Search PubMed⌕ Search

Biomedical subjects

A Ganser

Publications and source records attributed to A Ganser.

At least 217 records · Page 12Linked to original sources
PubMed1991

In vivo effects of granulocyte-macrophage colony-stimulating factor and interleukin-3 on clonal and non-clonal cell populations in patients with clonal hematopoietic disorders.

Restriction fragment length polymorphisms (RFLP) of the X-chromosome genes phosphoglycerate kinase and hypoxanthine phosphoribosyl transferase were used in conjunction with cytogenetic analysis to study the clonality of hematopoiesis in four female patients with myelodysplastic syndromes, treated with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3), and in one patient with essential thrombocythemia (ET) treated with IL-3. Both conventional karyotyping and X-inactivation analysis demonstrated the persistence of a monoclonal pattern of hematopoiesis in the two patients with refractory anemia (RA) treated either with GM-CSF or with IL-3. The partial restoration of non-clonal hematopoiesis was observed in one patient with RA and an excess of blasts following treatment with a combination of GM-CSF and low dose cytosine arabinoside. In a fourth patient with RA and in the patient with ET, treatment with IL-3 resulted in the complete restoration of a non-clonal pattern of peripheral blood cells. In contrast, the bone marrow cells remained monoclonal by Southern blot analysis in the patient with RA in whom it could be tested. Non-clonal lymphocytes appear to have been released into the peripheral blood in the two latter cases and are responsible for the non-clonal RFLP pattern. These results suggest that cytokine therapy may have diverse effects on hematopoiesis, including the release of residual normal cells into the peripheral blood.

Adult↗
PubMed1991

Regulation of early hematopoiesis in serum-deprived cultures of mafosfamide-treated and untreated CD34-enriched bone marrow cells.

Our experiments have addressed the regulation of early hematopoietic progenitor cell expansion by interleukin 3 (IL-3) and interleukin 1 beta (IL-1 beta) and its modulation by bone marrow fibroblasts in vitro. In a two-stage assay utilizing serum-deprived (SD) presuspension cultures of CD34-enriched bone marrow (BM) cells followed by clonal cultures, absolute numbers of granulocyte-macrophage progenitor cells (day-14 granulocyte-macrophage colony-forming units [CFU-GM]) increased progressively to 164% and 204% of input levels after 12 days of culture in the presence of IL-3 alone or in combination with IL-1 beta, respectively. Multilineage (granulocyte erythrocyte macrophage megakaryocyte colony-forming units, CFU-GEMM) and erythroid (erythroid burst-forming units, BFU-E) progenitor cell numbers increased above or were maintained at input levels after 4 and 7 days of liquid culture in the presence of IL-3 and IL-3 plus IL-1 beta, respectively, but in contrast to granulocyte-macrophage colony-forming units (CFU-GM) they were essentially undetectable after 12 days of culture. Progenitors more primitive than colony-forming cells (pre-CFU) were assessed in SD-presuspension cultures of CD34-enriched BM cells purged with mafosfamide to eliminate base-line CFU-GM, CFU-GEMM, and BFU-E. Under these conditions and in the absence of stromal elements, CFU-GM but neither CFU-GEMM nor BFU-E developed in response to cytokines alone. In the additional presence of passaged bone marrow fibroblasts, however, IL-3 plus IL-1 beta and to a lesser degree IL-3 alone induced a pronounced amplification of BFU-E and CFU-GEMM, indicating that their development from a more primitive progenitor compartment requires growth activities in addition to IL-3 and IL-1 beta that are provided by marrow-derived stromal cells such as fibroblasts.

Adult↗
PubMed1991

Clinical use of recombinant human hematopoietic growth factors (GM-CSF, IL-3, EPO) in patients with myelodysplastic syndrome.

We have conducted several phase I/II clinical studies in a total of 65 MDS patients utilizing recombinant human hematopoietic growth factors including GM-CSF, IL-3, and EPO. Twenty-seven patients with MDS were treated with either continuous i.v. infusion or single daily s.c. injection of rhGM-CSF at dosages from 15 micrograms/m2 to 1000 micrograms/m2. All of them exhibited white cell responses during the treatment cycles, but no sustained rise in reticulocytes or platelets was recorded. In four of the patients, all with > or = 15% blast cells in the bone marrow, the percentage of circulating blast cells increased during treatment with rhGM-CSF (at dosages of 500 micrograms/m2 and 1000 micrograms/m2, respectively), although no leukemic conversion occurred. Of 9 patients treated so far with rhIL-3 at single daily s.c. dosages of 60 micrograms/m2, all exhibited white cell responses; 8 exhibited significant improved platelet and reticulocyte counts. Nineteen further patients received rhEPO for a period of 14 weeks by s.c. (10,000 U five times weekly) or i.v. bolus administration (150-450 U/kg). None of these patients experienced an increase in white cell and platelet counts. A significant increase of the reticulocyte count was recorded in 3 patients only. Another strategy involves the recruitment of leukemic cells into the cell cycle by hematopoietic growth factors followed by treatment with cycle-specific cytostatic agents. Therefore in 10 patients administration of rhGM-CSF (250 g/m2/day x 14, s.c.) was combined with Ara-C treatment (20 mg/m2/day x 14; s.c.). Initial results of this pilot study available in 5 patients indicated that this approach may control leukemic cell proliferation and may increase number of mature myeloid cells in both bone marrow and peripheral blood. A similar approach utilizing rhIL-3 in conjunction with Ara-C is on-going.

