Anti–Platelet-Derived Growth Factor Receptor Alpha Chain Antibodies Predict for Response to Nilotinib in Steroid-Refractory or -Dependent Chronic Graft-Versus-Host Disease

Abstract

Imatinib has clinical activity in chronic graft-versus-host disease (cGVHD), a significant complication of allogeneic hematopoietic cell transplant. Nilotinib is a tyrosine kinase inhibitor that targets the same receptors as imatinib but with different affinities. We tested the hypothesis that nilotinib is safe and has clinical activity in cGVHD. Thirty-three participants were enrolled in a phase I/II dose escalation and dose extension clinical trial of nilotinib for the treatment of steroid-refractory or- dependent cGVHD (ClinicalTrials.gov, NCT01155817). We assessed safety, clinical response, and pretreatment anti-platelet-derived growth factor receptor alpha chain (anti-PDGFRA) antibody levels. The 200-mg dose was identified as the maximum tolerated dose and used for the phase II dose extension study. At 6 months the incidence of failure-free survival (FFS), cGVHD progression, and nilotinib intolerance resulting in its discontinuation was 50%, 23%, and 23%, respectively. cGVHD responses in skin, joints, and mouth were observed at 3 and 6 months based on improvement in respective National Institutes of Health organ severity scores. Pretreatment anti-PDGFRA antibody levels ≥ .150 optical density as measured by ELISA correlated with longer FFS time (P < .0005) and trended with time until cGVHD progression (P < .06) but not drug intolerance. Nilotinib may be effective for corticosteroid-resistant or -refractory cGVHD in some patients, but its use is limited by intolerable side effects. Selection of patients with high pretreatment anti-PDGFRA antibody levels might improve the risk-to-benefit ratio of nilotinib and better justify its side effects.

Myeloablative vs reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chronic myeloid leukemia

“…[33][34][35][36][37] It is also possible that a higher frequency of TKI use after RIC allo-HCT for treatment or prevention of CML relapse may have curbed the cGVHD risk. [38][39][40] In multivariable analysis, no significant interaction was found between conditioning intensity and disease status at the time of allo-HCT. The survival outcomes in patients who were in AP or CP21 at allo-HCT were not significantly different between the conditioning cohorts.…”

Anti-Ro52 Autoantibodies Are Related to Chronic Graft-vs.-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation

“…Chronic GVHD is an autoimmune-like syndrome caused by the interactions of donor CD4 + T and B cells and production of IgG (7)(8)(9)(10)(11). Recently, antibodies have been reported to play an important role in the development of cGVHD (12)(13)(14)(15)(16)(17)(18)(19). Previous studies showed that donor B cellderived antibodies augmented the development of bronchiolitis obliterans and perpetuated cutaneous cGVHD in mice (7,9).…”

Outcomes and toxicity of allogeneic hematopoietic cell transplantation in chronic myeloid leukemia patients previously treated with second-generation tyrosine kinase inhibitors: a prospective non-interventional study from the Chronic Malignancy Working Party of the EBMT

“…GvHD was the leading cause of death with an incidence comparable to that observed in patients not treated with 2GTKIs [ 13 , 31 , 32 ] (50/383 patients,13%), followed by infections. Given the increasing experience on the efficacy of TKIs as GvHD treatment [ 39 – 41 ], the question of influence of the immunomodulatory potency of TKIs [ 42 – 48 ] on GvHD incidence and severity could be raised. Significantly lower incidence of cGvHD in patients pre-treated with imatinib compared with a historical group control has been reported [ 15 ], but it can be attributed to differences in GvHD prophylaxis and mainly a more frequent use of antithymocyte globulin in imatinib group.…”