B-Cell Depletion for Two Years after Autologous Stem Cell Transplant Reduces Lymphoma Relapse but Induces Prolonged Hypogammaglobulinemia beyond the Rituxan Maintenance Period.

Although autologous stem cell transplant (ASCT) may benefit patients with relapsed or high risk non-Hodgkin’s lymphoma (NHL), many patients still relapse and die of their disease. Most relapses occur during the first three years after transplant. In an attempt to reduce disease relapses, we have applied a maintenance regimen to patients after ASCT for B-cell NHL. In this regimen, all patients received low dose rituximab infusion (375 mg/m2 for one day only) every three months starting D+100 for a total of 2 years or until disease relapse. We reasoned that rituxan infusion given for only one day every three months may be sufficient to prevent disease relapse during this post-transplant period when any residual tumor bulk is likely low. Fifteen patients (eight men, seven women) with high-risk B-cell lymphoma have been treated. Their diagnoses: advanced mantle cell lymphoma in first complete remission (CR1) (8), refractory advanced marginal zone lymphoma (2), refractory follicular large cell lymphoma (1), high risk T-cell rich B-cell NHL in CR1 (1), Stage IV diffuse large cell lymphoma in CR1 (1) and relapsed B-cell NHL in CR2 (2). The median age was 59 years (range 38–72 years). CR was achieved using R-CHOP (10) or R-DHAP/R-ICE (5) and autologous hematopoietic stem cells were harvested during hematopoietic recovery from the last course of chemo-immunotherapy. With a median follow-up of 46 months (range 12–66) for the group and 47 months (range 16–66) for patients with advanced mantle cell lymphoma, the projected 5.5 years relapse-free survival for the group is 100% and the overall survival 80%. Two patients with mantle cell lymphoma died, one due to metastatic breast cancer and another a stroke at 40 and 41 months respectively. Unlike patients who underwent ASCT without rituximab, in whom B-cell recovery occurred between 3–6 months, we observed severe delays in the immunoglobulin recoveries in these patients (Figure 1). With a median immunoglobulin follow-up of 28 months (range 6–64), none of the fifteen patients showed normalization of total IgG. Two patients achieved a normalized total IgA and two a normalized total IgM. This hypogammaglobulinemia persists beyond the rituxan maintenance period. The median time to attainment of 75% normal level of immunoglobulin is 36 months for IgG, 48 months for IgA and not reached for IgM. The severe immunoglobulin deficiencies may be clinically relevant. Six of fifteen patients developed recurrent upper respiratory tract infection. No fatal infection was observed among any of the patients. Our results, therefore, suggest that low dose rituximab administration every three months after ASCT for high-risk B-cell lymphoma may prevent lymphoma relapse. However, this is associated with severe and prolonged delays in immunoglobulin recovery beyond the rituxan maintenance period. Careful monitoring of the immunoglobulin recovery and intervention as appropriate should be done routinely in these patients.

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