scholarly journals Cytokine Analysis in 154 Patients with Transient Abnormal Myelopoiesis: Jccg JPLSG TAM-10 Clinical Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2362-2362
Author(s):  
Genki Yamato ◽  
Myoung-Ja Park ◽  
Akira Shimada ◽  
Norio Shiba ◽  
Yoshiyuki Yamada ◽  
...  
Keyword(s):  
Growth Factor ◽  
Early Death ◽  
Therapeutic Interventions ◽  
P Value ◽  
Gm Csf ◽  
Transient Abnormal Myelopoiesis ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Wbc Count ◽  
Stimulating Factor

Abstract Introduction: Transient abnormal myelopoiesis (TAM), also known as transient leukemia or transient myeloproliferative disorder, is a unique clonal myeloproliferation characterized by immature megakaryoblasts occurring in 10% of neonates with Down syndrome. Although most patients show spontaneously resolution of TAM without therapeutic interventions, approximately 20% of TAM cases result in early deaths, i.e., within 9 months, and approximately 20% of the survivors develop acute megakaryoblastic leukemia (AMKL) within 4 years. A somatic GATA1 gene mutation that leads to the exclusive expression of a truncated GATA1 protein is shared by both TAM and AMKL cells. According to previous reports, cytokine levels are associated with liver failure, which is a cause of early death. Here, we analyzed 154 DS patients with TAM enrolled in the TAM-10 prospective observational study conducted by the Japan Pediatric Leukemia/Lymphoma Study Group to determine the association between clinical characteristics and cytokine levels in such patients. Patients and Methods: A total of 167 neonates (89 boys and 78 girls) diagnosed with TAM were prospectively registered in the TAM-10 study between May 2011 and February 2014. We analyzed cytokine levels in 154 of the 167 enrolled patients whose samples were available. Somatic GATA1 gene mutations were confirmed in 151 (98%) of 154 patients using Sanger and/or next-generation sequencing. Using the Bio-Prex cytokine assay, serum concentrations of the following 27 cytokines were measured: interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), platelet-derived growth factor-BB (PDGF-BB), basic fibroblast growth factor (bFGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins alpha and beta (MIP-1α and MIP-1β), eotaxin, interferon gamma-induced protein (IP-10), regulated upon activation, normal T-cell expressed and secreted, interleukin I receptor agonist (IL-RA), and 13 different interleukins (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, and IL-17). For all analyses, P values were two-tailed and a P value of <0.05 was considered statistically significant. Mann-Whitney test were used as appropriate for comparisons between groups. Moreover, the cumulative incidence for competing events was compared with the Gray test. Results: The median (range) white blood cell (WBC) count at diagnosis was 37.2 (2.4-478.7) × 10 9 cells/L. Forty-seven (31%) of 154 patients received low-dose cytarabine. When we compared 29 patients with a high WBC count (≥100 × 10 9 cells/L, known as a poor prognostic factor in TAM patients) to 125 patients without a high WBC count for 27 cytokine levels, the levels of 16 cytokines (IL-1b, IL-1ra, IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, Eotaxin, PDGF-bb, basic FGF, G-CSF, GM-CSF, MCP-1b, and VEGF) were significantly higher in patients with a high WBC group. Early death occurred in 14 (9%) of 154 patients. Cytokine levels were compared between the early death group (n = 14) and remaining patients (n = 140) and it was observed that the levels of 10 cytokines (IL-1b [p = 0.016], IL-1ra [p < 0.001], IL-6 [p < 0.001], IL-7 [p = 0.009], IL-8 [p < 0.001], IL-10 [p = 0.014], IL-13 [p = 0.002], MCP-1 [p = 0.030], MIP-1b [p = 0.024], and TNF-α [p = 0.008]) were significantly higher in the early death group. When the patients were divided in two groups according to the median IL-1β concentration showing the lowest p-value, the early death rate in the IL-1β high group was significantly higher than that in the IL-1β low group (16% vs. 3%, p < 0.001). IL-1, IL-6, IL-8, and TNF-α are proinflammatory cytokines induced by MCP-1 and MIP1-b. Early death was strongly associated with hypercytokinemia, suggesting that therapeutic interventions (e.g., systemic steroid therapy) may be effective in patients with hypercytokinemia. However, there was no relation between the levels of 27 cytokines and leukemia development. Conclusion: Our findings suggested that measurement of cytokine levels may be a useful marker for predicting early death and an indicator of therapeutic interventions required in TAM patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Predictive Factors of the Development of Leukemia in Patients with Transient Abnormal Myelopoiesis and Down Syndrome: The Jccg Study JPLSG TAM-10

