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  • 1
    In: European Journal of Haematology, Wiley, Vol. 77, No. 3 ( 2006-09), p. 226-232
    Abstract: Abstract:  Objectives : Some studies have indicated patients who received rituximab as adjuvant to stem cell transplantation had an increased risk of developing severe hypogammaglobulinemia. The mechanism of this hypogammaglobulinemia is unknown, although investigators have hypothesized a further delay in the B‐cell recovery as one potential etiology. The aim of this study is to clarify the mechanism(s) of this hypogammaglobulinemia. Methods : A total of 14 patients with high‐risk CD20 + lymphoma underwent an autologous peripheral blood stem cell transplantation (APBSCT). After a hematological recovery, rituximab was given weekly for up to four doses as an adjuvant therapy. Results : After a median follow up of 33.5 months, we found six patients (group A) who had hypogammaglobulinemia, while the eight other patients (group B) had normal serum immunoglobulin levels. A phenotypical analysis revealed that group A patients had already achieved B‐cell recovery. However, we found a severe delay in the recovery of CD27 + memory B cells, especially in the IgD − /CD27 + switched populations in group A, but CD27 negative naive B‐cells reverted to a normal range in both groups. Consistent with this, reverse transcriptase‐polymerase chain reaction studies with peripheral blood mononuclear cells revealed that most patients in group A lacked more than two classes of isotype transcripts. Conclusions : Abnormal repertoires and impaired isotype expression are seen in patients with common variable immunodeficiency, these data suggested that rituximab after APBSCT can affect not only the B‐cell quantities, but also the recovery of the B‐cell repertoires.
    Type of Medium: Online Resource
    ISSN: 0902-4441 , 1600-0609
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2006
    detail.hit.zdb_id: 2027114-1
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  • 2
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 938-938
    Abstract: Rituximab (RT) has been proven to be very effective in depleting normal and malignant B lymphocytes in vivo and it is widely used for the treatment of B cell malignancies, particularly B cell non-Hodgkin’s lymphoma (NHL). RT alone does not appear to cause severe hypogammaglobulinemia according to initial clinical trials. However, recent studies revealed that patients who received RT as an adjuvant to stem cell transplantation (SCT) demonstrated an increased risk of developing severe hypogammaglobulinemia. We have found such hypogammaglobulinemia to be due to the delayed recovery of CD27 positive memory B cells and an impaired isotype expression. (Nishio et al. Eur J Haematol, 2006). This finding suggests that RT can influence not only the quantity, but also the quality of B-cell redistribution. Nevertheless, to our knowledge, precisely how the B-cell repertoire regenerates after anti-CD20-mediated transient B-cell depletion in patients with NHL remains to be elucidated. To clarify this, we performed a phenotypical analysis of B cells. A total of 22 patients with NHL who received RT combined with autologous SCT (n=17) or CHOP (n=5) were evaluated to identify their immunophenotype. The median period after the last administration of RT was 33.5 months (range from 12 to 56 months). We investigated the expression of various markers, including CD27, CD38, CD40, CD80, CD86 and CD95 on B cells by immunofluorescence staining with a flowcytometry analysis. A statistically significant difference was noted in three of the six surface antigens when the expressions of those antigens were compared with those in the healthy control populations (N=14). The most striking differences we found was the expression levels of CD27. The healthy control group had a much higher expression of CD27 in comparison to those of the patients treated with RT (28.1±14.1% vs 8.2±6.1%, p & lt;0.001). In addition, significant differences in the expression of CD40 and CD80 were also noted. While the positive rates of CD80 and CD40 on B cells from healthy controls were 21.5±10.8% and 80.5±16.7%, those of patients treated with RT were 9.9±6.9% and 49.7±33.5%, respectively (p & lt;0.01 and p & lt;0.05). Since CD40-CD40L and CD80-CD28 pathways between B and T cells are necessary for the development of CD27 positive polyclonal B-cell activation and immunoglobulin production, we hypothesized that the B cells from patients treated with RT thus had a reduced ability to differentiate into plasma cells and immunoglobulin production in vitro. To test this hypothesis, we purified the B cells from ten patients with NHL treated with RT and then cultured them upon the engagement of immunoglobulin receptor and CD40 in the presence of IL-2 and IL-10. After eight days of stimulation, the supernatants of the culture were harvested and the concentrations of immunoglobulin were measured by ELISA. As a result, the IgG production was found to be significantly impaired in patients with NHL in comparison to those from the healthy controls. The observation of a delayed recovery of the memory B cells with an abnormal cell marker expression and function demonstrates that naive B cells may therefore be responsible for their failure to differentiate into plasma cells after RT therapy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    In: British Journal of Haematology, Wiley, Vol. 137, No. 4 ( 2007-05), p. 349-354
