Rituximab Administration within 6 Months of Allogeneic SCT Carries Risk of Prolonged and Life Threatening Cytopenias.

Abstract 793

The use of the monoclonal anti-CD20 antibody Rituximab to treat chronic graft-versus-host disease (c-GVHD) occurring after stem cell transplantation (SCT) is generally effective and well tolerated. However this agent can cause neutropenia. Here we describe cytopenias following Rituximab treatment in patients developing c-GVHD after allogeneic SCT. Between 2006-2009, 50 patients received a myeloablative matched-sibling T-cell depleted or selectively-depleted SCT for a variety of hematological malignancies, mainly AML, ALL, CML, and MDS. Median age was 43 years (range, 13 – 68), and median CD34+ cell dose was 6.1 × 10⁶/kg (range, 3.1-10.1). Thirty-one patients developed acute GvHD; 13 grade 1, 16 grade 2, and 1 patients with grade 3. Twenty-seven patients had chronic GvHD (17 limited, 10 extensive). Nineteen patients were treated with Rituxmab; 15 within 180 days, and 4 between 1- 7 years following SCT. Patients receiving Rituximab one year after SCT experienced only moderate neutropenia 3-5 months after treatment lasting 10-20 days while maintaining ANC > 1.0× 10⁹/L. In contrast, neutropenia occurring within 4 weeks of treatment occurred in all 15 patients given Rituximab within the first 180 days after SCT. Twelve of these patients developed severe neutropenia (ANC < 0.5K/μL) lasting 2-8 months in duration, with 10 out of the 12 patients requiring hospitalization to treat neutropenic infections. Six of the 12 patients died of infection complicationg GVHD treatment. Six patients treated with Rituximab within 120 days of SCT experienced the worse complications. All 6 developed neutropenia within 4 weeks of treatment lasting 3- 7 months. Five required recurrent hospitalization for neutropenia associated infections; one died of invasive fungal pneumonia, one died of gram negative bacteremia and relapsed disease, and one required prolonged intubation for parainfluenza type 3 infection associated ARDS. Recovery of both neutrophil and lymphocytes was extremely delayed in this group, with a significantly lower ANC and ALC at 9 months and 12 months post SCT compared to patients with GvHD not treated with Rituximab (p < 0.02). Investigation of the etiology of neutropenia revealed evidence of T cell clonality in 4 patients; 2 patients were diagnosed with LGL with evidence of restricted rearrangement patterns detected by PCR, one patient had 95% NK cell dominated bone marrow infiltrate seen on flow cytometry, and one patient had idiopathic thrombocytopenia purpura and responded to appropriate immunosuppression. Although Rituximab resulted in rapid control of c-GVHD, we conclude that administration of Rituximab early after SCT is associated with prolonged, possibly autoimmune mediated profound cytopenias, and should be avoided.