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3833-3833 ◽  
Author(s):  
Genki Yamato ◽  
Hideki Muramatsu ◽  
Tomoyuki Watanabe ◽  
Takao Deguchi ◽  
Shotaro Iwamoto ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Blood Transfusion ◽  
Steroid Therapy ◽  
Early Death ◽  
Therapeutic Interventions ◽  
Systemic Steroid ◽  
Transient Abnormal Myelopoiesis ◽  
Systemic Steroid Therapy ◽  
Leukemia Development ◽  
Wbc Count

Introduction: Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) is characterized by the transient appearance of blast cells that harbor somatic GATA1 gene mutation. Although most patients show spontaneously resolution without therapeutic interventions, approximately 20% of TAM cases result in early deaths within 9 months and 20% of survivors develop acute megakaryoblastic leukemia (AMKL) within 4 years. Although the risk factors associated with early deaths are known, the definite clinical predictive indicators of AMKL onset in patients with TAM remain unclear. Therefore, we analyzed 167 TAM patients with DS enrolled in the TAM-10 prospective observational study conducted by the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) to determine the clinical characteristics of TAM and predictive factors of leukemia development. Patients and Methods: Between May 2011 and February 2014, 167 neonates (89 boys and 78 girls) diagnosed with TAM were prospectively registered in the TAM-10 study. Somatic GATA1 gene mutations were confirmed in 163 (98%) patients using Sanger and/or next-generation sequencing. Minimal residual disease using flow cytometry (FCM-MRD; cut-off level, ≥0.1%) was monitored at 1 (n = 133) and 3 months (n = 104). Results: Median (range) gestational age, birth body weight, white blood cell (WBC) count, and percentage of blasts at diagnosis were 37 (29-40) weeks, 2,612 (1,066-3714) g, 38.3 (2.4-478.7) × 109 cells/L, and 37% (0.5%-95.5%), respectively. Systemic edema and organ hemorrhage was observed in 31/167 (19%) and 14/167 (8%) patients, respectively; 68/167 (41%) patients received some therapeutic interventions, including low-dose cytarabine (LDCA; n = 52), exchange blood transfusion (n = 20), and systemic steroid therapy (n = 31). Early death (<9 months of age) occurred in 22/167 (13%) patients. In multivariate analysis, early death was significantly associated with a high WBC count [≥100 × 109 cells/L; HR (95% CI) = 5.329 (2.194-12.945), P < 0.001] and systemic edema [HR (95% CI) = 8.073 (3.130-20.823), P < 0.001]. Subgroup analysis in patients with such high WBC count (n = 36) showed that LDCA therapy significantly improved survival [1-year OS (95% CI) = 78.3% (55.4-90.3; n = 23) vs. 38.5% (14.1-62.8; n = 13); P = 0.009]. Among 145/167 patients without early death, 28 (19%) developed AMKL. FCM-MRD positivity at 1 month [positive, n = 107; negative, n = 26; cumulative incidence ratio (CIR) (95% CI) = 25.2% (17.3-33.9%) vs 3.8% (0.3%-16.8%), P = 0.022] and 3 months (positive, n = 20; negative, n = 84; CIR (95% CI), 45.0% (22.3%-65.4%) vs. 16.0% (9.0%-24.8%), P = 0.002] was significantly associated with leukemia development. However, other clinical covariates, including sex, birth weight, gestational age, WBC count, blast percentage, and GATA1 gene mutational types, could not predict AMKL development. Considering their severe clinical conditions, 13/31 (42%) patients who received systemic steroid therapy died before AMKL development; interestingly, none of the remaining 18 patients developed AMKL but they showed significantly lower CIR than those who did not receive this therapy [CIR (95% CI), 0% vs. 19.4% (10.9%-29.6%), P = 0.010]. Other therapeutic interventions, including LDCA and exchange blood transfusion, were not associated with AMKL development. Conclusion: FCM-MRD positivity at 1 month and 3 months might be a useful marker to predict leukemia development in patients with TAM. Although LDCA therapy significantly decreased the rate of early deaths, it did not suppress leukemia development. Interestingly, systemic steroid therapy might suppress leukemia development. These results pave the way to design clinical trials for developing MRD-directed leukemia prevention therapy for patients with TAM. Disclosures No relevant conflicts of interest to declare.

