincubated monocyte-macrophages and T lymphocytes, we simultaneously prepared conditioned media both from the coincubated monocyte-macrophages and T lymphocytes (ratio 1:3) in the presence of phytohemagglutinin (1%) or methanol extraction residue of bacillus Calmette-Guerin (50 micrograms/ml) and from the isolated T lymphocytes that had been primed with monocyte-macrophages in the presence or absence of phytohemagglutinin or methanol extraction residue of bacillus Calmette-Guerin. Subsequently, colony-simulating activity in various conditioned media was assayed using light-density (less than 1.070 g/ml), nonadherent normal human marrow cells. Live monocyte-macrophages synergized with and significantly (P less than 0.01) agumented the T lymphocyte-derived colony-stimulating activity elaboration; while killed monocytes-macrophages had no such effect. Similarly, actinomycin D and cycloheximide not only diminished monocyte-macrophage colony-stimulating activity elaboration but also reduced their synergistic interaction with T lymphocytes and their ability to augment the T lymphocyte-derived colony-stimulating activity elaboration. In contrast, mitomycin C failed to diminish both - monocyte-macrophages' ability to synergise with T lymphocytes and also to augment T lymphocyte-derived colony-stimulating activity. These data suggest that monocyte-macrophages require an intact transcriptional and translational processes, but not DNA synthesis for synergising with T lymphocytes or for augmenting T lymphocyte colony-stimulating activity elaboration.
Cell Adhesion↗
Cells with Fc gamma receptors from normal donors suppress granulocytic macrophage colony formation.
We investigated the role of normal human marrow cells with Fc receptors for IgG (Fc gamma+) on autologous granulocyte-macrophage colony (GM-CFC) formation. It was found that Fc gamma+ normal human marrow cells, both with (E+) or without receptors for sheep erythrocytes suppressed GM-CFC at as low a concentration as 0.25 X 10(5) cells/ml of culture. A similar effect was observed with E- Fc gamma+ but not E+ Fc gamma+ peripheral blood cells. Suppression by Fc gamma+ cells did not require mitogen activation and was not inactivated by irradiation (2000 R). This report presents a new in vitro regulatory mechanism for GM-CFC growth in normal donors.
Bone Marrow↗
An essential role for polyamine biosynthesis during human granulopoietic differentiation.
The role of polyamines during the process of colony-stimulating factor-induced proliferation and differentiation of human granulocyte-macrophage progenitor cells was studied using in vitro liquid cultures and semisolid agar cultures. Human placenta-conditioned medium, a partially purified preparation of colony-stimulating factor, rapidly and significantly increased the intracellular putrescine concentration of light-density, non-adherent, T-lymphocyte-depleted human marrow cells, Inhibition of polyamine biosynthesis with alpha-difluoromethylornithine, a catalytic, irreversible inhibitor or ornithine decarboxylase, resulted in an accumulation of blasts, promyelocytes, and myelocytes with a concomitant decrease in metamyelocytes and polymorphonuclear granulocytes, suggesting a granulopoietic differentiation block. The observed inhibition of differentiation could easily be reversed with exogenously added putrescine. These data indicate clearly an essential role for polyamines during the process of human granulopoietic differentiation.
Bone Marrow↗
Human adherent cell contact-mediated modulation of normal myeloid colony formation.
The effects of coincubation of normal nonadherent bone marrow cells on adherent monolayers created from human peripheral blood mononuclear cells or marrow cells were investigated. Nonadherent marrow cells were coincubated for 4 hours with peripheral blood adherent cells at ratios of adherent cells to marrow cells of 2:1 to 5:1. This coincubation suppressed subsequent neutrophilic agar colony growth but not eosinophilic growth. Further studies suggested that this suppression was a cell-cell-mediated process and not secondary to soluble factors. However, coincubation on marrow adherent cells caused increased neutrophilic colony recovery. The possible in vivo relevance is discussed.
Agar↗
High-dose AMSA and bone marrow rescue in patients with solid tumors.
The feasibility of high-dose AMSA followed by autologous bone marrow rescue was studied in seven patients with solid tumors. They received a total of 12 courses of treatment. Total doses ranged from 600 to 1000 mg/m2/course. Major toxic effects were myelosuppression, fever of unknown origin, and stomatitis. One patient with malignant melanoma had stable disease lasting 2 months; the other six had progressive disease.
Aminoacridines↗
Testosterone and synthetic and androgens improve the in vitro survival of human marrow progenitor cells in serum-free suspension cultures.
The direct effect of testosterone and its synthetic analogs on the maintenance of human erythroid progenitor cells (BFU-E) and GM-CFC was studied in suspension cultures. To avoid interference by serum components, the experiments were conducted in serum-free media containing insulin, transferrin, selenium, BSA, and alpha-thioglycerol. When added at concentrations between 10(-7)M and 10(-9)M, testosterone improved survival of BFU-E and GM-CFC. Of the nine analogs tested, eight improved BFU-E maintenance in vitro: nandrolone norethandrolone, and oxymetholone were most active, whereas etiocholanolone had only marginal effects. The influence of these compounds on GM-CFC was less pronounced, with testosterone showing the highest activity. It is concluded that testosterone and some of the synthetic analogs tested exert their hemopoietic effect, at least partly, by affecting the maintenance of erythroid and granulocytic stem cells, directly by increasing their survival or proliferation or indirectly by increasing the input from multipotent stem cell pool, or by both mechanisms.
Cell Count↗