GM-CSF, G-CSF or no cytokine therapy with anti-GD2 immunotherapy for high-risk neuroblastoma.

Colony-stimulating factors have been shown to improve anti-disialoganglioside 2 (anti-GD2) monoclonal antibody response in high-risk neuroblastoma by enhancing antibody-dependent cell-mediated cytotoxicity (ADCC). A substantial amount of research has focused on recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant to anti-GD2 monoclonal antibodies. There may be a disparity in care among patients as access to GM-CSF therapy and anti-GD2 monoclonal antibodies is not uniform. Only select countries have approved these agents for use, and even with regulatory approvals, access to these agents can be complex and cost prohibitive. This comprehensive review summarizes clinical data regarding efficacy and safety of GM-CSF, recombinant human granulocyte colony-stimulating factor (G-CSF) or no cytokine in combination with anti-GD2 monoclonal antibodies (ie, dinutuximab, dinutuximab beta or naxitamab) for immunotherapy of patients with high-risk neuroblastoma. A substantial body of clinical data support the immunotherapy combination of anti-GD2 monoclonal antibodies and GM-CSF. In contrast, clinical data supporting the use of G-CSF are limited. No formal comparison between GM-CSF, G-CSF and no cytokine has been identified. The treatment of high-risk neuroblastoma with anti-GD2 therapy plus GM-CSF is well established. Suboptimal efficacy outcomes with G-CSF raise concerns about its suitability as an alternative to GM-CSF as an adjuvant in immunotherapy for patients with high-risk neuroblastoma. While programs exist to facilitate obtaining GM-CSF and anti-GD2 monoclonal antibodies in regions where they are not commercially available, continued work is needed to ensure equitable therapeutic options are available globally.

Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor (rhu GM-CSF) as Adjuvant Therapy for Invasive Fungal Diseases.

Background: Sargramostim (yeast-derived, glycosylated recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]) augments innate and adaptive immune responses and accelerates hematopoietic recovery of chemotherapy-induced neutropenia. However, considerably less is known about its efficacy as adjunctive immunotherapy against invasive fungal diseases (IFDs). Methods: The clinical courses of 15 patients with pediatric malignancies and IFDs treated adjunctively with sargramostim at a single institution were analyzed in a retrospective cohort review. Further, a systematic review of published reports of rhu GM-CSF for IFDs was also conducted. Results: Among 65 cases, 15 were newly described pediatric patients and 50 were previously published cases of IFDs treated with rhu GM-CSF. Among the newly reported pediatric patients, IFDs were caused by Candida spp., Trichosporon sp., and molds (Aspergillus spp., Rhizopus sp., Lichtheimia sp., and Scedosporium sp). Twelve (80%) were neutropenic at baseline, and 12 (80%) were refractory to antifungal therapy. Among 12 evaluable patients, the overall response rate was 92% (8 [67%] complete responses, 3 [25%] partial responses, and 1 [8%] stable). Treatment is ongoing in the remaining 3 patients. Among 50 published cases (15 Candida spp., 13 Mucorales, 11 Aspergillus spp., 11 other organisms), 20 (40%) had baseline neutropenia and 36 (72%) were refractory to standard therapy before rhu GM-CSF administration. Consistent with responses in the newly reported patients, the overall response rate in the literature review was 82% (40 [80%] complete responses, 1 [2%] partial response, and 9 [18%] no response). Conclusions: Sargramostim may be a potential adjunctive immunomodulator for selected patients with hematological malignancies and refractory IFDs.

Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders.

Introduction: Endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF. Methods: We reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy. Results: We discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events. Discussion: We identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need.

Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time?

