53 research outputs found
Amphiregulin modifies the Minnesota acute graft-versus-host disease risk score: Results from BMT CTN 0302/0802
Patient-reported treatment response in chronic graft-versus-host disease
Chronic graft-versus-host disease (GvHD) treatment response is assessed using National Institutes of Health (NIH) Consensus Criteria in clinical trials, and by clinician assessment in routine practice. Patient-reported treatment response is central to the experience of chronic GvHD manifestations as well as treatment benefit and toxicity, but how they correlate with clinician- or NIH-responses has not been well-studied. We aimed to characterize 6-month patientreported response, determine associated chronic GvHD baseline organ features and changes, and evaluate which patientreported quality of life and chronic GvHD symptom burden measures correlated with patient-reported response. From two nationally representative Chronic GVHD Consortium prospective observational studies, 382 subjects were included in this analysis. Patient and clinician responses were categorized as improved (completely gone, very much better, moderately better, a little better) versus not improved (about the same, a little worse, moderately worse, very much worse). At six months, 270 (71%) patients perceived chronic GvHD improvement, while 112 (29%) perceived no improvement. Patient-reported response had limited correlation with either clinician-reported (kappa 0.37) or NIH chronic GvHD response criteria (kappa 0.18). Notably, patient-reported response at six months was significantly associated with subsequent failure-free survival. In multivariate analysis, NIH responses in eye, mouth, and lung had significant association with 6-month patient-reported response, as well as a change in Short Form 36 general health and role physical domains and Lee Symptom Score skin and eye changes. Based on these findings, patient-reported responses should be considered as an important complementary endpoint in chronic GvHD clinical trials and drug development
Axatilimab for chronic graft-versus-host disease after failure of at least two prior systemic therapies: Results of a phase I/II study
PURPOSE: Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity after allogeneic hematopoietic cell transplantation. Colony-stimulating factor 1 receptor (CSF-1R)-dependent macrophages promote cGVHD fibrosis, and their elimination in preclinical studies ameliorated cGVHD. Axatilimab is a humanized monoclonal antibody that inhibits CSF-1R signaling and restrains macrophage development.
PATIENTS AND METHODS: This phase I (phI)/phase II (phII) open-label study (ClinicalTrials.gov identifier: NCT03604692) evaluated safety, tolerability, and efficacy of axatilimab in patients age ≥ 6 years with active cGVHD after ≥ 2 prior systemic therapy lines. Primary objectives in phI were to identify the optimal biologic and recommended phII dose and in phII to evaluate the overall (complete and partial) response rate (ORR) at the start of treatment cycle 7.
RESULTS: Forty enrolled patients (17 phI; 23 phII) received at least one axatilimab dose. In phI, a dose of 3 mg/kg given once every 4 weeks met the optimal biologic dose definition. Two dose-limiting toxicities occurred at the 3 mg/kg dose given once every 2 weeks. At least one treatment-related adverse event (TRAE) was observed in 30 patients with grade ≥ 3 TRAEs in eight patients, the majority known on-target effects of CSF-1R inhibition. No cytomegalovirus reactivations occurred. With the 50% ORR at cycle 7 day 1, the phII cohort met the primary efficacy end point. Furthermore, the ORR in the first six cycles, an end point supporting regulatory approvals, was 82%. Responses were seen in all affected organs regardless of prior therapy. Fifty-eight percent of patients reported significant improvement in cGVHD-related symptoms using the Lee Symptom Scale. On-target activity of axatilimab was suggested by the decrease in skin CSF-1R-expressing macrophages.
CONCLUSION: Targeting profibrotic macrophages with axatilimab is a therapeutically promising novel strategy with a favorable safety profile for refractory cGVHD
Standardizing definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism in allogeneic hematopoietic cell transplantation: A report on behalf of the American Society for Transplantation and Cellular Therapy
Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for certain hematologic malignancies and nonmalignant diseases. The field of allo-HCT has witnessed significant advances, including broadening indications for transplantation, availability of alternative donor sources, less toxic preparative regimens, new cell manipulation techniques, and novel GVHD prevention methods, all of which have expanded the applicability of the procedure. These advances have led to clinical practice conundrums when applying traditional definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism, because these may vary based on donor type, cell source, cell dose, primary disease, graft-versus-host disease (GVHD) prophylaxis, and conditioning intensity, among other variables. To address these contemporary challenges, we surveyed a panel of allo-HCT experts in an attempt to standardize these definitions. We analyzed survey responses from adult and pediatric transplantation physicians separately. Consensus was achieved for definitions of neutrophil and platelet recovery, graft rejection, graft failure, poor graft function, and donor chimerism, but not for delayed engraftment. Here we highlight the complexities associated with the management of mixed donor chimerism in malignant and nonmalignant hematologic diseases, which remains an area for future research. We recognize that there are multiple other specific, and at times complex, clinical scenarios for which clinical management must be individualized
Glycoprotein YKL-40: a novel biomarker of chronic graftvs- host disease activity and severity?