    Type of Medium: Online Resource
    ISSN: 0007-1048 , 1365-2141
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2007
    detail.hit.zdb_id: 1475751-5
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  • 4
    In: European Journal of Haematology, Wiley, Vol. 75, No. 6 ( 2005-12), p. 527-529
    Type of Medium: Online Resource
    ISSN: 0902-4441 , 1600-0609
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2005
    detail.hit.zdb_id: 2027114-1
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  • 5
    In: Experimental Hematology, Elsevier BV, Vol. 30, No. 11 ( 2002-11), p. 1238-1247
    Type of Medium: Online Resource
    ISSN: 0301-472X
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2002
    detail.hit.zdb_id: 2005403-8
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  • 6
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4544-4544
    Abstract: Abstract 4544 Background: Current prognostic models, including the International Prognostic Index (IPI), incorporate both patient and tumor characteristics. In contrast, recent studies show that variables related to the host adaptive immunity and the tumor microenvironment are significant prognostic variables in cases of diffuse large B-cell lymphoma (DLBCL). Recently, Wilcox and co-workers reported that lymphopenia, defined as an absolute lymphocyte count (ALC) 〈 1,000/μL, and an elevated absolute monocyte count (AMC) 〉 630/μL, at diagnosis was associated with inferior survival in patients with DLBCL treated with CHOP/R-CHOP (Leukemia, 2011). The same group also reported that the ALC/AMC ratio at diagnosis can be a biomarker to predict the clinical outcome in DLBCL patients treated with R-CHOP (Porrate et al. ASH 2011). However, it remains to be determined if these parameters can predict the outcome of autologous peripheral blood stem cell transplantation (APBSCT) in patients with DLBCL in the first remission. Methods: We retrospectively examined the predictive value of the AMC and ALC in a cohort of 55 consecutive DLBCL patients who uniformly underwent APBSCT in their first remission at Hokkaido University Hospital and Sapporo City General Hospital. At presentation, all patients were at high risk (Coiffier et al. J Clin Oncol, 1991) (1997 to 2000), or high (H)/high-intermediate (HI) risk, in the age-adjusted IPI (aaIPI) (2001 to 2012). After six cycles of CHOP (before 2000, N=16) or R-CHOP (after 2001, N=39), all patients were treated with APBSCT, followed by the MCVC regimen, consisting of ranimustine, carboplatin, etoposide and cyclophosphamide. We performed a receiver operating characteristics (ROC) analysis to determine the optimal cut-off point for both the AMC and ALC in our patients, and values of 551/uL and 1,000/uL were set for the subsequent analyses. The disease free survival (DFS) and overall survival (OS) were estimated using the Kaplan–Meier method and two-tailed log-rank test. Results: Twenty-five patients were male and thirty were female. According to the aaIPI, 15, 31, and nine patients were classified as H, HI, and low (L)/low intermediate (LI), respectively. The median duration of follow-up after APBSCT was 85 months (range 1 to 179 months). At diagnosis, the median ALC was 1,095/μL (range 286–3,396/μL) and the median AMC was 551/μL (range 63–1,870/μL). The estimated 5-year OS and DFS for the entire cohort were 78% (95% confidence interval (CI) 64–88%) and 73% (95% CI 59–83%), respectively. In contrast to the previous study, the ALC did not predict an inferior OS or DFS in a univariate analysis of dichotomized variables. The estimated 5-year OS and DFS for those who had lymphopenia (ALC 〈 1,000/μL) were 86% and 74%, and those for patients who did not were 77% and 70%. In addition, an elevated AMC ( 〉 551/μL) had no significant impact on the 5-year OS, with rates of 88% for those who had an elevated AMC and 73% for those who did not. However, an elevated AMC was associated with a superior 5-year DFS of 88% compared to that of 59% in the cohort which did not have an elevated AMC (hazard ratio 3.18, 95% CI 1.10–11.41, p=0.03). Conclusions: Lymphopenia or an elevated monocyte number at diagnosis did not predict a poor outcome for high-risk patients with DLBCL when APBSCT was given in the first remission. Our results suggest that the dismal outcome obtained with CHOP/R-CHOP in high risk DLBCL patients who concomitantly had lymphopenia and elevated AMC could be overcome by an APBSCT in the first remission, although these results should be confirmed in a prospective study. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 7
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1412-1412
    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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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    detail.hit.zdb_id: 80069-7
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