Addition Of Colony-stimulating Factors Research Articles

Strategies for Empiric Management of Pediatric Fever and Neutropenia in Patients With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: A Systematic Review of Randomized Trials.

To describe treatment failure and mortality rates with different antibiotic regimens and different management strategies for empirical treatment of fever and neutropenia (FN) in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients. We conducted a systematic review and performed searches of MEDLINE, Embase, PubMed, and Cochrane Central Register of Controlled Trials. Studies were included if pediatric patients had cancer or were HSCT recipients and the intervention was related to the management of FN. Strategies synthesized were monotherapy versus aminoglycoside-containing combination therapy; antipseudomonal penicillin monotherapy versus fourth-generation cephalosporin monotherapy; inpatient versus outpatient management; oral versus intravenous antibiotics; and addition of colony-stimulating factors. Of 11,469 citations screened, 68 studies randomly assigning 7,265 episodes were included. When compared with monotherapy, aminoglycoside-containing combination therapy did not decrease treatment failures (risk ratio, 1.13; 95% CI, 0.92 to 1.38; P = 0.23), and no difference in mortality was observed. Antipseudomonal penicillin and fourth-generation cephalosporin monotherapy were associated with similar failure and mortality rates. Outpatient management and oral antibiotics were safe in low-risk FN with no infection-related mortality observed in any patient and no significant differences in outcomes compared with inpatient management and intravenous therapy. Therapeutic colony-stimulating factors were associated with a 1.42-day reduction in hospitalization (95% CI, 0.62 to 2.22 days; P < .001). There were a moderate number of pediatric randomized trials of FN management. Monotherapy for high-risk FN and outpatient and oral management for low-risk FN are effective strategies. These findings will provide the basis for guideline recommendations in pediatric FN.

5-Azacitidine in aggressive myelodysplastic syndromes regulates chromatin structure at PU.1 gene and cell differentiation capacity

Epigenetic 5-azacitidine (AZA) therapy of high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) represents a promising, albeit not fully understood, approach. Hematopoietic transcription factor PU.1 is dynamically regulated by upstream regulatory element (URE), whose deletion causes downregulation of PU.1 leading to AML in mouse. In this study a significant group of the high-risk MDS patients, as well as MDS cell lines, displayed downregulation of PU.1 expression within CD34+ cells, which was associated with DNA methylation of the URE. AZA treatment in vitro significantly demethylated URE, leading to upregulation of PU.1 followed by derepression of its transcriptional targets and onset of myeloid differentiation. Addition of colony-stimulating factors (CSFs; granulocyte-CSF, granulocyte-macrophage-CSF and macrophage-CSF) modulated AZA-mediated effects on reprogramming of histone modifications at the URE and cell differentiation outcome. Our data collectively support the importance of modifying the URE chromatin structure as a regulatory mechanism of AZA-mediated activation of PU.1 and induction of the myeloid program in MDS.

Genetic Determinants of Mycophenolate-Related Anemia and Leukopenia After Transplantation

Mycophenolate-related anemia and leukopenia are well-known toxicities after transplantation. Toxicity leads to dose reduction, addition of colony-stimulating factors or erythropoietin, or discontinuation of immunosuppressive therapy. The causes of and risk factors associated with toxicity are unclear. We studied the association between mycophenolate-related anemia and leukopenia and 2724 single nucleotide polymorphisms (SNP) in 978 patients undergoing living or deceased donor kidney transplant. Patients were followed up to time of first anemia (hemoglobin<10 gm/dL or hematocrit<30%) or first leukopenia (white blood cell [WBC] count <3000 cells/mm), which required clinical intervention in the first 6 months after transplant. Anemia occurred in 87 (9.5%) subjects and leukopenia in 224 (22.9%). In single SNP analyses, none of the SNPs were associated with time to leukopenia at a false discovery rate (FDR) of 20%. However, SNPs from the IL12A, HUS, CYP2C8 genes were associated with time to anemia, allowing for an FDR of 20%. To assess the independence of these SNPs as predictors of anemia, we conducted a multi-SNP analysis including one SNP from each of the three genes. All three SNPs were associated with time to anemia, after adjusting for recipient age, weight, posttransplant dialysis and antiviral drug use, and stratifying by clinical center. Although these SNPs require validation in an independent population, our results suggest that genetics may play a role in risk of mycophenolate-related hematologic toxicity. This may ultimately provide for better management of maintenance immunosuppression and gives insights into potential mechanism(s) by which toxicity occurs.

Chemotherapy

Chemotherapy

Cisplatin, carboplatin, and cyclophosphamide combination chemotherapy in advanced-stage ovarian carcinoma: an Eastern Cooperative Oncology Group pilot study.

