Prospective evaluation of sequential treatment of sclerotic chronic graft versus host disease with rituximab and nilotinib

Abstract

Sclerotic chronic graft vs. host disease (cGVHD) still has a large impact on morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). We performed the first prospective study to test whether sequential therapy of the anti-CD20 antibody rituximab followed by 6 months treatment with tyrosine kinase inhibitor nilotinib is a favorable treatment strategy for patients with sclerotic cGVHD. Twenty-nine patients were included, 24 were available for analysis. We observed objective responses in 71% of patients (two patients CR, 15 patients PR). Moreover, two out of five patients suffering from severe ulcerations showed complete resolution of ulcers. Observed responses lasted until the end of study follow-up. The majority of responding patients could reduce daily corticosteroid dose with more than 50%. Furthermore, CD5+ B-cells are significantly lower (p = 0.007) in responding patients at baseline, proposing a new biomarker predictive for response. In conclusion, sequential treatment of rituximab followed by nilotinib associates with a very high response rate in this difficult to treat patient population. CD5+ B-cells could assist in guiding treatment choices and might be a first step toward more personalized cGVHD treatment. This trial was registered at the Dutch clinical trial registry as NTR1222.

Modifying Graft-versus-Host Disease in a Humanized Mouse Model by Targeting Macrophages or B-Cells

“…Tregs have a suppressive effect by downregulating the proliferative activity of T-cells [2]. For B-cells, a positive influence on GvHD activity has been noted when using Rituximab, a B-cell-depleting antibody [3–6]. Rituximab was originally developed to treat non-Hodgkin lymphomas [4, 7] but is successful in a variety of autoimmune diseases as well [8].…”

Rational use of chronic graft-versus-host treatment alternatives: A systematic review

“…No data suitable for the study criteria were found for dasatinib. One prospective study was found on nilotinib, and it was given sequentially with rituximab [38].…”

New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions

“…Binding of rituximab to CD20 results in destruction of the lymphocytes by several mechanisms, including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and direct apoptosis ( 124 , 125 ). It is usually employed at 375 mg/m 2 weekly for four doses; it represents the mAb that is most frequently employed in cGvHD treatment ( 126 – 128 ), including Scl-cGvHD ( 129 ) in addition to other types of cGvHD ( 37 , 130 , 131 ). Recently, it has been reported that rituximab offered 41% of responses at 1 year, 69% at 2 years, and 77% at 3 years.…”

“…Finally, combining B cell depletion with rituximab (375 mg/m 2 , once per week, for 4 weeks) followed by TKI inhibition with nilotinib (200 mg, twice daily, for 6 months) have shown a more profound and long-lasting response (8% CR, 63% PR) with a higher survival rate (96.6% in 1 year) in patients with Scl-cGvHD ( 129 ).…”