scholarly journals Granulocyte-Macrophage Colony-Stimulating Factor-Deficient Mice Have Impaired Resistance to Blood-Stage Malaria

2001 ◽  
Vol 69 (1) ◽  
pp. 129-136 ◽  
Author(s):  
Julie Riopel ◽  
MiFong Tam ◽  
Karkada Mohan ◽  
Michael W. Marino ◽  
Mary M. Stevenson
Keyword(s):  
Blood Stage ◽  
Colony Stimulating Factor ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Tnf Α ◽  
Macrophage Colony Stimulating Factor ◽  
Ifn Γ ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Blood Stage Malaria

ABSTRACT The contribution of granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic and immunoregulatory cytokine, to resistance to blood-stage malaria was investigated by infecting GM-CSF-deficient (knockout [KO]) mice with Plasmodium chabaudi AS. KO mice were more susceptible to infection than wild-type (WT) mice, as evidenced by higher peak parasitemia, recurrent recrudescent parasitemia, and high mortality. P. chabaudiAS-infected KO mice had impaired splenomegaly and lower leukocytosis but equivalent levels of anemia compared to infected WT mice. Both bone marrow and splenic erythropoiesis were normal in infected KO mice. However, granulocyte-macrophage colony formation was significantly decreased in these tissues of uninfected and infected KO mice, and the numbers of macrophages in the spleen and peritoneal cavity were significantly lower than in infected WT mice. Serum levels of gamma interferon (IFN-γ) were found to be significantly higher in uninfected KO mice, and the level of this cytokine was not increased during infection. In contrast, IFN-γ levels were significantly above normal levels in infected WT mice. During infection, tumor necrosis factor alpha (TNF-α) levels were significantly increased in KO mice and were significantly higher than TNF-α levels in infected WT mice. Our results indicate that GM-CSF contributes to resistance to P. chabaudi AS infection and that it is involved in the development of splenomegaly, leukocytosis, and granulocyte-macrophage hematopoiesis. GM-CSF may also regulate IFN-γ and TNF-α production and activity in response to infection. The abnormal responses seen in infected KO mice may be due to the lack of GM-CSF during development, to the lack of GM-CSF in the infected mature mice, or to both.

scholarly journals Characterization of Mast Cell Activation Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3683-3683
Author(s):  
Lawrence B Afrin ◽  
Sally Self ◽  
Jeremiah Menk ◽  
John Lazarchick
Keyword(s):  
Flow Cytometry ◽  
Mast Cell ◽  
Chronically Ill ◽  
Mast Cell Activation ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Tnf Α ◽  
Stimulating Factor ◽  
Activation Syndrome

