Bone Marrow Transplantation (2012) 47, 737-738
`© 2012 Macmillan Publishers Limited All rights reserved 0268-3369/12
`
`www.nature.com/bmt
`
`LETTER TO THE EDITOR
`
`Lack of efficacy of rituximab in refractory sclerodermatous chronic GVHD
`
`(2012) 47, 737-738;
`Bone Marrow Transplantation
`doi: 10.1038/bmt.2011.150; published online 25 July 2011
`
`Advances in the understanding of cGVHD have implicated
`B lymphocytes in its pathophysiology.' A number of
`studies have explored the use of the antiCD20 MoAb
`rituximab
`in
`the
`treatment of patients with steroid(cid:173)
`refractory cGVHD. These studies yielded varying findings
`regarding organ-specific responses. Data on cutaneous
`cGVHD are available from two prospective studies and
`four retrospective studies involving a total of 67 patients so
`far. In a recent review and meta-analysis, Mohamed
`et al. 1 reported that responses were impressive in cases
`of sclerodermatous or lichenoid cutaneous cGVHD. We
`detail our experience with
`the use of rituximab
`in
`sclerodermatous GVHD, which is different from that
`reported previously.
`We retrospectively reviewed the medical records of
`patients with steroid-refractory cutaneous cGVHD treated
`with rituximab. Patients were
`treated with rituximab
`375 mg/m 2 weekly for three to four doses. Determination
`of response was based on the records of the clinician
`and whether additional immunosuppressive agents were
`added after rituximab
`therapy for non-response or
`progression of disease. We followed the response criteria
`given by Zaja et al.: 1 CR in case of complete resolution
`of cGVHD manifestations; PR in cases of 50% or more
`regression of cGVHD manifestations; no response (NR)
`less than 50% improvement, or exacerbation during or
`after therapy.
`Nine patients received rituximab for cGVHD. All were
`males with a median age of 53 (34-61) years (Table 1).
`Eight patients had extensive cGVHD with sclerodermatous
`involvement of skin and s.c.
`tissues, and one had
`erythroderma. All patients had at least one other organ
`involved along with the cutaneous GVHD. Four patients
`had two or more organs affected (Table 1). The median
`time from transplantation to the diagnosis of chronic
`GVHD was 14 months (range 6-60 months). The median
`time from chronic GVHD diagnosis to rituximab admin(cid:173)
`istration was 16 months (range 2-61), and the median
`time from transplantation to rituximab administration
`was 33 months (range 13-81 ). The first line of treatment
`was prednisolone in all patients. Subsequent treatments
`included a variety of immunosuppressive drugs such as
`CY A, tacrolimus, mycophenolate, sirolimus, etanercept,
`acitretin, UV B radiation, extracorporeal photopheresis
`and romidepsin, or combinations of those, generally
`combined with prednisolone. Patients had received these
`drugs for a median of 17 months (range 3-55 months)
`before starting rituximab. Rituximab was used at the
`
`conventional dose of 375 mg/m 2 weekly. It was the third
`line of treatment for two patients and the fourth line or
`more in seven cases. Five patients received three and four
`patients received four i.v. infusions. The median follow-up
`after rituximab was 19 months (range 1-27 months).
`During rituximab administration, patients continued on
`baseline immunosuppressive therapy. None of our patients
`achieved a complete or partial response. Although there
`was an initial temporary improvement in two patients
`during the first couple of months, both patients failed to
`sustain their response. Six months after initiation of
`rituximab, there was no improvement in four patients,
`and progression of disease with extension of sclerosis in
`two patients. At the end of one year, among the six alive,
`sclerosis had progressed in three, remained stable in two
`patients, with one patient showing slight improvement
`with softening of skin in one area. Four patients were
`treated with additional immunosuppressive agents such as
`acitretin, imatinib and MTX following the administration
`of rituximab.
`A prospective study in Japan,3 observed histological
`improvement
`in
`three patients with sclerodermatous
`cGVHD who had responses occurring between 60 and 90
`days from initiation of therapy. Maximum follow-up in
`this study was only 4 months, and the patients who showed
`improvement had only ocular and oral
`involvement
`together with the skin. Cutler et al. 4 reported a decrease
`in median body surface area involved with sclerodermatous
`GVHD from 35 to 25% after two cycles of therapy,
`followed by a further decrease to 20% at 1 year after the
`initiation of rituximab. The outcome in our patients has
`been disappointing. This may be related to the use of the
`medication in a different population cohort. Our patients
`had a severe form of the disease and were started on
`rituximab as a third or more line of treatment, and
`compared with the other studies mentioned, the median
`transplantation-rituximab interval in our cohort was higher
`(23/33 months), although the interval between the onset of
`GVHD and rituximab was comparable (13.8/16 months). 4
`All had at least one other internal organ involved together
`with extensive sclerodermatous skin involvement and other
`comorbidities. It could also be possible that more than one
`cycle of rituximab (consisting of 4 weekly doses) should be
`used. In some cases, up to three courses of rituximab were
`used to elicit some response. 4 Finally, although the efficacy
`of rituximab in cGVHD is thought to be due to depletion
`of CD20 + B cells, other mechanisms not involving B cells
`might also be dominant in sustaining the dysregulated
`immune response in cGVHD leading to the cutaneous
`and systemic manifestations. 5 Further clinical studies are
`needed to evaluate more precisely the outcome ofrituximab
`in steroid refractory sclerodermatous cGVHD.
`
`Pharmacyclics Exhibit 2053_
`Sandoz v. Pharmacyclics
`IPR2019-00865
`
`

`

`738
`
`Letter to the Editor
`
`Conflict of interest
`
`The authors declare no conflict of interest.
`
`, DJ Gottlieb2
`
`·
`
`L George 1
`
`, B George 2
`
`3 and
`, M Hertzberg2
`3
`•
`
`P F ernandez-Peiias 1 3
`•
`1 Department of Dermatology, Westmead Hospital, Sydney,
`New South Wales, Australia;
`2 Department of Haematology, Westmead Hospital, Sydney,
`New South Wales, Australia and
`3 Sydney Medical School Westmead, The University of
`Sydney, Sydney, Neil' South Wales, Australia
`E-mail: Pablofernandezpenas@Jydney.edu.au
`
`References
`
`Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, Cutler C,
`Mohty M, Kumar A. Efficacy of rituximab in the setting of
`steroid-refractory chronic graft-versus-host disease: a systematic
`review and meta-analysis. Biol Blood Marrow Transplant 2009;
`15: 1005-1013.
`2 Zaja F, Bacigalupo A, Patriarca F, Stanzani M, Van Lint MT,
`Fili C et al. Treatment of refractory chronic GVHD with
`rituximab: a GITMO study. Bone Marrow Transplant 2007; 40:
`273-277.
`3 Okamoto M, Okano A, Akamatsu S, Ashihara E, Inaba T,
`Takenaka H et al. Rituximab is effective for steroid-refractory
`sclerodermatous chronic graft-versus-host disease. Leukemia
`2006; 20: 172-173.
`4 Cutler C, Miklos D, Kim HT, Treister N, Woo SB, Bienfang D
`et al. Rituximab for steroid-refractory chronic graft-versus-host
`disease. Blood 2006; 108: 756-762.
`5 Ratanatharathorn V, Ayash L, Reynolds C, Silver S, Reddy P,
`Becker M et al. Treatment of chronic graft-versus-host disease
`with anti-CD20 chimeric monoclonal antibody. Biol Blood
`Marrow Transplant 2003; 9: 505-511.
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`Bone Marrow Transplantation
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