Nilotinib as Salvage Therapy In Patients with Chronic Graft Versus Host Disease
Authors: Terriou Louis , Magro Leonardo , De Berranger Eva , Jouet Jean-Pierre , Yakoub-Agha Ibrahim 
Published: October 2019

Abstract
Abstract 2329
The mainstay of treatment for Chronic Graft Versus Host Disease (cGVHD) is steroids, but there are limited treatment options for steroid refractory cGVHD particularly in its sclerotic and fibrotic form (ScGVHD). We initially reported the efficacy and safety of imatinib mesylate (IM), a first generation tyrosine kinas' inhibitor, as a salvage therapy for ScGVHD patients (Magro L, et al. Blood, 2009). However, about 50% of the patients (Pts) became refractory or intolerant to IM. Nilotinib, a second generation tyrosine kinas' inhibitor, is labelled for IM resistant and advanced Chronic Myeloid leukemia and could be an attractive alternative to IM especially in refractory and intolerant patients.
We studied the clinical outcomes of 7 Pts who developed extensive ScGVHD at our institution. Among them, 5 had received prior IM. Patients' characteristics and transplantation modalities are summarised in table 1. Acute and cGVHD was scored according to standard criteria. All pts but one failed at least 3 lines of prior systemic immunosuppressive therapy.
CGVHD features, responses to nilotinib and patients' outcomes are described in table 2.
To our knowledge, this is the first report relating the impact of nilotinib on cGVHD setting. Although, tolerance to nilotinib has not been as good as we could expect, this drug appeared to be effective with manageable side-effects in some patients. One of the limitations of this study, is that nilotinib was used in patients with advanced cGVHD. Prospective studies are, therefore, warranted to investigate the efficacy and the tolerance of nilotinib in patients with less advanced disease.
Table 1. Patients and transplantation characteristics Case N Age, y Sex, R/D diagnosis Conditioning/Stem cell source GVHD prophylaxis cGVHD sites Immunosuppression before nilotinib 1 30.5 M/F ALL MAC/BM CSA-MTX Mouth, skin eyes,liver CS-CSA-MMF-RTX-EVE 2 31 F/M AA MAC/PBSC CSA-CS-MMF Skin, mouth, eyes,bronchiolitis,joint contacture CS-TAC-MMF-EVE-IM 3 51.6 M/M HODG RIC/PBSC CSA-MTX Skin, mouth CS-CSA-MMF-IM 4 45.3 M/M AML MAC/BM CSA-MTX Skin, mouth, bronchiolitis, joint contracture CS-CSA-MMF-INO-ECP-RTX-AZA-IM 5 57.5 M/M MDS MAC/BM CSA-MTX Skin, bronchiolitis, joint contracture CS-CSA-MMF-RTX-ECP-IM 6 50.3 M/F CML MAC/BM CSA-MTX Skin, mouth, eyes, liver, joint contracture CS-CSA-MMF-ECP-IM 7 53.3 M/M AML MAC/BM CSA-MTX Skin none R/D: recipient/donor; aGVHD: acute graft versus host disease; cGVHD: chronic graft versus host disease; CML: chronic myeloid leukemia; MAC: myeloablative conditioning; BM: bone marrow; PBSC: peripheral blood stem cells; CSA: ciclosporine A; CS: corticosteroids, RIC: reduced intensity conditioning; MMF: mycophenolate mofetyl; AZA: azathioprine; MDS: myelodysplastic syndrome; MTX: metothrexate; RTX: rituximab; ECP: extracorporal photophere-sis; INO: inolimomab; HODG, hodgkin; AA: aplastic anemia; TAC: tacrolimus, ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia.; EVE: everolimus and IM: imatinib mesylate. Table 2. Outcome after nilotinib therapy Case N° Maximal tolerate dose of nilotinib, mg Nilotinb therapy duration at last follow up, mo Side effects/nilotinib discontinuation at last follow up cGVHD status at 2 mo of nilotinib cGVHD response in other organs at last follow up cGVHD status at last follow up Overall follow-up, mo Status at last follow up 1 800 3 None/yes failure – PR 69 alive 2 400 0.5 Pain swallowing, diarrhea/yes failure – progressive 46.8 Died of infection 3 800 2.5 Nausea, diarrhea/yes PR Mouth PR (>90%) 73.1 alive 4 800 7.5 None/yes MR Mouth progressive 72 alive 5 800 1 Cough, dyspnea, muscle cramps/yes PR bronchiolitis PR 59 alive 6 800 0.5 Headache, diarrhea/yes failure – PR 60.3 alive 7 800 7.5 None/no PR – PR 32 alive cGVHD indicates chronic graft versus host disease; PR, partial response and MR, minor response.

Disclosures:
No relevant conflicts of interest to declare.