BACKGROUND: Sargramostim [recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF)] was approved by US FDA in 1991 to accelerate bone marrow recovery in diverse settings of bone marrow failure and is designated on the list of FDA Essential Medicines, Medical Countermeasures, and Critical Inputs. Other important biological activities including accelerating tissue repair and modulating host immunity to infection and cancer via the innate and adaptive immune systems are reported in pre-clinical models but incompletely studied in humans. OBJECTIVE: Assess safety and efficacy of sargramostim in cancer and other diverse experimental and clinical settings. METHODS AND RESULTS: We systematically reviewed PubMed, Cochrane and TRIP databases for clinical data on sargramostim in cancer. In a variety of settings, sargramostim after exposure to bone marrow-suppressing agents accelerated hematologic recovery resulting in fewer infections, less therapy-related toxicity and sometimes improved survival. As an immune modulator, sargramostim also enhanced anti-cancer responses in solid cancers when combined with conventional therapies, for example with immune checkpoint inhibitors and monoclonal antibodies. CONCLUSIONS: Sargramostim accelerates hematologic recovery in diverse clinical settings and enhances anti-cancer responses with a favorable safety profile. Uses other than in hematologic recovery are less-well studied; more data are needed on immune-enhancing benefits. We envision significantly expanded use of sargramostim in varied immune settings. Sargramostim has the potential to reverse the immune suppression associated with sepsis, trauma, acute respiratory distress syndrome (ARDS) and COVID-19. Further, sargramostim therapy has been promising in the adjuvant setting with vaccines and for anti-microbial-resistant infections and treating autoimmune pulmonary alveolar proteinosis and gastrointestinal, peripheral arterial and neuro-inflammatory diseases. It also may be useful as an adjuvant in anti-cancer immunotherapy.

Exposure-Based Methadone and Lorazepam Weaning Protocol Reduces Wean Length in Children.

OBJECTIVE: Determine if a standardized methadone and lorazepam weaning protocol that is based on dose and duration of exposure can reduce the length of opioid and benzodiazepine weaning and shorten hospital stay. METHODS: Retrospective cohort study performed in a 24-bed medical/surgical PICU. A total of 177 patients on opioid and/or benzodiazepine infusions for >3 days were included; 75 patients pre protocol (June 2012- June 2013) were compared with 102 patients post implementation of a standardized weaning protocol of methadone and lorazepam (March 2014-March 2015). The recommended wean was based on duration of infusions of >3 days up to 5 days (no wean), 5 to 13 days (short wean), and ≥14 days (long wean). RESULTS: Median number of days on methadone for patients on opioid infusions for 5 to 13 days was reduced from 8.5 to 5.7 days (p = 0.001; n = 45 [pre], n = 68 [post]) and for patients on opioid infusions for ≥14 days, from 29.7 to 11.5 days (p = 0.003; n = 9 [pre], n = 9 [post]) after protocol implementation. The median number of days on lorazepam for patients on benzodiazepine infusions for 5 to 13 days was reduced from 8.1 to 5.2 days (p = 0.020; n = 43 [pre], n = 55 [post]) and for patients on benzodiazepine infusions for ≥14 days, from 27.4 to 9.3 days (p = 0.011; n = 9 [pre], n = 8 [post]). There was no difference in methadone or lorazepam wean length for patients on 3 to 5 days of infusions. There was no difference in adverse events or hospital length of stay. CONCLUSIONS: A methadone and lorazepam weaning protocol based on patient's exposure to opioids and benzodiazepines (dose and duration) reduces weaning length.

Antithrombin III Doses Rounded to Available Vial Sizes in Critically Ill Pediatric Patients.

OBJECTIVES: Children have decreased levels of antithrombin III (AT III) compared to adults. These levels may be further decreased during acute illness. Administration of exogenous AT III can increase anticoagulant efficacy. The objective of this study was to evaluate AT III doses rounded to available vial sizes compared to partial vial doses in critically ill pediatric patients, including patients receiving extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). METHOD: This retrospective review evaluated pediatric patients 0-18 years of age admitted to a 24-bed medical/surgical pediatric intensive care unit between June 1, 2012, and December 31, 2014, who received plasma-derived AT III. Patients received unfractionated heparin, low-molecular-weight heparin, or no anticoagulation. This review included patients who received ECMO and CRRT. RESULTS: Eighty doses of AT III were administered to 24 patients (38 full vial size doses and 42 partial vial size doses). The AT III level following dose administration was ≥80% for 26 full vial doses (70%) and 16 partial vial doses (41%; p = 0.010). For patients who received multiple doses of AT III, the median time between doses was 45 hours following full vial doses, and 23 hours following partial vial doses (p = 0.011). Seven patients (29%) had documentation of new or increased bleeding. The median waste prevented from rounding doses to full vial sizes was 363 units. CONCLUSIONS: After receiving AT III doses rounded to full vial sizes, patients were more likely to have a therapeutic AT III level and a longer interval between administrations. Rounding AT III doses to full vial sizes reduces waste and can result in cost savings.

