Rituximab Administration within 6 Months of T Cell-Depleted Allogeneic SCT is Associated with Prolonged Life-Threatening Cytopenias

Abstract

The monoclonal anti CD20 antibody Rituximab (RTX) is increasingly used in allogeneic stem cell transplantation (SCT) to treat lymphoproliferative disorders and chronic graft-versus-host disease (GVHD). RTX administration can be complicated by delayed and prolonged neutropenia, but the mechanism is unclear. We report the occurrence of profound cytopenias following RTX given in the conditioning regimen or early after T cell deplete-SCT to treat B cell lymphoproliferative disorders or c-GVHD. Between 2006–2009, 102 patients (median age 43, range 13–68 years), received a myeloablative matched-sibling T cell-deplete SCT for lymphoid or myeloid hematological disorders. Neutropenia occurring within 4 weeks of treatment developed in 16 of 17 patients given RTX within the first 190 days after SCT. Fourteen patients developed severe neutropenia (count < 0.5K/μL) lasting up to 10 months and 12 required hospitalization to treat severe neutropenic infections. Six of the 14 patients died of infection complicating GVHD treatment. Recovery of lymphocytes and immunoglobulins was also delayed, with a significantly lower ALC at 9 months and 12 months post SCT compared to patients with c-GvHD not treated with early RTX (p < 0.02). In contrast, patients receiving RTX one year after SCT experienced only moderate neutropenia 3–5 months after treatment lasting 10–20 days while maintaining ANC > 1.0 × 109/L. Although RTX rapidly controlled c-GVHD, we conclude that its administration early after T cell deplete-SCT is associated with prolonged profound and life-threatening cytopenias, and should be avoided.

Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial

“…41 Others have also demonstrated cytopenias commonly when rituximab was administered early after T-cell-depleted transplantation. 19,25 In addition, we did not note excess opportunistic infections despite persistent hypogammaglobulinemia, which was treated at investigator discretion. Because rituximab administration ended at 12 months from transplantation, B-cell recovery occurred in the majority of patients between 18 months and 2 years after transplantation.…”

“…B-cell-dependent processes have thus been implicated following several lines of evidence: antibodies against minor histocompatibility antigens have been associated with the occurrence of chronic GVHD 11 ; B-cell depletion in the peritransplantation period has been correlated with a reduction in chronic GVHD incidence 12 ; and most important, B-cell-depletion therapy with rituximab is effective in the therapy of established chronic GVHD. [13][14][15][16][17][18][19] In addition, murine models of chronic GVHD and bronchiolitis obliterans have implicated donor B-cell alloantibodies in the pathogenesis of this disease. 20 Much work has focused on the potential role of B cells in pathobiology of chronic GVHD.…”

EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT

“…9 In addition, the administration of anti-CD20 Abs represents a potent tool to unselectively destroy the viruses target cells finally limiting B-cell proliferation and reducing the risk of malignant transformation but also interfering with the immune reconstitution. 35 In the pre-emptive setting, the administration of the anti-CD20 Ab rituximab has been reported to be capable of preventing EBV-PTLD in roughly 90% of the cases. Applying rituximab in therapeutic intention, however, was associated with a reduced but still remarkable response rate of 63%.…”

Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines

“…69 Low risk of EBV-PTLD was observed also after the use of post-transplant high-dose cyclophosphamide, 23 or sirolimus as GvHD prophylaxis. 20 Since rituximab treatment after allo-HSCT has been related to an increased risk of life-threatening cytopenias 71 and bacterial infections, …”