Blood Cell Count↗
PubMed1991

Successful stimulation of autologous bone marrow recovery by GM-CSF and IL-3 after an unrelated donor BMT for juvenile CML complicated by graft failure.

We report the case of a boy with juvenile chronic myeloid leukemia (jCML), who after initial treatment with interferon alpha-2 (IFN) and hydroxyurea underwent bone marrow transplantation (BMT) from a matched unrelated donor complicated by graft failure. Subsequent stimulation of hematopoiesis by GM-CSF and IL-3 promoted autologous recovery. In contrast to the course of disease pre-BMT, the boy is now off any therapy remaining in complete remission more than 500 days after BMT.

Bone Marrow↗
PubMed1991

Remission of juvenile chronic myeloid leukemia following graft failure of an unrelated marrow transplant and autologous recovery of marrow function promoted by GM-CSF and IL-3.

The unusual course of a boy with juvenile chronic myeloid leukaemia is presented. After bone marrow transplantation (BMT) from an unrelated donor followed by graft failure and subsequent stimulation by rhu GM-CFC and II-3, this patient experienced complete recovery of autologous haematopoiesis. At 17 months post-BMT the patient was off any therapy with completely normal blood counts and no signs of disease.

Bone Marrow Transplantation↗
PubMed1990

Effects of recombinant human interleukin-3 on human hematopoietic progenitor and precursor cells in vivo.

DNA-synthesis rates and concentrations of bone marrow (BM) and peripheral blood (PB) progenitor cells were studied in 22 patients treated with recombinant human interleukin-3 (rhIL3) as part of a clinical phase I/II study. Recombinant hIL3 at doses of 60 to 500 micrograms/m2 was administered by subcutaneous bolus injection for 15 days to 13 patients with solid tumors and preserved hematopoietic function and to nine patients with bone marrow failure, including five with myelodysplastic syndromes. Following treatment with rhIL3, the percentage of actively cycling BM erythroid (BFU-E) and multilineage (CFU-GEMM) progenitors in patients with preserved hematopoietic function increased from 16% to 36% (P less than .05) and from 10% to 40% (P less than .01), respectively. The DNA-synthesis rates of early and late granulocyte macrophage progenitor cells increased from 11% to 26% (CFU-GM day 14; P less than .02) and from 13% to 30% (CFU-GM day 7; P less than .05). There was an increase in BM cellularity from 37% to 58%, and of the myeloid to erythroid ratio from 1.4 to 3.2, while the concentration of marrow progenitors on a per cell basis was unchanged or slightly decreased. The frequencies of blast cells in the BM were unchanged. Mean levels of PB CFU-GM day 14 and CFU-GEMM were 100% and 72% above baseline values after 7 days of rhIL3 but only 25% and 28% above initial levels at the end of treatment. Peripheral blood BFU-E were reduced in the majority of patients with normal marrow after both 7 and 15 days of rhIL3. No augmentation of circulating BFU-E and CFU-GEMM was seen in 5 patients with MDS who had few or no PB BFU-E or CFU-GEMM initially. Total leukocyte, neutrophil, and eosinophil counts increased significantly (P less than .01) in 21 of 22 patients with a peak response after a median of 13 days of rhIL3. While a small increase in reticulocytes was not accompanied by an elevation of the hemoglobin or hematocrit, platelet counts increased by 50% in patients with preserved marrow function. Thus, rhIL3 induces a multilineage response in vivo, apparently by stimulating proliferation of multipotential and lineage-restricted progenitors. It remains to be determined whether this is due to direct or indirect effects on the progenitor cells.

Adult↗
PubMed1990

Effects of recombinant human interleukin-3 in aplastic anemia.

