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Safety and efficacy of rituximab in steroid-refractory chronic GVHD

Bone Marrow Transplantation volume 48, pages 734–736 (2013)Cite this article

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Chronic GVHD (cGVHD) is the most important determinant of late morbidity and mortality in long-term survivors after allo-SCT. Because of the increasing age of recipients, the use of alternative donors and the more frequent use of G-CSF-mobilized PBSCs as stem cell source, cGVHD is increasingly becoming a matter of concern. cGVHD patients who fail first-line therapy have a poor outcome. Recent data suggested that B lymphocytes may have a major role in cGVHD pathophysiology.1 Several authors reported promising findings with the use of rituximab for salvage therapy of cGVHD.2 However, late onset neutropenia (LON) has been suggested by some investigators as a potential complication associated with rituximab therapy, especially in the context of allo-SCT.3 This retrospective study aimed to report the safety features of rituximab salvage therapy in a series of 18 consecutive patients with refractory cGVHD treated between 2008 and 2010 at the University Hospital of Nantes (CHU de Nantes, France). Patients, transplant, graft and GVHD characteristics are summarized in Table 1. Written informed consent was obtained from each patient and donor. The study was performed according to the principles of the declaration of Helsinki. All allogeneic grafts were obtained from HLA-A, HLA-B, HLA-C, HLA-DR and HLA-DQ-matched donors. A single HLA mismatch of 10 (at HLA-Cw) was allowed at the allelic level. HLA-DP typing was not routinely performed at the time of this analysis. Supportive care and antimicrobial prophylaxis were reported previously.4, 5 For GVHD prophylaxis, patients in this cohort received either CsA alone (n=5; 28%) or CsA and mycophenolate mofetil (MMF, n=9; 50%), or CsA and MTX (n=4; 22%). CsA was administered at a dose of 3 mg/kg/day by continuous i.v. infusion starting from day 3 or 2 before graft infusion. MMF was given at a fixed oral dose of 2 g/day. MMF was tapered over 4 weeks starting from day +60 and CsA from day +90 if no GVHD appeared. During the whole study period, supportive care and CMV infection management was the same. Acute and cGVHD were evaluated according to the Seattle standard criteria. Data were computed using the Prism 5.0 (Graphpad Software Inc., La Jolla, CA, USA).

Table 1 Patients, graft and GVHD characteristics
Full size table

In this cohort, the median age was 54 years (range 21–68) with 61% males, and 50% of patients having a myeloid malignancy. At the time of rituximab initiation, all patients presented with extensive and refractory cGVHD, which received and failed (in addition to corticosteroids) several lines of prior immunosuppressive therapy: CYA (n=14), MMF (n=6), imatinib (n=2), dasatinib (n=1), low-dose MTX (n=2) or PUVA therapy (n=3). The median time between cGVHD diagnosis and rituximab therapy was 5 (range, 0.5–38) months. On an intention to treat, patients were scheduled to receive rituximab 375 mg/m2/week for 4 consecutive weeks. All patients received paracetamol plus antihistaminic plus corticosteroids as a pre-medication before therapy to minimize infusion-related manifestations. The median number of rituximab infusions was 4 (range, 1–16). All patients, but four, received the scheduled four infusions of rituximab. One patient (5.5%) had to discontinue treatment after one infusion because of worsening cGVHD, whereas two patients (11%) with a partial response received a second cycle of rituximab according to the attending physician's decision. Finally, one patient (5.5%) completed the four courses treatment and received subsequent maintenance therapy for 6 months (one rituximab infusion per month).

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Acknowledgements

We would like to thank the nursing staff for providing excellent care for our patients. We also thank the ‘Région Pays de Loire’, the ‘Association pour la Recherche sur le Cancer (ARC)’, the ‘Fondation de France’, the ‘Fondation contre la Leucémie’, the ‘Agence de Biomédecine’, the ‘Association Cent pour Sang la Vie’ and the ‘Association Laurette Fuguain’, and the IRGHET for their generous and continuous support for our clinical and basic research work.

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Authors and Affiliations

  1. Centre Hospitalier et Universitaire (CHU) de Nantes, Service d’Hématologie Clinique, Nantes, France

    A Clavert, P Chevallier, T Guillaume, J Delaunay, S Le Gouill, B Mahe, V Dubruille, T Gastinne, N Blin, P Moreau & M Mohty

  2. Université de Nantes and INSERM CRNCA UMR 892, Nantes, France

    S Le Gouill, P Moreau & M Mohty

  3. Centre d’Investigation Clinique en Cancérologie (CI2C), CHU de Nantes, Nantes, France

    S Le Gouill & M Mohty

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  1. A Clavert
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Correspondence to M Mohty.

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Competing interests

Mohamad Mohty and Steven Le Gouill received lectures honoraria and research support from Roche whose product is discussed in this study. The other authors report conflict of interests that have a direct link with the subject matter or products discussed in this study.

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Clavert, A., Chevallier, P., Guillaume, T. et al. Safety and efficacy of rituximab in steroid-refractory chronic GVHD. Bone Marrow Transplant 48, 734–736 (2013). https://doi.org/10.1038/bmt.2012.203

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