Abstract Mast cell (MC) activation syndrome (MCAS) is a recently recognized, heterogeneous disease of chronic multisystem inflammation (CMI) ± allergy. MCAS features aberrant MC reactivity and constitutive MC activation with little accumulation of MCs, distinct from mastocytosis [Afrin, Ann Med 48:190-201]. Whether clonality in MCAS is common is debated. Symptoms (sxs) range from mild to disabling, even life-threatening; prevalence may be as high as 17% [Molderings, PLoS One 8(9):e76241], underscoring the importance of studying MCAS. Notwithstanding case reports, small case series, and reviews to date, we report the first systematic characterization of a large MCAS cohort. Methods: Under IRB-approved (Pro00015852, Pro00015857), Mastocytosis Society-sponsored protocols at one center, charts of 298 MCAS pts accrued retrospectively ("retro," diagnosed Nov 2008 - Sep 2012), plus 115 accrued prospectively (diagnosed Apr 2012 - Oct 2013), were reviewed for demographics, comorbidities (probs), sxs, family histories (FHs), physical exam and lab findings. For purposes of follow-up (f/u), data cut-off was June 30, 2014. Data were abstracted by LBA from available records. All were diagnosed with MCAS per criteria [Molderings, J Hematol Oncol 4:10] which in our experience (>1,000 pts) reflects MCAS behavior better than other proposals [e.g., Valent, Int Arch Allergy Immunol 157:215-25]. Blood samples from prospective pts were examined by flow cytometry for clonal MC disease (co-expressing CD45 and CD117 plus CD25 and/or CD2) and tested (ELISA kits, RayBioTech (Norcross, GA)) for elevated (↑) serum levels of cytokines (monocyte colony stimulating factor (M-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3), and tumor necrosis factor alpha (TNF-α)) potentially driving the mild relative monocytosis often seen in MCAS [Afrin, Blood 122:5240]; samples for cytokine testing were kept chilled from collection through assay, including centrifugation. Results: Most of the 413 pts were female (69%) and Caucasian (75%). Median (med) ages at sx onset and diagnosis (dx) were 9 yrs (range 0-88) and 49 yrs (range 16-92). Med time from sx onset to dx was 30 years (range 1-85). Med number of probs was 11 (range 1-66). Med number of sxs was 20 (range 2-84). Med number of FH issues was 4 (range 0-33). Tables 1, 2, and 3 show pts' common clinical and lab characteristics and relative utility of various MC mediators in dx. Frequencies of clinical findings in our pts likely are underestimates due to retro assessment in 298/413 (72%). As reported before for the retro subset [Blood 122:5240], general laboratory abnormalities in these MCAS pts were common, modest, and persistent. Most of our pts (72%) appeared chronically ill at times but overall healthier than expected from their many complaints, contributing to prior dx of somatism in most. Many pts "learned to live with it," no longer reporting some sxs unless asked. In the prospective pts, flow cytometry failed to find the targeted signature of clonal MC disease. Serum M-CSF, GM-CSF, IL-3, and TNF-α levels were assessed and, despite correct negative and positive control results, were not found ↑ in any pt. As of f/u cut-off, 388 pts (94%) were alive, 1 was lost to f/u and 24 pts (6%) had died of many causes (most commonly (25%) cancer). Data were insufficient to calculate meaningful survival statistics from time of dx. Discussion: Long sx duration in MCAS - and cessation, of futility, in reporting sxs - show comprehensive history in pts with CMI is important. Routine lab abnormalities are seen long before dx but are modest and thus given short shrift by busy practitioners, but this study suggests they should spark thought of MCAS in pts with CMI and no unifying dx. Relative utilities of MC mediators for dx in our pts were similar to a recent report [Zenker, Blood 126:5174] and further suggest serum tryptase - while still a good screen for MC neoplasia - poorly reflects MC activation. Conclusions: MCAS is challenging to recognize, but its prevalence, morbidity, chronicity, and ability of most pts to identify helpful therapy merit attention to dx and treatment. Our data, characterizing MCAS more comprehensively than ever before, may facilitate its clinical recognition. More research is needed to identify etiologies (and linkages with chronic inflammatory diseases), facilitate dx, and guide therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hematopoietic progenitors in cyclic neutropenia: effect of granulocyte colony-stimulating factor in vivo

Blood ◽  
1990 ◽  
Vol 75 (10) ◽  
pp. 1951-1959 ◽  
Author(s):  
AR Migliaccio ◽  
G Migliaccio ◽  
DC Dale ◽  
WP Hammond
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Blood Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Cyclic Neutropenia ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Stimulating Factor

Abstract The number and growth factor requirements of committed progenitor cells (colony-forming units-granulocyte/macrophage and burst-forming units- erythroid) in three patients with cyclic neutropenia (two congenital, one acquired) were studied before and during therapy with recombinant human granulocyte colony-stimulating factor (G-CSF; 3 to 10 micrograms/kg/d). When the patients with congenital disease were treated with G-CSF, the cycling of blood cells persisted, but the cycle length was shortened from 21 days to 14 days, and the amplitude of variations in blood counts increased. There was a parallel shortening of the cycle and increase of the amplitude of variations (from two- to three-fold to 10- to 100-fold) in the number of both types of circulating progenitor cells in these two patients. In the patient with acquired cyclic neutropenia, cycling of both blood cells and progenitors could not be seen. In cultures deprived of fetal bovine serum, erythroid and myeloid bone marrow progenitor cells from untreated patients and from normals differed in growth factor responsiveness. As examples, maximal growth of granulocyte/macrophage (GM) colonies was induced by granulocyte/macrophage (GM)-CSF plus G-CSF in the patients, whereas a combination of GM-CSF, G-CSF and interleukin- 3 (IL-3) was required in the normals, and erythropoietin alone induced fourfold more erythroid bursts from cyclic neutropenic patients than from normal donors (46% versus 11% of the maximal colony number, respectively). The growth factor responsiveness of marrow progenitor cells slightly changed during the treatment toward the values observed with normal progenitors. These results indicate that treatment with G- CSF not only ameliorated the neutropenia, but also increased the amplitude and the frequency of oscillation of circulating progenitor cell numbers. These data are consistent with the hypothesis that G-CSF therapy affects the proliferation of the hematopoietic stem cell.

