Assessment of bone marrow stem cell reserve and function and stromal cell function in patients with severe congenital neutropenia

OBJECTIVE: To investigate further the cellular defect responsible for impaired granulopoiesis in severe congenital neutropenia (SCN), we have evaluated bone marrow (BM) stem cell reserve and function and BM stromal cell myelopoiesis supporting capacity in two patients with SCN. METHODS: BM primitive stem cells and myeloid progenitor cells were assessed using flow cytometry, limiting dilution assay, clonogenic assays, and long-term BM cultures (LTBMC). BM stroma function was assessed by evaluating the ability of irradiated stromal layers from the patients to induce granulocyte-macrophage colony formation (CFU-GM) by normal CD34+ cells. RESULTS: Compared to the normal controls (n = 37), SCN patients displayed a low percentage of CD34+/CD38+ cells (P < 0.05), low CFU-GM colony formation by highly purified CD34+ cells (P < 0.05), low CFU-GM recovery in LTBMC (P < 0.05), and normal primitive stem cells as indicated by the frequency of CD34+/CD38- cells and the number of long-term culture initiating cells. Patient BM stromal layers exhibited normal myelopoiesis supporting capacity as shown by the CFU-GM content of irradiated LTBMC recharged with normal CD34+ cells. In addition, patient LTBMC supernatants displayed 20-fold normal granulocyte colony stimulating factor and 2-fold normal granulocyte-macrophage colony stimulating factor levels. CONCLUSION: These data show that primitive BM stem cells and stromal cells are not affected in SCN patients, while they support further the concept of a primary defect at the myeloid progenitor cell level. To know the differentiation stage at which the underlying defect causes the malfunction will be relevant for further elucidation of its nature at the molecular level.     

Low-risk febrile neutropenia in a medical oncology unit

Background: Febrile neutropenia occurring in patients receiving chemotherapy for solid tumours or lymphoma is usually of short duration, and therefore may have a better outcome compared to patients with acute leukaemia or patients receiving myeloablative chemotherapy. Aims: To review retrospectively the outcomes for febrile neutropenia occurring in patients of the Medical Oncology Unit at our institution, and to identify factors associated with worse outcome, particularly prolonged admission or death. Methods: We reviewed 102 episodes of febrile neutropenia occurring in 85 patients treated between 1992 and 1994. Demographic factors, tumour-related factors and clinical aspects of the episodes were correlated with outcome. Results: The median age was 60 years (range, 18–87), with 56 (55%) episodes occurring in females. Twenty-eight (27%) episodes occurred in patients with lymphoma, with the remaining 74 (73%) occurring in patients with solid tumours. At presentation, the median absolute neutrophil count (ANC) was 0.14×10⁹/L with a median duration of significant neutropenia (ANC<0.5×10 ⁹/L) of three days. The median duration of fever was two days. Twenty-nine (28%) episodes had positive cultures; of these 11 had bacteraemia. Forty-four (43%) episodes were classified as unexplained fevers. The remaining 29 episodes were associated with clinically documented infection but negative cultures. There was a high treatment success rate (81%) with first-line empirical antibiotics. Of 19 treatment failures, 13 were due to the necessity for antibiotic modification; the other six patients died from infection. Factors associated with a worse outcome (including prolonged admission and death) include: diagnosis of lymphoma; increasing number of chemotherapy courses; early onset of neutropenia; pneumonia; severe hypotension; and multiple co-morbidities. Conclusions: Febrile neutropenia in adult patients with solid tumours or lymphoma is associated with a relatively good outcome, possibly due to the short duration of neutropenia. A future prospective study to validate the risk factors indentified in this study would be useful for defining patients at low risk for the adverse outcomes examined, in whom less intensive management for this condition may be possible.     

Pediatric patients who receive antibiotics for fever and neutropenia in less than 60 min have decreased intensive care needs

Background

Antibiotic delivery to patients with fever and neutropenia (F&N) in <60 min is an increasingly important quality measure for oncology centers, but several published reports indicate that a time to antibiotic delivery (TTA) of <60 min is quite difficult to achieve. Here we report a quality improvement (QI) effort that sought to decrease TTA and assess associated clinical outcomes in pediatric patients with cancer and F&N.

