After allogeneic hematopoietic cell transplantation (HCT), approximately 8% of patients develop a syndrome of cutaneous sclerosis which can severely affect their mobility and quality of life, and is often refractory to standard immune suppressive therapies. Recent clinical and translational data suggest that alloimmune B cells and in particular, agonistic antibodies against platelet derived growth factor receptor (PDGFR), may be responsible for cutaneous collagen deposition. We hypothesize that targeting this pathogenic mechanism using either rituximab (a FDA-approved humanized anti-CD20 antibody) to eliminate alloimmune B cells or imatinib (a FDA-approved tyrosine kinase inhibitor) to block PDGFR activity will effectively treat cutaneous sclerosis. To test this hypothesis, we propose a 70 patient two-arm phase II crossover trial of imatinib and rituximab to determine efficacy against HCT-associated cutaneous sclerosis. Correlative studies of skin biopsies and blood samples will confirm target specificity. Blood measurements include: 1) B cell subsets, 2) B cell stimulatory factors and 3) allo- and auto-antibody changes. Skin assays include: 1) phosphorylation status of PDGFR, ABL, and other tyrosine kinase receptors, 2) B cell infiltration, antibody deposition, and complement activation, 3) collagen deposition, and 4) gene expression studies. Ancillary studies will evaluate clinical assessment tools and patient-reported measures. This project will provide insights into the pathogenesis of and best treatment for HCT-associated cutaneous sclerosis.
Cutaneous sclerosis (skin thickening causing decreased flexibility) poses a vexing clinical problem with high morbidity due to ineffective therapies. By treating 70 people with HCT-associated cutaneous sclerosis with either rituximab or imatinib and testing skin and blood samples, we hope to learn how to prevent the disease or develop better treatments. Knowledge gained from these studies may help us to treat other patients with sclerosis
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