scholarly journals Cytokine regulation of colony-stimulating factor (CSF) production in cultured human synovial fibroblasts. II. Similarities and differences in the control of interleukin-1 induction of granulocyte-macrophage CSF and granulocyte-CSF production

Blood ◽  
1992 ◽  
Vol 79 (6) ◽  
pp. 1413-1419 ◽  
Author(s):  
JA Hamilton ◽  
DS Piccoli ◽  
J Cebon ◽  
JE Layton ◽  
P Rathanaswani ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Synovial Fibroblasts ◽  
Cyclooxygenase Inhibitors ◽  
Northern Analysis ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Stimulating Factor ◽  
Csf Production

Abstract Synovial fibroblasts are likely to be a significant source of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte-CSF (G-CSF), which could be crucial to the pathogenesis of rheumatoid arthritis. Using specific enzyme-linked immunosorbent assays (ELISAs) and Northern analysis, GM-CSF and G-CSF expression were followed in human synovial fibroblast-like cells in response to a number of agents, either alone or in the presence of an optimal stimulatory concentration of interleukin-1 (IL-1). For both CSFs, interferon-gamma (100 U/mL) did not increase their levels but dramatically suppressed the stimulatory action of IL-1, while basic fibroblast growth factor (10(-8) mol/L), although nonstimulatory by itself, potentiated IL-1 action. The glucocorticoid, dexamethasone (10(- 7) mol/L), inhibited IL-1-stimulated CSF production. However, evidence was obtained for noncoordinated CSF regulation. Cyclooxygenase inhibitors potentiated the action of IL-1 on GM-CSF synthesis but suppressed G-CSF synthesis, suggesting that endogenous cyclooxygenase products can have opposite effects in modulating the levels of each CSF. Also, the lymphokine, IL-4 (250 pmol/L), slightly inhibited GM-CSF formation in the presence of IL-1 but elevated the G-CSF levels in these cultures without having an effect by itself. Transforming growth factor beta (less than or equal to 20 ng/mL) did not modulate levels of either CSF. Mesenchymal cell production of both GM-CSF and G-CSF is generally viewed as being under coordinate control; our findings suggest that their synthesis in IL-1-stimulated human synoviocytes can be modulated by a number of agents, in some cases with divergent actions depending on which CSF is examined.

PU.1 and the Granulocyte- and Macrophage Colony-Stimulating Factor Receptors Play Distinct Roles in Late-Stage Myeloid Cell Differentiation

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2310-2318 ◽  
Author(s):  
Karen L. Anderson ◽  
Kent A. Smith ◽  
Hugh Perkin ◽  
Gary Hermanson ◽  
Carol-Gay Anderson ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Myeloid Cell ◽  
Growth Factor Receptors ◽  
Retroviral Vectors ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Molecular Events ◽  
Myeloid Development ◽  
Stimulating Factor

PU.1 is a hematopoietic cell–specific ets family transcription factor. Gene disruption of PU.1 results in a cell autonomous defect in hematopoietic progenitor cells that manifests as abnormal myeloid and B-lymphoid development. Of the myeloid lineages, no mature macrophages develop, and the neutrophils that develop are aberrantly and incompletely matured. One of the documented abnormalities of PU.1 null (deficient) hematopoietic cells is a failure to express receptors for granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF, and M-CSF. To elucidate the roles of the myeloid growth factor receptors in myeloid cell differentiation, and to distinguish their role from that of PU.1, we have restored expression of the G- and M-CSF receptors in PU.1-deficient cells using retroviral vectors. We have similarly expressed PU.1 in these cells. Whereas expression of growth factor receptors merely allows a PU.1-deficient cell line to survive and grow in the relevant growth factor, expression of PU.1 enables the development of F4/80+, Mac-1+/CD11b+ macrophages, expression of gp91phox and generation of superoxide, and expression of secondary granule genes for neutrophil collagenase and gelatinase. These studies reinforce the idea that availability of PU.1 is crucial for normal myeloid development and clarify some of the molecular events in developing neutrophils and macrophages that are critically dependent on PU.1.