Cyclophosphamide (CTX) 600 mg/m2, carboplatin 280 mg/m2, and cisplatin 50 mg/m2 were administered on day 1 every 4 weeks to 41 previously untreated ovarian cancer patients with residual disease greater than 2.0 cm after primary laparotomy. Of 22 patients with measurable disease treated with up to eight cycles of therapy, the overall clinical response rate was 73% (exact 95% confidence interval [CI], 50% to 89%), with 50% complete response (CR). Six of 11 clinical CR (cCR) patients underwent surgical restaging; three pathologic CRs (pCRs) and three pathologic partial responses (pPRs) with residual disease less than 2.0 cm were documented. Fourteen patients had nonmeasurable but assessable disease; the clinical response rate was 57% (Cl, 29% to 82%) with two (14%) CRs. Second-look surgery was performed in one of the two cCR patients; a pPR was documented. Five patients with nonassessable disease were stable during chemotherapy; two underwent surgery and had pCRs. The median time to treatment failure (TTF) was 14.8 months, and median survival for the 41 patients is 26.7 months. Overall, 37% of the patients had progression-free intervals of at least 2 years, and 27% have survival times in excess of 3 years. Hematologic toxicity was substantial but manageable, with 58% and 66% experiencing a granulocyte nadir less than 500/microL and a platelet nadir less than 50,000/microL, respectively. One treatment-associated fatality occurred as a result of leukopenic sepsis and renal failure in the setting of progressive disease and ureteral obstruction. Mild to moderate nausea and vomiting occurred in most patients, but none experienced severe ototoxicity or peripheral neuropathy. Over all courses, 73% of the projected dose intensity of CTX and carboplatin and 86% of cisplatin were delivered. Since granulocytopenia and thrombocytopenia were dose-limiting, the addition of colony-stimulating factors that support both myeloid and megakaryocyte precursors may permit further dose intensification.

Human Recombinant Multilineage Colony Stimulating Factor (Interleukin-3): Stimulator of Acute Myelocytic Leukemia Progenitor Cells In Vitro

Acute myeloid leukemia colony forming cells (AML-CFU) require the addition of colony stimulating factors (CSFs) for in vitro proliferation. Recently, we isolated a human recombinant multilineage CSF (hMulti-CSF). We investigated the ability of hMulti-CSF to stimulate AML clonogenic cells in seven patients in direct comparison with the effects of human granulocyte CSF (hG-CSF), human granulocyte-macrophage CSF (hGM-CSF), and feeder leukocytes. We show that hMulti-CSF is an efficient stimulator of AML colony formation in four of seven cases. In these patients, hGM-CSF was also capable of stimulating AML colonies in vitro. In two of seven cases hMulti-CSF appeared to be a weak stimulus of AML-CFU proliferation. In these latter two cases, however, hG-CSF and in one case hGM-CSF effectively stimulated AML-CFU growth. In one patient none of the hCSFs, either alone or in combination, induced AML colony formation, whereas AML colonies consistently appeared in the phytohemagglutinin (PHA) leukocyte feeder assay. This finding suggests that PHA stimulated leukocytes produce components other than the tested hCSFs that may have a role in the proliferation of AML cells in vitro. Multi-CSF, like hGM-CSF, revealed a limited capacity to induce progressive maturation during AML colony growth, ie, not beyond the promyelocytic stage. On the other hand, in one case, hG-CSF stimulated the growth of AML colonies containing (meta)myelocytes and granulocytes. We conclude that hMulti-CSF is a regulator of AML-CFU proliferation in a significant number of cases. The patterns of responsiveness of AML precursors to the three hCSFs in different patients show a striking variability, which may indicate that AML-CFU are the neoplastic representatives of normal bone marrow progenitors at different stages of maturation and with distinct CSF requirements.

Human recombinant multilineage colony stimulating factor (interleukin- 3): stimulator of acute myelocytic leukemia progenitor cells in vitro

Acute myeloid leukemia colony forming cells (AML-CFU) require the addition of colony stimulating factors (CSFs) for in vitro proliferation. Recently, we isolated a human recombinant multilineage CSF (hMulti-CSF). We investigated the ability of hMulti-CSF to stimulate AML clonogenic cells in seven patients in direct comparison with the effects of human granulocyte CSF (hG-CSF), human granulocyte- macrophage CSF (hGM-CSF), and feeder leukocytes. We show that hMulti- CSF is an efficient stimulator of AML colony formation in four of seven cases. In these patients, hGM-CSF was also capable of stimulating AML colonies in vitro. In two of seven cases hMulti-CSF appeared to be a weak stimulus of AML-CFU proliferation. In these latter two cases, however, hG-CSF and in one case hGM-CSF effectively stimulated AML-CFU growth. In one patient none of the hCSFs, either alone or in combination, induced AML colony formation, whereas AML colonies consistently appeared in the phytohemagglutinin (PHA) leukocyte feeder assay. This finding suggests that PHA stimulated leukocytes produce components other than the tested hCSFs that may have a role in the proliferation of AML cells in vitro. Multi-CSF, like hGM-CSF, revealed a limited capacity to induce progressive maturation during AML colony growth, ie, not beyond the promyelocytic stage. On the other hand, in one case, hG-CSF stimulated the growth of AML colonies containing (meta)myelocytes and granulocytes. We conclude that hMulti-CSF is a regulator of AML-CFU proliferation in a significant number of cases. The patterns of responsiveness of AML precursors to the three hCSFs in different patients show a striking variability, which may indicate that AML-CFU are the neoplastic representatives of normal bone marrow progenitors at different stages of maturation and with distinct CSF requirements.