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

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

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