Rituximab for the Primary Treatment of Denovo Extensive Chronic Graft Versus Host Disease (GVHD)

• To estimate the requirement for and duration of systemic corticosteroids [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Steroids can be added to the treatment regimen if cGVHD progresses after 2 weeks of therapy and shows no improvement after 5 weeks. It a patient responds to steroids, they will be tapered every 4 days and should be discontinued in </= 4 weeks.
• Estimate the time to immunosuppression withdrawal [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  We will evaluate patients at 1, 2, 3, 6, 9, 12, 18 and 24 months from the start of treatment. Steroids can be added to the treatment regimen if cGVHD progresses after 2 weeks of therapy and shows no improvement after 5 weeks. It a patient responds to steroids, they will be tapered every 4 days and should be discontinued in </= 4 weeks.
• Estimate incidence of non-relapse mortality, disease-free and overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Patients will be evaluated at 1, 2, 3, 6, 9, 12, 18 and 24 months after the start of treatment.

Rituximab is an attractive agent to bring to the upfront treatment of chronic graft-versus-host disease (cGVHD) due to its favorable toxicity profile, its proven efficacy in the treatment of steroid-refractory cGVHD, and its ability to serve as a steroid sparing agent in other autoimmune diseases. The investigators hope to demonstrate that Rituximab has significant activity in cGVHD when utilized early in the course of the process. In addition, the investigators hope to show that the early use of Rituximab may allow for the earlier discontinuation of immunosuppression while obviating the need for long courses of systemic corticosteroids, which should translate into reduced treatment-related morbidity and mortality associated with cGVHD.

Although allogeneic hematopoietic stem cell transplantation (HSCT) remains an important curative therapy for many patients with hematological malignancies, treatment-related morbidity and mortality continue to be a major challenge. Chronic GVHD remains a major complication following allogeneic HSCT, with more than half of patients being affected. Although cGVHD has been associated with decreased relapse risk due to the well documented graft-versus-malignancy effect, it is also associated with significant adverse consequences in terms of morbidity, mortality, quality-of-life, and treatment costs associated with HSCT.

Rituximab has been investigated in a small number of patients with refractory cGVHD using the standard regimen of 375 mg/m2/week for 4 weeks. Ratanatharathorn et al. documented a sustained response in four of eight patients with steroid-refractory cGVHD with diffuse or localized sclerodermatous manifestations. Similarly, Canninga-vanDijk et al. and Okamoto et al. observed cases with clinical, laboratory and histological improvement after Rituximab treatment. Cutler et al. reported the results of their phase I-II study with Rituximab in 21 patients with steroid-refractory cGVHD. Treatment was well tolerated, and toxicity limited to infectious events, without any hematological toxicities and only a significant reduction in circulating immunoglobulins documented after therapy. Objective responses were documented in 70% of patients (including 10% complete response) primarily for those with skin and musculoskeletal involvement, allowing tapering, and in some cases withdrawing, of previous immunosuppressant therapy. A correlation between clinical response and decrease in the titre of antibodies against Y chromosome-encoded minor HLA antigens was shown. The results of these preliminary studies highlight the potential therapeutic activity of Rituximab on some cGVHD manifestations and a particularly high efficacy for skin involvement, including scleroderma. Recently, Zaja et al. confirmed the activity of Rituximab in refractory cGVHD in a larger series of 38 patients. Treatment was generally well tolerated and nearly 60% and 50% of patients had a clinical improvement of their skin and mouth manifestations, respectively. The median time-to-response was nearly 2 months and in some cases responses were durable. Responses were also detectable in some patients with eye, liver, lung, gut and joint involvement, allowing reduction and/or suspension of previous baseline immunosuppressive therapy in a significant number of patients

• Canninga-van Dijk MR, van der Straaten HM, Fijnheer R, Sanders CJ, van den Tweel JG, Verdonck LF. Anti-CD20 monoclonal antibody treatment in 6 patients with therapy-refractory chronic graft-versus-host disease. Blood. 2004 Oct 15;104(8):2603-6. Epub 2004 Jul 13.
• Ratanatharathorn V, Carson E, Reynolds C, Ayash LJ, Levine J, Yanik G, Silver SM, Ferrara JL, Uberti JP. Anti-CD20 chimeric monoclonal antibody treatment of refractory immune-mediated thrombocytopenia in a patient with chronic graft-versus-host disease. Ann Intern Med. 2000 Aug 15;133(4):275-9.
• Ratanatharathorn V, Ayash L, Reynolds C, Silver S, Reddy P, Becker M, Ferrara JL, Uberti JP. Treatment of chronic graft-versus-host disease with anti-CD20 chimeric monoclonal antibody. Biol Blood Marrow Transplant. 2003 Aug;9(8):505-11.
• Okamoto M, Okano A, Akamatsu S, Ashihara E, Inaba T, Takenaka H, Katoh N, Kishimoto S, Shimazaki C. Rituximab is effective for steroid-refractory sclerodermatous chronic graft-versus-host disease. Leukemia. 2006 Jan;20(1):172-3. No abstract available.
• Zaja F, Bacigalupo A, Patriarca F, Stanzani M, Van Lint MT, Filì C, Scimè R, Milone G, Falda M, Vener C, Laszlo D, Alessandrino PE, Narni F, Sica S, Olivieri A, Sperotto A, Bosi A, Bonifazi F, Fanin R; GITMO (Gruppo Italiano Trapianto Midollo Osseo). Treatment of refractory chronic GVHD with rituximab: a GITMO study. Bone Marrow Transplant. 2007 Aug;40(3):273-7. Epub 2007 Jun 4.
• Cutler C, Miklos D, Kim HT, Treister N, Woo SB, Bienfang D, Klickstein LB, Levin J, Miller K, Reynolds C, Macdonell R, Pasek M, Lee SJ, Ho V, Soiffer R, Antin JH, Ritz J, Alyea E. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood. 2006 Jul 15;108(2):756-62. Epub 2006 Mar 21.
• Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, Hansen JA, Appelbaum FR, Carpenter PA, Sanders JE, Kiem HP, Nash RA, Petersdorf EW, Moravec C, Morton AJ, Anasetti C, Flowers ME, Martin PJ. Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood. 2004 Dec 1;104(12):3501-6. Epub 2004 Aug 3.
• Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003 Apr;9(4):215-33. Review.

Inclusion Criteria:

• First episode of extensive chronic GvHD, without residual or concurrent acute GvHD.
• Age 18 - 75
• Any primary diagnosis requiring treatment by allogeneic HSCT
• Recipient of an allogeneic stem cell transplant (bone marrow, peripheral blood stem cell, or cord blood) from a related or unrelated donor, minimum 80 days ago
• Conditioning regimen: Myeloablative or non-myeloablative
• Patient gives written informed consent

Exclusion Criteria:

• Creatinine > 2.0 mg/dl
• Uncontrolled, active infection
• Recurrent or progressive malignancy
• Anticipated life expectancy of less than 1 year
• Pregnant or breast feeding
• Contraindications to administration of the study intervention or known inability of the patient to tolerate the study intervention
• Patients with perceived fixed, irreversible defects (pulmonary involvement, contractures, etc.) which would not be expected to improve with the study intervention
• Residual or concurrent acute GVHD