Nobuo Masauzi

Reactivation of hepatitis B virus with rituximab.

Rituximab has become a useful drug for the treatment of non-Hodgkin’s lymphoma (NHL) and such autoimmune diseases as idiopathic thrombocytopenic purpura and rheumatoid arthritis. When combined with cytotoxic agents, rituximab showed synergistic effects for the treatment of NHL. In such treatment, hepatitis B virus (HBV) reactivation is a crucial complication when patients are treated with immunosuppressive or chemotherapeutic agents. Despite its treatment efficacy, several studies have pointed out unusual viral infections after its administration that resulted in fatal hepatitis due to HBV reactivation. In the cases at the authors’ institute, the authors analysed the kinetics of HBV antibodies, HBV-reactivation timing, and the prophylactic efficacy of lamivudine. The authors reviewed their cases and the previous literature to clarify the characteristics of HBV-reactivated patients who were administered rituximab.

Possible efficacy of lamivudine treatment to prevent hepatitis B virus reactivation due to rituximab therapy in a patient with non-Hodgkin's lymphoma

We used regimens containing rituximab in the treatment of five hepatitis B virus surface antibody (HBsAb)-positive patients with non-Hodgkins lymphoma (NHL). Serum levels of HBsAb were obtained and analyzed in four of these patients. Two patients were HBs antigen (HBsAg) positive. One of these HBsAg-positive patients was treated with lamivudine because the patient developed fulminant hepatitis from hepatitis B virus (HBV) infection prior to chemotherapy. However, none of the other patients were administered lamivudine. An HBsAg-positive patient who did not receive lamivudine treatment later developed fulminant hepatitis. Another HBsAg-positive patient receiving lamivudine prophylaxis did not develop severe hepatitis arising from HBV. In the three patients not receiving lamivudine treatment, serum HBsAb titers decreased soon after the administration of rituximab. These results suggest that rituximab reduced the antibody titer for HBV, thus inducing an immunological environment leading to easy reactivation of HBV. Lamivudine prophylaxis was effective, at least when rituximab was given to an HBsAg-positive patient with non-Hodgkins lymphoma.

Cytokine gene expression in peripheral blood mononuclear cells during graft-versus-host disease after allogeneic bone marrow transplantation

Summary. Cytokine gene expression in peripheral blood mononuclear cells during the development of graft‐versus‐host disease (GVHD) in patients who underwent allogeneic bone marrow transplantation (allo BMT) was analysed using a semiquantitative reverse‐transcriptase polymerase chain reaction (RT‐PCR). The expression of interleukin (IL)‐lβ, IL‐6, and tumour necrosis factor (TNF)‐α mRNA was increased during the development of GVHD and the degree of this increment depended on the severity of the disease. IL‐2 expression was not detected at all and interferon‐γ expression was not much changed during GVHD. In patients with hepatic veno‐occlusive disease (VOD), another transplantation‐related complication, the expression of IL‐1β and TNF‐a mRNA was increased but IL‐6 mRNA expression showed little increase. These findings suggest that IL‐lβ, IL‐6 and TNF‐α produced by peripheral blood mononuclear cells play an important role in the development of GVHD. Furthermore, liver dysfunction due to GVHD or VOD may be distinguishable by this type of cytokine analysis. Analysis of cytokine mRNA expression in peripheral blood mononuclear cells after allogeneic bone marrow transplantation may provide important information concerning the immune response and the cytokine network system in marrow transplant patients.

Hepatitis B Virus Reactivation in a Case of Non-Hodgkin's Lymphoma Treated with Chemotherapy and Rituximab: Necessity of Prophylaxis for Hepatitis B Virus Reactivation in Rituximab Therapy

A patient with Non-Hodgkins lymphoma is reported, in which reactivation of the hepatitis B virus was achieved from treatment with rituximab. The patients HBs antigens were positive on admission, and she tested positive for HBs, HBe, and HBc antibodies, and negative for the HBe antigens. She was treated with a regimen of three courses of rituximab-containing anti-cancer drugs and one course of combined anti-cancer drugs. Throughout these chemotherapy courses, prednisolone was not given. After the fourth course of chemotherapy with the third rituximab she developed hepatic dysfunction, and the serum titers of HBs and HBc antibodies suddenly decreased. After administration of lamivudine, however, she gradually recovered from liver failure.

Randomized study of Helicobacter pylori eradication therapy and proton pump inhibitor monotherapy for idiopathic thrombocytopenic purpura

Helicobacter pylori (HP) eradication therapy is a useful treatment for idiopathic thrombocytopenic purpura (ITP). Some investigators have also reported the effects of proton pump inhibitor (PPI) monotherapy on ITP. We performed a randomized study of HP eradication therapy and PPI monotherapy on ITP. Four of nine patients achieved complete remission (CR), two of nine achieved partial remission (PR) in HP eradication therapy, three of eight achieved CR, and two of eight achieved PR in PPI monotherapy. No significant differences were observed in the CR + PR of these patients between HP eradication therapy and PPI monotherapy. As for cost comparisons, HP eradication therapy is cheaper than PPI monotherapy, but it is less effective.

Analysis of reactivation of hepatitis B virus in the treatment of B cell non-Hodgkin's lymphoma in Hokkaido.

