A woman in her early 60s with stage 3A diffuse large B-cell lymphoma developed anaphylaxis to pegfilgrastim after her first cycle of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy, presenting with syncope, severe diarrhoea and persistent hypotension requiring hospitalisation. Three further cycles were given without growth factor support. After cycle four she developed neutropenic fever and received sargramostim (granulocyte-macrophage colony-stimulating factor) under intensive premedication and intensive care monitoring, which she initially tolerated; on the third administration she developed anaphylaxis requiring epinephrine. She completed all six cycles of R-CHOP without growth factor support, using prophylactic antibiotics and close monitoring, achieved complete remission and remains disease-free 41 months after treatment. To our knowledge, this is the second documented case of anaphylaxis to agents from both the granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor classes in one patient, and the first involving pegfilgrastim.

A 46-year-old man was diagnosed with autoimmune pulmonary alveolar proteinosis (aPAP). Despite repeated segmental bronchoscopic lavage, his symptoms, pulmonary function, and radiological findings gradually worsened, and he declined whole-lung lavage. Although classified as disease severity score 2 (partial pressure of arterial oxygen 75.2 mmHg), inhaled granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy (sargramostim) was initiated. After 6 months, a marked improvement was observed, and the alveolar-arterial oxygen difference decreased from 21.8 to 1.1 mmHg. Given the limited evidence in milder cases, this report suggests that early intervention with inhaled sargramostim may be effective in relatively mild but progressive aPAP.

Pulmonary alveolar proteinosis (PAP) is a rare granulocyte-macrophage colony-stimulating factor (GM-CSF) dependent lung disease treated primarily with whole-lung lavage (WLL); recurrence after lung transplantation is uncommon and poorly characterised. We present a 73-year-old Hispanic man with PAP who developed recurrent disease more than 3 years after bilateral lung transplantation. High-resolution CT showed evolving ground-glass opacities and crazy-paving, and anti-GM-CSF antibodies were positive, yet repeated bronchoalveolar lavage and transbronchial biopsies were initially PAS-negative. Concomitant Mycobacterium avium complex, Aspergillus and Nocardia infections mimicked recurrent PAP and coincided with an atypical shift in spirometry from supranormal airflow (FEV1 110% predicted; FEV1/FVC 91%) to obstruction (FEV1 99% predicted; FEV1/FVC 68%). Ultimately, repeat lavage revealed PAS-positive lipoproteinaceous material, and treatment with inhaled sargramostim plus two sequential WLLs produced marked radiographic clearance, symptomatic relief and partial spirometric recovery. Our case highlights how multimodal, longitudinal clinical surveillance remains essential in lung transplant recipients.

Hematopoietic acute radiation syndrome (H-ARS) elicits multidimensional effects, as total-body irradiation (TBI) induced myelosuppression results in distinct patterns of loss and recovery across blood cell lineages. This study aimed to characterize the sequence of pancytopenia after TBI in male and female non-human primates (NHPs) with and without sargramostim treatment using unsupervised machine learning (ML). Longitudinal blood cell measures from three 60-day randomized, controlled trials of NHPs (N = 501) exposed to TBI and administered either vehicle (n = 173) or sargramostim (n = 328) were pooled for analysis. Hierarchical clustering of blood cells was performed using dynamic time warping (DTW) distances. Summary metrics of longitudinal trends were compared across treatment groups and sex. All analyses were performed in Pumas 2.0. Trends in each cluster showed that lymphocytes and reticulocytes are the first two cell populations to deplete rapidly, almost immediately after TBI, followed by white blood cell (WBC) related cells, platelets, and red blood cell (RBC) related cells. Reticulocytes reach nadir at day 8, followed by WBC-related cells at day 12, platelets at day 13, and RBC-related cells at day 17. The characterized pancytopenia sequence aligns with the typical lifespan of impaired blood cells, except for RBCs. Comparison across clusters between treated and untreated NHPs showed that sargramostim-treated animals started to recover earlier or at the same time as untreated animals. Female NHPs generally experienced deeper nadirs than males. In summary, characterizing pancytopenia using unsupervised machine learning improves understanding of the pathogenesis of H-ARS, which can enable improved therapeutic care, countermeasure development, and efficient medical triage.