Comparison of Intravenous Palivizumab and Standard of Care for Treatment of Respiratory Syncytial Virus Infection in Mechanically Ventilated Pediatric Patients.

OBJECTIVES: Evidence suggests palivizumab may be beneficial for respiratory syncytial virus (RSV) infection in pediatric patients, although it is only approved by the US Food and Drug Administration for RSV prophylaxis. The objective of this study is to compare outcomes among pediatric patients with RSV infection who received intravenous palivizumab and standard of care versus standard of care alone. METHODS: This is a retrospective, single-center cohort study conducted between November 2003 and October 2013. Pediatric patients with active RSV infection treated with intravenous (IV) palivizumab after initiation of mechanical ventilation were matched 1:1 to a control selected from ventilated patients who received standard of care. The primary end point evaluated the duration of mechanical ventilation between groups. Secondary end points included hospital length of stay, intensive care unit length of stay, duration of respiratory support over baseline, time to RSV microbiologic cure, duration of antibiotic therapy, and in-hospital mortality. RESULTS: A total of 22 patients with a median age of 3 months were included in the study. Patients in the treatment group received a median of 2 doses of IV palivizumab, with a mean dose of 14.2 mg/kg. All patients received bronchodilators and corticosteroids, with the exception of 1 patient in the control group, and only 1 treatment group patient received IV ribavirin. Duration of mechanical ventilation was longer in the treatment group (18.9 ± 9.5 vs. 14.3 ± 9.3 days; p = 0.26). No statistically significant differences were observed between groups for any of the secondary end points. CONCLUSIONS: Pediatric patients who received IV palivizumab in addition to standard of care for treatment of RSV infection following initiation of mechanical ventilation experienced similar outcomes to those who received standard of care alone. Further studies are necessary to evaluate the potential benefit of IV palivizumab in addition to current standard of care.

Alteplase infusion versus dwell for clearance of partially occluded central venous catheters in critically ill pediatric patients.

OBJECTIVE: To evaluate the efficacy and safety of alteplase infusions and alteplase local instillations (dwells) to clear partially occluded central venous catheters in critically ill children. DESIGN: Retrospective study. SETTING: PICU in a single, tertiary care, academic children's hospital. PATIENTS: Retrospective review of the medical records of all critically ill pediatric patients less than 18 years old who received an alteplase infusion or dwell as the treatment for a partial central venous catheter occlusion. The typical infusion regimen was to administer 0.1 mg/kg of body weight (maximum, 2 mg/dose) of alteplase in 25 mL of 0.9% sodium chloride over 3 hours. The standard dwell was to administer and aspirate alteplase in a 1 mg/mL concentration as a fixed dose as ordered by the prescriber (maximum, 2 mg/dose). Efficacy was defined as documentation of positive blood return from the catheter. Radiology reports, nursing and physician documentation, and laboratory values were reviewed to assess for bleeding events. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred fifty occlusion events were included for analysis. Overall, 72 of 84 alteplase infusions (86%) and 53 of 66 alteplase dwells (80%) resulted in resolution of the lumen occlusion event as documented by positive blood return from the catheter after a maximum of two doses (p = 0.39). One major bleeding event occurred in each arm; both were deemed unlikely related to alteplase. CONCLUSIONS: Alteplase infusions to clear partially occluded central venous catheters appear to be as efficacious as alteplase dwells in critically ill children. In occlusions treated with an infusion, more occlusions resolved in older and larger patients and in patients with catheters in place less than 7 days. In occlusions treated with a dwell, more occlusions resolved in smaller catheters. The safety profile for both infusions and dwells was acceptable for the pediatric critically ill population.