ABSTRACT
Philadelphia-negative myeloproliferative neoplasms (MPN) comprise a heterogeneous group of chronic hematological malignancies with significant variations in clinical characteristics. Due to the long survival and the feasibility of oral or subcutaneous therapy, these patients are frequently treated outside of larger academic centers. This analysis was performed to elucidate differences in MPN patients in three different health care settings: university hospitals (UH), community hospitals (CH), and office-based physicians (OBP). The MPN registry of the Study Alliance Leukemia is a non-interventional prospective study including adult patients with an MPN according to WHO criteria (2008). For statistical analysis, descriptive methods and tests for significant differences were used. Besides a different distribution of MPN subtypes between the settings, patients contributed by UH showed an impaired medical condition, a higher comorbidity burden, and more vascular complications. In the risk group analyses, the majority of polycythemia vera (PV) and essential thrombocythemia (ET) patients from UH were classified into the high-risk category due to previous vascular events, while for PV and ET patients in the CH and OBP settings, age was the major parameter for a high-risk categorization. Regarding MPN-directed therapy, PV patients from the UH setting were more likely to receive ruxolitinib within the framework of a clinical trial. In summary, the characteristics and management of patients differed significantly between the three health care settings with a higher burden of vascular events and comorbidities in patients contributed by UH. These differences need to be taken into account for further analyses and design of clinical trials.
Subject(s)
Delivery of Health Care/statistics & numerical data , Myeloproliferative Disorders/therapy , Severity of Illness Index , Symptom Assessment/statistics & numerical data , Aged , Aged, 80 and over , Chi-Square Distribution , Delivery of Health Care/methods , Female , Hospitals, Community/statistics & numerical data , Hospitals, University/statistics & numerical data , Humans , Male , Middle Aged , Myeloproliferative Disorders/complications , Myeloproliferative Disorders/genetics , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Philadelphia Chromosome , Physicians/statistics & numerical data , Physicians' Offices/statistics & numerical data , Prospective Studies , Registries/statistics & numerical data , Risk Factors , Symptom Assessment/methodsABSTRACT
Amifostine increases in vitro burst-forming unit-erythroid and colony-forming unit-granulocyte/granulcoyte-macrophage cultured from bone-marrow cells from patients with myelodysplastic syndrome (MDS). Several small clinical studies give divergent informations about the potential of amifostine as single agent to improve hematopoiesis in MDS patients. In these studies, patients with refractory anemia (RA), RA with excess of blasts (RAEB), and RAEB in transformation (RAEB-T) were analyzed together, resulting in response rates varying from 8% to 30%. The present multi-center study evaluated whether treatment with amifostine is of clinical benefit in patients with RA who are transfusion dependent. The effect on transfusion frequency as well as on platelets and absolute neutrophil count (ANC) was examined in 14 patients with RA [median age 67 years (55-72 years), male:female 9:5]. Four treatment cycles were planned, each consisting of intravenous amifostine at 200 mg/m2/day three times per week followed by a 2-week interval. Since tumor necrosis factor (TNF) alpha is a main suppressive cytokine for hematopoiesis in RA patients, serum samples for analyzing endogenous levels of TNF alpha were collected prior to the study and after four treatment cycles. In three patients (21%), reduced transfusion requirement with prolongation of the transfusion interval from 4 weeks to 8 weeks (two patients) and 4 weeks to 6 weeks was seen. An increase in ANC from 400/microliter to 2600/microliter and 200/microliter to 3400/microliter was observed in two patients. Platelets increased from 129,000/microliter to 277,000/microliter in an additional patient. In one patient, disease progression from RA to RAEB was observed. Serum TNF alpha levels were increased in MDS patients compared with normal controls (18.8 pg/ml vs 9.1 pg/ml), and there was no change during the treatment with amifostine (17.5 pg/ml). In conclusion, treatment with amifostine as a single agent was of limited benefit in patients with RA. The serum TNF alpha levels were unchanged during treatment with amifostine in RA patients.