Aim To investigate whether increased YKL-40 levels positively
correlate with graft-vs-host disease (cGVHD) activity
and severity and if YKL-40 could serve as a disease biomarker.
Methods This case-control study was conducted at the
University Hospital Centre Zagreb from July 2013 to October
2015. 56 patients treated with hematopoietic stem
cell transplantation (HSCT) were included: 35 patients with
cGVHD and 21 without cGVHD. There was no difference
between groups in age, sex, median time from transplant
to study enrollment, intensity of conditioning, type of donor,
or source of stem cells. Blood samples were collected
at study enrollment and YKL-40 levels were measured with
ELISA. Disease activity was estimated using Clinician’s Impression
of Activity and Intensity of Immunosuppression
scales and disease severity using Global National Institutes
of Health (NIH) score.
Results YKL-40 levels were significantly higher in cGVHD
patients than in controls (P = 0.003). The difference remained
significant when patients with myelofibrosis were
excluded from the analysis (P = 0.017). YKL-40 level significantly
positively correlated with disease severity (P < 0.001;
correlation coefficient 0.455), and activity estimated using
Clinician’s Impression of Activity (P = 0.016; correlation coefficient
0.412) but not using Intensity of Immunosuppression
(P = 0.085; correlation coefficient 0.296).
Conclusion YKL-40 could be considered a biomarker of
cGVHD severity and activity. However, validation in a larger
group of patients is warranted, as well as longitudinal
testing of YKL-40 levels in patients at risk of developing
cGVHD
Patterns of infectious complications in acute myeloid leukemia and myelodysplastic syndromes patients treated with 10-day decitabine regimen
Refined National Institutes of Health response algorithm for chronic graft-versus-host disease in joints and fascia
Encouraging Results of a Phase II Trial of Inhaled Fluticasone Propionate, Azithromycin, and Montelukast (FAM) May Maintain Lung Function in Bronchiolitis Obliterans Syndrome (BOS) after Hematopoietic Cell Transplantation
Biomarker Panel for Chronic Graft-Versus-Host Disease
PURPOSE:
To identify diagnostic and prognostic markers of chronic graft-versus-host disease (cGVHD), the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT).
PATIENTS AND METHODS:
Using a quantitative proteomics approach, we compared pooled plasma samples obtained at matched time points after HCT (median, 103 days) from 35 patients with cGVHD and 18 without cGVHD (data are available via ProteomeXchange with identifier PXD002762). Of 105 proteins showing at least a 1.25-fold difference in expression, 22 were selected on the basis of involvement in relevant pathways and enzyme-linked immunosorbent assay availability. Chemokine (C-X-C motif) ligand 9 (CXCL9) and suppression of tumorigenicity 2 (ST2) also were measured on the basis of previously determined associations with GVHD. Concentrations of the four lead biomarkers were measured at or after diagnosis in plasma from two independent verification cohorts (n = 391) to determine their association with cGVHD. Their prognostic ability when measured at approximately day +100 after HCT was evaluated in plasma of a second verification cohort (n = 172).
RESULTS:
Of 24 proteins measured in the first verification cohort, nine proteins were associated with cGVHD, and only four (ST2, CXCL9, matrix metalloproteinase 3, and osteopontin) were necessary to compose a four-biomarker panel with an area under the receiver operating characteristic curve (AUC) of 0.89 and significant correlation with cGVHD diagnosis, cGVHD severity, and nonrelapse mortality. In a second verification cohort, this panel distinguished patients with cGVHD (AUC, 0.75), and finally, the panel measured at day +100 could predict cGVHD occurring within the next 3 months with an AUC of 0.67 and 0.79 without and with known clinical risk factors, respectively.
CONCLUSION:
We conclude that the biomarker panel measured at diagnosis or day +100 after HCT may allow patient stratification according to risk of cGVHD
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