Growth Factor Usage Patterns and Outcomes in the Community Setting: Collection Through a Practice-Based Computerized Clinical Information System

2000 ◽  
Vol 18 (8) ◽  
pp. 1764-1770 ◽  
Author(s):  
Grant Swanson ◽  
Kim Bergstrom ◽  
Eva Stump ◽  
Tammi Miyahara ◽  
E.T. Herfindal
Keyword(s):  
Information System ◽  
Growth Factor ◽  
Practice Patterns ◽  
Clinical Information System ◽  
Clinical Information ◽  
Actual Practice ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Medical Oncologists ◽  
Stimulating Factor

PURPOSE: Although use of colony-stimulating factor (CSF) is widespread and guidelines for use have been disseminated, actual practice patterns of medical oncologists are unknown. The purpose of this study was to collect these data using an office-based computerized clinical information system. PATIENTS AND METHODS: Data were collected on patients at 10 community-based oncology practices. Information regarding CSF use was captured at the time of prescribing through a computerized clinical support tool and stored in a data warehouse, and an analysis was carried out retrospectively. RESULTS: A total of 6,813 cancer regimens administered to 5,034 patients were evaluated for growth factor use. Overall, CSFs were used in 14% of regimens, with breast, lymphoma, lung, and ovarian being the most common cancers for which CSFs were used. In 49.4% of regimens, CSF was initiated during cycle 1, with an average duration of 1 week, and was used in two or three cycles per regimen. Afebrile neutropenia is rarely followed by CSF initiation. Granulocyte colony-stimulating factor (G-CSF) is associated with fewer dose adjustments, delays, and hospitalizations when compared with granulocyte-macrophage colony stimulating factor (GM-CSF). There is wide variation among oncologists in CSF use, and several substantial differences were noted between the prescribing behavior of American Society of Clinical Oncology (ASCO) survey–reported oncologists and actual clinical practice, as captured by the computerized clinical information system. CONCLUSION: Computerized clinical information systems can collect detailed information regarding practice patterns of medical oncologists. ASCO physician practice survey data do not accurately reflect actual practice patterns and must be interpreted with caution. Substantial deviations from ASCO growth factor guidelines remain, and oncologists’ use of CSFs demonstrates wide variation. There may be important clinical differences between G-CSF and GM-CSF, but definitive phase III trials are needed for confirmation.

scholarly journals Synergistic effects of nerve growth factor and granulocyte-macrophage colony-stimulating factor on human basophilic cell differentiation

Blood ◽  
1991 ◽  
Vol 77 (5) ◽  
pp. 971-979 ◽  
Author(s):  
T Tsuda ◽  
D Wong ◽  
J Dolovich ◽  
J Bienenstock ◽  
J Marshall ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Colony Stimulating Factor ◽  
Nerve Growth ◽  
Basophilic Cell ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract We have recently shown that nerve growth factor (NGF) promotes human granulopoiesis, specifically augmenting basophilic cell differentiation observed in methylcellulose hematopoietic colony assays of human peripheral blood. Because the NGF effect was seen in the presence of conditioned medium derived from a human T-cell line (Mo-CM) containing granulocyte-macrophage colony-stimulating factor (GM-CSF), we examined interactions of purified NGF and recombinant human GM-CSF (rhGM-CSF) on granulocyte growth and differentiation. rhGM-CSF stimulated a dose- dependent increase in methylcellulose colony growth at concentrations between 0.1 U/mL and 10 U/mL, and in the presence of NGF at 500 ng/mL this effect was enhanced. The number of basophilic cell colony-forming units (CFU-Baso) and histamine-positive colonies increased synergistically when NGF was added to rhGM-CSF. Furthermore, because Mo- CM acts with sodium butyrate to promote basophilic differentiation of alkaline-passaged myeloid leukemia cells, HL-60, we also examined the interaction of NGF and Mo-CM or rhGM-CSF using this assay. In the presence of NGF, Mo-CM at concentrations of 0.5% to 20% vol/vol, and rhGM-CSF at concentrations of 0.1 U/mL to 100 U/mL synergistically increased histamine production by butyrate-induced, alkaline-passaged HL-60 cells; this was associated with the appearance of metachromatic, tryptase-negative, IgE receptor-positive cells. The effects of rhGM-CSF or Mo-CM were completely abrogated by a specific anti-rhGM-CSF neutralizing antibody in methylcellulose, with or without NGF; the NGF synergy with rhGM-CSF in the HL-60 assay was also inhibited by either anti-rhGM-CSF or anti-NGF antibody. These studies support the notion that differentiation in the basophilic lineage may be enhanced by NGF acting to increase the number of GM-CSF-responsive basophilic cell progenitors.