Subject(s)
Amifostine/therapeutic use , Anemia, Refractory/blood , Anemia, Refractory/drug therapy , Tumor Necrosis Factor-alpha/metabolism , Aged , Amifostine/administration & dosage , Amifostine/adverse effects , Anemia, Refractory, with Excess of Blasts/drug therapy , Drug Administration Schedule , Female , Humans , Injections, Intravenous , Male , Middle Aged , Nausea/chemically induced , Treatment Outcome , Venous Thrombosis/chemically inducedABSTRACT
Osteoporosis is frequently seen in systemic mastocytosis. Although diphosphonate therapy has been shown to be transiently effective, therapy options for this form of osteopenia are very limited. We have treated three patients with systemic mastocytosis and osteopenia successfully with interferon alpha-2b. Two patients had urticaria pigmentosa and two severe back pain due to vertebral compression fractures. All patients received a daily interferon dose of 3 x 5 mio units/week s.c. for a period of 6 months. Therapy was well tolerated, and back pain resolved in both patients. A marked decrease of mast cell numbers in the bone marrow and a significant increase of bone mineralization and bone density was observed in all patients. Our data suggest that alpha interferon may be a new treatment option for osteopenia in systemic mastocytosis.
Subject(s)
Interferon-alpha/administration & dosage , Mastocytosis/therapy , Osteoporosis/therapy , Adult , Female , Humans , Male , Mastocytosis/complications , Osteoporosis/etiologySubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Small Cell/drug therapy , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Lung Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Small Cell/radiotherapy , Chemotherapy, Adjuvant , Clinical Trials as Topic , Drug Administration Schedule , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Humans , Lung Neoplasms/radiotherapy , Pilot ProjectsABSTRACT
Hemodialysis (HD), especially with cellulosic membranes, leads regularly to a transient but marked drop of peripheral neutrophils. Such neutropenia during the initial 10-30 min of HD is followed by a reincrease in granulocyte count up to a mild leukocytosis. Although this phenomenon accounts for the best documented side effect of HD, little is known about the underlying regulatory mechanisms. Therefore in this study the blood levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured during HD. Previous investigations have demonstrated that GM-CSF plays the central role in controlling the homeoiostasis of leukocytes by up- and downregulation of proliferation and efflux of cells out of the maturation compartment within the bone marrow. Three patients with chronic renal failure underwent HD with cuprophane membranes. In all cases a significant drop of peripheral granulocytes occurred, but GM-CSF levels remained unchanged and were found in the normal range during the whole period of the treatment. It is therefore concluded that GM-CSF may not be significantly involved in the regulation of peripheral leukocytes during HD.
Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/blood , Leukopenia/blood , Leukopenia/etiology , Renal Dialysis/adverse effects , Cellulose/adverse effects , Cellulose/analogs & derivatives , Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Granulocytes , Humans , Kidney Failure, Chronic/therapy , Kidneys, Artificial/adverse effects , Leukocyte Count , Membranes, Artificial , Time FactorsABSTRACT
We report a case of Felty's syndrome in which infectious complications due to severe neutropenia could be overcome by short-term treatment with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF, 7 micrograms/kg/day s.c.). Leukocyte counts rose from 1,050/mm3 at presentation to 4,470/mm3 after 15 days of treatment. A flare-up of arthritis was not noted. Defects in granulocyte function and clinical improvement prior to leukocyte rise suggest that the beneficial effect of GM-CSF is mainly due to an improvement of granulocyte function.