The connection between immunity and Parkinson’s disease (PD) is well-established. Myeloid immune responses influence the microenvironment of the central nervous system (CNS), which can be modulated by sargramostim, a recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF). Previous studies have demonstrated sargramostim’s neuroprotective effects, which are linked to its safety and tolerability, as well as its ability to regulate innate immunity. Changes in myeloid biomarkers correlate with clinical responses. PD symptoms were assessed using the Unified PD Rating Scale (UPDRS). Ten subjects received sargramostim through subcutaneous injections of 3 µg/kg, administered five days every week. Myeloid biomarkers were measured before treatment and at six and twelve months of treatment. Protein expression by Western blotting and gene expression by transcriptomic analysis was correlated with UPDRS III scores. Recognizing the exploratory nature of this study, patient responses were classified into potent, moderate, or no change groups based on UPDRS III score reductions of 9–13, 5–7, or none, respectively. Biomarkers from all 10 patients identified FOXP3 as a “potential” signature biomarker. The potent responders showed biomarkers linked to autophagy, inflammatory, and antioxidant proteins, including ATG7, HMOX1, RELA, and TLR8. Moderate responders displayed biomarkers associated with RELA and LRRK2. Transcriptomic analysis revealed over 2000 differentially expressed anti-inflammatory, calcium-binding, and epigenetic genes. Among these, genes such as ANXA9, CALM3, CY7B1, HDAC4, HMGB2, NR2F6, PDIA3, REST, SACS and SOX4 were identified as potential predictors of changes in UPDRS III scores. Baseline levels of ATG7, CARD9, and SACS may serve as initial biomarkers to identify subjects likely to respond to sargramostim. Female patients exhibited unique UPDRS III scores in response to sargramostim treatment. Novel cell-based biomarker signatures were identified that may predict responses to sargramostim treatment in this hypothesis-generating study. We acknowledge the inherent study limitations by limited patient numbers. This was reflected in the comparisons offered for the patient sub-groups in the year-long trial.Trial Registration The trial is registered on ClinicalTrials.gov under identifier NCT03790670, dated 01.30.2019.

Hematopoietic acute radiation syndrome (H-ARS) elicits multidimensional effects, as total-body irradiation (TBI) induced myelosuppression results in distinct patterns of loss and recovery across blood cell lineages. This study aimed to characterize the sequence of pancytopenia after TBI in male and female non-human primates (NHPs) with and without sargramostim treatment using unsupervised machine learning (ML). Longitudinal blood cell measures from three 60-day randomized, controlled trials of NHPs (N = 501) exposed to TBI and administered either vehicle (n = 173) or sargramostim (n = 328) were pooled for analysis. Hierarchical clustering of blood cells was performed using dynamic time warping (DTW) distances. Summary metrics of longitudinal trends were compared across treatment groups and sex. All analyses were performed in Pumas 2.0. Trends in each cluster showed that lymphocytes and reticulocytes are the first two cell populations to deplete rapidly, almost immediately after TBI, followed by white blood cell (WBC) related cells, platelets, and red blood cell (RBC) related cells. Reticulocytes reach nadir at day 8, followed by WBC-related cells at day 12, platelets at day 13, and RBC-related cells at day 17. The characterized pancytopenia sequence aligns with the typical lifespan of impaired blood cells, except for RBCs. Comparison across clusters between treated and untreated NHPs showed that sargramostim-treated animals started to recover earlier or at the same time as untreated animals. Female NHPs generally experienced deeper nadirs than males. In summary, characterizing pancytopenia using unsupervised machine learning improves understanding of the pathogenesis of H-ARS, which can enable improved therapeutic care, countermeasure development, and efficient medical triage.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare interstitial lung disease characterized by surfactant accumulation within alveoli due to impaired clearance or GM-CSF signaling defect. Whole lung lavage (WLL) removes accumulated surfactant but is invasive and does not correct macrophages dysfunction. Recombinant GM-CSF (molgramostim or sargramostim) aims to restore macrophage activity¸ enhance gas exchange and reduce dependence on WLL. OBJECTIVE: This systematic review and meta-analysis evaluated the efficacy of recombinant human GM-CSF (molgramostim or sargramostim) compared with placebo in patients with aPAP. METHOD: Following PRISMA guidelines, PubMed, Cochrane CENTRAL, and Scopus were searched for randomized controlled trials in adults with aPAP receiving molgramostim or sargramostim versus placebo. Primary outcomes included changes in alveolar–arterial oxygen gradient (A-aDO2) and diffusing capacity of the lung for carbon monoxide (DLCO). Secondary outcomes included St. George’s Respiratory Questionnaire (SGRQ) scores, radiologic ground-glass opacity (GGO) scores, vital capacity, six-minute walk distance, serum biomarkers (CEA and KL-6), and GM-CSF autoantibody levels. Data were analyzed using a random-effects model RevMan 5.4.1, and risk of bias with ROB 2.0. RESULT: Four RCTs involving 338 participants (190 interventions,148 control) were included. Recombinant GM-CSF significantly improved gas exchange, with decreased A-aDO2 MD of -4.67 (95% CI: -8.49 to -1.42, p = 0.006) and increased DLCO (% predicted) with a mean difference of 6.13 (95% CI: 3.36 to 8.89). Significant improvements were also observed in SGRQ-T scores (MD = –6.60; p < 0.00001) and GGO scores (MD = –1.98; p = 0.0007). No significant differences were found for six-minute walk distance, vital capacity, or serum biomarkers. Most included trials showed low to moderate risk of bias with a few high risk. Egger’s test (p = 0.37) showed no publication bias and overall certainty of evidence ranged from moderate to high. CONCLUSION: Recombinant GM-CSF (molgramostim and sargramostim) is an effective, disease targeted therapy for aPAP. It improves pulmonary function gas exchange and radiological outcomes while reducing reliance on whole lung lavage. TRIAL REGISTRATION: PROSPERO reference number CRD420251165258.

