Absence of an IgD−/CD27+ Switched Memory B Cell Population with Persistent Hypogammaglobulinemia after Rituximab Administration as an Adjuvant Therapy after Autologous Stem Cell Transplantation for Non-Hodgkin Lymphoma.
Authors: Nishio Mitsufumi , Fujimoto Katsuya , Yamamoto Satoshi , Sakai Toshiya , Obara Masato , Kumano Koki , Minauchi Koichiro , Yamakura Masayuki , Sato Norihiro , Koike Takao 
Published: April 2020

Abstract
Some studies have indicated that rituximab (RT) may be an effective adjuvant therapy after stem cell transplantation (SCT) to improve the outcome in high-risk lymphoma. Early experience with a single course of RT in patients who did not undergo SCT showed a prompt B-cell depletion with a recovery to the normal range by 9 to 12 months. However, patients who received RT as adjuvant to SCT also had an increased risk of developing severe hypogammaglobulinemia (Blood, 2004;103:777). The mechanism of this hypogammaglobulinemia is unknown, although investigators have hypothesized a further delay in the B-cell recovery as one potential etiology.
A total of ten patients with high-risk CD20+ lymphoma underwent an autologus peripheral blood stem cell transplantation (APBSCT). All patients were prescribed high-dose chemotherapy consisting with ranimustine, carboplatin, etoposide and cyclophosphamide. After a haematological recovery, RT was given weekly at a dose of 375 mg/m2 for up to four doses as an adjuvant therapy. After a median follow-up of 37.5 months, we found five patients (Group A: 2FL, 2 DLCL and 1MCL) who had hypogammaglobulinemia, as defined by serum IgG levels of less than 800 mg/dl (normal range 870–1700 mg/dl), while the five other patients (Group B: 3 FL and 2 DLCL) had normal serum IgG levels. The median serum IgG levels in Groups A and B were 477 mg/dl (range 363–742 mg/dl) and 1058 mg/dl (range 801–1455 mg/dl), respectively. A routine phenotypical analysis revealed that Group A patients had already achieved B-cell recovery although the absolute B-cell number was lower in Group A than in Group B (Group A 95±40/μl and Group B 288±97/μl, mean±SD). Recent studies have shown that CD27 positive memory B-cell defected, especially IgD- switched populations, in some patients with common variable immunodeficiency (CVID). As most patients with CVID have a normal number of B-cell, we hypothesized that the hypogammaglobulinemia seen after APBSCT and RT may therefore be caused by the same mechanism(s) as CVID. To test this hypothesis, we performed a detailed phenotypical analysis on these ten patients by FACS.
The backgrounds of the two groups were not different, including follow-up period or the dose of RT after APBSCT. We found a delay in the CD27 positive memory B-cell recovery in Group A (Group A 3.8±2.2% and Group B 9.0±4.4%), especially in the IgD- switched population (1.1±0.3% in Group A and 6.0±3.0% in Group B). On the other hand, both groups showed a comparable recovery of CD27 negative naïve B-cells (Group A 95.2±3.8% and Group B 88.0±5.7%) or IgD+ nonswitched memory B-cells (Group A 2.7±2.0% and Group B 3.0±1.7%). In contrast to the B-cell subset, the number and ratio of either CD4+ or CD8+ T cells and CD56+ NK cells did not differ between the two groups. We also found the IgA levels to be significantly lower in Group A than Group B (37±18 mg/dl and 142±41 mg/dl), but that was not the case for IgM. One patient in Group A developed repeated bacterial infections, but other four are asymptomatic.
These data suggested that RT can affect not only the B-cell quantities, but also the recovery of the B-cell repertoires. These imbalances in the B-cell recovery may therefore contribute to the persistent hypogammaglobulinemia seen in patients who received RT as an adjuvant therapy after APBSCT.