Subject(s)
Felty Syndrome/drug therapy , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Acute Disease , Aged , Blood Cell Count/drug effects , Felty Syndrome/blood , Felty Syndrome/immunology , Granulocytes/drug effects , Humans , Immunoglobulins/blood , Immunoglobulins/drug effects , Male , Recombinant Proteins/therapeutic useABSTRACT
In three consecutive pilot studies the effect of recombinant human granulocyte/macrophage-colony-stimulating factor (rhGM-CSF) on haematopoetic recovery after chemotherapy in patients with small-cell lung cancer was investigated. In study I, 20 patients received AIO chemotherapy (A, Adriamycin 25 mg/m2 on days 1 + 2; I, ifosfamide 2 g/m2 on days 1-5; O, vincristine 2 mg on day 1) at 4-week intervals either with or without rhGM-CSF (250 micrograms/m2 sc) from day 8 until recovery of leucocytes. Neither the degree nor the duration of myelosuppression was markedly influenced by rhGM-CSF. Suggesting that these disappointing results were caused by the late onset of GM-CSF application, in the following study we shortened chemotherapy to 3 days and started with GM-CSF on day 4. The main objective of this study was to test whether the earlier administration of GM-CSF allowed treatment intervals to be reduced or the dose to be escalated. After 10 patients had received a starting dose of AIO (A, 50 mg/m2 on day 1; I, 2 g/m2 on days 1-3; 0,2 mg on day 1) alternating with cisplatin (90 mg/m2 on day 1) and etoposide (150 mg/m2 on days 1-3), the dose of ifosfamide and etoposide was escalated to 2.5 g/m2 on days 1-3 and 200 mg/m2 on days 1-3 in the next 10 patients. Treatment was given at 2-week intervals when leucocytes were greater than 3500/mm3 and thrombocytes were greater than 100,000 mm3 on day 14. At each dose level patients were randomized to receive either rhGM-CSF 250 micrograms/m2 s.c. on days 4-12 or no GM-CSF. In this study, rhGM-CSF markedly shortened the duration of leukopenia. Reinstitution of chemotherapy on day 15 was possible at dose level 1 in 1/4 patients without and in 3/4 patients with GM-CSF, and at dose level 2 in 0/5 patients without and in 5/5 patients with GM-CSF. However, the degree of myelosuppression was not improved by GM-CSF. In a third study we tried to apply rhGM-CSF simultaneously with chemotherapy. After 3 patients had received GM-CSF starting on day 1 concurrent to AIO chemotherapy, we noticed an increase of myelosuppression with prolonged neutropenia and thrombocytopenia and stopped this investigation. Considering all patients included in these three consecutive pilot studies, there is no difference in response rates and survival between patients with and without rhGM-CSF treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Small Cell/drug therapy , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Hematopoiesis/drug effects , Lung Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Dose-Response Relationship, Drug , Drug Administration Schedule , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Humans , Middle Aged , Pilot Projects , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacologyABSTRACT
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.
Subject(s)
Anemia, Aplastic/drug therapy , Interleukin-3/therapeutic use , Adolescent , Adult , Blood Cell Count/drug effects , Bone Marrow/drug effects , Drug Evaluation , Female , Hematopoiesis/drug effects , Humans , Injections, Subcutaneous , Interleukin-3/administration & dosage , Interleukin-3/adverse effects , Male , Middle Aged , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic useABSTRACT
We investigated the interaction between GM-CSF and its receptor on human granulocytes and on several human tumor cell lines. Specific high-affinity binding for GM-CSF was characterized by Scatchard plot analysis. The specific radioactivity of the 125I-labeled derivative of rH. GM-CSF was determined by self-displacement analysis and calculated to be 30 microCi/micrograms. The maximum concentration of binding sites (B max) in granulocytes was 40 fmol/mg protein (2,200 molecules GM-CSF bound/cell) and the dissociation constant (KD) was 0.42 nM. No binding sites for GM-CSF were found in two lung cancer cell lines, SCLC-16HV and NCI-N417 or in the urinary bladder carcinoma cell line 5637, whereas the promyelocytic leukemia cell line HL60 was positive for GM-CSF binding. Time course experiments showed maximum binding of GM-CSF in granulocytes after an incubation period of 60 min and a decrease in binding after an incubation period of 2 h. In parallel, we found a maximum biological signal when granulocytes were preincubated for 90 min with GM-CSF, and a decrease after an incubation time of 120 min. Preincubation of the cells with rH. GM-CSF induced an enhancement of the production of activated oxygen species by the cells in response to PMA.