A World Health Organisation panel previously recommended the use of hematopoietic cytokines to manage H-ARS within 24 h of exposure to ⩾2 Gy radiation dose, a recommendation that has been endorsed by hematologists and oncologists with expertise in radiation management. Nevertheless, no state-of-the-art consensus has been reached regarding categorical selection of cytokines for emergency scenarios involving accidental exposures where implementation of planned and/or extended countermeasures is certain or likely (International Nuclear and Radiological Event Scale levels 5, 6 and 7) or an exposure from a detonated nuclear weapon. A systematic review of the published literature was conducted (422 citations identified, 391 of which were screened) in non-human primates 9 meeting inclusion criteria), and in reviews of human cases treated with cytokines in a search of the MEDLINE database (1970-present), websites/official publications of major national and international organisations and radiation societies, cytokine reviews and full prescribing information. In contrast to filgrastim, pegfilgrastim and romiplostim, sargramostim augments the differentiation and proliferation of multiple lymphohematopoietic lineages. NHP survival benefits without the support of blood products was reported with sargramostim or pegfilgrastim plus romiplostim. Four cytokine reviews met criteria for summarising published reports of 63 human cases that included at least one case meeting inclusion criteria. Cytokine efficacy was documented when administered at up to 96 h after NHP exposure for sargramostim and at 24 h but not 48 h after exposure for filgrastim, pegfilgrstim or pegfilgrastim plus romiplostim. Ease of use favoured pegfilgrastim (administered weekly x2) and romiplostim (administered once), compared to filgrastim and sargramostim (administered daily x5 and x14, respectively). Formal assessment of the published evidence is urgently needed to provide categorical guidance regarding cytokine use for patient management, and to public health officials involved in establishing a national or shared regional radiation stockpile for immediate use in a mass casualty radiological/nuclear (R/N) emergency.

A 91-year-old woman diagnosed with rheumatoid arthritis (RA) in her 40s achieved disease stabilization after salazosulfapyridine (SASP) treatment. In May 2025, chest computed tomography (CT) revealed bilateral ground-glass opacities with interlobular septal thickening, presenting a crazy-paving pattern. She was diagnosed with autoimmune pulmonary alveolar proteinosis (aPAP) based on positive serum anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies and periodic acid-Schiff (PAS)-positive fluid accumulation in the alveoli identified on transbronchial lung biopsy (TBLB). The development of aPAP is considered extremely rare in patients with RA, as the disease is typically characterized by elevated GM-CSF activity, creating a pathological paradox. Previous reports have revealed that almost all patients with aPAP and RA receive SASP treatment. We hypothesized that aPAP associated with RA developed due to a dual suppression of GM-CSF: drug-induced inhibition of GM-CSF at the alveolar level and acquired production of anti-GM-CSF antibodies.