Procedure

We used Lean‐Methodology and a Plan‐Do‐Study‐Act approach to direct QI efforts and prospectively tracked TTA measures and associated clinical outcomes (length of stay, duration of fever, use of imaging studies to search for occult infection, bacteremia, intensive care unit (ICU) consultation or admission, and mortality). We then performed statistical analysis to determine the impact of our QI interventions on total TTA, sub‐process times, and clinical outcomes.

Results

Our QI interventions significantly improved TTA such that we are now able to deliver antibiotics in <60 min nearly 100% of the time. All TTA sub‐process times also improved. Moreover, achieving TTA <60 min significantly reduced the need for ICU consultation or admission (P = 0.003) in this population.

Conclusion

Here we describe our QI effort along with a detailed assessment of several associated clinical outcomes. These data indicate that decreasing TTA to <60 min is achievable and associated with improved outcomes in pediatric patients with cancer and F&N. Pediatr Blood Cancer 2015;62:807–815. © 2015 The Authors. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.     

Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia

Summary. Serum concentrations of tumour necrosis factor alpha (TNF-α), interleukin-1 receptor antagonist (IL-1ra), interferon gamma (IFN-γ), interleukin-6 (IL-6) and interleukin-10 (IL-10) were studied in 31 patients with haematological malignancies during febrile neutropenia. Samples were obtained when blood cultures were performed (time 0) and, when possible, after 2, 4, 6, 12 and 24 h. Increased levels of all cytokines were detected after start of fever with peak values in gram-negative (Gr⁻) bacteraemias after 2 h (TNF-α, IL-lra and IFN-γ), 4h (IL-6) and 6 h (IL-10), respectively. At time 0 the median TNF-α value was higher in the Gr⁻ group (80 pg/ml; range 54-516 pg/ml) as compared to both gram-positive bacteraemias (Gr⁺, 14pg/ ml; range 7-60 pg/ml; P < 0 05) and blood culture negative episodes (BCN, 8pg/ml; range 0-87pg/ml; P<0 05).
Furthermore, the peak values of TNF-α, IL-lra, IL-6 and IL-10 during the 24 h study period were significantly and/or numerically higher in the ^Gr- group in comparison to the Gr⁺ and BCN groups, respectively. It may be concluded that neutropenic patients have increased levels of both pro- and anti-inflammatory cytokines at start of fever, with the highest values recorded during the first hours in ^Gr- bacteraemias. Prospective studies will show whether monitoring of serum cytokines may be used as an early diagnostic tool before results of blood cultures are available, which may have important therapeutic implications.     

Granulocyte transfusions in the management of neutropenic fever: A pediatric perspective

Severe neutropenia-associated invasive bacterial or fungal infections are still the major cause of mortality and morbidity in children receiving cancer chemotherapy. Granulocyte transfusion therapy has been used for many years in the management of neutropenic patients with severe infections in whom the clinical condition deteriorated despite appropriate antimicrobial treatment. Transfused granulocytes can increase the recipient’s blood neutrophil count and accumulation of them into the site of infection. There are some data obtained from retrospective or prospective observational studies in pediatric granulocyte transfusion therapy, but results are not conclusive. This review appraises the potential benefits and risks of the use of granulocyte transfusion in children with neutropenic fever.     

Two Cases of Autoimmune Neutropenia Complicated with Other Lineages of Autoimmune Cytopenia,Successfully Treated with Prednisolone

Though adult-onset primary autoimmune pancytopenia (AIP) rarely follows a self-limited course, a standard treatment strategy has not yet been established. We herein report two cases, each involving primary autoimmune neutropenia complicated with autoimmune thrombocytopenia or Evans syndrome. They were refractory to granulocyte-colony stimulating factor, but all lineages of cytopenia promptly recovered with prednisolone (PSL). In case 1, PSL was tapered and discontinued six months after its initiation without AIP relapse. In case 2, PSL has been tapered for five months without relapse. To establish an optimal treatment strategy for AIP, it is necessary to accumulate more cases.     