Subject(s)
Colony-Stimulating Factors/metabolism , Granulocytes/metabolism , Growth Substances/metabolism , Binding Sites , Cells, Cultured , Granulocyte-Macrophage Colony-Stimulating Factor , Humans , Neutrophils/metabolism , Oxidation-Reduction , Tetradecanoylphorbol Acetate/pharmacology , Time Factors , Tumor Cells, Cultured/metabolismABSTRACT
Besides its effect on bone marrow progenitors, GM-CSF is able to modulate functions of mature cells such as neutrophils. It inhibits random migration and chemotaxis through action on both cells and chemotactic factors, and stimulates oxidative metabolism as well as elastase release. Furthermore, it strongly enhances the response of the cells to the usual stimulants such as f-Met-Leu-Phe and phorbol esters. The role of neutral proteinases and activated oxygen species in different diseases such as ARDS, emphysema, coagulation defects, arthritis, and inflammation, is recognized. The remarkable in vitro release of neutral proteinases and activated oxygen species from granulocytes after GM-CSF stimulation may be of importance in vivo. This should be considered in clinical application of GM-CSF, particularly with high-dose therapy.
Subject(s)
Colony-Stimulating Factors/pharmacology , Neutrophils/drug effects , Cell Movement/drug effects , Chemotactic Factors/pharmacology , Chemotaxis, Leukocyte/drug effects , Colony-Stimulating Factors/therapeutic use , Humans , Luminescent Measurements , Neutrophils/physiology , Pancreatic Elastase/metabolism , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic useABSTRACT
Besides its effect on bone marrow progenitors, GM-CSF is able to interact with mature cells such as granulocytes which express GM-CSF receptors at their surface. Using an incubation period of 90 min, which corresponds to the maximum expression of GM-CSF receptors, we studied oxidative metabolism, random migration and chemotaxis as well as elastase release. Elastase was chosen as a marker for primary granules. We observed inhibition of chemotaxis and random migration, and stimulation of oxidative metabolism as well as elastase release in presence of rh GM-CSF. These different effects were dependent on the dosage of rh GM-CSF applied.
Subject(s)
Colony-Stimulating Factors/physiology , Granulocytes/physiology , Growth Substances/physiology , Recombinant Proteins/pharmacology , Chemotaxis, Leukocyte/drug effects , Granulocyte-Macrophage Colony-Stimulating Factor , Granulocytes/drug effects , Humans , In Vitro Techniques , Kinetics , Luminescent Measurements , Oxygen Consumption/drug effects , Pancreatic Elastase/blood , Reference ValuesABSTRACT
Neutrophils (PMN) are the major host defence cells protecting the body against invasion by microorganisms. Products of oxidative metabolism mediate PMN microbicidal and tumoricidal activity, but the mechanisms by which these pathways become activated are not well understood. The colony stimulating factors (CSF) are known to stimulate proliferation and differentiation of committed bone marrow stem cells. These regulators may probably play an important role in non specific resistance to infections. We studied the oxidative metabolism of neutrophils after stimulation with recombinant GM-CSF (r.GM-CSF) and the concentrated conditioned medium of the UBC-5637 cell line (UBC-CM) showing CSF activity. It could be demonstrated that the r.GM-CSF, as well as the UBC-CM, induce an activation of the neutrophil respiratory burst without any cofactors such as f-MLP, PMA, or zymosan. In addition, we observed an increase of the response to those stimulants in the presence of either r.GM-CSF or UBC-CM. These effects were not endotoxin-induced, since stimulation persisted after addition of Polymyxin B, which is known to inhibit the action of endotoxins.