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G Seipelt

Publications and source records attributed to G Seipelt.

50 records · Page 3Linked 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

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↗
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

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↗
PubMed1990

[Effects on bone marrow during stimulation of hematopoietic stem cells with recombinant human interleukin-3].

Bone marrow aspirates and biopsies of 20 patients with malignant tumors (n = 6), bone marrow failure due to chemotherapy (n = 4), myelodysplastic syndromes (n = 5) and aplastic anemia (n = 5) were analysed before and after treatment with recombinant human interleukin-3. rhIL-3 led to increased overall bone marrow cellularity with trilinear stimulation of hematopoietic cells. In all patients marked eosinophilia and, in some, fibrosis was observed. These results show that rhIL-3 stimulates the proliferation and differentiation of pluripotent hematopoietic progenitor cells and may contribute to the treatment of bone marrow failure.

Anemia, Aplastic↗
PubMed1990

[In vitro and in vivo effects of recombinant human interleukin-3 on hematopoietic progenitor cells].

As part of a phase I/II clinical trial with recombinant human Interleukin-3 (rhIL-3), bone marrow and peripheral blood cells from patients treated with rhIL-3 were assessed in vitro for effects on the cycling status and frequencies of erythroid, myelomonocytic and multilineage progenitor cells. Treatment with rhIL-3 induced a pronounced increase in S-phase rate of BFU-E, CFU-GEMM and day 14 CFU-GM. Circulating CFU-GEMM and day 14 CFU-GM were increased on day 7 of therapy whereas circulating BFU-E were reduced in the majority of patients. After i.v. bolus injection of IL-3 an acute effect on the peripheral blood count with neutrophilia and, after an initial nadir, monocytosis was observed. IL-6 serum-levels increased in 5 out of 14 patients after IL-3 administration with concomitant side effects in 2 patients in whom IL-6 levels increased above 75 pg/ml. In the majority of the patients a stimulation of peripheral leukocytes and platelets was observed during the 15 day treatment course. In conclusion rhIL-3 induces a multilineage response in vivo by stimulating proliferation of hemopoietic progenitor cells with a resulting elevation in peripheral blood counts.

Bone Marrow↗
PubMed1989

Immunohistochemical assessment of splenic lymphocyte and macrophage subpopulations in patients with gastric cancer.

In order to assess the effects of malignant tumors on the immune system, 25 spleens from patients with gastric carcinoma were studied by in situ immunohistochemical methods for lymphocyte subsets and cells of the mononuclear phagocyte system. Highly significant reductions of CD4+ T cells (P less than 0.001), Ki M2+ and Ki M-3+ MPS cells (P less than 0.02 and P less than 0.05), and a stage-dependent reduction of Ki 67+ B cell proliferation activity (P less than 0.05) were seen in spleens of patients with gastric cancer. These results, which were obtained by morphologic methods in a noninvolved lymphatic organ, reflect the systemic immunosuppressive and immunodepleting effects of malignant tumors that are probably mediated by tumor-associated cytokines.

Adult↗
PubMedDate not supplied

Comparison of toxicity and outcome in patients with acute myeloid leukemia treated with high-dose cytosine arabinoside consolidation after induction with a regimen containing idarubicin or daunorubicin.

The toxicity and outcome after high-dose ara-C/daunorubicin (HDara-C/DNR) consolidation therapy in de novo AML was compared in 11 patients who received an idarubicin-containing induction therapy (IDA; from June 1995 to March 1997) and 16 patients pretreated with daunorubicin (DNR; from July 1990 to May 1995) for induction. The DNR group consisted of two cohorts, one (n = 6) of patients who had received, as had the IDA group, two induction and one intermediate-dose ara-C consolidation courses, and another (n = 10) of patients who had been pretreated with one induction and one consolidation course prior to HDara-C/DNR. There was no difference in the relative dose between the three cohorts. Following HDara-C/DNR, the IDA-pretreated patients experienced a more prolonged myelosuppression during consolidation therapy compared with the DNR group. Duration of neutropenia (< 500 neutrophils/microl) following HDara-C/DNR was 31.2 +/- 16 days (mean +/- SEM) in the IDA group compared with 18.7 +/- 5 days in the DNR group (p < .001 Mann-Whitney U-test). The duration 'of thrombocytopenia (platelets < 25000/microl) was 34.8 +/- 20 days in the IDA group vs. 18.5 +/- 6 days in the DNR group (p < .005). The more prolonged myelosupression was associated with a longer duration of fever (18.9 +/- 24 vs. 6.9 +/- 5.2 days). A greater incidence, length (11 +/- 8 vs. 1.2 +/- 2 days), and severity of diarrhea were observed in the IDA-pretreated group. Three of 11 IDA patients experienced WHO grade III-IV diarrhea. In the IDA group two patients developed severe enterocolitis with Candida septicemia, and one of these patients died. One patient in the IDA group died during prolonged aplasia. In the DNR group 6/16 patients experienced grade I-II diarrhea. Two patients in each group died during consolidation therapy. The CR rate was 87% in the IDA group and 79% in the DNR group. Relapse-free survival after HDara-C is 50% at a median follow-up of 60 months in the DNR group and 45% after a median follow-up of 17 months in the IDA group. Whether the advantage of the superior response rate in the IDA-treated patients may be lost during HDara-C consolidation treatment due to increased toxicity remains to be proven in larger trials.

Acute Disease↗