The growth capacity of hematopoietic progenitor cells in severe neutropenia induced by famotidine

Summary In four cases of severe neutropenia of unknown origin we found a strong inhibition of the growth of granulocyte-macrophage (GM) progenitor cells. The development of GM colonies in culture (GM-CFU-c) was more than 80% reduced in comparison to the control group. In particular, the interleukin 3- (IL-3) and granulocyte macrophage colony-stimulating factor-(GM-CSF) dependent growth was affected; a combination of growth factors (IL-3, GM-CSF, and G-CSF, the granulocyte colony-stimulating factor) resulted in a less reduced growth. The findings were primarily compatible with drug-induced bone marrow failure. Among the medications given to the patients, famotidine, an H2-receptor blocker, was discussed as an agent which possibly triggers off this process. After the withdrawal of famotidine, in three cases a continual increase of the growth of GM precursors was detected, reaching the normal level 7–17 days later. In one case, further investigations of the progenitor cells could not be carried out due to the death of the patient, but the rapid increase of neutrophils in the peripheral blood after withdrawal of famotidine pointed to the recovery of hematopoiesis. In vitro studies showed that famotidine, depending on the dose, inhibits the single growth factor-dependent colony growth (IL-3, GM-CSF, or G-CSF) of bone marrow progenitors from a concentration as low as 10g/ml. With the combination of all three growth factors only slight inhibitory effects were detectable (up to 150g/ml famotidine). These results indicate that famotidine, in common with other H2-receptor antagonists, can affect hematopoietic progenitor cells. However, the plasma concentration of famotidine normally used in ulcer therapy does not seem to influence the hematopoiesis. Apparently, the progenitor cells of only a few patients possess a higher sensitivity to the blockade of H2-receptors at this concentration of famotidine. This was demonstrated in one case (patient 3) 2 years after the patient had recovered from famotidine-induced neutropenia. The growth of peripheral myeloid, erythroid, and multilineage progenitor cells of this patient was remarkably reduced even at famotidine concentrations of 0.1–5.0g/ml whereas in the control group no inhibition was detected at these famotidine concentrations. Again, the IL-3-dependent colony formation was more affected than in the case of the combination of IL-3, GM-CSF, and G-CSF. After the removal of accessory cells the inhibitory effect of famotidine persisted, demonstrating that accessory cells do not play a major role in this process.     

Successful treatment of autoimmune neutropenia with recombinant human granulocyte-colony stimulating factor (R-metHuG-CSF)

Autoimmune neutropenia (AIN) is characterized by antibody mediated peripheral destruction of neutrophils. Since there is no effective treatment, antibiotics have to be used frequently for recurrent infections. Five selected patients with serologically proven AIN were treated with r-metHuG-CSF at 5–8 μg/kg body weight (300–480 μg) daily; the dose and frequency of r-metHuG-CSF was reduced after neutrophil counts above 1.0×10⁹/l were obtained. R-metHuG-CSF is effective in AIN and causes a sustained rise in ANC which can be maintained on a low dose administered twice or thrice weekly.     

预防性使用聚乙二醇化重组人粒细胞集落刺激因子在肺癌患者同步放化疗中的作用

目的 评价预防性使用聚乙二醇化重组人粒细胞集落刺激因子(PEG-rhG-CSF)在肺癌同步放化疗期间预防中性粒细胞减少症的作用。方法 回顾性分析2020年4月至2021年4月于北京大学肿瘤医院接受同步放化疗的149例肺癌患者的临床资料,其中预防组79例,包括初级预防组(全程同步放化疗中预防使用PEG-rhG-CSF)48例,次级预防组(出现粒细胞减少后的化疗周期中预防使用PEG-rhG-CSF)31例;未预防组70例。对比预防组和未预防组之间3~4级中性粒细胞减少症的发生率、同步放化疗完成率、放化疗剂量减量和治疗时间延迟发生率。结果 全组患者在放化疗中出现3~4级中性粒细胞减少症的发生率为32.2%(48/149)。其中,初级预防组的发生率为6.3%(3/48),次级预防组的发生率为9.7%(3/31),未预防组的发生率为35.7%(25/70)。预防组(初级预防+次级预防)与未预防组中性粒细胞减少症的发生率差异有统计学意义(χ²=17.81,P＜0.001)。全组粒细胞缺乏伴发热的发生率为3.4%(5/149),未在初级预防组出现。同步放化疗足量完成率在预防组为96.2%(76/79),明显高于未预防组的82.9%(58/70),差异有统计学意义(χ²=7.30,P=0.007)。预防组放化疗剂量减量和治疗时间延迟发生率为19.0%(15/79),未预防组为40.0%(28/70),差异有统计学意义(χ²=7.98,P=0.005)。结论 PEG-rhG-CSF的预防使用可以有效降低3~4级中性粒细胞减少症的发生,更好地保证肺癌患者同步放化疗按计划完成。