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B-cell depletion for 2 years after autologous stem cell transplant for NHL induces prolonged hypogammaglobulinemia beyond the rituximab maintenance period

Although autologous stem cell transplant (ASCT) may benefit patients with relapsed or high-risk nonHodgkin lymphoma (NHL), many patients still relapse and die of their disease. Most relapses occur within three years after transplant. In an attempt to reduce disease relapses, we have administered maintenance rituximab infusions to these patients. In this approach, all patients received rituximab infusions (375 mg/m for one day only) every 3 months starting Dþ 100 after ASCT for a total of eight infusions or until disease relapse. We reasoned that rituximab infusions given for only 1 day every 3 months may be sufficient to prevent disease relapse during this post-transplant period when any residual tumor bulk is likely low. We observed that low dose maintenance rituximab given to these patients over a 2-year period after ASCT was associated with severe delays in the immunoglobulin recoveries in these patients, during the 2-year periods when the patients were receiving the rituximab maintenance therapy [1]. However, it remained to be determined how long the hypogammaglobulinemia would persist when more patients are studied in longer follow-up periods. Here, we have analyzed the immunoglobulin recovery in the 15 consecutive patients (eight men, seven women) with high-risk B-cell NHL who have received the post-transplant maintenance rituximab therapy. Their diagnoses were advanced mantle cell lymphoma (MCL) in CR1 (n1⁄4 8), refractory advanced marginal zone lymphoma (n1⁄4 2), refractory follicular large cell lymphoma (n1⁄4 1), high risk T-cell rich B-cell NHL in CR1 (n1⁄4 1), Stage IV diffuse large cell lymphoma in CR1 (n1⁄4 1) and B-cell NHL in CR2 (n1⁄4 2). The median age was 59 years (range 38 – 72 years). CR was achieved using R-CHOP (n1⁄4 10) or R-DHAP/R-ICE (n1⁄4 5) and autologous stem cells harvested during hematopoietic recovery from the last course of R-CHOP or the first course of R-DHAP/R-ICE. Conditioning regimens for the transplant consisted of high dose melphalan (n1⁄4 14) or total body irradiation, cyclophosphamide and thiotepa (n1⁄4 1). In keeping with the preliminary observations we previously made in B-cell NHL [1] and multiple myeloma [2] and unlike patients who underwent ASCT without rituximab in whom B-cell recovery occurred between 3 and 6 months [3 – 5], severe delays in the immunoglobulin recoveries were observed in all 15 patients (Figure 1). In addition to our previous findings, these defects were observed beyond the rituxan maintenance periods. With a median immunoglobulin follow-up of 28 months (range 6 – 64), none of the 15 patients showed normalization of total IgG. Two patients normalized total IgA and two patients total IgM. The hypogammaglobulinemia persisted beyond the rituximab maintenance period. The median time from transplant to attainment of 75% normal IgG level was 36 months and 75% normal IgA level was 48 months.