Prospective Study of 168 Infants with Transient Abnormal Myelopoiesis with Down Syndrome: Japan Pediatric Leukemia/Lymphoma Study Group, TAM-10 Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1311-1311 ◽  
Author(s):  
Hideki Muramatsu ◽  
Tomoyuki Watanabe ◽  
Daisuke Hasegawa ◽  
Park Myoung-ja ◽  
Shotaro Iwamoto ◽  
...  
Keyword(s):  
Risk Factors ◽  
Down Syndrome ◽  
Gestational Age ◽  
Early Death ◽  
Study Group ◽  
Pediatric Leukemia ◽  
Factors Associated ◽  
Transient Abnormal Myelopoiesis ◽  
Lymphoma Study Group ◽  
Wbc Count

Abstract Introduction: Transient abnormal myelopoiesis (TAM) occurs in approximately 10% of infants with Down syndrome (DS). Although most patients achieve spontaneous remission, some develop severe organ failure and die in their infancy. Previous studies have identified several risk factors associated with early death in such cases, including a high white blood cell (WBC) count, early gestational age, and ascites (Massey GV, 2006; Muramatsu H, 2008; Klusmann JH, 2008). Although chemotherapy with low-dose cytosine arabinoside (LDCA) has been applied for severe cases, its side effect profile has not been fully demonstrated in an adequate number of patients. Here we prospectively analyzed 168 infants with DS who were diagnosed with TAM, including 52 patients treated with LDCA. We assessed the efficacy and safety of LDCA therapy in these cases. Patient and Methods: Between May 2011 and February 2014, 168 infants (90 boys and 78 girls) were diagnosed with TAM and prospectively registered in the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) TAM-10 study. GATA1 gene mutations were identified in all except 7 patients who had a very low blast percentage. The median (range) of WBC count was 38.6 (2.4-478.7) × 109 cells/L, and the median (range) of gestational age was 37 (29-40) weeks. Thirty one (18%) patients developed anasarca at diagnosis, and 23 (14%) patients developed acute megakaryocytic leukemia. Results: The overall survival (OS) rate and the event-free survival (EFS) rate at 1 year from diagnosis [95% confidential interval (CI)] were 86.3% (80.1-90.7), and 80.2% (73.2-85.5), respectively. Univariate analysis identified the following covariates as risk factors associated with early death (<9 months): early gestational age [<37 weeks; hazard ratio (HR; 95% CI) = 4.482 (1.826-10.997), p = 0.001], parenchymal bleeding [HR (95% CI) = 5.746 (2.241-14.734), p < 0.001], anasarca [HR (95% CI) = 13.344 (5.419-32.860), p < 0.001], and high WBC count [ ≥100 × 109 cells/L; HR (95% CI) = 8.013 (3.354-19.144), p < 0.001]. The multivariate Cox hazard model identified anasarca and a high WBC count (≥100 × 109 cells/L) as independent risk factors for early death. With regard to the 52 patients who received LDCA therapy, only anasarca remained an independent risk factor for early death. Subgroup analysis in patients with a high WBC count (≥100 × 109 cells/L; n = 36) showed that LDCA therapy significantly improved survival [1-year OS (95% CI) = 78.3% (55.4-90.3; n = 23) vs. 38.5% (14.1-62.8; n = 13); p = 0.009]. In contrast, the survival rate of patients with anasarca (n = 31) did not improve on receiving LDCA therapy [1-year OS (95% CI) = 58.3% (27.0-80.1; n = 12) vs. 47.4% (24.4-67.3; n = 19); p = 0.525]. The most common side effect of LDCA was neutropenia (grade 3-4 = 59%), and one patient died due to tumor lysis syndrome. Conclusion: This prospective study confirmed that a high WBC count and anasarca are risk factors for early death in patients with DS who were diagnosed with TAM. Although LDCA therapy could significantly improve the survival rate in patients with a high WBC count, it failed to change the prognosis of patients with anasarca. A new treatment modality is required for most severe TAM patients with anasarca at diagnosis. Disclosures No relevant conflicts of interest to declare.

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