Dear Editor, Despite the low immunosuppressive effects of rituximab, severe viral infections due to varicella zoster virus, parvovirus B19, cytomegalovirus, and JC papovavirus are sometimes associated with its use [1–5]. Several investigators have also reported fatal hepatitis due to hepatitis B virus (HBV) reactivation [6–9]. Because HBV reactivation has been observed frequently since the administration of rituximab was approved in Japan, we analyzed HBV reactivation in non-Hodgkin’s lymphoma patients treated with chemotherapy at seven institutions in Hokkaido between 1997 and 2007. We sent research heads at these institutions questionnaires asking them to evaluate HBV reactivation after chemotherapy with and without rituximab and lamivudine prophylaxis. The physicians at all seven institutions responded to these questionnaires, and in this retrospective analysis we evaluated the data for non-Hodgkin’s lymphoma patients with HBsAg (HBV carriers). All the patients enrolled in this retrospective study were examined for HBsAg and HBsAb positivity, and some were also examined for HBcAb, HBeAg, and HBeAb positivity. Our analysis showed that HBV reactivation was associated with rituximab-containing chemotherapy and rituximab monotherapy. Eight hundred and twenty-nine patients were treated with chemotherapy during this period. Fifty patients were positive for HBsAg, and the records of 47 of those patients could be analyzed (Table 1). Twenty-two of the patients were treated with chemotherapy without rituximab, five patients were treated only with rituximab, and the other 20 were treated with chemotherapy and rituximab. Twelve of the patients treated with chemotherapy without rituximab had also been given a steroid, as had three of the patients Ann Hematol (2009) 88:375–377 DOI 10.1007/s00277-008-0585-6

Evaluation of mixed chimaerism and origin of bone marrow derived fibroblastoid cells after allogeneic bone marrow transplantation

Summary We assessed the origin of bone marrow derived fibroblastoid cells (BMF) in long‐term cultures of 13 samples obtained from nine patients after allo‐BMT by polymerase chain reaction (PCR) amplification of MCT118, one of the variable number of tandem repeats regions (VNTR). BMF showed a complete recipient pattern in nine samples obtained from seven patients; however, a recipient‐predominant mixed chimaeric pattern was detected in BMF from four patients. Also, two of the four patients died with bone marrow hypoplasia. These data suggest that mixed chimaeric pattern of BMF may be correlated with bone marrow hypoplasia.

Reduced-intensity allogeneic hematopoietic stem-cell transplantation as an immunotherapy for metastatic colorectal Cancer

Background. Allogeneic stem-cell transplantation (allo-SCT) can induce curative graft-versus-leukemia reactions for hematologic malignancies through allogeneic immunity. Because the gastrointestinal tract is a target of graft-versus-host disease (GvHD), colorectal cancer might be a candidate for allo-SCT. Methods. Four patients with metastatic colorectal cancer underwent reduced-intensity stem-cell transplantation (RIST) in the National Cancer Center Hospital between July 2002 and February 2003. Three patients received transplants from an human leukocyte antigen (HLA)-identical related donor, and the remaining patient received selected CD34-positive cells from a two-loci HLA-mismatched donor. The basis of preparative regimen was busulfan 4 mg/kg for 2 days and fludarabine 25 mg/kg for 6 days. Results. All the patients tolerated the preparative regimen and achieved engraftment without significant toxicities. All developed acute or chronic GvHD. Although serum levels of CA19–9 and carcinoembryonic antigen were transiently elevated after RIST in all the patients, the levels subsequently decreased below the levels from before RIST in all but one patient. Three had measurable lesions before RIST, one achieved partial response, and the others stable disease, which was durable for 120 and 60 days. Three patients died; the causes of death were progressive disease, GvHD, and accident. Postmortem examination was obtained for two patients; in one patient, the peritoneal metastatic lesions macroscopically disappeared, and in the other patient, the supraclavicular lymph node disappeared while the other measurable lesions remained stable. Conclusions. All the patients showed some evidence suggesting the presence of a graft-versus-tumor effect for colorectal cancer, which should be confirmed in a future prospective trial.

Prevention of hepatitis B virus reactivation under rituximab therapy

Rituximab is a useful drug for the treatment of B-cell non-Hodgkins lymphoma, and its use has been extended to other diseases such as idiopathic thrombocytopenic purpura and chronic rheumatoid arthritis. One serious complication associated with rituximab use is reactivation of hepatitis B virus, and the search for methods to prevent this occurrence has resulted in a rapid accumulation of knowledge in recent years. In this review, we will discuss case studies from our group, as well as other groups, and outline current knowledge on the topic together with issues that remain to be resolved.

Delayed reduction in left ventricular function following treatment of non-Hodgkin's lymphoma with chemotherapy and rituximab, unrelated to acute infusion reaction.

We report 3 cases of reduced cardiac function with complications in non-Hodgkin’s lymphoma patients who were treated with rituximab. Patients experienced reduced cardiac functions after the administration of rituximab; there was no evidence of any preceding infusion reactions. Reticulin fiber was observed diffusely in cardiac muscles. Transforming growth factor-β levels were elevated after the administration of rituximab. We believe that continuous elevation of transforming growth factor-β may promote the growth of reticulin fiber in cardiac muscles. Reduction in cardiac functions is a severe complication that must be considered when rituximab is administered.