In a phase I/II study, nine patients with aplastic anemia were treated with recombinant human interleukin-3 (rhIL-3) to assess the toxicity and biologic effects of this multipotential hematopoietic growth factor. Doses ranging from 250 micrograms/m2 to 500 micrograms/m2 were administered as subcutaneous bolus injections daily for 15 days. An increase in platelet counts from 1,000/microL to 31,000/microL was induced by rhIL-3 in one patient, and an increase in reticulocyte counts by more than 10,000/microL in four patients. The blood leukocyte counts temporarily increased in eight patients 1.5- to 3.3-fold (median, 1.8-fold), mainly due to an increase in the number of neutrophils, eosinophils, lymphocytes, and monocytes. In two patients, bone marrow cellularity increased from 7% to 33% and from 10% to 80%, respectively, but without resulting in a substantial improvement of peripheral blood counts. Mild side effects (headache and flushing) were observed in some patients, while low-grade fever occurred in all patients. Transient thrombocytopenia necessitating discontinuation of rhIL-3 treatment occurred in one patient. In conclusion, rhIL-3 can stimulate hematopoiesis in patients with aplastic anemia; however, no lasting effects were obtained.

Adolescent↗
PubMed1990

Effects of recombinant human interleukin-3 in patients with normal hematopoiesis and in patients with bone marrow failure.

In a phase I/II study, 19 patients with advanced tumors but normal hematopoiesis and nine patients with bone marrow failure and prolonged severe cytopenias were treated with recombinant human interleukin-3 (rhIL-3) to assess the toxicity and biological effects of this multipotential hematopoietic growth factor. Doses ranging from 30 micrograms/m2 to 500 micrograms/m2 were administered as subcutaneous bolus injection daily for 15 days. A dose-dependent increase in platelet counts ranging from 1.3-fold at 60 micrograms/m2 to 1.9-fold at 250 micrograms/m2 was induced by rhIL-3 in 15 of 18 evaluable patients with normal hematopoiesis. An increase in reticulocyte counts was observed in 14 patients. The blood leukocyte counts dose dependently increased 1.4- to 3.0-fold. In patients with bone marrow failure, platelet counts increased by a mean of sixfold (range, 1.3-fold to 14.3-fold) in five of eight evaluable patients. Reticulocyte counts increased 4.4-fold in six patients, and neutrophil counts increased by a mean of 3.1-fold in all eight patients. Platelet transfusions could be discontinued after treatment with rhIL-3 in two of three transfusion-dependent patients. Only mild side effects, mainly fever, headache, and flushing, were observed. These results indicate that rhIL-3 functions as a multilineage hematopoietin in vivo in patients with normal bone marrow function and in patients with secondary bone marrow failure.

Adult↗
PubMed1990

Effects of recombinant human interleukin-3 in patients with myelodysplastic syndromes.

In a phase I-II study, nine patients with myelodysplastic syndromes and concomitant severe transfusion-dependent cytopenias were treated with recombinant human interleukin-3 (rhIL-3) to improve hematopoietic function. Doses of rhIL-3 ranged from 250 micrograms/m2 to 500 micrograms/m2 and were given as daily subcutaneous bolus injections for 15 days. Blood leucocyte counts increased 1.3- to 3.6-fold in all nine patients, including neutrophils, eosinophils, lymphocytes, basophils, and monocytes. The mean absolute neutrophil counts increased from 1,350/microL (range, 150 to 2,420) to 2,660/microL (range, 300 to 9,380) (P less than .05) immediately after the end of rhIL-3 therapy and to a maximum count of 4,096/microL (range, 350 to 10,820) (P less than .01). Platelet responses were seen in two of four profoundly thrombocytopenic patients, resulting in discontinuation of platelet transfusion. The requirements for red blood cell transfusion temporarily improved in one patient. Stimulation of plasma cells was evident by a significant increase in serum IgM and IgA levels. Mild side effects (fever, headache, local erythema, and bone pain) were observed in some patients, while transient thrombocytopenia developed in two patients. Disease progression with an increase in blast cells was seen in one patient. These results suggest that rhIL-3 is effective in stimulating hematopoiesis of all lineages in patients with myelodysplastic syndromes and may produce at least short-term hematologic improvement.

Adult↗
PubMed1990

Treatment of relapsed acute lymphocytic leukemia in adults.

Thirty-three patients with ALL/AUL in first relapse were treated with an induction of prednisone, vindesine, daunorubicin, Erwinia asparaginase, i.t. MTX (phase I), high-dose cytarabine, and etoposide (phase II). Twenty-one (64%) achieved a complete remission, one a partial remission. Side effects of induction-phase I were predominantly hematological with subsequent infections and gastrointestinal toxicity. In phase II some patients had additional cutaneous, ocular, and hepatic toxicity. The treatment efficiently induced remissions with tolerable toxicity in relapsed ALL. The disease-free survival, however, needs to be improved.

