ABSTRACT
The impact of Janus kinase (JAK) 1/2 inhibitor therapy before allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into 5 groups: (1) clinical improvement (n = 23), (2) stable disease (n = 31), (3) new cytopenia/increasing blasts/intolerance (n = 15), (4) progressive disease: splenomegaly (n = 18), and (5) progressive disease: leukemic transformation (LT) (n = 13). Overall survival (OS) at 2 years was 61% (95% confidence interval [CI], 49% to 71%). OS was 91% (95% CI, 69% to 98%) for those who experienced clinical improvement and 32% (95% CI, 8% to 59%) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors (P = .03), dynamic international prognostic scoring system score (P = .003), and donor type (P = .006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, 2 patients developed serious adverse events necessitating delay of HCT and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose ≥6 days before conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post-transplantation outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy before HCT were particularly encouraging, and need further prospective validation.
Subject(s)
Hematopoietic Stem Cell Transplantation , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Primary Myelofibrosis , Protein Kinase Inhibitors , Adult , Aged , Allografts , Disease-Free Survival , Female , Humans , Middle Aged , Primary Myelofibrosis/enzymology , Primary Myelofibrosis/mortality , Primary Myelofibrosis/therapy , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Retrospective Studies , Survival RateABSTRACT
BACKGROUND: Resurgences of Staphylococcus aureus infection continue globally, with antibiotic resistance increasing dramatically, making these infections more difficult to treat. S. aureus epidemics impose public health threats, and economic burdens on health care costs worldwide, presenting challenges modern medicine struggles to control. OBJECTIVE: In order to answer today's call for effective treatments against S. aureus, we evaluated and compared various botanical extracts that have historically been suggested as useful for their antimicrobial properties against S. aureus. DESIGN: Briefly, S. aureus cultures were treated with selected botanical extracts and the minimum inhibitory concentration (MIC) determined. In addition, to obtain more quantitative measures on bacterial growth, 24-hour growth studies were done to examine the temporal activity and stability of various botanicals on bacterial replication. RESULTS: The antimicrobial activity observed for the botanical extracts used in this comparative evaluation of efficacy included both bacteriostatic and bacteriocidal activity against S. aureus. Highly effective botanicals including Salvia officinalis, Eucalyptus globulus, Coleus forskohlii, Coptis chinensis, Turnera diffusa, and Larrea tridentata exhibited MIC values ranging from 60 to 300 µg/mL and a 10(6)-fold reduction in bacterial replication. Arctostaphylos uva-ursi and Allium sativum were slightly less effective, exhibiting MIC values ranging from 90 to 400 µg/mL and a 10(5)-fold reduction, while Anemopsis californica gave MIC value of 360 µg/mL and a 10(4)-fold reduction in bacterial replication. Many botanicals, especially at lower doses, had an initial inhibitory effect followed by a recovery in bacterial replication. Such botanicals included E. globulus, C. chinensis, T. diffusa, A. californica, and Berberis vulgaris. CONCLUSIONS: Our data demonstrate that S. officinalis, E. globulus, C. forskohlii, A. uva-ursi, C. chinensis, T. diffusa, A. californica, A. sativum, and L. tridentata all show promising direct antimicrobial activity against S. aureus. For many of these botanicals, strong bacteriocidal activity was observed at higher concentrations, but even at lower concentrations, bacteriostatic activity was evident. Other botanicals including B. vulgaris, Baptisia tinctoria, and Glycyrrhiza glabra showed moderate activity against S. aureus, while Schisandra chinensis, Echinacea angustifolia, and Polygonum multiflorum were shown to be ineffective.
