Koichiro Minauchi

Hypogammaglobulinemia with a selective delayed recovery in memory B cells and an impaired isotype expression after rituximab administration as an adjuvant to autologous stem cell transplantation for non-Hodgkin lymphoma.

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.

Persistent panhypogammaglobulinemia with selected loss of memory B cells and impaired isotype expression after rituximab therapy for post-transplant EBV-associated autoimmune hemolytic anemia

To the Editor: Miles and McGratten (1) reported persistent panhypogammaglobulinemia after CHOP-rituximab for HIV-related lymphoma. Prolonged hypogammaglobulinemiawith rituximab has also been seen in patients with post-transplant Epstein–Barr virus (EBV)-associated lymphoproliferative disorder (2, 3), as well B-cell lymphoma when rituximab is used as maintenance after stem cell transplantation (4, 5). We report a case of severe persistent panhypogammaglobulinemia after treatment of a posttransplant EBV-associated autoimmune hemolytic anemia (AIHA) with rituximab. The patient is a 32-yr-old Japanese woman with severe aplastic anemia who underwent non-myeloablative allogeneic peripheral blood stem cell transplantation from her HLA-matched sister in September 2000 (6). On days 90 and 150, chronic graft versus host disease occurred, but was alleviated with tacrolimus and predonisolone. In April 2002, 19 months after transplantation, the serum immunoglobulin M (IgM) level increased and immuno-electrophresis analysis revealed monoclonality of IgM. A remarkable proliferation of EBV-DNA also occurred. Tacrolimus and predonisolone were rapidly tapered off and the IgM level and EBV-DNA decreased. At that time, the IgG level was 757 mg/ dL (normal range 870–1700); low but stable after tapering of these immunosuppressive agents. In July 2002, severe AIHA occurred (7). Due to the existence of predictive factors of post-transplant lymphoproliferative disease (PTLD), conventional immunosuppressive therapy for AIHA was not considered. We gave rituximab (Chugai Pharmaceutical, Tokyo, Japan), 375 mg/m once a week for a total of four doses. The clinical and laboratory signs of hemolysis rapidly improved and the hemoglobin level began to improve 2 wk after the start of rituximab treatment. B cells in her peripheral blood rapidly disappeared, as expected. But all serum immunoglobulin levels kept on decreasing and remained extremely low (IgG < 200 mg/dL, IgA < 10 mg/dL and IgM < 10 mg/dL) unless intravenous immunoglobulin (IVIG) was administered for more than 2 yr. She developed repeated bacterial infections, such as pneumonia and sepsis, and was treated with IVIG and antibiotics. In February 2005, 30 months after last administration of rituximab, we found her blood B-cell number reverted to a normal range (8% of total lymphocytes, 180/lL), despite the still severe hypogammaglobulinemia. Flow cytometry analysis revealed that her B cells were composed with only CD27 negative naı̈ve B cells. CD27 positive memory B cells, both IgD-positive non-switched and IgDnegative switched populations, were hardly seen (Fig. 1A). In addition, we evaluated immunoglobulin isotype production by analyzing immunoglobulin transcripts with reverse transcriptase-polymerase chain reaction as described (8). Her peripheral blood mononuclear cells (PBMC) only expressed the transcriptions of IgM, IgG1, IgA1 and IgA2, but no IgG2, IgG3 and IgG4 (Fig. 1B). Rituximab is known to induce B-cell depletion for up to 6 months post-treatment (9). Moreover, in patients treated with high dose chemotherapy and maintenance rituximab, it takes longer (18– 24 months) for B-cell recovery (4). This delay of B-cell recovery is likely to contribute to hypogammaglobulinemia, especially when rituximab is used for treatment of EBV-PTLD (2, 3, 10). But this does not seem to be the case in our patient who Eur J Haematol 2005: 75: 527–529 doi:10.1111/j.0902-4441.2005.t01-1-EJH2327.x All rights reserved Copyright Blackwell Munksgaard 2005

Prospective Trial of High-Dose Chemotherapy Followed by Infusions of Peripheral Blood Stem Cells and Dose-Escalated Donor Lymphocytes for Relapsed Leukemia after Allogeneic Stem Cell Transplantation

To determine whether induction of graft-versus-host disease (GVHD) improves the outcome of acute relapsed leukemia after stem cell transplantation (SCT), we used high-dose cytarabine (ara-C) followed by infusions of donor-derived buffy coats containing peripheral blood stem cells to treat 12 patients with relapsed leukemia. Donor lymphocyte infusion (DLI) was repeated at least twice over a 5-week interval for patients in whom grade II to IV acute GVHD did not develop after the first DLI. Grade II to IV acute GVHD developed in 4 (33%) of the patients. Chronic GVHD developed in 3 patients, 2 of whom had not experienced acute GVHD. Four (67%) of the 6 patients who developed grade II to IV acute and/or chronic GVHD after DLI responded, but none of the other 6 patients responded. Four (33%) of the patients (2 with acute myelogenous leukemia [AML]and 2 with acute lymphoblastic leukemia [ALL]) achieved complete remission lasting longer than 4 months after the first DLI, but 3 of them had relapses in bone sites. Of these 4 patients, 1 patient with AML and 2 with ALL were alive 8 to 27 months after DLI. These findings indicate that high-dose ara-C combined with megadose DLI may produce durable remission of acute leukemia that has relapsed after SCT when GVHD is induced. The low induction rate of GVHD and extramedullary relapse after remission is achieved with DLI are problems yet to be solved.

Hepatosplenic alpha/beta T cell lymphoma presenting with cold agglutinin disease

Title Hepatosplenic alpha/beta T cell lymphoma presenting with cold agglutinin disease. Author(s) Minauchi, Koichiro; Nishio, Mitsufumi; Itoh, Tomoo; Yamamoto, Satoshi; Fujimoto, Katsuya; Sato, Norihiro; Koike, Takao Citation Annals of Hematology, 86(2): 155-157 Issue Date 2007-02 Doc URL http://hdl.handle.net/2115/18872 Rights The original publication is available at www.springerlink.com Type article (author version) File Information AH86-2.pdf

Targeting complete response with upfront bortezomib consolidation versus observation after the achievement of complete response following autologous transplantation for multiple myeloma (TUBA study)

Complete response (CR) after treatment for multiple myeloma is associated with superior progression‐free survival (PFS). Multiple myeloma patients were prospectively recruited for induction treatment with bortezomib and dexamethasone (BD) followed by autologous hematopoietic cell transplantation (auto‐HCT) between 2010 and 2012. If patients did not achieve CR after auto‐HCT, BD consolidation therapy was added to target CR.

Rapidly progressing central nervous system involvement despite of steroid pulse therapy in a case of systemic lupus erythematosus presented as mononeuritis multiplex

A 31‐year‐old‐woman with a 6‐month history of systemic lupus erythematosus (SLE) was admitted because of severe mononeuritis multiplex. Although she initially responded well with steroid pulse therapy, she developed unconsciousness again 3 weeks later just after a second course of steroid pulse. Laboratory evaluations revealed a high titre of anti‐DNA antibody, low complement levels, and positive lupus anticoagulant. She was treated with intravenous cyclophosphamide pulse therapy with immediate response. The clinical course of central nervous system involvement was very unusual for the response to steroid pulse therapy.