Adolescent↗
PubMed1990

Recombinant human granulocyte-macrophage colony-stimulating factor and low-dose cytosine-arabinoside in the treatment of patients with myelodysplastic syndromes. A phase II study.

As part of a multicenter trial 12 patients with myelodysplastic syndromes (MDS) were treated with 14-day-cycles of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; 250 micrograms/m2 day s.c.). In addition, all patients received 20 mg/m2/day s.c. cytosine-arabinoside (Ara-C) 12 h after GM-CSF except for patients suffering from refractory anemia (RA) according to FAB classification. Courses were repeated after 4 weeks. In 11 evaluable patients, results according to FAB-classified MDS were as follows: RA, 1/2 response (R), 1/2 stable disease (SD); RAEB, 2/3 R, 1/3 SD; RAEB-T, 1/6 CR, 1/6 PR, 2/6 R, 2/6 progression; CMML, 1/2 SD. In 2 patients with RAEB-T, overt acute myeloid leukemia was observed 2 and 10 weeks after initiation of treatment. With few exceptions, treatment resulted in a prompt increase in granulocytes and eosinophiles. This was associated with improvement of infectious complications. Increases in red cells and platelets occurred variably and was apparently associated with responses of the underlying disease. Dose limiting side effects consisted of fever, severe fatigue and dolent local reactions at the site of GM-CSF injection. In addition, nausea and diarrhoea occurred frequently. Less often, respiratory and cardiovascular side effects were encountered. In summary, GM-CSF +/- Ara-C in MDS results in objective remission with manageable toxicity. Conceivably, this regimen will serve as a base for future treatment strategies against MDS.

Colony-Stimulating Factors↗
PubMed1990

[Evaluation of 196 patients with chronic myeloid leukemia based on a standard prognosis model].

The clinical course of 196 patients with chronic myelocytic leukemia (CML) was studied. Prognostic factors were analyzed using a standard prognostic model. From a univariate analysis of patients with nonblastic Philadelphia chromosome-positive CML, splenomegaly, bone marrow fibrosis, percentage of blasts and promyelocytes in the peripheral blood and LDH activity were shown to be factors with a significant negative influence on survival. However, age and the platelet count did not influence survival. The standard prognostic model, generated with the 4 variables (1) percentage of blasts and promyelocytes, (2) spleen size, (3) platelet count and (4) age did not provide a useful representation of risk status in this heterogenous patient population. However, the addition of further variables (LDH, additional chromosomal aberrations, percentage of basophiles/eosinophiles and percentage of bone marrow blasts) to the standard model allowed a separation into 2 patient groups: one with low and the other with intermediate to high risk. Our data support the general validity of the prognostic model; however, the applicability of the model may be compromised in hematologic centers with a heterogenous CML population due to the selection of high-risk patients. In this situation additional risk factors may have to be added to the prognostic formula.

Biomarkers, Tumor↗
PubMed1990

Histamine release from basophils after in vivo application of recombinant human interleukin-3 in man.

Interleukin 3 (IL3) is known to stimulate progenitor cell proliferation and maturation as well as differentiated cell functions, e.g. direct or anti-IgE-mediated histamine release (HR). We investigated 14 patients with malignant diseases being treated with recombinant human IL3 (rhuIL3) as a daily subcutaneous bolus injection for 15 days. For analysis, patients were combined in a 'low-dose' [30 (n = 1), 60 (n = 3) and 125 (n = 2) micrograms/m2/day] and a 'high-dose' [250 (n = 6) and 500 (n = 2) micrograms/m2/day] therapy group. In the high-dose group there was a 2-fold increase in total leukocytes, and 8-fold increase in basophils, and a 23-fold increase in eosinophils. Histamine content per basophil decreased rapidly after rhuIL3 administration. Anti-IgE-induced HR increased in a dose-dependent manner after rhuIL3 therapy (low-dose group: HRmax 47.5 vs. 53.3%; high-dose group: HRmax 57.8 vs. 75.4%, p less than 0.05). In contrast to anti-IgE-induced HR, HR with ionophore (78.0 vs. 50.3%, p less than 0.05), FMLP (32.3 vs. 11.4%, p less than 0.05), sodium chloride (31.8 vs. 22.6%, n.s.) and mannitol (56.3 vs. 47.8%, n.s.) decreased. There was no histamine release from basophils upon in vitro stimulation with rhuIL3 alone. The kinetics of the increase in anti-IgE-induced histamine release did not parallel the rapid histamine depletion of cells. We conclude that rhuIL3 therapy may cause a rapid HR from basophils which cannot be observed after stimulation of cells in vitro. The clinical importance of this HR remains unclear as side effects could not be correlated with HR.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